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Regeneron reports results of its “antibody cocktail” treatment for COVID-19: news release

2020-10-30
EM of SARS-COV-2 from Groopman lab

Regeneron has published a news release on October 28, 2020 giving results of its ongoing Phase 2/3 trial of its “antibody cocktail” treatment for COVID-19, showing a greater than ten-fold reduction in viral load and:

“Treatment with REGN-COV2 reduced COVID-19 related medical visits by 72% in patients with one or more risk factor.”

This treatment, called REGN-COV2, is the one touted by our current president after he spent three days in hospital with COVID-19 at the beginning of October. It appears to be highly successful and to have a low incidence of side effects.

From the news release:

Results showed no significant difference in virologic or clinical efficacy between the REGN-COV2 high dose (8 grams) and low dose (2.4 grams). Based on this finding, Regeneron is reviewing potential changes to dosing in the ongoing outpatient clinical trial given the current limited supply of REGN-COV2…

Serious adverse events were numerically more frequent with placebo than REGN-COV2 treatment (0.8% high dose, 1.6% low dose; 2.3% placebo). Numerically more infusion reactions occurred with the REGN-COV2 high dose compared to placebo (1.5% high dose; 0% low dose; 0.4% placebo)…

REGN-COV2 is a combination of two monoclonal antibodies (REGN10933 and REGN10987) and was designed specifically to block infectivity of SARS-CoV-2, the virus that causes COVID-19.

To develop REGN-COV2, Regeneron scientists evaluated thousands of fully-human antibodies produced by the company’s VelocImmune® mice, which have been genetically modified to have a human immune system, as well as antibodies identified from humans who have recovered from COVID-19. The two potent, virus-neutralizing antibodies that form REGN-COV2 bind non-competitively to the critical receptor binding domain of the virus’s spike protein, which diminishes the ability of mutant viruses to escape treatment and protects against spike variants that have arisen in the human population, as detailed in Science.

https://investor.regeneron.com/news-releases/news-release-details/regenerons-covid-19-outpatient-trial-prospectively-demonstrates

This monoclonal antibody treatment appears very promising, but unfortunately it is in highly limited supply. Only some 50,000 treatment courses are currently available, less than the daily number of new cases appearing in the US presently. Large quantities of this antibody are unlikely to become available in the future.

Since it is most effective when given early in the course of infection, we are left with the dilemma of choosing to whom it should be given. It is difficult or impossible to predict at the outset which patients will be most affected by the disease, so prioritizing treatment to the sickest will not be possible. Most likely, the treatment will be given to those who can pay the most or who are considered the most valuable to society– not an equitable strategy.

Transmission of SARS-COV-2 Infections in Households: CDC via MMWR, October 30, 2020

2020-10-30
SARS-COV-2 EM photo courtesy NIAID

The Centers for Disease Control (CDC) published a Morbidity and Mortality Weekly Report (MMWR) on October 30, 2020 titled “Transmission of SARS-COV-2 Infections in Households– Tennessee and Wisconsin, April-September 2020.” This report states that 102 of 191 contacts of 101 patients with positive RT-PCR (reverse transcriptase polymerase chain reaction) tests for SARS-COV-2 developed positive RT-PCR tests during follow-up. The secondary infection rate was 53%.

From the report:

For this analysis, 101 households (including 101 index patients and 191 household members) were enrolled and completed ≥7 days of follow-up. The median index patient age was 32 years (range = 4–76 years; interquartile range [IQR] = 24–48 years); 14 (14%) index patients were aged <18 years, including five aged <12 years and nine aged 12–17 years. Among index patients, 75 (74%) were non-Hispanic White, eight (8%) were non-Hispanic persons of other races, and 18 (18%) were Hispanic or Latino (Table 1). Index patients received testing for SARS-CoV-2 a median of 1 day (IQR = 1–2) after illness onset and were enrolled in the study a median of 4 days (IQR = 2–4) after illness onset.

The median number of household members per bedroom was one (IQR = 0.8–1.3). Seventy (69%) index patients reported spending >4 hours in the same room with one or more household members the day before and 40 (40%) the day after illness onset. Similarly, 40 (40%) of index patients reported sleeping in the same room with one or more household members before illness onset and 30 (30%) after illness onset.

Among all household members, 102 had nasal swabs or saliva specimens in which SARS-CoV-2 was detected by RT-PCR during the first 7 days of follow-up, for a secondary infection rate of 53% (95% CI = 46%–60%) (Table 2). Secondary infection rates based only on nasal swab specimens yielded similar results (47%, 95% CI = 40%–54%). Excluding 54 household members who had SARS-CoV-2 detected in specimens taken at enrollment, the secondary infection rate was 35% (95% CI = 28%–43%).

