Hi, my name is Liam Rowe, currency trader and trading coach at Trading180.com. Welcome to this week's supply and demand for us in gold fundamental and technical analysis. So let's get into the week ahead starting the 17th of July and the release of the latest UK CPU report for June. We're going to track more attention than normal in light of the ongoing hawkish repricing of the Bank of England rate hike expectations. And you've seen that recently in the market, which we'll get into when we get into the technical side of things. The latest CPU report from Canada, New Zealand and Eurozone in Japan will also be released in the week ahead. The Bank of Canada has expressed disappointment recently that core inflation is coming down more slowly than expected with three month rates running around 3.5 to 4% since last September. And in contrast to that, the RBNZ which is the Reserve Bank of New Zealand has just paused the hiking cycle and further evidence of slowing inflation alongside recessionary conditions in New Zealand would reinforce expectations that the hiking cycle is over and bring forward rate cut expectations. And so the latest CPU report from Japan is unlikely to materially alter expectations ahead of the Bank of Japan's upcoming policy meeting on the 28th of July and the Bank of Japan is already expecting or expected to raise their inflation forecast this year. And this is from the latest MUFG report. So lots of market moving news on inflation and some central bank announcements. So getting into some technicals and some further fundamentals on things and starting off on the dollar index and the dollar. This week or last week I should say was really kind of suffered in terms of the valuation which actually ironically is what the central bank really kind of want in terms of inflation going in the right direction. So we had this week, sorry not China, the US inflation hit two year lows giving hope for an end to Fed hikes. So the Fed's job is actually to get inflation down to a 2% target and inflation is trending in that direction. And as long as it keeps trending in that direction the Federal Reserve are less likely to hike rates and hiking rates typically supports a currency. I'm going to say supports meaning the effect of a rate hike is to appreciate a currency to bring down inflation. But inflation is already coming down. They don't have to to hike rates, right? And so that's the hope, right? Is that the end of Fed hikes is coming soon. But the Fed kind of pushed back slightly and said Fed Open are open to another rate hike after expected increase this month. And so officials say it's too soon to declare victory over inflation. Investors betting July rate hike will be the Fed's last. And so that's what's happening on a price chart is that the market is pricing out I guess two rate hikes, which was what was expected to now price in maybe one more. And so we zoom out a bit further dollar index coming down to what that 99 area. And so let's see what demand zones if you are looking at demand are in this area of around 99 ish, probably somewhere back in April 2022 and around here as well. So we could see actually I think this might have pushed just below that. Yeah, so maybe you're looking at prices hovering somewhere around it because there is some long term support and resistance in that zone as well. So that may support the dollar just technically. But I think fundamentally that the path for these resistance is probably now looking to the downside. So I personally think any moves back any pullbacks on the dollar are going to be shorting opportunities into some sort of supply zone. On the dollar index, the nearest supply zone is actually going to be all the way up into the 102. So unless you get something like that, or if you get lower highs and lower lows being made, what you would do is just use that as a confluence into some sort of supplies on a forex pair like the dollar yen, or maybe Australian dollar US dollar to look for confluence levels with shorting the dollar. So yeah, it looked like the hedge funds as well are abandoning their bullish dollar bets on peak fed speculation. So leverage funds go to net short dollar for the first time since March and US inflation report. This was before the inflation report and it was talking about the US inflation was the next big risk for markets. And that turned out to be true, right? So inflation came out. I think it was the Wednesday and pretty much drove prices to the downside. So as long as the market is pricing out rate hikes, we could see further dollar depreciation. And going back to the China story, China's economy is struggling to gain traction. And that actually could support the dollar based off of risk, off-central and global growth slowing down. And if China are slowing and struggling to gain traction and their economy is, then money tends to flow into more safe haven currencies, which is basically like the dollar, right? And so that could be a supporting factor in dollar downside. But I do think any pullbacks into areas of supply or lower highs, lower lows and pullback into a lower high, is going to be a really nice opportunity to look for some short trades on the dollar yen. And again, this week and from last week, we've just seen the dollar kind of, you know, devaluing in price. And the yen, in fact, increasing value over there was speculation when over it last week on the fact that the bank of Japan could adjust monetary policy sooner rather than later. And so the market has priced that in alongside, obviously, some pricing out of the dollar rate hikes. And so let's see what happens at the moment. We still, technically, we do have a nice area of resistance as well as support within that demand zone, which adds some confluence. So if you are looking to buy the dollar, that would be a nice area to buy the dollar. I think, again, sell trades on the dollar you're looking at either pullback into that area there, or at least a lower high, lower low to be made in a pullback into the supply zone. So that demand zone would have to be kind of taken out if you're looking at going short on the dollar yen, buying the yen. If you're looking to actually potentially get involved in buying the dollar, then I think this area is quite nice and its price on the 138 is actually quite decent for a potential buy, technically, or down into the 135s for a potential buy on the dollar. Dollar Swiss. And again, we've just seen this level from December 2020, January 2021. Yeah, just totally get taken out based off of, again, dollar depreciation. So rather than looking at anything even longer term and going back further than that, what I would probably do if you're looking to get short again is look for either massive, that's about what's that five, that's a good 500 pit pullback. Not sure that's going to happen anytime soon. So but you will probably see some sort of maybe move back into, you know, a level and start to create that kind of move where you get either lower highs, lower lows, or higher lows, higher highs, then a break of some sort of structure and then move back up into that zone where we get an opportunity to short. But for now, going short, I think that the area that most traders would look towards a short is going to be the underside of either that zone there, or probably that ultimate zone there is where traders are going to look towards going short. But I like to look for supply zones and demand zones first, and then, you know, any kind of support and resistance as confluence is kind of secondary. So wait for price to prove that there is supply there, then look for a pullback into that supply zone. So I think those really are the options. But for now, I think this week is going to see how it plays out. Again, the Swiss franc are still looking to high crates and are quite hawkish, even though they have reached their 2% target. Moving on to the dollar CAD and the Canadian dollar. Again, this week, strengthening, and then on Friday, we had a bit of a massive outside candle move. And I think that's probably anticipation of the potential inflation numbers that coming out, inflation year on year forecasted to come down to 3%, and the previous was 3.4%. So it is trending lower. But as we said at the beginning of this video, it's about the pace of inflation coming down that will determine whether the Bank of Canada will continue to high crates or not. So I think if inflation does stay sticky or come in higher than expected, then the Bank of Canada will continue to high crates which should push prices either to the downside or maybe move up to that area there before going lower. There is actually a supply zone around here as well. I'm dragging it down to that zone there. So that's where the trading opportunities are at the moment. Again, you do have a decent area of support and resistance within that zone there. So that adds a little bit of confidence to your trades if you do want to get short on the dollar CAD and buying the Canadian dollar. But it all depends on what happens with inflation because inflation comes in lower than expected than any kind of rate hike going forward for the Canadian dollar are going to be priced out of the market. And you're likely to see the Canadian dollar actually sell off across the board just like you've seen with the US dollar. Now, the New Zealand dollar has benefited not really from its own strength but just from the weakness of the US dollar. And we've seen it actually come all the way up to this supply zone here. Stop hunting a little bit above that level and then you've got another zone right above there. So this pair goes higher just based off of really kind of dollar weakness. But I wouldn't necessarily be buying the New Zealand dollar unless inflation does come out this week. And sorry, one second. Yeah, inflation does come out this week and remain sticky. Because again, the RBNZ are going to have to potentially have to hike rates or reintroduce hiking rates after holding rates if inflation is remaining a problem. So let's see what happens to the most obvious opportunity is really either down to 62s for a long trade or prices make higher highs and a pullback into that demand zone which would have been created. So that's really where we are. If you're looking to buy the New Zealand dollar against the US dollar going on to the pound. The pound has reached some targets. I know a few months ago there was reports that it could reach the 130s and it eventually did. So those forecasts came in correct. But the pound, although I am bullish on the pound in the short term, they did have some good data. So UK economy stronger than expected during coronation holiday. Figures will return the focus to inflation and wages and outlook for stagnant sparring growth in coming months. So short term wise data came out which was quite decent. But also we had the UK wage data keep spotlight on the Bank of England rate hikes. So wage data being an inflation measure and so if wage inflation is going higher, it contributes to overall inflation and inflation really wants to come down. So UK wages rose more than expected to a level that Bank of England Governor Andrew Bailey said is fueling