Posts Tagged ‘medcram’
covid19 – the European CDC shows the way
poverty and crowding in Peru – BBC picture
Canto: The US response to the pandemic continues to be massively hampered by political muzzling of and interference with the science, especially at the federal level, but the Medcram updates continue to inform us, and to be, or pretend to be, indifferent to this political interference.
Jacinta: Yes, and update 109 has introduced us to the European CDC’s website, which provides us with a wealth of information, on the progress of the pandemic itself in European countries, but also in the political response to it, and how those two things interact.
Canto: The country overview page, and it’s currently updated to week 39 of the pandemic, is as data-rich as anyone can imagine, a statistician’s wet dream, but interpretation of the data needs to be handled carefully.
Jacinta: Dr Seheult does some interpretation of some of the data in his medcram update 109, but there’s so much more in there, and so much more to say. So let’s take a European country at random – Denmark – and look closely at the stats.
Canto: But before that, let’s look at some general European trends they report. It’s fascinating:
By the end of week 39 (27 September 2020), the 14-day case notification rate for the EU/EEA and the UK, based on data collected by ECDC from official national sources, was 113.6 (country range: 9.9–319.9) per 100 000 population. The rate has been increasing for 70 days.
So the EU is the European Union and the EEA is the European Economic Area. I’m not sure what is meant by ’14-day’ but I presume the case notification rate is simply the case rate, as far as they can ascertain from the data supplied to them – the cases they’ve been notified about. It’s good that they make that distinction, shifting the onus on the notifiers. So it’s 113.6 cases per 100,000 population over the whole region, and has been rising for over two months – a second wave.
Jacinta: I think ’14 day’ just means the rate over the previous 14 days. They report every seven days for the previous 14 days, so there’s a 7-day overlap. That data is not only dependent on the reliability of particular reporting countries, it’s also dependent on testing levels, obviously. So in the general trends they tell us which countries are doing the most testing. Highest is Denmark, followed by Luxembourg, Iceland, Malta and Cyprus. Small countries, unsurprisingly.
Canto: With all this, it’s interesting from Dr Seheult’s analysis of the data that the death rate isn’t mapping with the case rate, thankfully, and that the age of people contracting the virus in the second wave is much lower, which seems weird.
Jacinta: Probably explained by an increase in testing since the early days. Now they’re catching milder and asymptomatic cases. It suggests, of course, that the case rate was much higher during the first wave, when the testing regime was still being put together. So let’s look at Denmark, and now we have data for week 40. There are four graphs, and in the first we see the case notification rate experiencing a big bump peaking in April with the death notification rate mapping pretty closely with that bump. Then there’s a gradual falling away in both figures, until August when the case rate starts to rise again, but not the death rate. Then in September that case rate rises very sharply, rising well above the April bump, though in the last week it seems to have leveled off at this high level. But the death rate has stayed pretty well level and quite low. Now that raises questions that the other graphs might help to answer. The second graph looks at the testing rate – tests per 100,000. The testing rate was pretty flat and low from February into April, but after the April rise in cases the testing began to rise from late April into May. It flattened and even dipped a bit into June. It stayed fairly steady through the northern winter, but of course at a high level compared to the earliest period, then it started to rise in August, presumably in anticipation of a rise in cases as the colder weather arrived. That rise in testing peaked at a very high level in late September, but has dropped quite sharply in the the last week or so.
Canto: Interesting, so that does strongly suggest a sharp rise in mild cases being ‘caught’, and presumably dealt with, as the death rate hasn’t spiked at all.
Jacinta: Yes, though we don’t know how well those cases have been dealt with – people are talking about ‘long covid’, people possibly having long-term issues. The two graphs don’t really give us granular detail – hospitalisation rates for example. So the third graph breaks the notified case numbers into age groups, and the results are fascinating. The first wave bump shows that most of the cases recorded were in the older age groups, particular those at 80 or over. There were cases in all age groups, but very few under 15. However, in the second wave, the cases found were predominantly in the young. In fact the 15-24 age group was way out in front, followed by the 25-49 group. Even the under 15s were well above the oldest age groups. So what does this mean? It seems to suggest that the older, and perhaps wiser, are recognising the dangers, especially to their age group, and taking fewer risks, and that the younger are still not very sick but can be carriers of the virus and more than ever a danger to the older generation.
Canto: I wonder is Denmark ‘typical’ in this regard?
Jacinta: There are variations of course, but the general trend is much the same. The fourth graph shows test positivity – the percentage of people who tested positive. There was a massive spike in positive test results in March, up to around 16 -17%, but this dropped as sharply at it rose, due presumably to the rapid rise in testing from that period. By May it was around 1% and it has remained much the same since, as the number of tests administered has never been higher, in spite of the recent drop I mentioned. It’s still much higher than it was pre-September.
Canto: But there are more than four graphs as we’ve found. We’ve looked at the data for notification rates and testing, there are other graphs which look at ICU and hospitalisation rates, public health response measures, and which break the nation down into specific regions.
Jacinta: Yes, it’s particularly important to look at public health measures – restrictions on mass gatherings, closures or partial closures of public spaces, workplaces and schools, the mandating or recommendations around face masks, and map them against notification rates, hospitalisations and so forth. The picture that emerges is generally pretty clear, though sadly some countries, such as the USA and Brazil, aren’t paying heed to the fact that public health measures save lives as well as a lot of suffering.
Canto: Well we should be talking about the governments rather than the countries, when we’re talking about public health measures. So I’ve assumed that the CDC in the USA has been hobbled by the Trump debacle, so I’ve gone to the Johns Hopkins site to see what detailed info they provide. Indeed they do have a lot of useful data both for the USA and other countries, though little on the effect of public health measures. An interesting graph they present on mortality shows that, in terms of deaths per 100,000 persons – and they show only the top 20 nations – Peru is on top, followed by Brazil, Ecuador, Spain, Mexico, the USA and the UK, in that order.
