For this What's Neat This Week, it's January. Happy New Year! In this episode, I start talking about soundtracks, decoders, and a feature inside of them called Dynamic Digital Exhaust, which is a really cool feature. I show how it works on the video with hill tests. Later on in the show, Jeff Meyer stops by with some gorgeous tangent. Illinois Central Golf Hopper City has just finished with his weathering effects, and he discusses with us and shows us how he achieved those effects. A little bit later in the show, I talk about my photographic props, my roller carts that I use and I put all the props on, whether it's other people's props or dioramas and things that I've finished. These things fit in the car, they're versatile, I discuss that a little bit, and at the very end of the show, I talk about weather, and that is what one-inch hail does to garden railroad track, and also what happens when you get six inches of rain and your house is not a boat. I literally, my layout got really wet that day. So enjoy the footage and the clips, a lot of high 8mm stuff this time. For this January, 2015, What's Neat This Week? For this segment of What's Neat This Week, I want to talk about soundtracks, digital decoders, and something inside them called Dynamic Digital Exhaust. Now, you may or may not know, the soundtracks and Blackstone models are one of my new accounts for the past, I want to say, past year, and I went kicking and screaming at the electronic stuff because A, I didn't understand it, but B, once I read the manuals, I completely understood it. I could not believe how simplistic it was, and there's a couple of features that I'm going to talk about over the next few months on my What's Neat This Week segments, and the one I'm going to talk about today, and the reason that I've got all these crazy hills that I've created in dual gauge and narrow gauge, is to demonstrate dynamic digital exhaust. And what that is, is when you adjust CV 177 through 188, and you kick in a little bit of delay, a little bit of CV 3 and 4, adjust though so that when you adjust the throttle, you've got a slower response, I call that delay. And what that allows you is that triggers what's already in all tsunami digital decoders, inner mountain steam, ather in steam locomotives, the narrow gauge Blackstone steam locomotives. This features already in the decoders, you don't know it because you've got to activate it, again by adjusting CVs 177 through 188, 3 and 4 with a little delay. And what you end up with is as the engines are going up the hill, they're lugging, they're chugging, they're making heavy exhaust sounds, and then as a crest to come over the other side of the hill, you hear a little rod clank, the chuff subsides, and it's all automatic because inside the decoder and inside the locomotive, it senses the load. And as you're going downhill, or you're coming to a stop, you get the brake squeal, you get the rod clank, it's an incredibly effective feature and I want to demonstrate it in this What's Neat this week with this upcoming video clip that really kind of shows you all the features. Sure can also be demonstrated on a short level track on your layout. As I give the locomotive some power with the throttle, you'll hear the locomotives labor with a deep chuff. Then as I back off the throttle, they'll get quieter and you'll hear the rod clank. Experiment with this, I think you'll find that this is going to make your locomotives brand new all over again. Hey, Ken, what are you doing? Well, I'm going to tell you, if you ever get into model railroad photography, you're going to find that you need photo props, you can set your dioramas on top of. Now for the last 15 years now, I've been using these wooden props that fit real well into my automobile. I can put anybody's diorama on top of them and then shoot their models live on location or shoot them here in my backyard. Today I'm refinishing them. You've got to do that about every two years, put a nice fresh coat of polyurethane on it just to keep the wood from rotting. This is one that I just finished yesterday. And as you can see, she's shiny, waterproof, and it's going to be good for another two years of use. So I suggest to you guys that you build something like this, because in the last 10 or 15 years, I've perfected the fact of taking these out, putting my models on them and shooting them. It works really well for me and it's going to work really good for you too. What are you shooting today, Jeff? Illinois Central, Illinois Central Golf, tangent hoppers that I finished a while back. Oh, these are tangent. These are very nice, aren't they? Yes, probably some of the best freight cars out there. I can see your oil paint weathering effects here. Yep. Weathering's pretty nice on this car. How did you get this darkened effect like this? Most of it started out with some oil paint washes and filters and then for some of the wavy panel grime effect, dry brushed on just a little bit of oil paint on your brush and kind of feather it out and blend it in to give it kind of where it's got the wavy panel, where the grime collects and the waves of the sheet panel on the hopper. It looks really good, man. Thanks for sharing it with us. Thank you. A segment of What's Neat this week, I want to discuss a new video that I have available at KenPatterson.com. It's building trestles and bridges and in this video, I discuss and show you the process of how I built Leitner trestle on the Rio Grande Southern, mile post 159, bridge 168. And this is the famous bridge where Bob Richardson shot number 464 running across it on one of its final runs plowing snow. So I will show you from start to finish how I built the bridge, went about building the diorama, building the road, scenery construction, talking about creeks, pouring creeks out of envirotex, talking about girder structure building and overall complete scenery. And then we go further and discuss how to wrap the diorama in black oak to make a flexible, movable section of your layout that's completely safe because you know if something like this flexes, the bridge is going to break into pieces. So watch this, look forward at KenPatterson.com, a video on building trestles. In large scale and HO scale, we cover an awful lot in an hour and five minutes on this new exciting video. So go check it out. For this portion of What's Neat, I want to bring you in from the very bottom floor of designing a photograph from the very start. That's the design, the concept, and then the final product. And I want to walk you through the construction. For this assignment, this is an athern project. Chris Palomeras at athern found this really cool photograph on the internet by Steve Patterson. And what it is, is it's a blur shot where somebody in a vehicle driving pacing alongside a DD-40 shot this incredible photograph, Steve Patterson shot this photograph, and it exemplifies power, it exemplifies, it shows speed, it shows movement. So how could we design a photograph like this for athern in the HO scale dimensions that we need in order to create the shot? We could use Photoshop and maybe go with the blur effect to get the blur of the grass effects. But that still means that we've got to design a scene that matches the prototype location exactly. That's easy because all the answers are in the photograph right before our eyes. My theory on designing something like this would simply to be design a double track mainline, put the locomotives on the back track, have the front track and the whole front foreground scene be movable. Maybe we can design it, spray some pledge on the foam, slide it while I shoot the photo and create the same movement effect. So let me think about this for a few hours and see if I can come up with a design concept and show you how it progresses. And this is the design of what I've come up with. What I've created here is a scene where the front portion like I said will slide. So while I'm shooting the photograph, I can take long exposures. It's a cloudy day shot that'll help me with the sliding movement to show it on film. So I'll slide this at various speeds and go through the photographs.  First, I experimented with foam and sliding sections just to see if the feasibility was doable.  The foam glue, they come out with a really nice nozzle to putting it down. And I glued all the sections down and then I weighted them. I put a lot of heavy weights on. This foam doesn't expand very much and it glued, the glue sets up in about two hours. So after all the weights set on it, I then started gluing down the track, experimenting with the sliding just to make sure everything worked out the way it was supposed to work out. Then I started carving the foam. I used a Stanley Schurf planer, the small handheld planer, and I used a large rasp to go through the contours and match the topography that was in the photograph and started and carved through the foam. Then what I wanted to do is create the grass effect. Use a good old fashioned fake fur. So I put the fake fur down and then what I did was I came along with hair clippers and I shaved and I broke up the fake fur so that it looked like individual weed tufts so that it would look really good for the blur shot. Then what I did was I sprayed it with some green paint. I used hunter green paint, just sprayed it out of the can, which works really well. Set it to dry for about three hours. And then what I did, I needed to build a road. I needed the road with the line in it. So I took patching cement and what I did was using a four inch trowel, I built, I formed on each side and poured the road about an eighth of an inch thick and then pulled it smooth with water and the putty knife, which makes for a great cement road using this latex cement patch mix.  And so this is the reels results that I've come up with. So let's see what happens next during the photo shoot. Here we are at shoot day. This is when all the efforts come down to just one moment. This is where it all counts. So we've got our scene setup that I designed out of foam. It's all set up now so that while I'm shooting the photograph, this is going to slide and allow me to create the effect of blur, which is what we're after. Plus the benefit is the prototype shot was shot during a cloudy day. I've got great clouds today. I never imagined the time that I would call clouds great. I always want sunshine for my shots. But in this case, in order to create the mood and atmosphere for the photograph, and one other thing is because it's cloudy and it's a little bit darker, I can shoot longer exposures. So I'm going to be shooting exposures of exactly one second, and then I'm going to try one and a quarter second long exposures while I'm moving this. So that means I'll just move it about a sixteenth of an inch to an eighth of an inch while the shutter is open, which should give me just the right amount of blur to look good in the photograph. So let's see how this turns out. Okay, what I'm doing is I'm sliding this, like I said, and I'm shooting one half to 1.3 second exposures on this. And let's just see how this turns out right now. Let's do this for real. I didn't move it that time. Here we go. We're sliding it. I'm shooting shots while it's moving. Everything's set up. This should work out really well. Not very complicated. The telephone pole right there should look good. The rarotide should look blurred. The grass should look blurred. And I've got plenty, plenty of shots here. All right, one more time and I think we're done. And that's it. I figure I'm going to give this to Chris Palomar. Is it athern? He'll add a little bit of smoke, maybe a little bit of lighting effects, and we should have one really interesting