Search Results

1.5 billion people worldwide are affected by hearing loss. That's 1 in every 6 New Zealanders. And for some, the loss can happen almost overnight. Are you curious to learn more about what can be done to treat hearing loss, or even prevent it? For those facing challenges with hearing health, everyday conversations can present just one of many challenges. And what's more, there's a growing body of evidence linking hearing loss to the development of serious conditions and diseases including walking difficulties, falls and increased risk of dementia. Understanding the significant impact that hearing loss can have on people of all ages is critical. Thanks to the generosity of AMRF supporters, incredibly talented researchers like Professor Peter Thorne and Dr Haruna Suzuki-Kerr are able dedicate their days to identifying the many causes of hearing loss and searching for more effective treatments. To view Prof Thorne and Dr Suzuki-Kerr's latest update on their ground-breaking work, watch their insightful webinar, and catch-up on how the latest technology really can get inside your head. The video comes complete with captions and is here on our AMRF YouTube channel. Or if you are more of a reader and would like a transcript of the presentations, click here to email your request to us. It's also been said that "the most important six inches on the battlefield is between your ears!" Have you ever paused to consider how many people are going to battle for you and your ear health every day? The answer is many, many thousands and amongst those warriors are Prof Thorne and Dr Suzuki-Kerr's and their teams, with over 20 research warriors on a mission to uncover life-changing solutions for hearing loss. It's worth saying again and again: research like this just simply wouldn't be possible without the wonderful support of donors like you. Over the past 13 years, donors have played a pivotal role in contributing to the $1.3 million of funding awarded to critical hearing health projects that Prof Thorne and Dr Suzuki-Kerr have worked on. Whether as Principal Investigators or as integral members of the research team, donor support of Prof Thorne and Dr Suzuki-Kerr's work has helped to make a profound impact. Thank you for helping them to find solutions to treat hearing loss or even prevent it in the first place and as they continue in their unrelenting quest for advancements in hearing health, your generosity can make an even greater difference. Donate now to help researchers make a difference for everyday people. All donations, large or small, are always welcome.

From “intermediate kid who got lost in the pages of a book about the brain at Central Library, Palmerston North” to academic neurosurgeon who is improving patient care, AMRF congratulates Dr Sang Ho Kim. In 2021 Dr Kim was a junior doctor who received an AMRF Doctoral Scholarship to become a clinician-scientist. His achievements in testing the human suitability of an implantable device for measuring pressure in the brain was recently rewarded with a Health Research Council (HRC) Clinical Research Training fellowship. Sue Brewster, Executive Director of Auckland Medical Research Foundation, says, "We are delighted to have been a springboard for Dr Kim's career and supporting emerging researchers is what AMRF is renown for. His AMRF scholarship and now his HRC fellowship show his immense capability and the merit in his research goals, as both have been rigorously reviewed by medical, scientific and research experts." My career goal is to become an academic neurosurgeon who is a leader in their field and at the forefront of cutting-edge technology to identify and pursue new opportunities for improving patient care. "The generous funding from the AMRF will allow me to undertake a PhD, full time. My PhD work is particularly relevant to my career aspiration as the Implantable Devices Group (IDG) at the Auckland Bioengineering Institute (ABI) is nearing their first human safety and feasibility study," says Dr Kim. "Hydrocephalus is the abnormal build-up of brain fluid that requires urgent neurosurgical intervention. The condition cannot be cured but is treatable by installing a tube (shunt) to drain the excess fluid and avoid high pressure inside the head. Unfortunately, these shunts have a 60% chance of becoming blocked within the first two years. "Shunt blockage results in a life-threatening increase in pressure inside the head. As a result, frequent visits to the Emergency Department ensue as the signs of shunt failure are subtle and look like the common cold. Shunt failure can only be confirmed with a brain scan involving radiation. Having a shunt means living in a perpetual state of anxiety, not knowing when it will fail, and being exposed to unnecessary radiation every time it is suspected. "Thus, there is an unmet clinical need for a technology that allows accurate long-term measurement of intracranial pressure (ICP) and the prompt early recognition of imminent shunt failure. "The IDG is developing a small implantable pressure sensor that senses and wirelessly transmits pressure measurements inside a person’s head for the long-term monitoring of ICP." To date, "we have achieved wireless measurements of sheep brain pressure. The analysis of this data will support the previous work and publication I was involved in regarding the implant's efficacy and safety. We are making progress towards the first in-human study, scheduled to begin in 2024. To prepare for this, I am currently working with the group to develop the ethics and study protocol. "I am excited about the project's potential impact on patients with hydrocephalus. Our technology can produce a substantial change in their care from reactive to proactive monitoring. The device will significantly reduce the uncertainty and associated anxiety of not knowing whether a shunt is failing." This research into hydrocephalus-measuring implantable medical devices was recently profiled by NewsHub. Click here to watch the interview. Have your explored our web page to find out more about how you can contribute to medical research, like neuroscience, heart health, cancer, prenatal development and more? And don't forget, donations, large or small, are always welcome.

A marathon effort in Aoraki Mount Cook National Park and a musical theatre gala evening raise funds for brain cancer research. Read more now in the latest AMRF newsletter. In this edition, we highlight the dedication of a group of families afflicted by the same devastation of losing loved ones to brain cancers. Their commitment to supporting research to prevent further suffering is shown in the achievements of physical challenges they set for themselves, as well as a night of songs and performances and the funds they raised in 2023. We also showcase several researchers who are making strides in a variety of disciplines: Dr Lisa Douglas seeks to improve outcomes for mothers and babies after gestational diabetes mellitus Dr Lola Mugisho has leads on a promising combination therapy for Alzheimer’s disease treatment Dr Rachael Sumner wants to know "Why does the menstrual cycle cause seizures to worsen in thousands of Our cover story is about the amazing hearing research being conducted by Dr Haruna Suzuki-Kerr and Prof Peter Thorne. Want to hear more? Register your interest for our webinar featuring these two excellent hearing researchers to be held on 21 February at 7 pm with a quick email to events@medicalresearch.org.nz. Have your explored our web page to find out more about how you can contribute to medical research, like neuroscience, heart health, cancer, prenatal development and more? And don't forget, donations, large or small, are always welcome. Click below to read and download the PDF newsletter

Auckland researchers aim for breakthroughs in diagnosis, treatment, and prevention that could reshape the landscape of women's health in New Zealand. Funding Grant Awarded for Endometrial Cancer Research The Equity Team within Service Improvement and Innovation unit of Te Whatu Ora Auckland - Waitematā has successfully secured a $174,834 project grant for pioneering endometrial cancer research. The grant from the Auckland Medical Research Foundation (AMRF) is the first to be awarded to a study run by the Māori Health Pipeline, and will progress work aimed at improving diagnosis, treatment and ultimately prevention for this significant health issue for women in this country. While endometrial cancer incidence has been rising internationally, Aotearoa has observed even more rapid increases in incidence, particularly among Pacific women - now one of the highest in the world and is continuing to climb steeply. Endometrial cancer related mortality is now also the most significant contributor to the life expectancy gap for Pacific women. Research Manager Roimata Tipene explains, “wāhine Māori and Pacific women are more likely to get endometrial cancer, get it at a much earlier age and have worse outcomes. Relevant research in Aotearoa is urgently needed to make a difference to these statistics.” The benchmarking study will work with Mayo Clinic (US) investigators to understand whether the relationship found in their work, between a bacteria called Porphyromonas somerae and endometrial cancer can also be found here, where women are more likely to be younger and premenopausal. The New Zealand study aims to determine the proportion of women with and without endometrial cancer who have carriage of P. somerae and to characterise the baseline endometrial microbiome in diverse subpopulations. The study, set to start in 2024, involves over 250 women and many specialists and researchers across the country. It will form part of a broader endometrial cancer work programme, Pacific Health Pipeline, which the Equity team is developing with the Pacific Health Group. Interested in participating? Contact Roimata Tipene, Māori Health Pipeline, Te Whatu Ora, Auckland - Waitematā. Phone 021415266, email roimata.tipene@waitematadhb.govt.nz

Each year the Auckland Medical Research Foundation awards $4 million in grants from donations to a wide range of medical research and researchers. Deciding which applications are successful involves a rigorous, in-depth review process undertaken by our AMRF Medical Committee. Read more now in the latest AMRF newsletter. In this edition, you'll delve into the heart of our mission, with a spotlight on members of our Medical Committee who are the linchpins of our charitable funding system. You'll gain insights into their personal journeys, motivations, and the transformative impact your donations have on this work. Their passion, expertise, and unwavering commitment are the driving force behind our success and sets us apart from other charities - our esteemed panel of researchers and scientists who evaluate all the applications we receive, spanning across the vast spectrum of medical research, so you can have the confidence that every dollar you contribute is channelled towards the highest quality of projects. Have your explored our web page to find out more about how you can contribute to medical research, like neuroscience, heart health, cancer, prenatal development and more? And don't forget, donations, large or small, are always welcome. Click below to read and download the PDF newsletter

Presenting A Night On Broadway: A Concert in support of Auckland Medical Research Foundation's work with brain cancer. Emma's Story: On January 24th 2022, Emma Cawood lost her father to glioblastoma. With a year left of high school, she turned to performing arts to work through her grief. "Family has always been incredibly important to me. When my family decided to care for Dad until the end, we came together in a way I never thought possible. Mum remained my figure of strength throughout everything, and when she decided to raise money for this charity via a half marathon, I knew I needed to support her. However, I am far from a runner! Instead, the gift Mum and Dad gave me was love for the arts," she says. This event honours the strength of my mother and father, the art form that continues to carry me through grief, and the others in our community who are fighting a similar story. Many others in the arts community will share a similar story. She says this is why this concert is so important. "The Arts is an act of human connection. And after his passing, arts was the one way I could be with my dad again. Brain cancer has destroyed so many families within our community. I am passionate about the power the arts community in Christchurch holds. I am organising an event where we can stand together and fight against such a life-altering disease." 100% of the proceeds from this event will go to the Auckland Medical Research Foundation, for their work on glioblastoma. Glioblastoma is one of the most aggressive brain cancers, with a shocking life expectancy. For one night only! Join Emma and friends as they take you through the world of musical theatre, and raise money for a good cause at this evening showcase of some of Christchurch's finest performers. Featuring Christchurch Musical Theatre Stars: Amanda Atlas Ali Harper Jonathan Densem Warwick Shillito James Foster Catherine Hay Monique Clementson Juliet Reynolds-Midgley 4 November 2023 7pm at The Charles Luney Auditorium Get your tickets now! Click here to learn more about the Cawood family, their friends and their connection to brain cancer research.

