has to change, and we have to become uncomfortable with what we are trying to do. We tend to be afraid of risk, because Congress will smash us as an agency, we will get smashed by our constituencies. Why are we doing this? But the greater risk comes that if we do not try to find novel ways of improving the number of lives saved, of people of ending hunger of dealing with disease, if we do not try to do that experiment, those opportunity costs may be actually a greater risk, because if we do the same thing and expect different results, we are taking a risk in being able to do that. I do believe, and it's interesting that my colleague here is from the Mars Innovation District. I encourage you to look at it. It's really cool. But it made me think of another example I like to give, which is the fact that we have put a VW-sized rover on the surface of Mars and used a crane hanging from the middle of space on an alien planet to lower it onto the surface of that planet. If we have got the ability to do that, then we have got the ability to address some of these other problems. One complication is NASA doesn't have to deal with humans, which is why social science, anthropology, economics are a critical part of science as well in solving these problems. But we have got the ability to do and take new approaches to solve these problems. Thanks. Thanks, Alex. Here, when I took away from your comments where this issue of the new solvers and these new collaborations, I think, Ilse, your new life at Mars is, I think, indicative of this, the Mars Discovery District. I noticed that Rich has a BlackBerry. I just wanted to do a quick product recognition given that BlackBerry is from RIM and RIM is a Canadian company. So I think it's very appropriate. You had a past life in venture capital. You also have a deep private sector background, so I particularly appreciate you making the trip down to be here because I think we've talked about science and pure research and the importance of it in the way it's evolving, but also the importance or the central importance of commercial applications to this. And so I think that, I suspect that was part of the premise for the Mars Discovery District. So please share with us a little bit about Mars Discovery District and also how should, and I hope you'll also take a little bit of time to think about Canada's in the process of thinking about multi-sector approach to science and technology and applying it to development, how in your mind should Canada be thinking about this? How should Canada bring in its universities and research institutions? And so if you were advising the Canadian aid minister and supposing he was in the room or just down the hall or maybe watching this, what would you advise him on this as well? So also the floor is yours. Thanks. Thank you, Dan. And thanks to Richard and Alex. It's fantastic to be part of a conversation where we all share the enthusiasm of the capacity of science, technology and innovation to make change in the world. And maybe, maybe let me focus as you say a little bit on sort of our window from the Canadian science and technology and academic engine. And I think I want to just in the context of development policy make a bit of a plea that we do not lose sight of the importance of partnerships with academic and other research institutions around the world. And I think to Richard's point, the science enterprise is becoming a lot more collaborative and we're seeing such extraordinary growth in the participation from emerging economy players. And I think in that context it's often easy to think that the researchers are entrepreneurial and they'll find their way in terms of partnering or universities will set up the collaborations that make sense for them. But I think it's really important to take a long-term view from a development perspective of the role of academic institutions and the entire spectrum from basic research to applied research as a capacity builder for future innovation and future trade collaborations. I'll just give you one small personal story. I grew up in South Africa, left South Africa and went to do graduate work in the UK and then in Canada. But in the late 80s I was invited by the then head of the Council for Scientific and Industrial Research to come back and look at their material science programs and make some recommendations going forward. What was interesting about that in South Africa and what was interesting about that time was political change was clearly in the air and the institution wanted to get ready for some of the tough decisions that needed to be made. And so we looked at the internal programs, the partnerships with academic institutions and industry and so on. And through a really quite amazing set of leadership attributes at the time, decisions were made to sort of deepen and maybe narrow some of the basic research there, build partnerships with local and international academic institutions and then begin to very specifically focus on applied research challenges that were relevant to the local environment. And because I became so interested in that, I've been tracking what happened out of that, what seems like a fairly modest piece of interaction and frankly, extraordinary solutions for health and environment, extraordinary companies that are now providing solutions across Africa. And the most important piece actually to me is the lineage of talent and scientific leadership talent that took advantage of those decisions locally but then also mentored a new generation of science leaders both in business and in academia. And many of them are names that you know in the U.S. today. So it's amazing how important it can be and I would just encourage us not to assume that that part of the innovation food chain will take care of itself but to be cognizant of its potential for the long haul. Certainly from my window at Mars, the early stage start-up SME part of the innovation enterprise globally is also becoming a very critical piece. And there's no question that the global forces are very much part of driving what people do in science and technology ecosystems in North America, certainly in our own, because it's totally changing. I mean ideas are more mobile than ever, entrepreneurial talents more mobile, capital is more mobile, market opportunities are opening up in new places and frankly competitions coming from places where you wouldn't have normally expected it. And then global supply chains are becoming much more complex for young emerging companies to insert themselves effectively into that process. But when I look at how we think about entrepreneurial ecosystems in North America today, there's a kind of a patriotic thing. It's about growing local jobs. There's a big piece of that. I think through the lens of this conversation today, maybe we should start to think much more about that global start-up system as a multi-nation enterprise and focus on being brokers and celebrators of entrepreneurial talent and breakthrough companies, wherever they come from, and knowing that they will move as they need to and focus our important initiatives on opening up challenge for them to raise capital or to access markets here and elsewhere. Because that sort of builds on that assumption that the entrepreneurial lever is one of our most important long-term levers for driving change. And then as a geek, I love technology and science and technology and I certainly live in a world where the classic view of an important idea that becomes a product or a service that makes it into a market is a big part of the entrepreneurial thinking. And we often get trapped, I think, when we think about technology and science solutions coming to emerging markets to be fixated on the gadget, to be fixated on the cool thing. When in fact the challenge is to actually scale and diffuse those gadgets or those solutions into new systems. And that means that we need to think much more holistically about the system into which we innovate. And it becomes as much a social innovation challenge as it becomes a technology challenge. And the flip side of that, and we heard this a little bit from Alex and Richard too, is that the solutions that are being developed now for our big hairy challenges, and some of those are extraordinarily daunting, are forging new collaborations that are driven much more from where those problems originate. Have a new set of problem solvers around the table. And I think our challenge is how do we effectively insert ourselves and our knowledge and expertise into those issues. The question I'm particularly interested in is how do we insert the true breakthrough innovators in our small and medium sized startups, because they're often working at the bleeding edge of the solutions. But our systems don't really know how to accommodate them because they're a messy bunch, they're not represented by anybody. So how do we insert them into the process to get their best thinking into that? And then if we put on a trade hat, is those solutions will then migrate, I think, among emerging economies more so than from us to them. And so how do we become part of that solution set in the long haul? So these are very complex challenges that I think are in front of us, and we will need to rethink not just the way we do business, but how we bring new players to the table. One of the opportunities I'm the most excited about from our ecosystem is the role of the diaspora.  