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Archive for the ‘covid19’ Category

more covid 19: vitamin D, helper T cells, testing

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I’m continuing with my gleanings from the Medcram Covid-19 updates presented by Dr Roger Seheult, though I’m not up to date with them, because they’re quite comprehensive and nuanced, and I want that detail more than anything. I’m also reading the book Outbreaks and epidemics: battling infection from measles to coronavirus, by Meera Senthilingam, which among other things, highlights the importance of preparedness, co-ordination and resourcing to deal with new and unexpected pathogens but also upsurges and cross-border spread of diseases we haven’t sufficiently dealt with in the past. As we hurtle at an unprecedented rate towards a number of vaccines against SARS-CoV2, for example, we may have to deal firmly, on a governmental level, with the anti-vaccination movement and its disinformation campaigns, but we also have to deal with grossly uneven levels of healthcare within and across nations. This current pandemic has been revelatory, for all but those on the front lines, of the variable impact such outbreaks have on the different levels of empowerment within societies. To take a stark example, Boris Johnson, the British Prime Minister, very likely owes his life to the fact that he is the British Prime Minister. Had he been a fifty-something person of colour living in Dagenham (or most anywhere outside of a UK city), his Covid-19 case would surely have turned out quite differently.

Update 74 is quite brief and mainly touches on vitamin D, the ‘sunlight’ vitamin, also obtained from foods such as fish, especially salmon and tuna, and egg yolks, and mushrooms raised using UV light – but mostly from the sun’s UV. Vitamin D enhances bone and muscle strength and function. A Lancet article is discussed, which correlates ‘vitamin D status’, presumably meaning bodily levels, with Covid-19 mortality. Some surprises in the data – vitamin D deficiency was common in ‘sunny’ Italy and Spain, but less of a problem in Nordic countries, perhaps due to a high vitamin D diet. Deficiencies were greater in poorer regions and in black communities, as of course were higher Covid-19 mortalities. in fact, ‘black people in England and Wales are 4 times more likely to die from Covid-19 than white people’ according to the UK’s Office for National Statistics.

The Lancet article referred to points out two aspects of vitamin D’s possible protection against Covid-19. First, it ‘supports production of antimicrobial peptides in the respiratory epithelium’, which sounds positive, and second it may help to reduce the inflammatory response to the virus because it’s known to interact with and promote the ACE-2 protein, which the virus suppresses. Other articles emphasise the benefits, with no attendant harm, of vitamin D supplements, particularly for the elderly. There have been no systemised, detailed trials as yet relating vitamin D levels to Covid-19 outcomes, but it seems like a no-brainer.

Update 75 continues the argument about SARS-Cov2 attacking the lining of the blood vessels, i.e. the endothelium, with the resultant effect on von Willibrand factor. This happens in the lungs as well as the vascular system, creating clots as well as the growth of new blood vessels as a type of immune response. This essentially marks it out from any kind of influenza. The New England Journal of Medicine has an article, published late May, looking exactly at these differences in the autopsies of Covid-19 victims – endothelialitis (inflammation of the endothelium) and angiogenesis (the formation of new blood vessels). They compared Covid-19 lungs with the lungs of ARDS (acute respiratory distress syndrome) victims, associated with influenza A (H1N1), and with uninfected lungs. They found ‘alveolar capillary microthrombi’ – often difficult to detect with scans – in the Covid-19 lungs at nine times the level of the influenza lungs, and new vessel growth at almost three times that of the influenza lungs. Clearly the new vessel growth is caused by the blockages, and the need to circulate around them. Microscopic analysis shows lymphocytes infiltrating the lungs, adding to inflammation, stiffness and tissue damage. The clotting prevents oxygen being picked up from the alveolar space, leading to low oxygen saturation of the blood. Scanning electron micrographs of the lung endothelium revealed viral particles in the extracellular space, suggesting strongly that the virus itself, and not simply the immune response to it (perivascular inflammation) is causing damage. Dr Seheult brings up NAC again here, as a possible disruptor of the cascade of events, especially in the suppression of superoxide and in the cleaving of disulphide bonds in VWF.

An article in Science, which refers to the adaptive immune system, is next discussed. The adaptive immune system, as opposed to the innate immune system, is a system that creates a memory of a pathogen in order to develop an enhanced response, a system exploited by vaccines. This system includes T cells, of which there are three types, memory, cytotoxic and helper. These cells are apparently involved in lifelong immunity. Vaccine researchers are concerned to create antibodies as protection against the virus, but T cells are also important in this regard, and researchers have found that many infected patients, and non-infected people, do have T cells that attack the virus, probably because they have been infected with other coronaviruses that share proteins, such as the spike protein, with SARS-CoV2. Researchers in fact found that Covid-19 patients all harboured helper T cells that recognised the SARS-CoV2 spike protein, and other SARS-CoV2 proteins, again suggesting the possibility/probability of lifelong immunity. Many others harboured the same helper T cells, which may be protecting them against the worst Covid-19 symptoms, before the fact. This is possibly a very important, and highly explanatory finding. Or maybe not. T cells are long-lasting, so these findings are certainly positive.

Update 76 starts with antibodies, and it’s a bit difficult to follow. It looks at the CDC’s ‘interim guidelines for Covid-19 antibody testing’, and a CNN health article summerizes it thus:

The CDC explains why testing can be wrong so often. A lot has to do with how common the virus is in the population being tested. For example, in a population where the prevalence is 5%, a test with 90% sensitivity and 95% specificity will yield a positive predictive value of 49%. In other words, less than half of those testing positive will truly have antibodies’, the CDC said.

This is hard to follow, but 5% prevalence is fairly standard for this virus, at least at the outset. And so false positives are a problem. To be clear about testing – a person either has the disease or not. If you have it and you test positive, fine, that’s a true positive. If you have it and test negative, that’s a false-negative. If you don’t have it and you test positive, that’s a false-positive. If you don’t have it and test negative, that’s a true negative.

So we can look at percentages and maths, and I’m following Seheult strictly here. So imagine we’ve tested 2100 people in a particular region – that’s everyone in the region. At this stage the disease has a prevalence of 5%, so about 100 out of 2100 have the disease (strictly speaking that’s 4.76%). The test has a sensitivity of 90% and specificity of 95% as above. 90% sensitivity means that the number of true positives from the test will be 90% of the number of those who actually have been infected by the virus. That means 90 people. 95% specificity is about those not infected. So you divide the true negatives by those uninfected to arrive at the 95%. The true negatives will amount to 1900. So 10 people will be false positive and 100 false negatives. When specificity rises, false positives decrease. When sensitivity increases, false negatives decrease. So with high sensitivity a negative result is more conclusive, and with high specificity, a positive result is more conclusive.

Imagine then that the prevalence of the infection has risen to 52% in the same population of 2100. That gives us 1094 with the disease, 1006 without. With the same values for sensitivity and specificity of testing, you’ll have 985 true positives and 50 false positives, and 956 true negatives and 109 false negatives. What you need to know with these results is how things stand for patient x, the person you’re dealing with. This means you need to know the predictive values, positive (PPV) or negative (NPV). This requires some simple maths. Given a positive test result, what chance is there of x having the disease? Or vice versa for a negative result. This means that for the PPV you divide the true positives by the total number of positives, and the same process applies for NPV. Going back to the situation where the prevalence was 5% we get a PPV of 47% and a NPV of 99%. What this means is that when the prevalence is low, the negative predictive value is much higher than the positive predictive value. The implication is important. It’s just not clear at this stage whether you have antibodies against the virus. So you need to raise the specificity of the test, especially if the virus or pathogen has a low prevalence. But looking at the 52% prevalence case, and using the same simple maths we find that the PPV is up at 95% and the NPV goes down to 90%. Prevalence, then, is the main determinant of predictive values.

For testing, this means, just as the disease is becoming prevalent, that’s to say, as it’s just being detected, you need a test with a very high specificity (admittedly a big ask) and/or you need to test those with a high probability, based on current knowledge, of being infected, and those in contact with them.

References

Coronavirus Pandemic Update 74: Vitamin D & COVID 19; Academic Censorship

Coronavirus Pandemic Update 75: COVID-19 Lung Autopsies – New Data

Coronavirus Pandemic Update 76: Antibody Testing False Positives in COVID-19

https://en.wikipedia.org/wiki/T_helper_cell

Written by stewart henderson

August 9, 2020 at 12:34 pm

covid-19 stuff: NAC, glutathione, RT-PCR testing, re-positives

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So, more struggles with biochemistry. Update 70 talks again about N-acetylcysteine (NAC), but goes on to talk about glutathione, and whether glutathione itself might be a type of medication. So let’s get clear, or try to.

Glutathione is a naturally occurring and abundant thiol polypeptide in animal cells. A thiol has an SH (sulfanyl) group attached to a hydrocarbon chain, essentially. As we know, it’s an antioxidant which can be reduced by NAC, and they have structural relations. As Dr Seheult describes glutathione, it’s a combination of three amino acids, with cysteine at the centre. The other two are glycine and glutamate, and the cysteine and the glycine together effectively make up N-acetylcysteine – so NAC is described as a by-product or precursor of glutathione. A case report (regarded as the weakest level of scientific evidence) describes efficacious treatment of two patients with Covid-19-type symptoms using IV and oral glutathione. This and other studies and analyses seem to be begging for full-scale clinical trials to be carried out, but nothing as of mid-May. The treatments could be effective for hypoxemia in particular, due to the action on the disulphide bonds in VWF which are leading to platelet-rich thrombosis.

In his update 71 Seheult broaches the controversial topic of hydroxychloroquine, along with azithromycin and zinc. He suggests there’s evidence that hydroxychloroquine can act as a ‘zinc ionophore’, inducing zinc uptake into cells. Zinc inhibits the RNA-dependent RNA polymerase which SARS-CoV-2 utilises to reproduce. There has been a retrospective study suggesting that treatment with this combination may ‘result in a statistically significant reduction of mortality’, though maybe this hasn’t borne more careful analysis considering the cold water being poured on chloroquine as a treatment in recent months. It may be because it just doesn’t raise zinc levels sufficiently. The findings of the study do suggest the treatment has a statistically significant effect on reducing symptoms in hospitalised patients who are not in ICU – that is, they have relatively mild symptoms. No significant effect for ICU patients.

