Tales from the Ward

A Night in A&E

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By the time I got to my third shift in the emergency department, I thought I had gotten into a comfortable rhythm.

I would find a registrar who had lots of patients to see, offering to see some of those patients for them. After finding the patients and bringing them to an examination room, the standard routine would begin, a rigmarole which consisted of asking about what brought those patients to hospital and inspecting for any important signs on a physical examination. The end result of this would be a short summary of the patient prepared in my head, delivered to one of the junior doctors and documented in the emergency department’s electronic records system.

With a fair number of these done in the days before, my competence felt like it was growing – I felt confident and comfortable doing histories and examinations, although speed was an issue. At this point, each patient would take me nearly 20 minutes to see. Nonetheless, the variety of patients I managed to speak to in the previous 2 shifts refined how I gathered information from patients – a variety of pre-planned yes-or-no questions proved useful in ruling out specific causes (e.g. did this happen because of an infection, a problem with the patient’s vasculature, etc) early on, so I could start trimming down my list of possible diagnoses.

The start of this shift wasn’t unlike the last few. I was clerking patients for a junior doctor and had just come back to present the most recent patient to him.

“Alright, so what would you do next? You’ve said she has a yearlong history of palpitations and some recent chest pain, with no abnormal bloods or ECGs.”

“I think doing a 24-hour ECG (halter) might be merited.”

Pfoooooot.

I turned around to see one of the consultants blowing a raspberry.

“Wrong,” he says, getting up, explaining that the role of the emergency department is to rule out pertinent negatives (like heart attacks or traumatic lung injuries), not to investigate things like this.

“We refer them to their GPs and let them handle it. There are patients in far worse states who we need to dedicate our time to.”

“But given that she does have these palpitations somewhat regularly, shouldn’t we still organise the halter?” I regretted these words as soon as they were out of my mouth, realising that an ED referral would probably trigger a GP organised halter test. To use a military metaphor, consultants are the officers, the junior doctors are the sergeants, and the medical students are the newly enlisted recruits. What I had just done was akin to a recruit questioning an officer, and I had just provoked the wrath of the officer in question.

I saw a kind of sadistic glint in the eyes of the consultant, who reiterated his point, but now tacked on something else.

“Right, I want you to get this patient, Sandra Dumas, take a history and examine her. You have 9 minutes, starting now. Better get a move on!”

Foolishly, I replied confidently, “done,” while screaming internally, desperately trying to figure out how to compress everything he asked of me into 9 minutes. Even in exam settings (which we only had once before!), we have 10 minutes for a history and 10 minutes for an examination, never 9 minutes for both of them together.

I strolled away, trying to project an air of confidence, but the second I was out of his eyesight, I ran towards the waiting room and shouted out for Sandra Dumas, actively trying to avoid a nervous crack in my voice.

Sandra looks rather bored, sitting in a wheelchair with her adult daughter by her side. Her head perks up as she hears her name called, and looks up inquisitively at this person approaching her, someone who is far from an actual doctor.

I introduce myself to both of them and bring them into a side room, explaining that one of the doctors has asked me to see her. You could tell that she had used the long waiting time to think about what she wanted to say – she was incredibly systematic and organised in explaining how she had a fall 6 months ago which broke her pelvis in 3 places. She mentioned that an orthopaedic rod had to be put in to stabilise it and that some pain in the front of her hips began a few days ago.

Sandra looked down at me with fear and a tinge of exasperation as I examined her hips and legs, revealing that her surgeon had said that this sort of pain might begin if the rod slipped out.

Both her angst and anger that this might be happening were palpable in the consult room, and I was at a loss for what to say. I stood up, slightly panicked. What could I say? I was an underqualified medical student, who couldn’t really tell her with absolute certainty what was going on. This was someone who wanted to know right away why she was in pain and how it could be fixed – these were two questions I wished I could answer, but was all too aware that I didn’t know the answers.

“I’m not sure what is going on here, but the good news is that there is no shortage of people in here who will be able to tell what’s going on. The doctor who I’ll be bringing around is one of those people. The important thing is that you’ve come in here today to be seen by those who will know how to handle this situation.”

She smiles as I think about how cringy this soliloquy would have sounded to any observer.

Smiling back, I strip off my gloves and let her know that I’ll be bringing the consultant around. Once I know they can’t see me anymore, I race back to the consultant. “I’ve clerked her,” I announce, a little out of breath. He spins around, an eyebrow raised. “Really?” He queries. “Present her.”

In an excessively verbose way, I try summarising everything she’s told me. He nods at the pertinent parts of the story, particularly about how the rod could have potentially become displaced, and when I finish, he says “let’s go see her.”

We headed back to the consult room, where the consultant took the lead immediately. He introduced himself and was able to use an enviable charm which quite clearly put Sandra at ease. Summarising to the patient what I told him, he then began a more focused history, asking about specific changes to her walking to begin with. I couldn’t help but be awed by the slickness with which he was able to gather information, without being pushy or rude, but instead, with an air of grace and most importantly, kindness.

“My student and I are going to discuss your case and we’ll be back soon, just sit tight.” He announced, turning on his heel and beckoning for me to follow.

“What do you want to do next?” he asks, as we walk back towards the hub of computers around which a mass of doctors are huddled.

“X-ray her pelvis, get a full set of bloods to establish a baseline, possibly group and save if we think she might need surgery soon?”

“Not bad, I agree, let’s put it on the system,” says the consultant as he sits down at a computer, rapidly keying in orders for those tests. I thank him and start walking off to join the registrar I was originally working with, but without turning around, he says, “No, you’re sticking with me tonight. You’ve got a new patient to see,” gesturing at a new name on his screen.

“Grab him and do a full history and exam, this time you have 10 minutes,” he smirks, the first time I’ve seen him break into anything resembling a smile up until that point.  

And so the night went on…

Cambridge

Part II Pharmacology

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Introduction

Welcome to part II pharmacology!

This year is going to be a lot of fun, trust me. However, it is still worth considering that your grade this year will be the grade you graduate with (for the B.A), so there is still some work to be done (but not too much, ~50% of pharma people get a first :D). 

The course runs with 10 lectures per week in Michaelmas and 5 per week in Lent (none in Easter). In Lent, you’ll be working on your project/dissertation alongside this sort of work. Towards the second half of Michaelmas, you’ll have to get cracking on the drug review (piece of coursework where you have to explain how a drug works and how it was developed) – you can also do this over the Christmas holidays (I did). 

Exams consist of 4 papers (nice reduction from the 12 in 1B).

Paper 1-3 -> essay papers, pick 3 from a choice of 8, 5 hours.

Paper 4 -> data analysis paper (similar to 1B Natsci Trace Analysis questions)

For those who are thinking about part II pharmacology, here is a presentation I gave explaining how the course works generally, and why I would recommend it as a part II option.

part-ii-eveningDownload

Making the Most of Term-Time

My recommendation is to make all your notes in term time – given that Pt II exams are open book exams, notes are the currency of success and should be optimised extensively. Make your diagrams in term time as well and revisit the notes during the holidays, flicking through to see if you can make stuff more concise and if you can rework/improve diagrams. Don’t worry too much if you fall behind – the low lecture count means you can catch up fast. 

Lent gets a bit trickier because of the project. I wrote my methods and results in term time, finishing the discussion and introduction over the Easter holidays – this makes sense to me since the methods and results are what you’re really sinking your teeth into during the term anyway. You don’t necessarily have to finish the first draft within term (which is often very busy in itself).

I also think you should aim to write 1 essay a week in term. This isn’t too much work in the grand scheme of things and is VERY helpful. Make mistakes, screw up (this is particularly important), and try new tactics as early as you can. Identify what works well and what doesn’t and always keep track of this for future essays. It really helped me towards the end because I had such a clear idea of what I had to do in my essays going into the exams. Also, be warned that some lecturers won’t mark essays closer to the exams, so it does make sense to do the essays earlier – Easter term is a better time for essay plans rather than essays (more efficient).

Easter term is (in my opinion) the absolute best term during part II pharmacology. After you finish your project presentation, all you really need to do is prepare for the essays and practical paper for about 1 month. This is a pretty huge amount of time if you already made notes and diagrams in Michaelmas and Lent (+ holidays maybe). It would be completely fair to limit yourself to an hour/2 hours of work a day in this case (I did). 


Essays

Part II essays are a bit of a step up to 1A+B essays. To get a first, it is now absolutely necessary to have extra reading in, and to critically appraise evidence (this skill gets built up massively as you write your project I think). It’s also good to think about things from a bird’s-eye view – what are the major themes that link the ideas you are thinking about, and how can you organise the essay based on these themes?

As I alluded to earlier, it’s important to make mistakes early on. The words of Viper from Top Gun are particularly relevant here – “A good pilot always evaluates what’s happened, so he can apply what he’s learned.” By doing lots of essays early on and trying new things, you can figure out what you did right, what was wrong, and what you should be doing differently. I can’t emphasise how important this is in part II – there is a steep learning curve with part II essays and it makes sense to tackle this head on as soon as you can. 

In addition, the “pre-mortem” is a very useful tool for essays. It’s helpful to anticipate what you think you are likely to do wrong in essays because it allows you to acknowledge and deal with those impediments before you even start writing. I made a huge pre-mortem document summarising mistakes I thought I was likely to make, together with suggestions for how to work around these.

Paper 4

This is an interesting one – it’s all about analysing figures and data, which you’ll slowly get better at throughout the year, via discussion groups as well as your project. You can probably start working for it the week before, just practice 1B NatSci trace analysis questions (in their practical papers for pharma). There is usually a question at the end asking you to summarise all the data to a layperson as well – this can be quite fun, but be ready for it. Think about the audience indicated in the question as well, this tells you how basic your scientific explanations have to be.

Project

As I said, you can use the holidays to write up the discussion and introduction. Bear in mind that the discussion is where the majority of the marks come from, so you should weigh the word count accordingly – I allocated about ⅓ of my word count to the discussion. 

You can also put diagrams in your discussion (and conclusion) if you think you can nicely summarise your findings pictorially. I did my introduction last – it meant I knew exactly what bits of context I needed to have for my methods, results, and discussion to make sense. 

