Category: Medicine

The tubarial salivary glands

In case you think any of us understand the world very well:

Oncologists have stumbled on a “previously unnoticed” pair of salivary glands while studying the effect of radiotherapy on salivation and swallowing. The elusive glands are in an inaccessible spot and can be spotted only with very sensitive imaging, such as positron emission tomography and computed tomography. Researchers say the glands could help to explain why cancer treatment can cause dry mouth and swallowing problems, especially because doctors haven’t known to spare the organs from damage.

Here is the link, here is an associated NYT piece.  Here is the original research.

How much does it matter who dies from Covid-19?

In this latest Bloomberg column, I am referring in particular to the ages of the victims.  The subtext of course is that many of the herd immunity theorists repeat (again and again) that most of the victims are quite old, which is indeed correct.  Here is one excerpt:

By contrast [to 9/11], about 3,500 Americans die each year in fires. To repeat: That is each year. Yet Americans have not responded to deaths by fire as they did to 9/11, nor has a major public discussion ensued.

To be clear, the U.S. probably should do more to limit the number of fire deaths. But they do not threaten the nation and constitutional order in the way that terrorist attacks do. How people die is crucial in helping a nation and society scale its response and frame the debate over what to do.

Covid-19 is obviously more like 9/11 than it is like the annual toll of fire deaths. It commands the headlines every day, has created a global economic depression, is reshaping global politics and the balance of power, causes extreme stress for millions and has significantly harmed America’s global reputation. Yes, there have been some anxiety-driven overreactions, but it is inevitable that humans will respond dramatically to a major worldwide pandemic.

To be sure, the number of U.S. victims is high — 220,000 and counting, plus some number of excess deaths from broader causes. But the event itself is so cataclysmic that “downgrading” those deaths by saying many of the victims were elderly doesn’t make a big difference in terms of formulating an optimal response.

And to close:

Pandemics have been civilization-altering events since the beginning of human history, and they still are — especially if we do not respond properly. The need to get the response right, not the relative worth of the young to that of the old, is the main thing that we should be obsessing about.

Recommended.

Should government improve the quality of its software?

From a GitHub repository:

This GitHub repository is a back up of my FAERSFix scripts.

The FDA Adverse Effect Reporting System is a horrifically dysfunctional quagmire of shockingly bad data. The data is not just bad for severe epistemological reasons, it is also poorly organized and riddled with flagrant absurd errors.

These scripts smooth over the very messy process of acquiring and basic debugging of the data. At the end of the process a user can arrive at a local repository of the FAERS data that is sane enough to begin to think about some kind of sensible analysis. To understand the disastrous state of the original source data, see the source code of the scripts which is designed to be a readable self-documenting manual demonstrating how to correct this mess.

Since the FDA’s gremlins never rest, these scripts will become obsolete. If you would like to contribute updates or fixes, feel free to send me a patch or a pull request. Good luck!

I thank Chris E. for the pointer.

The AstroZeneca saga, according to one source

This seems unconfirmed, and do note some sources in the story do not believe this account, but here goes:

AstraZeneca, whose Phase 3 coronavirus vaccine clinical trial has been on hold for more than a month, did not get critical safety data to the US Food and Drug Administration until last week, according to a source familiar with the trial.

The FDA is considering whether to allow AstraZeneca to restart its trial after a participant became ill. At issue is whether the illness was a fluke, or if it may have been related to the vaccine.

The source said the root of the delay is that the participant was in the United Kingdom, and the European Medicines Agency and the FDA store data differently.

“They had to convert data from one format to another format. It’s like taking stuff off a PC and putting it onto an Apple. They had to spend a lot of hours to get what they wanted,” the source said.

On Friday, a federal official hinted there might be some word this week on the trial’s future.

Or maybe they just fooled CNN with it?

Otherwise, good thing we are kept safe from such dangerous data formats!  Would it really not be better to move to reciprocal recognition procedures?  Not to mention a unified data format, or perhaps some FDA methods to read data produced for the EU?

For the pointer I thank Jackson Stone.

From the AstraZeneca comments

Transverse Myletitis has a background incidence of 4/million in the US. Currently there are 2 cases reported out of 18,000 people who have already been administered the vaccine. Of those two, one was diagnosed with concurrent MS (another neurodegenerative autoimmune condition known to cause TM and whose population has a 2000% relative risk increase in developing TM depending on criteria used) and one has not had details released.

With 18,000 data points, a “1%” risk would require there to be 178 missed cases. Odds of that are astronomically low. Much more likely, if there were any real correlation (which again seems rather unlikely) we are looking at something 80+) and would STILL result in fewer deaths than waiting. If the choice were this or letting Covid become endemic with just an influenza fatality rate, this would again be the more ethical choice. Economically 1.1 million being totally disabled would be somewhere around $3 trillion, which again would be vastly cheaper than ending transmission through current social policies. In terms of raw lives lost, a 1% incidence would easily be less than letting Covid run.

