Prediction: It will end up being used by the military and/or fighters to provide instantaneous muscle strength coupled with pain relief from overexertion.
With soldiers it makes sense to use it explicitly to enforce the "fight" mode as needed. This can range from "occasionally in emergencies" to "all the time".
But militaries have famously not cared about the long term health and well being of their forces past their active use. So any consequence of "long term fight mode" past victory day are just the cost of doing business.
The problem with this drug is that it inhibits one of the final stages in viral replication. This means that before it can work the virus has already infected the cell and added its RNA to the host cells DNA permanently.
So if a patient is exposed to HIV while on the drug, this will not prevent their cells from being infected with the virus. The infected cells will not subsequently create any virus, and therefore additional cells will not be infected, however nothing prevents actual exogenous HIV from infecting cells while on this drug.
That means that if someone discontinues the drug, cells that have been infected with HIV during the time they were on the drug can start producing it causing AIDS.
It’s great that there’s a drug that works as well as this for chronic use, but nobody should think that it’s actually preventing infection. It’s allowing infection but inhibiting viral replication post infection.
> The medication works in two ways: First, it interrupts viral replication by preventing HIV from reaching the nucleus of an infected cell, which then blocks reproduction.
> The second mechanism is for cases in which integration of the HIV genome has already occurred. In this instance, lenacapavir interferes with production of viral progeny
In other words, it has multiple mechanisms of action and you are only discussing one of them.
> Its multistage inhibition entails the process of selective binding to the interface between capsid subunits and such interaction determines the inhibition of capsid-mediated nuclear uptake of HIV-1 proviral DNA (by blocking nuclear import proteins binding to capsid), virus assembly and release (by interfering with Gag/Gag-Pol functioning, reducing production of CA subunits), and capsid core formation (by disrupting the rate of capsid subunit association, leading to irregularly formed capsids)
This sounds like a sort of plausible mechanism, but do you have any actual evidence that this occurs in real life? I admit that I’ve wondered whether the PrEP studies with lenacapavir actually measure what they thing they measure given that the same lenacapavir may prevent HIV from replicating enough to be detectable.
That being said, Wikipedia doesn’t really agree with your mechanism. See:
I think, though, that the underlying assumption is that the old virus hangs out, forever waiting for the moment to strike.
Cells senesce and die and get replaced, and the immune system is always active in the background. If the virus particles are released, the immune system is going after it and cleaning up. As essentially no new virus is being created, this is the body's opportunity to clear the virus at a slower, manageable pace where it doesn't have to contend with a rapid, expanding infection.
It feels like one of those ideas that's technically true in all the right ways, but misses one crucial piece that would make the whole thing accurate.
> Cells senesce and die and get replaced, and the immune system is always active in the background. If the virus particles are released, the immune system is going after it and cleaning up. As essentially no new virus is being created, this is the body's opportunity to clear the virus at a slower, manageable pace where it doesn't have to contend with a rapid, expanding infection.
If this really applied to HIV, then people with HIV who take effective antivirals for long enough would be cured. But they generally aren't.
This is great information and obviously new to me. I had thought it only interfered with cap formation but it appears to also interfere with capsid penetration of the nucleus and therefore integration of the virus with the host cell genome.
This is incredibly misinformed, the drug has been specifically studied as prep, and this is in fact not at all what happens, despite your theories about the drug's mechanism of action. It does prevent infection.
How, exactly, does the “specifically studied as prep” process determine whether a person *who is taking a very long-active antiviral medication” acquired HIV?
It gives no details whatsoever about how testing was performed except to mention that both rapid and central laboratory tests were used. It does not discuss whether the study medication could interfere with testing. It does not even say whether the tests looked for antibodies, RNA or something else. The actual study protocol is in the paywalled supplement information.
I’m not saying the studies are wrong. But I would be a lot more impressed if the studies actually discussed the issue.
I want to emphasize that the parent comment of all this is straight up incorrect on the mechanism of action of this drug class.
"This means that before it can work the virus has already infected the cell and added its RNA to the host cells DNA permanently." is not correct, capsid inhibitors interfere before both reverse transcription and nuclear import.
Both of the drugs in Truvada, which was has had 13 years of use in the wild since approval and is very successful, are NRTIs, they work at the reverse transcription step, they are literally later in the cycle than the new drug (but before nuclear import also) and work just fine as prep.
So the whole premise for why this drug in particular shouldn't work in theory is flawed.
