Human genetic variation, and in fact, I'm sure most of you did it when you came in the room. You looked around, you said, are there any relatives here? Anyone that's a threat? Anyone that's a mate? Even some of you did that that won't admit to it. But behavioral genetics is a different topic. And what I, my goal today is to talk specifically about kind of the nuts and bolts of human genetic variation. To answer some of the questions, they just came up from the back. And it, starting with this as kind of a segue from Emily's talk. Anyone here from this publication? I use this because it actually highlights a little bit of human genetic variation and that there's probably some genetic variation between here and here. You'll note that there's practically no variation between hair color here. And that's probably an environmental influence, I would guess. I don't have any firsthand knowledge or anything about that. So if you look around the room, you look on this slide, you'll see that humans come in a lot of shapes, sizes, colors. And what I'm going to talk to you about today is not how that happens. Because I can tell you that we don't know it all, the whole genome association studies will help us start answering that question. But I'm going to tell you about what the raw material is in our genomes that produces these diverse phenotypes. And not spend much time on the commercial products that produce hair color. So these are the topics, the three that I'll cover in the last one is the one we're talking, we're here about today. It's a human genetic variation. What is it? Where did it come from? How is it scored? And we're here today to figure out what use it is, especially from the biomedical realm. We will dip a little bit into anthropology because there's a lot of ancillary uses to these kinds of data sets that we're generating. So genetics, as most of you know, starts here with Mendel and his peas. And if you look on this slide, you'll see there are peas that, at least from up here, don't look like they're yellow and green, but they come in two flavors. And this is a product of a cross where you get essentially peas of two kinds.  If you look at the peas in here, it does bring up one human analogy which is peas in a pod, like peas in a pod. And so these humans are like peas. They're identical twins and they share exactly 100% of their DNA, at least initially. So in this case, if we have 100% of the DNA, it's the same. We produce traits or phenotypes that are very, very similar. It's a rare occurrence, but most of you probably have met identical twins in your life. I actually lived next door for about a decade to a pair of identical twins. It started when they were four years old, so I saw them from four to 14. And it was amazing how much over that period, when they were four-year-olds, I could not tell them apart. They finished each other's sentences. They dressed alike. But by the time they were 14, they started to separate. And so to underscore what Emily said, as we age, our environment starts to influence our genetic. Our genetic kind of sets the stage. Here's another pair of individuals. Obviously not the same, although from the point of view of accomplishment in their fields, they're probably somewhat equivalent in being at the best of the time. They obviously don't share 100% of their genes. They do in some way share some of their environment, but I can tell you that my dad went to school with one of these guys. And it's not the short guy like me. It's actually the tall guy. And even though they had shared environment, they didn't turn out the same way. So what explains this? The other take-home message, and I forgot to tell you, there's a quiz during this talk and some homework. So if you're typing your assignment, wait till I give it to you. Let underlies that. In fact, in human beings, we're not like peas. And almost all genetic traits, in fact, I challenge audiences of geneticists to come up with more than five Mendelian traits. So things that are inherited just like the peas, either green or yellow, that occur in humans that aren't diseases. And I won't ask, that's not the quiz. The quiz is actually easier than that. If you try to think of human traits that are influenced and inherited just like Mendelian disorders in humans, there just aren't very many. Most of them look like this. And so this is a snapshot taken 1914 of British military recruits lined up in height order. And as most of you who have had statistics at some point can kind of see, it's roughly a bell curve. And this is what human phenotypes or traits look like, is that they come in a range of flavors. And we know that if you were to, and let's just assume you could do that, cross this person and this person, the tallest and the shortest on this picture, you would not get offspring that were all shorter, all tall. What you would get are offspring that show the full range. And so what happens, the reason we get this is two reasons. One, there are little variants in the genome that have small effects and then there are also a lot of them that kind of add up to this kind of distribution. And so now I'll talk about exactly what they are. All of this that produces what you are is encoded in all of your genes, your genome. So this is a cell, this is the chromosomes from the cell just kind of spewed out onto a slide and this is them in size order. So all of the information you need to make you is stored in these chromosomes. By way that's about half protein, half DNA. We're going to talk about DNA as information part of it now. And so here's your homework assignment. This is what DNA looks like. It's just four letters repeated roughly a billion times or so depending upon what organism you are. But the entire story is told with four letters. So the homework assignment is your next story. File it using only four letters. You can choose whatever you want. So you have 26, if you're writing in English, you have 26 to choose from. This is what codes us. And if you look at the information on the screen, it doesn't really tell you a huge amount. The other important thing about this system is that it self replicates. And so this is another amazing property other than the fact that you can convey all the information to make a human being using four letters. It actually has enough information to copy itself. And that brings up the one feature of DNA that we're going to talk about today in that DNA replication is essentially almost perfect. And some of you probably had to take a information theory class in college at some point. Information theory tells us that if we have a self replicating system, it can be no better than making one mistake per replication event. And in fact, DNA and its self replicating actually approaches close to that theoretical limit. Every time a DNA molecule replicates, it makes a couple of mistakes. So every time it copies itself, it makes one or two mistakes out of a couple of billion. Now it does that by a complicated system that Emily kind of talked about. It's not only is there people who type, there's copy editors who take out the mistakes as they go, but the result is some mistakes are made. Now mistakes aren't necessarily thought of usually as a good thing. The reason I say luckily they've been made because imagine primordial organism that first started encoding itself in its information in DNA. What if it never made a mistake? We wouldn't be here because the mistakes lead to changes in DNA and raw material for selection. And these kind of mistakes or errors in self copying kind of come in three flavors, the good, the bad, and the indifferent. And I will tell you now that we tend to focus on the bad because those are the ones that cause disease. But almost 99.9% of all the mutations or variants in our genome are essentially indifferent. They don't matter. So you could imagine if you were typing on your laptop and you had two keys for the letter T, and sometimes you hit one and other times you hit the other key, it wouldn't really make any difference. It wouldn't change the meaning of the word, it wouldn't change what happens. Most of the errors in DNA come in that flavor that they don't make a difference. And that's good because we actually have a lot of them. It also means that we all walk around with differences. And so that everyone in this room is different from everyone else in this room because of these changes in their DNA. So what I'd like to do is to stage as to how these happen. And this is the only math in the talk. But think about a new mutation. They don't happen by direction, they happen by chance for the most part. And so what happens if this is a population and this is time measured in generations so your distant ancestors are here and today we're about up here. And this is the frequency of mutation. All the mutations that we have for the most part started in one person. And when that happens and they pass it on to their children, that child can either pass the mutation on to their children and their children and so on. Or what happens most often is the mutation might get up into the population at some frequency and almost all of the mutations then die out of the population, the frequency goes back to zero. Occasionally mutations, so if this was one variant here, say this was a C at this position, over time it could be completely replaced by a T. And so that we would all have, this could be a very successful variant and in fact it could have some advantage so that everyone who had a C at this position, if I come back years later they know I'll have a T. What happens more often is that these things just kind of drift around a bit. And so if we come in today and ask what do we see in the genome today, so we take a slice through it, we see variants at all different kinds of frequencies. If we were to come back a long time from now in our population because it's so large, those variants would probably still say at the same frequencies. If we go and someone was asking about isolated populations, in isolated populations because they're small, the variants can change frequency a lot more readily. But this is what we look at when we're looking at variants in the genome. We're taking a cross-section looking at things that are currently variable. As Francis mentioned they come in two flavors for the most part. The SNPs are single nucleotide polymorphisms which we're going to spend most of the time on today and put duplications, deletions or segmental variants in your genome on your radar screen because we think they might be important but we don't necessarily test for them very well and we don't necessarily understand what they do yet. So these are cases where instead of having the same address but different color doors, in this case there's whole blocks, city blocks missing. And what we've discovered over the last couple of years is that people in this room might have genomes that are different sizes. Some of your genomes might be missing, thousands of kilobases of DNA, some might have maybe not thousands but hundreds of bases of DNA and others might have more or less. But today we're just going to focus in on single nucleotide polymorphisms because that's what we're using in these studies that you'll hear a lot about. And why are we working with single nucleotide polymorphisms? The first you already heard about, they're numerous and I'll tell you how numerous the second. The second is that they're stable and I'll talk about how they are stable and how stable they are. The third and probably the biggest reason is they are very easy to score using carrying technologies and I will show