Good afternoon Welcome to our grand rounds my name is Mira ctis and I’m the center for individualized medicine education director really excited to join you here on the Florida campus and to introduce our speaker today as a reminder our lecture series is designed to highlight two main objectives showcase the latest in
Scientific discovery and Innovation and then demonstrate how individualized medicine can be translated into practice to meet current and future patient needs it’s my absolute pleasure to introduce today’s presenter Dr Megan Alise Dr Alise is an associate professor of biomedic Ethics in the biomedical ethics research program and she’s also an
Associate consultant in quantitative Health Science with a joint appointment In Obstetrics and Gynecology her research focuses on the translation of emerging Medical Technology from research Endeavors into clinical practice particular interest around reproductive he Health ethics and Women’s Health and health disparities and access to care her previous research work examined the intersection of
Assisted reproductive care with embryonic stem cell and human cloning research and management of oite exchanges and more recently she’s developed a portfolio around the clinical translation of innovative uh non-invasive prenatal genetic screening including informed consent patient education a stigma in the disability community and understanding the impact of prenatal genomic information on
Patient care and the experience of pregnancy she’s also uh interested and has uh uh great work in the area of um providing highlevel care regardless of socioeconomic status and in fact today’s talk will highlight to us how tradition models of clinical translation of genetic therapies have focused on
Metrics of safety efficacy and cost uh however there’s wide disparity in the use and benefits of genetic medicine using these metrics and she’ll be proposing to us a fourth metric and showcase how it can be operationalized to uh increase accessibility um to all individuals as we go through the talk
Today please use the Q&A um section in your Zoom to submit your questions there will be a segment at the end of the talk to address those questions and as you recall from one of our announce announcements in order to claim CME credit uh please type in the code
Justice all in capital letter um and we’ll send a message about that in the chat so without further Ado please join me in welcoming Dr Elise as she presents on the translational Justice and health disparities research in genomics thank you all for coming today I’m uh happy to
Be sharing this New Concept concept uh that we’ve been working on developing I’m going to apologize in advance whatever respiratory disaster is going around has found me so I will try not to cough during this presentation I make no guarantees uh just to start off I I have no
Disclosures so I want to start off by um outlining what we mean by translation so I think that for some of us translational medicine is a sort of a GI thing that we all do but not necessarily everybody so when we say translation we generally mean the process by which we
Get from something that’s been discovered in a bench lab or a wet lab and that is uh moved through a series of validation procedures until it becomes uh clinical medicine and then it ends up in the patient so when I say translation uh during this talk that’s what I’m
Referring to is how do we go from biological or chemical discoveries into things that actually touch patients in the clinic so as we all know um especially in this day and age clinical translation is governed by three principles safety efficacy and cost Effectiveness and historically uh if you met all of these
Three criteria through very rigorous clinical trials or other forms of validation measures you were considered to have the gold standard however if you look at what things look like out in the world it’s not clear that these three principles are doing the work that they say we say they’re doing right so this
Is a quote from a woman who gave birth during covid and she’s talking about the fact that because the covid-19 vaccines the clinical trials that validated them specifically excluded pregnant and lactating individuals which is not uncommon from clinical trials the result was that a wide variety of pregnant women that we spoke
To during the covid-19 uh pandemic were unwilling to become vaccinated because they said there was no safety data available for them so they didn’t know the impact of their uh of the vaccine on their pregnancy Argo they declined to get vaccinated now as we later found out uh covid-19 is very
Very dangerous for pregnancy it has significant impacts on the possibility of pre-term birth and so we should have been vaccinated pregnant women uh we should have been making a concerted effort in fact to vaccinate pregnant women but because they were excluded from The Trial we didn’t have safety data if you look at
Efficacy uh it’s not entirely clear what efficacy has come to mean so if you look on a CDC website they will say very clearly that many of the therapies that we have available today were not researched in the population that they’re actually designed to be used in
So the vast majority of clinical trials are uh include almost exclusively not almost exclusively predominantly uh individuals of European background and many of them are largely skewed towards uh male uh because of the exclusion of reproductive age women it should be pointed out that not only are currently pregnant
Individuals excluded from most trials most trials will also require some form of birth control for any participant who wants to participate uh and multiple pregnancy tests and so that’s a decentive for people women of reproductive age to participa in clinical research so we have a large body of research that is based in