photograph to share with everybody. So let me show you now this is how the photograph came out. See the shot? It matches the prototype shot. It's got the blur effect in it. I'm very satisfied with the results on this. Chris Palomar is, in fact, did add the smoke. He did add the running lights to the truck and just kind of tweak the color a little bit in the photograph to add a little bit more yellow to the gray skies that I've got right now. So thank you very much for watching this. What's neat this week? Photographic tip for this month of January. It's nothing like a great storm for the grass in the summertime to help cool things down. But one time, there was an area where it rained just over an area of, I want to say, from where I live, maybe a mile and a half in all directions, and it rained, and it rained, and the storms kept training and building right above where I lived. And what ended up happening was, even though I live on the very top of the hill, somehow with about six inches of rain that we got within that hour and a half period of time, railroad tracks washed out down below, the cliff washed out in 33 places between here and Peaveley, Missouri, just down to the Soto sub, and my layout inside was absolutely unindated with water. Let me show you a video clip of the scenario and sort of how it went down. I know that looks crazy, and that was a lot of water coming in here, but I'm happy to say it didn't do any damage to the layout, partially I believe because everything's sealed with polyurethane, and underneath everything's held up with metal studs, so no damage from that little episode of water, and it's never happened again. One thing that I do remember was another weather event, and that's hail. Hail one time, golf ball size, the great big stuff, took out 50% of the railroad ties in the garden railroad in the backyard. Let me show you that real quick clip. Twice real hard. And what hail does to garden railroad track is as it impacts it, it just breaks the spikes right off. So I lost about 200 feet of track outside that afternoon of 400 that's out there, so I lost half of it, and what I say when I lost it, what I mean is the ties were broken off the rail, and what I had to do is get new ties, six inch sections, and just simply re-slide them on to the six foot pieces of track that are flex track that's out there. So not too bad. I appreciate, I apologize for the lack of quality of the weather footage because this is all high eight material that I was able to capture. The hail storm took place in 2003, and in 2009 is when this place flooded out the way it did. So appreciate high definition with this next clip that I'm working on a sunrise shot to end this January's What's Neat This Week. I hope winter is being good to you wherever it is you are.


All right, those of you who are here, if you can settle down in your seats, please. So, before the break, we very, very briefly summarized Chapter 4 and looked at the story of Deborah and Parak. But just to actually look at those verses, you know, in a slightly greater detail. So, if we were to turn to Judges Chapter 4, and if we were to look at verse 3, that is where it explains to us that the commander of the Canaanite army, his name is Cisera. And it says over there that he had 900 chariots pitted with iron. And we see this mentioned in other places in the Book of Judges where it talks about chariots made of iron. Up to that time, they only had the wooden chariots and, you know, with wear and tear because they are made of wood. Even the wheels, you know, would be made of wood. You would not exactly have rubber tires and all of that because, you know, those things were not created at that time, invented at that time. So, the chariots were not very fast, very efficient. But once people began discovered iron and once they started using iron for their weapons, you know, it advanced their entire warfare. It took it up to a higher level. So, now they would fit the wheels with iron, you know, as a framework around the wood. So, now those chariots would be able to move faster. And so, all the foot soldiers who are on foot would be at a great disadvantage. And if you notice, the Israelites did not have any chariots with them. So, they were all literally infantry. They were, you know, on foot. So, whenever they had to face this iron chariots, it was more difficult for them. They would be more afraid, but God said that He would be with them. So, now again, it's a step of faith which they need to take. And so here, Deborah comes to Barak and says, the Lord has commanded this. That would be in chapter 4 verses 6 and 7. She says, the Lord, the God of Israel commands you. Go, take with you 10,000 men of Naftali and Zebulun and no lead them to that particular mountain near the river. So, it is the command that she delivers from the Lord. So, this was not just a suggestion. The Lord Himself wanted Barak, the judge, to go and bring judgment upon these Canaanite people. But Barak was afraid to do that and he says, if you come along with me, then I will go. Otherwise, I will not go is what he says. And so in verse 8, you know, Deborah says, no honor will come to you from this conquest. And in verses 14 and 15 is where we see what God does. So, if we can have someone read out for us, judges chapter 4 verses 14 and 15, please. Judges chapter 4 verses 14 and 15. Yeah, even if you don't have the mic, if anyone is willing to read, go ahead. The people online also have their Bibles, so they also will be able to follow it. If we can have someone read out over here. It doesn't matter whether you have the mic, don't have the mic. If you can just read out, please. Am I right, sister? Judges chapter 4 verses 14. Then Deborah says to Barak. Can you hear, sister? I want to read. Yeah, the audio was not very clear. So, okay, maybe you can read out the next verse. I mean, the next verse, which we require. Thanks. Yeah, there was a little problem with the audio, but it finally actually came through. So, yeah, the next verse that needs to be read out. You know, maybe you could do that for us. Thanks. Thanks a lot, Gerdrud. So, yeah, here we see in verses 14 and 15, judges chapter 4 verses 14 and 15. It says, has not the Lord gone ahead of you? So, it's not like as if Barak is being sent alone by himself. The Lord has gone ahead of him. Whenever there is a conquest, whenever there is warfare, whenever you're facing a situation where you feel the odds are rather high, you feel that you will not be able to gain victory. The point, the script, the spiritual point that this passage is making is that the Lord has gone ahead of you. He has gone before you. You are just following behind him. So, he will take care of the details. He will ensure the victory.  So, it says the Lord has gone ahead of you. And when they reach that place, when they reach the Kishan River, God has already made arrangements for the defeat of the enemy. Barak did not know the details. Barak was just asked to step out in faith. But God had already arranged for a mudslide. Who knows how many days before that? You know, already somewhere higher up in the valley, the river has been blocked. So, there has been some kind of a mudslide in the catchment area higher up of this particular river Kishan. So, now at this point of time, when Barak and his soldiers arrive at that place and there are 900 chariots waiting for them in that place, you know. And Cesare and his army are very confident that they will have victory. Because they are the ones with the chariots.  So, they believe that the victory is guaranteed.  So, once that mudslide is released, once that mud clears up, all the water which is collected over there comes gushing down with great force. So, what do you think would have happened when it reaches this point, you know, near the foot of Mount Taber where all the where the two armies are facing each other. All the waters come rushing down. And so, the waters would have spilled the banks and would have flooded the entire area. And so, because of that, these heavy iron chariots get stuck in the mud. And it says over there that, you know, Cesare, he gets down and he starts running away on foot is what it says in verse 15. It says, Cesare got down from his chariot and fled on foot. A powerful commander is reduced to that condition. God took care of the details. So, Baruch should not have been in fear. He should have obeyed right in the beginning and said, yes, I will lead. He should not have said to Deborah, oh, if you come, then I will go. Otherwise, I'm not sure if I want to go. All of that was a lack of faith.  But because of his lack of faith, we see that it's a lady. We see that later on in verses 17 and 18, you know, he goes to that tent and it's that lady who kills Cesare. So, the details regarding the flood are not mentioned over here in your chapter four. We only get to know about this in chapter five, in verse 21 where it says, the river Kishon swept them away. The age old river, the river Kishon, march on my soul, be strong. So, the Baruch and Deborah sing a song of deliverance in chapter five. And in the song, we have this detail being mentioned that God used the river Kishon to cause a flood to defeat the enemy. So, in the book of Joshua and also here in the book of Judges, we see that whenever the people place their faith in the Lord and obey Him, you know, with submission, then He can do any miracle. And the same applies even to us today because the character of our God, the power of our God has not changed at all. So, the kind of miracles we experience today may be different. You know, at that time, their technology was at a different level. Their culture was different. So, He worked among them in a particular way. Today, He may not bring floods. Today, He may not operate in the same manner. Today, there would be miracles of a different kind. But when God's people step out in faith in obedience and submission, then God can cause any miracle to take place because He has no limitations. So, even though such a beautiful deliverance takes place, Baruch gets no honour out of it due to his lack of faith. That should not happen to us. If we poorly go out and do what the Lord says, then the Lord will see to it that we are honoured. The Lord will lift us up because we placed our faith in Him. So, we should not be living in fear as Baruch did. So, that is the lesson that comes through from this particular passage. So, we could just dwell on a few incidents which took place in the book of Joshua. And we could just maybe look at a couple of incidents which took place in the book of Judges. Moving into the third historical book which would be the book of Ruth. Now, why is the book of Ruth mentioned directly after the book of Judges? Because they belong to the same time period. This whole story of Ruth takes place during the time of the Judges which is why this particular story has been placed here in our English Bibles. So, in Judges chapter 3 verses 12 to 30, we get to know something about the Judge Ehud. You know, where we are told that Ehud defeats the King of Moab. So, at that point of time in chapter 3, Judges chapter 3, this is the background that we are looking at of the book of Ruth. So, if you want to know the background of the book of Ruth, you would look in the book of Judges. You would look at chapter 3. You would look at the verses 12 to 30 which talk about what took place in the land of Moab. We see that the Moabites have placed the Israelites under captivity. They're attacking them. They're destroying their property. They're doing all of that.  