Posts Tagged ‘health’
what is this thing called lymph? some more…
Canto: So we learned a lot about lymph recently, but strangely enough, it made us hungry for more. So, it has two functions, circulatory and immunological. I’d like get more detail on both those functions, and in particular I’d like to know more about lymphocytes, what they are, how they’re made and what they do.
Jacinta: Sounds like a plan. So first, lymph in the circulatory system. Here’s what I’ve gleaned from an online video. This system brings oxygen and nutrients to all our bodily tissues, as well as removing waste materials. Ultimately this feeding and removal process occurs in the smallest vessels, the capillaries, which penetrate into tissues and organs. Nutrient-rich blood plasma moves out of capillaries ‘at the arterial end of capillary beds, while tissue fluid containing wastes reabsorbs back in at the venous end’.
Canto: Okay, whoa. First, I have difficulty separating left from right, and east from west, what they call directional dyslexia. I also, in a probably related way, have problems with arteries and veins. One goes into the heart, the other goes out….
Jacinta: Haha, think arteries away (AA), and that’s all you need to know. I have the same problem, quelle surprise!
Canto: So I get that nutrient-rich ‘blood plasma’, presumably some kind of mixture of blood and plasma, moves out of arterial capillaries into tissues, to feed and energise and rejuvenate them and such, but I’ve never heard of capillary beds, and ’tissue fluid’ sounds a bit questionable…
Jacinta: These are all good issues to raise. Apparently there’s a whole capillary bed network. So, getting back to basics, our cardiovascular system is this super-complex network of veins, arteries and capillaries that move oxygen, nutrients, hormones and waste materials to and from our tissues and organs. It’s often analogised as something like a city road network, highways with off-ramps leading to main roads, side-roads and such. And capillary beds are the network of smaller vessels leading into and out of particular tissues. Anyway here’s a useful definition from a medical website:
Capillaries do not function independently. The capillary bed is an interwoven network of capillaries that supplies an organ. The more metabolically active the cells, the more capillaries required to supply nutrients and carry away waste products. A capillary bed can consist of two types of vessels: true capillaries, which branch mainly from arterioles and provide exchange between cells and the circulation, and vascular shunts, short vessels that directly connect arterioles and venules at opposite ends of the bed, allowing for bypass.
If all of the precapillary sphincters in a capillary bed are closed, blood will flow from the metarteriole directly into a thoroughfare channel and then into the venous circulation, bypassing the capillary bed entirely. This creates what is known as a vascular shunt.
And, since I know you’re wondering:
A metarteriole is a short microvessel in the microcirculation that links arterioles and capillaries. Instead of a continuous tunica media, they have individual smooth muscle cells placed a short distance apart, each forming a precapillary sphincter that encircles the entrance to that capillary bed.
And as for tunica media, I won’t quote, I’ll put it in my own words. Arteries and veins have three-layered linings called tunicae. The tunica media, as the name suggests, is the middle layer between the inner tunica intima and the outer tunica externa. The make-up and structure of this layer (and the others) varies in relation to the size of the artery. For example, there’s a lot more tissue in the layers of the aorta, the body’s largest artery.
Canto: Great, and yes, intrinsically interesting, but let’s return to lymph. So the lymphatic system is a ‘cleaning up’ and drainage system among other things. There are some 700 lymph nodes throughout the body – armpits, groin, throat, and in the intestines where they’re involved in the absorption of fat. A node in this context is a bean-like structure which filters the lymph passing through it. It contains lots of lymphocytes for combating/consuming pathogens. If the system fails to function properly, oedema or lymphoedema results (a swelling or puffiness). As well as these numerous tiny nodes, there’s the spleen, a multifunctional lymphatic organ located on the left side of our bodies next to the stomach. It produces a range of cells including many types of white blood cells such as murderous macrophages and of course lymphocytes. The spleen is divided into a ‘red pulp’ and a smaller ‘white pulp’ section, and I could go into greater detail about T cell zones and B cell zones and the various functions of these cells and their subdivisions.
Jacinta: Yes I think we have a general sense in that the lymphatic system of nodes and spleen improves circulation through removal and replacement, and immunity through renewal of ageing cells and production of lymphocytes and other antibody-type cells. All of this started with our attempt to get a handle on CFS or ME/CFS or CFIDS and its relation to the immune system. It’s been an interesting little journey into an unknown land for us, and my impression is that there’s still a lot to be learned even by researchers steeped in lymph, so to speak.
Canto: Yes, and it’s given us some little background into immunology and the amazing complexity of the animal body…
References
https://www.betterhealth.vic.gov.au/health/conditionsandtreatments/lymphatic-system
https://en.wikipedia.org/wiki/Lymphatic_system
https://en.wikipedia.org/wiki/Metarteriole
exploring chronic fatigue syndrome, myalgic encephalomyelitis, etc
Canto: What do you know about chronic fatigue syndrome (CFS)?
Jacinta: Not much. I read somewhere recently that it’s a term not so much used now. Maybe because the term ‘syndrome’, I think, is a kind of ‘placeholder’, like a collection of symptoms – adding up to a regular feeling of fatigue for no clear reason, or without an established cause, or set of causes. And now maybe they’ve established some causes, and the ‘syndrome’ has been divided up into a few more clearly understood disorders.
Canto: Well, that may be so, but I know that, some twenty years ago or so, there seemed to be a spate of people coming down with what they called CFS – sports people, entertainers, people in the limelight for one reason or another – but I don’t hear so much about it now. So I’m wondering – can a person have this syndrome, or one of its instantiations, on and off for, say, 27 years?
Jacinta: I’ve no idea? Why do you ask?
Canto: Well, I know of someone who still attributes her aches and pains – at least some of them – to chronic fatigue, some twenty-odd years after getting that diagnosis, and it bothers me… I know that there’s an issue out there about women’s health, and women not being believed, particularly by male doctors, and I’m male…
Jacinta: Well recently what they call ‘long Covid’ has cropped up, and it seems to be similar. I know from experience that you can have a serious illness, I mean an infection, one that really puts you on your back and takes a long time to recover from, and it really changes your life in a ‘before and after’ sense. That’s to say, after that illness you never feel quite the same again, as if your immune system has been permanently compromised, damaged in some way. That seems to be happening with long Covid, and maybe it’s an issue for CFS. Maybe CFS starts with an infection that more or less compromises the immune system. Of course I’m no expert on matters medical…
Canto: So some research is required. As I recall, another name for CFS is myalgic encephalomyelitis (ME), which at least sounds like a right proper disease, one to scare the bejazus out of people – especially the ‘encephalo’ part. Clearly it eats your brain.
Jacinta: The ‘myalgic’ term has to do with muscles, tendons, ligaments and stuff. And muscle etc pain, or myalgia, can have an astronomical number of causes. The ‘encephalomyelitis’ term can be broken into two parts. The ‘myelitis’ part refers to myelin, the white-coloured material that sheaths our neural circuitry. ‘Encephalo’, as you say, refers to the brain in general. Encephalomyelitis is defined as ‘inflammation of the brain and spinal cord’, of which there are many types. For instance, Encephalomyelitis disseminata is another name for multiple sclerosis. So ME, if this is just another name for CFS, involves the muscles and associated tissue, and the nerves leading to and from them.
Canto: Okay, that’s all useful, but I’m just wondering whether, if you come down with CFS, or ME, it might be with you, like, forever.
