If you are digitally contestable, you have to face it. Uber is a great example. I don't know if you know Uber. It's an on-demand taxi ride service that's peer-to-peer with independent contractors that you use to the app. You just hit the button and people turn up. So there's been lots of global unrest about Uber. In fact, it was just outlawed in Berlin last week for insurance, you know, I would say, lobby reasons. But the bottom line is this, right? If you're managing dissatisfaction, like most taxi drivers are, right, we're essentially not that satisfied with them, but what else are we going to do, right? Go to New York to figure this out. Managed dissatisfaction is not a sustainable business model. So the good exercise for your company is to go home and say, okay, let me look at all those things in my company that are sort of dissatisfying, that we're sort of navigating around, and then eradicate each one of them.


Proudly, we hail. From New York City, where the American stage begins, here is another program with a cast of outstanding players. Public service time has been made available by this station for your Army and your Air Force to bring you this story. As proudly we hail, the United States Army Engineer. Our story is entitled Floodwaters, a tale of courage and scientific skill backed by years of thrilling experience in the continuing battle of the rivers by the United States Army Engineers. Our first act curtain in just a moment, but first, young men, why not let a thought for tomorrow be your thought for today? Right now, your United States Army needs qualified technicians in such varied and interesting fields as radio, radar, meteorology, photography, and many, many others. Yes, you can be trained to do a job and acquire a skill that will be of great benefit to you for the rest of your life. You can also take pride in the fact that you answered your country's call in time of great need. Why not let a thought for tomorrow be your thought for today? Visit your nearest United States Army and United States Air Force Recruiting Station and enlist in the United States Army. And now, your Army and your Air Force present the proudly we hail production, Floodwaters. Quite an outfit, the Army Engineers. Give you cold, pure drinking water out of a lister bag before you know it. Sling a bridge across a gully or pontoons over a river before you can think of the right word for the job. Busy guys. Sometimes they're busier in peacetime than in war. That's a fact. Talk about service to your country. If there's one bunch who serve their country all the time, it's the United States Army Engineers. Cast your mind's eye over continental United States. Note the fine coasts, the great harbors on both east and west. Admire the forested beauty of the Appalachians. Earthworks ranging from Georgia to Maine. Gasp at the awesome granite peaks of the Rockies in the Sierra's battle-minted bastions that divide the continent from Mexico to Canada. This spectacle is the glamour of a continent. And in between, so unobtrusively in between, lie two-thirds of the nation, a storehouse for the world. Here is the golden grain of Kansas and Nebraska, the rustling corn stalks of Missouri and of course of Iowa. The russet orchards of Ohio and Indiana, the clover of Kentucky, the cotton of Mississippi and Alabama. This is the richest farmland on the earth. Deep, black, fruitful. And overall, within all, the life force of it all is the silver lace-like fan of the rivers. Call them by their names, those rivers. The lovely names that flow silver on the tongue like flowing water. Ohio and Missouri. Illinois and Wabash. Canadian and red. Cumberland and Tennessee. Platon, Arkansas. Yellowstone and Wachtawe. Manonga, Gila and Allegheny. Add them all together. Add their history, their cascading waters out of the mountains to the east and west. Run them all together into the greatest of them all. The loveliest in tradition and in liquid-sounding name, the Mississippi. These are the tributaries from mountain streams to deep-flowing highway for the steamboats. These give life to the Great Valley. Life and sometimes despair, destruction and death. Word that makes black headlines in the spring that clutches at the hearts of valley dwellers with blacker fear. Flood, the rivers loose out of their banks, out of their containing walls, drowning in the countryside, sweeping over the levees. The levees, banks of earth and concrete built by man to help nature. Miles and miles of sea wall up and down the valleys along the rivers. Whose hands put them there? Whose brain plant them? Whose genius devised these bulwarks on the rivers? The Corps of Engineers, United States Army, was first called upon to function in the conservation and development of streams for navigation under authority of an act of Congress approved April 30th, 1824. In addition to improving waterways and harbors and safeguarding navigable waters, the Corps of Engineers has been called upon to build highways and railroads and plan the development of streams in the interest of flood control, hydroelectric power development, pollution control and conservation. To plan the development of streams in the interest of flood control. The answer is in a half dozen words. The Corps of Engineers, United States Army, all things have their beginnings somewhere, perhaps deep in the shadows of history. 1824 is 128 years past, and yet the Corps of Engineers dates back well before that. June 16, 1775. May it resolve that there be one chief engineer for the Army in a separate department and two assistants under him by authority of the Continental Congress. June 16, 1775. The Department of Army Engineers created by act of Congress. The news was welcomed to a man named Washington for the next day, June 17, 1775. Dig a hole, carry the dirt, dump it here. As if it made a difference where we dump it. Perhaps it does. I didn't volunteer for this Army to dig holes and carry dirt. You'll have plenty of chance to use your musket for it.  I know, I know, but I don't see the plan. You don't have to. It works where they want them. Colonel Gridley has a plan. Gridley, who's he? Chief Engineer. It's said he chose this hill because it's easily defended. Command's all Boston. Maybe he's right about that. Hunker Hill was never much good for anything else. Right. So get busy with that shovel, friend. Hey, British aren't gonna wait for you, you know. And if we hold this hill, General Washington have time to organize against him. The first job of the Army Engineers is to organize the first real battle of our revolution, June 17, 1775, the Battle of Hunker Hill. But engineering must be learned, and learning calls for schools. General Washington knew the truth of this, and in the weary days at Valley Forge, his thoughts bore fruit. June 9, 1778, by order of the commanding general, three captains and nine lieutenants are wanted to officer the companies of sappers. As this corps will be a school of engineering, it opens a prospect to such gentlemen as enter and will pursue the necessary studies with diligence of becoming engineers and rising to the important employments attached to that profession, such as the direction of four to five places and so forth. The qualifications of the candidates are that they be natives and have knowledge of the mathematics and drawing, or at least be disposed to apply themselves to these studies. They will give in their names to headquarters. And so it began. Washington broke camp at Valley Forge and the school of engineers moved north to the storied shores above the Hudson River. And there it stayed until the day that Congress made it all official some 24 years later. By act of Congress, March 16, 1882, a corps of artillerists and engineers will establish a military academy for the study of their respective arts in the state of New York at West Point. West Point created of and by and for the army engineers. Their school, the first school of engineering in our history, the base from which the men went forth to serve their nation in both war and peace. Yes, peace. For the battle against nature is longer, wider and more deadly with a greater goal ahead than most any battle fought with guns. The engineers are in the forefront of this battle and have been there since it first began. The chronology is found in acts of Congress. The river and harbor acts beginning back in 1820 execution of a survey of the tributaries of the Mississippi west of the river and those northwest of the Ohio river is assigned to the corps of engineers. 1836 improvement of the Ohio river is assigned to the corps of engineers. 1850 funds are herewith approved for the survey of the Mississippi Delta by the corps of engineers. Over a hundred years have passed since then.  And yet the work begun in the 1850s is still the foundation of the battle of rivers waged today. The commanders in the field that spring of 1857 were Captain Andrew Humphries Lieutenant H.L. Abbott, corps of engineers, United States Army. Looks like a big job, Burger. Looks like a mighty big river, Captain. Not so big that it won't be controlled someday. Sir, if I may. Of course, Burger. Thank you, sir. See, I come from Missouri around the valley of the St. Francis River. That's why I volunteered for this job, sir. I thought maybe what we do here might help save our farm, sir. Well, I hope it will. A possible amount of water flowing into and through this Mississippi river and measure it accurately, we'll have laid the ground work for controlling floods almost forever. But fortune was against the engineers that time. In the summer of 1851 Captain Humphries was stricken with fever. He gave up his assignment and when his health returned went to Europe to study flood control over there. Six years later in 1857 Humphries was back at his job as enthusiastic as ever. At this time his enthusiasm was tempered with apprehension. What's bothering you, Andy? The size of the job, Hal, I guess. Well, I've never bothered you before. Well, fools go in. I didn't know as much in 51 as I know today. Well, all the more reason then for for peace of mind? On the contrary, Hal. Andy has shared worry as half a worry. Well, the laws on which we are basing this survey the laws of flowing water in natural channels are not based on good enough experience. But all through Europe they are. The rivers of Europe aren't the Mississippi basin, Hal. There's too much artificial channeling, canals and all. So the laws of hydraulics for rivers based on European observations may not hold true over here.  