 Good morning and welcome to Grand Rounds. We have a really, really cool opportunity today to hear from someone who's really integrated herself into the Moran and is doing some really amazing work. So this is Dr. Brittany Koch. She's an assistant professor in the Department of Mechanical Engineering on lower campus. Much of the focus of her work has really involved in blast injuries. Dr. Julia Burda and I last week, we were in Washington, D.C., where we had an opportunity to go on the hill, meet with our representatives and some of the staffers in our senators offices. One of the things that we ask them for every year is for an increase from $10 million to $15 million for funding for the Department of Defense grants for our fiscally conservative representatives that generally land on dead ears. But then when I talk about Dr. Koch's work that she's doing and actually the return on investment that that can have for our veterans returning from service, their ears peek up a little bit and they actually tend to listen to that. You may not be aware of that. For eye injuries, the return to service is about 20 percent and that's one of the lowest return to service of all types of injuries. Return to service for other types of injuries, all comers is between about 60 and 80 percent. So eye injuries have an incredible impact. And then when you look at the long-term impact of productivity loss for eye injuries, specific police and blast injuries, it's billions of dollars over lifetimes of the cost to society and the cost of these patients. So without further ado, I'm going to turn it over. Thanks. Thank you so much, Joe. Great introduction, by the way. I was fascinated. And thank you for plugging for more money for us. That's awesome. It's always great. Oh, man. So thank you for giving me the opportunity to present my work here. I am going to talk about the progression of ocular injury from blast exposure. But before I start, I always, especially when I talk to a more clinically-based audience, I like to explain how mechanical engineering actually fits in to this world. So just to give you an overview, I don't think I'm getting any slide advancement. Now it's frozen. It was just working, but now it's frozen. Do you want me to work on it for a second? Sure. You can ramble. I'll ramble. But I think it's literally frozen. So just to give you an idea of what mechanical engineering does. So mechanics is all about how forces act on the human body. Or how forces act on any object, really, and how that object responds to those forces. Biomechanics, the object is the human body. And more particularly, in my case, the object is the eye. So I study how forces act on the eye, and then how the eye responds to those forces. Not just mechanically responds through stretching and deformation, but also biologically responds or potentially chemically responds. In this case, when we apply... Sorry, I'm lost now without my slides. So you guys have probably heard of biomechanics most often in glaucoma, right? Increased interocular pressure creates all kinds of changes in the eye. In my case, I'm looking at injury, so any kind of trauma that occurs to the eye. And to achieve this understanding of how forces affect the eye, we have a lot of different skills and tool sets that we deal with. Some is mechanical characterization, where we take different pieces of the eye and different tissues and we deform them and we stretch them in different ways and see if I apply this force, how do they deform and how do they are stretched? How does the sclera respond in one direction versus another direction? How does it respond with age? How does the retina respond? How's the optic nerve? All the different components of the eye. We also do a lot of imaging to look at how the microstructure of the eye affects this mechanical response. So as we grow, kids are very different than adults who are very different than an elderly. The microstructures are constantly changing and so that means the mechanics are constantly changing. We also do a lot of animal studies in order to understand how do these forces lead to the biological or chemical response, the injury cascade. We also...good? You're amazing, Jeff. Okay, I did it right. Yeah, that's good. Okay, so this is my lab and I was just talking about the different skills and tool sets. So we have animal models to give us that biological response and then we also have something called finite element modeling, which is computer modeling where we put all this information into a computer model and we can simulate different events to try to understand what's going on. And so those are the skills and tool sets and the overall objective of our lab is to utilize principles of engineering to develop injury tolerances and understand how things change with age. So my training was actually in pediatric head injury, not eye injury, but it evolved into pediatric eye injury, which has now evolved into blast eye injury in adults. So things evolve over time and all the principles remain the same. Just the application is different. I also wanted to highlight some of the other projects going on in our lab to also give you a sense of the variety of things that we do. So I do have some traumatic brain injury projects, but these days a lot of my projects are about the eye and in collaboration with many at Moran. So here, just to look at how