Are you curious about the latest developments in cancer research? Are you curious about how new cancer treatments and approaches are changing patient outcomes? Watch now to learn more about the Auckland researchers who are investigating opportunities and possibilities in personalised cancer treatments. Professor Peter Browett is curious, too. He is using next generation sequencing and more to understand more about the best treatments for patients to achieve better outcomes and minimize side effect. He is joined by A/Prof Nuala Helsby who is curious about the implications of inherited and environmental factors on the treatment of diseases. They are working on solving the puzzles associated with the future of cancer therapies. Generous donors -- people just like you! -- to Auckland Medical Research Foundation enable researchers like Prof Jennifer Weller and Dr Tim Angeli-Gordon to continue their life-changing work. Make your tax-deductible donation to the Auckland Medical Research Foundation and support our future today. Remember 100% of your donation supports researchers, scientists and clinicians -- never AMRF overheads! Video transcript follows. Presentation by Prof Peter Browett, director for the Centre for Cancer Research at the University of Auckland and clinical haematologist at Auckland Hospital “Personalised haematology – Giving the right treatment to the right patient at the right time" My name is Peter Browett. I'm a director for the Centre for Cancer Research at the University of Auckland. I'm also a clinical haematologist at Auckland Hospital, and my research interests are around the genetics of leukaemia. Today, I have an opportunity to talk to you about our research on personalised haematology. Our goal is to improve outcomes for patients with leukaemia by giving the right treatment to the right patient at the right time. If we look at the whole area of cancer, one of the biggest advances over the last decade has been the understanding of the genetics of cancer and looking at the changes that occur in the genome of cancer cells. This has allowed us to help with the classification of cancers and also identify potential targets for therapies. The goal of our research is to assess the impact of genomic testing on the management of patients with blood cancer. This is the clinical problem that we're dealing with. I look after patients with acute leukaemia. On the left-hand panel, you can see a blood sample from a patient with leukaemia. These are the leukemic cells that proliferate in the bone marrow, take over the normal bone marrow, and spill over into the peripheral blood. On the right-hand panel, you can see two tubes of blood. The left-hand one is what our blood would look like if we took a blood sample and let it sit on the bench. The red blood cells would fall to the bottom, the plasma would sit on top, and across here, you can see a hazy layer. That's the white blood cells. Here is a blood sample from a patient with leukaemia. Here are the red blood cells, a lot fewer of them. Here's the plasma, and this layer here consists of all the leukaemia cells. In fact, when you look back into the historical medical literature, you'll find that leukaemia got its name from "leukos," meaning white, because of these leukemic cells in the blood. As I mentioned, leukaemia is a cancer of the bone marrow and blood. It starts off in the bone marrow. On the left is a normal bone marrow, what yours or my bone marrow would look like. Here's a part of the bone, and this is the bone marrow with fat cells and developing blood cells. On the right is a bone marrow sample taken from a patient with leukaemia. You can see in pink the little bone fragments, but here, it's just replaced. All the normal developing blood cells are replaced by this infiltration of leukaemia cells. Consequently, the patients we look after, when they present, have signs and symptoms due to the failure of the bone marrow. Patients are anaemic, with a low haemoglobin, resulting in less oxygen being carried around the body. Presentation includes tiredness, fatigue, and shortness of breath on minor exertion. There's also a failure of production of the normal white blood cells, our infection-fighting cells, known as neutrophils. Patients present with infections. Here's an example, a chest X-ray of a patient with pneumonia, where you can see additional white material in the upper lobe of the left lung. On the left-hand panel, you can see a patient with ongoing fever, a common presentation in patients with leukaemia. And finally, patients may present with abnormal bruising and bleeding, and that's because the platelet count, which is the clotting cells, is low. Here you can see bruises and these little fine petechiae, often over the foot due to gravitational effects, and in the mouth on the mucosa, you can see bruising and bleeding. This is the issue that patients with acute leukaemia present with. The problem we have when we're managing these patients in the field of personalized haematology is that, up until recently, we treated all patients the same way. The presentation is similar, clinical features are similar, and patients would usually be treated with curative intent, with the goal of putting the patient into remission and ultimately curing them. However, all patients received the same type of chemotherapy, resulting in variable outcomes. Not all patients went into remission, and some experienced subsequent relapses. The goal of our research is to delve deeper and try to find out what the differences are between these patients with acute leukaemia and how we can individualize therapy for each patient. This approach can potentially improve their outcomes and reduce the side effects of therapy. Our focus is on understanding the genetic changes that occur in leukaemia. We started over two decades ago by looking at chromosome changes, which are part of the DNA of the cell that controls its functions and activities. Many blood cancers, particularly acute leukemias, have characteristic chromosomal abnormalities. For example, about half the patients we see with acute leukaemia have chromosome changes, which can help predict outcomes and sometimes alter our therapy approach. However, not all patients have chromosomal changes, and this approach can only detect changes in the number and structure of chromosomes. It can't identify small mutations or changes within the genes themselves. This limitation led to the need for advancements in the field of molecular genetics. We've compared the study of leukaemia genetics to an iceberg, where the chromosome changes represent what's visible above the waterline. But the majority of changes, or the bulk of the iceberg, is below the waterline in the field of molecular genetics. This involves looking at spelling mistakes and small mutations within the genes themselves, which has become possible due to advancements in science and technology. Initially, we could only examine a small number of genes, but in the last decade, there have been significant technological advancements in gene sequencing. With modern technology and next generation sequencing platforms, we can now analyse the entire human genome in a 24-hour period. This has provided us with much more information about the genetic changes in leukaemia and other cancer cells. Our study, the Auckland Myeloid Gene Panel study, aims not only to count the number of books in the library (representing genes) but also to examine each page for any missing pages and spelling mistakes that might occur within those books. So, within the DNA and the controlling pathways for the leukaemia cells, we developed a panel initially with a 78 gene panel. These genes are involved in blood cancers, and we've now expanded that to 110 genes that we look at. The goals of our study were threefold: first, to identify specific mutations within the leukaemia cells that might change a protein we could then target with a specific therapy or drug; second, to find information that could guide treatment and alter the prognosis, indicating a more favourable or unfavourable outlook; and third, to investigate molecular biomarkers for monitoring the patient's response to treatment. Here is an example of the type of report we generate from our myeloid gene panel study. It includes patient details, genetic and chromosome information, and identified mutations within the patient's leukaemia. Each patient undergoes this analysis, generating additional information alongside conventional data about the leukaemia’s appearance and chromosome studies. One of our initial findings was that every patient's leukaemia was different at the genetic level, even if it appeared similar under the microscope. This diversity in genetic profiles highlighted the need for personalized treatment approaches. Large international studies, in which we participated, demonstrated that in addition to chromosome changes, different molecular changes could predict outcomes for patients. These predictions were based on probabilities of remaining in remission, with some mutation profiles indicating better outcomes than others. In our analysis of the first 100 patients in the myeloid gene panel study, we detected an average of just over three critical mutations per patient. These mutations play a vital role in the development of leukaemia. We also observed variations in the frequency of specific mutations, with some being more common than others. Moreover, our research aimed to determine whether these genetic analyses influenced our treatment decisions and patient outcomes. We classified leukaemia into risk groups, such as good, intermediate, and unfavourable, using both conventional information and molecular classifications. The addition of molecular classification led to changes in risk group assignments for some patients, potentially impacting their treatment choices. In approximately 50% of patients, we identified mutations that could potentially be targeted with drug therapy. These mutations altered proteins within leukaemia cells, making them "druggable" targets. For instance, we found that about 10% of our leukaemia patients had mutations in the IDH2 gene, which could be targeted with specific drugs, leading to improved blood counts and bone marrow appearances in some cases. Furthermore, our research explored using mutations as biomarkers to monitor therapy and assess the depth of remission. We employed minimal residual disease monitoring, which allows us to detect leukaemia markers at a much lower level than conventional criteria. Lower minimal residual disease levels correlated with better outcomes, enabling us to refine treatment approaches. Unexpectedly, our research revealed a higher incidence of familial predisposition to blood cancers than initially anticipated. While solid cancers typically have a 5% inherited genetic predisposition, we discovered that among the first 200 patients we studied, eight had an inherited predisposition. One example was the DDX41 gene, where an inherited mutation was identified in patients without a family history of leukaemia. These findings have implications for treatment recommendations, genetic counselling, and potential donor screening for stem cell transplants. In summary, our research in personalized medicine for acute myeloid leukaemia goes beyond targeting specific mutations with novel treatments. It also enhances diagnosis and subtyping, predicts patient outcomes, identifies potential druggable targets, provides biomarkers for monitoring therapy, and uncovers familial