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  • Josh Schiffer

May 7, 2020

Hi everyone! I have been on clinical service for the last 2 weeks seeing patients on our infectious diseases service at the Fred Hutch and had a host of other deadlines. So much has happened, and the volume of incredible journalism and scientific work continues to grow exponentially. I am sure that I have lost track of multiple important topics but have tried to keep up as much as I could.

Before the review of this week’s literature, a brief word on scientific incrementalism. Science is often portrayed in the media as a series of massive unprecedented, joyous breakthroughs. The reality is much more plodding. New publications bring small bits of new knowledge which are then retested, potentially refuted and tweaked many times over. Progress is halting. It is important to keep this in mind when processing the massive deluge of COVID-related scientific information coming our way.

I have had the good fortune of working with some extraordinary scientists within my team and as part of larger collaborations over the last decade. On perhaps four or five occasions, we generated ideas that at some small level overturned a bit of dogma. It has even happened a couple of times in the last few months. The feeling associated with such discoveries or new ideas is excitement but also a bit of terror. There is always this lingering feeling that a new idea or discovery may be terribly wrong and in retrospect even a bit silly. Usually our practice is to sit on these concepts for weeks and to consider ways to refute our own ideas. In the current environment, this period of reflection is truncated if not eliminated. Scientists are rushing their work to preprint and then to publication. Ideas are not fully parsed. Errors are more common. Even the most exciting scientific discoveries should be greeted with more caution in skepticism than usual. With this in mind, here are a few great reads that I hope you enjoy.

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Mandatory reading about what comes next. For my money, Tomas Pueyo has provided the most thoughtful and realistic overviews of how governments should strategize for the next year. I read his articles and reread them 2 weeks later and would suggest doing the same.

https://medium.com/@tomaspueyo/coronavirus-learning-how-to-dance-b8420170203e

https://medium.com/@tomaspueyo/coronavirus-the-basic-dance-steps-everybody-can-follow-b3d216daa343

https://medium.com/@tomaspueyo/coronavirus-how-to-do-testing-and-contact-tracing-bde85b64072e

Ed Yong of the Atlantic has also been out of this world. His level of perception and intuition is unmatched. This piece covers how the avalanche of daily information, some of which is correct, some of which remains to be proven, some of which is not even falsifiable, and a lot of which is just nonsense, can be so personally destabilizing.

https://www.theatlantic.com/health/archive/2020/04/pandemic-confusing-uncertainty/610819/

For the general public and experts alike, this environment is dizzying and confusing. Given this degree of uncertainty, it is not surprising that conspiracy theories, nearly all of which quite obviously make no sense and are just extraordinarily stupid, are attractive and probably comforting to a gullible, superstitious and statistically / scientifically unsophisticated subset of the population. Not sure how to correct this.

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Epidemiology riddle. In a post ~2 months ago I wrote about the factors which allowed COVID to take off in certain countries versus others using an analogy of forest fires, sparks, fire departments, etc.:

https://www.jtsid.com/post/march-12-2020

At the time, it seemed possible to explain the trajectories of outcomes in many countries based on initial responses, degree of contact tracing, and availability of testing. The picture is no longer so clear to me. I consider this piece in the Times to be one of the essential pieces of journalism since the start of the pandemic. They highlight the mysterious global situation in which neighboring countries are having vastly different outbreaks (Haiti vs the Dominican; Peru vs neighboring countries; Greece vs. Italy). India and much of sub-Saharan Africa have been spared to a degree that few epidemiologists predicted. The article does a brilliant job outlining various drivers of more severe outcomes including age demographics, cultural greeting practices, percentage of time spent outside, climate and timing of lockdowns.

The conclusion is that in some countries, particularly those in Asia with highly organized lockdowns and test / trace strategies, we can infer why the disease incidence behaved the way it did. The shit show in the US is also a deterministic outcome relating to lack of preparedness and a cynical and incompetent central government. However, in many other countries, the underlying drivers of failure or success are considerably harder to discern.

