Administering immunotherapy in the morning seems to matter. Why?(owlposting.com)
owlposting.com
Administering immunotherapy in the morning seems to matter. Why?
https://www.owlposting.com/p/the-time-of-day-that-immunotherapy
194 comments
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.
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.
? The other replies don't dismiss it...
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.
As a younger person what are the best habits to get into to maintain optimal long term immune health?
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
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
Plus, fix your gut.
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.
[1] https://en.wikipedia.org/wiki/List_of_U.S._states_and_territ...
[1] https://en.wikipedia.org/wiki/List_of_U.S._states_and_territ...
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.
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.
Above 50? My 30+ year old American friends are all running on pills, daily, many different of them. I was shocked.
So I am rather with you. It should be normal not to take medicines.
So I am rather with you. It should be normal not to take medicines.
What sort of pills? Vitamins or ?
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.
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.
Normal weight and enough sleep.
You want to live a long time? Avoid any of the things that make it worthwhile.
- 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
- 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
Don't compromise it chronically. Protected sex etc.
Amazing. And shameful (for them.)
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.
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.
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.
[1] https://lowninstitute.org/stents-dont-work-a-look-back-at-th...
[1] https://lowninstitute.org/stents-dont-work-a-look-back-at-th...
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.
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.
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.
https://pmc.ncbi.nlm.nih.gov/articles/PMC9599830/
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.
https://pmc.ncbi.nlm.nih.gov/articles/PMC9599830/
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.
Agreed. Scheduling is patient discretion anyway. It's the lowest bar possible as far as I can tell.
> 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".
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.
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.
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Barry James Marshall
Prof. Barry Marshall is an example of why Evidence-Based Medicine works against community sentiment.
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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.
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.
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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.
If you wouldn't mind reviewing https://news.ycombinator.com/newsguidelines.html and taking the intended spirit of the site more to heart, we'd be grateful.
If you wouldn't mind reviewing https://news.ycombinator.com/newsguidelines.html and taking the intended spirit of the site more to heart, we'd be grateful.
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.
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.
Sorry! You are right.
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.)
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.)
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You crossed repeatedly into personal attack in this thread. That's not ok and not allowed here.
If you wouldn't mind reviewing https://news.ycombinator.com/newsguidelines.html and taking the intended spirit of the site more to heart, we'd be grateful.
If you wouldn't mind reviewing https://news.ycombinator.com/newsguidelines.html and taking the intended spirit of the site more to heart, we'd be grateful.
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.
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.
Though it could certainly inspire such a study.
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.
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.
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.
> 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.
> 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.
> the process has become more important than the problem you’re trying to solve.
We have a word for this, which roughly translates to "rule of paperwork". Bureaucracy.
And I think there is a reason why the bureaucracy exists in these cases. "Move fast and break things" doesn't work very well there.
Indeed, as any ethicist worth his salt would argue: we don’t want anyone saving lives without proper approval.
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.
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.
What a intellectually lazy response.
No, it would be more accurate to say "any ethicist worth his salt would argue: don't make changes that could be harmful based on a hunch"
No, it would be more accurate to say "any ethicist worth his salt would argue: don't make changes that could be harmful based on a hunch"
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.
Nope. We're in the stone age.
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.
Nope. We're in the stone age.
It's almost as if your undergrad biology gave you just enough information to make assumptions that aren't true?
The medical journals are filled with studies that "should have worked" and didn't.
Heck, there are a ton of studies that "should have worked" that were harmful.
So much for "we're just scaled up molecular machines".
The medical journals are filled with studies that "should have worked" and didn't.
Heck, there are a ton of studies that "should have worked" that were harmful.
So much for "we're just scaled up molecular machines".
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.
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.
I don’t disagree but the guy below you wants to grow human shells and try head transplants.
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.
good! old, dinosaur like systems need to be forgotten already.
Transplant a few heads and suddenly you never get invited to another Christmas party
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We've been able to clone mammals for 30 years and haven't acted on it. We're still toying with molecular systems beyond the limit of detection.
Clone humans. Cut off their brain stem during development. Turn off cephalization signals for good measure. Scale it up to industrial scale.
Research problems solved.
We'd have every study at our fingertips. We'd have organs and tissue and blood for everyone.
We could possibly even do whole head transplants and cure all non-blood, non-brain cancers.
But we're playing in the sand.
Clone humans. Cut off their brain stem during development. Turn off cephalization signals for good measure. Scale it up to industrial scale.
Research problems solved.