inflation, maintaining pressure for higher interest rates. And so yeah, in the short term you have the Bank of England looking to hikes rates which should appreciate the currency whereas for example you had recent data for the US which came in, inflation data came in lower. So you have a divergence there between central bank policy at least in the short term which is driving the pound dollar to the upside. Now one of the downsides to hiking rates and the high inflation is that it weighs on the economy. So UK's inflation crisis expected to last another 10 months so the average household to be £2,300 worst off says report and researchers predict £65 billion wiped off spending power. So cost of living crisis still has nearly a year to run with calculations showing that the average household will be £2,300 worst off by the time inflation eases. So inflation expected to remain sticky which will have a knock on effect on the economy and if the economy starts to contract then the UK may start to be in a worse situation, stagflation and the market may actually start to kind of price out maybe the bullishness that they kind of have been on the pound. So just be mindful of that but as we see, we've just seen prices go from strength to strength again you're looking for either a massive pullback down to these one, two, six, five or again higher highs to come in and then a pullback or you could see prices do something like this make a new high and then pull back to that kind of demand zone. So again this week we do have for the pound we have inflation year on year so what we're looking towards there is if inflation starts to come down more than expected so forecast is 8.2, if it comes down to maybe 8 or even into the 7s in fact what you may see is the pound start to sell off in fact because then the Bank of England, the market will price out Bank of England the need for more aggressive hikes so that's going to be quite an important data point to watch this week and yeah just wanted to give a bit of a shout out to Sunday 1994 who's in the Trading 118 Mentoring Group and he said hello everyone hope you're doing well just wanted to share some exciting news with you after months of hard work, dedication and learning from my trading experiences I'm thrilled to announce that I have finally reached a break-even point in my trading journey it hasn't been an easy road and there were definitely some ups and downs along the way however with the support and knowledge shared within this fantastic trading group I was able to stay focused and push through the challenges he wants to express his deepest gratitude to all of us who have provided valuable insights and advice and encouragement throughout the process and our contributions have played a significant role in the man in his growth as a trader and he couldn't have achieved this milestone without our help while reaching break-even isn't accomplishment and it absolutely is he understands that there's still much to go much more to learn and improve upon and his next step is to stay break-even for as long as possible and make some profits where possible and this was so amazing to finally reach this milestone after losing thought so long and he also says that I have consistently gone above and beyond to share my wisdom and answer questions and provide me with the tools to succeed and he's truly grateful for my mentorship and the impact I'm having on his trading journey and I just want to say again congratulations to signing for Legion Break-even people might think that break-even isn't a major achievement if you go on YouTube you know it's all about doubling, tripling, quadrupling accounts in a short space of time which isn't necessarily the realistic in trading and if you can get yourself to break-even you're at a really really great point especially from losing a losing position and it can only get better from here it's just about eliminating the trades that you don't necessarily need to take maximising the trades that you are in and your profitability and the reality of trading is that you will get break-even days, weeks, months and even break-even years but ultimately we're here as a group to support each other and get everybody to profitability if you put in the work and it just shows that Sunny has been putting in the work and you know it's a great achievement and well done break-even is better than probably 80% of the market because 80% of the market if you go into brokers their websites and see the stats it's maybe between 70 to 80% lose money so you're in a maybe the top 20, top 25% of people that are at least breaking even so now is to get him to profitability so congratulations on that and also as well you can watch several of my 4x student mentoring interviews I have a playlist here that you can look towards and I'll put that in the top right hand side of the screen right now so you can click on that and watch some of what the students have been achieving in the Trading 180 Mentoring Group so moving on to the Euro Dollar and the Euro Dollar again strength to strength right Dollar weakness is probably the more driving factor of this short term the recent price action to the upside I'm not necessarily convinced that the Euro is an absolute out and out buy but in comparison to when it comes to inflation and central bank rate hikes you're seeing that the ECB really are one of the most hawkish central banks and so yeah it wasn't necessarily although technically although technically this was a decent area to look for some short trades you would have had to have believed that inflation was to remain sticky for the US Dollar which it actually didn't obviously it came out you know lower than expected PPI came out lower and inflation rate the inflation measures came out lower than expected which then drove prices a lot higher so as I always say you know that there's no technical level that's going to stand in the way of fundamentals right you need fundamentals on your side when taking any kind of technical trades because there are things going on beyond the price chart that move the actual price right prices are moving because there's an Elliott Wave 1, 2, 3, 4, 5 nonsense it's more it's to do with what the market values currency exchange rate at and that's driven by many things but the main thing is central bank policy and so yeah that trade obviously didn't work out if you got short so now it's really again looking for kind of pullbacks into areas you can look for a pullback into some sort of resistance zone which would be somewhere around here but from a supply from a demand perspective there's no really demand here so I would work for demand to pretty much appear on a price chart and then look for any kind of pullbacks into that demand zone so let's see what happens there but yeah fundamentally we have the ECB stuck with 25 basis point June hike after call for more so core inflation still too fast account of June meeting shows officials plan to raise interest rates again on July the 27th and so yeah they are they're still very very hawkish looking to hike in also September and so whereas you know the Fed are looking to a potential of the market thinking that the Fed are not going to hike after their next meeting so we have a bit of a divergence there and so I think for now the ECB is a buy unless something again changes there's a surprise and I think one of the main surprises that may be on the horizon is if the GDP data comes out for the euro and it comes out as in the contraction so a negative growth again and the euro kind of remain in a recession that may put a cap to the upside of the euro dollar so I think we're already stretched so I wouldn't necessarily look to buy a highs looking for pullbacks proof of demand and then look for a pullback if the data supports that narrative so the euro yen we did get a pullback down deep into the lower end of this demand zone here higher lows higher highs being made so you can see it kind of here where you had high low and then high low high prices pullback into that there's a bit of a move to the upside pullback into this demand zone and then has moved to the upside again so yeah the euro I would I would expect the euro to appreciate against the yen at least in the short term reason being is because the Bank of Japan switched policy but in anticipation of the Bank of Japan potentially adjusting their yield curve control you could have a situation where prices could start to turn around if they do then I expect actually prices to come probably way down to this 150s because it will be a shock to the market but yeah I think any pullback into these highs in anticipation of some sort of change to monetary policy getting ahead of that is actually a riskier trade but there's lots of potential downside in that but for now I think the path of this resistance is to buy the euro against the yen and so there are those your options at the moment let me just pull that down to here so it's not necessarily the strongest area of demand at the moment there is demand there but I think a pullback into the one five freeze I think is going to be decent for a potential buy for the euro if not then all the way down to the 150s is going to be where the next zone potentially is unless of course we get some sort of proof of value within that zone moving towards the euro pound and the euro pound again two central banks being quite hawkish I said I think last week I expected prices to kind of go into this this auction in this range what traders would describe as a range where prices aren't necessarily trending and I was right so again when you get two central banks that are competing two strong central banks then you tend to have an auction and a ranging market whereas if you have two central banks that are one is stronger than the other or hiking then you tend to get a trending market so yeah I think for now the nearest demand zone is somewhere around there again I would probably say that absolute highs you'd have to look for a decent area to look for short trades if you want to buy the British pound against the euro and a pullback into these lows before looking at getting long on the euro but not really a pair I'm interested at all in trading but those are the technical options that you have on this currency pair Aussie US dollar and again the US dollar being beaten up and so the prices to the upside the Australian dollar was appreciated based off of some dollar strength I'm sorry dollar weakness but also as well the RBA are looking to potentially hike they did a hawkish hold maybe a week or two ago and so the market is now pricing in some potential hike so any pullbacks into that zone there I think is decent or if you get a higher high and then move back into that higher low that's going to be a really nice area to look for some long trades if you think the Australian dollar is a buy for a sell trade I think this is a really nice technical level at the moment and it's got lots of confluence there of support and resistance it's even had a previous supply zone that supply zone has been touched actually several times so I wouldn't expect it to necessarily remain strong more times the level it's touched the weaker it