And we see in verses 29 and 30, Judges chapter 3 verses 29 and 30. Maybe we can have someone read out that. So, yeah, maybe we could have Gertrude read out that. Judges chapter 3, 29 and 30. Yeah, go ahead Gertrude. Which one, sister? Judges. Judges chapter 3 verses 29 and 30. Okay. And at that time they killed about 10,000 men of Moab. All stout men of Valar, not a man expected. So, Moab was subdued that day under the hand of Israel and the land had rest for 80 years. So, we see here that for 80 years, there's peace established in the land of Israel and peaceful relationships are there between Moab and Israel. So, around that time they say is when the famine takes place. So, there's a great famine in the land of Israel. But at that point of time, it's no longer under the subjection of the Moabites. And so, they say that this is the background for the book of Ruth. A man named Elimelek takes his wife Naomi and takes his two sons and they want to escape from the famine which is there in the land of Israel. And so, they choose to go and settle down in Moab during these 80 years when there is a time of peace between Moab and Israel. Now, would God have approved of Elimelek's decision to take his family to leave Bethlehem and go to Moab? Most probably not because this is what God says regarding the Ammonites and the Moabites in Eutronomy chapter 23 verses 3 to 6. So, if we can have someone read out for us, Eutronomy chapter 23 verses 3 to 6. Eutronomy 23 verses 3 to 6. If someone can read out. An Ammonite or Moabat shall not enter the assembly of the Lord. Even to the 10th generation, none of his descendants shall enter the assembly of the Lord forever because they did not meet you with bread and water on the road when you came out of Egypt and because they heard here against you, Balaam, the son of Bohr from Bethlehem of Mesopotamia because you nevertheless the Lord your God would not listen to Balaam but the Lord your God turned the curse into a blessing for you because the Lord your God loves you. You shall not seek their peace nor their prosperity all your days forever. The Lord is very clear in his instructions regarding the Ammonites and the Moabites. He says in verse 6, do not seek a treaty of friendship with them as long as you live because of the way they have treated Israel. When the Israelites requested that they would peacefully go through their territory and they just want to use the road the highway they refuse to do that and also they tried to hire a prophet to bring curses upon the Israelites because of all of these things which they have done. The Lord says do not have any friendship with them. So when Elimelek makes this decision to take his family from the land of Bethlehem and go and settle down in Moab, he is directly going against the will of God. This is not something that he is doing with the Lord's blessings because why we see again and again in the book of Judges it says there was no king at that time and the people did whatever they wanted what they felt was right in their own eyes because at least if a king was there the king maybe would have imposed the law of God upon them and said you must keep the law of God and because there was no one in authority to control them and make them follow the laws of God the people did whatever was pleasing in their own eyes and so Elimelek decides that he's going to take his family of all places to the land of Moab when God said do not even have any friendship with them he takes his family and goes and settles down over there and he goes one step further he gets his sons married to Moabite women is what he does and so obviously the covering of God the protection of God was not upon his family and we see that Elimelek dies both his sons die and now we have Naomi and the two daughters in law left and all three of them are now widows so good things do not happen when we deliberately go against the Lord's wishes and make our own decisions according to what is right in our eyes so we need to ask the question is it right in God's eyes does he approve of this decision which I wish to take regarding my family so we need to place the Lord's wishes first so this is the background of the book of Ruth and the highlight that we see in the book of Ruth is that in this time of judges where an entire nation of Israelites are living in utter faithlessness no loyalty to the Lord no love for God no mercy or kindness towards their own people you know when you look at Judges Chapter 17 up towards 21 the horrible stories recorded there no mercy towards their own people that is the kind of Israelite nation that we see in the book of Judges in the middle of all of this unfaithfulness we see a cursed morbidness coming and showing them how a person should live so it's very ironical a woman who is not even you know who is part of a nation that God has condemned she rises up and she presents an example of what loyalty should look like what faithfulness should look like so there is a contrast drawn between the book of Judges in which people of God are living in horrible disloyalty and the contrast is with the book of Ruth where an outsider someone who has been placed under God's curse she chooses to take a stand and she presents a different picture and she teaches the Israelites what loyalty should look like so we see a lot of irony in this in the way God you know brings out this story of this woman so Ruth chooses to show faithfulness in a time when nobody even understood what faithfulness and loyalty was so if you were to look very briefly at the structure of this book we only have four chapters so chapter one gives us the background we get to know that all the husband and his two sons are now dead so we have the three widows who are left so Naomi gives permission to her daughters in law to go back to their hometowns to get remarried and have families of their own because now she has nothing to offer them so she is willing to come back to Bethlehem alone by herself even though she has no help no support, nothing so one of the daughters in law says alright I will go back because if she comes over here to the land of Israel she knows that she is not going to be received well she is a Moabite test, remember who she is and the Israelites have no respect for the Moabites so if she comes over here she will not know the language she will have to learn the language and she is not going to be respected so she decides to go back home Ruth on the other hand she looks at this old lady and she thinks if I to go away who will look after her who will be there for her so Ruth says I choose to come along with you and even though I am a Moabite I will make your people my people I will make your God my God even though God has spoken against that nation and so because of the stand which this lady takes God makes an exception for her and in fact we go on to see what a huge exception God makes for her because God what did he say in Deuteronomy in the passage that we read he said up to the 10th generation these people will not even come near my tabernacle they are unacceptable and who is the man who becomes a king and a priest David who is a descendant of this Ruth he is what 4th generation he is not 11th generation God says up to the 10th generation I don't want any of them even coming near my temple and a 4th generation man he goes on to become a king and a priest to serve the almighty God and 5th generation Solomon literally builds the temple for the Lord this is the way the Lord looks upon those who have a heart to be loyal and faithful and choose to place themselves under him what a contrast between the faithless Israelites of the Book of Judges and this outsider who owes nothing to Naomi but chooses just out of the kindness of her heart to stay loyal so it's a beautiful contrast that is drawn between these two books in chapter 2 we see that she goes to the field of Boaz and starts collecting the grain which is over there because again that we are told in the Book of Deutronomy and also Numbers where it says when you people at harvest time when you are gathering all your crop and getting it ready to sell and all of that don't take every bit of the crop leave some of it over there in the fields so that the poorest of the poor they can come over there and at least take that to their homes and have food to eat so it's a commandment which the Lord gives don't pluck up every single bit of grain leave some of it in the field so that the poor people can come and take it to their homes so that they can feed themselves so when Naomi and her daughter-in-law come back over here they are in that category the poorest of the poor they have no territory they have no money they have nothing so she says to her daughter-in-law our relative is Boaz so maybe he will show you kindness so why don't you go to his fields and glean the wheat from glean the grain from his fields so which is what we see in chapter 2 chapter 3 is where Naomi tells Ruth to go and request Boaz to become a kinsman redeemer so we will look a little bit at those details later and in chapter 4 of course they get married and you have Obed being born so he becomes the grandfather of David so these are the 4 chapters so let's understand what this whole concept of kinsman redeemer is all about I think for us to understand this we would have to go back to Deuteronomy chapter 25 and we have a lot of verses but it gives us a very clear picture of what exactly happened in the story of Ruth so for us to understand that we need to look at this passage Deuteronomy chapter 25 verses 5 to 10 so if we can have someone read out Deuteronomy chapter 25 from verse 5 all the way up to verse 10 please concentrate even as we are reading because you will understand the background of this whole kinsman redeemer concept someone can read out Deuteronomy 25 5 to 10 if brothers go together and one of them dies and has no son the widow of the dead man shall not be married to a stranger outside the family her husband's brother shall go into her take her as his wife and perform the duty of her husband's brother to her and it shall be that the first born son which she bears will succeed to the name of his dead brother that his name may not be blotted out of Israel but if the man does not want to take his brother's wife then let his brother's wife go up to the gate of the elders and say my husband's brother refused to raise up a name of his brother in Israel he will not perform the duty of my brother's husband's brother then the elders of his city shall call him and speak to him but if he stands firm and says I do not want to take her then his brother's wife shall come to him in the presence of the elders remove his sandals from his foot split in his face and answer and say so shall it be done to the man who will not build up his brother's house and his name shall be called in Israel the house of him who had his sandals removed okay so the property in the promised land was given by God as a divine inheritance to the Israelites and each tribe was given a certain territory and told this is yours I Yahweh is giving this to you you know so the land was valuable in God's eyes so each tribe was supposed to hold on and preserve the land which has been given to them so the people who are living the families of each tribe which are living in their territories if somebody dies then the property of the dead man will just go off to the brothers so what will happen in the title deed in future generations the name of the original holder of the land will no longer be there now the other living brother who has taken over the land his name will start coming over there but the Lord wants each family to continue having its own property which has been divinely gifted to them and so the Lord says if one of the brothers dies don't just let his name be wiped out