European descent males but is therefore Unknown about its efficacy in other populations and so this is a woman that spoke with us as one of our trials uh and she’s a black woman and she has had breast cancer and one of the things she expressed frustration was that the
Genetic testing um that her family was offered was not specific to uh black women and that you know there are different mutations in black women we know that they have a higher inance triple negative breast cancer for instance uh and so if we don’t do the research in the population we’re trying
To help can we really say that we’ve met this threshold of advocacy and finally cost Effectiveness I think cost Effectiveness uh is measured as willingness to pay per quality adjusted life year or some other standard that you’ve used um but it’s not really clear that this applies
Especially in the US system in which we don’t have a centralized payer who’s invested in for instance preventative health because of future cost savings later down the line and so the question of cost Effectiveness is actually very um contingent on the socio and political setting in which you are trying to
Implement this standard of care so this is a woman um again pregnant during covid um different cohort this is a a lowincome uh black and ltin cohort and uh the interviewer is asking her how much she would be willing to pay for self-free DNA testing of fetus uh which
Tests for down syum tric 1318 XY variations and she said the most she could pay is $50 and that’s only because she gets a child tax credit that credit by the way was covid specific uh I believe um and so may no longer be available but it’s worth noting that the
Minimal billable reimbursement for this cfdna test is $250 so when we say cost effective I think we have to ask ourself coste effective uh in what context and and for whom so all of this leads us to question or at least leads me to question whether safety efficacy and cost Effectiveness
Really add up to the gold standard of translational success that we think they do and the answer in the US is pretty clearly no uh because it becomes pretty clear that safety eacy and cost Effectiveness as a standard um are insufficient to help medicine meet its moral
Obligations and I in saying that am asserting that Justice is a moral obligation of medicine we could have that conversation but we can see that because our health care System demonstrates so many disparities and such wide differences in health status Health Care access and morbidity and mortality between different groups it is
Clear that the standard of justice is not being met so we would like to suggest that rather than only and not instead of but rather than only uh safety ocine cost Effectiveness we need to attend to a some principle of Justice when translating genetic Technologies or any technology uh from scientific knowledge
Into Medical Care and so we Define uh translational justice as procedural and outcomes based attention to how clinical Technologies move from bench to bedside in a manner that equitably addresses the values and practical needs of affected stakeholders with attention to the needs the most morally impacted
So what we mean by that basically is that when we are conceiving of a translational pathway starting as early as possible as far back as when we are making that hypothesis in the lab all the way through the process to the end of dissemination and evaluation we need
To be thinking about who is this for where is it going to be used how can it be used best for the most people in that setting rather than getting to the end of the translational pathway realizing that there are going to be inequalities and then trying to retroactively address
Them because as we have seen based on the level of disparities in this country that’s not working so I’m going to give you a couple examples of uh how our group has been uh operationalizing these kinds of Concepts so the first is in hereditary breast and ovarian cancer um as I’ve
Mentioned there are differences um between white and black populations with um hereditary breast and ovarian cancer so if you’re not familiar with hereditary breast and ovarian cancer uh it is a heritable form of several mutations the one that most people are aware of is bracka one and
Bracka 2 uh and it relies on what we call um Cascade screening so basically if we have an affected individual we test them is shown to be a germline mutation we would then recommend testing all of their uh first order relatives uh because it’s possible that they have also uh inherited the
Mutation if we can do that if we can catch people before we know that they become symptomatic uh we have seen in the literature that pre-diagnostic awareness allows us to begin screening earlier via MRI rather than just mamogram the earlier we Di diagnose any form of breast and ovarian cancer the
Obviously better our outcomes are the more likely we are to be able to clear it surgically and so hpoc when we looking at Cost Effectiveness uh is estimated to generate 75 fewer mortality cases and 288 adjusted life years per 100,000 women so from a Health Systems perspective from a Health’s perspective
Uh this kind of screening can be highly effective in reducing overall morbidity and that is why NCC and the national uh cancer Collective Network recommends that we should be testing um susceptibility genes in any individual with a blood relative with a known or likely pathogenic variant in a
Cancer suceptibility Gene and that is why uh most of us if not all of us have been asked to fill out a form like this on the left at some point in our medical Journey generally when you’re coming to your primary care physician of all of
The relatives that you have that have uh ever experienced cancer and what kind of cancer so again this is uh the sort of principle of cascade screening is that you have an affected individual you test all of the family members and all of the family members who find mutations in