we characterize how things change with age, I primarily got into this field because there wasn't anything in the literature about how the pediatric eye responds to forces. So it was very challenging for me interested in pediatric head injury to really understand how to characterize this and how to model this. So I began looking at how the immature eye is different than the adult eye and not just qualitatively but quantitatively. These are some... One of the first studies we did was where we actually quantified the vitreous of an immature eye compared to a mature eye. And the mature eye has been characterized, the vitreous has been characterized pretty well, but the immature eye has not. And we all know that it's fairly different. So we did some dynamic tests to measure the properties in shear and really characterize the vitreous. We're still working on this because we want to get more localized measurements, regional measurements in the vitreous. We did some inflation studies on an immature eye. If we inflated it and pressurized it, we can use something called digital image correlation to quantify how it deforms and actually see it deform but measure the 3D deformation of the eye. And we can use this also to validate some of our models to make sure that our models are predicting real life. And we've tested the retina, we've tested the sclera, we've tested the optic nerve, the anterior lens capsule. I believe those are all the tissues that we've tested so far, looking primarily at the immature eye, where this data is lacking and then comparing it to the adult, where the data is present. All of this goes into a computational model. So we create 3D representations of the eye and using a certain computational modeling approach called finite element analysis, we can perform really complex scenarios to really understand what's the response of the eye in different force loading scenarios, as well as how does the eye interact with different objects. This study, which is vitrorenal adhesion and its relation to collagen microstructure, that's a study that recently got funded with Emmy Hartnett. And this is us looking at the vitrorenal interface and trying to quantitate the force that requires to peel that away, as well as relating that back to the microstructure. So what about, how does it relate to the collagen density or the directionality of the collagen fibers? Here's the vitreous, here's the retina. Here's the collagen fibers. You see some are going parallel, some are going perpendicular. And of course in different regions of the eye, you've got more primary, the collagen is more primarily perpendicular or more primarily parallel. And so we're trying to tease that out. Can we predict where more adhesion is? We're also looking at laminin and fibronectin, as well. Some of it's for modeling. Oh, this is actually a peel test on an eye where there's an entire eye in here. This is kind of the visuals represent of an entire eye. And it just basically peels away that retinal layer from the vitreous. This is another study that I'm doing. It's actually with Bob Hoffman and Julia Byrd, where we're looking at tortuosity and evaluating tortuosity. Some of the earlier studies I did with Bill Binnenbaum at University of Pennsylvania, we were trying to look, evaluate certain mechanisms of retinal hemorrhages, particularly an immature eye. And we started with an animal model and we wanted to verify that we could actually get retinal hemorrhages in this animal model. So we did a central vein occlusion. And during that time, we saw a lot of the tortuosity increase. And as a mechanical engineer, he knew that that was going to happen. But as a mechanical engineer, I came from a different viewpoint of why is that happening. And tortuosity is really an increase in transmural pressure in the vessels. And it made me start to evaluate if the tortuosity could be predictive of the retinal hemorrhage that came. And in the animal studies, it was. If the tortuosity reached a certain level, eventually hemorrhage would occur. Every single animal that reached a certain tortuosity eventually had retinal hemorrhage. So that was interesting to me. And then I wanted to evaluate in a more clinical population whether we could also come with some kind of threshold as well as can we use it to deduce what's going on in the eye. So if we see a disease state that results in tortuosity that's known to be pressure-related, can we calculate what that tortuosity is? And then if we see some kind of state where we're not sure what it is, but we see this tortuosity, can we now infer that it's also pressure-related? So with the help of Dr. Hoffman and Dr. Byrd, we're actually collecting clinical images and evaluating the tortuosity in a lot of kids who had multiple diseases and diagnoses. And then, of course, the last thing which you guys are here for is the visual changes following blast exposure. This was one of those studies where my training was in pediatrics and everything here is pretty pediatrics-related, except for this. And it's because I saw a call for proposals and I had an idea and I saw a problem and I had an idea and they liked it. So that's why it was funded and now we're kind of in the blast realm which is new and exciting. And that's how research goes, too. So visual injury from blast exposure, let's go ahead and start with that topic. So 13% of all battlefield injuries in the Iraqi wars are ocular injuries and that's both open and globe injuries. And one of the interesting things is it's been a sharp increase in the last years just due to the change in warfare. The inclusion of IEDs and other blast mechanisms has really substantially increased the number of ocular injuries, especially back in the days where it was definitely a spear or a musket and you had to be in close range. Now you don't have to be in close range and you can still cause significant damage. I didn't realize I was doing that. 80% of the severe eye trauma in the military is caused by a blast exposure. There are still some blunt impacts. That's probably the secondary cause of eye injury. 