The next coming in our case study lecture is named selectivity of binding of vector molecules to the fallout receptor alpha observed by molecular dynamics, and it will be presented from professor Anelay Ivanova from the physical chemistry department, faculty of chemistry, pharmacy, University. So I'll ask once again for your attention this time to professor Ivanova. Let me first start by saying that this is the team from our lab, the colleagues together with whom we have been working on these projects during the last five years already almost. And I would like to start the talk by saying that we did this computational study in the framework of drug delivery. As we have chosen, as our model drug, the same actually chemical therapeutic, as we was talking about through within. The reason to select a chemical therapeutic for the study was that, as we all know, chemotherapy is the most usual treatment of cancer, but together with the positive effects it has also some very unpleasant I would say severe side effects, which are listed here. One of the main problems with chemo therapeutics is that these aggressive substances, aggressive to our body, they kill the cancer cells, but they also affect in an undesired way the health issues. One of the strategies to alleviate this undesired side effect is to create their delivery systems which are based on the so called active targeting. Active targeting in principle means that there are some additional, let's say component together with the pharmaceutical that are able to steer it primarily to the tumor cells to the neoplastic cells. And in this way, reduce the side effects by not affecting the healthy issues. There are different strategies to achieve this. They are listed here, but I will focus on the implementation of small organic molecules, which are able to if bound to the drug, they are able to steer it towards a particular part of the cell membranes. And then targeting usually a membrane embedded receptor, and then sometimes in our case together with part of the membrane using endocytosis, the drug is internalized into the side role of the neoplastic cell cells. This is the pair of proteins that we selected to test whether we are able to describe computationally this targeting affinity of the protein. The ligand is the well known folic acid, which in the human body and physiological conditions is doubly charged, and the anion is usually called folate. The naked receptor of this ligand in the human organism is the so called well it has several maybe receptors but one of them is the so called folate receptor alpha which is the crystal structure which is depicted here on the screen. This is the primary transporter of this ligand across the cell membrane. And we decided that it's a good pair to study not only for several reasons, one of them is that this receptor is over expressed mostly on the surface of cancer cells. Of course, this present also on the normal tissues but in very, very much lower quantity than on the cancer cells. Also, it is available, not only on certain type of cancer cells but on many types of cancer cells. And it has been reported that the over expression can reach from 100 to even one million times compared to the healthy cells. Another advantage of this pair is the high affinity of the ligand for this receptor. Here you can see that the association constant is small. Also, the sector is rather small which from computational perspective is an advantage. It has well defined crystal structure which was published several years ago, and which we used as the basis for our models. And also folate the natural ligand it's simple. It's organic compound with, let's say standard functional groups in it, and it's simple and abundant also experimentally. This was the reason to choose this pair. And what were our goals. First, we decided to describe the molecular structure of a series of folate like vector ligands in Salin, only the folate but also some of its derivatives which could have the potential of steering some drugs to the folate receptor alpha. The second goal of the study was to construct a model cancer cell membrane with an embedded receptor and to simulate its dynamics so these were the two preparatory steps for the actual part of the study. Then we monitored by molecular dynamics, I think of these set of ligands to the folate receptor alpha and characterize their interactions and try to rationalize the selectivity of binding of these ligands to the particular protein receptor. And finally, we tried to assess the effect. We tried to connect carbon to the targeting ability of these vector molecules. And all the stages of the study were carried classical or to me stick molecular dynamics in relations. So let's discuss about the models. Here is the set of ligands that we tried to, that we decided to investigate. First, of course, is the folate, folic acid in the W ionized state. So, the other four ligands from this set, they are all the anions so negatively charged. This is an abrogation to a Routy traxate and metal traxate. They are available synthetically and they are used as chemo therapeutic on their own. This ligand here, which we abbreviated MTHF is another form of folic acid, which is slightly different but actually it is more bio available inside the human body than the folate which we intake with the food. This ligand is a bit different. Okay, in red, you can see everywhere on the molecular structure. What are the differences compared to the initial folic acid molecule. So this bond here, which is a therial ornithin molecule is different than the others in the sense the only three therionic molecule in the set. It's also synthetically available and was suggested by a group of researchers as an inhibitor of one of the other folate receptors. So you see the compounds are somehow related. But they also have differences which might affect their behavior toward their receptor. The model membrane just a couple of words about it. We tried to construct this model, mostly based on experimental data or I would say as much as possible based on experimental data. That's why our model consisted of 370 molecules distributed asymmetrically both in terms in terms of number and in terms of charge, which is typical for the human cell and race. And the bilayer consisted of five different types of lipids, which were obtained by combining these lipid head groups, the standard for sort of your committees and so on we also included higher amount of cholesterol, which is known for cancer cells and so I'm not going to go into detail here just I would like to mention that we have several kinds of lipids that are negatively charged, and all of them are situated in the inner liquid of this model membrane. And then we have here the protein receptor which is embedded into the outer leaflet of the model membrane by because you also deal in a total anchor by a GP anchor that is what happens also in experiment according to the literature sources. And you see that. Yeah, something else that might be important for the membrane model. The parts of the lipids were not only saturated alkane residues, but they, some of them contained also more non saturated. It means one double bond or with multiple bottom double bonds along the carbon chain. The composition is practically taken from these two experimental studies. And finally the protein. This is the crystal structure again. This is the BB ID which we used for this protein molecule it consists of 204 amino acids and the overall charge is plus four. Again, the construction of the protein bound to the GP anchor was based on experimental data. And this GP anchor serves to immobilize the receptor on the surface of the cell membrane that's what we did also in the model where this receptor is usually found in the so called liquid crafts which are rich in transport proteins and different proteins. In this case, there were experimental measurements that it is usually found either as a monomer or as dimer so we used a single receptor molecule anchored into the model membrane. And the overall charge of the GP anchor is minus one so you see we have a lot of charges in addition to that. And this is how the four different types of models so that we study to look like the first one is contains one legumes on each of the series of six immersed in saline and we maintained their physiological concentration of sodium chloride also in all of the models. The second is immersed in a cubic periodic box and simulated with order on the boundary conditions in the three dimensions of space. This is the first type of models, the second type contains a membrane with one molecule of unembedded protein receptor immersed in water and sodium chloride. And of course in a larger box here we imposed hexagonal periodic boundary conditions because this is the normal packing type of the little thing in the membrane. In the third model into this we also put a ligand in the system, three ligands on bounds and let it move the model system and observed whether and how it will interact with the protein receptor or with the membrane or with the components model. And finally, we also test the performance simulations, almost the same model, with the exception of the three ligand was not any more free, but we attached a peptide complex, a drug peptide complex to it to test how to attach the drug carbon. Just in short, the simulation protocol of mystic molecular simulations, they are all followed by some additional DFT calculations to assess the binding energy between the protein and the ligand. We used the charm 36 to describe the protein, the sugars and the lipids. And we use them and for the ions and we use CGN effects for the ligand molecules and for the drug peptide for the drug and for the peptide of course charm 36 again. And water was deep, very standard protocol for the MD simulations, with the exception that we maintain some constant surface pressure on the models with the membrane corresponding to the surface pressure that is measured for human living cells and the temperature was physiological and the pressure was ambient. Here are some details about the MD simulation, I will not go into detail here if you have questions we can discuss later. Just the trajectory lens did 150 nanoseconds for the three ligands, one microsecond for the receptor embedded membrane, and from 20 to 400 or 500 nanoseconds for the systems containing those ligands. I would like to mention that we also performed four independent trajectories for the three ligands and two independent trajectories for the drug peptide complexes models. Final