People say we need more numbers, but funny enough their doom and gloom scenarios invariably involve scenarios that are necessarily imply that all the trial data to date is spurious and/or that even if true are less deadly than waiting.

And note that this argument has no justification for pausing the trial. With 2 data points, 1 of which is almost certainly spurious for the general population, the solution is to keep administering it.

Reality is that regulators and drug companies are simply not doing a cost benefit calculation that weights the currently dying at all in the US. I am hoping that the drug companies are being amoral profit seekers and are hoping to just browbeat the FDA once the Brits get things settled and the US policy scene (one way or the other) stops being about Mr. Trump.

That is from MR commentator Sure.  And also from him:

The other thing to remember is that a lot of pharma’s actual business is not as much discovery of new entities, rather they buy up rights to a lot of those and then take somebody else’s work through the years long process of approval. For big pharma much of their comparative advantage is in navigating an expensive, byzantine approval process. Take that away and they might face far more competition from smaller firms and potentially foreign firms that can manage the new landscape better.

Lastly, pharma lives in fear of the regulators while trying to suborn them. Going against them FDA bureaucrats (who are unlikely to want to de facto kill their own jobs) risks one of them grinding an axe and slow walking a blockbuster approval or fast walking a biosimilar approval. Either of those actions will easily change the net profit for a pharma firm by more than they could possibly make off a Covid vaccine.

Currently, faster has very little upside for them. They have pre-commitment so they are going to get paid even if they are slow. There are dozen odd vaccines coming down the pike and one, maybe two, will take the lion’s share of the market once the immediate crisis is over. They are mostly doing this to win goodwill and being the guy whose vaccine kills 2,000 people is bad if your competitors kill only 5. From a public health perspective, we would be better with the less safe vaccine a month sooner than the safer vaccine a month later (and ideally we would get both and swap promptly). For the pharma firms, the calculus just goes towards being as slow as the rest of pack and being ungodly thorough.

Perhaps things will improve in a few weeks’ time.

And yet the American trial remains suspended

Those nasty, reckless Brits:

The NHS is preparing to introduce a coronavirus vaccine soon after Christmas. Trials have shown it will cut infections and save lives, Jonathan Van-Tam, the deputy chief medical officer, has privately revealed.

He told MPs last week that stage three trials of the vaccine created at Oxford University and being manufactured by AstraZeneca mean a mass rollout is on the horizon as early as December. Thousands of NHS staff are to undergo training to administer a vaccine before the end of the year.

The government changed the law this weekend to expand the number of health professionals able to inoculate the public. The regulations will enable pharmacists, dentists, midwives and paramedics to administer jabs.

C’mon U.S. public health authorities, let’s get on this one and demand a resumption of the suspended AstraZeneca trial.  You are advocates of science, right?  You don’t actually want to make Donald Trump correct, do you?  (Maybe that one will work.)

You don’t have to make it the vaccine, as the Brits seem to be doing, you just have to resume the trial, as the even more reckless Japanese did weeks ago.  How about it?

Here is the article from Times of London (gated, but a cheap and worthwhile subscription for foreigners), via Linda Yueh.

New results on the Chinese vaccine

Importantly, this was the first study of an inactivated SARS-CoV-2 vaccine to include participants older than 60 years—the most vulnerable age group for this infection. In the phase 1 dose-escalating trial, the vaccine was given at a two-dose schedule at three different concentrations (2 μg, 4 μg, and 8 μg per dose) and was well tolerated in both age groups (18–59 years and ≥60 years). The older age group had lower rates of solicited adverse events than the younger adults: the overall rates of adverse events within 28 days after vaccination were 34 (47%) of 72 participants in the group aged 18–59 years, compared with 14 (19%) of 72 participants in the group aged 60 years and older. At the same time, in both age groups the vaccine was similarly immunogenic: the geometric mean anti-SARS-CoV-2 neutralising antibody titres measured by a 50% virus neutralisation assay 14 days after the booster dose were 88, 211, and 229 in the group aged 18–59 years and 81, 132, and 171 in the group aged 60 years and older for 2 μg, 4 μg, and 8 μg vaccine doses, respectively. Moreover, the authors tested cross-reactivity of the neutralising antibodies against several drifted SARS-CoV-2 isolates and showed the potential of their vaccine to protect against evolutionary diverged viruses, should they appear in circulation.

And:

The current study is the second to report the interim results of safety and immunogenicity of inactivated SARS-CoV-2 vaccine, with the first being the another β-propiolactone inactivated aluminium-adjuvanted whole-virion SARS-CoV-2 vaccine developed by Wuhan Institute of Biological Products.