Jacinta: Well we know about the macho governments of Brazil, the UK and the USA – not that government is always entirely to blame, but it’s a key indicator – so what about the national governments of those other countries?
Canto: Well other key indicators would be the country’s wealth, or lack thereof, and its healthcare infrastructure, but as to government, Peru had a federal election in January this year – it’s a multi-multi-multi-party system with the most popular party getting only 10% of the vote. The result was that Martin Vizcarra retained the presidency. He appears to be a genuine reformist who has tried to implement stay-at-home orders, but widespread poverty and overcrowding are major problems there. Brazil we already know about. Ecuador’s current President is Lenin Moreno, a right-wing figure who has slashed government funding and seems obsessed with destroying political opponents. He has a popularity rating of 8%, according to an article in Open Democracy, and his mishandling of the pandemic has been extreme. Spain is a ‘parliamentary monarchy’, and its current Prime Minister is Pedro Sanchez, leader of a leftist coalition. Currently there’s a battle with right-wing local authorities, especially in Madrid, to enforce lockdowns as a second wave hits the country. So it’s the usual problem there of non-compliance, it seems. And Mexico is, as is I think well known, a country with a lot of poverty and a lot of problems. Its governmental system has long been a minefield – in fact I’d love to learn more about its chequered history. Currently the President is Andrés Manuel López Obrador, a veteran politician who has been a member of various parties and is essentially a political centrist. So again it’s about lack of political control, poverty, lack of services, overcrowding and so forth. As to the UK, years of conservative government have gutted the NIH, there has been a ton of mixed messaging from the top… I’m getting sick of all this. I want to go to Taiwan.
Jacinta: Hmm. How’s your Chinese? Things are pretty covid-safe here in South Australia. Here’s hoping a safe and effective vaccine is ready by next year, and some big improvements are made in certain countries, with a return to justice and human decency…
References
Coronavirus Pandemic Update 109: New Data From Europe As COVID 19 Infections Rise
https://www.ecdc.europa.eu/en/covid-19/country-overviews
https://coronavirus.jhu.edu/us-map
https://www.bbc.com/news/world-latin-america-53150808
https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(20)31955-3/fulltext
covid19: ivermectin, the Moderna vaccine, vitamin D
Canto: So we were looking at the role of increased VWF and megakaryocytes in the blood, causing embolisms and clotting, and how to prevent or reduce such responses to the virus.
Jacinta: On the subject, Dr Seheult looks at a paper about the anti-malarial drug ivermectin and ‘CD147-mediated vascular occlusion’, CD147 being a protein attached to red blood cells (RBCs), which is apparently the entry pathway for malaria, and may also be a binding site for the S-protein of SARS-CoV2. However, binding to a CD147 protein on an RBC will not be a pathway for SARS-CoV2 as these blood cells don’t have nuclei, and so no mechanism for the virus to replicate. Still it’s possible, or likely, that this binding does take place, affecting the RBCs in such a way that they tend to aggregate. This is where ivermectin (IVM) comes in as a possible treatment:
The potential for major dose-response gains is evaluated based upon studies indicating that IVM shields SARS-CoV2 spike protein and that this spike protein binds to the CD147 transmembrane receptor, as well as to ACE2. The abundant distribution of CD147 on RBCs suggests a possible ‘catch’ and ‘clump’ framework whereby virally-mediated bindings of RBCs to other RBCs, platelets, white blood cells and capillary walls impede blood flow, which in turn may underlie key morbidities of covid19.
Now all of this is quite speculative as yet, and they quote an unpublished retrospective study with positive results from IVM treatment. Another study in Nature presents a systematic review of IVM use in covid19 and other infections – it’s apparently a medication which has ‘a good safety profile with low adverse effects when orally prescribed’. Clinical trials are necessary to appraise its use against covid19 however.
Canto: Yes they point out that in vitro studies often involve higher dosages, and so results may not be replicable in vivo, where safety requires a lower dosage range. So now to the Moderna vaccine trials. Here’s the news from a July 14 article:
Moderna’s Covid-19 vaccine led patients to produce antibodies that can neutralize the novel coronavirus that causes the disease, though it caused minor side effects in many patients, according to the first published data from an early-stage trial of the experimental shot.
The data was published in the New England Journal of Medicine, as a preliminary report. As Seheult points out, this is a new type of vaccine, an mRNA vaccine, rather than a vaccine that introduces a protein into the body to stimulate the production of antibodies. In this vaccine the mRNA harnesses the mechanisms of the cells as the virus does, to produce the proteins that produce the immune response. Me think it mazing.
Jacinta: Yes, this is reporting on dosage variation and response, and the data is pretty detailed, but the conclusions at this stage – and the vaccine is called the ‘mRNA-1273 vaccine’ – are that it ‘induced anti-SARS-CoV2 immune responses in all participants, and no trial-limiting safety concerns were identified’. So it’s steady as she goes at this stage.
Canto: Quite exciting really – until someone gets really hurt. As you say, they tried different dosages, (25, 100 and 250 micrograms) and from the graphed results it seems fairly clear that they’ll go on in the next trial using the 100 microgram dose, which balances positive effects with negative effects in the most effective way, effectively. Effects seem to have been minor even in the highest dosage.
Jacinta: And remember we’re almost two months behind the times here. Phase 3 trials were expected to begin in late July early August I think. That’s the real test, but even that won’t guarantee an entirely safe vaccine for everyone. Nothing can.
Canto: Interesting that they required the subjects to have two injections each to get the best response. And as to side-effects, there were some severe ones at the 250μg dosage but very few at 100μg.
Jacinta: There will inevitably be problems, I foresee that, and the anti-vaxxers will make a meal of any negative responses. In any case it’s unlikely that a virus will be available till next year.
Canto: So now to update 97, which starts with a revisiting of vitamin D, which it seems a lot of health experts are raving about at the moment.