note on the protocol we saved snapshots into the trajectories every 10 seconds. Okay. So the preparatory steps we wanted to learn more about the ligands and about the membrane themselves without when they are not together. I will tell you here that the whole series of ligands turned out to be quite flexible. The state had definitely judging the square deviation of the atoms. For late during the last 15 nanoseconds of the MD simulation, but we can see that it definitely preferred conformations and interchanges between them quite fast. The main thing is true about PMPTX about bone and the other three ligands they have more or less one preferred conformation, but nevertheless, all of them are very mobile. Here is some summary of the cluster analysis, and they have at least two preferred structures which are populated in different share throughout the trajectories. So that this flexibility might be important for the binding to the receptor. Concerning the membrane and the lipid bilayer as part of this membrane model. It is more or less different to try whether we have obtained the correct structure of the lipid bilayer, it seems to be the case of the thickness of the bilayer experimental bounds. It is also known that in the increased presence of cholesterol, as is our case, the lipid bilayers are usually in the so-called liquid ordered state, and this analysis corresponds exactly to such a liquid ordered phase state of the membrane. We can see also for most of the lipids, we have areas per lipid molecule, occupied on the surface of the bilayer that are very, very close to the experimental data. The order of the lipid tails is an essential determinant of the phase state of the lipid bilayer, and as we can see from these order parameters of the lipid tails. They such tails are the most ordered one. The more unsaturated are the least ordered one, so the closer to zero these values are the disorder, so the closer to a liquid state the membrane is. And finally the poorly unsaturated fatty acids, of course, they are known to be the most disordered ones, once which is reproduced by our results. So the overall picture of this lipid tail order parameters corresponds exactly to a liquid ordered state. So we assume from this analysis that our model is correct. The results of the protein, how do we behave during the MD simulations, some extracts of the results about the protein structure at half of the trajectory at about 550 nanoseconds, this is the X-ray structure. So even visually you can see that the secondary structure is quite well preserved. Here is the numerical comparison here. The structure from the molecular simulations is very close to the experimental one. There is some unfolding of the helical regions and some slight changes in the secondary structure. But when we did a more careful analysis of the data, it turned out that this partial, let's say unfolding of the protein is caused by interactions of its Germany with the molecules from the membrane. Since the experiment was done in the absence of a membrane for the protein as it is without a membrane. So we believe that this is okay as a structure of the protein. And here just to have an impression about the flexibility of the bite, which is in this part of the protein of the ligand binding site. We have estimated the fluctuations of the volume of this binding pocket during a piece of the trajectory. And this is the experimental value, this here. So you can see that the pocket fluctuates, it's relatively mobile but the volume predicted by the simulation is very close to the experimental value from the X-ray structure.  I think I need the other way to be able to start. So I'm going to show you how each of the six ligands bind or interacts with the receptor. Before showing the movie, I would like to underline once more that there was no bias in our end situations. So we just monitored the natural dynamics of the... Here is the folate and here in this movie we have tried to capture the moment when it binded to the active site territory. So these residues here in gray, they represent the ligand binding site of the protein and folate did not have doubts where to bind. It went directly to the pocket and bound there. And as you can see from the minimum distance and the protein, the ligands remain there till the end of the simulation. Here is a... happened in the four independent trajectories well for folate the same in four out of four cases it went to the pocket and bound. And in most of the trajectories in three of them, it stayed there just in the fourth trajectory it was more mobile and also... I'm close to the base of the protein somewhere here. Here is an illustration of what RTX did. Okay, let me play the movie. Well, the same. It found the active site of the protein and bound there. Pay attention now it will rearrange for some time and then assume it's just even going away for a while. And this is the right post of the correct post of binding into the active site of the protein, which was not the same by the way for the... And here is the plot showing the binding time of the ligand and that it remains in the active site until the end of the simulation. This is a summary of the behavior of RTX. Yeah, in two out of four times it was able to identify it and stay there, bind there. But in the other two, so in 50% of our fourth trajectories, it found an allosteric site on the... This allosteric site at least to our knowledge was not reported for the folate receptor alpha and it is here just opposite the binding. This one here in dark gray and RTX is immobilized there by the amount of clasts of the protein and it's also very stable binding poles for this ligand. Okay, oh, sorry. Sorry, sorry, sorry. I'm going to share it again for this interaction. But yeah, even from this small number of trajectories, we were able, I hope you see the screen again. Yes, it's visible again. Okay. We had a good explanation of the relative affinities of the two ligands measured experimentally. It is known that RTX has about 60% for this receptor compared to folate. Of course we cannot be quantitative but qualitatively we were able to explain the distance due to the binding. Okay, so what made these ligands bind at this spot of the protein? We did analysis of the ligand protein ligand interaction in molecular dynamics trajectories and they showed that it's a complex of interactions which were reported also for the crystal structure. So we were able to detect some by stacking of the aromatic parts of the ligands and some kind of gen bonds. Just be aware that these are very persistent kind of gen bonds because we were extracting snapshots at very long intervals of 10 seconds from our trajectories and for RTX the difference is that the most intensive stacking is between the so-called tearing part of the ligand and some aromatic amino acids from the pocket. While folate, the most intensive stacking is between the middle part of the ligand, the glutamate, and also the charged part of the ligand, and the middle part with some other amino acid just from the pocket. So they really have two different binding modes, these two ligands. To rationalize this difference in the binding, we calculated with the DFT with dispersion corrections presented to snapshots from the molecular dynamics trajectories taking the structures from there and extracting just the ligand together with its very closely lying amino acids. So we calculated binding energies, so which are quite strong with you can see, of course, this is due to the very intensive electrostatic system. Again, when having a set of binding energies, we use the components analysis to correlate these binding energy values, here they are scaled down for the purpose of the statistics. So we saw from the molecular dynamics trajectories that might be important for the binding of the ligand to the number and length of hydrogen bonds, number of contacts, so as a measure of the van der Waalsen corrections, number of stacking partners, the number of electrostatic partners, number of closely lying amino acids. And here I have highlighted the most important coefficients of the first three principle components which were able to explain more than 80% of the binding energy that the two ligands have different, slightly different mechanisms of binding to the protein. While the whole eight relies on van der Waalsen correction on piloting bonds and on analytics, but they can be somehow compensated for each other because they are found in the three different principle components. These are RTX, almost all of the important interactions are concentrated in the first principle component. These are again the number of piloting bonds, dispersion, but acting together at the same time to keep this RTX bound to the pocket. And they are complemented taking and by the closely lying amino acids to get a more visual impression on the, on the mode of binding here I have extracted some sensitive interaction maps, and you see the amino acids from the pocket which contribute to the interaction with the ligand by van der Waalsen mostly. And those are other amino acids which contribute with quite strong some of them. So it's a really collective interaction of the ligand with several amino acids at the same time to accomplish this to the active site of the protein. And by the way, most of these amino acids are the same, which were outlined in the crystallographic of the for later protein complex. So we were able, however, to identify a new amino acid this article in 61, not listed in the crystal structure interaction map, but we saw in the molecular dynamics that it is very important for initially attracting the ligand to the binding pocket. Okay, what happens with the other ligand here is ptx. Contrary to what we might expect the similar chemical structure did not behave in the same way it near the pocket but it never went into it and didn't bind in the cavity. So in summary, it was very much attractive overall to the surface of the protein. As you can see from the distance it's really sticky to the protein, but it goes all over the place. Either to the other side, the same, which was registered for a text or to the surface, whatever it likes and scan virtually the surface of the project. Some hydrated form of the folate. It examples the folate itself to some extent, because it was stable in three out of the four to check to restore identify the point there. As you can see also here that it's coming close to the pocket, but as you can see also from the fluctuations of the minimum distance, the binder as stable as that of the