WEBVTT 00:00:00.453 --> 00:00:01.549 It's a pleasure to be here 00:00:01.549 --> 00:00:03.544 in Edinburgh, Scotland, 00:00:03.544 --> 00:00:06.891 the birthplace of the needle and syringe. 00:00:06.891 --> 00:00:09.732 Less than a mile from here in this direction 00:00:09.732 --> 00:00:11.706 in 1853 a Scotsman 00:00:11.706 --> 00:00:13.996 filed his very first patent on the needle and syringe. 00:00:13.996 --> 00:00:16.236 His name was Alexander Wood 00:00:16.236 --> 00:00:19.987 and it was at the Royal College of Physicians. 00:00:19.987 --> 00:00:22.465 This is the patent ... 00:00:22.465 --> 00:00:25.176 what blows my mind when I look at it even today 00:00:25.176 --> 00:00:27.349 is that it looks almost identical 00:00:27.349 --> 00:00:29.106 to needle in use today. 00:00:29.106 --> 00:00:32.666 Yet, it's 160 years old. NOTE Paragraph 00:00:32.666 --> 00:00:35.161 So we turn to the field of vaccines 00:00:35.161 --> 00:00:37.390 most vaccines are delivered with 00:00:37.390 --> 00:00:41.534 the needle and syringe, this 160 year old technology. 00:00:41.534 --> 00:00:43.445 And credit where its due on many levels 00:00:43.445 --> 00:00:47.096 vaccines are a successful technology. 00:00:47.096 --> 00:00:50.985 After clean water and sanitation, 00:00:50.985 --> 00:00:55.259 vaccines are the one technology that has increased 00:00:55.259 --> 00:00:57.789 our life span the most. 00:00:57.789 --> 00:01:00.618 That's a pretty hard act to beat. NOTE Paragraph 00:01:00.618 --> 00:01:02.057 But just like any other technology 00:01:02.057 --> 00:01:03.902 vaccines have their shortcomings 00:01:03.902 --> 00:01:06.538 and the needle, the needle and syringe 00:01:06.538 --> 00:01:08.741 is a key part within that narrative ... 00:01:08.741 --> 00:01:11.670 this old technology. 00:01:11.670 --> 00:01:13.969 So let's start with the obvious: 00:01:13.969 --> 00:01:17.451 many of us don't like the needle and syringe. 00:01:17.451 --> 00:01:19.365 I share that view. 00:01:19.365 --> 00:01:22.557 However, 20 percent of the population 00:01:22.557 --> 00:01:25.003 have a thing called needle phobia. 00:01:25.003 --> 00:01:26.364 That's more than disliking the needle 00:01:26.364 --> 00:01:29.063 that is actively avoiding being vaccinated 00:01:29.063 --> 00:01:30.927 because of needle phobia. 00:01:30.927 --> 00:01:33.304 And that's problematic in terms of the rollout 00:01:33.304 --> 00:01:35.253 of vaccines. NOTE Paragraph 00:01:35.253 --> 00:01:37.079 Now related to this is another key issue 00:01:37.079 --> 00:01:39.412 which is needlestick injuries. 00:01:39.412 --> 00:01:41.384 And the WHO has figures 00:01:41.384 --> 00:01:45.219 that suggest about 1.3 million deaths per year 00:01:45.219 --> 00:01:47.611 take place due to cross contamination 00:01:47.611 --> 00:01:48.895 with needlestick injuries. 00:01:48.895 --> 00:01:51.577 These are early deaths that take place. NOTE Paragraph 00:01:51.577 --> 00:01:54.558 Now these are two things that you probably may have heard of 00:01:54.558 --> 00:01:56.438 but there are two other shortcomings of 00:01:56.438 --> 00:01:58.922 the needle and syringe you may not have heard about. 00:01:58.922 --> 00:02:00.903 One is it could be holding back 00:02:00.903 --> 00:02:02.382 the next generation of vaccines 00:02:02.382 --> 00:02:04.671 in terms of their immune responses. 00:02:04.671 --> 00:02:07.598 And the second is that it could be responsible 00:02:07.598 --> 00:02:12.210 for the problem of the cold chain that I'll tell you about as well. NOTE Paragraph 00:02:12.210 --> 00:02:14.008 I'm going to tell you about some work that 00:02:14.008 --> 00:02:15.860 my team and I are doing in Australia 00:02:15.860 --> 00:02:17.601 at the University of Queensland 00:02:17.601 --> 00:02:21.998 on a technology of design to tackle those 4 problems. 