My name is Tata Steven Tseng, I'm a graduate university student. Steven has a long career in Gino engineering and he's an expert in stem cells. He was active in the photo-technology firm in the early 1990s. He was one of the first to produce knockouts, most knockouts. A particular topic was the PDE gamma knockout. PDE gamma has been in many of you probably don't know. It's an inhibitor and its knockout actually decreased the activity of PDE which was a very surprising result in the 20s. So here, Steven Tseng is an expert in many, many different topics. CRISPR-S9, viral vectors, proteomics, invasive imaging, gene therapy. So he's a really versatile clinician-scientist and he's giving a presentation today on gene-typing of patients without high CTX10, which is a whole genome sequencing method. All right, Steve, looking forward to your talk. Thank you Wolfgang for the generous introduction and also thank you for the opportunity to visit the Moraine Eye Center. So for the residents and fellows, this is a clinical case presentation similar to the Foresting Conference, how I guess Paul and I learned it at the Georgetown Foresting Conference style. So just imagine that you are in a busy morning clinic. So every time you see a picture of Columbia, that means that there's a new patient walking to your office. So advertise that we have anybody interested in genome engineering on Saturday before Apple, mostly by people that know a lot more than I do, but from Bruce Cochran and Howie Wang, they hold a record in terms of engineering IPS efficiency and Howie Wang in terms of nobody can do CRISPR, but knocking in mouse oversight for more than 4KB. So they still hold a record. So to summarize, in case you need to get paged out, you get paged out during the case presentations, this is the summary. So I have inquired in ophthalmology, you can, at beginning residents, you should feel fortunate in this part of medicine that you can look at the patient and you know except what nucleotide change the patient has. Just by clinical examination, you do not need to do sequencing. Sequencing is just for confirmation. And I posed this question to Victor McCusick that what are the areas in internal medicine that you can look at the patient and know what the nucleotide change, just by clinical examination alone. And he can come up with the acondiplation, so 99% of patients, if you make a clinical diagnosis of acondiplation, it's going to have this 380 residue change in the fiber growth factor receptor 3. In posterior, you make a diagnosis of posterior, 80% of the patient is going to have this mutation in the laminin aging in the 1824 residue. And then there's some conditions, but in ophthalmology, I'll show you that the more than a dozen conditions in the retina, you can look at the patient, you know what residue the patient has. Sometimes you can look at the patient, you do not know what residue, but you can narrow down what gene it is. For example, you make a diagnosis of congenital fibrosis, you know that this is going to keep 21A gene. The list is growing, the number of genes causing RP, so I try to convince you that you do. In the East Coast patients get consultation in many different clinics. In Boston, they seem to like DNA sequencing, exome sequencing as a primary technique to make a diagnosis. I'll tell you that maybe you can be more cost-efficient. Just look at the patient first. Do a few candidate genes before you do to hold genome or hold exome sequencing. The reason we need to know the gene is because many times now we had better genotype phenotype correlationships, then we can now give a patient a prognosis, and of course this is important for family genetic counseling, pre-symptomatic counseling, or carer detection. And most likely in the next two decades, gene therapy, gene specific, so you need to know the gene before gene therapy can be applied. As we know more and more about the phenotype, then we can correlate with genotype and they can go back and inform us what kind of phenotype we expect when a patient has certain genotype and vice versa. For the beginning resident, we will do a couple of imaging techniques to help us to discern the genotype just by in the clinic. Typically, if you use the government program, IGN, to do DNA testing, you may take four years before you get results. So for now, a lot of times you can look at the patient, you can give the patient results at the end of the day. So this is all the fluorescent imaging. We are focused on some of the work done by Janice Barrow. We do quite a lot of all the fluorescent imaging. This is very free. This is how the fundoscopy looks like, and this is infrared. So the first patient comes to the consultation. Who has the pointer? Okay, you can describe. So if a patient comes to the consultation, they want to know whether or not they want to take vitamins. This is the fundoscopy picture. So there is a yellowish coloration. So if a patient wants to know whether or not he should be taking vitamins. So with autophoresis imaging, would it help? And this is a very characteristic pattern. It gives a petaloid, like a covalent kind of atrophy. The punctate hyperphoresis. The bullseye is an actinopathy. So bullseye by definition has to be a continuous atrophy. So the atrophy has to join each other. Unlike what the bullseye manual wrote, this is not exactly bullseye atrophy. Bullseye has to be a continuous atrophy by definition. So this is kind of a little spotty. And the atrophy, they don't join each other. So by bullseye, they join each other. So in the clinic, sometimes we need to look at other family members. So the daughter came with the father as a symptomatic. Do you want to describe the picture? 2015 vision for the daughter, the right eye. There is some... And the left eye. So autophoresis helps to discern. This is a symptomatic daughter, 2015 vision. You can also see this kind of spic code, hyperphoresis around the area. So we generally do electro-diagnostic, and ERG testing was normal. So this is actually a... This will be sufficient to tell the resident. So any suggestion, what condition first? You remember the paper, then this is what the cathartic phenotype described by Adam Bird and Tony Moore. At least the diagnosis, the name of the conditions. What's most likely, though? This is very cathartic, the spic code type for us and the cobalt leaf type of pattern atrophy. The gene was described by a neurologist. Unfortunately. Not by an automologist. So this is a... The residue is 172 of the LDS. So this is very cathartic. You can see this sort of a... Puntate all of the hyperphoresis and with a cobalt leaf type of pattern atrophy. This is an LDS periferant. So this is a form of pattern macrodistrophy. And in this case, it's very specific to this 172 residue. I'm not sure why, but this is how... All the patients with this 172 residue will show up at this... But this residue gives very specific phenotype. So a different patient, you can pass your pointer to your neighbor. Another patient came for a consultation. 2424 division. It's a fundus picture. And then you need to notice that there is a drusen on nasal side or this. Anybody want to describe this picture? Yeah, so nasal side is very cathartic. So most of the time you don't see drusen on nasal side. On the disc. And it looks like they're drusen or drusen loin. And some yellowish discoloration. Hi, I'm Agon. How do you describe this pattern of drusen? But that's not so cathartic. But the cathartic one is the one on the disc. But what do you call this kind of drusen? Yeah, both eyes are nasal. So on the disc. It's just diagnostic for this condition. And you should maybe even know the residue of the gene. So I'm not sure the exact word that you used to describe this pattern. But it's kind of almost stellate or projecting out. Yeah, so kind of... It's called radio, by the way. Radio. You can see that on the disc. So usually AMD drusen, usually do not hyperphorest. For some reason drusen are associated with macaditrophy. They tend to hyperphorest very well. And all the fluorescent imaging. I think we'll see. Maybe you can dim the lights in the front. You'll see a little bit better. This is infrared, higher mac. You can see kind of the radio pattern. These are the OCT. These are all the drusen loin deposits. Right eye, left eye. You can get some tubulation also. Does anybody want to suggest? Yes. Very good, very good. In Europe, they call it malatia. In Europe. In the Anglo-Saxon speaking world, then it's called Dorian centricone, described by professor Dorian Oxford. But in Europe, because of the... This is a Swiss-Italian valley. So they all have this mutation in this fibrillant... I think a fibrillant 5-gene, EGF-containing fibrillant-like exosalem matrix motif. And everybody is going to have this 345-residue, with this mutation. So a different patient drusen on nasal side of the disc. We even have two families in Washington Heights in Manhattan. So sometimes their family do not know and they're somehow originated from Switzerland. But they have a big pedigree in Iowa and also a big pedigree around Oxford, where professor Dorian had worked. And it's the most one to be made. Yes, so the knock-in mice in a single allele has almost no phenotype. Only the double dominant has a phenotype. Double dominant. So in patients, it's dominant, one allele. In mice, you need two allele to see phenotype. So this is just another patient. You can see... I think this one is actually from Washington. She lives around Washington Heights in uptown Manhattan. So you see drusen on nasal side of the disc also. Of course, around the drusen, you get a little bit of decreased sensitivity on micropermitry testing. So now you can pass on, point it to another different patient. This one, actually, I took it from the internet, from some grand rounds case, but I do not agree with the diagnosis of someone posted their grand rounds on the website. So the patient came for diabetic screening. That's very typical. This patient usually comes for diabetic screening. Vision is excellent. Every time... This is not my patient. This is taken from somebody else's grand round. But this patient, typically, they don't know why when they come to the eye clinic that there's a long line of residents and fellow want to look at them. And the vision is very excellent, 20-20, usually. Do you want to describe this patient? So this is a forest. In the context of time, I went through the foresting quickly. Yeah. So this is a classic presentation of something called a window defect for the resident. When the RPE is gone, the window, you can see the coroid RPE window. So in the list of the... somebody else's grand round presentation, they post it on the web. These are the differential diagnosis that they offer. But I don't agree with any one of them, though. So this... And then this is one of my patients. You can want to describe it. I think they