folate. So we attribute this by analyzing the data to the larger volume of distance, which led to the inability of this reduced ligand to fit well into the charity of the protein will be part of, or to take part in all of the necessary interactions. The key is to ligands were still able to identify the protein and beats. Unlike. Okay, what were the respective functions. Yeah, much weaker by stacking also for empty chiefly registered some surface activity. It was attracted from time to time by the membrane, which also prevented stable binding to them to the pocket of the protein. And as you hear, wonderful interactions are much more expressed there, but that's most of it. It is not able to form such strong hydrogen bonds as for late in its non reduced form. So for PTX here in Brown, you can see all the amino acids that interact in the four different trajectories that we generated, and you can see also on interaction map and on the PC a insult that was stabilized by a non specific of underval center interactions. So this ligand behaving somewhat different way than the first two but okay they still bind to the protein, irrespective of the nature of the binding. So this is to the final two and metal tech state and aerial or anything. As you will see from the movie for mpx he doesn't like the protein. It works much more to bear into the membrane or to stay in the solution. So this is also evidence from the table. Why this is happening because the mpx has the smallest structural difference than for late but it turned out that this is enough to make it a special. And finally the last thing that the period or meeting well it did bind to the protein only in the first trajectory for a very short or relatively short time at the end, and you see very far from the pocket. None of the other three trajectories. The state goes to the protein for a measurable amount of time. Well, of course this is really explainable. This was the only Twitter I am in the series so this was an evidence that the double negative charge for these ligands to be able to bind to this receptor. Okay to summarize the results from. Yeah. Both a positive and a negative charge and the protein surface is really highly charged. It just so randomly to some of these charged residues. Okay, but, yeah, this is proof. I just explained to you that the mpx very much likes to stay on the surface of the membrane. This is the interface of the outer one, and that it is, whenever it binds to the protein very rarely stays here at the allosteric site and stabilized by a high number of hydrogen bonds. And one has you see very high number of charged amino acid as the pre 14 production partners on the other side of the protein. Okay, so to summarize the results from the unbounded they are able to detect the protein at least some of them. And if I have to to sort them in terms of capability to be or potential to use this vector ligands for cargo, maybe our text and for late will be applied first and then followed by PTX and MTHF so we decided to keep these four ligands and they are targeting the ability by attaching bioactive cargo. Again, we took from experimental data. Biodegradable linker that has been tested experimentally to be suitable touch to it. The two valence complex of the same chemotherapeutic dogs will be seen that was talking about absorb those are especially tailored to binding that so this is our bioactive cargo and tested by molecular dynamics whether the two ligands will be able to carry this system to the protein as they did as they interacted in the free state and here are some short movies. This is complex, as you can see, it goes to the protein but unfortunately they're okay in much the complex way to the active site and in none of the cases was the ligand able to bind in the same way to the active site of the protein as it did when there was no cargo and only the four days. Sorry for the interruption just to mention approaching half an hour. One slide away from you. Thank you. Thank you. Okay. So yeah, as we suspected, PTX and MTHF didn't do so well. They were not able even to stay behind the bioactive cargo to the protein so here is a summary of what we learned from these studies. We found out that the different ligands have specific structure in shape and which is important in a way for their binding but mostly the chemical composition turns out to be the important one for the selectivity of binding. We maintained the liquid order state in all simulations. The structure of the receptor locally solution close to the membrane and only locally when the ligands were bound to it. And I'm not going to read this in detail because I told you about the behavior of the different ligands. We discovered another state center which attracts most of the four leg derivatives but not itself. And this leads to diminished specificity of the binding of these derivatives. And then we found that the cargo, the drug conflicts and fears quite significantly with the steering affinity of the vector molecules and that's why this carbon needs to be tuned carefully to enable efficient functioning of the target in ligands. But apart from that, we can outline RTX and as the most promising candidates for this targeted drug delivery. For fully this is known but for RTX at least we couldn't find our reports so far. And finally, I would like to acknowledge the support both in terms of funding for the research and the computational resource and thank you for your attention. If you have some questions, of course, I will be happy to answer them. Thank you, Professor for the wonderful and interesting presentation. Are there any questions from the audience. I think it's visible till now in the chat. Yes, but to be able to see them. Okay. Sure. Okay, I think this is not a question for me but yes she's here with me in the room. Okay, thank you. I have a question that is not exactly in the focus of your expose but I was wondering, you mentioned that the receptor for the for late was overexpressed in some types of cancer cells. What kinds of cells. Muscle cells. Thank you.  Most of the solid tumors over expressed this receptor. The primary reason is that the cancer cells need to feed the vote and for the case. It is required for the growth of the cells and for feeding this division process. So that's why it is there on many types of cancer. Even on bank cancer cells, they register over expression of this receptor. Okay. Thank you. Thanks for the answer.


What's up everybody, I'm TheMangoose and you are awesome and it's time for another edition of The Road Back to Paragon where I give you a snapshot of what's been going on in the third person MOBAs that I track. I'm going to change things up a bit this time and do away with the summary and history of the games instead of just giving you the down and dirty of what happened during the month of July. I will say right up front that all of these games plan for a eventual PlayStation release and other consoles are not out of the question, however all of the alphas will be PC exclusive. I also do not know any firm alpha dates at this time. So let's kick things off with Metabuff and Core. The big news out of Metabuff this month was that Sylphin left the team. Now whether that's a good or bad thing is kinda up to the individual and how much you liked Sylphin and his ideas. I personally have always been a Sylphin fan, however I was not a fan of the Proof of Concept series that Metabuff released and that was heavily influenced by the ideas gathered during some of Sylphin's live streams. I'm sad to see him go but in the end it may turn out to be a good thing for Core. Metabuff in general has been in a rough spot lately with a few other people leading the team, however I've been staying in steady contact with the leadership of the company and they have assured me that everything is still moving forward. While my overall excitement for this particular project has dwindled I still have faith that they will eventually come through with their planned sequel to Paragon. I have one of their game testers as a guest on this week's Four of the Minions. Hopefully he can clear the air and extinguish some of the doubts that the community seems to have. Moving on to Omega Studios and Predecessor. Omega has begun internal testing of the new build for the game to see if they resolve some of the bugs found during the initial alpha test. According to their founder, Sergeant Smokey, the tests have been going really well. They've been able to iron out the hero kits as well as test out the minion and tower AI. Now they plan to rebuild the item system and run more tests once that's finished. Also for Predecessor their level designer Fringe has been hard at work redesigning some aspects of the map and making it not only look better but the changes will help your computer run the game better. He's also been employing some new assets for the towers and core and I think they look a little better than the monolith assets that they were using before. I like the monolith towers but they did seem a bit out of place in a very legacy inspired map. Things seem to be going quite well for Omega. Hopefully they'll be ready to re-release their alpha soon and wipe the memory of all the bugs that plagued the initial release out of our collective memory. I had quite a bit of fun setting foot back in Agora in March and I'd definitely look forward to their next round of alpha tests. Onward to Undying Games with Ethereal. Ethereal this month released some of the artwork and a bit of information about their item system. Not much to talk about here without knowing any of the stats for the game but we can see that they put just as much attention to detail into their items as they have with voice lines, map design and hero design. Undying continues to impress with everything they put out. If you've been watching my channel you'll know that I'm a hardcore Ethereal fanboy. As much as I look forward to core predecessor and Phoenix Rising and as much as I value the friendships I've made with the leadership of those companies I can't help but look forward to Ethereal the most out of all these games. That's going to close things out for this month we unfortunately didn't have anything to announce for Visionary however I assure you that project Phoenix Rising is still going strong. If you're just now finding out about these games I encourage you to take a look at some of the other Road Back to Paragon videos I've done where I go into more detail about the origin of each game. For now this is the Mangoo signing off, you guys have a good one. Mangoo!