00:02:21.998 --> 00:02:26.343 And that technology is called the Nanopatch. 00:02:26.343 --> 00:02:32.817 Now, this is a specimen of the Nanopatch. 00:02:32.817 --> 00:02:34.466 To the naked eye 00:02:34.466 --> 00:02:36.650 it just looks like a square 00:02:36.650 --> 00:02:39.549 smaller than a postage stamp, 00:02:39.549 --> 00:02:42.215 but under a microscope 00:02:42.215 --> 00:02:44.533 what you see is thousands of tiny proejctions 00:02:44.533 --> 00:02:46.754 that are invisible to the human eye. 00:02:46.754 --> 00:02:48.511 And there's about 4 thousand projections 00:02:48.511 --> 00:02:50.341 on this particular square compared 00:02:50.341 --> 00:02:51.907 to the needle. 00:02:51.907 --> 00:02:54.551 And I've designed those projections 00:02:54.551 --> 00:02:56.841 to serve a key roll which is to work with the skin's 00:02:56.841 --> 00:02:59.033 immune system. 00:02:59.033 --> 00:03:00.996 So that's a very important function 00:03:00.996 --> 00:03:02.452 tied in with the Nanopatch. NOTE Paragraph 00:03:02.452 --> 00:03:04.699 Now we make the Nanopatch 00:03:04.699 --> 00:03:07.236 with a technique 00:03:07.236 --> 00:03:09.615 called deep reactive ion etching ... 00:03:09.615 --> 00:03:11.306 and this particular technique is one that's been 00:03:11.306 --> 00:03:13.286 borrowed from the semiconductor industry 00:03:13.286 --> 00:03:15.122 and therefore, is low costing 00:03:15.122 --> 00:03:17.316 and can be rolled out in large numbers. NOTE Paragraph 00:03:17.316 --> 00:03:20.722 Now we dry coat vaccines to the projections 00:03:20.722 --> 00:03:22.336 of the Nanopatch 00:03:22.336 --> 00:03:24.201 and apply it to the skin. 00:03:24.201 --> 00:03:28.757 Now the simplest form of application 00:03:28.757 --> 00:03:30.779 is using our finger, 00:03:30.779 --> 00:03:33.399 but our finger has some limitations. 00:03:33.399 --> 00:03:35.653 So, we've devised an applicator 00:03:35.653 --> 00:03:36.786 and it's a very simple device -- 00:03:36.786 --> 00:03:39.088 you could call it a sophisticated finger. 00:03:39.088 --> 00:03:42.128 It's a screen operated device. 00:03:42.128 --> 00:03:44.169 What we do is when we apply the Nanopatch 00:03:44.169 --> 00:03:48.460 to the skin, as so ... 00:03:48.460 --> 00:03:50.736 immediately a few things happen. 00:03:50.736 --> 00:03:53.046 So firstly, the projections 00:03:53.046 --> 00:03:54.830 on the Nanopatch 00:03:54.830 --> 00:03:56.460 breach through the tough outer layer 00:03:56.460 --> 00:03:58.506 and the vaccine is very quickly released, 00:03:58.506 --> 00:04:00.854 within less than a minute in fact. 00:04:00.854 --> 00:04:03.420 Then we can take the Nanopatch off 00:04:03.420 --> 00:04:05.358 and discard it. 00:04:05.358 --> 00:04:07.385 And indeed we can make a reuse 00:04:07.385 --> 00:04:11.876 of the applicator itself. NOTE Paragraph 00:04:11.876 --> 00:04:13.811 So that gives you an idea of the Nanopatch 00:04:13.811 --> 00:04:16.280 and immediately you can see some key advantages. 00:04:16.280 --> 00:04:18.496 We've talked about it being needle-free, 00:04:18.496 --> 00:04:20.730 These are projections that you can't even see 00:04:20.730 --> 00:04:22.441 and of course we get around 00:04:22.441 --> 00:04:25.514 the needle phobia issue as well. NOTE Paragraph 00:04:25.514 --> 00:04:27.445 Now, if we take a step back and think about 00:04:27.445 --> 00:04:30.841 these other two really important advantages: 00:04:30.841 --> 00:04:34.877 one is improved immune responses through delivery 00:04:34.877 --> 00:04:38.610 and the second is getting rid of the cold chain. NOTE Paragraph 00:04:38.610 --> 00:04:39.599 So let's start with the first one, 00:04:39.599 --> 00:04:41.501 this immunogenicity idea, it takes a little while 00:04:41.501 --> 00:04:43.126 to get our head around but 00:04:43.126 --> 00:04:46.578 I'll try to explain it in simple terms. 