The Wry Observer’s Covid-19 update (170)

“The Lancet” has finally abandoned its uncritical support of the “SARS-CoV-2 originated in the wild” statement issued by a number of authors (with a conflict of interest) about 18 months back. It appears to have heeded the growing evidence that such a theory has had little to support it, while the circumstantial evidence for a laboratory leak, with or without some sort of genetic manipulation in the Wuhan lab, cannot be ruled out. It has done this by publishing a letter from Van Helden and others (DOI: https://doi.org/10.1016/S0140-6736(21)02019-5) titled “An appeal for an objective, open, and transparent scientific debate about the origin of SARS-CoV-2”.

Better late than never. Regular readers of my blog will recall that I suggested the original statement should be retracted in my blog of 7^th June. The suggestion that the whole thing be debated is very polite, but given the obfuscation of the Chinese authorities which have withdrawn quantities of data previously available publicly it is unlikely that there can ever be a debate. The suggestion of examination by experts who no conflict of interest has already been partly fulfilled; as there is no suggestion that this could be considered a criminal case, but remains a civil one, there is no legal requirement to prove the case beyond reasonable doubt, but proof can be on the balance of probabilities. If so, I now firmly believe that there was a lab leak in Wuhan. The evidence for this is overwhelming and there is no evidence to support an alternative conclusion. Van Helden et al state “There is so far no scientifically validated evidence that directly supports a natural origin.” What went on in the lab that made the virus so contagious will, I fear, never be known, unless a whistleblower from within it comes forward, but the likelihood of this is rather remote given the risk that such a person would take. And, of course, if there was admission of a leak then a criminal prosecution might follow – the consequences might be considered a crime against humanity.

What a mess.

The Wry Observer’s Covid-19 update (169)

Not dead yet, but the long gap since my last blog is thanks to brain fog – not, I might add, anything to do with long Covid or dementia but simply because there has been so much contradictory data and interpretation thereof.  Is there another wave coming? Maybe, because there is a new Mu variant leaking in from Colombia, and it looks as if new waves do relate to new variants. It also appears that the fall in cases from a peak are independent of direct interventions and reflect developing herd immunity to each variant.  Do lockdowns work – an important question because today we learn that the UK government has not ruled out re-imposing one if there is a rise in cases?  My answer is no, because what is called a lockdown has too many let-outs to deserve the term – delivery drivers, essential workers, people coming in from abroad (and particularly in regard to the last of these the revelation that around a third of those who are supposed to be quarantining are not doing so).  And see what Defoe thought  below. Should we vaccinate the 12–15-year-old cohort?  You say yes, I say no (always nice to get a song reference in).  If the evidence suggests that vaccination does not affect transmission but only reduces the risk of getting very sick with Covid-19, then it is futile to presume that mass vaccination might stop spread, and the young do not get very sick.  It is odd that the government’s own vaccination committee came out with a contrary recommendation, only to be overruled because, it was claimed, it had not taken economic effects into account. And after that, that it was the medical advisors who stood up to justify the decision. I suppose it doesn’t much matter if parents can refuse, but bizarre that it is considered reasonable for a 12-year-old to be allowed to overrule their parents if they are considered competent, which seems to alter the definitions of age of consent.  If vaccination, why not sex? Let’s not go there. And again today the modellers are making gloomy predictions of the size of the new wave and when, not if – which is rich given their previous track record.

Time now for another look at the issue of numbers of new “cases”. In a way it’s a pity that there cannot be some sort of mechanism to account for the national differences in how tests are done and on whom, but I present to latest OurWorldinData graphs for the UK and our neighbours, as well as that for the UK alone because the first image is rather busy, and I have spent decades railing against busy slides.  But as can be seen the percentage of positives remains very low at present.

Do we need masks?  I would still wear one in a shop, but outside the benefit is I think minimal, though I do still stick one on when it’s crowded; all these tourists in Rye, where do they all come from (note the second Beatles reference. I thank you). And the argument about where the virus came from continues, though the evidence that it was indeed a lab leak is becoming increasingly compelling, especially with the revelation that the laboratory safety procedures were not at the grade 3 level required.  So long as the Chinese withhold data the suspicion will remain.  Perhaps Bellingcat should get in on the act.  I have just finished the book by Eliot Higgins “We Are Bellingcat: An Intelligence Agency for the People”, and a very good read it is.  There are many parallels with the work it has done on other projects, such as MH 414 and the Skripal case, and it might at a stroke remove the conflict of interest concerns that have bedevilled the discussion to date. I think it would be interesting – if it’s possible – to do a satellite analysis of traffic patterns in Wuhan from September 2019 through to March 2020, and see whether there was some dramatic change around the postulated leak point.