Well, I guess we are. I guess we are at that. I wonder if Congress realized that when they blessed the engineers with this project. It's possible. Maybe that's why they gave it to the engineers. One year later, Andrew Humphries and Hal Abbott had their chance to study the rampaging Mississippi at first hand. Word came to them. Captain Humphries, message from up river for you, sir. Ah, thank you. Hal. Hal, here it is. Here's what? It's our chance to do a real job. Message from Cairo, Illinois. Flood crest on Ohio threatening entire city. St. Francis River Valley underwater have sent warnings through to Memphis, Vicksburg and Natchez. Can you send us help? Hal, this is it. Sounds like the end of our work to me. It's the beginning. We're going to send all the help we can. And the men we station in those cities all along the river are going to take daily readings of water level, silt content, speed of the crest, everything we can think of. We're going to learn about a Mississippi flood at first hand. You are listening to the proudly we hail production, Flood Waters. We'll return to our story in just a moment. Today, you young men of America have an excellent opportunity to learn a trade that will assure your future. The many fine technical schools of the United States Army are training men in such interesting fields as radio, radar, meteorology, mechanics, electronics and many others. You can become a qualified technician trained to do an important job and do it right. For full details about an exciting career, visit your nearest United States Army and United States Air Force Recruiting Station. There's no obligation, so plan ahead. Face your tomorrow today. You are listening to Proudly We Hail and now we present the second act of Flood Waters. Report to the Congress of the United States and the Physics and Hydraulics of the Mississippi River by Captain Andrew Humphreys H. L. Abbott. It may be stated that laws governing the flow of water in natural channels have been determined which were never revealed before. New formulas have been prepared. Improved methods of gauging the amount of water in streams have been devised. This portion of our work exceeded even our expectations. Furthermore, it has been determined beyond a reasonable doubt that the bed of the Mississippi is formed of alluvial soil deposited by the river, but is a stiff, tenacious clay of an older geological formation. This fact is of the utmost importance in preparing plans for flood protection. In view of the work done and the experience obtained under actual flood conditions, we recommend the plan of levees. It is simple, direct and will protect the vast majority of alluvial bottom land in the Mississippi Valley.  A war between the states. But Andrew Humphries never let the battle of the rivers escape his mind for long. Or the minds of the men of the engineers charged with controlling the mighty waters of the Central Plains. With the war behind them, the work went forward once again. Humphries and Abbott both passed into memory. Year by year as Congress authorized the funds, the engineers fought on, driving back the rivers until at last in 1929. The Congress of the United States called upon the Army engineers to control the Mississippi River and its tributaries. 1945. 291 projects are authorized under a river and harbor act. Through years of history, through disaster, depression, prosperity or war, the battle of the rivers whose first blow was struck by two Army engineers in 1857 has been waged without cease and without rest. Day and night, year in year out the water flows. Cities grew and flourished. The forests gave way to open fields. The land prospered. The nation grew. And time and time again and time again the waters took back what they had given. Even life itself. The pictures of the silent swirling water or the roaring crashing crests. The pictures of the rooftops like so many Noah's arcs riding the rivers with their helpless human freight. The pictures of the wasted wrecked and helpless land in the Mississippi Valley all became too familiar to the people of the nation. 1927 was the worst. 20,000 miles of fertile plain ruin. 4 million acres of food destroyed. 600,000 people homeless. Damage in one city alone, in one house. Then it was the Congress gave the call. The Army engineers must control the Mississippi. What a job this is. Pal Joshua stopped the sun. We can stop a mere river, I suppose. Who do they think we are, Moses? If we could just see the whole thing at once. Get yourself an airplane, fella. Fly high enough and it'll all be laid out for you like a map. Hey, that's an idea. What's an idea? Lay it out like a map. You're nuts. Remember the old Humphrey's Abbott book on the Mississippi? They said the bed of the river is clay. They were right. Now suppose we build a model sort of a relief map of the valley with the main channels in concrete maybe. Then we turn in the water in the same proportion as the model is to the whole valley. We can see what happens when a flood comes down. Hey, you may have something there. May have something? What do you talk to? This idea will take toll. The engineers got the money and built the model. An exact reproduction of the river and the tributaries from Helena, Arkansas to the Gulf of Mexico. Every island, sandbar, obstruction, and bend of the rivers was there. Every detail of those hundreds of miles was reproduced in that 1,500 feet of model down near Vicksburg, Mississippi. And then they turned the water into it. I was right. You see, I was right. Stop growing and tell me what you were so right about. You see how the crest come down the valley? Of course. Now, what happens when it reaches the lower stretches of the river? Where all those bends and sandbars are. It, uh... Well, backs up. Sure, it backs up because the water can't escape through those bends as fast as it coming down. Okay, what happens? We slow down the crest? You're kidding. No one slows down the crest of a flood. We do let it through faster, so it won't back up. Hey, you mean we straighten out the Mississippi? Exactly. We straighten out the Mississippi. Yes, the engineers took over Old Man River and gave them a face-lifting. They made them flow a straight, true course from Helena to the Gulf. Removed 120 miles of bends and bars and other obstacles. The current moves quite swiftly now. When there are floods above Helena, the crest moves down the river, never backing up and pouring over dams and levees the way it used to. And this has been proved true. Proven before the work was completed. Proven in the upper valley in 1937. January of 1937 saw six inches of rain fall on the valley of the Ohio within two days. Half the years, full quote of rain fell in just 25 days. On the 24th of January, the call went out to all amateur radio operators this wavelength. Stand by. Important communications from District of Army Engineers. Stand by. This is the message. You are ordered mobilized to maintain communications under the Chief of Engineers in flooded areas. You are ordered mobilized to maintain communications in flooded areas. The fight was on. Wires down, roads out, railroads ruined. Communications were maintained by amateur short wave radio men. Thousands of men fought seepage and sand boils on the levees. Grimly, without rest, weary until they dropped. Citizens and soldiers fought the river side by side. Below Helena, all was well. The levees held. Almost no water backed up into the tributaries of the straightened river. Above Helena, it was bad. Cairo, Illinois, where the Ohio joins the Mississippi, felt herself safe behind a sea wall 60 feet in height. Headquarters of the fight was at the office of District Army Engineer. From there, the orders flashed. And grim-faced men rolled into action on the roads of Missouri a few miles south of Cairo. What's up out there?  What for? Levees holding? We know, but not for long. Why not? Good, built wall, that levee. We can't waste time. Water's 58 feet at Cairo and more coming. Engineers have to blow the fuse between Bird's Point and New Madrid. You're living in the spillway. Okay, soldier. I know when I got to get. Have I got half an hour? Just about. Good luck, mister. Hey, soldier! Don't forget to stop by the Kromitz Place. Army Engineers. District Engineer, Cairo. When can you blow the fuse? Anytime you say, sir. Is the spillway clear? As far as we know, sir. Rescue boats will follow the water into the area. And blow it now. River's rising here. It's almost 59 feet now. Yes, sir. Stand by the plunger, fellows. Here we go. All set. Ready? Fire! They blew the fuse plug in the levee at the Bird's Point, New Madrid, floodway. Water raced through the gap, spreading its muddy flood over 131,000 acres of Missouri. The crest raw had passed Cairo down the valley, but the pressure was relieved. Not one engineer built levee crumbled. The danger was passed. The water slowly receded. On February 12, 1937, by proclamation of the mayor of Cairo, Illinois, with the consent of the United States Army Engineers in charge, I hereby proclaim the removal of all restrictions and requests made as to the leaving and entering of this city and the transmission of business. And as the mayor's words returned the city and its people to a normal life, by a strange coincidence, the marquee on a moving picture theater announced for all to see. Opening Wednesday, Rainbow on the River. Rainbow on the River, yes. A rainbow whose colors are the dungary blue and olive drab of the United States Army Engineers. But this is a battle whose end is not quite yet. The waters still flow down from Minnesota and Wisconsin, Montana and Colorado, Pennsylvania and Ohio, and so the work goes on. Fought on the river banks with concrete blankets, pontoons, derricks and the ever-present sandbag. The work goes on near Jackson, Mississippi. What's going on, even as the comrades of these Army Engineers were fighting out ahead of other troops in Europe, the Pacific, all around the world. For a Jackson with pick and shovel, Wheelbarrow and Gunny Sack was building the greatest project of its kind the world has ever seen. 4,500 feet it runs, east and west, 3,500 north and south, 200 acres overall, a gigantic, true-scale model of the central plain of these United States. The entire Mississippi basin, nature duplicated will be there for men to study and control. The mightiest of rivers reduced to size that man can handle, turning on and off the water as the rains and snows fall far to the north. Here, on this model, homes will be protected, lives saved, and the valleys kept fertile for the good of the people in whose service this battle is waged by the Army Engineers. Called them by their liquid-sounding names, rivers who have not all been bound, constricted hand and foot, as they will be someday in the future. Call them Wash-Tor, Cumberland and Platt, call them Illinois, Wabash, Monongahela, sing songs of rivers and the good they bear upon their glowing bosoms, love their beauty and their silver quiet, weave memories around the willows on their banks, and romance round their levees. Yes, name them, love them, and always deep within your hearts. Remember those who fought more than a hundred years to keep them flowing in their places, forever bringing fertile wealth to the great plain of this nation. Remember, the Army Engineers! This message is of vital importance to every American, but it's particularly important to the young men who are listening. For today, the rapidly expanding United States Army is depending on you to do a vitally important job. Qualified technicians are needed, and the Army is prepared to train you in one of the interesting career fields necessary to its operation. You can become a radio or radar technician. You can study meteorology, mechanics, electronics, photography, and many others. Yes, the finest technical training schools in the world will be available to you when you enlist in the United States Army. Why not visit your nearest United States Army and United States Air Force Recruiting Station today? The need is urgent. This has been another program on Proudly We Hail, presented transcribed in cooperation with this station. Proudly We Hail is produced by the Recruiting Publicity Bureau for the United States Army and United States Air Force Recruiting Service. This is Kenneth Bangward speaking and inviting you to tune in this same station next week for another interesting story on Proudly We Hail.