Jacinta: So it’s a lipid-soluble vitamin, which means it retains its value in cooked foods, it’s stored in the liver, and when you’re exposed to ultraviolet light, it can transform cholesterol derivatives in the body to a form of this vitamin. Really sunlight exposure seems to be the best way of improving vitamin D levels.
Canto: So this update looks at a paper published in early July, called ‘Vitamin D status and risk of all-cause and cause-specific mortality in a large cohort: results from the UK Biobank’. The results are a bit technical, but over a nine-year period for this cohort of older subjects, ‘higher 25(OH)D [that’s the active type of the vitamin] concentrations are non-linearly associated with lower-risk of all-cause, CVD [cardiovascular disease] and cancer mortality’. They recommend a particular threshold level of the vitamin as ‘an intervention target to reduce the overall risk of premature death’.
Jacinta: Yes it certainly was a large cohort – over 365,000 subjects in a retrospective study. And Dr Seheult highlighted a comprehensive review article, ‘The immunological effects of vitamin D on human health and disease’, which I plan to read in full, in order to live forever, but the key element for now is the effect of vitamin D on innate immunity. It ‘exhibits direct antiviral activities against many respiratory viruses by disrupting viral envelopes and altering viability of host target cells’. Further to this it has a section on ‘endothelial fuction and vascular permeability’. It’s pretty technical but the bottom line, they reckon, is that vitamin D3 is a helluva good product, in the correct form, for stabilising the endothelium, and Dr Seheult speculates that this is why it’s associated with a lower risk of mortality in covid19. It also appears to be associated, in the 1,25(OH2)D3 form, with increased endothelial production of nitric oxide. They make these interesting concluding remarks – ‘it is evident that vitamin D and its metabolites exert pleiotropic effects on the vascular endothelium that are protective against vascular dysfunction and tissue injury as a result of local and systematic inflammation’. Pleiotropic meaning multiple effects from a single gene. Vitamin D also has an effect on adaptive immunity – the helper and memory T cells, important as we don’t know whether these will develop a memory with respect to covid19.
Canto: The question of re-infection.
Jacinta: Indeed. But the review goes on and on about the positive effects of high vitamin D levels as a risk reducing factor in a range of conditions. And it goes specifically to covid19 which is, or starts as, an acute respiratory infection. Here are some fascinating results:
A prospective cohort study in healthy adults living in New England showed a two-fold reduction in the risk of developing acute respiratory tract infection (ARI) in those with serum 25(OH)D levels of 38ng/mL (95nmol/L) or more. A case-control study in children aged less than 2 years reported that children requiring hospitalisation for ARI had significantly 1.7 times higher odds of vitamin D deficiency as compared with those with mild ARI. This indicates the protective effects of sufficient vitamin D status against respiratory viral infection.
And they go into the reasons why vitamin D might be protective, which I won’t detail here, but on covid19, they very reasonably claim that ‘one should maintain adequate vitamin D intake to achieve the desirable serum 25(OH)D level of 40-60ng/ml in order to minimise the risk and severity of covid19 infection’.
Canto: Yes I notice they’re generally emphasising that 40ng/ml lower limit, which so many people are below.
Jacinta: Yes, as they say, it’s been documented that about 60% of children and adults have circulating levels of less than 30ng/ml of 25(OH)D. So they reckon it reasonable that presenting covid19 patients will have insufficient vitamin D levels and so should be given supplementation on admission to hospital. However, overdosing on vitamin D can be an issue, so be very aware of dosage levels in consultation with your physician, if you’re self-medicating.
Canto: Which I’m not sure if you should be doing.. please take my advice…
References
Coronavirus Pandemic Update 96: RNA Vaccine; Ivermectin; von Willebrand Factor and COVID-19
Coronavirus Pandemic Update 97: Vitamin D & COVID-19 Immunity, The Endothelium, & Deficiencies
covid 19: health in Kazakhstan, megakaryocytes, the endothelial hypothesis
two megakaryocytes in the bone marrow, arrowed
Jacinta: So just to point out, from our last post, that Dr Seheult described long-term inhaled corticosteroid as sometimes having serious side-effects, such as cataracts, osteoporosis and pneumonia. He also presented contradictory rat studies on using NAC as a supplement, highlighting the need for more systematic RCTs in humans.
Canto: And what do we make of the Chinese embassy in Kazakhstan warning of a pneumonia outbreak there, which they claim is deadlier than covid19? Can we trust this?
Jacinta: Well, the Kazakhstan government has denied that the pneumonia problem was new and unknown, but it is clearly a problem, and sadly I can’t find any news about it that’s less than a month old, at about the time the news broke internationally. Some Chinese health officials are claiming that the pneumonia outbreak is related to covid19, but there’s no clear evidence about that, and this pneumonia problem in Kazakhstan is well over a year old, though it has become more of a problem with the advent of covid19. More research and information required.
Canto: Update 95 is dated July 14, and starts with conditions in Dr Seheult’s own county in California, where as we know the cases numbers have risen almost catastrophically. Some parts of the county’s hospitals have been newly transformed into ICUs. He presents a graph showing the recent increase in covid19 patients, but also a diminution in the number of suspected cases, indicating an improvement in diagnosis. And then he looks at a paper about ‘megakaryocytes and platelet fibrin thrombi [which] characterise multi-organ thrombosis at autopsy in covid19’..
