quiz part of things are supposed to have a quiz. So first question would be we know that ROPs are all caused by oxygen if we just crank the oxygen down it'll go away and there we are to our faults. Second question will be screenings easy should be the interns job or first-year resident of the consult service and there you are and then the third question would be I've heard that a vast and makes ROP go away we should just inject them they could be on their way and be done with it and then the third or fourth issue would be that we've heard that you know ROPs the same all over the world we should apply the same screen criteria there's no reason to really stress about making it different different places and you could be thinking about those and we'll talk about those questions later now the topic for today is ROP is one of my favorite topics and we're going to talk a little bit about what we know about it in the past from historical standpoint what we know about classifying it which allows us to talk to each other about it cause treatment and where things are in terms of ongoing research now to put yourself in a historical perspective in the 1940s when the first epidemic of retro-lental fibroplasia as it was called in occurred the only instrument available to look at the fundus was the direct ophthalmoscope it had been around since 19th century Germany which was where it was developed and good morning and this is the view that you might have at the bedside in this wave of blindness and relatively large in infants who'd been exposed to large amounts of oxygen what you're seeing the reason was called RLF is when you look at this those are very miserable pointer these new batteries that's a retinal blood vessel that's the retina against the back of the lens this is what we would now call a stage 5 totally detached I'm not going to see retina hence the term retro-lental fibroplasia with the instrument today the direct ophthalmoscope and so it was a different time the issue then once they figured out what was going on was to cut back on the oxygen probably not your generation but I went to school with a couple of kids who were lights out blind in both eyes from RLF they were part of that group and now in the 40s this was first described in the took till the 50s with ongoing investigations looking at various possible causes including fluctuations in temperature background like pH oxygen and once that was figured out they cut back on the oxygen and said well this has gone the way a smallpox you know it's it's going away and there you are but with advances in neonatal care saving smaller and sicker infants there was a need to use oxygen to prevent bad brain and heart and long outcomes and on the other hand cranking the oxygen up caused ROP to come back RLF and this got to a point in the 80s where it was a really pressing problem and there were a number of people interested in it around the world they all got together in the about 1984 in a hotel room in Calgary Alberta Canada and came up with this international classification of ROP which allows us again to put things in a computer database tell her acuity cards of helmet Dobson who was a good friend of mine passed away from ALS a number of years ago was Dr. Teller's graduate student and Velma and David Teller developed these grading cards that is the source of all of the initial up until kids could read an iChart if they could ever eat an iChart acuity information outcome data from all of the ROP studies and then following that once we had a way to talk about it came the question what do we do about it and that led to the first prospective randomized trial which was the cryo ROP study at 86 now that showed that if you intervene in a timely manner with cryotherapy which was the only treatment modality that was generally available enough that you could do a big multicenter trial with it the laser indirect ophthalmoscope had not been developed the Japanese had taken kids and put them on a mayo stand and used the xenon laser which was delivered through a direct ophthalmoscope to look around and try laser kids and it didn't I mean it had some promising results but as you can imagine there was some significant downsides to trying to do that one of which was the back injury to the individual who was trying to deliver the laser treatment in that awkward position and that led to these other studies that bring us up to where we are today where we've looked at you know does treatment help absolutely it achieves about a 50% decrease in bad outcome can we do the same thing with laser every available study as I'm going to tell you would suggest that laser is as good or better than cryo less collateral damage equivalent outcomes then other questions to be answered included if we intervene earlier for some kids if we kind of change how we're delivering the care can we get a better outcome and that's what the early treatment study was about the electronic the EROP study different you know kind of tack on things the question was can we get reasonable information to make decisions about who needs to be looked at to be treated using photographs a resounding yes with that although it's not in general usage across the country that gets us up to the present where we've got various aspects of if we inject a VEGF inhibitor inside the eye at a appropriate time can we reverse the changes of acute ROP the answer to that is yes but there are a lot of questions that remain to be answered some of them that are being worked out including some people that you know here Dr. Hartman her lab looking at a lot of the issues going on you know with ROP now there were 7,000 kids blinded in the 40s in the US that initial epidemic where they figured out what was going on as recently as 1991 which if you look at the calendar you can figure out that's after we were treating kids with cryo when it was appropriate there were still about 650 kids across the US that entered the blind school ranks and it turns out if you want to know about blind children in a developed country you look at the blind school population if you want to know about severe vision loss you can find out you know how many there are that have been entered in that we use that actually all over but the data is less useful in some developing countries now in 2001 there were still 44% unfavorable outcome in the kids who had crowd therapy at threshold I mean did it decrease the bad outcome you bet it did but is there still work to be done yes and that's one of the kind of underlying themes I want to leave you with now classification if we're going to talk about ROP we need to be able to go through and describe it one of the questions I asked at the beginning here in our little quiz time and I did try to put a quiz in and follow up to your wonderful lecture the you know you know what's the big deal it's easy to do just send the intern and for those of you who have done ROP exams with me is it easy to do to get in and get out and get a look at what you need to look at and be able to play the ROP game and find the nasal auricirata the temporal auricirata in most infants safely do they ever try to die during the exam yes so no it's not easy but it is definitely worthwhile and I would urge you all I mean one of my goals in your training here is to get you to a point where you can safely interact with the patients and the staff in the newborn ICU and get useful information from patients now I crop this was arrived at again by a group like this sitting in a room saying how do you want to describe this what should we do and they hammered this out and there are three iterations of it in 1984 the initial classification of stages and zones and plus disease 87 a description of the late stages the various stages of retinal detachment for a 4b5 open closed funnel things that may not matter greatly at times in terms of the visual outcome initially but they're going to make huge differences when it comes to what sort of vitro or rental interventions are going to occur and how easy it is to do them and then in 2005 there was a revision with some of the original authors those that were still alive that updated and added this issue of what we call aggressive posterior ROP ROP and zone one poster zone two that behaves differently it's very active and leads to disaster if not dealt with very quickly it's also unfortunately hard to see when you look you don't see the neobascularization it's flat it's on the surface of the retina and can be difficult to pick up the other thing we fine-tuned was how we describe plus disease and those were the major things to come out of that now location staging and severity are the ways we describe it if you look at this if you make a draw a circle that the radius is twice the distance from optic nerve to fovea everything inside there is own one by definition there's no line in the eye if you take the same eye you draw a circle whose radius goes from optic nerve to the nasal auricirata and this is right eye left eyes you're looking