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https://soundcloud.com/thedrnimanshow/11192024a1 You Hello and welcome to the doctor Niman show today is Tuesday, November 19, 202 4 and here we are with our expedition is Dr. Niman Dr. Niman OK, thank you, Ryan I thought it'd be good to kind of cover the teenager in British Columbia. I got hit it shouldn't take his their mutations and we've kind of covered this a little bit but the reason I want to. Give a little more detail tonight is is starting to actually get out of the media and people are kind of looking at the teenager with respect to the sequences and Most specific one was by Helen branch while she had the first one that came out and she talked to a couple of the scientist who had comments largely on the tea changes in the receptor by the domain and those were the E190 D and the Q226 eight and They did verify that they were important and they didn't really talk about the PB2E627 K and and there is some comments in the in the article that said that they don't really know where it came from and without saying that they don't really know if The changes were in the virus that infected the teenager or if they happened after the teenager got infected, and as you know, I feel fairly strongly that most if not all of them happened Before the teenager got affected because He hadn't been sick that long between the time that he was symptomatic and a sample was collected. He actually got sick. After the sample was collected and he's been sick a long time now, but that's probably what happened to the source of the virus. It probably was in. That Hannibal and I'd say almost definitely once in that mammal for probably an even longer time than the teenager when the sample was collected, and The mammal, if it was his dog with apparently a possibility that doing that crap on the family dog and it turns out the dog has some a lot of virus in his lungs didn't tested negative, but initially, but initially was probably a A throat swab not sure exactly what they take, but be in the upper respiratory track initially on necropsy they can go and look at individual tissues, including the lines and would be able to get a much better idea whether the dog was infected in. They'll probably be able if he was they'll be able to get a. A full sequence and see how many if any, but I don't think the F is realistic, but how many of these changes that were in the teenager were also in the man that infected the teenager and I think he can make a good case for For the dog and you should hear about that fairly soon it doesn't take that long to do these, but anyway, as far as the mutations were concerned They they kind of sound interesting in the teenager had two receptor bonding domain plus the PB 2 and I had mentioned earlier that there were similarities in the in the gain of function studies that have been done with influence to see what it would take to To get each died and want to transmit through the air and effect another mammal affair model use where they inject the ferrets in their one cage, and they have other ferrets in a nearby case and they don't have any physical contact but they can Cough season on each other and see if the ones that weren't infected by the experiment or actually did get infected but when I describe these that they kind of fit that, but they don't quite because the key markers in those kind of functions were the were changes in at 2:26 and 2:2 8 in the H 5 And then they all ended up having the PP2E627 K and the case of the teenager they certainly had the E627K but the queue was right position and 226 but the teenager has a H and the band function had an L teenager kind of close to those, but not quite And so then, I thought I would look at the the E190 D and I knew that the E192D was involved with the 19 18 pandemic and That pandemic there was one donor who was Up in Alaska and she died in 19 18 and the perm frost up there pretty well preserved Her body and they were able to get almost a full sequence from the I think they were probably from her lungs. I'm not sure exactly what the source of the. Are they was but they got quite a bit of it and and it's it's she said it's it's you're not surprisingly it's Brad mission one 1918 the name of that so it's not a stand out that respect but I took a look at it and indeed it did have E190 D so it has the exact changed that the teenager has and that I looked at the changes that at 2:26 and 22 8 and it actually didn't have either of them, it has the sequence of the wild type so they had a cute position 226 and a G 22 8 and that's what all of the H5 sequences are that that have a taste anything and the receptor by nitro look at PB two the action should a full sequence of PB to the The H one from the pandemic they had a partial sequence, but it had the front end of the of the protein and the receptor body in full receptor body domain and sure enough it had E6 to 7 K so if you just kinda looked at these markers that scientists have been very interested in Of the four markers The two 226228 it didn't have and the other two it had and those two are exact matches what the teenager has so these are important markers and Yeah, I looked this up. The CDC has kind of a whole story on Bradley ignition and how bad things were there and a couple of numbers were quite striking that they they had 80 adults in the village and 72 of them died and it only took five days so they all died in the five day . And so they the virus, you know, obviously was fairly devastating, but the genetic show that it really only took two changes and just to remind the listeners that they gain a function Did they deliberately change the the? H5 to add 22 6 8 and I'm sorry 226 hours so they put it in 228 S and then they actually sell well. Ron Fauci actually added E627K so those are the three he added. And Yoshi Yo karaoke Wisconsin use a slightly different used position 22 5 but is very close and the cell line he used already had E627 K and the controversy was over those two, but the CDC had already done the experiment already published it before the controversy of the controversial papers were held up while it was debated and one was in nature, and the other was in science and then the CBC published and I'm more specialized priority paper Journal I should say and as I was already out there so I mean part of the argument with all you're gonna give away the secret is what it takes to change the virus and everybody knew about those changes anyway because those are what we're involved with the pandemic and 195 7 where H2 and two replace one and one And in 19 68 or H3 and to replace dates Two and two so the changes are important and I wanted to get those out there and if you look at the 1918 pandemic that was an H1N1, but if you look at the HDH there is keychain was E190 D and I'd also had PB2E627K so that's kind of the a little more on the importance of these changes and then the other part is the likelihood that these three changes found in the teenager. What all happened in the teenager I think it is highly unlikely that but like I said the sample teenager I think started having symptoms on November 2 and the sample was collected on November 8 so he he had only been six for sick for six days And when the sample was collected, I don't think you should say the teenager was Wasn't really critical until right after they took the sample so some of the viruses in the eyes, the teenager had conjunctivitis and So the virus wasn't doing that much changing as there are a lot of copies of it in it. It had a lot more opportunity to change before the sample is collected so it was a relatively short period of time and and these are very specific kind of changes like I say there's three changes and they all seem to link to. Changing the Host of the of the virus to make avian go to my mailing and to be able to infect and transmit more easily and do damage to the lawn and lead to these fatal infect it So that's kind of the highlight of the teenager and then there was another story that was kind of bomb Breaking today and that was a toddler that ended up testing positive and the toddler actually went to daycare with symptoms The initial test was positive and then test four days later was negative indicating it wasn't that since Serious and the recovery was fairly soon. At least after they did the first collection I'm not sure how sick the child was that they decided to test for age 5, but he was had enough symptoms to to to do that part and then. Apparently, there was another infection that the parents got so they that they had whatever the second affection of the child was and being symptomatic at the daycare may have been the second infection, which obviously was an H5 and they didn't