75% of soldiers with traumatic brain injury also have visual dysfunction. That complicates matters, right? Because you always have to distinguish whether it's the brain injury that's causing some visual dysfunction or if it's an eye injury that's causing visual dysfunction. I don't know why this is going forward. One of the interesting things is that blast injury research for ocular trauma hasn't really started except in the last few years. It was focused primarily on lung injury. We started having devastating lung injuries in our veterans and now they have a lot of protective gear that's really protected that but that's brought out other injuries that are now important. Brain injury, that was the second probably most popular field study of blast injury and only recently is eye injury starting to be studied. In order to understand the injury you have to understand what causes the injury. What's a blast exactly? When we think of a blast we always think of a big explosion, fire, debris being thrown. When you think of eye injury you always think of shrapnel, you think of burns but there's something a little bit more subtle than all that and this is an example of an explosion and you get that fiery heat you get the explosion ball where if you're close in that vicinity there's a lot of trauma involved a lot of burns, a lot of damage but you also see the expanding blast wave right here so this is the pressure wave front and that expanding blast wave can travel quite a bit and it's a pressure wave that's moving outward so there's no burns it may throw you back and in fact being thrown from this blast pressure wave is called a tertiary injury and of course being thrown could cause a traumatic brain injury which could leave the visual dysfunction but if you're far enough away you may not be thrown and just to prove that point here's a description of a blast experience from veterans so we've done a retrospective review and I just pulled this from some of the histories provided by the veterans and I just generalized them instead of the explicit but one gentleman saw a bright flash of light felt the blast wave so you actually feel the blast wave had a few moments of confusion and then felt fine another was eating dinner heard a loud blast and felt a shock wave next thing he remembers he was waking up on the floor rocket explosion occurred near a base it caused dizziness, nausea and patchy memory unsure if he actually lost consciousness saw explosion above felt the blast wave felt mildly disoriented and dizzy for a few minutes and then felt fine so a lot of this is far enough away that they're not caught up in the debris in the shrapnel what they're feeling is that pressure wave go through them and what does that actually do and that's one of the things that we wanted to find out and obviously if you read each of these you definitely see signs that the brain was affected confusion, dizziness, disoriented loss of consciousness so definitely the blast wave is affecting the brain as well the question is what is it affecting and is there also visual system injury there was a study by Cochrane I believe in 2012 where because of a lot of this he wanted to evaluate anyone who had a blast exposure and they were getting evaluated for TBI that became mandated because of a lot of these findings and he wanted to look at vision so initially they were just looking at TBI causing TBI and then they began including vision into that because of all the visual difficulties and challenges that occurred and so he wanted to see the relationship of those with TBI what was the percentage that actually had visual dysfunction and that was the primary goal of the study but in the study if you read the discussion he actually talks about a small subset of patients that did not appear to have a TBI but had some visual dysfunction so that suggests that there might actually be some damage to the eye now a lot of it is probably brain damage but perhaps some of it is also to the eye and so teasing that out is very challenging so that study that he did was not a formal study so we decided to evaluate this topic a little bit more oh the other interesting thing about the Cochrane study is these soldiers were 6, 12 months out so they weren't really having any visual issues until much later after their blast exposure it wasn't immediate and obvious it was more subtle so to evaluate this we designed a study that's more that's both experimental and clinical and I will say that I am an experimentalist by heart and a computational modeler definitely not a clinical person so the clinical side has moved a lot slower unfortunately but the experimental side is nearing