at them everything inside that let me see if this will show up long enough to be useful and unfortunately no everything outside zone one in that circle is zone two the stuff that's left on the temporal side is zone three why is there that crescent temporally well as you know from anatomy and embryology the you know the optic nerve does not insert square in the middle of the back of the eye it's off-center nasally so there's more temporal retina to vascularize vascularization is something that is kind of key in terms of r.o.p. will come back to now staging in complete development of vessels then stage one stage two stage three are the initial stages we talked about stage one two and three in terms of the active stages of r.o.p. with normal vascular development you just see blood vessels stop you see translucent I don't yet have blood blood vessels retina beyond it stage one there's a line at the end of normal vascular development stage two you have a raised ridge stage three you've got extra retinal knee vascular tissue growing up over or on top of the ridge now stage four five are types of retinal detachment and this is immature vascular development any time you see something like radiologic studies and someone has taken the time to put arrows on it's good to direct your attention there those arrows show where normal blood vessels stop and there is yet to be development of blood vessels this whole process is driven by development of vascular endothelium in the cells that become vascular endothelial cells now stage one r.o.p. you see that white line there we see that see the big blue arrows that's stage one r.o.p. and this is stage one if you look right here and you have to kind of look carefully you'll see a line right there and that is stage one r.o.p. and notice that it's not a straight line when you see this come up here and go like this this is because blood vessels fan out they're not growing in a strictly linear fashion and often you'll see curved arborization of vessels and that line isn't a straight line like we draw it in the chart now stage two this line now is a three-dimensional raised structure and what you'll see here is this is now we're going to this is some stage three r.o.p. this developer you see the double arrows there's extra retinal fiber proliferative tissue there more aggressive there and you'll notice that the blood vessels the arterial our vessels and the venous vessels the narrower vessels here this is an arterial this is a venous vessel you'll see more dilation of venous vessels and tortuosity of arterial vessels those are the things that are harbingers of I have active r.o.p. what we call plus disease this is more aggressive stage three and you could imagine as this structure contracts it's going to pull the retina off the detachments that occur in active evolving r.o.p. are almost always tractional detachments and more stage three here and notice that super temporal vein you see there in that arcade how dilated that is that is definitely plus disease this is very involved stage three with big dilated vessels but when we're looking peripherally you can't see anything about plus disease the termination of plus disease is based on the appearance of vessels right around the optic nerve that's just by definition and so going back historically this is what we call threshold I'm ready for treatment where the thick white lines represent stage three so if we had eight non contiguous not all linked together clock hours of stage three or five contiguous clock hours in this left eye going from one o'clock to six o'clock that would be threshold r.o.p. we don't use that anymore unless the patient actually gets there and bypasses our usual time of treatment but useful to know about and someone might ask you that on one of these examinations that you have to take now practical issues look at the posterior pole first before you mash on the eye because you can cause blood vessels to become dilated and precipitate what looks like plus disease just because of extended mashing on the eye with a scleral depressor look nasally first if vessels go to the nasal aura everything you see temporarily is in zone three by definition there's no line out there to tell you when zone two stops in zone three starts so by definition if vessels go to the nasal aura the stuff on the temporal side is out in zone three if on the other hand things don't go to the nasal aura then you know you are at least in zone two and if they're posterior enough you could still be in zone one now when you put the optic nerve at the nasal edge of a field with a 28 or 30 doctor indirect lens the where the temporal edge is is about the outer limit of zone one sometimes useful thing if you can see if you can still see active ROP when you've got that nasal you've got the edge of the optic nerve at the nasal edge of the field chances are you're looking at zone one ROP which should cause you'd have a little bit of angst about where things are headed now for a partial detachment fovea not involved similar to adult ribotages detachments if I have a detachment my fovea is attached you're going to worry about getting things reattached because you think you can preserve vision whereas if I come in and my fovea is detached it's off macule off RD and it's been that way and I've got some pdr chances are my test he's going to put me on the schedule sometime in the next few weeks not tonight right and after a trip somewhere I'd say but you know there's a difference in the urgency and the likelihood of getting a good outcome when you come in and you've got a Mac on you know detachment the idea is to get the retina attached now so that you preserve good vision and this patient right here this is a for a detachment there is detachment of retina extending towards the fovea right there and this is a schematic of a for a detachment you can see the fovea is still attached and then for B this is the same patient a week later with the detachment extending right back to the optic nerve and this is difficult OCT has made it much more easy to kind of separate these because otherwise it can be very difficult to tell that the retina is detached there now the retina can go on to become a fold as things contract and if you can imagine our ability to fix this and get a good outcome is pretty non-existent so the name of the game is to prevent it this is a for B detachment and then doesn't matter to me and it probably doesn't matter to the baby whether they have an open or a closed funnel the retina is going to work just as badly they may have light perception some hand movement moving around kind of vision but it's going to matter to Eileen Wong greatly when she's trying to put the truck to me probes in and worrying about what she's putting them through and is she getting them into a space where she can then push retina back and then do retinotomies or whatever she has to do to try to get things reattached this is a total exudative retinal detachment this was taken at the Moran Eye Center by Paula Morris one of our photographers with a Zeiss fundus camera with this baby on its side we're holding the kid on a male stand I brought the kid over to the old Moran and that's where that picture was taken and Paula was a pioneer and get pictures of these kids and so she participated in many of those photos that I showed you before and this is a total detachment looking down into the funnel the jaws of blindness as it were and this is that closing funnel and this is where the retinas all watered up like a piece of chewing gum as one of my mentors used to describe it and and it's not very easy to get that fixed so we don't want it to get there now severity plus disease post your pole Venus dilatation arterial or tortuosity and with this latest iteration of eye crop instead of leaving it vague came up with the idea that you've got two quadrants thinking about the four vascular arcades two quadrants were more involved to call a plus disease this is still the sticking point for most people who do work with RLP day in and day out and describing whether there is plus disease or not and this is where all the impetus for Michael Chang and his work on trying to use computer assessment of dilation and tortuosity still not at the point of you know general utility but it will be this is plus disease big dilated veins tortuous arterial or vessels and this is also plus disease with very active stage three and this is an eye that if we treat again we can save vision this is very fulminant plus disease and now pre-plus disease what about that that was also added and that's I'm almost plus but not quite that's really all it means and it's a judgment call and this is pre-plus disease you've got dilation tortuosity not enough to call it plus not normal enough to call it normal and aggressive posterior RLP zone one very posterior zone two when you see active RLP there you need to get the 20 doctor lens out and look carefully to see if you see neobascular tissue which can be flat in some kids