say what it was, but So how symptomatic the child was from the H5 when he went there with the child to get the gender on the on this child either isn't clear but this is like that the Teenager the child didn't have any Known exposure and he's in Alameda county which is in the Bay Area and that's not quite where all of the dairy category. It's a little bit north a little bit west, but I would take they get a lot of milk. In the Bay Area, they came from the cows that are in the central Valley and are loaded About 30 % there is 11 00 Dairy hurricane in California the number one milk producer in the United States and about 30% of the farms have I've had confirmed these five and one and I'm sure that the level is going up in the milk and and the pasteurization does kill The virus by the summer concentration dependent so if you get enough virus in the milk may only kill 99% of the virus or something so so the pasteurization is gonna knock the virus down but it's a little clear with this gonna knock it down to zero all in every day it's kinda like rolling dice if you get It's pulled milk so it kind of depends on which farms all the milk comes from but yeah that that thing is so pretty much by the secret secrets that and this child assuming it's real it went to the CDC CDC hasn't confirmed it yet but generally It's a big lab in California and the chances that their PCR is gonna be right this is pretty slim so they probably will be confirmation. Hopefully, they'll be a sequence and if there's a partial sequence distinguishing. The one that one which would or even 1 2 would indicate there's some type of Wildberger burden involved with the tiles Infection or if it's B3, that 1 3 I'll be toddlers drink a lot of milk so It'll probably be time for California starts getting a little more serious about how much viruses in the milk from the grocery shelves and how does the frequency and either percentage or I mean they can do this quantitatively just how much virus is actually in The milk and is the amount of it's dead. Is that going up with all of these fire sitter that are contaminated or infected and and water I mean, they are picking it up in some of the wastewater plants but the problem you don't know whether it's coming from the cows, if it coming from birds are coming from people that are affected or it's just coming from milk that They drink and they're not affected, but the virus is still gonna be detected is the waste water so yeah I gotta be a real busy week this week. I think that's all dude just to give a quick update. Try to do what each day  You OK, thank you for the information. We will be doing another one tomorrow as usual. Thank you. Were on for listening. 

https://soundcloud.com/thedrnimanshow/11182024a1 You Good evening and welcome to the doctor Niman show today is Monday, November 18, 2 02 4. This is our next series of daily updates. Dr. Niman will now do his talk.  Dr. Niman Thanks for tonight. I thought I would focus on the teenager and I kinda go through. How you can use the sequence to identify Where this virus came from in its recent past, and then I'll talk a little bit about the mutations and how they always can be used to to figure out how it got from entering British Columbia and ending In the ICU in the teenager The virus has most of the listers now it is in a teenager who's in critical condition and Went to the emergency room and got turned away at least once and Eventually got into admitted, and shortly after that, it was determined that the teenager had H 5 which then went to H5 and one in the sequence Came out over the weekend and I had put out some data today too, so that is a spoiler alert so if you don't wanna wait till the end that the virus actually came from wild birds, they probably even came from a cackling goose, and that wild bird was in British Columbia And the way you get to that is is using the sequence and Comparing with what other sequences are in the databases, there's a big database and she said, and most of the sequences get uploaded there from the various labs that get the samples and generate the sequence I meant this little earlier but for influenza it's a segmented genome so it's really eight different pieces and so full sadness to get a full sequence for All eight of those pieces and the full sequence is usually starting. It's usually covering the region that codes for the water or more proteins that are in there and and so you have a kind of a standard size that you can see out of the number of positions how many of those positions match that tell her what I put up the day I took the sequence from the teenager and. Ran the sequence for each of the eight segments and saw which sequences in the database matched the most closely and then put the top matches up on the On Twitter and a blue sky So just as a An example on how this is done your technically you can kind of just think of it out. It is a Google search and it's kinda like if you found a paragraph out of a book and you kinda knew it was a famous book and you knew the text to that book was probably. On the Internet in Google and search it, you could find that book by probably in both cases. You could take one sentence out of one paragraph and search that one sentence and you'll get a matched and they'll usually be. Unique match you're only gonna get one sentence at max is that Word for Word was this a very short sentence but it's the sentence with 10 or 15 words you're likely to get only one and One exact match and even if you're not get exact match, you'll have a pretty limited numbers that are close to that sentence and if you got the whole paragraph, you can either look at the sentences that are the top matches and see which one comes from a paragraph paragraph that matches the whole paragraph for you can go back and do the search account use five sentences and then you're guaranteed you're only gonna get one match and If that paragraph on the Internet, you're gonna get the whole paragraph and if you have the whole paragraph, it's probably in the book and you're gonna know where that satins are. Five sentences came from and you'll be able to do that identification so you do the same thing with the sequences of the virus The virus like I say is divide up eight pieces and so you can search each piece individually and The two that are really the simplest if you take the sequence for the MPG and that's got 982 positions and you take those 982 position from the teenager and you Basically put it into the search box and hit the search button and it'll kick back the top matches and a few seconds, and in the case of the teenager if you do that for the MPG out of all the sequences that are in the flu sequences that are in the database and that's gonna be I don't even know what it is for. I know what it is for for for Covid. It's like 17 million for fluid is it's it's probably less than that but flu in general it's gonna be hundreds of thousands and even eight. Five is gonna be tens of thousands of sequences and out of all of those sequences could be theoretically this isn't even a nature and this is an internal gene and all the flu. All the influenza. A sequences anyway will have will have an MTG and some of them be fairly close to this, even though. They may not be HI they may not be high path they couldn't even be but anyway the answer to the initial search there's only two exact matches so the two sequences at G said that exactly matched the MPG of the teenager in the hospital are To cackling, goose sequences, and there's information about each of these sequences that they go along with the actual name of the sequence add in this case The way influenza viruses are named is the first field is to type and these are all gonna be influenza so they all start with an a and then the second field is the species end of the case of the teenager since that a human species the species is an included that they can and I'll put in human or whatever you wanna Homosapien or whatever they just leave that field blank and they go right to the next field, which is the Location so in case of the geese there they're not human so the second field is cackling, goose and then the third Field is the location and these two castling geese. The location is BC for British Columbia and then you get to the actual number of the that's aside to the sequence and that's generally assigned for. By the lab that does the sequencing and I'll usually have a number and then they'll have some type of abbreviation that gives you an idea who the lab is and This one the letter is actually RAI D PH L and I would assume it stands for area influenza virus public health lab, which is what the lab in Columbia called to self and then what is the dash 253 5 The other one is 