To your questions about how the lenacapavir trials were run and why they rule out occult infection (which is the term for what you're describing): I'd like to find more details on the study honestly. But do I think the multiple studies that convinced the FDA to give approval just completely overlook this well known concept/possibility? Not really?
My general level of trust in the FDA to ask the right questions is low enough that I certainly don’t believe any argument of the form “if it’s good enough for the FDA, it’s good enough for me.”
That being said, I would expect that the possibility of widespread occult infections with Truvada would be ruled out because such infections would be noticed quickly when a patient stops taking Truvada. But the newer PrEP drugs are much longer acting. Maybe the lack of occult infections with shorter acting drugs makes everyone confident that they won’t happen with longer acting drugs? Maybe the tests used are so sensitive that they would detect infections anyway? If nothing else, I would have expected the papers to have some discussion of the matter.
> Maybe the lack of occult infections with shorter acting drugs makes everyone confident that they won’t happen with longer acting drugs?
Previous experience is definitely part of it. It's not just Truvada, this isn't the first long acting injectable prep. Cabotegravir (integrate inhibitor) was approved 4 years ago for this use and is given every two months, so there's already information from how that was studied, approved and what's happened with several years of actual use.
If the virus doesn't replicate, does that also means it doesn't transfer from an infected person to their partners? If so, that would also fall under "provides protection against HIV infection" for me.
It’s an insightful and society-forward observation, but I do think a person taking the drug who found they were infected but not contagious might take issue with the “prevents infection” framing.
Assuming GP is correct, from other comments it sounds like that’s in question.
Initial infection and persistence are different things, and the reservoir for HIV builds up early on, but not immediately. There is definitely at least one reproductive cycle in between the first infected cells and the creation of a reservoir.
This happened to me with Claude code, although on my local machine and not with the production database.
I had it work on one set of tasks while monitoring and approving all the diffs and other actions. I tell it to use test driven development which seems to help a lot, assuming you specify what tests should be done at a minimum, and tell it the goal is to make the code past the tests, not to make the tests pass the code.
After it successfully completed a set of tasks, I decided to go to sleep and let it work on the next set. In the morning, my database was completely wiped.
I did not interrogate it as to why it did what it did, but could see that it thrashed around on one of the tasks, tried to apply some database migrations, failed, and then ended up re-initializing the database.
Needless to say, I am now back to reviewing changes and not letting Claude run unattended.
Seems convenient. I have a couple of different Claude accounts, so I switched between them when one gets exhausted. Sometimes they both get exhausted. If other people have a couple of accounts then that would be a nice feature to add to this: switching between accounts and then resuming when either of them becomes available again.
I read the first few screens and still had no idea what we were talking about. I came to the conclusion that maybe it was a paperwhite display of some sort.
Apparently it’s an app. I suppose that blog post is only for people who already know what the app is?
If the author is reading this, and hasn't looked into it yet, there is a reasonable probability that he has a parasite infection.
My family lived in rural Malaysia for some time and some of us had similar symptoms for years before it was determined that parasites were at fault. Once they were killed, recovery was fairly quick.
You could probably shoot in apple raw with the built in app and then find a free Lightroom preset (I think Lightroom mobile can have custom presets uploaded to it) and get better results.
Lightroom mobile also actually might require a subscription to edit raw files however (then again it can do a lot more for the price). It also has a free version and you might have good results shooting in a high quality .heif
My father was on chemotherapy with fludarabine, a dna base analog. The way it functions is that it is used in DNA replication, but then doesn’t work, and the daughter cells die.
Typically, patients who get this drug experience a lot of adverse effects, including a highly suppressed immune system and risk of serious infections.
I researched whether there was a circadian rhythm in replication of either the cancer cells or the immune cells: lymphocyte and other progenitors, and found papers indicating that the cancer cells replicated continuously, but the progenitor cells replicated primarily during the day.
Based on this, we arranged for him to get the chemotherapy infusion in the evening, which took some doing, and the result was that his immune system was not suppressed in the subsequent rounds of chemo given using that schedule.
His doctor was very impressed, but said that since there was no clinical study, and it was inconvenient to do this, they would not be changing their protocol for other patients.
You were obviously on to something and it's frustrating yet completely expected to see all replies with pat dismissals that anything like this gets when there is some real potential innovation in healthcare.