Forty percent (41 of 102) of infected household members reported symptoms at the time SARS-CoV-2 was first detected by RT-PCR. During 7 days of follow-up, 67% (68 of 102) of infected household members reported symptoms, which began a median of 4 days (IQR = 3–5) after the index patient’s illness onset. The rates of symptomatic and asymptomatic laboratory-confirmed SARS-CoV-2 infection among household members was 36% (95% CI = 29%–43%) and 18% (95% CI = 13%–24%), respectively.

https://www.cdc.gov/mmwr/volumes/69/wr/mm6944e1.htm

The report states that, “About 75% of secondary infections were identified within 5 days of the index patient’s illness onset.” As noted in the excerpt above, 54 of the household members were already infected at the time the index patient was enrolled, that is, nearly simultaneously. The report gives recommendations for immediate self-isolation and mask-wearing for all household members. However, that would be too late for those 54 patients.

The data presented in this report are from an ongoing study in two locations: Nashville, Tennessee and Marshfield, Wisconsin. Additional information from this study is likely to be forthcoming.

The study shows that household infections occur commonly and quickly after a member of the household brings home the virus. This makes it imperative for control of this virus that everyone in an affected household be aware of infection status for household members and take appropriate precautions at once.

The CDC is still functioning despite attempts by this administration to undermine and politicize it. This study shows that it is still producing important science and publicizing it to everyone who will listen.

Autoantibodies appear during severe COVID-19 illness: MedRxiv

2020-10-28
EM of SARS-COV-2 from Groopman lab

A preprint (not yet peer-reviewed) article (.pdf full-text version here) appeared on MedRxiv on October 23, 2020 that described the frequent presence of autoantibodies in patients with severe COVID-19 disease.

In these patients, critically ill with COVID-19, more than half showed autoantibodies to a variety of normal constituents of the cell. Some factor that contributes to serious COVID-19 illness also results in the development of autoantibodies.

This has relevance to treatment, explaining why dexamethasone (which suppresses immune reactions) is so effective in severe disease, and suggesting that additional immune suppressive treatments may be helpful.

This also has relevance to explaining why some patients have persistent symptoms long after the viral infection has resolved. Autoantibodies may be causing brain cell damage, damage to both skeletal and heart muscle, and lung problems. Further research will clarify this issue.

Prior to this research, there were findings that anti-interferon antibodies were present in 10% of patients with severe COVID-19 pneumonia. This underscores the importance of interferon in mediating the systemic response to coronavirus infection. (See this article in Science magazine if you dare to learn too much about this.)

The research described in the paper we are talking about today involved 52 patients, almost all of them critically ill with COVID-19 (only two were described as “severe.”) Two-thirds of the patients were male, and 54% of them were African-American (this corresponds to the demographics of serious COVID-19 infections generally– most patients are nonwhite men.)

None of the patients in this study had a prior history of auto-immune disease such as systemic lupus erythematosus or rheumatoid arthritis. Most of the patients had extremely high C-reactive protein (CRP) levels, from 17 to 473 (normal is less than 10; CRP almost always is high– though not this high– in the presence of any infection or inflammation.)

23 of the patients had positive anti-nuclear antibody (ANA) tests, 19 of them with titers of 1:160 or worse (positive ANA is normally found in the setting of lupus erythematosus.) Follow-up testing in seven patients, two weeks later, included four with positive ANA at the outset; one with a titer of 1:80 had resolved at follow-up, but the other three showed 1:360 or worse, one increasing to 1:2560.

Twelve of the patients showed positive rheumatoid factors (RF) (normally seen in rheumatoid arthritis), and ten showed a variety of other autoantibodies (normally seen in other auto-immune diseases.) Some of the patients had both rheumatoid factor and ANA autoantibodies; the number with both is unclear from the figures.

Details of the autoantibodies are shown in Table 1 and Figure 1 of the full-text version of the paper. There are some inconsistencies in the data shown, no doubt due to the fact that the paper has not been reviewed or editorially corrected.

The conclusion of the paper states:

Our findings invite two interpretations. Either patients with undocumented and pre-existing autoimmunity comprise the majority of the critical illness within our Atlanta-based cohort, or more likely, the immunological environment of serious COVID-19 infection, including TLR7 activation by SARS-CoV2 ssRNA [single-stranded ribonucleic acid], is sufficient to drive de novo autoreactivity against a variety of self-antigens.