module 58, production function. Production function basically refers to the physical relationship between output and input. It basically depicts how a different level of output can be produced by using different quantities of input. Now to understand this, if we assume that Firm is producing output that we are denoting with y. And for the production of that particular output, Firm is using n different inputs. And in the form of a functional association, I am depicting that y is a function of x1, x2, x3 up to xn. And when this functional association is denoting y in the output, x1 denotes quantity of input factor 1, x2 denotes quantity of input factor 2, or the same way up to xn denotes quantity of input factor n. We measure the output and input here in physical units. How will I measure the output? If I talk about weight, it might be possible we are measuring the quantity of output of weight in the form of months. If I talk about milk here, then it might be possible we are talking about the quantity of output of milk in the form of liters. If I talk about inputs in the same pattern, then how will we denote those inputs by using their physical units? If I talk about fertilizer, then how will I measure fertilizer? It might be possible we are measuring the quantity of fertilizer in the form of pounds. How many pounds of fertilizer is used to produce output? When you talk about milk, it might be possible we are using here an input in the form of fodder. And which form of fodder will I measure? It might be possible I am also measuring the quantity of chara in the form of months. If we use chara, then how much output will be produced in a particular form? If there is, what we do is to study the association between output and input. We do that there is only one variable factor of input while we keep the quantity of other inputs constant. Sometimes instead of varying all the inputs, we talk about there is only variation in one input. Then what will we say? Suppose I am writing in this function, output is a function of labour for given amount of capital, land and management. Here there is only one factor that is variable factor production, that is labour. When we assume capital, land and management, we are using the given quantities of those inputs. And I move a little bit specifically that the output of a wheat is a function of fertilizer against the given quantities of seed, land, labour, capital, number of plowing and watering and many other inputs. Now what I am denoting here is that this bar basically separates the inputs, first input with other input. What we have separated from the first input is that first input is a variable input while all other inputs are given. We can represent this production function in the form of a schedule. And what does that schedule indicate? Again this schedule basically depicts an association between output and one variable input factor while we keep the quantities of other inputs as given quantity. My assumption here is that output of wheat is a function of fertilizer against the given quantities of all other inputs. And this hypothetical schedule indicates that if a farmer is using 0 pounds per hectare of fertilizer, then there is 0 months of wheat per hectare. If farmer chooses 50 pounds of fertilizer, then he is in a position to produce 10 months of wheat per hectare. What we are observing here is that there is some association between output that is wheat per unit of land. We are measuring the quantity of wheat in months and we are basically reporting here production of wheat per hectare. And one thing that you can observe here is that there is some association between these two variables. The quantity of input is increasing, the output is increasing. But at one stage, when we are using too much quantity of one input, keeping the quantity of other inputs constant, it might be possible that there is a decrease in output. Now you might have understood what is the production function. Production function is a physical association between output and inputs. But to simplify things, we have explained this association here in a table form, by wearing one quantity of one input only while keeping the quantity of other inputs constant.


Hello, I'm Roberto Parisserma and I'm going to present Efficient Musics for Algebraic Studies. This is a joint work with Prof. Pnajoto, Elgar Lipma, and Arneto Diaz-Oderberg. A language associated to a relational heart is defined by the set of statement axes for which there exists a witness such that the statement witness is in the relation. Not in the language would be called as true statement, element not in the language would be called as false statement. An interactive zero-knowledge proof is a protocol initiated by two parties. One of them, the pruber, has an input-to-pay statement witness, has to convince Diaz-Oder, the verifier, that is, as the witness, without revealing any additional information. The parties exchange interaction and the verifier, at the end, having an input-to-statement and the whole set of messages, which is also called proof, has to out-put-accept or reject. And it out-put-accepts if it convinces that the verifier knows the witness. We require those protocols to enjoy the following three properties. They have to be complete, which means that honest pruber always convinces the verifier. They have to be sound, which means that malicious pruber cannot convince the verifier. Particularly, it should be impossible to make the verifier accept for any false statement, and they have to be zero-knowledge in the sense that, at the end of the interaction, the verifier cannot learn anything about the witness. We are also interactive in non-interactive zero-knowledge proof, which are a particular kind of zero-knowledge proof that consists only of one message sent by the pruber to the verifier, which has only to output-accept or reject. We are interested in a non-interactive zero-knowledge proof, which we shortly called musics, not only because verification is possible even when the pruber is offline, but also because they are used in many applications and they are used as a primitive to build more complex cryptographic tools. However, in order to define a musics, we must oppose the existence of a trusted third party that computes and make available to both pruber and verifier a common reference link or shortly CRS. For instance, this CRS can be the description of a Nash function, or an element from some distributions, or, as in our case, an element sent from the universal distribution over a cryptographic group. And the existence of this trusted third party is necessary in order to define musics which are sort of sound and complete. Let's move on with an overview of the existing musics construction and let's compare them in terms of efficiency, competitiveness, and security, and at the end, I also compare our new musics construction to show how it performs compared to the other. The first musics construction is due to Fiat and Shamir, and their core idea is a compiler that define a musics from a particular class of three-round public coin interactive proof of knowledge, which is called Sigma Protocols. Their compiler uses cryptographic hash functions. So those musics have all the advantages of the underlying Sigma Protocol, which means that they performs very well in terms of efficiency and expressivity. In fact, for many applications, they are still the most efficient musics we have, and they are defined for all MP languages. However, their security is defined only in the random oracle model, where we model the cryptographic hash function as a truly random oracle. It took quite a while before GLUT and TENSAI were able to define musics from standard well-established cryptographic assumptions. Those musics were an outstanding result, however, they had some limitation, which makes them sometimes impossible to be used in practice. First of all, they are often just not efficient enough, and then they are defined only for payment product equation, which means that in order to define a GLUT sign using four specific applications, one must first find the representation of a given problem as a set of payment product equation, which sometimes is a very hard task. Lastly, recently, Kuto and Artman developed a new framework for defining musics. Their idea is a compiler that, as for future metastore, define musics from Sigma Protocol. However, their compiler only works for a specific Sigma Protocol. So even though those musics have some very few features such as efficiency comparable to fiascia metastore for some application, they also have some critical limitations. For instance, they are defined only for algebraic languages, which is a very restricted class of languages. Moreover, their assumption is based on a novel x-temp VH assumption, which can be a problem because it was a novel assumption, and maybe it was also not enough motivated to the original paper. Finally, with our music, we built on top of the framework, and we overcome their main limitations. So, we define musics that performs slightly better than C8 musics for most of the application. But more important, our musics are defined for algebraic sense, which are, I would say, a wide, expressive class of languages. But also, it relies on C8 in the assumption, which is less a weaker version of the x-temp VH assumption that I will define later. So in the rest of this presentation, now that I give you a motivation of why our result is needed, I move on to present our result in details. Let's first start with some notation. I use bracket notation, so I actually assumed in this paper that we are using type 3 pages, which means that we suppose no efficient isomorphism exists between group 1 and group 2. We use bracket notation, so x in bracket is the exponentiation of x with respect to a pixel generator. This big circle is indicated for the paving operation. We indicate vector with this arrow, and we indicate matrices with upper letters with no arrows. We also need some preliminaries from CUTO and Dartmouth paper. So as I said before, their idea is to take a compiler that define a music from one specific Sigma protocol. Here in figure, I just sketched some of the peculiarities of the Sigma protocol, which are required in order to understand how their compiler works. So the statement and the first message are vectors of group elements, the witness and the third message are vectors of file elements, and the challenge is one single file element. And the verification question is linear. The core idea of CH20 is taking the challenge embedded in group 2 and publish it once and forward in the CRS. So now the compiler will compute the first message as before, and intuitively, since it has the challenge already in group 2, it cannot explore this knowledge in order to achieve it. Then it will compute the second message, the third message directly in group 2, and it will send the proof, or leave one message to the verifier, which now performs the same verification equation, but using Baylicks. And as I mentioned before, this music is sound under the novel x-carenvh function. So those musics enjoy some very appealing features. I would say that most of all, they have some very efficient music for specific applications with efficiency comparison to fiat-shaming musics. However, they have some critical limitations. The first issue arises with the assumption. So first of all, the x-carenvh assumption is not always a classifiable assumption. Basically, they have classifiable x-carenvh only for all of linear languages. And then