Google 'chronotherapy' with some chemo/cancer/immunotherapy related terms and you'll find a ton of research being done. Given that most of it seems to have evolved in the last 8 years my guess is that the concept was 'vetted' by a nobel prize in 2017 for molecular circadian clock, so people feel safe putting their name on studies in this area.
Is it the time of day or how long the patient has been awake that matters? It seems like someone could change their sleep cycle to match the doctors schedule if the latter.
Sleep, exercise, a balanced diet of mostly whole fruits and vegetables, and a moderate amount of whole grains, legumes and fresh meat/fish/eggs if you're not choosing a vegan lifestyle. Avoid ultra processed foods, cured meats, alcohol and other recreational drugs. Make sure you get enough vitamin D, which can be hard with certain diets if you're not supplementing, or getting the right amount of sunlight(latitude and time of year matters).
Try to stay low stress, spend time out in nature, maintain good relationships, etc.
Edit: caveat to spending time out in nature: be vigilant of ticks. A tick-bourne disease can mess up your immune system pretty well
Maybe your schema will work for someone who’s on the very top point of the bell curve of human population but human genetic and environmental variability will over rule your advice for the majority of people.
The states known for “hippie”/“granola” attitudes, which largely align with the advice given here, tend to live longer than the states that don’t (scroll through the list in [1] to see this). Usually I would insist on a study, but the effect is so striking, and the mechanism by which it would work is so obvious, that I think this simple list is enough. And I’m sure there are studies too, I’m just too lazy to find and link one.
Don't be a germaphobe. Don't wash your hands a lot. Give your immune system a little work out each day by not babying it.
Try not to take any medicines unless you absolutely need them, and stay away from hand sanitizers. If you do need to clean anything, soap is more than enough and water is usually enough.
I thought it was normal to be over 50 and not take any medicines, but all the doctors and staff were surprised by this when I got my colonoscopy recently.
Some yes, and then all sorts of mood boosters, painkillers, etc. Basically all the stuff I later saw during a commercial break at a bar during some sports game. (this should be banned, TBH)
By hand sanitizers, do you mean something other than the isopropyl-gel based hand sanitizers? If not, I would have guessed that would be little different than using a strong soap.
That said, unfortunately there's some element of luck to it. There's compelling evidence that C-section babies have abnormal immune responses and less diverse body flora. And I imagine childhood circumstance affects things too, city vs country affecting the childhood exposure to pathogens and non-pathogens for training.
- Get vaccinated fully and regularly. Any kind of infection is much harder to deal with for the body than a vaccine. Particularly important are the measles and Covid shots, an infection with either of the actual pathogens can wipe out your immune system history and you lose a lot of protection.
- practice safe sex, get tested regularly (even if both you and your partners are exclusive) and get that HPV shot. Yes, even if you're male. Cancer on your bits ain't pretty.
- keep the drug consumption reasonable, especially smoking and alcohol
- the better quality the food, the better your health. Should be a no-brainer and I know about food deserts, lack of time etc
It’s not shameful, it’s how evidence based medicine works. One case is interesting but not a basis for changing a protocol by itself. Tons of things could have influenced the outcome and you need a proper study to know that.
The razor to use to determine whether something is actually evidenced based under uncertainty is whether you would follow the same policy if it was your own child.
There are many things that are simply uncertain and “untrue until proven otherwise” isn’t an exclusively optimal policy.
> The razor to use to determine whether something is actually evidenced based under uncertainty is whether you would follow the same policy if it was your own child.
What? This makes no sense. How do you explain anti-vaxxer parents with this perspective? Parents may feel they know best, but feeling and fact have nothing to do with each other.
It's ok, the strongest defenders of EBM are never going to discover anything worthwhile as they get caught in a loop of "no evidence enough to test" and "no evidence for this because nobody tests it"
The opposite approach exposes people to a lot of unnecessary and dangerous medical treatment. The evidence based approach has uncovered that stenting doesn't work[1], yet a lot of do something proponents are still installing them at great risk to patients and at great cost to medical systems.
Counterpoints: the detractors of this purported loop would likely neither fund the vast amounts of research they’d demand be done nor believe the results if they conflicted with their anecdata. I have yet to see a good faith argument against evidence based method that provides an effective and realistic alternative. Because that would take evidence.
It is not shameful indeed. One never knows what the father had experienced if he had been given the therapy during the day.