have the same diagnosis. Although I cannot genotype the patient from the Internet. But I think they have the same diagnosis. Yeah. Yeah, there's a name for this also. There's a name for this kind of pathometrophy. The right eye, the left eye. So it's kind of the mid-face of the foresting. Just want to show you at the end... So the system also has some similar problem. So when you describe this, this is all the forest imaging. So usually for the resident, you wait a minute, maybe five more years later, the area, the hyperphoresis, will be the area that's going to have atrophy, usually. It kind of suggests where the future atrophy is going to be. Hyperphoresis. So it's also spared the centrophobia in this patient also. There's another patient with the same condition. So it's also trying to spare the centrophobia in the left eye. And also for these deposits on the nasal side, also this is also not quite common in terms of other kinds of genes. But for this one, it's more common. Does anybody want to suggest what this is? What the patient has? We can see a couple more cases, though. I guess we saw this one already. This is maternal inherited diabetes and deafness. So this is called annual atrophy. It's spared the centrophobia. Usually they come for that. It's not uncommon that maybe 5% of patients that come through diabetic screening, they have this. But they are usually asymptomatic. They would not develop hemorrhages. They would not develop the proliferative diabetic retinopathy. So the problem is this is in the mitochondria. So sometimes it may or may not because of the threshold effect. It depends on the number of mutations in the retina, the number of mutations in the cochlea, the number of mutations in the pancreas. They may not all have hearing loss and they may not all have retina finding. But you make a diagnosis. Normally we have this 3, 2, 4, 3 residue in the tRNA losing gene. Sometimes this mitochondrial DNA sometimes is difficult to capture by whole exome sequencing. So you send a patient for whole exome sequencing, you may miss it. Unless you tell the lab you're looking for mitochondrial DNA. So the whole exome sequencing for clear testing costs about $6,000. If you just do one residue, it's going to be less than $100, maybe like $40. So it's a little more cost efficient. But some reason in Boston they like to do whole exome sequencing. Is the speed of the mitochondrial stay intact? No, a long time.  This is called annular atrophy by the way. This is called annular atrophy. This is a patient referred to me by John Flint. I'm going to describe this. What do you think of the nerve? What about outside the nerve? Pericaptor. Yeah, pericaptor. There's a right eye and there's a left eye. This is a three-year-old child. So notice how to describe the shape of the atrophy. Maybe it's easy to see on infrared and autofluorescent. So I want to note to you that infrared imaging goes more deeper to the chloride. So you can see that this is a loss of chloride. Autofluorescent mostly is from the retinopigmented epithelium, RPE. This is actually quite intact on the RPE. And that gives you a clue of where the gene is supposed to express. So this gene probably initially affects the chloride before the RPE. OCT is not too special. So in the context of time, I'll go through that quickly other than just a loss of RPE. So the patient was sending this. This could be a toxel. So anybody agree? Toxoplasmosis. We can look at the mother first. Mothers say it's symptomatic. They're from New Jersey, though. They're from New Jersey. But typically it's more common in certain parts of the world. I'll tell you where later. The patients from New Jersey. The right eye, left eye. You want to just describe the left eye? I need to point out the differential diagnosis. There's no cells in the vitreous in this patient at all. They involve the child and the mother. And grandma, associate grandma later. This is still the mom. So this will radiate up the white area, the hyperforestation area. It will be the future part of the goniatrophy. So these patients, maybe by the time they're 80, they will affect the fovea. But typically it's symptomatic. Left eye. You can see that there's some names for this, though. They term the radios up. So lots of RPE. You can see the Colorado shadowing much better. So we did electro-diagnostic also. Electro-diagnostic is pretty normal. Both mom and grandmother. Grandmother looks the same also. We saw grandmother. Does anybody want to suggest what this could be? It's more common in Iceland. But the parents, the patients from New Jersey, it's more common in Iceland. There's many different names for this condition, though. The reason I brought this case up, because in the Grand Rounds presentation from the internet, they said their case could be atrophic areata. But the diagnosis for these patients is atrophic areata. There's one of the names, but they have other names also. We also call the circumperiority this genesis of the pigment epithelium. I think this is a misnomer, and I'll show it to you that this is not a pigment epithelial disease. This is probably a Colorado disease. So there's another name. It's called horticoidal peripapylchloro-retinoid degeneration. There's no cells in the vitreous, and the patients are young, but it's on a differential. You need to consider that as a pigeoness because of the tongue-like lesions radiating out from the disc. So I think this is a... We take donor eye bank, and also one is from the mouse. I think this is from the eye bank, and this is from the mouse. Looking at antibody to this gene, this is a transcription factor called T-net, T-net1. This transcription factor is not found in the RPE. So this is a misnomer. So it cannot be a disgenesis of the pigment epithelium. And then another fluorescent imaging, I showed to you earlier that the RPE looks intact in the child, but it's expressed high in the chloride and no sensory retina, also expressed in the muscle. Also, this is from the mouse, and this is from human, from eye bank, so it's not in the RPE. It's found in the chloride. So this time, I'll give you a clue where the patient comes from. And they will give you the gene kind of... because this is not found in other ethnic groups. So typically, they don't have symptoms until they're close to 60. And the name for this condition contains this feature. You look at the periphery. So the pigment are deep, so they don't have pigment migration. Typically, photoreceptive disease, you will get pigment migration. This one don't have much pigment migration. The pigment are kind of deep. You cannot tell unless you do with a 90-day after-lens, so there's not much pigment migration. The pigment are kind of deep in the RPE level. So this is a typical scarlet type of atrophy. So for Randy, I bought an anterior segment photo. So what do you think of the lens? So the problem is that in New York, at the time, these patients are pseudo-fake already. So it's very difficult. But this one, at least, you can see the... So what do you think of the lens? What do you think of the residents? The lens. So what are those? No. So it's probably going to be more kind of like cloudy, right? Yes. Yeah, zoners are inserted quite anteriorly. In combination with this fundus photofinding, anybody have a diagnosis? Yeah, that's on a different show. It's very good. Yeah, why would there be a color difference? I'm not asking the residents why. It was on the first slide. Yes. His father was... Yeah, so that should not be a great remand. I will show you that. Yeah, it could be. It would be a very high end differential. Yes. What are the conditions you get this zoners inserted so anteriorly? So these are autofluorescent imaging. It just shows highlight the center. Now you see corridor autofluorescent. Corridor autofluorescent. So this is called LOD, late onset retinal degeneration. And once you make a diagnosis of LOD, this is dominant, then you know that everybody is going to have this 163 residue in the CTRP5 gene. The gene is still unknown, but it dimerize with another interesting gene that I'll talk about this afternoon, which is an infrasurative-related protein. So the onset is quite late for this patient, so they are not symptoms until almost in the 60s. And it behaves like retinitis paymentosa. They typically have complain of nectonopia. And this is the peripheral finding that can look like caudoremia, or gerid, as Paul pointed out. So this is quite... I think maybe... the condition gives you this kind of insertion or lenson interior. So today is another one. You can look at the patient and you know what residue. Without sequencing. If you want to get a diagnosis. So this is just a distinguishing caudoremia. But the... at least the caudinitis may have some more of this bridging. Sometimes it gets this bridging type of preservation. More common than late onset retinal degeneration. We'll skip through this. So now we... As I've gone over with you, at least for this part, you can look at the patient and you know what residue. So if you think of diagnosis of this punctate, spiccote, ring odour fluorescent, and then with scallops atrophy in the center, this is most likely to be LDS peripheral 172. Actually, in cases, this is more common in Iceland. But my patient came from New Jersey. And then you get... this transcription factor is 421, once you make a diagnosis of atrophic areata. The other name is called Stevenson's caureo-retinal atrophy. I'll show you an example of a maternal inherited diabetes and deathness. Once you make the diagnosis, you know that this is a 3-2-4-3 residue in this T-aluminate losing gene. During honeycomb, once you make a diagnosis, you know that it's going to be fibrillant 3,345. Late onset retinal atrophy they just show you the CTRP5 gene. I didn't have time to show you most cases of sector RP in this country. It's going to be Rodoxin protein HIST-23. But now we're going to have some genes. We can look at the patient. You do not know residue, but at least you can have which gene? I'll show it to you. So there would be something similar to congenital fibrosis. Once you make the diagnosis of congenital fibrosis in Taiwan, you know that this is canizine KIF-21 aging. So this child is from Greece, came for consultation. He has loaded lots of steroid before I saw him. Vision continued to drop and loaded lots of steroid with no improvement. Vision become worse and worse. Want to describe this? This particular condition like to affect the vessel more than the other forms of retinal degeneration. You can see some exodate at the periphery. This is what we call colts like response. I'll show you some photos in picture later. You can see some leakage at the periphery. In the context of time, I wanted to show you the most permanent finding. So how to describe this? I'll show you the time later sequence. For some reason, not all the photos have popped up or show