The most recent edition of my old school magazine “The Cholmeleian” (Highgate School for the uninitiated) has an interesting collection of essays by current pupils and old students, with an amusing introduction by Simon Appleton, who re-visited Defoe’s “Journal” and invoked Defoe’s shade to comment on today’s pandemic.  Noting Defoe’s scepticism about both lockdowns (unenforceable then as now) and Test and Trace, Appleton imagines a discussion:

“I flattered him that with his experience of the Great Plague of 1665, his spirit should guide the government’s SAGE committee. He stared at me first quizzically, then sceptically.

‘In the 21^st Century do you believe that herbs will protect you from the plague?’ he snorted. I struggled to explain acronyms to him and how modern people spoke in fluent acronym, and how the government was guided by ‘the science’.

“Which one?” asked Defoe.

‘They’re not clear,’ I replied, ‘but whichever one it is, they follow it to the letter except when it contradicts their own interests.’”

Remember what Humpty Dumpty said to Alice?

“When I use a word,’ Humpty Dumpty said in rather a scornful tone, ‘it means just what I choose it to mean — neither more nor less.’

’The question is,’ said Alice, ‘whether you can make words mean so many different things.’

’The question is,’ said Humpty Dumpty, ‘which is to be master — that’s all.”

The Science… which science?  What is science if it can be so many different things? Answers on a single side of A4.

Time for a gin and tonic to clear my brain.

The Wry Observer’s Covid-19 update (168)

I was sorry to learn that my medical colleague Malcolm Kendrick has decided to stop blogging about Covid (see https://drmalcolmkendrick.org/2021/09/03/i-have-not-been-silenced/). I wrote a response as follows:

“Malcolm, you were not a lone voice questioning the system’s response to the pandemic; as you know (but other readers of this blog may not) I too have been blogging regularly since February 2020 (https://bamjiinrye.wordpress.com for those interested – I have written over 160 of them to date). Like you I have questioned whether to carry on blogging, given that my various interventions have met with an almost complete lack of response, but correspondents have asked me to continue so I will. At least as a retired consultant physician I have not been threatened by the establishment. At least for you the Spanish Inquisition (sorry, General Medical Council) found no case to answer, so automatic guilt has perhaps been left behind in the 16th Century. But punishment by cancellation of those who question orthodoxy is alive and kicking; my email address is now on spam lists thanks to the NHS, I believe as a response to my gadfly correspondence.

I could not agree more with the overall sentiments in this last blog of yours. Data has been presented with bias and spin and there has been both mis- and disinformation. In my view the planners and prophets have been drawn from the wrong places; when an infection results in a severe illness that can be caused by other triggers it would make sense for experts in managing that illness to be embedded in the process. They have not been. There have been unnecessary trials that have proved efficacy of treatment regimes already known to work. There has been a failure to introduce investigatory measures that predict deterioration, so many patients have been seen too late. There has been focus on epidemiology without clinical awareness – prevention of infection has overridden treatment, despite which infection control in hospitals has often been lamentable. What makes matters worse is that many of the lessons we are learning from this pandemic are lessons that were learned – and forgotten – in previous ones. And of course there has been heavy emphasis on “The Science” without any understanding that research can contradict, that trials can be wrongly designed, that multifactorial influences can confound.

Good luck! I look forward to your continuing contributions to the cholesterol-heart disease debate, not least since Inclisiran has just been approved by NICE…”

I was rather hoping my cross-reference might draw a few surfers towards my own blog, but my response does not appear on Malcolm’s website for some reason. Maybe I too have been silenced…

UK numbers continue to bobble about, with every change being interpreted in obsessional and over-zealous detail. Why have numbers gone up? Big events? Holidays (not least in Cornwall)? Why have numbers gone down again? What is the overall excess mortality (not a lot). Is the NHS to be overwhelmed again (probably not – yet)? Should 12-15 year olds be vaccinated (in the UK, only if they are vulnerable, while elsewhere more widespread child vaccination seems to be taking hold). And of course the dragon in the room remains the origin, as to be detailed in a new book which was excerpted in today’s “The Times”. See https://www.thetimes.co.uk/article/how-us-cash-funded-wuhan-lab-dealing-in-deadly-viruses-rjddc6jbt.