I should add here that now in August health authorities are warning against any unprescribed use of hydroxychloroquine as a prophylactic due to ineffectiveness and side-effects.

Update 72 began by looking at the sensitivity and specificity of antibody tests available, presumably in the USA. A study examined ‘four new commercially available serological assays [i.e blood serum tests]’, from three German and one US company, and it was found that they all ‘have a sufficient sensitivity and specificity for identifying individuals with past SARS-CoV2 infection’. Of course, the principal issue with the testing is the time it takes to receive results, but maybe that’ll be addressed anon.

Apparently (news to me in very safe – so far – South Australia where hardly anyone I know has had to be tested) there’s a difference between sensitivity and specificity, illustrated by the ‘spin’ and ‘snout’ mnemonic. For a highly specific test if you test positive you’re very sure to be in trouble, and for a highly sensitive test if you test negative you’re sure to be out of danger.

Dr Seheult next describes a retrospective study which looks at glycosylated haemoglobin (HbA1c) as a Covid-19 risk factor. A person’s HbA1c levels (how much glucose is attached to their haemoglobin) are a measure of diabetes. A1c (blood sugar level) is measured in percentages, with 5-6% being normal. The study found that ‘high HbA1c levels is associated with inflammation, hypercoagulability and low SaO2 [oxygen saturation] in Covid-19 patients, and the mortality rate (27.7%) is higher in patients with diabetes’. So HbA1c levels need to be looked at as a priority.

The update next looks at dentistry during the pandemic, for which there’s been little guidance, at least from the CDC. Apparently, during the AIDS crisis, dentists were viewed as modes of transmission, partly due to a NYT article on the subject. In any case, fewer people are now seeing their dentists for obvious reasons, which could lead to an oral health crisis. A number of diseases, including coronary disease, are linked to periodontal problems, so this can exacerbate the pandemic – and dental health, in Australia as in the USA, is not treated with the same gravitas as other forms of health.

Update 73 starts with a look at testing, particularly the reverse transcriptase polymerase chain reaction (RT-PCR) test. So the coronavirus has these spike proteins protruding from a bilipid membrane, with the RNA wrapped inside bound together by disulphide bonds and the like, I think. The protein shell around the virus is called the nucleocapsid. Of course the RNA’s code is specific to SARS-CoV2, so a test needs to look at a segment of the viral RNA and identify it with sufficient – essentially total – specificity. RNA is made up of the four base pairs adenine (A), uracil (U), guanine (G) and cytosine (C), with A pairing always with U and G with C. With that I’m going to switch to Scientific American for more detail.

A test starts with a sterile swab from the back of the nasal passage, aka a sample. Sample collection needs to be done properly, or it could lead to a false-negative result. If there’s viral RNA present, it’s extracted and used to produce a complementary strand of DNA – that’s where the reverse transcriptase enzyme comes in, reversing the usual transcription process from DNA to RNA. This material is then amplified – thousands of copies are made – to ensure a measurable result. The different available test kits generally vary in the segment of genetic material chosen.

I’m hearing that there are serious delays, in the USA at least, in delivering test results. This is extraordinary as, according to the Scientific American article, which is dated late March,

the FDA recently began granting emergency use authorization (EUA) to rapid diagnostic PCR tests that manufacturers say can deliver results in less than an hour. The authorization allows medical devices that have not yet been approved by the agency to be used during public health emergencies. 

What’s happening? According to very recent article from Quartz magazine, the problem is that there are too many kinds of tests. The EUA system was utilised, partly because of the urgency, partly because of the disastrous problem caused by the use of faulty reagents by the CDC back in February. Now there are about 150 tests that have been given EUA approval. Testing delays at first resulted mainly from lack of general lab equipment and PPR for the testers, but increasingly there are problems due to different types of tests, the variability of the tests, knowing which test to use, having the right equipment for each test, the prioritising of certain groups, such as front-line health workers, over others, confirmation of test results by other labs, and of course the overload in demand. We’re talking about the USA here, of course, and it just seems another case of lack of centralised control and uniformity in a state with a failed federal government.

Returning to update 73, Seheult describes a situation in which a SARS-Cov2-infected individual’s immune system has broken down the virus into ineffectual strands of RNA, proteins and other particles. It’s possible that a RT-PCR test could pick up on an RNA fragment, and produce a positive test result in these apparently recovered patients, and in fact this has often occurred. This is called a re-positive. The update describes a study by the South Korean CDC which provides valuable evidence on these re-positive cases. Some 280 re-positive subjects were studied, and about half of them displayed Covid-19 symptoms (on average 14 days after ‘recovery’). Presumably this re-positive finding was after they’d tested negative, i.e they’d first tested positive, then negative, then later positive again, though this isn’t clear. In any case, they checked a percentage of the subjects for antibodies and the result was almost entirely positive. They checked a larger sample for viral particles and found ‘not a single whole viral particle’, according to Dr Seheult, by which I presume he means anything that was replicable or active. They also looked at close contacts of the subjects, in large numbers, and all of them tested negative. So the finding was that these re-positives were, it seemed, the results of ultra-sensitive testing that was picking up viral RNA fragments that were in effect innocuous. This would seem to be a lesson for developing the right types of test. Hopefully a lesson learned.

References

Coronavirus Pandemic Update 70: Glutathione Deficiency, Oxidative Stress, and COVID 19

Coronavirus Pandemic Update 71: New Data on Adding Zinc to Hydroxychloroquine + Azithromycin

Coronavirus Pandemic Update 72: Dentists; Diabetes; Sensitivity of COVID-19 Antibody Tests

Coronavirus Pandemic Update 73: Relapse, Reinfections, & Re-Positives – The Likely Explanation

https://www.scientificamerican.com/article/heres-how-coronavirus-tests-work-and-who-offers-them/

https://qz.com/1886940/why-covid-19-test-results-take-so-long/

Written by stewart henderson

August 5, 2020 at 2:34 pm

update 69: NAC, glutathione, oxidative stress, thrombosis

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glutathione – far more than just an antioxidant

So we start with a closer look at glutathione, and its backbone amino acid chain, including the amino acid cysteine. Cysteine has the formula HO2CCH(NH2)CH2SH. The thiol sub-chain (SH) is important because it can bind to another form of the molecule, with S binding to S (oxidised form) rather than binding to H (reduced form) as here. So, as Dr Seheult explains, if you have two glutathiones, in this reduced form (2GSH), oxidised via hydrogen peroxide (H2O2), you will create a bond (GS-SG) between the two oxidised glutathiones, together with water. This happens in the oxidisation processes in our cells.

Seheult next mentions ADAMTS13, which is also known as von Willibrand factor-cleaving protease, so it’s a zinc-containing enzyme. VWF polymerises via disulphide bonds, and ADAMTS13 can help in disrupting that process, I think. Seheult diverts us by mentioning the disulphide bonds that connect the spiral strands of keratin in hair. A ‘perm’ reduces the molecular structure, breaking the disulphide bonds, so that the individual strands can be straightened, or made more curly, after which ‘you neutralise the perm agent’?? via H2O2, allowing disulphide bonds to re-form keeping the new hair structure in place. That was almost interesting.

So what can we do to assist these glutathione-based processes in relieving oxidative stress? This is apparently where N-Acetylcysteine (NAC) comes in. This molecule, which is ‘the N-acetyl derivative of the natural amino acid L-cysteine’, is ‘an antioxidant and disulphide breaking agent’, according to a 2018 review article in the Journal of Free Radical Research (not a political journal). So NAC is a reducing agent, which, like cysteine, has an SH bond. It breaks disulphide bonds and adds hydrogen, reducing viscosity. NAC has been used as a mucolytic inhalant, and as an agent against tylenol (paracetamol) overdose. How this last effect works is complex and I’ll try to comprehend it.

As Seheult explains it, NAC would act on the metabolite of paracetamol in situations of overdose. In such cases the liver metabolises paracetamol via an alternative pathway, by means of the toxic metabolite NAPQI, which depletes the liver’s glutathione. NAC replenishes the glutathione, but I won’t try to analyse the mechanism here. The main point is that NAC’s glutathione-boosting effects may have potential in dealing with Covid-19 symptoms. According to the above-mentioned review article, glutathione depletion is related to oxidative stress associated with a wide range of illnesses and pathologies, as well as in general ageing. So, a 1997 study in Italy looked at H1N1 flu and NAC treatment in a randomised, double-blind trial of 262 individuals of both sexes, most of them suffering from non-respiratory chronic degenerative diseases. They were divided into a placebo group and a NAC tablet group for a period of six months. No difference was found in both groups contracting the virus, but the majority of the placebo group (79%) came down with symptomatic forms, compared to only 25% of the treatment group, a significant difference. The study concluded that NAC treatment ‘appears to provide a significant attenuation of influenza and influenza-like episodes, especially in elderly high-risk individuals.’

So, recognising that this update is 2-3 months old now, I went online to see if NAC treatment is being used, or more comprehensive trials are being undertaken, as I note that, though case-rates are still disturbingly high, especially in the USA, death-rates are somewhat reduced.

An article from NCBI (the National Center for Biotechnology Information), which post-dates update 69 by a couple of weeks, presents only a hypothesis:

that NAC could act as a potential therapeutic agent in the treatment of COVID-19 through a variety of potential mechanisms, including increasing glutathione, improving T cell response, and modulating inflammation.

However, it didn’t seem as if any effective clinical trials focusing specifically on Covid-19 had been completed at the time of the article. A much more recent article (July 14) in Future Medicine (not such a promising name, given the urgency), presents more biochemical detail of NAC’s action, along with the anticoagulant heparin, and mentions ongoing clinical trials, but not specific results. It also mentions NAC treatment as a preventive for frontline ICU workers and general healthcare workers. It may be that such treatment is already being applied.