becomes and so I would expect prices to probably continue to the upside as long as the Fed remain a bit more dovish or the market thinks that the Fed are not going to hike twice and the RBA actually are going to hike twice to try and get inflation to the downside so I think any moves to the upside are probably where the path of these resistance is and finally gold and gold benefiting from lowering inflation which seems to be a bit strange because gold is a hedge against inflation historically but a weak dollar tends to push gold prices to the upside so any pullbacks into this demand zone if anyone did get involved in this level we'd point this out from obviously a couple weeks ago really nice buy technically against that zone and our prices have actually worked out so any pullbacks into this area here the one, the 1910s, 1913s all the way down to maybe the 1893s to the absolute lows I think a decent buying opportunity is if you think that the dollar is going to continue to be weak in the future if you do think that there's an opportunity to buy the dollar in short gold then I do think that you may want to look for prices to go somewhere around the 1980s maybe just above there and look for some sort of short trade around the 1985s so yeah that's where we are with gold did I have any news on gold? I don't think I did actually I think, here we go is it China gold? Surgeon China's demand for gold is slowing as economy stumbles so there is China central bank was buying gold I think a few weeks ago a report came out and it looks like it's still out so this is the latest report from June the 19th the jitters effect in the world second biggest economy are starting to feed through into China's gold market and so that also is going to potentially support gold prices going forward but also as well I think it actually might still support the the US dollar as well so this is a bit of a tricky trade to be fair because if the world is worried about global growth in China the Chinese economy weakening then in fact money typically tends to flow into the US dollar so let's see what happens there but either way I do think that with the dollar if the dollar continues to weaken then any pull backs into demand for gold should be potential buys so that's it for this week hope you have a great trading week take care and speak to you all soon


Let's start out with strengthening our world and that seems to be particularly fitting for the elements that we'll be producing at NIO Corp. It consists of niobium as our foundational product but we also have scandium trioxide and niobium as you'll hear in just a minute basically strengthens and lightens steel and scandium interestingly enough does for aluminum what niobium does for steel. So it's a very interesting combination of elements out at the site and one that we're awful excited about. Now I will give you our disclaimer. The other thing that was very interesting to me this morning was listening to Natasha and so I'm going to try my best not to bore you with this presentation and hopefully create some excitement about this project but this is kind of a standard presentation that we do give publicly right now and I'll try to make it as fun as I can. So NIO Corp is traded on the TSX under the symbol NB and we really like that since that's the elemental symbol for niobium. We had a lot of very good fortune in 2014 the lower left-hand side of that slide you'll see a couple of different areas that we excelled in and the very fascinating part to me is all the accolades that you get for stuff like that but it all originated from our main course of business which is doing technical work programs to increase the value of the company and that's what all of those share performance attributes were a result of was hard work by a very good group of people. I'm very blessed to have a group of people with me that I know and I trust these are very experienced people they know how to take a resource and put it into production and that's our goal in life is we want this project put into production. We also have the good fortune of having some board members on our team as well Joe Caraba who many of you may know from Cliff's Natural Resources he only has about 40 or 44 years of experience something like that another gentleman by the name of Dave Bealing who thinks that I'm still a kid so I really like him and he's got over 50 years of experience including underground mining so the team that we've put together and the resources that we can tap into are really quite amazing. On top of that we have excellent people like Eric and Elaine from Roche Engineering and that's just meant to let you know we're partnering with the right people as well. We're partnering with Roche Engineering they're doing most of the detailed feasibility study level engineering right now we have partnerships with SRK Engineering we have partnerships with SGS with Corum with Hazen we have partnerships with Morgan Stanley and Credit Suisse and Mackie Research so those are just some of the names that we've decided to do business with and a lot of it has to do with their core values as companies they're good honest people that work hard. So what is niobium? Niobium is an element that when added to steel makes it lighter and makes it stronger the other thing that it does is it has very good corrosion resistance and very good temperature resistance so there are certain applications where it actually there are no substitutes there are other applications where there are the largest use of the materials actually in the construction industry and that is largely because of the lightweight and strength that it provides. The picture there on the right is one of those amazing things that you look at and you say there's just no way that that could be but first of all it came from CBMM which is the authority on niobium in the world and second of all I had it checked by two different engineers as well and it came back just fine. But I was quite amazed at this and if you think about 60% weight reductions in steel and concrete for a structure like that over in France just think of the fuel savings alone transporting your materials of construction out to the site. So there are a lot of pluses that we can look at for niobium. The automobile industry is the one that I like to talk about the most because when you look at every automobile and you know wherever you fly in the world there are cars everywhere and wherever there is a steel automobile body or chassis that is more likely than not made with a niobium based steel. I like to point that out because people can really relate to how prominent niobium is in our economies today. Some additional uses and the top one is the one I'll focus on is oil and gas pipelines and this is where in the deep sea drilling and in the oil fracking business in particular the strength of the steel, the corrosion resistance and the temperature resistance actually mandate that niobium be used for those pipelines and those drill bits. So that is an area where no other substance will do the trick. There are a couple of other minor uses. You do get into some more specialty applications at that point in time. It's a very good market growing at about four to six percent per year and we'll get into this in a little bit more in just a minute but you very rarely hear or see much about niobium and there's a good reason for that. There is currently three producers in the world of niobium and the largest one is CBMM and CBMM is a privately held company out of Brazil so they do not have to publish anything that they do and they don't. So a lot of people don't understand when 85% of that material comes out of one source how prominent it is. However, there is one other small mine in Brazil that produces about six percent of the world's supply and then there is a facility here in Canada as well, Nilebeck, that produces about eight percent of the world's supply. So about 92% of the world's production of niobium comes out of one country, Brazil, and the remainder comes out of Nilebeck here in Canada. It's a very good average growth for the mineral and the pricing for this is just extremely stable. You can take a look here, we've got two graphs here on the slide. The larger graph really shows from 2009 through 2014 very flat compared to most minerals that are sold in the world today and then the insert really is meant to show you that there's really only been two pricing points for this product in the history of niobium. CBMM used to charge $10 to $15 a kilogram for it and in 2007 they basically doubled almost tripled the price and now it sells for $35 to $45 a kilogram. Very steady and when you show these types of charts to banks you're financing possibilities drastically improve. So we have another element, scandium out at this site as well and scandium is one of those amazing elements that has latent demand but we just don't have supply of this material right now. There's currently only 5 to 12 tons of this material produced in the world today. That comes out of China and Russia and Niocorp once it comes online will become the largest producer of this material in the world at 97 tons a year. Here is one of the uses for scandium. It's in the solid oxide fuel cells and what you'll note is that there are really two basic technologies for the fuel oxide cells and that involves yttrium or scandium. The yttrium although it's been the primary focus for the fuel cell industry for some time, it has its limitations. First of all it only has about a one to two year life associated with that fuel cell and it has something in the neighborhood of about 55% reliability. So it really hasn't served the purpose for which people are buying it for whereas if you do a scandium doped Zirconia fuel cell you change the fuel cell industry overnight. Now you have something that lasts for a decade or more and you have four nines reliability. So this actually can be considered base load generation of your electricity and there is a company here actually not here in the United States called Bloom Energy that is producing these fuel cells right now and there are buildings in the Silicon Valley in California running off of these fuel cells. So this is a way to generate power in the future. You eliminate the grid lines that are associated with it and I think we're going to see particularly with more scandium coming on to the market we'll see this market increase quite a bit. Scandium as I mentioned earlier can be alloyed with aluminum and the scandium does for the aluminum what niobium does for steel it makes it lighter and it makes it stronger. And this picture is worth a thousand words because the picture on the left is just regular aluminum metal and you can see there's kind of a chunky appearance to the structure of that whereas if you alloy it with scandium you get what you show on the right and that's a very fine grained material it can be welded it is much lighter it is much stronger and this is an area that the aerospace industry has been aware of for quite some time but again they haven't had a reliable supply of the material so they haven't been able to convert a lot of the aerospace construction over to the