As for the lay summary, the heuristic I used was “if it seems way too simple, it’s probably at the right level.” It’s very easy to overestimate how easy to read your lay summary is – don’t just send it to science friends to check. My quality control test for the lay summary was checking if my best friend (who did MML+Management) could understand it. 

Drug Review 

Honestly, this bit of coursework has the best input:output ratio out of anything in part II pharmacology (or possibly Cambridge as a whole) – it took me about 21 hours to write my first draft and I only spent about 30 minutes a day after that reading it and making corrections. It’s pretty easy to write, just make sure you don’t miss any of the key findings with respect to the drug you pick. I would recommend picking an antibody-drug conjugate, considering that you have many mechanisms of actions (easy diagram for this too) and pharmacokinetic issues to talk about. 

To sum up – you’re likely going to have a fantastic year ahead with pharmacology – you’ll enjoy a huge amount of breadth, with lots of opportunities to read into what interests you.

Cambridge

Medical Tripos 1B

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Introduction

1B Medicine has gained a somewhat infamous reputation for being a really tough year, and this may seem daunting at first. However, it can be managed. Remember, you’ve already been through a year of Cambridge, you’re probably more set up to deal with this year than you were to deal with 1A when you first arrived.

However, there is definitely a lot of work to be done this year, just think about the light at the end of the tunnel (part II in third year is supposedly way more chill). Pace yourself, this is a marathon, not a sprint, keep up a reasonable level of work over the holidays and you should be fine!

Score Calculations

1B is out of 460, with 140 from NHB, 100 each from MODA and BOD, 80 from HR, and 40 from HNA. Of each of those subjects, half the marks come from essays.

The weightage of different subjects is kind of interesting, because it does show you that you can’t really neglect HR. However, the low weightage of HNA does make cramming it close to the exam quite a tantalising prospect.

HNA

  • There are 5 major segments to the manual, with 5 corresponding prosection sessions
  • This course only runs in Michaelmas, with an exam in Lent comprising of MCQs and short essays 
  • The MCQs are much more chill than FAB
  • The “essays” are really 3 paragraph long short answer questions, so it’s quite easy to plan most of the past paper questions
  • The embryology ones (there is usually 1) are often neglected, so the mark range is insane (10%-90% for one year)
  • If you can master your embryology, I would recommend going for this essay 
  • What I did for these exams
    • Learnt all of the manual + lecture content in the Christmas holidays and wrote myself mock MCQs (available on the drive)
    • Made a limited number of essay plans
    • Started memorising the manual and lecture content 1 week or so before the exams 
    • In tandem with this, I planned quite a lot of the essay questions, which was very helpful – the embryology ones are all pretty much cut from the same cloth, you can always chuck in CHARGE, DiGeorge and the other neural crest cell disorders
  • Interestingly, you can link this stuff to FAB embryology (for bonus marks I reckon)

NHB

  • Section I -> short answer questions, Section II -> Neuroanatomy and Neurophysiology paper, Section III -> tripos essays
  • I opted to make my own notes using lecture slides + notes, and just made flashcards off those to prepare for section I
  • My approach as a whole was to try to gain marks from the essays, so I made sure I planned at least 5 or 6 essays over Christmas
  • I also learnt all of the content for the prior terms over the succeeding holidays (e.g. Michaelmas content over Christmas, Lent content over Easter Holiday)
  • Biology of Neurons
    • Relatively easy, and always comes up as a essay title
    • I would try learning the experiments and the corresponding diagrams (particularly the LTP experiments), as this works well for essays
  • Senses
    • Generally, there is 1 essay a year asking you to compare and contrast senses, so it’s worth coming up with a broad framework for doing this
    • My framework (which is probably a bit too limited) operated along these lines (TET-C)
      • Transduction
      • Encoding
      • Thalamic Analysis
      • Cortical Analysis
    • From each of these ideas, I’d usually branch off to stuff like the molecular mechanisms of transduction, long v short receptors etc
    • Also I’d consider checking for plasticity under thalamic and cortical analysis, this is not usually covered, but worth talking about
  • Vision
    • Probably the most difficult NHB topic in Michaelmas, I went through this lecture by lecture, and the first time I did struggle to learn it
    • However, revisiting it a second time closer to exams, it felt a lot easier to learn, so I would suggesting learning this as soon as possible in Christmas, then revisiting it in Easter term
    • The diagrams for the last lecture are super confusing, especially those related to threshold, so maybe make a note of those axises and why they are what they are
    • Lots of definitions to cover, make sure you get them all!
  • Chemotransduction
    • Really quick and simple lecture
    • Make a note of TET-C for the senses
  • Hearing
    • Pretty chill set of 3 lectures
    • Make a note of TET-C for the senses
  • Somatosensation and Pain + Pharma of Pain
    • A bit trickier, worth knowing specific laminae levels for different pain/touch pathways
    • Again, experimental evidence introduced in this series is great for essays
    • The pharma of pain lecture is really good, ties in nicely with inflammation MODA lectures that you do at the end of Lent, so you could easily wait for that, and learn them together – I wish I had done this
  • CNS development and regeneration
    • The lecture notes alone probably will work for this, but know the little details, like which chemicals promote growth, what strategies there are for repairing nerve damage etc
  • Motor
    • Probably my favourite of the lot, very detailed but also quite logical
    • The essay questions tend to revolve around feedforward v feedback, so know which systems/reflexes would fall under which!
    • The basal ganglia stuff can almost be entirely learnt in diagram form, so this should speed up revision
  • Arousal, Motivation, Sleep
    • Pretty detailed for 3 sets of lectures, but sometimes you get an essay question on it
    • Know which lesions lead to what and why
    • Learn the sleep mechanisms well
  • There is usually an intro to psych lecture after this, but it’s pretty pointless, I didn’t bother learning it, apart from 1 or 2 experiments they mentioned in it
  • Emotion and Anxiety
    • Pretty chill lecture series, good tie in to the hypothalamus and amygdala stuff discussed in the arousal and motivation lectures, learn the links
    • There’s a good diagram for the roles of the amygdala in fear, it’s pretty complex but well worth learning for essays/section I
  • Attention – short lecture but quite dense
  • Cognitive Memory
    • 2 lectures, really easy stuff
    • Learn the models and know them well, also make sure to learn how to test for implicit vs explicit memory
  • Neurobiology of Memory
    • One of the harder bits of the psych course, there’s a good diagram that summarises information transfer into and out of the hippocampus that simplifies it massively
  • Addiction – 1 lecture, a bit tricky, but supervisions should help clear this up
  • Language – pretty chill I think, you can learn this in terms of the models and how they evolved
  • PFC + Cognitive Development – the former is in lent and the latter is in easter, but worth learning them together
  • Decision making and IQ – v little content, so you can distill this down to the essentials
  • Psychopathology
    • Irritating because there is a fair amount of content, and can come up as essays
    • However, you can add loads of extra stuff in essays for this

BOD

  • 30% MCQs, 20% prac, 50% essays
  • Essentially this is pathology, so you start off with immunology, followed by viruses – this is all of Michaelmas really
  • In Lent, you do bacteria, parasites, vascular and cancer (+ a small summary immunology lecture, which is super helpful for essays!)
  • Among the “big 3” (MODA, BOD, NHB), this is the shortest course, as you do not have any Easter lectures.
  • There is an initial introductory lecture which has some stuff on heat shock and cell injury, but I don’t think it ever got tested
  • Immunology
    • This is the nicest bit of the BOD course, it’s quite logical and easy to follow
    • However, the lectures can be up to 1hr 30 min long, so you could easily skip those, and just use the slides and the notes
    • If you want a jump start/want a clearer explanation of certain concepts, I highly recommend this book, it’s a fast read and isn’t quite as clunky as most other textbooks 
    • I didn’t like the way the concepts were divided up, so I made my own notes along these lines
      • Innate 
      • Complement
      • MHCs
      • Adaptive 
      • Autoimmunity and Hypersensitivity
      • Transplantation
      • Responses to Pathogens (Lent lecture)
  • Viruses
    • 7 lectures, all quite dense, but well taught for sure
    • For the classification system, I recommend drawing everything out and then learning that diagram, rather than testing yourself on individual groups
    • You can tie in loads of immunology to the immune response to viruses/evasion of the immune system by viruses, this is critical for essays, and there is a Lent lecture which deals with this
  • Bacteria
    • Probably the most interesting of the pathogens, but this lecture series is arguably the densest of all the BOD topics
    • You can use diagrams here to streamline your learning and improve your essays
    • The practical stuff is also really important here, you can do a flowchart for all the different bacteria types and how to identify them. Alternatively, a table works pretty well too
    • You can also tie in loads of 1A MIMS to this topic, particularly apoptosis – the intrinsic apoptotic pathway diagram works wonders when you have to discuss H. pylori! 
  • Parasites
    • I found this to be the most boring part of BOD, but you do need to learn this stuff, thankfully it’s only 4 lectures
    • I just compressed all of the slides + notes into 4 pages worth of notes and just memorised those
  • Vascular
    • I thought this whole series was just a test of brute force memorisation, because it just comprises of a series of lists you just have to know
    • However, since you would have done clotting + atherosclerosis in MODA prior to this, there is some familiarity
    • Diagrams here can also help, and would be useful in a vascular essay (usually 1 each year)
  • Cancer
    • The lectures mainly recapitulate loads of MIMS cell cycle and apoptosis signalling, so if you know this, you’re set
    • In addition, if you bring in the cancer stuff from MIMS, it looks like you’re going above the lecture material
    • Examples of MIMS stuff you can use
      • Myc, Ras, and Src
      • P53 pathway
    • Beyond MIMS stuff, there is so much out there you can add onto your cancer essays (usually 1 a year), and this would push you really high up 
    • I did a talk about how to approach cancer essays for the university’s Oncology Society – the slides are shown below.
Ardon’s Oncology Society TalkDownload

