0:00:00.602,0:00:04.160
The first patient to ever be [br]treated with an antibiotic

0:00:04.160,0:00:05.693
was a policeman in Oxford.

0:00:05.693,0:00:07.800
On his day off from work,

0:00:07.800,0:00:11.173
he was scratched by a rose thorn[br]while working in the garden.

0:00:11.173,0:00:14.848
That small scratch became infected.

0:00:14.848,0:00:17.163
Over the next few days, [br]his head was swollen

0:00:17.163,0:00:18.884
with abscesses,

0:00:18.884,0:00:21.167
and in fact his eye was so infected

0:00:21.167,0:00:23.070
that they had to take it out,

0:00:23.070,0:00:26.050
and by February of 1941,

0:00:26.050,0:00:28.487
this poor man was on the verge of dying.

0:00:28.487,0:00:31.685
He was at Radcliffe Infirmary in Oxford,

0:00:31.685,0:00:33.991
and fortunately for him,

0:00:33.991,0:00:35.041
a small team of doctors

0:00:35.041,0:00:36.930
led by a Dr. Howard Florey

0:00:36.930,0:00:38.997
had managed to synthesize

0:00:38.997,0:00:41.820
a very small amount of penicillin,

0:00:41.820,0:00:43.901
a drug that had been discovered

0:00:43.901,0:00:46.223
12 years before by Alexander Fleming

0:00:46.223,0:00:49.930
but had never actually been [br]used to treat a human,

0:00:49.930,0:00:52.340
and indeed no one even [br]knew if the drug would work,

0:00:52.340,0:00:55.980
if it was full of impurities [br]that would kill the patient,

0:00:55.980,0:00:57.894
but Florey and his team figured

0:00:57.894,0:00:59.616
if they had to use it, [br]they might as well use it

0:00:59.616,0:01:02.181
on someone who was going to die anyway.

0:01:02.181,0:01:05.836
So they gave Albert Alexander,

0:01:05.836,0:01:08.715
this Oxford policeman, the drug,

0:01:08.715,0:01:11.132
and within 24 hours,

0:01:11.132,0:01:13.394
he started getting better.

0:01:13.394,0:01:17.370
His fever went down, [br]his appetite came back.

0:01:17.370,0:01:19.683
Second day, he was doing much better.

0:01:19.683,0:01:21.921
They were starting to [br]run out of penicillin,

0:01:21.921,0:01:23.983
so what they would do [br]was run with his urine

0:01:23.983,0:01:26.833
across the road to re-synthesize [br]the penicillin from his urine

0:01:26.833,0:01:28.768
and give it back to him,

0:01:28.768,0:01:30.016
and that worked.

0:01:30.016,0:01:32.496
Day four, well on the way to recovery.

0:01:32.496,0:01:34.134
This was a miracle.

0:01:34.134,0:01:38.370
Day five, they ran out of penicillin,

0:01:38.370,0:01:40.637
and the poor man died.

0:01:40.637,0:01:43.350
So that story didn't end that well,

0:01:43.350,0:01:47.700
but fortunately for [br]millions of other people,

0:01:47.700,0:01:50.706
like this child who was treated [br]again in the early 1940s,

0:01:50.706,0:01:53.740
who was again dying of a sepsis,

0:01:53.740,0:01:56.890
and within just six days, you can see,

0:01:56.890,0:02:00.243
recovered thanks to this [br]wonder drug, penicillin.

0:02:00.243,0:02:02.201
Millions have lived,

0:02:02.201,0:02:05.785
and global health has been transformed.

0:02:05.785,0:02:08.578
Now, antibiotics have been used

0:02:08.578,0:02:11.705
for patients like this,

0:02:11.705,0:02:13.842
but they've also been [br]used rather frivolously

0:02:13.842,0:02:15.586
in some instances,

0:02:15.586,0:02:17.949
for treating someone [br]with just a cold or the flu,

0:02:17.949,0:02:20.423
which they might not have [br]responded to an antibiotic,

0:02:20.423,0:02:24.161
and they've also been [br]used in large quantities

0:02:24.161,0:02:27.803
sub-therapeutically, which[br]means in small concentrations,

0:02:27.803,0:02:30.986
to make chicken and hogs grow faster.