its end and the benefit of each of those is as follows with the clinical study we could characterize what are the ocular injuries that are associated with and without a diagnosed TBI now we all know the diagnosis of TBI can be great at some times but that's the best we can work with we want to identify timelines of injury diagnosis and awareness after the blast exposure how long has it been until they started seeing symptoms or were diagnosed with any kind of visual issue and then we want to determine are there early identifiers or something early on that could be used to predict that vision dysfunction or degradation is going to happen on the experimental side there's a lot of limitations with the clinical studies the data on the blast could be very minimal it's based on memory based on the person's report of what happened so it could be inaccurate or even just absent and we really want to link as mechanical engineers what are the mechanics of the blast the time frame to the injury so the only way to do that is to control it ourselves so it allows to determine what blast mechanics are associated with what type of ocular injury we can identify timelines a lot better and cleaner and we can do a lot more to determine early identifiers of injury than you can do at the moment clinically or it'll inform us what we need to be looking for clinically so most of my talk is going to focus on the experimental studies at the end I am going to show an update of the clinical studies and what we're finding so far so how do we create a blast in a lab my grad student when he was presenting his proposal he actually presented Wiley Kod and getting exploded and he said he didn't want to be that person so that's not my reason I didn't a blast you can do a blast you can recreate a blast in an open field it's more expensive and it's costly and I don't think the University of Utah would like that very much but you can also recreate a blast in a tube it's called a shock tube or a pressure tube and how you create a blast exposure is you pressurize this section of the tube with a lot of air or a lot of some gas and there's a membrane that separates this long grey section to this pressurized section and at some point that membrane's being stretched and stretched and stretched and it's going to rupture and this is what a rupture looks like there's a membrane in here if you can see it and when it ruptures it sends this immediate pressure wave down the long end of the tube there's also a pressure wave that comes back into this tank system bounces off the back wall and then follows, chases that other pressure wave and when those two catch up that's when you actually get this kind of a waveform and this waveform recreates an open field blast so the type of pressure waveform that you might experience in an open field so that's how we recreate it in a lab setting other people have used other devices to simulate a blast some have used a paintball gun those will not achieve this kind of a waveform one of my colleagues Dr. Monson on lower campus he has a long shotgun barrel that fires blanks and then as the pressure wave exits the barrel then all of a sudden you have an open field and so you can develop the waveform pretty quickly for our studies we found the ideal location to place the animal in this tube so that it experienced this waveform and then we had to be very careful we don't want any of these animals to die because of this pressure wave even though it's just a pressure wave we've known that it causes lung injury and so we were very careful to protect their body we actually housed their body outside of the tube so they weren't directly exposed we wrapped them in Kevlar so the only thing exposed was their head note that it's a lateral exposure so it's going to impact the right eye but the interesting thing with that is you have a directly exposed blast eye and then you have an indirectly exposed blast eye so you can see the difference between the two eyes and what their effects so it's almost similar to if I was facing the blast or my back is to the blast or if there's some barrier in between we selected Long Evans rats for our study group primarily because we had discovered that they have slightly better vision than other rat species not anywhere close to humans but still a little bit better than most other rats so that's why we selected them the rats are anesthetized when they are exposed to these blasts I'll go ahead and do the experimental procedure so our experimental timeline was as follows so one day prior to the blast exposure we did some visual acuity behavioral testing which I'll go over in a little bit we performed OCT analysis to look at the structures of the eye and then at day zero they experienced the blast and then we repeated all these tests one day after the blast and then weekly up to eight weeks and the eight week time point was important because up to that time the only results that had been in the literature were primarily up to five days after the blast or a week after the blast there was one group that looked up up to four weeks after the blast and what we discovered from looking at their data is it looked like the injury wasn't over yet and that we needed to go further so that's what we did we took it pretty far out up to eight weeks we had a blast insult of 207 kilopascals which is just the magnitude we had ten