MODA

  • Probably the best organised 1B course
  • Same exam layout as BOD basically, but the MODA MCQ is generally much easier
  • What I found helpful was writing all my drug flashcards in term, and learning those in term time, it made revision later much easier, and also made supervisions bearable
  • Over the holidays, I made a bunch of drug tables as a revision exercise, and found this to be quite useful
  • There are also a bunch of drugs that are in the footnotes of the lecture notes which can be tested, so learn these too!
  • Receptors/Pharmacodynamics
    • This covers all the 5 main receptor classes, as well as all the pharmacodynamics stuff you need to know for the practical
    • I recommend making some sort of sheet that summarises all the equations you need
    • The receptor bits themselves are very simple, it’s mainly MIMS rehashed again, so it should be familiar (for the most part, there are some new things)
  • PNS
    • Even though this is only 5 lectures, it’s probably the densest lecture series
    • Thankfully, the lectures are really well structured, and the drugs come after the concepts are presented, so you can understand how they mess with the systems involved
    • Don’t neglect NANC transmission in essays on PNS stuff, usually this is what you would need for a good essay, whether it’s an essay on the sympathetics, parasympathetics, or even generally on uptake or termination
  • Cardiovascular
    • 6 lectures shared with vets, and then 4 medic specific lectures
    • Quite chill, recapitulates a lot of HOM, with the addition of drugs that control certain processes
    • Lots of ion channels in the first 1-2 lectures, detail on these would serve you well in essays, e.g. Nav essays which are common
    • The clotting lecture overlaps massively with BOD vascular lectures, so learning the cascade early in Michaelmas/Christmas break is a big help for Lent
    • Don’t worry if the anti-dysthymic drug lecture (lecture 10) feels confusing, the drugs in question are really tricky
  • Pharmacokinetics
    • Unlike pharmacodynamics, which is concerned with drug-receptor interactions, this is all about how the drug gets to the receptor
    • First 2 lectures are about the principles of administration, distribution, metabolism and excretion
    • Metabolism’s pretty cool, learning the specifics will help massively for the practical paper
    • Just like PD, I suggest creating sheets that summarise the equations you need to know
  • Chemotherapy
    • Likely ties with PNS for densest lecture series, although this is slightly more boring
    • The antibiotic stuff is really heavy, but diagrams help to expedite the learning process
    • Antiprotozoal drugs are really chill, especially since you’ll have done parasites in BOD before this
    • Antivirals are more tricky, and it’s worth splitting these up into the stages of the viral life cycle that the drugs interfere with, makes for a good essay structure as well
    • Anticancer drugs are pretty ok to learn, at time the names of the monoclonal antibodies can get complicated, but once again, diagrams help massively!
    • The last lecture is on resistance, and is probably the most interesting, but is also quite difficult
  • Immunology/Inflammation
    • After BOD immunology, first few lectures should be chill
    • A diagram for all the lipid mediator synthesis pathways is super helpful, especially for leukotrienes (which can get complicated)
    • Links nicely to pharmacology of pain when you get to NSAIDs and COX-2 selective drugs
    • Can combine the paracetamol stuff with the PK stuff in earlier lectures, might make for a good essay link
    • The monoclonal antibodies and DMARDs are horrendously named, so make some time for learning these, it will be difficult
  • Neuropharm (Easter Term)
    • I’m not very qualified to speak on this; crammed this in Easter term, and hoped I wouldn’t have to resort to doing an essay on it

HR

  • This subject only gets introduced at the start of Lent, usually 3 lectures a week
  • Sadly, not all lecturers provide lecture notes so I would recommend making your own for most of this course (I have starred(*) the bits which might require this)
  • Populations etc*
    • 4 or 5 lectures which deal with quite mundane stuff
    • Make sure you know how to calculate life expectancy and things like that
    • The Barker Hypothesis gets more grounding in the Easter lectures, so I wouldn’t worry too much about this till then
  • Gonads*
    • All about male and female gametogenesis + ovarian cycle and puberty
    • Lots of good diagrams to be learnt here, also commonly gets tested as an essay question
  • Fertilisation + Placenta
    • Super long block, with about 10 lectures or more
    • Coition, fertilisation, and implantation are best learnt together
    • Both placenta lectures are easily combined too
    • There’s a lecture on the immunology of pregnancy which gives you loads to use in placenta development essays
    • Then there are 3 lectures* which involve IVF, embryo loss and prenatal testing
  • Preparing for Birth
    • My favourite lecture block, very easily to understand and rooted in basic physiology
    • Maternal adaptations, fetal growth, parturition, fetal physiology, and finally, fetal adaptations
    • Lots of cool diagrams here, and also, you can very easily reuse 1A HOM knowledge to score high, like the resetting of the chemoreflex and baroreflex, how T3/4 and GH work, + 1A FAB (fetal circulation and shunts) + MODA re prostaglandins
  • Epigenetics + Sexual Health (Easter Term)
    • Crammed this in Easter, so not sure I’m qualified to advise on this

All the best with 1B!

Cambridge

Medical Tripos 1A

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The Basics

The 3 years of your undergraduate at Cambridge can be divided up into parts 1A (first year), 1B (second year), and part II.

1A encompasses 3 major subjects, Functional Architecture of the Body (FAB), a.k.a Anatomy, Molecules in Medical Science (MIMS), aka Biochemistry, and Homeostasis (HOM), which is physiology.

FAB

  • You’ll have 2 dissections in one week, and then 1 dissection the following week
  • There will be lectures that run in parallel, these can also be tested in MCQs
  • I’d recommend memorising the parts of the manual corresponding to each session before the sessions -> this really helps you to get the most out of dissection
  • Course Breakdown
    • Upper Limb – really make sure you know the origins and attachments of the muscles, this is very valuable for the MCQs
    • Thorax – probably the easiest topic there is, very easy to visualise
    • Abdomen and Pelvis – the hardest topic to visualise, it’s worth putting in the work to make sure you understand this during term, because it’ll be a pain to go over it in the holidays
    • Lower Limb – same advice as for upper limb, this topic is probably the smallest one
    • Embryology – these lectures run in parallel with what is covered during dissection, and also can come out in the MCQs

MIMS

  • 3 lectures a week, 1 practical a term (with a discussion session 2 weeks later), 2 PBL presentations across Michaelmas and Lent 
  • Michaelmas
    • You’ll start off with an introduction to diabetes, with 5 lectures on protein structure and enzyme activity
    • After this, the more nitty gritty stuff comes in, in the form of metabolism
    • This carries on for a while, the term finally ends off with cell signalling and protein sorting, the former is very useful for HOM, so I’d make an effort to try to learn this during term
  • Lent
    • The major theme of this term is molecular biology and the clinical linker is cancer, so the prologue and epilogue lectures will be centered on this
    • You’ll start off with the basics of the genome, then gene expression, followed by broad genetics 
    • The term ends off with the cell cycle and cell death 
    • There are also 2 lectures just on cancer; you can build on these for essays to score.
  • There is a lot of very specific detail you are expected to know, so build a system over the Christmas vacation that lets you learn it efficiently 
  • The practical paper is quite challenging, and doesn’t really get much attention in the practical sessions themselves, so I would recommend practising these over the Easter vacation
  • Make a list of experimental techniques so when you’re asked to suggest further experiments, you can jot down some good ideas when asked in the practical paper

HOM

  • 3 lectures a week
  • HOM doesn’t require as much brute force memorisation as MIMS or FAB, but you do have to make an effort to wrap your head around the logic of certain concepts. 
  • These are the major topics with some advice for each
  • Nerves
    • Quite a mathematical topic, you can usually relate most concepts to the Nernst equation, which I’d recommend understanding the derivation of
    • Learn the experiments; they could test them in MCQs, or you could use them in essays
    • Supervisions should give you some additional diagrams to use in essays, the ones brought up in lectures are a bit basic 
  • Muscles
    • Create a table comparing the different kinds of muscles, it helps to produce a nice mental schema for compare and contrast essay questions
  • Cardiovascular
    • Very content heavy topic, but well taught 
    • Make sure you understand Starling’s Law, because a good understanding of it helps for both respiratory and renal 
  • Respiratory
    • Get your head around what increases/decreases compliance early on, it makes life much easier later 
    • There are a lot of numbers to know for this topic, so make sure you use the right units for them
  • Renal
    • Again, very content heavy, and it’s the longest lecture series
    • Make a table for all the transporters, and for hyper and hypokalaemia/calcaemia
    • Get the Koeppen monograph – it explains stuff clearly and has loads of extra stuff you can use in essays 
  • Digestion
    • One of the easiest HOM topics, but the most content per unit lecture
    • Create a table for the GI hormones
  • Endocrine
    • This is actually a pretty good lecture series, probably worth going for, even though it’s in Easter

Some of My Resources

FAB

  • A set of tables I made summarising the anatomy of the upper limb, with blanked out tables by the side for testing

MIMS

HOM

Have fun!

Oncology

Cops and Robbers

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Cancer and the Immune System

Deep within us, an arms race rages, an evolutionary arms race which began eons ago, back when we were simple celled organisms. I speak of the immune system’s constant battle to deal with rapidly evolving pathogens, with its own unique strategies for developing highly specific weapons that selectively target these dangerous organisms. What seems curious, upon first inspection, is that if such a system exists to detect dangerous cells in the body, and can eliminate them, why is cancer even a problem?

To understand why this is, we need to consider some basic immunology before applying that knowledge to the challenge of cancer.

A (not so brief) overview of the immune system

Ed Yong, in one of his many excellent pieces on the Atlantic, illustrated the frustration associated with immunology very succinctly with a joke.

“An immunologist and cardiologist are kidnapped. The kidnappers threaten to shoot one of them, but promise to spare whoever has made the greater contribution to humanity. The cardiologist says, “Well, I’ve identified drugs that have saved the lives of millions of people.” Impressed, the kidnappers turn to the immunologist. “What have you done?” they ask. The immunologist says, “The thing is, the immune system is very complicated…” And then, the cardiologist says, “Just shoot me now.””

As with most jokes, this one has a basis in fact; the immune system is pretty complex. Let’s try to break it down, using the example of some nasty bacteria getting into the subcutaneous tissue beneath the skin of my arm.

The first thing to consider is that there are 2 branches of the immune system, the adaptive system, and the innate system. My innate system is the “quick and dirty” fix, detecting the bacteria using special receptors called Toll-like receptors (TLRs) present on macrophages, neutrophils, and Natural Killer (NK) cells. This recognition is very important, because it activates the “effector” components of these system, the parts that directly deal with the virus.

A particularly fun way of thinking about the interplay involved in this is to consider a classic scene from any mafia movie.

