Results for “human challenge” 104 found
A vaccine for COVID-19 is urgently needed. Several vaccine trial designs may significantly accelerate vaccine testing and approval, but also increase risks to human subjects. Concerns about whether the public would see such designs as ethically acceptable represent an important roadblock to their implementation, and the World Health Organization has called for consulting the public regarding them. Here we present results from a pre-registered cross-national survey (n= 5; 920) of individuals in Australia, Canada, Hong Kong, New Zealand, South Africa, Singapore, the United Kingdom, and the United States. The survey asked respondents whether they would prefer scientists to conduct traditional trials or one of two accelerated designs: a challenge trial or a trial integrating a Phase II safety and immunogenicity trial into a larger Phase III efficacy trial. We find broad majorities prefer for scientists to conduct challenge trials (75%, 95% CI: 73-76%) and integrated trials (63%, 95% CI: 61-65%) over standard trials. Even as respondents acknowledged the risks, they perceived both accelerated trials as similarly ethical to standard trial designs, and large majorities characterized them as “probably” or “definitely ethical” (72%, 95% CI:70-73% for challenge trials; 77%, 95% CI 75-78% for integrated trials). This high support is consistent across every geography and demographic subgroup we examined, including people of diverging political orientations and vulnerable populations such as the elderly, essential workers, and racial and ethnic minorities. These findings bolster the case for these accelerated designs and can help assuage concerns that they would undermine public trust in vaccines.
Here is the paper by David Broockman, et.al.
As I have been warning, social distancing measures are making it more difficult to test COVID vaccines even as the cost of COVID remains very high.
WashPost: The Oxford group earlier boasted that it had an 80 percent chance of developing an effective vaccine by September. Hill said the difficulty of testing the vaccine in Britain may mean there’s only a 50 percent chance of success within that time frame now.
The probability of an Oxford vaccine by September has fallen by 30 percentage points. Oxford isn’t the only vaccine and we may be able to find clinical trial candidates in Brazil and the United States where infections continue to occur. So let’s be generous and convert this into say a 10% increase in a one month’s delay of any vaccine. The world economy is losing $375 billion a month so this means we have lost an expected $37.5 billion. That number highlights why we should be willing to pay large sums to speed vaccines and it also indicates the immense value of human challenge trials.
More than 28,000 people have already volunteered to be part of a challenge trial and if we paid a few hundred volunteers a million dollars each it would be worthwhile (and would surely increase the number of volunteers).
The main impediment to human challenge trials appears to be skittish firms rather than bureaucratic governments which is why challenge trials should test multiple vaccines under the auspices of the NIH. The NIH umbrella can protect the firms and increase the efficiency of the trials.
Addendum: China is adopting a bold approach. We used to be bold. Apathy is killing us.
In Why Human Challenge Trials Will Be Necessary to Get a Coronavirus Vaccine I asked, “What if we develop a vaccine for COVID-19 but can’t find enough patients–healthy yet who might get sick–to run a randomized clinical trial?” Exactly that problem is now facing the Oxford vaccine in Britain.
An Oxford University vaccine trial has only a 50 per cent chance of success because coronavirus is fading so rapidly in Britain, a project co-leader has warned.
…Hill said that of 10,000 people recruited to test the vaccine in the coming weeks — some of whom will be given a placebo — he expected fewer than 50 people to catch the virus. If fewer than 20 test positive, then the results might be useless, he warned.
As I wrote, “A low infection rate is great, unless you want to properly test a vaccine.” Challenge trials have issues of external validity and they take time to setup properly but they produce results quickly and they can be especially useful in whittling down vaccine candidates to focus on the best candidates.
1DaySooner now has over 25 thousand volunteers from over 100 countries.
What if we develop a vaccine for COVID-19 but can’t find enough patients to run a randomized clinical trial? It sounds absurd, but this problem has happened in the past. Ebola was identified in 1976, and candidate vaccines were proven safe and effective in mice and primates in 2004 and 2005, respectively. But no human vaccine was produced [at that time] because it was extremely difficult, bordering on impossible, to trial an Ebola vaccine. The problem? Ebola is so deadly that people take precautionary measures long before a vaccine can be tested.