I am at least slightly reassured by a note from an intensive care consultant who says that in his own hospital the steroid/tocilizumab combination is being employed, and he understands that it is being widely used in the UK. I do hope so. It would be nice to know whether there is any difference in death rate between those who got it and those who didn’t, but we would also need to know the point at which it was given in any patient – too early, about right or too late. Only a casenote audit will determine the answers, but I fear it is too big and complex a task, so like the origin we may never know.

Still no feedback on my RCP audit question. I give up on that one for now.

The Wry Observer’s Covid-19 update (167)

Another year older but fortunately, as the song goes, not deeper in debt*, although we have not yet had the bill for our radiator refurbishment, which was completed today and we once again have warmth (some nights have been chilly) and heated towel rails. No feedback yet on my query about the RCP audit as outlined in the last blog.  Am I surprised? Not very.

Meanwhile New Zealand and Australia are locking down again following the import of a handful of cases from outside, which for me serves only to confirm that we cannot isolate ourselves forever from the virus and we will have to learn to live with it. There is increasing evidence to suggest that vaccination does not stop one from getting infected, but it does reduce the risk of serious illness if you do. So vaccine passports are a waste of time. I suppose that the pattern is very similar to that of flu vaccination where the risk is reduced but not abolished.

“Cases” in the UK are fluctuating but hospital numbers and deaths appear to be reasonably steady here, although not in the USA it seems, where numbers are again rising. I am asked why and have taken to saying it is multifactorial, which I am sure is true, but seems to stop the conversation. There is no evidence that Freedom Day has caused a sudden rise to follow the dire prophesies of – the dire prophets. There have been slightly conflicting prophesies anyway because of the mismatch between different sets of data – the King’s study, Zoe, as reworked some of its figures to the confusion of many, while the DoH and ONS figures point to different conclusions. Overall though it still looks as if lockdowns are not synchronous with improving numbers, so it still looks as if the focus should be on timely treatment of those who get ill. I can still find no evidence that national policy and practice on treating Covid-19 are consistent. If someone knows where I can find it please let me know.

Today’s “The Times” is hailing Ronapreve which has been approved for use in the UK; I do hate the use of commercial names but concede in this case that calling it casirivimab/imdevimab is a bit clumsy. The “ab” endings give away that this is a pair of monoclonal antibodies. It appears that President Trump was given it when ill last year; the European Medicines Agency has been considering it since February this year and it appears to have been trialled in India in May, so it’s not exactly new – but it binds to the virus spike pprotein and thus prevents it from infecting cells. Early administration is therefore needed, obviously, for once the virus has got in the cells the real fun begins. Perhaps it will have an impact on hospital and particularly intensive care admission rates. I did however note that the Health Secretary’s response includes this: “This treatment will be a significant addition to our armoury to tackle COVID-19 – in addition to our world-renowned vaccination programme and life-saving therapeutics dexamethasone and tocilizumab.”

Well, well. About time. We could have got there a bit sooner.

Over a year ago, in anticipation of Roche shares taking a leap because of worldwide demand for tocilizumab, which it makes, I made a tiny investment. Roche also makes Ronapreve. Today the share price is disappointing; it remains under my purchase price, but my loss on paper is fairly small – £11. So I shall be patient.

* The song being 16 tons, by Merle Travis

The Wry Observer’s Covid-19 update (166)