even doing fluorescent angiography at bedside which you can do with the camera that we have if they have ID access is a possibility and people have done that in the NICU we don't do it here regularly prominent plus disease and again the retina the active RLP can be very difficult to see and if you look where the blue arrows are there is flat need of vascularization on the retina both of those areas but when you first glance at that you would say well there might be some stage one RLP let's not worry about that we'll look at this kid in a week and this is a kid that needs to be treated this is a child that we saw here at the University of Utah with fulminant posterior you know vessel dilation look at how big those those vessels are and 360 degree flat neobascularization in zone one the difference with cryo is that almost a hundred percent of these eyes with or without treatment had bad outcomes part of it was we treated so much of the eye with cryo the eyes didn't survive the treatment this is a close-up now regression this is the most common thing that happens with RLP this means that it gets to a certain point and then it gets better but often there are things left behind areas of peripheral abascularity abnormal branching pigmentary changes and the one that's probably the most worrisome to me are these vitreous retinal interface changes because that is where later in life when the vitreous becomes mobile you'll have traction on the retina that's a place where you're going to develop retinal tears and if you follow kids who've had severe RLP that we're lucky enough not to have a disastrous outcome initially there is a trickle of kids as time goes on who have what are called late retinal detanchments due to those changes and this is a patient who has had three successive areas that you can see where they had ridges developed and then get better and you see blood vessels growing out right here down through this and in the retina and so vascularization to some extent is continued but not normally if you see that third bridge there are no blood vessels that go beyond that and here you can see where there was a rage and vessels are clearly going beyond it but again the vessels don't have a quite normal appearance here what we're seeing is an area where the changes that drive vascular anethereal development become fibroblasts laid on collagen cause scar the form that contracts and then pulls the retina so that this are these are caves that once way out here are now pulled together and pulled in this direction and that results first of all in distortion of the normal architecture in the foveal area so instantly your chance of having wonderful vision goes out the window and a lot of these eyes will go on to develop total detachments over time now straightening a temporal vessels ectopic ectopic fovea dragging of the retina the thing that causes us to have a positive angle cap of an eye that looks like it's turned out because the fovea has been pulled temporarily retinal folds and late detachments are all things to worry about and these are you see those straightened vessels in that super temporal arcade in this right eye that's what we're talking about there this is a fold now threshold we talked about already and we're not going to dwell on that because there's a new deal as it were and this was based on the early treatment of rlp study et rlp and what we did is retrofit the data to come up with this scheme that appeared to mimic what we would have accomplished if we made everybody run around on the NICU and you all had a an app on your phone that you had to enter all kinds of data in on each kid and decide are they at high risk or not at high risk and this seemed to be a lot simpler and easier to apply so the idea with this is that type one rlp is rlp if you've got any rlp with plus disease in zone one that stage three whether you have plus or not or out in zone two if you have any stage two or three with plus disease so if you think about what I said about threshold you've got five contiguous or eight nine contiguous clock hours we sat and waited for a lot of kids to develop enough stage three or plus disease to say it was time to treat and what we're saying with this is if you've got one clock hour stage three you've got plus disease we treat type one rlp we treat and type two this is I'm almost ready we're going to worry about you but we're not going to treat you today and this is stage one or two without plus disease in the zone one so we can have a little bit of rlp in zone one and watch it zone two and this is the most common scenario we've got some stage three but we don't have plus disease in zone two and all of you that have seen kids with me doing rlp exams know we've seen kids where we've got a little bit of stage three we're not calling it plus disease we say well let's come back in a week so this is a common scenario for this type two rlp so treat type one or if they progress the threshold you look in and last week they had incomplete vessels and this week they've got eight you know non continuous clock hours of stage three with plus disease by all means you treat them they've gone past this type one thing and again the reason this was decided upon was we thought myself among those who were worrying about this that there were kids where we waited till they had enough stage three to treat or wait until they had plus disease where we would have gotten a better outcome and they went on to bad outcomes some of those kids and that's what drove this now what do we know about etiology normal vascular development begins at the optic nerve at about four months gestation it reaches the auricerata asymmetrically nasally at about eight months in a term infant temporarily nine months in a term infant but once you develop rlp those things go off the window you can't count on a kid who's in the nicu who has got you know rlp and they say well by their they should be termed now they should be completed and that isn't how it works unfortunately the that timetable goes right out the window now vascular precursors come from the hyeloid system what else do we think about the hyeloid system from forward what other vascular developmental abnormality in the eye yeah bfv remember it's the hyeloid blood vessels that primary blood vessel system that comes forward and when the lens placode separates from surface ectoderm provides nutrition to developing lens then it's supposed to go away some of the cells that were involved in forming the hyeloid system are the cells that are the precursors of the endothelial cells that drive retinal vascular development and these what they call vanguard and rear guard cells the vanguard are the spindle cells that are driving the process and then they morph into endothelial cells the rear guard cells and i'm not big on past slides i'm not a pathologist but going from your left to right you see vanguard cells going to the right rear guard cells trying to organize into a vascular channel on the other hand this process has gone awry in this infant and this is extra retinal neavascular tissue and and realize that i mean the reason we have this slide is that this infant had an unfortunate outcome in terms of prematurity in general this is another autopsy specimen that shows first the extra retinal fiber proliferative tissue here and you can clearly see traction on the retina in the vitreous this is a stage five i'm totally detached retina now what about oxygen back in the fifties arle pats kenzie john flinn who just passed away during the last year and helen hitner more recently have driven this whole idea that oxygen is the culprit in some version of what's happening with oxygen oxygen metabolism initially oxygen was cut back they thought it had gone away dr hitner has been the main mover and shaker talking about oxidative damage initially in all of the events that led to using vegef inhibitors a lot were driven by her relentless enthusiasm for pushing this agenda and we have a lot to you know big go to thanks to her for doing that because there are a lot of people who are seeing bad things about her when that was all going on and with the beat rock study and things that have come out of that she's pretty much been vindicated um people looked initially at vitamin e acth ambient light surfactant with vitamin e it turns out if you give kids high doses of vitamin e it doesn't decrease rlp it does increase the incidence of necrotizing enterocolitis sepsis and death so that was not pursued there was the light rlp study looking at ambient light levels again that local story we were not part of that study our neonatologists elected not to support us in participating in it but pristine a class one of our nurses in the nicu here and susan bracken my original study coordinator developed the goggles they used in that study so that part of that was developed here at the university of utah the idea was that you cut down on ambient light using neutral density filters do you decrease the incidence of active