A few pieces have been written about human challenge trials, clinical trials in which healthy people are infected with a disease in order to see if a treatment or vaccine works, but most of them focus on the ethical issues. I don’t think there are serious ethical issues so writing at The National Interest I focus on why challenge trials are useful statistically and why they may even be necessary.
Even health care workers, however, have a low enough infection rate that you either need many months to determine if there is a significant effect, or you need large populations. In Italy, about 6,000 doctors were infected over two months, out of a population of about 241,000 Italian doctors. This is a monthly infection rate of 1.2 percent. If the vaccine is 50 percent effective, then to detect this within a month, you need a sample size of 7,776 people equally divided between a vaccinated group and a non-vaccinated group. You could run the test in a smaller sample of 1,322 but then the trial would take six months. A more effective vaccine would make detecting an effect easier, but flu vaccines work at 40 to 60 percent effectiveness, so an assumption of 50 percent is not unreasonable.
But will Italian doctors still be getting infected at a rate of 1.2 percent per month when a vaccine becomes available for trial in six months or a year? We hope not. The hope is that social distancing and the use of personal protective equipment will have greatly lowered the infection rate. A low infection rate is great, unless you want to properly test a vaccine.
…The virtue of a challenge trial is that the results would be available very quickly, within a few weeks, and using only a small population. If the vaccine is 50 percent effective, for example, then we would need around 100 volunteers or perhaps even fewer depending on how many people exposed to the virus in laboratory conditions contract the disease.
By advancing a vaccine by many months, a challenge trial could save many thousands of lives and spare the world the huge economic costs of the lockdowns and social distancing that we will be using to combat the virus.
Challenge trials, however, don’t solve all problems. In particular, to limit the risk we would want to restrict the patients in a challenge trial to be young and healthy. But that raises a problem of external validity. We also want the vaccine to be safe and effective in less healthy and elderly people which requires secondary challenge trials or field testing in that population. Nevertheless, as Athey, Kremer, Synder and myself argue in our NYTimes op-ed, the high risk of vaccine failure means that we would like 15-20 vaccine candidates and challenge trials could help us whittle this number down to the best two to three substantially speeding up the vaccine discovery process.
One more point is worth bearing in mind.
[A]n ordinary vaccine trial is not without risk—a vaccine could backfire and make the disease worse—so exposing fifty or so volunteers to the virus in a challenge trial must be balanced against exposing thousands to a potentially dangerous vaccine in an ordinary clinical trial.
Thus, the total risk may be lower with a combination of challenge trials and longer, larger field trials.
Challenge trials have a long history in medicine and their statistical advantages make them powerful and even necessary. As The Guardian notes:
Scientists, however, increasingly agree that such trials should be considered, and the WHO is the latest body to indicate conditional support for the idea.
“There’s this emerging consensus among everyone who has thought about this seriously,” said Prof Nir Eyal, the director of Rutgers University’s Center for Population-Level Bioethics in the US.
From an anonymous reader:
As you are of course aware, testing on vaccines for Covid-19 are beginning to be undertaken. The scientific community has seemingly decided that Human Challenge Trials (HCT) where test subjects are directly exposed to the virus following vaccination are unethical, instead using the typical protocol of vaccine/placebo inoculation followed by months of observation in order to observe effectiveness. This seems to me a grave moral error based on the following argument.
1) There exists a large cohort of young, healthy, fully informed, willing participants who would undergo HCT.
2) Given the mortality profile of this disease, these participants would be undertaking an exceptionally small mortality risk (perhaps 5-10 per 100k, based on data from Spain/Italy/NYC, assuming zero vaccine effectiveness).
3) Society deems acceptable other activities with much higher fatality risk (at least 5-10x) in both professional (soldiers, logging workers) and recreational (motorcycling, mountaineering) capacities.
4) HCT would speed up the vaccine testing process by many months, saving tens of thousands of lives and avoiding enormous economic damage.
5) HCT actually poses significantly less risk to participants in terms of allergic reaction or ADE risk compared to a standard testing protocol since the number of participants could be much smaller and they would be medically observed.
I fail to find any ethical justification for the current stance of the medical community, from either a utilitarian or deontological perspective, and believe a highly consequential error is being made. This error may be based on false analogies to past unethical testing practices in history where participants were not informed or willing and danger was significant. The current case bears no ethical resemblance, in my judgement, to these past cases.