Rather a busy week, hence the gap. One thing however has become clear. As a result of having a strange unilateral face pain I have undergone a series of investigations. Thinking from the symptoms that I might have developed giant-cell arteritis I got my bloods done. ESR and CRP were normal, so it wasn’t that. Having found a trigger point at the back of my jaw I visited the dentist, who noted only that I had a mainly unerupted wisdom tooth, but the pain came and went, waking me at night with exacerbations to 10/10 and then dying down again, inconsistent with underlying infection, and dental X-ray was normal, so it wasn’t that either. Not glaucoma; I had only just had an eye review. I know what migraine is like, having suffered intermittently for decades, and it was quite unlike that, nor did it fit with cluster headache. Not trigeminal neuralgia. I have had that in the past. Quite different. I was stuck, and sought a neurological opinion. The neurologist suggested immediately that I had chronic paroxysmal hemicrania, something I hadn’t heard of, but the textbook description fitted like a glove. The cause of this is not clear, but it may be a symptom of an underlying brain or pituitary tumour, so I had an MRI scan. Nothing. I mean nothing abnormal; a brain was present with no evidence of cerebral atropy, just “minor ischaemic changes” which might, I suppose, reflect recurrent microthrombi that you get with migraine (hence the visual disturbance due to platelet aggregation in small vessels). I began the specific treatment, who is indomethacin (a powerful anti-inflammatory) and the pain almost disappeared. QED? I have always taught that if the specific treatment for a condition doesn’t work then the diagnosis is wrong. I would like to think the reverse is true.

Conclusions:

• However much you think you might know, someone else will know something you don’t. But I can now pontificate in expert fashion on chronic paroxysmal hemicrania.

• Entirely normal investigation findings do not mean there is nothing wrong, only that you have done the wrong investigations or that there are no appropriate ones, so you make a diagnosis of exclusion.

• I do not have cerebral atrophy (the radiographer flattered me by saying I had a young brain), so a diagnosis of dementia does not explain my increasingly poor memory for names.

That last is the thing that is most importantly clear, to me at least. Almost more satisfying than knowing I don’t have a brain tumour.

Last week I had a letter in the BMJ pointing out (yet again) that SARS-CoV-2 infection is not the same as Covid-19, and that a case rise of 50% is hardly a cause for concern if it means an increase from two to three.

All sorts of conflicting things have emerged in the last week, including the gloomy Neil Ferguson doing a U-turn on projected numbers, data emerging to suggest that vaccination doesn’t stop you getting infected (but probably does stop you getting very sick) and mixed messages from the prophets and lockdown fanatics on numbers and why they don’t behave as the experts expect. Ooh! The numbers are rising! Oh, they are falling again. Aargh! They are rising again – must be because lockdown has ended. Oh, the rise doesn’t fit, timing-wise. Oh yes it does. Oh no it doesn’t. If the experts are confused what hope is there for the rest of us (leave aside my contention that we are burdened with the wrong experts). For the moment I decline an invitation to enter this argument, as there are still not enough data in my view. However the whole business again underlines the fact that scientific conclusions are not immutable, and some of the vitriol aimed at dissidents like Sunetra Gupta diminishes SAGE and its acolytes to the establishment (and Inquisition) versus Galileo and Copernicus.

On, then, to the Royal College of Physicians report on standards of Covid-19 hospital care titled “Caring for hospital patients with COVID-19: Quality of care in England examined by case record review” (you can find the full report at https://www.rcplondon.ac.uk/projects/outputs/caring-hospital-patients-covid-19). It is based on a casenote analysis of just over 500 patients from 19 centres. It concludes that hospital care was overwhelmingly good.

I have read it, and my conclusion is the same; care was good, but the definition of “care” excludes specific medical treatment, or at least so it appears from the evidence, which is all about care in the sense of looking after, rather than care in the sense of giving drugs. There is one reference to therapy: “Several individual mSJR reviews articulated the notion that some patients would have survived the illness in the early weeks had steroid therapy and anticoagulation been available earlier.”

No mention of interleukin antagonists and no elaboration of this statement. So what I need to know is the dates that the patients whose notes were examined were in hospital (so I can judge whether they had the right specific treatment at the right time, or not) and what treatments they all actually had (so I can decide whether their therapy, as opposed to their care, was appropriate), and indeed whether those who eventually survived had different therapy from those who did not. Early patients will not have had the opportunity to receive the right pharmacological interventions, because my advice on this was ignored, overlooked or both, and so was not implemented for many months. But one could argue that this failure actually meant that patients received suboptimal care. I think that further analysis of the case files is not only necessary but essential. As it stands I don’t think the conclusions are valid.

If I get any feedback I will write about it. Possibly before I turn 71 on Saturday. Possibly not.

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Last night we had a strange sight; a large bird on a nearby roof, which turned out to be a peacock, shortly afterwards joined by a second. Where did they come from? There was a Peacocke in Rye once; he founded the Grammar School in 1636, but I am not aware of many since, certainly not ones of the avian variety.