predisposition to blood cancers. This comprehensive approach aims to improve the care and outcomes of leukaemia patients. This work is in the blood cancer area, but I think the findings here also become applicable to other cancers. There's a lot of work going on both within the University of Auckland and the precision medicine field, and internationally looking at the impact of genomic testing and cancers. So thank you very much for tuning in. Thank you very much for your attention. Can I just acknowledge I'm a very small part of all of this research? So this work was done in the Leukaemia and Blood Cancer Research Unit within the Centre for Cancer Research at the University of Auckland, led by Stefan Bohlander, my co-director of the LBCRU, and Purvi, who's the scientist who's driven through all our molecular work. We also work closely with our colleagues in molecular haematology at Auckland Hospital and our clinical colleagues at Auckland City Hospital who care for these patients. Finally, the patients and their families who consented to having their leukaemia DNA analysed as part of the study. Presentation by A/Prof Nuala Helsby, Department of Molecular Medicine and Pithily, The University of Auckland “Cancer Pharmacogenetics” Hello, I'm Nuala Helsby, and I'd like to talk to you today about my research interest, which is cancer pharmacogenetics. As we've understood more and more about the cancer genome and the importance of the genome in both prevention of cancer and also our improved understanding of how to treat cancer, and by the genome, I simply mean the DNA molecules within the nucleus of cells. We've understood for a number of years now the role of the important role of environmental chemicals that can cause damage to the DNA, and they're called mutagens. If we can avoid those environmental DNA-damaging agents, we can help prevent and minimize the chances of getting cancer. So that's an important part of our understanding of the cancer genome. Over the years, we've also understood that certain cancers can run in families, and these are called inherited cancer syndromes. Our ability to understand the genetic changes and the changes in the DNA in those individuals within families help us not only understand who's going to be at risk of developing some of these cancers but also developing screening programs to try to minimize or prevent the risk of people developing cancer. Over the years, we've also improved our treatments of cancer by understanding more about how the cancer genome, the DNA inside cancer cells, works. One of the things that we do know is that cytotoxic chemotherapy drugs and radiation therapy damage the tumour cells by causing a lot of DNA damage inside those cells. But over the years, more recent years, we've also been able to start to understand that within one's cancer, a cancer type, there may be lots and lots of subtypes, and we call these molecular subtypes. They are because within each type of cancer, there might be lots and lots of different changes in the DNA, so somatic mutations in the DNA in those tumour cells. That might mean that some of those subtypes of cancers are overexpressing certain proteins and certain pathways, and that means we can then target those proteins or pathways with very selective new drugs that have more recently become available on the market. I'm interested in something slightly different, though. I am interested in the person, not the tumour, not the cancer. I'm interested in something called cancer pharmacogenetics, and these are the inherited differences in how each individual person responds to therapy. In the context of cancer, I'm particularly interested in cancer chemotherapy. So I'm interested in pharmacogenetics, and that is simply trying to study and understand the inherited differences or differences in our genes between individuals that might mean that in some people, a drug doesn't work very well, and in other people, a drug might not be safe. So it's this real balance between the benefits and harms of a drug that might relate to your differences that you've inherited from your parents. Now I work on both sides of this balance, but what I want to tell you about today is some work that we've been doing for many years now to try and understand why one particular cancer drug might not work in some people. So what I want to talk to you today about is this drug cyclophosphamide. Now it's one of the oldest chemotherapy drugs, and it's given as an intravenous drip to patients, and it's used. It's really key for the treatment of cancers such as breast cancer but also haematological malignancies which are blood cancer cycle lymphoma and leukaemia and also in some of the very rare childhood cancers. Now, cyclophosphamide is this compound here. This is the chemical structure of cyclophosphamide, and it works by these two arms of the molecule attaching to DNA. And once it's attached to the DNA, it stops cells being able to divide, so that stops the cancer cells growing. So one of the other advantages of this ability of cyclophosphamide to bind or attach to DNA to prevent the ability of DNA to then copy itself to replicate, which is a key thing that's required for cells to grow and proliferate in your body. This ability to stop this process, stop DNA replication, means that cyclophosphamide is also very good at helping to treat certain autoimmune diseases. Those diseases are things like systemic lupus erythematosus and vasculitis. And that's because in autoimmune diseases, you've got a very activated immune system and lots of proliferating white blood cells that attack your normal tissues. So cyclophosphamide can dampen down and stop those proliferations of those very active cells. But in the context of cancer, cyclophosphide has been increasingly used because of its immunosuppressive properties too. And in one context is where it's been used when patients have got haematological malignancies, some of those blood cancers. And one of the ways to treat that is to give patients a bone marrow transplantation. But if you don't dampen down your normal immune system with a little bit of a small dose of cyclophosphamide, then your normal immune system will start to attack that bone marrow transplantation. And that's called graft-versus-host disease, and it's one of the newer ways that cyclophosphamide is being used to help treat cancer patients with cancer. It's also being used in another very new approach to the treatment of cancer, and that approach is called CAR-T therapy, where T cells are taken out of your body. They are trained and adapted to help them identify your tumour cells as foreign. And then they're put back into your body to help target those and be able to attack and target your cancer cells. But to put these CAR-T cells, these altered T cells back into your body, you need to provide a little bit of space inside all of your immune system. And one way to do that is, again, to give a little bit of cyclophosphamide just before you give the reinfused these T cells back into the body. And that's called a preconditioning to give a niche or a tiny little space to help these T cells be able to repopulate into your body. So why does this drug cyclophosphamide not work in some people? Cyclophosphamide is actually a very complicated drug. So cyclophosphamide itself isn't active. It's called a prodrug. It has to be converted. It has no activity. It has to be converted in our bodies, in our livers, into a molecule called 4-hydroxy-cyclophosphamide that then converts and balances itself with a compound called aldo-phosphamide. And then there's one further step where aldo-phosphamide gets converted into a molecule called phosphoramide mustard. And it's this phosphoramide mustard that attaches itself or alkylates DNA, and that attaching and alkylating DNA is what stops the DNA being able to replicate. So it stops the cell growth. But it also, in a cancer cell, will tell the cell to undergo cell death, to go onto a process called apoptosis. Using human liver, that some individuals are very good at activating cyclophosphamide into this 4-hydroxy-cyclophosphamide metabolite. So some of us are very high activators of cyclophosphamide. Other livers are very poor activators of cyclophosphamide. And again, some are somewhere in between, so intermediate activators of cyclophosphamide. This activation of cyclophosphamide in the liver is undertaken by some enzymes, and the enzymes involved are called CYP2C19 and CYP2B6. Now, these enzymes, we've inherited differences in the activity of both of these enzymes, and the differences in the activity that we've inherited are simply due to something called single nucleotide polymorphisms or single nucleotide polymorphisms or Snips in the genes that code for each of those enzymes. So if you're not sure what a SNP is, it's basically the code for within each gene that encodes for a protein has a series of letters within it. And if one of those letters gets changed, for example, a change from a G to an A, then that is a single nucleotide polymorphism. And if you have one of these very small letter changes in the gene for either CYP2C19 or CYP2B6, then the activity of that enzyme is very low or non-existent. And because we have inherited two copies of the gene from our parents, one from our mother and one from our father, then the children of the parents can have either inherited two normal copies, in which case CYP2C19 and CYP2B6 enzyme would say that they've got normal activity of those enzymes that can activate cyclophosphamide. Or they might have inherited two changed copies of the gene from their parents, and that means that then they've got very poor activity for either CYP2C19 or CYP2B6, and their ability to activate cyclophosphamide in their liver. Some individuals will have inherited one normal copy and one changed copy of their genes, and they will have intermediate activity for activating cyclophosphamide by their liver. Unfortunately, the pattern of these letter changes, these SNP changes in genes, is actually quite complicated. But all you really need to remember is that for CYP2C19, there are two common SNP changes that occur. And if you inherit any pattern of these SNP variants and you inherit two of these copies that are variant genes with low activity, then you will be a poor metabolizer of drugs such as cyclophosphamide because you've got no enzyme and therefore no activity. And that's sometimes called null. For CYP2B6, though, it's a bit more complicated because it's a very complex gene. But all you really need to remember for in the context of today is that if you've inherited a pattern of two variant SNP changes in your gene, which is called the star 6 variant, then you will have low enzyme activity. And if you've inherited essentially two copies of this star 6, which has two SNPs in it, then you are also likely to be a poor metabolizer of cyclophosphamide with very low activity of being able to activate the drug. A number of years ago now, we were able to demonstrate using human liver material that individuals who had inherited at least one variant copy of their gene in either CYP2C19 or CYP2B6 were poor metabolizers of cyclophosphamide and had much lower activation of cyclophosphamide in their liver. So we've been able to show that if you've inherited a low-function enzyme for either CYP2C19 or CYP2B6, that certainly, within liver samples, you can see decreased activation of cyclophosphamide into 4-hydroxycy-clophosphamide. But that's only the first step in the activation of this drug to form that agent