254 1 and they were both collected in last month and the last field this year and they both stay 202 4 that tells you from just that one search of One of the jeans that these are the top Canada, these these two sequences out of Hundreds of the house At least 100, 000 there's only two sequences that are exactly the same as the sequences in the teenager and there are two years that were from British Columbia and were collected last month. I mean the last month part is it in the name but the name is associated with meta-data. Which which lab did it who the scientist were when they actually collected it unfortunately with the with the teenager all it actually says it's November usually they keep the day and I'm not sure why they had trouble figuring out what day it was in November since it was deposited In November So they just got the sample a little while ago and they they should've known what day it was collected on, but they did not put that in and there's a lot of little things that are a little a little fishy about the The whole situation On these particular viruses but getting back to the next sequence and hold on one second here OK and then the next sequence was used as the NS sequence, which is a non- structural S stand for The MP action stands for matrix protein and in the case of the NST it's it has 238 positions and the Quence for the teenager again Came up with two sequences that were exact matches so they had 238 out of 238 of the positions and not surprisingly the two sequences that were an exact match for the N Were the same two cast duty geese so now it was Up to two out of the 18 were exactly the same in these cackling feast and then the next sequence that was done was the PB two sequence and let me get that from me and that case that the PP2 sequences Considerably bigger and The one cackling goose that was 253 5 Was the number one matched and that there was only one difference and it was it was 2 279 out of 2 2 80 so too much bigger jeans and there was only one difference between the cat one of the cat gees And then the one that came to number two was the other Kathleen juice and that match was 2 0 2,278 out of 2200 days so they're only two differences so they they were exact matches on to the jeans all by themselves and Now they were the top two for this larger team one had one difference and one the other had two differences. The next one that was done was the PB one Jane, which is also a big Jean and this time the other Catholic goose so this number 254 1. What's the top match? And again there was only one difference, though it was 2273 out of 2 27 4 and then the other cackling goose had two differences that goose was tied for second place there were there were three other wild birds that also had only Two differences and one was a snow goose one was a Canadian goose and one was another cat goose and I'm going to the next run. It was the polymerize a the P 18. And in that case 253 5 gas clean goose Was an exact match it was 2251 out of 2251 but that was shared with three other wild birds were exact match for the P 18 and then for the there were two that only had one difference and one of the two was the other cackling goose so the two cackling goose these one was exact one had a single difference And then going down to the H 5 Dean the They had three differences with the H 5 and they both had 17 oh one out of 170 4 so that was the three differences and they were tied there with Six other sequences that were also that close that they basically only had three differences and so they were among the most closely related to the key, but they were their brothers that were at that level and then Going to the next sequence was the N teaching as a nuclear protein and in that case both of these cackling gees were exact matches 1497 out of 149 7 and there were I'll see what would that be? There would be 10 others that also wear exact matches and those 10 others included five of the colors at the Franklin County. Layer farm in Washington state and five were wild birds and one was from a turkey farm. The wild birds and the turkey farm were off from British Columbia. And then the last one is the the N one And the one in this case it's the genotype is D one.1 and one.1 has a North American They are in one and so any any matches I gotta be with North American, wild birds, and the two Kathleen geese were again of the number one physician out of all the other sequences in the database and they both were 1406 out of 1410 so there were four differences, but that was the best and the sequence could do and the database and that was shared with one other Wildbird sequences and so The upside is that if you take all those matches, you'll see these two cast these were at the top of the list in And everyone of the 18 segments and that's a strong indication that this virus before it got into the team was in a wild bird almost certainly likely to be a cackling, goose almost certainly a wild bird And that's where it was when I came into British Columbia or evolved in British Columbia as the other part of the question is what happened to that goose Before the virus in the goose ended up in the teenager and there as I had mentioned yesterday that the sequence of the teenager has three very critical Changes and these to who them are changes that are widely studied as changes that Move the virus from being an alien virus to being out my mail virus and why does PB two change E2 80 627 K with the primary to be more most efficient at 33° C which is much closer to human than the bird temperature which is 41° C And if the Position didn't change to OK it would've been eating and he is is optimal at the same temperature. It's as a bird. It's at 41° seven grade and the other one is. E1 90 D and that's a keychain that kind of loops around him and comes in close contact with The other chain it has which is Q226 8 and position 2 26 and 228 are kind of the key positions and the reason they keep positions is The H5 are somewhat analogous to H2 circulating in wild birds and then it acquired those three changes the 1 22 62 2 8 and the eight and 62 7 and the PB two And that took That H2 from an avian H2 to a human H2 and led to a pandemic. The pandemic began in 1957 and started in Singapore and it ended when it was displayed by another pandemic, which was. The Hong Kong flew where it was originated in Hong Kong and the H2 that replaced by H 3H3 and two is the other seasonal that started as a pandemic back in 19 68 and the question is number one how easy is it to make those changes and the answer is it's not that hard to make the PB two change but it is hard to make The two changes on the H5 and the reason it's hard is I'm the only have to change one of the three nucleotides in the codon for position 1 90 are the same thing for position 22 6 but the change that you have to make to go from Adrian to my mail is what referred to as a transversion and just briefly to think about the model biology kind of background / Genetics the the virus is actually have RNA but the difference between an RNA and DNA is is just one of the letters a T is in DNA and you was an RA But they have the same base pairing the keys or use pair up with a and then like I said there's only four letters so it turns out to the four letters represent two different types, appearing in a remedy and For the DNA to form a nice double helix they They the pairing up rules, always pair up with one pairing with one perimeter, and in this case, these transfer since kind of breaks that rule that they come up with another Another letter that that ends up either having to purines at the position or to perimeter at the position and that all the way that genetic code is set up It harder for that to happen and it really doesn't I'm not gonna go to the details as to why it's easier while it's hard but trust me that the two trans versions are much rare than the new permitting for perimeter or appearing for pure color. Transition transitions are a lot easier and the PB twos the transition and the two changes in the H fiber transversions so. The time just calling, you know that level of detail, it would be very unlikely that all three of these changes would happen to the teenager between the time The teenager was infected, and the time they collected the samples and is much more likely that these three male changes evolved in other mammals before they got out of the teenager and So there is the story that the family dog was was ill and had to get put down. It seems that the prevailing story now is right about the time the team developed symptoms and they initially tested the dog and it was negative. But as I said yesterday, the virus sometimes could move by the time they they got to get a sample from the