So, returning to update 69, Seheult cites another article from 2010 in Biochemical Pharmacology which showed that NAC inhibited viral replication (here the virus was H5N1) and reduced inflammatory cytokines, and again they suggested it as a potential treatment in the case of future influenza pandemics. Another small trial suggested some limited efficacy for NAC in the treatment of acute respiratory distress syndrome (ARDS).

So on it goes. A 2018 article found that ‘[NAC] improves oxidative stress and inflammatory response in patients with community acquired pneumonia [CAP]’. This oxidative stress reduction may be more important for Covid-19 cases because of the possibility of thrombosis due to the effect on VWF. A 2013 study found a significant decrease in a number of coagulation factors with NAC treatment. Of course, with this blood-thinning facility, NAC should not be used for patients with increased bleeding risk during or resulting from surgery. In any case I note that NAC is on the WHO list of most safe drugs or treatments.

And there are more studies. Another 2018 study found that NAC could reverse cerebral injury from strokes exacerbated by diabetes. The study concludes that ‘the diabetic blood and brain become more susceptible to platelet activation and thrombosis’, and that NAC appears to offer protection against the risk of stroke. The study’s explanation of the process here gives me an opportunity for further revision:

[NAC protects against stroke] by altering both systemic and vascular prothrombotic responses via enhancing platelet GSH, and GSH-dependent MG elimination, as well as correcting levels of antioxidants such as SOD1 and GPx-1.

So that’s platelet glutathione, and glutathione-dependent methylglyoxal, and the antioxidants mentioned are superoxide dismutase 1 and glutathione peroxidase 1. The ScienceDirect website does an amazing job of informing us about every known aspect of molecular biochemistry, just saying. Its material on glutathione and its catalysis is exhaustive and exhausting. And it looks as though the silver lining to the tragedy of Covid-19 may be a spike in further research into this and other essential elements of the molecular basis of immune systems.

Dr Seheult goes on to cite one more study, which found that ‘NAC administration promotes lysis of arterial thrombi that are resistant to conventional approaches…’, principally by acting on VWF, and that it is even more effective in combination with ‘a nonpeptidic GpIIa/IIIb (glycoprotein) inhibitor’, with no observed worsening of symptoms or outcome vis-a-vis normal haemostasis.

So I’ll end this piece wondering how things are going with NAC and other applications to reduce both respiratory and thrombotic symptoms in regions where the virus continues to be spread through a mixture of government, business and personal irresponsibility and stupidity. The battle to keep people alive and relatively healthy will, I think, ultimately win over the stupidity of some, but at a terrible and tragic cost. Vaccines are in the offing, but fear, indifference and ignorance will probably have the most adverse influence on their effectiveness.

References

Coronavirus Pandemic Update 69: “NAC” Supplementation and COVID-19 (N-Acetylcysteine)

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7261085/

https://www.futuremedicine.com/doi/10.2217/fmb-2020-0074

https://www.sciencedirect.com/science/article/pii/S0304416512002735

https://www.sciencedirect.com/topics/biochemistry-genetics-and-molecular-biology/methylglyoxal

Written by stewart henderson

August 2, 2020 at 12:46 pm

more Covid-19 gleanings from MedCram updates 67-69

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polymorphonuclear leukocytes (white blood cells)

I’m continuing my self-education re everything Covid-19 thanks to Dr Seheult’s updates and other useful sites. Update 67 carries on from where we left off, summarising again how SARS-CoV2 induces endothelial dysfunction, before focusing on thrombosis. So we repeat again that a key molecule in normal endothelial function and in the working of AT-1,7 is nitric oxide (NO). Endothelial function (and, to be clear, the endothelium lines the vasculature, which means the body’s blood vessels) is also dependent on the various other enzymes mentioned in the last post, e.g. superoxide dismutase (SOD), and glutathione peroxidase (GPx).

So how does Covid-19 bring about oxidative stress and how does this effect thrombosis? Seheult discusses an article from April this year which addresses this. It describes a previously healthy elderly male admitted to hospital with fever and respiratory symptoms. After rapid deterioration he was sent to ICU, having developed ARDS, acute renal insufficiency and other health problems. Among various measures noted was a ‘massive elevation of von Willebrand factor (VWF), as well as ‘factor VIII of the coagulation cascade’. To quote from the article:

The increased VWF points toward massive endothelial stimulation and damage with release of VWF from Weibel-Palade bodies. Interestingly, endothelial cells express ACE-2, the receptor for SARS-CoV2, thus possibly mediating endothelial activation.

To explain some of these terms: Weibel-Palade bodies are found only in epithelial cells, and they contain VWF, which are released when required for haemostasis and coagulation. VWF is a stringy material of amino acid proteins which combine with platelets (aka thrombocytes) to coagulate the blood. When endothelial cells suffer serious damage, Weibel-Palade bodies inject large amounts of VWF into the bloodstream. Dr Seheult presents the abstract from a 2017 article on the topic:

The main function of VWF is to initiate platelet adhesion upon vascular injury. The hallmark of acute and chronic inflammation is the widespread activation of endothelial cells which provokes excessive VWF secretion from the endothelial cell storage pool. The level of VWF in blood not only reflects the state of endothelial activation early on in the pathogenesis, but also predicts disease outcome. Elevation in the blood level of VWF occurs either by pathologic increase in the rate of basal VWF secretion or by increased evoked VWF release from dysfunctional/activated endothelial cells. The increase in plasma VWF is predictive of prothrombotic complications and multi-organ system failure associated with reduced survival in the context of severe inflammatory response syndrome, type 2 diabetes mellitus, stroke and other inflammatory cardiovascular disease states.

The article points out that an over-production of VWF in highly elongated form is an indication of pathology. This is apparently being seen in serious Covid-19 patients. On the molecular level, the VWF is able to remodel itself from its usual globular conformation when it senses shear forces – note this definition from Science Direct: Shear stress is defined as the frictional force generated by blood flow in the endothelium, that is, the force that the blood flow exerts on the vessel wall, expressed in force-area unit (typically dynes/cm2). The VWF, under this stress, ‘turns into an extended chain format that forms ultra-large strings to which platelets bind to initiate clot formation at sites of vascular damage’. When the shear stress reaches a certain level, factor VIII is released. All of this can be essential for haemostasis, but too much of the multimeric, elongated form of VWF will lead to thrombosis, as appeared to be occurring in the patient described above.

So, as Seheult summarises, SARS-CoV2 binds to ACE-2 receptors and reduces ACE-2 production. This reduction has the effect of increasing AT-2 production and reducing AT-1,7. This results in an increase in superoxide production, oxidative stress and endothelial dysfunction. This in turns leads to an increase in VWF activity in the bloodstream, and local thrombosis. There is evidence from autopsies that thrombosis is a feature of Covid-19 mortality.

In his update 68 Dr Seheult looks at the predisposition of some ethnic groups (in the USA) to the more severe symptoms associated with Covid-19. He discussed a May CDC MMWR (morbidity and mortality weekly report) on 580 hospitalised Covid-19 patients which found that 45% were white, as far as they could ascertain, compared to 55% in that region’s community. 33% were black, compared to 18% in the community, and 8% were Hispanic compared to 14% in the community. A smallish sample, but suggestive. The CDC also reported on New York figures showing that Covid-19 death rates among black/African Americans and Hispanic/Latino persons were substantially higher than in the white population. Many possible reasons – work and living conditions, lower access to care – all generally related to relative poverty. There may also be other, purely physiological grounds for the disparity. A 16-year-old research article published in Circulation describes the results of placing nanosensors in isolated human umbilical vein endothelial cells (HUVECS) from blacks and whites (pardon the over-simplification, I’m only the messenger), as an attempt to measure endothelial oxidative stress. I can’t follow the details of the research, but what they found was that blacks expressed much more NADPH oxidase than whites (that’s bad). Nitric oxide, a reducer of oxidative stress, was produced in greater quantities in whites than in blacks, and the bad superoxides were produced in greater quantities in blacks. I won’t go further into the complex biochemistry, but I must say I find these apparent racial differences very surprising.

Update 68 also looks at increasing hospitalisations (at least in May) of young children due to Kawasaki disease, or something similar. The disease is characterised by inflammation of blood vessels. Symptoms include fever, high heart rate and possibly sepsis. There are a number of similarities to Covid-19, including ‘systemic vascular lesions’. Kawasaki disease is normally rare, and believed to be viral, or a response to a virus. A ten-year-old research paper on the disease hypothesises that the infection enters through the respiratory or gastro-intestinal systems, and so unsurprisingly there are similarities to the reaction to SARS-CoV2. Whether there’s a connection between Covid-19 and an uptick in Kawasaki disease has yet to be confirmed (but I’m behind the times on the research on this).

I’m moving now to update 69, and I’m going to follow Dr Seheult through the whole oxidative stress process again. It’s about reduction of oxygen – the adding of electrons. Adding an electron to oxygen, mediated by NADPH oxidase, produces superoxide. Add another electron and you get hydrogen peroxide. Another electron produces hydroxyl, and yet another produces water, moving from most oxidised to most reduced, and adding electrons also brings on protons. So at both ends of this chain you have neutral or positive molecules, but in between you have, I think ROS, reactive oxygen species, which are a problem. The body’s defence against these include the enzyme superoxide dismutase (SOD), which converts superoxide into hydrogen peroxide and also back into oxygen, and catalase which converts hydrogen peroxide into water and oxygen. Another important enzyme which protects against oxidative damage is glutathione peroxidase (GPx). It takes reduced glutathione (2GS-H, called a sulph-hydryl group) and uses it to reduce hydrogen peroxide into water, in the process oxidising the glutathione into a form of disulphide G-S-S-G. This oxidised form is in turn ‘regenerated back’ by taking the reduced form of NADP+ (NADPH) and converting it via glutathione reductase to NADP+.