The garbagemen working for one mob clear out the trash from another mob’s nightclub, and see that the rival boss is just about to make his exit. They quickly signal the hitmen, who come in, and eliminate the threat to their organisation. In a very similar way, macrophages first detect the bacteria in my skin, and signal to the NK cells that there is a threat, and to be ready to recognise it and kill it, as well as to increase their number (akin to calling for reinforcements!). I’ve tried to illustrate this graphically below, marking the chemical signals involved for anyone who’s interested.

Image

Normally the innate immune system would deal with this bacteria really quickly (within 6 hours or so, quite often), but if this bacteria is a tricky customer, and one that really gets under my skin (excuse the dreadful pun), the adaptive system steps in.

There are certain cells which sample the bacteria, and take up some of its proteins, degrading parts of them. These dendritic cells then present the peptide fragments on their surfaces, while simultaneously being activated directly by the pathogen, through TLR interactions. This allows it to express molecules which it needs to interact with other components of the adaptive system, of note, the B7 molecule.

These activated, antigen presenting, dendritic cells now move down a chemical gradient to reach a lymph node close to my arm. They first present this antigen to a naïve T lymphocyte, and if recognised, the T lymphocyte could become active! However, an important factor to consider here is that we need that B7 molecule on the dendritic cell to activate the T cell fully, and thankfully, this molecule becomes expressed after the dendritic cell is activated by the pathogen via TLR interactions.

This activated T cell now goes on to activate a B lymphocyte, which will form an antibody producing plasma cell. The antibody that it produces will be specific to the pathogen, because the activated T cell could only activate a B lymphocyte that recognises the same antigen as it does. Pretty clever!

Here’s a snapshot of these 3 cell types interacting with one another.

Image

Antibodies are not the only factors at play with the adaptive response, important though they are. We can also produce a type of T cell, the appropriately named killer T cell. This cell recognises foreign cells and kills them directly, by activating the program for cell suicide. The antibodies and killer T cells help the tissue in my arm rein in this bacterial infection, and eliminates it from my body.

Huzzah!

Now that we have a functional idea of how the immune system works, let’s think about cancer.

Cancer

Siddhartha Mukherjee described cancer as a “distorted version of ourselves”; this is quite a telling metaphor, after all, cancer cells are just human cells with a few mutations in the right places. Since these grossly perverted versions of human cells are so unnatural, surely the immune system can deal with them!

One of my teachers in Cambridge proposed an excellent framework for thinking about how the immune system is linked to cancer. He said that the key is to ask 3 important questions.

  1. Does the immune system recognise cancer?
  2. If it does recognise cancer, does the cancer escape it?
  3. Can we use the immune system as a weapon against cancer?

Let’s start with the first question.

Does the immune system recognise cancer?

With the sea of mutations that a cancer cell accumulates, it’s quite likely at some point that some of parts of these mutated proteins might end up getting displayed on the cancer cell’s surface. We call this “neoantigen,” a new antigen formed by the cancer mutations. This is quite common in cancers where we see single DNA base changes, like in melanomas (because of how UV light interacts with particular bases in DNA), or lung cancers.

In addition, because the cancer signalling pathways might activate some stress mechanisms, stress signals might also become expressed on the cancer cells, allowing for recognition by NK cells. Cancer cells also sometimes reduce the expression of carrier glycoproteins which give immune cells a view into their transcriptional activity – these molecules are called class I MHCs. This reduces the risk of being picked up as a cancer cell by T cells, but these molecules also typically prevent NK cells from attacking cells, so by removing them, there is a higher probability of NK recognition, and NK mediated death.

I want to come back to the point about neoantigens, as despite the fact that we have this very clear danger warning for T and B cells to pick up on, it’s unlikely that they will. This is because the T and B cells are typically confined to the lymph, plasma and lymph nodes, unless a clear signal for their movement becomes activated. Therefore, it is unlikely that these cells would simply wander into a tumour environment. Ultimately this is symbolic of a much larger conflict; the need to preserve tolerance against self-cells, and the need to provide surveillance against cancer.

If we opened up tissues to B and T cells, there is a chance that some antigens that B and T cells were not trained to treat as a self-marker will be recognised as foreign, increasing the risk of a catastrophic autoimmune reaction. Although being able to surveil against cancer cells would be great, the risk of autoimmunity is probably too great.


There is some evolutionary logic to this as well; cancer was never a big problem for us until recently, mainly because humans rarely lived long enough to develop this horrific disease. Autoimmune disease was probably more of a concern, so in the evolutionary development of the immune system, there was likely greater pressure to minimise the production of autoreactive B and T cells rather than to increase surveillance against cancer cells.

So to circle back to the first question, it looks like the answer is, “it depends,” but for the most part, it seems unlikely that we would have immune recognition of cancer cells due to the complex distribution of lymphocytes in the body.

If the immune system does recognise cancer, can the cancer escape it?

Now, let’s say we’ve got our ideal situation. A T cell has identified a cancer cell and has received all the signals it needs to become active (an assumption we will get back to in a minute). What are its odds of being able to attack a cancer cell?

The issue is that cancer cells have a bag of tricks to outfox immune cells. For one, they can upregulate an enzyme called IDO in lymphocytes, which, when overly active, results in excessive tryptophan metabolism. When these lymphocytes become starved of tryptophan, they stop proliferating and enter a state of non-responsiveness.

Cancer cells can also create an immunosuppressive environment around them, by secreting anti-inflammatory chemicals like TGF-B and IL-10. The TGF-B acts on T helper lymphocytes, triggering their differentiation into a helper subtype called the iTreg, which is anti-inflammatory. This potentially reduces the risk of activation of immune cells which recognise a cancer cell.

The way in which this TGF-B production can occur is interesting, and merits some further discussion. The signalling pathway that eventually triggers TGF-B production involves a transcription factor called STAT5, which is quite pleiotropic, which is to say, it influences a number of signalling pathways and proteins. This transcription factor is implicated in the expression of cyclin D, the first cyclin in the cell cycle, which possibly explains why constitutively active versions of STAT5 are seen in certain cancers.

On the other hand, it is known that there are immune infiltrates in cancers, comprising mainly of killer T cells, which likely do some good in terms of slowing down tumour progression. In fact, patients with higher killer T cell levels in their tumours tend to have better event free survival rates.

So it sounds like having killer T cells in the mix is key to having an immune cell both detect and attack a cancer. However, it is not quite as simple as this. As I explained in my earlier diagram, T cells require a second signal, the B7- CD28 interaction. The major issue to activating killer T cells in a tumour is that the tumour cells do not generally display the B7 which is needed to effectively stimulate the killer T cell response. Therefore, that ideal scenario I posed at the start of this section is unlikely to come to fruition all the time.

However, one of the times when we might have such a situation developing is in blood cancers. This is for 2 key reasons. The first is that blood cancers are in the blood (forgive the axiom), so this means they exist in the same place as KT cells might. The second is that blood cancers can sometimes express high enough levels of B7 to stimulate a KT cell.

As great as this sounds, this indicates the KT cells do provide some surveillance, albeit what must be incomplete surveillance. If it were complete, leukaemias and lymphomas probably would not exist.

Since the last question is probably the most involved of the trifecta, I’m going to save it for a future post, so I can discuss it in the detail it deserves.

Image Riders on the Cytokine Storm
COVID-19

Riders on the Cytokine Storm

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In 1991, a storm struck North America’s eastern seaboard. Only this was a storm like no other. There was a strange set of circumstances that built this storm, with conditions rarely ever seen independently, let alone together. There was warm air that was moving in from a general low pressure area over the Atlantic Ocean, cold air coming in from a high pressure area closer to the shore and an unusual level of moisture in the air. This unique set of weather conditions led to what Sebastian Junger called, “the perfect storm” in his book of the same title.

perfect storm

A satellite image of the 1991 “Perfect Storm”

This occult combination of circumstances led to an Air National Guard helicopter crashing into the ocean, and a sword fishing boat going down, with all hands lost.

Similarly, there are certain conditions within some COVID-19 patients with can rustle up a different kind of storm; a cytokine storm.

 

What is a cytokine storm?

Cytokines are soluble factors that are produced to direct the aggressiveness and nature of the body’s immune response against a pathogen. In essence, a cytokine storm occurs when the immune system produces excessive, uncontrolled quantities of cytokines in response to a pathogen, which can lead to severe conditions, such as Acute Respiratory Distress Syndrome (ARDS) and multi-organs system failure.

According to WHO reports on the first outbreak in China, 13.8% of COVID-19 patients had severe responses to the disease, with difficulty breathing and blood oxygen saturation below 93% (blood oxygen saturation is ≥ 95% in healthy individuals). 6.1% of patients were classed as critical cases, with respiratory failure, septic shock and/or multi organ system failure.

A probable cause of these severe and critical clinical manifestations of the disease is cytokine storm; it can lead to respiratory failure, septic shock and multi organ system failure1. In fact, some of the severe cases of COVID-19 might be experiencing early signs of cytokine storm, and perhaps determining if this is the case might be helpful.

 

How does SARS-CoV-2 cause cytokine storms?

As I explained in my previous post, viral particles released by infected cells can be detected by alveolar macrophages (a white blood cell which is a part of the innate immune system). If it has been primed by interferon gamma, it can become hyperactivated, and will produce TNF-A, IL-1 and IL-6. These are all cytokines. The hyperactivated macrophages will also secrete chemokines, a type of cytokine that serves as a signal to attract specific cell types to the source. In this case, the CCL2, 3 and 5 chemokines act on circulating neutrophils and monocytes and pull them towards the site of infection, from the blood in neighbouring capillaries.

Elevated cytokine and chemokine levels in the lungs of SARS-CoV-1 patients2 is linked to increased neutrophil and monocyte levels in the lungs. This encourages a positive feedback cycle, because when these neutrophils and monocytes enter the lungs and encounter the viral particles, they too will secrete pro-inflammatory cytokines, mainly comprising of the same trinity we encountered earlier; TNF-A, IL-1 and IL-6. This leads to cytokine levels building up, potentially to very high levels.