We'd have every study at our fingertips. We'd have organs and tissue and blood for everyone.
We could possibly even do whole head transplants and cure all non-blood, non-brain cancers.
But we're playing in the sand.
This comment, more than any other, has sold me on the value of red tape in 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.
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.
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.
We're not at all trying.
If you toss out the old rule book and provide unlimited funding, it can be made to work.
If you toss out the old rule book and provide unlimited funding, it can be made to work.
That's why doctors publish case studies all the time -- to inspire larger scale and statistically sound studies.
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.
> And shameful (for them.)
1. A single positive outcome with N=1 should generally not be the basis for making a medical recommendation.
2. It takes a mountain of research work to go from that to a study that you can draw meaningful conclusions from.
3. The hospital is not in the business of doing research, it's in the business of treating patients.
1. A single positive outcome with N=1 should generally not be the basis for making a medical recommendation.
2. It takes a mountain of research work to go from that to a study that you can draw meaningful conclusions from.
3. The hospital is not in the business of doing research, it's in the business of treating patients.
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.
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.
It is at cancer centers. Community oncologists don’t have the resources to do it.
Example: https://www.medicalnewstoday.com/articles/cancer-time-of-day...
Example: https://www.medicalnewstoday.com/articles/cancer-time-of-day...
This was Sloan-Kettering.
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.
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.
Yes, it should.
But cost is also important to patients. Or it would be in any universe that made sense.
But cost is also important to patients. Or it would be in any universe that made sense.
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.
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.
And if the A/B test says that your intervention made the situation worse? Now the doctor is held liable for that.
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.
Its not easy to ask if it messes with staff scheduling.
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.
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.
Nowhere do you start from 0 and go to 100. You take baby steps scaling up to see if the results hold.
I posted this above, but for clarity:
This was Sloan-Kettering.
They gave morning infusions because it was convenient for them.
To get my father the evening infusion we had to hire private duty nurses to come to his apartment.
This was Sloan-Kettering.
They gave morning infusions because it was convenient for them.
To get my father the evening infusion we had to hire private duty nurses to come to his apartment.
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.
> 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.
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 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.
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.
What's the p value? 0.5?
I've heard similar things about fasting.
It's frustrating (but not surprising) that even with a clear positive outcome, the system couldn't adapt without a clinical trial to back it up
Isn't it also quite understandable? Otherwise we risk the new way working well for half the patients and killing the other half, to exaggerate.
I used to be on a chemo drug and had to take folic acid every day to stop it from doing bad things to me.
I had awful ulcers in my mouth from the chemo drug and had been taking the folic acid in the morning. Through forgetfulness I ended up shifting the folic acid to the afternoon and the ulcers went away and never came back.
I had awful ulcers in my mouth from the chemo drug and had been taking the folic acid in the morning. Through forgetfulness I ended up shifting the folic acid to the afternoon and the ulcers went away and never came back.
Thanks for sharing, and I’m very glad you are here to discuss it.
How many side effects people just accept because no one thought to tweak the schedule
And to think about how often such things are figured out individually, but go unnoticed, because there's basically 0 chance for the average person to get anyone to do a study on it.
My guess on some of this has to do with a few things. Hormone levels vary throughout the day along with immune system activity; My allergies are always worse in the morning than the day. I'm sure time is a huge component in a lot of medical things but I haven't personally seen any studies on this.
Most people also fast at night (sleeping) and are less physically active etc etc.
Most people also fast at night (sleeping) and are less physically active etc etc.
I did make sure to bring it up to my doctor in case the idea could help anyone else.
Hazard ratio of 0.45 seems implausibly high, especially when it's just the exact same treatment dichotomized to before/after 3pm. My money is on something other than a real circadian effect: either the result of a 'fishing expedition' in the data, or some other variable that incidentally varies by time of day. Maybe breaking randomization, leaving the drugs out for too long at room temp, etc. If you really believe this is an important and biologically plausible effect it should be a top candidate for a replication attempt.
>some other variable that incidentally varies by time of day.
glucose level? low in the morning, and cancer likes glucose (among other effects of low glucose a cancer site would probably have lower local acidity, and the high local acidity is one of the tools used by cancer to protect and spread itself) .
glucose level? low in the morning, and cancer likes glucose (among other effects of low glucose a cancer site would probably have lower local acidity, and the high local acidity is one of the tools used by cancer to protect and spread itself) .
AM/PM glucose differences are probably going to be swamped by mundane stuff like who has a snack before treatment vs. who doesn't. Are you not supposed to eat before immunotherapy? If so, maybe (non)compliance with that requirement is what's underneath.