We are seeing a huge shift in our startup companies, particularly in areas like health and energy and where they do business, because we don't have the luxury you have in the US of a big local market. So our startups have to be global companies from the day they're born. And Canadians have been, frankly, quite lazy, because we've had this big US markets out of the border, and you've had a great appetite for our innovation. But what I'm seeing now is, you know, as US markets and European markets have become a little more sluggish, what we're seeing is young companies designing products entirely for emerging markets. They're skipping over, you know, trying to even do anything in the US. And that is a huge opportunity by itself, I think, for Canada. The second piece I would say is we have a new generation of technology entrepreneurs who are also social entrepreneurs. And their contribution to development solutions that are science and technology based, but also have a mission to make a different positive difference to the societies in which they apply is an extraordinary opportunity that we need to try and tap more effectively into our more formal trade and development systems. Thank you very much. I want to take a couple questions. This has been a very patient and supportive audience. So I know I see some hands. I'd like to get some hands for the conversation on science and technology and innovation. I see a gentleman back there, and I see my friend over there, so that we're going to take these two folks. Yeah, if we've got a microphone, if not, we'll just speak up and I'll use your big room voice. So go ahead. Can we start with, can we start with our verbiage and stop referring to the industrialized countries as donor nations and call them partner nations? Second question is with regard to USG being the lender of the last resort of becoming comfortable with the idea of making very difficult decisions about lending and accepting risk. My observation is that there is a staggering lack of competence among federal agencies for analyzing business risk. There is a great deal of understanding of the need for it, but what we end up with are iconic examples like CELANDRA, in which there are a successive series of decisions were made, which in retrospect, a businessman probably never would have allowed. And so I'm wondering if there should not be some consideration given of how you balance the interest in being willing to lend the money with the expertise it takes to actually monitor the business as it goes along. Okay, so let's get a couple. I'm here for my friend up front here, Maggie, this woman up front, please. Good morning. My name is Barbara Simmons. I'm Dean of International Education at William V. S. Tubman in Liberia. This was, this panel is just, all I can say is wow, because you touched on all the points. Last week, we hosted through the constituency for Africa at the Microsoft Innovation Center, a session on African and African-American universities, the diaspora stakeholders and STEM. And people were so enthusiastic. What we want to do now, and what I'm asking of you, is how do we get started on implementing or moving forward some of the ideas of bringing people together, being inclusive, and then mapping out a way that we can go forward. Thank you. Thanks very much. I'm going to take a third. If we've got a third hand here, this gentleman here, then I'll do another round. Thank you. My name is Frank Barone. I live here in Arlington, Virginia. I have been in science and technology myself professionally for some 40 years after graduating from Berkeley with a PhD in chemical engineering. I have seen, as you have Richard, many, many generations of evolution. Recently, I have gone back to the Bay Area and have been a significant investor and founder in what's called the Tech Shop Movement, part of the Maker Movement, which is encapsulating a significant number of what you've all talked about today. One of the things we are experiencing here is that we are observing people who are artistic, who are finding a very easy path to transition to S&T and I as opposed to the inverse for the S&T and I element to transverse into the artistic. It was brought out to me one day by one of the art students that was there from San Francisco State College that Picasso effectively created art first and then used the technologies of enabling the materials, secondly, to create a preservation product such as Michelangelo did. So our thrust of the Tech Shop in San Francisco, which we've propagated it now to Arlington, we have one over in Crystal City, a Tech Shop, which we put right in the artistic community, right in the underground in Crystal City, I invite any of you to come and see it. We're actually working hard to change the STEM to steam. We believe that the common denominator between science, technology, engineering, and math centers around art, which is the enduring human aspect of civilization throughout many histories. So I'd like to ask your opinion, if any of you have a thought on that, just what your personal observations have been, is where does art fit in the midst of the STEM? Okay, let's get Joana Nessa, the title here. Maggie. Joana. Hi, I'm Joana Nessa. I'm with Chevron. And I wanted to ask you to comment on something that each of you mentioned, which is really technology transfer and the fact that there's a lot of technology in existence. There are a lot of current innovations that haven't been picked up. I think about this a lot in the ag sector. And a lot of that engagement has to be around people-to-people interaction and extension systems. I think there's an interest in scaling up, but the fact is that people don't often pick things up until they learn about it from another person. And I wanted to ask what your thoughts are in terms of how you reinvent that exchange of information and ideas and adoption of technology. Well, these are some great questions. Richard, I'm going to have you go first. We'll just go down the path. I think Ilsa, anywhere where there was a US centric question, I'd like you to answer that in the Canadian context, if you would, please. Richard. Sure. Terrific questions. Thank you for picking up on some interesting issues. I'll briefly address the issue of terminology. This is certainly the dead hand of the past that still controls a lot of the terminology. And much of that is multilaterally driven. We still have something called official development assistance, for those of you in the room who know ODA. And believe it or not, people still believe that that is a critical defining factor in terms of determining both outputs and outcomes in development. I don't agree with that, but I ran at that particular windmill some years ago and got beaten off. So secondly, re-raising the issue of risk, which Alex had highlighted as well. This is actually a very crucial issue as a context for S&T to play any serious role in particularly US bilateral assistance. But I think it also affects the private sector. And to me, it's been a great concern of the extent to which large companies have been dismantling and outsourcing their R&D operations because, in fact, the risk involved in the rate of return on that would detract from their bottom line. And so risk has actually now been sort of almost ghettoized into a startup world. And many of the VCs don't even want to fund sort of the first stages of research because it's unclear it doesn't meet their probability tests about success. So as a society, we have an issue about risk. It's not just USAID. Although I must say that that is critical and I know one of the first sort of startling comments I heard from the current administrator when he took office was that he thought a central challenge he had was to persuade his overseers that, in fact, risk was not a dirty word. And I can't say they succeeded because, in fact, the systems that were in place then are still in place. And despite Alex's wonderful efforts in creating the development lab to try to create a different aura for possible acceptance of risk in an official US government agency, which I hope pay off. But it is truly a cultural challenge we have because the fact is that by never describing what it was for all my years as an assisted administrator, I was able to put $20 million a year, and that was real money then into looking at malaria vaccine research that never produced a vaccine. But the research is absolutely crucial for exploring pathways, for learning more about the organism, and laying the foundation for what will one day produce a really good malaria vaccine. But if anybody had known about that, if any congressman ever asked me to testify about it, it would have been dead, because it did not produce a success in their terms. So risk, I think, is a big issue. And one day we will figure out as a society and as a government how to deal with that. And examples like Cylindra do damage that. But I differentiate in the sense that Cylindra was a technology choice. And the government does not show itself being very good at that. Further upstream, in terms of funding research, I think that the scientific community has an excellent job of sorting out, in fact, what should be invested with an appropriate level of risk. Actually, the only thing I'll pick up in the other question, because I don't want to take too long, is that I think tech transfer and extension and adoption of technology remains a key issue. Although I think it's much easier today with communication systems and so forth. And I think we should have very high expectations for much more rapid adoption of new technologies than we may have experienced in the past. Yeah, a lot of things. The first question is to partner nations, I totally agree. You look at the Pew polls and the number one thing the United States is respected for above everything else, above naked dating or looking at us from the outside is science, technology and innovation. One of the things just to recognize is if we take that framework of partner nations, we'll recognize that reverse innovations actually can be really useful. We spend 10 times the amount on healthcare as other countries that have the same outcome. So what could we actually learn from innovations that are better designed, worked for achieving some of our goals in the developing world and how do we bring them back and the US, the development labs that USAID funded in places like Duke and the Duke Medical Center system, which is one of the biggest in North Carolina and one of the best in the country are actually looking at how they can take those innovations from the developing world and put them back into our healthcare and I think that's really smart. In terms of business risks, the one thing I would just say is people bring up Selindra and there's a great story of Secretary Chu when no one was paying attention to him, the crowd wouldn't quiet down, just decide to say the word Selindra, Selindra, Selindra to get people to listen in which they immediately did. But we don't talk about how many actually good ideas, good programs and great things are funded where we did take risks. How many great corporations and startups have we had? And the fact is there is a real serious problem when institutions like the National Institute of Health is well known when I was a grad student in terms of the applications, you have to have 70% of the research done to actually get accepted was the mantra and now our acceptance rates on those institutions are really low. So people aren't taking risks, which means we're not advancing the science and the way you set up an experiment, whether it is a development program or anything else, the way you set it up is so you learn either way. But there's ways we can think about innovations that we can borrow from the private sector, which is, you know, 70% of your work is your core work. 20% is in an adjacent space and 10% is allowing you to take those approaches to rethink assumptions. The last thing is I just think we don't learn enough from failure and there are ways to mitigate that risk by partnering with other places. So almost every single thing my former office in the US Global Development Lab did was in partnership with other institutions around the world, DFID, Gates, anywhere at private sector, Duke Energy, which was a way to actually get the benefit and the advice of them looking at these programs and to share the risk across many. Barbara, Dean Simmons, there is a great, I totally agree about the diaspora as well. Just for the US, 30% of our startups in California are