To circle back chronologically, let us consider those primed macrophages, which were ready to be activated by the detection of viral particles. What primed them? In this case, it seems likely that natural killer cells (NKs) might have done the job. When NK cells encounter viral particles, they produce interferon gamma which hyperactivates the macrophages. They also produce interferon alpha and beta!

These two interferons are quite important at the start of an infection. This is because their binding to interferon receptors on infected cells triggers the “suicide” of the infected cell. If it encounters an uninfected cell, it “primes” the cell, such that when it does become infected, it will commit suicide. Therefore, early on in an infection, interferons help to clear off a fair number of infected cells, which at the time, would constitute a larger portion of the viral load. Quite an elegant system (when it works).

A problematic situation might develop if interferon alpha and beta are only released in the later stages of an infection, when the monocytes and neutrophils have already entered the lungs. These interferons act on the monocytes and neutrophils to trigger the production of more chemokines (like CCL2) that bring even more monocytes and neutrophils in. This exacerbates the issue of overproduction of cytokines. Therefore, it would appear that the timing of interferon release is quite important; early on, it has a greater chance of slaying the virus, whereas in later stages, this might come at the cost of rampant cytokine production.

In addition, it was found that COVID-19 patients requiring ICU admission had higher levels of CCL-2 and TNF-A compared to COVID-19 patients with less severe disease.

This paints the picture of a physiological landscape filling up with excessive levels of cytokines, in an uncontrolled fashion.

Why is this so dangerous?

In the words of Jim Morrison, with such high levels of cytokines, “there’s a killer on the road.” The riders on this chemical storm enter the pulmonary circulation, which collects newly oxygenated blood from the lungs, and delivers it to the heart. From here, the blood containing the cytokines is pumped throughout the body. These cytokines are now placed to affect any organs that are perfused by the systemic circulation, and to exert their key effects.

IL-1 and TNF-A trigger vasodilatation of blood vessels, widening them, and thus decreasing the resistance against the flow of blood. This therefore drops the total peripheral resistance of the body’s circulation. These 2 cytokines also increase capillary permeability, allowing more fluid from the capillaries to enter tissues, decreasing the volume of the fluid in the circulation.

These 2 changes have quite a significant impact on arterial blood pressure. The drop in total peripheral resistance directly drives a decrease in arterial blood pressure, because arterial blood pressure is equal to total peripheral resistance multiplied by cardiac output!

The drop in circulating blood volume decreases the stroke volume of the heart (the volume pumped out of the heart with each contraction), which in turn decreases the cardiac output, driving a further decrease in arterial blood pressure.

The drop in arterial blood pressure, if severe, is very dangerous. It essentially reduces the perfusion of the organs in the body, and this compromises their abilities to carry out their various tasks. They become starved of oxygen and other key nutrients, leading to multi organs system failure.

Chemokines and Neutrophils

As I mentioned earlier, chemokines act as chemoattractants for inflammatory cells. Neutrophils that have infiltrated the lungs, upon detection of the presence of viral particles, release CXCL-10, which helps to recruit even more inflammatory cells in , through a positive feedback cycle. This particular chemokine is closely linked to the manifestation of ARDS, and high serum levels of CXCL-10 are found in patients with severe cases of COVID-19.

What is interesting here is that there may be a causative link between the damage that comes with ARDS and the release of CXCL-10. A study in mice found that if one were to induce ARDS (via the injection of an endotoxin), there would be higher serum levels of CXCL-10, and the administration of an anti CXCL-10 antibody treatment actually reduced the damage that the ARDS caused to the lungs.

It’s an interesting point in favour of using anti CXCL-10 antibodies to treat ARDS in COVID-19 patients, but obviously, what may be true in a mice might not hold true in humans, so further research is needed.

IL-6

IL-6 actually has quite a fascinating activation pattern; although it is produced by macrophages in tandem with IL-1 and TNF-A, both of these cytokines serve to increase production of IL-6 by white blood cells, driving a further increase in IL-6 levels.

IL-6 serves to trigger the formation of Th17 helper T cells from naïve helper T cells, and these Th17 cells produce IL-17, which recruits more neutrophils to the site of infection (which is most likely to be the lungs at the start of a SARS-CoV-2 infection). As we’ve established, this isn’t necessarily a great thing, because the neutrophils both directly and indirectly drive further cytokine production.

IL-6 also plays a role in triggering a litany of pro-inflammatory events, contributing to the terrible outcomes associated with cytokine storm. In fact, serum levels of IL-6 in COVID-19 were found to be correlated with the severity of the disease, potentially reflecting the magnitude of its role in cytokine storm. IL-6 also has some interesting effects on the liver, such as ramping up production of C-reactive protein (CRP). This can act as a useful biomarker of cytokine storm in a clinical setting, but further tests would still be necessary to confirm the diagnosis.

Tocilizumab

In light of IL-6’s involvement in COVID-19 induced cytokine storms, a drug previously approved to treat cytokine storm coming about from CAR-T therapy, the “wonder” immunotherapy for cancer (which isn’t quite as wonderful as it would seem), is being investigated for treating COVID-19 patients. The drug, known as tocilizumab, is a humanised anti IL-6 receptor antibody, which binds to IL-6 receptors to inhibit downstream signal transduction. This has the effect of inhibiting the pro-inflammatory effects of IL-6.

An analysis published in the Lancet on 24 June 2020 looked at the results of a retrospective study that compared tocilizumab treatment with the standard of care (which included hydroxychloroquine) across 3 tertiary care centres in Italy. The study was specifically concerned with 544 COVID-19 patients with severe pneumonia, so this was looking at patients that fit within the WHO’s definitions of “severe” and “critical” cases. Interestingly, there was a statistically significant difference in deaths between the tocilizumab group (7%) and the standard care group (20%), with a p value < 0.0001. In fact, the group that received tocilizumab intravenously had a hazard ratio of 0.55 compared to the standard care group when invasive ventilation and death were considered as a single composite outcome (p value = 0.044).

Admittedly, I was quite excited by this paper when it was first announced, because the authors initially planned to use the Sequential Organ Failure Assessment (SOFA) as one of their outcome measures, which would help to establish a stronger link to cytokine storm suppression. Unfortunately, they replaced this metric with a more generic comorbidity index in the final results. Therefore, these results don’t strictly show if tocilizumab was working to improve outcomes by disrupting cytokine storms.

There are also some caveats to tocilizumab use that we have to consider. First, by actively suppressing the immune system, there is going to be an increased risk of secondary infection, as this study proved, showing that 13% of the tocilizumab treatment arm were diagnosed with new infections, versus 4% for the standard treatment arm. Secondly, tocilizumab has some prominent side effects, such as hypertension and headaches.

Admittedly, the theory supporting the use of tocilizumab, and indeed this paper, makes the idea of administering it to treat possible COVID-19 induced cytokine storm quite seductive. However, we have to be aware that there still is not a large enough body of evidence that supports or discourages its use to treat COVID-19 induced cytokine storm. As with many facets of COVID-19, more data is needed.

Corticosteroids

Another class of drugs that have been put forward as a possible treatment line for the overactive immune response to COVID-19 are corticosteroids. These drugs have the capacity to decrease interleukin production, so in theory, this could be helpful for treating cytokine storm in COVID-19 patients.

However, a systematic review in the European Respiratory Journal looking at 771 publications found that there was no significant evidence that the use of inhaled corticosteroids directly led to beneficial outcomes with regards to the treatment of ARDS (which can be a manifestation of cytokine storm) in COVID-19 patients.

On the hand, a cohort study completed just earlier this month compared ICU admissions and in-hospital deaths between a group of COVID-19 patients (whose disease had progressed to ARDS) that was given methylprednisolone (MP), and a group that was not given methylprednisolone. 18.1% of the group treated with methylprednisolone were admitted to the ICU over the course of the study (versus 30% in the non-MP group). 7.2% of the MP treated arm of the study died in hospital, whereas 23.3% of the non-MP treated group died in hospital. This suggests that intravenous MP might bring about positive improvement in outcomes for COVID-19 induced ARDS, which occurs in part due to overactive cytokine production.

Conversely, we need to consider the fact that this study only included 173 patients, and a full review of the data has not been completed yet; I’ve been eyeballing the raw data thus far. Further statistical analysis is definitely needed, preferably as part of a larger meta-analysis.

I’d be remiss not to discuss dexamethasone, another corticosteroid that has been widely reported to be effective in the treatment of COVID-19 patients with severe infections. It’s important to note that the RECOVERY trial which tested its efficacy only showed this benefit for critically ill patients, with severe complications including cytokine storm. There’s no need to stock up on dexamethasone for your house!

To sum up

It’s strange to think that the SARS-CoV-2 virus itself does not directly cause some of the most severe symptoms associated COVID-19. A lot of the damage comes from the immune system activating excessive pro-inflammatory responses through uncontrolled cytokine production, leading to ARDS and, possibly, multi-organs system failure.

I suppose a question that might be worth looking into is why some individuals are more vulnerable to COVID-19 induced cytokine storms relative to others. Perhaps this might have to do with higher TLR (toll-like-receptors) or PRR (pattern recognition receptors) expression due to a preceding infection, allowing for an overly robust response to SARS-CoV-2 viral particles.

However, even then, a major challenge remains with pre-empting a cytokine storm. Timing immunosuppression would have to be key; too early and the virus gains a foothold early, too late, and the cytokine storm begins its deadly rampage.

Identifying the right moment to act will be key.

Footnotes

1 There are other mechanisms by which COVID-19 can cause multi-organ system failure, but I’m restricting my discussion to cytokine storm induced multi-organ system failure

2 There’s not a lot of research that has been done on this specific relationship for SARS-CoV-2 (that I could find anyway!)

Further Reading

  1. Tocilizumab in treating COVID-19 – https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7118634/
  2. Systematic Review on Inhaled Corticosteroid Use – https://erj.ersjournals.com/content/early/2020/04/20/13993003.01009-2020
  3. Methylprednisolone study – https://clinicaltrials.gov/ct2/show/results/NCT04323592
  4. WHO report on the first outbreak in China – https://www.who.int/docs/default-source/coronaviruse/who-china-joint-mission-on-covid-19-final-report.pdf
  5. A discussion on COVID-19, cytokine storms and how we can treat cytokine storm – https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7194613/pdf/main.pdf

Image The Pathophysiology of COVID-19
COVID-19

The Pathophysiology of COVID-19

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Introduction

A health crisis is upon us at the moment, affecting nearly everyone in the world. It is a pandemic on a scale never before seen in the 21st century. The SARS-CoV2 virus, the cause of the disease we now know as COVID-19, has spread insidiously across the globe. This highly transmissible virus incubates in a human host for between 2 and 14 days, biding its time. During this time, a patient could be asymptomatic despite the presence of the virus, which has yet to rear its ugly head.