“Let’s pretend you have very early-stage cancer. The dendritic cells are in their normal cycle of desperately presenting tumor fragments to T cells, the T-cells rightfully getting upset, activating themselves, and going off to hunt the cancer. But cancer simply shuts them down by expressing an immune blocker protein: PD-L1. In response, the T-cell mostly shuts down, wanders back to the lymphatic system, and gets a little bit more ‘exhausted’. It believes that it activated itself for no reason, and thus will require a much higher bar for doing anything else in the future. The more times this occurs, the more exhausted the T-cell becomes, the more unwilling to ever activate again. In the limit, it will simply kill itself. Hence why you need immunotherapy to revitalize these cells!”
That’s a powerful analog for depression and burnout in humans.
That’s a powerful analog for depression and burnout in humans.
And not necessarily just an analog, given how there is an immune component to stress.
Yeah, so many things use the same memory response curve to adjust their behavior, but that model can fail rapidly in these conditions. Very interesting to read though.
I wonder if other basic processes could be at play here like when patients go to the bathroom. If you do this in the morning they may be more likely to not need that for a while while in the evening they may do that immediately. I'm not saying this is the mechanism, just pointing out that there are a lot of timing dependent things in a person's schedule that could be a factor here. It is a great thing to point out though. I hope a lot more research goes into the idea of timing and integrating medication into a schedule most effectively.
We tend to treat the body like a static system when it's actually dynamic across the day
I'm doing CedarCure. You're required to not exercise or bath/shower for 2h after taking, which is fairly difficult in the morning, so I asked the doc if I could do it in the evening instead (despite explicit instructions to do it in the morning). The doc said it was fine, confirmed by the pharmacist.
I should know better by now than to trust doctors to act based on research and not gut feeling, but I hope this doesn't mean the last year of taking it was a wash...
I should know better by now than to trust doctors to act based on research and not gut feeling, but I hope this doesn't mean the last year of taking it was a wash...
a brand new study comes out and you're mad the doctors didn't know about it a year ago?
do you carry any of the blame on yourself since you knew there were explicit instructions but apparently waiting to shower or exercise was too much of an inconvenience for you?
do you carry any of the blame on yourself since you knew there were explicit instructions but apparently waiting to shower or exercise was too much of an inconvenience for you?
If the medicine instructions didn't state that they should be taken in the morning it might be reasonable, but presumably the producer had some reason for including that instruction. Furthermore, the linked study implies that this effect was suspected before but not confirmed - it's possible and even likely that the CedarCure makers knew this and specified the instructions as such.
> There’s a really interesting phenomenon in the immunotherapy field that has been going on for what seems to be several years now
> All of this culminated in a really incredible review paper
(review paper references papers from multiple years prior)
And no, it's absurd to imply I do carry blame here. I'm not a medical professional and that's exactly why I asked two specialists for help understanding the criticality of the instructions... that's the point. Even if they didn't know, they could have deferred to the written instructions rather than coming up with an original conclusion.
> There’s a really interesting phenomenon in the immunotherapy field that has been going on for what seems to be several years now
> All of this culminated in a really incredible review paper
(review paper references papers from multiple years prior)
And no, it's absurd to imply I do carry blame here. I'm not a medical professional and that's exactly why I asked two specialists for help understanding the criticality of the instructions... that's the point. Even if they didn't know, they could have deferred to the written instructions rather than coming up with an original conclusion.
If the reasoning in the OP is right, then one might infer that the evening is the right time to take it. The goal of cancer immunotherapy is to convince your body to treat the cancer as harmful. The goal of allergy immunotherapy is to convince your body to tolerate allergens. If you are more likely to consider antigens harmful in the morning and tolerable in the evening, then evening is better.
As a giant confounding effect, it seems that allergy immunotherapy might work, at least in part, by convincing your body to make large amounts of IgG antibodies to the allergen, and IgG antibodies are in the “kill it but don’t sneeze at it” category, which isn’t same thing as having your T cell population tolerate the antigen.
As a giant confounding effect, it seems that allergy immunotherapy might work, at least in part, by convincing your body to make large amounts of IgG antibodies to the allergen, and IgG antibodies are in the “kill it but don’t sneeze at it” category, which isn’t same thing as having your T cell population tolerate the antigen.
> I could do it in the evening instead (despite explicit instructions to do it in the morning)
Have either you or your doctor identified the reason for the morning recommendation?
Maybe restart consideration of timing there?