and aggressive rlp and the answer to that based on the best available information is no you don't i thought when surfactant came out they were going to be able to you know get better pulmonary outcomes better systemic outcomes and that we're all going to be able to do other things and not deal with rlp unfortunately what it did instead is allow them to save smaller secret kids who went on to have worse rlp so i i didn't see that one coming now current thinking is that we've got a schemic retina local tissue hypoxia production of veg f so it's production of things that are produced in the face of hypoxia tissue hypoxia that drive active rlp and veg f mediated events include this endothelial cell replication vascular overgrowth external proliferation and lack of planned cell death apoptosis uh the various all of these uh growth factors have been implicated and have been looked at in one way or another in studies and you will hear a lot more about that aspect of things in your practice careers lia owens research career is built around looking at epigenetic phenomena that may be associated with rlp and related vascular diseases that affect infants now from natural history the significance of this if you stratify kids into these birth weight ranges under 750 grams 750 to 1000 and 1250 notice that the incidence of rlp goes way up the smaller you are at birth the incidence of threshold rlp goes from 2 percent to 15 percent if you look at those same birth weight strata and other significant factors race being non-caucasian was protective against developing threshold rlp clearly the events based on the cryo rlp study data of active rlp are related to post-conceptual age not chronologic age from birth and that allowed us to change the screening criteria so we weren't looking at kids at 26 27 weeks of age if they're born 23 weeks of age we waited until based on their post-conceptual age we thought they were at risk because looking at a 26 week gestation infant and doing an rlp exam is fraught with apnea bradycardia and bad things happening the other issue is if you were born in the hospital where you received your rlp care you did better than if you were born elsewhere and transported in now screening exams currently we look at all kids under 1500 grams or born less at 28 or less weeks gestation birth and we look either at four to six weeks or we stall it to 31 to 33 weeks if that occurs later and that that helps us not doing what i term fetus exams on these very very small infants that were hard on the babies really hard on me and didn't really add to the infants care we were just doing it because we said we ought to this has all been published again if you're interested in looking at it both the american academy pediatrics journal pediatrics apos and the aio came out with a joint statement back in 96 talking about changing these criteria and and so timing of exams and again this data as far as timing of the exams was fine-tuned based on that early treatment of rlp study data and um so if they're less than 28 weeks we examine at 31 weeks we stall it till then if they're later than 28 weeks at birth we wait and we look four to six weeks down the road and then the follow-up exams are based on what we saw on the exam today if we think they are still at risk of going to type one rlp needing treatment we see them weekly until they're not and then we spread things out now new additions and when i was in your shoes the reason i asked the question initially about shouldn't the intern do this it turns out that that was indeed at the university of michigan the case when i was a resident all rlp screening was done by residents they were never seen by a faculty member and the reason for that was there wasn't a darn thing you could do to change things and so what we did is we identified kids that needed to be referred to the blind school and that was all that came of those exams and that was very unfortunate that got my attention in a big way but exams were scheduled if somebody thought about it when i came back to salt lake if the neonatologists said i think we should have this kid looked at to see if they have rlp that was the way things were done and it wasn't um till much later that the idea that we need to look at babies as they come into the nicu and say this baby needs to be looked at on this date that's what happens now and we now have our uh uh you know melissa chen we're our first rlp coordinator and she is going to put all these kids in a database and we can follow them forever we'll know where they are it's going to be really cool now what else do we need to talk about with this for most infants you look twice why well if i look today and i was in a hurry or i didn't get quite the look i should and i thought things were out in zone three but i look a week or two from now and i see gosh we're still in mid zone too does that happen you bet it does and so to avoid missing that child going on to needing treatment each child who is at risk initially should be looked at at least twice and then what i just mentioned about when we follow the kids that's one issue the other issue is that let's say we're seeing a child here at the university today that child is being transported to piner valley hospital because they have a nicu and the parents want to be close to home they couldn't possibly drive all the way to the university we need to arrange follow-up we need to hand off that baby's care to somebody that's going to see him or one of us that might be me has to jump in the car and run there and see that kid when they need to be seen and have people been successfully sued for not handing off that care you bet um and those have been um you know in the tune of one of my colleagues being sued for 67 million dollars and even though that was ultimately dismissed having that hang over her head for the two years it took to work through the courts absolutely ruined her life during that period and she still to this day will not do r.o.p exams won't participate in it will have nothing to do that because of that experience it was awful for the other thing to do is to communicate with the parents health jobs is going to be to interact with the parents to educate them um and actually as we're sitting here my daughter who is a nicu nurse at primary is interviewing for a position to be the parent educator um to talk about things like r.o.p with parents in the nicu so the nicu takes it seriously on their end as well and there's a consensus statement in 2001 again by all of our organizations that published in various places that deals with this issue of needing to coordinate things to hand patients off and partly this was driven by the need to let people know that people are being held accountable for it but bottom line is these are important things to do not just threaten lawsuit you know if we were worried terribly here about lawsuits I mean we have huge medical legal exposure just doing r.o.p but I'm committed to seeing these babies because I think it's an important thing to do we can help them and that's why we all want medicine now what about long-term follow-up it turns out that kids who've had r.o.p are more at risk for very high myopia kids who have had significant intraventricular bleeding our kids who develop cp they have central vision loss due to damage to the optic radiations as they wrap around the posterior part of the lateral ventricles when you talk about grade three and grade four intraventricular hemorrhage you're talking about damage to those brain tissues things that you can see in an MRI scan now can you lose a lot of those pathways and still have pretty darn normal vision yes but it makes you and I need to worry about it follow that child till they're an age that we can settle that to make sure that they're seeing well enough to get the education that they deserve retinal outcomes as far as late detachments visual field loss those are all issues that need to be looked at and then developmental delay which makes it at times very difficult to examine these kids but it is worthwhile now what about developing world applications one of the questions I asked the beginning quiz was you know RLP is the same I mean they make infants the same in Thailand as they do here or in Bhutan so what's the big deal and why should we worry about changing things the issue is the quality of neonatal care there may be genetic differences as well with infants that are born at high altitude in Nepal and Bhutan separate discussion but the big issue here is the standardization of the lack of oxygen blenders I personally smuggled oxygen blenders into Bhutan because their neonatologist could not get them the health service in the country wouldn't get them and she having trained in Japan knew that if she could control the oxygen saturations better she could get better outcomes and they'd have fewer blind kids which wasn't a big issue until they started having blind kids which they do have a trickle of now every year so the issue here is that these