Our attitude to ear wax is in some ways surprising. A review of impacted ear wax estimates that 2.3 million people a year in the United Kingdom suffer problems with wax needing treatment, with some 4 million ears being syringed annually.2 This makes it possibly the the most common therapeutic procedure carried out on any part of the body. Symptoms of excessive wax or impaction, especially in the elderly, include not only hearing loss but tinnitus, dizziness, infections, social withdrawal, poor work function and mild paranoia. Other problems include general disorientation and loss of an aural sense of direction. With unilateral wax, sounds can appear to be coming from the wrong side, leading to accidents as a driver or especially as a pedestrian. Inappropriate self-treatment (or even treatment by health professionals) can cause perforated eardrums and in very rare cases cochlear damage, leading to nystagmus and sensorineural deafness. In spite of this catalogue of harms, the clinical profile and management of excessive wax are poorly understood. The evidence base is poor and inconsistent, leading to few strong recommendations, even relating to the most commonly used treatments.
Low esteem for ear wax is surprising in other ways too. As a substance, it is unique in the human and mammalian body. This is due to its position in our sole anatomical cul-de-sac. Everywhere else on our body surface, dead and redundant skin cells fall off or are scrubbed away when we wash. In the ear canal – which points forwards and downwards and might otherwise turn into a dermatological garbage dump – ear wax binds these together, along with other assorted detritus that may have entered from the world outside. It is then moved up to the exit by jaw movements and as a result of the skin of the canal slowly moving outwards like an escalator. Wax also prevents multiplication of micro-organisms and infection. It is as essential as sweat and tears, although perhaps not quite as vital as blood. Wax is also fascinating in its own right.
Imagine an ear wax post that is not solely about Q-tips! (Have you ever wondered why they have to be so dangerous? Can’t you just put them in a little way? Or is there some indivisibility here? I have never understood the anguished warnings here. If you are not using Q-tips at all, you only have to put them in a little way to pull out a lot of earwax, right? Solve for the equilibrium!)
In The Premonition Michael Lewis brings his cast of heroes together like the assembling of the Avengers. In the role of Captain America is Charity Dean, the CA public health officer who is always under-estimated because she is slight and attractive, until she cracks open the ribcage of a cadaver that the men are afraid to touch. Then there is Carter Mecher, the redneck epidemiologist who has a gift for assembling numbers into coherent patterns. And Richard Hatchett the southern poet who finds himself at the head of The Coalition for Epidemic Preparedness (CEPI), the world’s most important organization during the pandemic; and Joe DiRisi the brilliant, mad scientist picked by the Chan Zuckerberg Initiative as the person most likely to cure disease…all of them. As you might expect from Michael Lewis, it’s all terribly well done, albeit formulaic and sometimes over-the-top, e.g.
Charity’s purpose was clear….she was put on earth to fight battles, and wars, against disease. To save lives and perhaps even an entire country. p. 200-201
But Lewis has a bigger problem than over-the-top writing.
The heroes were defeated. Lewis likes to tell stories of brilliant mavericks like Billy Beane and Michael Burry who go against the grain but eventually, against all odds, emerge victorious. But six hundred thousand people are dead in the United States and whatever victory we have won was ugly and slow. Indeed, Lewis assembles his mighty team but then The Premonition trails off as the team is defeated by bureaucracy, indecision, complacency and malaise before they even have a chance to enter the real battle against the virus. It’s telling that none of Lewis’s heroes are even mentioned in Andy Slavitt’s Preventable (about which I will say more in a future post).
To be fair, Lewis’s heroes are fascinating, brilliant people who did some good. As part of the Kremer team I interacted a bit with Richard Hatchett and CEPI. Hatchett headed CEPI and understood the danger of SARS-COV-II before anyone else and with Bill Gates’s support started funding vaccine production and shoring up supply lines before anyone else was off the starting line. CEPI was magnificent and their story has yet to be told in full measure. Had Lewis’s heroes been in charge I have no doubt that many lives could have been saved but, for the most part, the heroes were sidelined. Why and how that happened is the real question but Lewis’s story-telling skills aren’t the right skills to answer that question.