Doctors are going to take your practical need to break one part of protocol, to maintain the rest of the protocol, seriously. They can't resolve the practicalities of patients' lives.
Have either you or your doctor identified the reason for the morning recommendation?
Maybe restart consideration of timing there?
Doctors are going to take your practical need to break one part of protocol, to maintain the rest of the protocol, seriously. They can't resolve the practicalities of patients' lives.
I looked up CedarCure and what I found is that it is a pesticide. What is the treatment about?
looks like a sublingual immunotherapy treatment for allergies to japanese cedar pollen.
OP is an insect going in for assisted suicide.
It's an immunotherapy drug for cedar pollen allergy.
I think you are misunderstanding a couple of things. The label for Cedarcure doesn’t have timed dosing, just says take it during the day. Furthermore this research article would actually indicate it’s better to take it in the afternoon for your particular drug, if there really is any connection. Which is still a crazy connection to make because you are complaining about a specific immumotherapy regimen finding not being applied to an allergy-style medication. Why not apply this logic to every drug that interacts with the immune system (which is all of them)? Furthermore as other comments pointed out, you’re mad your doctor didn’t know about a brand-new study that didn’t exist when they made a recommendation?
Doctor’s have a wide discretion and often get things wrong. But in your case, that’s not what happened. If anything your doctor actually got it right either by chance or intuition.
Doctor’s have a wide discretion and often get things wrong. But in your case, that’s not what happened. If anything your doctor actually got it right either by chance or intuition.
There is always an option what taking it in the evening is magnitudes better than not taking it in the morning at all because you skipped it because you need a shower.
Always remember what you are just an another patient with your own quirks.
Always remember what you are just an another patient with your own quirks.
For the drug I take every day (Levothyroxine), research found that evening was worse, but the explanation was poor compliance - people forget to do it more often compared to the morning. Same reason the contraceptive pill is less effective than you'd expect in real populations, compliance is poor. If you're the sort of person who can actually take it on time, every day, without fail, it's extremely effective, if you aren't, not so much. The choice to include "dummy" pills is because of improved compliance - remembering to take it every single day on the same schedule is just easier, so adjust the medication not the instructions.
What annoys me here is that these things are hidden - if the patient knows that compliance is better (ie their chance of staying with the medicine and so of getting better) does it really reduce said compliance?
What's hidden? Compliance means you directly benefit from the intended functionality. Like anything else in life you can insist on more documentation but most people don't care.
From a lazy search, the measures are to trigger a reaction, but not intense enough send you to hospital. Fasted state (first thing in morning) can enhance absorption and avoid interference with food. (hot) showers cause vasodilation and exercise causes increased heart rate, both which increase allergen absorption enough trigger adverse reaction. If you have taken it for a year, your doctor may probably not worry about a too-intense reaction.
I'm also taking dust mite immunotherapy and assumed this article applies to me.
I'm also taking dust mite immunotherapy and assumed this article applies to me.
Explicitly clear, but otherwise not overly specific, medication instructions would be best.
Say exactly what matters.
E.G. 'Take once a day at a similar time.' VS overly specific but not required 'take in the morning / evening / lunch / some other assumption that doesn't matter.' HOWEVER maybe "Take once a day with your first (full) meal." OR "Take once a day with your primary meal." might make more sense for medications that interact with food.
Say exactly what matters.
E.G. 'Take once a day at a similar time.' VS overly specific but not required 'take in the morning / evening / lunch / some other assumption that doesn't matter.' HOWEVER maybe "Take once a day with your first (full) meal." OR "Take once a day with your primary meal." might make more sense for medications that interact with food.
Yeah, that tension between convenience and protocol is so real and frustrating
If you’re interested in circadian biology, which underlies chronoimmunotherapy, please check out UCSD’s BioClock Studio. We create tutorial videos and other media to teach circadian biology concepts:
https://bioclock.ucsd.edu/
Perhaps it's due to overnight fasting, that people in the morning don't eat yet/as much?
Autophagy is increased during fasting, it usually takes 3 days of water fasting to fully ramp up to its maximum, so no food overnight might just slightly start it up.
I watched a youtube video of guy who did low carb and fasted at least 24h before and after chemo (or even 48h, forgot which) and he didn't experience the negative side effects of chemo as much.
Autophagy is increased during fasting, it usually takes 3 days of water fasting to fully ramp up to its maximum, so no food overnight might just slightly start it up.
I watched a youtube video of guy who did low carb and fasted at least 24h before and after chemo (or even 48h, forgot which) and he didn't experience the negative side effects of chemo as much.