0:02:30.986,0:02:34.552
Just to save a few pennies[br]on the price of meat,

0:02:34.552,0:02:37.252
we've spent a lot of [br]antibiotics on animals,

0:02:37.252,0:02:39.614
not for treatment, not for sick animals,

0:02:39.614,0:02:42.730
but primarily for growth promotion.

0:02:42.730,0:02:45.587
Now, what did that lead us to?

0:02:45.587,0:02:48.298
Basically, the massive use of antibiotics

0:02:48.298,0:02:49.783
around the world

0:02:49.783,0:02:53.587
has imposed such large[br]selection pressure on bacteria

0:02:53.587,0:02:56.240
that resistance is now a problem,

0:02:56.240,0:02:58.010
because we've now selected for just

0:02:58.010,0:02:59.985
the resistant bacteria.

0:02:59.985,0:03:02.825
And I'm sure you've all read[br]about this in the newspapers,

0:03:02.825,0:03:04.629
you've seen this in every magazine

0:03:04.629,0:03:06.528
that you come across,

0:03:06.528,0:03:08.328
but I really want you to appreciate

0:03:08.328,0:03:10.499
the significance of this problem.

0:03:10.499,0:03:11.950
This is serious.

0:03:11.950,0:03:16.766
The next slide I'm about to show you is [br]of carbapenem resistance in acinetobacter.

0:03:16.766,0:03:19.154
Acinetobacter is a nasty hospital bug,

0:03:19.154,0:03:20.487
and carbapenem is pretty much

0:03:20.487,0:03:22.265
the strongest class of antibiotics

0:03:22.265,0:03:24.721
that we can throw at this bug.

0:03:24.721,0:03:27.990
And you can see in 1999

0:03:27.990,0:03:30.185
this is the pattern of resistance,

0:03:30.185,0:03:33.218
mostly under about 10 percent[br]across the United States.

0:03:33.218,0:03:37.215
Now watch what happens [br]when we play the video.

0:03:46.461,0:03:48.516
So I don't know where you live,

0:03:48.516,0:03:51.418
but wherever it is, it certainly is a lot worse now

0:03:51.418,0:03:53.915
than it was in 1999,

0:03:53.915,0:03:57.886
and that is the problem of antibiotic resistance.

0:03:57.886,0:03:59.573
It's a global issue

0:03:59.573,0:04:02.001
affecting both rich and poor countries,

0:04:02.001,0:04:04.242
and at the heart of it, [br]you might say, well,

0:04:04.242,0:04:06.170
isn't this really just a medical issue?

0:04:06.170,0:04:08.731
If we taught doctors how not [br]to use antibiotics as much,

0:04:08.731,0:04:11.676
if we taught patients how [br]not to demand antibiotics,

0:04:11.676,0:04:13.131
perhaps this really wouldn't be an issue,

0:04:13.131,0:04:15.120
and maybe the pharmaceutical companies

0:04:15.120,0:04:16.875
should be working harder to develop

0:04:16.875,0:04:18.511
more antibiotics.

0:04:18.511,0:04:21.890
Now, it turns out that there's something [br]fundamental about antibiotics

0:04:21.890,0:04:23.673
which makes it different from other drugs,

0:04:23.673,0:04:25.694
which is that if I misuse antibiotics

0:04:25.694,0:04:27.431
or I use antibiotics,

0:04:27.431,0:04:31.291
not only am I affected but [br]others are affected as well,

0:04:31.291,0:04:33.629
in the same way as if I [br]choose to drive to work

0:04:33.629,0:04:36.268
or take a plane to go somewhere,

0:04:36.268,0:04:38.242
that the costs I impose on others

0:04:38.242,0:04:40.682
through global climate change go everywhere,

0:04:40.682,0:04:43.455
and I don't necessarily take[br]these costs into consideration.

0:04:43.455,0:04:46.334
This is what economists might [br]call a problem of the commons,

0:04:46.334,0:04:48.314
and the problem of the commons is exactly

0:04:48.314,0:04:50.739
what we face in the case [br]of antibiotics as well:

0:04:50.739,0:04:52.889
that we don't consider —

0:04:52.889,0:04:55.891
and we, including individuals, patients,

0:04:55.891,0:04:59.050
hospitals, entire health systems —

0:04:59.050,0:05:01.198
do not consider the costs [br]that they impose on others

0:05:01.198,0:05:03.554
by the way antibiotics are actually used.