If there is one central villain in The Premonition, it’s the CDC. Lewis acknowledges that his perspective has changed. In The Fifth Risk, the system (the “deep state” used non-pejoratively if you will) is full of wisdom and power but it’s under threat from Trump. In The Premonition, Trump is an after-thought, at best a trigger or aggravating factor. Long before Trump or the pandemic:
Charity had washed her hands of the CDC. “I banned their officers from my investigations,” she said. The CDC did many things. It published learned papers on health crisis, after the fact. It managed, very carefully, public perception of itself. But when the shooting started, it leapt into the nearest hole, while others took fire. “In the end I was like ‘Fuck you’, said Charity. “I was mad they were such pansies. I was mad that the man behind the curtain ended up being so disappointing.” p. 42
As the pandemic starts the CDC fails repeatedly. At the beginning of the pandemic on January 29 the government had started to repatriate Americans from Wuhan bringing some of them to a National Guard base just outside of Omaha. But shockingly the CDC doesn’t test them for the virus.
Never mind that every single one of the fifty-seven Americans in quarantine wanted to be tested: the CDC forbade it. And [James] Lawler [US Naval Commander and national security coordinator on pandemic response] never understood the real reason for the CDC’s objections…Whatever the reasons, fifty-seven Americans spent fourteen days quarantined in Omaha, then left without having any idea of whether they’d been infected, or might still infect others. “There is no way that fifty-seven people from Wuhan were not shedding virus,” said Lawler. p. 176
Many of the people brought home from China are not even quarantined just told to self-quarantine:
…When local health officers…set out to find these possibly infected Americans, and make sure that they were following orders to quarantine, they discovered that the CDC officials who had met them upon arrival had not bothered to take down their home addresses.
…[Charity] posed a rude question to the senior CDC official moved on the call: How can you keep saying that Americans are at low risk from the virus if you aren’t even testing for the virus. She’d been answered with silence, and then the official move on to the next topic. [p.206-207, italics in original]
And all of this is before we get to the CDC’s famously botched test an error which was amplified by the FDA’s forbidding private labs and state governments to develop their own tests. Charity Dean wanted California to ignore the CDC and FDA and, “blow open testing and allow every microbiology lab to develop its own test.” But Dean is ignored and so by as late as February 19, “Zimbabwe could test but California could not because of the CDC. Zimbabwe!” p. 223. The failure of testing in the early weeks was the original sin of the crisis, the key failure that took a containment strategy ala South Korea and Taiwan off the table.
Lewis’s most sustained analysis comes in a few pages near the end of The Premonition where he argues that the CDC became politicized after it lost credibility due to the 1976 Swine Flu episode. In 1976 a novel influenza strain looked like it might be a repeat of 1918. Encouraged by CDC head David Sencer, President Ford launched a mass vaccination campaign that vaccinated 45 million people. The swine flu, however, petered out and the campaign was widely considered a “debacle” and a “fiasco” that illustrated the danger of ceding control to unelected experts instead of the democratic process. The CDC lost authority and under Reagan the director became a political appointee rather than a career civil servant. Thus, rather than being unprecedented, Trump’s politicization of the CDC had deep roots.
Today the 1976 vaccination campaign looks like a competent response to a real risk that failed to materialize, rather than a failure. So what lessons should we take from this? Lewis doesn’t say but my colleague Garett Jones argues for more independent agencies in his excellent book 10% Less Democracy. The problem with the CDC was that after 1976 it was too responsive to political pressures, i.e. too democratic. What are the alternatives?
The Federal Reserve is governed by a seven-member board each of whom is appointed to a single 14- year term, making it rare for a President to be able to appoint a majority of the board. Moreover, since members cannot be reappointed there is less incentive to curry political favor. The Chairperson is appointed by the President to a four-year term and must also be approved by the Senate. These checks and balances make the Federal Reserve a relatively independent agency with the power to reject democratic pressures for inflationary stimulus. Although independent central banks can be a thorn in the side of politicians who want their aid in juicing the economy as elections approach, the evidence is that independent central banks reduce inflation without reducing economic growth. A multi-member governing board with long and overlapping appointments could also make the CDC more independent from democratic politics which is what you want when a once in 100 year pandemic hits and the organization needs to make unpopular decisions before most people see the danger.