The role of stochasticity is likely to be important. Stochasticity refers to random events that occur when case numbers are small, which could lead to extinction or take off. Consider South Korea where one woman initiated a super spreader event that seeded a large national outbreak: without this event, Korea probably looks more like Taiwan with a handful of rapidly contained mini outbreaks. Consider the single case that seeded Washington State: remove this case and Seattle looks like Portland, Oregon with a later initiation date and far fewer cases and deaths. Consider even the entire pandemic which might have occurred because a single virus leaving a single animal and infecting one human. The difference between Greece and Italy, or Haiti and the Dominican may really be as simple as good versus bad luck in the initial stages of the pandemic. Of course, policy can greatly impact whether a country is more susceptible to good or bad luck, but randomness appears to be a fundamental ingredient of SARS Co-V-2 epidemiology.

https://www.nytimes.com/2020/05/03/world/asia/coronavirus-spread-where-why.html?action=click&module=Spotlight&pgtype=Homepage

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Excess mortality. This informative article shows estimated excess deaths not attributed directly to COVID. The numbers are so high in Italy meaning that many people died at home alone. Even if flatten the curve saves no lives in the end (which of course it will), it will be worth if it saves people from the indignity of suffering alone.

https://www.economist.com/graphic-detail/2020/04/16/tracking-covid-19-excess-deaths-across-countries?fsrc=scn/fb/te/bl/ed/covid19datatrackingcovid19excessdeathsacrosscountriesgraphicdetail&fbclid=IwAR0mN68sTySNQ28ExeaE_aDpRXlYZzrifNv3IQ3eWuZQT5n8LvfM6sGnyqQ

User friendly model. I really, really like this model from MIT. It is simple, based on sound epidemiologic principles, easy to interpret, accurate so far and projects enormous uncertainty as time passes which is very appropriate.

The structure is a very standard “SEIR” model (susceptible -> exposed -> infected / infectious -> recovered). The novel piece is the use of a machine learning approach to update the rates which govern transitions between these states.

https://covid19-projections.com

https://covid19-projections.com/model-details/

https://covid19-projections.com/#view-projections

https://covid19-projections.com/#us-deaths-likelihoods

https://covid19-projections.com/us-wa

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Herd immunity overshoot. This is a really important point to understand. Once herd immunity is achieved, the game is not over. In fact, hundreds of thousands of cases will continue to accrue over subsequent months though at an increasingly slower rate. This is why the goal must be herd immunity via vaccine and not via infection.

https://twitter.com/CT_Bergstrom/status/1252075528711860224

https://www.nytimes.com/2020/05/01/opinion/sunday/coronavirus-herd-immunity.html

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Duration of shedding. This is a very nice paper showing that shedding is longer in stool than in saliva than in blood; longer in severe versus mild cases; and at higher respiratory viral load in severe versus mild cases. This is very important and diligent work. Note that respiratory shedding sticks around for an average of 18 days but often for 1-2 months. This is consistent with past data (https://www.medrxiv.org/content/10.1101/2020.03.24.20042382v1.full.pdf)

and I suspect that transmission probability at late stages is much lower.

https://www.bmj.com/content/bmj/369/bmj.m1443.full.pdf

I did a video piece with the Wall Street Journal about the mechanisms and meaning of prolonged viral shedding at low viral loads. Thanks to Daniela Hernandez for a fun project.

https://www.wsj.com/video/why-fully-recovering-from-coronavirus-might-take-longer-than-expected/985A51E7-D3C9-4375-BC3B-9E5E2E03691E.html?fbclid=IwAR2uz0U_7P01LGIibo2qsbt4MTq8wbWEKPAn3I6LWwqxE_Yg1LOF-lDEZPc

Here is our pre-print modeling the initial very high viral loads followed by much lower viral loads over the subsequent week or two. We predict there are 2 phases to the immune response. Remarkable the early, innate immune response is predicted to eliminate millions of infected cells during the first few days of infection but cannot finish the job. A mounting B or T cell response kills the rest of the infected cells 1-2 weeks later. We are able to use the model to project the effects of different therapies assuming different potencies.