0:05:03.554,0:05:05.959
Now, that's a problem that's similar

0:05:05.959,0:05:07.941
to another area that we all know about,

0:05:07.941,0:05:09.870
which is of fuel use and energy,

0:05:09.870,0:05:11.369
and of course energy use

0:05:11.369,0:05:14.451
both depletes energy as well as

0:05:14.451,0:05:17.713
leads to local pollution [br]and climate change.

0:05:17.713,0:05:19.523
And typically, in the case of energy,

0:05:19.523,0:05:21.831
there are two ways in which[br]you can deal with the problem.

0:05:21.831,0:05:25.576
One is, we can make better[br]use of the oil that we have,

0:05:25.576,0:05:27.691
and that's analogous to making better use

0:05:27.691,0:05:29.239
of existing antibiotics,

0:05:29.239,0:05:30.930
and we can do this in a number of ways

0:05:30.930,0:05:33.160
that we'll talk about in a second,

0:05:33.160,0:05:36.847
but the other option is the [br]"drill, baby, drill" option,

0:05:36.847,0:05:41.038
which in the case of antibiotics [br]is to go find new antibiotics.

0:05:41.050,0:05:43.100
Now, these are not separate.

0:05:43.100,0:05:46.522
They're related, because if we invest heavily

0:05:46.522,0:05:48.806
in new oil wells,

0:05:48.806,0:05:51.760
we reduce the incentives [br]for conservation of oil

0:05:51.760,0:05:54.286
in the same way that's going [br]to happen for antibiotics.

0:05:54.286,0:05:56.454
The reverse is also going [br]to happen, which is that

0:05:56.454,0:05:58.792
if we use our antibiotics appropriately,

0:05:58.792,0:06:01.573
we don't necessarily have [br]to make the investments

0:06:01.573,0:06:03.750
in new drug development.

0:06:03.750,0:06:06.466
And if you thought that these two were entirely,

0:06:06.466,0:06:08.288
fully balanced between these two options,

0:06:08.288,0:06:10.471
you might consider the fact that

0:06:10.471,0:06:12.743
this is really a game that we're playing.

0:06:12.743,0:06:15.184
The game is really one of coevolution,

0:06:15.184,0:06:18.116
and coevolution is, in [br]this particular picture,

0:06:18.116,0:06:20.472
between cheetahs and gazelles.

0:06:20.472,0:06:22.090
Cheetahs have evolved to run faster,

0:06:22.090,0:06:23.667
because if they didn't run faster,

0:06:23.667,0:06:25.613
they wouldn't get any lunch.

0:06:25.613,0:06:28.300
Gazelles have evolved to run faster because

0:06:28.300,0:06:31.509
if they don't run faster, they would be lunch.

0:06:31.509,0:06:34.395
Now, this is the game we're[br]playing against the bacteria,

0:06:34.395,0:06:36.452
except we're not the cheetahs,

0:06:36.452,0:06:37.929
we're the gazelles,

0:06:37.929,0:06:40.716
and the bacteria would,

0:06:40.716,0:06:42.549
just in the course of this little talk,

0:06:42.549,0:06:43.975
would have had kids and grandkids

0:06:43.975,0:06:46.360
and figured out how to be resistant

0:06:46.360,0:06:48.834
just by selection and trial and error,

0:06:48.834,0:06:50.746
trying it over and over again.

0:06:50.746,0:06:54.518
Whereas how do we stay [br]ahead of the bacteria?

0:06:54.518,0:06:56.572
We have drug discovery processes,

0:06:56.572,0:06:58.202
screening molecules,

0:06:58.202,0:06:59.930
we have clinical trials,

0:06:59.930,0:07:02.078
and then, when we think we have a drug,

0:07:02.078,0:07:05.823
then we have the FDA regulatory process.

0:07:05.823,0:07:08.001
And once we go through all of that,

0:07:08.001,0:07:10.266
then we try to stay one step ahead

0:07:10.266,0:07:12.562
of the bacteria.

0:07:12.562,0:07:15.339
Now, this is clearly not a [br]game that can be sustained,

0:07:15.339,0:07:16.476
or one that we can win

0:07:16.476,0:07:18.313
by simply innovating to stay ahead.