The latter possibility has been documented in the setting of other serious infections (reference 10: Isenberg, D.A., et al. “Profile of autoantibodies in the serum of patients with tuberculosis, klebsiella and other gram-negative infections” Clin Exp Immunol 67, 516-523 (1987)), and is now mechanistically supported through independent validation of autoimmune-prone EF [extra-follicular] response activation in serious disease (reference 6: Kaneko, N., et al. “Loss of Bcl-6-Expressing T Follicular Helper Cells and Germinal Centers in COVID-19” Cell (2020)).

These findings may be consequential for the identification of patients in whom immunomodulation may be beneficial and suggest the value of autoreactivity measurements for proper segmentation and allocation of properly targeted therapies.

They further suggest that simple clinical testing for ANAs or RF may be able to distinguish those groups. Longitudinal study of recovered patients will be critical in understanding the persistence of this autoreactive state, its role in the increasingly documented cases of ‘lingering’ COVID-19 (reference 11: Carfi, A., Bernabei, R., Landi, F. & Gemelli Against, C.-P.-A.C.S.G. “Persistent Symptoms in Patients After Acute COVID-19” JAMA 324, 603-605 (2020)), and its propensity for conversion into self-sustaining autoimmunity– in order to devise early rheumatological intervention strategies and establish effective long-term care protocols.

https://www.medrxiv.org/content/10.1101/2020.10.21.20216192v1.full.pdf

In other words, testing for ANA and RF in serious cases of COVID-19 may identify patients who would benefit from immune-modifying drugs.

More reviews of “What were we thinking”: How 150 books were written about one subject. That’s not including some other important books, named below.

2020-10-27
cartoon courtesy of pixabay.com

The Los Angeles Times published a review of “What Were We Thinking” on October 6: “The meta [redacted] book you didn’t know you needed (and wanted) to read.”

The book’s author states, from the review:

“I imagine that for some people, my book will serve as a ‘He read it so I don’t have to’ rundown of these books,” said Lozada, the Pulitzer Prize-winning nonfiction book critic of the Washington Post, from his home outside Washington, D.C. “Maybe you’ll pick up one or two as a result. That’s great.” But, he adds, “I do hope that there is also a sense of an underlying critique of this moment in American intellectual life.”

https://www.latimes.com/entertainment-arts/books/story/2020-10-06/carlos-lozada-what-were-we-thinking-trump-book-q-a

The Guardian also had a review, on October 10, subtitled, “The Washington Post critic read 150 Trump books, somehow stayed sane and wrote an elegant yet lacerating response.” The reviewer states:

I am both politically liberal and horribly arachnophobic. To liberal readers [redacted] and his presidency resemble footage of a Goliath birdeater. A crawling, creeping horror, an object of terrible fascination, a shifting dark mass from which one cannot tear one’s gaze. Traffic figures to news websites say so. So do publishers’ profits.

https://www.theguardian.com/books/2020/oct/10/what-were-we-thinking-review-carlos-lozada-trump-books

The book is available from Simon and Schuster at their web site. It is also available from Amazon.com, which gives it 4-1/2 stars on 23 reviews and says it’s the number one seller in their “political literature criticism” section.

To be fair, one reviewer mentions that Mr. Lozada left out David Bromwich, American Breakdown: The [redacted] Years and How They Befell Us (London, 2019). The reviewer thinks that is one of the most important books. He states, “Bromwich is a serious omission–one for which there is no excuse, especially since so many of the authors examined aren’t worth the time and trouble.” The reviewer dismisses books by Hugh Hewitt, Michael Wolff, Charles Sykes, and Brian Stelter, among others.

Another reviewer quotes Lozada: ‘One of the ironies of our times is that a man who rarely reads, preferring the rage of cable news and Twitter for hours each day, has propelled an onslaught of book length writing about his presidency’. The reviewer recommends, among Lozada’s 12 most memorable, ‘Know My Name’ by Chanel Miller, and ‘The Fifth Risk’.

Yet another reviewer mentions that Lozada could not include books by  Mary [redacted], Michael Cohen, Peter Strzok, Andrew Weissman, Michael Schmidt, and Bob Woodward, as they were too recent for him to read and still get his book published before the (possible re-) election. This reviewer also mentions the following missing books: Martha Nussbaum (The Monarchy of Fear: A Philosopher Looks at Our Political Crisis) and Adam Gopnik (A Thousand Small Sanities: The Moral Adventure of Liberalism) – plus: Jane Mayer (Dark Money: The Hidden History of the Billionaires Behind the Rise of the Radical Right) and George Packer (The Unwinding: An Inner History of the New America).