https://www.medrxiv.org/content/10.1101/2020.04.10.20061325v2.full.pdf

This is the best review of viral immune interactions during COVID-19. No surprises really relative to other acute viral infections.

https://www.nature.com/articles/s41577-020-0311-8.pdf

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Problematic ecologic studies. This is a wonderful piece on the inherent limitations of ecologic studies in which 2 populations are compared without controlling for confounding variables. In brief, these studies are designed only to identify correlations, and are nowhere close to establishing causality. They generate hypotheses, and do not test them. Most of these hypotheses will be proven wrong, or at least will be associated with major caveats. There are many ideas regarding COVID-19 that are widely circulating which are based on ecologic studies and nothing more: the idea that the BCG vaccine may protect against COVID (the articles lists the many confounding variables which could explain this); the idea that masks are responsible for lower SARS Co-V-2 incidence in Asian cities (maybe, but contact tracing is also superb in these places). Beware the ecologic study. Accept the uncertainty.

https://www.forbes.com/sites/madhukarpai/2020/04/22/a-skeptics-guide-to-ecologic-studies-during-a-pandemic/#726aca346894

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Challenge studies. This is a cogent argument for doing human challenge studies with SARS Co-V-2. The downside of such an approach is the potential for harm to study participants. The upside is the ability to test vaccine efficacy much more quickly than using traditional study designs awaiting natural infection in population cohorts and will also provide vital information about the natural history of infection.

I support this initiative in well-educated willing study participants. Years ago, I served as a study clinician for several malaria challenge studies which were invaluable for learning about the infection and for malaria vaccines and new treatments. Participants received treatment immediately after developing symptoms or other signs of infection. While the risk for harm was low it was not zero.

Humans take considerable risk in their work lives and in recreation. Consider firefighters, policemen, and frontline health care providers. Consider skiing, motorcycle riding, biking or any other outdoor activity. If a consenting young adult is willing to participate in a SARS Co-V-2 challenge study to benefit the greater good at relatively low personal risk, with the possibility of saving thousands of lives, then we should honor this and go forth, albeit with utmost care and planning. I hope this happens.

https://www.theatlantic.com/ideas/archive/2020/04/challenge-trial-ethical-imperative/610309/?utm_source=twitter&utm_medium=social&utm_campaign=share

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Corona cross protection. A tantalizing hypothesis is that infection with one of the more commonly circulating mild strains of human coronavirus which typically start infecting children at a young age may provide some protection against SARS Co-V-2. Alternatively, there is a theoretical concern that having antibodies against one coronavirus could facilitate the entry of the more dangerous SARS variants into cells and make disease worse. This review tackles the existing literature and shows that for all coronaviruses antibodies typically emerge approximately 2 weeks after infection, that cross protective antibodies against more than one coronavirus strain are not yet known to exist, but that having any bodies against one coronavirus may lessen the impact of subsequent infection with a different strain. This is clearly an area that will be explored in enormous depth but will take years for a clear picture to emerge, if it ever does. These will be very, very difficult studies in terms of establishing causality.

https://www.medrxiv.org/content/10.1101/2020.04.14.20065771v1.full.pdf

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Contact tracers. An interesting debate is brewing about how best to perform contact tracing when the epidemic hopefully subsides in the summer to prevent large outbreaks again in the event of inevitable new infections. Some are advocating for traditional contact tracing methods which would necessitate the hiring of thousands of people to track down all potential Contacts have an infected person. More tech minded approaches are also being considered using cell phones in specialized apps as now exists in Korea, Hong Kong, Taiwan and mainland China. It will be interesting to see how this evolves in different parts of the United States given the lack of centralized organization I predict widely heterogeneous implementation of these policies.

https://www.buzzfeednews.com/article/carolinehaskins1/coronavirus-contact-tracing-google-apple

https://www.brookings.edu/techstream/inaccurate-and-insecure-why-contact-tracing-apps-could-be-a-disaster/

