Vegan Dog Food... it's complicated!!

I was to write an irreverent blog on this, but I just did not get around to it yet
Here is a link to a more sensible one, co-written with my colleague Alex.

RBJ & Alex German Blog

Our full paper

Very Short Range HRV

OK, this blog is not ready for publication yet. Essentially, there has long been a question about how long a recording should be in order to capture a given frequency power of heart rate frequency.  In this paper, amongst other things, we test this with a computational experiment.   

and we conclude.....

/to be continued.

O'Brien et al 2022

DeepGANnel

Single channel analysis is tricky when you have busy channels

So it is down the rabbit hole we go.

DeepGANnel …finally published …and here is a blog about it.  So Blogging 101 says “your blog post should have a point”.  So this was my first stumbling point.  …what would be my point?  It could, of course, be the power of AI (that’s what we use in the paper), or the genius of our team that developed the idea? Well, OK taking all that as read; how about a blog about the “Trials and Tribulations of Publishing a Crossover paper?” It will be preaching to the converted I expect.  Long ago, as an early career scientist (PDRA), I submitted a nice little pharmacology paper to Journal of Physiology.  Senior author shall remain nameless.  This paper was rejected and this was somewhat of a shock to the said Senior Author: “I have never had a Journal of Physiology paper rejected before” he pronounced. A then colleague (now wife) whispered… “well he has now” which gave us all a good titter. The fail, was probably, not just my fault to be fair, but the aura of an impending change of tide.   I bet the days are gone where a few influential Senior scientists have their pet journals with guaranteed publication.  But here is the story of DeepGANnel's publication which as been... quite a journey!

I figured after chatting with Yalin, Jaume and Frans, oooh around 2018(?) that a deep neural network would probably be pretty good at identifying single molecule level activity in ion channel data records.  Thing is, by eye, you can often see the openings and closings of these proteisn, and sort of filter out the crap in your head.  But to have an algorithm do this is pretty tricky….  So I presumed some AI might be just the ticket to do this.   It works in our hands, yes, we’ve had deployment problems, changes to the underlying TensorFlow package we used etc…. But the basic principle is sound.  Published here. Blogged previously here.   

But the thing that makes this development really tricky is the need for masses of labelled training data.  Not just for ion channels, but scFRET, Nanopore or ECG etc.  You can’t just record these training data on a regular rig and go, because you don’t have the “ground truth” necessary for supervised training… essentially, you have no way to know whether a molecule was really open or closed to check if the AI actually worked.  We found some devious methods to get around that, but it left Numan and I wondering whether you could actually use a different neural network to create the training set with which you could later train a detection network?!  …so a simple idea was to use a GAN (first heard of after Numan/Jaume told me about them I think).  

Now the clever bit is really not our usage of a GAN, but the very idea of a GAN.   Here’s how they work.  One neural network draws essentially a random picture of a thing….  A second neural network tries to see if it looks like the real thing or not.  They then wrangle against each other until the picture gets more and more realistic. Forger versus Art Inspector...

So to deploy for electrophysiological data; we kind of turn a graph into a picture and then off you go.  Turning a graph into a digital picture and visa versa is really trivial since of course, in computing terms;  a picture is just a matrix of numbers anyway. 

One of the fun (relatively!) things about these networks is you can watch the neural networks “learn” in real time.  I’ve made a couple of cartoons of the training process here:  First the generator (forger) spews out nonsense….  But the discriminator (inspector/or art critic) keeps correcting it and gradually the generator starts to learn to produce the desired output.

Ion Channel Data: Top pair of graphs are raw data, simulated data below.  The orange waveforms are the labels [genuine at the top, simulated at the bottom] the blue lines are the raw data [genuine at the top, simulated at the bottom].

We had ion channels as our first target, but actually, with minor mods ECG is also pretty good. Although none perfect.  It should also be fine with Nanopore or single molecule FRET.

Rodent ECG Data: Top pair of graphs are raw data, simulated data below.  The orange waveforms are the labels [genuine at the top, simulated at the bottom] the blue lines are the raw data [genuine at the top, simulated at the bottom]. For ideal usage you have to stop it at the right moment too or you get "mode collapse" (don't ask!).