dog. He was probably in while it was right before he was he was put down, so the dog would've been very ill and is very possible that the virus was in the dog salon, causing serious problems and it already been cleared from the dog nose when he got first infected, which is probably many days before the sample is collected. As the nose may be negative, but that doesn't mean that there's not virus in the lungs and it doesn't mean there wasn't virus in the dog nose when he was getting sick and was Probably in close contact with the teenager that's in the hospital now, but it's not even clear that that would be enough just to go through one mammal so it could very well be that that the dog ended up getting affected from some other mammal that eats Wild birds like a possum I don't know if you did that but other carnivores would would Feast on a bird and could get infected and that could've caused some of the changes to happen in that mammal and that more changes happened in the dog and then The team got infected and has these three very rare you take sense so it's a concern because of the origin it was in the wild birds and probably not that many wild birds are flying around with all three of these changes but There can be other other mammal certified cut us had a similar situation or somehow I had A mammal to mammal transfer that Ended up, causing other humans to be affected now How transmissible this virus would be yeah In the eighth, it's only got one of the two that that make it very transmissible, but it's probably more transmissible than The virus doesn't have the changes that are in most of the wild birds, but it is an example that that this is already happened once and there are a lot of wild birds that are that are going through the area out there that they basically spent the summer up and In Canada, probably northern Canada or Alaska and they breed it over the summer and then when the the newborns are ready to fly, they they go they head south for the for the winter and that's what's going on right now and unfortunately, it's not just in the Pacific flyway, the Pacific flyway is getting a lot of Positive farms now both in British Columbia and now starting to pick up in Alberta first case went back once confirm today And I think there's one that says Saskatchewan rather than any event they're heading south. They're starting to show up in other flyways in the United States also. Right now there's more activity in the Pacific fly away. It's gotten all the way down to Arizona now there's a lot in California. They were there a number of poultry farms that were announced today. In California, it's a little bit confusing it with the virus. It is because they've got the beef free at 13 which is the dairy farm one and those numbers are going up very dramatically. I think there was something like 40 farms that were identified since Friday. And they're up to I think there's 11 00 dairy farms in California. There's the number one built. Pretty sure the country in about 30% of now have been infected with the B31 3 and when there's a lot of that that virus present there is spill over isn't just the Gary fire to virus. Manages to get from the dairy farms to the poultry farms and that's primarily done Small animals like nicer cats can get affected as far as mammals are concerned then the various small birds like sparrow or starling or pigeons Can get infected and they're smaller so that even if there's some type of Barrier to try to keep the wild animals out they have an easier time getting in and they frequently go inside to get to the to get to the food and they get to the food deal Defecate into the food and then the cow eat the food or the chickens or turkeys. I'll eat the food and then they'll get affected with the with the same virus that in this case get affected with the virus it's normally found in the dairy so that's gotta wrap it up for tonight it's just a little bit of molecular biology and. The main point is you can tell a lot of information from the sequence and I've always maintained the stories in the sequence and in this case you can get the origin you could see how complex it changes are and you have a better idea of why the teenagers in the ICU  You OK, the information will continue to do these as time permits. Everyone have a great evening. 

https://soundcloud.com/thedrnimanshow/11172024a1 You Good evening and welcome to the doctor Niman show today is Sunday, November 17, 2 024. I think we're gonna start doing these a lot more often and Dr. Niman will give a daily update so would today's update Dr. Niman you have the floor  Dr. Niman OK, thanks Ryan. Yeah today I'd focus a little bit more on the teenager. That's in the hospital now still in British Columbia and secrets came out a couple days ago. Just to give some background on on the human cases the outbreak they are going the existing outbreak really started a couple of years ago and and in 2022, but there was a prior outbreak this in the United States. There's another prior outbreak in 20 14 and all of these were the same played, which is 2.3. 4 B And that is in reference to what the H5 was this is H5 with a poly basic TV beside which is kind of the Define high that all the viruses that have this type of this number of basis at the site in H5 or 8 7 end up being high Pat is the high pass virus, but Initially, it seemed to be pretty Specific for the Birds and so like I say it started in 20 14 Back then, there were even three different stereotypes there was HI than one and two and an eight at the end all came from North America and zero down and two which created most of the damage of the damage was significant there were over 50 million birds that ended up being infected or called and dumb, and that particular outbreak went away and then it came back in 202 4 and the end of the earlier ones there were actually zero human cases and then the ones that began in 202 2 there was again 50 million birds that got killed either by infection or euthanized and And that year there was actually only one human case and then there were no human cases in 202 3 and 202 4 things changed fairly dramatically and they began with the viruses is given different genotypes and the genotypes are Based on what the eight segments look like and like I said the last podcast influencers Gino is split up in the eight segments in those segment can shuffle around if one host Factor by two different viruses, they cannot mix and Matt and the virus that end up emerging has usually some of the sickness from one of the viruses and some of the segments from the other since it's called reassortment, but the the genotype really is based upon what the constellation is of these eight different segments And that can have a significant difference and they can have a different certainly in the sequence, but what what does the biological affect that has is not that clear and it turns out the The virus ended up, probably with wild bird that it really wasn't that widespread in wild birds, but infected the cattle and in the panhandle of Texas and it was designated B3. 13 and it had actually evolve from another similar virus, which is B 3– 7 and the difference was the 13 had picked up a M P, I'm sorry An NP segment in the NP was one North American sequence segment exchange with another and emerge A particular change at position 52 and it changed the Y to H and that particular mutation had been associated her has been associated with The alien virus evading the human and human response to that virus and so this was a bit of like an escape mutant Was as affected by the human response and that may have something to do with disability to get the catalog there was a significant delay in identifying the H5 and one in the cattle because they've never been seen before and frankly it hasn't been seen anywhere outside of the United States, but they started out in the panhandle and then it spread to Adjacent states, and so it was in the north east of New Mexico and the southwest of Kansas and it Finally got identified in March of this year and Then it's spread out further through the sale of the cattle of the cattle and not going to other states and that's why all of the dairy actually has the same that they're all B3. 