The New York Times had a review that came out on the book’s official publication date as well, October 8. From that review:

In 2015, Carlos Lozada, The Washington Post’s Pulitzer Prize-winning book critic, took on a harrowing task: He read eight books “written” by [redacted]. Soon, he expanded the mandate, reading everything he could about [redacted] and the [redacted] era — 150 books in all. It was an act of transcendent masochism, but we should be grateful he did it because “What Were We Thinking” looks past the obvious and perverse — that is, past [redacted] himself — to the troublesome questions raised by the elevation of a soulless carnival barker to the nation’s highest office. 

https://www.nytimes.com/2020/10/06/books/review/what-were-we-thinking-carlos-lozada.html

So many books (and so many reviews of this one book), so little patience. I won’t say I don’t have enough time to read all these books, because actually I do. I just can’t stand the subject material– it’s too enraging to take a chance on. I’d rather read some ancient history.

“Declining prevalence of antibody positivity to SARS-COV-2” in UK seroprevalence study: MedRxiv and Imperial College London.

2020-10-27
sars-cov-2 virions by EM: NIAID

A new study, published on MedRxiv on October 27, 2020, shows a decrease in antibody positivity to SARS-COV-2 among randomly selected UK (United Kingdom) patients over a period of three months. The specimens were collected at three times between late June and September 2020 and showed positivity rates of 6.0%, 4.8%, and 4.4%– a drop of 26%. Evaluations of subgroups, however, showed only 22% loss of antibodies among those who had definitely or probably been sick with COVID-19, as is explained below.

The study collected finger-prick blood specimens at home and performed surveys over the phone or online. The three rounds of testing used roughly 100,000, 106,000, and 159,000 patients. The tests were conducted about 12, 18, and 24 weeks after the peak of the pandemic in England in early April.

The results showed the highest prevalence of antibodies among people who had confirmed COVID-19 with RT-PCR tests at the first round: 96% had antibodies. On the second and third rounds, these rates fell to 90% and 75%. Those who did not have RT-PCR tests, but were suspected by a doctor to have COVID-19, showed 35% positive antibody tests. Those who thought they might have had COVID-19 were 19% positive, whereas those who didn’t think they had it had a 0.9% prevalence.

People who had no symptoms had a 1% prevalence of positivity; those who had atypical symptoms were 10.5% positive, and those who had typical symptoms were 25.1% positive.

Among demographics, those in the youngest group (18-24) had the highest prevalence of antibodies: 7.9%. Those who lived in London had a 13% prevalence of antibodies. Those who were Black had a 17.3% prevalence, versus a 5% prevalence among White people.

Those in the lowest socioeconomic group had a 7.3% prevalence, versus those in the highest, who had a 5% prevalence. Those in the smallest household group, of one person, had a 4% prevalence, versus 9.8% in the largest households of 7 or more people. Those in the lowest population density areas had a 3.2% prevalence versus 7.4% in the highest density areas.

Those who worked in healthcare with patients had 12.9% positivity at the first test, increasing to 13.4% at the third test. Those who worked in nursing homes with patients had 19.6% positive rates, decreasing to 11.1% at the third test. Those who worked in jobs outside healthcare had 6.5% positive rates at the first test, decreasing to 4.3% at the third test, and those who did not work had 4.2% positive at first, decreasing to 3.1% at the end.

The greatest declines in positivity were among those with the lowest rates to begin with: those who had no symptoms and no positive tests had antibody positivity rates fall by 64% (from 1% to 0.4%) and 59% (from 0.9% to 0.3%) respectively. Those who had confirmed COVID-19 by RT-PCR only had positivity rates fall by 22%. Residents of nursing homes actually had rates increase by 82%, but the total numbers of people in that group was small, only 150-348 patients.

These numbers indicate that the rate of antibodies among people in England fell over the three-month period after the sudden onslaught of cases that peaked in the second week of April. Numbers of new cases fell precipitously three weeks after the country was locked down around March 23. The antibody positivity rates fell the most among people who probably had mild or inapparent infections, while those who had confirmed infections retained most of their antibody prevalence.

Those who worked in health care, whether they worked with patients or not, had increasing rates of antibody positivity– more than double the rates for the entire group. Essential workers had decreasing positivity rates, overall similar to the average rates for the whole population.

Most important, those who had confirmed or suspected COVID-19 lost their antibody prevalences at a less than 10% rate, while those who were not thought to have been sick lost antibody prevalence at a 45% rate. This suggests that most people who clearly had COVID-19 retained antibodies after three months. The overall decrease in antibody prevalence of 19% includes a lot of people who were not thought to have been sick; many of these people must have had mild, inapparent infections.