Jacinta: Yes it looks at some autopsies and finds these megakaryocytes, which are precursors to platelets – they’re large as the name suggests, and they’re produced in the bone marrow, and are normally relatively rare, constituting 1 in 10,000 bone marrow cells, but can rapidly increase in response to some infections – they found these cells throughout the body. So how did they get to these multiple organs? Thrombosis was a feature of multiple organs regardless of anticoagulation treatment, suggesting that this thrombosis process started early in the infection cycle. The paper presents some fairly graphic images of large-scale thrombosis in the pulmonary artery and thickening of alveolar walls, with diffuse alveolar damage (DAD) preventing effective oxygenation, and also megakaryocytes in the kidneys. Other sites, such as the heart epicardium, feature large numbers of white blood cells and megakaryocytes. We also see ECGs apparently during myocardial infarction (heart attack) but I don’t know how to read those. The conclusion of the paper finds that the many thrombi found throughout the microvasculature of principal organs occurred in situ and before death. This was confirmed by ‘lines of Zahn’, visible layering which reveals clot formation while the blood is flowing, pumped by a beating heart. Now, this is very complex but important stuff, so I’m going to quote from the paper and try to make sense of it:
The extensive nature of platelet-fibrin thrombi in the alveolar capillaries in our patients may explain the observation that oxygenation is disrupted in an exaggerated fashion early in the disease course of patients with covid19, as this suggests evidence of ventilation-perfusion mismatch unrelated to hyaline membrane formation. Our patients’ lungs all had histopathologic findings of DAD, which has been the most frequently reported finding in covid19 autopsies thus far.
So firstly, what are hyaline membranes? They’re a composite of fibrin (an insoluble protein used in blood clotting), cellular debris, including various blood cells or parts thereof, and other eosinophilic stuff – stuff that boosts inflammation and curbs infection, or tries to. So what’s being said here is that the ‘ventilation-perfusion mismatch’, the problems with oxygenation, may be more related to the platelet-fibrin thrombi than the hyaline membrane formation, found mostly in the lungs. So now I’m going to quote something even more technical – it’s all a learning process:
Thrombi were located in veins and in the pulmonary arteries and arterioles and in microvessels, but not in systemic arteries. Despite elevated fibrin degradation products, in only one case of a patient with cirrhosis did we observe glomerular thrombotic microangiopathy, arguing against disseminated intravascular coagulation, haemolytic-uremic syndrome, or thrombotic thrombocytopenic purpura as a predominant pathophysiological pathway. Schistocytes may suggest endothelial damage, but we found them only rarely. We found no endothelial abnormalities on microscopic review, in alignment with previous studies, but we cannot rule out increased exposure of tissue factor, erosion of the endothelial glycocalyx, or other mechanisms of endothelial dysfunction that could be pro-coagulant without showing histopathological evidence of activation or erosion.
Canto: Scheisse! I can’t unpack too much of that, but I do note they ‘found no endothelial abnormalities… in alignment with previous studies’. I thought we were establishing that this is an endothelial disease, über alles? Are we being led up zie garden path?
Jacinta: Well let’s look more closely. The systemic arteries are those that carry oxygenated blood away from the heart to the other organs, and return deoxygenated blood to the heart. The pulmonary arteries, on the other hand, carry deoxygenated blood to the lungs. What this means in terms of thrombi I’m not sure. Fibrin degradation products (FDPs) (one sub-type of which are D-dimers, types of protein fragments) are produced by clot degeneration. Clotting creates a net of fibrin as part of the healing process, and after this process the net is broken down by an enzyme called plasmin, releasing protein fragments – FDPs. Now, they say that they observed ‘globular thrombotic microangiopathy’ in only one case of a patient with cirrhosis. Cirrhosis is essentially scar tissue of the liver, and it’s generally permanent – you can’t really unscar it, though you can of course prevent more damage being done. The scarring is a kind of self-repair of damage from a variety of sources – hepatitis, alcohol abuse and other liver diseases. As to glomerular thrombotic angiopathy, a glomerulus is a network of capillaries at the end of each nephron in the kidneys. Thrombotic microangiopathy is a rare but serious disease of those capillaries or microvessels, mostly in the kidney and the brain, obviously involving thrombosis.So the general lack of globular thrombotic microangiopathy – and remember they were only looking at at a handful of autopsy subjects – argued against these other pathologies as a pathway in the aetiology of covid19. But let’s look at them – disseminated intravascular coagulation (DIC) is as it sounds, blood clots forming throughout the body, often blocking small blood vessels…
Canto: But I thought that was just what was happening with covid19? That it was proving to be a a vascular, endothelial disease.
Jacinta: Yes I’m a bit confused too. I just tell myself I’m only the messenger.. So haemolytic-uremic syndrome (HUS) is a group of blood disorders in which the red blood count goes down, platelets are also very low and the kidneys are failing. Very nasty symptoms.
Canto: Right – that hasn’t been associated with covid19 before.
Jacinta: Not that I know of, FWIW. Finally, thrombotic thrombocytopenic purpura (TTP) is another blood disorder with clots forming in small blood vessels throughout the body, and a drop in red blood cells and platelets. Its weird, but perhaps what is written next about schistocytes is key here. They didn’t find many schistocytes in these bodies. These are fragments of red blood cells, broken down, jagged pieces of cells that are characteristic by-products, I think, of the the above-mentioned diseases. So that’s something that marks off covid19. So they found no evidence of endothelial dysfunction, though they couldn’t rule out such things as ‘erosion of the endothelial glycocalyx’. This glycocalyx is a mesh of bound glycoproteins and such covering the lumen side of the endothelium. Anyway, all in all this seems a blow, though maybe only a minor one, to the endothelial hypothesis.
Canto : Well, that was all very technical. Time for a rest….
References
Coronavirus Pandemic Update 94: Inhaled Steroids COVID-19 Treatment; New Pneumonia in Kazakhstan?
Coronavirus Pandemic Update 95: Widespread Clotting on Autopsy; New COVID-19 Prognostic Data
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1915585/
https://en.wikipedia.org/wiki/Schistocyte
https://en.wikipedia.org/wiki/Thrombotic_thrombocytopenic_purpura
covid19: corticosteroids, male susceptibility, evaluating health, remdesivir, coagulation factors
from The Lancet, ‘the four horsemen of a viral apocalpse’
Canto: So short-course use of some steroids was being advocated in the medcram update 88, though without thorough RCT evidence.