control and ten blast animals at each time point the brain and the eyes were harvested for histology vitreous proteomic studies the histology that we performed was H&E and tunnel staining we did a protein analysis where we looked at in the vitreous of the eye we extracted the vitreous in the eye at each sacrifice point immediately froze it and then we looked at inflammatory cytokines using just a commercially available rat cytokine kit you can look at VEGF, TNF alpha the interleukins we also looked at neurofilament heavy chain and we picked this because it's known to be a marker for ganglion cell degeneration so we wanted to evaluate that as well for the visual acuity assessment this is where I'm nervous this is where I'm nervous presenting to a clinical audience we used an optic kinetic nystagmus test and it's just a we're used contrast thresholding as kind of a marker for visual acuity we didn't buy our system we built it so this is one of the benefits of being a mechanical engineering and stealing a robotic student for my project is he was able to design a lot of things for us and we had a lot more control on the program and what we could get out of the program the data that we could get out so we followed the same protocols that are in the literature where you vary the contrast gradients and you do both left and right sweeping of the bars and based on whether the animal tracks the lines are not determined whether he sees them and based on that we can come up with some kind of contrast threshold to kind of as a marker for visual acuity we did we replicated it three times as well per animal per test for the OCT we have a bioptogen and Visu R22 R220 OCT we evaluated both the retina and the cornea we actually started out just wanting to evaluate the retina but due to the advice of Dr. Borosco we should look at the cornea and we are very thankful she told us to do that because we found a lot of stuff in the cornea but for the retina we broke it up into eight radial regions medial versus lateral or central versus more lateral and then temporal, nasal, superior, inferior and so forth we looked at overall retinal thickness we also want to look at the nerve fiber layer thickness as well as the RPE thickness for the cornea we look at the overall corneal thickness as well as the epithelium and the stroma so some of the visual acuity results so this is a percent change in contrast threshold so an increase is a decrease in vision and then a decrease in the percent change in contrast threshold is an increase in vision so with our experimental eyes our blast exposed eyes we saw an immediate decrease in this visual acuity measure and it was sustained for several weeks and may even be slightly increasing though that's not significant towards the end the interesting thing about this and this is where this comes a little controversial is that we actually found an improvement in our other eyes and this is supposed to be a reflective test we do think it's a comfort level with the test they're very agitated and unsure of what's going on so we do think that that does play a role that's why we actually saw an improvement in our control eyes but I think it also just emphasizes the difference between the two animals and that we definitely had a decrease in vision in our blast exposed animals this decrease was significant at these time points relative to the controls and significantly different at these time points relative to their own baseline measurements so it was a significant change in vision but it was immediate and sustained for the thickness of the cornea this was actually very interesting you can see the baseline measurements look pretty nice at four weeks we had some amazing swelling going on and at six weeks sometimes we had scar formation sometimes the swelling actually diminished but oftentimes we were left with these kind of epithelial defects and things going on the thickness if you focus here on the epithelium thickness these stars right here indicate where they're significantly different from baseline so our controls really didn't change at all it was really our blast exposed eyes and the right eye was the one directly exposed to the blast that definitely had the most significant changes we did see a slight thickening in the epithelium this is just the epithelium by the way just a slight thickening in the left eyes but not really anything significant if you look at the stroma however then you see a lot of dramatic changes so here is the stars again indicate significant differences now here the blast exposed eye this is the left eye so it's actually the indirectly exposed eye this had an initial stromal swelling that resolved and went back down so that was interesting and then the right eye had swelling about week two and week three and week five this probably would have been significant if the variability was a little bit smaller so what that shows us is that there is some kind of delayed response and corneal swelling following this blast exposure and it's dependent on where you're looking in the eye so the epithelial layer did have some swelling the stromal layer definitely had quite a bit of swelling and some in the left eye before the right eye so it just really compounds a multiplex temporal response of the cornea to this blast pressure wave and we're doing some analyses now to try to figure out exactly what went