called phosphoramide mustard that interacts with DNA and causes all the stopping cells, like cancer cells, from proliferating and growing. So do these inherited differences in activation matter? Do they have a clinical outcome? We decided to look at that in two different ways. And the first way we was we decided to look to see what was already known in the literature. So we had an extensive look through all the material that had been published in the literature. And we found that when we looked at the data, there were a number of studies, 13 studies, which had shown that in patients, you could see differences in how much of that activated four-hydroxy-cyclophosphamide was formed and circulating in their blood supply ready to interact with tumour cells and kill tumour cells. But what we also found was that there were 17 studies which had shown that if you've inherited any of those SNPs in either CYP2B6 or CYP2C19, then patients will have worse outcomes when they're treated with cyclophosphamide. So they'll have worse survival following treatment with cyclophosphamide, whether it is breast cancer treatment, leukaemia, lymphoma treatment, or another blood cancer called multiple myeloma. And even worse treatment outcomes in that. And one of those autoimmune diseases that cyclophosphamide is sometimes used for, a disease called lupus, there was very variable quality of the data. So some studies had only looked for changes in inherited differences in CYP2B6, and other studies had only assessed CYP2C19. So there is still a little bit of uncertainty in the literature as to the importance of the inherited differences in both of these genes. So we then wondered if there is this strong signal from the overseas literature, can we see the effect of these inherited differences in CYP2C19 and CYP2B6 in New Zealand patients? So we decided to look to see if we could see these inherited differences in how patients can activate cyclophosphamide in patients who were being treated with cyclophosphamide for breast cancer. And what we did was we took blood samples from the patients while they were receiving their cyclophosphamide and measured to see if we could detect the formation of that four-hydroxy-cyclophosphamide metabolite in relation, and not to see the differences in the levels of that metabolite in comparison to their inherited differences in those two genes, CYP2C19 and CYP2B6. And that's exactly what we saw. When we measured the concentrations of four-hydroxy-cyclophosphamide in their blood samples, we could see that if you've inherited a low-function of CYP2C19, you had lower metabolism, lower formation of that metabolite, lower activation of cyclophosphamide. And the same was also true of inheriting increased inherited variant copies of the CYP2B6 gene. Too many copies of variant copies, and you have lower bioactivation of cyclophosphamide. It is well established across different geographical regions of the world there are different prevalences of genetic variants. And it's fairly well understood that people from parts of Asia and Southeast Asia tend to have a higher prevalence of variants in the CYP2C19 and CYP2B6 genes. And that means people from those regions of the world are more likely to be poor metabolizers of drugs like cyclophosphamide than people of European ancestry. Now, we don't know very much at all about the prevalence of these gene variants in people of Māori and Pacific ancestry. But in our study, what we did note was that people who self-identified as not Pakeha had much lower activation of cyclophosphamide than individuals who identified as Pakeha New Zealanders. Unfortunately, it's a little bit more complicated, and that's because there are some other factors affecting the enzyme activity of those cytochrome P450 or CYP enzymes that are involved in the activation of cyclophosphamide. And that's because there's increasing awareness that other factors, environmental factors, can interact with your genes to decrease the activity of these enzymes. And one of those environmental factors is the body's inflammatory response to the presence of a tumour in your body. And in this case, you might have inherited normal copies of the gene, so you should be a normal metabolizer. But the environmental effect of all this inflammation that occurs in your body is it switches it down-regulates or essentially switches off how well that gene is processed. And so you become a poor metabolizer. And this difference between your genes saying you're a normal metabolizer and your body's actual process, where you're a poor metabolizer, is called a phenocopy. And so, importantly, your genotype will not predict your phenotype when you have a large inflammatory response. And these individuals are sometimes called discordant from their genotype. Now, CYP2C19, which is one of those enzymes that's important in the activation of cyclophosphamide, is particularly vulnerable to this down-regulation or changing the activity of the gene for CYP2C19. And we've been able to show over a number of different studies over the years that there are a substantial number of cancer patients who are discordant for CYP2C19. So they've got normal CYP2C19 genes, but they've got poor metabolism of the enzyme with this enzyme. And we can do that by probing the activity of this enzyme with prodrugs for CYP2C19. And we've done that over a number of different studies, and typically it's about 25% of patients at any one time have very low CYP2C19 activity that has nothing to do with their genotype. So it is a little bit more complicated than just simply your inheritance. CYP2B6, in contrast, just doesn't seem to have the same gene-environment effect. And that means that after a patient has had multiple cycles of chemotherapy treatment with cyclophosphamide, the CYP2C19 gene no longer predicts whether they're going to be a poor activator of cyclophosphamide or not. However, the inherited differences in the CYP2B6 gene still strongly predict which women are going to have low activation of cyclophosphamide. So I hope I've been able to explain to and persuade you that that first initial step of converting the inactive cyclophosphamide into an active compound by the human liver does involve these two enzymes, and is particularly inherited differences in CYP2B6 are probably very important in patient outcomes. But what's this four-hydroxy-cyclophosphamide metabolite has been formed, it readily forms another compound called aldo-phosphamide. And this compound is complicated because this metabolite can then be detoxified, it can be removed from the body by an enzyme called aldehyde dehydrogenase. And this enzyme also has a lot of inherited differences in its activity. And this is just not well-studied in any population anywhere in the world, and is something we still need to understand more about. And it's important because we do know that tissues that have high levels of this enzyme aldehyde dehydrogenase are protected from the toxic effects of cyclophosphamide. And that's how some of the bone marrow stem cells are protected from very high concentrations of very high doses of cyclophosphamide. But once aldo-phosphamide has been formed, the way that it can convert into phosphoramide mustard, interact with the DNA, stop DNA being able to copy itself, replicate, and let cells, cancer cells in particular, proliferate and grow has always been assumed that this step is a simple chemical conversion, and that it doesn't involve any enzymes. However, we've very recently been able to show that we think that this final step is actually an enzyme-catalysed step. So, as I said, it's always been assumed that this conversion of aldo-phosphamide into this final reactive compound that interacts with DNA, binds to DNA, in a process that's called alkylation, that this process has always been assumed to be a simple chemical reaction. Simple conversion. And we think that we've been able to show now that it's actually an enzyme-catalysed reaction. And we think that this enzyme is not actually an enzyme. We think it's actually an enzyme-protein. So it's a protein-protein complex that's involved in this final step. And we also think that the enzyme-protein complex is not just a simple enzyme. It's what we call a multiprotein complex. And a multiprotein complex is where you've got a number of different enzymes and proteins that all work together to help catalyse a reaction. And so we've done some experiments with purified human proteins that are involved in the activation of cyclophosphamide. And we've also been able to show that, in particular, when we look at a protein that's important in forming the aldo-phosphamide, so it's important in that step just before the last step, we've been able to show that if we remove that protein from a human liver cell, then you lose the ability of that liver cell to form the final activated compound that interacts with DNA and causes DNA alkylation and binding of that to DNA. So that's a critical step for killing tumour cells. We've also been able to show in that same study that, importantly, if we remove that particular protein from a normal human liver cell, then that cell also loses its ability to alkylate DNA. So what this means is that this enzyme, and this protein-protein complex that we've shown is involved in this final step, it suggests that they are key to forming the DNA alkylating agent that causes cancer cells to undergo cell death. And so we think that they might be a key therapeutic target that might allow us to improve the ability of cyclophosphamide to treat cancer cells and to kill tumour cells. So in conclusion, cyclophosphamide is actually quite a complicated drug, and its activation by the liver involves a number of different enzymes. And we've been able to show that there are quite large inherited differences in the activity of these different enzymes, in particular, CYP2C19 and CYP2B6, that seem to be able to influence the outcome of treatment with cyclophosphamide. And we've also been able to show that there are some environmental factors, such as the inflammatory response in the body, that can also interact with the activity of these enzymes. But it's also a reminder that we still don't fully understand all of the factors that influence the activation of this particular drug in patients, and it's something that we're continuing to work on. And finally, the initial process of forming an active DNA alkylating agent that allows us to kill tumour cells does involve enzymes and protein-protein complexes. And this complex may also be a therapeutic target to try and improve the effectiveness of cyclophosphamide for treatment of cancer. Thank you very much for your attention. Can I just acknowledge, I'm a very small part of all of this research. So this work was done in the Leukaemia and Blood Cancer Research Unit within the Centre for Cancer Research at the University of Auckland, led by Stefan Bohlander, my co-director of the LBCRU, and Purvi, who's the scientist who's driven through all our molecular work. We also work closely with our colleagues in molecular haematology at Auckland Hospital and our clinical colleagues at Auckland City Hospital who care for these patients. Finally, the patients and their families who consented to having their leukaemia DNA analysed as part of the study. Thank you very much for your attention, and I'm happy to take any questions. I hope this formatting helps make the text more readable and comprehensible. If you have any more questions or need further assistance, please feel free to ask.