the assumption is not studied enough. Actually, Kuto and Dartmouth pointed out the assumption is trivially secure in GGM. Most important, those musics are limited to algebraic languages, which are, in principle, not as expressive as Baylick's product equation, and as Baylick's product equation, to find representation of a given problem as an algebraic language is an ARC's task, which requires several hours of work from dedicated exercises. It will be much more considerable to have a framework to define a music directly and automatically from an IP level description of a given application. With our work, we overcome those limitations. First of all, our main idea is to define a different noble sigma protocol and then apply the CH compiler to the sigma protocol in order to define a new music. Actually, the sigma protocol is not explicitly defined in the conference version of the paper, but the sigma protocol can be found in the full version of the paper. In the conference version, we just define the inactive music resulting from CH compilation. So, the reason why we were able to overcome the previous limitation was the following. First of all, we relied on a CAD assumption, which is a weaker flavor of the X-CAN MDH assumption. Here, we use weaker in the sense that stronger conditions are required for the adversary in order to win the underlying security game. Using the CAD assumption, we were able to show that more cases are based on falsifiable CAD, and also, even in the general case where CAD is non-facifiable, we were able to reduce CAD to a single and very plausible gap assumption. But more important, instead of algebraic languages, our sigma protocol and to our music relies on algebraic sets. So, algebraic sets are well-studied in classical algebra, and we know many properties, and we can use this property in our paper in order to define music for a wide class of languages and application. One important property is that it is possible to reduce circuit satisfiability to membership of some algebraic sets efficiently, as we pointed out in the paper. But more important, maybe, using algebraic set, we are able to define directly and almost automatically music from a very IP-level description of a given problem. Let's now define formally how our languages are defined. So, first, we pick a finite set of polynomials over a finite file. An algebraic set is the set of axes such that f of x is equal to zero for each f that are part of the set of the polynomial we have chosen before. Then, we choose a publicly linear-neumomorphic encryption scheme, and the language is defined by the algebraic set and the encryption scheme as an encryption of an x that is in the algebraic set. So, an element in the language could be an encryption of a common root of a given public set of finite polynomials. As I said before, our main contribution is a framework to define directly and music from a very IP-level description of a given application. So, let's start with the first point of this framework. The first task of this framework, which is find a good basis for the algebraic set. An algebraic set can be seen as an idea in a polynomial ring. So, from classical algebra, we know that many algorithms are known to find a basis of ideal in the polynomial ring. We have to run one of those algorithms only once to find a good basis of the algebraic set. We point out that this is a non-critographic problem, and this is not solved, but we have methods to find a solution that is efficient enough for many interesting applications. And digging into this problem is beyond the scope of this paper. So, the language is defined by encryption, as I said before, encryption of element axis, such that f of x is equal to zero for each polynomial that form the basis of a given algebraic set. The second step is now to define a music given a base of an algebraic set to completely and almost automatically solve this second point is our main technical contribution. And this is what I will explain now in this presentation. For the sake of clarity, throughout the rest of the presentation, I just pick with the simplest case of algebraic set generated by one single polynomial. The generalization will just be trivial and can be found in the paper. So, we choose to use Elgamal's Dlean Encryption Scheme, but actually any publicly Dleaner Leomomorphic Encryption Scheme sub-piece in order to instantiate our music. We use those two because with Elgamal we have the best efficiency, and with the Dlean Encryption Scheme we have some music with some properties that we'll present later. In order to define a music, we have to solve three steps separately. The first one is to define a possibly small affine matrix C of x, such that the determinant of C of x is equal to the given polynomial f of x with some properties on top of that. The second step is to define an efficiency map protocol to show that the determinant of C of x is equal to zero given an encryption of x. And the third step is to use CH compiler to define a music. As I said before, the second step is not explicitly defined in this paper, but interested reader can find the sigma protocol in the full version of the paper. So, to explain the first point how to define this matrix C of x, let's start with the definition of the quasi-determinant representation. A given matrix is a quasi-determinant representation or short QDR of a given polynomial f if it enjoys the following property. First, each entry is an affine map of the given f, then the determinant C of x is equal to f of x, and note that those two properties define the well-known notion of matrices in the determinant representation of a given polynomial. But on top of that, we require these third properties. If we say that the first column of C is H and the rest of the matrix is T, we require this first column dependent. So, for each f that is actually a root, f, we require that H of x is in the span of the other columns of the matrix, of course, evaluated in the given x. An intuition why those properties are needed in order to define our matrix. The matrix has to be affine because the verified will only have an encryption of x, and it has to homomorphically compute an encryption of C of x given the encryption of x. The properties that the determinant of C of x is equal to f of x is needed in order to guarantee soundness. Roughly speaking, if x is a false statement, then f of x is not equal to 0, which by this property means C of x is correct, which means that we are able to break the underlying K and D H-based assumption. And finally, the third property, the first column dependent, is a technical detail needed in order to ensure that the honest bloomer is efficient. Okay, so far, another viewer could aptly think that finding a QDR matrix could be just a task as finding an algebraic representation or a parent product equation representation. Even worse, if it is known that many interesting polynomial are a bit determinant representation, maybe those results doesn't carry out through the less general requirement for QDR form. We show that this is not the case, defining a QDR matrix directly from an algebraic branching program, or ADP. An ADP is a directed acyclic graph with two vertices, S and T, and the labeling function feed, such that feed assigns an affine function to each edges. And a polynomial, f of x associated to the ADP, is computed taking the sum over all the possible paths from S to T of the product of the label across the path. Here a simple example, so f of xy is a b-variate polynomial, which is equal to x to the third plus a x plus b minus y square. And we can see that x square is the product over edges of the blue path, a x is the product of edges of the green path, b on the red path, and minus y square on the black path. We are able to deterministically and efficiently define a QDR matrix from an ADP. As it was already known, we started from the adjacent semantics of the graph, we remove the corresponding to the vertex F, we remove the row corresponding to the vertex and we have a matrix which is a determinant form of the given polynomial. That is already known. Then, on top of that, we just noted that if we replace zero with minus one on the lower diagonal, we have a matrix in QDR form. So, at best of our knowledge, defining an easy directly and deterministically from a very simple representation of an ADP is a useful and good result, and different from previous construction of musics doesn't require dedicated expertise. Now, I can show in the test how our musics is defined. So, the language, the statement would be an encryption of a given element under random SR such that the determinant of c computed evaluated in that element is equal to zero and the witness would be the element key and the randomness R. The zero R as I said before would be a uniform in random element in group two. The brewer will have the statement witness and CRS, the verifier is only CRS and the statement, so the encryption. So, the brewer act in the following way. First, it uses two algorithm to compute two vector gamma and theta. Gamma is computed using the description of c and only x as input. Delta is computed using as additional input some internal states and the challenge. Then the proof will consist of gamma in group one and delta in group two. And I point out again that the first column dependence that we require for our matrix, it is needed in order to ensure that those two algorithms are efficient. So, particularly this property ensures that the brewer is able to efficiently compute gamma independently from c. Then gamma and theta and delta has to verify the verification question that we found here in the right bottom of the slide. So, gamma plus c of x times e concatenated to delta must be equal to zero. And verify, we just check this verification equation using papers. Of course, that was a mock version of our music. Now we can see the figure out the music is actually defined. The first, the real first message would be an encryption of gamma on freshly generated randomness. The real third message would be delta computed in group two because the prover has the challenge e only group two. And some auxiliary element z also computed in group two. And verify instead of checking the plain verification question without going too much into details, just check an encrypted version of the verification equation using the dos element z in order to eliminate randomizers. Soundness can prove under the x KMDH assumption, which basically is an extension of the well-known external KMDH assumption. As for the case of KMDH assumption, we received an input in group two, and we have to have the matrix in group one, such that the input is the kernel of the matrix, and the matrix is of rank i nine. But in this case, we allow the adversary the power to expand the vector it receives as input. So this gamma in group two will actually be the extension of the input. And the adversary can extend this vector as long as for each element it added, it also outputs an additional element in group one. So as long as an high enough number of vectors in group one are linearly dependent, then in order to compute them, the adversary must have found no trigger relation between input in group two and output in group one, and this should be i. And so we say that the adversary needs to again, if it outputs this matrix gamma to the concatenated c, such that the extended vector the concatenated gamma is in its kernel, and the rank of this matrix in group one is i nine. In in our case is n. Why is this a bit for soundness? Well, because