It's 7.04. I'll call them in order. We do have a quorum and we have one item of the agenda. The application by the state of Vermont petitioning our permit for an adjustment. And I'm gonna ask those that tend to give testimony before this board tonight to please raise your right hand and swear to the truth and the penalty is appropriate. My apologies. I was gonna say attorneys don't need to do that as you know that. Sometimes the transportation board makes me swear. So, I would. Really? What board makes me swear all the time? So the item before us is this petition by the state of Vermont. Age of transportation and this really has to do with jurisdiction of the state versus the towns. And they've recommended some alternatives to us in terms of our permit that we granted and the conditions. And so I'm gonna basically turn this over to Beatrice. Are you gonna start Tina or who? I was just gonna say that Jenny's our assistant attorney general and she'll be doing the, what we wanna say for the conditions. That's all I was gonna say. Jenny, can you just give your full name for the record here? Yes. My name is Jenny Ronas, R-O-N-I-S. I'm an assistant attorney general for the state of Vermont and I represent the Vermont Agency of Transportation. And I am here tonight to talk to you about the conditions imposed on the Berlin Park and Ride and our request for amendment of those conditions. I can give you a brief statement just, while the original proposed conditions on their face, unfortunately violate certain statutory authority between the state and the town, we definitely recognize that Berlin's interest is in making sure that the parking ride is adequately maintained. And we certainly take, there's no dispute here that Beatrice is responsible for that maintenance. We are under our own statute responsible for that. And so we're certainly happy to take it on. So the proposed changes are essentially aiming to bring the language in line with 24VSA 4413, which is limitations on municipal bylaws while still recognizing that Beatrice has the obligation to maintain the parking ride to a level that's satisfactory to all parties. So if you have any, if anyone needs the language that we're proposing and be happy to circulate it around, please let me know if you have any questions. I should point out that we've had a number of discussions with Tina and Jenny. And as you instructed us to, both myself and Tom, and I think this is a reasonable, my personal opinion, this is a reasonable compromise on the conditions, recognizing that arguably this town does not have statutory authority over some of these issues. And we thank them for their time. So I have a question in terms of definition of maintenance because at one point Tina had said the maintenance was like snow removal. And I was just wondering, Jenny, what is each of us proposing for maintenance? Well, so snow removal is a part of maintenance, but we also understand maintenance to include things like maintaining the landscaping, trash removal, things like that. Pretty much anything, Tina can correct me, but I understand V-trans maintenance to be anything short of construction activities, essentially. Okay. Thank you. Tom, did you have some comments? Oh, I think as you mentioned, Bob, we met with the folks from V-trans. And my personal opinion is that this is a good compromise that satisfies both the towns and V-trans needs. Okay. Jenny, did you have an additional comment you wanted to make about your proposal? No additional comments other than to thank you guys for the ability to have such productive conversations. And I hope that we can all come to a solution that helps, that works for everybody. Because as we mentioned at the last meeting, V-trans and the town of Berlin are on the same page here that we want to be able to provide high quality facilities for Vermonters. And so our ability to maintain our park and ride to a size faction of everybody here is a big part of that. I think, I'd like to speak on behalf of the board. I think the board is sort of speaking from a point of view that what's happened in the past is not necessarily acceptable in terms of maintenance. I personally observed drug paraphernalia laying around up there. I personally observed yard, garbage up there. And for weeks, same bags, same two bags. And we have some neighbors that have strong complaints. So, and I'm sure you've heard this before and I understand budget constraints and programming but we feel that something needs to be done to make this more secure and more plain. Well, if I may respond, I would, I admit that yes, during the redistribution of some of our maintenance districts, there was some confusion as to which district was responsible for the park and ride. And I do think that its maintenance was not up to the standards that we would regularly hold ourselves but as part of the work that we've been doing with you guys in the last few weeks, we've essentially made sure that we have a district that maintains response that is taking responsibility for this park and ride. I've spoken with Joseph Rizzo who's the maintenance of the district manager, district transportation administrator for district four and he's aware of the issues that have been going on with the park and ride. And he has a plan that he in order to do twice weekly sweeps for trash is what he told me but he also provides his contact information for you here because obviously folks in the, if things aren't up to the towns, if the town has concerns about the maintenance, then the best way to deal with this is to just, so that we can talk straight to the folks that are responsible for it. Where should I go? No, I think it sounds good. Yeah. Is everyone in agreement with the proposed changes to the conditions? Yes. Yes. Yes. If we have no further questions for the applicant, some requests to make changes or suggestions, I'm open to a request to adjourn the hearing. I move to adjourn the hearing. I'll second it. Motion to made, my poll is seconded by Josh. Yes. Yeah. Thank you. Stretch the motion. All those who fail that motion, please sit down and be saying aye. Carla, aye. Aye. Holly, aye. John. Josh, aye. Thank you. Thank you very much for joining us tonight. Yeah. Thank you. Thank you. Councilor brief. Have a good evening. Thank you. Thank you. Before the board disappears, we have a couple of other items on our agenda tonight. Yeah. One is the approval of the minutes of September 1st, which I believe you all received. I wasn't sure. Christy, were you not done? I thought you were going to add to them or something. So I didn't really, I mean, I read them, but didn't you say you wanted to add to them or something? Yeah. I think she needs some input on September 1st meeting. Right. Kristi, you're on. Kristi, you're on. Yeah. I was just going to say that I apologize for taking so long, but I left my stuff at home and I did the minutes at work today during my lunch hour. And I didn't have the written testimony from from Chris and Mark Nicholson on the site plan standard. And so that's why I said the application, which I'm sure that's not what you really want. So I can put that in there. However you want me to do that is perfectly fine, but that was what I had planned to do after the meeting today. I didn't have time to read them today. I just saw them. Just, you know, just. Polly, Polly, you always read them. I do, but today I was watching my grandson. Much better, much better today. Yes. So I had a couple of comments with regard to the minutes. I'll go first if I can. Chris drank off. You had a parenthesis behind him. I would call him consultant. That's funny because I had consultant that took it out. He's a site technician, consultant, same thing. All around a good guy. I've known him since he was six. Other than that. There is a typo in the first full bar paragraph under new business. Yes, thank you. The. The. Yeah. Well, sort of. And. Got it. And in regard to the sections, and I appreciate you didn't have the stuff in front of you, I would like to do more than just see the application. Obviously, perhaps you could paraphrase the sections. Yeah. You're missing several sections 305, 3205, 30 or 6, 30, 207. So if you would just either paraphrase them or but I'm actually open to discussion. I don't want to make us have regurgitate the application. But if the application is stands as is, perhaps we could do some way of saying I'm open. Well, it's legal to do it the way she's doing it. But I understand what you're saying, Bob, because it what happens is then they're not stand alone kind of thing. You have to. I think we think we need to speak for my findings of that too. So yeah, yeah. So I would I would paraphrase. When testimony is considered to be adequate. In this case, we have written testimony, paraphrase. Yeah, they're written testimony and just, you know, point out that the landscaping and screening, no change or whatever. And lighting, no change or the lighting was there was a change. So I think I do think you need to include that. And now I understand why you did what you did. You didn't have the stuff front of you. Right. We accept what they had. But anybody see that differently than I do? No, I think the findings have to have it. The minutes have to have it because we have to have in the findings and therefore it has to be part of the record. Tom, do you see it differently? Oh, I do not, Bob. Other than those, those three comments I had. I had none. Does anybody have help for Kristi on the time of. The exiting of the. Little recession. No, I mean, I can try to read them in the morning, Kristi, and get you any comments that I have. Well, that's fine. We're not worried about. I want to say that you guys got came you adjourned about 828 and you went into the lower session at 824. And then I think I joined you like right as you were leaving. You did. So that would I mean, that was my that would be my guess. But I I don't really know. No, you're right. You came right at the end. And I remember that. Yeah, you guys are about the same time. I don't mean to. Yeah, we have a very brief deliberation. And then we obviously adjourned immediately there afterwards. The consensus was we were not going to deliberate the big guys. Right. Right. Yeah. So I could say you exited at 827 and you adjourned at 828. Sure. Where's to me? I'm not. I don't like to adjourn it. Pick a face who did the second. OK, we'll do using jobs. Johnson one always wants to want to adjourn. Yeah. And I wasn't there. So. Yeah, leave Josh out. Yeah. And I have the written testimony in front of me. So I will all revise that tonight and send it out to you.