The figures for “cases” are bouncing around a bit, but are nowhere near the apocalyptic forecasts of the SAGE doom merchants.  Just over 26,000 today, but then large numbers of people are having multiple tests, so if you have a positive you will likely get another test.  If “cases” are being judged on tests, rather than individuals, this will seriously skew the numbers.  The percentage of positives remains low, however, and hospitalisations and deaths have not moved up as one might have expected, even accounting for the lag between having a positive test and developing symptoms requiring admission.

However there is a further spanner in the works of the gloomsters; new statistical interpretation has enabled the identification (at last) of those coming into hospital ill with Covid-19, and those who have arrived for an unrelated reason but happen to have a positive test.  This breakdown reveals that the number of “real” Covid-19 admissions is some 20% lower than the total quoted in the news releases. And it looks as if the Delta variant is not more lethal than its predecessors, either.

The Lockdown Sceptics site run by Toby Young has rebranded itself as the Daily Sceptic – underlining the things that matter other than lockdowns (which don’t matter much anyway).  I am still bemused by the cancelling of those with valid clinical viewpoints (including myself). So I am losing heart.

Do I go on blogging, or call it a day?  The thing about banging your head against a brick wall is that it’s nice when you stop.

The Wry Observer’s Covid-19 update (164)

Well. One week on, and what pops up in the BMJ? A revision of the living WHO guideline on drugs for Covid-19. And what does it recommend? Steroids and tocilizumab. And the numbers of new cases seems to be falling again, despite no lockdown and despite the eerie wailing of the SAGE prophets who predicted a tsunami of a third wave (never mind that it’s actually a fourth wave, because there were two joined peaks over the winter months).

I penned a Rapid Response:

It gives me little pleasure to revisit and enlarge the comment I made in October 2020. The guideline revision vindicates my original contention at the end of April last year that severe Covid-19 is a cytokine storm. Why else would you use drugs that treat a cytokine storm? Why, given extensive prior evidence of benefit of steroids and IL-6 blockers in cytokine storm syndromes, has it been necessary to do new trials? In my Rapid response to the BMJ of 28th April 2020 I wrote:

“I believe that an open trial of a combination regime of high-dose steroids and cytokine inhibitor(s) should be started at once, although I believe the evidence supporting such a regime is almost so powerful as to obviate the need for one.”

Subsequently I pointed out that the pre-Covid textbook on cytokine storm syndrome (1) has 12 references to the use of tocilizumab. I also outlined a clear way to assess whether an infected person was a risk of cytokine storm using a combination of tests, ranging from pulse oximetry to inflammatory markers such as ferritin and D-dimer. I was not alone in this, but I have never seen any acknowledgement of any of those who proposed such assessment.

There have been conflicting data on efficacy of tocilizumab in Covid-19, but this is in my view almost certainly related to the timing of treatment. Notwithstanding that small caveat, I consider that, in retrospect, the government’s advisers made a grave error in not immediately recommending the steroid/IL-6 antagonist combination. If a disease has all the clinical features of a known syndrome it makes no sense at all to ignore this and insist on trials. And the evidence has been overwhelming for months. All of the systemic manifestations of Covid-19, be these cardiac, renal, neurological, dermatological (and respiratory) can be explained by the development of a hyperimmune state. “Long Covid” has so many features of autoimmune disease that it becomes impossible to ignore the likely success of treatment (of, for example, rheumatoid arthritis or SLE).

From a personal perspective I am both disappointed and angry. Disappointed because, despite my best attempts, I have failed to breach the fortress of SAGE and government. Angry because part of that failure is the result of a deliberate turning of a blind eye by SAGE, government ministers and the media. They have all refused to engage. I do not know why; I am an experienced physician who has treated cytokine storm syndrome (and has read the book, and I would bet that none of them have). I have provided plausible (and evidence-based) explanations for why some patient groups have a higher risk than others. I have drawn exact parallels with known diseases. If there were faults in my logic why has no-one put me right? Could it be because I was right? So why do I not get the T-shirt?

I have a final question, which might be answered by an audit of casenotes of those who died. How many of them actually received steroids, or tocilizumab, or both? And if not, why not? And if not, would it not be appropriate for relatives to take legal action, on the basis that medicine had (at least since April 2020) ignored existing evidence and failed to act on appropriate treatment recommendations? I doubt it would have saved all of them, but no doubt that it could have saved some.