you some of it. There's actually show and tell in addition to the quiz and the homework. I'll show you some of the technologies that are used to score this. And the third is that sometimes they're actually in genes and we can interpret them. So this is what a SNP looks like. It's not very fancy. Here's, let's pretend that this is Larry Thompson's DNA, this is my DNA, this is Terry's DNA. If we were to sequence along the same stretch in the chromosome, most of the bases would match. But occasionally we would hit variants where, and I think this was me, where I have a T, Terry has a C. Over here you can see, was this you Larry? This is Larry, he has an A, the rest of us have a G. These are simply nucleotide changes that happen due to this replication error, lack of DNA repair. They are all over the genome. In fact, if you compare any two chromosomes and all of you have for each part of your genome, you've inherited two copies, one from your mom and one from your dad, those chromosomes will differ about one every thousand bases. And so I don't know at what rate errors creep into the columns you write, but I'm sure that your copy editors pointed out to them when you make one. One in a thousand, you guys probably do better than one in a thousand. But our genomes have these errors, sorry. If you compared more chromosomes there'd be even more variants. So it's not that every fixed thousand bases, so if I count out to base 500, there might be a variant there. That doesn't mean the next one's not to 1,500. There could be another variant over here that is just in different populations. So the more, the more chromosomes you look at, the more variants are possible. And so it's been estimated that there could be 20, 30 million different variable sites just out there in the population. And not all of them are common. And when Terry will discuss how we use these in studies, we're going to focus mainly on the common variants. This is the quiz. So the concept of linkage disequilibrium, which I agree is an awful name and a hard concept, is also linked with this other awful name and concept which is called haplotype. And it's actually hard to describe but easy to understand if we do it in the form of a quiz. So shown here is this stretch of a chromosome and shown here is the stretch of chromosome from someone else. And in that case, if I know they have a T at this position, if I look downstream and I see an A and I realize I look at a lot of people and see every time I see a T here, I see an A here. That means that those two are in disequilibrium. They don't have to be, but they are because we've observed them. And so here's the quiz. What color socks do I have on? I can't tell. Christine, what color socks do I have on? What color sock do I have on my left foot? Maggie? That's linkage disequilibrium. Once you know through probability that if I have a gray sock on, on my right foot, I'm most likely to have a gray sock on my left foot, will that hold true for all populations? I have an eight-year-old daughter. And in her population, she often goes to school wearing two different color socks, which is a relief in the morning and maybe fashionable, I don't know, but at least we don't have to find matching socks in the morning. So the degree of disequilibrium you see between markers can vary between populations. I'm going to discuss a little bit why, due to the population structure, it actually does vary. But simply it's a probable ability statement that if I know what's here, I can guess what's here. Now some of you may be hardcore investigative reporters and you'll have to wait until afterwards to look at my left foot. But most of you will take it for granted that I have a gray sock on my left foot. And that... Oh, you guys don't ask each other. You can independently verify. Yes? How far away in the stretch of DNA does the other one have to be to count? It's a good question. The closer they are, the more likely they'll be the same, and knowing one, you'll know the other. As you get further away, that relationship becomes less certain. In human genome, in most populations, that can extend from hundreds to thousands of bases so that if I know where this T is and I look in a specific population, I may know exactly what all the snips are, actually a wrap around the room, almost a thousand bases. And we don't have to guess because that cover with the fancy diagram that Francis showed you is the hat map data, which we've gone out and looked at several major populations in the world and mapped this relationship already so that we can pick the markers we want and they will report. And it varies a lot. There are some places where, maybe not on this scale, where an A here would not be associated with a T here because there's been ancestral recombination, we call it. So it varies. We actually had to go out and map it in the genome before we could use it. And that was the hat map project. Now that we have that, we could say, if we're in an area where the distances are very tight or the relationship is tight, we'd say, we only have to genotype this one and then we'll know that one. Other areas we'd have to put markers in much more densely. And that's what these tools that I'll finish off with actually do. They've taken this haphalotype relationship into account. I want to diverge a bit for the last five minutes on where this stuff came from, which will have some bearing into the issues that Vence is going to touch on and does, hard fact, a little bit to the hat map. As humans, we're actually a relatively young species or population. We tend to think that modern humans came from a core population that existed about 100,000 years ago. It probably was a relatively small population for long periods of time. We use this awful term, effective breeding pool, which I don't know whether you're in the pool or not in the pool. It sounds awful, but because the populations were small, that allowed different things to rise to frequencies using that graph that I mentioned. And then at some point we got much more stable food supplies, coincident with agriculture. Our population kind of exploded. And things changed much less readily in large populations. And so now we've reached somewhat of a stable degree of genetics except for these smaller, isolated populations. And again, we're coming in here, and this process I'm showing here to go from this point, from zero frequency to 100% frequency, we know statistically takes about four times the effective breeding population, which in humans would be about 40,000 generations, which means it would be about a million years to go from zero to 100% for a particular variant. So if we're looking at intermediate variants, some of them may have been around in the population for a half a million years or 100,000 years. So these SNPs that we're genotyping for these assays have been around in our population a long time. And that gives rise to the prediction that you would find them across the world, which in fact you do. And the reason you do find them across the world is because if you go back 100,000 years ago, all of our ancestors lived in Africa. So the pool of all human genes existed in Africa. Now remember, the SNPs are older than this. So almost all of the SNPs that we're going to look at were present before we migrated out of Africa. Well, and what these colors show, and this is a slide bar from Ken Kidd, what these colors show you is range of genetic variants. And so Africa is the source of all the genetic variants we have. And so you'll see lots of different colors. Now what we think happened is that a subset of this population, a small subset, left the continent of Africa. And what happens, remember that lesson, if the subset is small, you might have more rapid changes in frequencies of variants. And then eventually this population spread throughout the world in different continents. And what's shown here is that the variants, although the variants are all the same, the frequency of particular variants may vary across the globe depending upon what we call continental origin. And this explains why we see different frequencies of different variants in different populations. It has nothing to do with evolution, selection, probably 99% of the time it's just chance and who happened to leave Africa. And one time I showed this slide and someone said, well, these people must be smarter because they knew to go this way instead of that way. And if you think about 100,000 years ago, this is random wandering. This has nothing to do with selection. There are no GPSes 100,000 years ago. And so this out of Africa theory kind of explains the spectrum of genetic variation and the frequency differences in variation we see throughout the world. The last thing I want to finish up on, and Emily, if you could pull out, there's a plastic bag in my bag right down there, is... Nope, not that one. I have more than one plastic bag. That one, yeah. Is how we score this thing. And Francis mentioned the technology that has changed over the last five years has been amazing. So I'm going to pass... These are glass slides that can break. Usually with high school kids, I warn them about safety, but for you guys, I don't. The other thing that will be going around and you can just spread them out are chips. There's some glass in there, but it's in plastic, so I can trust you. What I'm passing around are examples of the platforms. You can take the slides out that are in the box. If you look at those slides, which are shown over here, or those chips, which are shown here, there are two different systems for doing SNP genotyping. And within a year, both of these systems will allow us to do one million SNPs in a single experiment. And for those of you that have been covering the genetics beat for a long time, that may be stunning to you. It's even more stunning to me, because we used to look at them one at a time and it used to take years. So in one experiment, what we would do is either wash it over the slide, or if you look at those DNA chips, squirt it in the back, there's some holes in the backs of those chips. In both cases, there are things that will be on the surface of glass where the genotypes will be scored. And in both cases, and these are two different platforms, and I don't have any, in fact, I'm not allowed to have any affiliation with any of these companies. One of the plastic encased ones with glass slides are from a company called Illumina. In both cases, what we do is we wash over the person's DNA, and the chip has specific features that will tell us what the genotype is. Do you have a C or a T here? And in the end, in both cases, what has happened is whether you have a T or C is highlighted by a fluorescent molecule, and a camera and a microscope objective takes an image of the chip. And so in both of these, what's generated is a giant image file. And so for those of you who do digital photography, you've seen the megapixels go creep up and up and up. The data for these experiments are giant image files, which are then analyzed. And Terry will show you some of the crunched numbers. But what is actually analyzed is how bright these spots are. And for those of you that use laptops, I'm sure most of you know they've gotten smaller, better, faster. All of the genotyping's gotten smaller, better, faster, cheaper, but it's also been coupled very tightly with advances in computational biology and storage. The raw data for a project of 1,000 cases, 1,000 controls that Francis just mentioned in these image files covers about a terabyte of data. And when I first heard the word terabyte, there were a few people in