you know some one of the living brothers must marry her the widow and the child that is born then this property will now go to that child and the child will carry on the name of the original holder of the land so that in the title deeds the name of the original holder of the land will continue so it's like a divine duty that God is placing upon the the living surviving brothers what is the disadvantage for these living brothers you see what would happen is if they don't put the property in their own name rather if they continue to allow the property to be in the name of the brother the future descendants will not gain so this living brother will invest in the land he is the one who will provide the fertilizers he is the one who will provide the cattle you know to do the to plow the land and all of that he's investing a lot into that land but it's not going to be in his name it's going to be in the name of the dead brother so in a way it's financially not very profitable so so some you know like it says over here in this Deuteronomy passage a brother living brother may say no no I don't want this responsibility you know I want the land but I don't want to marry the widow and then you know it will no longer be the property will not be in my name I am the one who's buying it but it will no longer be in my name and it will continue in the name of the other brother so if someone says that it says in the Deuteronomy passage the widow actually has the right it says first that the elders will try to persuade the man and tell him this is your responsibility this is something you should do God wants you to fulfill this but if the man still refuses and it says that this widow has the right to actually go over there it says that she can take the sandal off his foot and spit in his face and say this is what is done to the man who will not build up his brother's family line and there's a negative name that is given to that entire man's family it says he will be known in Israel as the family of the unsand sandaled this was a kind of symbolic thing if he has fulfilled his responsibility it's like he has both his sandals he's done something honourable but if he has failed to fulfill his responsibility it's like his sandal has been removed he has lost his honour now all of this background becomes important when you are trying to understand the story of Ruth because that's exactly what happens in the story of Ruth so we know in the story of Ruth in chapter 3 Naomi says to Ruth you know this Boaz is showing kindness so maybe he will be willing to redeem the property which my husband had lost when Elimelech was leaving Bethlehem and going away to Moab he would have sold the land to somebody and with that money they would have gone and settled down in Moab so now the property is no longer in their family anymore so her hope is that Boaz will buy that land put it in the name of her dead son and continue fulfilling the responsibility that is her hope so but she's not very sure whether Boaz will say yes or not because Boaz is a wealthy man he's got enough fields will he be willing to take on this responsibility buy the land from whom you know to whomever they had sold it buy it back from that person invest in it and not put his name on the title deed will he be willing to do all of that so she comes up with a very very unpleasant scheme she says in the night time when he's sleeping over there in the warehouse that's basically the harvest season so all the crops will be piled up over there all the grain will be piled up over there so he probably would go and sleep over there to guard the grain so she says when he's sleeping over there you go over there and sleep because then when he gets up in the morning and sees her over there he may feel kindness in his heart he'll not want her name to be disgraced so then he'll be willing to marry her so she's coming up with this very very disgusting scheme actually instead of that if she had just honorably decently gone up to Boaz and opened her mouth and said we want you to be the kinsman redeemer I'm sure Boaz would have said yes there was no need for her to try this very unpleasant scheme to pressurize him into saying yes in fact when Boaz sees her lying over there he's shocked and he says before any of the others see you go back home which is when she opens her mouth and says please we want you to be the kinsman redeemer are you willing to take this step for us and this is what he says to her in chapter 3 he says what an honorable woman you are he says that once earlier to her in chapter 2 he says you came back over here and now you're looking after your mother in law what an honorable person you are he praises her in chapter 2 and he says the same thing in chapter 3 he says I'm an old man now and you're willing to marry an old man just to do this for your mother in law what an honorable person you are and he says there is a younger person someone who is a closer relative than me he should actually be fulfilling this responsibility so it would be good to know if she can marry a younger person rather than marry an old man in this case I will go speak to this kinsman redeemer and if he is willing to do it good but if he refuses then I will take up the responsibility I will help you regarding this matter so we see all of those things happening in your chapter 4 of this book of Ruth where Boaz goes to the elders who are sitting at the town gate and he calls this man who is the closest relative and he says to him see this property was sold by Elimelech to some person and now are you willing to buy it back are you willing to redeem the land and the man is very happy I mean he doesn't mind so he says yes yes I am willing and then Boaz says but one condition you will also have to marry the widow of you know Mahalon Mahalon is the son so if he marries the widow then that property will no longer be in his name it will come into the name of Mahalon so he will his descendants will not gain from that property so when he hears this condition being put so in verses in chapter 4 in verse 4 he says I will redeem it so Boaz says to him if you will redeem it do so but if you will not tell me so I will know for no one has the right to do it except you and I am next in line and the man says I will redeem it then in the next sentence in verse 5 Boaz says then in that case you must also marry the widow and then once he hears that this is what the man replies he says in chapter 4 verse 6 he says then I can't redeem it because I might endanger my own estate you redeem it yourself I cannot do it is what he says because he is going to be investing a lot into this land but he is not going to gain his descendants are not going to gain anything out of it so he says no I don't want to do it so then Boaz you know honorably steps forward and he says yes I will do it so he takes on the responsibility and look at the outcome of that when we look at the genealogy which is mentioned later in the genealogy technically speaking it should say that obey when the child obey this born in the genealogy it should be written son of Mahalon because you see this marriage is being done to continue to extend the name of Mahalon but God makes an exception over here he decides to put Boaz name directly over there so over there in the genealogy it does not read as obey the son of Mahalon rather it directly says obey the son of Boaz so God so you see two things God is doing first he made a commandment regarding the Moabites and he decides to go back on that you know make an exception for Ruth and her family and now again we see God making another exception the name of Mahalon should have continued but because of the honorable manner in which Boaz you know chooses to become kinsman redeemer his name is put in the genealogy rather than Mahalon's name and the child which is born is called son of Boaz rather than being called son of Mahalon so what lessons come across from this when a person chooses to honor God even in normal earthly you know things over here there is no spiritual war being fought there is no great religious ceremony being conducted normal everyday things buying off land helping a widow showing kindness to someone who doesn't have anything in their hand very normal everyday activities are going on but there is a God watching from above and when he sees the conduct of these two people Boaz who is honorable in the way he treats these two widows and Ruth in the way she treats her mother-in-law very small incidents these are not great warriors who went into battle and did great things they did something very ordinary most people would not even have observed what they did but God noticed he completely changed their history their entire future was changed because of the heart which they had so imagine the value of the little decisions that we take in ordinary things there will be great battles of course which we will face and you know we will go out in the name of the Lord and conquer those but everyday things also matter the Lord was watching the heart of Ruth the Lord who saw how Boaz showed honor and kindness and help you know when that other kinsman redeemer was not willing to do his duty the Lord observed all these things and the Lord lifted up these people high very very high so that even up to this day their names are remembered their names are known that man who said no I don't want to take up our duty his name is not even mentioned we don't even know who he is he just passed into history nothing great happened to him or his descendants on the other hand Ruth's lineage or Moabites from her lineage come the people who actually honor the temple build the temple and God chooses to attach his name to such people because when you come down to it David is half Israelite but is half Moabite and the beauty of you know we see of how God looks at the heart so which is why this should remind us of that Jeremiah passage you know where the Lord says look you are like the clay you know in the potter's hand and if I have declared judgment against you but if you repent and you change your ways and you turn to me I the potter can use this clay instead of making it a vessel of judgment I can make it into a vessel of blessing and bless you so we all are like the clay in God's hands and these little little decisions that we take regarding how we treat the people whom we know the loyalty and the kindness that we show God is looking at that and so even if judgment has been spoken upon us God will say I will change my mind and rather than bring brought upon you I will bring blessing upon you and that is what we see happening to Ruth. Ruth was clay in his hands and judgment was spoken upon her and her entire nation of Moab but because of the heart which she had God changes his mind regarding her and uses her lineage to bring out his Messiah I mean the ultimate honor was given to this outsider to this Moabite person so let us be very aware that we are clay in his hands and he is watching to see how this clay will behave how are we going to be living in a way that honors God in small things nobody in the world will care what you are doing to your mother in law but the Lord who is watching he cares for him it matters nobody will care whether one field got sold or not but God is watching he saw Boaz honorable attitude in helping these two widows and in purchasing the land and so God puts his name in the genealogy not Mahalon's name and so we see all these out workings of God's you know glory in the middle of this judges period where people filled with disloyalty and unfaithfulness and here you have two people shining examples of what loyalty should look like Boaz and Ruth we see the story of these two people