The reproductive number of an infectious agent can be broadly defined as the number of people that one person with the disease will infect on average, and for SARS-CoV-2, the reproductive number is approximately 2.2. Although this is lower than that of influenza (3), we should not take this disease lightly; it is far more complex than meets the eye.

With all the information publicised by governments and health organisations, the symptoms of this disease are well known, but how does the virus itself work within the body?

What I hope to do today is shed some light on the pathophysiology of COVID-19, looking at how various physiological equilibria in the body are disrupted by the disease. I’m going to be focusing very specifically on the lungs in this post, since the most common complication associated with COVID-19 is severe acute respiratory distress (SARD).

The Basic Structure of the Virus

SARS-CoV2 is a betacoronavirus, which consists of 4 structural proteins; the spike protein (S), the envelope protein (E), the membrane and the nucleocapsid. The S, E and M proteins make up the entirety of the viral envelope, whereas the nucleocapsid contains a strand of positive sense single stranded RNA (ssRNA). The spike protein is key here, because it enables entry into alveolar epithelial cells, the cells which line the inner surface of the alveoli in the lungs.

Interactions with Alveolar Cells

A key player that participates in the pathogenesis of COVID-19 is ACE2, (angiotensin converting enzyme 2), a membrane bound metalloenzyme. This enzyme has a very interesting function under normal circumstances; it acts to counteract the normal ACE enzyme. ACE is an enzyme which cleaves isoleucine and valine off angiotensin I to form angiotensin II, a potent hormone with various effects on the body’s vasculature and renal system. ACE2 counteracts the activity of ACE by cleaving angiotensin II to form the vasodilator angiotensin 1-7, reducing the concentration of circulating angiotensin II.

To get into alveolar cells, the S protein on SARS-CoV-2 must bind to ACE2. Prior to this binding, the S protein must be primed by a transmembrane serine protease on the host, a protease known as TMPRSS2. We could relate this process of entry to the firing of a two stage sniper rifle; the priming of S represents squeezing the trigger partially, and pushing to the second stage would represent successful binding following priming. This successful binding results in endocytosis, bringing the viral particles into the cells.

The viral ssRNA is uncoated within the cytoplasm, and makes vampiric use of the host cell’s ribosome to produce proteins. One of the first proteins made from the ssRNA will be RNA polymerase, which allows for the reading of the positive sense (+) ssRNA to produce negative sense (-) ssRNA. The newly produced -ssRNA will be used to produce +ssRNA and other small RNA strands. The +ssRNA will then be used to produce proteins in the rER, and which will then be trafficked to the Golgi apparatus. From here, the progeny viruses will be released by exocytosis into the extracellular space, increasing viral counts, and allowing the virus to gain a foothold. These processes can be represented in quite simply in diagrammatic form, as shown below.

Screenshot 2020-05-02 at 18.32.54.png

This process of viral self-replication within the alveolar cells triggers an inflammatory response, as it elicits the release of inflammatory molecules such as interferons, cytokines, DAMPs (damage associated molecular patterns, such as alarmin). These function as alarm signals to warn the surrounding cells, and components of the immune system, that a foreign pathogen may have entered the body.

The Immune Response

This klaxon reverberates throughout the body, but the alarm hits the lungs first. Interferons act on surrounding alveolar cells, mainly acting to provide protection against viruses. Alveolar macrophages detect DAMPs (through pattern recognition receptors) or respond to cytokines released by the infected alveolar cells, moving towards these cells. These macrophages can also detect the virus using a special kinds of receptors, known as toll like receptors (TLRs), which allow them to engulf viral particles through phagocytosis. TLR7 in particular is key here; it detects the ssDNA of the virus in the phagosome within the cell. This detection contributes to macrophage hyperactivation. The macrophages can also present the S protein on their plasma membranes, allowing for specific helper T cell recognition. This therefore creates the capacity for a more specific, T cell dependent immune response against the viral S proteins. In addition, the hyperactivated macrophages release more cytokines, including TNFA, IL-1, 6 and 8, as well as certain chemokines.

The release of some of these substances explains some of the symptoms of COVID-19. The characteristic dry cough that we all have been warned about is triggered by some of these cytokines stimulating nerve endings in the lungs. TNF-A, IL-1 and IL-6 play a role in triggering the high fevers associated with the disease, via interactions with the hypothalamus.

TNFA and IL-1 are also pro-inflammatory cytokines and make the capillaries around the alveoli far leakier. These factors also trigger the production of molecular anchors which recruit certain types of white blood cells; neutrophils and monocytes. The neutrophils and monocytes become trapped in the alveolar capillaries, stuck to the anchors. They then slip through the wider gaps in the endothelial cells lining the capillaries, moving into the interstitium and alveoli.

The neutrophils tend to release certain toxic substances (such as hydrogen peroxide) to kill the viral particles, and these substances can damage surrounding alveolar tissues, such as pneumocyte type II cells. These cells secrete pulmonary surfactant, which reduces surface tension in the alveoli. This is critical because the minimisation of surface tension is what allows the alveoli to stay open, allowing them to carry out gas exchange. Thus, the loss of surfactant production due to damage to pneumocyte type II cells can potentially cause atelectasis – the collapse of alveoli. This decreases the number of alveoli available to carry out gas exchange, which impairs the oxygenation of the blood, a point that I will return too later.

As mentioned earlier, SARS-CoV-2 indirectly increases vascular permeability in the alveolar capillaries via TNFA and IL-1. To understand how this can lead to comprise of lung function, we need to introduce an equation which neatly describes a number of physiological processes – Starling’s law.

Screenshot 2020-05-02 at 18.41.09.png

σ  is an important variable to consider here; it is a measure of the permeability of the capillary. An increase in capillary permeability will decrease σ. This therefore decreases the value of σ (Δπ), which represents the oncotic gradient which channels water into the capillary. As a result, there is reduced resistance to the hydrostatic gradient (as represented by the difference between Pc and Pif), which moves water into the interstitium.

This therefore increases net flow into the interstitium, causing interstitial oedema, which in itself increases diffusion distances for oxygen and carbon dioxide, impairing gas exchange.

This can progress to pulmonary oedema, with water entering the alveoli. This, combined with the interstitial oedema, can cause dyspnoea (difficulty in breathing) and hypoxaemia (low oxygen arterial partial pressure).

This explains 4 key symptoms of COVID-19; a dry cough, fever, dyspnoea and hypoxaemia. However, in more severe  COVID-19 cases, patients also exhibit higher heart rates and ventilation rates – tachycardia and tachypnoea. How do these symptoms come about?

Detection and Response to Hypoxaemia

Nestled in the bifurcation of the right and left common carotid arteries, and in the arch of the aorta, are carotid and aortic bodies respectively. These masses of cells consist of peripheral chemoreceptors, which detect low oxygen arterial partial pressures. If they detect reduced oxygen partial pressures, the chemoreceptors signal to the nucleus of the tractus solitarius, which then acts on the vasomotor centre to promote an increase in heart rate, producing tachycardia.

They do play a role in stimulating the lungs, but it is important to note that they are not alone in doing this. Central chemoreceptors, found on the surface of the brain, also play a role in producing tachypnoea.

However, to understand how these chemoreceptors work, we must consider what happens to the carbon dioxide levels in the blood of a COVID-19 patient.

Carbon Dioxide

As we would expect intuitively, the quantity of carbon dioxide in the blood would be high. The question is, how does this come about? The reality is that there are a number of causes, which tend to supplement one another.

First, because of pulmonary and interstitial oedema, the diffusion distance for carbon dioxide removal is increased, leaving a greater quantity in the blood. This increased diffusion distance also applies for oxygen movement into capillaries, thus decreasing the oxygen content of the blood. This plays a role in increasing the carbon dioxide content of the blood, via the Haldane Effect.

Why is this the case? Well, haemoglobin actually serves to transport some carbon dioxide, using its carboamino groups. Under low oxygen partial pressures, deoxygenated haemoglobin is a weaker acid, thus it would bind to more protons (acting more like a base).

CO2 + H2O <-> H2CO3 <-> HCO3– + H+

As a result of this, it reduces the number of hydrogen ions in the blood, shifting the basic equilibrium for the dissociation of carbon dioxide to the right (as seen above), producing more bicarbonate, which acts as a store of carbon dioxide.

Secondly, the decreased alveolar ventilation due to atelectasis has the effect of increasing the partial pressure of carbon dioxide in the arteries (PaCO2) directly, as seen by the alveolar ventilation equation.

Screenshot 2020-05-02 at 18.42.55.png

This equation relates PaCO2 to Va (alveolar ventilation), showing how as alveolar ventilation decreases, PaCO2 increases in an inversely proportional manner.

Central Chemoreceptors

Now that we have established how the carbon dioxide content of the blood has increased, we must consider how this is detected.

The group of cells to whom this responsibility falls to are the central chemoreceptors. They are found bilaterally at the levels corresponding to the origins of cranial nerves VIII to XI. We can imagine these chemoreceptors as being placed between the cerebral capillary circulation and the cerebrospinal fluid (CSF) circulation, within the extracellular fluid.

Screenshot 2020-05-02 at 18.33.05.png

Because the capillaries here are permeable to CO2, and not hydrogen or bicarbonate ions, only CO2 can move from the capillaries into the extracellular fluid and CSF. Thus, a rise in CO2 content of the blood causes increased CO2 movement into the extracellular fluid and CSF, reduces the ratio between bicarbonate ion and CO2 concentrations beyond its normal value of 20. This manifests in a decrease in pH, which is detected by the central chemoreceptors. As a result, the central chemoreceptors, via the central pattern generator in the medulla, trigger an increased rate of ventilation – tachypnoea.

Conclusion

Hopefully, this post has managed to shed a little light on how the SARS-CoV-2 virus affects the lungs.