the country, a few places in the country that could deal with a terabyte. Now you can buy this portable, not disposable, portable hard disks that'll hold a terabyte for a couple hundred dollars, which is pretty amazing. Both of those things have pushed this whole field forward. And so I'm happy to close with this and remember the homework, we got the quiz right, and I'd be happy to take questions. Do both the chip platforms have the same snips on them? Or would you find something different in an mathematics chip from an aluminum chip? And also... Chips on them. The same snips on them. Sorry. I'm sure there's some overlap and I haven't looked at the data files. People can get this and compute comparisons. They're slightly... The problem is that just like software, there's different versions all the time. So the working versions of the aluminum platform, the working versions, the commercially available ones now were designed slightly differently to cover areas. There are also issues in how you design the assay that will event one from working in one platform and will work on the other. And one more follow-up. It's Bobby Ergoth. Who... These chips used to be used years ago mostly for expression levels. Who first said, hey, let's use these for, you know, whole genome associations. Was that the chip company's idea? It just kind of happened? Or did you guys or someone in the generalist community says we really need you guys to do this? The chips, especially the apometrics chip, was invented to determine sequencing originally. Now, it failed at that. In fact, it doesn't work very well to determine new sequences. But it can determine re-sequencing. And so one of the things we did, and a lot of this is done, we talk to these people all the time and there's public and private official partnerships as well as unofficial partnerships. They knew that there would be a real need to do this. And these are the two platforms that have risen at least now to the top. There's other ways of doing synaphenotyping that have been out throughout the years. But the ability to synthesize in the api case or in Illumina to do this combinatorial process on very small surfaces has really been the big plus. Hi, it's Joe Palcott, NPR. I wonder if you could go back a couple slides to the one that's titled, Fate of New Mutations. That's so pretty. Okay, so I take it the arrow is sort of, you can think of that as today. Yeah, in this case. The problem that I've been trying to wrestle with, and I know this isn't particularly the focus, but since you brought it up in your talk, I'm going to ask anyway, you've got data up at the top of the slide that says, well, by fiat or by experimental evidence or by something, the data about the change of the mutation rate. But I'm still confused about how you infer backwards to what was from what you see in a single population today. I'm not sure what you mean. Well, you're making some assumption about, for example, in the next slides about where people moved to. You're making an assumption about how long ago they left Africa based on the frequency of certain mutations today.  So I was wondering if you could try to come up with one. Part of the problem is that what really is very important, it's based on modeling, and people model the different scenarios and come up with something to stop them. And what's really important to know, which we don't know, are these population histories' effective breeding sizes. They're essentially estimates. And these conclusions are drawn in conjunction with archaeological anthropological evidence as well. So from the analogy point of view, how do we know that out of Africa happened just looking at mutations or looking at variants in this case? And if we want to talk, I use mutations and variants interchangeably. There's a slide in there that discusses the formal definition of both. And I think the easiest way to do it now is with looking at hat map type data in that, and this gets to the question from over here, in that the areas of disequilibrium, if you go in and look in African populations, they tend to be smaller, implying that they've been there longer. So if, and if I go back to this slide, what occurs when these two mutations are next to each other over time due to reproduction and recombination is they get separated eventually. And the more generations that happen, the more chances that an event will separate them, so this will get recombined and be on this chromosome now. And so when we look at African populations, the areas that we see of disequilibrium are actually smaller, implying that there's been more time to have them divided. When we go out to European populations, then we go to the more isolated populations. We find the area of disequilibrium gets larger and larger, implying that they've been separated in shorter amounts of time. Does that help? No, it's not a... I mean, it's definitely, I mean, it's helpful conceptually, but in terms of trying to... I mean, without using the word disequilibrium, I'm trying to come up with a comfortable analogy because I've been trying to explain the genetics of population movement through Europe, for example. And at some conceptual level, I get several steps down the road and then I get to linkage disequilibrium and I see ice glaze over. So I'm hoping at some point to come up with the perfect analogy, and I'm not sure I've found it yet. It's actually one of the things that we'll talk about at lunch because I think the language in this field is... I hope my nice colleagues will forgive me, but it's dreadful. And it's really, really hard for me to even talk to my mother about it. And she knows what she's been listening to me for years, so... Thank you for that, Vodacamp. What's your life in the already given example? End up in the dryer? Sharon Bagley from Newsweek. Does SNP analysis generally find the variation in both copies of a particular chromosome? And similarly for a whole genome analysis, does that generally run both chromosomes and does it matter for an estimation of the increased risk of a disease? Yes, the answer is yes, yes, and yes. So when we do these analyses, we take a blood sample from your finger and we isolate DNA from it. They're no longer in these chromosomal packages. They get all broken up. So your maternal and your paternal copies are all kind of mixed. And when they get put on this chip, they're all mixed. And it's very important that we query both flavors and there'll be a spot. We won't know which one came from which unless we have your parents, too. But it does answer... It is very important that we get both copies recorded. There are some cases where there can be interference and we might miss one and the people who produce these platforms have gone out of their way to avoid those issues. And yes, it's very important to know both in the whole genome association that we're scoring broken copies. It's not as important... This is the breakthrough in the past analysis of how to study animal husbandry by pulling people from the population no longer in animal studies. What we're doing is combining this deep relationship of human families when we do this whole genome association study. So we don't need to know parental copies when we're just studying them individually. In fact, they shouldn't be related. So yes, Sharon, that's a really important question because I think sometimes the way the data analysis can be confusing. So each SNP has two possible spellings. Let's say a T and a C, two alleles, as we say. But because we all have two copies of everything, unless you're talking about X and Y, that means there are three possible genotypes. You could be AA, you could be AT, or you could be TT. Some people, when they do the analysis in a whole genome study, will simply say, is the T allele more common in the affected than the unaffected, and therefore it's a risk? And some will instead say, do you see TT individuals, homozygotes, more commonly in the affected than in the unaffected. So they're looking at genotype instead of just allele frequencies. And sometimes the result can be sort of tweaked a little bit by which of those methods you choose. One is more looking at a dominant effect. One is more looking at a recessive effect, actually. And I think when one looks at the details of those papers, it's probably important to see exactly what was it that they claimed represented that association. Was it just the allele, or actually the genotype? Yeah, David Brown from The Post. My question is a little bit like Joe's, if I understood his, and that is that the... What confuses me is that when sort of driving the relationship between a founder population and a descendant population, there seems to be the suggestion that one of them stays the same and one of them changes. But of course, for any given locus, the founder population in Africa has been breeding, and thousands of years have gone on, and it has just as great a likelihood of that locus changing as the ones that went out and founded another population. So I guess my question is, do you always need at least two and many different ones in order to get the sense of stasis in one population and change in another population? I think in the context of these kind of association studies, it doesn't matter so much. In the context of reconstructing population history, it doesn't matter as much either because these snips are older than the populations. And so there is a rate of change, but the rate of change is that the introduction of new snips at high frequency is slower than the migration of the populations through modern human times. So it doesn't really factor in that much, and that all of the variants, and there's two things that I want to... There's two nuances that I want to make sure that you get, is that we oversimplify a point to Africa and say it's everything. There is a microcosm of lots of different populations, and one that we haven't plumbed a lot of what the variation is. We just had some evidence that a lot of the variation came from. The other extreme is the homogeneous populations that you asked about earlier, that homogeneous is maybe a bit of a strong word as a member of one of these homogeneous populations. I know we're not all the same, and there's just chunks of our genome that we tend to share that you can see when you look by standard. But I don't think the changes that have happened over the last 100,000 years on the SNP landscape, and we used to do things on microsatellites with which change over that area. On the SNP landscape, they just don't change that much, so that if I find something where I find variants in Japan, and I find populations that are T or C here, if I go to Africa, I'll find that there's people in Africa that are T's and C's in there. So I'll do a lot of them. When you do these genome-wide studies, are you looking at the nuclear DNA only, or the mitochondrial, or both, or what? It's a good question. So as far as I know, the SNPs, and maybe Francis or Terry know, I don't think the mitochondrial DNA is on most of the SNP chips. We're missing 17 kilobases, and an important 17 kilobases out of 3 billion. The problem is there's a little bit of a mismatch. There's about 1,000 copies of your mitochondrial DNA in each cell, and only two copies of your nuclear DNA, and so they would have to balance the probes in some way. But there's no reason they couldn't put them on there, especially because the variants in mitochondrial DNA are well-described, and there aren't very many of them. Now, some of them are length polymorphisms, which makes it harder, but for the most part, we'll serve a nuclear DNA.


