Paul Has Measles is a free children's book about viruses and vaccines available in 16 languages (link). Paul Stays Home is a free children's book about COVID-19 (link).

Daniel Griffin provides a clinical update on COVID-19, then we review TETRIS by Paterson NJ, modeling the effects of intervention in the US on cases and deaths, mixing PCR and serology data, and much more, including listener email.

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By David Tuller, DrPH

In the past week, I have written three posts about a Norwegian study of cognitive behavior therapy plus music therapy for adolescents with chronic fatigue after acute Epstein-Barr virus infection–an illness known as mononucleosis in the US and glandular fever in the UK. The corresponding author of the study is Vegard Bruun Wyller, a professor at the University of Oslo’s Institute of Clinical Medicine.

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CoV2-cigaretteSome evidence suggests that cigarette smokers are more likely to develop severe COVID-19 disease than non-smokers. Chronic smoke exposure appears to trigger the expansion of cell types in the respiratory tract that produce ACE2, the receptor for SARS-CoV-2. This observation provides a plausible hypothesis to explain why cigarette smokers might experience more severe COVID-19.

A number of independent observations show that cigarette smoke increases expression of the ACE2 gene:

  • Mice exposed to cigarette smoke daily for 5 months had up to 80% more ACE2 expression in the lung compared with control mice
  • Human lung epithelial cells from the bronchi of smokers had 30-55% more ACE2 expression than cells from non-smokers
  • Lung samples from patients who smoked more than 80 pack-years had 100% more ACE2 expression than those who smoked less than 20 pack-years
  • Quitting smoking was associated with a 40% decrease in ACE2 expression
  • In murine and human lung, ACE2 is expressed at high levels in secretory and goblet cells and alveolar type 2 cells. Chronic smoke exposure leads to expansion of mucus-secreting goblet cells, and consequently higher levels of ACE2.

There are two caveats to this study. In the observations listed above, ACE2 expression was assessed by quantifying RNA, not protein. While the authors show a correlation between ACE2 RNA and protein in selected cell lines, the same correlation might not extend to tissues. In other words, increased ACE2 RNA might not lead to increased ACE2 protein.

An important question not considered by the authors is how increased levels of ACE2 would lead to more severe COVID-19. One explanation is that the effect is mediated by increased susceptibility of cells to infection: more ACE2, more virus produced. Whether this situation holds true is unknown, as experiments to address it have not been done. Another issue is that severe COVID-19 typically occurs after a few weeks of virus multiplication in the upper tract, and is accompanied by decreasing viral loads in the respiratory tract. Furthermore, how increased ACE2 might affect the immune imbalance that contributes to severe disease is not known.

These observations make it clear that cigarette smoke increases ACE2 expression; however they do not provide an explanation for how smoking might exacerbate COVID-19. Despite this uncertainty, there are many other good reasons not to smoke cigarettes.

Vincent, Kathy and Rich discuss COVID-19 research paper overload, Moderna’s mRNA vaccine Phase I results, increase of ACE2 RNA by cigarette smoke, and answer listener questions.

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Download TWiV 616 (62 MB .mp3, 103 min)
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Nels and Vincent continue their discussion of SARS-CoV-2 evolution, including understanding recurrent mutations in the viral genome, and the potential for re-emergence of the virus from an animal reservoir.

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By David Tuller, DrPH

Norway’s got a double whammy going on. First there’s the group of investigators that seems to have had trouble determining whether their newly published research on CBT and music therapy was an actual randomized trial or merely a feasibility study. (More on that below.) Then we have Dagbladet, a widely read tabloid, promoting a new study of the Lightning Process–with the same senior investigator as the music therapy research. Dagbladet has so far published two stories about the matter (here and here), with perhaps more on the way.

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Vincent speaks with Peter Daszak, President of EcoHealth Alliance, a global nonprofit organization dedicated to protecting wildlife and public health from the emergence of disease.

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By David Tuller, DrPH

In a well-designed clinical trial, the protocol, the registration and the statistical analysis plan should complement and not contradict each other. Investigators spend huge amounts of time developing clinical trial protocols. These are road-maps to the project, complete with (hopefully) well thought-out and clearly defined primary and secondary outcomes. These documents have to pass muster with oversight and ethics committees and often go through multiple iterations before final approval–and funding.

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Daniel Griffin provides a clinical update on COVID-19, then we review results showing requirement for the furin site in the SARS-CoV-2 spike for replication, US state vaccine exemptions, concerns with a rapid diagnostic test, and answers to listener questions.

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Download TWiV 614 (100 MB .mp3, 167 min)
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UPDATE, MAY 16: As I mentioned, the trial registration did not cite “recovery” as an outcome. However, the various study documents include a number of different statements about the status of physical activity, fatigue, and recovery as endpoints. Of four relevant documents besides the trial registration, one included the definition of recovery used in reporting the study results–three, like the trial registration, did not.

I will outline in more detail when time permits. Those too impatient to wait can access the documents here.

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By David Tuller, DrPH

After the debacle with the Lightning Process study, you would think that BMJ would have learned an important lesson—editors and peer-reviewers should scrutinize the background materials for the trials they publish. That’s the best way to prevent selective outcome reporting and ensure that findings are reported as described in the trial registration and/or protocol.

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