so that would be the main learning that comes out from this book of Ruth and so we have this very superficial interpretation of the book of Ruth where they say oh Ruth this is a love story this is a love story but it's not about the old Boaz and Ruth this is the love story of the love shown towards a widow named Naomi she says my name is supposed to mean pleasantness now there's no pleasantness left in my life all I have is empty hands there's nothing in my hands is what she says in chapter one so she says call me bitterness from now on and Ruth shows kindness love and loyalty towards this widow and Boaz does the same thing so yes it is a love story but it's a story of the love and loyalty shown towards a widow who comes back to her to her nation with nothing empty hands you know and her husband is dead her sons are dead and we see faithfulness being shown towards her and God rewards the people who show this kindness so which is why the term kinsman redeemer is also used for Christ so in the same way Boaz even though he did not need to he chooses to redeem that land and marry Ruth because in the same way she is willing to be a redeemer they use this as an example of Christ and they say that Boaz is a shadow is a representation of what Jesus Christ will do one day where he will redeem people who are not really deserving it technically Naomi did not deserve all the kindness she and her husband went against God's instructions and went to Moab got their children married off to Moabites did all of that so even though they did not deserve it Boaz shows kindness and redeems in the same way we have Christ coming to sinners and even though we do not deserve it he chooses to redeem us so these are all the learnings which come out of the book of Ruth so if there are any questions we can cover those if someone wants to post something in the chat a question we can address that otherwise we will just close with the word of prayer that's it I hope you guys were listening so anyway let's close with the word of prayer Lord we just thank you so much for the lessons spiritual lessons that we could learn from these three historical books Joshua, Judges and Ruth Lord we saw in all of these three books that people even though they were put in tough situations when they chose to submit to you and obey you trustingly then the most impossible miracles happened for them because nothing is impossible for you so we pray oh lord that you would help us to live our Christian walk in the same way no matter how difficult or unpleasant a situation is help us a lot to be people who will humbly obey you submit to you trust in you so that you can make the most extraordinary miracles happen for us we ask that you would prepare our hearts and change us transform us into that kind of a people oh lord thank you lord in Jesus name amen all right we will continue next week those who are in the class you can go ahead and leave there is a person Jairam who has lifted a hand so if you have a question maybe you can ask your question quickly if you have raised your hand to ask a question you can unmute yourself and I will address this those of you who are leaving if you can do it quietly please so that I can concentrate here yeah please go ahead brother if you have a question if you have raised a hand for a question no maybe okay maybe it's just accidentally raised fine all right


Good morning everyone. Welcome to Grand Rounds today. If you don't mind going ahead and having a seat. We'll go ahead and get started. I'm very pleased to introduce one of our retina surgeons. With us today we'll be speaking Dr. Hartnett and this should be a very interesting topic for us all. I think it would be a great review for the residents as well. Should be talking about retinopathy of prematurity from both the clinical and laboratory aspect. Thank you, Kenden. All right. So I have no relevant financial disclosures and I may be discussing about a baston as it relates to a new clinical trial. So in this talk I'd like to first give a definition on how we classify and manage retinopathy of prematurity and then discuss a little bit about how we've come to recognize that ROP is really a complex disease having environmental genetic and perhaps epigenetic associations. And then I'm going to discuss a little bit about research findings in our laboratory and end with a new clinical trial that's combining pediatric ophthalmology and pediatric retina in a multi-center fashion. So retinopathy of prematurity is one of the leading causes of childhood blindness worldwide. It only occurs in preterm infants. Full term infants do not develop ROP although there are conditions that look like ROP in full term infants like familial exudative vitriol retinopathy. It's thought that in the United States about 16,000 preterm infants develop ROP yearly and even with our management strategies the numbers are still similar that approximately 550 still become blind. Our goal is to prevent stage 5 ROP or total retinal detachment and this is a picture of an eye with stage 5 ROP so here's the iris and the posterior synechia and although it looks like there's a cataract the lens is clear it's that there's a retrolental fibrous membrane behind which is a total retinal detachment. So first classification how do we classify ROP? So based on a number of studies mainly the international classification of retinopathy of prematurity we use several parameters the zone, the stage, the presence of plus disease and in the past the extent of stage although that's become less important with time. So the zone it gives an idea of I think of it as how mature the retinal vascular development has become. Vessels start to pour out or precursors develop into vessels from the optic nerve at about 16 weeks gestation and then move out toward the auricirata. So zone 1 is considered a circle centered around on the optic nerve and the radius is twice the distance between the optic nerve and the macula. Zone 2 is also centered on the optic nerve a circle the radius of which is the distance from the optic nerve to the nasal auricirata and zone 3 is the temporal crescent. The stages of ROP are how severe it is and it's really usually we think of it as the appearance between the vascular and avascular retina.  Stage 2 we see some volume developing along that line avascular retina peripherally. Stage 3 we have this blood vessel growth into the vitreous into vitreous neovascularization and stage 4 can be partial retinal detachment either involving the fovea in stage 4b or missing the fovea in stage 4a. And as I mentioned stage 5 was total retinal detachment. Now I wanted to put this slide up to discuss the differences we often hear about animal models of retinopathy prematurity and then human retinopathy prematurity the animal models are all limited. First of all they're not in preterm infants are preterm animals they're in full term animals and none of the animal models develop what we see in stage 4 stage 5 retinopathy prematurity. So in the human we really think of two phases we have this vascular phase where we have severe retinopathy prematurity we have blood vessel growth into the vitreous we have something called plus disease which is a dilation and tortuosity of the vessels currently that's a qualitative assessment based on our memory of an image from multicenter clinical trials as to whether or not the severity of dilation and tortuosity makes true plus disease. So this is what most of the animal models mimic and we rarely get into the fibrovascular form of ROP where the blood vessels start to play less of a role and we start to see vitreous membranes and pre-retinal membranes that cause traction on the retina and pull the retinal off into retinal detachment and that's shown here in stage 4 ROP. So the fibrovascular phase we really don't have any way of modeling that in animals and so most of what we know is based on our experience in human infants. So we have the stages and I think back on the first slide where I was showing the stages I presented the four stages. Stage 4 ROP is when the fibrovascular phase starts where retinal detachment occurs and this just gives an idea of what actually occurs because we often look at images like this. This is a red cam image of an infant eye showing some dilation and tortuosity of the veins. The veins being pulled to this elevated area. This is actually retina that's pulled up into a fold and this white area is fibrous tissue. So a cross section might look like this. So we see how the fibrous membranes pull the retina off and how we know when we're looking at a flat two dimensional image is that the vessels around the optic nerve appear out of focus when we're focused on the fibrous membrane here. And then stage 5 ROP as I mentioned which is total retinal detachment. So here is an example this is the example I showed in the first slide the white membrane behind which is a total retinal detachment. So this would be if we were to take a ultrasound through the eye or could look through the eye with X-ray vision this is kind of what we would see. So a total retinal detachment and even with the ability to reattach the retina surgically the visual acuity in these infants is often very poor. You know less than 2200 less than legal blindness and so we do everything possible to try to prevent this. So what is our current management of retinopathy of prematurity? So retinopathy of prematurity as I said develops only in preterm infants it develops after birth. And there are certain characteristics that put a preterm infant at greater risk of developing severe ROP. In the United States based on a number of studies we found that infants born less than or equal to 1500 grams or less than or equal 30 weeks gestation are the ones at high risk for developing some ROP. Also any infants that fall outside these parameters but have an unstable course. So basically anyone that the neonatologist feel are at risk either high oxygen, not feeding well, lots of infections. Any time that there's an infant that there's some concern about poor postnatal waking we will take a look and screen these infants. ROP develops after birth and we don't have any symptoms from the preterm infant to clue us in to look at their eyes. So we automatically do examinations at between four to six weeks chronologic age or 31 weeks post menstrual age and the post menstrual age is the sum of the chronologic and gestational age in weeks. So for example if you had a 24 week gestational age baby who is about four months old or 16 weeks gestation that baby would be 40 weeks post menstrual age. So when you say the first exam is four to six weeks chronologic or 31 weeks well which is it? It's the older of the two. So if you had a 23 week gestational age baby who is six weeks old so therefore 29 weeks post menstrual age you would wait in additional two weeks to examine that baby and all this is based on studies and information that we've gotten from multi center trials. Now these parameters differ in other areas of the world where ROP occurs in infants born at larger birth weights or at older gestational ages. So screening occurs they do screening at earlier time points. Then based on the examination we do follow up examinations and these can be every one to two weeks and we do this until retinal development is complete. So beyond zone three to the aura serata or until severe retinopathy or prematurity occurs. And severe retinopathy or prematurity is stage three ROP with plus disease or stage two and I'll show you some of the early or some of the parameters that we use for that now. If severe ROP occurs laser treatment is performed and the patients are followed very carefully for regression of the