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Hello, my name is Christopher. I'm from the United States and I live in the beautiful state of Nebraska And I've completed the 120 hour online TEFL course now I haven't even graduated from high school yet, but I'm on my last year and once I graduate I plan on flying over to Portugal and volunteering by Helping kids learn English now about the course itself. I Felt it was very enjoyable. It was very organized You could set your own pace, which I felt was very very comfortable and But the videos were a little dry to be honest I mean it was very hard to keep interest after a while while watching the videos but none of the less great content very informative and very enjoyable thank you ITTT for allowing me to participate in this course and Allowing me to get my certification. Thank you


It's January the 26th, 2022. It's Wednesday, 11 o'clock. That can mean only one thing. Time for What Now America? I'm Tim Apachele, your host. Today's title is State of the 2022 GOP and Democratic Party. You know, the parties have transformed. They've always transformed in the past. Both parties are evolving always. Yet, this time around, it seems like one side or the other has really transformed into something that we haven't seen or recognized for quite some time. And that's why we're here to discuss is the nature in the state of both parties. And with me today is Jay Fidel and Winston Welch. Good morning. Morning, Tim. Well, Jay, we've watched the GOP kind of transform over the last five years under the dictatorship of Donald Trump and it's his influence over the party. But it's worth asking the question, what are the attributes, either positive or negative, the attributes of the GOP today? Staying in power, increasing power. And that means, you know, self-interest, not interest for the country. It's completely irrational. I'll tell you why I've been thinking, we all been thinking about this, is that, you know, for some reason, they, and including especially including the base, think that if you ignore the norms, and if you ignore, you know, the American place in the world, global leadership, and if you ignore, you know, your neighbor, so to speak, the social network of the country, the social fabric mesh of the country, that you can get away with that, that your life continues, that it won't affect you. You can get up in the morning, you know, have breakfast, go to the dentist, I always focus on that. And it'll be the same. And that's the craziness. It's not gonna be the same. And the question, the looming question, which we have discussed many times on the show, is what happens when they succeed? I didn't say if they succeed, that's when they succeed in destroying the democracy, in destroying the social norms, in ignoring a good part of the country and the people in the country, what happens? It isn't simple, but it isn't pretty. And if we, you know, draw a line, connect the dots into that, what you have is a total disaster for everyone, including them. So this is irrational, it's cult. It's hard to understand how people can understand one side, but not the other. You know, not the consequences of what they do, but that is exactly what's happened. It's cult, it's power, it's following Trump and Trump's messaging, and it is ignoring the reality. That's what the Republican Party stands for, and it is a recipe for total disaster here, there and everywhere. All right, you know, Jay, sometimes we get comments on our show after the show's over, and a lot of them are people that were Trump followers or still are Trump followers, and the comments range from a wide variety of, you know, liked or dislike. But I'm gonna ask you to, for one second, put yourselves in the shoes, if you can, of a Trump supporter, and have those shoes filled with your feet, respond to the comments you just made, and what would a Trump supporter say to what you just said? What would be their comments? Hey, Jay, you didn't know what you're talking about. Trump was the best president the country has ever had, and he may be a nasty person, and he may be as a deficient personality, but he knows the swamp, he has drained the swamp, he has dealt with, you know, the deep state in our country. There are so many problems in our country. Would you rather have had Hillary Clinton? That's what he would say, and all of that is complete poppycock, but that's the bubble that the Trumpers live in. And so, you know, that's what they would say. It's not a response, but that is the response that you would hear. Well, the fact that you were able to transition so well quickly tells me you're an attorney of training. Winston. Consider that a tremendous insult, but it's okay. Winston, to you about the Democratic Party, list a few attributes, either positive or negative, about where we are with the Democratic Party and some of the trials and tribulations they now face. Oh boy, the trials and tribulations they face, they're not organized. They're not, don't have messaging that's really hitting to the core of what we're looking at here, which is the loss of our basic democratic institution and values, they really need a new marketing campaign, honestly, to reach the hearts and minds of the American public for the folks that Jay so eloquently just represented. They need to reach those folks and say, okay, yes, we get that, right? They had a good message, the Republicans were on point, they're unified, they're organized, they're lockstep behind their leader and they don't deviate one iota. If the Democrats showed half of that medal, then we could have a reasonable, some policy discussions and move the needle a little bit, but right now, they need to focus on saving our nation and working with those who share those values and Jay talked about the base, but I think we need to separate out and save the people that are honest, principled Republicans, conservatives, we can call them, that we would have recognized six years ago who share conservative values who are part of, who agree that the process that we have in this country, while it may have its faults and difficulties is still the best thing going and the alternative is very eloquently laid out by Jay on almost every show that we have, which is talked about the dentist, no worry about the dentist so much as show me your papers at every street corner or building when you go in and if you got the wrong of Facebook post up there, you know, you're, well, we're not there and we don't need to go there, but I think we need to go there so that we don't go there on some level. And I think Jay makes a much better case of it than I do because I'd like to remain a little bit Pollyannish. You know, you passed on an article I think is either yesterday or maybe it was this morning as an op ad from Rick Scott. Now, Rick Scott, of course, is the head of the Lincoln project and Rick Scott was a long time Republican. I think he still is, but not a Trumper. He started to use the F word and the F word being fascist. Is that a fair characterization of the GOP in today's environment? You know, I don't know that labels are going to help anything. It just inflames things. I think what we can do is go back and say, hey, the process is that we go towards the middle that this is a country of ideas rather than and the best idea floats to the top rather than blindly following a cult leader who has a very simple and deceptive message, which is confusion and chaos. I think an article that also hit me well this morning was in the Star Advertiser in our paper. There was an article from Will Bunch from the Philadelphia Inquirer. And he talks about how things are not going very well for Donald Trump this week from the news of Georgia that special grand jury is being convened that we had the Washington Post talking about how apparently Rudy Giuliani was an architect and organizer in sending false forms claiming that to the National Archives that these states had elected Donald Trump. We have other things about people that are being called before the House Committee and the Supreme Court saying you have to surrender these documents. So there's been a lot of, and then of course New York about with Leticia James and investigating the Trump Organization. So, but he says at the end of this thing, so what he says he's, at the end of the day is this, if we find out in possibility in real time that our president was a crook and then doing nothing, it feels like that could be the fatal blow to our American experiment. So what do we do to counter that? We continue working on better messaging to reach good decent honest Americans who have been rightly sick of a lot of the shenanigans that they see across the board. And when you have someone coming in saying only I can save you, only I can clean up this mess, I am your savior. That's an appealing simple message in a time of chaos. The Democrats don't have somebody like that. And I don't think that they're going to. We need Joe Biden to step up, send out his messengers, get better messaging. We need people on principle conservatives to also step up and join that messaging. And the article on the Lincoln Project, which you mentioned a second ago, it's an op-ed of the 24th of January. What can I do seven rules for defending our democracy? And they talked about Stalin and working with Stalin in World War II. They said he was the second worst person in the world. But they said the reason we worked with them was to defeat the first worst person in the world, the analogy not being persons, but rather systems. And so that we have to, we may not approve of Liz Cheney's policies and her stance is on certain issues, but fundamentally, she wants to come back and have proper debate in our system of government, which, so we align with the Liz Cheney's of the world who want to come back and see America still be America at the end of the day. All right, thanks Winston. Hey, Jay, Winston just mentioned the name of Liz Cheney. Do you foresee or do you think there's any possibility that between now and 2024 a Liz Cheney type of personality or persona would run for president as an independent and would another conservative like yet very interested in preserving our democracy joins up with her? I'm thinking of Adam Kinzender as a potential candidate. What's the viability or the possibility of such an independent party? We've had them before, we've had Ralph Nader and all sorts of different candidates of the Ross Perot. We've had independent parties. What's the prevent one from happening now? Sorry, but I don't see that being meaningful. So she could declare as an independent. Okay, fine. Can she win? I think her star has gone up to the top and it has started to float down. The notable thing about Liz Cheney is that it's still just Liz Cheney. She's the leader of the, what do we call it, the enlightened Republicans, but it's not a movement, sorry. It's not a whole bunch of people changing their way of doing business in the Senate or in the House for that matter. They're still in lockstep and she's still outside of that. Well, historically- Whether an independent in a world of two bubbles, whether an independent means a hill of beans in 2022, the elections this year or next year, I have yet to see. You mentioned a lot of candidates, but you didn't mention any presidents who were independent. Well, to go to that point is, yeah, there's no history of an independent party in winning the election, but they sure that has prevented one from winning. The other party that would normally draw votes, they prevented those parties from winning. Ralph Nader comes to mind as preventing the 2000 election from occurring in Al Gore's favor. I don't think it means that much. I think what means something is Winston's thought and our discussion earlier for the proposition the Democratic Party has got to get its act together. That's where my heart lives. And a lot of people, a lot of people like my whole world really wants to see them succeed. You wanna see Joe Biden succeed, although he seems to be stumbling and bumbling. Wanna see them come together. You look back maybe 20 years and you find that the Republicans were really well organized 20 years ago and they're much better organized today. They're the party of organization, the party of lockstep, the party of follow me this way even if you don't completely agree with me. And so what's happened is the issues have conflated thanks to social media and Fox News that if you follow one issue they put out you wind up tagging along for all their issues and you live in that bubble. On the Democratic side, you squabble about everything. It's a big tent, but everybody is fighting under the tent which is really regrettable in these times because that system doesn't work right now. But Joe Biden's gotta be the leader of the Democratic Party or if not him, someone else. My own view to sort of wrap around this whole discussion is take it one step further is the Democratic Party has gotta come up with a ticket that works and they gotta do it right away. And they gotta get behind that, they gotta agree to get behind that person and work that initiative right on through because that person can encourage a Democratic voting not only in Congress, but also in the elections 2022 and 2024. Biden himself has demonstrated that his star is not rising. He's not that popular even among the Democrats. He's not gonna be able to win an election in 2024. I really don't think so. And he's losing steam, losing mojo all the time. And this thing in Ukraine is not gonna help him. This is a recipe also for the embarrassment of the administration of Tony Blinken, of Ron Klain and the Democratic Party in general. They've gotta get their act together. It's really critical. Alrighty. Well, listening to you