0:07:18.313,0:07:21.618
We've got to slow the pace of coevolution down,

0:07:21.618,0:07:25.300
and there are ideas that we [br]can borrow from energy

0:07:25.300,0:07:27.070
that are helpful in thinking about

0:07:27.070,0:07:28.607
how we might want to do this in the case

0:07:28.607,0:07:30.153
of antibiotics as well.

0:07:30.153,0:07:32.393
Now, if you think about how we deal with

0:07:32.393,0:07:33.816
energy pricing, for instance,

0:07:33.816,0:07:35.665
we consider emissions taxes,

0:07:35.665,0:07:38.249
which means we're imposing [br]the costs of pollution

0:07:38.249,0:07:41.080
on people who actually use that energy.

0:07:41.080,0:07:44.060
We might consider doing that for antibiotics as well,

0:07:44.060,0:07:46.771
and perhaps that would make sure that antibiotics

0:07:46.771,0:07:49.172
actually get used appropriately.

0:07:49.172,0:07:51.200
There are clean energy subsidies,

0:07:51.200,0:07:54.255
which are to switch to fuels[br]which don't pollute as much

0:07:54.255,0:07:57.100
or perhaps don't need fossil fuels.

0:07:57.100,0:07:59.960
Now, the analogy here is, perhaps we need

0:07:59.960,0:08:02.220
to move away from using antibiotics,

0:08:02.220,0:08:05.936
and if you think about it, what are [br]good substitutes for antibiotics?

0:08:05.936,0:08:08.100
Well, turns out that anything that reduces

0:08:08.100,0:08:10.343
the need for the antibiotic would really work,

0:08:10.343,0:08:13.485
so that could include improving[br]hospital infection control

0:08:13.485,0:08:16.380
or vaccinating people,

0:08:16.380,0:08:18.677
particularly against [br]the seasonal influenza.

0:08:18.677,0:08:21.208
And the seasonal flu is probably

0:08:21.208,0:08:24.212
the biggest driver of antibiotic use,

0:08:24.212,0:08:27.131
both in this country as well[br]as in many other countries,

0:08:27.131,0:08:29.151
and that could really help.

0:08:29.151,0:08:33.254
A third option might include[br]something like tradeable permits.

0:08:33.254,0:08:37.500
And these seem like faraway scenarios,

0:08:37.500,0:08:39.927
but if you consider the [br]fact that we might not

0:08:39.927,0:08:43.310
have antibiotics for many [br]people who have infections,

0:08:43.310,0:08:45.547
we might consider the fact that we might

0:08:45.547,0:08:47.858
want to allocate who actually gets to use

0:08:47.858,0:08:50.572
some of these antibiotics over others,

0:08:50.572,0:08:53.898
and some of these might have to[br]be on the basis of clinical need,

0:08:53.898,0:08:55.833
but also on the basis of pricing.

0:08:55.833,0:08:57.743
And certainly consumer education works.

0:08:57.743,0:09:00.344
Very often, people overuse antibiotics

0:09:00.344,0:09:02.621
or prescribe too much without necessarily

0:09:02.621,0:09:04.227
knowing that they do so,

0:09:04.227,0:09:05.658
and feedback mechanisms

0:09:05.658,0:09:07.560
have been found to be useful,

0:09:07.560,0:09:09.489
both on energy —

0:09:09.489,0:09:11.029
When you tell someone that they're using

0:09:11.029,0:09:12.946
a lot of energy during peak hour,

0:09:12.946,0:09:14.416
they tend to cut back,

0:09:14.416,0:09:16.183
and the same sort of example has been performed

0:09:16.183,0:09:17.993
even in the case of antibiotics.

0:09:17.993,0:09:19.974
A hospital in St. Louis basically would put up

0:09:19.974,0:09:24.166
on a chart the names of surgeons

0:09:24.166,0:09:26.385
in the ordering of how much antibiotics they'd used

0:09:26.385,0:09:28.329
in the previous month,

0:09:28.329,0:09:30.671
and this was purely an [br]informational feedback,

0:09:30.671,0:09:31.854
there was no shaming,

0:09:31.854,0:09:33.989
but essentially that provided [br]some information back

0:09:33.989,0:09:35.943
to surgeons that maybe they could rethink

0:09:35.943,0:09:38.172
how they were using antibiotics.