screening criteria because of this and because RLP occurs in kids who are born later post-conceptual age and at a larger birth weight getting bad RLP and winding up with poor visual outcomes in developing countries the local criteria need to be adjusted we also have an obligation to work with our pediatrics and neonatology colleagues to kind of let them know that we need to kind of grow that whole system together and hopefully provide better neonatal care and enable them to get oxygen blenders and and and have trained neonatologists and this shows and this is a busy slide but this is birth weight at the top and post-conceptual age at the bottom if you look at where you'll see kids there that are over 3,000 grams in Argentina you know there are getting threshold RLP you know there are these are kids that that need to be attended to right now the Pan-American Association for Ophthalmology recommends all kids in Latin America 1700 grams or less not in our we don't see RLP here in kids over about 1250 almost ever but there there are another almost 500 grams heavier in terms of the kids that they're screening because of their local experiences Clara Gilbert who is the author in that paper is an ophthalmologist in the UK she has been instrumental in almost everything that's happened of note in international developing world RLP for the last 20 years if you get a chance to meet her she's wonderful and she doesn't get a lot of credit for a lot of the stuff that she does but she's been a major force she and my colleague Ram Quinn at CHOP they're evolving epidemics in the Middle East Africa and Asia it was a huge meeting in South Africa year ago this past fall the focus of which was to get ophthalmologists pediatric ophthalmologists retina specialists actively engaged in looking at RLP and setting up screening and treatment programs I've been involved in helping the programs in Ghana and in Ethiopia yet they're starting this um and so we've talked about now what about management what do we do we've talked about these issues before and we're going to do the best we can in terms of oxygen management and they keep trying to fine tune this you'll hear more about it but kids will still get to a point where we need to intervene and do corrective things cryo therapy remains the only type of treatment that has been shown in a prospective multi-center randomized control treatment group in RLP and the reason for that is it's no longer ethical to randomize a child to no treatment you can't do it so subsequent studies show you know compare cryo to laser and various and all of the vegev studies basically have compared vegev inhibitor injections to the current gold standard which is laser treatment now when you do cryo therapy you have to keep in mind that you put the cryo probe on conjunctiva and you're freezing full thickness through conjunctiva sclera muscle coroid all these tissues to get to the retina where you're trying to destroy retina why are you trying to destroy retina because that ischemic retina that you're trying to destroy is what's driving the production of vegev and all these vegev mediated events that caused active RLP but in the process you have all this collateral damage and we treated kids with cryo you couldn't even see the eyes for two or three days they were so massively swollen they require general anesthesia in our study center for cryo rock we had one cardiac arrest during treatment due to an overly aggressive treatment by a retina surgeon in the community that i had to be one of our our treaters that child didn't survive the arrest but it was a real scary moment for me when i got that phone call clinic and had to go run into the NICU to help certain things out they wanted us to stop the study and i had to do a lot of talking to keep going with it because i was convinced that it was going to help it turns out i was right that we've talked about this shows cryo burns and this is the stage three RLP down below in the avascular peripheral retina that has been treated with chronic liver cryo burns and and we randomized 4,000 infants under 1251, 291 of them were randomized to either treatment or control what i treated what i control even if they had symmetric disease in the two eyes and then results were to you know describe various intervals up to 15 years of age and basically this showed that yes it's safe and effective we learned a lot about epidemiology and natural history and also out of this came timing of screened exams linked to post-conceptual age which i think is key in terms of not picking on kids too early and doing unnecessary exams and if you look i'm just going to flip through these both at three months the outcomes were so striking that the data safety and monetary committee said you can no longer randomize any child to control which was really cool the results showed about a 50 decrease in both bad structural and functional outcomes as you go through all of these studies realizing we're getting better data as kids get older and those who can read acuity charts rather than look at the teller cards because you could overestimate acuity with those teller cards and so now what about contrast sensitivity it turns out that compared to no r.o.p hang on a second the treated kids were about half normal half of them were in the normal range and the control group if i had bad r.o.p but i didn't get treated or wasn't quite ready for treatment those kids had poorer outcomes in terms of contrast sensitivity so it did not appear one of the questions was would we hurt contrast sensitivity by doing treatment the answer to that is no the other thing was visual fields when we first started using cryo i told parents in our study center that there was a very good chance that those kids would have very very poor peripheral vision they may not drive they may have trouble getting around but their straight ahead vision should be good and it turns out that what you lose is you lose about a 30-year visual field due to ipad severe r.o.p and you lose a little bit more just you know if you've had treatment and that's about a five percent reduction and it turns out that the eyes that that had treatment overall did better than those stuck through that had severe r.o.p didn't get treated so the amount of visual field loss is not as significant as we thought it was going to be and in fact most of it has to do with some of those changes in the peripheral retina due to having severe r.o.p not to the treatment itself and then in 15 years we've still got very significant improved structural and acuity outcomes now i mentioned before new folds detachment bad things happening it occurred less in treated eyes than in control eyes well what i do now with all kids who've had severe r.o.p is i tell their parents that they have to have an eye examined by somebody who knows what they're looking at once a year for life and i tell them that when i see them back their first visit clinic after they leave the nicu because there's a lot of stuff going on has dropped on them when they're in the nicu and they're not going to remember a lot of what you tell them what about laser treatment these were the initial studies and they showed excellent regression of r.o.p i remember still remember the first kid that i had mike teski treat here with zone one r.o.p with laser that kid as opposed to the cryo kids where the eyes just gave up and became ticycle had attached retina and looked wonderful now it did take the kid two years because of the bad brain outcome he had from pre-majority to act like he saw anything but for me this was a game changer for the posterior very posterior involvement kids what we now call aggressive posterior r.o.p we could treat them with laser the retina was attached and if their brain had the capacity of doing it they could see and these are photos that i took with a handheld film fundus camera as we were treating a kid those are laser spots that's the plus disease that you're seeing down below and again you see a little bit of hemorrhage laser may have been a little close to the ridge right there but that's what the view looked like and so we're holding the fundus camera and doing this trying to get those pictures and this these studies compared laser to cryo and still going through that and then these studies looked at laser treatment in zone one and again supported what i just mentioned to you and then vigil retinal surgery bottom line is that yes they can get the retina reattached but it doesn't work like it was intended to in almost all circumstances can those kids function better and are the eyes happier with the retina attached you bet they are and again scleral buckling so we wind up realize the good outcome here is 2,300 or better okay that's not what we're shooting for um and so for protracted means again you'll find anatomic success rates vary a lot but grand quince paper in ophthalmology in 1991 looking at the visual outcomes would suggest that very few of these eyes that you compare groups of i had no surgery