Read more now in the latest AMRF newsletter. Our latest newsletter is testimony to the life-changing medical research that is being undertaken and we hope you enjoy reading about our early career researchers' work that features: One family's heart-wrenching experiences with Parkinson's disease and end of life choices The urgent need for financial support to maintain career continuity for early career medical researchers Early detection in a family with early-onset dementia New faces on our board of trustees Interested in the latest advances in cancer research? Click to send us an email to register your interest in our upcoming August webinar with LIVE Q&A with researchers. Have your explored our web page to find out more about how you can contribute to medical research, like neuroscience, heart health, cancer, prenatal development and more? And don't forget, donations, large or small, are always welcome. Click below to read and download the PDF newsletter Learn more at this free webinar, hosted by A/Prof Gary Cheung. The research team for The End of Life Choice Act 2019 at the Department of Psychological Medicine and School of Nursing, University of Auckland, invites you to a free webinar on assisted dying research in Aotearoa New Zealand on 4 April 2024. In a two-year project (funded by the Auckland Medical Research Foundation) the researchers explored the experiences of health practitioners who have been directly or indirectly involved in providing assisted dying under the End of Life Choice Act. They also explored the perspectives of Māori whānau and non-Māori families of individuals who used the Act, considered using the Act but ultimately did not, or did not use the Act. This study provided an opportunity for health professionals and whānau/families to reflect on their experiences of assisted dying in Aotearoa. Learn more on the event flyer: https://bit.ly/2024-Assisted-Dying-Webinar Add the event to your Calendar: https://bit.ly/2024-Assisted-Dying-webinar-calendar

How do we make operating theatres safer, and lower risk for patients? What are some minimally invasive alternatives to gastrointestinal and stomach surgery? Curious? Watch now to learn more about the Auckland researchers who are investigating opportunities and possibilities in surgery. Professor Jennifer Weller is curious, too. She is using 'real life' simulated dummies to improve safety for patients in operating theatres. She is joined by Dr Tim Angeli-Gordon who is curious to learn about less invasive alternatives to surgery. They are working on solving the puzzles associated with the future of surgery. Generous donors -- people just like you! -- to Auckland Medical Research Foundation enable researchers like Prof Jennifer Weller and Dr Tim Angeli-Gordon to continue their life-changing work. Make your tax-deductible donation to the Auckland Medical Research Foundation and support our future today. Remember 100% of your donation supports researchers, scientists and clinicians -- never AMRF overheads! Presentation by Dr Jennifer Weller, Head of the Centre for Medical and Health Sciences Education, The University of Auckland and Specialist Anaesthetist at Auckland City Hospital. “NetworkZ – Better Outcomes in Acute Care” Thanks for the kind introduction, and welcome everybody this evening. I am going to talk very briefly about our NetworkZ programme. This is a national program, multidisciplinary in-situ simulation-based team training for surgical and emergency departments. I would like to acknowledge a large number of collaborators in this work and our funders and also the NetworkZ team and the current NetworkZ team, which are currently delivering the training around New Zealand, and also the network of our NetworkZ instructors, and convenors and participants, and thank them for giving permission to use a lot of these photographs. This reminds me that I should give a warning that is there are some very explicit photographs of goriness in this presentation, but they all simulated. So just a very brief history, which began with the pilot project back in 2014, which was partly funded by Health Workforce New Zealand and a project from an AMRF grant. That showed sufficient evidence of some effect and feasibility that we were able to secure ACC funding and that's allowed us to roll this training out across the whole of New Zealand. What we have really established is a network of simulations, simulation, capacity, so ability for teams all around New Zealand to train using this really high fidelity program. We rolled it out, starting in 2017, and have just completed the roll out last year. We are now moving into a business model run by UniServices, and in parallel there’s been a lot of research along the way. I just wanted to outline what I am going to talk about and very briefly what NetworkZ is. I wanted to talk about three key patient safety contributions that arise from the program – crisis management, speaking up and latent safety threats – and then touch on some research and evaluation that is wrapping around this program. The rationale for this sort of training is that adverse events occur in health care and there is not always the optimal outcomes that we would hope for. So adverse events are common, and if you look at the literature in New Zealand about 10% of hospital admissions are associated with some unintended event that caused some degree of patient harm. That is something that happens all around the world, and something that's quite a burden of disease for our communities. In terms of the surgical setting many of the peri-operative events that were adverse were considered to be avoidable, and a lot of those avoidable incidents comes down to teamwork and communication. Just getting the information through to the right people and getting the team organised -so some things that we can actually do something about. In addition to this, it's a lot of the way we design things, the way we set up our environment, there are a lot of hidden threats in those environments that can also lead to patient harm. I'll touch more on that later. The program of NetworkZ - I’ll try and give you some picture of what it looks like over the next few minutes - but one of the things it does is it engages the entire team. It is actually very rare in healthcare training to get all of the members together. Surgeons train separately to anaesthetists, who train separately to nurses and getting them all in the same room is quite a feat. We have been able to do that through creating very realistic simulations that everybody can engage in as if they would with their real work. Surgeons are able to operate on the mannequins, anaesthetists are able to anaesthetise them, and nurses are able to work in their own environment to support the surgical operation. This is also national. Because of the funding we receivered we were able to establish this sort of training in every hospital that provides surgical care around New Zealand and that's speaks to equity in that usually those little places don't get to get the big training events that are available for the big hospitals. It's accessible nationwide, and our aim is to build more resilient teams that are more resistant to error. The training is in situ, which means that it actually happens in the workplace, so in an actual operating theatre, in an actual cubical in the emergency department and that, in addition to being very realistic and more likely transfer to practice, it also offers us a chance to stress the system, to stress the environment and uncover those hidden threats to patient safety. It is also a trainer- trainer model. We train a whole lot of instructors and they then go back and deliver the training in their own environment. It is local ownership. In a NetworkZ course a typical morning would be introductions and familiarisation. We think it is really important that let's get to know each other and get familiar with the environment, so that it's not a big surprise when they go in there. Then there are 2 or 3 simulated clinical scenarios, each lasting about 30 minutes or so, followed by debrief. We really dig into what happened during those simulations to make sense of it. Also, within the training there are communication workshops - looking at how we can improve the way we communicate with each other. This is a model that we have been using around team work to assist with teamwork training and it seems to have stood the test of time. It is a model that was developed by Eduardo Salas and it's based on observations, empirical evidence of thousands of different teams across a whole lot of different industries. It might also apply to the teams within which you work or move. Think about these components of what an effective team looks like. An effective team has somebody that is in charge - a leader. In an effective team the whole team is able to contribute to the problem solving, the decision making, speaking up with their concerns. It is not just up to one person. The team is able to monitor each other and see where there are areas of high workload and can help each other out. Or you can anticipate what somebody might need and when something changes in the situation they can adapt and rapidly change course. The way they can do this, and the key requirements are, that they've got a shared understanding of what the situation is and what's the plan and what's likely to happen. They all have a shared concept of what they are doing and they must have some pretty good ways of communicating with each other to capture those communication failures, and they also have to have a lot of trust and respect. This comes down to this idea of, if you want to be able to speak up with concerns and share ideas you do have to have a lot of respect, so part of it is about relationship building. They of course work in an environment, in a culture, and they have their own things they bring to this to the situation that will affect how the team works. Some pictures of simulations. This is a surgical simulation. You can see how realistic it looks. This is in ED where we are running simulations in ED departments across a lot of the country - at country hospitals and city hospitals. A lot of engagement. This is in the post-operative care unit. You can just see from these pictures how engaged people are with this sort of training. It really is a wonderful way of teaching. People love it and get really into it, so it is very rewarding. Over the years we have had participation from all hospitals, either in the operating room, PACU or in the ED. We have had over 3,500 people go through our training programs. That is quite a lot of health care workers and a lot of people have been involved in the instructor training. We get very positive reviews. People fill out an evaluation form at the end of every course, and it is always extremely positive. People like this sort of training, despite the effect that it might feel a bit threatening. I just wanted to show you one or two minutes of a trauma scenario from one of our NetworkZ courses, and this is portrayed by two people that are acting. This is role playing, and it is a simulation. It is not a real person. This is a simulation of a trauma where a patients come in and they have got a knife in their belly and they've cut something, and things are happening. This is the middle of the operation. The anaesthetist is really worried about the blood pressure, which is really low; the surgeon is trying to find where the bleeding is coming from, and the nurses are trying to deal with all of the equipment. The suction is filling up and they haven’t got enough swabs and things. You may have noticed that there wasn't a great deal of communication between the teams. The anaesthetist, surgeon and the nurses. It seems like they didn't all have a clear picture of what was what was going on together. That is one of the things that we really draw on in these sort of experiences, to promote that with more of a feeling of it being in a whole team and getting on to the same page. That us leads me on to one of the things I want to just touch on - how we can improve patient safety through this training around crisis management. Our courses are training people to respond to particular critical events, for example, to a major haemorrhage, major trauma, or anaphylaxis, so that we do get training on specific events but there's also this more general training for teamwork which can apply, not only to other critical emergencies, but also to routine daily care. Capturing some of the lessons learned from teamwork and communication in this stressful situation and applying them to a routine daily practice. A little bit about what it is like being in a clinical emergency. It is quite stressful and a lot of the information that you are getting in an emergency is unclear, it's ambiguous and you just