00:04:46.578 --> 00:04:48.290 So I'll take a step back and explain to you 00:04:48.290 --> 00:04:51.838 how vaccines work in a simple way 00:04:51.838 --> 00:04:54.600 So vaccines work by introducing to our body 00:04:54.600 --> 00:04:56.518 a thing called an antigen 00:04:56.518 --> 00:04:59.695 which is a safe form of a germ. 00:04:59.695 --> 00:05:01.715 Now that safe germ, that antigen, 00:05:01.715 --> 00:05:05.220 tricks our body into mounting an immune response, 00:05:05.220 --> 00:05:09.288 learning and remembering how to deal with intruders. 00:05:09.288 --> 00:05:11.656 When the real intruder comes along 00:05:11.656 --> 00:05:13.417 the body quickly mounts an immune response 00:05:13.417 --> 00:05:15.053 to deal with that vaccine 00:05:15.053 --> 00:05:16.953 and neutralizes the infection. 00:05:16.953 --> 00:05:18.643 So it does that well. NOTE Paragraph 00:05:18.643 --> 00:05:20.980 Now, why it's done today with the needle and syringe 00:05:20.980 --> 00:05:23.431 is most vaccines are delivered that way -- 00:05:23.431 --> 00:05:24.885 with this old technology and the needle. 00:05:24.885 --> 00:05:26.677 But it could be argued 00:05:26.677 --> 00:05:29.191 that the needle is holding back 00:05:29.191 --> 00:05:30.358 our immune responses; 00:05:30.358 --> 00:05:32.237 it's missing our immune sweet spot 00:05:32.237 --> 00:05:34.106 in the skin. 00:05:34.106 --> 00:05:36.702 To describe this idea 00:05:36.702 --> 00:05:39.191 we need to take a journey through the skin 00:05:39.191 --> 00:05:41.815 starting with one of those projections 00:05:41.815 --> 00:05:44.260 and applying the Nanopatch to the skin. 00:05:44.260 --> 00:05:46.660 And we see this kind of data ... 00:05:46.660 --> 00:05:48.469 now this is real data ... 00:05:48.469 --> 00:05:50.815 that thing that we can see there is one projection 00:05:50.815 --> 00:05:53.271 from the Nanopatch that's been applied to the skin 00:05:53.271 --> 00:05:55.196 and those colors are different layers. 00:05:55.196 --> 00:05:56.480 Now to give you an idea of scale, 00:05:56.480 --> 00:05:58.420 if the needle was shown here it would be too big. 00:05:58.420 --> 00:05:59.945 It would be ten times bigger 00:05:59.945 --> 00:06:02.637 than the size of that screen going ten times deeper as well. 00:06:02.637 --> 00:06:05.482 It's off the grid entirely. 00:06:05.482 --> 00:06:06.952 You can see immediately that we have those 00:06:06.952 --> 00:06:08.252 projections in the skin. 00:06:08.252 --> 00:06:11.327 That red layer is a tough outer layer of dead skin 00:06:11.327 --> 00:06:12.773 but the brown layer 00:06:12.773 --> 00:06:13.841 and the magenta layer 00:06:13.841 --> 00:06:17.530 are jammed full of immune cells. 00:06:17.530 --> 00:06:18.878 As one example, in the brown layer 00:06:18.878 --> 00:06:20.956 theres a certain type of cell called Langerhan cell -- 00:06:20.956 --> 00:06:23.445 every square millimeter of our body 00:06:23.445 --> 00:06:26.465 is jammed full of those Langerhan cells, 00:06:26.465 --> 00:06:28.368 those immune cells, and there's others shown as well 00:06:28.368 --> 00:06:30.363 that we haven't [unclear] in this image 00:06:30.363 --> 00:06:32.543 but you can immediately see that the Nanopatch 00:06:32.543 --> 00:06:34.280 achieves that penetration indeed. 