The Stop COVID-Dets shorts make it easier for you to go to the presentations that you are interested in. I'm Dr. Raymond Sarmiento, director of the National Telehealth Center. And I'm Dr. Susy Pineda Mercado, adjunct faculty of the National Telehealth Center. Together, let's stop COVID-Dets. So the topic assigned to me is COVID-19 vaccines in children and I would like to thank everyone here for inviting me to give this talk. Sorry. Okay. So for my disclosure, in relation to this topic, which is on COVID-19 vaccines, I'm a member of the VEP and NAFIC. And so I will be mentioning the names of these vaccines, but I am not personally endorsing any of these vaccines. So for this afternoon, we will be discussing considerations for the use of the COVID-19 vaccines in children. What is the evidence for the safety and efficacy of these vaccines? And what are the current recommendations for the use of these vaccines in children and adolescents? Okay. So let's start. So we do know that children comprise just a small proportion of the diagnosed COVID-19 cases. They say 2% to 3% to less than 10%. However, because we do not do systematic testing of cases, of pediatric cases for COVID and because most of these children may present with mild disease or are actually asymptomatic, we don't actually know the true burden of pediatric COVID infections. So as we already mentioned, COVID-19 disease in children is generally mild with an overall good prognosis compared to adults. However, the presence of underlying medical conditions or certain co-infections may actually increase the risk for severe or critical disease in children. So the classification of COVID-19 disease in children is based on severity and 80% would present with mild to moderate COVID. 2% to 12% would be severe and about 2% to 10% critical. So 80% moderate to mild and only about 20% would be severe or critical. So what are these risk factors that increase the severity of COVID-19 in children? So the presence of cardiovascular disease, neurologic conditions, neurodevelopmental disorders, chronic lung disease, immunosuppression, cancer or malignancies, genetic endocrine diseases, as well as obesity and prematurity would increase the risk for severe COVID in children. And we also have what we know as this hyper inflammatory syndrome in children, the multi-system inflammatory syndrome in children, which resembles Kawasaki disease and is actually considered as severe COVID. So this disease might occur during, so with the COVID infection or may present after COVID infection. So what are the considerations for use of the COVID-19 vaccines in children and adolescents knowing that background? So we have a certain considerations starting with the epidemiology or burden, the safety and efficacy or effectiveness of the vaccine. So mathematical modeling relating to population level impact of vaccinating this age group. What are the programmatic implications, potential vaccination delivery challenges and acceptance of the vaccination in this age group? So we heard what the person on the street or what the parents were actually saying about accepting this COVID-19 vaccines for their own children. So let's start with the epidemiology or disease burden of COVID-19. So in countries where the proportion of young in the population is high, over one-third of COVID-19 cases occur in children. And most of the cases are mild as we already said, but still a significant number, about 20% will present with severe or even critical disease that will require ICU admission or even result in mortality. And there are some children who experience long COVID symptoms. Increased transmissibility of the Delta variant across all age groups results in maybe that's the reason why we are seeing an increasing number of cases in children. And the emergence of new variants may also pose a greater risk if the children and adolescents remain susceptible or non-immune. And with older age, the older age groups being increasingly protected by vaccination, a greater proportion of COVID-19 is now anticipated to occur in the younger age groups, so the adolescents and children. And the growing number of these unvaccinated children with increase in the numbers added to the birth cohort with the deliveries. This will result in ongoing transmission. So this is the latest data that I was able to get as of September 29, I'm sure meron ng September 30, but there were 2.5 million cases of COVID-19. And of these positive cases, about 10% would be less than 20 years old and of that around 6% would be less than 15. So we see that there are children who are being infected. And if we take a look at the population pyramid of the Philippines, which is very similar to what we would expect in developing countries, we have a young population. So more of our people, our population would be in the younger age groups. So for example, in this 2020 population pyramid, about 30% would be less than 14, and about 20% would be 15 to 24 years old. So this is in contrast, for example, to industrialized countries where you expect more of the population to be older and even elderly population. So we are a young population. And this is important to consider when we talk about herd immunity. So herd immunity can only be achieved if we have a significant proportion of the population who are immune either through vaccination or from getting the infection. And of course, we want to make sure that we achieve herd immunity by increasing vaccination coverage, not by increasing the exposure of our people because that would result in unnecessary cases and even deaths. So what we want to do is to increase the vaccination coverage in order to reach herd immunity. Now the threshold to be able to reach that herd immunity is based on a number of factors, including the contagiousness of the virus, which is given here as the basic reproduction number or the R naught, as well as the efficacy or effectiveness of the vaccine. So for COVID, for example, for SARS-CoV-2, the herd immunity threshold is placed at 60% to 80%. Now, as I mentioned, it will depend of course on the efficacy of the vaccine. For example, on the graph on the left, if you have a vaccine efficacy of about 90 to 95% with an R naught or contagiousness of 2.5, which means that for every infected individual, he or she will now spread it to 2.5 more people. With that, you will need a vaccination coverage of around 70% to 80%. But with lower vaccine efficacy, for example, if the vaccine efficacy is only 62%, then take note, you will need to vaccinate almost all of the population. And this includes children. So when you say that you will vaccinate 80% to 90% of the population, that does not mean 80% to 90% of those who are 60 years old and above or 80% to 90% of the frontliners. No, it means 80% to 90% of the entire population and that will of course include children. So this just shows you how important third immunity is. And if I may borrow a saying, it mentions that no one is safe unless everyone is safe and that of course includes your children and adolescents. So let's move on to the next consideration for introducing vaccines in children. And this should be based on vaccine safety, efficacy and effectiveness that we derive from clinical trials as well as effectiveness data from real world vaccination program experiences. And what we know is that there is actually high level evidence with regards to safety, strong immunogenicity and efficacy of the COVID-19 vaccines for adolescents for the two mRNA vaccines. So in this first study, this is a phase three trial to determine the safety, immunogenicity and efficacy of the Pfizer, which is now called the Comir Nati vaccine in adolescents 12 to 15 compared to young adults 16 to 25 years. So in this trial, they enrolled or included more than 2200 adolescents aged 12 to 15 to receive two doses of the Pfizer vaccine given 21 days apart. And the data would show that it has a favorable safety and side effect profile. If you take a look at the right side on the bar graphs here, we show that most of the side effects are mild as seen here by the green bars or moderate as seen here by the blue bars. So for the local side effects, the most common would be injection side pain. And for the systemic side effects, the most common would be fatigue, headache and chills. So these are not uncommon reactions seen with other vaccines. So they are not unusual. And severe reactions occurred, but in fact, they were even lower in the younger age group compared to the young adults. And fortunately in this trial, there were no vaccine related serious adverse events and only a few overall severe adverse events seen. Now what about the antibody titers? So if we take a look at the geometric mean neutralizing antibody titers for the 12 to 15 year age group, it was 1239. And this is 1.8 times higher than the 16 to 25 years age group. So it means that it is immunogenic. The vaccine is immunogenic in the 12 to 15 year old age group. And in fact, it even gives rise to higher neutralizing antibodies compared to the young adults 16 to 25 years. For vaccine efficacy in preventing COVID-19, symptomatic COVID-19 after two doses in participants without evidence of previous infection. And even in those who were previously infected, the efficacy is 100%. So with a range of around 75 to 100%. So it's a very good efficacy. Now this second study is a phase two, three clinical trial evaluating the Moderna vaccine in adolescents 12 to 17 years compared to the young adults 18 to 25 years. So Moderna or the Moderna vaccine is also given as two doses 28 days apart. And what was shown is that the side effects or the adverse events that were seen were also not unusual. So the most common solicited adverse reactions after both the first and second injections were injection site pain, headache and fatigue. So similar to the Pfizer vaccine. Most of the reactions were seen after the second dose and most were mild or grade one. Again, represented by the green bars or moderate represented by the blue bars. So there were no serious adverse events related to the study vaccines. There were a few severe reactions, local and systemic reactions represented by the orange bars, but they were very few. Now with regards to immunogenicity, the geometric mean titers in the 12 to 17 year age group compared to the 18 to 25 year age group is not really significantly different, but not inferior. So it is not inferior and it is similar. The titers in the younger age group 12 to 17 is not inferior to the antibody titers seen in the 18 to 25 year age group. And for vaccine efficacy against COVID-19, there were no cases of COVID-19 seen in those who were given the Moderna vaccine, but there were four cases of COVID-19 given seen in the placebo group, which gives vaccine efficacy of 100%. Now using a different definition, a more, what do you say, a more not stricter, what's the opposite? Easier definition, just respiratory symptoms, any respiratory symptom with a positive test. Then the vaccine efficacy is