up. Anyway, there are some extensive leakage at the periphery but not all the, for some reason, not all the photos in frame show up. So the most important one maybe this may not be the best one. There's a left eye both are the same. So what do you call this? This is this is a vein or artery. Maybe I have some better picture. So some reason not all the pictures I see on my computer didn't show up on the screen. So this is I tell you this is an artery and this is a vein. So what do you call this feature? This may be a better one. So this is an artery and this is a vein. There's some leakage. I'll show you the imaging. Okay. So what do you call this? This is an artery. So this is all for us imaging this is an artery and these are veins. This is a different patient by the way. But this patient cooperate better so we can get better all for us imaging. And the other feature is that what do you think of the retina on OCT? So I can tell you this was described by John Hecker Lively and this feature was described by Sam Jacobson. So in the combination of this you should know the gene. So steroid steroid did not help because it came from the uveitis clinic. The referral in this patient. And then this is I think this is also a different patient. It's very common to have the demon also to this group of conditions and then you also see the arteries are more spared compared to the vein. Maybe I made some more pictures. It shows that it's easier for us imaging. So the veins are the RP around the veins are affected but the RP around the arterios are not affected. So right eye, the left eye. So the veins are affected RP and the arterios are not affected. So there's no other gene will give you this kind of gene feature. Any suggestion? What gene to this be? What do you think the most likely diagnosis first? So this is a cold side response with peripheral ischemia in this patient. The one from the uveitis clinic. This will be on the differential diagnosis but this is a CRB1 crumbs. So a lot of the colds response in patients with retinitis paymentals that they turn out a mutation in the patient. So Sam Jacobson described the inner retina get thickened but in this condition with the CRB1 gene is the gene is probably more often retinal organization but I don't know why they get the paraterios bearing. They have mutation in CRB1. Usually typically not, don't have deafness though. CRB1. So this is a found in the fly. Probably in some kind of epithelial cell junction development in the fly. But in the context of time I skip you through the biology of CRB1. So you can also cause our people can also cause labors, congenital amaurosis depends on the mutation. So the cotton official use power arterios bearing described by John Lively. The power arterios bearing. She likes to have coats like response. It was said that it can cause pyrovenous RP but I screen all my pyrovenous patients but they don't have a CRB1 mutation. But that's in the literature. No, the CRB1 was described but I think that one is just a SNP so we cannot find any mutation in CRB1 in pyrovenous RP. So now we just diverge a little bit to show you the labors and as a segment to labors and I go through them quickly because there's one more case at the end. This is in the, I think it's the MoMA Metropolitan Museum. So this is probably a patient of labors. They rub the eye.  Typically we at least we try to do skin electrode. We learn it from Graham Holder and Dorothy Thompson they do skin electrode for labors so they are pretty extinguished. And also in the context of time I would not tell you too much about the biology of different genus. Just try to show you the phenotype. Maybe so these are my limited experience. Maybe also maybe Paul can chime in and see this is a constant phenotype. This is a CEP 290. Quite early one they have a central atrophy and sometimes younger patient you have dots. So CEP 290, yellow dots in the peripheral retina. CEP 290 formal labors. Sometimes they come with jovial syndrome but sometimes just CEP 290. So these are babies with labors extinguished ERG. Cyclase one of used to be Wolfgang most favorite gene but maybe not anymore. Cyclase typically have a normal fundus. So ERG is complete extinguished with a normal looking fundus in the baby. Cyclase would be very high in your differential. They are very photophobic as opposed to some other gene that I'll show you for cyclase. When they get older they get a bit atrophy, sort of pathotrophy in the peripheral retina. That would be a more typical form of cyclase presentation. Some cyclase patients can be severe to get a central atrophy but typically the fundus can be normal. I show you the phenotype for CRB1 already. CRX is a transcription factor in embryogenesis. They usually have a funny looking fovea. Maybe it's only some better picture. They were more typical of a funny looking fovea development or macro development for CRX. This is probably the only form of labors early onset retinal dystrophy that are dominant or the other ones are recessive. Skip through RP65 quickly in the context of time. RP65 the resident and fellows need to know because this one gene therapy is being done. This is probably the only one together with LRAD that you do not have fundus autophoresis. This is another one you can look at the patient you know what gene it is. All the other forms of labors have early onset retinal dystrophy would have autophoresis. RP65 and LRAD and LRAD is so rare I don't have seen any. Do you have any LRAD patients here? In fact we don't even have any RP65. So the typical description of RP65 are soft and pepper retinopathy absence of fundus autophoresis and they like to stare at light as opposed to cyclase. The cyclase patient are rare photophobic and this patient they like to stare at light. We eventually get some atrophy but this is the classic soft and pepper retinopathy that you see in RP65 and just show you another patient is soft and pepper retinopathy. You can skip through the the gene there. When you get older they just look like any other kind of RP patient when you get older for RP65. So just show you the classic soft and pepper retinopathy. RDAX-12 is also very cathartic phenotype. In addition to A, B, C, A4 I didn't show you any for STAGA your peripeptus bearing of the RP. RP around the nerve is not affected and it is kind of numeral round atrophy. I don't know why but this is very cathartic for RDX-12 retinopathy hydrogenase and you can see this kind of macular phenotype. There's no other gene will give you this kind of very round numeral atrophy around the macular. So a different patient you can see that the central macular finding is very cathartic for RDX-12 and I think this is a gene that Robin Ali and Dorothy Thompson also try to bring it to human treatment trial. The peripheral fundage is not so specific but the macular phenotype is very specific together with peripeptus bearing of the RP. This is another patient so you get this kind of numeral round pigment in the center. ARPR-1 this is a chaperone protein in folding the phosphodiesterase. So very severe. They get a pretty much a central atrophy very early on as a newborn baby. And the retrophy is not just over time. Let's get through this. RPGR grip is not so specific but you get this a lot of pigment quite early on as a baby. I want to go through at least one more interesting case. There may be two, I can pass your pointer, there are two more cases before the hour. So this is from our neighborhood. We have more people that live in Washington Heights from the Dominican Republic than in the Dominican Republic. So every time they election for president all these booths set up around Washington Heights. So we did some foresting at that point. Yeah, just the same patient, just window defect, a lot of part of the retina. So I will confess at this point she came back, she came back. And this is a fundus finding. Is anybody? Same patient. Fairly preserved, the Mac, I would say. You just look at this, it's very sharp. Yeah, and then the left eye. Peripheral retina. And then we have a different patient also in Washington Heights that wants to show you how the autofluorescent looks like. So what tests will you do next for this patient? There's very few treatable forms for retinal degeneration so residents should know. Well, what kind? So the problem is that every time I order this test in New York Pasadena hospital they don't know how to do it. That's the problem. I need to go back a couple of times and tell them I don't want the full panel. Very good. So you can... Yeah, they're very serious and this is gyrate atrophy and if you patient are complying with this diet I haven't tried it myself but I heard they taste like cardboard. But if patient are complying with this diet they completely will stop the degeneration. This is one of the few that we can treat. This is a quick case, intermission before the last interesting case that I want to suggest. It will be easier if I tell you this patient came from the dermatology clinic. The right eye. Left eye. He came from dermatology. So he's a young girl. What do you think of this? He came from dermatology clinic. So this is a Puder Ranch. Puder Ranch. This is an interesting patient that I share also with people in Boston when they describe the fundus. This will be the last case before your hour. More periphery. Left eye. What level do you think this lesion is? What level? In the retina. What level? You talk periphery also. So what do you think happened before in the right eye? In a child, in a young child 16 years old. So for the resident Coretone vascularization in a child there's a limited number of differential. I can tell you this is what this is not. You need to consider best for Coretone vascularization in a child sometimes so speak. But this patient does not have those. Trauma. Coretone vascularization in a child. This is the other differential for that. Not in children though I think. So do you see all these? Left eye. You can do OCT finding though. So what do you consider this in OCT? I think this corresponds to the white dots. I think these are photoreceptors actually. So this patient actually already been to Boston before he came to New York to see me. So they have a lot of work up in Boston.  