00:06:34.280 --> 00:06:37.709 We target thousands upon thousands of these particualar cells 00:06:37.709 --> 00:06:40.047 just residing within a hair's width 00:06:40.047 --> 00:06:43.328 of the surface of the skin. NOTE Paragraph 00:06:43.328 --> 00:06:45.444 Now, as the guy that has invented 00:06:45.444 --> 00:06:47.074 this thing and designed it to do that 00:06:47.074 --> 00:06:51.080 I found that exciting. But so what? 00:06:51.080 --> 00:06:52.310 So what if you've targeted cells, 00:06:52.310 --> 00:06:55.558 in the world of vaccines what does that mean? 00:06:55.558 --> 00:06:57.702 The world of vaccines is getting better. 00:06:57.702 --> 00:06:59.426 It's getting more systematic. 00:06:59.426 --> 00:07:01.648 However, you still don't really know 00:07:01.648 --> 00:07:03.392 if a vaccine is going to work 00:07:03.392 --> 00:07:04.731 until you roll your sleeves up 00:07:04.731 --> 00:07:06.946 and vaccinate and wait. 00:07:06.946 --> 00:07:09.648 It's a gambler's game even today. NOTE Paragraph 00:07:09.648 --> 00:07:12.160 So, we had to do that gamble. 00:07:12.160 --> 00:07:14.640 We obtained an influenza vaccine, 00:07:14.640 --> 00:07:16.256 we applied it to our Nanopatches 00:07:16.256 --> 00:07:19.235 and we applied the Nanopatches to the skin 00:07:19.235 --> 00:07:20.460 and we waited -- 00:07:20.460 --> 00:07:22.288 and this is in the live animal. 00:07:22.288 --> 00:07:24.139 We waited a month 00:07:24.139 --> 00:07:25.951 and this is what we found out ... 00:07:25.951 --> 00:07:28.276 this is a data slide showing the immune responses 00:07:28.276 --> 00:07:30.599 that we've generated with a Nanopatch 00:07:30.599 --> 00:07:34.375 compared to the needle and syringe into muscle. 00:07:34.375 --> 00:07:37.969 So on the horizontal axis we have the dose shown in nanograms. 00:07:37.969 --> 00:07:39.351 On the vertical axis we have 00:07:39.351 --> 00:07:42.654 the immune response generated and that dashed line, 00:07:42.654 --> 00:07:46.189 at that dashed line indicates the protection threshold. 00:07:46.189 --> 00:07:48.642 If we're above that line it's considered protective; 00:07:48.642 --> 00:07:51.568 if we're below that line it's not. 00:07:51.568 --> 00:07:54.136 So the red line is mostly below that curve 00:07:54.136 --> 00:07:55.860 and indeed there's only one point that is achieved 00:07:55.860 --> 00:07:57.737 with the needle that's protective 00:07:57.737 --> 00:08:00.869 and thats with a high dose of 6 thousand nanograms. 00:08:00.869 --> 00:08:03.402 but notice immediately the distinctly different curve 00:08:03.402 --> 00:08:06.913 that we achieve with the blue line. 00:08:06.913 --> 00:08:08.366 That's what's achieved with the Nanopatch 00:08:08.366 --> 00:08:10.103 the delivered dose of the Nanopatch is a 00:08:10.103 --> 00:08:13.464 completely different immunogenicity curve. 00:08:13.464 --> 00:08:15.297 That's a real fresh opportunity. 00:08:15.297 --> 00:08:17.675 Suddenly we have a brand new lever 00:08:17.675 --> 00:08:19.203 in the world of vaccines. 00:08:19.203 --> 00:08:20.714 We can push it one way 00:08:20.714 --> 00:08:23.305 where we can take a vaccine that works but is too expensive 00:08:23.305 --> 00:08:24.964 and can get protection 00:08:24.964 --> 00:08:27.788 with a hundredth of the dose compared to the needle. 00:08:27.788 --> 00:08:30.424 That can take a vaccine that's [unclear] 10 dollars 00:08:30.424 --> 00:08:33.380 down to 10 cents and that's particularly important 00:08:33.380 --> 00:08:35.497 within the developing world. NOTE Paragraph 00:08:35.497 --> 00:08:36.886 But there's another angle to this as well -- 00:08:36.886 --> 00:08:39.938 you can take vaccines that currently don't work 00:08:39.938 --> 00:08:41.134 and get them over that line 00:08:41.134 --> 00:08:43.092 and get them protective. 