The first draft models were created quickly by Numan, but there was a problem.  We needed both the ion channel signal… and the underlying ground truth to be perfectly synchronised.  There was, so far as we (or the reviewers!!) were aware, no existing way of doing this? Sure various methods for associating the picture (say 512x512) produced with a particular label (cat vs dog vs car), but not a pixel by pixel ground truth.  So the “simple” trick we used was essentially to make a picture that was 512x2 pixels in shape.  Sort of a two lane picture.  The first 512 pixel lane is the current converted to a pixel grey scale value…. The second 512 pixel lane is the ground truth; probability of a channel being open or closed, again converted to pixel greyscale.  So they train perfectly together.

And it works!  We also tested it with an ECG record, as you can see above, it was fine with this too.  The signal is not absolutely perfect, but pretty good.  Anyway; now just needed to publish it.

Time Table: 

Beginning of the year, 2019… tossing around these ideas for synthesis of electrophysiological data with deep networks (Jaume, Numan and I).  Firstly using, so called “autoencoders” which rand quite nicely with 1 channel ECG data.  That was February 2019.  Then we started to try with the GAN approach.

13th December 2019 the name of the network; “Deep-GANnel” is coined….  Feb 2020 Numan published a conference abstract on this, but still just generating one channel of (unlabelled) data. The idea at this point was to then feed the output into a new network that would label it, datapoint by datapoint.  For me this didn’t really cut the mustard; what we really needed was this full annotation coming right out of the generator.  So we treated, as described above, the image then as a 512x2 (in fact many different widths) and hey presto it worked! 

Initially, we thought we just wanted it to generate any old ion channel data, so rather foolishly, we fed a wide range of different ion channel phenotypes in.  This was actually an epic fail.  It was like feeding in the images of a horse and a monkey and expecting it to simulate a realistic animal….. no you want it to produce horses right? ….so just feed it horses.  We realised you needed to feed in a seed of the exact type of ion channel you wanted it to simulate.  Now it really worked well.  

17th April 2020. First draft of the paper ….

25th June 2020. Submission numero uno:  Frontiers in SomethingorOther.  

10th July 2020

They’d had it for over a month; could not even find an appropriate editor and reviewer set.  AI-versant ion channel physiologists obviously far too rare!  

10th August 2020….  Frontiers (lovely office staff) still not found an Editor comfortable with dealing with this!! …So I officially withdrew Frontiers Submission to go elsewhere.

14th August 2020…. submitted to PlosONE!!

2nd Sept 2020… PlosONE start to admin process DeepGANnel.

2nd October 2020…. Rejected!!!!   …moderate rejection.  To me there are three possible responses to paper submission.  1) Never darken our door again, 2) Do a load more stuff… 3)  Make some little changes.     Option 4) “Sure!!”.  Is not something I have ever seen!!!!  So of course, there were some silly comments in the rejection (along with very good points!!), there always are, I don’t take it personally.  I may have been unclear, they may have misunderstood, I may have misunderstood them etc etc…. But the main thing they wanted was statistical evidence our methods were better than previous and wider examples of use (we only gave one previously).  Of course the first of these is strictly impossible. There is no statistical measure of “better” and so we added a whole series more ion channels, and also added UMAP and TSNE clustering to show, more objectively, how realistic the data are.  Also, and this is something I enjoyed including… a table of strengths and weaknesses of our method.  It was actually really nice to just ‘fess up to the limitations”!!! Less pressure.  So often in publication, you are trying to make something look as good as possible.  Total openness is refreshing!!  All the data; all the code, are on GitHub and FigShare.  Despite the disappointment the original rejection brought….   The next version is oh so much better!!!! So thanks to the co-authors AND the editor/reviewers for this …and I learned some new techniques in those fancy clustering methods.  As always, I was introduced to them by Jaume.

Took over a year, all the extra channels and experiments, to go again.

9th December 2021

Third Submission: 

OK, Admin fail here….  Some error in the format of our resubmission.  I think I highlighted changes, but tracked changes were necessary.

12th December 2021

Submitted again, with the change in format.  This time makes it through the office checks by 14th December 2021.