Here’s a link to the abstract:
https://ascopubs.org/doi/abs/10.1200/JCO.2025.43.16_suppl.85...
apparently it was prospective and randomized. I’m a little shocked by the effect size.
apparently it was prospective and randomized. I’m a little shocked by the effect size.
This paper was not a retrospective analysis, it was a randomized clinical trial.
Yeah I’m checking - I saw several other oncologists suggesting song a separate discussion.
If a hospital cannot serve everybody in the morning, should they create a dorm with only artificial light that has sunrise at 12 pm and sunset at 12 am to shift circardian rythms?
I once accompanied a family member through immunotherapy. The treatment times were mostly arranged by the hospital, and the doctor suggested doing it in the morning.
We just thought it was to avoid the afternoon rush.
Looking back, though, they really did seem to feel better with morning treatments.
Now I realize the timing itself might actually affect how well it works.
I really hope that in the future, doctors will consider not just the drug and the dosage, but also when it’s given.
They do - for metastatic melanoma, the goal is before 4:30, which is linked to higher survival rates.
I didn’t know there were already examples like metastatic melanoma where the timing is clearly defined.
It makes me wonder if other treatments could also benefit from getting the timing right.
Thanks for sharing this. I’ll definitely look into it more.
They changed the study target effect (which hour range), design (interventional vs observational) and inclusion/ exclusion criteria multiple times.
I don't really care at that point what their conclusion says, because I have no idea how to interpret the statistics in a theoretically sound way now.
I don't really care at that point what their conclusion says, because I have no idea how to interpret the statistics in a theoretically sound way now.
I wonder if the same would also be true for immunosuppressants administered for autoimmune conditions. Given they mostly interact with the signaling pathways, I guess in theory they should also be more effective in the morning if there is more immune cell activity going on.
Light affects us deeply. Very probably true for more than immunotherapy.
Because the immune system sleeps at night and wakes up in the morning?
In a way it feels like we're scratching the surface of a new layer of treatment optimization
Not a medical doctor. Does this also have implications for other immunotherapy like allergy shots?
Body meridian clock, that's why.
Sicker patients get emergency treatment in the hospital in the afternoon while healthier ones in the morning in the clinic
The article is reporting on randomized clinical trials, which are not subject to this dynamic.
Cancer treatments typically don’t happen in an inpatient setting.
Of course they do
tl;dr
Administering immune system related drugs in the morning improves success rate. This is because the immune system is more receptive in the morning, due to evolutionary adaptation. The authors even seem to have isolated the gene sequence that leads to the "sensor" which generates the necessary "data" for the immune system to optimize on.
Really cool research imo
Administering immune system related drugs in the morning improves success rate. This is because the immune system is more receptive in the morning, due to evolutionary adaptation. The authors even seem to have isolated the gene sequence that leads to the "sensor" which generates the necessary "data" for the immune system to optimize on.
Really cool research imo
Fasted state?
A while back, a colleague told me his doctor always scheduled his immunotherapy infusions for the morning, saying it would be more effective. I thought it was just something they said, but seeing all this new data, I’m realizing there’s actually real science behind it.
This is bad science. Patients schedule when they go to immunotherapy appointments. People who go in the morning are still working/doing things, where once you get _really_ sick, you end up scheduling mid-day, because its such a hassle to do anything at all.
From the article -
> this paper was not a retrospective study of electronic health records, it was a randomized clinical trial, which is the gold standard. This means that we’ll be forced to immediately throw away our list of other obvious complaints against this paper. Yes, healthier patients may come in the morning more often, but randomization fixes that. Yes, patients with better support systems may come in the morning more often, but randomization fixes that. Yes, maybe morning nurses are fresher and more alert, but, again, randomization fixes that.
> this paper was not a retrospective study of electronic health records, it was a randomized clinical trial, which is the gold standard. This means that we’ll be forced to immediately throw away our list of other obvious complaints against this paper. Yes, healthier patients may come in the morning more often, but randomization fixes that. Yes, patients with better support systems may come in the morning more often, but randomization fixes that. Yes, maybe morning nurses are fresher and more alert, but, again, randomization fixes that.
> Yes, maybe morning nurses are fresher and more alert, but, again, randomization fixes that
How does randomization fix that?
How does randomization fix that?
exactly. that one clause casts doubt on all the other reasoning; randomization controls for patient selection bias but not diurnal clinic performance
It would if the clinic is a controlled setting and they can control when the nursing shift begins.