So the point is that the accumulation of superoxide in people with diabetes, hypertension, coronory disease etc will be exacerbated by Covid-19. And going through that once more, Covid-19 blocks the ACE-2 receptor, causing an accumulation of AT-2 which stimulates superoxide production, and also a deficiency of AT-1,7, which, mediated by nitric oxide, inhibits superoxide production. The SARS-CoV2 virus also attracts PMNs (polymorphonuclear leukocytes – immune cells including neutrophils), which boost superoxide production, with attendant endothelial damage.

I’ll be continuing this series, and no doubt getting further behind, over the next few weeks.

References

Coronavirus pandemic update 67, presented by Dr Roger Seheult, as with all other updates

Coronavirus pandemic update 68

Coronavirus pandemic update 69 (first 5 minutes or so)

https://www.verywellhealth.com/polymorphonuclear-leukocyte-2252099

Written by stewart henderson

July 29, 2020 at 11:11 am

more on oxidative stress and covid-19

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So, much of this piece will rely on Dr Seheult’s coronavirus update 65. We have this constant set of reactions in the body that reduce oxygen – adding electrons – until we get to water molecules, producing reactive oxygen species (ROS) along the way. This is often described as the oxygen metabolism process. Reactive oxygen species come essentially in three types, superoxides, hydroxy radicals and hydrogen peroxide. The three forms of the enzyme SOD, superoxide dismutase, convert superoxide into oxygen and hydrogen peroxide (H2O2), and then the H2O2 is reduced to H2O by means of glutathione peroxidase (GPx). The GPx, which is broken down in the process is recharged by the enzyme glutathione reductase (GR), which is in turn recharged by other antioxidant products. Also the enzyme catalase, which requires iron, can break H2O2 down into O2 and H2O.

People with diabetes, hypertension and overweight issues, among other things, may have compromised antioxidant systems (too many ROS), linked to angiotensin-converting enzyme 2 (ACE-2) and angiotensin-2. In creating ROS, oxygen is reduced to superoxide by means of the enzyme NADPH oxidase. So, as part of the renin-angiotensin system, angiotensin-2 (AT-2) is converted to angiotensin 1,7 (AT-1,7) by means of angiotensin-converting enzyme 2 (ACE-2). This is important because AT-1,7 effectively blocks superoxide production, while AT-2 promotes it. The virus SARS-CoV2 binds with, and so inactivates, ACE-2, preventing the production of AT-1,7. This action also means that there will be more AT-2 available, and so more superoxides. SARS-CoV2 also, according to Seheult, causes inflammation by recruiting polymorphonuclear neutrophils (PMNs), which stimulate production of superoxides by means of NADPH oxidase. So this, in essence, is why Covid-19 is bringing about oxidative stress.

Seheult next goes on to look at the research evidence for the preceding. A review article from 2005 points out that evidence from animal studies and cell culture studies shows that NADPH oxidase-derived oxidative stress is increased in vascular cells by AT-2, among other ‘agonists’ (chemicals that bind to receptors, thereby producing a response). Another article from 2012 describes several enzyme systems that act to form ROS, including ‘mitochondrial electron leakage from the electron transport chain’ as described in my previous post on the subject, and in Seheult’s update 63. It points out that ROS levels can rise dramatically in older people suffering from oxidative stress due to heart issues such as ischemia-reperfusion (referring to problems with oxygenated blood supply to the heart or other organs). It also points out that it has been shown experimentally that AT-2 stimulates an increase in ROS. A more recent article pertaining to SARS-CoV2 looked at patients in Wuhan and found a substantial increase in neutrophils in the most severe cases. Neutrophils cause ROS to be generated by NADPH oxidase. So Dr Seheult is carefully building up evidence for the case. The last point to deal with is AT-1,7 effects. Seheult has found a 2008 article entitled ‘Angiotensin converting enzyme 2 confers endothelial protection and attenuates atherosclerosis’. Seheult quotes the last line from the abstract:

These data indicate that ACE-2, in an AT-1,7-dependent fashion, functions to improve endothelial homeostasis via a mechanism that may involve attenuation of NADPHox-induced reactive oxygen species production. ACE-2-based treatment approaches may be a novel approach to limit aberrant vascular responses and atherothrombosis.

Atherothrombosis involves disruption of atherosclerotic plaques, which can be an immediate cause of heart attacks. Another article from 2015 essentially confirms the findings, as indicated by its title, ‘ACE-2 and AT-1,7 protect endothelial cell function and prevent early atherosclerosis by inhibiting inflammatory response’. A more recent article, from January 2020, describes how AT-1,7 administration improves endothelial function in women who have suffered from preeclampsia (vasoconstriction, high blood pressure and organ damage due to pregnancy). To give more detail, women in the last stages of pregnancy often suffer vasoconstriction and high protein levels, which is believed to be related to AT-2 levels. Researchers administered local AT-1,7, which is ‘an endogenous inhibitor of... AT-2′, to see if this reduced vasodilation and other symptoms of preeclampsia. What they found was that ‘AT-1,7 increased endothelium-dependent vasodilation via nitric oxide synthase-mediated pathways and attenuated AT-2-mediated constriction in women who have had preeclampsia, suggesting that AT-1,7 may be a viable therapeutic target for improve d microvascular function in women who have had a preeclamptic pregnancy’.

All of this is interesting in itself, of course, and is a little crash course in how research is helping us to tweak our immune systems, but in relation to Covid-19 these finding are of importance due to the comorbidities and general characteristics of patients being hospitalised with Covid-19. Dr Seheult, in his update 65 video, shows that, contrary to what was initially thought, i.e that Covid-19 is primarily a virus affecting the lungs and respiratory system, it may be much more of a problem for those with hypertension, cardiovascular issues and obesity – all of which are related to oxidative stress, as are diabetes and many forms of cancer. They contribute to endothelial dysfunction, which inevitably leads to oxidative stress, and may lead to thrombosis. Seheult here refers to a lengthy 2018 review article, ‘nutrients and oxidative stress: friend or foe?’, which among other things makes useful dietary suggestions for the combatting of oxidative stress – whole grains, nuts, fruit and vegetables, fish and legumes.

It’s been known for some time that endothelial cell dysfunction (ECD) can lead to thrombosis, as it is a major function of these cells to prevent thrombosis. The abstract from a 2002 study finds that ECD ‘is associated with decreased synthesis and oxidative inactivation of nitric oxide (NO)’ and it lists four types of antioxidant enzymes ‘essential for eliminating ROS that can inactivate NO’. It seems that the promotion of these enzymes can be associated with diet as above and with the reduction of risk factors such as hypertension, hypercholesterolaemia (high blood cholesterol), hyperhomocysteinaemia (homocysteine is an amino acid which can contribute to arterial damage and blood clots, and the condition is often associated with lack of vitamin B-12 or folate), cigarette smoking and diabetes mellitus. NO is the key molecule in maintaining endothelial function through these enzymes.

Now I’m having a look at Dr Seheult’s update 66 on blood pressure medications known as ACE inhibitors or ARBs. He cites an editorial article for the New England Journal of Medicine, on ‘inhibitors of the renin-angiotensin-aldosterone system and Covid-19’. This is a triple hormone system responsible for blood pressure regulation and fluid balance. Now, to return to what was outlined before, angiotensin-2 (AT-2) is converted to AT-1,7 by an angiotensin-converting enzyme (ACE-2). The SARS-CoV2 virus binds to the ACE-2 receptor and inhibits the enzyme’s production. This is problematic because AT-2 stimulates superoxide production (that’s bad), while the antioxidant AT-1,7 blocks it, so reducing oxidative stress. SARS-CoV2 also stimulates the production of PMNs, as above, which activates oxidative stress. Another part of this picture is that AT-1 is converted to AT-2 by ACE. There are blood pressure lowering medications, such as benazepril and lisinopril, aka ACE inhibitors, which reduce the production of AT-2. There are also angiotensin receptor blockers (ARBs), which may up-regulate ACE-2 (it isn’t clear, apparently). ACE inhibitors may do the same. The question being asked is, assuming these medications produce more ACE-2, will this lead to more infections because SARS-CoV2 has more ACE-2 to work with? Clearly it would be important to know whether to maintain these medications or not, that’s to say, whether these medications are a risk factor for contracting the virus or recovering from it. The above-mentioned article discusses three studies from different parts of the world, each involving thousands of participants. They all found no risks associating ACE inhibitors and ARBs with a higher risk of infection, severity of illness or death from Covid-19. One of the studies found that ACE inhibitors and statins were associated with a decreased risk of mortality, but these are observational studies and further research would need to be done.

So the above is a rather technical piece, highly reliant on the experts. I write to inform myself, and I’ve certainly been informed by writing this one. Apologies for its laboriousness, but I’ll be continuing… Please consult the references yourself if there’s anything you don’t understand.

References

Coronavirus Pandemic Update 65: COVID-19 and Oxidative Stress (Prevention & Risk Factors)

Coronavirus Pandemic Update 66: ACE-Inhibitors and ARBs – Hypertension Medications with COVID-1

https://www.mayoclinic.org/diseases-conditions/high-blood-pressure/in-depth/ace-inhibitors/art-20047480

https://www.healthline.com/health/homocysteine-levels

https://www.mayoclinic.org/diseases-conditions/high-blood-pressure/in-depth/ace-inhibitors/art-20047480

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5831951/

Written by stewart henderson

July 16, 2020 at 4:21 pm

SARS-Cov2 and oxidative stress

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Dr Roger Seheult, just doing his job, workaholically

So I feel it’s time for me to get back to the epidemiology and immunology stuff that I know so little about, especially as it pertains to SARS-Cov2. Watching Dr Seheult’s Medcram updates again after a long hiatus, and catching up with them from the end of April, I note that he’s arguing – and I presume this is a mainstream view, as he clearly keeps an eye on the latest research – that the virus mostly does its damage in attacking the body’s endothelium, and that this in turn causes oxidative stress. The endothelium is a thin layer of cells, or a layer of thin cells, that form the inner lining of the blood and lymph vessels (one day I’ll find out what lymph actually is and does).