Jacinta: It’s interesting that ME suggests there is evidence of damage to myelin in this condition. That needs to be explored further. I’ve accessed a book published in 1990 called The disease of a thousand names, by Dr David Bell, a pioneer in exploring this syndrome. The name he gives to it is Chronic Fatigue/Immune Dysfunction Syndrome (CFIDS), and on the cover he gives no less than 37 alternative names, some of them, such as Yuppie Flu and Yuppy plague, less serious, or more dismissive, than others. In the foreword he presents the hope that the book will be a starting point for further study, and makes his view of the disease/syndrome/condition clear:
I freely admit to bias in writing this book. I fully believe that CFIDS is a specific, organic illness, caused by a specific agent or agents. I make no claims to be impartial in the argument of whether the illness is real or not. It is interesting that of those researchers directly involved in epidemics of CFIDS, there is no discussion of this question. Personal experience has made the issue irrelevant and even insulting.
Canto: So that’s over 30 years ago, and now I’m watching a disturbing DW documentary from just under a year ago, telling the story of three German sufferers from this condition – and they’re suffering very badly, without a doubt. It also focuses on the doctors, neurologists and researchers trying to get a handle on it. One of them, Dr Carmen Scheibenbogen, an immunologist and oncologist, points out that still, after 30 years, we’ve made little progress, and that very few scientists are working on the disease (which for convenience, let’s call CFS), especially compared to the number of sufferers. They estimate that 17 to 24 million people have it worldwide, with women outnumbering men. They also estimate that only half of sufferers have been diagnosed – but whether that means they think the number may be as much as 50 million or that only 8 to 12 million have been diagnosed isn’t made clear.
Jacinta: Well Dr Bell’s intro ends optimistically:
It is my hope that by the time this book is published, much of the speculation presented here will have been confirmed. If so, the absurd argument of whether this illness is ‘real’ will have ended, an unnecessary argument that has caused so much pain and added so greatly to the burden of those ill with chronic fatigue/immune dysfunction syndrome.
I’d guess he’d be sadly disappointed if he’s still around today. As he notes in the first chapter, the number of names given to the illness is a testament to ignorance more than anything else. And the term CFS arguably downplays the seriousness and debilitating nature of the symptoms, and suggests nothing about damage to the immune system, for example.
Canto: Hearing the stories of the sufferers, and watching them actually and obviously suffering, is itself painful. They seem in a sense like the disappeared. Their illness causes them to disappear from the workplace, from civic or social activity, from any circle wider than immediate family. And all of them seem lost in the mystery of their condition. The term ME is suggestive of inflammation, but often there’s no detectable inflammation. The symptom most common to all sufferers according to Dr Scheibenbogen is a very low tolerance of exertion.
Jacinta: I note that Dr Bell writes of the difficulty of defining a precise set of symptoms, which ‘has surrounded the illness for the past 20 years’, which dates the illness back to 1970 or before. He mentions recent recognition by the CDC, as ‘an illness characterised by months or years of severe pain and exhaustion nearly everywhere’. He also expresses his view, and hope, that ‘it is most likely caused by a single specific agent’. From my laywoman’s perspective, I’m very doubtful about that.
Canto: One of the subjects in the documentary, a teenager, contracted mononucleosis two years before, and hasn’t been the same since. Mononucleosis, often called the kissing disease, is carried by the Epstein-Barr virus (EBV), and so no doubt this virus and/or its relatives have been focused on as possible sources of the illness. Listening to her describing the problem as like a faulty battery which doesn’t recharge properly suddenly made me think of a far more horrific illness, encephalitis lethargica, which killed hundreds of thousands of Europeans from when it first appeared there in 1916. In their case, the battery often ceased to function, leaving them in a state something like total paralysis – but with some mental processes intact. In her book of the epidemic, Asleep, Molly Caldwell Crosby describes a very young woman struck down by the disease, visited by a physician, who rather unprofessionally told her family at the bedside that there was no hope. Her eyes welled with tears. She died shortly afterwards. The image it brings to life still haunts me. No cure or cause of the disease has ever been found.
Jacinta: So, as we explore this current ‘disease of a thousand names’ it does certainly seem that some manifestations can be lifelong. However, because they tend not to be life-threatening, and because causes can’t be found via biopsies, blood tests and the like, it’s generally seen as a ‘diagnosis by exclusion’. And of course it’s likely believed to be psychosomatic by many more than care to admit…
Canto: And yet the WHO recognised it as a neurological disease back in 1969. Perhaps that designation doesn’t help, because it’s often seen as a ‘mind’ disease, something like depression. But getting back to mononucleosis, which has been seen as a stepping-stone or trigger in some cases, it does seem likely that CFS starts with infection, particularly viral infection (SARS, enteroviruses), though again, not in all cases. It does seem to be a case of excessive immune reaction, which can perhaps also be triggered by injury or surgery. EBV is very common – more than 90% of humans catch it, usually in childhood, when it’s more often than not asymptomatic. But in can re-appear as mononucleosis later, usually in early adult life, according to the documentary, though it’s not clear whether that means reinfection, or a virus that lies dormant for a period. In any case, the symptoms are swollen lymph nodes, fatigue, sore throat and a high temperature.
Jacinta: I’ve heard of it, but I thought it was some exotic virus, nothing that I’d ever catch. Sounds like I’ve already been infected…
Canto: Perhaps, but not reinfected – and there can be much more serious, even life-threatening complications, such as spleen damage, low blood cell count and respiratory disease. And CFS.
Jacinta: Well it seems to me that the great mystery of encephalitis lethargica is an object lesson as to how little we know about the ailments and infections our bodies are prey to. It seems that they’re prone to over-reaction, as is the case with allergies, and the ‘cytokine storm’ in Covid-19. But the problem with CFS is that, quite often, no previous infection can be pinpointed.
Canto: Well, this may tell us something new about viruses, and about the immune system, as, to some extent, Covid-19 has. Mononucleosis, for example, is generally seen as a mild illness, but not always, and in some cases it can be life-threatening, or it can somehow stuff up the immune system, leaving sufferers prey to a range of ailments. Some of these are clearly described from symptoms rather than causative agents – for example post-exertional malaise (PEM). Without a clearly defined cause, one can only treat symptoms. And because the symptoms are mostly not life-threatening in any obvious way, it can easily be seen as ‘psychosomatic’, and it doesn’t attract funding. And even with encephalitis lethargica, a killing disease, no causative agent has been found. We just hope it has permanently disappeared, which isn’t very satisfactory. Also, with CFS there are generally no visible symptoms, so physicians must rely on reported symptoms, which actually takes the power out of the hands of the ‘expert’. So, the condition has this difficult status – difficult to attract funding, and virtually impossible to insure against.
Jacinta: Yes, so the hunt is really on for causal factors. It seems to be all about the immune system being ‘overactive and/or misdirected’ as Dr Scheibenbogen puts it. The argument some are putting forward is that it interferes with the autonomic nervous system, taking over much of its function. The autonomic nervous system controls our breathing, our heartbeat, our digestion, and our blood flow. Without effective blood flow, there will be muscle problems, dizziness, poor concentration and general feelings of weakness. Oxygenating the blood helps to energise our whole system. Key to all this is our beta 2 receptors. Here’s something about them from a NIH article:
Beta 2 receptors are predominantly present in airway smooth muscles. They also exist on cardiac muscles, uterine muscles, alveolar type II cells, mast cells, mucous glands, epithelial cells, vascular endothelium, eosinophils, lymphocytes, and skeletal muscles.