So far, we do not have any such population statistics for the United States. These statistics would probably be very different from those in the United Kingdom.

“Declining prevalence of antibody positivity to SARS-COV-2” in UK seroprevalence study: MedRxiv and Imperial College London.

2020-10-27
sars-cov-2 virions by EM: NIAID

A new study, published on MedRxiv on October 27, 2020, shows a decrease in antibody positivity to SARS-COV-2 among randomly selected UK (United Kingdom) patients over a period of three months. The specimens were collected at three times between late June and September 2020 and showed positivity rates of 6.0%, 4.8%, and 4.4%– a drop of 26%. Evaluations of subgroups, however, showed only 22% loss of antibodies among those who had definitely or probably been sick with COVID-19, as is explained below.

The study collected finger-prick blood specimens at home and performed surveys over the phone or online. The three rounds of testing used roughly 100,000, 106,000, and 159,000 patients. The tests were conducted about 12, 18, and 24 weeks after the peak of the pandemic in England in early April.

The results showed the highest prevalence of antibodies among people who had confirmed COVID-19 with RT-PCR tests at the first round: 96% had antibodies. On the second and third rounds, these rates fell to 90% and 75%. Those who did not have RT-PCR tests, but were suspected by a doctor to have COVID-19, showed 35% positive antibody tests. Those who thought they might have had COVID-19 were 19% positive, whereas those who didn’t think they had it had a 0.9% prevalence.

People who had no symptoms had a 1% prevalence of positivity; those who had atypical symptoms were 10.5% positive, and those who had typical symptoms were 25.1% positive.

Among demographics, those in the youngest group (18-24) had the highest prevalence of antibodies: 7.9%. Those who lived in London had a 13% prevalence of antibodies. Those who were Black had a 17.3% prevalence, versus a 5% prevalence among White people.

Those in the lowest socioeconomic group had a 7.3% prevalence, versus those in the highest, who had a 5% prevalence. Those in the smallest household group, of one person, had a 4% prevalence, versus 9.8% in the largest households of 7 or more people. Those in the lowest population density areas had a 3.2% prevalence versus 7.4% in the highest density areas.

Those who worked in healthcare with patients had 12.9% positivity at the first test, increasing to 13.4% at the third test. Those who worked in nursing homes with patients had 19.6% positive rates, decreasing to 11.1% at the third test. Those who worked in jobs outside healthcare had 6.5% positive rates at the first test, decreasing to 4.3% at the third test, and those who did not work had 4.2% positive at first, decreasing to 3.1% at the end.

The greatest declines in positivity were among those with the lowest rates to begin with: those who had no symptoms and no positive tests had antibody positivity rates fall by 64% (from 1% to 0.4%) and 59% (from 0.9% to 0.3%) respectively. Those who had confirmed COVID-19 by RT-PCR only had positivity rates fall by 22%. Residents of nursing homes actually had rates increase by 82%, but the total numbers of people in that group was small, only 150-348 patients.

These numbers indicate that the rate of antibodies among people in England fell over the three-month period after the sudden onslaught of cases that peaked in the second week of April. Numbers of new cases fell precipitously three weeks after the country was locked down around March 23. The antibody positivity rates fell the most among people who probably had mild or inapparent infections, while those who had confirmed infections retained most of their antibody prevalence.

Those who worked in health care, whether they worked with patients or not, had increasing rates of antibody positivity– more than double the rates for the entire group. Essential workers had decreasing positivity rates, overall similar to the average rates for the whole population.

Most important, those who had confirmed or suspected COVID-19 lost their antibody prevalences at a less than 10% rate, while those who were not thought to have been sick lost antibody prevalence at a 45% rate. This suggests that most people who clearly had COVID-19 retained antibodies after three months. The overall decrease in antibody prevalence of 19% includes a lot of people who were not thought to have been sick; many of these people must have had mild, inapparent infections.

So far, we do not have any such population statistics for the United States. These statistics would probably be very different from those in the United Kingdom.

Cell: SARS-COV-2 Disrupts Vital RNA functions and suppresses interferon-1 production to interfere with host defenses.

2020-10-26
EM of SARS-COV-2 from Groopman lab

Cell journal published a paper on October 8, 2020 that describes as-yet unknown functions of the SARS-COV-2 virus NSPs (non-structural proteins) 1, 8, 9, and 16. These proteins interfere with messenger ribonucleic acid (mRNA) activity in the host (human) cell and prevent the cell from producing interferon to warn other cells about the COVID-19 infection.