Oxidative stress is associated with an imbalance in the level of oxidants such as super-oxide anion and hydrogen peroxide, reduced forms of oxygen (with extra electrons). I don’t really understand this, so I’ll start from scratch. But just preliminary to that, the effects of oxidative stress are manifold. Here’s a summary from news-medical.net:

Oxidative stress leads to many pathophysiological conditions in the body. Some of these include neurodegenerative diseases such as Parkinson’s disease and Alzheimer’s disease, gene mutations and cancers, chronic fatigue syndrome, fragile X syndrome, heart and blood vessel disorders, atherosclerosis, heart failure, heart attack and inflammatory diseases.

It’s known that SARS-Cov2 enters via the lungs, and does damage there, but it’s now thought that most of the damage is done in the endothelium. To understand this, Dr Seheult is going to teach me some ‘basic’ stuff about metabolism, oxidation, energy production and such. So, we start with mitochondria, the energy-producing organelles inside our cells, which have their own DNA passed down the female line. Looking into a mitochondrion, we have the matrix inside, and around it, between the inner and outer membranes, is the inter-membrane space (IMS). Our food, broken down into its essential components, carbs, fats and proteins, is absorbed into the matrix, and somehow turned into ‘two-carbon units’ called acetyl coenzyme A. This is metabolism, apparently. These molecules go through a famous process called the Krebs cycle, of which I know nothing except that it’s about more metabolism… Although now I know that it produces electrons, tied up in two important molecules, NADH and FADH2. These electrons ‘love to be given up’, a way of saying they ‘want’ to be reduced. The molecule that gives up electrons is said to be oxidised, the receiving molecule is reduced. So think of a molecule being reduced as the opposite of losing, rather counter-intuitively. The oxidised molecule is the one that loses electrons. All this is about energy production within the matrix, and the aim is to end up with a molecule I’ve heard and forgotten much about, adenosine triphosphate (ATP). This molecule is the energy molecule, apparently, and the energy is produced by ‘knocking off’ one of the phosphates, according to Dr Seheult, leaving, apparently, adenosine diphosphate (ADP) plus ‘energy’ (clearly, this part needs a little more detail). So going from the diphosphate form to the triphosphate requires energy, going the other way releases energy – none of which really explains why ATP is the body’s energy source. Anyway…

Returning to the carbs, fats and proteins, they go through these mitochondrial processes to produce electrons which want to reduce stuff. So NADH goes to the membrane which separates the IMS from the matrix of the mitochondrion, where proteins can be found that are willing to accept electrons, i.e. to be reduced. The electrons are brought in ‘at the very top of the scale’ (?) and lose some of their reducing ability, so they go down to a lower state of reduction, and protons are pumped into the IMS. (I’m sure this is all true but making sense of it is another matter. It certainly makes me think of proton pump inhibitors, drugs that reduce gastric reflux, but that would be the subject of another set of posts). Then ‘it goes to another species’ by which I think Seheult means another protein, judging from the video, but what he means by ‘it’ I’ve no idea. The NADH? The wave/body of electrons? Anyway, things keep going down to a lower level, becoming more oxidised, and more and more protons are pumped out. So there comes to be a very high concentration of protons (H+) in the IMS, creating a very low PH (high acidity). Meanwhile, the electron transport chain has gone down so many levels that it can only reduce oxygen itself, which by accepting electrons turns finally into water. It’s apparently essential to have sufficient oxygen to keep this cycle going, and to keep the protons pumping, because the protons in the IMS want to move to a place of lower concentration, in the matrix. In doing this, they pass through a channel, which involves, somehow, a coupling of ADP to ATP. Without enough oxygen, this process is stymied, ATP can’t be supplied, leading to insufficient energy and cell death.

So, I think I understand this, as far as it goes. Now, if you over-eat, with lots of high-calorie fats and carbs entering the cells, you’ll likely end up with a surplus of electrons, tied up in NADH and FADH2, which can cause problems. This is where super-oxides come in.

Oxygen is the final electron acceptor in the electron transport chain, and when you add an electron to this final acceptor you get a super-oxide, an oxygen molecule with an additional electron, aka a radical. These are very reactive and dangerous. They can cause DNA damage and serious inflammation, and the body uses them to kill bacteria. If you add another electron, you get H2O2, hydrogen peroxide, and another one again produces a hydroxy radical, OH. Another electron gives water, so it’s these intermediate molecules that are called ‘dangerous species’. Cells such as neutrophils (a type of white blood cell) make these, via an enzyme called NADPH oxidase, as part of their defence against antigens, but an accumulation of these radicals is problematic and needs to be dealt with.

from Dr Seheult’s presentation, showing the production of reactive oxygen species (ROS) – super-oxide, hydrogen peroxide and hydroxy radicals

One enzyme the body uses to bring down these accumulating radicals is super-oxide dismutase (SOD), which takes two super-oxides and converts them into O2 and H2O2. SOD comes in three types, related to where they reside – in the mitochondria, the cytosol and the extracellular matrix. These enzymes are powered by zinc, copper and, in the mitochondria, manganese. So what happens to the extra hydrogen peroxide created? An enzyme called glutathione peroxidase (GPx) reduces H2O2 to water by giving it two electrons. Where do these electrons come from? According to Seheult, and this is presumably ‘basic’ microbiology, the antioxidant glutathione has two forms, oxidised and reduced. The reduced form is 2GS-H, with a hydrogen bonded to the sulphur group. The oxidised form is G-S-S-G, a disulphide bond replacing the hydrogen. With the reduced form, GPx donates its extra two electrons to H2O2, reducing it to water. The glutathione system is recharged by reducing it back with NADPH, which has two electrons which are converted to NADP+ (?) Glutathione reductase is the key enzyme in that process. It might take me a few lifetimes to get my head around just this much.

Meanwhile there’s another system… Catalase, an iron-boosted enzyme, can convert two molecules of H2O2 into O2 and H2O. This occurs in organelles called peroxisomes. The major point to remember in all this is that super-oxides are harmful species that can cause oxidative stress, and the major solutions come in the form of SOD and GPx. In fact the general name for these harmful molecules – super-oxides, hydrogen peroxide, and hydroxy radicals – is reactive oxygen species (ROS).

So we have to relate all this to the effects of SARS-Cov2, which enters the body through the ACE-2 (angiotensin-converting enzyme-2) receptor. According to a 2008 research paper, ACE-2, the receptor for which is blocked by SARS-Cov2, ‘confers endothelial protection and attenuates atherosclerosis’. Quoting from the paper, we find a section called ‘ACE-2 modulates ANG II(angiotensin 2)-induced ROS production in endothelial cells’. The researchers’ essential finding was that ‘ACE-2 functions to improve endothelial homeostasis’, and it seems this function is being disrupted by SARS-Cov2. As Dr Seheult puts it, SARS-Cov2 inhibits the inhibitor, that is it inhibits ACE-2, which normally acts to regulate angiotensin 1,7 (not explained in this particular video), thus allowing NADPH oxidase to keep producing super-oxides, with the resultant oxidative stress. As Seheult concludes here, subjects with compromised systems caused by diabetes, cardiovascular disease or obesity, affecting the production or effectiveness of SOD and GPx, might be relying on ACE-2 and angiotensin 1,7 to maintain some semblance of health. Are these the subjects that are succumbing most to the virus? That’s to be explored in future videos, and future posts here.

Reference

Coronavirus Pandemic Update 63: Is COVID-19 a Disease of the Endothelium (Blood Vessels and Clots)? (video by Dr Roger Seheult – clearly a hero in this time)


Written by stewart henderson

July 5, 2020 at 11:46 pm

Covid-19, politics, government – some observations

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No society can legitimately call itself civilised if a sick person is denied medical aid because of lack of means.

Aneurin Bevan, founder of the UK’s NHS

Dr Anastasia Vasilyeva, engaged in the dangerous task of exposing Putin’s lies

Let me look at Covid-19 cases and deaths in different countries in terms of the political persuasions (and gender) of their leadership, with some obvious caveats and reservations, e.g. that correlation isn’t causation, that there are a whole host of factors influencing how well or badly particular nations are faring, that the data coming from many nations is highly suspect, etc. My statistics come from the Worldometer site, which names a wide variety of sources, and notably tends to be slightly less conservative than the WHO and Johns Hopkins sites in terms of numbers. The differences aren’t great, but I think it’s reasonable to assume that the overall numbers are greater than even the Worldometer site has been able to confirm.

I’m doing this because I’ve been checking the stats on a daily basis for weeks now, and impressions have, not surprisingly, been forming about the relationship between national leadership and the impact of the virus. So here are some statistics, and some speculations on them, for what they’re worth.

The UK (I was born in Scotland) has fared worse than any other country, apart from Belgium, in terms of deaths per million. Conservative PM Boris Johnson, prior to catching the virus himself, seemed to suggest letting it run its course through the community, which of course would have led to a huge death rate, and generally the messages from the beginning were confused, and mostly of a softly softly nature, which has clearly proved disastrous. The NHS has suffered years of severe cuts under ten years of conservative government, and mixed messaging has continued to damage what has been a truly woeful governmental response to the crisis. Scotland, which has a female First Minister and a centre-left government, has a slightly lower ‘excess death toll’ than England, but it’s still high compared to most countries, and higher than those of Wales and Northern Ireland. England is, of course, by far the most densely populated of the four UK nations.

Belgium wears the shame of having the worst Covid-19 mortality rate of any significant-sized nation (of say, 5 million or more) on the planet. However, to be fair, Belgium appears to have an accounting system for the virus which is as anomalous as is that of Russia at the other end of the spectrum (a spectrum from inclusive, i.e Belgium, to exclusive in Russia’s case). This issue of accounting is too enormously complex and fraught to be dealt with here (though many are suggesting that measuring ‘excess mortality’ might be the best option), so I’ll take Belgium’s disastrous figures at face value for now. The country’s PM, Sophie Wilmès, is a member of the centrist Mouvement Réformateur, and heads a coalition government. In fact Belgium has long been so factionalised that coalition governments are a more or less permanent feature of government there, and internal squabbling in recent years has led to a lot of government inertia. Though clear information is hard to find, the lack of strong, supported central government is very likely negatively affecting the country’s Covid-19 experience.