and Winston talk about both the GOP and the Democratic Party, I get a visual of well-disciplined ant farm versus a troop of wandering meandering cats. But let me go back to Rick Scott's point about if the GOP wins the 2022. And his point he makes is that the Democrats will be put off balance. They'll be put on the defensive because if the house is taken by the GOP, the first thing they'll do, the first order of business is not pass legislation but to do investigations. Specifically bring back Benghazi 2.0 or Hunter Biden's laptop or possibly try to create articles of impeachment against Joe Biden. Certainly trying to validate the big lie that the 2020 election was stolen from Donald Trump and a big investigation goes to that point accusing the Democrats and thereby keeping them off balance. What do you think about that? Rick Scott's comments in that lane. Well, I think it's a delicious possibility for the GOP and it's one of the reasons they're working so hard to stay in power and to take the house and the Senate. Can you imagine how that's gonna work? It means that Biden, whose star is falling, will be completely defruct after 2022. He just won't have any clout in the Congress at all. Secondly, aside from embarrassing him and embarrassing the Democrats to the maximum extent, they will, in order to prevent any possibility of a Democratic win in 2024 or thereafter, they will also have their way, a betcha five, they knock off the filibuster, right? And they'll control every initiative in Congress and they'll do things that you will hate. Winston talks about having your papers checked at every street corner. It'll be like that. It will be the empowerment of autocracy. And we will see the emerging intersection of this country and the autocrats in Europe in the 30s. We will see the demise of civil rights. We will see the emergence of supremacy and racism. All those initiatives will become law. It goes beyond what the Republican states are doing now for suppression. It'll be really awful if they take over in the house and there's a likelihood they will, gentlemen, there is. Yeah. Winston, the Democratic party right now is struggling between the progressives and the moderates. Joe Manchin is positioned himself as a moderate Democrat and he's the defender of sane and sane spending and things of such nature versus the progressive who came to a $6 trillion package for Build Back Better and then it was whittled down to $3 trillion and then now it's whittled down to God knows what if it's whittled down to anything. How does that get resolved in the Democratic party? How does the progressives and their agenda and their wish list coincide with Democrats who are more of the moderate flavor? It doesn't, the progressives continue to, they don't have anywhere to go. I mean, they're already on one side. This is their natural party, so they can try and move it, but they've seen in reality, I won't say complete failure of what they were hoping for, but Joe Biden wasn't elected to bring a sea change of policies or spending priorities or anything like that to America. He was elected because he wasn't Donald Trump. He was elected to bring some calm and unity. To what extent he's been able to do that, I don't know, but I can understand why he's frustrated certainly in his talk that he gave and Mitch McConnell sort of lambasted him for some position saying, Joe Biden says, we're the enemy now, I don't think that's what Joe Biden was saying. I think he was saying, folks, we need to wake up here and smell the coffee. And so maybe what it is, is Joe Biden needs to reach out to Republicans who are in the row but those who have the R after their name who don't wanna be held hostage as it were and say, hey, you know what, there's room here. He's supposed to be a great facilitator. There's room here for us to create this moderate middle. Maybe he calls, I don't know what it is. And he says, and if you are being primaried by forces against you because you actually believe in America and the values of having two, we are a two-party system and you believe in that, then we will help raise money for you if you're in the moderate middle. And I guarantee you, even if it's Liz Cheney and you're a progressive Democrat, you will donate money to Liz Cheney and the Liz Cheney's of the world to see them reelected because they believe in the system itself. And when the system itself collapses, then all bets are off, like Jay was saying, let's also look at that there is a possibility here for Americans to change their perception of what has happened before as new information comes out. Now, if they're only watching Fox News, it's probably not gonna happen, but let's just assume they're able to see a headline somewhere outside of the bubble. And it's hard because we're all on an algorithm. But for vaccines, just look at vaccines, we still have people who are rabid anti-vaxxers and for whatever reasons, those are from the insane to the concerned, they exist and they're going to continue to exist. But if you went a year ago and you looked at polls and you asked, are you four vaccines? You get vaccinated. You had less than half of the people say, oh yes, I'm definitely gonna get it as soon as I can. And then you had a good third of people saying, I'm just gonna wait and make sure that everyone's not dropping dead from the vaccine or sprouting two heads or whatever it is. That third has now become vaccinated to the point where we're about 75% of the population, not in Wyoming. So Liz actually, strange that she's from the, one of the least vaccinated states, I think they're like 42%, but the point being that if people can change their minds on something as being injected with a relatively new substance that's designed to save their lives, maybe their minds can be not injected but presented with information that will help them save their country and their very way of life and being and understand what's at stake here to the same point that they went out and got vaccinated and said, this is the right thing to do, not just for me, but for my nation and my neighbor as well. So I'm hopeful that in this next year as these lawsuits come about, as the drips and drabs come about, as more comes out that we will see, we are at the precipice, we need to pull back and we need to vaccinate ourselves against so much misinformation and what is fundamentally detrimental to our society. And I think you do it. Yeah, thanks, Winston. Hey, Jay, we got a question in from a viewer and we always appreciate that and it adds to the flavor of our discussion and this particular question, it's my screen's not quite getting into the way I want it to so I'm just gonna summarize it and that is the two-party system, is it tired? Is it past its benefit? Compare that to other countries where they have a multi-party system and then the second part of this question is, is it time, do we expect to get popularity of a president by their status as a celebrity? Donald Trump is a celebrity yet and he became president because everyone knew who he was. Is it time for the Democrats to start looking at celebrities that are actually have a name familiarity? Yeah, well, I think both of those are really excellent questions and suggest answers. Maybe it's more, Tim, than going with Liz Cheney and an independent party. Maybe it's encouraging lots of parties and requiring a consolidation and alliance, combination of alliances in the Congress. Maybe we should follow the European system. It's a big umbrella and somehow it works. Somehow, sometimes it doesn't work though. In any event, what's happening right now is simply not working. And what this questioner is suggesting is really appealing in the sense that you don't have to have a constitutional amendment. You don't have to throw out the baby and the bass. You can just sort of agree, including the Democrats, the right thinking Democrats and maybe some Republicans, let's have a bunch of parties here and let's try to consolidate. Well, that might be his point is that, we have the Green Party, we have the independent parties, but they're just never a candidate that's popular enough for name recognition and people to rally around. Yeah, I wanna go to that. I think the American culture has elevated certain people to celebrity status. I mean, we live in a world of Hollywood. We live in a world of familiarity with celebrity faces, names, even their histories. And if you look at the public media, you see so much time is spent, not only with celebrities in Hollywood, but celebrities in the sports world as well, who are completely unqualified to serve politically. Let me say that again, completely unqualified and the same, frankly, with the celebrities out of Hollywood, they don't know anything about running a country. They don't know anything about participating in a legislature. And yet we treat them as worthy and qualified, shouldn't do that. But here's the thing, that's the reality. We've been doing that for a long time. And so if the Democrats or the Green Party or the independence or anybody wants to get in on the fray, they have to find name recognition. They have to find celebrity. But you can have a celebrity who is a little more qualified, rather than less qualified. And the point is you get behind him and you pump that sucker. You do public relations and publicity. You make them look good or her. And I think at the end of the day, although it's not a perfect system, it's not what the founders would have contemplated, at least maybe there's a chance with that kind of diversity, if you will, we can catch the middle and we can catch all those kids that were following Bernie Sanders around. Where are they now? They're the real constituency. They're the future.  And people in the African-American community, they must wonder the same thing in general. And so what I worry about is if they are so discouraged and so frustrated, we've talked about that, that they don't care about voting anymore. A, they won't vote. And B, they'll express themselves in other ways and we won't like it because it'll be in the street. And then we'll have what one commentator wrote this week, we'll have the civil war. And civil wars can be different than they were in 1861 that they can nevertheless be very destructive. And I think we're cruising for that. So all in all, the press seems to be Winston, the articles that you send us around, the links and all that. And the ones that I look at too, suggest that it's falling apart, the David Brooks approach and even Newt Gingrich and the Lincoln Project commentary on him. I mean, it's more and more of that kind of rhetoric is coming into play. And I start to believe it. I do believe it that we're falling apart. So many bad things are happening. And query, how are we gonna deal with the next generation? How are we gonna get them involved again? And really at the end of this, it's maybe a reorganization of political parties. That's the subject of our show, Tim, isn't it? Yeah, it is. Okay, Jay, we've run out of time but I'm gonna do a quick wrap up. Winston, your final comments, please. Well, Jay brings up a good thing that maybe some part of the old order is falling apart. So what's coming next and how can we shape it? How do we shape it? Do we, maybe we could do something like not entirely European thing, maybe something a little bit more like our neighbor to the North. They've got about five parties that they work with, the Bloc Quebecois and the New Independence, whatever they are, the conservatives and the liberals and the greens. So they have a little stake in there. They're able to cobble things together. But again, that presupposes that they all have a vested interest in having the system itself work and that they're competing for the best ideas among the hearts and minds of the people, not just to destroy once they get into power. So we're dealing with some fundamentally different ideas here. I'm hoping that over the course of the year that our good and great country wakes up, it does smell the coffee. It realizes the grievous danger that we're in right now and that we can do something about it. We can do something about it and we must do something about it because the alternative is simply untenable. It's horrible to think about and we need to focus on solutions now as best as we can. And so I'll just leave it with that, whether personal, statewide, civically, nationally, we need to focus on the solutions from here on out because we're very good at where the problems are. All right, Winston, well, you leave it well. Thank you. Jay, you get the final word. Hey, when I get out of this conversation is the word share. Because the parties have somehow drifted to places where they don't share power. Trump is a perfect expression of that. You just, you denigrate the other side, they denigrate you, two separate bubbles, two separate camps, you can't share powers and you can't run a democracy that way. You tell a two-year-old, look, share. Share your toys, share your stuff, share your space. And the country has forgotten to do that. And I'm not saying that the Republicans are right about this. I believe they're wrong, but the total view of it is we're not sharing. And so we have to learn within the political system to share. And we should modify the political system without a constitutional amendment. And of course, we have to teach people about the value of sharing to share power, such as this questioner who suggested we look at the European system of multiple parties. And maybe that's an answer, simple basic norm about sharing. All right, well-stated as Winston, well-stated. Thank you so much. We've run out of time. Please join us next Wednesday at 11 o'clock for What Now America. I'm Tim Apachele, your host, and we hope to see you then. Aloha.