still high, it's still 93%. So again, very good. Now let's talk about vaccine effectiveness. There are really no published effectiveness studies of the COVID-19 vaccine in adolescents or children. And vaccine effectiveness can however be inferred from the immunogenicity data that we have. So this is called immunobridging analysis. So the effectiveness is inferred from the neutralizing antibodies that is considered to be clinically relevant to infer effectiveness in the pediatric age group. And of course we do not have yet a specific antibody titer to establish or predict protection. But what we want to show is that it is not inferior or better if it is similar or even greater compared to the young adults. And that is what we have demonstrated in the two of the important studies regarding the mRNA vaccines. So we consider both the geometric mean titers and the zero response. And we compare the response that we see in adolescents versus the young adult populations. And again, as we mentioned, similar or not inferior. Now there is actually one vaccine effectiveness study in children and adolescents. But this is not published yet. This is just presented in this editorial. And what I am presenting now is the interim analysis. So this study was conducted in Israel. As we know Israel is one of the countries with the most rapid and effective successful vaccine rollout. So they started during the last quarter of last year. And then in January of this year, they already included the 16 to 18 years, a 16 to 18 year old in the priority vaccination group. So they were able to vaccinate more than 200,000 at the time that they did the analysis. And it showed a vaccine effectiveness against symptomatic COVID-19 of 98% and a similar effectiveness against hospitalization in the 16 to 18 year old age group. And there were no cases of severe or critical COVID-19. And in those who were vaccinated, whereas in the unvaccinated group, 15 were hospitalized to in critical condition and one died. So they had very good experience in Israel. So to maybe summarize what we have seen, the data we have seen in the two studies as well as the vaccine effectiveness study in Israel, the mRNA vaccine, so both the Pfizer and Moderna vaccines produced a greater or similar immune response compared to young adults. Both had a favorable safety profile and both were highly effective against COVID-19. So let's talk a little bit more about adverse events and side effects because as we heard from many people, this is actually a concern. So as we saw from the clinical trials and even from the real world experience in Israel, there were no unusual side effects. Most of the side effects were local or systemic adverse effects and these were mild to moderate. Allergic reactions, mild allergic reactions were seen, but anaphylaxis was rare. And rarer still is the immune-mediated adverse event of immune thrombocytopenia seen in less than one in a million. But what was truly concerning were the reports of myocarditis or pericarditis or myopericarditis in 12.6 per one million vaccinated individual, vaccinees. So this was a bit concerning because it is greater or higher than the expected rates. So in the United States, they have two vaccine safety surveillance systems. The first is the Vaccine Adverse Events Report System or the VAERS. And the other is the V-Save Health Check-In Survey which is a smartphone-based safety surveillance reporting system. So here, the adolescents who were vaccinated can register and actually directly report whatever side effects they are experiencing. And we see here that again, no unusual adverse effects, local and systemic reactions were reported, especially after those two, but nothing unusual. This is what we usually see with the other vaccines. Now, there were also a few who actually needed medical care or were hospitalized, very few, but because it is a passive type of reporting, we don't really know what was the cost for the vaccination. So in terms of the V-Save Health Check-In Survey, involving 129,000 adolescents aged 12 to 17, no safety alarms. However, for the Vaccine Adverse Event Reporting System or the VAERS from December to July 16, so although 90% would be non-serious, 10% reported serious adverse events. And here, you will notice that myocarditis was actually reported in 40% of the serious or 397 out of a total of 9,246 reports, so that's about 4.3% reported myocarditis. And you will also note that many of the side effects reported were actually related to myocarditis such as chest pain, increased troponin, normal echocardiogram. So these may be related to the myocarditis. So how was the myocarditis diagnosed in patients who received the vaccine? So by echocardiography, what they usually would see would be a reduced or diminished ventricular function or abnormal ejection fraction. And some of the cases would present with mild blural effusion. These figures, these pictures actually show results from the cardiac MRI, cardiac resonance imaging after receiving the vaccine. And what is demonstrated here is enhancement of the subepicardial and mid-myocardial sections, particularly the inferior and inferior ventricular walls. So this is what you would demonstrate when you do a cardiac MR for patients with myocarditis. So what do we know about myocarditis or pericarditis after the mRNA vaccines? So we do know that myocardial injury has been reported in 36% of hospitalized COVID-19 patients. So it's actually part of COVID-19 infection and it can occur even after the patients have recovered from COVID-19. And 36% is higher than what we see in patients, in normal people who received the vaccine. So myocarditis or myocardial injury occurs in a higher percentage of those who are infected compared to those who are vaccinated. So the overall incidence of myocarditis per one million doses administered is 12.6% for both mRNA vaccines combined. The incidence is greater in male, adolescents and young adults 12 to 29 years, so less than 30 years old. Usually seen in the first seven days or within three weeks after the second dose. So the risk is greater in males and after the second dose. How do they present? They present with chest pain, shortness of breath or palpitations. And how they are diagnosed either by elevated troponin levels or abnormal findings on the ECG, echocardiogram or cardiac MRI such as what I showed you earlier. But the good thing is in those cases of myocarditis that develop after vaccination, 95% of the cases were mild and recovered on their own. It was transient lasting only for about two to three days and were just given minimal treatment with for example, incense and rest. So they were very mild and transient. Now the CDC, before they recommended to include vaccinating children, conducted this risk benefit analysis to compare the benefit of giving the vaccine in terms of preventing COVID-19 cases, hospitalization, ICU admissions and even deaths and compare this with the risk of myocarditis. And what we see here is that across the ages, the benefits actually outweigh the risk. However, the benefit and the risk is not balanced across the ages. Why? Because we see poorer outcomes of the COVID-19 disease in those who were greater than 30 years old and a greater risk of myocarditis in those who are younger. So if, for example, we take the age group 12 to 17 because that is our focus for this morning and per 2 million mRNA vaccine doses administered among the males, we see that there will be 5700 cases prevented, 215 hospitalizations prevented, 71 ICU admissions and two deaths prevented. However, there will be 56 to 69 cases of myocarditis that can be reported. So with this particular data, the CDC ACIP advisory group with regards to vaccination concluded that for COVID-19 vaccines, the benefits will still outweigh the risk even for the younger age group, including adolescents. And the risk meaning including myocarditis. And it is important to monitor the outcome of the myocarditis in those who develop this after vaccination. So there is continued monitoring of these cases because we do not know what the long-term effect will be. And thirdly, they would like this information to be disseminated so that people will be aware of what to watch out for after vaccinating. But I guess the bottom line is the myocarditis and pericarditis are much more common if you get the disease rather than from the vaccine. And the risk to the heart from the infection can be more severe, okay? And there is another risk-benefit assessment this time conducted by UK by the Joint Commission on Vaccination and Immunization. Again, they did this because they also were studying whether to recommend the COVID-19 vaccines for adolescents. And here they showed that the benefit of the vaccine for the first dose, it will prevent two intensive care admissions and 87 hospital admissions, but may result in three to 17 cases of myocarditis. And they saw that this was more acceptable, the first dose. But for the second dose, they are a little bit wary because it would prevent 0.16 ICU admissions, six hospitalizations, but will result in a higher number of cases of myocarditis. I guess this is the reason why in their recommendation, they would rather focus on giving the first dose first to all the adolescents before they give the second dose. So what are the benefits of COVID-19 vaccination? It will prevent COVID-19 and its complications. It will reduce transmission in the broader population and in this specific setting, which is children adolescents in the schools, it will prevent transmission. It will mitigate the psychosocial impact resulting from disruption in school, sports, other organized activities, socializing because of the isolation of this age group. That are key to adolescent physical and mental well-being, and I think that is very important also to consider. So what are the recommendations? I'm into my last few slides. AAP, as of August 2, 2021, they recommend vaccinating all children and adolescents 12 years of age and older who do not have contraindications. What vaccines do they use? Those vaccines that have been approved by the US FDA and recommended by the CDC. And lastly, because of the importance of routine vaccination and rapid uptake of COVID-19 vaccines, then they support co-administration with the other routine and adolescent immunizations. So CDC recommends vaccination for everyone age 12 years and older to prevent the corona disease 2019. So adolescents age 12 to 17 are eligible to receive the Pfizer vaccine and they may be vaccinated with appropriate consent and assent. Children younger than 12 years are not eligible to receive Pfizer vaccine at this time. And children and adolescents younger than 18 are not eligible to receive the Moderna or Janssen COVID-19 vaccine at this time. So only Pfizer is recommended or approved for children less than 18, 12 to 17 years old. So what are the countries with an EUA for this vaccine, for the Pfizer vaccine? You have quite a number and some of them have actually already