Germany is generally regarded as the success story of Europe. It’s Europe’s largest country, and currently the 19th most populated country in the world. It is 12th overall in the number of cases, and 11th in the number of deaths. This may look bad, but we know that western Europe has been particularly hard-hit, and it’s worth comparing Germany to its neighbouring countries. Interestingly, Germany shares its border with no less than nine different countries, and in terms of deaths per million, which I think is a good guide of a nation’s internal handling of the pandemic, it is doing far better than its westerly neighbours (Switzerland, France, Luxembourg, Belgium, the Netherlands and Denmark), and considerably worse than its easterly ones (Austria, Czechia and Poland). Again I’m skeptical of some of the stats, especially in a country like Poland, which has descended into a quasi dictatorship under its all-powerful Law and Justice party, but there does seem to be a radical divide between the eastern and western halves of Europe in terms of the pandemic’s impact. Anyway, Germany’s centrist Chancellor Angela Merkel has been in power since 2005, and she’s recently suffered under the description, ‘leader of the free world’ in lieu of the USA’s absence of leadership. Being a former research scientist, she’s been credited, rightly or wrongly, with having shepherded the country through this crisis better than most. Wikipedia has this to say about the country’s response:

The country’s low fatality rate, compared to fatality rates in Italy and Spain, has generated a discussion and explanations that cite the country’s higher number of tests performed, higher number of available intensive care beds with respiratory support and higher proportion of positive cases among younger people.

Italy, a country renowned for its political instability, fared disastrously early on (in March and April) in terms of cases and deaths, but has reduced the numbers greatly in recent weeks. Even so, Italy’s deaths per million is one of the worst rates in the world, five times that of Germany. Italy has in recent years developed closer ties with China than any other country in western Europe, and evidence points to the virus arriving in northern Italy via a Chinese couple from Wuhan. It’s clear that there was early skepticism and government officials were caught unawares by the magnitude of the crisis, and the rapidity of spread. The wealthy and densely populated Lombardy region has been disproportionately affected. Italy’s PM, Giuseppe Conte, has held the position for two years, making him one of the longest serving leaders in Italy’s post-war history. The nation’s volatile political history makes co-ordinated strategic planning for pandemics very difficult. This article on Italy from the Harvard Business Review, aimed at an American readership, captures the problems that face individualistic nations who favour rights over responsibilities:

Consider the decision to initially lock down some regions but not others. When the decree announcing the closing of northern Italy became public, it touched off a massive exodus to southern Italy, undoubtedly spreading the virus to regions where it had not been present.

This illustrates what is now clear to many observers: An effective response to the virus needs to be orchestrated as a coherent system of actions taken simultaneously. The results of the approaches taken in China and South Korea underscore this point. While the public discussion of the policies followed in these countries often focuses on single elements of their models (such as extensive testing), what truly characterises their effective responses is the multitude of actions that were taken at once. Testing is effective when it’s combined with rigorously contact tracing, and tracing is effective as long as it is combined with an effective communication system that collects and disseminates information on the movements of potentially infected people, and so forth.

Clearly this information-collecting, when it isn’t coercive, requires compliance and collaboration for the broader good. Libertarians are reluctant, it seems, to admit this.

Sweden‘s record on the pandemic is worth comparing to the other four countries comprising Scandinavia – Norway, Finland, Denmark and Iceland. Sweden is certainly the most populous of the five, but its deaths per million tell a grim story – more than five times those of Denmark, around ten times those of Norway and Finland, and almost 20 times those of isolated Iceland. The rate is higher than that of the USA and France, and not far below that of Italy. Currently, the centre-left PM Stefan Löfven heads a highly unstable coalition, which clearly isn’t able to provide the co-ordinated response required in a pandemic. In fact the country deliberately took a ‘relaxed’ attitude to the virus, and are now paying the price, though some of the country’s epidemiologists are still standing by the nation’s approach, astonishingly enough. Around half of the country’s fatalities have occurred in nursing homes. Apart from Sweden, all of the Scandinavian countries have female leaders. Just saying.

Russia, which has recorded the third highest number of Covid-19 cases in the world, has a bizarrely low death-rate, which can’t be accounted for from an epidemiological perspective, as I’ve reported before. Dmitry Peskov, one of Putin’s favourite arse-lickers, defended the record, saying “Have you ever thought about the possibility of Russia’s health care system being more effective?” This in fact caused a spike in fatalities, as several thousand Russians immediately died laughing. A very brave doctor, Anastasia Vasilyeva, founder and head of the medical trade union Alliance of Doctors, is creating videos exposing Putin’s lies about Russia’s handling of the pandemic, showing run-down hospitals, sick and unprotected medical staff and a generally under-funded and unprepared healthcare system. She has, of course, been viciously attacked by Putin’s media thugs, arrested and generally harassed. It’s safe to say that nothing credible is coming out of Russia’s state reporting of Covid-19, and the same must be said of China, or any other state which has more or less complete control of its media. So the full truth of what is happening in Russia, and in other closed societies, will likely not come out for years.

Final remarks – from what we’ve seen so far, right-wing, limited government, libertarian-type governments do worse than strong, centralised governments, especially those led by women. Closed societies generally can’t be trusted on their reporting, so it’s virtually impossible to judge their performance vis-à-vis  the pandemic.

Next time I’ll look at some countries in Eastern Europe and the Middle East.

References

https://www.worldometers.info/coronavirus/

https://www.theguardian.com/commentisfree/2020/apr/04/tories-protect-nhs-coronavirus-slogan

https://www.abc.net.au/news/2020-05-18/why-belgium-has-a-high-number-of-coronavirus-deaths/12259032

https://www.theguardian.com/world/2020/apr/26/virologist-christian-drosten-germany-coronavirus-expert-interview

https://www.livescience.com/results-of-sweden-covid19-response.html

https://hbr.org/2020/03/lessons-from-italys-response-to-coronavirus

https://www.abc.net.au/news/2020-06-02/anastasia-vasilyeva-doctors-alliance-russia-coronavirus/12276094?nw=0

Written by stewart henderson

June 29, 2020 at 10:08 am

Covid-19: lies, damn lies and statistics

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Brazilian President Bolsonaro, explaining how government mismanagement and corruption is a good thing

Canto: So Russia is being described as a ‘late arriver’ with regard to Covid-19. It now has the second-highest number of cases, as everyone knows. Yet the mortality figure is astonishingly low. It’s only natural to be suspicious as there’s surely no obvious epidemiological explanation. It’s worth comparing Russia to Germany, whose figures few would quibble with, given its reputation for efficiency. It’s been treated as the European outlier in terms of its response, but nobody appears to be praising Russia for its tiny mortality rate. Why would that be?

Jacinta: Just looking at some reporting, various reasons have been given. Take this one from Dr. Elena Malinnikova, the chief of infectious diseases in the Russian Ministry of Health:

The low mortality is due to timely detection of infection as well as the fact that that Russians tend to see their doctor soon after symptoms appear.

Canto: Hmmm. Other nationalities don’t see their doctor, when there’s a killer pandemic on the loose? And ‘timely detection of infection’ sounds overly vague to me.

Jacinta: Let’s try another one. ‘Russian journalists have reported that more than 60% of all cases diagnosed in the country have been in Moscow, which has a younger and healthier population than rural areas’.

Canto: Yeah, but in the USA it’s the richer, more heavily populated regions of the north-east that have been hardest hit. The rural regions much less so.

Jacinta: Okay. In the article linked to above, Kent Sepkowicz, a physician and infection control specialist, provides good reasons why Russia’s mortality figures don’t make much sense on their face. And before I report on that, let’s look at rough reported mortality rates of a few countries, for comparison. I’ve just looked at total reported deaths as a percentage of total cases. As of May 20, the USA’s mortality rate is around 6%, the UK’s a horrendous 14%, Germany’s has gradually risen to 4.6%, and Brazil, another latecomer like Russia, and now with the fourth largest number of cases, is at 6.5%. Russia, on the other hand, is at 0.95% mortality. That’s a huge disparity, which we might call ‘Russia’s miracle’. But, as Sepkowicz points out, despite reports that Russia is doing well on testing (more than ten times that of Brazil, and somewhat more than the USA, and they might’ve started earlier too), Russia scores poorly on the comorbidity front, otherwise known as ‘pre-existing conditions’, such as heart disease, chronic lung disease, diabetes and obesity. It has an ageing population, and smoking is far more prevalent there than in European countries and Brazil. The testing regime is definitely not so much better than other countries to account for Russia’s apparent success – both Spain and Italy have done more tests per population.

Canto: Hello, are you saying there’s something shifty in the works? Vlad and and his charming circle would never lie to us, surely?

Jacinta: I don’t know that they’d gain much from fudging the figures…

Canto: Are you kidding? Isn’t that like saying Vlad wouldn’t gain much from rigging his election results? What he loses in international credibility, he might gain on the national scene, and that’s more important for him. But maybe there’s some less nefarious reason for the low mortality – I know they’re counting the numbers differently in some way. But the deaths from Covid-19 are the deaths from Covid-19. It should be a straightforward matter.

Jacinta: What about the deaths from x, y or z, exacerbated by Covid-19 infection?

Canto: I think that’s what they’re doing in Russia. Unless they’re certain that it was Covid-19 directly, they’re not counting it, even if they’ve tested positive for the virus, and then they die. They might be arguing that they were going to die anyway, Covid-19 just hastened the end.

Jacinta: Very dodgy if true. You could say that about anyone who’s a bit peely-wally.

Canto: Anyway let’s look at another country in this very complicated trans-national battle against the virus. Brazil’s an interesting one. I’m noting that countries with right-wing laissez-faire governments tend to be killing their citizens at a faster clip than leftist or centrist governments. Whadyareckon?