0:09:38.172,0:09:40.186
Now, there's a lot that can be done

0:09:40.186,0:09:42.335
on the supply side as well.

0:09:42.335,0:09:44.112
If you look at the price of penicillin,

0:09:44.112,0:09:45.763
the cost per day is about 10 cents.

0:09:45.763,0:09:47.521
It's a fairly cheap drug.

0:09:47.521,0:09:49.658
If you take drugs that have[br]been introduced since then —

0:09:49.658,0:09:52.302
linezolid or daptomycin —

0:09:52.302,0:09:54.180
those are significantly more expensive,

0:09:54.180,0:09:59.631
so to a world that has been used to[br]paying 10 cents a day for antibiotics,

0:09:59.633,0:10:02.163
the idea of paying 180 dollars per day

0:10:02.163,0:10:03.730
seems like a lot.

0:10:03.730,0:10:05.717
But what is that really telling us?

0:10:05.717,0:10:07.682
That price is telling us

0:10:07.682,0:10:09.580
that we should no longer

0:10:09.580,0:10:13.697
take cheap, effective [br]antibiotics as a given

0:10:13.697,0:10:15.464
into the foreseeable future,

0:10:15.464,0:10:17.994
and that price is a signal to us

0:10:17.994,0:10:19.603
that perhaps we need to be paying

0:10:19.603,0:10:22.156
much more attention to conservation.

0:10:22.156,0:10:24.860
That price is also a signal

0:10:24.860,0:10:27.735
that maybe we need to start[br]looking at other technologies,

0:10:27.735,0:10:30.387
in the same way that [br]gasoline prices are a signal

0:10:30.387,0:10:32.977
and an impetus, to, say,

0:10:32.977,0:10:34.845
the development of electric cars.

0:10:34.845,0:10:36.622
Prices are important signals

0:10:36.622,0:10:38.208
and we need to pay attention,

0:10:38.208,0:10:40.660
but we also need to consider the fact that

0:10:40.660,0:10:44.912
although these high prices[br]seem unusual for antibiotics,

0:10:44.912,0:10:47.151
they're nothing compared to the price per day

0:10:47.151,0:10:48.535
of some cancer drugs,

0:10:48.535,0:10:51.905
which might save a patient's life only[br]for a few months or perhaps a year,

0:10:51.905,0:10:53.675
whereas antibiotics would potentially

0:10:53.675,0:10:55.501
save a patient's life forever.

0:10:55.501,0:10:56.820
So this is going to involve

0:10:56.820,0:10:58.782
a whole new paradigm shift,

0:10:58.782,0:11:00.638
and it's also a scary shift because

0:11:00.638,0:11:02.967
in many parts of this country,

0:11:02.967,0:11:04.711
in many parts of the world,

0:11:04.711,0:11:06.780
the idea of paying 200 dollars

0:11:06.780,0:11:09.671
for a day of antibiotic treatment

0:11:09.671,0:11:12.213
is simply unimaginable.

0:11:12.213,0:11:13.947
So we need to think about that.

0:11:13.947,0:11:15.760
Now, there are backstop options,

0:11:15.760,0:11:18.436
which is other alternative technologies

0:11:18.436,0:11:19.630
that people are working on.

0:11:19.630,0:11:22.282
It includes bacteriophages, probiotics,

0:11:22.282,0:11:26.330
quorum sensing, synbiotics.

0:11:26.330,0:11:29.369
Now, all of these are useful avenues to pursue,

0:11:29.369,0:11:31.979
and they will become even more lucrative

0:11:31.979,0:11:35.060
when the price of new [br]antibiotics starts going higher,

0:11:35.060,0:11:37.957
and we've seen that the[br]market does actually respond,

0:11:37.957,0:11:39.965
and the government is now considering

0:11:39.965,0:11:43.732
ways of subsidizing new [br]antibiotics and development.

0:11:43.732,0:11:45.455
But there are challenges here.

0:11:45.455,0:11:47.030
We don't want to just throw money at a problem.

0:11:47.030,0:11:48.549
What we want to be able to do

0:11:48.549,0:11:50.828
is invest in new antibiotics

0:11:50.828,0:11:53.804
in ways that actually encourage

0:11:53.804,0:11:56.824
appropriate use and sales of those antibiotics,

0:11:56.824,0:11:59.287
and that really is the challenge here.