13 and they're all fairly close to be related to each other and And in addition, you know they call dairy, but In the spread, they ended up spread spreading to poultry farms, and and that was where a couple of the larger clusters were so the first cluster actually did happen in Texas That did have one of the changes the mail changes which is in the PB 2 segment and it's called E627 K and that's kind of a temperature sensitive mutant that allows the virus to grow more efficiently at 33° C was a lack of human body temperature than 4 1 for the birds, and if it had to eat that position, it was most efficient at the bird temperature, but but that was a keychain, and that was tested And various to see if it was More easily spread through the air the way those experiments or they affect ferrets and they have them in one cage and they have uninfected ferret and a second cage, and They don't they don't have direct contact with each other and they see whether the second cage, parents end up getting infected by air from the Infected ferret, which she with cough or sneezing, aerosolized the virus and frankly they did get positive of the viral. The Ferris did show some ability transfer from one mammal to the other mammal and what was unusual is all of the fairies that were initially inoculated ended up dying, and that that usually doesn't happen, the ferrets are used all the time in this animal bottle. They were used some of the gain of function studies where they deliberately made some changes in the virus. Affected the ferritin, then saw whether they could transferred it and they were able to do that and under those circumstances also and I'll probably get that another session. I wanna kind of stay at what's going on this year and that's all that was a little bit concerning, but then there they've been quite a few that have been identified in humans with this b3. 13 and. This first case out of Texas is the only one with 67K so The largest cluster is really came out of spill true a couple layer farms in Wells County Colorado, and that resulted in one cluster of six and one cluster of three. These layer fires were relatively close to each other and. The affections were only a couple. I didn't know those couple is probably about a one week apart, but those were the two biggest clusters that had been reported to date and that got a lot of attention and a lot of the sequences that are that are still being positive really hard these very sequences whether they came from. Dairy cattle humans Layer farms or Actually gotten into the milk supply so I knew that's where the milk supply the milk pasteurized. The virus is still detected and those are the key areas but then there was a new outbreak fairly recently and that was in Franklin County Washington, and that had a different constellation that those had it was designated the one that one. And that cluster, which was Definitely the largest actually nine and they take two more so it's really up to 11 now and other than it's three more that were initially PCR confirmed and so they're just suspect because they didn't get confirmed by the CDC so there's been 14 people that they came out of the same fire and That had created some concern, and then the concern increased when this teenager and British Columbia ended up getting a serious case of the virus. These other cases were mostly conjunctivitis some hits of mild conditions. They were pretty much all farmers on the farm or colors and in general. Especially the colors got treated relatively quickly with Tamiflu and they all recovered and didn't really end up in the hospital. This teenager though. Didn't do that well The teenager initially went to the emergency room and And probably being tested for seasonal flu when he was they were negative and then They were actually sent home and then they ended up coming back at least one more time and Possibly too, but even if it was only one, they came back a second time and then they got admitted and they did more sophisticated testing, and they found out that the teenager had been affected with with H5 and then they were subsequently confirmed that it was five and one and the sequence was just released A couple of days ago, Friday night actually, and the sequence ended up being quite concerning that there are specific positions that have been monitored Because that is kind of a model on the 1957 pandemic and in that case H2 and two ended up replacing seasonal fluid with his H one and what add the What the sequences were were compared to what they found is that the that they were really three different positions that were changed that whoever were in the H 5 and they were at position to 26 to 28 20 16 with a Q changing to 28 was a G S and then there was this the same chain that I've mentioned in the PB 2 DE on 62 7 Main to K And it turns out that H 5 has the Has the bird version for all three of those and so when there would be an outbreak in China for instance, and that they were to be an outbreak it could just be people that were very, very sick or actually might've been fatal and they would sequence that individual to see if they had One or more of these changes and they would always come back and say they looked at it, and it doesn't have any changes that worked out for more efficient transmission from human to human and the sequence came back from this teenager and Teenager actually had Change that to out of these three positions and then there was a there was a fourth position which was a position 1 90 on the eighth on the eighth and that was E changed the D and the teenager had that The EEE 1 90 D and they also had to change out the 22 6 but the queue at that position didn't change the Allen started to change the H and they had E 67 And so it really they really had three changes that were gonna make the virus infect other mammals more easily. Now the sequence that came out I really did. These weren't that clean they had mixed signal and which meant they had. This mutation, I said plus they had the original secret they had wow type so they were about 50-50 for each of these three, but those were the only three positions that actually showed dis mixed signals and kinda indicated that they had a virus that didn't have these changes that Was mixed with a virus that had all three of them and and the teenager kinda had this mixed version and in all likelihood the sample that will get clones so they can get a clean version that has all three of these without the wild type Signals in the background and and they might even get more of that by just taking out a new sample from the teenagers, it's lungs, which is where the virus seems to be causing the pneumonia and the recent day the patient is now critical condition with heart, which is acute Respiratory disease syndrome and that's when the lungs and pneumonia is bad enough that is very hard for the patient to oxygen their blood and they may actually be on a ventilator to help do that So the question is, where did he get infected and is still under investigation? It seems likely that the team was probably infected by another mammal the fact that all three changes. You know these are really key changes that they're exceedingly rare in And HI don't want the E 67K it's probably the the more common one that the same but the other two the other three are pretty are pretty rare and they have two of the others 3 + this actually have three It's almost like experiments that are done in the lab where a sample is serial passage and by taking an alien sequence in putting into a mammal and then taking the virus, incubate the mammal and put it into another mammal and do that multiple times and you end up selecting for The mail Changes to make it easier and easier to to move from one man to the other and so there's a good chance that that's what's happening with this particular virus in the team picked it up from mammal that was probably infected by another mammal. It had gone through this process several times and it's a bad news part of that would mean that. There's other mammals out there that have the sequence. They just haven't been identified yet and it's it's concerning that this teenager has all three of these changes. That's where things stand right now I mean, there's there's one story that's in development. It's a little bit. Couple different stories on it that the family dog had actually Been ill and had been euthanized and there's a mixed story as to whether that dog had been sampled or another dog had been sampled it, but there was a dog sample there was it was negative, but even if it was the family dog Since the dog was euthanized, very close to when it would sample is possible that The virus had already removed to the dog salons, and then taking swab the dog's throat by Not of yield it positive because it already cleared it from his throat, but didn't really clear from the lungs. That's why it was causing all the problems so that dog apparently is under. More Investigation where they're probably gonna take Oregon from the dog and And look at The levels of virus and see if they can pick the virus up their deck that that would be a pretty Tidy kind of explanation that teenager prior expose contact with this dog as the dog was staring, and the dog