Lewis hasn’t lost his ability to write exhilarating prose about heroic oddballs. Page by page, The Premonition is a good read but the heroes in Lewis’s story were overshadowed by politics, bureaucracy and complacency–systems that Lewis’s doesn’t analyze or perhaps quite understand–and as a result, his hero-centric story ends up unsatisfying as story and unedifying as analysis.
Long-term complications after coronavirus disease 2019 (COVID-19) are common in hospitalized patients, but the spectrum of symptoms in milder cases needs further investigation. We conducted a long-term follow-up in a prospective cohort study of 312 patients—247 home-isolated and 65 hospitalized—comprising 82% of total cases in Bergen during the first pandemic wave in Norway. At 6 months, 61% (189/312) of all patients had persistent symptoms, which were independently associated with severity of initial illness, increased convalescent antibody titers and pre-existing chronic lung disease. We found that 52% (32/61) of home-isolated young adults, aged 16–30 years, had symptoms at 6 months, including loss of taste and/or smell (28%, 17/61), fatigue (21%, 13/61), dyspnea (13%, 8/61), impaired concentration (13%, 8/61) and memory problems (11%, 7/61). Our findings that young, home-isolated adults with mild COVID-19 are at risk of long-lasting dyspnea and cognitive symptoms highlight the importance of infection control measures, such as vaccination.
That is from a new Nature paper by Bjørn Blomberg, et.al. Via SK. On vaccinating the young, here are further relevant observations from Francois Balloux.
Some quick comments in response to questions and discussion about my paper Could Vaccine Dose Stretching Reduce COVID-19 Deaths? (written with the all-star cast of Witold Więcek, Amrita Ahuja, Michael Kremer, Alexandre Simoes Gomes, Christopher M. Snyder and Brandon Joel Tan.
1) Any method of increasing vaccine supply will require other changes in the supply chain such as more needles. We think alternative dosing can increase supply quickly with the fewest supply chain disruptions.
2) If we had started Moderna with 50 ug dosing no one would be advocating for 100 ug dosing, thereby halving supply. Rather than “full” or “half-doses,” which bias thinking, we should talk about alternative dosing and ug.
3) Judging by neutralizing antibodies, a 50 ug dose of, for example, Moderna looks to be more effective than standard dosing of many other vaccines including AZ and J&J and much better than others such as Sinovac. Thus alternative dosing is a way to *increase* the quality of vaccine for many people.
4) A 50 ug dose vaccine available today is much higher quality than a 100 ug dose vaccine available one year from now.
5) There are substantial risks from following the current approach, as India and now parts of Africa illustrate. Alternative dosing has a very large upside but small downside since we could switch back to standard doses. For example, Great Britain and Canada delayed the second dose to 12 and 16 weeks respectively but have since reduced the dosing interval as more supplies have become available.
6) The greatest risk to immune escape comes from the unvaccinated. Alternative dosing protects not only those who are dosed but by reducing transmission also reduces risks to the unvaccinated.
7) The key question we face now is not whether there are objections and complications to alternative dosing (there are) the key question is what additional information, available quickly could resolve the most uncertainty? In other words, what can we learn soon that would most aid decision makers?
See the paper for details and also my previous post, A Half Dose of Moderna is More Effective Than a Full Dose of AstraZeneca.
Addendum: It should be clear that this isn’t about the United States, it is about getting high-quality vaccine to places that have little to none.
I was surprised by how good this NYT piece was, for instance here is one of the better diagnoses of the problem, or at least part of it:
Allen disputes the notion that she and her colleagues are doing work that the C.D.C. itself should be doing; in fact, she says, the task force and the federal agency have worked closely together. But she acknowledges that the interdisciplinary approach of the collaborative — it consists not only of doctors and public-health professionals but also of political scientists, economists, lawyers and M.B.A.s — enables it to spot problems that the federal institution can’t necessarily see. Infection control is a good example. “This is not a public-health problem, or even a medical one,” she says. “It’s an issue of organizational capacity.” The C.D.C. is not equipped to identify organizational issues, let alone resolve them.