When God speaks, there is lightning in the sky. When God cries, rain pours down from on high. When God laughs, thunder rolls across the plains. I will listen again and again. When God moves, the waves crash upon the shore. When God gives, there isn't proof for anymore. When God helps, you are rescued evermore. I will thank him again and again. When I'm washed, with my eyes I can see. When I'm silent, then he speaks to me drawn. And he fills up my heart with his song. When God calls, there is fire in the trees. When he answers, there's a whisper in the breeze. When I meet him, I will fall down on my knees. I will listen again and again. I will listen again and again. I will listen again. Welcome to Discovery Mountain Fall Camp. Will the campers be rescued and be safe in Jesus? Let's take a Discovery Mountain Vacation Bible School adventure. God answered our prayers. The storm wasn't nearly as bad as expected. And, no flash flooding. Now, we have two campers and a junior counselor that are missing. No need for alarm. Reader's out looking for him right now. Jake, I pre-empt Madison was right. Oh, me too, me too. I'm going to read a name and you yell if you're present. Seth Atkinson. Jamie. Jamie. Connor. Hailey. I just knew they'd be here. Madison's logic made so much sense. Reader, is that you? Jamie, you're here. You're all right. Yeah, we could have remembered the way to the safety cabin. We? Are Connor and Hailey with you too? We're here. Camp Director Reader, I forgot my allergy medication. I'm sorry. Well, I'm so glad you're okay. Me too. We couldn't remember the way to the safety cabin, but then I remembered the cave. This is a perfect spot. Quick thank you, Jamie. Thank you. Now, Connor, why didn't you make it to the safety cabin? I just didn't take the warning seriously. Well, young man, you know... I'm sorry. I'm sorry. Well, I'll let your counselor and you work out the consequences.  Is the camp okay, Reader? Yeah, it is. There's just a few puddles. That's a relief. There's a lot of people who are worried about you guys. Shall we go back down and let them know you're okay? Yeah, sure. Let's go. All right, Connor? Yes, sir. Lead the way, camper. Yes, sir. Ian Zacherson. Oh, hold on a minute. It's Camp Director Reader. Reader, have you found the missing campers and junior counselor? The water's rose and got to care of him. That's true. I'm so brave. Me need... Connor's got to pay the consequences. This could have been a disaster. I need to talk to you. Counselor Jake, I need to apologize. Connor, you shouldn't have stayed behind in the cabin.  I know. You're right. Well, good. I was expecting an argument. Counselor Jake, I didn't take the wording seriously. I wanted I could find you guys. I was scared. Oh, I'm glad you found Jamie. Me too. Connor, I'm still going to have to tell your parents what happened. I know, I know. But, Jake, got taught me an important lesson. Oh, he taught you that your counselor's always right? No. He taught me that his warnings are there to help me and keep me safe. Connor, you are always safe in Jesus. He'll rescue you. I know. Campers and camp staff, may I have your attention, please? God answered our prayers. Jamie, Connor, and Haley, God kept you safe through this whole thing. And now I have two announcements. Number one, listen up. First thing tomorrow, there'll be signs posted all over the camp leading the way to the safety cabins. And second, I know you're all hungry, so everyone to the cafeteria for hot cocoa and cookies. Everyone still watching? Oh, good. You know, everyone else is going into the cafeteria, but I want to talk to anyone who's still watching at VBS. In Discovery Mountain, my name is Jamie Simon, but in real life, I'm Naomi, and this is Glacier View Ranch. A few years ago, I actually came here as a camper. My cabin was right over there, and my week at camp changed my life. I learned how to trust in God fully, and I gave my heart to Him. Have you ever talked to God about giving your heart to Him? If not, there's no better time than right now. Take Him with you all year, okay? I hope you had fun at Rescue Safe in Jesus. Hey, I just had a thought. There might be real hot chocolate and cookies in the cafeteria. I'm going to go find out. Bye. This has been a Discovery Mountain Vacation Bible School adventure. Remember, you're always safe in Jesus. Discover sunshine. Oh, hi, children. How are you this day? Welcome again. This is day five. You mean day five is already here? That was too fast. We didn't even get enough of treasures of the Bible. Did we? No, we didn't. Come, come, come to your screens right now. Before we say any further, let us sing the songs we've been learning throughout the week. And we'll start with the theme song, Discovery Mountain. Discover sunshine. Experience fresh mountain air. Discover nature. Experience friends that really care. Discovery mountain. The place I want to be. Discover more. Discover care. Also, the second song we did on day one when God speaks, do we know what happens when God speaks? Enough of them. Tining over a new leaf. When we do this, what happens? Which song is it? Tining over a new leaf. God's love. What does God's love do for us? Let's sing and just make the noise. It will be all our strength. In shining bright. We sincerely apologize for the technical issues that we had, but we will repeat the Noah song once again. Oh, Noah. Before you leave, I have a few announcements for you. For tomorrow, I want you to tell your mommy and daddy to wake you up very early in the morning for Sabbath because your classes are going to be starting early, okay? So by 7.45 a.m., you should be logged into your Zoom classes. And then thereafter, once the class is over, you log into the YouTube main platform, okay? For the rest of the program of the Sabbath. And then announcement number two, for those who learned turning over a new leaf song. Just like teacher Abie told us yesterday that we have to record ourselves, or you can tell mommy or daddy to record you. So as you're recording yourself, you put your phone or your device like this and not like this, okay? And don't put it too close to your face that we cannot see other parts of your face, okay? So just put it close enough, but not far enough, not too far, okay? And that is it for today. Thank you for joining us. Wait a minute. Do not leave, okay? There is someone who is about to tell you something very sweet.  Good morning. After so many thousands of years that have passed, how did that happen? I want to talk to you guys. Guys, tell him if it is all. This is our ring. When it teaches us that God keeps his word, because he said he will never send a flood again. Children, wherever you are, just get that deep exercise. And remember, our theme is always when God says something, we... Wow, that was a good session. Wow, good job.