on where's the damage occurring we're looking at the endothelial layer as well as we're doing epithelial cell counts so for the retinal thickness this is one that was a little bit more challenging we actually found that overall it was really mixed there wasn't a really clear trend at any time point Aranova showed that we had a few significant changes it was really dependent on the region and the time sometimes it was thickening, sometimes it was thinning so it really didn't make much sense and so we're hoping that by teasing out some of the different layers this was the overall retinal thickness we're hoping that by teasing out some of the layers we'll get a clear picture of what's going on in these structures the histology are my ocular pathologist is Dr. Robert Piper I met him at Penn a while back he's actually a veterinarian ocular pathologist so very handy to have he's evaluating the eyes right now these are images that I took before I even sent him the slides I'm one of those people that just can't wait and so I just start looking at some of the histology that I get back before I send him to him and one thing I noted that was very interesting in addition to some of the separation which I'll let him determine whether that's artifact or not though this is extremely interesting as well I saw an increase in cell definition and cell proliferation basically an increase in cell density and eventually led to this which at first I thought was neovascularization but then when I looked closer it doesn't look like red blood cells so I'll let him tell me what that is but very interesting things in the cornea some things that he has told me that he's seen is swelling of the lens epithelium, corneal edema which we've seen already belay epithelial irregularities superficial scarring which I mentioned superficial calcification and he has seen some vascularization though he said he saw it on the tunnel standing not on the H&E so I'm waiting to work with him to actually get a full view of what we have going on findings in both the left and the right eye not just the right eye so as I move forward I'm also curious to hear if there are thoughts of other things that we should be looking at just with our histology as well as anything else to help evaluate our animal model with the vitreous protein analysis this was actually really interesting it didn't matter which eye you were looking in there was an immediate increase in neurofilament heavy chain concentration so you can see our controls are right here these are one day, one week, four week and eight week and you can see an immediate significant increase and then by eight weeks it drops back down so this suggests that there could be some kind of retinal ganglion cell degeneration but we're not seeing it at least in our overall thickness measurements and talking with Dr. Piper I'm not sure we're seeing it in our histology either so this is something we got to figure out why there's an immediate increase in this with the cytokines if you look generally at the entire trend of the cytokines what you'll see, and this is all normalized to controls with various cytokines, inflammatory cytokines and what you see is an immediate increase again, that seems to taper off by one week and is pretty much non-existent by eight weeks so there's an immediate inflammatory response that decreases over time similarly, you, just looking at some of these proteins a little bit closely so some of these are not, we're not shown on the previous slide here you can see the controls, you can see a significant increase at one day in one week we added a four week group to try to understand what was going on in between and you'll see for nearly all of these at the four week time point it actually returns back down instead of the eight weeks so it's probably returning back to normal levels around week four interleukins have significant increase, MIP LAX was an interesting one it's known to be involved in neutrophil recruitment for the cornea so that makes sense according to some of our corneal injuries the timing however is what's fascinating so again, these are all immediate responses but remember our corneal swelling was delayed it started really around week two to three and in fact this is a week four image but at week four these levels are returned to normal so maybe the eye's given up, I don't know but these are some of the interesting timing issues that we're seeing so some of our experimental conclusions are that the low level blast exposure that we're providing does result in some kind of decrease in visual acuity we can't distinguish whether it's between it's in the brain or in the eye but there's some immediate effect there's potential structural changes in the retina but we're still teasing some of that out there's dramatic structural changes in the cornea both in the stroma and the epithelium an increased inflammatory and neutrophil recruitment in the eye increased neurofilament heavy chain potentially indicative of ginglion cell degeneration but we're still trying to figure that out the measured visual acuity and the vitreous protein changes were rapid and quickly almost immediate after the injury whereas the structural changes were delayed and followed so this suggests that there is a unique timeline for everything and perhaps that's indicative of when we should be applying treatment or that there's