Over the last 18 months everything has been thrown at prevention of viral spread, although the measures have been patchy and often ineffective. Time and again I have said that this is a waste of time; what matters, given the spectrum of infection from asymptomatic to fatal, is to prevent severe disease. The delays in doing this have been unconscionable and I fear that clinicians who have also failed to listen and act on the evidence must shoulder some of the blame.

Oh, and as I write I have just watched the re-run of Adam Peaty’s gold medal swim (we watched Tom Daly and Matty Lee in the diving win theirs live). And then Tom Pidcock… a great start for GB (not forgetting Northern Ireland, which is part of the UK with Great Britain). I feel better now!

In fact I am now wondering whether to stop my Covid-19 blog. An inquiry will happen, whether it’s run by the government next year (or whenever) or the British Medical Association this year. Re-reading my contributions over the last 18 months or so there is a recurring pattern which I don’t think is likely to change:

Identification of a problem
Panic
Gloom
Prophecy of disaster
Institution of policy
Recommendations of outside experts (ignored)
My predictions
My recommendations (ignored)
My representations to the media (ignored)
Fake news
Improvement in situation; prophecy proved wrong
Fake news not fake after all
My predictions come true
My recommendations are correct (but partly ignored)
Worsening of situation
Panic
And so ad infinitum

In particular this evening the number of positive cases (I mean tests) has dropped for the 6th day in a row in the UK. So much for another exponential take-off with hundreds of thousands of cases, not forgetting, of course, that positive tests are clearly not translating into hospital admissions and deaths.

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Cry Freedom! 

Perhaps not quite yet, although we are now supposed to be free from social distancing and masks. It looks a bit edgy again; numbers going up (including hospital admissions, maybe not deaths) and suggestions that vaccine passports will be required for nightclubs. How about hospitals? They too are closed indoor spaces with close contact and inadequate ventilation, made worse by the fact that many inmates will be highly infectious, more so than nightclubs.  Libby Purves exhorts us in “The Times” today to open all the windows, to let in the fresh air.  Try that in a double-glazed hospital where the windows do not open by design, and where the air-conditioning is switched off because the system has legionella in it.  Back to the 19^th century, please, with well-spaced wards, large open windows and a central fire to pull in the fresh air and incinerate the bugs as they are sucked over it.

I will still wear a mask in an indoor public place.

Much drama on BBC News over the latest announcements on rules and regulations, not to mention the projections of trouble ahead from the medical top brass.  It is time for rational debate rather that hysterical catastrophising.  What I still fail to work out is whether those who get sick with SARS-CoV-2, ie those who develop Covid-19, are actually getting the right treatment at the right time.  The NICE guidelines are confusing; each potential drug is dealt with individually, but there still seems to be a lack of any coherent protocol which every hospital should be following – like the protocol I suggested, recommended even, over a year ago.  I say yet again – if Covid-19 is treatable, then it doesn’t matter so much if someone acquires the virus.  Vaccination or no there will still be those who get very ill (and I still think it’s unlikely to be the immunosuppressed, because if you are immunosuppressed then you won’t develop a cytokine storm).  If I were to get Covid-19, I would still opt for steroids and tocilizumab (and maybe throw in the ivermectin).

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I wonder whether the French will celebrate Bastille Day with an uprising against President Macron’s decree that all children will be vaccinated.  Just a thought.

Anyway – back to leptin.  My further interest was piqued by an article in “The Times” on the 12^th July headlined “Hormones found in fat may help against prostate cancer”.  It reported a 3 year study suggesting that people (surely that should be men? – Ed) with a BMI of more than 30 had a 10% higher survival rate than thinner patients.  The patient group was highly selected being patients with metastatic disease that was resistant to medical castration.  You can find a summary of the conference presentation at https://www.eurekalert.org/pub_releases/2021-07/eaou-ois070721.php.

Now many years ago, BIBG (before Internet, Before Google) I was asked to review a paper reporting three cases of reflex sympathetic dystrophy following herpes zoster infection.  RSD is also known as Sudek’s atrophy after the physician who first described it.  The authors stated that their cases were the first reported with this trigger in the English literature.