I’d like to take this opportunity to reiterate the importance of practising social distancing. It’s difficult not being able to see dear friends and family, and to be stuck in our homes. However, we must remember that doing this allows us to flatten the exposure curve, reducing the risk to the most vulnerable members of society. We can help to spare them from the drastic effects that the virus can have on the body, most notably, the lungs.

I hope to further elaborate on this point in future posts about SIR modelling of the spread of the virus, if not, at least more on the immune system’s response to the virus.

Until then, keep safe and healthy!

*DISCLAIMER: I am not a medical professional; this material is purely for educational purposes.

Biology

Brain Size and Intelligence

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Not too long ago, I was reading about the differences between the human brain and the brains of chimpanzees. It got me thinking about how we as humans somehow possess a greater level of intelligence than primates (at least, that we’ve observed) despite similar brain morphologies.

Mainly to satisfy my own curiosity, I wrote a piece about brain size and intelligence in humans versus other primates. It’s been written in a bit of a pop science style (thought it was worth giving it a try).

Enjoy!

 

To what extent is higher-level intelligence in humans (relative to primates) attributable to brain size (cm3)?

 

Outline

  1. Introduction
  2. Background Information
  3. Discussion
    1. Immediate implications of a larger brain
    2. White matter and grey matter
    3. The cranial radiator hypothesis
    4. Neurotransmitters and GLUD2
  4. Conclusion

 

Introduction

Human civilisation can be traced back through millennia, from the time of the Mesopotamians and Aztecs, to the world as we know it today. As humans, we have formed cultures and traditions that have survived for centuries. We have created areas of knowledge, like science and literature, for which we have designed frameworks and sub-domains for people to produce more knowledge. We build skyscrapers, each taller than the last, we ponder over investments, driven to earn, and we perform experiments, always eager to expand our understanding of the world around us.

Our ability to do all of these things has been well established, but why is it that the other animals that belong to the primate order cannot perform the advanced cognitive functions that underwrite those processes?

The answer is simple and somewhat intuitive. Of the discovered species of animals on the planet, we display the greatest capacity to process and integrate large amounts of incoming sensory information, and compare this new information with the existing information that we hold. We also can think conceptually, as well as in abstract terms. In short, we display higher-level intelligence.

So how did this unique intelligence that humans possess come about? Why is it that we can feel that almost electrical tension in the denouement of Macbeth, and an orang-utan cannot?

This essay seeks to evaluate the extent to which higher-level intelligence in humans (relative to primates) can be attributed to brain size by considering the primate order and looking at how human brains in particular have evolved.

 

Background Information

First, let us establish some facts about the primate order. As we can see from the cladogram below, humans and chimpanzees both diverged from gorillas before splitting into two separate species. Interestingly, out of all the great apes, humans are outliers in terms of chromosome number; we have 23 pairs of chromosomes whereas the rest of the great apes have 24 pairs. Our second chromosome was formed millions of years ago from the end-to-end fusion of 2 ancestral chromosomes (Ridley, 2000)

cladogram

Following this divergence from the great apes (through the fusion of the 2 ancestral chromosomes), the animals in the homo genus (which initially started as australopithecines) underwent periods of evolutionary change, which gave rise to several distinct features, the most prominent of which is encephalisation – an increase in the volume of the brain. During the evolution of Homo sapiens, it is estimated that our brains were adding 150 million new neurons to its own vast array of neural circuitry every 100,000 years (Matt Ridley jovially labels the scientist who calculated this figure “a mathematical masochist”).

To translate this from the cellular to the physiological, the volume of the human brain increased nearly threefold, to its present volume of approximately 1400cm3 (Hofman, 2014). At the same time, the volume of grey matter and white matter in the brain increased, in conjunction with further cortical folding (the folding of the cerebral hemispheres). The brains of the great apes and primates, on the other hand, tend to be far smaller (350-450cm3), but display similar patterns of organisation in the brain; they too have the forebrain, which holds the cerebrum, the midbrain, in which the limbic system resides, and the hindbrain, where the medulla oblongata and cerebellum are found (Hofman, 2014).

 

Discussion

Immediate implications of a larger brain

Let us now move on to the question at hand, and consider the extent to which we can attribute the intelligence of modern day humans to brain size. As mentioned previously, it is clear that human brains are larger than the brains of other primates. So what does this higher brain size translate into?

The most obvious answer to this question is that a larger brain would have a higher number of functional neurons, as substantiated by the fact that humans have 86 billion neurons, whereas chimpanzees have 26 billion (Hofman, 2014). In particular, humans have a larger cerebral cortex, the centre for higher order processing in the brains of primates. The immediate result of a larger cerebral cortex is a greater number of neurons and nuclei dedicated to specific tasks, thus increasing the potential of the human brain to carry out a greater number of cognitive functions than our primate cousins.

White Matter and Grey Matter

However, it may not be the size of the cerebral cortex that has given the human brain an intellectual advantage over other hominids and primates. 50% of the human cerebral cortex (by volume) is composed of grey matter (Hofman, 2014). Grey matter consists of sections of the central nervous system that carry the cell bodies of neurons, their axons, their dendrites, the capillaries that nourish them, and most importantly, their synapses. The synapses are the points of communication between individual neurons. They are fluid filled gaps over which neurons will exchange chemical information to determine the direction over which an impulse will be propagated. In essence, they are connection points between different neurons, which may be associated with different nuclei (clusters of neurons with similar functions) in the brain, enabling different impulses from different parts from the brain to be linked and integrated to be sent to other nuclei. This forms the basis for higher order thinking – it is based on the summative effect of multiple pre-synaptic neurons producing a response in a particular postsynaptic neuron. In plain English, it allows us to synthesise new knowledge from multiple pieces of existing knowledge.

To sum up, the higher proportion of the human brain (relative to other primates) devoted to grey matter supports the argument that the size of the human brain may not be the main factor that has led to human intelligence.

However, we have to consider the fact that the human brain is, inexorably, larger than the brains of other primates. As a result, the higher proportion of the cerebral cortex dedicated to grey matter physically manifests as a higher volume of grey matter and therefore, a greater number of synaptic junctions, which forms more complex circuitry in humans than in primates. Hence, we have to consider the proposition that the higher-level intelligence that humans possess can be indirectly attributed to brain size.

Another point in favour of the latter argument relates to the proportion of white matter in the human brain. White matter, unlike grey matter, is comprised of the elongated axons that connect different nuclei. Hence, we can think of grey matter as holding the switches in the brain with the white matter forming the “wires” that connect a series of “switches” together.

As we can see below, the proportion of white matter as a function of brain volume in primates increases at a near exponential rate with brain volume.

IMG_0863

Does this correlation imply a causative influence conferred by brain volume? To answer this question, we must once again venture into the history of the evolution of the human brain.

As we know, there was a definite increase in the volume of the human brain as we diverged from primates. With this larger volume came with it a diaspora of different nuclei distributed around the vast neural landscape of the brain. This created a need to generate high interconnectivity between different nuclei, with short conduction delays. To strike a compromise between these two factors, the human brain evolved to create greater interconnectivity between nuclei by dedicating more of the brain to white matter, and reduced conduction delays by developing myelinated axons in the white matter.

Due to the development of this system, humans are able to integrate information from multiple sources seamlessly, establish patterns, and generate new information rapidly. We can therefore attribute these characteristics, which form part of what we define as “human intelligence,” to evolutionary changes that were necessitated by an increase in brain volume.

 

The cranial radiator hypothesis

On the other hand, brain size may not necessarily be the main reason why humans are the most intelligent primates. The human brain can only work as hard as it does, firing off countless action potentials in a second, because heat, a metabolic waste product of its activities, can be removed at such a rate that it does not inhibit brain function.

Unlike most other primates, humans have a shunt of veins that flow close to the surface of the cerebral cortex, helping to remove excess heat generated by the activity of the 86 billion neurons in the brain (Falk, 1990). This cranial radiator removes temperature as a limiting factor and facilitates greater neuron activity per unit time, thus increasing processing speed and possibly contributing to the development of human intelligence.

 

Neurotransmitters and GLUD2

Let us consider something we have touched on briefly, the neurochemistry of the brain, specifically the neurotransmitters found in primates. How do the neurotransmitters used in the human brain differ from those found in other primates? The minor role the size of the human brain plays in the development of human intelligence is most clearly illustrated when one considers the neurochemistry of the human brain. Although we share a large number of our neurotransmitters with other primates, we have different mechanisms to recycle them for later use. Could this be main reason why humans have higher-level intelligence than primates?

Take for example, the GLUD2 gene. The human version of the gene differs from that of other primates by simply 2 amino acids, but this change is sufficient in producing a more efficient version of the glutamate dehydrogenase (GDH) enzyme that GLUD codes for (Bradbury, 2005). GHD can catalyse the decomposition of glutamate (a neurotransmitter) into alpha ketoglutarate, or catalyse the reverse reaction. Thus, the more efficient GDH produced by the human GLUD2 gene gives rise to greater glutamate turnover, which could have facilitated a greater rate of synaptic transmission in humans relative to other primates.

 

Conclusion

Let us circle back to the question posed at the very beginning of this essay – to what extent can human intelligence relative to primates be attributed to brain size? Weighing all of the factors we have considered, it becomes clear that our larger brain size is, inexorably, the main reason we have a greater capacity to interpret and analyse information relative to primates. There is also an ineluctable correlation between brain size (cm3) and the proportion of white matter as well as grey matter in the brain. As a result, the larger size of the human brain allows for greater interconnectivity (brought about by a larger amount of white matter) between greater numbers of nuclei (conferred by a larger amount of grey matter).

Although the cranial radiator hypothesis accounts for higher neuronal activity, such activity would likely be impossible without the vast number of neurons already present in the brain, which exist in such high quantities due to the large volume of the brain.

However, the role of genes in giving rise to human intelligence through influencing the behaviour of neurons cannot be understated. Up to 100 genes are expressed differently in the human brain than in the brain of a chimpanzee. This piece of evidence lends itself to the idea that human intelligence could be a product of genetic factors, rather than morphological features. On the other hand, the two may not be mutually exclusive, as these genetic factors could also be responsible for the morphological differences in the brains of humans and other primates.