hope that if we apply treatment within a certain time frame then maybe we can reverse some of these later effects a summary of the clinical studies so I said we were doing clinical studies and our clinical studies are a retrospective review of the VA's here in Salt Lake City how many have been exposed to a blast what kind of visual complaints are they having what's the delay between the blasts we're also doing a prospective study where from that we're going to actually invite several veterans to participate in our study and get really detailed eye exams because one of the things that we're finding is that the description of the visual complaints is not unless Dr. Petty saw him or someone else in ophthalmology it's just not very detailed some are really detailed some aren't the other thing that we're doing is we're trying to access a database that links both the DOD side as well as the VA side data and it's a national database so it should give us a larger pool so this is a summary we've just finished the retrospective study and are trying to find participants for the prospective study and we're working with statistician to work on the retrospective so this is just a summary of some of the findings or the general description I should say so predominantly male not too surprising the mean age is 31 years old the oldest person we have is 58 and the youngest is 21 the primary mechanism for blast exposure is an IED rocket propelled cadets and mortars are next but IEDs definitely dominate this was interesting is the number of blast exposures so while you have just shy of 50% that have a single blast exposure the rest of them so a little over 50% have more than one blast exposure and if you look at the greater than 5 category that wasn't 6 that was really 20 or 30 or sometimes even 100 so it's a lot of blast exposures the unknowns but greater than one were typically just too numerous to count or they just didn't specify so definitely a lot of repetitive exposures and there's a group I think it's at Johns Hopkins that's looking at the repetitive exposure effect of ocular trauma for a TBI diagnosis most of them have a TBI diagnosis not surprising these are patients that actually went through the polytrauma group of the VA and they're looking to see if anyone has a TBI so most of them have a TBI some without behavioral health issues and some with behavioral health issues there is a small percentage that is not diagnosed with a TBI and that's one of the groups that we're going to be targeting is trying to get as many of those participants in our study to look at their visual effects versus the yes without behavioral issues visual effects group to see if there's any kind of vision differences between the two and there's very few that don't have any diagnosis recorded because that's again what they're looking for trying to determine if a TBI is present the vision complaint severity so this is just generic right blurring, trouble seeing, so forth 23% have none but the vast majority have some kind of visual complaint the most dominant visual complaint is photophobia again some have none but if you look at the percentages nearly most of the people in our study have at least a mild or very severe visual complaint or photophobia complaint so that's something else that we're trying to tease through and see what that means okay so there's a lot of limitations to these studies experimental the limitation with our visual acutting testing is it wasn't independent eyes we had different exposures to the eyes so it would be nice to do independent testing we did find out that we can actually back that out based on the directionality of the grading so if it goes one direction rats more likely to use one eye than if it goes another direction and so we started recording this more towards the end of the studies when we started realizing that we need to start looking at the individual eyes so we have some of that data and we're doing a few more studies to get some more data points but we don't have that separating brain damage versus eye damage that's a challenging one and we actually tried to do VEP on the rats but we couldn't get a good signal so we couldn't do those studies and I'm hoping in the future we can actually buy a device because again we were making our own device which that's what we do but I'm hoping to buy a device that's specifically designed for rats in future studies to separate out what's the brain injury from the eye injury we did collect the brains in all of these studies and as I said my training is in traumatic brain injury however when I've not necessarily blast and so I'm trying to figure out what it is exactly I want to look for in these brains typically if I were looking into any other kind of brain trauma or an axonal injury using beta-APP staining but in these I'll probably do that but I also want to figure out what else do I want to be looking at my colleague Dr. Monson he focuses on cerebral vasculature changes from blast and he's been staining looking just for bleeding in the brain and his findings are that it's just all over the place and so there's really not a good trend we're also comparing our two models because remember he has like a shotgun tube model mine's the shock tube so he has an animal outside of this gun barrel and as soon as the pressure wave exits the barrel it expands rapidly outward whereas