I thought this was surprising, so I went to the library to search the giant volumes of “Index Medicus” which most young folk won’t have heard of, but which contained the titles and authors of all medical papers arranged by author and by category.  Nowadays you just type your search terms into Google and up pop the relevant things, but this was a lengthy manual process, and once you had found what you thought might be useful you had to order a copy through the library staff.  In the list I found a review article with a vast list of references, but no mention of zoster.  However one of the references was to Sudek’s original paper and thought it would be interesting to read, relevant or not.  It was in German, so it took me a while to go through it. You can guess that I found a mention of cases triggered by zoster.  Of course the new paper had been specific in saying that their finding was the first in the English literature, but the fact that Sudek himself had described it meant that it was far from new – about 100 years late, in fact. No publication followed.

You may also need to look for original documents.  Having a passing interest in phalloplasty (penile reconstruction) after discovering the case file of the first ever female to male surgical transition I investigated the history of the procedure, which in all of the literature was attributed to a Russian surgeon, Nikolai Bogoraz.  Now Harold Gillies (the surgeon in my case) had written a paper in the 1940s which described a case he had performed.  All the references to Bogoraz’ work mentioned this, but gave the surgical date as the date of the paper; reading between the lines it was clear it had been done earlier.  But no-one had read between the lines (indeed I wonder whether many authors had done more than find the reference, and quoted it without reading the paper itself – a common fault). A bit of research in the archives of St Bartholomew’s hospital found the relevant details in the admissions and operating theatre books, and as a result that attribution of “the first” has moved to Gillies.  There’s an abstract at https://link.springer.com/article/10.1007/s00238-019-01539-5.  In similar vein to the Sudek story the invention of the tube pedicle (the basis of early phalloplasty) was almost simultaneous in England, Germany and Russia, but the issues of translation obscured this for a long time.

The moral of this tale is that you need to search the literature for precedents, and read it properly.  This is vital if you have a research idea.  Then decide whether you really want to do the study, or if you do it, refer to anything contradictory that has appeared before (because you need to postulate a mechanism for why your study shows something different).

What, you ask, is the relevance of this?  Well, I was intrigued by the reference to fat hormones, of which leptin is one, so I had a look to see whether any work had been done before. You too can play this game; type “leptin prostate cancer” into Google and see what happens.  In case you cannot be bothered – it has been done. Much of the research suggests that high leptin levels (which occur in the obese) are a risk factor for the development of prostate cancer.  So far from being protective, fat hormones may in fact be detrimental.  This work is 20 years old.  I use this example to show that science can be completely contradictory.  That said, I concede that the new study is looking at outcomes in established prostate cancer, not at the risk factors in its development.

Take a look at one of the papers that appears in the search results: Ribeiro, R., Lopes, C. & Medeiros, R. The link between obesity and prostate cancer: the leptin pathway and therapeutic perspectives. Prostate Cancer Prostatic Dis 9, 19–24 (2006). https://doi.org/10.1038/sj.pcan.4500844 (or go straight to https://www.nature.com/articles/4500844).  There you will read:

“Tumor and host produced proinflammatory cytokines (IL-6, IL-1, TNFα) upregulate the OB gene in adipose tissue, while leptin induces IL-6 and IGF-I production. This self-perpetuating loop allows tumor growth, involving leptin and other adipocytic molecules, contributing for tumor progression to advanced disease.”

Do you see where I am going? No?  So look again at https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2846344/ – “Role of Leptin in the Activation of Immune Cells”.  This one is only 10 years old.  It says, among the complex and almost impenetrable analysis, “The overall leptin action in the immune system is a proinflammatory effect, activating proinflammatory cells, promoting T-helper 1 responses, and mediating the production of the other proinflammatory cytokines, such as tumor necrosis factor-α, interleukin (IL)-2, or IL-6.”, and concludes “… leptin plays a role in the activation of the immune system, and it is a mediator of inflammation. In this context, leptin may be one of the mediators responsible for the low-level systemic inflammation that may be present in metabolic syndrome-associated chronic pathologies such as atherosclerosis, which is associated with obesity, especially central obesity. Therefore, leptin may be considered as a therapeutic target in some clinical situations, such as proinflammatory states or autoimmune diseases, to control an excess of immune response, as well as in other clinical situations, such as starving, to control an excess of exercise, or immune deficiencies, to improve the impaired immune response. That is why the investigation of the role of leptin in the regulation of the immune response remains a challenge for the future.”