funded by people who are foreign born. So that diaspora is important for our security in the United States. But there's great programs that we set up at AID. Peer is one of them, where if you have an existing NIH or NSF grant, USAID will connect an American researcher with a researcher in the developing world. Canada has been doing these kind of programs for a very long time. The GCDs and the whole purpose of things like DIV was to actually make that was a recognition that talent is everywhere, but opportunity is not. Does it go that what is DIV? DIV is a development innovation ventures, which is now this larger collaborative US Global Development Fund. It is really opening up the doors to people around the world to co-solve and co-create these problems, which gets us to the tech transfer issue. And I don't think it's tech transfer. I don't think it's one way anymore. I think it has to be a multiple directions. It has to be around co-creation. We need to look into networks and network science, and there's a great field in biology called coupled human natural systems that has done that. But looking at human behavior and what it means to be able to transfer and help people share information better and I don't think we've done enough of that in terms of thinking about scale and demand. Again, there's a lot we can learn from the private sector. I used to work. I created the first National Park in Afghanistan. This year, they just created the second one there in a place called the Wachong Corridor. And one of the things, Wachong is really close to something called the Eurasian pole of inaccessibility. It is so remote that it is the most remote place. Six weeks by Yak is the usual round trip. Kid you not. No roads. This is the Silk Road.  So how in the hell they get the Pringles there and why can't we use that for global health? Honestly. And that's understanding demand. That's understanding scale. That's understanding local people and that's understanding knowledge. And that's what we should tap into for tech transfer. Last two points, which are sort of extraneous points, going back. The problem with universities and right now I'm the first David Rubenstein fellow at Duke. They've now created a fellowship to help the university think about how it addresses big global challenges. I'm there for a year. It's a phenomenal place. The problem is our university's relevant is research how we actually have it relevant. And it's not unless we think about how we translate that. And how do we actually cut across the disciplinary boundaries that are there. And that comes to changing tenure and promotion. And how do we actually evaluate people. And that's got to be part of it. In the developing world, we've got a bigger problem. Those people who are in charge of the universities and who are sort of at the upper echelons of the universities may not be the most innovative have the most capabilities to actually solve this problem. I saw this at McCary University. It was unbelievable that there was a student there who developed a cell phone app that he had done a million dollars of sales on that was an auction site to do arbitrage between people within the remote communities in Uganda and people in the city to sell fruit back and forth. And completely he was at the university come up completely ignored by the university. And that's where some of these solutions are going to come for the last very, very, very last thing. I think that they're we're not recognizing that there's these huge changes that are going on. And part of it is because these communication tools right it's now 700 million cell phones in sub Saharan Africa right took 20 years for the first 100 million it took three years for the next 200 million that 20% of our smartphones that's doubling every year. So the penetration is is is is unbelievable in terms of the access that is infrastructure as much as roads are those are pathways into education pathways into finance ways of leapfrogging failed financial infrastructure. And they are also ways of new economic opportunity. And you see this now we're seeing a separation of work and geography around the world. There is a global community that I work with to get me products from my company that are based in Philippines and Pakistan and a lot of places I wouldn't have expected people to be doing design and innovation and tech work for me in the past that I now have access to because they now have access. And I think that's really significant. Also, if you could welcome your response to these questions, but I also want to put an additional question to you, which is given this conversation. What does this mean for DFATD? What does this mean for Canada? Just give you know, this is a I'm all ears. I'd like to hear, you know, I suspect you have something to say about this. So answer some of the questions, but I'm going to come back to you and say, tell me what is this? What does it mean for for our friends in in in Canadians, Canada's foreign affairs, a ministry? Yeah, but that's a that's a tough question. But just to show you some of the I've never heard the word donor nations until today, so it's not in use in Canada. This the second the second comment I would make is is just around, I think, following up on on Alex and I think what we're talking about here today is we are absolutely in a time of extraordinary transformation of both the global science enterprise, but more importantly, our institutional capacity to deal with it. And I think the challenge for all of us is going to be, you know, how do we rethink the way we partner? How do we rethink the way we we organize how we convene who's at the table in such a fundamental way that it's going to be where the strains are. I'm not so worried about our ingenuity and our ability to come up with with solutions. And that goes to the steam question. You know, I, I think our challenge is always going to be as you've you've heard from from Alex, some of these challenges are still so myopically specialized, that, you know, we need to continue to to build that sort of trunk of deep expertise and not ever shy away from that, but then get the integrators working and whether that's T shaped people or steam people. I think these are these are just inevitable and the the solutions will come from these adjacent spaces, but then, you know, are our formal institutions even including our academic institutions equipped to allow for that trans disciplinary expertise? I will just make one comment for you on tech transfer because we we're running an interesting experiment in Toronto, where we literally have in the downtown core, the University of Toronto, 10 affiliated teaching hospitals, some of the largest academic research centers you would find. Historically, each had their own tech transfer office. So if you came from Boston to Toronto, you'd have to visit 16 tech transfer offices all under resourced results, you know, terrible, even though we perform with some of the best in the world on the scientific output. So so about four, five, five years ago, we went through a process where we've in change that process to now have a single commercialization platform where all the IP from 16 academic institutions come into a single storefront to be bundled to be accessed. What was very interesting as this as the the steam part of of that solution was because you broke down the silos of these these proud institutions in this process, they were all putting their IP into a thing that didn't have their name on. That opened up a whole new process to bring other actors into the tech transfer and commercialization process from students who are often the vectors of of tech transfer to industry secondees to to other agents from law firms from other places. It's just fascinating how that single sort of decision changed the way the whole organism sort of does its work. You know, from a Canadian perspective and advice to the fact that I personally think that Canada Canada has a number of features. It's a small country in the scheme of things. It has a huge long history of being a active global citizen on a number of different levels. There's no question in my mind that the recent leadership from Canada on child and maternal health would not have happened if it wasn't decades of global health research in our academic institutions that go back before anybody had a name for it. That's just, you know, part of our global persona. And I think it's important for us to stick to that knitting of Canada as a broker and particularly leveraging our diaspora communities, which which I think is, you know, is a very powerful feature for Canada just because we're we're a little bit in the in the glue, you know, rather than than being a power broker at either end. In terms of risk and the the management of risk, Canadian governments are pathologically adverse to to making choices and choosing winners. So much so that our science and research economic tax credits, which is a very big system in Canada, we choose that over direct investment because we refuse to choose winners. Of course, you know, that that's a debatable debatable strategy. But I think we have no choice in this new world of public private partnerships as the only mechanism to do business at home and to do business in the world to create mechanisms where we can share not just the money coming from public and private sources, but actually the expertise, including risk management expertise. We're very active at Mars in the area of impact investing. And again, you know, very powerful sort of diaspora contributions there. But the reason why I'm excited about impact investing, one of the reasons is that it actually creates formal structures for public and private financiers to bring their expertise in terms of selecting investments, managing investments, and also mobilizing capital to that process. And the young talent from the traditional financial institutions are flocking to this field. So again, it's an opportunity for us to tap into that capacity.  So I think we'll also make different choices when we have more women making those investment decisions, which by the way, in venture capital, in Canada, in the United States, is still pretty pathetic. And, you know, it's great that we focus on child and maternal health, but women globally are stepping up in the innovation systems. And I think it's a really interesting challenge for us is, you know, what is what is Canada going to do to actually play a role in that part of the global female talent that's going to emerge on the global stage? Okay, folks, please join me in thanking the panel. We're going to take a 10 minute, but you have a promise you're going to come back in 10 minutes, a 10 minute coffee break, there's sodas and coffees outside, see it in 10, and there's also food. Food, if you wanted to grab lunch, you can grab lunch now or you can grab lunch after the keynote. We'll also do a brief break. But if you want 10 minutes, come back in 10 minutes. Thanks very much.