Jacinta: Well, data was presented from the Oxford RCT on those on oxygen or on ventilators showing a statistically significant reduction of mortality from short-course (up to 10 days) low dosage of dexamethasone, a freely-available steroid medication. The study involved some 2000 patients, but only those severely afflicted were helped by the medication.
Canto: An interesting aside to the data is that in the study males outnumbered females by almost 2 to 1, and that accords with the overall ratio of male to female covid19 patients Dr Seheult is finding, which rather shocked me. Why would more males be coming down with the disease? Presumably that’s not the infection rate, but the rate at which they need to be hospitalised.
Jacinta: Yes, you’re right, according to this Australian site (unfortunately undated):
Reports continue to emerge that men are significantly more vulnerable to COVID-19 than women. The commonly held perception that more men smoke and this makes them more susceptible along with other lifestyle factors does not tell the whole picture. White House COVID-19 Task Force director Dr Deborah Birx highlighted a “concerning trend” that men in all age brackets were becoming seriously ill from the virus at a higher rate than women, including younger males.
They’re suggesting more research needs to be done on this gender difference, for health issues in general. Some are claiming that estrogen makes a difference. In any case I think cardiovascular problems are more common in males – but maybe not so much in younger males.
Canto: So update 89 is fairly short, and deals with US data about cases and deaths, most of it out of date now, and more on corticosteroids and the dangers of unsupervised use. Update 90 introduces us to a tool I’ve never heard of called ‘Discern’. Very useful for we autodidacts in helping us, for example, to enlighten our doctors as to our condition. Discern is a tool for evaluating internet health info, such as medcram’s updates on youtube, or anything else on youtube. The instrument asks you to evaluate the material according to 16 different criteria. Interestingly, this tool has been tested on covid19 material by a study out of Poland done in March. The results weren’t so good, especially for news channels.
Jacinta: Yes, physicians’ information did best – but of course we don’t go to news channels for health information, and we’d advise against anyone else doing so. The study evaluated the Discern tool itself and found it excellent, then used the tool to evaluate health information, specifically on youtube. Of course know that there’s ‘viral misinformation’ from various news outlets that gets posted on youtube. And good to see that the medcram updates were some of the most highly rated using the Discern tool.
Canto: So we’re now into reporting from early July with update 91. It starts by looking at a ‘covid risk calculator’ in which you can type in your age, gender, BMI, underlying conditions, waist circumference, and other data which you might need a full medical checkup to find out about (and that’s overdue for me), including, for example, %FMD, a measure I’ve never heard of, but which has to do with endothelial function.
Jacinta: FMD stands for fibromuscular dysplasia. The Johns Hopkins medicine site describes it as a rare blood vessel disease in which the cells of some arteries become more stiff and fibrous and less flexible. This leads to weakness and damage. Not sure how it relates to covid19 but surely any pre-existing blood vessel damage is a danger for those contracting the virus.
Canto: Right, so it’s unlikely anyone will know offhand their percentage of FMD. I don’t even know my HDL and LDL levels, never mind my HbA1c or lipids. I’d love to be able to take measures of all these myself, without visiting a doctor.
Jacinta: Typical male control freak. So all of this is to measure your risk of covid19 hospitalisation, ICU admission or mortality. Fun times. So next the update looks at Gilead, the makers of the antiviral remdesivir, who donated all their supplies of the drug to the USA in early May. But of course they kept manufacturing the drug and have to recoup the money they spent researching, developing and trialling it etc. The Wall Street Journal reports that a typical course of the drug will cost over $3000 per patient. Interestingly the Trump administration is wanting the drug to stay in the USA as much as possible, rather than be available overseas, and is spending money to that effect.
Canto: Hmm. Is that protectionism?
Jacinta: Yes I suppose. It’s not surprising that a country wants to look after its own first, especially via a product produced within its own borders. But I suspect this government would’t be interested in helping any other country – unless there was a quid pro quo. And there’s another antiviral, favipiravir, currently being trialled in Japan and the USA (I mean as of early July), and a vaccine, developed in China, is being used on the Chinese military in what seems a rather rushed and somewhat secretive fashion – we don’t know if they got the soldiers’ permission on this seemingly untried vaccine. At least at the phase 3 level.
Canto: Very CCP.
Jacinta: So onto update 92, and we revisit the electron transport chain, with four successive electron transfers converting molecular oxygen into water. Problems within this chain can produce reactive oxygen species (ROS) such as superoxide, hydrogen peroxide and hydroxy radicals, which are destructive in excess. We also look, yet again, at covid19’s impact on angiotensin and particularly the production of superoxide, which in turn causes endothelial dysfunction, increased von Willebrand factor activity, which leads to thrombosis. People were presenting as ‘happy hypoxics’, looking and feeling fine but with very low oxygen levels, and autopsies revealed ‘microthrombi in the interalveolar septa’ of victims’ lungs. All this leading to a paper published in The Lancet which looked at factors in this process of coagulation and thrombosis:
We assessed markers of endothelial cell and platelet activation, including VWF antigen, soluble thrombomodulin [a marker of endothelial cell activation], soluble P-selectin [a marker of endothelial cell and platelet activation], and soluble CD40 ligand [a marker of platelet and T-cell activation], as well as coagulation factors, endogenous anticoagulants, and fibrinolytic enzymes.
So this was about getting to the bottom of the increased clotting. And the results were hardly surprising, but the final discussion section is worth quoting at length, as it seems to capture much that we know about covid19’s effects (at least short-term effects) at the moment:
We therefore propose that COVID-19-associated coagulopathy is an endotheliopathy that results in augmented VWF release, platelet activation, and hypercoagulability, leading to the clinical prothrombotic manifestations of COVID-19-associated coagulopathy, which can include venous, arterial, and microvascular thrombosis. The factors responsible for this endotheliopathy and platelet activation are uncertain but could include direct viral infection of endothelial cells, collateral damage to the tissue as a result of immune infiltration and activation, complement activation, or any number of inflammatory cytokines believed to play a role in COVID-19 disease.