Jacinta: That’s a bit crude, but let’s look again at the reported figures and give number of deaths per number of cases as percentages. I’m going to leave out Russia and China, as I don’t trust what they’re reporting – which isn’t to say I entirely trust the other nations, but you have to draw the line somewhere. Britain, as mentioned, is very high at 16%, and has a conservative government. A very interesting country to look at is Belgium, which has the highest death rate per million of population of any major country in Europe. It’s death-to cases percentage is also high, at just over 16%. The country’s political situation is horrendously complex. They’ve had a caretaker PM for a year or so, and there’s basically a caretaker government after messy election results in March, in the middle of the Covid-19 crisis. This interim government is supposedly in place just to manage the crisis. Clearly it’s not going well. It would be reasonable to put their problems down to no strong central government, à la the US. Now, Brazil has a notoriously extreme-right government at present, and I’ve already given its deaths-to-cases ratio, but the number of cases is rising rapidly, as are the number of deaths. Now, let’s have a look at Scandinavian countries, often glorified as models of good government. I’ll include in that vague grouping, in order of population: the Netherlands (17m), Sweden (10m), Denmark (5.8m), Finland (5.5m) and Norway (5.4m), and I’ll exclude Iceland, which has all the advantages of a distant island re isolation (it’s 87th in the world for cases). On deaths-to-cases: The Netherlands 13%, Sweden 12%, Denmark 5%, Finland 4.7% and Norway 2.8%. On those statistics, it seems that the smaller the country, population-wise, the better managed it has been in terms of preventing mortality, which does make some sense.

Canto: Okay so I’ll look at their current governments. the Netherlands is clearly hard-hit, Covid-19-wise. It has a multi-multi-party system (that’s not a typo) and is currently governed by a centre-right or conservative-liberal party, VVD, presumably supported by the next largest party, PVV a right-wing nationalist group. The left appears to be divided amongst a number of smaller parties, and the current government has been in power for ten years. Sweden, also faring badly under Covid-19, currently has a minority government with a social democrat PM after a controversial and inconclusive election in 2018. So it’s a centre-left government relying on centre-right parties. The social democrats have been in power, mostly as a majority, since 1917, but there has been a movement towards the right in recent years. Denmark, doing better than the previous two, but faring much worse than we are here in Australia, where we have a death-to-case ratio of 1.4%, has again a multi-party system – and by the way, all of these Scandinavian countries, except Finland which is a republic, are constitutional monarchies practising parliamentary democracy like Britain, and, in a weird way, Australia, New Zealand and Canada. The leftist social democrats are currently in power in Denmark, and they have a far tougher position on physical distancing than the Swedish government. Finland Has both a President and a Prime Minister, somewhat like France. The Prime Minister, Sanna Marin, made news worldwide as the youngest PM in the world when elected late last year. She’s a social democrat and heads a coalition government, which seems to be the case with most Scandinavian governments.

Jacinta: Yes, They seem designed that way so the parliament is more or less forced to collaborate in order to get things done. It seems a much better way to run a country, a far superior system to that of the USA, much more team-based. Anyway, statistics seem to suggest that, overall, strong central governments that can co-ordinate efforts effectively, and have the support of the people, are doing better at saving lives. It’s not a conclusive finding though, and no doubt each country has its confounding factors.

Canto: Norway, finally, has handled things in much the way you would expect of the nation rated first in the world by the OECD. On March 19 this year, their federal government was granted emergency powers by parliament until December. That’s one way of creating strong central government, albeit temporarily. The current government is essentially right-centrist, within a multiparty system where the balance is usually held by left-centre parties. Clearly, though, this is a nation where people place more faith in government than, say, in the USA. And speaking of libertarianism and such, it’s interesting to look at Brazil more closely. When we began this post a couple of days, ago, Brazil was fourth in the world in terms of confirmed cases. Now it’s up to second, that’s how fast-moving things are.

Jacinta: And it’ll never reach top spot, surely – the USA is way way ahead of the rest of the world.

Canto: So Brazil is a republic, and currently has an extreme right-wing government under Jair Bolsonaro, who, according to this very recent New Yorker report, seems to be doing everything he can to exacerbate the situation. Brazil’s rise in cases has been more recent than most, and the death toll is now rising rapidly, now up to sixth in the world.Bolsonaro is shrugging it off and encouraging defiance of state restrictions in much the manner of Trump, whom he idolises. So it seems that when you get extreme anti-government government – negligence mixed with incompetence – as in the case of Trump and Bolsonaro, the death toll will likely be devastating, and will impact mainly the poor, elderly and disadvantaged. Who would’ve thunk it?

References

https://www.worldometers.info/coronavirus/

https://edition.cnn.com/2020/05/13/opinions/russia-low-covid-19-mortality-rate-sepkowitz/index.html

https://www.washingtonpost.com/world/europe/without-a-government-for-a-year-belgium-shows-what-happens-to-politics-without-politicians/2019/12/19/5c13cb48-20de-11ea-b034-de7dc2b5199b_story.html

https://www.nationsencyclopedia.com/economies/Europe/Belgium-POLITICS-GOVERNMENT-AND-TAXATION.html

https://en.wikipedia.org/wiki/Politics_of_the_Netherlands

https://en.wikipedia.org/wiki/Politics_of_Sweden

https://en.wikipedia.org/wiki/Politics_of_Denmark

https://en.wikipedia.org/wiki/Politics_of_Norway

https://www.forbes.com/sites/carmenniethammer/2019/12/12/finlands-new-government-is-young-and-led-by-women-heres-what-the-country-does-to-promote-diversity/#28236f8835aa

https://www.newyorker.com/news/daily-comment/the-coronavirus-hits-brazil-hard-but-jair-bolsonaro-is-unrepentant


Written by stewart henderson

May 23, 2020 at 10:47 am

The Epoch Times and the ‘CCP virus’

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a man lies dead in the street in Wuhan in late January – this image was also used on p3 of The Epoch Times

Jacinta: So something unusual arrived in our letterbox the other day – a newspaper of sorts. Made out of paper.

Canto: Weird. Haven’t read one of those for a while.

Jacinta: Yes, nowadays we read those things on tablets, just like the Flintstones of yore. It wasn’t a big newspaper – an 8-page broadsheet – but it was unusual in other respects. It was all about China, or rather the Chinese government – the Chinese Communist Party (CCP). And none of it was positive.

Canto: Yes, the newspaper is called The Epoch Times, and has an ‘about us’ column on page 2, which tells us it’s ‘dedicated to seeking the truth through insightful and independent journalism’.

Jacinta: ‘Standing outside of political interests and the pursuit of profit, our starting point and our goal is to create a media for the public benefit, to be truly responsible to society’. All very commendable of course, but the whole paper is devoted entirely to criticising the CCP, highlighting its nefarious tactics and giving a voice to silenced, and sometimes disappeared, Chinese citizens, and also to Australian critics of the CCP.

Canto: So it’s Australian-based, operating out of Hurstville, a southern suburb of Sydney. Apparently founded back in 2000, it also states ‘we stand against the destruction wrought by communism, including the harm done to cultures around the world’. So, what do you think?

Jacinta: Well… we’re no admirers of so-called communism (which is always dictatorial or oligarchical rule in fact). We’re into open, progressive and collaborative societies. So, while I’m sympathetic to the cause of this newspaper, here’s a criticism. It’s interesting that we’ve had this in our mail now, from this 20-year-old organisation. It comes at a time when the CCP is undoubtedly weakened by the spread of SARS-CoV-2, and will be scrambling to improve its reputation and to limit the economic damage done to China by this disaster. It’s a bit like these China critics and journalists, many of them of Chinese backgrounds themselves it seems, are ‘going in for the kill’ against a weakened adversary. All very ‘nature red in tooth and claw’. And of course I sympathise to a degree, but note that I mentioned ‘collaborative’ before, and in our last post we talked about not playing the blame game at this time. The Epoch Times has an editorial on its second page, entitled ‘Giving the Right Name to the Virus Causing a Worldwide Pandemic’. Their decision is to call it the CCP virus, a name they use throughout the newspaper. I respectfully disagree for a number of reasons. First, it would be a step backward to the Spanish influenza days. As we know, the Spanish flu didn’t originate in Spain, but much of the early reporting of it came from there, while other nations, still engaged in the HSW (Horribly Stupid War) of the period, suppressed the news to maintain morale. This was unfortunate geographical nomenclature, as many people still confusedly believe it came from Spain. Today we wisely use scientific names which refer to the type of pathogen – coronaviruses have their characteristic s-proteins, hepatitis viruses affect the liver, from the ancient Greek root hepat-, etc. This helps make clear that viruses and other pathogens have no nationality and know no borders. It also helps to internationalise science. Second, while we need to know the precise origin of this virus, and to try to shut down what at this stage looks to be the passage from bats to humans via one or more intermediaries, the priorities right now are to stop or reduce its spread, to reduce its effect on human bodies, and ultimately to develop a vaccine to stop it in its tracks. Only after we’ve achieved these things should we be looking at causes and blame.

Canto: Right, like when the Titanic’s sinking, it’s no use wasting time on causes or human failings before the event, all your energies should be spent on saving lives, getting others to collaborate on rescue efforts, and getting the hell away from there. Those other enquiries come afterwards.

Jacinta: Right. Now China is apparently trying to help with supplies of PPE and with its own clinical trials of antivirals and vaccines. Obviously there are political motives there, but if it’s providing effective assistance we shouldn’t reject it. Now, there’s a massive amount of journalism being produced as to the CCP’s motives and its effectiveness in, for example its assistance to Italy, with which it has had long-standing relations, and we shouldn’t be naïve about the CCP’s misinformation campaigns, its dubious politicking, and its cyber-warfare activities, and all of that should be reported on, but in my view, the reporting should always have this question in back-of-mind: Is it (I mean the reporting) helping or hindering the spread and/or defeat of Covid-19? That s the one and only priority at the moment. If the CCP is saving lives and reducing suffering in its own country and elsewhere at the moment, that’s a good thing, and should be welcomed.