scandium aluminum alloys. All the intellectual property has existed for this for some time matter of fact the Russians were pretty smart in this regard and in the late 60s and early 70s they were building their migs out of the scandium aluminum alloys. You can see in the blue ribbon at the bottom what the economics look like for a scandium aluminum alloy used in the aerospace industry about one to one and a half million dollars of scandium will provide a 10 to 15 million dollar savings in terms of fuel costs over the life of that plane and those are both on present value numbers. Another application that we think is going to be extremely interesting as well there's a lot of desalination plants that are being considered. If you take a look at the state of California down in the United States right now they probably don't have a lot of choices other than to continue to build these plants to create the water that the population there needs. Well historically those plants are built with a titanium based piping material and that's because if you take a look at the top picture on the right there that's what would happen to aluminum just straight aluminum tubing in that type of environment but when you put the scandium and alloy it with the aluminum you get performance that you see in the lower right hand side and it's really not impacted at all by the salt environment and can handle that corrosive atmosphere. This will save a tremendous amount of money on the cost of building one of these plants. We had a third party study done on what the pricing would be for this material and we do just simply use the pricing the third party expert came up with as part of our PEA which I'll go through in a little while here but there are two cases that they propose one is kind of the base case where the aerospace industry gives credit for the reliable supplier and that would be the blue line and if the aerospace industry takes a little bit longer to bring their platforms up to the use of these alloys then there would be a second pricing case and then what we do from everything 2023 on is just keep it at those prices that are shown for 2023. A quick note on the strategic and critical importance of these materials simply put for niobium if you don't live in Brazil or Canada it by definition is a critical and strategic element in the country you live in and for scandium if you don't live in China or in Russia by definition it is a critically and strategically important element because those are the only places where it is produced so needless to say we do have a lot of interest right now out of the Department of Defense in the United States and they're watching our project very carefully and very closely let's talk a little bit now about the project itself there will be a picture that comes up here shortly shows you the aerial extent of this carbonite structure which is located in the southeast corner of the state of Nebraska it's about 10,000 acres in size it is just absolutely gigantic we've only drilled a very small piece of it so far but we have done a lot of drilling out there over 18,000 meters total of drilling and we have published a 43-101 compliant report we've got a couple of different categories here we've indicated an inferred and then we have PTA-1 and PTA-2 and the only thing I'll make a point of here is that the drilling that we did starting in April of 2014 and finishing up with that in December of last year that was very targeted drilling what we wanted to do was to do enough infill drilling to create enough measured and indicated resource for a 30-year mine life and lo and behold we hit that pretty good we didn't waste any additional money on extension drilling or anything else we'll show how big it is later when we need to but we ended up with a 31-year mine life using measured and indicated material so we tried to use shareholders money very judiciously in that regard we've got all the 3D views of the resource itself this will be an underground mine it's about 200 meters the ore body is about 200 meters below the surface we've drilled down to 900 meters and the grade is increasing we stopped the drilling after 900 meters because it does get quite expensive at that point and once we put the underground mine in then we'll drill deeper when we can start halfway or more down there's been a lot of resource work we've also done a lot of metallurgy work and you can see here that we've used 6 different labs for the metallurgy work we've done over a thousand different bench tests and we've run 8 different pilot plants we have one more pilot plant tests that we're going to be running and that's just for optimization purposes on the Scandium trioxide solvent extraction circuit we were happy to report I believe it was in September a lower left hand picture there that we had actually produced our first ferroniobium and the great news about that was it met the specs for the customer that we have lined up Teeson Krupp who has a contract with us for 50% of our ferroniobium production but after all that testing here's what you end up with a very simplified process flow sheet and this is what the plant is being designed around right now and again the excellent job that Roche Engineering is doing for us is really putting this together and getting our CAPEX numbers where they need to be here's what our numbers look like when we run them through preliminary economic analysis pre-tax NPV of a little over 3 billion dollars after tax NPV of 2.3 billion dollars average pre-tax cash flow of 438 million dollars per year total upfront capital of about 979 million dollars we do include in the upper right hand corner there an analysis for the base case for Scandium and the lower or slower uptake by the aerospace industry on the right hand side we also provide a breakdown of the CAPEX costs in the lower right hand side and you'll see that we do plan to produce about 7500 tons a year of ferroniobium about 97 tons of Scandium trioxide and roughly 24,000 tons of titanium dioxide the titanium dioxide is actually very prevalent in this ore body and so we're producing it just to generate extra revenue and it just goes almost to the bottom line because the CAPEX to do that and the OPEX to do that is very small so we're moving our project along this is an area in the state of Nebraska that has excellent infrastructure I know that everybody hears all these things but there actually is a state highway right next to the resource electricity grid lines are already in the area we just have to build the substation to provide the actual power it all comes from a nuclear power station that has more than enough capacity for our needs plenty of water in the area if anything maybe a little more water than what we would like but plenty of water and the community support out here is something that I have to talk about because I've never seen this level of positive community support ever in my 34 years of being in this business we have town halls out in Elk Creek, Nebraska on a regular basis so we can keep the community informed the sign at the entrance of the little town is actually a chalkboard so that in case somebody is born or on the other hand they can adjust the handwritten number on the sign and there are 114 inhabitants in Elk Creek, Nebraska we have yet to have a town hall in that area where we don't have more than 114 people present every time this is an engaged community almost every member of the community is a shareholder they believe in the project they want the diversity of business in their area and we're excited to be where we are


With respect to India we consider India a strategic partner and I think our navies continue to operate together in a very very strong and positive way and so we want to maintain those close relationships. We want to operate in a critical critical area I believe is the Indian Ocean region. Out here right now during exercise Malabar we're operating very closely with the Indian Navy. Our intention over the coming weeks, months, years is to operate much more closely with them. We feel we're natural partners not only with the nation of India but also with the Indian Navy.


The entire program has been such a valuable thing for me. Doing Passport to Business has definitely made me a lot more forward-thinking. Compared to other first year students, I definitely feel a lot more prepared. Passport to Business has solidified what I should be doing. A lot of people come into university and they're really not sure what they want to do. Passport to Business helped me find that and then confirmed that yes, I am good enough and I am the right sort of person to be doing these jobs. Passport to Business is a program that students actually sign up for so they volunteer to do it and it gives them the extra skills and knowledge that they need to effectively apply for jobs. Students really do need to have an understanding of their transferable skills themselves, the type of job and industry they would like to go into and then they also need to be able to promote themselves to an employer. So if a student comes on Passport to Business, they can expect to have five sessions to come to in the evening. They will also have workshops that happen during the day and then there is extra homework such as CVs, cover letters, LinkedIn. They will do an informational interview and they will have a reflective log to complete. Then we also have a session on networking and that's immediately followed by speed networking with employers. One of the biggest benefits was just awareness because when you do it in a degree, you kind of imagine it will put me for everything but doing Passport to Business, you realise there is so much more and you just didn't know. Networking, testing, how testing is done, what employers look for. You wouldn't know about these things until you do a programme like this because this kind of stuff, you can't really be taught through books. All the activities were done like the networking event, the mock interview, the card sorts, the MBTI has really helped solidify the decision that I've made at the end of the journey. I want to focus on the commerce side of things, lean away from the law side of things. Everything we've done through Passport to Business has really helped confirm that I think that's the right decision. You progressively learn more about yourself, more about your strength, your weaknesses and it just gives you a lot more insight into what you really want to do. I think having been to an interview and had the networking night, I've got a more concrete idea of my goals. I know where I want to be and I can visualise it. It's just given me confidence to know that the time I am spending at university, the student loan and everything else that goes with it is actually going to be worth something at the end because I will get a career out of it and it will be something I enjoy. Overall I definitely recommend Passport to Business. It's helped secure my current job. It's got me into the final round of internships a year and a half early and I'm a lot more aware of the industry and the jobs available and I'm a lot more confident of myself as a person and where I'm heading.