Both studies showed very similar levels of adverse events and neutralising antibody titres post vaccination, which indicates the reproducibility of clinical results of similar vaccine modes produced by different manufacturers.

All good news of course, and this vaccine exists right now.  Just not for you!  Here is the piece from The Lancet, and here is associated commentary, also seeming to confirm the positive results.  A phase III trial is underway in the UAE to measure efficacy.  I cannot speak to data reliability issues, but presumably the referees at The Lancet find this credible enough to recommend publication.

Via Alan Goldhammer.

Why I reject the Great Barrington Declaration

Here is my 2x normal length Bloomberg column on that topic, as had been requested by Daniel Klein.  The argument has numerous twists and turns, do read the whole thing but here is one bit (I will indent only their words):

“Here are the key words of the Great Barrington Declaration on herd immunity:

The most compassionate approach that balances the risks and benefits of reaching herd immunity, is to allow those who are at minimal risk of death to live their lives normally to build up immunity to the virus through natural infection, while better protecting those who are at highest risk. We call this Focused Protection.

What exactly does the word “allow” mean in this context? Again the passivity is evident, as if humans should just line up in the proper order of virus exposure and submit to nature’s will. How about instead we channel our inner Ayn Rand and stress the role of human agency? Something like: “Herd immunity will come from a combination of exposure to the virus through natural infection and the widespread use of vaccines. Here are some ways to maximize the role of vaccines in that process.”

And the close:

“In most parts of the Western world, normal openings for restaurants, sporting events and workplaces are likely to lead to spiraling caseloads and overloaded hospitals, as is already a risk in some of the harder-hit parts of Europe. Reopenings, to the extent they work, rely on a government that so scares people that attendance remains low even with reopening.

In that sense, as things stand, there is no “normal” to be found. An attempt to pursue it would most likely lead to panic over the numbers of cases and hospitalizations, and would almost certainly make a second lockdown more likely. There is no ideal of liberty at the end of the tunnel here.

Don’t get me wrong: The Great Barrington strategy is a tempting one. Coming out of a libertarian think tank, it tries to procure maximum liberty for commerce and daily life. It is a seductive idea. Yet consistency of message is not an unalloyed good, even when the subject is liberty…

My worldview is both more hopeful and more tragic. There is no normal here, but we can do better — with vigorous actions to combat Covid-19, including government actions. The conception of human nature evident in the Great Barrington Declaration is so passive, it raises the question of whether it even qualifies as a defense of natural liberty.”

MR Tyler again: You will note I do not make the emotional, question-begging argument that herd immunity strategies will kill millions (though I do think more people die under that scenario).  If you argue, as many herd immunity critics do, that the elderly cannot be isolated, it seems you also should not be entirely confident that the currently non-infected can be isolated.  The brutal truth is simply that a Great Barrington strategy put into practice would lead to rapidly spiraling cases and a rather quick and oppressive second lockdown, worse than what the status quo or some improved version of it is likely to bring.  Total deaths are likely higher, along with more social trauma, due to the more extreme whipsaw effects, but no not by millions.

Let’s accelerate those biomedicals, people!

From the comments, on AstraZeneca vaccine trial resumption

America is really, really messed up.

The only place with such intensely wasteful discussions about a disease is the U.S. And it is getting increasingly easy to ignore the U.S. as the world continues to respond to this pandemic.

And it is not just the British based trial. This is from Reuters on Sept. 14 – “Clinical trials for the coronavirus vaccine being developed by AstraZeneca PLC and Oxford University resumed in Brazil on Monday after the country’s health regulator got confirmation over the weekend that its British equivalent MHRA had approved the restart, a company representative said.

The Federal University of Sao Paulo, which is running the trials, said in a statement that 4,600 of the planned 5,000 volunteers have been vaccinated in Brazil without any of them reporting any serious health issues.”

This from the Times of India on Sept 20th -“The phase-III human clinical trial of the COVID-19 vaccine developed by Oxford University and being manufactured by the Serum Institute of India (SII) will begin at the Sassoon General Hospital in Pune next week. Dean of the state-run Sassoon General Hospital Dr Muralidhar Tambe told this to on Saturday.

“The phase-III trial of ‘Covishield’ vaccine will begin at Sassoon hospital from next week. It is likely to start on Monday. Some volunteers have already come forward for the trial. Around 150 to 200 volunteers will be administered the vaccine candidate dose,” he said.

Regulators in Japan and South Africa also have no problem with the trial continuing.