Around half of the agency’s domestic budget is funneled to the states, but only after passing through a bureaucratic thicket. There are nearly 200 separate line items in the C.D.C.’s budget. Neither the agency’s director nor any state official has the power to consolidate those line items or shift funds among them. “It ends up being extremely fragmented and beholden to different centers and advocacy groups,” says Tom Frieden, who led the C.D.C. during the Obama administration.
How about this?:
This funding system also hobbles emergency-response efforts, because there is no real budget for the unexpected.
Highly recommended, one of the best pieces of this year, here is the full article by Jeenen Interlandi.
Or he could let a surgeon cut two nickel-size holes in his skull and plunge metal-tipped electrodes into his brain.
More than 600 days after he underwent the experimental surgery, Buckhalter has not touched drugs again — an outcome so outlandishly successful that neither he nor his doctors dared hope it could happen. He is the only person in the United States to ever have substance use disorder relieved by deep brain stimulation. The procedure has reversed Parkinson’s disease, epilepsy and a few other intractable conditions, but had never been attempted for drug addiction here.
The device, known as a deep brain stimulator, also is recording the electrical activity in Buckhalter’s brain — another innovation that researchers hope will help locate a biomarker for addiction and allow earlier intervention with other people.
Here is the full story.
Mask-wearing has been a controversial measure to control the COVID-19 pandemic. While masks are known to substantially reduce disease transmission in healthcare settings (Howard et al 2021), studies in community settings report inconsistent results (Brainard et al 2020). Investigating the inconsistency within epidemiological studies, we find that a commonly used proxy, government mask mandates, does not correlate with large increases in mask-wearing in our window of analysis. We thus analyse the effect of mask-wearing on transmission instead, drawing on several datasets covering 92 regions on 6 continents, including the largest survey of individual-level wearing behaviour (n=20 million) (Kreuter et al 2020). Using a hierarchical Bayesian model, we estimate the effect of both mask-wearing and mask-mandates on transmission by linking wearing levels (or mandates) to reported cases in each region, adjusting for mobility and non-pharmaceutical interventions. We assess the robustness of our results in 123 experiments across 22 sensitivity analyses. Across these analyses, we find that an entire population wearing masks in public leads to a median reduction in the reproduction number R of 25.8%, with 95% of the medians between 22.2% and 30.9%. In our window of analysis, the median reduction in $R$ associated with the wearing level observed in each region was 20.4% [2.0%, 23.3%]. We do not find evidence that mandating mask-wearing reduces transmission. Our results suggest that mask-wearing is strongly affected by factors other than mandates. We establish the effectiveness of mass mask-wearing, and highlight that wearing data, not mandate data, are necessary to infer this effect.
We find that people diagnosed outside of quarantine are 89% more infectious than those diagnosed while in quarantine, and infectiousness decreases as a function of the time spent in quarantine. Furthermore, we find that people of working age, 16-66 years old, are 47% more infectious than those outside that age range. Lastly, the transmission tree enables us to model the effect that given population prevalence of vaccination would have had on the third wave had they been administered before that time using several different strategies. We find that vaccinating in order of ascending age or uniformly at random would have prevented more infections per vaccination than vaccinating in order of descending age [emphasis added].
That is from a new paper by lots of people with Icelandic names, via Eric Topol. This is not yet confirmed or general, but it does resurrect the idea of vaccinating many younger people first, due to their (possibly) greater ability to spread the virus. Note also the data here are taken from Iceland’s third wave, which might further limit the generality of the result.
Here is my new piece with Patrick Collison and Patrick Hsu. The title says it all, here is one excerpt:
…we recently ran a survey of Fast Grants recipients, asking how much their Fast Grant accelerated their work. 32% said that Fast Grants accelerated their work by “a few months”, which is roughly what we were hoping for at the outset given that the disease was killing thousands of Americans every single day.
In addition to that, however, 64% of respondents told us that the work in question wouldn’t have happened without receiving a Fast Grant.