And of course a textbook writer said that the patient have bilateral dosen. Bialateral dosen. Dosen is Diffused Ural Neural Retinitis. Diffused Ural Retinitis Diffused Ural Retinitis Diffused Ural Retinitis and the diagnosis from Boston was bilateral dosen. Bilateral. So this was the diagnosis from a textbook writer. So we did the ERG in New York. So the normal trace is down right here. The normal trace. So this is the rota extinguished. As you can see here in the child. And the cone has a special shape. Usually the shape of the maximal ERG is very different from the shape of the single flash cone ERG. This is a 30-hertz flicker. And also notice another feature. Usually the A-wave for single flash is quite small. And this way it's smaller than the 30 hertz. In this patient this A-wave is bigger than the 30 hertz. And there's no other gene will give you this feature. What's described by, I can tell you maybe it will help the clue. Well first described by Mike Marmer and Peter Goros. The ERG feature. This is the rota extinguished. So the shape looks very similar to a single flash. Yes. You should give the resident a chance. Okay, I'll go through this quickly. So usually the A-wave normally is smaller than the 30 hertz flicker as I've shown previously. So this is normal. A-wave is much smaller than the 30 hertz. But in this patient the A-wave is bigger than the 30 hertz flicker. This is a normal situation and this is our patients. So this official enhanced S-con. And then the we don't have a lot of S-con control from just standard ERG is enough to make a diagnosis for icing in the cake with the S-con ERG. But we don't have a lot of control for children. So a fellow, one tier his son of the S-con ERG. So this is his son. And this is our patient. So this is enhanced S-con. So typically the rod responses are completely extinguished. The patient no rod. Usually I tell the children that you have enhanced S-con syndrome your retina looks like a dinosaur's retina. Dinosaur's retina don't have any rods. And this patient has a homozygous mutation in this transcription factor. And now to E3. Homozygous. So you should be able to in older patient. I'll show you the picture. The fundus is more characteristic in older patient. They have nominular pigment around the arcade. And then there's something new is here that we found that they have this kind of retina rosettes. Showing you in here. Let's go and skip through this. So in mice you get this kind of rosettes in enhanced S-con RD7 mouse. They get also white dots also in mice. So you get this folded rosette. And it looks like the same as our patient. So the patient have the let's see. So this I think interpreted as the same kind of rosette. You saw it as in this is a mouse retina. When they get older they become flatter degenerate. So these are actual macrophages. There's little dots here. And then the round ones are rosettes in the mouse. These are typically round pigment and the level of pigment is at the RP level. They don't have pigment migration. Let's see some more. RP patients typically have a high density ring and in enhanced S-con you get kind of a amorphous ring in the macular. And also RP patients you don't get ring on the nasal side in enhanced S-con. You also got on the nasal side also in the retina. So with some other pictures in enhanced S-con this is an older patient. You get this round luminal pigment. So these are very round and they're sub-retinal. Most of the patients with retinitis pigment have sharp edges and most of the pigment are intra-retinal. But in enhanced S-con these patients are sub-retinal. Sometime on the referral letter they said that other patients don't have diabetes but the comprehensive ophthalmologist will write that they don't accept a patient got PRP scars but they don't have diabetes. They don't know why. So they send a patient in. So typically because you don't have enhanced S-con the transcription factor is required to convert to push the cone fate into rods so you don't have the transcription factor for the enhanced S-con gene or your retina become cones and there's no rod and that's why they are night blind. It's the same gene as Gorman-Farré syndrome. Eventually they get a lot of vitreous changes and it gets gaises. So this is just the same gene. A 9-tascone Gorman-Farré. I'll go to the conclusion slide. Let's see. So just looking, I'll show you examples this morning. Just looking at the patient. In many cases you can just look at the patient, you know what resident. So ophthalmology is unusual compared to medicine because in internal medicine you can only meet a victim can only find out two conditions. Acontroplasia. Every patient with acontroplasia pretty much is going to have a mutation in the 380 residue for the fibroblast growth factor receptor 3. You make a diagnosis of progeria then you're going to know the patient is going to have a mutation in the laminate A gene in 1824 residue. In other cases including a lot of disorder, you look at the patient in combination with imaging in actual diagnostic testing you cannot tell which residue but you can tell which gene. So doing one single gene testing it took you like $200 clear testing. Whole exome sequencing, clear testing will typically cost you like $6,000. So now you can help you to target DNA screening instead of just doing whole genome sequencing. Knowing the gene give patient better prognosis allow pre-symptomatic testing and carrier detection and this all this is because in the future gene therapy will actually be gene specific. And then also we can now determine what gene even with pharmacological treatment then maybe we can determine what gene that would be more treatable. And so we learn more and more that we can get better genotype and phenotype correlationship. Genes can cause retinal degeneration I'll show you in the case of pattern macrodistrophy make the diagnosis with the spit code order for us. You know there's going to be LDS periferin at the 172 residue at trophic areata it's going to be the T net gene 421 residue maternally inherited diabetes and deafness it's going to be the TRNA losing gene the mitochondrial 3243 residue Doin honeycomb malatia is going to be fibrillin 3 345 residue late onset retinal degeneration is going to be CTRP5 gene and in the other cases you can tell what gene and you can focus your screening. So this is one of the ophthalmology one of the few areas in medicine you can look at the patient and you can tell what gene I suppose a lot of the in pediatrics and in neurology they're moving toward whole exome genome sequencing as a diagnostic primary diagnostic too because when they look at the patient they cannot tell what gene the patient got but in ophthalmology most many cases we can tell the patient what gene so we can focus your gene screening that's why you can start doing genotyping in your own clinic this afternoon Everybody's invited we have a course in January we have about 60 residents from all over the country and different people have come and teach our course in January we have Dr. Japs, Marco Peter Goros Don DeMico come to teach Graham Holder, Yajik Joe Deema, Ralph Eagle Alan comes to teach in January Larry teach also Tom Sakma even Mike Woodruff came all the speakers are based on cost evaluation the resident did not like photo transduction so we didn't have that we didn't have Tom Sakma and Mike Woodruff came back to teach anymore all of us SACs used to teach also, Andy Lee Tony Moore and Irene Momely also came to teach he deserve an angle also came to teach our course Ian McDonald to return for your hospitality all the residents and fellows they invited to come also to our course in January Thank you Any questions? I'd like to ask a question How about I think those students that you presented are really nice and that there is like a great relationship what about those students for example the pattern of this how do you compare your thoughts on that so we always look at the family because your differential sometimes there is some overlap between Stargard and Pedestrian so look at the family first to see if this establishes dominant or recessive and then you do the most likely gene first which is LDS is this negative you can consider do a retina panel if there is still negative whole exome sequencing or whole genome sequencing as a backup but there are still cases there with with whole exome sequencing we can now probably solve about 80% of our cases though so the whole exome sequencing depend on insurance New York New Jersey Blue Cross Blue Shield you can get them done pretty easily Aetna is quite difficult to get whole exome sequencing done but the National Health Service the National Health Care is offering whole genome sequencing as a pilot study for 100,000 patients and many of the more fused patients already gotten the whole genome sequencing already so sometimes national health care can be good I think in Germany also do a lot of whole exome sequencing also covered by private insurance Thank you


Dear students, in this topic we shall discuss the agonistic behaviors in animals. The agonistic behaviors are those behaviors which involve confrontation, aggression, threat displays, attacks and fights between animals. Such behaviors are displayed by individuals of many animal species. The reason for such behaviors is the limited resources, that is, limited food, limited shelters and limited mates. The agonistic behaviors are usually used only to intimidate the enemies. They are usually not lethal. There are fights in animals, but they don't kill each other. These behaviors are seemingly, on the surface, these behaviors are anti-social behaviors. But they are still important in maintaining social order, in maintaining the territories and in maintaining the dominance hierarchies. There are two types of agonistic behaviors. First are the territorial behaviors and second are the dominance hierarchies. The territorial behaviors include territorial ownership and defense. To seize a place and protect it, this is territorial behavior. Territory is a fixed area in which an animal spends most of its time. It also protects the area and does not allow any other member of its species to go. The territorial behavior is found in most social animal populations. For example, territorial behavior is found in insects, crustaceans, fishes, amphibians, lizards, birds, mammals and humans in all types of animals. Now we shall discuss the purposes of territorial behavior. The first purpose of territorial behavior is to occupy a defined territory for breeding, as it is the main purpose of male birds and mammals. Males actively defend their occupied area against other males. A male who makes a territory there attracts a female, then performs courtship and mating without interference. Another purpose of territorial behavior is to occupy a territory with abundant food supply. Another purpose is to occupy a territory that provides shelter to the animal from predators and unfavorable climate. Dear students, now we shall discuss the dominance hierarchies. Dominants hierarchies are the organization of groups in such a way that some members of a group have greater access to resources, for example to food and to maids than the others. Some animal groups show dominance hierarchies in which some individuals are considered at the top of the order. Some members are considered at the top of the order and they have the first choice of resources. Those members who are at the bottom of this hierarchy do not get sufficient access to resources. This is how hierarchies exist in many vertebrate groups.