And as Josh alluded to, Chris Ricks will be giving us a brief overview or a brief review of Oculocutaneous Albinism. He is from UT Medical School in Houston, so welcome him. My name is Christopher Ricks. Glad to be here. I'm a fourth year medical student. I'm going to talk a little bit about Oculocutaneous Albinism. So when we think about Albinism, several images might come to mind. Maybe something like this. Maybe this. Maybe something a little more tragic like this. This is an article from National Geographic about the alarming number of albinos that are killed in places like Tanzania where people don't understand what they are and have false beliefs about magical powers that they might contain. So my goal is to kind of clear up some of these misconceptions and give us a review of what Albinism really is and what we can do about it. So a patient like this comes into your clinic. Several diagnoses are possible, including Oculocutaneous Albinism, Oculocular Albinism, Chediaki Gashi, Hemeniki Pudlak Syndrome, and Vici Syndrome, among others. So there are several important clinical findings that are common in almost every type of Albinism. The first picture here is Fovial Hypoplasia. To visualize this is with an OCT. You can see the top OCT is normal here and on the bottom there's no foveal pit and the neurofibrillator has overgrown, is overlying foveal. Another common finding is found on a retinal angiogram to get an invasion of the vasculature into the foveal and inocular area. This is a translumination technique that Josh talked about where you can see the light, red reflex coming off of the retina and shining right through the iris due to a lack of pigment. This picture you can actually see the outline of the lens which is pretty cool. A really important finding that I think we're all familiar with here because of Dr. Creel is the abnormal decussation of the visual pathway and pigmented individuals get 55-45% crossing and then individuals with Albinism get upwards of 90% they cross. This can cause a lot of problems with stereo vision and a good way to visualize this and to confirm it is with a VEP, normal individual you can see here on the left and on the right you can see what happens with individuals with Albinism. You get this reversal of the pathways. So some other important clinical features are pendulum stagmus which is different from normal and stagmus in the fact that there's no fast and slow phases. It's just a steady kind of pendulum like movement. Strabismus which can lead to amblyopia, photophobia, refractive errors, basically overall poor vision. There are several different types of Albinism that I want to talk about today. First is Oculocotaneous Albinism. There are seven main types. All of these are inherited in an autosomal recessive pattern and Oculocotaneous Albinism which there's two main types and these are all inherited in an excellent recessive pattern. So Oculocotaneous Albinism type one is due to a mutation in the TYR gene. There's over 200 mutations that are known in this gene, codes for tyrosinase which is the enzyme responsible for converting tyrosine to dopa and dopa to dopaquinone which are part of the pathway and inflammation of melanin. So there's two subtypes that we talked about a lot. Tyrosinase positive and tyrosinase negative. Tyrosinase positive individuals have some tyrosinase activity, therefore they have some melanin and overall better prognosis whereas tyrosinase negative individuals have very little to no tyrosinase activity. OCA type one is the most common type. Due to a mutation, the OCA2 gene which is formerly known as the P gene causes dysfunctional molyanosomes, has less visual impairment than individuals with OCA type one. I didn't just want to mention briefly, they're very rare, usually only occurring in certain subpopulations and worth noting, but I'm not going to go into a lot of detail right now. Oculoralbinism type one and two. Type one is also known as Nettleship Falls Oculoralbinism. This is inherited in an excellent recessive pattern so it's mostly a disease of males. An interesting finding is the carrier mothers can have what we describe as a mud splattered fundus. These patients use a very priori poor vision and you can diagnose this by visualizing macromelanosomes on a skin biopsy. OCA type two is a very rare type also inherited in an excellent recessive fashion. The next type I want to talk about is Chediakigashi syndrome. This causes intermediate severity ocular albinism. It's associated with recurrent pyogenic infections, dysfunctional lysosomes, and progressive neurologic abnormalities. Unfortunately, most of these patients don't live past childhood and you can diagnose this by visualizing giant azero-filic granules in the granulocytes. Another type that's important to recognize is Hermanski-Pudlak syndrome. This is most commonly found in individuals of Puerto Rican but also Swiss descent. This is associated with platelet dysfunction, bleeding disorders, interstitial lung disease, and granulomatous colitis. The last type I want to talk about today is called Vici syndrome. This was just recently classified in January of this year. It's the only form of albinism found on chromosome 18. It's very, very rare. Has several ophthalmic findings and overall systemic findings that are important. So you get bilateral cataracts, mild fundus hyperpigmentation, and bilateral optic nerve atrophy. The systemic findings include agenesis of the corpus closum, cardiomyopathy, and immune defects. So you can get characteristic abnormal fundus seen here. You can get an abnormal OCT, and this is kind of a poor OCT, but because of the extremely poor health of these individuals, this had to be done with a hand unit rather than the type we're used to. So you can see the lack of a foveal pit and a little bit of the overlying nerve fiber layer. So these individuals have very, very bad health problems. Vision is one of the least of their concerns, but it does help us with diagnosing what their syndrome is. So management of all types of these individuals. There's not a ton we can do for them, but what we can do is evaluate them regularly. Make sure we treat any misalignment present. Try to minimize any amblyopia that could occur. Maximize their visual potential with glasses and other low vision aids. Obviously recommend they still wear sunscreen, because skin cancer is a very real problem for these individuals, and refer them to a genetic counselor. So their prognosis. They're actually very much the same as the rest of us. They can have normal lifespan, development, intelligence, fertility, as individuals that aren't affected. Really, their biggest problem is poor vision. This is a family that I saw in the clinic yesterday with Dr. Hoffman. I told them I was giving this presentation, and they agreed to let me show their picture. So this guy here on the right or on the left, excuse me, 15 years old just trying to get his driver's license on the basketball team, 4.0 student, and his sister, the member of the volleyball team, and their normal happy individuals that aren't really any different than the rest of us. So, any questions? I want to thank Dr. Creel, who unfortunately couldn't be here today. He helped me with a lot of the photos, diagrams, and a lot of the information, including the Vici syndrome. And here are my references. Thank you.


Victor, the next question is for you. The viewing group at Embassy Port Louis Mauritius asks, are there costs associated with integrating fintech into a startup? As far as costs associated with integrating fintech into your solution, if you are a fintech company, obviously that's the overhead that you're incurring is to build a solution. However, if you are a high-tech company, if you're building a medical device, if you're building some manufactured product, if you are shipping, my advice to give you is to seek out those people who are now really pushing the envelope in these advances. They're really big names. They're people like IBM, they're people like DHL, they're people like Samsung, who are pushing the logistics and the financing piece for industry. So that I will tell you that in the ideal world, unless you are directly involved in fintech, these expenses are going to be invisible to you. They will be just the operating system that runs your business from a logistics point of view, from a payments point of view and a financing point of view. If you are a fintech company, you're going to have those same type of expenses that any high-tech software company is going to have. You're going to have primarily programming, human resource type expenses, as well as the hardware and the software tapping into and working with those pieces. So the barriers, as an expense, are relatively low, I would say, if you are a non-fintech company. You will be tapping into somebody else's solution and it will be your computer system tapping into the internet, into the cloud. And so they're relatively inexpensive from an entrepreneur's point of view.