The oncologist could have written a paper (there are many single case papers), or started a trial by himself (requires a lot of organizing) if he was very intrigued. But of course one can’t do that for every above average case.
I have to say, in this particular case there is a very plausible mechanism and the trial would not be that hard. So it is a real shame that nothing was done with this.
Previous rounds of chemo were done on the normal morning infusion schedule and he ended up with a completely depleted immune system and was put in strict quarantine. He also got multiple infections that were life threatening.
This is the reason I started looking into the alternate dosing schedule.
Well the concept is now being studied quite closely. Had someone taken it seriously thirty years ago it's quite possible that the net amount of suffering that millions of patients have endured since then could have been reduced.
I'm comfortable calling that shameful. Not on any one in particular, it's a systemic problem that could be reduced with sufficient tenacity and courage to take risks.
There's limited time and a finite supply of doctors and researchers. They can't study everything that's promising all at once, and good ideas fall through the cracks all of the time.
I think this clears a bar of things that are useful and simple to study. Theres basically no effort involved. If it ends up beneficial we just update job postings from 'daytime infusion tech' to 'nighttime infusion tech'. Instant improvement in outcomes. I doubt you even need to clear this in any way to get the study greenlit.
> Had someone taken it seriously thirty years ago it's quite possible that the net amount of suffering that millions of patients have endured since then could have been reduced.
You can only say that with hindsight because of the data over the past 30 years.
What if the data showed the opposite? Then the doctor would have given his patients a worse outcome all on a "hunch".
> It’s not shameful, it’s how evidence based medicine works.
Yeah, but I'll bet nothing happened as an outcome of this. No study, no communication to anyone else. That information probably just withered on the vine.
I did a molecular bio undergrad and had classes with a bunch of pre-med students. They had zero interest in the science, just getting A's. They did care about appearance and money, driving cool cars, and dating hot partners. I know my experience is purely anecdotal and not indicative of all doctors, but I came away from my undergrad experience highly unimpressed with our medical feedstock. The only students in upper level electives that cared were the research-track students.
I talk to my doctors regularly about medicinal chemistry and biochem -- they don't know anything. It's embrassing how little they retain or care.
"Evidence-based" is a really problematic term when it is used to protect bureaucracies and medical managerialism, rather than actually interact with scientific processes in an ethical way. Their anecdote is actually a good example of why evidence-based logic is not the end-all.
So if one person injects themselves with honey and wakes up tomorrow cured from Covid, we should inject everyone with honey? That’s the exact opposite of a scientific process.
Evidence-based medicine is the scientific process. Love seeing the grandstanding on this thread against EBM without a single practical alternate proposal. Instead of complaining, what do you propose instead?
Since no one wants to explain and you I just got downvoted, Barry James Marshall is ironically an example of EBM and is HIMSELF an active proponent of EBM.
He had a biological hypothesis that the scientific community disagreed with and tested it on himself for a case study to get data. That case study was successful and then became a clinical trial. That trial was replicated and shown to work. He then won a Nobel prize for that work and the risk he took. This is an evidence-based process. EBM doesn’t mean you disregard a N=1, it means you expand N=1 into N=10, then N=100,… before you apply something to the general population. This is loosely how phase-1,2,3,4 trials work in the US.
Dismissing EBM because of Marshall is like dismissing all of math because someone disproved a popular conjecture like the local-to-global conjecture. Sure the community sentiment had it wrong, but the systematic logical approach of Math got it right. In Marshall’s case the community sentiment had it wrong, but the EBM approach eventually got it right. Half this thread doesn’t even know what they are arguing against.
The other commenter already said, ought not to let the information wither on the vine. That's a reasonable take.
Second, "evidence-based X" is largely a euphemism and increased usage under political austerity. In Western society especially in academia by "medicine" we already assume some semblance of applied science, and so "evidence-based medicine" has been well critiqued in medical and other scientific literature, in relation to how institutions like hospital administrators and (austerity) state policies might misuse the term, etc. You are not aware of this issue, so just read some of the literature.
I’m in medical school and very aware, thank you for your condescension. Less important than my practical experience, I also have an academic degree in medical, health, and societal systems alongside my other more technical degrees. And none of my background even matters. This thread is just complaints all the way down with no actual practical solutions being mentioned. Frankly almost everyone in this thread has a fundamental misunderstanding of how the scientific process works in practice and isn’t even ready for a discussion about evidence based medicine. I’m not even a die-hard supporter of EBM, I think it has several apparent failures some of which are in this thread, but I do believe it is the best approach we practically have. I also don’t believe a collection of N=1 anecdotes means we should dismantle everything the past century in medicine has brought.
