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.
Nearly a year ago, I wrote Frequent, Fast, and Cheap is Better than Sensitive, arguing for rapid antigen tests:
A number of firms have developed cheap, paper-strip tests for coronavirus that report results at-home in about 15 minutes but they have yet to be approved for use by the FDA because the FDA appears to be demanding that all tests reach accuracy levels similar to the PCR test. This is another deadly FDA mistake.
See also my posts Infected versus Infectious and Rapid Tests. The EMA and then the FDA finally did start approving these tests. So how well are they working? Pretty damn well. Canada has two innovative programs. First, in Nova Scotia pop-up clinics have been using rapid tests for asymptomatic people:
During the third wave that hit Nova Scotia over the past month, the province’s community rapid testing centres have correctly sniffed out at least 285 COVID-19 cases in asymptomatic people, or about 10 per cent of all confirmed cases in this time period, according to the Nova Scotia Health Authority.
While most provinces reserve testing only for symptomatic people or close contacts of a case, Nova Scotia’s pop-up centres allow asymptomatic people to simply show up and get a rapid test for free, with results sent to them within an hour. The whole process relies largely on volunteers without a health-care background.
Furthermore, the true number of cases credited to rapid testing is probably much higher. When a rapid test correctly identifies a positive case, the person’s close contacts such as their family get PCR lab tests that don’t show up in the rapid test statistics.
Lisa Barrett, an infectious diseases specialist and the driving force behind the rapid testing program, said it’s hard to say for certain, but taken altogether it’s possible rapid antigen testing has helped Nova Scotia find up to 18 per cent of all cases during the third wave.
“This is the early detection system,” Barrett said. Rapid testing tends to catch people early on in their infection when they’re full of virus, meaning positive cases are found and put into isolation fast — likely days before they would have been found with a PCR test, if they were found at all.
Michael Mina argues that since the rapid antigen detected cases are among the most infectious cases, detecting these cases is probably worth half of all the PCR testing.
Second, Canada’s CDL Rapid Screening Consortium is now in 200 sites with 50 large companies and rapidly expanding. A very interesting, just published paper in The Lancet runs an experiment that suggests that these testing regimes can work. The experiment rapidly tested 1000 people and the negatives were then randomly assigned either to be sent-home to conduct their regular life or to attend a multi-hour concert with masks but also singing, dancing, alcohol and no-social distancing. After 8 days there were two infections in the at-home group and no infections in the Concert group which suggests that this type of rapid testing can be used to open and keep-open concerts, schools, universities, airplanes and workplaces.
What’s the point of testing now that we have vaccines? Two reasons. First, most of the world still hasn’t been vaccinated so testing will be a very useful stop-gap measure until vaccination is more widely distributed. Indeed, the success of these programs shows what we lost by not acting more quickly a year ago. Second, although the pandemic is (essentially) over in the United States (as predicted) there will likely be an uptick in the fall among the unvaccinated and you want rapid tests to be available rapidly in hot-spots. In other words, rapid deployment of rapid tests will help us to avoid outbreaks in the future.
Often yes, but this is a shibboleth of economics that doesn’t always fit the facts, as has been illustrated starkly by our behaviors during the pandemic. Many people have taken too much risk, or been too risk-averse, even with high stakes on the line. Here is one excerpt from my recent Bloomberg column:
You might wonder why we are getting these big, important decisions so wrong. I have at least two hypotheses. One is that anxiety causes people to make worse decisions. Facing the danger of a deadly pandemic, for example, the higher stakes might induce me to shift into denial, if only to protect my sanity and peace of mind. I might make worse decisions than if I were simply trying to avoid the common cold, for which the stakes are far lower.
My other hypothesis involves identity and the desire for belonging. It is no accident that red states in the U.S. are under-vaccinated relative to blue states; vaccine skepticism is in part an identity marker for Trump supporters. People tend to see big decisions as more important in shaping their identity than small ones. In essence, the significance of a decision induces all kinds of surrounding social forces to “infect” that decision with partisan influences, and that decision in turn becomes a truly credible signal of what we believe.
For most economic decisions, people do still make better choices when the stakes are higher — but this isn’t a universal principle. Are you so sure, for example, that decisions about who to marry are made more rationally than those about which TV show to watch? Maybe they are, but it’s not entirely obvious.
Note that it is now much easier to make good small stakes decisions, largely because of the internet:
An accompanying change is that low-stakes decisions are easier than ever, due largely to the internet, with one crucial caveat: The decision-maker must be relatively rational. Several decades ago, if you wanted to figure out the best paper towels to buy, you might have asked around and then collated a lot of information yourself. These days it is easy enough to search the internet for the answer. Or consider the example of credit-card rewards, which are far easier to collect, manipulate and use because of the internet.
The danger of course is that the sum of all these smaller triumphs convinces people that they are rational about big dilemmas too — despite the fact that they choose rather poorly on some of them. We are not used to a world where we are worse at big decisions than the small ones. But it has been hurtling our way for some while now.
Recommended. I also cite this: “Bryan Caplan, a colleague who studies human rationality, has put the individual Covid response in only the second percentile of “my initially mediocre expectations.””