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True seroprevalence. The Santa Clara study is one of several studies reporting higher seroprevalence than many expected. This data has been politicized unfortunately. Its strengths and limitations are best viewed in an unbiased fashion. This is a nice peer review from Natalie Dean highlighting reasons that the estimates could in fact be overestimates. The first issue is technical and involves techniques for population weighting to make the demographics of the sampled population matched those of the real population. The second issue is that in a low prevalence environment such as Santa Clara even if a test has relatively good performance characteristics, a majority of positive tests may still be false positives. (As an aside, in a high prevalence environment many negative tests may in fact be false negatives.) A final issue is self-selection bias meaning that people who wanted to know if they had been infected before may be more likely to self-enroll into the study. My take is that studies of this nature provide an upper bound on what the true prevalence might be.

https://twitter.com/nataliexdean/status/1251309217215942656

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Abbot serology. This study from colleagues at UW virology appears to show that the Abbot serology provides very reliable results on the likelihood of pass infection. They validated the essay by using specimens from years ago in an era when SARS Co V2 was clearly not circulating in the general population as well as specimens from people who were recently infected. The predictive value of both a negative or a positive, test approach 100%. If this is validated in other studies, then this suggests the ability to perform very accurate surveys of the level of prior infection in a community as the investigators did in Idaho in the second part of the paper.

https://www.medrxiv.org/content/10.1101/2020.04.27.20082362v1.full.pdf

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Vaccine. I reviewed this paper from Sinovac a Chinese vaccine company at our Fred Hutch virology Journal club. The paper is exciting because it is the first to show protection in a nonhuman primate model against SARS Co-V-2. The figures are inexcusably terrible. They inactivated a live version of the virus with a chemical making it unable to replicate beyond a single cycle in animals or humans, and then used this as a vaccine. It appeared to almost completely protect animals from infection. However, the investigators clearly cherry picked the timing of infection after giving a total of three vaccines. It is fairly common practice in the field to first perform studies in which the cards are stacked in favor of the vaccine rather than the virus.

Similar exciting news has emerged from Oxford regarding a vaccine. This product uses a common cold virus called adeno virus to express the SARS Co-V-2 spike protein such that subsequent exposure to the live virus will hopefully lead to its rapid elimination by pre-existing antibodies. Of particular excitement, is that this adenovirus backbone has been used in human studies to protect against MERS. Therefore, it is possible to move directly into human vaccine studies without preclinical animal studies. For this reason, the Oxford candidate is the leading horse in the race at the moment. Stay tuned as this may be big news

https://www.biorxiv.org/content/10.1101/2020.04.17.046375v1.full.pdf

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Vaccine development. The focus of this article is the typical time frame for vaccine development. It is so important for the public to understand how lengthy and involved this process is and that the development of a vaccine in the next 18 months would be unprecedented. I do wish the article had made fewer parallels between drug and vaccine development as these really are two different time scales in manufacturing challenges.

https://www.nytimes.com/interactive/2020/04/30/opinion/coronavirus-covid-vaccine.html?utm_source=pocket-newtab

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Viral mutations and vaccines. This is a nice journalistic take on how viral mutation may or may not impact the effectiveness of future vaccines.

https://www.nytimes.com/interactive/2020/04/16/opinion/coronavirus-mutations-vaccine-covid.html So far, data from our collaborator Morane Rolland suggests this is not yet an issue. https://www.biorxiv.org/content/10.1101/2020.04.27.064774v1

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Clinical cases in NY. This very large case series from New York City received considerable attention for its notably high death rate among patients who ultimately required mechanical ventilation. Of great importance will be whether outcomes were worse in New York city Detroit in New Orleans relative to other cities based on this surge of extremely sick patients. This would provide the most compelling reason to avoid similar surges during the predicted 2nd and possibly third waves of infection coming later this year

https://jamanetwork.com/journals/jama/fullarticle/2765184?guestAccessKey=906e474e-0b94-4e0e-8eaa-606ddf0224f5&utm_source=For_The_Media&utm_medium=referral&utm_campaign=ftm_links&utm_content=tfl&utm_term=042220