Some basic information about SARS-COV-2 and its proteins: The four proteins that are associated with the virus genome RNA in its native state are nucleocapsid, envelope, membrane, and spike, or for short, N, E, M, and S. These are known as structural proteins. In addition, after the virus gets into the human cell, its RNA codes for RNA polymerase, helicase, and other proteins required for reproduction; these are, in shorthand, NSP (non-structural protein)1 through 16. There are also seven other proteins, labelled ORF (open reading frame) 3a through 8, whose functions are unknown. This makes a total of twenty-seven proteins, four in the virus itself and twenty-three produced after insertion into the host cell.

This article in Cells from May 2020 explains many of the details of the virus replication machinery and its proteins. Don’t read it unless you want to get really deep into the biochemistry of the virus. Just skim this blog post.

When the virus gets into the human cell, the cell detects its presence with proteins in the cytoplasm. There are several of these proteins including TLR7 (which I mentioned in an earlier post) RIG-1, and MDA5, but they all stimulate IRF-3 (interferon regulatory factor), which is specifically designed to detect single-stranded RNA. This protein stimulates the production of interferon. The virus is able to compete by shutting down interferon production, and the paper explains one way that it does this.

The new paper elucidates the functions of four of the virus proteins, as described in the abstract:

NSP16 binds to the mRNA recognition domains of the U1 and U2 splicing RNAs and acts to suppress global mRNA splicing upon SARS-CoV-2 infection. NSP1 binds to 18S ribosomal RNA in the mRNA entry channel of the ribosome and leads to global inhibition of mRNA translation upon infection. Finally, NSP8 and NSP9 bind to the 7SL RNA in the signal recognition particle and interfere with protein trafficking to the cell membrane upon infection. Disruption of each of these essential cellular functions acts to suppress the interferon response to viral infection. Our results uncover a multipronged strategy utilized by SARS-CoV-2 to antagonize essential cellular processes to suppress host defenses.

https://doi.org/10.1016/j.cell.2020.10.004

To amplify on the abstract: the protein NSP16 attaches to specialized RNAs (called “spliceosomes”) U1 and U2 that splice new RNA after it is transcribed from DNA in the cell’s nucleus. Normally these RNA-protein complexes modify the RNA by removing introns, leaving the parts that code for a new protein. Inhibiting the “spliceosome” prevents nuclear DNA from producing mRNA that crosses the membrane from the nucleus into the cytoplasm– where it is supposed to be translated into proteins.

The viral protein NSP1 binds to the entrance channel on human ribosomal RNA and prevents human messenger RNA (mRNA) from passing through, which stops mRNA from being translated into a protein. This shuts down the human cell’s protein production facility in the cell cytoplasm.

The virus is apparently still able to produce proteins from its own RNA. It does this because the virus mRNA contains a sequence at its beginning that releases NSP1 and promotes the translation of the rest of the virus mRNA.

The viral proteins NSP8 and 9 bind to RNA-protein complexes that help fold proteins and transfer them to the cell membrane– where they are normally released into the extracellular space and can travel through the blood to distant cells. In the presence of NSP8 and 9, proteins cannot transfer out of the human cell.

The most important human protein affected by these virus is interferon, which would normally signal to other cells that an infection is in process and stimulate the host to defend the system against the infection. In severe COVID-19, there is a notable deficiency of interferon. Many other proteins that the human system uses in defense against viral infections are also affected by this interference.

These virus proteins are produced in the early stages of COVID-19 infection, to prevent the host cell from mounting a defense while it gets to work reproducing itself. The virus RNA is exposed to detection early on in the cell’s cytoplasm and vulnerable to host defenses, but later, during replication, it forms a network to protect itself (this is described in the Cells paper mentioned above.)

The work reported in this new Cell paper is complex and involves the use of human cell lines as well as the SARS-COV-2 virus and mutant viruses. The paper shows how the virus is able to suppress the immune response during early infection and helps to explain some of the effects seen in severe infections.

This work will help us to find treatments that can inhibit the effects of these virus proteins and ameliorate severe infections. We should remain aware that procedures to prevent infection are the most powerful “treatment” for the virus available. This is because not getting infected in the first place gives us a better result than being infected, getting sick, being treated, and surviving.

This means that using face masks (and goggles or clear plastic face shields in high-exposure situations), washing our hands, and staying physically separated from strangers will help more than any treatment. A vaccine will provide an additional barrier against infection, when it is available.

“The revolution will be contextualized”: a review of a review of books about the current president: New Yorker.

2020-10-24
photo courtesy of pixabay.com and Erika Wittlieb

The New Yorker on October 24, 2020 published a review of a book about books about the current president, titled “the lessons of reading every book about [redacted].” There have been over a hundred and fifty books written about the current president over the years, many more in the recent past, several despite the best efforts of His lawyers.