For example, SalivaDirect, the highly successful spit test from Yale University, was not able to get timely funding from its own School of Public Health, even though Yale has an endowment of over $30 billion. Fast Grants also made numerous grants to UC Berkeley researchers, and the UC Berkeley press office itself reported in May 2020: “One notably absent funder, however, is the federal government. While federal agencies have announced that researchers can apply to repurpose existing funds toward Covid-19 research and have promised new emergency funds to projects focused on the pandemic, disbursement has been painfully slow. …Despite many UC Berkeley proposals submitted to the National Institutes of Health since the pandemic began, none have been granted.” [Emphasis ours.]
57% of respondents told us that they spend more than one quarter of their time on grant applications. This seems crazy. We spend enormous effort training scientists who are then forced to spend a significant fraction of their time seeking alms instead of focusing on the research they’ve been hired to pursue.
The adverse consequences of our funding apparatus appear to be more insidious than the mere imposition of bureaucratic overhead, however.
In our survey of the scientists who received Fast Grants, 78% said that they would change their research program “a lot” if their existing funding could be spent in an unconstrained fashion. We find this number to be far too high: the current grant funding apparatus does not allow some of the best scientists in the world to pursue the research agendas that they themselves think are best.
Some of the other Fast Grants investments were speculative, and may (or may not) pay dividends in the future, or for the next pandemic. Examples include:
- Work on a possible pan-coronavirus vaccine at Caltech.
- Work on a possible pan-enterovirus (another class of RNA virus) drug at Stanford University that has now raised subsequent funding.
- Multiple grants going to different labs working on CRISPR-based COVID-19 at-home testing. One example is smartphone-based COVID-19 detection, being worked on at UC Berkeley and Gladstone Institutes.
Initial replication of SARS-CoV-2 in the upper respiratory tract is required to establish infection, and the replication level correlates with the likelihood of viral transmission. Here, we examined the role of host innate immune defenses in restricting early SARS-CoV-2 infection using transcriptomics and biomarker-based tracking in serial patient nasopharyngeal samples and experiments with airway epithelial organoids. SARS-CoV-2 initially replicated exponentially, with a doubling time of ∼6 h, and induced interferon-stimulated genes (ISGs) in the upper respiratory tract, which rose with viral replication and peaked just as viral load began to decline. Rhinovirus infection before SARS-CoV-2 exposure accelerated ISG responses and prevented SARSCoV-2 replication. Conversely, blocking ISG induction during SARS-CoV-2 infection enhanced viral replication from a low infectious dose. These results show that the activity of ISG-mediated defenses at the time of SARS-CoV-2 exposure impacts infection progression and that the heterologous antiviral response induced by a different virus can protect against SARS-CoV-2.
That is a just published paper, supported by Fast Grants, by Nagarjuna R. Cheemarla, Timothy A. Watkins, Valia T. Mihaylova, Bao Wang, Dejian Zhao, Guilin Wang, Marie L. Landry, and Ellen F. Foxman.
Another girl did ask if she could call me Fauci during sex. She said it with a straight face. I pretended that I didn’t hear and kept going, because how do you even address that? I’m not going to say yes, because that’s going to be weird. And if I say no, that kills the vibe. She didn’t say anything else, and she never called me Fauci. I think the only way you can make that weirder is if she had brought a Fauci mask and asked me to put it on.
Here are other anecdotes from the DC area, no photos but the text is somewhat risque.
Today we are releasing a new paper on dose-stretching, co-authored by Witold Wiecek, Amrita Ahuja, Michael Kremer, Alexandre Simoes Gomes, Christopher M. Snyder, Brandon Joel Tan and myself.
The paper makes three big points. First, Khoury et al (2021) just published a paper in Nature which shows that “Neutralizing antibody levels are highly predictive of immune protection from symptomatic SARS-CoV-2 infection.” What that means is that there is a strong relationship between immunogenicity data that we can easily measure with a blood test and the efficacy rate that it takes hundreds of millions of dollars and many months of time to measure in a clinical trial. Thus, future vaccines may not have to go through lengthy clinical trials (which may even be made impossible as infections rates decline) but can instead rely on these correlates of immunity.