Hey guys, how are you doing? This is your boy Rich from Rich TV Live, and you can join the club at richpictaili.com where you too can learn how to win in the markets. We've got some big breaking news that we're gonna break for you right here, right now, only on Rich TV Live, Pharma there, PHRM, PHRRF. Here it is, you can see the symbol PHRM, PHRRF, Pharma there enters into research collaboration agreement with revive therapeutics for development of psilocybin, micro needle patch, big breaking news and focusing on partnership model for micro dose, MN trademark and macro dose, MN trademark patches to deliver psychedelics, creating value and intellectual property protection for psychedelic programs, providing pathways for partners to enter FDA phase one and two clinical studies in 2022 with psychedelics. This is the big breaking news for pharma there holdings limited. The big breaking news for pharma there holdings limited, a clinical stage psychedelics biotech company is pleased to announce it has entered into a research collaboration agreement with revive therapeutics, revive therapeutics on the OTCQB exchange under the symbol RVVTF in Canada on the Canadian security exchange under the symbol RVV and in Frankfurt, Germany under the symbol 31R, a specialty life sciences company focused on the research and development of therapeutics for medical needs and rare disorders to evaluate the delivery of psilocybin with pharma there's proprietary micro needle MN patch technology for neuro psychiatric disorders. Guys, we brought you guys pharma there first they've been a big winner for our community. They've been very volatile as well like all psychedelic stocks that come up and down. We will look at the chart of pharma there and revive. I just wanna go through the news and make sure everybody's aware of it because this is some very big news. Pharma there is currently conducting IND enabling research studies with micro dose MN trademark, a patent pending biocompatible and biodegradable gelatin, methacrylolial micro needle patch to deliver psilocybin to support an IND application with the FDA for clinical studies in 2022. Research results with micro dose MN trademark for psilocybin will be made available in November, 2021 which is right now. The company is also conducting research studies with its micro dose MN trademark and macro dose MN trademark patch as a next generation delivery system for psychedelics with ketamine, three and four, methylenedoxylamide, methamphetamine, MDMA, lysergic acid, diethanilamine, LSD, and NN demyndium T. So let's just, some hard words to say, we're gonna use the words MDMA, LSD and DMT. Also the company has decided to expand research to include ibogaine and mescaline. Partnership opportunities currently exist with MDMA, LSD, DMT, ibogaine and mescaline for specialty pharmaceutical companies seeking a differentiated and validation and validated delivery system for psychedelics. Desired pharma-co-kinetic profiles, intellectual property protection, CGMP microneedle patches for IND enabling and clinical studies and a clear pathway towards FDA phase one and two clinical studies in 2022. The company's micro dose MN trademark and macro dose dash MN trademark patches have the potential to efficiently penetrate the stratum, corneum layer, outer layer of the skin enabled flexible drug load capacity and combinations and control release delivery which may overcome the potential drawbacks of oral administration, subconscious injections, topical and nasal delivery systems in addition to the potential of maintaining constant plasma levels for more than 24 hours, the MN patches aim to empower patients to dose their medication remotely, safely, conveniently rather than under supervision by a healthcare provider at a certified medical office. To achieve this, the company will incorporate anti-tampering and anti-abuse features that would parallel the approach used for the tamper resistant, transdermal, fentanyl patch. We are pleased to collaborate with Revive in achieving their product portfolio objectives with psilocybin, our microneedle patch technologies aim to become next generation delivery system for psychedelics for various indications and healthcare environments. Although our focus remains on building our ketamine based product pipeline, we will continue to partner with specialty pharmaceutical companies seeking a delivery solution for psychedelics and proprietary drugs to unlock significant value and return on investment for a pharma there, said Fabio Cianelli, CEO of Pharma there. Michael Frank, CEO of the company commented, our focus is developing and commercializing a specialty psilocybin based product portfolio and to research collaboration with Pharma there, compliments our psilocybin product offering as potential treatment for mental illness, substance abuse and neurological disorders. We believe that there is no one fits all product profile solution with psilocybin. Let me reiterate that. We believe that there is no one fits all product profile solution with psilocybin for psilocybin to be a next generation therapeutic different use and delivery forms will be required to achieve the intended target indications as such we aim to become a leader in psilocybin based solutions for unmet medical needs by collaborating with companies that have intellectual property and experience in their delivery techniques such as Pharma there. What do you guys think about this partnership? Revive therapeutics and Pharma there. Revive is a life sciences company focused on the results research and development of therapeutics for infectious disease and rare disorders. And it is prioritizing drug development efforts to take advantage of several regulatory incentives awarded by the FDA such as orphan drug fast track, breakthrough therapy and rare pediatric disease designations currently the company is exploring the use of Bucillamine for the potential treatment of infectious disease with an initial focus on severe influenza and COVID-19 with its acquisition of psilocybin Pharma corp. Revive is advancing the development of psilocybin based therapeutics in various diseases and disorders. Revive cannabinoid pharmaceutical portfolio focuses on rare inflammatory disease and the company was granted FDA orphan drug status designation for the use of cannabinoidial CBD to treat autoimmune hepatitis liver disease and to treat eschema and reperfusion injury from organ transplantation. For more information, you can go to revivethera.com. Now let's tell you a little bit about Pharma Thera Holdings. We brought you guys Pharma Thera first. The been a big winner for our community. Congratulations to investors. Pharma Thera Holdings Limited, PHRRF in America. PHRM in Canada is a clinical stage psychedelics biotech company focused on the research, development and commercialization of novel uses, formulations and delivery methods of psychedelics such as ketamine to treat mental health, neurological and pain disorders. Pharma Thera is currently advancing an FDA approved phase two clinical study with ketamine to treat Parkinson's disease and is developing a novel micro needle patch for the intradermal delivery of psychedelics and infectious disease treatments. You can go to pharmathera.com and see their website. You can follow them on Twitter. You can follow them on LinkedIn and we've gone through all of their different platforms that you can review and watch them on. So once again, the big news, Pharma Thera enters into a research collaboration agreement with Revive Therapeutics for the development of psilocybin micro needle patch. So the big news, now let's just go through the charts. I'm gonna share my screen with you right now and we're gonna go through the charts. So first and foremost, the first chart you see here is Pharma Thera PHRM and you can clearly see that we had our buy zone here at 20 cents. They went all the way up to a high of $1.23 where hopefully investors locked in profits and then they've come all the way back down. So this is extremely, extremely volatile. You can see that it's made this big move up where it was a five bagger from 20 cents to $1.20 and now it's made this move down where it's given back a lot of those gains and it's all the way back down to now 45 cents. So like all psychedelic stocks, it's been extremely volatile, had some good moves up and just recently taken this move back down. So the question is, where does it go from here? So this is the symbol in Canada, PhRRF is the symbol in America, looks a lot of the same as you can see here, made us move up and then came back down. And like all psychedelic stocks, they've been really struggling because they are all lacking in revenue and revenue growth and the street wants to see revenue. Now let's take a look at revive therapeutics. This is their one-year chart. So you can see that they've been pretty choppy, a lot of up and down movement. You can see here that they have trended up. RVV is a symbol in Canada and RVVTF in America.  