What's up guys? Kevin here. I always wanted to shoot a video series that I go buy the printers that people gave up and then I fix it and sell it on eBay. So doing this COVID, the printer press has been jacked up a lot and there are lots of people asking me where to buy cheap printers. So let me first go over a couple of sides. I go to get cheap printers and then we're going to take one of the printer I bought and fix it. I used to use a crackless a lot, but not recently because recently press hasn't been really reasonable. Let's start for a printer. So this guy sell a printer for 200. That's a pipe dream. And this one you can get a Walmart brand new for about $35 with cartridge. Let's try Epson. So $4,150. Maybe. Yeah, that's reasonable. And this printer, no, just don't ever buy this guy. Remember the name 4630. Burn to your brand. Never, never, ever buy this printer. And yeah, that's what I'm talking about. $20. Okay, excellent condition and needs cartridge. So this guy use up all the cartridge and sell it for $20. Okay, let's do a really quick check on the ink chip.net and see if there's a cheaply solution to it.  So let's see how much model XP 434. And let's see how much it costs. Select our model year. So it costs $25 to make into chipless. Okay, so totally you're going to spend $45 plus gas and then you're going to turn into chipless. And then I have a video show you how to modify the cartridge and then you can refill the cartridge again. And the ink probably costs $20 for 600 mils. And that's enough for two, three years of ink. Okay, so get the whole thing set up under $60. That's what I call a good deal. Another place is a Facebook marketplace.  Let's try to search for Epson so we can compare that $20 deal. Here's a free one. Pages come out with a light blue ink versus black. You guys know how to fix that one, right? Yeah, if you don't, follow my channel. Okay, so free versus $20, of course free. Okay, next one, how do you pronounce this? Somebody told me Mercury or somebody called McCurry, whatever. Sounds Italian, okay. The printers here are not cheap. However, you can get a really good deal on the specific model that you're looking for. Actually, somebody sell a piece of HG ink here. Okay, at least this guy's happy about the product. Oh, there you go, $25. So the printer still works, so it just doesn't need anymore. You can see you have to pay shipping here, so it's not comparable to our Facebook marketplace. However, if you look for a specific model, this is the place to go. Let me search for a model that I'm looking for. It's for Epson 1430. That's a really hot model. Whoa. That's cheap. That's cheap, really cheap. Let's see what's wrong with it. This guy, I mean, for brand new, it should be around $700 range. Oh, sold. Oh, too late. Okay, this one I bought for $30. The owner says there's something wrong with a printhead. Whenever she goes to print, they only produce blank pages. Actually, she never could set it up properly, so that's a good thing for us because if something wrong, we can actually call Epson's warranty. Oh, by the way, Epson will owner the warranty even if you bought it from a third party. The supply line looks good. Let's take a look at the printhead and make sure it has enough ink. So we'll turn the printer off first. See that white lock? That locks the printhead in place. We need to unlock it. Just use the finger to push this wheel forward and that will move the lock. See it is unlocked now. You can move it. Now we remove that screw from the top. And then we can remove the cover. The ink looks filled. And let's check the colors. Pay attention to the bottom. Look, the bottom is kind of solid, so it should provide enough ink for the printhead. Let's put it back on the print. What I worry about is maybe the fuse to the printhead is going to blow out. In that case, the printer still functions, but there is no electricity goes to the printhead. So you get blank pages. What I had hoped is the user didn't know they have to press and hold the stop button for three seconds to get the ink to charge to the printhead before using it. That's why she got blank pages. However, this doesn't seem to be the case. We look at the ink box and they are charged already. Yeah, it's blank. Just like what she says. As white as snow. Okay, our plan is to do nine cleanings and do nine of them in a row. If there's any ink comes out, we just keep cleaning. But if there's no ink come out after nine cleanings, we're going to open it up and look at the motherboard. Okay, after four or five cleanings, the colors start coming out. So we don't need to worry about taking the mainboard out and test the fuse. And we're just going to keep cleaning until the pattern is perfect. So this person just keep printing blank pages, printing like 40 pages after bought it. And three months ago and the printer still under full warranty. Even she couldn't figure out how to use the cleaning function. She could just call Epson and rather than selling on Facebook for $30. Anyway, I kind of feel guilty buying this printer now. If you enjoy the scavenger hunt, please join me at the next video. The next printer just arrived today. I haven't opened it yet. It's a ET4700 and I paid a whopping $53 plus $20 for shipping. The problem is I always, the paper always jam. So it seems they have a good printhead and everything works except the paper. I hope so. Hit the subscribe button, subscribe to my channel and hit that bell button. So you will get alert when this printer get the work done. Thank you. Cheers.


Britt says, hello, I'm having issues getting logged into the Microsoft 365 suite. This is the message coming up when I try to log in to Excel Word and Teams. Can anyone help? Obviously I don't have the message up here to see, but thank you. Another account from your organization is already signed in on this device. Try again with a different account. So they're trying to get into an Excel form. My uncle literally just had this, yeah. Yeah. So what's the answer there? So at the moment, and what literally got an email two days ago from my mom that my uncle has this going on. Usually they've got it where and in his situation, his PC is signed in with one account. He's already got his OneDrive assigned to that account and now he's trying to log into OneDrive with a second account or he's gone into office and it's got the main one. And it comes down to if it's a personal compared to business, like personal accounts and only wants one personal account. So is he trying to authenticate with another account? I've also had it where it's it's hung and I've had to do a reinstall. Usually the easiest one is go to your account, log out, log out of it and then log out, make sure everything is logged out of all of the accounts and then log back in again. As I find is the simplest way to help them out. Well, the business account, what is to allow you five instances of the software? I don't have any personal accounts, but isn't personal account that a check lashes on doesn't it also give you a says if you're another account from your organization is already signed in on this device that will depend on the organization and this and what they've actually said that you can do where it's a managed device. If it's a managed device that will stop it. But if it's not a managed device, you'll be able to have multiple.  I've had where my login show that I've logged in multiple times. I've only logged in once, but because they're essentially connected, I had to go in there and disconnect those in my logins. And then and I was fine. Yeah, I've only ever had once where it was it was a profile issue, like it was a real problem and it wouldn't allow me to log out. I couldn't log back in. It was defaulting. I was having some pretty big issues around it and I was I was chatting with another MVP were on a call and I just said I ended up having to create another profile on that device and then allowed it like I was admin and then did a complete swap over and then remove that whole profile where it was just it just had really corrupted and it wasn't allowing me to do anything, didn't matter what I did. I had tried all of the fixes online and I just went create another profile so that I didn't lose everything on the device. I could still work on it and just did a swap over, frankly. Yeah, that's a that's a that's a full like end like couldn't solve it. But extreme or couldn't solve it at all. But it's interesting I saw one one case out there in computer land where someone was able to actually fix this doing an SFC scan now there was apparently some system corruption that was able to square away. So, you know, the old standbys use SFC and Dism. Yeah, that would have fixed my log in, you know, in me manually going out there and deleting those that would have fixed that too. So typically cleans any of those up. I'm trying to remember I remember an experience. I don't know the detail. So whether it fits this where I had a similar message about that that's already signed in the device and then it asked me if I wanted to to log out on behalf of the other and like take it over. And so I'm not sure what the scenario is there, whether they are given that option. If this is all that was in the message, you know, saying try with a different account, you may not have had that option, but I've seen that before as well. Yeah, you see that a lot with managed devices and in tune, because you can say prompt log out so you can log in the other blah, blah, yeah. Yeah. I would love one of those times, Christian, when we have some of these people live, we can say, give us more info. Yeah, yeah, absolutely. I have more questions. That's half the fun of answering questions in news groups and places like that. Maybe that's trying to figure out what they were asking. And then if you can't figure that out, then tastefully trying to pry the information out of them so that you know what they're really asking you for in the first place. You can only ask questions that you're looking for help on. If you include a personal number, a phone number and a work number, a way to multiple ways to reach you. I think that would be. We do like a radio show, right?


Welcome back to MedSmarter where we're taking a smarter approach to preparing future physicians. Let's continue on and discuss Some of our Medicare and Medicaid policies. So what is Medicare and Medicaid? Well, these are social health care programs that originated from the Social Security Act in 1935 So Medicare Medicare ends with an E Medicare that is for the elderly patients So Medicare is for elderly Specifically anyone that is Equal to or greater than 65 years of age is eligible for Medicare There are other groups of people that are eligible for Medicare Insurance as well and those are going to be people that are less than 65 that have certain qualifying disabilities or patients with in-stage renal disease or ESRD Medicaid on the other hand Medicaid which ends in a D is for the destitute This is going to have a mixture of our federal programs and state programs that provide assistance for patients that have limited income So patients that are on food stamps patients that are on welfare people that are poor that is going to be the patient population for people on Medicaid So back to Medicare particularly Medicare has four different parts to it. All right. We have part a b c and d part A is going to be coverage for hospitals and home hospice. So if you Need coverage for a hospital visit. You have to have Medicare part a Medicare part B. This is What helps pay for your medical bills when you go see a doctor when you have tests run that kind of thing That's Medicare part B Medicare part C is a combination of parts A and B and that is usually provided by a private company A lot of times people have supplemental insurance on top of their Medicare to help cover anything that Medicare doesn't cover And that's typically going to be a part C plan And then finally part D is what covers prescription drugs So patients need to choose which of these parts that they want with their plan and may have to pay some out-of-pocket To add certain parts of this specifically prescription drugs. So if you are Needing prescription drug insurance coverage, you may have to pay some out-of-pocket on that All right, finally, we're going to talk about hospice care. What is hospice care hospice care is Patient care that is focused for end-of-life patients So we're trying to provide comfort and palliative care for patients that are at the end of their life What is considered end of their life? Well, typically based upon their diagnosis We're talking about their life expectancy is going to be less than about six months Can patients go into hospice care and then maybe make a turn for the better and come off of hospice care because we think that Their life expectancy is greater than six months. Absolutely there is Instances where patients will go in and out of hospice care because they may make a turn for the worse and they think and Based upon the medical evidence they have less than six months to live or they may Come back out of it and start doing well and go off of hospice care hospice care specifically is going to be prioritizing comfort and relieving pain so we will give opiates sedatives anti-exiety medications probably at higher doses and higher intervals Then a normal patient because we're really trying to make sure that patients comfortable at the end stage of their life We are prioritizing that over potential side effects like respiratory depression if we give more oral morphine to patients It's going to depress their respirations, but it's also going to make them more comfortable the prioritization of these positive effects of Helping patients feel more comfort and less pain. That is what is called the principle of double effect