i had aggressive vigil retinal surgery actually saw better now pat drosti who's one of my pediatric ophthalmology colleagues and mike tracy the guy who trained mike teski in detroit looked at this visual function battery question of if i put a chair in the middle of the room and ask the child to come over and pick up a twinkie on the floor do they walk around the chair things that are of practical significance can they navigate an unfamiliar surroundings and kids with vitro retinal surgery a-tashed partially attached retinas that are steamed stable did better and it's time to kind of wrap things up here but we are you know if you look at kids over time they have increased need for vitrectomy, lens accuracy, sturdiness surgery and shunts keeping in mind the neural you know surgery outcome the i have you know bad hydrocephalus obstructive hydrocephalus due to my intraventricular bleeding and then what about a veg f inhibitors these are used in a variety of pediatric vitro retinal diseases you'll see dr hartnett dr wong both using them in various forms in these diseases and there were initial clinical reports of using this back in about 2008 and it looked like there were initial good responses that were reported and dr hitter her initial report was in retina in 2009 about i think 11 patients that had stage 3 rop posterior rop and looked like she had good outcomes and then the beat rock study which was published in the new england journal february 2011 looked at 150 infants i want you to notice the point 65 milligram dose that was just pulled out of the air because that's what we use in adults with amd so you're taking a child that's this big and you're taking somebody that's my size and age and you're injecting the same in that infant as you wouldn't and me that's changed but that's where we started with this and even with that though they found a decrease of recurrence of rop that was their outcome does rop come back in zone one disease more normal vascularization and less myopia and so what have we learned and i'll close here veg f inhibitors do work the minimal effective dose has not been firmly established the rop one study we're one of the study centers for it done by the pd group dose deescalation decrease dose every time we find a dose that appears to work for everybody we go down and they're down now as far as published data to 120th of the dose that's used in adults for amd and it still appears to work and uh um why are we concerned about that well it turns out that veg f is important in developing vascular beds in all sorts of organ systems in a neonate and can you measure it systemically does it get suppressed systemically with this intraocular injection you bet it does and and so people are tinkering with dosing with using different veg f inhibitors and that is something that uh this dosing trial that we're part of in the rainbow study which we're also part of comparing a vast and leucinus you'll hear more coming out about that this is going to involve in your practice careers now back to our our quiz so should it be just the intern doing our own piece grading the answer that is obviously no um and why don't we just cut the oxygen back it worked in the fifties increased death that's right now every time you know every time you cut back the oxygen to save vision you've got the other side of that teeter totter are increased deaths from bad neurologic cardiovascular and pulmonary outcomes and so you have to juggle those things and in this is a you know kind of a teamwork situation um questions the high myopia and it isn't just later in life these are kids that may be minus fifteen or minus twenty at six months of age or nine months of age and so the the the feeling there is there's something about the abnormalities in the peripheral retina that are driving that um but the exact mechanism of it has not been worked out nobody knows these are not mean it's clearly different than the kids who have a highly myopic you know mom and dad and have recessively inherited pathologic high myopia um they show up being myopic usually in their preschool years early school years but these are kids that you know we sometimes have in glasses at six or nine months of age because they can't see from themselves to a parent um but the mechanism of it isn't well worked out the results of some of the vegev I mean one of the proposed advantages of vegev inhibitors is that you have less high myopia and the studies would indeed suggest that that is the case that will turn out to be a huge advantage why treating it effectively with vegev inhibitor versus treating it effectively with laser would have that much difference because that's what they're comparing are the laser outcomes versus the vegev inhibitor outcomes and um so that is yet yet to be worked out the other thing that's yet to be worked out is where the kids because commonly now we'll have a child and I know all of you Nikki with us we see a kid who's had vegev inhibitor ejection acute ROP has gone away but as that's gone away what's happened is that we're worried about it coming back the recurrence is a big issue and if that kid is being back transported to somewhere on the novel reservation we may well laser that kid so then you're muddy in the water because they've had both vegev inhibitor and they've had laser and how that's going to shake out in large-scale fashion is still to be worked out as well but now when you figure that one out you'll you'll be famous and it'll be a big paper but I don't know the answer that I don't know that anybody does exactly other questions about ROP so I think that this is something that you know if you're interested in it please stay involved in it don't be too worried about you know you hear all the scary medical legal things but to date knock on wood I have not been involved in any medical legal action that has to do with ROP you know ever and we see a lot of kids here you know I think it's rewarding it's fun to do what else did we have on our quiz what other questions were there anybody remember talked about the developing country thing we talked about the need to not just cut back the oxygen not just have the infant do it it is it is tedious and it is somewhat difficult to learn to do it well but I you know my goal and this really is that let's say you're doing comprehensive ophthalmology you know in do you want to base it and we send a child home and you look at the child I want you to feel comfortable knowing that if there were something bad going on you may not see the entire extent of the retina you'd be able to sort out I'm doing okay from I need to hot foot it back to Salt Lake to have something done and and that you know beyond that if you're going to do something with it you will do it regularly it will become a lot easier for you it's never really easy I mean bad things do happen in the NICU that's why we you know we try to stay up on things and the other you know question is what role will cameras play and am I going to be replaced by a camera and somebody at a remote center you know looking at the photos it turns out that's what we did in that early you know the electronic RLP studies we had a central reading center but to the best of my knowledge no one is using that central reading center even the folks who were most hot about it the folks at my buddy Graham Quinn and Gil Benamon at CHOMP they're still if they're taking photos they're doing the same thing that we do they take photos to document things so many centers do that we take photos here every baby we do an RLP exam on every visit so that if someone has a question about it we can go back and look at it as a group that also allows for a good communication between the screeners and the treaters where they can look at the same photo and come to some consensus and hopefully about what's going on thanks for your attention get on with your day and happy new year