0:11:59.287,0:12:01.616
Now, going back to these technologies,

0:12:01.616,0:12:03.979
you all remember the line from that famous

0:12:03.979,0:12:06.205
dinosaur film, "Nature will find a way."

0:12:06.205,0:12:09.524
So it's not as if these are [br]permanent solutions.

0:12:09.524,0:12:13.610
We really have to remember that,[br]whatever the technology might be,

0:12:13.610,0:12:16.486
that nature will find some [br]way to work around it.

0:12:16.486,0:12:18.557
You might think, well, [br]this is just a problem

0:12:18.557,0:12:21.301
just with antibiotics and with bacteria,

0:12:21.301,0:12:23.247
but it turns out that we [br]have the exact same

0:12:23.247,0:12:25.981
identical problem in [br]many other fields as well,

0:12:25.981,0:12:28.933
with multidrug-resistant tuberculosis,

0:12:28.933,0:12:32.495
which is a serious problem [br]in India and South Africa.

0:12:32.495,0:12:34.282
Thousands of patients are dying because

0:12:34.282,0:12:36.116
the second-line drugs are so expensive,

0:12:36.116,0:12:38.343
and in some instances, even those don't work

0:12:38.343,0:12:40.413
and you have XDR TB.

0:12:40.413,0:12:42.224
Viruses are becoming resistant.

0:12:42.224,0:12:45.390
Agricultural pests. Malaria parasites.

0:12:45.390,0:12:47.173
Right now, much of the world depends on

0:12:47.173,0:12:50.870
one drug, artemisinin drugs,

0:12:50.870,0:12:52.826
essentially to treat malaria.

0:12:52.826,0:12:55.413
Resistance to artemisinin has already emerged,

0:12:55.413,0:12:57.767
and if this were to become widespread,

0:12:57.767,0:12:59.115
that puts at risk

0:12:59.115,0:13:02.006
the single drug that we have to [br]treat malaria around the world

0:13:02.006,0:13:05.220
in a way that's currently [br]safe and efficacious.

0:13:05.220,0:13:07.018
Mosquitos develop resistance.

0:13:07.018,0:13:09.255
If you have kids, you probably [br]know about head lice,

0:13:09.255,0:13:10.968
and if you're from New York City,

0:13:10.968,0:13:13.701
I understand that the [br]specialty there is bedbugs.

0:13:13.701,0:13:15.956
So those are also resistant.

0:13:15.956,0:13:18.835
And we have to bring an[br]example from across the pond.

0:13:18.835,0:13:21.190
Turns out that rats are [br]also resistant to poisons.

0:13:21.190,0:13:23.891
Now, what's common [br]to all of these things is

0:13:23.891,0:13:26.597
the idea that we've had these technologies

0:13:26.597,0:13:31.218
to control nature only for [br]the last 70, 80 or 100 years

0:13:31.218,0:13:34.246
and essentially in a blink,

0:13:34.246,0:13:36.797
we have squandered our ability to control,

0:13:36.797,0:13:39.288
because we have not recognized

0:13:39.288,0:13:42.100
that natural selection and [br]evolution was going to find

0:13:42.100,0:13:43.274
a way to get back,

0:13:43.274,0:13:45.323
and we need to completely rethink

0:13:45.323,0:13:47.666
how we're going to use

0:13:47.666,0:13:50.760
measures to control biological organisms,

0:13:50.760,0:13:54.224
and rethink how we incentivize

0:13:54.224,0:13:56.450
the development, introduction,

0:13:56.450,0:13:59.118
in the case of antibiotics prescription,

0:13:59.118,0:14:02.890
and use of these valuable resources.

0:14:02.890,0:14:05.270
And we really now need to [br]start thinking about them

0:14:05.270,0:14:07.228
as natural resources.

0:14:07.228,0:14:09.466
And so we stand at a crossroads.

0:14:09.466,0:14:12.625
An option is to go through that rethinking

0:14:12.625,0:14:14.438
and carefully consider incentives

0:14:14.438,0:14:16.992
to change how we do business.

0:14:16.992,0:14:19.253
The alternative is

0:14:19.253,0:14:22.336
a world in which even a blade of grass

0:14:22.336,0:14:24.765
is a potentially lethal weapon.

0:14:24.765,0:14:26.565
Thank you.

0:14:26.565,0:14:29.300
(Applause)