The simplest model of such errors is that many members of the biomedical establishment do not wish to have bad feelings about any “sins of commission” and to see their status lowered as a result of “dirty hands,” and the readily criticized logistics of Human Challenge Trials. Since HCTs do not “feel right” to them, they self-deceive into associating that feeling with a concern for the greater public good.
You should not be surprised to see grave moral errors committed in a crisis, however. Our “mainstream” protection against grave moral errors, in normal circumstances, simply is that usually we are not given the opportunity to commit them.
I do understand that a Human Challenge Trial does not necessarily suffice to show that a given vaccine is safe. Nonetheless it should be in the “armor of our discourse,” so to speak, as a morally acceptable alternative. So if you are a biomedical professional, or a public intellectual, I hope you will speak up.
London is to host the world’s first Covid-19 human challenge trials — in which healthy volunteers are deliberately infected with coronavirus to assess the effectiveness of experimental vaccines. The UK government-funded studies are expected to begin in January at a secure quarantine facility in east London, according to several people involved in the project, which will be announced next week.
…The project’s academic leader is Imperial College London, and it will be run by hVivo, a spinout from Queen Mary University of London that was bought earlier this year by Open Orphan, a Dublin-based pharmaceutical research organisation.
…The petition organiser of 1Day Sooner in the UK is 18-year-old Alastair Fraser-Urquhart who is devoting his time to the campaign before going to University College London to study cancer biology next year.
All hail Alastair Fraser-Urquhart!
This part enraged me:
The NIH is also investigating the technical and ethical requirements for challenge trials. But Nadine Rouphael, a leading vaccine researcher at Emory University in Atlanta and one of several scientists who are keen to carry out challenge studies in the US, said: “There is no urgency at NIH. The UK is well ahead — and that’s great.”
No urgency!!! I raised challenge trials with the administration in April.
CNN says “In one word, this is why there likely won’t be a vaccine available before Election Day: biology.” Wrong. The one word is complacency. What CNN refers to as biology is the time it takes to run clinical trials.
Here’s how the trials work: You take 30,000 people, give half of them a vaccine and half of them a placebo, which is a shot of saline that does nothing. Then those 30,000 people go about their lives, and you wait to see how many in each group become infected and sick with Covid-19, the “endpoint” in medical parlance.
That waiting takes time, especially since the coronavirus vaccines currently being studied in the US are two-dose vaccines with each dose several weeks apart.
But it gets worse because trial volunteers are not random:
“Who’s in the trials – the kind of people who tend to stay at home or the kind of people who attended the Sturgis rally?” said John Moore, an immunologist at Weill Cornell Medicine, referring to a motorcycle rally in South Dakota that led to at least dozens of cases of Covid-19.
Historical precedent, as well as the demographics of the participants in the current coronavirus vaccine trials, suggest more the stay-at-home type.
That does not bode well for bringing the trials to a speedy conclusion.
Typically, those who volunteer for clinical trials tend to be “White, college-educated women,” said Frenck, who has been the principal investigator on dozens of vaccine clinical trials, and has served on the Data and Safety Monitoring Board for many others.
All three of those factors are potentially bad news for the coronavirus clinical trials, because data indicates White college-educated women are at lower risk for being exposed to the novel coronavirus.
None of this, however, is actually about biology. It’s about complacency. We could have run human challenge trials and paid for diverse volunteers but we decided that was too risky or too new or too radical or too something and so thousands of people die every week as we wait.
Addendum: Previous posts on challenge trials.
I am one of the signatories to an open letter from 1DaySooner on challenge trials sent to Dr. Francis Collins at NIH. A major development announced with the letter is that 1Day Sooner and Oxford’s Jenner Institute are collaborating to prepare viral production for use in challenge trials.The Jenner Institute is the creator of the AstraZeneca produced vaccine, the vaccine farthest along in development.
A key goal of the letter is to encourage the NIH to start its own preparation for challenge trials:
The undersigned urge the U.S. government…its allies, international funders, and world bodies (e.g. the World Health Organization), to undertake immediate preparations for human challenge trials, including supporting safe and reliable production of the virus and any biocontainment facilities necessary to house participants.
Among the signatories are 15 Nobel prize winners including Oliver Hart and Al Roth, Molecular geneticist Mario Capecchi, professor of medicine William G. Kaelin and physician Barry Marshall (who knows a thing or two about volunteer trials.)