Canto: So, beta 2 receptors, something to be researched and kept in mind. The documentary presents a CFS sufferer whose autoimmune neurotransmitters are considerably elevated – whatever that means. They’re also described as ‘antibodies’. Dr Scheibenbogen suggests that CFS is disrupting their functionality. Muscles are not being properly supplied with blood, leading to pain and exhaustion. And all this has something to do with a dysfunctional immune system, and a possible problem with the normal dilation of the blood vessels, which carry oxygen to all the body’s muscles and organs. Which takes us back to the beta 2 receptors, located on the blood vessels in muscles. They’re controlled by adrenalin, released during exertion, and antibodies. These antibodies have been found to be dysfunctional in CFS sufferers, resulting in problems with oxygen supply. Dr Scheibenbogen describes one patient’s results:
We know the patient has antibodies against the beta 2 receptor. What we want to know is, which part of the receptor. We’ve divided up the beta 2 receptor into 15 small pieces and stuck each piece onto a different little bead. They glow in slightly different colours, and then we can see…We can compare these reactions to those of healthy subjects. This will help us understand the disruptive receptor pattern better. If there are distinct differences, a clear pattern, we could use this as a diagnostic test.
Samples from different patients are sent to the Julius Maximilians University in Wurzburg, where a team led by Dr Bhupesh Prusty, a microbiologist and virologist, are trying to find infectious agents that might be responsible for or contributory to the disease. Dr Prusty has been studying the role of viruses for many years and was the first to discover the link between EBV and CFS. Here’s what he had to say:
‘What we have found is that herpes viruses, particularly human herpes virus type 6 (HHV6), and Epstein-Barr virus, are the most interesting candidates which can contribute to the development of the disease. We have found that HHV6 produces a small RNA, and that this small RNA can directly target mitochondria to fragment, and it’s already known that in EBV infection mitochondria is also fragmented, so we believe that this virus-induced mitochondrial fragmentation is one of the most important steps in the development of CFS’.
So the documentary turns to mitochondria, the energy organelles in all our somatic cells.
Jacinta: So we turn to ATP and all that. Fragmented mitochondria aren’t going to bode well for our energy levels.
Canto: Dr Prusty’s team have injected antibodies from the blood of CFS patients into healthy cell cultures to see if a factor in the serum of those patients affects the healthy mitochondria. The experiment resulted in mitochondrial fragmentation, which would result in a weakened immune response in the event of future infections, and a generally slower metabolism. Tests of this kind could be used in the diagnosis of CFS – an enormous advance (I’m quoting or paraphrasing the documentary of course). Dr Prusty says the test works for seriously ill CFS patients, but much less so for milder cases. So it would be diagnostic in some cases and it also points towards something causal, though the precise mechanisms would have to be worked out. And there are funding problems hampering further research.
Jacinta: Dr Bell was writing about the lack of funding in his 1990 book, so nothing has changed. And as with the documentary, case histories are presented, of people cut down by this illness, unable to work, unable to obtain insurance or compensation, unable to find solutions, and suspicious or aware that health authorities, family members and others feel that they’re exaggerating or malingering. Often diagnoses cite depression, and of course depression does set in after a long period of incapacity.
Canto: The doco presents a graph that is, well, graphic, in comparing USA funding for multiple sclerosis and HIV compared to CFS (HIV outscores both of the others by a vast amount). Grassroots funding groups are struggling to make a difference, to amplify the issue and combat stigmatisation. Pharmaceutical companies have shown no interest, no doubt because the symptoms seem vague and lacking in ‘acuteness’, and there are no biological markers to provide focus for a cure or a clear form of relief. Meanwhile, the sufferers themselves feel a sense of being useless or having ‘disappeared’ from active social life. A possible drug for treating CFS, Rituximab, was recently trialed in Norway, based on the hypothesis that it is an auto-immune disease, ‘with a role for auto-antibodies and B-lymphocytes’, according to Dr Oystein Fluge, who led the trial. The documentary explains:
B cells are important immune cells in our body that produce antibodies that destroy viruses and bacteria. Unfortunately this process sometimes goes awry, and the B cells produce antibodies that don’t work properly, or actually attack the body itself. This occurs in many auto-immune diseases, like lupus or myasthenia gravis [a chronic autoimmune, neuromuscular disease that causes weakness in the skeletal muscles]. Scientists believe that ME/CFS is one such auto-immune disease. Rituximab is a medication which temporarily destroys B cells, preventing them from producing antibodies to attack a person’s own body.
Three small trials showed considerable promise, so a ‘phase 3’ randomised, double blind trial, involving 152 patients, was next conducted. One of the major hopes was that a diagnosis could be made based on defective antibodies, and ‘whether a marker could be found in the blood that could simplify the diagnosis’. Could they have been previously infected with EBV? There is apparently a diagnostic test for this, and this has been found in some CFS sufferers, but more proof, through larger-scale testing, is needed. Meanwhile, the SARS-Cov-2 pandemic has left many people with CFS-like symptoms, and while this is in one sense disastrous, it could be a wake-up call for trying to better understand auto-immune diseases – of which CFS is likely one. So far, we have associations rather than proven causes, but the association of a CFS-like illness such as ‘long Covid’ with a disease that clearly plays havoc with our immune system is, to say the least, extremely suggestive. As one researcher points out, being able to establish a cause will encourage people to seek treatment earlier, reducing the damage that time brings about.
Jacinta: Yes, people suffering from ‘long covid’, as it’s called, are of course making the connection with CFS and highlighting the lack of progress re this presumably auto-immune disease.
Canto: Yes, Dr Scheibenbogen is concerned that an after-effect of the pandemic will be a spike in long-term CFS sufferers, which we may already be seeing. The silver lining, though, may be an increased focus on, and increased funding for, solving its current mysteries. Dr Prusty is still of the view that latent herpes viruses are reactivated after covid and perhaps other autoimmune infections. It just isn’t known whether long covid and CFS are essentially the same condition. Meanwhile as Dr Uta Behrends, another frontline researcher in CFS, points out, sufferers need to have a diagnosis made as soon as possible so that they can be supported, so that they don’t feel isolated and become depressed, as so often happens.
Jacinta: Supported, but how can they be treated, when there’s no clear cause?
Canto: Indeed. The Norway trial returned a negative result. This may have been because the Rituximab dosage was low due to lack of funding. Still, the researchers have collected a sizeable bank of blood samples to test with other drugs or enhanced versions of Rituximab. There is also a problem with correct diagnosis of CFS, and perhaps a reluctance to diagnose such a condition in the absence of clear biomarkers. Meanwhile the suffering continues, and an untold number of people remain in limbo…
References
Dr David Bell, The disease of a thousand names, 1991
https://www.ncbi.nlm.nih.gov/books/NBK559069/
https://www.ninds.nih.gov/health-information/disorders/myasthenia-gravis
catching up on SARS-CoV-2
Canto: So, having largely ignored COVID-19 in the last few months, since having my fourth vaccine, which came before or after having tested positive (a RAT test) for the virus, with minimal symptoms – and I suppose it may have been a false positive – I hear that it’s still causing serious problems two years on. And I’m still encountering people who make light of the virus, and are ‘on the fence’ about ‘the whole vaccine thing’, so I think we should explore the situation anew – variants, comorbidities, actions to be taken, long covid etc etc.
Jacinta: Okay, another interminable conversation perhaps. Where do we start? According to a graph (see below) on the situation in South Australia, case numbers have spiked a few times in the last year, but the graphic gives no indication of severity of symptoms. The reporting on new cases seems to be more sporadic at the moment, which explains the gap between the lines, which are getting disturbingly longer. We’ve noticed of course, that mask-wearing and other precaution-taking has slackened off during the year, and government-enforced mandates were lifted months ago….
Canto: And few people seem to be concerned about crowded settings any more… The ABC has a state-by state report, referenced below, which gives weekly stats. It shows that in every single state and territory the case numbers for the last week were higher than those of the week before. Their site presents a rather alarming graphic of case numbers over the last four months, which speaks for itself:
Jacinta: And yet, as you say, covid fatigue, or rather covid restrictions fatigue, has set in, and governments are no doubt reluctant to get tough again, unless things get even worse. What I’m hearing, from people much younger than me, is that it’s no big deal for the young and healthy, only elderly people or those with comorbidities need to worry – and of course it’s all a bit overblown. I hesitate to ask if they’ve been fully vaxed – they’ve obviously never heard of Typhoid Mary.