00:08:43.092 --> 00:08:45.320 And certainly in the world of vaccines 00:08:45.320 --> 00:08:46.540 that can be important. 00:08:46.540 --> 00:08:48.038 Let's consider the big 3: 00:08:48.038 --> 00:08:50.735 HIV, Malaria, Tuberculosis -- 00:08:50.735 --> 00:08:53.220 they're responsible for about 7 million deaths per year 00:08:53.220 --> 00:08:56.534 and there is no adequate vaccination method for any of those. 00:08:56.534 --> 00:08:58.960 So potentially, with this new lever that we have with the Nanopatch 00:08:58.960 --> 00:09:02.332 we can help make that happen. We can push that lever 00:09:02.332 --> 00:09:05.771 to help get those candidate vaccines over the line. 00:09:05.771 --> 00:09:07.589 Now of course we've worked within my lab 00:09:07.589 --> 00:09:09.379 with many other vaccines that have attained 00:09:09.379 --> 00:09:12.197 similar responses and similar curves to this -- 00:09:12.197 --> 00:09:15.962 what we've achieved with influenza. NOTE Paragraph 00:09:15.962 --> 00:09:18.121 I'd like to now switch to talk about 00:09:18.121 --> 00:09:21.361 another key shortcoming of today's vaccines 00:09:21.361 --> 00:09:24.873 and that is the need to maintain the cold chain. 00:09:24.873 --> 00:09:27.547 As the name suggests -- the cold chain -- 00:09:27.547 --> 00:09:30.487 it's the requirements of keeping a vaccine right from production 00:09:30.487 --> 00:09:33.163 all the way through to when the vaccine is applied 00:09:33.163 --> 00:09:36.261 to keep it refrigerated. 00:09:36.261 --> 00:09:39.507 Now, that presents some logistical challenges 00:09:39.507 --> 00:09:42.851 but we have ways to do it. 00:09:42.851 --> 00:09:47.033 This is a slightly extreme case in point 00:09:47.033 --> 00:09:49.224 but it helps illustrate the logistical challenges 00:09:49.224 --> 00:09:51.906 in particular in resource poor settings 00:09:51.906 --> 00:09:55.192 of what's required to get vaccines 00:09:55.192 --> 00:09:56.910 refrigerated and maintain the cold chain. 00:09:56.910 --> 00:10:00.724 If the vaccine is too warm, the vaccine breaks down 00:10:00.724 --> 00:10:02.931 but interestingly it can be too cold. 00:10:02.931 --> 00:10:05.492 and the vaccine can break down as well. NOTE Paragraph 00:10:05.492 --> 00:10:08.874 Now, the steaks are very high. 00:10:08.874 --> 00:10:11.409 The WHO estimates that within Africa, 00:10:11.409 --> 00:10:14.060 up to half the vaccines used there 00:10:14.060 --> 00:10:15.913 are considered to not be working properly 00:10:15.913 --> 00:10:18.903 because at some point the cold chain has fallen over. 00:10:18.903 --> 00:10:21.469 So it's a big problem and it's tied in with the needle and syringe 00:10:21.469 --> 00:10:26.702 because it's a liquid form vaccine and when it's liquid it needs refrigeration. NOTE Paragraph 00:10:26.702 --> 00:10:29.213 A key attribute of our Nanopatch 00:10:29.213 --> 00:10:31.186 is that the vaccine is dry. 00:10:31.186 --> 00:10:33.975 And when it's dry it doesn't need refrigeration. 00:10:33.975 --> 00:10:36.387 Within my lab we've shown that we can keep 00:10:36.387 --> 00:10:39.067 the vaccine stored at 23 degrees celcius 00:10:39.067 --> 00:10:42.783 for more than a year without any loss in activity at all. 00:10:42.783 --> 00:10:45.170 That's an important improvement. 00:10:45.170 --> 00:10:51.770 (Applause) 00:10:51.770 --> 00:10:54.233 We're delighted about it as well. 00:10:54.233 --> 00:10:58.529 And the thing about it is that we have well and truly proven 00:10:58.529 --> 00:11:01.192 the Nanopatch within the laboratory setting. 