In a set, repeated elements are not permitted. So we could have a set of friends, since each person is distinct, this is a set. Or we could have a set of silverware, one fork, knife, and spoon is a set. But a set of four forks is not a set, instead it is a multi-set. In a multi-set, we could list the repeated elements. So a set with four a's, two b's, and three c's would be, and as with sets, the order we list elements doesn't matter, so this could also be. However, we usually indicate the number of each type. So we have four a, two b, and three c, where four, two, and three are referred to as the repetition numbers. If we want to leave the number of each element unspecified, we'll use numbers as the elements. So here we have n-one-ones, n-two-twos, n-three-threes, and so on. And this helps avoid confusing expressions like n-one-a's, n-two-b's, and n-i-z's. If we know both the number of each element and the number of types, we'll continue to write things like five a's, two b's, and three c's, unless we forget. So we could ask, given a multi-set, how many combinations can we make of a given size? But this is too hard. To start with, we'll get there eventually. Instead we'll ask, given a multi-set, how many permutations can we make of a given size? Suppose we have a multi-set and want to form a permutation of n elements from the multi-set. We'll call this an n permutation. There are two possibilities. We have enough of every type of object so we won't run out, or we might run out of some objects. Suppose we want to find the number of n permutations on the multi-set, with i distinct elements, one through i. If nk is greater than or equal to n for all k, then we won't run out of any element. And so by the multiplication principle, we have our first, second, all the way up to our nth choice, and we always have any one of the i different elements. So we have i possibilities for the first choice, i for the second, and so on up to the nth choice, and so we have i to power n permutations. So how many i permutations can you form using any number of a's, b's, and c's, but at most five d's? Note that we can describe this as the five permutations from the multi-set, an infinite number of a's, an infinite number of b's, an infinite number of c's, but only five d's. We won't run out of a's, b's, or c's, and since we'll need at most five d's, we won't run out of d's either. And since we won't run out of any element, the number of five permutations will be, well there's five choices, and four possibilities for each choice. So we get four to the fifth permutations. How about nine permutations of this multi-set? Since nine is greater than four, two, and three, we could run out of any of the elements. And since four plus two plus three is nine, we in fact must use all of each type of element. Now in mathematics it's sometimes useful to engage in wishful thinking. If all the elements were different, there would be nine factorial permutations. Let's see if we could transition from the multi-set to a set where all the elements are different. So let's consider a permutation of the multi-set, for example. If the a's were actually different, say this one permutation of the multi-set would correspond to four factorial permutations of the multi-set with different a's. Like, so if we multiply the number of permutations of the multi-set by four factorial, we'll get the number of permutations of the multi-set where the a's are distinct. But wait, there's more. Now consider any permutation of this multi-set. If the b's were different, say, then any permutation of this multi-set actually corresponds to two permutations of a multi-set where the b's are distinct. So if we multiply the number of permutations by two factorial, we get the number of permutations in the multi-set where the b's are distinct. And again, any permutation of the multi-set would produce three factorial permutations of the multi-set where the c's are distinct. So if we multiply our permutations by three factorial, we'll get permutations of our new set. But notice that our elements are distinct. And since the elements are distinct, the number of permutations of our final set is nine factorial and so we can find the number of permutations of our original set as... And this suggests the following. Given a multi-set where n is the sum of the repetition numbers, then the number of n permutations of m times the product of the factorials of the repetition numbers will equal n factorial. And we could turn this into a formula, but remember, understand concepts. Don't memorize formulas. And the important concept here is we took our multi-set and gradually transformed it into a set whose permutations could be computed easily. Ah, well, here's the formula anyway. So a polypeptide chain is a sequence of amino acids. How many different polypeptide chains can be formed from three arginines, five lysines, and six glutamines? So here we're forming a polypeptide chain for the multi-set 3a's, 5l's, 6g's. And since we're using all of them, we're actually forming a 14 permutation. And a theorem says the number of 14 permutations will be 14 factorial divided by 3 factorial, 5 factorial, 6 factorial.