Hi everyone. In this video, I'd like to talk about the critical lens of erotic analysis in our larger discussion of critical media studies. Now, before we jump in, just take a deep breath. We're not talking about that kind of erotic analysis. We're not going to talk about, we're not jumping into porn or anything like that, really. That's not the kind of erotic analysis we're going to be looking at. I mean, I suppose you could if you really wanted to choose that as an artifact, but what we mean by erotic analysis is something a little bit different. So let's just, first of all, start by defining that. Erotic analysis examines artifacts in relationship to the sensuous, transgressive, and productive pleasure exhibited by the audience. And the key word there really is pleasure. When we talk about erotic analysis, we're talking about what is it that gives the audience pleasure in this artifact? Why is the audience taking pleasure in this artifact? And what ways are they expressing that pleasure with this artifact? So that's what we mean by erotic analysis in general. So let's take a little bit deeper look here. Some of the major premises for erotic analysis, first of all, number one is that people engage with media that bring them pleasure. It's not terribly surprising that we tend to want to do things, we choose to do things that bring us pleasure, that bring us some happiness and some joy, some contentment and some, you know, or bring us some sort of pleasure in any way. So people engage with media that bring them pleasure. And we find that there are two kinds of pleasure in particular that people draw from these types of artifacts. The first is what we call transgressive pleasure, which has to do with being different. We enjoy artifacts, we enjoy different types of media that are different, that stand out because of that, that don't necessarily, I mean, that there's something to be said for, you know, doing the same thing as everybody else. That's why there are, you know, after friends had such popularity, there were a run of shows that tried to be the new friends, so to speak, right? And that's why there's, you know, 15 versions of NCIS and four versions of CSI, whatnot. So there's that pleasure that comes from from familiarity and things like that, but we really take a great deal of pleasure audiences do in transgressive pleasure in something that is different from the norm. Something that zigs when everybody else is zagging, right? That's what we do by transgressive pleasure. So one example this week, see, in the mid-20th century, Norman Rockwell was one of the great American painters, right? But painted scenes that were familiar and were comfortable for people, painted scenes like this, the after-prom, where, you know, these are things that we know that we're familiar with, plus the art itself is pretty straightforward. I mean, it's really incredible. I don't have that kind of talent, but the scene and the way that it's painted, there's nothing really that starkly different from other standard painters of that time. But then you see the emergence and real popularity of artists such as Andy Warhol with his version of Pop Art, what's called Pop Art there, with the different colors, but familiar topics, but different colors and painting them in a different way than they'd ever been envisioned before, maybe. And then also things like Jackson Pollock and the abstract art scene, very, very different from Norman Rockwell, right? He's not painting Jackson Pollock, is not painting a scene of kids at the soda shop during the after-prom, right? It's confused in some ways. It's messy, but it's different, and that's what makes it stand out. That's what kind of gives us pleasure, not only the discovery of something different and being kind of on the cutting edge, but the leading edge of that type of thing, but just that it's so different from anything else that was available at that time really makes it stand out and makes it something that audiences take a great deal of pleasure in. So we have that kind of transgressive pleasure there. We go to a more modern media, a little more modern. Seinfeld is a great example of transgressive pleasure. It's hard to imagine that because it became such a jugger, not such a huge hit that it was so well-known. But at the beginning, they had trouble getting any episodes first it was just going to be one episode special, and then they gave them a couple more. They gave them like four episodes, and then it was eight, and then it was eventually it took off and found its footing. But the reason it was so slow going is that it was so different from anything else that was on TV at that time. It was just not like anything else. It was proudly a show about nothing. There was no purpose to the show. They had a whole episode. Well, half hour episode where they're doing nothing but waiting for a table at a Chinese restaurant. That's the whole episode and they're having conversations and it's funny and there's some comedy, you know, that type of thing. But really, the whole episode is just there's no purpose to it. There's nothing special going on. They're just waiting for a table at a Chinese restaurant. That's what made it so different. There was no larger theme. There was no real sense of major drama. There's no any of this kind of thing. So and there were never any very special episodes of Seinfeld's right. I mean, in that sense of the back in the eighties and nineties, there were lots of very special episodes, right? Even on comedies. They had these very special, very serious episodes. But not in Seinfeld. It was just very different and that made it a transgressive pleasure. It was just something that was, you know, so different from the norm. A little more. Currently, you can see that in the office, too. We're going to great detail on this, but but we see that very much so in the office. Again, from the slow start, it's slow to pick things up because it was so different.  You know, there were all these different questions that was so different and it's become very, very popular, obviously. But but it was a real transgressive pleasure, especially at that time when it first started in the United States and especially when it was the original British version was even more transgressive, obviously. So anyway, so we take pleasure when things are different, things are new, things are not what we expect from them. We also have this type of pleasure that comes from what we call productive pleasure. And these two things are not usually exclusive. Lots of times, things that are transgressive are also productive, but they don't have to be connected all the time. But productive pleasure has to do with this creation, this idea of creation, that we as an audience, especially with the technological means that are available to us in the new media era, we can be productive as well. We can be creators. We can be co-creators really and expand upon these things that we love and if we really have a piece that moves us, we can become a part of that by by creating alongside that piece. So one kind of easy example of seeing this as a fan fiction, you know, when fans pick up these storylines and we take these beloved characters and these stories and these familiar worlds and we create within them. Then we create our own things. We write stories about what if Harry Potter was a Jedi or what if Kirk and Spock were gay and a couple and, you know, all this kind of stuff and just all kinds of things that we can write. If we can imagine it, then we can set it out in this fan fiction that we can be productive. We can do some creation or maybe we're inspired by something that we see to create our own type of thing. One of the most famous examples of this is 50 Shades of Grey, obviously, actually, is started out as fan fiction for the Twilight series, you know, that the author, EL James, which is her pen name, EL James, started writing fan fiction based on the Twilight series. In fact, the original characters were based on characters from the Twilight series. And then as it grew and grew and popularity, you know, she changed the names and gave it a whole different world, so to speak, but really started out as fan fiction based on the Twilight series and then grew into this idea of 50 Shades of Grey over time and that kind of productive pleasure, this idea that we can be a part of something and we can create in that world, we can expand upon that world. That really excites us and brings the audience pleasure of that sort as well. There are two different kinds of really transgressive texts as well. When we think about transgressive texts and the categories there, the first is what we call a readerly text. A readerly text is, it's just, you know, it's the captain obvious of transgressive texts. A readerly texts are what they seem to be. There's not a whole lot of subtext there. Really, there's not a whole lot of subtlety going on. You know, the Jaws movies are about a shark trying to eat somebody, and so really it's about having the trap scared out of you, and liking that. I mean, that's what they're there for. That's what they're, there's no real subtlety or subtext behind the Friday the 13th movies, right? They're slasher movies, and that's what they're there for. And that's fine. There's, there are lots of movies and TV shows that are just very surface level, and that's what they are. That's what we call readerly text. When it's right there on the surface, and it's really obvious what that show is trying to accomplish or what they're trying to say or do. The other type of text though is what we call writerly texts, writerly texts, and these are texts and artifacts that are not so obvious, that may have a little more subtle message, may have some subtext going on, may engage the audience a little more in, in, you know, what is this saying? How do I interpret this? And how is this different from other people and the way that they're seeing it? What do I think that means? And these are the types of shows and articles and books and things that really develop those strong online communities where people are sharing ideas about, well, what do you suppose that meant? What do you think this means for the show or whatever? So just as an example, again, kind of contemporary media terms. And one of my favorite shows is 9-1-1, Love 9-1-1, I think is an awesome show. But, and it's pretty, there's not a lot that's, that's below the surface. I, I think it's well done. It's well acted, it's well shot. So I'm not criticizing the show. I really do enjoy it. It's one of my favorite shows, but it is what it is. It's a show about rescue attempts and people getting in the craziest situations, right?  