As I discussed earlier, since challenge trials restrict the volunteers to be young and healthy, you can’t apply their results directly to the sick and elderly (the external validity problem) but “challenge trials could help us whittle down [candidate vaccines]… to the best two to three, substantially speeding up the vaccine discovery process.” You could also use challenge trials to help figure out the right dosing which is unusually important in the current situation because if a vaccine can work with .5ml instead of 1ml that’s equivalent to doubling the available supply. The Director of the Jenner Institute, Adrian Hill, agrees writing:
We see considerable potential in the use of human challenge studies to accelerate COVID-19 vaccine development, down-select and help validate the best candidate vaccines, and optimise vaccination approaches.
You can read the whole letter here.
How realistic is it to directly send data in and out of the brain? That is the core scientific innovation underlying my novels. From a longer piece in which I discuss neurotechnology. (The Ultimate Interface: Your Brain):
Neural implants could accomplish things no external interface could: Virtual and augmented reality with all 5 senses (or more); augmentation of human memory, attention, and learning speed; even multi-sense telepathy — sharing what we see, hear, touch, and even perhaps what we think and feel with others.
What’s actually been done in humans?
In clinical trials today there are brain implants that have given men and women control of robot hands and fingers. [..] More radical technologies have sent vision straight into the brain. And recently, brain scanners have succeeded in deciphering what we’re looking at.
In animals, we’ve boosted cognitive performance:
In rats, we’ve restored damaged memories via a ‘hippocampus chip’ implanted in the brain. Human trials are starting this year. [..] This chip can actually improve memory. And researchers can capture the neural trace of an experience, record it, and play it back any time they want later on.
In monkeys, we’ve done better, using a brain implant to “boost monkey IQ” in pattern matching tests.
The real challenges remain hardware and brain surgery:
getting even 256 channels in generally requires invasive brain surgery, with its costs, healing time, and the very real risk that something will go wrong. That’s a huge impediment, making neural interfaces only viable for people who have a huge amount to gain, such as those who’ve been paralyzed or suffered brain damage.
Quite a bit of R&D is going into solving those hardware and surgery problems:
Researchers across the world, many funded by DARPA, are working to radically improve the interface hardware, boosting the number of neurons it can connect to (and thus making it smoother, higher resolution, and more precise), and making it far easier to implant. They’ve shown recently that carbon nanotubes, a thousand times thinner than current electrodes, have huge advantages for brain interfaces. They’re working on silk-substrate interfaces that melt into the brain. Researchers at Berkeley have a proposal for neural dust that would be sprinkled across your brain.
You can read the whole thing here:The Ultimate Interface: Your Brain.
In our textbook, Modern Principles, Tyler and I write:
In the United States, diarrhea is a pain, an annoyance, and of course an embarrassment. In much of the developing world, diarrhea is a killer, especially of children. Every year 1.8 million children die from diarrhea. To prevent the deaths of these children we do not need any scientific breakthroughs, nor do we need new drugs or fancy medical devices. What these children need most is one thing: economic growth.
Economic growth brings piped water and flush toilets, which together cut infant mortality from diarrhea by 70 percent or more.
“No innovation in the past 200 years has done more to save lives and improve health than the sanitation revolution triggered by invention of the toilet,” Sylvia Mathews Burwell, president of the foundation’s global development program, said in a statement. “But it did not go far enough. It only reached one-third of the world. What we need are new approaches. New ideas. In short, we need to reinvent the toilet.”
So what is wrong with the current commode?
It’s too expensive for people in the developing world; it requires water and a sewer-system hook-up, which aren’t always available; and it does nothing to actually treat human waste, said Frank Rijsberman, the foundation’s director of water sanitation and hygiene.
Gates is to be credited with taking on an important and unsung task. Some of the ideas he has spent money on, however, seem to be highly unrealistic. Consider:
Professor Georgios Stefanidis and his team at Delft University of Technology propose to develop a toilet system that will apply microwave technology to transform human waste into electricity. The waste will be gasified using plasma, which is created by microwaves in tailor-made equipment. This process will yield syngas, a mixture of carbon monoxide (CO) and hydrogen (H2). The syngas will then be fed to a solid oxide fuel cell stack for electricity generation. This toilet system will be able to serve single households or groups of households.
My rule is that any society capable of managing and maintaining such a system will already have flush toilets (either that or they live on the space station).