don't get the whole story. There is a lot of uncertainty. You might be in a strange environment and the environment may suddenly become very full of stuff and people, and so it can be quite unnerving, stressful and there is also time pressure. You really have to get stuff done. It is amazing how many things you need to get done all at once, and how difficult it sometimes feels to just do them. There is this fear of consequence, a bad outcome for a patient. It really is stressful. There is a lot of sensory input coming in and you can see that this is not an untypical - sort of messy environment. This is what it looks like in some of our theatres during a high stress event, and there is a lot of input coming in there. This is a combination of cognitive overload and stress. It really makes it very difficult to think - you get tunnel vision, you miss some really important cues coming in because you just focus in on one thing, so you lose that overview of the situation. It becomes really hard to think and it's just too much for any one person to take in. If you look at the graph of performance versus stress. This left side of the graph where there's no stress - that's probably not enough, you’re probably basically asleep at that point. Up at the top this is where we want you to be for optimal performance, but if the stress gets too much you descend into this stage of panic, and really, very little gets done at that point. We are trying to modify that stress and that overload, so that it's a manageable situation for people. We do that in a number of ways, so that it is a way of spreading that cognitive load around the whole team rather than it all being on one person and it can make the whole thing really easy. We start with the planning. If we have got a little bit of time to plan, and we don't always use it in the clinical environment, but we're teaching people to try and get together and do that. Get together with a briefing and plan for what might happen. Think about potential threats. Allocate roles. Consider more resources. In the simulation we are applying that teamwork model that I described before, and people get a chance to apply it. I love this picture. This chap in ED - that was his stance. He was a stand back leader by not having his hands on anything not engaging in any task he had mental capacity to think. He was there doing the thinking and you can see how much easier that would be to control the situation if you are standing back and thinking. That is one of the things we talk about. Afterwards we get an opportunity to talk about it. It is a very structured debrief. We talk about how people are feeling when they come out of it and we get a description of the scenarios so that everybody has got a clear understanding and an analysis, and then we very much concentrate on what have we learnt that we can take back to practice. That is how I think our teamwork training works to build more resilient teams. One of the things that has come up in what I have been talking about so far about crisis management training is speaking up. Speaking up is not easy. Thinking of your own situation where you thought, I should have said something then - there must have been lots of instances where you thought that yourself. You think about why you didn't speak up and it's possibly because you thought you might get a hostile response or maybe you thought you weren’t right about what you're thinking, or maybe it wasn't your business even. I guess it's becoming a real thing in health care settings to teach about speaking up now, because we do see it as a real concern, and we think it does need to be everybody's business. There are a lot of moves around speaking up for patient safety. You will see posters up around hospitals and the interventions team seem typically to be aimed at this little guy. This assertiveness training and it is something like; probe, alert, challenge, emergency. It is escalating the challenge and trying to make it easier for people to challenge somebody that's more senior to them or across a professional group. There is not much evidence that this works. Perhaps it works a bit, but people still don't speak up. We thought the position should be that it shouldn't really require an act of bravery to speak up - it should just be normal. We flipped it on its head and started thinking about what is it actually like from the perspective of the big guy; the person that you are speaking up to? What does it feel like? How do you normally react? I guess this is a little bit like somebody giving you feedback possibly a spouse or anybody. If somebody raises a concern about something that you have said or done, it’s pretty instinctive often to react defensively. You can probably relate to that, and I think that is a natural reaction. We wanted to get people to reflect on what it is like to be spoken up to and what sort of things might subsequently unfold after their response. How might it affect patient care? In one of the studies we did, we interviewed a whole lot of senior doctors, senior nurses, anaesthetic technicians, and did an interview analysis using thematic analysis. It came up from what they were telling us, that this model of what it's like being spoken up to, and it does matter what the speakers tone and content is - it can be more or less offensive - but it's filtered through your lens and so it might depend on how you are feeling at the time, whether you’re really stressed, whether you're really trying to concentrate, whether you've had a really bad day or something else is going on in your life which may influence how you interpret that that message. You might have your own beliefs about personal fallibility, and I think possibly, as we get more experienced, we experience fallibility more often, and realise that it's a really good idea if people speak out with their concerns because it's actually helping us and somebody's got your back so that tends to change with experience. Obviously, you are less likely to be offended by somebody that you have got a good existing relationship with, which speaks to this idea of building teams and mutual trust and respect, and vice versa. If somebody says something, and you already don't like them, then you’re more likely to respond negatively. You might have experienced how difficult it is to speak up. So you might have some empathy for the person that is trying to give you this message and be more forgiving of their possibly bluntness. There are also, in our operating theatres, there is a mix of cultures and mix of ethnicities, and there is a lot of different ways of perceiving culture and hierarchy in different cultures and different professions. You might find some more hierarchical structures where you would never dream of challenging somebody more senior than you and you might find that some cultures say things more directly or bluntly. It also came up that you were more likely to respond positively to somebody who you thought had a lot of medical knowledge or expertise. This was interesting and you can consider it good and bad in that it certainly makes sense, but also it might mean that you just ignore the health care assistant in the corner that says, hey, I'm not sure that this is the right patient and some vital piece of information, because you're not expecting it to come from that quarter. All of these things influence how you respond. It could be very positively; it could be very negatively. A positive response is going to encourage the whole team to keep contributing to the patient decision making but a negative response - everybody’s there and it's not called the theatre for nothing – so you're in a theatre your responses are observed, and everybody says, well, I'm not going to say anything from here on in and people start withdrawing their contributions, and it's less people putting into decisions making, less effective teamwork and patient care is less likely to be optimal. This sort of work has informed our course. We are using that model to guide reflective exercises, to try and help people to unpack that immediate defensive response and perhaps moderate it, explore the facilitators and barriers to speaking up and aim to create, in your own environment, a space for people where they are more likely to speak up and contribute. Next is a piece on patient safety I wanted to touch on, and this is the latent safety threats. Latent safety threats are issues that are waiting to happen but haven't. They haven’t harmed anyone yet but they might. And so they are errors in design, organisation, training, or maintenance, and they may contribute to medical errors and patient harm. In-situ simulation - stresses the system and uncovers latent safety threats, so we don't need to wait for a disaster to happen before we realise that our systems weren’t up to it. We can find that out without having the actual disaster and so resolving these threats can prevent future unintended patient harm. Our first study a was retrospective audit of the post-course reports that people filled in after each of our courses, and we got reports from 21 hospitals. 77 of these contained reports of latent safety threats across a wide range of things. We thought this was actually quite a lot of things to be identifying in people's departments that were accidents waiting to happen. They occurred across a range of things which fitted in with this classification system. Some were as simple as just not knowing team members names. If you are trying to ask somebody directly to go and do something, and you don't know their name it a lot harder, and it delays that communication. As an example, there is a massive haemorrhage protocol which helps us to organise how the blood gets to the theatre. The request goes from the patient to the blood bank and then the blood comes, and it comes in a certain order. It is quite a complex system, but there are protocols for it, and testing that system through at simulation identifies often that people don't actually understand the protocol, or it's not been clearly written. Those practice runs help people to sort out those faulty design issues. We often find equipment problems. It is the defibrillator that doesn't actually work or the lack of equipment - something that you should have had available, but you don't. Other work environment things like, if you're interested in ergonomics, just where you put stuff makes a lot of difference to the flow of things whether you can see stuff. People say we shouldn't have that person standing there, we should have them standing here and that helps workflow. This is just an example. The nurses couldn't find the emergency bell in a theatre when a patient developed severe anaphylaxis and it was because it was hidden. They solve this problem by putting massive red tape right from the floor to the ceiling and so nobody is going to miss that emergency bell anymore. It is simple things that can make a difference. The current research project is a more prospective look at these post course reports that the course instructors fill in after they've seen stuff in the simulations and talked about it in the debrief. Getting them to fill post course reports in, following them up in 6 weeks and 3 months and seeing how these latent safety threats are resolved. Also doing staff interviews. We hope to identify at a national level the sort of threats that are hidden in our environments and there are likely to be some very common ones, and also how to get these things fixed. Barriers and ways to facilitate resolving these threats to make our environments safer for patients. Alongside this, and obviously the funding depended on this, was producing the evidence. So very briefly, we have had a parallel evaluation going right along since we began. Our primary patient outcome measure is trying to look at a holistic measure of outcome for an intervention like this. It is days alive and out of hospital, and it is instinctively true that you're better off the longer you are not in hospital, and whether or not your dead or alive. It is a holistic measure of goodness and we've luckily got a national minimum data set. That is an administrative data set that that has information on all hospital admissions. We can identify those surgical cases and look for that piece of evidence. We have got about half a million cases to analyse. We are also looking at costs and numbers of ACC claims. This is the trial design. It starts off on the left-hand side. That is the control - that is before we've done anything. In the middle is the intervention, and then after that is post intervention. We are looking to compare the pre intervention across all of the clusters with the post intervention. It is the nearest you can get to a randomised, controlled trial in a real-world quality and improvement initiative. There is no way that you