Chapter 48 All the evening Melbury had been coming to his door saying, I wonder where in the world that girl is? Never in all my born days did I know her bite-out like this. She surely said she was going into the garden to get some parsley. Melbury searched the garden, the parsley bed, and the orchard, but could find no trace of her, and then he made inquiries at the cottages of such of his workmen as had not gone to bed. Avoiding tangs, because he knew the young people were to rise early to leave, in these inquiries one of the men's wives, somewhat unconsciously, let out the fact that she had heard a scream in the wood, though from which direction she could not say. This set Melbury's fears on end. He told the men to light lanterns, and headed by himself they started, creedle following at the last moment, with quite a burden of grappinals and ropes, which he could not be persuaded to leave behind, and the company being joined by the hollow-turner and the man who kept the cider-house as they went along. They explored the precincts of the village, and in a short time lighted upon the man-trap. Its discovery simply added an item of fact without helping their conjectures. But Melbury's indefinite alarm was greatly increased when, holding a candle to the ground, he saw her in the teeth of the instrument some frayings from Grace's clothing. No intelligence of any kind was gained till they met a woodman of Delboro, who said that he had seen a lady answering to the description her father gave of Grace, walking through the wood on a gentleman's arm in the direction of Sherton. Was he clutching her tight, said Melbury? Well, rather, said the man. Did she walk lame? Well, it is true her head hung over towards him a bit. Creedle groaned tragically. Melbury, not suspecting the presence of Fitzpiers, coupled this account with the man-trap on the screen. He could not understand what it all meant, but the sinister event of the trap made him fall along. Accordingly they bore away towards the town, shouting as they went, and in due course emerged upon the highway. Nearing Sherton Abbas the previous information was confirmed by other strollers, though the gentleman's supporting arm had disappeared from these later accounts. At last they were so near Sherton that Melbury informed his faithful followers that he did not wish to drag them farther at so late an hour, since he could go on alone and inquire if the woman who had been seen were really Grace. But they would not leave him alone in his anxiety, and trudged onward till the lamp-light from the town began to illuminate their fronts. At the entrance to the high street they got fresh scent of the pursued, but coupled with the new condition that the lady in the costume described had been going up the street alone. "'Faith? I believe she's mesmerized, for walking in her sleep,' said Melbury. However, the identity of this woman with Grace was by no means certain. But they plotted along the street. There combed the hairdresser, who had despoiled Maddie of her tresses, was standing at his door, and they duly put inquiries to him. "'Ah! How's little Hintock folk by now?' he said, before replying. "'Never have I been over there since one went a night some three year ago, and then I lost myself finding it. How can you live in such a one-eyed place? Great Hintock is bad enough. Hutt little Hintock. The bats and owls would drive me melancholy mad. It took two days to raise my spirits to their true pitch again after that night I went there. Mr. Melbury, sir, as a man's that put by money, why not retire and live here, and see something of the world?' The responses at last, given by him to their queries, guided them to the building that offered the best accommodation in Sheraton. Nothing been enlarged contemporaneously with the construction of the railway, namely the Earl of Wessex Hotel. Leaving the others without, Melbury made prompt inquiry here. His alarm was lessened, though his perplexity was increased, when he received a brief reply that such a lady was in the house. "'Do you know if it is my daughter?' asked Melbury. "'The waiter did not. Do you know the lady's name?' Of this, too, the household was ignorant, the hotel having been taken by brand new people from a distance. They knew the gentleman very well by sight, and had not thought it necessary to ask him to enter his name. "'Oh, the gentleman appears again now,' said Melbury to himself. "'Well, I want to see the lady,' he declared. A message was taken up, and after some delay the shape of grace appeared descending round the bend of the staircase, looking as if she lived there, but in other respects rather guilty and frightened. "'Why? What the name?' began her father. "'I thought you went out to get parsley.' "'Oh, yes, I did. But it is all right,' said Grace, in a flurried whisper. "'I am not alone here. I am here with Edgar. It is entirely owing to an accident, father.' "'Edgar, an accident? How does he come here? I thought he was two hundred mile off.' "'Yes, so he is.  He has bought it with his own money, some that came to him. But he traveled here, and I was nearly caught in a man-trap, and that's how it is I am here. We were just thinking of sending a messenger to let you know. Melbury did not seem to be particularly enlightened by this explanation. You were caught in a man-trap? Yes, my dress was. That's how it arose. Edgar is upstairs in his own sitting-move, she went on. He would not mind seeing you, I am sure. "'Oh, Faith, I don't want to see him. I have seen him too often already. I'll see him another time, perhaps, if tis to oblige. He came to see me. He wanted to consult me about this large partnership I speak of, as it is very promising. "'Oh, I am glad to hear it,' said Melbury, dryly. A pause ensued during which the inquiring faces and whitey-brown clothes of Melbury's companions appeared in the doorway. "'Then, Baint, you coming home with us?' he asked. "'I think not,' said Grace, blushing. "'Mmm. Very well. You are your own mistress,' he returned, in tones which seemed to assert otherwise. Good night!' and Melbury retreated towards the door. "'Don't be angry, Father,' she said, following him a few steps. "'I have done it for the best. I am not angry, though it is true I have been a little misled in this. However, good night, I must get home along.' He left the hotel, not without relief, fought to be under the eyes of strangers while he conversed with his lost child had embarrassed him much. His search-party, too, had looked awkward there, having rushed to the task of investigation, some in their shirts-leaves, others in their leather aprons, and all much stained, just as they had come from their work of barking and not in their Sheraton-marketing attire, while treedle, with his ropes and grappinals and air of impending tragedy, had added melancholy to gockiness. "'Now, neighbors,' said Melbury, on joining them, "'as it is getting late, we'll leg it home again as fast as we can. I ought to tell you that there has been some mistake. Some arrangement entered into between Mr. and Mrs. Fitzpiers, which I didn't quite understand. An important practice in the Midland Counties has come to him, which made it necessary for her to join him tonight. So she says. That's all it was, and I'm sorry I dragged you out.' "'Well,' said the hollow-turner, "'here be we six miles from home and nighttime, and not a hawse or four-footed creeping thing to our name. I say we'll have a mossle and a drop of summit to strengthen our nerves before we vamp all the way back again. My throat's as dry as a kex. What do you say, souls?' They all concurred in the need for this course, and proceeded to the antique and lampless back street, in which the red curtain of the three tons was the only radiant object. As soon as they had stumbled down into the room, Melbury ordered them to be served. When they made themselves comfortable by the long table, and stretched out their legs upon the herringbone sand of the floor, Melbury himself, restless as usual, walked to the door while he waited for them, and looked up and down the street. I'd gear a good shaking if she were my maid, pretending to go out in the garden, and leading folk of twelve-mile traips that have got to get up at five o'clock tomorrow, said a backripper who, not working regularly for Melbury, could afford to indulge in strong opinions. I don't speak so warm as that, said the hollow-turner, but if it is right for couples to make a country talk about their separating, and excite the neighbors, and then make fools of them like this, why, I haven't stood upon one leg for five and twenty years. All his listeners knew that when he alluded to his foot-length in these enigmatic terms, the speaker meant to be impressive, and creedle chimed in with. Off, young women do wax-wanton in these days. Why couldn't she abode with her father and been faithful? Poor creedle was thinking of his old employer. But this deceiving of folks is nothing unusual in matrimony, said Pharma Baatri. I know to man and wife, faith, I don't mind owning, as there's no strangers here, that the pair were my own relations. They'd be at it that hot one hour that you'd hear the poker and the tongs and the bellows, and the warming pan flee across the house with the movements of their vengeance, and the next hour you'd hear them singing the spotted cow together as peaceable as two holy twins. Yes, and very good voices they had, and would strike in like professional ballet singers to one another's support in the high notes. And I know to woman and the husband or her went away for four and twenty years, said the Bach ripper, and one night he came home when she was sitting by the fire, and thereupon he sat down himself on the other side of the chimney-corner. Well, says she, have you got any news? Don't know as I have, says he. Have you? No, says she, except that my daughter by my second husband was married last month, which was a year after I was made a widow by him. Oh, anything else, he says? No, says she, and there they sat, one on each side of that chimney-corner, and were found by their neighbors' sound asleep in their chairs, not having known what to talk about at all. Well, I don't care who the man is, said Creedle. They required a good deal to talk about, and that's true. It won't be the same with these. No, he is such a project, you see, and she is a wonderful scholar, too. What women do know nowadays, observed the hollow-turner, you can't deceive him as you could in my time. What they know then was not small, said John Upjohn. Always a good deal more than the men. Why, when I went courting my wife, that is, now, the skillfulness that she would show in keeping me on her pretty side as she walked was beyond all belief. Perhaps you've noticed that she's got a pretty side to her face, as well as a plain one. I can't say I've noticed it particular much, said the hollow-turner, blandly. Well, continued Upjohn, not disconcerted, she has. All women under the sun be prettier one side than the other. And as I was saying, the pain she would take to make me walk on the pretty side were unending. I warned that whether we were going with the sun or against the sun, uphill or downhill, in wind or in luth, that water of hers was always towards the hedge, and