If you want a real conversation, every other alternative system of medicine has failures far worse than EBM. Which is why you don’t see practical solutions being offered anywhere in this thread just anecdotes and feelings about how the system has failed X or Y.
People don’t understand EBM is a consolidated approach to prevent anecdotal data from a single person destroying the lives of millions. Other non-scientific systems like Ayurvedic medicine are particularly susceptible and fail in multiple ways due to anecdotal data. Any holistic approach to medicine will necessarily include EBM such as an MBE or personalized approach, because holistic approaches cannot generalize research at scale. But nowhere in this entire thread do I see even a single named mention of an alternative or holistic system. Just anecdotes all the way down.
And you still didn’t answer my question. At least explain what an alternative would look like or give me a paper or link to educate my ignorant self. Instead of just saying “read some literature” like a conspiracy theorist and calling me ignorant.
It's great that you're in medical school and very aware, but that doesn't make it ok to break the site guidelines, which you unfortunately did repeatedly in this thread.
Sorry, I was definitely snarky in my comments and if I could edit my comments to remove the snark and change the tone I would.
However, your "It's great that you're in medical school and very aware" is very patronizing and pointedly dismissive. Its a superficially polite acknowledgment that feels sarcastic rather than genuinely complimentary. I don't really mind, and I acknowledge the point you're trying to make. But if your goal is to curate a curious discussion and avoid snark you should model it too.
It's all too easy to fall into, and we do it too. In such cases it's good when people point it out, and I'm happy to take my own medicine.
The fix is to be more mindful of how easily this happens and edit one's comments to err on the side of unsnark. That's what I will do. If you're willing to do that as well, then HN will be better off in both cases.
(I do think it's great that you're in medical school and willing to share some of what you know on HN, but I shouldn't have singled out the "very aware" bit - that was me being passive-aggressive.)
Your are projecting. Don't use my comment to complain about other people in this thread. If you had the cognizance to refrain from that, I would not appear to be so condescending to you. You may be in the field but if you can't be arsed to read a couple articles critiquing "EBM" then nothing will expand your understanding. You are using the boomer sophistry of "but nobody has solutions", "capitalism is the least bad system" nonsense. You talk about science at length but act like one of those EBM managerialists. It is evidently more political than science if you are so mad at me:
Here’s my anecdote for your anecdote. While there certainly are doctors who care about the flashy lifestyle, I know plenty more who truly care.
Also medicine is an evidence-based practice because fundamentally our knowledge is woefully incomplete. Doctors are basically applied statisticians, the chemistry and biochemistry people are the researchers.
Sure, but someone needs to fund, organize, and conduct the study. If you're not at a research hospital it's not as easy for a one off case to generate a study.
This is a fairly innocuous change the doctor should be organizing on their own to publish a pilot study. In terms of funding very little would be required since you’re just making a small adjustment to when an existing drug regimen is happening which you already isn’t a controlled factor requiring FDA oversight or anything.
Even simple studies are expensive and difficult. You need IRB approval, data collection and organization, staff to do those things. It seems simple from the outside but making it happen takes time, effort, and money which then means also applying for grants which is a process in and of itself.
If a study like this needs a complicated IRB approval or extra data collection vs what’s already being collected for health records, you’re doing it wrong and the process has become more important than the problem you’re trying to solve.
What happens if your study clearly hurts people? What happens if your study clearly helps people? You find out in the first few weeks, what do you do? How do you ensure you collected enough of a sample of a general population to make your study representative? How do you ensure your patients properly consented to the study (past shameful human experiments aside, you likely need many institutions participating, so you can't control everything yourself).
Do I keep going or is the IRB approval process clearer now? There is a reason it exists.
We can appreciate that process is important, but at some point you're falling down a slippery slope here, surely?
We're talking about a factor that no one has previously had reason to consider important.
Of course, I don't know hard it truly is to undertake a study. I have to imagine for something like this you could write up a basic study protocol in fairly short order.
I think once again - when the process becomes the metric it’s insane. What time things are being administered is already random and not regulated or organized. “What if it hurts” isn’t relevant for something like this because the reasoning is that the baseline is that “when” doesn’t matter, you’re still giving the same dosage. “What if it clearly helps?” What if. Then you publish a paper or give a talk at a conference and try to better mobile the medical community. Or see if the administrators are willing to help scale this up further.