Robin Hood Ransomware takes down Baltimore City government networks. Well, this actually happens to a lot of small businesses, a lot of big businesses, and it's noteworthy and very impactful when it happens to a city. This happened on 5-8 when the story was. And here on 5-18, 2019, we're still seeing that their network is down, and the city's actually come to a really big problem of they can't even close on a house right now because they can't file paperwork with the city to do closing paperwork for purchasing a home and many other city services including all the inspections. Everything's been impacted by this. It's a seriously big problem. So let's talk about and bring this up and it's been brought up before and we've done implementations with even cities with this particular methodology for helping mitigate the risk and problems created by ransomware. Combating WannaCry and other ransomware with OpenZFZ Snapshots is a May 18th of 2017, two years ago today, oddly enough, blog post by Ag Systems. And this is a great way to help mitigate the risk created from ransomware. The problem with ransomware is if a user, the general way it works right now, a user will have access to a lot of files that user somehow gets their system with the ransomware on her and it runs around encrypting everything that user had access to.  Even worse so, many times sometimes the same person is administrative and it then ties into their Active Directory and gives them access to the backups that get corrupted as well. These are some of the worst case scenarios and the other big challenge that's faced here is when you're dealing with these type of problems, restoring the backups even if they're not corrupted when you talk about massive amounts of data can be a problem into itself due to the time it can take to restore the backups. And this is where OpenZFZ Snapshots the rescue. Now, one of the things about this and like I said you can use Cloud Backup, you can use Offsite Backup but it comes back to how fast can you get restored and ZFS Snapshots are a great way to do this. And this is the important line that's really, really important to why this works because OpenZFZ Snapshots takes place at the block level of the file system. It is immune to any file level encryption by ransomware that occurs over it. Carefully plan Snapshot, replication, retention and restoration strategy can provide low level isolation you need for your storage infrastructure to quickly recover from a ransomware attack. Now I've got a video I can link to that I go more in depth and I'm probably going to make a new version soon to cover the new version of FreeNAS but it works the same way. You can set up Snapshots and the Snapshots can even be set up to run every hour. They can be set up to run every half hour. You can set these up to be very fine grained and depending on your use case and this goes into the storage planning and what these do is they're only taking Snapshots of the file system as it was at that time but not duplicating it which would be huge especially when you talk about 570 gigs worth of data which is my video folder. So you can see my video folder growing over time and I only do one Snapshot a day of my video folder to keep it really simple but if I deleted everything out of my video folder I could just roll back to that Snapshot very, very quickly because I can reference it. Now the Snapshots don't take up space because they're only as I said a differential between when you Snapshot it and changes that were made and on a general basis a city may have a lot of files but they don't change that much from hour to hour so as long as you have property planned storage you can keep these Snapshots and then the moment you get ransomware you can roll back and then only losing as much data from the time of that Snapshot to the other one. Obviously there's more time involved because you want to make sure you've removed a threat so it doesn't go back and do this anymore but this is how ZFS can help protect against that. To top that off, what about having two Franeas servers? Well I do and it makes that one more layer. So I have the Snapshots set up to do once a day and then I have it replicating once a day via replication tasks and I've covered a video on this too, I'll leave links to these below but that way it takes all the data and mirrors it over. Now one of the important things about when you integrate this and some of the planning that needs to go involved in here is some people like to start using the same password everywhere. They're like oh it'd be convenient to manage my Franeas system with the same password that I manage my Active Directory with. Well that's where some of the problems come in and if the attackers get in there and they realize they have access to this this is where I've seen people so to speak blame this but it really comes down to how you do your security. You need to make sure that they do not have the same password. I know it's convenient to federate everything and have one global login so you can just log in everywhere with the same credentials because it's convenient but do make sure because even if you present Franeas via an SMB share to a Windows machine as long as the root password, the admin password for Franeas is different than there it would be an entirely another isolated layer that would have to be correct and there's no known vulnerabilities as of right now in Franeas so for them to attack it if you have a good strong password for the admin and management of this you are safe as long as there's not any vulnerabilities that are found in it and like I said as of right now there are no known vulnerabilities there's no brute force method other than the fact that actual brute force where they guess passwords and that's not the most effective method anyways matter of fact it's really slow and hopefully you have some type of logging that will alert you that something on your network is attacking and brute forcing hopefully you have it on a separate network as well as far as the admin interface goes but as long as you keep this separate the want to cry attack if you're using an SMB share for example the ransomware can go through and modify all the files on the SMB share but does not modify this system inside of here it's immune to it because this is controlling things at the block level same thing as you present this to Windows as an iSCSI server you're going to have the same effect it's not going to have access to your Franeas machine it's going to have access to the data on it but Franeas snapshots work one layer below at the block level therefore are able to restore to those previous states provided you have snapshots so hopefully this was helpful and hopefully someone thinks about deploying this this is one of the reasons we like these as storage servers and not being the same as your Windows file server it offers that extra layer of protection because it's a separate system by which you're storing files and the ZFS file system is very robust and just in the case of people losing files having hourly snapshot backups we have had a lot of clients not because of ransomware but we've rolled back a snapshot because they lost something and you know you're talking about hourly backups versus a nightly backup system or something that goes off site it's going to be very quick just to roll back a snapshot and like I said I'll leave videos below where I go in depth to both snapshots and replications so you can kind of follow through on more of that they're done in the previous version of Franeas but they still all that carries forward into the new version of Franeas as well alright thanks and once again thanks again for watching this video and see you next time


Hey curlfriends, I'm Bianca Renee and you're watching Bianca Renee Today and today we're gonna be talking about fragrance free products. There's a lot of debate about if you should have products with fragrance or if they should just take it out but fragrance is used for the obvious reason of smelling good. I personally love when a product has a really good smell. It's also always differentiate between different brands because different brands have different smells hence why we have our favorites. But a fragrance might be just too much for some of you. You might have allergies, sensitive skin, sensitive nose, you might get migraines. If the scent is too like strong or overbearing. So this is going to be a great option for you because today I'm going to be reviewing some products that are completely fragrance free. Today's video is sponsored by Lust Love Your Curls. They are known for their three step system, their shampoo conditioner and then the styler depending on your curl pattern but they have the same products now fragrance free. So although I already know I love the original line I am going to be trying the fragrance free line today to show you exactly how it works and how to apply them. Now some of you may know I do have a challenge every year where I challenge my subscribers and this year's challenge is to switch it up. Switch up something in your routine. So I personally have never used a fragrance free line so that's gonna be switched up number one but I'm also going to be styling my hair with their one styler which is a cream styler. I'm a gel girl. I mean I used to be a cream styler girl then I became totally team gel but I am going to be applying their cream styler today specifically the one for curly hair. So how Lust works is they have their shampoo conditioner all sulfate, paraben, silicone free. These are also fragrance free and then you choose the styler depending on your curl type. So they have one for kinky hair, curly hair or wavy hair. I'm gonna be using the curly styler today. So before we get started I do want to point out that there is a difference between fragrance free and unscented. Many people often try to stay away from things with fragrance because sometimes supposedly brands can be putting a bunch of ingredients in their product but then just labeling it fragrance therefore we don't exactly know what is in the product. Although brands are required to put their ingredients on the back of their bottles they can't put everything where people would just steal their formulas. Therefore making it not unique and there would be a million dupes. So in order to protect their signature fragrance they just put fragrance but they don't tell you all the things that make up that fragrance. Therefore causing some people to be skeptical about what exactly is in the product. So many just choose to opt out of fragrance completely so they know exactly what's in it. There's no scents, no irritants, no allergens. Just good to go. So fragrance free means that there's no actual fragrance like materials in the product where unscented could still have fragrance in it but it has another type of chemical that is masking the scent.  