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Call center outbreak. Here is a very cool manuscript showing the spatial layout of infected people within a call center in Seoul. The intensity of infection in this closed environment suggests a possible super spreader event. The spatial distribution suggests droplet rather than aerosolized spread. It is beautiful example of the high utility of extensive contact tracing.

https://wwwnc.cdc.gov/eid/article/26/8/20-1274_article

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Early Wuhan. A brief report of influenza like illness in Wuhan suggesting community circulation as early as early January 2020

https://www.nature.com/articles/s41564-020-0713-1 ------ Drug repurposing. This is a paper in Nature that represents a tour de force massive drug screening of licensed for potential activity against SARS Co V2. The authors specifically looked for protein interactions against various steps in the viral replication cycle. Many of the emerging candidates have also been proposed against HIV cure so are quite familiar to me. It will be fascinating to see which of these agents actually makes it to a clinical trial and if any have true efficacy. Candidates include cancer drugs, antipsychotic agents, diabetes drugs and small molecules used to prevent organ rejection after transplantation, among others. https://www.nature.com/articles/s41586-020-2286-9_reference.pdf ----

Seattle vs NY. This is a story of how Seattle managed to react relatively quickly to the presence of SARS Co V2 based on the high number of infectious diseases physicians in the city who in a previous lifetime head trained at the CDC's epidemic intelligence service program. This includes several of my mentors who are not mentioned in the article. A very cool read

https://www.newyorker.com/magazine/2020/05/04/seattles-leaders-let-scientists-take-the-lead-new-yorks-did-not

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Infection in minorities and the working poor. This piece from San Francisco is an obvious reflection of what's truly happening nationally at this stage in the pandemic. It is now obvious that certain segments of the population particularly those in white collar jobs have the luxury to stay home and to afford various methods of childcare and home schooling. Sadly and predictably, minorities and the working poor still must take public transportation, still must work in jobs situations where social distancing is not possible are therefore disproportionately represented among new cases.

https://www.sfgate.com/news/editorspicks/amp/90-of-people-who-tested-positive-for-COVID-19-in-15247476.php?fbclid=IwAR3zcAGc8wNAnGDtdmAQVI1kVQ9rI1dt76dp_GsVv3R2PtzcoijdAcNmsQU

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Kids. This review of clinical illness in children infected with SARS Co V2 in China reflects a slightly higher proportion of illness than I might have expected with nearly half of kids having a fever and nearly half of kids having a cough. Nevertheless, the lack of critical illness remains reassuring. https://www.nejm.org/doi/full/10.1056/NEJMc2005073 ----

Saliva. this is one of a couple of reports highlighting that saliva may be a more sensitive way to test for the virus than any form of swab. This is nice because saliva will be an easier collection technique for many people relative to swapping. One limitation maybe sensitivity for other important respiratory viruses such as influenza or SV. This remains to be seen.

https://www.medrxiv.org/content/10.1101/2020.04.16.20067835v1.full.pdf

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Semen. SARS Co V2 was not detected in semen in the study. Good news

https://www.sciencedirect.com/science/article/pii/S0015028220303848?via%3Dihub#!

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The US is a failed state. At this point, it is just embarrassing. The rest of the world pities us.

https://www.theatlantic.com/magazine/archive/2020/06/underlying-conditions/610261/

We do not appear to be prioritizing the health of our own citizens.

https://www.theatlantic.com/ideas/archive/2020/04/trump-trading-lives-poor-economic-growth/610264/

Our hospital CEOs must purchase PPE on the black market.

https://www.nejm.org/doi/full/10.1056/NEJMc2010025

We suppress science and bad news. Like Russia would do. https://www.statnews.com/2020/05/05/vaccine-expert-says-he-was-punished-for-raising-concerns-about-trumps-coronavirus-response-nepotism/ We have an uneducated, stubbornly conspiratorial and terrifying subculture. https://www.nbcnews.com/tech/tech-news/what-are-we-doing-doctors-are-fed-conspiracies-ravaging-ers-n1201446 https://www.washingtonpost.com/opinions/firearms-at-protests-have-become-normalized-that-isnt-okay/2020/05/06/19b9354e-8fc9-11ea-a0bc-4e9ad4866d21_story.html We reward nepotism and deep incompetence. https://www.washingtonpost.com/opinions/2020/05/06/save-us-all-jared-kushner/?utm_campaign=wp_opinions&utm_medium=social&utm_source=twitter ----