> How do you ensure you collected enough of a sample of a general population to make your study representative?
You don’t need to. This would be a pilot study to check whether there’s maybe a there there before you do it larger scale to measure predictive power at population level.
> Do I keep going or is the IRB approval process clearer now? There is a reason it exists.
I think you’re completely failing to engage with the argument that this particular case about time shifting delivery of a drug should not need meaningful IRB engagement other than “I’d like to change the time I deliver the drug for 2 more patients because we had one patient respond positively and this isn’t believed to be a factor” “ok cool yup”.
You’ve jumped from no IRB to full IRB without considering the context of the problem being solved which is why I said when the process becomes the goal vs the problem you’re trying to solve - you’re imaging the worst and most complicated situations possible for a case that would never demand it.
You are approaching things from software development perspective of "what's the worst that can happen? I rollback". In the topic discussed, you cannot rollback. While you might have a reasonable suspicion that changing the time will improve some outcomes in most, you cannot be sure that it won't greatly reduce positive outcomes in many. The IRB is often in place not to stop positive outcomes, but to reduce negative ones.
No I'm not. I'm pointing out the time of administration literally is already under the discretion of the hospital. There's literally no recommendation one way or the other and hospitals administer randomly based on what's convenient for staffing (i.e. not a medical decision). A) there's nothing dangerous about taking something your doing randomly anyway and systematizing it. B) there's no plausible way this is even remotely dangerous.
> The IRB is often in place not to stop positive outcomes, but to reduce negative ones.
Research can literally be IRB exempt if it provides minimal or no risk to patients which is literally what this is. Even if you put this in the "minimal risk" category which would be extreme that's still minimal IRB oversight and approval takes ~1-3 weeks.
You're imagining IRB is something it's not even intended to be and then saying it's a reasonable bottleneck in general because of real problems it prevents and thus justified for this specific experiment (where it wouldn't be relevant).
This is top to bottom a failure to follow up - doctor's are overworked & fail to follow up on potential research results because they act more like mechanics.
Any ethicist worth your salt would presumably have no problem approving experiments that will also cost lives.
There are an endless number of parameters in medicine that can be fiddled with. If an N=1 sample were enough to convince you, all sorts of garbage would meet that pattern.
I think it was a bit tongue in cheek, not so much lazy. Also, considering the kinds of gatekeeping and forced "concerns" I've seen some ethicists push forth just for the sake of showcasing their fixations instead of really looking at costs and benefits, I don't think it's far off the mark on reality to argue that medical ethics is worth considerable scrutiny too, and shouldn't hid behind a mantle of being above criticism.
It's no wonder biology hasn't even entered into the punch-card phase.
When I did my bio undergrad I was keenly aware our bodies are just scaled up molecular machines. I was hoping for a future where we'd grow MHC-neutral clonal bodies for organ harvesting.
Move fast and break things in human medicine means unethical researchers maim and kill people, often marginalized people. Nazis, Japanese experimenting on prisoners, Tuskegee airmen syphilis experiments, Cincinnati radiation experiments and many others stand as testament to what ambitious unethical scientists will do to further their knowledge and career. Thus we have strict guardrails that slow down how we do things.
I am close with a few folks in medical research and the broken nature of the system and sheer amount of red tape has broken their dreams. It is impossible to get anything done.
There is a difference between "reasonable guardrails" and suffocating progress until it's nearly impossible barring Herculean efforts by multibillion dollar entities. It cannot be understated how badly the current bureaucracy has destroyed medical progress.
We are seeing the same problem with nuclear overregulation result in worse outcomes and more deaths for people globally.
There is real suffering and a human cost, measurable in lives, to slowing down progress - just as there is one for reckless progress.
This is why we can't have nice things. I don't (mostly) doubt that poster's good intentions, but it takes only a few people with undirected ideas and flexible morals or empathy to necessitate strict rules around medical research.
Our genome is a machine, from the nucleotides to the packing, to the enzyme activity, to the metabolic flux.
Our bodies are bigger machines made of lots of little machines.
Our minds or conscious egos or "souls" are the neurotransmitter and activation activity of the connectome and all of its cells and synaptic weights and metabolic activity. They're our lived experiences for as long as our brains can function. Minds experience and produce wonderful things.