So keep that in mind when you're trying to decide between unscented or fragrance free. I don't think I've even ever reviewed a fragrance free line on my channel and I've had my channel for like eight years because there's really not too many fragrance free curly hair specific products on the market. So I'm very excited that LUS has decided to create a fragrance free line to give you guys some more options. So let's get started in the shower. All right, we're gonna start off with step one. LUS makes it really easy to do these in the correct order because it has one slapped right on the bottle. So this is their sulfate free shampoo for all curl types and yes, it is fragrance free and it doesn't smell like anything. And of course this is a sulfate free shampoo that works for all curl types.  So I was very pleasantly surprised to see how well this did clean my scalp. It gave me a nice clean feeling but it didn't feel stripped. To make sure I'm really clarifying my scalp I do give myself a little scalp massage since I even use a scalp massager just to really get in there and then I rinse it all out. And now for step two, the silicone free conditioner. Once again, doesn't smell like anything. This one is also for all curl types with shade butter and merengue oil and it is of course fragrance free. So when I detangle my hair I usually split up into two sections. This conditioner is suggesting to apply it to wet hair and to leave it on your hair for three to five minutes. Then add some water and then detangle. So I just started detangling like out of habit on this side, which it was a decent slip but I decided to actually follow the direction the second time, put it in my hair for three to five minutes while I wash my body, shave, do what you gotta do. And then I came back to it to detangle. It was a little bit easier to detangle after waiting. So I too would suggest applying the conditioner and then coming back to it to detangle. Now it's time to style these curls. So let's grab the Love Your Curl step three all in one curly styler, which is also fragrance free. Here we go. Yep, fragrance free. We're gonna do smooth and scrunch. That looks good. Next side, doing about three pumps, raking it in, smoothing it down, smooth, smooth, smooth and scrunch. Okay, so I don't exactly want a middle part. So I am going to style the top of my head to give it some more volume. I'm gonna comb it forward a little tiny more. Now I'm gonna let this dry and we'll come back and see how it looks. And voila, here are my final results. I'm really, really happy with it. At first I was like, oh my God, there's no crunch, no hold, eek, but then I really looked at it and like look how big it is. Like it's so fluffy, but not fluffy as in frizzy but just like big defined soft curls. So I'm really, really happy with it. Like look how it just moves. Am I gonna go back to cream stylers? That would be insane. I might, I might have to switch it up for the rest of the year because like this volume, the definition's still there but it is really soft. Like there is no crunch at all. I do usually prefer my less styling products on day two. For some reason when I apply it to not as wet hair I do have a little bit more of a cast which I do like but even on this day one, it looks really good. So I think I suffer from like product amnesia. Like I use a product and if I don't use it for a while I totally forget how amazing it is. So this is why it's really good to switch it up and go back to some products that you might not have tried before or switch it up and try something new like a fragrance free cream styler. So if you're looking for a really good curly hair products that are fragrance free, definitely check out LUS and buy the styler that according to your curl type. I'll make sure to link this in the description box and they gave me a promo code. So if you use my code, you'll save some money. If you enjoyed this video, make sure to give me a thumbs up and subscribe. I post new videos every week. I'm gonna be switching it up all year long. So let me know what you guys want me to switch it up to next. Are you someone that has been looking for fragrance free products? Have you tried these? Let me know all your thoughts. If you enjoyed this video, make sure to give me a thumbs up and subscribe. I post new videos every week. You also should hit that bell so I'm gonna be switching it up and posting videos on different days about different topics and you don't wanna miss any of my videos. So hit the bell so you're notified as soon as I post that new video. You also can follow me on TikTok, Twitter and Instagram at Ms. Bianca Renee. I'll see you guys next time. Thanks for watching Bianca Renee today.


Highlights it is the first attempt to combine covalent organic frameworks with hexagonal boron nitride, HBN, to construct efficient metal-free photocatalyst. The composite displays superior photocatalytic hydrogen production performance in metal-free systems. The integrated porous HBN can suppress electron backflow to optimize the composite photocatalytic activity. This article was authored by Gu Yan, Xiaodong Sun, Yu Zhong, and others.


In today's Cobb Highlight, we introduce you to the Cobb Tuning Titanium Cat-Back Exhaust for the 2012 Plus Subaru BRZ, 2012-16 FRS, and the 2017 Plus Toyota FT-slash GR86 models. The successor to Takumi's Toku delivery machine is all about fun and satisfying lightweight performance, and so is this exhaust. Even with the dual-exit design, this 100% titanium exhaust weighs in at only about 20 pounds, which is roughly half of the stock system and even comparable to some of the aftermarket single-exit steel exhaust options. Starting with the two-bolt flange just after the factory mid-pipe, this entire section all the way back to the center of the muffler is a full 3-inch diameter, and features hand-tig-welded pie cuts around the differential to keep the pipe as straight and free-flowing as possible. Speaking of the muffler, a large suitcase-style muffler with the Cobb logo stamped on the bottom tucks neatly behind the rear subframe and produces a deep growling note that sounds great without being obnoxious. And amplifies the fun pops and burbles on downshifts that exist from the factory, but the stock exhaust tends to subdue. Then a matching pair of 2.5-inch exhaust pipes extend off to each side of that muffler with more sexy-tig-welded pie cuts to make 90-degree bends, leading to the twin 4.5-inch blue tips to perfectly fill in the stock bumper cutouts. A bonus note about those twin exhaust pipes and tips is that they're highly adjustable. The slip-fit design means that they pivot up and down, slide in and out, and have adjustable width so that you can dial in an absolutely perfect install. There's no need to choose between weight, performance, style, or quality. The Cobb Titanium Cat-Back for the first and second gen BRZ, FR-S, and 8.6 models combines all of that in one exhaust. So make your daddy proud by drifting on over to CobbTuning.com to grab one for your car today.


firstly illery building  ما akes y Let's go! So it's like 8.30 in the morning right now and the flight leaves around 10. I don't want to miss my flight. When I'm with Trudy, I always miss my flight back. When I'm alone, I'm always on time. Yeah, so I'm just going to the airport right now because I always don't like flying at night because in the morning you get to see whatever is going on in the plane outside the plane. And also when you get down like around 12 o'clock in the afternoon, you'll be able to do whatever you want to do because I always go to a country without doing research. So when I get to the country, the first thing to do is get my SIM card. You know what, you get a SIM card. I always book an Airbnb so I need to go to the location directly. Get a taxi.  