They suggest anti-platelet therapy and endothelial cell modification treatments as well as anticoagulation treatments, and they suggest some agents ‘which might have therapeutic potential’.
Canto: Potential? You’d think they’d be onto all this by now.
Jacinta: Well there’s also potential for untried medications – at least untried in this context – to go terribly wrong. And it’s also likely that some hospitals are already onto using the safer forms of treatment. Dr Seheult speaks of the antioxidant N-acetylcysteine (NAC) in this context, as it has been shown to be a thrombolytic when used intravenously. There are studies pending on the effects of NAC in treating covid19 patients.
Canto: Now, I’ve just been watching something on monoclonal antibodies as perhaps the most promising treatment yet, short of a vaccine. Can you explain….
Jacinta: Yes I’ll try, maybe next time.
References
Coronavirus Pandemic Update 88: Dexamethasone History & Mortality Benefit Data Released From UK
Coronavirus Pandemic Update 89: COVID 19 Infections Rising in Many States; Dexamethasone Cautions
Coronavirus Pandemic Update 90: Assess The Quality of COVID-19 Info With A Validated Research Tool
Coronavirus Pandemic Update 91: Remdesivir Pricing & Disparities in Drug Availability
Coronavirus Pandemic Update 92: Blood Clots & COVID-19 – New Research & Potential Role of NAC
amhf.org.au/covid_19
https://www.thelancet.com/journals/lanhae/article/PIIS2352-3026(20)30216-7/fulltext
covid-19, more on fructose, vitamin D, treatments and the vagaries of testing
Canto: Ok, so note that in the graphic from the previous post, Australia is third highest in the group of 31 countries studied for caloric intake from sweeteners, but we don’t use HFCS much at all.
Jacinta: It might be a misleading graphic too. You might be forgiven for thinking that it somehow shows the USA as the most unhealthy, sweet-toothy country on the list, and Australia in third position, but since we’re more concerned here with links between fructose and covid-19 co-morbidities such as obesity, diabetes, cardiovascular problems and oxidative stress, the graphic doesn’t tell us much.
Canto: Yes so I found on this indexmundi site a list of 195 countries – and that’s all of them – showing prevalence of diabetes 1 and 2. That’s to say, the percentage of the adult population (from 20 to 79) that is diabetic. The USA ranks 43rd on that list, and Australia is down at 137th, level with Finland and Japan. But the site doesn’t name sources, and provides an end-note on the unreliability of much evidence: ‘National health authorities differ widely in capacity and willingness to collect or report information’. I should also add that though the USA is 43rd, the only other major nations above them are just about every Middle Eastern country, Pakistan, South Africa, Egypt, Sudan and Mexico. Make of that what you will.
Jacinta: Let’s avoid that rabbit hole, and return to medcram update 83, which briefly describes vitamin D3 (cholecalciferol) metabolism. This may involve a bit of repetition but that’s rarely a bad thing for us. So the D3 that we absorb or ingest goes to the liver and is hydroxylased at the 25th position (25-OH), but it doesn’t become activated until it’s again hydroxylased at the first position by the kidney (1,25-diOH, aka 1,25 dihydroxy vitamin D). And there’s another enzyme that can convert the vitamin to inactive forms.
Canto: With that, Dr Seheult looks at another article from 2013 which describes a rat study that indicates that if fed on a high fructose diet, lactating rats suffered reduced rates of active intestinal calcium transport and active vitamin D. Or, more, accurately I think, they didn’t get the increased rates and levels that would be expected during lactation. So, because calcium is essential for skeletal growth, the study says ‘our discovery may explain findings that excessive consumption of sweeteners compromises bone integrity in children’.
Jacinta: Interesting, and I presume that means consumption by the mother during pregnancy. Anyway, in more detail, what they found was that increased fructose intake inhibited the enzyme that converted vitamin D into the active form in the kidney, and promoted the enzyme responsible for the inactive forms. Disturbing, as Seheult says, for the excessive fructose in American diets, which may consequently affect calcium and vitamin D levels, though that would surely require more research.
Canto: Well, the same group released more research in 2014 which found that chronic high fructose intake in calcium-sufficient rodents (rats and mice) reduced their active vitamin D levels. And a 2015 study from Iran looked at something different but again having to do with effects on enzymes and metabolism. They looked at S-methyl cysteine (SMC), and this recalls the investigation of N-acetyl cysteine (NAC) a few updates ago. Found naturally in garlic and onions, SMC is described as a hydrophilic cysteine-containing compound, which they investigated for its putative effects against oxidative stress and inflammation. So they induced oxidative stress in rats via a high-fructose diet over 8 weeks and then dosed them with SMC. Results from the high fructose diet were – here goes – increased blood levels of glucose, insulin, malondialdehyde, and tumour necrosis factor-alpha.
Jacinta: Okay so the increased insulin is presumably a reaction to the increased glucose. Its role is to absorb excess blood glucose, and too much of it can result in hypoglycaemia, low serum glucose levels. Malondialdehyde (MDA) is described as a marker for oxidative stress, so it’s not good. Tumour necrosis factor (TNF or TNFα) is a ‘multifunctional cytokine’, and although cytokines (types of proteins) perform many vital functions, the cytokine storm that appears to be associated with oxidative stress and covid-19 is a bad thing.
Canto: But there were also decreased levels of glutathione (GSH), glutathione peroxidase (GPx) and catalase as a result of this fructose diet, and Seheult talked about these enzymes and such as important in reducing oxidative stress. However, the SMC dosing improved antioxidant enzyme activities and reduced levels of glucose, insulin and TNFα.