if x is a full statement, then c of x has rank n, and then the grid adversary of the verification equation can be used to ensure that the adversary breaks the x kernel dh assumption. But actually, we require weaker condition in order to guarantee soundness, because we only require that the rank of c is equal to n. So previously, we say that the adversary wins if rank of gamma concatenated c is equal to n. While for soundness, it's a piece that the adversary wins only if rank of c is equal to n. Which means that we actually don't need the full power of the x kernel dh assumption, but only a weaker person of it. That is a piece of for soundness of our music argument. And that's why we introduce the cad assumptions. So here I just record briefly that we are in type 3 paintings. So the game is the same as the game for the x kernel dh. We sample the challenge. We give its vectoring loop 2 to the adversary. The adversary computed a matrix in loop 1 and an extension of the inputting loop 2. And the adversary wins the game if the extended battery is in the kernel of the matrix in loop 1, and the rank of c is equal to n. Using the set assumption means that we can guarantee better security condition. First of all, more cases are basic and falsifiable cad. Because basically every time we can check that given matrix c of x is full rank, given x as a loop element, we have falsifiable cad. For instance, every time f is a product of a fine function, we can efficiently check that f of x is equal to 0 given x as a loop element. And so those cases are always basic and falsifiable cad. Another case is that the algebraic set itself has only a polynomial number of elements, which is for instance the case of univariate polynomials. So univariate algebraic sets generated by univariate polynomials are sound under falsifiable cad. And our musics for those sets are sound under falsifiable cad. In the general case where cad is not falsifiable, we were able to reduce it to a single plausible cap assumption. A cap assumption is an assumption of the following time. Say that a given problem is easy, this doesn't mean that another given problem is easy too. In our case, we use the following cap assumption. If cdh is in group one, it doesn't mean that cannon dh is also easy too. This is a very plausible assumption that depends where exploiting some regularity in group one should not carry out in exploiting the same in group two. And lastly, slightly modifying our construction, we were able to show music to design a music based on falsifiable cad for each languages. Of course, this comes at the cost of efficiency. First of all, we have to use the less efficient real encryption scheme. And this is because the way we rely on falsifiable cad is because we force the prover to add additional elements and we check that f of x is equal to zero given an arithmetic circuit of the gate of the group two, that computes f of x, which means that we have to force the prover to output encryption of x group two, and that's why we need the real encryption schemes. So to show the goodness of our method, we have some applications of course. So we have to the best of our knowledge, the best music for set membership in term of efficiency of prover and purifier and also communication complexity. We also have very efficient music to show that a point belongs to a given analytic group, which is an application needed for some scenarios in blockchains and critical currencies. And we also have some very efficient musics for circuit satisfiability to the best of our knowledge. Those are the most efficient musics in a standard model for circuit satisfiability. As a side result, we also have a better representation of some algebraic languages with better year I mean shorter than the biggest state of art representation, which actually means we are better efficiency for primitive likes smooth project functions. But also we need that one of the very good selling point of our paper is its generality and how easy it is to define efficient music. So we hope that as it was the case for good side music, more application will come in the future. At the end, I have some concrete efficiency campaigns. For example, in this case, we have numbers for set membership proof musics where here we just embedded the set membership problem as a membership of an algebraic set generated by a univariate polynomial. So in the case of good side music, we didn't add proven verification complexity because numbers are not published. They are based on our estimation, but we can see how we prove also in the sides of communication complexity. Maybe it's not easy to see at the first slide, but let's recall that usually elementing group two are twice as long as elementing group one. So here the first line is for Optimized Prootzai proof for set membership. The second line is for previous state of art CH20 music. The third line is using directly CH20 with our new algebraic languages construction. And finally, the third line is our music. Another example, the comparison of musics based on falsifiable assumption for Boolean circuit satisfiability. Here, for example, we can see that we say several elements, particularly in group two. First of all, let's point out that the commitment, which in this case is the statement, in the case of groups I is to be given in both group one and group two, while in our case has to be given only in group one. So we actually just save a lot by that. And also the prover is more efficient. And also the computational complexity is way better. Thanks for your attention. And I hope you will find the paper interesting. And if you can, you can also find for the full version of the print.


This is an exciting time for the Canada Science Technology Museum Corporation as we look forward to launching the new Canada Science Technology Museum this fall. By the time it reopens in November 2017, a mere three years will have elapsed. This, as anyone will tell you, is nearly unheard of, timeline to decontaminate, empty, demolish a building, then rebuild and update the entire National Museum and its contents. The renewed Canada Science Technology Museum will feature 10 brand new highly interactive exhibitions. Among them, From Earth to Us, Steam a World Emotion, Technology in Our Lives, Medical Sensation and Zoom. Visitors' favorites will return, including a refreshed crazy kitchen and the museum's collection of steam locomotives. In addition, the museum will be showcasing its outstanding collection in the new artifact gallery, which will use augmented reality to connect with museum visitors. Either important features of the new museum will include a demonstration stage, classrooms and a makerspace. We're also working on the plans and design for a new collection Conservation Centre to properly house and maintain the National Science Technology Collection. A plan is currently in the works to develop a centre into shared facilities in consultation with the Canadian Conservation Institute and the National Gallery of Canada. The long-term vision for the centre is to expand as needed as the corporation's collection of Canada's scientific and technological heritage grows. There's just as much to celebrate at the Canada Agriculture and Food Museum and the Canada Aviation and Space Museum. Both institutions have continued to innovate along with Canada Science Technology Museum when it comes to engaging with visitors across Canada and around the world. One of the key ways in which our three museums connect with visitors is through exhibitions on-site, online and travelling. This past year, exciting new exhibitions and displays were, of course, presented at the museums and on our website, but they also travelled as far afield as Northwest Territories, Nunavut and Mexico City. We have also continued to develop new educates. These are made available to teachers across the country. These ever-popular resources help teachers present scientific principles from circuitry to principles of flight in an engaging way. I'm pleased to say that with the help of sponsors, we have been able to send educates to distant schools and northern communities as far as Nunavut. In addition to the educates, the museum offers a wide range of educational tools online tailor-made to support Canadian curriculum. And as benefits of organizations focused on technological innovation, we're also active in the visual world. This year, we produced highly popular apps on First World War flying aces and bees, introducing players to solid scientific and historical content in a fun way, in a space in which they feel comfortable. Equally important when it comes to digital innovation is a corporation's open heritage initiative, which makes our collections and documents readily available online. Rounding out our efforts to engage with Canadians wherever they may be, we have continued to create stories for Innovation 150.ca. In addition, we loan artifacts across the country and around the world and have taken our science mobile to a number of locations. We have also launched publications, produced discussion panels and delivered conferences, presentations both nationally and internationally. Partnerships also continue to be the mainstay of everything we do. Without partners, today's museum would not be able to deliver as many programs and services as they do. In addition to support from Canada's government and other federal institutions, we work with a wide range of corporations, companies and individuals. A complete list is provided in the sponsorship and partnership section of this report. Science and technology have been always felt welcoming to certain sectors of society. Chief among these are women and girls. As a result, we are currently trying to make science, technology, engineering and math STEM a more attractive option to this half of our population. We are doing this through videos and upcoming documentary series on women's scientific and technological achievements. We have established a STEM-themed fellowship at the University of Ottawa and we are researching content for women in STEM traveling display while also continuing to network with other stakeholders. In an effort to engage Indigenous peoples and showcase their ingenuity, we have undertaken consultations on collaborative research, collection development and exhibitions. This has resulted in integration of Indigenous elements in our galleries and the exploration of potential exhibitions and other initiatives on topics such as Indigenous astronomy and Algonquin cuisine. Youth are another important focus. They are the future of science and technology and we continue to encourage their interest and engagement. In addition to developing compelling programs and tools, often direct input from youth, we have launched an innovation influencers group. We have also created a STEM Horizon Award program designed to support youth education in science and technology. And we continue to engage with youth on their own terms through apps, social media and recent Facebook live events on climate change. The future remains bright for the corporation as three outstanding museums from physical renewals to new ways of delivering content. Our museums remain at the cutting edge of what's possible. Some of this innovation was spearheaded by our former president and CEO, Alex Binney. As we look ahead, it will be a pleasure to continue on the projects and initiatives he has set in motion while also continuing to innovate as we share Canada's remarkable scientific and technological heritage with the wider world.