So that's how it is. Yeah, today I'm going to talk a lot so I get to Zambia. You stay tuned and come fly with me. I live around Kemuronco, which is just five minutes away from the airport. And this guy got to know that I speak English. He said 10,000. My brother, I was like, no way. He said he's going to enter the airport. I was like, no, don't enter the airport, park somewhere. So yeah, he said he's going to use the meter rule. So let's see. I don't like spending too much man because I don't have enough money. He just want to cheat me, but you know, I'm also from Africa. You know, cheating is actually normal. How do I feel like this is doubled? And then he's telling me it's 5,000. Just five minutes away from the airport. This is ridiculous, you know, but sometimes I don't want to complain. But this is totally ridiculous. Five minutes away from the airport. I think he was adding his own figures and stuff. Yeah, it's crazy man. Anyway, five dollars. It's all right. Let's get to the airport. International airport, but first and first, I need to go find my drone. You know what, when I came here the first day, my drone was seized because drones are not allowed to fly in Kigali. So before I go check in, let me go pick up my drone. And yeah, I'll show you when I'm getting my drone. So whenever you come to Kigali, if you have a drone, make sure you register first. The registration takes like three months, man. It's really not easy, but yeah, I just came to promote the country without drone. But I think the videos did work. Yeah, so I'll see you when I get there. So this is the place that I'm coming for my drone. I got my receipt that, yeah, this is the receipt that I had when they seized my drone. But I came here and yeah, the police officer watched my videos. That's another amazing feeling that I love about Rwanda, man. Help you. Ah, hi. I'm good. So it's like this place, only time I come back here, I just always feel like home. Like everyone, hi, what am I? Hi, what am I? It's super crazy, yeah. But yeah, Rwandis, you have to know that I love you so much and I love your country. And I will definitely come back again. But next time when I'm coming back, I definitely register this drone, man. Because you know, I need to give drone footage of this beautiful country. So I finally got my drone and I'm heading to Lesaka. You know, it's a beautiful experience when you go there and all the police officers, everyone, it's like I watch your videos. You have the guy who ate in the gutter. Man, what else should I call home apart from Rwanda, man. But hey, it's all good. I got my drone and I expect drone footage from Lesaka. I hope they don't seize my drone too in Lesaka. That's how it is. But like I said, whenever you are coming to this country, make sure you register your drone. If you really want to fly drones in here, the law really works in this country. No bribery, no corruption. This is how it is, man. Sorry guys, I have no footage to support what really happened to me that very moment at the airport because security is really tight in Rwanda. So I decided not to film. But what really happened to me was one of my worst travelling experience ever. So I was supposed to fly from Kigali to Lesaka. This guy refused to check me in. Why? Because I don't have a return ticket. I explained to him, I even showed him a bus ticket. A bus ticket from where? Lesaka to Botswana. Yet he just want to see a flight ticket. Of which a bus ticket also work. This guy intentionally made me miss my flight. And I was so, so mad. And when I went there to change the flight, they said I have to pay $200 to change my flight. And everything changed. I was super mad. Came back to the airport. If I had a chance to fly, I would surely fly that day. But this really happened. So you know what? I was so mad because I missed my flight. The guy told me that I don't have a return ticket. But like I always say, everything happens for a reason. I've been looking for these people for so long in this country. And finally they are here. Finally. Anyway, who are you? They don't know you. We work for Akadjera Aviation. Akadjera Aviation. Akadjera Aviation. What is the function of Akadjera Aviation? Sorry? What is the function? What do you do? We do helicopter services. We do meet and greet. We do aerial photography. We do a whole lot of stuff. We even have an academy. Pilot academy. I want you to do a luxury trip from what do you call it? What's the name? I wrote you guys email. I even went to your office to find you guys. Not knowing that I'm going to meet you guys here. Everything happens. That's why I missed my flight. I met the main boss even though she doesn't want to show on camera. Or are you good? I'm one ready. So she's the one that I went to find. She never allowed me to see her. You're so busy that time. Too bad. But everything happens for a reason. So I'm happy to have met you.  So while you're very happy to meet me, I'm equally happy to meet you. Because they told me that you're at KBC. I went there, waited for you. Teo sent you emails. I was like, Akadjera people are always busy. Anyway, I'm so happy to see you. We'll definitely work together. Let's hope you come back to Rwanda. Rwanda has a lot of things to offer. Especially when it comes to luxury tourism. We represent that with the Kegari Aviation. And so many other amazing things happening in the country. So listen, I don't want to take much of the time. I don't want to steal your show. Peace out. After waiting for 12 hours at Kegali International Airport, we finally embarked. Guess what? It's this beautiful hostess who is also a fan. And she doubled my food. Oh my goodness. Lusaka at night is just breathtaking. We finally touch down and welcome to Zambia. Yo, so we finally arrived in Zambia. I got my visa, $50 man. Yo, travelling in Africa cost a lot of money. But hey, we are here. And there are expert videos from this country. I don't know what you expect. But it's my first time in a southern African country. And I'm kind of super excited. Let's see what Zambia has to offer within a week. I am Maya. Stay tuned and enjoy more amazing episodes from your boy, Mr. Ghana Baby. And Elvis Deri, the editor and the cinematographer. Stay tuned for videos. I'm Maya. Peace out.


We're a medical student from the Kirksville College of Osteopathic Medicine in Missouri, and he will be talking about minocycline-induced intracranial hypertension. Okay, thank you for this opportunity. And I think in the interest of time, and we do have a third presentation, correct, then we'll just cruise through this pretty quickly. The case is a patient who presents with a bilateral transient visual obscurations in a vision and the occasional dim-outs. The history of her presentation is a 23-year-old female. In August, she complained of a plugged sensation in her riot ear and a pulsatile tinnitus or a whooshing in the left ear greater than the riot ear. About a week later, she went to her ENT, who treated her for an internal ear infection and gave her mucinex to try to decrease the congested sensation, which offered no relief of her symptoms. About that same time, she began to notice gray spots in her vision. The ENT ordered an MRI of the brain without contrast, which came back unremarkable and recommended that she go to see an ophthalmologist. The ophthalmology exam showed bilateral discodema and decreasing visual acuity from her baseline, and she was then referred here to the Moran Eye Center in her ophthalmology department. Throughout this course of her history, she did have mild, I'm sorry, moderate to severe headaches, which were and postural dim-outs of her vision. As far as her pertinent medical history, it was pretty empty, except that she was being treated for acne vulgaris with minocycling. Family history, social history, and the review of symptoms was unremarkable. Her exam initially was also unremarkable, I'm unsure, about three months, but that does bring up a good question we'll talk about in a little bit. She was able to read the 2020 line on exam, although it did seem to be kind of eccentric and definitely slower than what she was used to. People showed no apparent pupillary defect, no apparent problem on confrontational visual field. Her interocular pressures were normal, and she had full color vision and full extracular movements. Here's a copy of 24-2 Humphrey visual field that was obtained in the clinic. You can see on this exam enlarged blind spots in both eyes, and maybe even a secocentral visual defect here. The foveal threshold in the large blind spots were bilateral in a mean deviation of minus seven in the right eye and minus four in the left eye. On slit lamp exam and neurological exam, those were unremarkable with no focalizing defect or apparent problem on the anterior slit lamp exam. Although fun, this exam, as illustrated here, revealed pretty strong stage four to five papillodema bilaterally with loss of the physiologic cup, parapapillary halos, obfuscation of the vesicles both as they leave the cup and even centrally as well with splinter hemorrhages. We begin thinking of how to build a differential that causes for papillaria edema. The best way to think through this is the Monroe Kelly postulate, which is based on three premises. First that the cranium is of a fixed volume and is non-compliant and non-expansable. The pressure inside the cranium is a function of the volume of the contents, so the contents of the cranium being brain tissue, blood, and CSF. An increase in the volume of any of the three components will either necessitate an increase in the pressure of the cranium or a lessening of the volume of a constituent component. Thinking through a possible differential list, you need to consider changes in brain tissue volume which may include cerebral edema or mass effects, changes in blood volume which may include things like hemorrhages, changes in CSF either by increased production like an inflammatory process or the reduction in outflow of CSF by a process which blocks the outflow. So you can create a differential along those lines and examples of these could include things like venous sinus thrombosis, intracranial mass, hydrocephalus as well as others. On workup, we are going to look to see if indeed she does have increased intracranial pressure associated with her papillodema. So we want to do a lumbar puncture. The opening pressure of this patient was 50 centimeters of water and the CSF analysis otherwise was normal with no left shift or increased proteins and negative cultures. And then we want to review the MRI to look for signs of increased intracranial pressure. On this axial section of a T2 weighted image, you can see here that she does have posterior flattening of the globes in the sclera. You could probably also appreciate some of the papillodema here into the globe although she doesn't have any of the other signs that we may see on MRI which includes increased signal intensity of the optic disc, optic nerve sheathing although it kind of looks like on this picture, it's kind of equivocal as well as a flattening of the pituitary glider and empty cell on a sagittal view. But I think that the negative findings are perhaps just as important especially when considering a diagnosis of increased intracranial pressure. For example, no mass