14th January 2022

Original Editor no longer able to be involved.  For all I know, they might not be well or just too busy.  Hope the latter, but never will find out.

21st January 2022

A new editor found!! Thanks so much!!

21st February 2022… REJECTED!. but a soft rejection really, kind of class “3” from above.

25th February 2022… resubmitted….

7th April 2022… admin office checks completed in PlosONE office and can move to editor… OMG. This means 6 weeks after submitting, we were told that it had passed formatting checks and would now be assigned to an editor, who would choose reviewers….  My heart sunk: Yet another delay!! This usually takes a couple of days max!

 But just 4 days after it landed back on the Editor’s desk…. Yay… deep joy!

11th April 2022 ACCEPTED… notwithstanding technical requirements, releasing the data we promised we would, clarifying funding etc. a further month of fiddling about with that type of thing. And proofs, as much as you get with PlosONE.

10th May 2022….. fully published….  So it was, off and on about 3 years.  Actually, by my standards this is typical or rapid :-)

And now on to the next paper…..

Some Selected Papers

Hey, I have just learned that, apparently, Altmetrics includes a tiny uplift every time a paper is cited in a blog.... so therefore, methinks.... better simply list a few recent papers here with Hyper-links and see if this works ;-)

I don't think I would sell my soul for bloomin' metrics, but I think I can stoop this low!!

This is probably the paper I am most proud of ever 😎. Interestingly, due to the Kaggle competition it is has received both some imitation AND some criticism. That's OK, nothing is perfect, it is all above board any errors are in plain cite. But the big picture is this is the first time anyone has seriously tried this whole new field of deep learning for single channel analysis and it works pretty well.  We need to develop it into a product now I think, but it was a pretty good start hey!!!

Celik et al 2020

We wrote this paper on the back of some combined patch-clamp and next generation sequencing.  It's OK and has some novel analyses in there, but of course it didn't pan out as we hoped. Essentially I feel that a lot of research is biased to studying the things you EXPECTED to see anyway. Put some Bayes theorem in there and plainly this biases sceintific progression generally. So I've launched a series of studies now that attempt to combine both the RNA sequencing and patch-clamp approaches! It's tricky 😂😂😂 Anyway, check it out and don't tell me what you think unless you think it is F.A.B. 😜

Haidar et al 2020

This is a review we wrote to try and big up, essentially, the study of ion channels. They influence resting membrane potential and end up having a far wider role in biology than people seem to recognise!  It seems to be doing quite well on citations etc, viewed more than 94% of all Frontiers articles.

Abdul Kadir et al 2018

Tail Docking - Again!

I was, with respect (as they say), very disappointed to read this recent tail docking monologue. OK, Prof Mellor accepts that there is no behavioural substitute for a dog-mounted tail, that tail docking is likely to result in chronic inflammatory pain and chronic neuroma pain..., but, he contests, that a puppy up to a few days old is incapable of feeling pain because they lack consciousness. He says that this is what the "science says", but I am sorry, but I think the science says no such thing.  I think the most straightforward uncontestable fact is that we don’t know, and maybe that we can’t possibly know.  

So what evidence does Prof Mellor present in this paper, to assuage us of the idea that neonates feel pain.  Well, this is a little embarrassing, because the paper is quite difficult to read from a critical perspective, it is written in many ways like a blog.  Whilst it includes about 25 self-citations these are kind of mostly references to the fact that he has argued previously that puppies don’t feel pain (or that different species attain consciousness at different times).  

At one point there is a line with 8 references followed by several sentences of the main argument (that puppies don’t have consciousness for several days)... but few specific facts in this section have their own citation! I am embarrassed to say this of someone so eminent, really, but that is no way to write a scientific paper. We want, in the main body, fact citation, fact citation et seq.  

I made the effort to try and track down those 8 references.  Most are simply self-citations of reviews. Not good enough. Mark = D- (not a U/E... because there was an attempt to use referencing). Whilst most are reviews, others were original scientific papers.  These were 1967 EEG papers showing that neonates have far less complex EEG than more developed puppies. Largely in the sleep state.  In fact, they DO SHOW that the EEG changes on nociceptive stimulus, but not as much as the adult.  It would be over-reaching to therefore state that they feel less pain (because we do not know categorically with old studies like that what the actual markers of pain would be except.. different to no pain), but that would be the most you could possibly say, from that data.  So cutting a puppy’s tail off would be, what 25% as painful as cutting an adult leg off? 15%? 30%? Still sounds pretty painful.