that dimple towards me. There was I, too simple to see her wheelings and turnings, and she so artful, though two years younger, that she could lead me with a cotton thread like a blind ram. For that was in the third climate of our courtship. No, I don't think the women have got cleverer. For they was never otherwise. How many climates may there be in courtship, Mr. Upjohn, inquired a youth, the same who had assisted at Winterborne's Christmas party? Five, from the coolest to the hardest, least wise there was five in mine. Can you give us the chronicle of them, Mr. Upjohn? Yes, I could. I could certainly. But it is quite unnecessary. They'll come to you by night, young man, too soon for your good. At present Mrs. Fitzpiers can lead the doctor as your Mrs. could lead you, the hollow-turner remarked. She's got him quite tame. But how long to elast I can't say. I happened to be setting a wire on the top of my garden one night when he met her on the other side of the hedge. And the way she queened it and fenced and kept that poor feller at a distance was enough to freeze your blood. I should never have supposed it of such a girl. Melbury now returned to the room, and the men having declared themselves refreshed, they all started on the homeward journey, which was by no means cheerless under the rays of the high moon. Having to walk the whole distance, they came by a footpath rather shorter than the highway, though difficult except to those who knew the country well. This brought them by way of great hentock, and passing the churchyard they observed as they talked. A motionless figure standing by the gate. I think it was Marty South, said the hollow-turner parenthetically. I think it was. I was always a lonely maid, said up John. And they passed on homeward, and thought of the matter no more. It was Marty as they had supposed. That evening had been the particular one of the week upon which Grace and herself had been accustomed to privately deposit flowers on Giles's grave. And this was the first occasion since his death, eight months earlier, on which Grace had failed to keep her appointment. Marty had waited in the road just outside Little Hentock, where her fellow pilgrim had been wont to join her, till she was weary, and at last thinking that Grace had missed her and gone on alone, she followed the way to Great Hentock. But saw no Grace in front of her. It got later, and Marty continued her walk till she reached the churchyard gate, but still no Grace. Yet her sense of comradeship would not allow her to go on to the grave alone. And still thinking the delay had been unavoidable, she stood there with her little basket of flowers in her clasped hands, and her feet chilled by the damp ground, till more than two hours had passed. She then heard the footsteps of Melbury's men, who presently passed on their return from the search. In the silence of the night Marty could not help hearing fragments of their conversation, from which she acquired a general idea of what had occurred, and where Mrs. Pittsburgh's then was. Immediately they had dropped down the hill, she entered the churchyard, going to a secluded corner behind the bushes, where rose the unadorned stone that marked the last bed of Giles Winterborne. As this solitary and silent girl stood there in the moonlight, a straight, slim figure, clothed in a plateless gown, the contours of womanhood so undeveloped as to be scarcely perceptible. The marks of poverty and toil were faced by the misty hour. She touched sublimity at points, and looked almost like a being who had rejected with indifference the attribute of sex for the lofty equality of abstract humanism. She stooped down and cleared away the withered flowers that Grace and herself had laid there the previous week, and put her fresh ones in their place. Now, my own, own love, she whispered. You are mine, and only mine. For she has forgotten yet last, although for her you died. But I, whenever I get up, I'll think of thee. And whenever I lie down, I'll think of thee. Whenever I plant the young lodges, I'll think that none can plant as you planted. And whenever I split a gad, and whenever I turn the side a ring, I'll say none could do it like you. If ever I forget your name, let me forget home in heaven. But no, no, my love, I never can forget thee. For you was a good man, and did good things. End of Chapter 48 End of the Woodlanders by Thomas Hardy Recording by James O'Connor, Randolph, Massachusetts, August 2009


Good morning, everyone. It's my pleasure today to introduce Barbara Orozco, so we can take our seats and get started, that would be great. It's my pleasure today to introduce Barbara Orozco, who has a very interesting history and is unusual, but wonderful role model for our trainees who are interested in drug development or technology. Barbara completed her ophthalmology residency at Columbia University in New York, and then did her glaucoma training at Cornell. Following that, she went on to spend ten years in private practice in Huntington, New York, and at the same time have four wonderful kids with her husband who's an anesthesiologist. About five years ago, she joined Pfizer and was a senior medical director for ophthalmology. So essentially, Barbara was the queen of Xalatan for five years. She oversaw all the phase one, two, and three clinical trials as well as obtained or led the European licensing of Xalatan for pediatric glaucoma. In addition, she oversaw the pipeline development for glaucoma therapy at Pfizer. In June of this year, her family relocated to the Salt Lake City area, and I have been very fortunate to have Barbara join my team in our company called Ivina, which we launched about two years ago for developing a drug delivery device. And in that capacity, Barbara has led a lot of the preclinical and regulatory work that needs to be done for development of a new medical device. In addition, Barbara serves as the chief medical officer for Altheos, which is a San Francisco-based biotech firm developing a kinase inhibitor for glaucoma therapy. So with that, I'd like to introduce Barbara Roscoe, and she will give the first talk. I believe there's a couple of patient presentations to follow as well. Thank you, Bala. So it's my pleasure to be standing up here today and for the University of Utah Moran Eye Center to have welcomed me. When I joined Pfizer, and it was kind of funny, it wasn't really that I was looking to join drug development, and I had no idea what it involved. It was a great learning experience, and it really opened my eyes to how we as physicians use medications and how medications get approved. And I look at diseases and I look at the challenges of getting new drugs into our hands different than we do now. Let me get to my slides. And it's been an absolute pleasure working with Bala. When I joined Pfizer, I actually joined the MacGin team, and I was thrown back into AMD, which I had chosen to forget in PDT. And I didn't want to learn all the therapies that were happening. But with the MacGin team came the understanding of VEGF and the whole world of vascular mediators, and it really opened my eyes to the vascular mediators and how they affect cell walls, endothelial cells, and vascular tissue, and channels. And I want you to keep that in mind as I go through the slide deck, because not only do we have vascular channels that carry blood in the eye, but we have the trabecular mesh work, which is a vascular channel. But instead of carrying blood, it carries aqueous, and it has the same smooth muscle, as the same endothelial cells as blood vessels. And that's how I started to think about glaucoma. You did tell me that I can't use this by the pointer. So again, in full disclosure, I am a consultant and the chief medical officer of Alpeos, and I do work here with Bala. And I do have an academic volunteer appointment. And I am available to residents and fellows if this should be your area of interest. So the objective here is to show you that there is a vascular scheme component to glaucoma that lowering IOP affects and improves the ocular blood flow to the eye to introduce some underlying pathophysiology of ischemic and systemic endothelial dysfunction. And to say, well, maybe we can look at a target in the future and approach glaucoma a little differently. I'm going to present the understanding and treatment of glaucoma, go through some of the evidence for systemic vascular factors, talk about how do you assess those vascular factors in the eye, and also then how do you target it. So we know glaucoma is a multifactorial progressive optic neuropathy. And it's got characteristic loss of retinal ganglion cells. There's several risk factors. And we always think about those as the IOP dependent and the non-IOP dependent. And IOP is indeed a key risk factor that impacts not only the development of glaucoma, but also its progression. And currently, it's the only risk factor that we can modify and actually treat and alter. And our current therapy is aimed at altering IOP. But people are hoping to change that. It's a continuum. We see structural and functional loss. And we're not treating the symptoms or I should say we're treating the symptoms, but perhaps not necessarily always the pathology. So we're not aiming at the retinal ganglion cells. We're aiming at a risk factor, which is a surrogate marker. And I think that's what we have to keep in mind. It's a progressive optic neuropathy. The surrogate marker is IOP, very similar to cardiovascular disease. It's a vascular disease with atherosclerotic plaques and the surrogate marker is cholesterol. So we treat cholesterol hoping to improve the progression and impact those vessels. So here we treat the surrogate marker IOP. We hope to slow down the progression and treat the disease. And there's numerous risk factors. Well, how are patients affected? And this is sort of more for the residents. Well, there's functional loss. And when we talk about visual function, that's visual field, end stage, we see changes in visual acuity because it's central. But there's also other things that can change. And in contrast sensitivity, there's numerous papers out there that show that patients with glaucoma have decreased contrast sensitivity. And I think that's very interesting from the standpoint that the regulatory bodies, the FDA, EMEA, the European Medical Agency will say that, yes, if you improve contrast sensitivity in a patient, that's clinically relevant. And we will approve a drug that impacts contrast sensitivity. We will also approve a drug that improves visual fields and will approve a drug that improves vision. So we have loose sentence for that example. Memantine try to improve or slow down progression of visual fields. I don't know how many of you remember the Memantine study. But again, it was a very difficult long study for various reasons, but it was looking at an endpoint of visual field as a marker of visual function. There's structural changes. The FDA and the NEI and ARVO have put out several recent collaborative meetings looking at structural changes as an endpoint for glaucoma. Up till now, they will not accept structural endpoints, retinal neurofiber layer as an endpoint. So if you develop a drug or some sort of therapy that slows down retinal