can do something like this in a randomised control trial. We are also using process measures looking at observations of teamwork in theatres and also surveys of how people perceive teamwork. This is some of the concurrent research we have been doing, looking at implementation, looking at how you sustain something like this. We have talked about speaking up, of latent safety threats, doing some work around teamwork and communication and the emotional impact on how this works in the operating theatre, and whether or not some of the strategies in NetworkZ are transferring to practice in fact. Also, looking at Māori perspectives on acute care and lessons potentially for NetworkZ from that work. In summary, I think NetworkZ has built capacity and capability for really high-quality teamwork training across New Zealand. To think this is actually probably a world first to have a national program like this and I think NetworkZ speaks to multiple components of patient safety and it actually presents both challenges and opportunities for the team training program in the new current healthcare environment. Thank you for your attention. Presentation by Dr Tim Angeli-Gordon, PhD, Auckland Bioengineering Institute, The University of Auckland “Minimally-invasive diagnostics and therapies for GI disorders: from engineering benchtop to clinical bedside” Thank you. That is a tough act to follow. Thank you, Jennifer. One thing I’ll take away is that stress versus productivity graph. I think I am going to apply that to my own work and try to decrease my stress and become more productive. So, thank you. Tena koutou, tena koutou, tena tatou katoa Nō Tiamana ōku tupuna, engari, nō Amerika ahau Heoi anō, kei Waitākere ahau e noho ana Ko Aotearoa tōku kāinga ināinei He Pākeha ahau Ko Tim Angeli-Gordon tōku ingoa. My name is Tim Angeli-Gordon. I am from the United States originally. I have been in Zealand for 13 years now and this is my home. I have got a whanau here. I have got a couple of daughters and a beautiful wife, who unfortunately couldn't join us tonight. I am very fortunate to get to work with the Auckland Medical Research Foundation and at the Auckland Bioengineering Institute here at the University of Auckland. I went to the University of Michigan in the States. Today I am going to talk a bit about our research on the gastrointestinal tract and specifically on developing minimally invasive diagnostics and therapies for gastrointestinal disorders with a focus on developing new technology in the engineering lab or on the engineering bench top, and then moving that technology towards the clinic. There is a lot of big words here, and I know Sue had a lot of very technical words in her introduction. Thank you for that Sue, but I will try and break it down as we go, so please bear with me. I thought I would talk first about my motivation. Why I do what I do and why it is important that we look into this. Gastrointestinal disorders affect about 40% of the world's population. That sounds very high, but that's everything from reflux after a meal, to very, very severe, debilitating complications with the stomach or intestines. I thought rather than talking about all the different disorders and all the different people - I am going to focus on one disorder as the motivation - that's gastroparesis. Gastroparesis literally translates to stomach paralysis. Gastro meaning stomach and paresis meaning paralysis. These patients, their stomach doesn't empty normally, and they have very severe nausea, vomiting, abdominal pain, bloating, and when they eat a meal they typically feel full very early but it's pretty much those 5 symptoms that they have an and really most patients with gastrointestinal disorders. I will actually focus on one patient in particular. This is Ruby Hill. She was quite a high-profile case in New Zealand. She was a real advocate for gastroparesis for a number of years while she was fighting it. There is a whole range of popular press articles. I got these images from a number of different publications, and they say a picture is worth a thousand words. That is Ruby on the left while she was healthy, and that's her in the middle while she was suffering from gastroparesis. The caption says that she is down to 47kgs at that point and this third photo - that's even more striking – when she is down to 22kgs at that point in 2019. Unfortunately, she passed away that year from complications from this disorder. She was 23 years old. Prior to that she was vibrant. I have talked to her family. I have actually been able to do some work with her mother who runs a website and an outreach group, generating awareness and support for gastroparesis. So it is really striking and so this is why I do what I do. There are many people like Ruby - tens of millions of people who suffer from these sorts of disorders. The diagnosis is very challenging. In talking with clinicians, they want to provide a diagnosis for people like Ruby, and they feel like they don't have all of the tools that they would like. It is difficult to even tell these patients a definitive diagnosis of what's wrong with them. And then when we are able to tell a patient that they have gastroparesis or one of the other gastrointestinal disorders there are limited therapies. Some patients respond well to pharmaceuticals, others don't and there aren't a whole lot of options. Myself and our team, we approached this from a little bit of a different perspective when we looked at the underlying electrical control of the stomach. What you are going to see here is a view inside of the stomach. It is very similar to your heart where each of your heartbeats, the actual contraction of your heart, is triggered by an electrical wave that causes the muscle to contract. What we see here is a video from inside the stomach. It is called an endoscopic video and we see these large ring contractions that are moving down the stomach. Each of those contractions is triggered by an electrical wave, and it is those electrical waves that we measure using new techniques to try and develop diagnosis and treatment options. If there is one thing you take away from my talk tonight, know that the stomach has electrical activity that coordinates the activity. If that is all you take away - I'm happy that's good because most people don't know that. I didn't know when I when I started this journey. I think it is always interesting to take a look back at history. Here is an image of Professor Walter C. Alvarez. He is an American based clinician and very prolific academic researcher and he is the person who is credited with discovering the electrical activity of the stomach. On the right-hand side, we can see an image from one of his very early papers. You can see on the bottom the date is 1922 when this was published and each of those little peaks in that is a deflection of the electrical activity. If you can see in the bottom left of that image there is a little diagram, a hand sketch of a stomach and a couple of lines that denote where the electrons were placed on the stomach. So this is the original discovery of electrical activity of the stomach. Now, if we fast forward 100 years, which I can do in this presentation, we get to more modern techniques called high resolution electrical mapping. This is some work that was developed by my research group, others in my research group, and we see on the left-hand side some of our electrode arrays. Each of those gold dots is an electrode. There is 256 of them and they are 4mm apart; so it's a very small patch or a relatively small patch, with many, many hundreds of electrodes which allows us to record this activity in very high detail. We are able to dictate what direction the activity is moving, how fast it's moving, and many different characteristics about it, that researchers and clinicians weren't able to do with less sophisticated techniques in the past. A couple of benefits of these specific electrode arrays, are that they are flexible, which means that they can adhere to the curved surfaces of the gut and they are also sterilisable which meant that we are able to translate them into human patients, whereas many of the previous techniques were limited to pre-clinical or animal work. We are actually able to record from human patients, and you can see an image of some of our electrodes inside a patient in surgery at Auckland City Hospital. What that has allowed us to do is create very detailed representations of what the electrical activity on the stomach looks like. You can see here a model that summarizes these data. There is a single pacemaker or a single origin where that activity originates. It is midway up the stomach on the right-hand side, called the greater curvature. That activity then propagates down the stomach, or moves down the stomach, and you can see that there is about 3, or even 4 of these electrical waves present at any one time on the stomach. It then terminates at the end of the stomach at what is called the pylorus sphincter, which is the barrier between the stomach and the intestine. So that is what a normal human stomach looks like - a healthy stomach. If we look in a different view, we can see this is an animation of electrical activity across those 256 electrodes. Again, you can see, it is moving from the top of the stomach to the bottom of the stomach. That is what we see in a healthy case. On the right is data that we recorded from a diseased case. This is a patient that had gastroparesis like Ruby, who I showed earlier. What we see is that the activation there is actually originating from lower down in the bottom of the stomach, its propagating in all directions, and it's actually propagating up the stomach. So, it is propagating in what we call retrograde - the wrong direction. We classified a whole range of abnormalities in these diseased patients and it was an important discovery because it linked these measurable electrical deviations with these really complicated challenging disorders. It means that we could potentially use this as a diagnosis - and if we can correct these, we can see if it will actually help as a treatment. But - the methods that I have described so far are surgically invasive, so we actually have to cut patients open to put these on the stomach, which means that vastly limits their applicability, and we can't go around cutting people open just to see if your electrical rhythms are abnormal. There is no current therapy so if we can find proven abnormalities there is no proven way to actually fix them. That forms the basis for my work and much of the work of the group. What I will talk a bit more in detail about tonight are three different projects. The first being to develop minimally invasive electrical mapping techniques. So, rather than having to be surgically invasive, can we develop techniques that are minimally invasive. The second being, can we develop a way to correct abnormalities when it goes wrong? And we are going to look at a technique called gastric ablation that we have been pioneering in our lab. Then, lastly, look at some new clinical applications of electrical mapping and whether we can define and give more certainty around diseased patients and what's actually wrong with them. So I’ll jump straight into the first one of these, which is looking at a new diagnostic tool - endoscopic mapping. I mentioned earlier in that endoscopic means down the throat. Accessing the stomach down the throat - it is minimally invasive, it is one of the first diagnostic procedures that you get when you have persistent symptoms. The clinician typically wants to go inside your stomach and have a look. Can they see anything that is wrong? We wanted to know - can we map the electrical activity of the stomach endoscopically using these minimally invasive techniques? We put our engineer hats on, and we borrowed some equipment and designed some new devices that you can see here. This is an endoscopic version of an electrical device. If you look in the middle that is the recording end. Each of those silver bands is an electrode. There is 64 of them and they're organised in a sphere. They are linear splines. 