is found, there are no filling defects found in the dural sinuses, no hemorrhage was seen, no edema, no chord plexus adenoma for example. And so these negative findings need to work into our differential as well. Using the modified dandy criteria, we are able to see that this patient does have signs and symptoms of increased intracranial pressure such as visual obscurations, dimouts, papillodema on exam, she does complain of a pulse tinnitus and headache, as well as no other focalizing neurological symptoms. Elevated intracranial pressure on CSF analysis was apparent and there was no ideology seen on imaging for that increased intracranial pressure. So let's talk a little bit about tetracycline and their relationship to intracranial hypertension. The first mention that I was able to find was an editorial comment by a physician Gellis in the yearbook of pediatrics where he was first to kind of put the label as a bulging-Francinel syndrome on infants who were being treated with tetracycline. This was done in 1956. It took a full 11 years for the first description of tetracycline-induced intracranial hypertension to appear by Dr. Koch Weiser and Gilmore in the Journal of the American Medical Association. During the intervening period, there were many descriptions of the bulging-Francinel syndrome and since this time in 1967, there have been quite a few case studies regarding the connection between tetracycline and intracranial hypertension. Minocycline is a semi-synthetic derivative of tetracycline. The advantage for treating acne vulgaris is that it requires only daily or bi-daily dosing rather than the four times a day of tetracycline or the first-generation tetracycline. And that the dosing strength is generally lower due to the increased half-life and the increased activity in the serum. One thing that is important to understand is that it is three to five times more lipophilic than tetracycline or the first-generation tetracycline which means that it penetrates into the CSF through the blood-brain barrier more readily and can sit there and cause effects. The link to intracranial hypertension was first described for minocycline specifically by Monica in 1978 and one of the interesting things through the research is that minocycline may cause intracranial hypertension in the atypical patient meaning non-obese females in males or in adults or children. So a few key questions will come up in relationship to minocycline and intracranial hypertension. First of which is what is the actual incidence of minocycline causing increased intracranial hypertension and that question can't really be answered very well. The reason that can't be answered very well is that there hasn't been any cross-sectional studies to show what the actual incidence is. Minocycline is pretty frequently and commonly used by dermatology to treat acne as a first-line therapy and as a result you would expect that if there was a very strong correlation or a direct action of minocycline raising intracranial pressures that the incidence of minocycline caused intracranial hypertension would be quite high just based on the prevalence of the use of minocycline as that was postulated by Chu in 1998. But in addition doctors Maroon and Mealy in 1971 suggested that there are cases of not only asymptomatic intracranial hypertension and incidental findings of papillodema on exam associated with minocycline use that the actual incidence may be under-reported or the prevalence of increased hypertension may be under-appreciated. Who is the population at risk? Generally the incidence across the broad population of people is about 0.9 per 100,000. That does increase quite a bit if you restrict the population to obese females of child-bearing age and that incidence will increase anywhere from 13 to 19 out of 100,000 in the literature that I have seen. The problem with the incidence associated with minocycline and assessing a population at risk again falls on the same problems of are there unreported cases because of asymptomatic papillodema or asymptomatic intracranial hypertension associated with minocycline use but it does seem that the power of minocycline to induce this is not simply associated with the common risk factors of the general population of gender, of weight and of age because as more Monroe and Brain and Walker have stated that you can have minocycline-induced intracranial hypertension associated with males, with children and as well as non-obese females. What is the prognosis? Prognosis for minocycline-induced intracranial hypertension is generally good but that comes with a caveat and one of the caveats is that some of these case studies have reported an apparent division in the population of those who are affected by minocycline and that is that some of them will have an indolent course. Often the majority of cases in the case studies will have a slowly progressive course on set of headaches that gradually worsen visual obscurations which gradually worsen and those respond very well and quickly to cessation of minocycline as well as treatment with dimox. But there is a smaller subset of patients for which the course of the disease may be much more fulminant that there is a more acute presentation of headaches, more acute vision loss and symptoms associated with intracranial hypertension which doesn't respond as quickly or as well to therapy. In fact Gardner has given the possibility that there may be a genetic predisposition in the population to a response from an adverse response to minocycline therapy which creates a debate about whether or not minocycline is directly involved or if it is affecting a different population in a different manner. Perhaps that minocycline may be something that pushes a patient across a threshold into intracranial hypertension which brings up the question of what is the mechanism by which minocycline may cause intracranial hypertension and that has been unknown although there have been reports by Stuart that minocycline has an indirect effect on cyclic adenosine monophosphate within the arachnoid granulation in the subarachnoid where CSF is drained back into the dural sinuses and by decreasing the activity of cyclic adenosine monophosphate you are decreasing the reabsorption of CSF back into the systemic circulation causing congestion but that has not been elicited in the literature. Going back to our case the final diagnosis then is the intracranial hypertension secondary to minocycline use. The plan and the general treatment guidelines include immediate discontinuing of minocycline therapy. Diamox sequels has become the standard of care although it has not been established by any prospective research. The known effects of diamox on reducing intracranial pressure kind of sets itself up for becoming the first line therapy although the dosing that we have given her can vary quite a bit on a per patient basis as you consider the clinical experience of the clinician as well as the clinical signs and symptoms of the patient as well as weight management and patient education regarding intracranial hypertension. On one month follow-up the patient reported improved vision. She denied any headaches and pulse of tiled tinnitus. Her vision was stable and improving. Papillodema was reduced at one month to a stage three and visual fields improved with decreased physiologic blind spots and mean deviations also decreased. She was continuing on diamox at her current dosing with the plan to return one month and reevaluate at that time. Now a lot of the research has been well actually all of the research that I have read on minocycline induced intracranial hypertension has been exclusively case studies or case series presentations and as such there hasn't been a formalized even retrospective study or prospective study of minocycline's connection although there have been reports of varying degrees of the duration of minocycline use leading into intracranial hypertension. Anything from three days from the onset of therapy to weeks or even years later where minocycline may cause this intracranial hypertension syndrome and the cessation of minocycline kind of follows the same course in regards to the resolution of the symptoms. There were some cases where especially in the sorry especially in the older literature in the 70s where cessation of minocycline or tetracycline is generally caused almost an immediate approval of symptoms within the same day to some of the symptoms being recalcitrant to therapy even months and years later. The most common persistent effects would be things such as reduced visual acuity and visual field defects and that's it. Are there any questions? She wasn't incredibly tall and she was obese and that was definitely a confounding variable in this case and something to consider which is why we included in the plan weight loss and education in that regard. I don't think that you can definitively parse out the two in this case although the reports in literature that minocycline has induced this syndrome in non obese females as well. She didn't have a significant weight gain history either. She didn't report sudden weight increases or fluctuations in her weight in the years prior to presenting to us so that may reduce a little bit of suspicion but we can't definitively say that that did not play a role. There are reports in the literature of using topomax based on the idea that it does lower intracranial hypertension but the biggest problem with that is that there's no prospective study comparing topomax to dimox or even alternatives like loop diuretics for example all of which have been used in treatment. I do think that there is a spectrum of therapy options available to the clinician which also includes eventual surgical intervention to help resolve the symptomatology after maximum medical therapy has failed. Unfortunately I have read that topomax has been used and has been used successfully in the literature but there's a pretty bad dearth of support for besides case studies. Dr. Warner.