ganglion cell loss or structural loss, Wiley Chambers, who heads upcedar of the FDA for ophthalmology, says, well, I don't know what that means to the patient. If you slow down the loss of neurofiber layer by five microns, well, what does that mean to the patient? Does it make the patient see better? Does it improve his clinical function? And he will say, no. And he will say, therefore, I will not accept a drug that slows down neurofiber layer loss. So it always comes back to the impact on the patient, the function of the patient, the clinical relevance to the patient. So we know that lowering IOP reduces the risk of glaucoma. And there's numerous studies, large, well-designed, prospective, randomized studies that have shown us that, yes, if you alter IOP, lower IOP, you will slow down the progression of this disease. And we can alter that. We can alter IOP. So we decrease aqueous production or we improve aqueous outflow. And we talk about other aspects of IOP. We talk about peak IOP, we talk about IOP fluctuation. Because when all is said and done, patients with elevated IOP, despite IOP lowering, can progress. And patients without elevated IOP can progress. So there's definitely a component to this disease that we're not treating when we manage IOP. Furthermore, studies have shown that despite IOP lowering with conventional one monotherapy by five years, 75% of those patients require combination therapy. So our IOP therapy is failing to maintain those patients in a therapeutic target area. What are we doing when we lower IOP? Well, could we be actually affecting other parameters? And the question is yes. There's non-IOP risk factors. So we have the ocular risk factors, the neurodegenerative risk factors, the cardiovascular risk factors, and primarily the vasospastic vascular risk factors. Migraines, vasospasms, rainotes, hypotension. Even positioning. If you lay a patient down and then sit them up, their IOP will vary. During nighttime hours, IOP tends to be higher, but yet blood flow and perfusion and blood pressure tend to drop. What's happening to the eye? Is that patient who's recumbent on their right side all their life? Are they going to have asymmetric glaucoma present later on? These are some of the questions that come up. One thing that I found that was very, very interesting is out of the Canadian glaucoma study, Bell-Shohan has been a big proponent looking at vascular mediators and different proteins that affect the vascular chirp. He looked at patients over several years, and he found that women who had elevated anti-cardiolipin actually had higher incidence and more progression of their glaucoma state. You think about your rainote's patient, your younger, thin woman, hypotensive woman. Maybe that's the woman that has normal tension glaucoma. That's more of a vascular component. But when we think about anti-cardiolipins, that's also a marker for endothelial damage. If you look into the cardiovascular literature, they'll show you that if you have elevated anti-cardiolipin antibodies, you may be at a higher risk for strokes, heart attacks, atherosclerotic plaques. So again, there seems to be some link there. The guidelines, which I thought were very interesting, this year now include low ocular perfusion pressure, is a risk factor for glaucoma. So as clinicians, are we supposed to be measuring blood pressure? Are we supposed to be calculating our ocular perfusion pressure in these patients? But what is ocular perfusion pressure? We look at comorbid conditions with these patients. So if we're not sure that IOP is the whole answer, what about systemic diseases? And there is a correlation with glaucoma patients and systemic diseases. But we're not clear if one is precipitating the other. Is it just that we're looking at elderly patients? And if you take a cohort of elderly patients, you're going to see a higher incidence of coronary disease and systemic hypertension. Or is one actually predisposing the patient to another disease? There is a rationale for blood flow as a risk factor, because the eyes end to organ. And if you think about the kidney, if you lower perfusion to the kidney, you end up with microinfarcts, glomerular nephritis, various nephropathies, because there's ischemia. Why is the eye any different? You have one major vessel coming in, a lot of small tributaries coming off. And if you decrease the blood flow coming through the ophthalmic artery, what happens to those other terminal arterials later down the road in distal? Well, they either constrict or dilate. And what happens if you lower blood pressure? So if you lower blood pressure, well, those terminal arterials are very sensitive to changes in oxygen. So you have these small posterior ciliary arteries that suddenly are seeing less oxygen. Well, they're either going to dilate or they're going to constrict. And there's watershed areas, which Anderson and a lot of Hayray's work focused on, and again show that if you change vascular chair or change the perfusion, you will see changes in the vascular chair, and you can actually see microinfarcts in the peripapillary area of the optic nerve. Is that what we see when we see disc hemorrhages in our glaucomatitis patients? And how many advanced glaucomatitis patients actually have attenuated, narrow retinal arterials and even sometimes shunt vessels? Well, can you measure it? So, okay, fine. Here it plays a role, but can we measure it? IOP is very easy to measure. You can measure perfusion pressure, and it's a measurement. And this is one thing I want to stress, that it's not a direct evaluation of the vasculature. It's a measurement. And it takes into account systolic blood pressure, diastolic blood pressure in IOP. It makes sense. You increase the IOP in the eye. That's pushing on the vasculature. There's less perfusion of blood to the back of the eye. We've all heard over and over again. And the blood, the optic nerve head, has been, the blood flow to the optic nerve head has been correlated with changes in mean arterial pressure. They talk about mean. And another thing just to keep in mind, when you hear ocular perfusion pressure thrown around, it could be diastolic perfusion pressure, mean perfusion pressure, or systolic perfusion pressure. And there is this theory that patients who have glaucoma cannot adjust their blood vessels to change in perfusion pressure. So if the perfusion pressure drops, these patients can't vasoconstrict. And again, this is very consistent with the migraine patient, the Reynolds patient. There is a dysregulation of their autonomic system to that vasculature. Numerous population studies, and this is why the AAO probably added in their guidelines that perfusion pressure is now a risk factor, you have population-based studies that show if you lower perfusion pressure, you can increase the incidence, the prevalence, and even the progression of glaucoma. And I thought what was Lesky presented, Mark Lesky in the Barbados I studied, at nine years, your relative risk is actually doubled if you have a lower mean perfusion pressure. Can we measure it in other ways? Can we measure it directly? So we can do that for our carotid disease patients. We can look at carotidoplar. We can measure blood flow elsewhere in the body. And again, we're dealing with very small vessels, and there's a lot of variability, so it's very difficult. But you can. You can look at your ophthalmic artery, you can look at your central retinal artery, and this is done with the carotidoplar imaging. And this is, for the most part, been standardized. It definitely is normative data looking at blood flow through those major tributaries with the CDI. The rest of the vasculature is much more difficult to assess. But you can. You can look at it with ICG, you can look at it with fluorescein, you can measure the vessel diameter, you can measure the velocity of the flow, or the velocity of the blood vessels passing, but you can't measure flow. Flow is a calculation. And it's prone to error, and it's prone to variability, and it's prone to technician variability and patient variability. So where this stands is this is still an experimental collection of technology that's usually used in a research department. Well, have some people try to incorporate it into drug development. So if you think you have a problem with blood flow and you want to improve your blood flow, well, you've got to measure it, because your drug has an effect on it. And people are starting to think about that. But again, it's very difficult. I can't go to most of you in a clinic setting and say, okay, enter a patient into this trial and I want to measure blood flow. And I want to look at this drug's effect on blood flow. So there's difficulty in recruiting patients, there's difficulty in finding sites, and there's difficulty in validating the equipment. Japan's a little bit more lenient and a little bit more accepting of different types of data to put into labels. And Tafloprost, which is a prostaglandin, recently got approved in Europe. Merck is actually marketing it. They were approved in Japan and in their label they actually show that if you apply Tafloprost to animal models and actually even to humans, you can improve blood flow. What does this mean? We don't know. What's the clinical impact? What are we helping? What are we doing to our patients eventually? We don't know. But this is sort of the first step that you have recognition that a topically administered drug is affecting blood flow and actually was measured reliable and repeatedly and some validated or actually some data that's yet to be validated but it was included in the label. Can we target the vascular check? Numerous targets. And I'm not even going to try to go through all of these. But I think one of the things that stands out as a pretty interesting target and that I have found of interest is the endothelial cell. And again, when we think about the eye and we think about glaucoma, the endothelial cells line the trabecular meshwork, the juxtacanular and Schemes canal and they also line the blood vessels. So it may be an interesting cell to look at and to target. And what happens if those endothelial cells don't function well? Well, they don't vasodilate or vasoconstrict to mediators. Nitric oxide. Very well-known vasodilator. If an endothelial cell is damaged and or dysfunctional and as you age, your endothelial cells become dysfunctional. They won't respond to your nitric oxide. So even if your blood vessels wanted to dilate, maybe they can't because the cells are older. One thing that's very interesting is VEGF. VEGF affects endothelial cells and endothelial progenitor cells. These are the bone marrow cells that get called into play in angiogenesis. You elevate VEGF in the eye. We know you get CNB, corneobascularization. Well, why? That VEGF activates those endothelial progenitor cells to come in and to form new vessels. But in a normal, healthy state, not in a pathologic state, but in your everyday state, if you want to repair those cells, you need VEGF. Maybe VEGF's playing a role. Another very interesting target is endothelin. Endothelin is very well studied in the cardiovascular literature because it causes blood vessels to constrict and it gets elevated if the endothelial cells are