Here is where fractional dosing comes in. We supplement the key figure from Khoury et al.’s paper to show that fractional doses of the Moderna and Pfizer vaccines have neutralizing antibody levels (as measured in the early phase I and phase II trials) that look to be on par with those of many approved vaccines. Indeed, a one-half or one-quarter dose of the Moderna or Pfizer vaccine is predicted to be more effective than the standard dose of some of the other vaccines like the AstraZeneca, J&J or Sinopharm vaccines, assuming the same relationship as in Khoury et al. holds. The point is not that these other vaccines aren’t good–they are great! The point is that by using fractional dosing we could rapidly and safely expand the number of effective doses of the Moderna and Pfizer vaccines.
Second, we embed fractional doses and other policies such as first doses first in a SIER model and we show that even if efficacy rates for fractional doses are considerably lower, dose-stretching policies are still likely to reduce infections and deaths (assuming we can expand vaccinations fast enough to take advantage of the greater supply, which is well within the vaccination frontier). For example, a half-dose strategy reduces infections and deaths under a variety of different epidemic scenarios as long as the efficacy rate is 70% or greater.
Third, we show that under plausible scenarios it is better to start vaccination with a less efficacious vaccine than to wait for a more efficacious vaccine. Thus, Great Britain and Canada’s policies of starting First Doses first with the AstraZeneca vaccine and then moving to second doses, perhaps with the Moderna or Pfizer vaccines is a good strategy.
It is possible that new variants will reduce the efficacy rate of all vaccines indeed that is almost inevitable but that doesn’t mean that fractional dosing isn’t optimal nor that we shouldn’t adopt these policies now. What it means is that we should be testing and then adapting our strategy in light of new events like a battlefield commander. We might, for example, use fractional dosing in the young or for the second shot and reserve full doses for the elderly.
One more point worth mentioning. Dose stretching policies everywhere are especially beneficial for less-developed countries, many of which are at the back of the vaccine queue. If dose-stretching cuts the time to be vaccinated in half, for example, then that may mean cutting the time to be vaccinated from two months to one month in a developed country but cutting it from two years to one year in a country that is currently at the back of the queue.
Read the whole thing.
The Becker-Friedman center also has a video discussion featuring my co-authors, Nobel prize winner Michael Kremer and the very excellent Witold Wiecek.
It is typically worth trying on such theories for size, no matter what their defects.
It is hard to avoid noticing that last year’s finalists — Miami and the Lakers — both exited this year in the first round, and ignominiously. Injuries and fatigue were part of the reason why.
The teams that are doing best — Phoenix, New Jersey, and Atlanta — had minimal or zero playoff responsibilities last time around. Usually of course playoff performance is positively correlated from one year to the next.
We will see if this theory has predictive value moving forward. In any case, it does seem the league has discovered the margin where player fatigue truly is a binding variable.
Addendum: ESPN provides the data on injuries to stars.
Fiocruz, the Brazilian public health institute, will test half doses of the AstraZeneca vaccine. Not much information available yet. From a Google Translate article.
BANDNews: Fiocruz, in partnership with the government of Espírito Santo, is going to carry out a study with the application of half a dose of the Astrazeneca vaccine to the entire population of the municipality of Viana, in Greater Vitória.
The city has about 35 thousand inhabitants.
The immunization will take place on Sunday, June 13, and residents will be able to choose whether they want to participate in the study.
According to the state secretary of Health, Nésio Fernandes, there is already evidence of the effectiveness of the application of half a dose of the vaccine in immunization against Covid-19.
If the experience is successful, it will be possible to double the number of people vaccinated in the country with the immunizing agent produced by Fiocruz.
See my previous posts on fractional dosing for why this is very important.
Hat tip: Cisco Costa.
Here is the close of my latest Bloomberg column:
On a related note: Have you noticed that private universities often have a stronger “woke” culture, and less free speech, than public universities? This fact is also somewhat of an embarrassment for many libertarians. Though libertarian-leaning, I am myself happy to be teaching at a public institution, with its stronger legal and normative free-speech protections.
Might the parallel run deeper here? Perhaps the currently enforced codes of wokeism at many universities and technology companies are like mask-wearing norms. Maybe people would be willing to relax more about these issues once someone gives the signal that it is OK to do so.
That would imply that extreme wokeism, like mask mandates, won’t last long. More than just libertarians, perhaps, can take comfort in that.
There is much more at the link.