Actually I quoted this before – in Blog 19, on 1^st May 2020… I had forgotten that!

Hypothesis: Covid-19 is a disease of hyperimmunity – a cytokine storm. Leptin levels are higher in the obese. Leptin stimulates the immune system.  Therefore Covid-19 is more likely in people with high leptin levels, viz the obese.

Observation: obesity is a known risk factor for Covid-19.  Q.E.D.

Conclusion: It is worth investigating the possible role of leptin antagonists as an additional way of damping the immune response (we already use a generic suppressant – steroids – and an IL-6 antagonist – tocilizumab). 

I have previously suggested using an IL-1 antagonist which is quicker and possibly safer (anakinra) which is already used in a childhood mirror condition, Kawasaki disease.

Now do you see where I was going?  From a report on the possible role of fat hormones on prostate cancer, through the mechanism of action of leptin, back to its possible role in Covid-19, which I flagged over a year ago.  Also have a look at https://www.acpjournals.org/doi/full/10.7326/L21-0062 and https://www.acpjournals.org/doi/10.7326/L21-0064

Time someone did a study?

The Wry Observer’s Covid-19 update (161)

The message from the last week is that misinformation, disinformation and obstruction abound in science. It is impossible to believe scientists who have been economical with the truth and journals that do not answer questions. In particular I have been disappointed with “The Lancet”, which has failed to respond to my letter requesting that the letter rubbishing the Wuhan leak theory last year, with head signatory Peter Daszak, be withdrawn because its content is questionable but, more importantly, that a significant conflict of interest was not declared.  This week’s British Medical Journal has a trenchant editorial which seems to suggest that the leak theory is gaining significant traction, and needs proper investigation. I note also that “The Lancet” has added a sort of conflict of interest declaration, but its record on publishing bad science is growing; Wakefield and MMR, hydroxychloroquine in Covid, it wasn’t a lab leak… all not very good from a reputation point of view, and people start to wonder whether they can trust its contents, or indeed the science published in other journals.

On past performance I doubt that there will ever be a definitive answer, but it’s a pity that there is a cover-up, whatever actually happened, and of a cover-up there is no doubt, given the amount of data that has mysteriously vanished from view. And it’s not as if lab leaks never happen; the last smallpox case in the UK, in 1978, was from a laboratory leak, and the department head committed suicide. See https://janetparker.birminghamlive.co.uk/ for the story; it’s a sad one. And a foot and mouth disease outbreak in Surrey was due to a leak in 2007 was due to a broken drainage pipe at the Pirbright research centre (https://www.newscientist.com/article/dn12615-faulty-pipe-blamed-for-uk-foot-and-mouth-outbreak/). So why not admit it, and the fuss will die down. Except, no doubt, the lawyers would get involved in developing compensation cases.

The other “it’s not rubbish after all” may turn out to be the ivermectin issue. Originally the research suggesting benefit was rubbished; now a new systematic review suggests it is more promising than previously thought. But the standard of evidence has been questioned: see https://ebm.bmj.com/content/early/2021/05/26/bmjebm-2021-111678 and https://academic.oup.com/cid/advance-article/doi/10.1093/cid/ciab591/6310839 for the one side, and https://journals.lww.com/americantherapeutics/fulltext/2021/06000/review_of_the_emerging_evidence_demonstrating_the.4.aspx for the other (which is critical of the second reference above from Roman et al, suggesting that that review was over-selective in the trials it analysed). At least the Oxford PRINCIPLE study is now looking at it seriously. Let’s wait and see what that shows before jumping to the conclusion (as some have) that its denigration is to maintain the use of higher-cost drugs, vaccines etc so that Big Pharma can make big profits, ivermectin being very cheap, as I have noted before.

And leptin has leapt in the news again (excuse the pun). At least, fat hormones are reported as being risk factors for prostate cancer. I’m not sure what other fat hormones there are, but this latest research suggests that obese people have a higher chance of their cancer progressing.

What has this got to do with Covid-19? More tomorrow. I have more reading to do, not least as the first thing that came up when I checked back the report in yesterday’s “The Times” was a paper published a little while ago. 2004 to be precise. But the evidence conflicts…