The main body does two things; one half attests that the reason we think they do feel pain is by ill-founded analogy with other species, and then... the other half rebuts this with, largely, analogy with rats.  

Unless you are prepared to read all the previous REVIEWS I didn’t feel there was any useful new information in this one paper. The basic mantra is: They don’t have consciousness, as evidenced by the fact that I have previously stated that they don’t have consciousness. 

So there’s a quoted paper (much more specific) showing the average yelps during the procedure is about 20.  Feeble-minded sorts like myself may assume that this is because it hurts, but of course the old argument is used that this a subcortical behaviour to signal the need for assistance from the mum. Clearly, as stated in this piece, nociceptive (pain) signal has traversed to the spinal cord and up to the sub-cortical yelp centres [partly agree], but it doesn’t reach the cortex because ...because he says so on the basis of previous reviews.  Why “partly” agree above?  Because studies have not even successfully located where the yelp centre is and how it is controlled even in adult dogs.  Big damage to pretty much any part of the cortex can suppress this “reflex” (reference: I say so - gosh isn’t academic writing easy once you can just quote yourself). 

So can I prove that puppies feel pain? Nope. I cite Occam's Razor (“the starting hypothesis should be the simplest”).  Now, this creates a problem.  If you really are deeply religious in a literal and creationist way you believe that man was created, then woman then animals. OR was it the other way around (Sunday School quite a while ago)? Anyway, they were created separately. Animals are sort of machines created for our entertainment.  So Occam's Razor could be that only humans feel pain.  In fact, I think some people believe that only they themselves feel pain!  ...my standpoint is that of evolution as a proven fact.  In that case, I would say that Occam's Razor is that all those responses that look the same are the same.  And you need an experiment to disprove it.  What experiment could you do? ...well it is tricky!! ...Maybe we should think about FRMI or something at least... are there cortical changes in the cortex of a puppy with pain... but even that means that we feel we really know where consciousness lies and we are not that sure.....  and anyway, those 1967 papers already showed that there is a cortical change on painful stimulus in a puppy.  So why would anyone be soooo desperate to dock a puppy that they would need to do those type of experiments just to shed light on whether the well recognised screaming really represents pain or not.... when we already no about the chronic pain, the neuroma and the tail’s central role in canine behaviour?

OARSI - Is pseudoscience making a come-back?

OARSI 2018, the international osteoarthritis conference is over, so what did I really think? 

What I liked:

• Friendly and lovely people, 
• Commitment to ultimately delivering improved patient care.  
• Enthusiasm from so many people.

And what I didn’t like:

• Food (lack of lunches!)
• Sending hundreds of tweets from the official OARSI account without being able to give my own opinion (I'm way too professional :-).
• An apparently general acceptance of “placebo”, “contextual response” and “clinical opinion”.

“Placeboists” & “Contextual Response”

Once upon a time, there were pretty much no effective medicines.  Gangrenous limbs could be chopped off and the joints cauterised, but that was virtually it. But plenty of “medicines” were still sold, mercurials, cupping, various charms and snake oils. These were all beneficial due to their placebo effect. …and when I was a child I was taught the purveyors were called “quacks” and charlatans.  

Remember Moniz’s leucotomy (pre-frontal lobotomy treatment of mental illness) and his Nobel Prize?

The leucotome, device invented by Moniz

Then these foolish things all started to lose out as science an medicine started to take over. We got water sanitation, antibiotics, anaesthetics, aspirin, opioids; wonderful painkillers, aspirin, the understanding of infection and the role of sterility in surgery, vaccinations… then antihypertensives, insulin injections, chemotherapy, antihistamines for acid, others for hay-fever, adrenaline AND anti-histamines for real bad allergies.  AND countless more.  The term placebo was then coined and we all knew what it meant: “patients were tricked into saying they felt better when really they didn’t”.