And a lot of this is due to the fact that these companies are really lacking in revenue. If and when we see these companies grow their revenues, then I think we could see them really expand and grow and maintain a higher share price. But this news is the type of news that can help them get closer to revenue. Once again, pharma there enters into a research collaboration agreement with revive therapeutics for the development of psilocybin microneedle patch. What do you guys think of this news? What do you guys think about these videos? If you like this news, please smash the like button, comment down below, share the video everywhere and subscribe. Remember Rich TV Lab is strictly for information and education purposes. Please do your due diligence, do your research before you invest anything that we talked about here on Rich TV Live. And let's just take a look at these two websites. So pharmathera.com. All right, so this is the pharmathera.com website where you can do your research and learn more about this up and coming small cap company and revivethera.com. And this is revivethera.com. So this is the revive therapeutics website and this is a big, big, big deal for the sector, for the psychedelic sector. And like I said to you guys, we're strictly for information education purposes. We love to bring you the news, we love to break it down and make sure that you understand exactly what's going on. So once again, this is the big breaking news today. Pharmathera Holdings, PHRM in Canada, PHRF in America, a clinical stage, psychedelics biotech company is pleased to announce it's entered into a research collaboration agreement with revive therapeutics, a specialty life science company focused on the research and development of therapeutics for medical needs and rare disorders to evaluate the delivery of psilocybin with pharmathera's proprietary micro needle patch technology for neuro psychiatric disorders. What do you guys think of this news? Love to know, please comment down below, share the video everywhere and subscribe. Take a look at revive therapeutics website, take a look at pharmathera's website and we're gonna be watching these stocks very closely all day today. Let me know what you guys think. Are you buying these stocks? Do you hold these stocks? Are you thinking about positioning yourself in these companies? Let me know what you think. Is your boy rich from Rich to be live? Told you guys, if you're not winning, you're probably not watching. We bring in the winners, we bring in the news, we break down the deals and we do it first. Thank you guys for watching. Is your boy rich from Rich to be live and join the club at richpictailie.com where you two can learn how to become a profitable trader. What do you guys think of this news? Could be a catalyst for the sector, could be a catalyst for pharmathera and revive therapeutics. Thank you guys for watching. If you're not winning, you're probably not watching. We bring in the winners, we bring in the news and we bring it to you first. Thank you for watching everybody. Have a great day. Is your boy rich from Rich to be live and richpictailie.com and I'm out. Peace. It's big news. It's true.


He's traveled Great Card, Scotia Bank Gold, American Express, now a cashback Great Card as well. Hello everyone, this is financial author Amit Don of Adon Journal. Today I'll talk about some recent changes Scotia Bank made towards its Scotia Bank Gold, American Express Great Card. Scotia Bank Gold, American Express Great Card is known for its mega proprietary points offered on selected categories beating any other Canadian cards. For example, 4 points per every dollar spent on eligible gas, grocery, dining and entertainment purchases in Canada. You can read my full review mentioned in the link below. However, a recent change made on Scotia Rewards Program starting November 2006 makes Scotia Bank Gold, American Express Great Card a cashback Great Card as well. In the past, Scotia Bank Gold, American Express Great Card members were only allowed to redeem points for travel purchases as it's a travel Rewards Great Card. But to make the use of this card more flexible and attractive, Scotia Bank is now allowing it to redeem points for statement credit on any purchases. This change of feature makes this card basically a travel Great Card that works as a cashback Great Card as well. However, this change puts Scotia Bank Gold, American Express Great Card in direct competition with Scotia's own cashback Great Card, the Scotia Momentum Visa Infinite Card which offers 4 points on gas and grocery and 2 points on pharmacy and recurring bills and 1 points on everything else. You can read my review on the Scotia Momentum Visa Infinite Card on eranjournal.com if you need to decide which one to choose. There's another travel Great Card, the MBNA World Elite Rewards Mastercard which offers a flat 2% per dollar on all spending and allows it to redeem points for cashback as well. I consider this change by Scotia Bank which is to redeem cashback for points on all purchases or on all statement transactions as a positive change as it provides greater flexibility for its customers. That's all for today. Thank you.


Somewhere lurking in those waters hiding is a submarine and during the exercise the U.S. and Republic of Singapore navies work together using a variety of assets to find it. As a destroyer I usually don't get the opportunity to be the anti-submarine warfare commander and so this presents us an opportunity for us to grow tactically to take that next step, the next level of warfare. The different platforms play a game of cat and mouse, each trying to find the other first. The U.S. and Singapore navies take turns as the leadership actively searching for their counterpart submarine. They can hide easily, because they're quiet, we're I guess the first defense, I guess in a world-like scenario against enemy subs so if we don't go to our job, chances are we're not going to make it.


So the wiring project here it rubbed up fun is done I'm gonna give you a little tour here of what we did what we built how we set things up and How we put this together and some of the planning that went into it I'm gonna do this as a voiceover because the place is live and open and it's too loud out there So I just want to do the intro here, but everything's built the racks built the answer mounted We have the nbr mounted over here same nbr. We talked about the link before for the build to that We chose a vertical mount for this Rack up here as you may have noticed I'm up on a ladder because all this goes way up to the top If you've seen some of the previous videos on this, you'll see how the wiring goes up and over But let's give you a tour of this So this is a wrap-up video to our revved up fun project. We started at ground zero We got in here at the very beginning with everything raw Waiting for the HVAC people to start getting their installed and they were the first installers there The way you do a project this is we start with the general contractor and coordinate all the times And we worked in shifts and off hours So we're able to share the man lifts with the other electrical contractors This allowed us to save the client money instead of us renting them and trying to use ours at the same time the Electrical people are working so we get to work on the off hours but then unfortunately we come in sometimes and find things like this where someone whacked into the rack and Busted a hole in the wall that happens the rack and everything is about 20 foot up And we have all the wires mounted and sailing one with all black cabling to help obscure it And then we have them all mounted very snuggled bridal rings You run those every few feet to make sure all the wires stay nice and tight and nothing's sagging the final product is Outstanding we're really happy with the way this turned out This entire project was really cool to watch it come the life and see all these different rides and all the different Gaming machines hooked up here, especially this one right here to my right called the dark ride really cool If you haven't seen it go look for a place it has one or come down to Detroit here and visit Revdup font Overall this project really wasn't very troublesome There was always little delays for some of the other contractors But in in the end it turned out really really nice the unified camera system We put in had no problem working with the laser tag room and the black lights here And then in the party rooms where you can rent for birthday parties We mounted some TVs and these what they refer to as the bays and then we put an HDMI port So you can just bring maybe an Xbox or PlayStation whichever device they want to plug in and run something on TVs It's easy and convenient for them to take care of that when they have a part of your family gathering But this is Revdup font in Woodhaven. It was a fun project and we're happy. It's done I'll have some other videos that dive deeper into some of the technical details coming soon. Thanks Thanks for watching if you liked this video go ahead and click the thumbs up Leave us some feedback below to let us know any details Which you like and didn't like as well because we love hearing a feedback or if you just want to say Thanks, leave a comment if you wanted to be notified of new videos as they come out Go ahead and to subscribe and the bell icon that lets YouTube know that you're interested in notifications Hopefully they send them as we've learned with YouTube. Anyways, if you want to contact us for consulting services You go ahead and hit launch systems comm and you can reach out to us for all the projects that we can do and help you We work with a lot of small businesses IT companies even some large companies and you can farm different workout to us Or just hire us as a consultant to help design your network Also, if you want to help the channel in other ways, we have a patreon. We have affiliate links You'll find them in the description You'll also find recommendations to other affiliate links and things you can sign up for on Lawrence systems comm once again Thanks for watching and I'll see you in the next video


I'm cooking dinner right now and I think I have time before anything burns to say something. Okay, two days ago, I did my usual Sunday live at five, give or take, four hours. But anyway, there's this one guy who made a comment that kinda like really irritated me and I blocked him and I didn't have time to talk about it then because it was getting toward the end of the thing but I wanna talk about it now because it brings up some really important points and it's important things about our society and it'll make sense in a minute. So first, the comment he said was something like, Jamie, you're really smart but your understanding of hydrofoils is laughable. And you know, it's kind of a snarky thing to say so that was a little bit irritating but that's not why it pissed me off. And one of the reasons it pissed me off was because if this guy's been watching my videos long enough to have seen the hydrofoil experiment I did like seven years ago, he should know better. So you should know better dude if you're watching this but I don't wanna beat on you but I wanna talk about the important point it brings up and it's not just you. So I hope I'm not like crapping on you or anything. Okay, so whenever I, and not just me this applies to a lot of people but I'm just gonna talk about myself. So whenever I build anything, I could divide it into two different categories, practical or experimental. Now the practical method is what we mostly learn in school like almost, that's almost all we learn in school which is you have to get to the final answer as quickly as possible with no mistakes or you