Canto: And that was 100 years ago – the germ theory of disease wasn’t fully accepted then, but now information is easily available.
Jacinta: And so is misinformation. Anyway, the ‘fourth wave’ is now underway, according to the media. According to Dr Nancy Baxter in an ABC interview, our vaccine immunity has declined over time and most covid restrictions are gone, so numbers are increasing again, and hospitalisations are rising.
Canto: My sympathies go to all the medicos, nurses and other such workers out there. What about death rates – and what about variants, where are we with those?
Jacinta: So just over a month ago the federal government’s Chief Medical Officer made this public statement:
We are seeing an increase in COVID-19 case numbers in Australia, reflecting community transmission of the Omicron variant XBB. We are also closely monitoring the overseas transmission of a second Omicron variant – BQ.1. While evidence is still emerging, the experience to date with these two variants overseas is that they do not appear to pose a greater risk of severe illness and death – and that the COVID-19 vaccines provide good protection against these outcomes. All indications are that this is the start of a new COVID-19 wave in Australia. This was to be expected and will be part of living with COVID-19 into the future. The overseas experience is that these new variants have driven increases in case numbers – and hospitalisations at a rate proportionate to these increases – because of their ability to evade the immunity provided by prior infection and vaccination.
So, not more deadly, but each new variant that comes to our attention does so because it has varied sufficiently to evade the immunity provided by previous infections and the vaccines created to target those earlier forms of the virus. So this could be an ongoing problem, as the CMO says.
Canto: So doesn’t this remind you of the antibiotics dilemma? Rapid reproduction means rapid variation, and we can’t keep up, with antibiotics or vaccines. We’re all doomed!
Jacinta: Well, the panic seems to be over – though panic is the wrong word, to be sure – but case numbers continue to be high, though they appear to go in waves, as every new more successful variant comes along. And death rates, which of course lag case rates and are complicated by comorbidity and age factors, are still higher than we’d like them to be. It’s a weird situation we’re in now, with so many people being in denial or just switched off, perhaps because they’ve made it okay thus far. But of course we’re not doomed – we just need to keep informed about our local area, keep up the vaccines as required, and take precautions as necessary. Remember it’s a largely airborne virus, and it loves crowds of people in enclosed spaces.
Canto: Well we might be keeping up with the vaccines, but are the vaccines keeping up with the variants?
Jacinta: Well this week the CDC in the USA came out with an advisory about updated (bivalent) boosters for adults and children – though the adult one came out on September 2, so not so recent…
Canto: What’s a bivalent booster?
Jacinta: That’s a vaccine that confers immunity to two antigens, such as two versions of a virus, as is presumably the case here. So they’re able to tweak vaccines to cover new variants, methinks. Seems to be a bit of a race between antigens and prophylactics. As to keeping up, an article from the Nature website (referenced below) provides reassurance:
Booster shots against current SARS-CoV-2 variants can help the human immune system to fight variants that don’t exist yet. That’s the implication of two new studies analysing how a booster shot or breakthrough infection affects antibody-producing cells: some of these cells evolve over time to exclusively create new antibodies that target new strains, whereas others produce antibodies against both new and old strains.
Canto: So the message clearly seems to be to keep up the boosters, which I strongly suspect young healthy people aren’t doing, so they’re playing dice with their own health as well as threatening the health of others inadvertently, as more of less healthy carriers of the virus.
Jacinta: Yes, it’s really a difficult message to get through to the young, especially if they’re not in contact with serious sufferers or the mortality of loved ones.
Canto: Okay, so it’s an ongoing drama at present. I’m hoping that we can look at the long covid issue sometime soon, another complex problem, due to symptom variety, skepticism, and the whole issue of treatment.
Jacinta: Yes – whether the pandemic is over or not is a live issue. Sometimes I get the impression that it’s over just because people want it to be over. They want to return to ‘normality’ whatever the consequences. The virus may teach us otherwise. We need to keep an eye on it.
References
https://www.health.gov.au/news/new-covid-19-variant-leads-to-increase-in-cases
https://www.cdc.gov/coronavirus/2019-ncov/vaccines/stay-up-to-date.html
https://www.cancer.gov/publications/dictionaries/cancer-terms/def/bivalent-vaccine
How Australia is faring on global indices
park yourself here?
Many Australians were greatly relieved at the change of Federal government from May 21 2022. Australia hadn’t been faring well on the international stage, especially with respect to the global warming crisis, but also regarding political governance and other issues. Of course the Labor government has only been in office for three months, so I don’t expect judgements to have turned around significantly at this point. The purpose of this piece is to describe Australia’s position on a number of international surveys, and then to return to those surveys in about twelve months’ time to see if and how the view of Australia internationally has changed.
I was motivated to write this by a passage in David Brophy’s book China Panic, in which he mentioned two such international surveys, the CIVICUS monitor, which apparently measures democratic credentials, and Transparency International’s Corruption Perception Index. I’d never heard of these surveys, which is hardly surprising for a dilettantish autodidact. Three surveys I have monitored are the Economist Intelligence Unit’s Democracy Index, the OECD’s Better Life Index and the UN’s Human Development Index. So now we have five, and counting. What follows is my attempt to summarise their most current findings.
The CIVICUS monitor. CIVICUS is, as far as I can tell, not an acronym. Based in Johannesburg, the organisation describes itself as:
a global alliance of civil society organisations and activists dedicated to strengthening citizen action and civil society throughout the world…. Our definition of civil society is broad and covers non-governmental organisations, activists, civil society coalitions and networks, protest and social movements, voluntary bodies, campaigning organisations, charities, faith-based groups, trade unions and philanthropic foundations. Our membership is diverse, spanning a wide range of issues, sizes and organisation types.
According to Brophy, the CIVICUS monitor downgraded Australia’a democratic status (in the broad sense described above) from ‘open’ to ‘narrowed’ in 2019. The latest findings, from 2021, are unchanged. To explain, the monitor divides the world’s nations into 5 levels, which, top to bottom, are open, narrowed, obstructed, repressed and closed. On further inspection, I’ve found that there’s a ‘live rating’, last updated for Australia on 25/5/22, a few days after the election. Hopefully things will have improved by 2023. To compare a few other countries – New Zealand, Canada, Ireland, Uruguay, Suriname, Taiwan, Portugal and most Northern European countries are classed as ‘open’. Other ‘narrowed’ countries include Namibia, Italy, France, the UK, Japan and Bulgaria. Obstructed countries include the USA, Brazil, South Africa, Ukraine, Poland, Indonesia and Morocco. A colour-coded map provides an at-a-glance reference to any country of interest. The repressed and closed countries can generally be guessed at. China, Vietnam and most Middle Eastern counties are classed as ‘closed’.
The Corruption Perceptions Index (CPI). The CPI is a product of Transparency International, which advertises itself thus:
Transparency International is a global movement working in over 100 countries to end the injustice of corruption. We focus on issues with the greatest impact on people’s lives and hold the powerful to account for the common good. Through our advocacy, campaigning and research, we work to expose the systems and networks that enable corruption to thrive, demanding greater transparency and integrity in all areas of public life.
First set up in 1993 by an ex-World Bank official, Peter Eigen and like-minded associates, first-hand witnesses of global corruption, the organisation was established in then recently re-unified Berlin.