But osteoarthritis? Well sadly, there aren’t really any great treatments.  There are painkillers and surgery; in fact, physiotherapy and exercise seem to be best if patients can manage it. Hopefully, soon there will be new and effective treatments.  …but now it is pretty poor.

A side-effect of the paucity of treatments….. placebo is making a remarkable comeback.

So question: Why might an osteoarthritis patient report that their symptoms have improved?

1. Well, it may be because they have.
2. It might be because they are reeeaaaally bad at judging their own pain.
3. It may be because they are embarrassed about how much trouble they are being and how much they have just cost/spent.
4. It may be that they so desperately want the treatment to work they kid themselves, even though their pain is unchanged.
5. It might be because they didn’t really have real osteoarthritis, but aches and pains to some other cause and these were now less bad; their chronic pain had “regressed to the mean”.
6. It may be because they have given up, and accept there is nothing that can be done and decide to move on.
7. It may be because the treatment was so unpleasant they say they feel better to avoid further treatment.
8. The degree of pain prior to treatment is so variable, either intensity or frequency (or both) that is is literally impossible for patients to report accurately and they throw a bone to the investigator and guess on the low side after they have received treatment from an obviously well-meaning and earnest person.

All these things are possible, but it would seem that some investigators ONLY consider (1) is viable.  Then, since placebo clearly leads a number of patients to report less pain, these investigators extrapolate that placebo has actually made their pain decrease.  …and, therefore, there are now investigators, “placeboists”, actively promoting the treatment of patients with placebo.  Sometimes they call it other things “contextual response” is another way of putting it; if you give a nice painful injection with a kind and persuasive caregiver in a very posh looking hospital they are more likely to tell you that their pain is less.

These other factors also all help to persuade patients to report less pain; the pain of treatment, injection, price, the novelty of treatment, the authority of the administrator of the “treatment”.  

So does it matter that investigators are promoting consideration of placebo as a viable treatment? Hell yes!  It brings snake oil, crystal charming etc all back into play.  Things that were marginalised in bygone days will return.  Now presumably, once a really genuine treatment for osteoarthritis, that really works is invented these placeboists will either change their spots or be themselves marginalised.

But currently, the law kind of makes it difficult for people to treat with anything that doesn’t beat placebo. At this OARSI, however, there was an increasing volume of calls for “contextual treatment”.  

So spelling out contextual once more.. it means all those factors that persuade a patient to report lower pain OTHER than a placebo (or something that does decrease pain). So, it has been discovered that patients are so suggestible that not only can you trick them to reporting lower pain with a big fancy pill (placebo), you can do it with the environment, consultations, appearance of care or just kind consideration.  

Clinical Opinion

Feeding into this, is my second bête noire (or third maybe?): “Clinical opinion”. There have been several calls at OARSI for decisions over licensing of treatments to include not just clinical trials… but also to include “clinical opinion”.  In other words, calls to unpick the very standard which has been developed (double-blind random control trials).  Why?? Well because this happens; someone treats loads of patients with X.  The experience of a clinician is that they seem to be better, but the clinical trial says they are actually no better than placebo.  So what is happening is that placeboists are starting to say that just the fact that a clinician feels that a patient got better should be enough (or more fairly, a part of the equation) to decide whether or not to adopt X as a standard treatment.  Now to a non-scientist or statistician, that kind of logic probably seems fine. But to me it is horrific.  It is EXACTLY the same logic that was used by Moniz and the snake oil salesmen of centuries past.  

….now all this is understandable; it must be so depressing to see patients for year after year of your entire career and never really be able to help them.  So any suggestion that they may be slightly better is clutched at like a drowning man/woman clutching at an undersized life buoy.  Whilst some people pillory Moniz and his “brutal” leucotome, others accept that this was a genuine and desperate attempt to treat a then intractable mental illness. Anyone looking for a big pharma conspiracy theory can take a long walk on a short pier because placeboists are really nice genuine people who sincerely want to help.

But, some would argue, placebo causes real biological changes in the brain so it must be working? Nonsense. EVERYTHING causes biological changes in the brain. Standing up, thinking, walking; the brain is a bag of swirling chemicals and there is nothing you can do or not do that won’t change chemicals. Thought and love are just chemical and electrical activity changing.  Increases in endorphins??  Causing stress or inflicting pain itself increases the endogenous release of endorphins, so that is a particularly bad argument to use.