neovascular or the vascular components of ROP. If the vascular components persist we do more laser. If fibro vascular components start to develop that's when we consider surgery for progressive stage for ROP. And in all these patients when we get the retina attached the most important thing is visual rehabilitation. To make sure that the infant can see and see as a child and infants with ROP are more likely to be myopic and also to have stroke business. So it's important to work very closely with pediatric ophthalmology. So what about this I said about severe ROP. So what is severe ROP and how did we come up with those terms. So in the multi-center cryotherapy trial that was to determine whether cryotherapy to the peripheral avascular retina would reduce the risk of a bad outcome in infants with severe ROP. And so they chose a threshold of severity where there was a 50% risk of a bad outcome in that infant if nothing was done. And so that threshold ROP was basically any infant in zone one or two with stage three that's the intra vitriol neovascularization having five contiguous or a total clock hours. So that's where the extended stage comes in. And then plus disease that dilation and tortuosity in four out of four quadrants. And it was found in that study that cryotherapy significantly reduced the risk of retinal detachment or poor outcome in infants with threshold ROP. But there were still a lot of infants that went on to develop stage five ROP or did not have good vision. And so the question was well maybe we should go earlier and then also around that time we had developed the technology to deliver laser with an indirect delivery system. So in the cryotherapy study we didn't have that ability and that's why it wasn't probably recommended or tried in that study. So based on the early treatment retinopthera prematurity study they developed or they divided pre-threshold ROP into two types type one or two and found that type one where there's a 15% risk of a bad outcome in natural history that those infants did better if they had laser treatment to the avascular retina. So this is when we now consider laser in most cases so any infant was zone one and stage three without plus disease and then the other two criteria have plus disease. Zone one any ROP or zone two stage two or three with plus disease. And here the definition of plus disease also changed. Plus disease was defined as two quadrants have dilated into tortuous vessels and the severity of the plus disease is not quite as severe as the picture that we know from the cryo ROP study. We prefer laser to cryotherapy. In some cases we can't get laser in because there's blood or the visualization to the retina is not good. We have better tools now. Cryotherapy tends to cause more inflammation to the eye and can also be associated with plaques in the macula post-operatively and these can interfere with visual development. I want to mention another form of severe ROP that we're seeing more of and that's aggressive posterior ROP. So the typical zone two stage three severe ROP tends to occur around 37 weeks post-menstrual age regardless of birth weight or gestational age of the infant. Aggressive posterior ROP however develop we often see that on the first or second exam. So this could be 33 to 35 weeks post-menstrual age. It's generally in zone one or posterior zone two and there are four quadrants of plus disease. So this does not tend to progress through the standard stage one, stage two, stage three but rather we look in and we see dilated tortuous vessels and this flat neovascularization which can be difficult to detect. So flat neovascularization is right here actually and it just looks like a brush fuzzy border. So how do we know that that's neovascularization? Well I guess we don't really accept that when we treat these infants with laser. So say for example we were treating with laser up to this point. What happens is there's regression and these blood vessels tend to regress and about 37 weeks post-menstrual age so the time when a typical post or typical stage two zone two, stage three ROP would develop neovascularization. We see new formation of intra vitreous neovascularization into the area where the new avascular zone developed. So here just shows this is actually after laser treatment. So this patient had been treated with laser here. There was an avascular area of flat neovascularization here and neovascularization then developed and new laser was placed in. So I often tell parents who have children or infants with aggressive posterior ROP that their infant will likely need more than one laser treatment. So this is neovascular. And that's definitely vascular activity and the best way to treat that is with laser. But then as we start to develop this progressive stage four ROP with fibrous changes, so what are the features that make us think about surgery for progressive stage four ROP? There can be ridge thickening at the junction of vascular and avascular retina and I reviewed a number of infants who this was years ago before we became a little more aggressive about doing lens sparing protractomies for these infants. And the features that I found predicted progression of stage four ROP were six clock hours of ridge thickening at the junction of vascular and avascular retina. Any type of fibro vascular proliferation or vitreous condensation and two of four quadrants of plus disease. And sometimes it appears that the plus disease comes back, so it regresses after laser and then reforms. And then others have found that any neovascularization, even in the treated areas of the avascular zone, that's another thing that should be watched and may indicate the need for surgery. So what surgery do we like to do in these infants? The lens is important in visual development. If we remove the lens in an infant, they can have a terrible aphake at Gambliopia. So we always try to save the lens and the type of surgery we do is a two port lens sparing protractomy when at all possible. And we try to remove the vectors of vitreous that are pulling the retina off between the ridge and the anterior part of the eye, the circumferential vector here, and also the ridge to the lens. And it's important to remember that in the preterm or in any infant, the pars plana, pars placata region is not mature. So whereas in an adult human, we might have four millimeters of a safe zone to enter into the vitreous cavity without tearing the retina. In a newborn full term infant, we have .87 millimeters, and in the preterm infants, it's even smaller. So we're going about a half a millimeter posterior to the limbus trying to avoid the lens and the retina. So we don't take this casually. This is not an easy decision to make to operate on these infant eyes. And yet if we wait, then this area of retina gets pulled up to the lens and it becomes virtually impossible to safely repair the retina without removing the lens. And remember also, if we get a hole in the retina in an infant eye, unlike in the adult, it's an inoperable retinal detachment often because the vitreous is not able to be mechanically removed from the retina at this point. So we take these decisions very seriously and I usually ask for multiple opinions to make sure that I'm keeping myself, you know, that I'm doing, that we're doing the best thing for the infant. And then as I mentioned, stage five, prevent it with careful screening, repeat examinations, and prompt treatment. I often, though, do offer surgery to reattach the retina. And my reasoning is that, you know, in research, we're doing so much to restore vision with computer chips, with various ways. We're learning more about ways that we may be able to provide hope for this infant 20 years from now with vision. And this is especially when it's bilateral, which it often is. So I will offer various ways to anatomically reattach the retina, either with a pars placata of the trectomy, often removing the lens or an open sky of the trectomy. And with an open sky of the trectomy, what we do is we remove the cornea and place it into, like, tissue culture, menia. And then we get this, and then we take the lens out with the cryoprobe and we see this pre-retinal membrane, and underneath it is the retina. So you have to do sharp dissection, like this, to remove the membrane from the retina so that you're left with the retina like this. And then we can use viscoelastic to help push back the retina. Sometimes we drain some retinal fluid and then we replace the same cornea. So that's one of the ways that we have to treat stage five ROP, but we're always trying to prevent it because that's when our outcomes are best. So now I'm going to just start to switch to what we know about ROP and then talk a little bit about what's going on in the lab. We've come to recognize that ROP is a complex disease, and what that means is that it has a number of factors that go into its pathogenesis. There are environmental associations, there are genetic associations, and we're getting more evidence that there may be epigenetic associations as well. There's variability and risk, so ROP can manifest differently throughout the world. In India, for example, where there are not the resources to implement oxygen monitoring and regulation, they often have the type of ROP that we saw in the 1940s with very high oxygen-induced retinopathy and ROP. So it's almost a different type of condition than what we have here. And they also see ROP in bigger babies that are born at an older gestational age and probably for that reason because oxygen plays a strong role. Frequency is different worldwide in Latin America and South America. ROP is one of the leading causes of visual impairment in infants, whereas in the U.S., it's not. And that, again, is because the countries are able to save the preterm infants and they may have variability in regulating and monitoring oxygen. There may be other reasons as well. Prenatal care, nutrition. Environmental associations that we know are affecting, they can affect ROP oxygen. We've seen that. I just mentioned how it differs throughout the world. Oxidative stress, maybe. I'll go through that briefly. And then nutrition is being recognized as an important factor in the risk of ROP. And then there are genetic associations. At least one paper suggested that 70 percent of the variants was due to genetics, but we don't have any strong candidate genes yet. And we want to be able to study genetics for that reason. So what about the role of oxygen? So in the United States, there was the initial ROP epidemic of the 1940s that was really associated with unregulated oxygen at birth. And when it became recognized through really animal models that oxygen was a culprit, oxygen was restricted, which reduced ROP, but then there was a higher incidence of infant mortality and cerebral palsy. And then over the decades, there was the technology for oxygen monitoring and regulation. And so with that also came greater survival of low birth weight infants. ROP virtually disappeared for a while, and then it came back to the second epidemic when we had lower and lower birth weight infants and younger gestational age infants in the 90s. And it became recognized that other oxygen stresses were important in ROP besides hyperoxyiberth. For example, fluctuations in oxygen, that was a high risk for ROP, and perhaps supplemental oxygen during the course of the infant's time in the NICU. What about oxidative stress? Well, oxidative stress has long been linked to ROP based on oxygen levels. So high oxygen can increase reactive oxygen species by donating electrons to oxygen and causing superoxide radical. But it's also been argued that low oxygen levels can increase