 

References + Further Reading

  1. Hofman, M.A., 2014. Evolution of the human brain: when bigger is better. Frontiers in neuroanatomy, 8, p.15.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3973910/

  1. Falk, D., 1990. Brain evolution in Homo: The “radiator” theory. Behavioral and Brain Sciences, 13(2), pp.333-344.

https://www.cambridge.org/core/journals/behavioral-and-brain-sciences/article/brain-evolution-in-homo-the-radiator-theory1/DC2C8FEF97A35B699DFE7BFEC2093CA9

  1. Ridley, 2000. Genome. Howes.
  2. Bradbury, J., 2005. Molecular insights into human brain evolution. PLoS Biology, 3(3), p.e50.

https://journals.plos.org/plosbiology/article?id=10.1371/journal.pbio.0030050

 

 

 

 

 

 

Cambridge

Applying to Cambridge

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An Introduction

Applying to Cambridge is not an especially easy process. There are a lot of steps involved, and some aspects of the application, such as the interview, are particularly challenging. What I hope to do here is shed some light on what applying to Cambridge entails, focusing in particular on Medicine, since that is what I applied for. However, this post may still be helpful for those of you thinking of applying to Cambridge for other subjects as well.

 

Why do you want to apply to Cambridge?

When I decided to do medicine, I decided to look into the frameworks that medical schools use to teach (for example, a large number of British universities teach Medicine through Problem Based Learning[PBL]). I found Oxford and Cambridge to be outliers; the traditional structure of both of their medical courses place heavy emphasis on aspects of Biology and Chemistry that underpin modern medicine. It’s quite a departure from PBL. In addition, the supervisions/tutorials they offer allow students to explore topics and walk away with a more complete understanding of them.

One of the reasons I ended up choosing Cambridge over Oxford is because in the third year, students can chose an area of their interest to specialise in, and will work towards a B.A in that subject. Oxford only awards their pre-clinical medical students with a B.A in Medical Sciences.

 

Some Statistics

What I’ve got below is a table with my calculated probabilities for getting into 3 British medical schools, based on data from Freedom of Information act requests. Note that this table only considers international applicants.

 

Application Statistics for International Students applying for 2018 Entry

University Number of Applicants Number interviewed Number of Offers Interview Rate (%) Offer Rate (%) Offer rate {after an interview} (%)
Cambridge 360 N.A 26 N.A 7.22 N.A
Imperial 716 74 34 10.3 4.75 45.9
UCL 728 78 37 10.7 5.08 47.4

It’s sobering to say the least, but one interesting thing to note is that Cambridge has a higher acceptance rate (for internationals) than UCL or Imperial.

I’ve put these statistics here because I’m sure that most people will find them anyway when they look into applying to Cambridge, but I want to make the point that these numbers should not disillusion anyone. They are cardinal, with no indication of how you, as an individual applicant with your own unique talents, would fare.

So don’t worry too much about this data.

 

The Application Process

In order, here are the things you’ll need to do if you apply to Cambridge (to do any subject).

Submit UCAS application

Submit SAQ (+ COPA if you are from outside the UK)

Sit for Admission Test (if applicable)

Attend Interviews

Wait for the outcome

Applying to Cambridge is fairly straightforward, it simply involves an earlier UCAS deadline and the SAQ, as well as COPA (if you’re an international applicant).

 

The Personal Statement

The UCAS personal statement is something that Cambridge focuses less on, relative to other medical schools. I would advise having at least one paragraph dedicated to an area of academic interest, as this will certainly get their attention. However, they will still want to see evidence of the other key attributes of a doctor (such as the ability to work in a team, empathy, communication skills, etc.). In fact, Cambridge is extremely candid about what they are looking for in their medical students; they have an excellent document here spelling out their criteria for admitting students to the course. I wouldn’t recommend mentioning extra-curriculars unless you can directly link them to the criteria that Cambridge has for medical students.

Be prepared to talk about whatever you wrote about in your personal statement – it may not happen, but the interviewers could ask you about anything you’ve written on it. In the COPA form, you have the option to write an additional “mini personal statement,” which I highly recommend writing. It is worth using this space to explain why the Cambridge course in particular suits you.

 

BMAT

After you send off your UCAS and COPA forms, you will have to sit for the Biomedical Admissions Test (BMAT). It consists of 3 parts, a data analysis and reasoning paper (section 1), a science paper (section 2), and finally, an essay (section 3). The first 2 sections are MCQ papers.

This test is a particularly difficult hurdle to cross, owing to the time limits. Section 1 has 35 questions and is an hour long, section 2 has 27 questions to be completed in 30 minutes, and section 3 is also to be finished in 30 minutes.

I found that the best way to prepare for this test was to do as many practise papers as possible. It helped me to get familiar with the techniques required in each section, particularly in section 1, where similar sorts of questions are often repeated.

Section 2 may present a challenge due to the time constraints and scientific knowledge required, particularly because knowledge of GCSE physics is required (and most prospective medical students likely have not touched physics since their GCSEs). To get around this, try working on completing past section 2 papers under timed conditions and get familiar with all of the scientific concepts that are required for section 2, by way of reading textbooks or making notes. I made some physics notes commensurate with the 2018 BMAT syllabus, which you can access here, together with the list of equations I used as a reference.

 

The Interview

The Cambridge interview is unlike most other medical school interviews.

In their interviews, they are essentially looking for a brain in a chair (as morbid as it sounds), someone who can work through problems in a biological or chemical context, and offer creative solutions to these problems. They aren’t expecting the correct answers; they want to see if you can provide possible explanations for particular phenomenon and if you can rationalise newly presented problems. The interviewers will also likely end up as your future supervisors, so they use the interviews to figure out if you’ll be fun to teach and if you’ll fit the Cambridge style of learning.

To prepare, I suggest going over material you’ve covered in Biology and Chemistry (or whatever your main subjects are), but with a minor change. Try verbalising the concepts that you are revising – it’s good preparation for the interview. Question why and how things happen in Biology and Chemistry, but try to work out an answer before googling it. A really fun one I worked out in school was why the equilibrium constant is not affected by pressure or concentration. Here’s the proof I came up with, try giving it a go yourself before you have a look.

At the interview itself, the best thing to do is to think out loud. Ensure that whatever is going through your head is communicated clearly to the interviewers. As long as your reasoning is correct, you should do fine (in theory).

 

How they decide

The interview is not the be all or end all for an application to Cambridge. In fact, they consider each application quite holistically. In reality, the director of studies for each college, together with the fellows, sit together and weigh each application on the merits of interview scores, grades (predicted or actual), fit for the course and various other factors.

 

Final Tips

  • Remember, your reference is important too – make sure you have a good relationship with your referee, and keep him/her up to date about your achievements.
  • If you’re going to mention any books, make sure you have a good grasp over what they cover.
  • Silence is your friend; take a moment or two after you’ve been asked a question to think about it, before you start speaking.
  • Get some practise for the interview – ask your teachers or friends to ask you some really probing technical questions about your subject.
  • Read widely about your subject. For those interested in Medicine, I have a book list up here.

 

All the best!

Books

Books

ardonp1 Comment

I’ve always enjoyed reading; it’s a great way to escape from the physical world around us, and offers us the chance to expand our knowledge within so many different fields. These are the books that I have found to be the best – in the sense that they are analytical, informative and well-researched. They also are just very fun to read, owing to the linguistic talents of their writers.

 

Medicine 

Complications – Atul Gawande 

An introduction to the complexities within medicine and an exploration of how in medicine, weighing the probabilities of possible outcomes is key. Gawande has 3 more books, but this is probably the best of the lot for those considering medicine.

Checklist Manifesto – Atul Gawande

I’d be remiss not to include this – it’s undoubtedly Gawande’s best book, but it does branch off from medicine occasionally. Gawande’s thesis is that a simple checklist could help to improve both accuracy and efficiency in medicine. The approach he takes is extremely analytical and evidence-based, which makes it a delight to read.

The Emperor of All Maladies – Siddhartha Mukherjee

This book sparked my interest in medicine; it is a brilliant exploration of the history of cancer, running in parallel with stories from the trenches, of people Mukherjee has treated over the years.

Do No Harm – Henry Marsh

Henry Marsh has put together an amazing compendium of stories from his time as a neurosurgeon. He discusses not just the scientific aspects of neurosurgery, but also the day-to-day problems that a large number of surgeons and doctors face, working in the NHS.

 

Science 

Surely You’re Joking, Mr Feynman! – Richard Feynman

Even as someone who has a minimal interest in physics, I found Feynman’s enigmatic recounts of his scientific endeavours, his own moments of personal exploration and discovery, and his tales of life as a teacher to be nothing short of page turning.

DNA – James Watson

James Watson’s “The Double Helix,” is by all accounts a brilliant book, but it is extremely anecdotal. His much meatier “DNA” is a more scientific exploration of not just the initial breakthroughs in the field of molecular biology, but also the subsequent advances in gene technology that it spurred. It covers events from the isolation of DNA to the current issues regarding the use of genetic technologies to produce designer babies.

The Music of Life: Biology Beyond the Genome – Denis Noble

The thesis of this book is, essentially, a well-mounted counterargument against the idea that life arises purely because of the existence of genes. It’s very well writen and extremely holistic, weighing the ideas put forward by prolific writers, like Richard Dawkins, and evaluating them thoroughly.

What is Life – Erwin Schrodinger

This is the book – the one that led to both James Watson and Francis Crick turning their attention to the then-expanding field of Biology (specifically molecular biology). It explores how the laws of physics can explain the behaviour of the gene, a very abstract concept at the time, which led to Schrodinger’s famous proposition that DNA was an “aperiodic crystal.” It took me a while to get through it, but I’ve made some notes on the links to Biology it proposes here.

 

Miscellaneous Books

These are books that I’ve mainly read for enjoyment; I’ve found them to be very informative and entertaining.

 

Algorithms to Live By – Brian Christian and Tom Griffiths

The Right Stuff – Tom Wolfe

Hiroshima – John Hersey

The Tipping Point – Malcolm Gladwell

Flash Boys – Michael Lewis 

 

This list isn’t meant to be definitive, there are a lot of other great books out there, these are just the ones I’ve found to be the most enjoyable and informative.

 

Enjoy!