lose points. And an example of this would be if someone hired me to build them a deck and I'm not gonna get paid more for trying out fancy things or trying to do anything experimental. No, I just need to go from beginning to finished deck as quickly as possible using as few resources as possible. So I'm just gonna build the same deck everyone else builds and it's gonna be easy to do because I know how to do that and I know how to calculate the wood I'm gonna get from A to B as straight line as possible. And then everyone's happy at the end and that's great. So why would anyone ever wanna do anything the experimental way, which is strongly discouraged in our society which is terrible and I'll explain why in a minute. Okay, there are a couple of reasons that a person would wanna do things the experimental way. One is that you've never seen the thing you're trying to build before. Like one doesn't exist, you're the first one making it or at least you're not aware of any other one. An example of this would be when I built the spider tanks. You know, I think pretty much everyone here knows about these spider tank robots I made that ended up being sold in stores and they sold really well and paid for my family to move to Central America. But when I first came up with the idea for those I wanted to build a prototype to learn a bunch of stuff. So I built this prototype and it was just garbage. It was a garbage prototype. It was like coat hangers and the joints were just like coat hanger wrapped around another coat hanger, a squeaky and it was held together with duct tape and it was just, it looked like garbage and it was crap but it functioned well enough that I was like, I'm pretty sure I can do something with this and make it really cool. So that's one thing I learned. And the other thing I learned was what is entailed in making one of these? So I learned basically what it's gonna take to develop this, because I know what I'm gonna have to do to make prototypes of this thing. And I got a glimpse of how cool it's gonna be. So I made a second prototype and a third prototype and none of those would have been called final products at all. But each one taught me a new thing and I tested limits of things and answered different technical questions and when I got to the fourth prototype I was like, all right, now I think I can make a final product that's really good. So I sat down, drew out things, did measurements and everything, got everything, oh, lately. Before I even started building thing and then I built the thing and I came up with this white plastic spider tank that was real slick and just, oh, it works so well. It was actually the first, I made a little video of it, just a seven second video, yeah, seven seconds and put it on YouTube. I think it was the first video I ever put up on YouTube and it got 200,000 views which was, it was a lot of views back then, trust me, like when YouTube was just starting. But people loved it because it was so cool, it was original, it was this weird thing no one had seen before and like it worked so well, it was so smooth and everything, it was pretty slick.  But say I built that first prototype and I looked at it and was like, well, that could be a pretty cool thing but that took kind of a lot of resources, a lot of time to make that first prototype, I don't think it's worth developing right now. So let me put that aside, you know, maybe I'll get back to it at some point. If I'd done that and stopped there, someone could easily come along and say, oh, it's that garbage, you really don't know how to make things. Oh, I wanna slap people who do that because this doesn't affect me really because long ago I learned to ignore that kind of garbage and I do whatever I'm gonna do regardless. But there are so many people out there who wanna try things, who wanna make something they've never seen before.  This is no one's done it before, right? And when people come along and say, I don't know what you're doing and critique like a beginning development or even a mid-development as if it's a final product, oh, I just wanna smack that person. But anyway, let's keep going here. Now, there's another reason you might want to use the experimental method, which is to learn all the stuff that people previously had learned to get to the point where they are.  And maybe you'll be like, well, I wanna explore this path and you can come up with different things and often you'll end up with a different final product that someone else did. And maybe you'll come up with a better final product that someone else did than anyone has done before or whatever, you know? It's how things improve and develop. And a perfect example of this, hold on, I gotta check my, let me just, boom. Okay, a perfect example of this would be when I started building boats. Now, I totally had a choice there. There are plenty of boats in the world. I could have just bought a boat. Go straight to practical. Quickest way, just buy what someone else has done. Or I could have just, I could have built a boat that's like some, that's just some plans from the internet or copy someone else's boat. I could get straight to a final product pretty quickly that way, right? On the other hand, I could say, okay, look, I'm gonna be living on the water probably for the rest of my life.  If I start development at the beginning, I'm gonna learn all this kind of, all this cool stuff that I wouldn't learn if I just leapfrogged ahead.  Like I'm gonna get somewhere that's not just the same as everyone else is doing. So the first boat I made, I just spent $200 and made this little catamaran. And then I, you know, paddled it around for a while. And then I put a sail up on it and sailed around for a couple of weeks. And then I put this fishtail that was like and flapped in thing. And then the first time I tried electric motors with solar panels. I just had these crappy car fan motors that I found in some place. And they were like kind of, it was just this jerry rigged together garbage and these junky propellers I made out of fiberglass that weren't very well shaped or anything. I was like, this will give me an idea. And then the solar panels, I just laid on the front of the boat precariously. And if one wave came by, this whole thing would have been wrecked. But I was like, no, I just gotta take this out in the calm water and do a little test. And the first time I turned those motors on, I didn't even turn them on. I just held two wires together, twisted them and was like, okay. And as soon as it started going, I was like, ah, I can do something with this. This solar boat thing can totally be good. Cause this is just a crappy model. It's garbage, right? Totally garbage. But it's got enough potential. I can see what's going on. And it's gonna be worth the amount of resources it's gonna take me to develop this to get it to be something really good. Now, if I had stopped at that point, someone could easily come along and say, eh, you don't know how to build a boat.  Ah. But I didn't stop there. I, you know, made more things, made new motors. I went through a whole, there was this whole evolution of motors that I went through to figure out how to make better propellers, you know, have the motors, all kinds of different things and the test different kind of bearings. You just make all kinds of different things to make the motors good, to make the boat go. And then I made different boat hulls over the years and I kept experimenting with boats. And I'll tell you, the boats that I have right now are awesome. They're really good. And they're not anything I could have bought anywhere. I couldn't buy my solar electric boats. I could maybe get someone else to custom make them, but there were no examples that I could find that were as good as my solar boats. And I think maybe I understate how good my boats are sometimes because sometimes people send me, this actually happens kind of a lot, people send me links to videos of other people's boats and they're like, hey, it's just like yours.  Definitely couldn't handle the wear and tear of everyday use.  Figuring things out, learning things, learning things, trying different paths and finally getting to a point where I'm like, oh, I can make this boat. I can drive it all over the place. The maintenance is like almost nothing and they're just really good. And I got there because I did the experimental path. And now I also understand tons of stuff about boats that I could not even teach you without making you go through the same development process. And the fact that schools don't teach us to do this is so frustrating. Anyway, and you know, schools teach us you gotta get to the final answer as quickly as possible. And if you don't, you lose points.  And you know, I've obviously gotten over the need of acceptance from people. I'm gonna build whatever I'm building and do what I'm doing.  And I don't care, it doesn't matter. I'm still gonna do my thing, right?   Like, yeah, I don't know what I'm doing. I'm doing a thing. I'm often, I'm purposely not knowing what I'm doing because I wanna throw out all the ideas that I have so I can start with zero first principles and actually start from the beginning and go through the evolution of the development and not necessarily go the same direction everyone else has gone. Because maybe I'm gonna come up with something new.   Because here's what happens. All throughout history, we've got these civilizations that grow and then fall and grow and fall and grow and fall, right? Who's building the civilizations? Who's pulling people up out of the mud, out of the muck and creating civilization, creating a life where things are easier, where people aren't just dying all the time. It's the creative imaginative people. It's the people, the weirdos and the nerds like me and like weirdo nerds like people who are looked down upon today. Those are the people who created our civilization. Those are the people who made everything we have around us. All the stuff, all this effing stuff we have. Like, whoa, like this didn't exist until some weird nerd was like, let me see if I can figure out how to make a better spoon than a wood spoon. Is there something, some way to make metal, not rust, stainless steel? That wasn't just given to us by the gods.  And that's how civilizations are built. And civilizations get built and life gets really easy.  