could very well have Eaten some mammal that he died from eating, potentially eating, wild birds that had been infected the sequence itself. You can do these kind of searches. It's kind of like a Google search if you're well you take the sequence and you search the database so you find sequences that are closest and it turns out that the teenagers sequence in. And three of these jeans Has exact matches with with with wild ducks, cackling geese Actually, there's two of them that are exact matches for two of the gene segments the the N P and the N S and then One of those two along with a couple of snow goose And the Canadian goose are exact matches with The plume, I say the PA and the Kathleen Is after the other two it's only got one difference in the in the PA so it does you're really point a while. This is where the sequence began, and how many mammals that went through before it got to the. To the teenager in the hospital might've been one or two and that was enough to evolve this the sequence so it's adapting to the mammal and that's what the concern is in general is the virus the HI and no one will do something similar to the H2 N2 Where started out it's just being an alien sequence and it ended up making these three key changes And then it was able to officially transmitted in humans and that they got established two and two started in 195 7 and then it went through 19 68 when I got Displace by another pandemic and and Started a Hong Kong that was H3 2 and so the bottom line is that this virus is evolving quickly and the teenager has three very important Occasions, they'll probably be more sequences coming from this samples from this teenager. They will probably clean up the wild type and they'll end up getting the virus that just has these three changes without. Competing type sequences for these positions and I'm sure this virus will be studying very very extensively as to how well it works in a model like the first one out of Texas to put this virus in the ferrets and they'll see whether the ferrets in the next cage end up getting infected to see how efficiently this virus will transmit through the air And surveillance I would imagine with would pick up significantly because this particular virus the D1 that one is very widespread in the wild birds. They tested 14 wild birds in British Columbia and 13 of them had this sequence. They tested for farms and we had the sequence and the other one was actually an H5 and two, but there was a derivative of the sequence and the wild birds are coming up positive all the way down to The wild bird and the poultry is in the United States. It's all the way down to Arizona and the Pacific fly away so they're heading south they're coming in very high numbers. It is no time with a fly out of Canada. They fly through the United States and end up going to southern areas in the US are not going. Central America down into South America so that's where we are right now will be doing some additional updates probably each day and maybe get more information on the family dog and potentially has some additional sequences even as earliest tomorrow  You OK, thank you for the information everyone. Thank you for listening and have a great day. 

https://soundcloud.com/thedrnimanshow/11162024a1 You Hello and welcome to the Dr. Niman show today is Saturday, November 16, 2 02 4H5 and one has been exploding in the United States with various human cases and also in many ways that never has before here with us is the aforementioned Dr. Henry Niman, he will give the talk  Dr. Niman Hi Ryan, thanks for the introduction and it's the recently events Make it necessary to start giving regular updates because I think this situation is is literally and figuratively evolving extremely quickly just to get a little background. I've been following each five and one probably since it. Cut a reappeared in in 2 00 4 HR and one initially Captured the interest to quite a few scientists in 199 7 when it was involved with an outbreak in Hong Kong I think there were 18 cases and six of the 18 died and There was a high fatality rate and A lot of signage just got interested in an H5 and one back then are they they ended up tracing it to wet markets in Hong Kong. They called all the all the birds there and that the human case is kind of bomb. Die down, the virus continued to infect, poultry fires, largely and in China, but then At the beginning of 2 00 4 children started showing up at emergency rooms in northern Vietnam and they are they they had flu like symptoms. They tested him for influenza a and they were positive and then they tried the sub type to find out if they had each one, add one or H3 and two. Two versions of seasonal flu and they were negative for both that make long story short they eventually tested them for H 5 and found out that indeed they had H5 and one That is five and one spread throughout stealthy Asia and the symbol. The sequences were similar and it was designated as I'm not surprisingly played one. But then things started to heat up more in the following year in 2 00 5 And one of the major incidents happened in the spring of 2 005 that Shanghai Lake in China Central China is the largest lake in China and there were all of these wild birds that were dead on the water And the Main species were actually Barrhead geese, but there were many different species that that were represented in the dead category and Initially, China denied it was H59 one but eventually Samples were collected, and indeed was a try that one and it led to actually two back-to-back publications, one in nature and one in science, and they described the sequences And what really stood out with the sequences is that they had this one particular change in the polymerase one of the three primary teams PB two and it was designated E62 7 K because the position 627 changed to a K and that was well known that was a change that The K is actually present in at the time all seasonal flew both each three and two add each one and one that That's the human version of flu and that was concerning because it was known that that mutation was temperature sensitive and the PB two is actually peace. Answer for polymerase is one of three liras the virus codes for the copies genetic information. And if there's a E at that position as position 62 7 The inside the ability to copy is is optimal at 41 ° C which is the body temperature of a bird but if the E K then at the enzymes optimal at 33° C which is much closer to the human body temp of 37° C And human outside in the cold in the winter there, their nose and throat would actually be a little bit cooler than their body temperature and it would be a lot closer to 33 ° C of the virus is very good at replicating in mammals, especially in mammals in the In the winter so That was one of the reasons there were so much interest in this played in the wild birds and they ended up dividing up H5 and one that wasn't played one in the three different sub plates clay too two point one was the five and one in Indonesia and it actually never got out of Indonesia actually 2.2 was the version of Shanghai Lake And played 2. 3 was the version of H5 and one that was circulated circulating its Fuji and pro at the time The I was interested actually in the wild bird version because you could actually track it in China initially which was not always that forthcoming because it actually did affect waterfall Whereas the earlier version of H5 $ one we're pretty lethal to chickens, but they really were tolerated relatively well by water, foul and part because they had been affected by low path HI they had some immunity the H5 in general And they were able to kind of handle the high H5 and one where the chickens were not there they were spread very quickly and it was very lethal, but you could see what the HI than one plate 2.2 was doing because it kind of went from the High Lake in central China, and move north Northwest in and through Northwestern China, and then it went into Kazakhstan and then it went into Siberia Russia, and this path really was the wild birds migrating to the north to To spend the summer in the in the cooler climate, and this was the place where the various bird flyway is overlapped and so the virus that was in China was able to get out of China by flying to Kazakhstan and Russia and then for the summer and then in the fall, they would infect birds and another fly waves that intersection intersect in Russia And turned off it ended up flying to Europe at the Middle East and northern Africa, and It was concerning because they had a 67 K but then it was also concerning because they had some receptor by the domain changes which made it more able to infect humans as you predicted one of those changes in position