Canto: Misinformation costs lives too though. It’s interesting that both Hong Kong and Taiwan, two regions that have reason not to trust anything coming out of the CCP, have performed far better than most in combatting Covid-19. Many Hong Kong residents have been wearing masks since the SARS outbreak of 2003, and the people themselves were ahead of their own government in wanting shut-downs. They’ve experienced only four confirmed deaths – an amazing feat. It really pays – and saves lives – not to trust the CCP, it seems.

Jacinta: So let me give a third reason. China is an economic giant, keen to expand its economic impact around the world. Twenty-five percent of Australia’s manufactured goods come from China. China is the largest customer for our Australian exports, by far. Successive Australian governments have been trying to diversify our trade relations, but it seems that market forces are moving us to an ever-closer reliance on China. So we know that too-strident criticism of the CCP, however deserving, may have a severe economic impact. It places us in a delicate position. The question then becomes one of leverage – finding ways to criticise from a position of amity, or at least some kind of partnership.

Canto: Good luck with that. And we need to show them that we know what’s what, and that we’re not weaklings. And join and participate in international forums that promote human and minority rights, and lend our weight to international criticism.

Jacinta: Yes, and with these caveats, I do want to endorse what The Epoch Times is doing. It’s important that people hear from and about the dissident voices within China, their courage and their suffering. Knowledge is power, and much anger and outrage is thoroughly justified. What has happened to Fang Bin? To Chen Quishi? To Li Zehua? To Ren Zhiqiang? How does the CCP justify its treatment of the late Dr. Li Wenliang and of Dr. Ai Fen? This will not be forgotten, nor will the CCP’s self-interested, deceitful, incompetent and bullying mishandling of the early stages of this outbreak. The party needs to be brought to account, by international forces, in the aftermath of the pandemic.

References

The Epoch Times, April 20, Special Edition

https://en.wikipedia.org/wiki/COVID-19_pandemic_in_Hong_Kong

https://www.australiachinarelations.org/content/understanding-australias-economic-dependence-china

https://en.wikipedia.org/wiki/Fang_Bin

https://en.wikipedia.org/wiki/Li_Zehua

https://en.wikipedia.org/wiki/Chen_Qiushi

https://en.wikipedia.org/wiki/Ren_Zhiqiang

https://www.ijidonline.com/article/S1201-9712(20)30111-9/fulltext

https://en.wikipedia.org/wiki/Ai_Fen

Written by stewart henderson

May 10, 2020 at 12:51 pm

Covid-19 – conspiracies, remdesivir

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tricky micky plumpeo, vying with old frumpy to become US muckraker-in-chief

Canto: So, getting back to Covid-19, I want to look at two unrelated issues – the limited approval of remdesivir as a treatment, and the claim by the US government that the virus escaped from a lab in Wuhan. What do you think?

Jacinta: Well let me briefly address the second matter – I haven’t yet looked into the claim, but I will say that, IMHO, the current US federal government is possibly the largest misinformation machine on the globe at present, and I won’t be happy till I see every member of that non-administration in jail.

Canto: Okay, be prepared for a life of misery. I agree though, that Pompeo is a slimeball, and it’s very likely that this is largely designed as another blame-shifting distraction by the US maladministration. I don’t remember hearing about this from any news source before Pompeo announced it.

Jacinta: Well it’s interesting that, in investigating this, we have to contend with, and generally ignore, two of the most untrustworthy governmental sources of information on Earth, the USA and China. So thank dog for independent journalists, scientists and investigators. We need them so much at this time. The Washington Post has a 2000-word article on the issue, posted on May 1, undoubtedly in response to moves by Frumpy & co to get the US public to blame China for the pandemic. The article describes an assessment from the US intelligence community:

While asserting that the pathogen was not man-made or genetically altered, the statement pointedly declined to rule out the possibility that the virus had escaped from the complex of laboratories in Wuhan that has been at the forefront of global research into bat-borne viruses linked to multiple epidemics over the past decade.

Canto: ‘Pointedly declining to rule out’ means very little. They’re making a point of saying it’s possible? Isn’t it more likely to have come from the ‘wet markets’ – wet with blood that is – as a result of that traditional Chinese fondness for dining and medicating on exotica?

Jacinta: ‘Murky’ is how the WaPo describes the origins. Some scientists are saying it’s highly likely to have been ‘naturally transmitted’, others, not so sure. But the thing is, the scientists are the ones to trust on this, certainly not the Chinese or US governments. And even then you need to check those scientists’ allegiances.

Canto: I should also point out, as so many scientists are doing, that now is not the time for playing the blame game. Knowledge is power, and we need to be pooling our global resources, and our knowledge, to combat this and future pandemics. We need to try and build trust, not to sow distrust. And this isn’t to say that accidents can’t and don’t happen in virology and microbiology labs around the world, including in the USA.

Jacinta: The WaPo also has much to say about renowned virologist Shi Zhengli, team leader at the Wuhan Institute of Virology, which is being targeted by the Trump administration’s propaganda campaign. According to Shi, ‘the institute never possessed the SARS-CoV-2 virus’, while Wuhan’s health commission has found, or claimed, that the first person who died of the virus purchased goods at the Huanan Seafood Wholesale Market.

Canto: So it may have come from seafood?

Jacinta: Don’t know. Probably they sold more than seafood there, or it was part of a wider market. Anyway, many virologists, including US scientists who’ve worked with her, vouch for Shi’s extreme rigour and brilliance. But clearly that won’t stop the US government’s attempt at character assassination. I’ve heard they’re trying to say, or infer, that the virus was engineered at the Wuhan lab – and no doubt millions of Yanks will believe this brilliant theory, that the virus was engineered by mad scientists and then let loose to kill thousands of their own people before being unleashed upon the world – to be followed up by Chinese chem-trails, no doubt.

Canto: And not just Yanks. Anyway let’s move on to a happier topic. Remdesivir.

Jacinta: Well the news is that the FDA in the USA has issued an Emergency Use Authorisation for remdesivir, and the Gilead company which owns this pharmaceutical, has issued a company statement (on May 5), and here’s a quote:

Gilead’s overarching goal is to make remdesivir both accessible and affordable to governments and patients around the world, where authorized by regulatory authorities…. Gilead is in discussions with some of the world’s leading chemical and pharmaceutical manufacturing companies about their ability, under voluntary licenses, to produce remdesivir for Europe, Asia and the developing world through at least 2022. 

I’ve listened to an interview with Gilead’s CEO Daniel O’Day, and he was making all the right caring-and-sharing noises…

Canto: Can we revisit what remdesivir is and does?

Jacinta: Of course. For starters it’s not a cure, it’s essentially ‘an investigational antiviral drug’ (I’m quoting again from the company statement) which, O’Day is careful to point out, ‘has not been approved by the FDA for any use’ (meaning presumably besides this emergency use). He also admits that the drug is the subject of multiple ongoing clinical trials and ‘the safety and efficacy of remdesivir for the treatment of COVID-19 are not yet established’. It’s a nucleoside analogue, one of many that have been formulated over the years, and dozens have been approved for use in treating viruses, cancers, bacterial and other pathogens. Nucleoside (and nucleotide) analogues are designed to resemble naturally occurring molecules used to build the RNA and DNA so essential to our biology. Some of the best-known nucleosides are cytidine, thymidine, uridine, guanosine, adenosine and inosine. The difference between a nucleoside and a nucleotide is that nucleosides are nucleobases linked to a sugar molecule while nucleotides are linked to phosphate groups (oxygen and phosphorus).

Canto: And the key is that in creating an analogue which functions differently from the real thing, they’re trying to obstruct the replication of the pathogen that takes up this analogue, right?

Jacinta: Yes, you’re getting it. Remdesivir actually has several modifications to the nucleoside structure while still functioning as an analogue – that’s to say it still manages to trick the virus into utilising it, and so becoming dysfunctional in terms of replication. A professor of chemistry and biochemistry, Katherine Seley-Radtke, describes the process in relatively simple terms:

Remdesivir works when the enzyme replicating the genetic material for a new generation of viruses accidentally grabs this nucleoside analogue rather than the natural molecule and incorporates it into the growing RNA strand. Doing this essentially blocks the rest of the RNA from being replicated; this in turn prevents the virus from multiplying.

She writes that remdesivir is a three-times-modified version of the adenosine molecule. Firstly, it’s a ‘prodrug’, in that it has to be modified in the body before it becomes active. The active form has three phosphate groups and is then recognised by the RNA polymerase enzyme of the virus. The second modification is a carbon-nitrogen group attached to the sugar, which is the key to terminating the RNA strand’s production. The third modification is a little change to the molecule’s chemical bond, replacing one nitrogen with a carbon, which prevents one of the enzymes of the virus from recognising and excising ‘foreign’ nucleosides. Remdesivir’s modified adenoside remains in the RNA chain, ultimately terminating further production. Got all that?

Canto: I refuse to confirm or deny. But I can read too. There’s a proper clinical trial of the drug being conducted in the USA at present, and other trials elsewhere. Preliminary results show faster recovery in a statistically significant number of patients, but it isn’t a cure, and will likely be part of a cocktail of treatments as other and hopefully even better antivirals are formulated. This follows the approach to treating other dangerous viruses such as hepatitis C and HIV. It’s about getting the death rate, and the badly-affected rate, down. This is as important as a vaccine, at present.

Jacinta: And I’ve heard it’s quite a tricky drug to manufacture, so getting supplies up and sharing expertise globally will be key factors in saving lives.

References

https://www.washingtonpost.com/national-security/chinese-lab-conducted-extensive-research-on-deadly-bat-viruses-but-there-is-no-evidence-of-accidental-release/2020/04/30/3e5d12a0-8b0d-11ea-9dfd-990f9dcc71fc_story.html

https://www.gilead.com/news-and-press/company-statements/gilead-sciences-statement-on-remdesivir-global-supply

https://theconversation.com/remdesivir-explained-what-makes-this-drug-work-against-viruses-137751

Written by stewart henderson

May 7, 2020 at 4:17 pm