Them that might be suggested of an increased risk of cancer however uh we do see that there are again significant disparities black women uh with breast and ovarian cancer have lower survival rates they tend to be diagnosed later in the diagnos or in the disease progress they experience
More delays in treatment and they are significantly underrepresented in clinical trials of Novel therapies for hereditary breast and ovarian cancer they are also less likely to be SE to receive genetic testing to understand their personal increased or decreased risk of hereditary cancer so we were asked by a group called The Coalition of
Blacks Against Breast Cancer which is founded by Dr Michelle hiard and Maran Kelly out of the Mayo Arizona site uh and we put together with some funding from the uh breast cancer Spore at Mayo Clinic Cancer Center to put together the advanced study and basically what the goal of the advanced
Study was to understand if there are barriers to genetic testing um among black women with personal history or family history of breast Ming cancer and how those barriers might be overcome so I’m just going to give you some stats for a minute this is the cohort um that was eventually recruited
We did have a first cohort which was recruited large through the divine nine and uh traditionally black sororities the second cohort was recruited in a general uh population Medicaid Clinic so a much lower um socio economic status and and income level so here are some of the things
That we learned uh we learned that in these communities there is a significant taboo about discussing health information and especially cancer so this is an individual who was eventually diagnosed with cancer at 55 so obviously was a significant increased risk she’s talking about the fact that
She didn’t even know that she had a family history of breast cancer until she got cancer and disclosed that to her family and then they responded to say oh yes your relatives have also had cancer so this obviously raises a problem because if you’re not discussing family
History then that form that you filled out in the doctor’s office is not very helpful to anybody cuz you don’t know that you do actually have a first-degree relative who has had cancer uh and this is another quote from an individual in the second cohart uh just talking about how her family never
Shared medical history uh and that the attitude was very much one of don’t ask don’t tell when we asked about perceptions of genetic testing uh this is a a woman who is his daughter uh an aunt and a mother with breast cancer at age 42 uh she thought when she say genetic
Testing she thought about Angelina Jolie which is a very high-profile case obviously uh and that she said I thought about it as a celebrity thing not something that somebody like me would get um I never hear about black women who’ve had genetic testing and she said
I’m the only black person I know who has had genetic testing and then finally we had asked them about their knowledge of genetic testing for hboc and whether they would be willing to do it and in fact we heard that most of the participants we spoke
With once it was uh introduced as a blood test not as a particularly invasive test uh so that they actually would be very likely um to to accept genetic testing if it was offered to them uh and that they didn’t see any significant barrier uh to doing that and
So what we learned from all of this was I think there was uh this qualitative research it’s not hypothesis driven but if you looked at the sort of General uh zeit G in the literature there was a lot of uh literature about trust black people don’t trust genetics they don’t
Want genetic testing because they don’t trust um and what we found was actually not bad uh what we found that the reason the most likely reason that we were seeing a lack of uptake of genetic testing was a lack of knowledge of family history which meant that they
Didn’t know they were eligible for genetic testing and also just not being offered it we had several women say nobody’s ever asked me if I wanted genetic testing so this is really when we think about how do we uh focus on the translational justice of hereditary breast and ovarian cancer we are seeing
A disparity it’s not the cause by what we thought it was caused by it’s caused by something else and so when we look at intervening uh we are trying to Target what our qualitative research tells us is the actual appropriate Target here which is knowledge of family history and
Not necessarily comfort with genetic testing or awareness of genetic testing or heredity so the this is a trial that uh we uh submitted to NCI um it has not been funded at the moment uh but it’s basically a two-part um intervention one which is an awareness campaign uh to help families understand
That the more conversations they have about history the more conversations they have about the possibility of somebody inheriting cancer that there are concrete health benefits to that and one of the things we did hear from a lot of women especially older women was that they do experience that taboo that
Reluctance to talk about um cancer and and they don’t want to be a burden on their family members we heard that a lot uh there’s a paper that just came out this week um talking about the Paradox of the strong black woman which is something that came up a lot in
This cohort where they felt like they had to be the strong black woman and not Place their their burdens and their problems on family members unless it was introduced to them that by telling their family members they might actually help family members especially younger daughters and granddaughters that there would be a