If you divorce the body from the mind, there is no "person". Just a very complicated machine. A very valuable machine full of parts.
A human body in a vegetative state is not a person. It's a dormant machine. People may have emotional attachment to that vestige, but it is no longer capable of being a person. It is not a person.
We use brain dead humans for organ transplant all the time. If you understand the premise, then it isn't that far-fetched that we might grow vegetative humans in a lab for medical use and research.
Bodies that never have brains can never become persons. They're no different from plants.
My guess is that you're either a dev or an orthopaedic surgeon, well-versed in managing the machinistic aspects of systems, but with little motivation to go beyond them.
There is decent experimental evidence to demonstrate that we are more than gene expression and the machine analogy you insist on is not a good one for understanding biological systems - see work by Michael Levin, as example.
There is a wider paradigmatic shift underway that moves from thinking about parts to processes. This refocus on relations rather than objects is very important and, for biological systems, points to a fundamentally social/collective aspect to their nature.
The machine metaphor also fails when you can no longer explain how the machine works. This is true in many areas of medicine (e.g. anasthesia) and, while we continue to believe (sometimes with enormous zeal) in the concepts that helped us in the past, we cling to them at the cost of building better understanding.
What you say isn't "wrong", but it is too limited to be a useful guide in asking new questions about things like immunotherapy treatments.
You might be surprised at how little of the body still functions without brain function, well, some bits of the brain, including basic homeostasis and immune system function.
Yeah, sure. There are probably going to be only a few tens of thousands "unknown unknowns" side-effects but hey, who cares? We will figure them out, we are out of the stone age cave now!
Or you could consider if there’s reason to believe there’s a causal relationship, if there is you could change your protocol (offer it in the evening as an option), measure the improvement, publish the result and simultaneously improve your patient outcomes and move science forward.
Regarding 3: Shouldn’t the medical system be optimizing for patient outcomes rather than the business their in?
Regarding the first two: I think the anecdote being from 1995 suggests there would have been time to put together said mountain of research.
I’m not agreeing that this is shameful for the original doctor, but I do think it’s shameful if avenues for potential research are not taken because it’s inconvenient for the hospitals.
They gave morning infusions because it was convenient. To get my father the evening infusion we had to hire private duty nurses to come to his apartment.
1. The N=1 positive result isn't the sole basis for expanded effort. The basis the is the compelling, research backed, causal mechanism that predicted the scheduling adjustment's success.
2. Does it? Speaking directly out of my butt here (not in healthcare, not an academic), but the OP spoke of pretty acute symptoms specific to a treatment plan. If the treatment program is at all common, then a very straightforward A/B split of non-intervention / intervention.
Heck, even a questionnaire of past patients cross-referenced with historical records of appointment times could go a long way to validate the hypothesis.
3. This degree of specialization is for insects. If literal MDs in the field are too atomized to even surface research proposals, then that feels like an awful waste of edge-research capability.
Not how it works. Doctors have wide latitude to treat patient based on their personal medical intuition. You already have doctors dosing patients at all times of day. If an A/B test shows evening is optimal, all the morning administrators will not suddenly become liable retroactively. Hell, they wont even be liable if they keep doing it in the morning because it fits their schedule better.
I agree n=1 generally isn’t enough, but something like this is easily something you ask for volunteers for as an experiment. There’s 0 risk, you’re taking the same drug. The only reason a given time is selected anyway is for administrative ease not because there’s medical requirements.
Clearly they did it for one patient and it was a good result. Doctors and staff generally care about their patients and given there’s plausible scientific reasoning why this worked, they’d help figure out how to make staffing work for 3-5 more patients for a limited time. Additionally, positive results like this start to travel by word of mouth so if this is successful it means more funding for the hospital and more patients seeking care from them. That’s how it should work but bureaucracy of medical care is typically resistant to things like that.
In any medical system in the world, you'll find that staff scheduling is the singular, most important constraint for patient care.
That they did it for one patient does not mean that they can do it for everyone - especially when it's not clear if it actually helped, due to a small sample size.
I didn’t say everyone. I said do it as a pilot for 2-5 more patients so that you don’t write it off as a fluke, then give a talk at a conference. If you’re having good results then you can talk with the administrators how to make this a more serious program if there’s actually good results and desire to scale this up.
Nowhere do you start from 0 and go to 100. You take baby steps scaling up to see if the results hold.