An article in The Conversation, posted in late January 2022, points out that in 2012 Australia ranked level with Norway in 7th position as to ‘cleanness’. The 2021 index, to which The Conversation refers, sees Australia as having slipped to 18th while Norway has risen to 4th, out of 180 countries. Much of what Brophy writes in China Panic is an account of why the country I happen to have ended up in has fallen so far so fast. The Economist Intelligence Unit, which publishes the Democracy Index, is one of the sources for this index, along with Freedom House and the World Justice Project. The three equal top countries on this index are New Zealand, Denmark and Finland, and the bottom three are Somalia, Syria and South Sudan. Anyway, re Australia, this one will be worth watching over the next few years.
The Democracy Index. I’ve written about the Democracy Index, inter alia, in a previous piece. It’s produced by the Economist Intelligence Unit, associated with The Economist magazine in the UK. Here’s their raison d’être blurb:
The EIU Democracy Index provides a snapshot of the state of world democracy for 165 independent states and two territories. The Democracy Index is based on five categories: electoral process and pluralism, civil liberties, the functioning of government, political participation, and political culture. Based on their scores on 60 indicators within these categories, each country is then itself classified as one of four types of regime: full democracy, flawed democracy, hybrid regime or authoritarian regime
Australia ranks a fairly creditable 9th on the Democracy Index list for 2021, well below NewZealand (2nd) but also well above the country we’ve been showing so much allegiance to in recent decades, the USA, which ranks 26th and is considered a flawed democracy. According to the index’s ratings, the world is inching towards hell in a hand basket – 70% of the world’s nations have become less democratic in the last twelve months, and this downward trend has prevailed for some years. Australia, though, has been faring worse than most. I don’t have access to the previous rankings, but each nation is given an annual score out of ten. Australia’s 2021 score is 8.90, compared to 8.96 in 2020. The score has regularly dropped from a high of 9.22 in the years 2010-2012, the period of the Rudd-Gillard Labor Prime Ministerships.
The OECD Better Life Index. This measures the ‘life experience’ of an ‘elite’ group of about 40 of the world’s wealthiest countries, members of the Organisation for Economic Cooperation and Development, according to eleven different criteria, including education, environment, safety and health. When I first accessed the index, about 6 or 7 years ago, Australia was ranked number 2 across all criteria, behind the ever-triumphant Norway, and well ahead of the US in around 12th spot. Currently Australia is ranked 7th, and the USA 8th. Norway still ranks first.
On looking into Australia’s ranking for each criterion (the 11 criteria are housing, income, jobs, community, education, environment, civic engagement, health, life satisfaction, safety and work-life balance) I can’t help but scratch my head at some of the results. Australia ranks 1st for ‘civic engagement’, but 20th for ‘community’ (!!??). I would have thought that one entails the other. Also, Australia ranks 2nd for housing (but city rental has become unaffordable for most young people), and 2nd for education, which again surprises me from a general persecutive, though our post-grad sector definitely punches above its weight. At the other end of the spectrum, Australia ranks 30th for safety, another surprise. The OECD claims that the average homicide rate for member countries is 2.6 per 100,000 inhabitants. According to the Australian Institute of Criminology, Australia’s homicide rate for 2019-20 was 1.02 per 100,000, the highest in nearly ten years, but clearly well below the OECD average. Of course, homicide is only one measure, but I’ve not heard of Australia having a high crime rate in general. Strange. But the worst ranking is 33rd for work-life balance!? But having rarely worked a day in my life, I couldn’t possibly comment.
The UN Human Development Index (HDI). Here’s the blurb about this one:
The Human Development Index, or HDI, is a metric compiled by the United Nations and used to quantify a country’s “average achievement in three basic dimensions of human development: a long and healthy life, knowledge and a decent standard of living.” Human Development Index value is determined by combining a country’s scores in a vast and wide-ranging assortment of indicators including life expectancy, literacy rate, rural populations’ access to electricity, GDP per capita, exports and imports, homicide rate, multidimensional poverty index, income inequality, internet availability, and many more.
The HDI website only provides information from 2019 and places Australia in a tie with The Netherlands at 8th in the world, with a score of .944 on a scale from 0 to 1. Norway again gets top spot, just ahead of Ireland and Switzerland. Interestingly, Australia ranks higher than four countries it likes to compare itself with, the UK, New Zealand, Canada and the USA, but little explanation is given for the ranking, which appears to be have been stable for a few years.
So, to summarise, I don’t know what to make of all these indices, which I suspect subtly influence each other in their ratings. We appear to always make the top ten, but rarely the top 5. If we could take advantage of our climate and resources to be be a greater power in renewables, instead of lagging (except in domestic rooftop solar) as we have done over the last decade, we could really make the world pay more attention to us, for better or worse.
References
David Brophy, China Panic: Australia’s alternative to paranoia and pandering, 2021
https://en.wikipedia.org/wiki/Democracy_Index
https://www.oecdbetterlifeindex.org/#/11111111111
https://worldpopulationreview.com/country-rankings/hdi-by-country
a post to send you to sleep, or not
Häggström, Mikael (2014). “Medical gallery of Mikael Häggström
Canto: Anything interesting you’ve learned lately?
Jacinta: Well, there’s so much, it’s hard to keep track of it all, before it slides down the slippery slope into a past of fragmented memories.
Canto: A pasta of memories? That’s food for thought. I know you’ve been reading up on sleep, among all your other heavy reading. Tell me.
Jacinta: Yes, I’ve been reading up on feminism and misogyny as you know, which is mostly depressing, but this sciencey but very accessible book, Why we sleep by Matthew Walker, is not so much depressing as worrisome, for those of us whose sleep patterns are all over the place, like mine. He’s a big-time sleep researcher, and what he says about sleep deprivation is all bad – even for a wee bit of it.
Canto: So, those dreams of doing away with sleep, of zapping your brain for a few seconds to provide the instant reinvigoration that sleep takes eight hours of wasteful oblivion to achieve, allowing us that much more time to ruin the biosphere and all, or just to read more books and shit, those dreams are just a waste of sleep?
Jacinta: No zapping will ever replace the complexity of sleep, with all its REMness and non-REMness, let Mr Walker assure you. Sleep is a restorative and builder, which has complexly evolved with the complex evolution of our brains and bodies. And by ‘our’ I don’t just mean humans, but every complex or not-so complex evolved organism. They all sleep.
Canto: Well, there are many questions here. You’ve mentioned REM sleep, which I think has something to do with dreaming – your eyes, presumably under their lids, are rapidly moving about. Why? It doesn’t sound healthy.
Jacinta: They’re responding to brain signals, and it’s perfectly normal. More specifically, they seem to be responding to the brain’s changing visual representations while dreaming. They used electrodes in the brain to discover this – which sounds Frankensteinish but in this case they were patients with epilepsy preparing to have very invasive treatment to stop their seizures. They looked at activity in the medial temporal lobe, a region deep in the brain which includes the hippocampus and amygdala, and is involved in encoding and consolidating memories, and found fairly clear-cut connections between that activity and patients’ eye movements.
Canto: But how could they ‘see’ the eye movements?
Jacinta: Oh god, I don’t know, for now I’m more interested in sleep deprivation, which raises concerns for everything from diabetes to Alzheimer’s. And, although I haven’t measured anything carefully, my guess is that I average 6 to 7 hours’ sleep a night, and I need to amp that up.
Canto: And you’ve recently been diagnosed as pre-diabetic, so do you think more sleep can help with that? It’s usually pretty strongly correlated with diet isn’t it?
Jacinta: Less time sleeping, more time for eating, Walker writes. I’m certainly trying to lose weight, but only by eating less. I think my diet’s not too bad, less wine though. And I suppose if I slept more, which is easier said than done, I wouldn’t eat so much. I’ve found in the past that just reducing the quantity of food I ingest, without changing its make-up – in other words, being more disciplined – can take the weight off quite quickly. The key is to make it life-long.
Canto: More fibre is good, I think. For the microbiome.