started vaccinating the adolescents. Initially, some of them would start with those with underlying medical conditions but would later on move to universal or routine vaccination of all children 12 to 17 years old. We see here that in the Philippines, we already actually have an EUA for Pfizer in May 2021 and for Moderna, an FDA EUA in September 2021. So for both for active immunization for the prevention of COVID-19 in individuals 12 years of age and older. So they had an amendment of their EUA because previously only for 18 and above. So what does the National COVID-19 Vaccination Operations Center have to say about this? So I think there is no argument that these vaccines, the mRNA vaccines are effective and safe for children. The Department of Health, all expert group, reiterates their initial recommendation that vaccination of children and adolescents, even those with comorbidities, shall only begin once the supply of vaccines is adequate and stable. So I think there is no issue about the efficacy, safety, it's more on supply. And this is reiterated by the PPS and PIDSP who recommend that the priority should still be the older and more vulnerable adult age group. And once we have a sufficient percentage of these priority adult groups that have been vaccinated, then we can start vaccinating children 12 years old and above. And priority is given to those in areas with high transmission and those with comorbidities. And the fear then was that if you give pediatric vaccination at a time when we still did not have sufficient numbers of our adult priority adult groups vaccinated or insufficient vaccine supply, then this may disenfranchise the limited supply of vaccines to the more vulnerable groups such as the senior citizens and adults with comorbidities. So in view of that, as of August 11, we were not yet vaccinating children 17 years old and below. However, two days ago, three days ago, President Duterte already announced that immunocompromised children 12 to 17 will be vaccinated and this vaccination will start in October. So the Department of Health announced that adolescents with comorbidities will be added to the A3 priority sector and they will be given Pfizer and Moderna or Moderna COVID-19 vaccines. So the government is aiming to start October 15 because the capital region in Manila already has an impressive vaccination coverage. And I think we have been assured that by October, we will have enough supplies. And then after Manila, then they could expand to other regions after the first two weeks of the pilot implementation. Now there are other vaccines, COVID-19 vaccines that have been, that are being studied. So Novavax, Janssen, AstraZeneca and the Pfizer and Moderna have ongoing studies in funds as young as six months.  They have actually published a paper, which is a phase one, two clinical trial and which concluded because this is the first report of an inactivated vaccine, the CoronaVac, being tested in children and adolescents 3 to 17 years old. And because it is just a phase one, two clinical trial, which is mostly safety and immunogenicity, they found that it was relatively safe and immunogenic in this age group. So we look forward to their later phase three trials that can be published soon. So the ongoing challenges in the COVID-19 vaccination of children and adolescents is again because of the constraints on vaccine supply. So that is a key determinant. And when we start vaccinating children and adolescents, we have to augment the existing infrastructure for vaccination. So we need to make sure that there are care providers that are experienced in dealing with children and adolescents who are being vaccinated. And of course, logistical concerns because we know that the Pfizer vaccine needs ultra low freezer storage requirements. So that might be an issue. And data on vaccine safety is ongoing. We are still following up these children who develop adverse events and we are continuously monitoring the long term effects of the vaccine in children and adolescents. So in summary, children and adolescents represent a growing proportion of new COVID-19 cases. Children and adolescents can experience serious outcomes from infection and can transmit the virus. COVID-19 mRNA vaccines have been shown to be safe, effective, immunogenic in preventing COVID-19, and vaccinating children against COVID-19 will be essential to protect their health and to establish higher population immunity. So that's the end of my slide. Thank you very much for listening. We hope that you learned as much as we did from that excellent presentation. We also hope that you will join us every Friday from 12 noon to 2 pm Manila time on Zoom, Facebook, or YouTube. So stay safe, stay connected, and see you online!


Welcome to Town Meeting TV. I'm here today with an incredibly special guest, Marge Berthel. Marge, hi. Hi, and you said that how we got to know each other over the years with me doing my shows, and we became friends, and sometimes we'd go like to Starbucks for coffee and other places, and the shows were very important, because it's an important message. It's that amount of health systems being unhelpful, being helpful, and you see, sometimes they didn't, I don't know why they didn't know that they were helpful, or they were stuck in their way, a certain way, instead of being helpful. Do you want to mention something about that? Yeah, so the title of your show is What's Not Working in Mental Health Systems and Other Organizations. And remember, you mentioned like a set way that some people, you want to mention about the set way that sometimes people do things? Well, something that I learned from you is this idea of getting the help you need, not the help that people give you. And that's one thing that I've learned from you is that from your experience of having to be an advocate for yourself over the years, through your experiences with organizations in Vermont and mental health organizations, is that sometimes people have systems set up that they think are helpful for people, but it's not the help that they really need or that they really want. And they have a certain set way. And they have a certain set way of doing that. So what's your experience been with that, Marge? Well, first, I want you to address that one question that I was going to say more about. You want to say, sure. Yeah, so one of the things that happens when you're not getting the help that you need is that you can become further and further stressed and be pushed into a point of crisis. And sometimes that crisis can result in serious health consequences that you suffer from because you're not getting the help that you really need. And so one of the things that you were asking is what do we have to wait until things are a crisis to address and to give people the help that they need? In 1983, when I collapsed on the sidewalk and I almost died before they took it seriously, and then in 2011, they said, you need nica-grisserin to continue to live. And then this last year, well, in December of 2022 and then 2023, January and February, I fell and didn't know it and went to the hospital. They said they did not think it was a stroke. They thought it was a seizure, but they didn't think it was a stroke, didn't know. They thought it was a seizure, didn't know. But they were giving me seizure medicine to prevent the seizures. And I have to think about these very serious health consequences because if I went too far where there weren't people outside or inside and I fell and I could die, because at a coffee hour at Grandway, if I fell, someone would call right away like they did call when I asked them to or when I was unconscious and blacked out they did or when I came to and asked them to, they did. But if I fell out on some sidewalk somewhere, and no one was around on South Prospect Parkway, I might end up dying. And they said that I should never go to the emergency room unless you call SSTA. Or you call 911, but if 911 won't take you, you have to wait till the next day.  And so I didn't have to think about seizures and falling before, which I do now. And like from stress, because stress contributed, and I asked the doctors, did it contribute? They said yes, and they said it might have been the whole thing, but at least didn't help it. And then recovering from burnout, will I ever recover? And I have some help that's helpful because some people listen and undertake it seriously, respond and help right away. Some people don't, they might not ever, maybe someday they will or after years some did, and some still don't. But some did right away, they always did. And it's like, do you think that, and when I had several hundred misunderstandings, I couldn't resolve it alone for Vermont systems. And having help by getting my message out like TV shows and other people that helped me that I found to help me, helped me. You're an advocate for yourself, but you're part of a network of advocates who work on behalf of folks who need help. But I feel that my message will not just help me, it will help other people, but it isn't something to do alone because solving it or being responsible for alone is too much. And you need lots of backing and help and support. And I felt despair when I didn't feel like I was having enough help, but I'm feeling like I'm having more help and more of enough help. I still could use some more because it's an enormous project. But the fact that I have some help. And when we talk about you needing help, talk about what kind of help is helpful for you, Marge. To be taken seriously, responded to, and listened to, having it happen right away, I don't have to explain and explain and explain to some of these people in Vermont systems that don't get it and don't listen or take it seriously. Some of your experience in those Vermont systems has been misunderstandings, but some of that experience has actually been more than not helpful but traumatic. That's right. And that, do you want to talk about that at all? Well, when I wasn't listened to or taken seriously, and so that's when we get to the point, does somebody have to collapse on a sidewalk to be taken seriously? They should be taken seriously without that.  