That is from Easy-Peasy.  And I did google to ensure that those claims about foreign trial resumption are correct, for instance Japan resumed no later than October 2.  This is one reason — not the only! — why I am puzzled when Derek Lowe claims on Twitter that American perhaps cannot go any faster with its vaccine.  If you think Japan and the Brits are irresponsible, by all means let us know.  Otherwise…it is time to speak up in favor of maximizing expected value.

Solve for the rational Bayesian equilibrium

I now read quite a few public health experts on matters of the day, and I have noticed that none of them have condemned the British government for proceeding with the AstraZeneca vaccine trial, even after two adverse health events experienced by participants, noting that those events presumably have been examined and considered by the oversight committee.

At the same time, the American trial for AstraZeneca has remained halted.  I also have not read any public health experts criticizing that decision either.

What is the most likely equilibrium to be holding here?

1. Public health experts don’t express many opinions, especially these days.

2. Plenty of commentators think the British decision to resume is rash, Tyler just isn’t reading enough of them.

3. Most public health experts think it is fine for the British to keep on going.  But they won’t criticize the American trial halt, because their incentives and natural temperamental tendencies are to express mainly the risk-averse opinions, and rarely if ever say that the regulatory process should allow for more risk to be taken.

4. The mainly American experts actually are happy to see America free-riding upon British data, so they are content with things as they stand, but don’t want to quite come out and admit they enjoy exploiting the Brits.

5. In reality the commentators think the whole trial is so risky it never should have been started in the first place.

6. What they really enjoy writing is philosophical pieces about how social process have all these twists and turns, and natural bumps in the road, and so they don’t wish to work too hard to remove those bumps.

7. The public health experts think that Americans and British have optimally different tolerances for risk, and the split regulatory outcomes reflect that difference.

Your choice?

Mormon markets in everything?

Or is it thwarted Mormon markets in everything?:

Brigham Young University-Idaho is warning students that if they try to get the novel coronavirus, they will be suspended from school.

BYU-Idaho issued a statement Monday, saying administrators are “deeply troubled” about students intentionally exposing themselves or others to COVID-19, with the hope of getting the disease so they can be paid for plasma that contains COVID-19 antibodies.

Here is the full story, via John Chilton.

The public is fine with Human Challenge Trials

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.

Herd immunity seems to be failing Manaus

For a short time the Brazilian city of Manaus, in the heart of the Amazon rainforest, offered a glimmer of hope in the search for herd immunity from Covid-19.

After a devastating wave in May killed about 3,400 people and infected many more, the prevalence of the virus subsided rapidly, leading some scientists to theorise that the city of 2m had reached a form of collective immunity.

That hypothesis is now in doubt as a resurgence in cases in Manaus poses fresh challenges to the authorities and difficult questions for the scientists and policymakers worldwide who have been edging towards herd immunity policies as an alternative to harsh lockdowns.

“How do you explain the number of [daily] deaths being in the 30s yesterday and the 50s today?” said Arthur Virgilio, the mayor of Manaus. “What has caused the death rate in Manaus to increase?”

Here is more from the Financial Times.

Model this

Nancy Pelosi warned that a Covid-19 vaccine should not be authorised for use in the US based on data from British trials, amid fears that the Trump administration is planning to rush out an inoculation before election day.

The Democratic speaker of the House of Representatives on Friday cast doubt on the British system for testing and approving medicines, further politicising the race to develop a vaccine for Covid-19.

“We need to be very careful about what happens in the UK. We have very stringent rules in terms of the Food and Drug Administration here, about the number of clinical trials, the timing, the number of people and all the rest,” Ms Pelosi told reporters in Washington.

Here is the full FT story, and here is a nice NYT piece, by Zeke Emanuel and others, on the superiority of the British clinical trials system, especially with respect to Covid-19.

Monoclonal antibodies are doing very well

In the study, 112 patients received 2.8 grams of each of the antibodies, and 156 received placebo. The difference in viral load was statistically significant at day 11, unlike some doses of Lilly’s single-antibody cocktail. There was also a statistically significant reduction in viral levels three days and seven days after infection.

The treatment also improved symptoms, according to a scored questionnaire, and resulted in fewer hospital and emergency room visits. Visits to the hospital or ER were made by 5.8% of patients in the placebo group, but just 0.9% of those who received the antibody combination. That difference, however, was just barely statistically significant.

Lilly said that it has already begun talking to regulators around the world about its single antibody treatment, and has filed with the Food and Drug Administration for an emergency use authorization…

Lilly said it anticipates it could have as many as 1 million doses of its one-antibody treatment, LY-CoV555, available in the fourth quarter of 2020, with 100,000 available this month. But for the combination therapy, just 50,000 doses will be available in the fourth quarter of 2020.

Both antibody regimens have been well-tolerated, with no serious side effects, the company said.

Here is the full story from StatNews.  Big news, but not a surprise to everyone.