Jacinta: So type 2 diabetes is generally about blood sugar levels and their regulation, or lack thereof. In a healthy person, eating a meal adds glucose to the blood, which triggers the hormone insulin, produced in the pancreas, to somehow bring about cellular absorption of the glucose as an energy source. In the case of diabetes, there’s usually a break-down in the cellular response to the insulin signal, I think, and so you become hyperglycaemic – not that this has ever happened to me, so far.
Canto: So how does this relate to lack of sleep, apart from giving you more time to guzzle sugar?
Jacinta: Walker describes a series of studies, independent from each other, in different continents, which found high rates of type 2 diabetes in people who reported sleeping for less than six hours a night on a regular basis. They controlled for other factors such as obesity, alcohol use, smoking etcetera. But of course correlation isn’t causation so they investigated further. They conducted experiments with a bunch of healthy people – no blood glucose problems or signs of diabetes. Firstly, they mildly tortured them – they permitted them only four hours of sleep per night over six straight nights. Then they tested their ability to absorb glucose, and found a 40% reduction in that ability. This would immediately classify them as pre-diabetic, and these studies, I’m assured, have been replicated numerous times.
Canto: That sounds incredible. And these guinea pigs quickly recovered? Or are they now full-blown diabetics? Doesn’t sound like mild torture to me. And do they know why a week’s sleep deprivation had such a dramatic effect?
Jacinta: Ha, well, Walker doesn’t mention the afterlife of the experimental subjects, but I’m assuming normality came bounding back after they recovered their sleep. As to the mechanism of action, Walker describes two options – sleep loss may have blocked the release of insulin by the pancreas, providing no signal for cell absorption to take place, or it may have interfered with the released insulin’s message to the cells. And though it seems that sleep loss probably had an effect on both, it was clear from biopsies taken from subjects that it was the latter, the cells’ lack of response to insulin, their ‘refusal’ to take up the blood glucose, that was the principal problem.
Canto: Just looking at the Sleep Foundation website, and they seem to get things the other way round, that diabetics are suffering from sleep loss. I must say, that, off the top of my head, I’d find being pre-diabetic easier to manage than my sleep behaviour. I mean, I can imagine changing my diet and exercise habits easily enough, but my sleep habits not so much. How do you turn off your brain?
Jacinta: Well, Mr Walker has some suggestions on that, which we’ll explore next time. And by the way, there seems to be tons of videos and websites providing knowledge and advice on the issue, which always makes me feel superfluous to requirements as a human being…
Canto: Well, try not to lose sleep over it.
References
Why we sleep, by Matthew Walker, 2017
https://www.sciencealert.com/scientists-have-worked-out-why-your-eyes-move-when-you-re-dreaming
https://en.wikipedia.org/wiki/Sleep_deprivation
https://www.sleepfoundation.org/physical-health/lack-of-sleep-and-diabetes
reading matters 12: food mysteries
New Scientist 3292 July 25 2020
Jacinta: So this cover story reminds me of something I read or heard a few years back – that if you were to list the chemical ingredients of a hen’s egg, you’d never come to the end, or something like that.
Canto: Well you’re on the right track, the cover story is titled ‘the dark matter in your diet’, but instead of a hen’s egg it starts with garlic. Both of these commonly consumed edibles, like just about everything else we eat, contain ‘nutritional dark matter’ that scientists have only recently started to focus on, surprisingly considering that we are, to a fair degree, what we eat.
Jacinta: Yes, so we all know that food components or nutrients are usually divided into fats, carbohydrates and proteins, though these three can be subdivided to a near-infinite degree, but there are also vitamins, minerals and other biochemical elements in various quantities, and with variously vital effects. Currently the US Dept of Agriculture (USDA) has a database of 188 nutritional components of food, under which some info is provided on many thousands of chemical elements.
Canto: So garlic, the USDA reckons, is found in 58,055 foodstuffs, including, uhh, garlic. Raw garlic itself is described as containing 67 nutrients, both macro and micro, some of which can only be found in very minute quantities. And yet many components, such as allin, which helps to give garlic its particular odour and flavour, aren’t listed on the database.
Jacinta: Allin is converted into allicin, through the enzyme allinase, when you crush or chop garlic. That’s when that lovely/notorious stink hits you.
Canto: Right, and this is apparently a major problem across the whole database. They added a few dozen flavonoids – plant compounds that can lower the prevalence of cardiovascular disease – in 2003, but recent researchers have been frustrated by the many gaps, and are building their own more comprehensive database, based on their own chemical analyses. It’s called FooDB, which now lists almost 400 times the number of nutritional compounds as the USDA database. 2306 for garlic, for example, compared to the USDA’s 67. But there’s a lot of work still to be done, even on garlic. Only a tiny fraction of those compounds have been quantified – we don’t know the exact concentrations. And this is a problem for the whole of FooDB, with about 85% of compounds unquantified.
Jacinta: Sounds like we need an equivalent of the old human genome project – but for every single edible product? Nice, a few hundred lifetimes’ work, if you can get the funding.
Canto: Well, it suggests that we’ve massively overlooked the complexity of our food – and not only the foods themselves, but their interaction with the microbes and enzymes in our body. But here’s the thing – brace yourself – some nutritionists disagree!
Jacinta: OMG! Scientists are disagreeing?
Canto: The counter-argument is that ‘dark matter’ in nutritional terms is a beat-up. That, though much research is still needed in nutritional epidemiology, in relation to particular conditions and so forth, we know what the essential nutrients are, so the ‘dark matter’, which tends to exist in ultra-minute quantities, would make little difference. But the researcher who coined the term ‘nutritional dark matter’, Albert-Laszlo Barabasi, begs to differ – of course. He points out, for example, that vitamin E, or its absence, can have adverse effects at minuscule quantities, and it may be that all the flip-flopping advice we’re given about nutrition may have much to do with the gaps in our knowledge. Taking garlic again, it was found that of the 67 compounds listed for it on the USDA database, 37 had health effects one way or another, but of the 2306 on FooDB, some 574 had what they called ‘potential’ health effects. In any case, it seems to me that a more complete knowledge of what’s in our food can’t be a bad thing, and will very likely be of benefit in the long run.
Jacinta: That makes sense, but isn’t everything even more complicated, when you think of how all these nutrients interact with our individual microbiota, and the enzymes that break down our food more or less efficiently, depending on how numerous and healthy they are, which no doubt varies between individuals?
Canto: Yes, Barabasi and others working on all this ‘dark matter’ are well aware of these complex interactions, but they reckon that doesn’t detract from the need to know much more about this particular component of the food-nutrient-digestion-health cycle. And Barabasi does in fact compare the current state of knowledge with the days before the human genome project, when much DNA was considered ‘junk’. It’s just not a good idea to assume that such a large proportion of nutrients are barely worth knowing about. Let’s return to garlic again. It features quite a lot in the Mediterranean diet, which seems protective against cardiovascular disease. Steak, on the other hand, can be problematic. Our gut bacteria breaks down red meat, in the process producing a compound, trimethylamine, which our liver converts into trimethylamine-N-oxide (TMAO). High levels of TMAO in the bloodstream are linked to heart and vascular problems. But allicin, from garlic, which we’ve mentioned before, and which wasn’t on the USDA database, is known to inhibit the production of trimethylamine, so a diet containing red meat – not too much mind you – can be rendered a wee bit safer, and tastier, with a nice garlic dressing.
Jacinta: And allicin appears to be an anti-carcinogen too. And luteolin, another component of garlic not on the standard database, is also reported to protect against cardiovascular disease. We love garlic! But what about processed foods. Surely there are all sorts of ways of processing, that’s to say transforming, foods and their component nutrients that won’t show up on the list of ingredients. And how do we know if those ingredient lists are accurate in the first place?