Jacinta: So this SNC seems another promising antioxidant treatment. Meanwhile, watch your sugar intake, especially with fructose. More studies required of course, but I suppose there are ethical issues involved in fattening up and inducing oxidative stress on human subjects with a high fructose diet. Okay updates 84 and 85 deal with questions that hospitalised covid-19 patients might want answered, so we’re going to skip those or we’ll never catch up on these updates. With update 86 they’re into the second half of June and noticing a resurgence of the virus. So at the Johns Hopkins site they’ve ‘working to fill the void of publicly accessible covid-19 testing data’, because without testing you obviously can’t work out the numbers.
Canto: But more than testing itself, the turnaround of results is a problem. A young woman was just on the tube saying it took three weeks to get her test results, which renders the test useless. And another person on the tube reported that she’d tested positive, felt generally okay or asymptomatic, then tested negative, after which she came down with a heavy case replete with many of the covid-19 symptoms, and then tested positive again. How can this happen?
Jacinta: It’s still a mysterious virus, but to return to the update and Johns Hopkins, they’re generally looking at US data, but I’m interested in understanding the testing process and how well it maps the prevalence of this virus. The website has a graphic which shows the fairly rapid rise in daily testing from March through to June (with a drop-off from mid-June, when perhaps they thought it was more under control), and the number of positive daily tests, which hasn’t of course risen so much, so that the percentage of positive test results has gradually fallen. The WHO recommends that the percentage of positive tests, the positive percentage rate (PPR), in nations or states where there’s widespread testing, should be under 5% for at least fourteen days before those states can start ‘relaxing’, but I’ve read different, more flexible recommendations elsewhere from health authorities, so it seems still a matter of educated guesswork with an unpredictable pandemic.
Canto: For the different US states, looking at the figures now in mid-August, the figures are weird. Washington has a PPR of 100% (?!) and are testing 1 in every 10,000, so it seems they’re only testing those they know are positive? That’s top of the list and bottom is North Carolina with a PPR of -13.1, and yes that’s a minus, and they’re testing -.09 in every thousand, and I’ve no idea what that means.
Jacinta: But most states’ figures are clear enough. New York is at 0.8% PPR with over 4 tests per 1000, which is good, but Nevada, Idaho and Florida are at over 16% PPR, each with around 1.5 tests per 1000, and that’s obviously a problem. An indication of the lack of centralised control of the situation – it’s hard to compare data from state to state. Anyway, the key, some say, is to scale the testing to the size of the epidemic in that nation/state, not to the state’s population – but how can you do that when you’re using the testing to determine the size of the epidemic?
Canto: Well presumably if nobody is reporting unusual, covid-like symptoms, as is the case here in South Australia, you don’t need to spend so much time, money and energy on testing. Not the case in the USA. Anyway, in this update, Dr Seheult noted, as we have been, that the case numbers for covid-19 are increasing, but the death rate is decreasing slightly, or at least levelling off. Possibly a result of more testing combined with better treatment. They may also be catching weaker levels of the virus due to measures put in place. But there’s no evidence as yet that the virus itself has become less potent, and this seems unlikely.
Jacinta: And speaking of treatments, the steroid dexamethasone is apparently reducing mortality by as much as 35% for covid-19 patients on ventilation, according to a WHO preliminary report of work done at Oxford. It’s only good for those with severe hypoxia and associated problems though, but its a cheap, off-patent medication which can be added to the box of tricks for ICUs, once the data is confirmed.
Canto: Okay, next time….
References
Coronavirus Pandemic Update 83: High Fructose, Vitamin D, & Oxidative Stress in COVID-19
Coronavirus Pandemic Update 86: COVID-19 Testing & Cases Increasing but Daily Deaths Decreasing
https://www.indexmundi.com/facts/indicators/SH.STA.DIAB.ZS/rankings
https://coronavirus.jhu.edu/testing
covid-19: vitamin D, fructose and oxidative stress
So looking at the Medcram coronavirus update 82, approaching mid-June, we find that many of the monitoring websites give the impression that case rates are falling in the USA and elsewhere….
The update also looks at diabetes as a risk factor for covid-19. It discusses data from China linking mortality to blood sugar levels. Glycated haemoglobin (HbA1c) was brought up in a previous post, though there are different ways of measuring it – I’ll keep to the percentages. The normal HbA1c should be below 6%, though presumably not too far below, as can happen for diabetics that over-medicate. Your HbA1c measure tells you what your blood sugar level has been over the last two-month period, approximately. So, to quote from the study:
the researchers found an increased mortality risk associated with any form of previously undiagnosed elevated blood glucose at the time of admission among 453 patients hospitalised with laboratory-confirmed SARS-CoV2 infection
One would imagine that, with the oxidative stress that SARS-CoV2 brings on, diabetics or pre-diabetics not on medication might be more at risk than those on regular medication with a consequently relatively low HbA1c. This is the kind of association found here.
The update goes on to discuss an article on race and covid-19 mortality in England, which has a supposedly open-access National Health Service (NHS), which in fact has been subject to savage cuts from successive conservative governments. The article concludes, unsurprisingly, that BAME (i.e Black, Asian and Minority Ethnic) persons are ‘at increased risk of death from covid-19 even after adjusting for geographic region’. Suggestions for reducing these apparent inequities include ensuring adequate income protection, reducing occupational risks, reducing barriers in accessing healthcare and providing culturally and linguistically appropriate services. Of course, these problems exist within all countries with substantial immigrant populations, many of whom are more exposed to the virus than others.
Vitamin D is next revisited, with an article entitled ‘Vitamin D deficiency in Europe: pandemic?’, which was actually published back in 2016. Now I note from some of the comments on this update that there’s a lot of hype and apparent misinformation on vitamin D out there, so I want to dwell on this, for my own education.