Korea. This is a fascinating piece on the delicate balances inherent to digital contact tracing. Note their concern for super spreaders above all else. I feel like the Korean government is being very transparent and thoughtful about tradeoffs between public safety and privacy.

https://www.newyorker.com/news/news-desk/seouls-radical-experiment-in-digital-contact-tracing

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Sweden. The results of the experience are accruing, and it looks worse in Sweden than other Northern European countries. This result disappointed me as I hoped that Sweden might provide a road map for gentle relaxation of physical distancing at home. This is a first warning for how difficult creating policies will be in the US

https://www.cnn.com/2020/04/28/europe/sweden-coronavirus-lockdown-strategy-intl/index.html

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Group homes. A central tragedy of America’s COVID story have been nursing homes. In some facilities, residents are sitting ducks. Staff are often forced to work at multiple locations to make ends meet and are involved in physically intimate care of residents including bathing, toileting and feeding. Elderly and chronically ill residents are obviously at greater risk of severe manifestations of severe outcomes. It is a perfect storm of sorts

I am proud to have been involved with the widespread testing in Seattle that is highlighted below and has been led by Thuan Ong and Alison Roxby. This mission has been incredibly well organized and efficient with volunteer teams visiting group homes most days including weekends. I wish my schedule permitted more of this type of work.

https://apnews.com/3f431d2d60c7f5f14236c496d6127109

https://apnews.com/e34b42d996968cf9fa0ef85697418b01


The paper below from Washington state highlights the importance of asymptomatic infection and pre symptomatic infection for the spread a virus within such facilities. The only way around this is clearly liberal use of testing for SARS Co V2.

https://www.nejm.org/doi/full/10.1056/NEJMoa2008457

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Fake photography. I have been somewhat reluctant to post on this issue because social distancing is a touchy, politicized subject. I have simply held to the scientific fact that this scientific method has now saved tens of thousands of American lives and millions of lives globally. I am very confident stating this.

I am far less confident in assessing what constitutes appropriate social distancing at parks and public places and have avoided jumping into this debate. I have also noticed that people get pretty uppity when posting about this on social media.

Today I am taking the plunge. There is a decent bit of shaming for people at parks and beaches, often substantiated with photos in the press. We live near Alki beach where there have been published photos which make it look packed. I cannot help myself and occasionally do a drive throughs when the area is theoretically most crowded: sunny, 2 PM on a Saturday. Almost always, I see >95% of people being extremely considerate and taking great lengths to avoid being within 6 feet of each other. There are exceptions, but not many.

I am calling BS on at least some (not all) of the photos turning up in newspapers. Here is some validation:

https://www.boredpanda.com/different-perspective-telephoto-lens-vs-wide-angle-philip-davali-olafur-steinar-ry/?utm_source=twitter&utm_medium=social&utm_campaign=organic

As a rule, try to save your anger for the selfish idiots who show up at state houses with machine guns, rather than people who are out for a walk with their family:

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Jon Oliver. This guy is brilliant. It is extremely distressing to watch the dishonesty from right wing media outlets flow directly into the moldy jello brain of our president. The whole segment is infuriating but poignant and is best summed up with Oliver’s summary of why Fox news celebrities continually tout misleading information about COVID while of course practicing strict social distancing themselves: “"They only pretend to believe these things on television for money."

https://www.youtube.com/watch?v=dRFbwjwQ4VE

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Bob May. One of the founders of math modeling of infections has passed away. This is a nice tribute highlighting his enduring perspective on our tribe’s role in science:

https://twitter.com/Caroline_OF_B/status/1255866546334961665

This is Bob’s famous essay in Science which provides qualitative benchmarks for every math modeling paper my group writes:

https://pdfs.semanticscholar.org/f31e/73ca33b8e8deee59c781b05e4c24dc4210da.pdf

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