The author of the book in question, “What Were We Thinking? A Brief Intellectual History of the Trump Era”, Carlos Lozada, has read most, if not all, of the books so far published about the current president. The author presents his review so that you do not have to read all those books. This is in itself a mercy. No-one should have to read even one such book except to satisfy a morbid imagination.

If you read this review, you will not even have to read the book. The review briefly summarizes the book’s most significant work, which is to categorize all the books on the subject: they are subdivided into approximately ten varieties. The first several are of interest: “chaos chronicles” (from officials “expressing concern”), “heartlandia” (about fans of the current president), “Russian lit” (about the current president’s ties to Russia), and manuals for the resistance (what to do if you oppose His policies.)

There are also hagiographies (written by fans of the current president) and dissections of the conspiracy theories spawned by those within and without the present administration. There are discussions of the main issues on which most of the public disagrees with the current administration, such as the issue of immigration.

Most important, the number of books written about the current president should not make you think that the subject of those books is complex. In fact, the current president has a rather limited vocabulary and little tolerance for details. He is a very simple-minded, albeit malignant, man.

I’m presenting this link because it is possible for the average internet lurker to access a limited amount of content from the New Yorker without a subscription. I believe that you can read two or three articles a month for free from any random Internet Protocol (IP) address. If you have an interest in the subject but no extra money to purchase a subscription, I suggest that you take in this particular article because it will allow you to avoid reading all 150 books about a rather disheartening subject.

That is the adjective that conservatives have used whenever some particularly egregious act by the current president is brought to their attention: “I am disheartened by [insert current outrage here].”

Rather than be disheartened, and to avoid being bogged down in depressing details, I suggest that we simply vote Him out of office so that we can forget Him.

Odd but true: FDA fully approves remdesivir for COVID-19 after negative WHO trial.

2020-10-23

The Food and Drug Administration issued a full approval for remdesivir to treat COVID-19 on October 22, 2020. This comes shortly after a negative trial was published on MedRxiv in an interim result (on October 15) by the World Health Organization (WHO), in a trial known as SOLIDARITY.

I posted about this trial yesterday; it showed no mortality advantage for remdesivir, lopinavir, interferon, or hydroxychloroquine (HCQ) in a large number of patients (over 2700 each for remdesivir and placebo) but may be flawed (it has not yet been peer-reviewed.)

Already, commenters on the SOLIDARITY trial (the Disqus thread) have had numerous questions. For example, how early in the course of infection were these drugs given? Detailed information about the age, degree of illness, etc. of the study subjects has not been fully evaluated.

The FDA’s justification for approving remdesivir with “substantial evidence of effectiveness and a demonstration of safety” rests on three randomized, controlled clinical trials which are described in the FDA announcement. Only the first and second trials, with over 500 patients each in drug and placebo arms in the first trial and 200 each in the second trial, shows “statistically significant” clinical improvement with drug over placebo. The third trial shows that the improvement was similar in 5 and 10 day courses of the drug.

The biggest trial was published in the New England Journal of Medicine as a final report on October 8. This was a randomized, double-blind trial done at sixty sites, mostly in the US and Europe, in February through April. It enrolled just over 500 patients each to placebo and remdesivir treatment. 90% of patients wound up in the severe disease category. 80% had a pre-existing condition; the average age was 58, and 64% were male.

The median time to recover was ten days in the remdesivir group and 15 days in the placebo group. Mortality at fifteen days was 6.7% and 11.9%, and at 29 days was 11.4% and 15.2%. Survival to fifteen days was significantly better with remdesivir, but 29 day survival did not quite reach statistical significance.

Remdesivir (trade-named Veklury by Gilead Sciences) was approved under special FDA programs designed to fast-track drugs for emerging infectious disease threats. No mention of the negative WHO trial was made in the FDA news release.

Whether the FDA has considered the WHO trial or taken into account its negative findings is not known. It is possible that the WHO trial was not released until the FDA had already decided on its approval; bureaucracy being what it is, the two publications may have “crossed in the mail.”

I am left with some few concerns about remdesivir, but I am comfortable with its use in COVID-19 for the reason that its mechanism of action is clear and convincing, and that it appears to be relatively safe (unlike HCQ on both counts.)

After further discussion among experts, we may discover that the WHO trial had some flaws that make it less persuasive. Or we may find that remdesivir is not sufficient to really help patients with late, severe COVID-19. The phenomenon often seen in severe cases of the immune system over-reacting to the virus may account for remdesivir’s insufficient efficacy.