Concrete benefit to them and that there would be a health benefit to them that was very helpful in helping them get over that unwillingness and say yes I will talk about my family history of cancer I will encourage my family member to get genetic testing because it could actually benefit
Them so this is a very complicated tree about the study flow uh but really um the point it is that what the focus is actually on at at every step is what’s called pathway we call Pathways to care right so genetic information independently cannot do anything really
It’s just data in a computer so first you need genetic information then you need interpretation of that genetic information and then you have something called knowledge but knowledge is dependent on action ability right so you you don’t get to power until you can actually do something about something and this was a
Problem with a lot of the earlier genetic um testing studies that were done where they got to information plus interpretation equals knowledge so they were testing people telling them they had you know for instance a gene for hypocholesterolemia but not taking it that extra step to action ability what
Can they do about it how are you actually improving their health and so that’s the important thing about this trial is taking from increasing information trying to get more people tested but also having a very concrete Pathway to care and so um you’ll see that we wanted to make
Sure at every stage that if we found somebody who was at increased risk we did test them there would always be access to genetic counseling and then into an enhanced Breast Clinic monitoring so that we weren’t giving people information but not providing in them with a way to use that information
And concretely benefit their health the second example I’m going to talk about is human gene editing this has been in the news uh a lot recently uh with the FDA approval of the uh latest trial for Gene editing in CLE cell disease uh we have a a current study
Which is is running now it started recruiting at the beginning of the year uh looking at the possibility of of Gene editing prenatally but this is founded on some studies that we’ve done previously um in tric 21 which I think everybody’s is fairly familiar with there was a trial a few years ago
Of a pharmaceutical that had shown some early promise in uh treating or or reducing certain signs and symptoms of trime 21 uh in children and it did go to a clinical trial um and that there were a number of children that were enrolled and the trial was actually shut down
Early due to what the researchers said was a lack of efficacy data that they didn’t think that they were finding any improvements and a lot of parents of children enrolled in the trial were pretty upset by that uh because they felt that they did actually see signs of
Efficacy that they did feel that there were behavioral changes in their children and furthermore that they would be more qualified to identify those improvements than whatever proxy measures the study had set up so in response to that trial we made the gifted study um and this uh was a
Study with caretakers of individuals uh with Down syndrome and we offered them five interventions so one was was a prenatal surgery prenatal Gene editing neonatal surgery pharmaceutical or vaccine for Alzheimer’s um if you’re not aware individuals with Down Syndrome uh have a 90 plus per uh risk of uh getting
Alzheimer’s generally fairly early on in their in their 50s uh and so we’ offered these five interventions would you be willing to accept each of these intervention so this is just a table of who was in the trial this was a survey it was disseminated online so we had more than 500 people
Responded and what you can see uh in this chart is that the blue lines are people who said yes I would accept this intervention on behalf of my child so pediatric physical intervention those are usually cardiac surgeries neonatal cardiac surgeries very very common pretty much everybody said they would do
That you can see strong support for the Pediatric um cognitive Intervention which would be similar to the pharmaceutical we discussed before but even fetal surgery which I think uh most people see as more invasive and problematic pretty strong support what we were interested in was the fact that
When we offered that prenatal gene therapy um not specifically Gene editing but some form of prenatal gene therapy we got a lot more influence and uh we thought that was interesting so some of the Conta that we talked about is that parents really felt that changing their kids on a genetic
Level rather than a physical level was especially problematic it was an extra layer of problematic um because it seemed to suggest that their children had a pathology in Down syndrome that they didn’t really see as a pathology so they it was easy to see a cardiac malformation as a pathology uh it was
Easy to see certain uh facial features clip all of those but they had struggled to find genetic changes um that made their child quote unquote who they were uh that they didn’t really feel like they would be comfortable changing that so we did another study uh with
Parents of individuals uh tric me 13 and 18 uh and you know these parents said it would be okay if that was available I wouldn’t object to it uh but I wouldn’t I wouldn’t have done it I wouldn’t have chosen it and in fact the mother of a living child would trust me
18 Again says she seems to be happy I’m not going to change her and change her genetics just because um I feel like it or just because I can we did another study with congenital and Progressive sight loss and you know this is an individual who has uh not had
Sight he’s uh not had cyers their entire life and they’re saying you know I actually wouldn’t make blindness um a target of Gene editing I’d be much more excited about breast cancer um and so I think that it was interesting to us because in fact um liever congenital