damaged. There's clinical evidence that these mediators are actually elevated. There's elevated VEGF in the aqueous of patients with glaucoma. Well, why? These are not neovascular glaucoma patients. These are just patients with glaucoma. Why? Is the eye trying to repair itself? Is it trying to heal itself? VEGF is not always pathologic and you need a low baseline and there's different mediators there. I defer to Bala on that one. It's a very interesting compound, a mediator or a protein. Endothelin 1 is elevated in the aqueous and in the plasma patients with glaucoma. Well, patients with cardiac disease have elevated endothelin. If the patient has an ischemic stroke, they'll have elevated endothelin. Again, we have another marker that's sitting in the aqueous that may be telling us that there's some ischemia going in the eye. There was also lower nitric oxide. Nitric oxide vasodilates. So you've got an elevated vasoconstrictor and a decreased vasodilator. What's happening to the trabecular meshwork? Maybe it's closing down. Maybe there's more resistance. Maybe it's constricting. Maybe it can't dilate like it should because these mediators are in the aqueous. Endothelium is very... is a really, really cool protein. If you think a protein can be cool. And again, if you go into the systemic literature, it is overwhelming with evidence that this is a very potent vasoconstrictor, causes fibrosis, causes inflammation, causes endothelial cells not to function properly and also may cause angiogenesis. If you give it to animals, and again, think about glaucoma and think about endothelium maybe being elevated in the eye because there's ischemia. If you give endothelium into the vitreous, you actually cause retinal ganglion cell loss.  And if you reverse endothelium or block it, you can block that glaucomatous change in the optic nerve. It's been looked at in glaucoma. It's been looked at to have a role in the anterior chamber. It's been looked at to have a role in the posterior segment as well. It's involved in retinal ganglion cell death. It could be involved in vasodilatation of the trapeculomesh work. It can also affect blood flow. There's antagonists to it. You can block it. And it's a very potent class of vasodilators because again, if endothelium vasoconstricts, you block it, you vasodilate. It's an established therapy for pulmonary arterial hypertension. And there's currently two drugs on the market. And I actually got interested in endothelium receptor antagonists when I was at Pfizer because they have one of these compounds by the name of Thelon, Cytaxotin. The other company is Cetlion, which makes Bosantin. They're looking at these compounds also in diabetic nephropathy, peripheral arterial disease, hypertension, kidney failure, anything that you would need to vasodilate. The problem is that these drugs have toxicity. So you can't give your glaucoma patient an oral drug long-term because of the systemic side effects, primarily liver. There is evidence that if you give endothelin, as I said, you can cause glaucoma if glaucoma changes. So if you block it, what happens? Well, there's studies that show that you can actually improve blood flow to glaucoma patients if you block endothelin. It's a very short dose. None of the patients had any toxicity issues. And they did show improved blood flow. Also, if you give it topically, it's blocking vasoconstriction. Vasodilates. It appears to vasodilate the trabecular meshwork at a lowered IOP. So in summary, are there possibilities to manage glaucoma differently? I would say yes. I would say we should look at these other mediators and think about the eye a little bit differently. Think about it as an end organ that has vascular neuronal components to it in addition to the IOP and the trabecular meshwork. So we could vasodilate. That may help. That'll help the trabecular meshwork. And the rokinase inhibitors that are actually being looked at are being borrowed from the vascular space. Vasodilate. Vasodilate trabecular meshwork. You could decrease constriction. You can block endothelin. And maybe again, open up those channels. Maybe you can improve the health of the vascular tissue. Is there any way that we can improve endothelial cell function? Well, in cardiac tissue we can with statins. There's some suggestions that statins can work in the eye. And we can also perhaps try to improve the inflammatory status. So what does this mean for drug development? How would you get a drug that works on vasodilature actually approved and into the hands of clinicians and into patients? Again, very, very difficult path because there's no clear endpoint. And when you think about the effects of glaucoma they're slowly progressive. And from a drug development perspective glaucoma is not very much different than Alzheimer's. You have some people progressing, some that are stable. And at the end, you want to show that your drug has a statistically significant impact on progression and or outcome. And it's very difficult when you're dealing with a slowly progressive disease. We saw that again with the Memantine Study. The challenge is yes, surrogate marker for IOP is easy. So you're going to keep seeing IOP lowering mediators. And that's the easy target for drug development unfortunately. There is this big push from Wine Reb and Paul Kaufman. They were the ones that led Arvo's NEI FDA meeting on endpoints to say we need to look at glaucoma differently. What I thought was very interesting and I just threw in at the end is we may get help from our neurology colleagues and I know some of you involved in neuroop. So Tarsiva is looking at a vaccine for optic neuritis, acute optic neuritis. And they're actually multiple sclerosis, but they're looking at an indication in optic neuritis patients. What that means is they are designing clinical trials phase three to show that this intervention slows down neurofiber layer loss secondary to optic neuritis. So they're actually looking at neurofiber layer structure in a clinical trial as an endpoint. And if the FDA chooses to accept this, this can really open up the way we look at retinal disease. And it can change our endpoints for drugs that treat retinal disease including glaucoma. So I'm very excited to see what happens with this optic neuritis study. You may have seen it in some of the throwaways. It gets a little press and ophthalmology. And again, it's the octagon study is the name of it. So the future, there's challenges. There's clearly an unmet need. We're not managing our patients the best we can. And an IOP lowering agent is not giving us everything we need to manage our glaucoma patients. And I think it comes down to the fact that we really don't understand the pathophysiology of the disease. We really don't understand what's happening to these patients. Glaucoma remains a leading cause of blindness. We're probably overtreat. And if you look at the recent papers that came out of oats, we probably do overtreat. And in fact, that's probably a result of the pharmaceutical companies. You know, they gave us IOP lowering agents. And Zalatan is a great example. Very safe, very low risk. So if you've got an ocular hypertensive with a family history of glaucoma, you may choose to treat that patient. But will that patient really progress? And our patients that we see with pressures of 8 and 10 that are continuing to progress, we're still pouring on our IOP lowering agents. But obviously, those aren't helping us because we would like them to do. So it needs to be looked at. It needs to be looked at better. And I believe that there is room to move this science forward and to look at the disease a little bit differently. And with that, I thank you. I thank you for your attention. I threw a lot of material at you. And if there's any questions, I'd be happy to answer any questions. Well, ocular migraine, I don't think not necessarily ocular migraine. But I know that the association has been drawn between classic migraine and then more so renal patients. But I don't know anything about unless other people can comment. I don't know if ocular migraine alone has been looked at. There's a lot of literature. And in fact, Jay and Bala's brother had several presentations on this where there's... So you need VEGF to maintain normal homeostasis and VEGF is very important in cellular repair, cellular function maintenance and retinal ganglion cell function. The concern was that when you blocked all of VEGF-A with your pan... anti-VEGFs, that you would have some decrease in normal function over time. There's a host of... Again, the retin specialist, please chime in. There's some thought that these patients who have long-standing anti-VEGF therapy over time, although their lesions dry up, there's some retinal thinning that's been shown to occur. And people are unclear as to whether an opus is related to that sort of continuous injections of an anti-VEGF. But yes, it was absolutely a concern that you would have decreased retinal ganglion cell and neuronal function. The other thing that's interesting too is the stroke literature and the neurology literature. VEGF is a key... is definitely involved in strokes and I think it's involved with Parkinson's and Alzheimer's as well. So if you have lower, you know, central levels of VEGF, you could have more likely developing some of these other degenerative diseases. That's a good question. So again, I feel like I'm speaking in an area, even my retina colleagues here, the retinal ganglion cells, primarily the macula, have the highest oxygen need of some of the cells in the body. So even a slight decrease in oxygen, those cells are very, very sensitive to any alterations in oxygen. That I don't know. That I don't know. I mean, I would assume the photoreceptor is more so than the retina, the retinal ganglion cells. In fact, George Spath, who's a leading, you know, well-respected opinion leader in Glaucoma, was proposing doing some studies in PET scans and MRIs because the thought is, from a neurologic standpoint, that perhaps some of the changes that we see in retinal ganglion cell thinning and loss actually originates in, you know, the cortex. There's studies that show that if you injure the, is it the striate nuclei, you can affect because of axoplasmic flow, retrograde axoplasmic flow, you can see retinal nerve fiber loss that actually correlates to that loss that originated, or that insult that originated in the CNS, in the central cortex. And they don't know. We don't know where. You know, people propose that the insult is right at the optic, you know, right at the optic disc at the lamina crevosa. Other people propose that it's an insult to the dendritic processes. Another person will say, no, it's the axonal body. They don't know. I think what's pretty neat, I think you can relate when you see patients, is patients with Parkinson's disease can very often have block-homes looking nerves. And that's where they don't, you know, so even if you vasodilate, you can decrease perfusion.  So you're right, it's a very, very fine balance. And I don't have the answer to that. I don't even go into the reactive oxygen species and the oxidative stress. That's a whole other area based on endothelial dysfunction in nitric oxide levels. Thank you. Thank you very much.