It is also possible that many people with severe disease have inherited or acquired defects in their immune systems that have not yet been found or clarified. Several research papers have already been published this year revealing inherited immune defects that were unknown before the pandemic struck.

As has so often occurred in this pandemic, further experience will tell us much more. We are certain to see more cases of severe COVID-19, and more research on patients with the disease.

Odds of Biden winning this year are better than the odds of Clinton winning in 2016, but the defeat of democracy is still possible. A personal note.

2020-10-22
dog and cat love in our front yard, circa 2016

Back in 2016, a commonly accepted prediction based on opinion polls was that Hillary Clinton had an 80% chance of winning the presidential election. This is actually worse than one in six, which is the chance of any particular number coming up when one throws a die.

So people who were “shocked” that Hillary lost have not played with dice much. Her chances were, even if the 80% prediction was correct, not really that good. This was because the right-wing propaganda machine was uncommonly effective during the 2016 campaign and long before. For 25 years, the propagandists had inveighed against Hillary, making her extremely unlikeable among even middle-of-the-road voters. Right-wing voters despised her, not because of her actual characteristics, but because they had been indoctrinated for years.

Most people were unaware of the virulent propaganda campaign being waged against Hillary, in part because it was so comprehensive. The invective was subsumed into popular discourse and infiltrated national media to such a degree that no-one noticed how extensive it was.

The campaign was already in high gear when Hillary said, “…the vast right-wing conspiracy” and people laughed… because they didn’t know it was true. They did know that Hillary had been duped by her own husband and that Monica was doing the dirty deed with Bill. A long story, better left untold, but few people know:

A holdover from the George HW Bush administration, Linda Tripp held a “low level” position in the Defense Department. She used her position to get Monica to confide in her, then she took the information she had gleaned to Ken Starr. He was the “independent counsel” (actually a right-wing conspiracist lawyer) who was “investigating” the failed Whitewater land deal. After finding nothing there, he broadened his investigation to Bill Clinton personally. Linda Tripp gave him the infamous dress with semen stains, and the impeachment was born.

Bill Clinton was impeached for lying about his sexual relationship with Monica Lewinsky. Today, the Department of Justice (DOJ) is personally protecting the president from a civil suit that claims that he defamed a woman that he (allegedly) raped many years ago… my, how things have changed in our government. Back then, a president was impeached for lying about a consensual sexual relationship; now, a president is defended by his own DOJ against a civil suit that claims he defamed a woman by lying about her claims that he raped her, saying “she’s not my type.” (Any unprotected woman is his type.)

Back to 2016, four years before a woman came forward with claims that the now-president raped her in a department store many years ago. How far our government has fallen.

I was recovering from major surgery: a laminectomy and fusion with hardware that included a rod extending from S1 to T10, roughly twelve inches. I had to have the surgery because I had spinal stenosis and severe compression of my spinal nerves (look it up if you don’t know how painful this is.)

The surgery was on August 8 and 9, 2016 (yes, two days in a row); the first surgery, from the front, was to insert spacers to restore the collapsed disks at several lumbar segments, and the second surgery, from the back, was to cut off the backs of the lumbar vertebrae (all five) and screw them to a rod that extended from the last two thoracic vertebrae across all five lumbar vertebrae to end at the top of the sacrum.

It took three weeks in the hospital to learn to walk again, with a walker and then with two canes. After that, it took three months of daily exercise to graduate to walking with a single cane.

At the time, I posted on this blog a picture of myself in a brace in the town where the surgery was done, my home town in fact, San Francisco, California.

During this time, I was blissfully unaware of the presidential campaign between Hillary Clinton and he-who-must-not-be-named. I can honestly say that I enjoyed the pain much more than I would have enjoyed the constant fighting, insults, and lies (mainly by he-who-must-not-be-named) that characterized that campaign.

I was not invested in the campaign, although I supported the Democratic side. I was deeply disappointed by the result, but I did not pay as much attention as I should have to the evil Republican who won.

Now, I am deeply invested in this campaign and I have done what I can to prevent a repeat of 2016. Not having any money as I am still disabled, I supported my wife in contributing what she could to Joe Biden’s campaign.

I can only hope and pray that Joe Biden, without the 25 years of propaganda and lies that Hillary Clinton was weighed down by, and not being a woman (which was still a major disadvantage, 96 years after women had gained the right to vote) will win the election that concludes in twelve days.

If you have not already voted, then mask up, bring a chair, snacks, and your favorite music, and go vote in person at the first opportunity. Do not use the mail. It is worth dying from the novel coronavirus to make sure your vote counts on November 3. Having read this far, I am confident that you, dear reader, will do the right thing and vote for Joe Biden.