Given the scheduling was clearly not based on a medical recommendation in the first place given they were prepared to change it, then even a single datapoint suggesting it might have an impact should be reason to do at least minimal investigation into whether #3 might be better served by altering the schedule.
Since they clearly could alter the schedule, offering a limited number of later slots and comparing results would seem like the prudent response.
> Since they clearly could alter the schedule, offering a limited number of later slots and comparing results would seem like the prudent response.
There's a difference between a doctor entertaining a medically-irrelevant suggestion from a patient (or patient's family), vs. assuming that the subsequent improvement was related to it, and then making that decision for some other patients (or suggesting it to them). The former is being accommodating, the latter is making treatment changes without good reason.
Improvement or no change aren't the only two possible outcomes for a patient. They could also get worse. What's worse, often neither improvement nor decline are obviously related to the treatment, or treatment changes.
Maybe it's the circadian rhythm thing. Maybe it's some delayed effects of something unrelated about the patient, that just coincided with your intervention. Maybe it's just a response to a change - any change. Or maybe it's just completely random. The point is, you don't know. You might feel like you do, or maybe it really looks obvious - but from N=1 you don't actually know, not enough to potentially bet other people's health on it.
Because maybe you do go ahead, and make a schedule change to another few patients - and few days later, suddenly and for no apparent reason, one of them goes into critical condition and dies soon after. Good luck convincing the grieving family, your colleagues, the board - and your own conscience - that the schedule change could not have possibly caused this. You won't, because you don't actually know.
They are already making treatment choices without good reason when they set or change the schedules.
They could already have made it worse with prior scheduling decisions, without having any idea.
Intentionally choosing to ignore a possibly harmful effect of the current lack of scheduling rules seems to me as blatantly unethical or worse as taking reasonable steps within what is already permitted to try to address a possible negative effect.
If concerned about making the schedule change for them: Provide the option. Add appropriate warnings if you like.
But also consider that any grieving families that finds out after the fact that there might be a known benefit to changing the scheduling would be equally hard to convince that you've not acted unethically and done harm.
> They are already making treatment choices without good reason when they set or change the schedules.
In a sense, yes - but there's a difference between following established protocol or understanding, vs. changing it; the difference comes from operating under extreme uncertainty. It's a version of "if it ain't broken, don't fix it" - especially if you're not able to fully commit to identifying the problem, devising a fix, and verifying it's actually doing what you expect for reasons you expected.
> They could already have made it worse with prior scheduling decisions, without having any idea.
Or they could've made it better without having any idea. Point is, they had no idea either way.
> If concerned about making the schedule change for them: Provide the option. Add appropriate warnings if you like.
Even providing an option is already biasing the patient's decisions. Especially in matters of health, people will happily ignore all the warnings you can give (especially if they're mostly philosophical points about ethics or epistemology) and grasp for anything that could help. They're not going to be making a calm and objective choice. Doctors are fully aware of this, and with that awareness, presenting an option is really making a decision for yourself, but dumping any potential fallout on a patient. It's the 21st century, we know what informed choice is, and that wouldn't be it.
> But also consider that any grieving families that finds out after the fact that there might be a known benefit to changing the scheduling would be equally hard to convince that you've not acted unethically and done harm.
For better or worse, that's a big part of what evidence-based medicine is - a shield to protect you in situations like these. It lets you say that "might" wasn't enough - that the benefit wasn't actually "known", but merely anecdotally reported; that the benefit could be real, or could be coincidence, and there could be drawbacks too, unknown or under-reported (so the family didn't stumble on anecdotes of failure like did on anecdotes of success). It lets you say that there is an actual framework for evaluating what's ethical under uncertainty, and it deemed the risk too high. Most importantly, it lets you say all that, and have the entire medical community back you on this. Whether or not your conscience agrees, at the very least the will judge you as acting ethically and in best interest of the patient.
EBM and standard protocols are far from perfect - but they have solid ethical and epistemological grounding, and achieve the goal of minimizing harm to the extent possible under extreme uncertainty the medical field operates in.
It shameful in the sense we all know there are circadian rhythms. We know the human body is not uniform from waking to shut eye. With this in mind health care therapies should be intentionally administered at various times - as wide as possible; from that perhaps outcomes will vary. You don’t need a study to look for opportunities to optimize a process.
Prediction: It will end up being used by the military and/or fighters to provide instantaneous muscle strength coupled with pain relief from overexertion.