reactive oxygen species generation because it tends to slow down the electron transport chain and you end up with more electron donors. So hypoxia may also increase ROS. And then the fluctuations with ischemia reperfusion may also increase ROS. And in the preterm infant, the infant is in utero. Oxygen is about 30 to 40 millimeters mercury. And so when the infant is born and placed into sometimes they were put into 100% oxygen at the time of birth, that was definitely hypoxia. And so it's not clear if that plays a role, but it may. The infants have been measured for oxidative compounds and they're found to have higher oxidative compounds when they're preterm than full term infants. There's also reduction in antioxidative enzymes. They don't have the reserve to be able to handle oxidative stress. And in a meta analysis from a number of studies done decades ago on trying vitamin E to reduce the risk of ROP, they found when they put all the numbers together, they found that there was reduced stage three in those infants with vitamin E. But I think vitamin E has risks and that's why it's not currently being used. I think those trials were stopped. The role of nutrition, there have been a number of studies done in the last decade that have found that low serum insulin-like growth factor is associated with poor postnatal weight gain in preterm infants and also with larger avascular areas of retina and severe ROP. And so in Sweden they developed a reference model based on weekly IGF-1 levels in the serum and safe postnatal weight gain for infants without severe ROP. And then they used this and whenever the infant's parameters fell beyond what their numbers were each week, an alarm went off. And so they then correlated the number of times of the alarms with those infants that went on to develop severe ROP. And they found 100% sensitivity in Sweden, but it's not been generally found to be as valuable in other areas of the world but still valuable. 90% in Brazil. And there have been several studies in the United States but they've been retrospective. And the goal is to do a prospective study to test this. So why do this? Because what's happening, especially in these countries that have so much ROP without the oxygen regulation and monitoring, is that they don't have enough people to do the examinations. And a lot of infants that don't develop severe ROP need examination. So how do they best use the resources? And this is one model that's being tested. As I mentioned in genetics, there's a retrospective study of monozygotic and dizygotic twins that's 70% of the variance in susceptibility to ROP is due to genetic factors alone. But no one gene strongly is associated with increased risk. And I'm working with Magdi Angelis here and with Kanyost and with the neonatology and pediatric ophthalmology and to be able to determine genetics in ROP. We've looked at studies done so far. There have been a number of candidate genes but there really has not been one candidate gene that's been found to be like a complement factor H in AMD. So nothing that really stands out as being helpful yet. And then I'll just briefly mention about epigenetic factors. So epigenetics can be things like if the DNA, if the proteins around the DNA, the histones interfere with the ability of having the gene transcribed, then that gene will not be able to be translated into protein. And what's been found is that intrauterine growth restriction can lead to dysregulation of angiogenic factors based on differences in being male or female. Rob Lane is doing a lot of this work in multiple organs and we're collaborating with him to look in the retina as well. And human's IUGR can increase the risk of diabetes later and obesity and risk can seem to be passed on to later generations. We've found in the retina that IUGR had a variability in the regulation of retinal IGF1 receptor and VEGF receptor one based on sex. And we're doing more studies with this right now. I don't have enough to be able to even conclude and tell you what it means. Okay, so I'm going to switch now and talk a little bit about what's going on in our laboratory. Some of this I've presented briefly before and some of it is new. So so the way that we think about R.O.P. is based on the avascular retina because that's a risk for severe R.O.P. It's a risk for intravitrile neovascularization. And it's long been thought to be the source of angiogenic factors. So based on what we see in nature, we've developed a mental model of what goes on in R.O.P. And that when a baby is born preterm, the peripheral retina is a vascular. Now 90% of these will vascularize their avascular retina and be fine and never develop R.O.P. But 10% will develop a severity of R.O.P. where there's intravitrious neovascularization. Even if we look at this group and look at the natural history, 50% will have regression of neovascularization with ongoing vascularization of a vascular retina. So we know that that's possible. And that's been our goal from the start is that we're not interested in just inhibiting neovascularization, but we want to redirect the blood vessel growth appropriately. And as I mentioned, R.O.P. is complex, there are genetic and environmental factors involved. So we have different models based on what the question is that we're trying to answer. So the for genetics, the hyperoxy induced vaso obliteration model that was developed by Lois Smith and Pat DeMory is probably the most well known. And in this mice are brought at postnatal day seven into high constant oxygen for five days and then placed into room air following that. And although these oxygen levels create arterial oxygen levels that are not consistent with what preterm infants develop, I mean, it's probably like over 300 millimeters mercury. But it does develop. It's it is still a very useful model for studying genetic genetic mechanisms because you can use use transgenic animals. The retinal flat mound here shown lectin stained. When we flatten the retina, it comes out looking like a clover leaf because the retinas round. We see central obliterated retina, and then these endothelial buds in the vasculature. So it doesn't really look like R.O.P. either but it's a very useful model. The model the 50 10 fluctuating model was developed by John Penn and the supplemental oxygen part of it was added by Bruce Berkowitz. And in this rat pups are put laced into 50% oxygen for 24 hours and then cycle down to 10% oxygen for 24 hours. This cycling is continued to day 14. When they're brought up from 10% into 21% or 28% oxygen. So these oxygen extremes create arterial oxygen levels in the rat that are similar to transcutaneous oxygen levels in a human infant that develops severe R.O.P. It also has fluctuation in oxygen, which is more similar to what the preterm infant experiences. And the retinal flat mound has the appearance more similar to severe R.O.P. with the peripheral avascular retina and this introvitory is the vascularization at the junction. So we mentioned about angiogenic factors being important in introvitory's new vascularization and certainly one of the ones that has become recognized as very important as vascular endothelial growth factor. It's associated with severity of a number of adult and infant diseases. It's regulated by oxygen and that's relevant in the preterm infant. And if we inhibit the bioactivity of VEGF we can reduce the severity of disease and this includes R.O.P. But VEGF is essential to retinal vascular development and therefore we have to remember that inhibiting it might have an adverse effect on the developing vasculature because it is an angiogenic inhibitor. So in the first part I'm going to show you some of the work we did to determine the effective relevant oxygen stresses on expression of VEGF to gain insight into the development of avascular retina and subsequently introvitory is neovascularization. So we used a number of outcomes. We can take whole retinas out and we can measure protein by Western blot and we can measure the mRNA by using real-time PCR. But we can also measure several parameters in the retinas themselves. So this is from a postnatal 14 room air race rat pup. This is a retina flattened sting with lectin showing that the retina is fully vascularized in the interplexus. In the 5010 OIR model at postnatal day 14 there would be about 33% avascular retina in the flat mouth. At postnatal day 18 in the 5010 OIR model we see that there's characteristic avascular retina about 25% and we see that almost if we were to measure by clock hours there are almost 12 clock hours of introvitory on the avascularization. And I'll also mention that in this model there's always regression of disease. So it gives us the opportunity to look at what things might be causing regression which is what we would like. So we first measured the VEGF mRNAs and protein in room air in 5010 OIR model at different postnatal day ages to find out the association of the VEGF with a vascular retina and introvitory on the avascularization. Now I'll mention that in the mouse model when the animals are in high oxygen and they have vaso obliteration in the central retina VEGF is very low in the retina. And then when they have endothelial budding into the vitreous VEGF is very high. So we thought well maybe since we are in the rat model and we're going from low oxygen at 10% to high oxygen at 21% maybe we would see a similar pattern. But we didn't find that. So here is VEGF 164 which is the most prevalent mRNA and we found this is full change in expression relative to beta actin. And using an ANOVA that accounts for multiple comparisons we found that both older developmental age as well as the model compared to room air were significantly associated with increased VEGF 164. And then when we looked at the protein we had a similar relationship and there were also several significant days based on post hoc protected T test evaluation including post natal day 14 when a vascular retina persisted in the model but room air retinas were fully vascularized. And at post natal day 18 when the vascularization was present in the model. So in the summary VEGF was increased at post natal day 14 in the model when a vascular retina existed compared to room air. So this is a little different than what we saw in the mouse model. It was also increased at P18 when intravitrile neovascularization was present. So then we asked the question whether if we inhibited the bioactivity of VEGF would we reduce intravitrile neovascularization but would it also cause persistent avascular retina or maybe even more avascular retina since VEGF is important in retinal development. And we found that neutralizing VEGF reduced clock hours of intravitrile neovascularization. So this is with a neutralizing antibody to VEGF. So similar to Avastin but not Avastin and an IgG control. And we found that it did not interfere with a vascular retina. So more avascular retina is high on this slide. And then when we used a receptor tyrosine kinase inhibitor for VEGF receptor 2 which is the angiogenic receptor we found a similar pattern that there was a significant reduction this time area of intravitrile neovascularization but it did not interfere with ongoing retinal vascular development. So that was a little bit unexpected and you know based on what we were getting I was we wondered G could VEGF VEGF receptor 2 signaling actually contribute to a vascular retina. So it's too much VEGF causing a vascular retina. And so how could that be? So we went back to what occurs in vascular development and when endothelial cells divide they undergo mitosis they set up a cleavage plane and the angle between the cleavage plane and the long axis of the vessel predicts