Earlier this week I asked whether we should value human life at replacement cost. Michael Vassar wrote me in response:
We should value human life at replacement cost, and we actually value generic human life less than that (negatively?), as demonstrated by the existance of late term abortion (there are almost certainly potential adoptees who would pay many women enough to motivate them to go through labor once late in a pregnancy in exchange for the child, especially considering the actual expenses many incur to adopt), but we should value a particular human life at the lower of total preference for the continuation of that life and replacement cost for that life. For the latter, today replacement cost is infinite, though it needn’t be forever. For the former, the preference varies dramatically depending on situation, but is frequently very high. For simplicity’s sake, and because economical thinking is confusing or corrupting to people below a very high IQ threshold, we maintain a convenient fiction of infinite value. Although we violate this fiction continuously, we do so in an extremely inconsistent manner because the cost of strict obedience or careful public analysis are greater than the costs of irrationality on particular instances. The "ethical questions" raised by science are rather consistently actually situations where new scientific data challenges the viability of convenient fictions, but in the end it always turns out to be possible to ignore the new data and maintain these fictions, or to integrate the new data into life rather seamlessly without disruption. However, the frequency with which these questions occur is increasing.
As expected, President Bush’s plan for a moon base and eventual trip to Mars failed to ignite. MR readers have some better ideas.
Honorable mention goes to Roger Meiners for suggesting that a moon base is a good idea so long as Congress and the President must occupy it. Now I am inspired!
Third place goes to Chris Rasch for brain freezing. Chris Rasch writes “I believe that reversible cryopreservation of the human brain could be developed. Remarkable advances have already been made on a shoestring budget. Such a technology would allow people dying today to halt the dying process until technology can advance to the point that we can cure their disease or repair their injuries. I would wager that, for a mere billion dollars, which is far more than has probably been spent on cryobiology during the entire existence of the field, we could have effectively unbounded lifespans. We could then use those extra years to pursue all of the other goals that other submitters may send to you.”
I like the cryonics idea and have thought seriously about signing up (believe it or not, one of my colleagues (not Tyler) has already done so). The reason the idea takes third place is that we don’t see a big private demand for cryonics and the public is more likely to think this idea crazy than inspiring.
Second place goes to Nick Shultz for suggesting that we “provide potable water for everyone on the planet.” A number of other ideas were also motivated by the goal of alleviating abject third-world poverty. I think these ideas are inspiring but am unsure whether we can deliver on them given that so many of the problems of the third world have to do with poor governance. My suggestion would be to work on something related but more under our own control. We could do far worse, for example, than following Bill Gates’s lead and put a billion or so into the Malaria Vaccine Initiative.
First place goes to David Wood and Robin Hanson both of whom suggested a space elevator. At first, the space elevator idea seems impossible, even absurd. The idea is to string a cable some 62,000 miles long from a spot on the equator up into outerspace. Wouldn’t it fall down? No, recall that a sateillite some 22,000 miles up is in geosynchronous orbit. The space elevator would extend enough past this point so that gravity at the lower end and centripetal acceleration at the far end would keep the cable under tension. Once the cable is strung, reaching outerspace is as simple as Jack climbing the beanstock.
The most difficult part of the space elevator is finding a material strong enough to carry a load yet light enough not to collapse under its own weight – a short time ago there was no such material but today it’s believed that carbon nanotubes could do the job (nano-technology more generally was another favourite of MR readers and this proposal would advance that cause.)
A space elevator is a game-changer because it dramatically lowers the cost of putting payloads into space. Moreover, once you have one elevator it becomes much easier to get a second. In contrast, rockets are always going to be expensive because you have to carry a lot of fuel just to lift the fuel and sitting on top of 4 million pounds of explosive is always going to be dangerous. The space elevator would provide a permanent access point to the stars and it can be had for less than 100 billion. Going up anyone?
Britain will start a human challenge trial in January.
The Sun: Imperial College said its joint human challenge study involves volunteers aged 18 to 30, with the project starting in January – and results expected in May.
Initially, 90 volunteers will be given a dose of an experimental nasal vaccine.
They’ll then be deliberately infected with Covid-19.
But this is really just the first part of an excessively cautious study designed to “discover the smallest amount of virus it takes to cause a person to develop Covid-19 infection.” Moreover:
… it’s taken a few months to come to fruition, as before any research could begin the study had to be approved by ethics committees and regulators.