Canto: Well, baby steps I suppose. Cooking, of course, has vital transformative effects upon many foods. And I recall that when you whisk an egg it becomes ‘denatured’ – how transformative does that sound! The more you think about the interaction of foods, with all their barely recognised components, with transformative processes occurring both outside and within our bodies, the more it makes your head spin, and the more you realise that dietary science has a long long way to go.
garlic cultivars from the Phillippines
covid19: sensible testing, mostly
Canto: So we’re looking at medcram coronavirus update 98 now, and it’s a fascinating one entitled ‘Rapid COVID 19 Antigen Testing at Home – A Possible Breakthrough’, though it comes with the clear proviso – this would require co-ordinated political action, and that won’t happen in the USA, not just under Trump, but at any time.
Jacinta: Well, but especially under Trump. But the issue is one of trying to get much more testing done, with far less emphasis on the sensitivity of the test, because rapid-fire, fast turnaround testing is far more useful than expensive, hard-to-evaluate slow-turnaround testing, which puts a premium on sensitivity. But before we get to all that, Dr Seheult looks at a paper on viral loads vis-à-vis covid19 patients. They looked at nasal and throat swabs, and then checked the Ct values over time.
Canto: The Ct values are a measure of viral load and it works inversely – a 3.32 reduction in Ct value means a ten-fold-increase in viral load.
Jacinta: Yes, so a low Ct value means a high viral load, and of course viral replication works exponentially, at least during the early infection period, so your viral load can be massively different from one day to the next – think about that for testing, and delayed results.
Canto: A Ct value of 40 is close to undetectable, depending of course on the sensitivity of the test. And the value can go down as low as 5, all approximately of course. The course of the virus is generally, exponential growth, then a tapering off of the growth rate, reaching a peak, then a descent to finally a remnant population of largely disabled viral scraps, with of course mortality intervening along the way in the worst cases.
Jacinta: Far from the majority of cases, thankfully. So the ‘gold standard’ test is the reverse transcriptase polymerase chain reaction (rt-PCR) test – also called real-time PCR, I’ve just found out. It’s relatively expensive at around $US100, with turnaround times – and this might depend on demand and other factors – of between 3 and 9 days. There aren’t enough of these tests to go round, but they are very sensitive, detecting the virus reliably from a Ct value of about 35, or maybe even 40 (for argument’s sake, Seheult says). But there are other, cheaper, less sensitive tests, called paper tests, that can be rolled out more easily to the general public. The paper is coated with monoclonal antibodies that can detect antigens – substances that evoke an immune response. These paper tests cost at most a couple of dollars each, and would be sensitive to a viral load measured at a Ct value of around 32. These figures aren’t exact but this would make the test around 50-55% sensitive.
Canto: But there’s this issue called the ‘threshold of transmissibility’, which is important in all this, and a virologist, Dr Michael Mina, shown speaking on this update, explains:
So people who are transmitting probably have Ct values that are below 30 and the vast majority probably have them below 25 or so.
As Seheult explains, people may be testing positive at that range above 30 (i.e. low viral load) but not transmitting the virus. This is especially so if they’re on the downward trajectory, as described above, and what the rt-PCR test (or assay) is detecting are those remaining viral fragments. And as Dr Mina points out, it’s the downward trajectory that’s being picked up for the most part, because the initial upward trajectory is exponential. Here’s what he says:
A lot of people are saying, ‘we need the really sensitive tests to be able to detect people early on in their infection’, but almost all the time that people spend with this virus near the limit of detection of PCR is on the tail end of their infection. This is a virus that, once it hits PCR positivity levels, it’s growing well in its exponential phase and it’s probably a matter of hours, not days, before it passes the threshold to be detected on some of these slightly lower sensitivity assays. And then it may persist for weeks or possibly months even in some cases at very low RNA levels. So it’s after people are well beyond their transmissible period that we’re actually seeing the loss in sensitivity of these assays. It’s very rare that you actually detect somebody with a Ct value 0f 39 in that window on their way up, because they’re only sitting there for a few hours before they get down to a 33, so if you’re missing Ct values of 39… it’s really not that important..
Jacinta: Not that important, but the point Dr Mina is making is really important – if the threshold of transmissibility is at 33 or below vis-à-vis Ct values, then a high-sensitivity test may even be a barrier to focussing on getting at the most transmissible subjects.
Canto: Yes, especially when you have an alternative test that can be applied much more regularly with a quick turnaround – results on these paper tests take ten minutes! And being cheap, you can test as often as you feel you need to. If you’re positive, you quarantine yourself for a while, keep testing, find yourself negative, wait for a few more days, considering the low sensitivity of the test, keep testing in case there’s a recurrence, and when it’s still ok after a few days you can resume your life, go back to work or school, whatever, being pretty sure you’re past the infectious phase.
Jacinta: Yes, as Dr Mina says, 9 out of 10 people go undiagnosed with the virus in the USA, according to the CDC – indicating the inadequacy of testing. And he goes on to say, of the other one out of ten, those that are caught, are mostly post-infectious, at the ‘tail end’. The point is that, because of the woeful lack of testing and the long turnarounds, they’re catching far fewer of the transmissible cases, the ones they want and need to catch, than the pitiful few that they actually find testing positive.
Canto: The bottom line being that if they tested with a far less sensitive, but cheap and readily available quick-result assay, they would capture far more of the transmissible cases, and save lives.
Jacinta: Dr Mina and many colleagues have written a paper on this, entitled ‘test sensitivity is secondary to frequency and turnaround time for covid19 surveillance’, and he points out that with this approach they would drive down the ‘r effective’ – the reproduction number – which is the number of people who can be infected by a carrier at any specific time – to well below 1. So if you were to give a significantly high proportion of people in in the worst affected areas these types of tests, you could bring the numbers down very rapidly, and this would eliminate the need for contact tracing. It would have an effect on schools, workplaces and so forth – because if you’re given one of these long-turnaround tests and your results eight days later turn out negative, that may be because you had just contracted the virus when the test was taken, but it didn’t show on the test – so you go back to school and infect people. With regular testing this problem would be eliminated. Hate to belabour the point, but – people are dying.
Canto: It seems the CDC put a high priority on sensitivity, and so rejected these cheap paper tests, neglecting the obvious problem of turnaround more or less completely. The low sensitivity tests usually miss the subjects that are beyond infectivity. If they were on the upward trajectory they would likely be caught by the next test. It’s this upward trajectory that is the infective period. You would think regulatory organisations like the FDA or the CDC would twig to this, but not so much in the Trump era, when non-scientists are put in charge. Yet another failing of the individualist, anti-collaborative, egotistical destruction of all government agencies…
Jacinta: Or just the unwieldiness, the lack of finesse, of lumbering bureaucracies. Or a mix of both.
Canto: Anyway, as things deepen and darken in the USA, we might have to skip a number of updates to keep up with the chaos, the failures, the resistance and everything else. It isn’t a great time to be living in the USA, but as outsiders we’re kind of ghoulishly fascinated by the mess they’re making of this pandemic, and much else besides.
Jacinta: But also genuinely sympathetic to those who are trying to make thing work in the teeth of all the craziness.
Canto: Today, September 16, marks the day that 200,000+ deaths from covid19 have been recorded next to the name of the USA, according to Worldometer’s stats. Taiwan, a country that is separated from the so-called ‘China virus’ only by the narrow Formosa strait, has suffered only seven deaths in the nine months that this virus has raged. It has a population of about 24 million, slightly less than that of Australia, into which we find ourselves thrown. Australia has had 824 deaths thus far, and we’re regarded as something of a model!
Jacinta: Yes, several cheers for Tsai Ing-wen and for female leadership, sans egotism. And a special thanks to Audrey Tang, Taiwan’s digital minister – but she’s actually real, and a life-saver. We need more of her.