where the daughter endothelial cells will migrate. Such that a 90 degree angle predicts vessel elongation, a zero degree angle predicts vessel widening and perhaps we thought that if you had a lot of irregular angles that maybe it would cause disoriented mitosis and sort of a pattern like what we see in intravitrile neovascularization. So studying VEGF is challenging because a single allele or either receptor knockout is lethal. So we went we collaborated with Vicky Bouch who has an embryonic stem cell model at the University of North Carolina and she has a VEGF receptor 1 knockout. So what that does VEGF receptor 1 combined VEGF but it doesn't have a very strong receptor tyrosine kinase to signal cell events and it binds the VEGF keeping it from VEGF receptor 2. So when we knock it out all the VEGF goes into VEGF receptor 2 and we get increased VEGF receptor 2 signaling. And indeed we found that this caused disoriented mitosis in the embryonic stem cell model and it was similar to the appearance of what we see with intravitrile neovascularization and further it could be rescued with a soluble flit one that's VEGF receptor 1 soluble form transgene linked to a promoter that was specific for endothelial cells. So we took it back to the model and we asked the question whether or not VEGF if we neutralized the bioactivity if we could reduce some of the tortuosity or disorientation of the dividing endothelial cells. And so this we used a neutralizing end of the body to VEGF and we took lectin state flat mounts. Here is the cleavage plane measured cleavage angles and then on this graph this is a number of mitosis and these are the angles the cleavage angles grouped by 10 degrees. And just to give a sort of a summary that the elongation would be toward 90 degrees dilation would be toward zero degrees. And we found that in veins that the neutralizing antibody tended to cause the veins to be less dilated than the IgG control. And when we looked at arterial tortuosity using the sort of a pre version of ROP tool we found that the neutralized nanobody significantly reduced arterial tortuosity compared to control or to the non-injected. So we've so far we've found that increased VEGF receptor 2 signaling disorders dividing vascular cells and contributes to dilation and tortuosity and may have an effect in plus disease. And now we're studying in the lab whether excess VEGF would disorder normal developmental angiogenesis and contribute to a vascular retina by permitting endothelial cells to divide outside the plane of the retina and proliferate in a pattern that looks like intravitrial nevascularization. And the clinical studies have provided support for the hypothesis and that anti-VEGF does reduce intravitrial nevascularization and permits ordered angiogenesis. But long term and safety results are lacking and more studies are warranted. So, you know, I don't know. Okay, I think, are we okay? We can go for 10 minutes. Okay. So, so I've just, we have, this is our current working hypothesis for the lab and we just showed that VEGF receptor 2 signaling leads to some, or we're studying disordered angiogenesis which increases a vascular retina. Some of this I've presented before but now I want to go through another mechanism because it's, a vascular retina is going to have multiple mechanisms. There's not going to be one bullet that cures it. And so I'm going to take you through this pathway where we find that VEGF receptor signaling actually activates the jack stack pathway and contributes to a vascular retina. This is the work of Haibou Wang who's a research associate in our lab and also a number of people in my lab. So the signal transducers and activators are transcription, stat and cytokine activation. These are, this is an important pathway whereby you have a cytokine receptor with two of these jacks. A cytokine can activate and then cause stats to form a dimer and they can translocate into the nucleus and then either with stimulators or repressors affect transcription of genes. And the cytokine growth factor can be erythropoietin, interferon, interleukins, possibly others growth factors like VEGF and it can also be activated by hypoxia, reactive oxygen species or supplemental oxygen. So it seemed like a good pathway to study. And our hypothesis was that jack stat signaling would contribute to a vascular retina through either apoptosis or death of endothelial cells or by affecting growth factor expressions such as VEGF. So we first looked at the, so when stat three is activated becomes phosphorylated. So jack stack goes through stat three and can be phosphorylated. So we first looked at the amount of phosphorylated stat three in retinas in room air and in the model at postnatal day 14 when a vascular retina was present. And basically we found that the model had increased phosphorylated stat three compared to room air. And this is just showing the western blots. Furthermore, we could use a chemical jack two, jack three inhibitor and we found that it significantly reduced phosphorylated stat three when we gave it as an intraperitoneal injection into these animals. We also found that when we use this inhibitor and inhibited stat three, it reduced the area of a vascular retina in the ROP model. So stat three activation or phosphorylation contributed to a vascular retina. And so then we wanted to set out to understand the mechanisms. Could it be affecting downstream VEGF expression? So if you, that would then lead to a vascular retina either by inhibiting VEGF or could it be causing apoptosis? So in this case we use the model at postnatal day 14 and we use AG490 which inhibits stat three versus PBS control but we found that there was no effect on either VEGF or on cleat caspase three which is downstream of two of the apoptotic pathways. So it didn't seem to be caused by either the mechanisms that we thought. So then we started to think about erythropoietin because it's been, it's shown to be neuroprotective, it can be thrombogenic, it can protect against hyperoxy-induced avascular retina in the mouse model of hyperoxy-induced vasodiliteration. But there have been studies where use of erythropoietin has been associated with severe ROP in preterm infants. So there's controversy as to its role in ROP. So we first measured erythropoietin in animals in the 5010 OIR model treated with either AG490 or PBS and we found that when we inhibited stat three that we had increased erythropoietin. And here I'm just kind of showing you what the signaling pathway might be. So jack stat seems to lead to decrease erythropoietin. And so then we asked, well, is VEGF involved because we know that VEGF is important. So we looked at animals that were treated with a neutralizing antibody to VEGF at a dose that we knew decreased intravitrile neovascularization or control and we measured phosphorylated stat three. And what we found is that in the neutralizing antibody to VEGF there was a significant reduction in phosphorylated stat three compared to the IGG injection. And these are intravitrile injections and the way we do these experiments we don't inject the fellow eye to look for crossover effect. So this suggested that VEGF was upstream of jack stat in this model. And we took these same eyes and probe for erythropoietin and we found that the neutralizing antibody increased VEGF. So this looked like VEGF was activating jack stat to cause decreased erythropoietin. And then finally we injected erythropoietin into the 5010 OIR model compared to control and we found that it reduced a vascular retina. So that's where we are right now and we're studying in vitro we're using in models of endothelial cells and Mueller cells to get at mechanisms. But stat three does seem to be activated after fluctuating oxygen in the rat model at postnatal day 14 when a vascular retina persists. It contributes to a vascular retina and VEGF appears to be upstream of stat three. And then stat three signaling seems to reduce erythropoietin and this is associated with a vascular retina. So our current working hypothesis is that VEGF fluctuations in oxygen may activate jack street to decrease erythropoietin in the retina and lead to a vascular retina. So our ongoing studies, anti-VEGF is not the only answer. Additional clinical studies are warranted. We had a grand rounds here talking about a clinical trial using a Vastin in infants with severe ROP compared to laser. So we need more clinical studies done. Erythropoietin may increase intravitrious neovascularization in models but it depends on the timing, apparently that it's given. And when we, stat three activation in our model reduced erythropoietin, we think that perhaps the neuroprotective effect of erythropoietin may be beneficial though in ROP by promoting vascular retina if it's given earlier. So all these things we are studying and it may mean that ROP is something that will require multiple drugs to treat it. And the update on the clinical trial is probably the most exciting thing is that pediatric ophthalmology and pediatric retina are coming together to form a multicenter clinical trial to study a Vastin versus laser in severe ROP and we'll be using photographs too to be able to characterize the severity of ROP rather than just mental images of what we see when we examine the infants. And then I wanted to acknowledge our funding sources and also the people in my laboratory who have done all this work. This is Yanchao Zhang, Shamie Kanakar, Manabu Makwaski, Haibo Wang, Tyler Smith, and Aichi Nishimura. Thank you. And any questions? Yes. Well, I think that could be the case. I mean, we're still, you know, it's evolving. ROP infants are younger and smaller and then new medications are being used for other complications that they have, so it is kind of an evolving field. And I think what you're seeing is very accurate and perhaps what we need is to have multiple tools kind of to be able to target this and figure out what's safe and what's not safe. Yes. No, no, that, in fact, those studies we gave intraperitoneal to the POPs. And usually, I don't know, is it given, how do you give it in infants? Is it sub-Q? So it's not, but it probably, you know, the studies that showed severity were retrospective studies. And I always question that because it's when do you take the infant? If the infant, you know, maybe those infants had they had EPO would have lived. You know, it might be those questions so when you say, well, we're gonna look at all infants that have survived to the time when they have ROP examinations, you're taking out a number of infants who may have died because they didn't have EPO. I mean, so I think that it depends on how the trial. Yeah, yes, anemia prematurity. And I don't know about any, are there other reasons that, we have our neonatal group here that came too as well. Thank you. Besides anemia prematurity, do you give it for brain? Right, I know of one study, I think it may have been retrospective just by looking in the literature that EPO was associated when infants had EPO, they had better cognitive scores or better mental development scores later on when they were children. And I think that in Europe, are they starting a study for EPO on preterm infants? I thought I heard that, but I couldn't find it on the PubMed. But I think it would be a good, I mean, I think what would be interesting is to do EPO and then if they get severe ROP, anti-vegeta, because maybe the EPO would be neuroprotective. We should try that in our model. And may not cause some of the problems that we're concerned about with a vastin into the vitreous, which then gets systemic and may have a negative effects on other organs. Oh yeah, yeah. So I don't know, maybe I shouldn't have you.