00:11:01.192 --> 00:11:05.165 And as a scientist, I love that and I love science. 00:11:05.165 --> 00:11:07.673 However, as an engineer, 00:11:07.673 --> 00:11:09.386 as a biomedical engineer 00:11:09.386 --> 00:11:11.589 and also as a human being, 00:11:11.589 --> 00:11:13.159 I'm not going to be satisfied until we've 00:11:13.159 --> 00:11:15.513 rolled this thing out, taken it out of the lab 00:11:15.513 --> 00:11:17.698 and got it to people in large numbers 00:11:17.698 --> 00:11:21.480 and particularly the people that need it the most. NOTE Paragraph 00:11:21.480 --> 00:11:24.182 So we've commenced this particular journey 00:11:24.182 --> 00:11:26.843 and we've commenced this journey in an unusual way ... 00:11:26.843 --> 00:11:29.926 we've started with Papua New Guinea. NOTE Paragraph 00:11:29.926 --> 00:11:32.032 Now Papua New Guinea 00:11:32.032 --> 00:11:35.961 is an example of a developing world country. 00:11:35.961 --> 00:11:38.773 It's about the same size as France 00:11:38.773 --> 00:11:41.563 but it suffers from many of the key barriers 00:11:41.563 --> 00:11:45.676 existing within the world of today's vaccines. 00:11:45.676 --> 00:11:47.289 There's logistics ... 00:11:47.289 --> 00:11:50.619 within this country there are only 800 refrigerators 00:11:50.619 --> 00:11:54.325 to keep vaccines chilled, many of them are old like this one in Port Moresby. 00:11:54.325 --> 00:11:55.940 Many of them are breaking down and many 00:11:55.940 --> 00:11:58.856 are not in the Highlands where they are required. 00:11:58.856 --> 00:12:00.319 That's a challenge. 00:12:00.319 --> 00:12:02.674 But also, Papua New Guinea has the worlds 00:12:02.674 --> 00:12:05.610 highest incidence of HPV, 00:12:05.610 --> 00:12:09.949 Human Papilloma Virus, the cervical cancer vaccine. 00:12:09.949 --> 00:12:12.434 Yet, that vacccine is not available in large numbers 00:12:12.434 --> 00:12:14.348 because it's too expensive. 00:12:14.348 --> 00:12:17.094 So for those two reasons, with the attributes of the Nanopatch 00:12:17.094 --> 00:12:19.709 we've got into field and worked with the Nanopatch, 00:12:19.709 --> 00:12:22.160 and taken it to Papua New Guinea 00:12:22.160 --> 00:12:26.143 and we'll be following that up shortly. NOTE Paragraph 00:12:26.143 --> 00:12:29.625 Now doing this kind of work is not easy. 00:12:29.625 --> 00:12:30.973 It's challenging, 00:12:30.973 --> 00:12:34.297 but there's nothing else in the world I'd rather be doing. 00:12:34.297 --> 00:12:36.320 And as we look ahead 00:12:36.320 --> 00:12:40.062 I'd like to share with you a thought ... 00:12:40.062 --> 00:12:44.070 it's the thought of a future where 00:12:44.070 --> 00:12:46.003 the 17 million deaths per year 00:12:46.003 --> 00:12:48.347 that we currently have due to infectious disease 00:12:48.347 --> 00:12:50.981 is a historical footnote. 00:12:50.981 --> 00:12:53.077 And it's a historical footnote that has been achieved 00:12:53.077 --> 00:12:56.545 by improved, radically improved vaccines. 00:12:56.545 --> 00:12:58.828 Now standing here today in front of you 00:12:58.828 --> 00:13:00.501 at the birthplace of the needle and syringe, 00:13:00.501 --> 00:13:03.298 a device that's 160 years old, 00:13:03.298 --> 00:13:05.634 I'm presenting to you an alternative approach 00:13:05.634 --> 00:13:07.883 that could really help make that happen -- 00:13:07.883 --> 00:13:09.805 and it's the Nanopatch with it's attributes of being 00:13:09.805 --> 00:13:12.124 needle-free, pain-free, 00:13:12.124 --> 00:13:16.296 the ability for removing the cold chain and improving the immunogenicity. 00:13:16.296 --> 00:13:18.249 Thank you. 00:13:18.249 --> 00:13:21.417 (Applause)