mine's in the tube using a formed wave so we're hoping to compare and see differences between the two mechanisms of blast the relatively small sample size given the variability so as within any animal study as well as clinical there's a huge variability and so we're trying to so we have about 10 per time point we did see some significant differences but that's always a limitation is having smaller values we had to deal with that in order to go longer term and to actually capture several time points for the clinical again it's a small sample size this group I didn't mention how many patients we had we have about 300 patients in our local retrospective review as I mentioned I've worked with I'm working with the vision center of excellence which is a national group who has their part of the deal part of the DOD and they have a database solely of vision it has all the visual metrics and measurements and diagnoses of pretty much every veteran and military personnel so we're working with them to tease out some of those some of that data to get a better, more cleaner picture of what was experienced on the battlefield what was experienced immediately and then now what's experienced long term because the time after blast exposure in our clinical study is long years these soldiers have been back for a while these veterans have been back and so capturing when it first occurred is going to be challenging and again as I mentioned before the blast details are based on the history provided so they may not be accurate and they may actually just be absent so that's a challenge that we're working with future directions so one thing we're doing right now is we want to measure what the IOP is during the blast so we know that we have this pressure profile that's coming into the eye but we want to measure what's in the eye and how is the IOP changing with this pressure profile and maybe this rapid onset of IOP is actually what causes some retinal damage in other studies we also want to create a finite element model to link the injury to individual tissue strains and deformation so this is the benefit of finite element modeling because now we have a pressure wave that we can simulate we know through mechanical testing how the eye responds and we know what injury we're seeing from the animal model let's simulate it and see on the tissue level what's going on is the cornea deflecting inward and that's what's causing a lot of injury in the cornea is it experiencing very rapid and high large deformations during this blast exposure what about the retina what's the deformation of the retina during this blast exposure and what about the nerve so these are all things that we want to investigate and we can do that with computational modeling and then the ultimate goal and that's the end goal of this project is really to correlate the OCT histology protein vitreous analysis to develop a big picture of what's happening in this model what is the time course of all these different injuries and what do they mean for developing any kind of treatment strategies to prevent some of the down term injuries not only just drug treatment but also protective gear so in the studies by Cochran where 80% of the soldiers have some kind of visual system injury with traumatic brain injury 50% of those had protective eye gear so even wearing protective eye gear isn't preventing eye injuries or any kind of damage the eye gear that's out there today was designed for blunt impact it's not designed for pressure waves which travel through things so one of the things we'd like to do in the next stage is actually take advantage of our understanding of how the pressure wave changes as it passes through different materials to change the pressure wave before it goes into the eye the other thing that's interesting that another group found is that your brow will focus the pressure wave into your eye so your eyes are not designed well to have pressure going through them because the pressure bounces off your eyebrow straight into your eye which magnifies the wave that it sees so we're hoping to design something that's multi-material that can go outside the eye which will adjust the pressure wave magnitude before it actually goes through clinically as I said we need a much larger database for the retrospective study with a lot more details so we're accessing this Deweyver database to get the national data and of course we still want to perform our prospective studies to obtain detailed visual evaluation measurements where we can control what we're getting out of the exams and so we're starting we're trying to identify participants right now for that study okay, so I need to thank a lot of people so this is in generally this is our lab we work hard, play hard type of group Dan Shed and Nick Benko are the students that work primarily on this project we have a lot of collaborators as I mentioned Ken Montz and the mechanical engineering Brad Katz and Jeff Petty here Moran and Brian Zog who've really helped with the clinical stuff and hopefully Brad will help me interpret the photophobia stuff and then Bob Piper is my ocular pathologist and of course our funding is through the DOD and typically when I do a TBI presentation talk my two little munchkins are the head models for helmets but they're right there so with that I'm happy to take any questions that you might have on the study