Osis is in fact one of the interventions that is currently undergoing Gene editing trials uh that this individual really didn’t think that you know not having was a legitimate Target or at least the most important Target of Gene editing technology even though it’s possible that they themselves might benefit might
Uh receive a a therapy that would make them able to see so those were the preliminary studies that led to the passage study so this is an R1 from nhg as I said currently began recruitment this week um and basically we were interested did uh
In much the same way uh that the gifted study is interested in how communities would react to the prospect of prenatal Gene therapies across the family system genetic illness framework so uh you can see on the left side these characteristics lethal penetrant and early onset um and then over to the
Right side not lethal only a risk factor and early on set I am going to say for geneticist here we understand that both autism and deafness are very complex genetically uh we are Gene editor um we have a coai who is an actual scientist who does Gene editing um but he agreed
To let us leave that because there is a lot of discussion in the autism Community about the possibility of Gene editing in much the same way that there have been discussions about previous neurological research really problematizing the idea of whether whether autism should be a target of those sort of normalizing
Influences and in fact uh before we even began formally recruiting for this study the first people to reach out to us were self- advocates in the autism Community volunteering to participate in the study because they really felt that they had strong uh things to say so this uh
Spectrum basically what we’re trying to understand is where on this spectrum do various communities Place themselves in terms of the appropriateness of prenatal Gene editing based on the fact that uh chars me 21 uh those families struggled uh with whether that was acceptable or not and so we’re
Interested in seeing what everybody else thinks as well um so CLE cell obviously is now in gene editing trials smas in gene editing trials uh there’s ongoing research on the rest of these which is why they were chosen and in fact our colleague who uh is doing Gene editing research their
Target is a gene editing technique that targets the liver and they’ve just received a very large Grant to do pre-clinical studies of PKU with the goal of entering clinical trials in humans in the next five years so we added PKU uh and then I was in a conversation yesterday about Gene
Editing for uh osteogenesis in perfecta prenatally so we may be adding that as well so the reason we chose prenatal Gene editing uh is because it’s a technology that’s on its way there’s definitely a fair amount of as we say animal research bench research that’s starting to show that this may be
Something that’s going to work prenatally in humans but it’s not there yet so like PKU is probably and PKU is starting in in uh children nobody’s really suggesting prenatal yet but there’s a lot of uh movement around you know if we can do it pediatrically would it then
Not reduce morbidity to do it prenatally so this gives us the opportunity to see this translational Justice question from more or less the beginning um to say what if we Trace prenatal Gene therapies all the way from the beginning of their their translation and stayed with them
Um all the way through and that’s the goal is that you know we’re now writing additional translational Justice questions into these additional grants so the next Grant is about regulatory approval clinical trials what are the translational Justice questions there then we’ll do the clinical trials and hopefully we’ll have translational
Justice elements there um and so some of the questions that we’ve started asking you know all the way back to the beginning about when you’re choosing your high hypothesis what about legitimacy right so there’s been a controversy recently in a condra plasia where there was a company that develops a pharmaceutical uh that
Basically if if children take it fairly early on it uh undoes the sort of some of the effects of condra plasia in making people short so it basically allows them to grow taller but there was a lot of actually push back from the conver plagia Community
Because they said look there are lots of things that we would like you to to study in a cond plagia but being tall wasn’t one of them that’s not our problem uh you know most of the disability that attains stro condr plasia is social right it’s because we
Have a society that is built for people of a certain stature and that excludes uh little people and we can address that socially we don’t need a drug to address that so conversations about where the legitimacy of the target is and again that’s why autism and deafness are on
This uh scale because there’s been a lot of push back from those communities about pathologizing uh the lack of hearing or pathologizing different ways of of thinking and reasoning in the world and you know people saying those are not legitimate targets of of gene therapy and we we don’t want to see
That obviously anytime time we talk about these sorts of studies uh commercialization comes up we’ve had a lot of ups and downs in the commercialization of genetic Technologies going back to braa 1 and two Myriad uh this sort of arms race with cystic fibrosis um and so we really want to see
If can we conceptualize a different pathway uh you know the the drug for SMA famously costs in excess of two3 million per child child uh and while that may make sense if you look at it from a life course model it’s not sustainable and so are there different translational