to 2 7 using H3 numbering and that was S 227 and and there was predicted because that had been seen in In China and I had looked to see what it would take to take the play 2.2 sequence and try and acquire that through recombination and it turned out the donor sequences that will allow it to acquire S27 and was was present in another Zero type H9 and two which was circulating in the Middle East and the prediction was these birds flew out of China and ended up in the Middle East. They were interact with the sky too, and they would end up creating scepter by domain change. And I wrote about that in November of 2 00 5 and then the birds arrived in the Middle East in Europe The fall of 200 5 and and the first human case I got inspected right at the end of 2 005 and turkey. There were four children that there were positive and they were hospitalized in early 200 6 and. I think possibly all four of them died, but I was waiting for the sequencing. It's really delayed and they were only four sequence sister came out of. Turkey and two out of the forehead the S22 7 and And those that particular virus, it was in cause a lot of problems and the problems were so bad that the WHO reports stop giving the Collection date, or the election date is on that date or the gender of those infected because if you had that information, it would be pretty clear to see that there were clusters that were arising in Turkey in fact, almost all of the infections and turkey were clustered. I think the clusters I think they ended up preferred me something like 20 some cases and they're always paired up. But eventually, this human case is faded that they were just a turkey. They were an answer by John they were in Egypt. They were actually even. Booty and then they made it all the way over to Nigeria that they were limited numbers of cases and most of the cases happened in early 200 6. I kind of persisted in Egypt that kept going for several years with H5 and one human cases, but eventually the. The virus flew back to To Siberia again and add the 2.2 prescient for several years and then it subsequently got replaced by the food version the clay 2. 3 and the current outbreak is actually a derivative of the 2.3 that's why it's called 2 .3 .4 . 4 B And that's based upon the 8 5 and It's got a poly basic clever site so it's got a bunch of basic amino acids right where the the H egg gets cleaned and it could be cleaned by a lot of different enzymes that are present a lot of different cells so the virus is able to get out of the respiratory track and attack many different Cell types or organs that's part of the reason so lethal with the chickens that they just die of organ failure because they have the virus throughout their their body so antifreeze fast forward out of Asia and Europe The first major H5 – one outbreak in the United States happened at 20 14 and and that did actually involve the same site that the 2.3 44. 4 and it came down the Pacific fly away, which goes down the West Coast of Alaska Canada in the United States and it started right about now Australia in 20 14. It started at the beginning of December and her first showed up the British Columbia and. And their poultry fires, and then it showed up in Washington state and the virus they came from Asia really had already picked up some North American sequences segment said that flu is a segmented genome so it's kind of like it's got eight different chromosomes. It's got eight separate segments for his genome and they can mix and mat. One host has more than one virus so they can end up taking the some of the segments from one of the virus and some from the other and come up with a new version and they're actually given Type names and it turned out that the original Sequences that showed up in North America in 20 14 really had a North American N and it really had three different serotype so there was H5 and one H5 then 2H5 then eight and like I say the N1 the N2 with the N8 all we're North American so they replaced the Eurasian version that the start out in in Asia And eventually, the H5 that two became dominant, and that started creating major problems in the spring when the virus headed back north and it killed a lot of turkeys in Minnesota, which is the number one turkey producer in the United States and I killed a lot of layer chickens in Iowa in Iowa is the wire chickens lay eggs And Iowa is the number one egg producer in the United States so in 2 0 15 there were there were major shortages of both Turkeys and eggs in the United States because the virus ended up killing over 50 million birds and in that case the virus went back to Canada and they kind of faded away and Created problems again, and 2 000 20 Hold on Like it was 20 18 and That that outbreak create a similar problem that there were Another 50 million birds that ended up dying and I'm sorry that there was a 2022 it's what happened it was in 2022 and that one spread All the way south it ended up coming down the Atlantic fly away from Europe and started Newfoundland. Then it went down to. In the United States that went down to North Carolina, and that was the eastern flyway, and then gradually spread to all four flyways in the United States was across the US and and then it went further south And it went into Central America and then it went into South America and it was pretty clear that five that one was in in the Americas for good and indeed it it moved around. He's here but it's been it's been circulating since. 2022 and the Situation kind of changed in the United States, which has been my focus in the United States to Canada really and the situation takes At the beginning of this year in 202 4 and it started out kind of is a mystery disease and it's kinda surprising that it would be a mystery of 2024 since the virus had been creating all kind of problems since 2022, but Dairy cattle in the Texas can't handle Started Losing their milk production that their milk production went down the milk they produced was was very thick and very yellowish and towels themselves were kind of sluggish and It took until March that they actually tested the cows for H5 and one and they indeed were positive and initially it was in the Texas panhandle by the time they identified H5 and one it had spread to north east New Mexico in Southwest Kansas so they were their areas that were close to the panhandle and Kind of had a unique genotype there was designated B3. 13 and it turned out that initially when it was positive not much was done Because in contrast to the wild birds, the cows had this reduction and milk production, but only about 2% of the cows died and they recovered so their milk production went back up although I think that it didn't quite get to the level it was before the infections And the farmers were necessary all that cooperative the cooperation was greater for poultry fires because once they had a side and one, it was the number of dead birds would increase on a daily basis and They basically called all the birds that they didn't call the birds in a limited number of days. All the birds would've been affected and died, except that they have a lot more virus that was gonna contaminate everything then if they killed off the whole fox. Earlier and So the problem with the infections in the cattle is that there's a lot of trading of the of the cows, and there were initially no restrictions and so a lot of cows that were infected with they tried that one were shipped to other states And that really spread the virus around in the US. They were just being moved around by my truck and the truck was carry out and in many cases the cows were asymptomatic when they were shipped and that they were at their new destinations and they were in fact those those. Herds They were frequently be local spread sometimes they weren't. I mean in Ohio I think only the initial far was positive in North Carolina at the same thing, but then other space like Michigan started at one county and then spread four or five other counties, and then it started to spill over into the poultry until then the poultry ended up getting the same virus the dairy attack that's B3. 