minute hall walk better. It prevents the decline So I endorse that Um, and we know that this disease is not linear in its progression And so probably when we're doing testing we may need to do testing more frequently You know at a certain point in time So you can see here people are pretty stable on this curve functionally We're here people are falling off the curve. And so probably as people progress We may need to change the frequency by which we monitor patients Frailty very very common in these individuals. This is what we call the clinical frailty score you After the dollhouse university one to nine and you can pick and this was Evaluated by the group in canada and sir cart failure and you can see there were people here who are not frail in a cfs one to three Pre frail four to six and frail and everything about them was uh much different, but interestingly Turntiles of frailty score were independent predictors of You know outcomes in these patients independent of their amyloid stage in new york art class and treatment with tifamidus We've actually become really interested in this which is called the short physical performance battery in my lab So this is a marker of physical function involves three items It's uh your balance. Can you uh, can you um Can you put your feet together and hold it for 10 seconds? Can you put one foot slightly in front of the older hand 10 seconds? Can you do a tandem for 10 seconds? You got four points if you can do all of that Second is we do gate speed right in meters per second And then the final thing we do is chair stands So the reason we like this is we don't have to get a hallway We don't have to block off things and so forth it takes about you know five or ten minutes to do And it's very very predictive of what happens to patients For those of you who read the rehab hf trial in the new england journal delaying kitsman use this as the primary endpoint So these are data just from our center that we are collecting you can see and here in attr patients One of the biggest problems they have is the chair stands. They have a lot of someone was mentioning muscle Loss before but they seem to do much worse and we're measuring it in scan np as well Um laboratory tests. We have lots of biomarkers and we can easily not only risk stratify patients, but we can follow them so These are the two staging systems one developed by martha grogan using a nt pro bmp above or below 3000 and troponin t above 0.05 And the other staging system is the gilmore staging system Which uses the same nt pro bmp cutoff but an egfr renal dysfunction above or below 45 So you can tell someone you know your early middle or late I would make sure patients want to know their prognosis before you tell them right many people don't want to know Often the wife wants to know but not the husband, you know, you got to be a little sensitive to all this It turns out these no surprise biomarkers are highly prognostic over time. And so you can see here These are changes in the next stage at six months one year in two years Stage changes people do worse and you can see the hazard ratios here for changes in nt pro bmp So a 10 point change in their nt pro bmp and the weekend call on saturday Oh, so what does it mean it went from a thousand to a thousand ten is it means nothing right, you know But a 500 a thousand or two thousand point change those really have a meaning for patients um If you really want to get into the weeds it turns out uric acid is really high in these patients and it's prognostic independent of their diuretics maybe sglt twos will modify that risk because they lower your uric acid And um, if you want to prove to a patient that defaminus is working They always want to know is it working you just measure their prealbum and before they take defaminus And after and it goes through the roof Obviously if we start silencer based therapy, the prealbums are going to go down It's going to be confusing But these are the changes that we see um in patients that we published on um, and then Not finally, but we can always use, you know, all these sophisticated, uh, cardiac testing. So, um, ekg's well, there's lots of afib There's lots of conduction disease and then there's A low lowering voltage over time and these are some of the findings that you could look at and see Um, this is the data I showed you about claudio rapetsis about who needs a pacemaker So pretty common. I think that's going to be the new horizon These drugs work seemingly well for heart failure But they're not really affecting in my experience patients risk of afib and the risk of needing a pacemaker So it's just that they're just plotting along in that regard Um, this is what my nurse practitioner won the heart failure society nursing award for we stuck xyle patches on 50 patients Expecting to see lots of heart block. We saw a nuance at afib and about 8% new heart block that was bad enough that we're like, hey, buddy, you should come in You had an eight second pause. You need a pacemaker like soon in eight percent So a yield of about 15% and ugly Hair raising. Oh my god. What's happening vt in like 70% and that has no prognostic significance So you can order this test, but you better be prepared not to start sticking a defibrillator because you're going to put a defibrillator in 7 out of 10 amyloid patients Because they have a lot of vt So, um, I think there's a useful thing to do and the frequencies probably should be modulated based on how You know severe the phenotype is Um, uh, what can we do to measure amyloid loads? So patients always want to know how much amyloid do I have and where is it what's happening? And the answer is this is not yet. I think ready for primetime outside of research But these are the things we could do and as you can see as we do more and more It'll get more and more costly and will be less widely available. But if we're going to spend A quarter of a million dollars a year a half a million dollars a year we may end up needing to get some tests To figure out are things really better or worse in this regard So, um, these are the data from the ATTR act trial just to share with you. This is the wall thickness change between tefaminis and placebo We're talking about less than a millimeter change in both So you could stare at the wall thickness and if the patient is asking you what their wall thickness is you can tell them But I usually say if your wall thickness changed a lot on the echo It's because a different reader read your echo not because your wall thickness changed because this is over 30 months It's less than a millimeter right in in hundreds of patients. So you can't use that EF didn't change stroke volume is where the money is as I said, but you could look at that But these are pretty small changes of you know over a long period of time And gls everyone talks about didn't change It turns out that the things that did change are circumferential and radial mid-strain So we're not even measuring those usually clinically, but we could look Um, uh, maybe quantitative bone Syntigraphy is a good idea You know, there are ways using ct to quantitate and these are provocative data from a center showing that This the the p yp scan with ct Quantification and so forth tended to change over time. Maybe that'll be a marker But we're just starting to I don't have a lot of confidence per se in that There's also these reports that are coming out with silencers Particularly that p yp scans can become negative right to go from grade three to grade, you know a half So um I'll touch upon that in a minute. These are data from the knack to the left with patisserie Patisserie didn't change the ecv whereas patients who got placebo they got worse So things weren't getting better But you could use ecv and these are data from a center also looking at To famines versus historical controls where they also measured mri and there were some changes But these changes are pretty small on group averages. Maybe as you're following an individual patient. It could hold some promise These pet imaging agents. I think are really where the money is going to be So this is floor beta pier and then to the right is what we're using a columbia A compound made by jonathan wall It's a small peptide that he's labeled with i124 and it images amyloid all throughout the body In every organ and you can get really fantastic images and then you can quantify How often will we do this? Once every few years is my sense, right? I don't think it's going to be like sarcoid that it's going to melt away in three months, you know with just steroids But this is an interesting patient. I just point out Who we had in the helios a trial and we argument here is we're going to need multimodal imaging So if you can see in the upper here's his baseline. You can see he's got a pyp. That's positive, right? He's got You know a clear grade three scan and you can see on spec. There's you know the circles there And then we gave him silencer treatment and we were kind of intrigued So we did another pyp scan all my colleagues called me and said, why'd you order another? I was like, I was just curious, you know, I wanted to see what happened is pyp's gone I mean there's no uptake anymore, right? So this is cool, right? And it's about, you know, 30 percent of patients with silencers This is happening too We then brought him in for the pet scan, right? This is his pet scan with the jonathan wall compound his heart's full amyloid still Right, I mean, so we never knew what pyp was even binding to we heard earlier. It's microcalcifications It's not measuring the amyloid load And so the changes that we're going to see with CT scans and those I have a lot of suspicions about and worry that we're going to make some Mis conclusions And and so these are the things that we could do but I just point out I think there's a big thing that we're missing and and that is Remember where all doctors just talk to the patient, right? Just ask them how they're feeling And these are the most engaged and erudite patients. I've ever encountered in my career in cardiology They know what's going on They can monitor their biomarkers and so just provocatively these are not amyloid data These are serial kcc cues that were given to patients remotely In an arnie trial paradigm in which they just measured it and guess what the patients when they were feeling worse on their kcc q That predicted their hospitalizations And they got better after them and so I think there are ways that we can really engage patients in a much better way Certainly all of this testing and everything is going to require as you have at your center is a bunch of experts, right? And it's amazing to see all the individuals whose expertise is essential, right? I mean you can't do this without a hematologist and a fantastic neurologist and pathologist It's not a cardiac disease. So it's going to require multidisciplinary care So I'll just stop by saying early identification of patients is feasible We don't know what the best strategy is right? So you want to create a screening program great? But don't tell everyone you've got the best one where we have five or six that are ongoing I'm convinced that there'll be a screening study strategy Excuse me in a guideline, but I have no idea is it lumbar spinal stenosis is a carpal tunnel What we need to do that's an area of science that should be checked out determined to be cost effective Even more in its infancy are how we monitor these patients So I encourage everyone who's taking care of patients to just get a database together And record what you're recording and see because you may teach us all That there'll be you know a better way And certainly we're going to need that in order to optimally take care of people because if we got to choose between therapies We're going to have to have convincing or add a second theory. We have to