That's not how it should be. They should say, what can I do to be of help? And it's like at Grandwood. It's very helpful there and where I live and people are, you know, always say, what can I do to be of help? And, you know, if the Vermont systems were like that, other systems, you know, where I went to for the day, I don't go there for the day anymore, but basically... Are there other organizations that are helpful to you? Vermont Disability Rights, Vermont Legal Aid, and those are helpful. And then Friends and Family, and then my health providers, they're learning how, like my primary care and the other doctors that I go to for physical health conditions, you know, they've learned how, but they're like right away. And well, like the health providers at Grandway right away or the health providers at primary care, what is it, University Health Network where your other doctors are? And you might have some doctors outside of that, or some medical people outside of that, but, you know, I feel like they're helpful. It's not like when I used to go to a day program in the Vermont system, which I don't, is that I felt like I wasn't understood or listened to, so I stopped, but it's like... What does it feel like? What is it like for you when you are listened to and understood? It felt terrible. When you are? Oh, I thought you said when you weren't. I know, yeah. That's what I thought you said? No. I misunderstood. Well, what does it feel like? Can I say I misunderstood? Yeah, I do. I hear you, yeah. When I'm understood and taken seriously, it feels great, and it feels great when it happens right away. And I thought you were saying when you aren't misunderstood and listened to, that's what I thought you said, but that's not what you said. Nope. I said, what does it feel like when you are understood or listened to? It feels wonderful. Yeah. And especially when it happens right away. Yeah. And sometimes it's a work in progress, but sometimes it's not a work in progress. Sometimes it happens right away. Yeah. And what... Did you know it feels great? That's awesome. I do know. I love when I feel misunderstood, not when I feel misunderstood, when I feel understood. And I think I... Do you feel like that happens a lot to you in your life? Do you feel well-understood? I feel, yes I do, but since there were so many people that I came across in my life, like in the Vermont systems, there's hundreds, thousands, and millions, most of the people understood, but there were a certain few that didn't that spoiled it for me. Because you know, if I went to a day program and there were all you need is a certain few that don't listen or misunderstood or take it seriously, that can spoil a program.   And they're suggesting that all these things that aren't working for you, they're saying, well, you know, this is what I feel you should do. And I'm saying, well, that's not working for me. And they're not listening to me. And so then I just... So then I finally said, well, goodbye. And you know, kind of what I'm saying, or do you? I do. So you have... Do you want to tell people a little bit about who you are and how they can learn more about your story? Well, how can they... If they want to... How can they watch... How can they get the TV tapes? Well, you've produced a bunch of programs here at Tom Meeting TV, and you've also produced a movie with Nora Jacobson called Tremors in the System.  You can use Marge's last name, Bertold, or Marge Bertold, and you'll see all of the programs that Marge has produced. Who are some of the people you've interviewed? Well, did you know that basically if they get in touch with you, your phone thing says it's blocked? Oh. Yeah, my phone has a lot of messages on it. Yeah. Well, I thought that one with Lindsay was good. Yeah, you did a program with Lindsay Owens for Disability Rights for Mott. Didn't you think that was good? Yeah, it's great. I thought it was really good. What did you think? I thought that was a great introduction. She's the new executive director at Disability Rights for Mott. And didn't you think it was good? Yeah. I feel good. I thought it was great. And I thought you were... I'm sending it to that person that's planning to change mental health systems. Did you send it to him? Who is that person? Well, I don't... Find me. I don't know him, but you mentioned him. Marge, you have a better memory than I, and I do not remember this conversation. I know, but isn't there somebody, you know somebody that's planning to change him, right? To change... You said listen to people's stories. Yeah, maybe. I'll have to look into that. I know, but you don't remember that person? I don't remember. Well, you said there's this person that's listening to people's stories, that wants to change the systems, and you said you sent them... Yeah, it sounds familiar. And you said... Give me a little bit to think about it, and I'll see what I can remember. And then you said you... I asked if you could send the interview of Lindsey, and you said you could. Yep. I do remember now, and I did send that. That was somebody who is working. There's a new human rights panel. There's a new human rights panel that's listening to the stories of Vermonters who have suffered trauma inside of our institutions. So just like you suffered trauma inside the Vermont Mental Health, the Vermont Mental Hospital. And what about the Vermont Mental Health System day treatment programs? Yeah.  But what I'm saying is I want them to know that the day programs are very traumatic, too. You know, I want... I mean, that is a very important message and point that did you know that they're extremely devastating? Or did you know? I didn't know. I mean, other than what you've said about them. Well, you knew before today, or didn't you? Well, because I've heard you talk about it, so I know your experience with those. But you knew before today? Yes. Didn't you know for a long time, or didn't you? Probably, yeah. Well, I've told you many times before today, so don't you remember them? Yep. If you've told me about it, I would remember it, yes. Well, I have many times, so don't you remember? I do remember. And can that guy or whoever it was you sent it to, if you can look up that person that you sent it to, because it would be helpful to me to know... To know if he's seen them, yeah. Yeah, and you can't, you don't remember? Well, what about that Human Rights Council? Why can't you look up that? That's the person that I'm thinking of, who's on the Human Rights Council, and so I did send that, and I'll follow up with him. Is there anything more that you want to talk about on the show today, because we're still on the TV? Well, is there anything else that you think that we should... Well, do you think you've covered the issue? Well, if Megan comes as my guest to a coffee hour at Grand Way and talks about Channel 17, my shows, or other shows, if people want to know them, and what she does, but she'd want to call me and make sure I was going to be there if she comes as my guest, but that would be something very helpful, and so I don't... I'm just mentioning that, and should I explain what that is? Well, you can, and you could explain it to me. What I'm saying is other people might not know what that is. They have a coffee hour on the first floor at Grand Way during the week. It's for residents. For residents, you know, Monday through Friday at 3 o'clock. There's not a lot of people that go now, but... Maybe this can be a public service announcement for folks who are watching this from Grand Way. Do you know that you have a coffee hour five days a week from 3 to 5 o'clock, and Marge and I did a presentation there probably a year or more ago about the programs and why you produce the programs. Yeah, but I'm saying that you could come and talk more about it sometime. But if you're coming as my guest, you'd want to make sure I was going to be there? Yeah, well, I think I would want to be there as your guest. I've enjoyed being there with other residents, too. I know, but if you were going to come as my guest specifically, wouldn't you want to make sure that I was there? Absolutely. But what I'm saying is it's not just to talk to me, it's to talk to other people. In fact, it's a chance to talk to other people that don't know about Channel 17. Yeah, although we're now Town Meeting TV. We've lost the name Channel 17, remember? We're no longer just Town Meeting TV. I know, but okay, but what I'm saying is Town Meeting TV. But what I'm saying is people that don't know about it, you would get to meet people, get to know them, but tell them about what you do. Well, we're doing it right now. This is the kind of thing that we're doing. The Town Meeting TV, we're doing it, but I'm saying I don't know if that many people are going to watch this. Maybe. It depends on how many people we send it to and how we share it. Correct. Marge, do you want to say anything more to viewers who are watching now before we say goodbye, or is it time to just say goodbye? Well, I think we've covered a lot. It's up to you. I'm asking you, do you think we've covered a lot? I think we've covered a lot. I think we've covered the idea of getting the help you need before you are suffering the consequences of not getting that help, and that sometimes the help you need is not. What's the phrase sometimes the help you need is not the help that's given. That's right. Thank you for the people that are listening. Yeah, thanks for watching, and keep tuning into Town Meeting TV for more programming. Thanks, Marge.


Welcome folks, we are the Dow Industries right now trading up $200, you get the NASDAQ up $53, S&Ps up $40, Gold Contract up $6.70, Traded $1,808, we have Silver up $0.09, $22.68, Light Sweet Crew $88.28, a barrel, notes and bonds, the 10-year update ticks, trading $120.04, the 30-year up $22 ticks and $156 flat and $1.00, continues to go lower, this is going to be pretty cool watching this whole baby shake out folks. The King Dollar right now trading down $451 ticks, $95, $934, Euro $113, yen $114.37, the British pound out here at $135 to $1 US dollar. We get over and take a look at the SPY, what you have out here, bottom line, you have higher price, we do have a contraction of volume, now yesterday folks, we'll go through it, we had a huge contraction of volume, you're going to get another one out here today, that being said, guess what, bottom line, the SPY still wants higher price. We look at the NDX100, the same type of setup, and what's really cool, the way this market traded today is this, if the market just continued to go up higher all day, I'd suspect it really ran out of gas, but what you had intraday folks, is that the bottom line is that you came down, and as we came down, the bottom line, you had contraction of volume once again, intraday, and then guess what, you go topside once again, we take a look at the NDX100, the 3Qs, what you have is this, is that the, see if I can get this better, you have the 3Qs, bottom line, going to higher price, the number that we're looking for in the 3Qs is 378, right now you're 367, so I expect we're going to get it, you're going to get a contraction of volume, but guess what, it wants higher price, we go over to the gold contract, gold contract also wants higher price, I expect we're going to see that this gold contract right now, you're at 1808, and this baby wants to run up to this next swing point here, pretty easy, which is the 1882, and if we do go over to the good old dollar, what you're going to see inside of the dollar, is that the fact of the matter is the dollar broke out, had a rejection of higher price, false breakout, you get three days now down, this is telling me the dollar wants to get all the way down to the 89 level, so this is going to be pretty while watching this whole baby shake out, stay right there folks, we'll come right back