13. And that ended up changing the situation for a few minutes were concerned that in 20 14. The number of human cases was zero in 202 2. The number of human cases was only one which is the color in Colorado, but then things began to change in 202 4 and of all of the human cases initially were the the Genotype that was found in the dairy farms and They generally started initially as one or two perform and then they had a significant outbreak in Wells County in Colorado. They had one layer farm that this was spill over to the chickens and the layer for farm had. It was fairly big had about 2 million birds and six of the colors ended up getting infected and then there was another 2 million bird farm not too far away also and well countering where three of them were affected so now it wasn't just Individual human cases there were actually colored clusters a few well where were multiple colors were positive and Then things kind of moved into a new version with an outbreak and In Washington state in Franklin County Washington state again it was a layer farm which had about 800, 000 birds and They initially had six of the colors that were positive and then they got three more and it turned out to the three more ended up traveling to Oregon after the color was done and they had a parent probably didn't given a prophylactic Tamiflu Just because they had been exposed to both the poultry as well as the six colors previously and they ended up developing symptoms probably in in Oregon and they ended up getting tester in Oregon and they were not only were they positive for five that one, but they all had A change in the and wanted a minute and it was the acid position 24 7 changed to an end and that made them somewhat resistant to the the also Tammy bear of brand names Tamiflu and so they were Tamiflu resistant But they did end up recovering, but all three of them ended up having the same mutation and they kinda indicated that they were fairly susceptible to this resistance and these didn't have the dairy type. Just be 3 13 they had. This newer one which was D1 that one and turned out the D1 that one was really in the wild bird this time that Canada released 14 sequences from wild birds from British Columbia 13 of them here to D1. One and then they had a teenager that was positive and that teenager. I don't know it's a little bit fuzzy on the timeline. It sounds like the teenager went to the emergency room and. Examined and sent home and then a few days later Said he is not really clear if it's your seat the teenager was went back to the emergency room and it was again sent home and then finally it was They were admitted and then that they actually did the next day. They were confirmed to have 85 and then the sample was sent to the national labs in Winnipeg and they confirmed it was eight by that one and then the reason we're doing these podcast is that last night. They released the sequence of the HI and one from the teenager and I kinda lifted the sequence last night night really started with the with the PB two and saw they did indeed had the E 67 K and it wasn't a clean signal. It was a mixture so it's all part of the signal came from the wild type, which was. The secrets with the E and part of the cave from is switching over to the K and so they represent that by saying that the nucleotide at the in this case, it was the first position coding for Code 62 7 it was a mixture out at the nucleotide level of a key in an a, and that would cause the changes in the protein to go from EK and that was concerning for two reasons that this change had been found previously and the first human that had the Dairy sequence and and that person they were, they weren't that sick that they just had conductor bites, but they that the sample the virus was sent well in Wisconsin that basically Put it into ferrets to see how well the ferrets would do and all the ferrets died and also it was concerning that the E62 7 K on the human that had it wasn't that bad but the human would've would've probably been given Tammy Foux fairly early on and Just had conjunctivitis where is the fairest actually died and so it was worried that this E627K which was an adaptation would cause virus to our replicate to higher levels in a mammal and they would get through a high enough level that it resulted And so the teen who was in British Columbia had the same change it was as a mixture, but it was E627K with you just the E And the teenager actually had deteriorated and was it Was actually in critical condition in the ICU where the teenager still is, but that was one change that was worrying and frankly, I didn't look at the sequence that closely last night but She said, which is the database to the sequences Has a kind of a running Violet genetic tree and they got that one for the H5 and they got one for the M1 and they actually have one for the PB two so three of the 18 segments they would have a treat that they were kind of update and the updated tree so that not only Did have the chain in 627K of the PB two but in the H 5 there were two changes and they were also mixtures and they use the sequence is actually in the The actual H 5 but a Lot of research on the H uses an H3 numbering that part because the sequences that we're studied initially came from seasonal flu H3 and two and the H 5 is slightly different numbers and so you don't get real confused A lot of the conversion is to put them all in the H 3 number at least so you can compare one from the other and add these two changes if you switched it over to H3 numbering When was that position 1 90 and the chain at 1 90 DN E I believe was was well known the exact letters, but it's definitely position 1 90 and That was present in a mix form and then there was another changed. It was that position to 2 6 and that's in the receptor body domain and the two key positions and the H using a street numbering is 226 to 22 8. And this had changed it to 2 6 also and it turned out this one changed from a Q to a H so it had two changes in the H5 sequence and it had one change in the PB two and all of those changes are linked to making the virus more the mail And since the teenager is in critical condition and his their sequence has three key changes There is quite a bit of interested in this particular case and there's quite a bit of concern that other human cases they are affected with the D one that one genotype could end up having these particular changes So I think we'll kind of stop the podcast there that's where things stand as of right now, but I can. I can certainly tell you that this sequence has caused a lot of interest online and a Saturday so yeah I would imagine even more interest will it will be a parent called Monday. When more people realize what the sequence is of this patient in the ICU in British Columbia and They'll be a lot more data than that there will be coming out. It is clear that the human cases are. Are on our up to 52 now are all of them this year and All of them except for these colors and in Washington state, and this teenager in British Columbia all the prior ones this year have all been dairy sequence and very large cluster in Washington state and this One teenager in British Columbia had this d1.one see type and Since most of the wild birds in the Pacific flyway had the same genotype and there's been an explosion of cases in commercial, poultry and backyard, farms and wild birds, and actually the wild birds unlimited the Pacific flyway they they're in all four of the flyways in the United States, but the The backyard farms are the commercial farms or the human cases. I have so far been concentrated in the pacifically fly away, and they sleep in in. The one in British Columbia the cluster Washington state and I think the number in California is now up to 2 6 and I believe that there was a report on Friday that indicated there were something like For five and something positive that had been reported at these would be cases that were positive in the state lab and I've been sent to the national lab and are waiting for confirmation, which would probably happen at the beginning of the week so the number of cases will be going up How many others have the changes they seen in the teenagers is I'm clear but the fact that the teenager had these three very important changes is a very strong argument that they didn't all just happened in the one or two days that they were in the teenager before the sample was collected because they like I say are very T And much more likely that they were already present in the the Wildbird, which is probably the source for this teenager. They were probably already in the wild bird by a low level so the bird had a mixture and it wasn't detected until I went into a mammal. The map selected this and then they got to the level that they are that teenager, where about half of the signal I'll each of these is. Is a keychain that makes the avian H5 that one behave more likely at HI that one and that is that's what the concern is and there should be a lot of information in the next week or two See how rare or cabin the sequence in British Columbia is  You OK, thank you for the information. Thank you for the  Dr. Niman OK, that's it  You information. We will be doing more of these podcasts in the near future please stay tuned.   

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