And does any of this matter? Oh yes, it matters, because when you treat with placebo and context you are with-holding real treatments however poor they are.  And if you end up treating with, for example, steroids which clinical trials show to not work (long term - they may help a bit over the first few weeks), you will do actual damage. Steroids for example do all sorts of awful things to people including weakening bones just for starters.

So what can be done: Well I could stop going to OARSI …. but to be honest, I firmly believe that once really effective treatments arrive it will be game over for “contextual treatments” and placebo.  Science and medicine will be able to fight back and I long for that as should patients and other investigators!!

Novichok/sarin/VX: The Science bit

The BBC report that comrade Sergei Skripal was poisoned with a nerve agent VX, and now we hear this is novichok and that “technically this is a nerve toxin”. Shocking. Shocking that the Science coverage can be so bad. For goodness sake “nerve toxin” is the “technical” term?? Seriously that is a classic case of the science bit having ….no science it. ….like a VSCI200 lecture. Shocking. This is, literally, the BBC’s full explanation: ”What are nerve agents? They are highly toxic chemicals that prevent the nervous system from working properly, and can be fatal:” Anyway, some waffle; then some science from me:
Russia must be a great place to be a pharmacologist. Not only are they making pharmacology a sport they are making sport, basically, pharmacology. Russian sports stars seem to dine on nothing but drugs; who needs milk and sugar on their cereal when they could have vodka and meldromium?

AND of course, the Ruskies have a long proud history of exotic poisoning…. That Bulgarian (Markov) killed with a ricin-tipped umbrella on London bridge, Hugh Gaitskill also to make way for Harold Wilson, and of course, poor Mr Litvinenko; Wall Street Journal and Business Insider lists a load of others too (they would).
Now Sergei Skripal. So questions: Why did they use novichok? and how does it work? How is it treated? What are the biological unknowns?

Why novichok? Well there is the political interpretation of which I am not qualified to answer. I am guessing they didn’t like him much (!) and wanted to make a very public statement that the KGB NEVER forgets. …but pharmacologically, novichok is very similar to VX and the magic of that, over say, sarin, will be it’s so-called ”*logP*” that’s a measure of how fat soluble a drug is. It’s one of the foremost chemical properties you think about when using drugs (medically). The point being that the more fat-soluble a drug is, the better it absorbs through the skin. VX itself has a much greater logP than good old fashioned sarin. Sarin would need to get in the body through mouth etc, but VX ought to absorb straight through the skin. That’ll be why. The next level of “why“ is why this family of drugs (organophosphates)? So many poisons,so little time. I don't have a crisp answer for this, but a guess: This family of drugs, the “organophosphates” were originally developed as pesticides. Most neurotoxic drugs are developed for research in minute quantities and quite tricky to deal with. The organophosphates were originally developed by the absolute bucket load and even dropped from planes. So it stands to reason that it must pretty easy to make in the large quantities you would also need for warfare. Yuk. What a thought.

How do novichok/VX/sarin work? Well that’s widely reported. Nerves communicate (signal to one another and to muscle) by release of “neurotransmitter” chemicals. …and it is important for this function that they act fast and are then removed from the system. In this case we are talking about nerves running to two major targets of interest, the diaphragm to allow breathing and the heart. The chemical in question is acetylcholine. When you breath, acetylcholine is released from the nerves and acts on (for example) the muscles of the diaphragm brings air in and out. The acetylcholine is then REMOVED from the tissue by the enzyme “acetylcholinesterase”. If it is not removed the muscle stays locked up and can’t relax…. you therefore can’t take another breath. Meanwhile, back at the heart, the heart rate would tend to increase to get some more of that oxygen-depleted blood around the system…. but it can’t, because acetylcholine, now at excessive levels acts at the heart to actively slow it. Usually, any ACh wafting about in the body is broken down in milliseconds in the actual place it is released (brain, heart, lung/diaphragm)… or just seconds if it over-spills into the blood. Now it is washing about slowing the heart and halting the breathing. Other effects? Of course, I anticipate some confusion, salivation and even stomach cramps…