It's something massive that's gone wrong and something spectacular and it is what it is. It's, it's there for your enjoyment to watch them try and get in out of these situations and it's, so it's action and it's, but it's right there. It's a readerly text. 9-1-1 is a readerly text. It just is what it is. As opposed to another show that we watch, my wife and I really enjoy, is The Handmaid's Tale. And if you're familiar with that, you know that it is very much a writerly text. There is so much there to try and interpret, to try and understand, to try and figure out what does that mean down to the idea of, you know, what are the different colors of cloaks mean? Why, why are the handmaids all wearing red, you know, and the, the, the, the wives of these, these men, the, the, the wealthier women are all wearing green and, you know, so there, I mean there's color coding obviously going on in this culture. What does that mean? What does that signify? What does it mean when this happens with the character? What are all kinds of discussion about, you know, what do you think that means? Or who's doing this? What's going to happen to this person? And what, you know, those types of things, that's a writerly text. It's not right there on the surface. There's, I mean there's plenty to enjoy right on the surface. But there's also a lot of ways to really dig into that and determine, you know, what's, not only what's this creator saying, what's the message of the show? What are they trying to convey with this? So there's a lot to be had there in terms of a writerly text in something like the Handmaid's Tale. So there are different types of transgressive text.  Every show exists kind of on this continuum of, you know, extremely readerly or extremely writerly and so forth. And so it just kind of depends on where it falls, I guess, in that situation. So those are some of the key premises. There's there's more to this, but but those are some of the key ideas here for understanding erotic analysis and really the idea of pleasure and how pleasure drives what we watch and how we watch it, how we interpret it. Some of the more common questions that we see in erotic analysis are things like in what ways does this artifact represent transgression in its historical context? Now remember, again, Seinfeld now and the office now are these huge hits. They set the stage that lots of shows are like that now, right? They're not. They're not going against the grains much. They're not stepping outside a convention as much now, but when they first started, they were. So we need to look at these things in context. So in the historical context of when that show first first appeared, first gained popularity and really was was at its peak. And what ways did it represent transgression? What ways did it go against the grain? What ways did it step outside of convention in that historical context? What's needed to consider? Is this artifact more readerly or writerly? Is there more to that beneath the surface? Is there or is it right there? Not a whole lot of guessing of what this shows trying to accomplish and what it's trying to do. And then why why do you say it's it's either readerly or writerly? What would lead you to that conclusion? How does the artifact invite productive interaction with this audience? Remember, production has to do with productive pleasure has to do with creation. So in what ways does this artifact get people moving in terms of creativity? How does it engage people? How do they notice are a lot of fan fictioners or cosplays? They're people showing up for conventions, those types of things. How does this artifact invite that kind of productive interaction? How does it encourage that? How does it help help help it manifest within its audience? And how does it take advantage of that? And then what evidence exists of transgressive and productive engagement on the part of the audience? So thinking about this strictly from the part of the audience, what do you see the audience doing? You know, and what ways are they engaging with this and interacting with the text itself? I hope this gives you a better understanding of what we mean by erotic analysis. Again, really didn't get into porn at all, do we? So erotic analysis has to do with pleasure. And I hope this gives you a new perspective on, again, just the impact that these things have on the audience and the response and the interaction that the audience can have with an artifact and the way that we can analyze that and consider that as a piece of our critical media studies. If you have questions about erotic analysis or anything related to critical media studies in general, please feel free to email me. Be happy to answer any questions that I can via email. In the meantime, I hope that you will get out there with your new understanding of erotic analysis, understanding that it's not a triple X feature necessarily, but it's just the idea of what is it about this that gives us pleasure? Why are people drawn to it? What pleasure do they take from it and provide as a result of this artifact? So I hope this helps you gain some perspective on that. And I hope that you go out there and have a new and enhanced appreciation for those types of things as we see them in our society.


One of the things to consider when you think about a stress-toned variety is that in the environment where you're targeting, the stress is not uniform. It's not going to be in every field or in every village. And so generally, when you have a new variety, that variety will be multiplied and disseminated over a particular area. And so ideally, you would like to have a variety that would grow well in the different conditions in that area, because the farmers who are growing it may have, they may have stress or they may not have stress. So that variety should have good agronomic characteristics. It should have high yield. It should have good quality. And in addition, it should fit into the cropping pattern. So once you have those conditions met, then you have the potential for a very successful variety. So what we'd like to do is build the stress tolerance into these kinds of varieties, so that even in the more unfavorable areas within a particular region, the farmers can still grow them and get a reasonable yield. And so in some areas you may have submergence. In some areas you may have risk of water stress. And in some areas you may have both that occur at different times of the season or over different seasons. So we think it's going to be useful to combine these various stresses together, appropriate for each location. There are a few examples where we have been able to combine, to some extent, the different stress tolerances. One of the early varieties that we developed with submergence tolerance was released in the Philippines as PSB RC68. It has some degree of drought tolerance also. And then we've developed, I would call them more like prototypes of varieties or breeding lines that combine drought tolerance with submergence tolerance and also salt tolerance and submergence tolerance. And it's generally relatively easy to combine submergence tolerance with these stress tolerances because it's a single gene trait and most of the tolerance comes from the sub one gene. And so you just need to introduce the sub one gene into those varieties and then they will combine the tolerances. There's also some speculation that the sub one gene itself could have a benefit on drought tolerance. For example, there was a paper that just came out this year in Plant Cell which indicates that the sub one gene may have a beneficial effect on drought tolerance. So it's certainly possible to combine multiple stresses and that's really one of the focuses we have now. The focus we have is to not only combine the different stress tolerances but to combine stress tolerance with other important traits like disease resistance. We haven't found anything like sub one, you know, the same level as sub one in other stresses. We found the, we will find genes that have moderate stress. Genes or QTLs, quantitative trait loci that have moderate stress tolerance and by combining several of them you can get a fairly good degree of stress tolerance. So one of the programs now is to introduce these kinds of genes for drought tolerance into widely grown varieties. And you know instead of introducing one sub one gene you have two or three drought tolerance genes that you're introducing.