Pathways we can Envision that can make these Technologies uh more accessible I I hesitate to just say cost because if you say more expensive then really that’s just a a call for insurance companies or or some other payer to step forward and pay for them but you know if
You look at the current Gene editing trial for Cle cell it requires a bone basically the equivalent of bone maror transplant so you’ve got you know weeks of hospital stays breaking down the immune system it’s a very very intensive uh trial to participate in and there’s
Many many people with CLE cell who are not going to be able to a enroll in the trial take that much time off work take their child and stay with them for seven weeks in a hospital and so we have to look Beyond considerations just of cost
To uh what is access look like so again there is a story recently of um a family where they had two children affected by a very rare genetic disease one uh is too far developed for therapy but the younger child is eligible for therapy there is a genetic therapy company is
Willing to give them the genetic therapy for free but Medicaid won’t pay for the hospital stay so they can afford it technically because it’s free but they also don’t have access and so I think when we talk about um these kinds of models we have to look Beyond just
Cost there’s also questions about scientific approach so if you look again at the example of cystic fibrosis where there were more and more and more mutations identified as being causitive of cystic fibrosis and those were integrated into testing and then we were basically able to capture a lot of young
People with uh cystic fibrosis the uh treatment has improved astronomically so we now see people living into uh later into life except for What’s called the last 10% and these are mutations that we can’t find uh in individuals that we know are affected and to go back to our
Earlier question about efficacy the mutations the individual in that 10% are very largely not European right so it surprises not very many people who are in this space that those last 10% those people who are being left behind by all of the the translation that we’ve already done are from populations that
Have historically been marginalized and so what does it look like to begin this process by saying we want to find the rare variants we want to find the variants that are more likely to be found in populations that have been marginalized historically and then regulatory uncertainty so again the reason to go
Back to that question of safety and researching pregnant people the FDA has made very clear that they will not allow for the inclusion of reproductive age women uh in gene editing trials uh without the standards of extreme double precautions on interception uh and that you know the
Same same question all over again right and how are we ever going to understand prenatal gene therapy if we are excluding Gene therap pregnant and lactating individuals from gene therapy trials there’s also a lot of uncertainty given the legal landscape surrounding the uh Supreme Court decision in DOS
Versus Texas uh that again enrolling pregnant people in any kind of research is going to become increasingly hard uh due to things called uh like heartbeat loss and so is this translational pathway really kind of blocked from the beginning to address questions in pregnancy um we don’t know that’s
Something that’s uh being developed as we speak uh but it’s certainly a question of of how we’re going to end up translating these Technologies so I just want to take a moment to thank thank uh the many many many excellent colleagues uh that we work with on all of the research
Presented here today and I’m happy to take questions uh my question is what can we do about it what are your strategies to overcome this issue of less communication among family members for cancer family history and for gaining trust among black people for genetic testing
Uh well we have a strategy it’s a in a protocol that is currently at the NCI um and that strategy is to uh really do culturally tailored communication um so there is actually um invite has a little app that they bought um from Clear communication that is an
Interactive sort of AI informed family history mapping app uh and that you can get on your phone and it allows people to get and document a family history in this app in the privacy of their own home at you know at leisure where they can talk to their mom or their aunt
Their grandmother and be like oh did anybody in our family have cancer so our strategy was to pair uh a sort of culturally appropriate um communication campaign that features black women talking to other black women that features breast cancer survivors uh who are black women talking about the importance of telling your
Telling your family about your experience and then uh everybody in the Gynecology practice would also get a link um to this little interactive app where they could uh before they come in for their annual exam they would be able to fill out their family history and the app actually Compares that family
History to the nccn guidelines for um sufficient family history to be screened high risk for hereditary cancer then when they and that app then sends a message back to the clinic that says this individual has screened his high risk when they come in for their Gynecology exam you need to ask also ask
Them if they would like genetic testing and the provider can actually the gynecological provider can actually order genetic testing straight from the clinic uh and then if the individual tests high risk they are reflexed to genetic counseling um at a high-risk uh breast clinic so that was the plan um
It’s in Partnership to with the University of Florida and Jacksonville uh which is a very high volume Gynecology practice and he’s a very very diverse uh population and we just need somebody to fund us to see if it works thank you for your question
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