How is it treated? It is widely reported that Vx and sarin are treated with atropine. This is a cheap and cheerful drug we use ourselves a lot experimentally (It speeds the heart in an interesting and predictable way). It is pretty safe, I have even seen a whole class (not mine!) given atropine as part of a class demonstration. It was originally a natural chemical extracted from belladonna. The story goes that Roman… ummmm… lady people in the “entertainment” industry of the time put it in their eyes; the pupillary dilation apparently conveys the impression that the wearer is full of lust? You know that look? …no me neither. Now a biological unknown. HOW atropine treats novichok/VX/sarin poisoning is NOT entirely clear. Let’s back up: Acetylcholine acts on two different classes of the target protein (“receptors”); so called muscarinic and nicotinic (yes nicotinic is the target also activated by cigarettes). The first of these targets (muscarinic) is found on the heart; the second (nicotinic) is found in the diaphragm. Yes, you will hear heaps of experts trotting out to tell you that it blocks the action of acetylcholine right? Wrong. Yes of course it does; but it only blocks muscarinics and typically you die to of nicotinic actions in the diaphragm. So this is my point (eventually); one expert after another trots out to explain that the muscarinic blocker atropine works by blocking the actions of acetylcholine even though they must know the fatal actions of novichok/sarin/VX mostly do no involve muscarinic protein targets!! So how does it really work? No one knows. OK, there is literature to suggest that, in contravention to 100 years of pharmacology, atropine has a small degree of “off-target effects” on the “wrong” type of acetylcholine target and this is JUST enough to save someone’s life. Other benefits will be that it speeds up the heart, under these circumstances that's a good thing. …the other unpleasant effects, salivation and cramps will be dealt with by atropine’s accepted actions. Of course (no time to check literature, but off the top of my head) oximes are also used. These seem to bind the organophosphate (VX/novichok/sarin) and take it out of action. Next, you’d have to keep people on a respirator until the agent eventually gets metabolised and clears. Eventually it should!!! Hang on in there guys.



Other recent Russian assassinations: http://uk.businessinsider.com/list-alleged-russian-assassinations-in-britain-litvinenko–2018–3

Do Lecturers Shit?

"Do lecturers get nervous?" 

I have been asked on more than one occasion the question "do lecturers get nervous before lectures?" So I thought I'd pull together to a few answers to potential questions like this.

1) Do lecturers get nervous before lectures?

Answer: Yes indeed some do. This is because they are animals closely related to humans and they have feelings, similar in a number of ways, to humans. To get stressed and nervous, to one degree or another is a common feature of animals including humans and lectures.


2) Do lectures get sad when told their lectures are rubbish?

Answer: Strangely some do. It is not fully understood why, but it could be the many hours they put into it combined with some genetic materials in common with humans.

3) Do lectures go to shops?

Answer: yes I often see the Tweet or hear the words "I just saw Dr X in xxxx (name of shop)" and also I have heard the comment "I just saw lecturer x walking along the street". Both of these phenomena are entirely possible. Like humans, lecturers sometimes have to move from one physical space to another. Often this involves walking or other form of transport. In fact some lecturers have dens, called "homes" where they go at night for shelter. These are often "off campus" and so they have evolved methods to get from Uni to their den and this sometimes involves some element of walking.

4) Do lecturers shit? 

Answer: (A) Indeed they do (not clinical lecturers obviously). Shitting is a naturally evolved process common to many types of human and animal. (B) Usually this is Done in private, and so reports of such activity are generally rare.

5) Do lecturers have to spend much time preparing lectures? 

Answer: Same answer as (4B).

6) Do lecturers mate? 

Answer: No. No they definitely don't do that. They just appear on campus one day.

Please Don't Wake Me Up Before You Go-Go

Just before Christmas @CVSControl portentiously tweeted a link showing that there is a spike in cardiovascular deaths over the Christmas period. One hypothesis was that people are dying of elevated emotional stress and that Christmas is an awfully stressful time for many. #Families. Come Christmas itself there was then a cluster of high profile deaths; Carrie Fisher and George Michael sadly died and initial reports (by the popular media) suggested that heart disease was involved. Then finally, in apparent response to the stress of the untimely death of her daughter, Debbie Reynolds too died of a cardiovascular event (stroke).  Now here are my questions: Firstly, is it even true that people die of sudden stress or what might be called “emotional shock”?  Secondly, if that is the case would there even be anything scientists could do about it anyway!!?  OK, spoiler alert: (1) Answer: Yes. (2) Answer: Probably, in the future.