8 linear splines with 8 electrodes each. Then we have added a balloon to the middle of that. It is actually a cardiac mapping device, the electrical device, and we've added a balloon and some additional components to make it more specific to our needs in the stomach. The balloon allows it to press those electrodes against the wall of the stomach, which is needed for the recordings, and you can see on the right-hand image from an endoscope of this device placed inside a pig stomach actually in our pre-clinical trials. Before I get ahead of myself. We first wanted to know - are we able to actually record these electrical data from inside the stomach? We started in our pre-clinical lab, and we surgically placed this new device that we created, and we compared it with our traditional electrode arrays that were placed outside of the stomach. We placed our new device inside, our traditional arrays outside, and we found that the data was very similar. In the middle we can see the actual electrode traces. Each of those sharp deflections downward is when the actual electrical wave is passing the electrode and then on the righthand side we have got these rainbow looking maps and so you'll see these quite often so I will talk you through this briefly. What this shows is the electrode array, each dot is an electrode and each colour represents the area that that electrical activity has moved per time unit. On the top one it looks like one second, so each second it moves from the dark red, the next second the light red, the next second the orange. What this shows is the direction of that electrical propagation over the array. What we see here is that we were able to record data from inside the stomach similar to outside the stomach. That gave us confidence that we could move forward with this and we are on to something new and valuable. One of the challenges was that this new device is very different to our old arrays, which were flat, two-dimensional, evenly spaced electrodes. Our new device is spherical and it is not evenly spaced electrodes - so there’s variable spacing. What that meant is that our software that we use to analyse the data from our old electrode arrays didn't work for this new device. That is where Alexander Chan came in, as a PhD student, and he developed custom software that was specifically designed to this new electrode device. I am not going to talk through all of it, because it would be hours of his PhD, which is currently under examination and very close to finishing. The take home message here is that we are able to design this new software specifically for the device that enabled us to carry on with the work and to actually analyse the data coming off of this device. It allows us to then create maps of activation from this endoscopic device placed inside the stomach. So here we see activation going from dark red to yellow across 8 seconds. That is showing the electrical propagation of this wave down the stomach. We thought this was very promising so let us try and put it in actual patients, which I will tell you is very difficult, but we made it. This is an image of the first ever patient. That's me on the right-hand side and Dr David Rowbotham, who is a Gastroenterologist at Auckland City Hospital on the left hand side and some very talented nurses in the middle and the patient is on the table. You can see our devices being placed on the TV screen. That is an endoscope that's been placed into the stomach. This was a very exciting day for us and we pushed on with this work and completed a feasibility trial of 13 patients at Auckland City Hospital and this is where another PhD student came on board - Peter Tremain who is here tonight - and he's running this work now in terms of the clinical trials and revisions to the device. We completed a feasibility trial on 13 patients at Auckland City Hospital along with David Rowbotham. The data was really promising. Above you can see an example of some of the electrode traces like I showed before. You may be able to notice that those little deflections I pointed out with those red marks aren't quite as clear as some of the other ones. The data from inside of the stomach endoscopically is not as high amplitude. It's not as strong as data from open surgery but we are able to capture it nonetheless. And the fact that we are able to do it minimally invasively, is incredibly valuable. We are also able to create these maps of propagation and here we can see that there is actually activity originating from low in the stomach, distal in the stomach, which is abnormal in this case. This is the first time that we, or anyone in the world, has been able to record in high resolution from many electrodes the spatial propagation from inside the stomach endoscopically or minimally invasively. So we're really excited about it. And now the question comes, can we correlate this endoscopic data with patient symptoms? This is where Peter is carrying on with this work and we have expanded to a multi-centre trial. We have now completed 20 out of 20 patients at Auckland City Hospital and 7 out of 20 at Christchurch Hospital, with a secondary gastroenterologist down there, and we are looking forward to trying to correlate abnormal or normal electrical activity with patients who are either sick or healthy. And so that concludes a new diagnostic tool and a minimally invasive one. But when we are able to diagnose and tell a patient you've got something wrong with your stomach, your electrical activity isn’t working well, what can we do, then? This is where we are looking at new therapeutic options as well. One of which is called gastric ablation. Ablation is a fancy word for essentially burning the tissue. It is very commonly used in cardiology. This is a diagram of the heart. A common complication with hearts is that you get abnormal heartbeats which are triggered by regions of the heart activating electrically that aren't supposed to activate. What they do clinically is they feed a catheter up into the heart and they burn those regions of the heart to prevent them from activating electrically. It then restores the normal activation pattern and fixes these patients. It is very commonly used in cardiology and it is a multi-billion dollar industry. Until we came along no-one had translated it to the stomach. And so we thought - can we use ablation to eliminate this abnormal electrical activity in the stomach? Another PhD student, Zahra Aghababaie, who has finished her PhD and she stayed on as a Post Doctoral Fellow with us. She is very talented and we're excited to have her. This time we did it all surgically because it gives us a more careful and managed approach to what we're doing. So we are in open surgery, using these electrode arrays - this is pre-clinical in pigs - put our electrode arrays on, recorded the activity, then identified a pacemaker location which naturally appears in our pre-clinical pig model, so abnormally low on the stomach. It is marked with a star in this diagram. We marked that with a suture so that we could identify exactly where in the stomach that was. We then use an ablation catheter, a common cardiac ablation catheter, that we repurposed for our gastric work. We surrounded this location of abnormality with a box, a series of points made with this ablation, and then we recorded the activity afterwards to determine whether or not we had eliminated it. Above is a surgical diagram. I show these nice schematics and then this is what it looks like in reality. This is what we are working with. That is the stomach through an open incision and the ablation catheter is that little blue stick looking thing and those white lines on the stomach are where we have actually performed the ablation. We are back to these rainbow maps. What we see on the top is that we had activation low on the stomach, where it shouldn't be, and we abladed around that. In the bottom one we could see is that our ablation is that black box and we have restored the normal activation of the stomach. We are back to red at the top, blue at the bottom or, in other words, the electrical activity is coming down the stomach again after we eliminated that abnormal location. We are really excited about that. We can now eliminate these abnormalities. We have got a new tool to do it. So the answer to our question – can we use ablation to eliminate abnormal electrical activation in the stomach – YES, we can!

Read more now in the latest AMRF newsletter. You can read about the progress of research and the researchers supported by donors like you including: Early career researcher investigates post-op recovery in older patients after elective abdominal surgery New doctoral awards for students researching Parkinson's disease and diabetic heart disease for their PhD Postdoctoral award for early career researcher investigating secondary eye disease following eye surgeries, like that for remedying cataracts FREE LECTURE: Learn about 'Surgical research past, present and future' featuring Prof Jennifer Weller and Dr Tim Angeli-Gordon at 7 pm on April 18. Register now to get the details to hear from these researchers with us live & in person! Click below to read and download the PDF newsletter

Learn how your support can help make a daily difference in the lives of those working to help people living with Parkinson's disease. Brownyn Riley is a perfect example of the difference 365 days can make. In 2021, Bronwyn completed her University of Auckland bachelor's degree, majoring in neuroscience. Fast forward on a year, Bronwyn was awarded an AMRF doctoral scholarship to research Parkinson's disease – work inspired by her revered grandfather, Emeritus Professor John Gavin, who was diagnosed with Parkinson's disease. Bronwyn is part of a laboratory group investigating the role of a region of the brain called the tail striatum. Their investigations are looking at symptoms of Parkinson's disease that are different from the usual symptoms affecting motor function. "Parkinson's is characterised by the death of dopamine-producing cells in the brain, a debilitating disease impacting over 10,000 New Zealanders. In another decade's time, this figure will climb to ~18,000," explains Bronwyn. "Although often considered a 'movement disorder', people with Parkinson's experience non-movement symptoms including impaired sensory perception. Vivid, detailed, visual hallucinations are common in up to 75% of patients. Less frequently there are auditory hallucinations, largely non-verbal muffled sounds. These non-movement symptoms can cause distressing disruption to daily life and overall well-being." The mechanisms behind these non-motor symptoms remain frustratingly elusive and to make matters worse, these symptoms are commonly triggered and worsened by existing treatments. In her quest to find answers around the causes of non-motor symptoms in Parkinson's, Bronwyn's daily spotlight remains firmly fixed on the tail striatum and its function in regulating how we experience and respond to sensory stimuli. "We know that the level of dopamine in the tail striatum determines how responsive it is to sensory input and in Parkinson's disease, dopamine is depleted – therefore, neurons respond to input abnormally. "So we're on a mission to determine how dopamine availability alters the response of tail striatum neurons to what we see, touch, smell, taste or hear in the different cell types and distinct regions within the tail striatum." "Evidence from my current research supports the idea that dopaminergic neurotransmission varies between the regions of the tail striatum. Using technology called 'fast-scan cyclic voltammetry' we can measure dopamine effects in the four different sub-regions of the tail striatum". The results from Bronwyn's ongoing study confirmed this novel variation within the tail striatum, emphasising further investigation being needed into the dorsal, lateral and medial tail sub-regions. And this leads us back to what a difference a day makes! Your support allows Bronwyn to don her lab coat every day and continue in her quest to find answers to help lessen the impact of Parkinson's disease. And what goes around comes around. Your support has meant Bronwyn will be supervised by a world-class researcher in Parkinson's disease – Dr Peter Freestone. Peter, who has been funded by AMRF donors since 2011, is working on a revolutionary new approach to help treat Parkinson's disease and is now giving back through assisting Bronwyn in her own research development. By supporting researchers like Bronwyn and Peter, you are making a daily difference in the lives of others. That's why a gift from you today is so vital for our tomorrow. Health and medical researchers in Auckland are working right now to build a better future for us all, from enhanced skin cancer diagnosis, improved outcomes for patients with brain cancer, identifying long-term effects of worldwide premature baby medication, finding a cure for tinnitus, better understanding of high blood pressure, to treatments for neurological conditions and much, much more.

So are the New Zealand medical researchers supported by the Auckland Medical Research Foundation. They are curious about what can keep the body working more effectively. Want to help the Auckland Medical Research Foundation support our NZ researchers? Click the green button below to learn more. Use the sign-up form to receive our newsletter. Or simply click on the blue button below to Donate Now. You could receive a 33% tax rebate on donations made before March 31.