The omission-commission error is deadly. Notice that giving less than one hundred volunteers the virus (commission) is ethically fraught and takes months of debate before one can get approval. But running a large randomized controlled trial in which tens of thousands of people are exposed to the virus is A-ok even though more people may be infected in the latter case than the former and even though faster clinical trials could save many lives. Ethical madness.
In the midst of his libertarian phase, Milton Friedman wrote:
As already noted, significant neighborhood effects justify substantial public health activities: maintaining the purity of water, assuring proper sewage disposal, controlling contagious diseases.
Yet today many libertarians shy away from the actual execution of this for Covid-19.
Here is a 2014 Reason magazine symposium on Ebola, by . Of those four I know Bailey a wee bit (not well), but from the entries and bylines and the very title of the feature — “What Is the Libertarian Response to Ebola? How a free society should respond to a communicable disease outbreak” — they would indeed seem to be self-described libertarians.
All four, as I read them, are willing to accept the idea of forced quarantine of individuals. Not just in extreme lifeboat comparisons, but in actual situations that plausibly might have arisen at that time. If you don’t already know, Reason, while not mega-extreme, typically would be considered more libertarian in orientation than most of the libertarian-leaning think tanks.
Maybe I was napping at the time, but I don’t recall any mega-scandal resulting from those proclamations.
Here is my earlier Bloomberg column rejecting the notion of forced quarantine of individuals for Covid-19, mostly on rights grounds, though I add some consequentialist arguments. I would not trade in the American performance for the Chinese anti-Covid performance if it meant we had to weld people inside their apartments without due process, for instance, as the Chinese (and Vietnamese and others) did regularly.
To be clear, Ebola and Covid-19 have very different properties, and you might favor forcible quarantine for one and not the other. Whether those differences in properties should matter for a rights perspective is a complex question, but still I am surprised to see that quarantine was — not long ago — considered so acceptable from a libertarian point of view, given the current pushback against pandemic-related restrictions.
(Speaking of shifts, here is Will Wilkinson on GBD. While I agree with many of his points, I am curious where Will stands on forcible quarantine of individuals on a non-trivial scale. He does say he favors a “supported isolation program,” so maybe he favors coercive quarantine but he doesn’t quite commit to that view either?)
I am surprised most of all how little interest current libertarians seem to have in the following “line”:
“A unregulated Covid-19 response would have been much, much better. We would have had a good vaccine right away, and tested it rapidly with a Human Challenge Trial. It would be sold around the world at a profit, with much quicker distribution and pandemic resolution than what we are seeing today. This pandemic was awful, but the market would have kicked butt cleaning it up.”
I am not here claiming that view is correct, only that a strong libertarian ought to be amenable to it. And yet I hear it remarkably infrequently, even though I think most committed libertarians would agree if you posed it to them as a direct question.
It is at least 20x more fashionable to obsess over the costs of lockdowns, combined with various denialist claims about the severity of the problem.
As for masks, how about this?:
“Masks? Masks are great, of course they are a public good. Markets are great at producing and maintaining value-maximizing voluntary norms such as mask-wearing!”
I cannot help but think that the views above in quotation marks would have been the dominant libertarian response in the 1980s or 1990s, and that the various brews appearing today are yet another sign of our Douthatian decadence.
The box most bioethicists are in is so small their thinking can’t extend beyond a few target people. In this case, the control group in a vaccine trial.
The subjects could be paid for the risk, which is what we do for jobs all the time. Those risk/reward amounts for risky jobs are used to make estimates for the value of human life. Life insurance would allow high-risk people (us geezers) to join the trials.
Their box doesn’t even consider human challenge trials (HCT) that give you very rapid and accurate data on efficacy even with pay and insurance to cover the risk. The lives saved by a month faster approval is in the 10’s of thousands more than offsetting and risk to a few people. Tracking the first million doses for side effects would provide the side effect data that is usually within days of injection.
Outside their mental box, 1000 people per day are dying for each day they study the issue and delay a decision, but those lives are not included in their thinking and analysis.
That is from Dallas. I would stress there are higher costs yet from delay, noting the hundreds of millions of people in developing nations who are falling back into poverty while the pandemic continues to rage. Some of them are dying too.