have convincing data I think we got a lot to learn from implementation scientists. I'm not those folks But they know how to engage patients a lot better You really in our shared mission of optimal monitoring disease And we really got to you know, bring the patients into all of this and they are really fantastic partners So again, thanks for allowing me to come out west. They're really appreciative I can have some time for questions Thanks for the fantastic talk One of the things that at least I've struggled with on the neurological side is the Asymptomatic or perhaps pre-symptomatic Family members Just wanted to get your thoughts Yeah, I mean, I think it's really look. I mean we have enough to do but remember those you're pointing out There are lots of allele carriers out there. So, you know, it's you know I jokingly say to the companies in this space are like, who can we find in screen? I'm like just screen the family members. You want you want 50 50 yield? You know, they have a brother or sister. There's a 50 50 chance I think they probably have a phenotype more than certainly cardiologists know. So, you know, I wish we had more bandwidth I mean my sense is that neuropathic findings are occurring much earlier than the cardiac findings They're very subtle things. We try to do compass questionnaires in patients And they often report a lot of as you were highlighting autonomic symptoms that may be subtle I'm professing. We don't know. We just got a grant with I didn't get it Justin Groden for those who don't know is at UT Southwestern Fantastic amyloid individual Julie knows him well. He got an R01 For v122 eye patients in which at the cleven clinic columbia and UT Southwestern We're going to be doing MRIs in allele carriers Because he has some evidence that they actually have a phenotype in their hearts Beforehand before we you know before all of these things change and so if the goal is really early diagnosis That may be useful the other intriguing thing that My former colleague Alan Castano when he went to industry. He was working with the idos who makes acaromidus So tifamidus is the stabilizer acaromidus is the next generation stabilizer They had planned they they bailed because of certain issues, but they had planned to do a prevention trial So actually to give allele carriers, you know, these drugs What do I do for patients when I find someone who's got you know, variant disease and is asymptomatic But is close to when I think the disease could penetrate I talk to them about difluenacil every single one of them and I usually give them if they're willing to take it difluenacil do I know that that's the right thing? I don't but I mean I watch their parent got forbid die of a miserable disease They watch the parent and they're pretty motivated Now if I wouldn't give difluenacil to a 30 year old who's got you know 30 years before they're going to develop the disease But you could argue that there's probably a right time to do that. It's an individualized decision Obviously the risk to non-steroidals that you take every day and people have to be aware of that But we're giving a dose that's below the non-steroidal dose. So those are some free flowing thoughts I don't know if that address is what you're talking about, but I think Early is the name of the game and with allele carriers We need to be a lot more vigilant at really getting them into the multidisciplinary team and scrutinizing them Because cardiologists miss it. I think often Yeah Yeah, yeah, so um, they get anticoagulated if they have atrial fibrillation Irrespective of their chad's vascular, right? So you see a fib they should get anticoagulated Doesn't really matter whether you give a dohac or warfarin in our experience Merging data suggests that Is true often all these patients go on a you know novel anticoagulant Some interesting things that we've observed So the london group has published this phenomenon of atrial electrical mechanical dissociation Which basically is they're not in a fib but their strain on their atrium is non-existent Like they are in a fib that is 22 percent of patients with ttr amyloid 22 percent, right? So you wonder, you know amyloid as we know from data from the mayo clinic is very thrombogenic al more than ttr But the worst thing that could happen to a patient is having a stroke. We probably need to anticoagulate them Maybe even sooner than we're doing So here's my quick observation v122i is a much worse outcome than wild type disease v122i almost exclusively affects blacks Who has more a fib with amyloid blacks or whites? Whites by far statistically significant in the general population who has more a fib blacks or whites? Whites there's actually a risk score for a fib and includes race nationally published from many studies but When you develop a fib in the general population and you're black or with amyloid Your risk of having an embolism is even worse much higher I think that uh african americans probably have an atrial cardiomyopathy They may be resistant developing a fib and when they develop a fib they're worse off if all this holds out I bet in 10 years Um amyloid may lead the way to a change in general clinical practice. I'm not sure we should be anticoagulating people Just because of a fib we should be anticoagulating people probably because of the atrial cardiomyopathy We may get to a point where we really just look at the atrium and go. This is the person who needs it right now We're doing something downstream. That's all you know hypothesis generation But what happens in amyloid seems to mimic what happens in the general population Thank you again as a non cardiologist I learned a lot, but my question to you is I think there should be a standard of care for screening considering the high percentage of occurrence or prevalence of In amyloid so are we going to develop those criteria that you have listed Eco criteria and the biomarkers as a means of putting something into a screening plan just like I mean We have smokers and we screen them for triplets. I think now time has come But with the aging population we may need to develop new screening You know guidelines Yeah, I completely agree with you I'm just trying to profess to you that I think it should be scientifically based and so You know, there are lots of benefits to the screening, right? We all have all these clinical clues It's somewhat of an unusual disease, but we could find it early It all seems to make a lot of sense But there are lots of things in medicine that made a lot of sense that didn't work out so well and look From a screening perspective everything's been met except cost effectiveness You know if you look at the who criteria, but that's important, right? Are we gonna have too many false positives, right? I mean Part of the impediment all this I don't mean to you know is I've been saying it for a long time is These drugs are way too expensive. I mean like there's no way that this could ultimately be that cost effective per se So don't misunderstand I'm 100 enthusiastic about a screening approach But when you say to me well, which one should you use the answer? I think honestly should be no one knows yet, right? I mean try one in your center. See what you're going to do collect data and so forth I we're planning to pool the finished data our own scan np data Omar Aberdesi's data and try to put it all together. We have different things But no one's I'm not sure like anything. It's going to be 100% You know exactly what you want to do for everybody You know set there may be different approaches as we heard when you're 95, you know My dad's 101. Unfortunately. He's not doing well. He's probably has amyloid. We didn't screen him Right. We just were kind of like he's got too many other things going on My colleague's like I love you map, but I'm not going to look for if he has amyloid I think she's doing the right thing, you know So Experience Yeah, I was a I was a big naysayer. I have to say I'm years ago I made that joke about this week in the peak because I was kind of annoyed, you know, no one was really looking I think it probably does have a pretty big role. I mean, especially What I was trying to make a point. I don't know if I made it well is that when the pretest probability is very low When you start screening, right, you're going to look for One patient out of 20 or You know one out of 10. That's really low prevalence, right? Not what we've done Then we're going to need some better techniques and I don't know what the right ones are but MRI seems to be You know one that can really suggest the phenotype in a lot more specific manner So the biggest concern I have about screening, like I said is given the current day that we have pyp scanning is going to be wrong 50 of the time if we don't do it really well If you're really looking at one in 10 people and it's not me making that up. We've known that. I mean here's an example, right Stress testing for coronary artery disease. It looks fantastic when you stress people in 1970 All who had left main in three-vessel disease and you know, it was always positive But we've all taken care of women who have like an isolated circulation and the stress test is negative or doesn't reveal things So when your pretest probability declines, it's an old, you know, well proven epidemiological phenomenon screening tests don't look as good So I think you just you as clinicians have to be a little cautious about you know You know who you're looking for I can't every month now I'm sure at every major center. We see someone who comes in who someone suspected amyloid They don't have amyloid right or worse than that someone who's been on to famine us for six months Spent the three or four grand for the first month a thousand dollars And now they spent 10 grand or five grand whatever out of pocket and you tell them Sorry, you don't have amyloid. They're like, well, why did I get on this drug? I'm like, I don't know like so, you know Be enthusiastic, but be I think sensible is my point I'm sure we have more questions Yeah, so, um, I mean, I wouldn't say at all beta blocker I would say high dose beta blocker for sure and the answer here is You know, these are individuals who how do they maintain their cardiac output, right? Remember your stroke volume normally is 70 your endiastolic volume is 100, right? So Right 70 divided by 100 is 70 percent injection fraction Right 70 milliliters Right times 70 a heart rate gives you 4900 milliliters a minute. That's five liters a minute. That's normal in amyloid Let's make up the numbers give them an endiastolic volume of 50 half a small right small chamber Their stroke volume is now 35 ml Their e f is 35 divided by 50 is still 70 percent. They got a normal ejection fraction, right? But their cardiac output even if they went at 100 times a minute, right is 100 times 35 They're delivering 3.5 liters of blood as output. How are they maintaining their output because they got a heart rate of 100 or 80 You start slowing them down Their blood pressure falls. They don't like that. That's how they physiologically maintain The state they're in a state of I would call it subclinical cardiogenic shock The one good news about ttr amyloid no doubt good news, right is it's a very Slow and indolent disease these people have had this disease the time you've diagnosed them even if early for five years It's been percolating in their body in the attr act trial. We had patients whose average age was 75 Their average nt pro bmp was 3000 their troponins were elevated their stroke volumes were 45 ml So their stroke volume indexes were 25 ml right and their wall thicknesses were 17 millimeters What was their new york heart class? Why was it two because this disease developed so slowly that these people can acclimate in a big way So a lot of messages there, but they need they need a faster heart rate Usually they maintain