Audrey Tang
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: hopes, failures, solutions
Covid-19 continues to be devastating, especially in the USA, where there are vastly more cases than anywhere else, and vastly more deaths, though the picture there is complex. The hardest-hit region, the New York area, is seeing devastation in poorer districts such as Queens, where the Elmhurst public hospital is inundated with uninsured, critically ill patients. New York has suffered almost half of US deaths. Some other states and regions, especially physical outliers such as Alaska, Hawaii and the Virgin Islands, have very low numbers, and it would be hard to explain why the spread of cases across the mainland has been so uneven. Of course it’s obvious that there has been no federal leadership on the pandemic.
Here in Australia, where the numbers seem to be improving (we’re 33rd on the list of total cases, down from 18th when I first started paying attention to the list about three weeks ago, and 52nd on the list of total deaths), our conservative federal government is keen to open up the country again, and has released modelling to the effect that the virus will be eliminated from the mainland if we maintain current physical distancing measures, though it’s likely to take weeks rather than months:
The model suggests that every 10 people infected currently spread the virus to five more people, on average. At that level, the virus would eventually be unable to circulate and would die out within Australia.
Sydney Morning Herald, ‘Australia in course to eliminate Covid-19, modelling shows’
Australia’s current reproduction number (R0) is just a little over .5. A maintained R0 of 1 or less will eventually eliminate the virus. Of course, there will be fluctuations in that number, so it will be difficult to project a time when things are ‘all clear’. Another difficulty with modelling is that the number of infected but asymptomatic people is unknown and difficult to estimate. For example, recent Covid-19 testing of the entire crew of the aircraft carrier Theodore Roosevelt found that a substantial majority of those who tested positive were asymptomatic, casting doubt on previous estimates (already worrying for transmission) of one in four cases being asymptomatic.
The asymptomatic/presymptomatic transmission issue was addressed by Bill Gates in this article back in February. It’s what makes SARS-CoV-2 a much more serious threat than the previous SARS and MERS viruses. Gates, in this very important article, also provides an outline of what needs to be done globally to fight this pandemic and to prepare for inevitable future ones. If only…
It’s worth comparing Gates’ call for national and global co-ordination, and more expenditure, in the fields of epidemiology and disease prevention, with another more recent article, also published in the New England Journal of Medicine, which tells a tale of Britain and its NHS, gutted by years, in fact decades of ‘reforms’ and budget cuts:
Thanks to government “reforms” of the NHS, it has become highly decentralized, with over 200 commissioning groups in England that can make independent decisions about staffing and procurement of equipment — far from the monolithic “socialist” health care system it is often assumed to be. The devolved governments in Wales, Scotland, and Northern Ireland have substantial health system autonomy. At a time when central management of staff and resources might be most helpful, the decentralized decision-making structure leads to competition for resources and inconsistent policies.
One can hope that the travesty of this virus, especially in places like the US and the UK, will lead to a rethinking of the importance of a well-funded, centralised, co-ordinating and interventionist government in modern states, with particular emphasis on the healthcare system. But I suspect that, in the USA at least, things will go the other way, and the government-hating and government-blaming will only intensify. I’d love to leave this topic and look at solutions – that’s to say I’d love to focus more on the science, but I’m barely equipped to do so. Still, I like to have a go. A very technical and comprehensive review review of pharmacological treatments has been posted recently on the JAMA website, which includes an account of how SARS-CoV-2 enters host cells and utilises those cells for reproduction.
The review claims that currently the most promising therapy is the antiviral drug remdesivir. So what is it and how does it work? I’ll try to answer that question next time.
References
https://www.nejm.org/doi/full/10.1056/NEJMp2005755?query=recirc_artType_railA_article
the science of Covid-19: possible treatments, herd immunity
Australia is now 22nd in the list of total COVID-19 cases and dropping down. There are still of course new cases every day, but far fewer than many countries below us on the list. Experts are now talking about a flattening curve, but they also warn that the virus is ‘here to stay’. Here in South Australia, there were no fatalities when I last posted, but there have been three in the last couple of days. There are a large number of cases recently linked to our Barossa wine-growing region, a popular tourist destination.
So let me take a closer look at the SARS-CoV-2 virus. It’s a positive-sense single-stranded RNA virus. RNA is generally single-stranded in nature, though apparently can be double-stranded on occasion. The positive-sense term refers to the polarity, or sense, of the RNA. It’s also called ‘positive-strand’, facing 5’ to 3’, which means it acts as mRNA and can be translated into viral proteins in the host cell.
These types of virus are very common. They include common cold rhinoviruses as well as the SARS and MERS coronoviruses. SARS-CoV-2 is genetically similar to bat coronaviruses, causing virologists to believe that it was transmitted from bats to humans through an intermediate species such as a pangolin. The reproduction number of the virus (R0) is currently ranged from 1.4 to 3.9, in a scenario of no immunity and no preventive measures taken.
It has often been repeated that a vaccine will take 12-18 months, if not longer, to be safe, ready and effective. Science communicators such as the ABC’s Dr Norman Swann are telling us that stay-at-home orders may need to stay in place until that time, which is surely alarming economists and the business community. So, unsurprisingly, people are looking to short-cuts and desperate remedies. Perhaps the most publicised of these is the anti-malarial drug hydroxychloroquine, aggressively promoted by the US President. It turns out, also not surprisingly, that he has some financial interest in the French company that has branded the drug, according to the New York Times. There doesn’t appear to be any clear evidence on the benefits of the drug. Best reports speak of ‘mixed results’.
There are reports also of the benefits of blood plasma from people who have recovered from Covid-19. A small Chinese study involved 10 severely affected patients being given a few hundred millilitres of ‘convalescent plasma’ containing viral antibodies, and results were described as promising. The approach is being tried in the US, with the Red Cross and the American Association of Blood Banks seeking to recruit suitable ‘fully recovered’ donors.
As people continue to be alarmed and frustrated at the massive disruption to their working and social lives caused by Covid-19, some world leaders (e.g Boris Johnson and his chief science adviser Patrick Vallance, and Netherlands PM Mark Rutte) have come up with not-so-encouraging solutions, such as allowing the virus to run its course so that the population can build up herd immunity. This would actually be a disastrous policy in the case of a virus with a high (but not precisely known) fatality rate, involving millions of severe cases requiring intensive care treatment at any one time.
Herd immunity occurs when enough people have antibodies to the virus that it has nowhere to go. This can occur through the work of our immune systems or through antibodies created by effective vaccination. The former obviously comes at a much greater cost in terms of lives lost, in the case of a highly infectious (the R0 is now estimated – the data changes as I write – at between 2.0 and 2.5), high-fatality virus. Also, because Covid-19 is new, we don’t have sufficient data as yet about the degree of immunity it confers upon recovered patients, or whether it is able to mutate to any degree. Experts are generally counting on low or no mutation, but none of them see relying on herd immunity to be a humane solution to the problem. Suppression is the name of the game at the moment (even though it will reduce herd immunity). That’s to say, the R0 mentioned above (which might be higher) is the figure without the application of physical distancing or other containment measures. The R0 number, if it can be ascertained, gives an indication of the percentage of immunity required to ‘protect the herd’. An R0 number of 2 will require about 50% immunity. If the R0 number is 3, some 66% immunity will be required. Measles has a very high R0 of 12, requiring 90% immunity, which explains why anti-vaccination movements can imperil whole communities.
So it’s a trade-off. Physical distancing measures will reduce the possibility of herd immunity – the production of antibodies. Going back to business as usual will increase infection rates – ok for those who recover, not so much for those who don’t. The cost of the second option, most will agree, is just too great.
References