Longer version. 

1. Does acute emotional shock/stress kill?

Now the Cardiovascular control Twitter Feed @CVSControl includes in its Bio: “Our live[s are] in the hands of the next rascal who chooses to annoy [us]”.  Sure enough, this phrase was written by Dr John Hunter (1728-1793) who subsequently, it is said, dropped dead of a heart attack during a particularly acrimonious University Staff meeting.

  …but, in fact, you will find the true dangers of getting cross or over-excited are not terribly well established. That said, we do know a fair amount about how the stress response (emotional shock) increases heart rate and blood pressure: What happens is that the brains of most animals from mice to people or dogs are wired to detect threats and send a burst of nerve (so called “sympathetic nerve”) and hormone activity to all those parts of the body involved with fighting or flight (aka escaping).  That’s great if you do need to fight or flight, but is it dangerous when this happens at other times?  You see the vast majority of people that die of heart disease actually have high blood pressure and atherosclerosis etc. Essentially they have their coronary arteries all furred up. In research terms, I don’t have the figures, but I am confident that the vast majority of cardiovascular research funding goes towards investigation of heart and blood vessels themselves, not their control. This perpetuates a myth that cardiovascular disease is all about those very hearts and blood vessels. So back to the question; does a sudden shock lead to cardiovascular deaths?  

Well there are lots of bits and pieces of data that suggest this is the case. For example there are spikes of heart related deaths during big football matches:

Three years worth of early summer sudden cardiovascular deaths are shown in Germany; 2006 (red) is the year of the World Cup and the numbers 1 to 8 indicate the dates on which Germany played. Spot the trend?

During the 17th January 1993 San Fernando Earthquake, many more people died of sudden cardiovascular death than would usually be expected for a normal January day. In fact the sudden cardiac deaths on 17th January 1993 were about 3x or more higher than the previous 3 years:

And yes Anger too; see (below) how many more people die shortly after bursts of rage:

And even just the shock of getting up in the morning is deadly:

I think the moral of this graph is you should definitely NOT wake me up before you go go.

...and now it would seem, Christmas is also a cause of sudden cardiac death!

Since, however, most of these sudden cardiac death victims have other types of cardiovascular disease too, believe it or not; this hypothesis is still not widely accepted. It will probably be impossible to ever prove it for sure, but I believe that the balance of evidence confirms that emotional stress can kill.

2. Could the acute stress/shock cardiovascular response be prevented?

Well, naturally that is something I, and a few other people are keen to explore.  Essentially, we think that if we can identify the exact nerves that cause sudden bursts of heart rate and increases of blood pressure we may be able to control them.  This might require a genetic approach.  Currently this is not possible, but it is coming.  Methods are on the horizon for making specific genetic alterations to specific nerves so we could literally turn them on and off.  Google “DREADDs” if you are interested, that is the name of one of the technologies!  (It kind of needs renaming though doesn’t it, because many people are already in “dread” of technology! ) So it's a tough ask, but this is the direction we are going. Hurdles: (i) finding the nerves involved, (ii) devising a genetic manipulation that allows limiting their function, without stopping them from working entirely i.e., if you are actually having a fight or making flight from a real threat! Finally, (iii) …eerm… the small matter of deploying these genetic manipulations in real people and other vulnerable animals. I think we can do it; but I have no idea of the timeframe. I expect it will be within my lifetime; unless of course, my own life is prematurely ended by some rascal that chooses to annoy me :-)

References:
Knight et al. 2016 J Am Heart Assoc, 2016; 5 (12): e005098
Mittleman MA, et al. 1995 Circulation; 92:1720-1725
Leor J. et al. 1996.  N Engl J Med 1996; 334:413-419.
Wilbert-Lampen U et al. 2008; N Engl J Med358:475-483.
Willich, S. N.,  et al. 1992.  Am J Cardiology, 70(1), 65–68 
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