It doesn't matter what we do anymore. There's no consequences anymore.  Life is so easy now that we don't have to struggle to survive. So we can put our efforts into being jealous of the creative, intelligent people who are trying experimental things and trying to figure out how to make life better. And instead of looking at them and saying, you guys are awesome, please keep doing your thing, these ignorant people say, I'm jealous that you can do that and I can't.  And that's why nerds and weirdos are looked down. We're at that point in our society where things are really easy.  And that's how civilization falls. And our civilization is falling right now.  I go back 500 years, it's so much better now than it was then. So what are you talking about? And like, yeah, it's better now because of all the weirdos who invented all this new stuff. Like, you know, in the United States, there was so much freedom for such a long period of time. And I don't wanna get into who had freedom and who did, but that's a whole can of worms. But there was enough freedom that people were experimenting with things and trying things and coming up with all this new stuff and creating all these amazing inventions that made life easy for a lot of people everywhere. And that's not the only place this was happening. But that was one of the major ones. And now we're enjoying all the fruits of all that labor, but our society's going downhill. Like, it's pretty hard to argue against that when we have more technology now, but we have to have two parents working at the same time to bring in enough money to live. Like, that didn't used to happen, right? Our society's going downhill. It's still really good, but you have to look at the direction. It's going downhill because we're stomping on the creative people and we're getting rid of the ideas and we're crapping on anyone's mistakes and experiments and stuff. So anyway, just to elaborate on the specific thing this guy was talking about, I did this hydrofoil experiment. I just made this crappy hydrofoil on a kayak just to get an idea of what it's gonna take to develop this thing. And after doing one quick prototype that I slapped together real fast, I was like, I don't think this is gonna be worth the amount of effort. So I'm gonna put it aside. And I didn't do anything with it.  You don't know what you're doing. So, you know, when you see someone trying something, especially a kid, but it doesn't have to be a kid. It can be an adult and they're experimenting and trying something and they're failing or they're not doing that a good job.   Hey, that's cool that you're trying something.  You know, that's how all the cool stuff in the world happens. You keep doing it, man. That's what you should be saying.  Oh, God.


Russian Defence Ministry is reinforcing Wagner rights to capture Barkhmut. Despite the fact that there is infighting between the Russian Defence Ministry and Yevgeny Prigozin, the founder of the Wagner Group, Wagner militants are being reinforced with modern means to capture the city of Barkhmut. The US-based Institute for the Study of War announced it. The report points out that the news of the reassignment of Russian Airborne Commander Mikhail Teplinsky indicates that the Russian Defence Ministry is seeking to work more closely with the Wagner Group to complete the capture of Barkhmut, despite the obvious tensions between Prigozin and the Defence Ministry leadership. In addition, experts say Prigozin has also reduced his outspoken attacks on the Defence Ministry in recent days. Russian military bloggers also report that Wagner's forces are using T-90 tanks in Barkhmut, indicating that the Russian leadership has provided the group with more modern means to capture the city. Experts point out that the Russian military command appears to be increasingly shifting responsibility for offensive operations in Ukraine to the Russian airborne forces. According to experts, it is unlikely that Teplinsky will be able to restore the previous status of the airborne forces as an elite unit due to the significant losses in Ukraine. Widespread losses to previously elite units that are now being restaffed with poorly trained mobilised personnel are likely to have long-term impacts on the combat effectiveness of these units and the replacement of a single commander is highly unlikely to be able to solve such pervasive damage, the report reads. Experts also note that Wagner's group released 130 Ukrainian prisoners of war on the 16th of April, which suggests that Wagner could have carried out the exchange independently of the Russian Defence Ministry. The report suggests that Wagner's group may be trying to force mobilised Russian servicemen to sign contracts with Wagner, possibly in an effort to compensate for losses in Ukraine. As an example, experts cite the fact that conscripts from Moscow and Ivanovo oblasts of the Russian Federation in a public complaint published on the 16th of April claim that the Wagner group forced 170 mobilised servicemen to sign contracts with it. Earlier, Russian sources claimed that 100 conscripts in Luhansk oblast disappeared on the 7th of April after refusing to sign contracts with Wagner.


So when it comes to that curiosity, what can I learn from someone in the workplace? How do we strengthen it with our peers and colleagues? Yeah, and I think it's really important that you highlight the perceived tension between being curious about other people versus solving a problem and getting to the answer faster. Where a lot of this methodology for me originated was in the context of management where we are solving problems all the time. And what we realized is that if we are just coming into our clients and saying, we've analyzed your problem, here's the solution, here's what you should do, and we don't ask them any questions, not only does that push them away and alienate us, but chances are the solution that we are coming up with is not a complete solution. It might even be the completely wrong solution. What we need to be doing is to say, here's what I'm thinking. What does that make you think? What am I missing? What is another way to look at this problem? And so the kind of connective curiosity that I'm talking about is not just about what are your feelings and what's our relationship like. It's what do you see? What information do you have that I don't have? What stories have you lived in this company, in this industry, in this life, all of these things that will literally help me to check my own thinking? It's even curiosity about what might be the holes in my own approach. If I could be curious about that and what might somebody else know about that, I'm getting to my answers so much better and so much faster. And sometimes it's as pointed as what is your reaction to what I just shared? What is your reaction? Yeah, we can talk about that again when we talk about questions. That is one of the most underutilized questions. What is your reaction? How does that land with you? Too often, we assume that once I say my view, if the other person has a reaction, of course, they're going to say it to me. But there's so many reasons, especially if we're working across any kind of lines of difference or power differences, et cetera, they're not going to tell you their reaction unless you communicate that you want to know their reaction. And just that simple question is so underutilized. Well, that reaction brings up a good point. That reaction is due to an emotion, a emotion from what was said and what is being discussed. Sitting in that emotion, sharing that emotion is what connects us. Just going through the logistics of here's the problem. Here's the solution. It's not going to bond anyone. It's not going to make anyone want to work with somebody. All it does is bring awareness to what this person, how they see what that problem solution is. I mean, we need that back and forth. And for us to want to work with somebody and then also in order to connect, we have to feel that the other person understands me. They get me. They see and hear me. And that can't happen unless I'm able to fully disclose how I'm feeling, the way I'm looking at things without that. How do I know that this other person is vibing with me, that they understand what I need from them in order for any solution to work? 100%. Yes, that builds the foundation of connection. And we videotape our clients. So getting back to your earlier point around body language, we will often ask them to read just off the cuff. What's their body language? And it's so funny how interesting and often it's mismatched. So the person who's actually reacting is reacting in a way that the body language doesn't actually match how they're feeling on the inside. Yet we have this view of body language, like it's this perfect reflection of how the person's perceiving what we just said, how they're reacting to what they just heard and what their next move or emotion is. When in reality, we are, again, as you said earlier, just guessing at chance, throwing darts at the wall. So delving a little deeper into curiosity, because this is ultimately the skill set that we want all of our listeners to master because it unlocks all of the other steps in the method. For those of us who like speed, like velocity, want to just move forward and plow ahead, curiosity and taking the time and the pause to survey and ask these questions can feel monotonous, sluggish and keep us from getting to the results that we want as fast as possible. What do you say to that person who wants to move quickly and maybe not be as curious as they should be? I mean, what I would say to that is if you are happy with the results you're getting in your work and your life, you're doing something right. But chances are for any one of us, there is some edge that we have. There's a learning edge, there's a performance edge, etc. There's some place where we're stuck. And it's at that moment that curiosity is going to be the thing that unlocks you. So I'm not saying you have to stop and ask yourself, do I shave this way in the morning? Do I get in my car? Do I have to ride? Like there's lots of things that we can just do their routine task or that we're good at or that we're successful at and it's working for us. Go for it. But when you want to level up, when you want to get over that challenge, that's the moment when curiosity is going to be your unlock.