their outputs and they don't usually like beta blockers very much The most important thing I do to a patient that I see when I first see them Medically is if they're on carvetal all I wean it off or shut it off It's a vasodilatory beta blocker or and I put them on a bio available loop diuretic They lose 10 pounds the heart rate goes up and they feel like normal again And then they realize you know I'm not the greatest doctor in the world because I don't have any more tricks up my sleeve You know a few weeks later, but they're like they do feel a lot lot better. So that makes sense Yeah Totally they became very differently than heffaff patients once you start seeing enough of them It's very obvious. I mean the bmi thing I told you is not not, you know unimportant You know They're almost never fat I mean I see a patient who comes in my office who's referred in with a grade 2 p y p scan That's been planar imaging and their bmi is 35 my antennas are up that this is not Amaloid right and it's just not you know like I can look at them ago I'm pretty sure when we do our p y p here at three hours and we do spec You're gonna not have amyloid and I start talking to them about No, you may not need that to famine us or what you were taking, you know kind of thing So screening is great But you don't want to miss a sign people to a disease that they don't have because this has emotional consequences financial consequences Yeah Eric Last but not least Okay One you mentioned the orthopedic data But the other Interesting thing anecdotally that dr. Rosenthal and I have been talking about and actually dr. Grogan up at Rochester Is that a lot of these ttr folks see to be In their pre-morbid lives Very athletic Yeah, all american football players black diamond skiers You know 60 year old mountain bikers So two questions one do you think that orthopedic issues Somewhat is a relationship to the fact they've led athletic lives If you believe that that observation is sort of True than having a separate different question So, you know dan judge also described data similarly So I give you the thoughts one would be it's a little bit of a fluke Those are the most active people in the world and as soon as they can't run as far They're on top of it and running to see you and so they're just more vigilant That would be therefore. It's non-association. I do believe it though And the reason I believe it is a guy in uh in london baladi who basically is shown. Well, how does ttr misfold You know and dissociate and certainly if you have a variation in ttr It's it's it basically falls apart a lot easier But um the kinetic stability assays that jeff kelly who invented to famine has developed Don't show that ttr is much less stable and wild type patients than normal controls We published it. No one seems to pay attention to it There's no doubt that if you more if used to feminists, you'll prevent the disease So um one other way you can you know break up ttr is by sheer forces proteolytic enzymes and so forth So one hypothesis is that the organs that it goes into are ones that um There's a lot of sheer forces in motion your heart's beating all the time So maybe you're shearing ttr aortic stenosis the blood's running through there Maybe you're sharing it and the other part of your body that you move a lot is your joints and your ligaments I personally think there's probably an epitope something in those tissues like in the Ligaments and also in the heart that attracts ttr. So if someone was interested smarter than me in biology They could take out those tissues and try to find I bet there's something That kind of brings ttr there for because ttr is made in the liver, right? And almost none of these patients no one gets liver involvement So why is the liver able to handle it on other tissues? Not but it's a great question. Um a lot of a lot of Athletes though. I do see that So as as the number of ttr patients grow as we make these diagnoses, how do you imagine we're going to sort of triage out these patients to those that are going to sort of tertiary referral amyloid centers versus the um amyloid programs, uh That hopefully will become more widespread as we're showing, you know here in arizona there's interest You know, uh, I'm shocked that in a great way that so many folks from around the valley are here And then you know back to the the role of the primary care doctor So after the diagnosis of ttr is made and we start treating where do you see all the the roles of those different groups of folks? Yeah, it's a great question. I mean look, um if we're right, there's going to be you know Hundreds of thousands of wild type ttr patient, right?  I mentioned, I mean Yeah, so it could become overwhelming Yeah, I think it I don't have a good answer. It depends upon your local resources It depends upon what their needs are clearly the need a heart transplant They're not going to go, you know, except to the center of excellence I mean, I think some of these therapies that are coming soon are, you know, patisserie would be great But it's pretty complicated IV infusions every three weeks. Can you imagine I have I have 840 people As of last week on Tofaminus I mean, can you imagine if 400 of them wanted to get IV infusions of patisserie and every three weeks? I need like 40 nurses to put the orders and I put nurse I put orders in for 10 patients in the Apollo B trial I spend, you know, so it could quickly overwhelm the health care system And I think that's part of what people I think appropriately in your state are discussing Which is this is only going to become a bigger bigger and bigger part of health care How do we organize ourselves to best take care of people? It's not rocket science I'm not a very brilliant guy. So it really it's it's pretty, you know Certainly the TTR patients I think are the ones who could be cared for by community providers most of the time With some advice and counsel if need be a visit once or twice a year with a Amaloid center, but they don't need day to day Especially in the early in the course of the illness there They basically, you know, take Tofaminus take a little bit of a diuretic and they live pretty functional and healthy lives Someone asked before like how much does it prolong life? It doubles their lifespan at this point people used to be dead in two years two and a half years people are now living More than five years So while I'm ticked at the pharmaceutical companies for cost charging too much and they know that Um, they certainly um, they could argue and they do that this is much more effective than You know chemotherapy that we give people to prolong their life by a few months That doesn't mean two wrongs make a right where every drug costs too much But you know, but I get that argument. This is pretty amazing treatment therapy for these folks I think that wraps up our Q&A. Dr. Mallor, thank you so much So dr. Vijay has assured me that he'll have the last word today, so I'll be brief First of all, um This uh, this event couldn't couldn't have been possible with all the help we've had Um here at ASU and from our partners our speakers and all of you as attendees I do want to single out, um, april johnson. Um, she's been my right-hand person in organizing this In addition, uh, Stephanie calderone, nicole, hernandez Craig woods and my colleague at IFH As well as the staff here at asu health futures And our live stream team Um And and matt I really want to thank you. I think I can't imagine A better person to come out to really kick off this effort in arizona Um, I have to say I think uh, I think we were really lucky to get you and it's really a pleasure to have you here Um, and in fact, I have to say, um I thought your slide deck was a little long until I heard you start speaking and I've never seen someone go through so much So quickly so effectively so that was amazing I wanted to say that but i'm glad you said it, um, and, um I do disagree with your your statement that cardiologists are not the sharpest tool in the shed But uh, otherwise I agreed a hundred percent with what you said um And you know a couple observations struck me that You know we talk about community and I think this is really a good example of our community coming together We have, um, arizona heart foundation Sonography students here and that was really kind of a bonus. Um, so thank you Um, we have you know practitioners from primary care from geriatrics. We have advanced practice providers We have pharmacists really have so many people that um, I think, uh, you know, I haven't seen in one place and furthermore, we also have great, um a specialist I think I probably learned the most from our pathologists or neurologists or hematologists I think for me as a cardiologist. It was really extremely instructive, but I think I've never Had that As well as our primary care representatives And so, you know in this world of zoom and post-covid it's just it's so it's so refreshing to be, you know, in the room with with people And uh, you know, just a couple housekeeping. We will have everything available online on youtube Uh, see me credit will be available if you fill out the survey Um, so here I'll turn it over to uh, dr. Vijay, you know Sunday's already summarized And really appreciated everybody's input of course input from all the faculty members Is really been phenomenal and all the principals are now hopefully Getting embedded into our dna, right? I mean it's phenomenal to give all the faculty members a bigger class And of course the class for the audience here and also the people who are online that the Authority might as well give them another round of applause because without you it wouldn't be possible You could declare a war and nobody came I don't mean anything, right So so and then thirdly, uh, of course, I want to uh, thank and appreciate what sunday just done it then really Aligned all the all the dots and and cross all the t's and really delivered something phenomenal and and brought this program to provision So give sunday a big a big hand and finally You know, I always believed uh that uh, you know being lighthearted You know Preventing from heart attacks and trolls. So that's been my philosophy and principle all my life So you like harder to joke around and have fun and do this and do that and and I thought that I was Doing pretty good in my practice and engaging patients like matt said that he's a patient's voice Okay, I wrote a book You know about my own patients are my through my life calling invoking your inner therapy that the title of my book I wrote it recently in hot failure And for the league community for everybody and and I thought I was doing a pretty good job And and I had this patient who had diagnosed with amyloid and had uh You know the severe aortic stenosis 84 years old and with vipers died 10 years ago And he had severe aortic stenosis. He had the loud murmur. He's awaiting waiting for a tabber and uh, he thought of hearing and so uh, he'd come to see me and he's waiting and So I see in the ball, you know, I never go to the ball I said no, I want you with me. I'm gonna go something other. Okay. I'm going to go suddenly I see is there a courier guy with the beautiful young brawn and he's on the other side of the mall And he's like waiting it to me And I mean, you know, the doctor the go So then he'll be later. He comes back to see me and he says Look at him and I say you're doing pretty good for yourself. All right. Yeah. Yeah. Yeah, doc. I'm calling your advice Following my advice, you know, I'm like suddenly So what did I say? He said well, you said get a hot mama and be careful And suddenly it occurred to me That between my accent and his hearing it's got lost in translation. Is it get a hot mama and be cheerful? No, no I said you got a hot murmur. Be careful Again, thank you all for coming be lighthearted. Have been have a fantastic