The article refers to a Vitamin D Standardisation Program (VDSP) which has developed protocols to look at serum vitamin D data from differently-aged European populations, ‘to better quantify the prevalence of vitamin D deficiency in Europe’. So they applied these protocols to 14 different population studies, looking at serum 25-hydroxyvitamin D [25(OH)D]. Vitamin D has five different types, but the pertinent one for human health is D3, aka cholecalciferol, which is made by the skin when exposed to sunlight, and is also found in foods and supplements. D3 is hydroxylated by the liver at the ’25 position’, according to Seheult. Presumably this is a position on the D3 molecule where a hydroxyl group is added. 25(OH)D refers to the molecule after this hydroxylation, but before it becomes activated by further hydroxylation at position 1 by the kidney. So they looked at this molecule in a number of studies using ‘certified liquid chromatography – tandem mass spectrometry on biobanked sera’. Combined with other standardised serum data, data was collected from almost 56,000 patients, and the findings were that 13% of them, regardless of category, had serum levels seriously below normal, especially during the winter months. 40% were below the generally accepted norm. The problem was considerably exacerbated in dark-skinned ethnic sub-groups.
Back to 2020, and an article looking at the role of vitamin D in the prevention of covid-19 infection and mortality. It noted that ‘Vitamin D levels are severely low in the aging population especially in Spain, Italy and Switzerland’, so this is obviously a covid-19 co-morbidity factor. The article goes on to describe the mechanism of vitamin D’s action in the body, the details of which I’ll pass over, but it does involve ACE-2 and angiotensin 1,7, and also many other factors including macrophage development. With all this they raise the question of widespread vitamin D supplementation, which is apparently a hot topic beyond strictly scientific media, as mega-doses of vitamin D are being argued for on certain social media platforms, and even in the comments to this update. There are messy arguments going around about safe upper limits. Dr Seheult simply reports the article’s concern about ‘popular information channels’ spruiking the use of vitamin D3 above the generally accepted safe upper limit of 4000 international units per day. There is of course a battle here, not only in relation to vitamin D3, between those who demand proper trialling and vetting of medications and supplements and those looking for quick fixes. In any case, modest, regular dosing of the vitamin seems to be most effective.
Update 83 goes intensively into a very important and interesting health topic, which has been quite controversial and also revelatory of late; the role of fructose in our diet, and how it works in our bodies. So to refresh – which is always good for me, at least – about the issue of oxidative stress and how it is exacerbated by SARS-CoV2. So we have oxidative stress in the form of an excess of superoxide and reactive oxygen species (ROS). The SARS-CoV2 virus enters the cell via the ACE2 receptor, blocking angiotensin-converting enzyme 2 (ACE2) from converting angiotensin-2 (AT-2) to angiotensin 1,7 (AT-1,7). AT-2 promotes superoxide production, while AT-1,7 inhibits it. This problem is in addition to the effect of SARS-CoV2 itself in bringing about an increase in polymorphonuclear leukocytes (PMNs), which are white blood cells such as neutrophils, basophils and eosinophils. These also lead to increased superoxide production, and more oxidative stress. An essential feature of oxidative stress is that it can result in endothelial cell dysfunction. These cells line the vascular system that feeds the body’s major organs. This dysfunction brings about an increase in von Willibrand factor which leads to clotting and thrombosis. Recent analysis of autopsies found that covid-19 patients had nine times more lung clotting than control groups including influenza patients.
So the point of all this is that not having oxidative stress in the first place will be an important prophylactic against the virus. As Dr Seheult relates from the coalface, it’s those with a high BMI, with kidney and cardiovascular issues, and with diabetes, that seem to be at most risk of succumbing to the virus. Also, those with apparently normal HbA1c but with increased glucose were about 10 times more likely to have serious complications associated with the virus. This raises the question of diet, specifically bad diet.
We then go back to 2017 and an article, or compendium of articles, published in Nutrients. Its title is ‘fructose consumption in the development of obesity and the effects of different protocols of physical exercise on the hepatic metabolism’. So fructose is a simple sugar or monosaccharide which combines with glucose to form the disaccharide sucrose. There are two forms of fructose (and of glucose), which are enantiomers, which is to say they have opposite chirality, which gives them different reactive properties. They’e called D-fructose and L-fructose. They’re six-carbon sugars, and D-fructose is the prominent form in the body. Sucrose links together a molecule of glucose with one of fructose, so that sucrose (table sugar) is essentially 50% fructose. Fructose is added to many foods as a sweetener, particularly in the form of high fructose corn syrup (HFCS) and this has become controversial, in case you didn’t know. It’s not such as issue in Australia, where we mostly use cane sugar as a sweetener, but it features in imported processed foods, and in many sweetened drinks. So how does fructose impact on obesity and oxidative stress? To quote from the abstract of the above-named article, ‘studies indicate that fructose may be a carbohydrate with greater obesogenic potential than other sugars’. The article provides a compendium of such studies and how fructose affects glucose metabolism in the liver, adversely affects hepatocyte function and engenders inflammatory responses. It also advocates physical exercise for reduction of symptoms and as harm-minimisation practice. An experiment on rodents in which half were fed on fructose, the other half on sucrose (50% fructose, 50% glucose), the fructose-fed rodents gained more weight, and over time that extra weight involved an increase in abdominal adipose tissue and increased serum triglyceride levels:
Moreover, several studies corroborated the evidence that high fructose consumption might lead to accumulation of adipose tissue, systematic inflammation, obesity, oxidative stress and consequently insulin resistance in different tissues.
And there’s much more on the same lines, with relevant references. Dr Seheult describes other articles and studies over the last ten years identifying fructose and HFCS and their relationship to type 2 diabetes prevalence. One interesting article, which looked at HFCS alone, and surveyed diabetes on a global level, found that ‘diabetes prevalence was 20% higher in countries with higher availability of HFCS compared to countries with low availability’ and these results were adjusted for BMI, population, GDP and other factors. Greatest use of HFCS was in the USA, which of course has the highest rate of diabetes, and is leading the world in covid-19 cases.
References
Coronavirus Pandemic Update 82: Racial Disparities with COVID-19 & Vitamin D
Coronavirus Pandemic Update 83: High Fructose, Vitamin D, & Oxidative Stress in COVID-19
https://www.sciencedirect.com/science/article/pii/S0899900714001920