"Forced to throw away" biases is strong. If run well, RCTs surely help manage potential biases, but it does not eliminate them. The slides saw available on X-itter didn't show a Consort diagram (accounting of patient count between screening and endpoint) or the balance of patent characteristics between the arms. This seems to be a single site study, which is significant caveat IMO. The lack of substantial mechanistic explanation, and alleged study redesign mid-stream are also caveats. All that said the reported effect is very large, and I'd like to see a more detailed reporting and analysis. If the effect that size is real, it should be able to be found in some relatively quickly retrospective studies (yes, many caveats there, but that could probably provide very large numbers rapidly in support of the RCT).
What does randomization mean in this context, and why does it fix those problems?
https://en.wikipedia.org/wiki/Randomized_controlled_trial
The same thing it means in every context: that (with enough samples) you can control for confounders.
The same thing it means in every context: that (with enough samples) you can control for confounders.
Supposing that patients did better in the morning because, say, the nurses were more alert, no matter how many samples you take you'll find the patients do better in the morning. How does "more samples" help control for confounders rather than just confirm a bias?
> How does "more samples" help control for confounders rather than just confirm a bias?
I think you're correct that randomising patient assignments doesn't control for provider-side confounders. Curious if the study also randomised nursing assignments.
I think you're correct that randomising patient assignments doesn't control for provider-side confounders. Curious if the study also randomised nursing assignments.
"more samples" is not what controls for confounders. Controlling for confounders is what controls for confounders, which you can only do with enough samples that you can randomize out the effect of the confounder.
Whether or not they controlled for nurse-alertness is something you'd have to read the paper (or assume the researchers are intelligent) for.
Whether or not they controlled for nurse-alertness is something you'd have to read the paper (or assume the researchers are intelligent) for.
I guess I'm asking, how do you randomize out the confounder in this case.
I imagine that that particular confounder is not possible to eliminate via randomization. Perhaps you collect a bunch of data on nurse awakeness--day shift vs night-shift, measuring alertness somehow, or measuring them on other activities known to be influenced by alertness--and then ensure your results don't correlate with that.
There is also the mechanistic side: if you have lots of plausible mechanism for what's going on, and you can detect indicators for it that don't seem to correlate with nurse alertness, that's a vote against it mattering. Same if you have of lots of expertise on the ground and they can attest that nurse alertness doesn't seem to have an affect. There are lots of ways, basically, to reach pretty good confidence about that, but they might not be as rigorous as randomized assignments can be.
There is also the mechanistic side: if you have lots of plausible mechanism for what's going on, and you can detect indicators for it that don't seem to correlate with nurse alertness, that's a vote against it mattering. Same if you have of lots of expertise on the ground and they can attest that nurse alertness doesn't seem to have an affect. There are lots of ways, basically, to reach pretty good confidence about that, but they might not be as rigorous as randomized assignments can be.
Have every dose be observed by another doctor?
Patients in the study are randomly assigned to the early group or the late group. They don't get to schedule their own appointments for whatever time of day they want.
How does this control for the "alert nurses" variable? In that case, patients would do better in the morning, regardless of the patient.
Based on these graphs and the differences in outcomes they show, you are not talking about "alert vs less alert" nurses but about "nurses doing their job vs nurses basically slowly killing dozens of patients".
Why would you assume nurses are scheduled on a 9-5 basis?
Why do you think you're going to poke holes in a research article when you've clearly only just heard of the concept and havent even read the article
If I thought I could poke holes in the research, I wouldn't be posting on HN. I'm asking questions to learn because obviously I don't understand :)
Patients are assigned the time for their visits. The time itself is randomized
How many dose this treatment has? How many between them?
How many patients dropped out? (Or requested a schedule change) Do they count like live or dead?
How many patients dropped out? (Or requested a schedule change) Do they count like live or dead?
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Writer of the article here: randomization fixes most of this, but the other commenters are correct in that doesnt fully account for the clinic performance (e.g. nurse performance, which does dip during the night according to the literature). I previously thought it wasn't a major issue for clinical trials, since a separate team independent from the main ward are giving the drugs, but there isn't super strong evidence to support that. I will update the article to admit this!
This said, I am inclined to believe that this isn't a major concern for chronotherapy studies, since I haven't yet seen it being raised in any paper yet as a concern and the results seem far too strong to blame entirely on 'night nurses make more mistakes'. Fully possible that that is the case! I just am on the other side of it
This said, I am inclined to believe that this isn't a major concern for chronotherapy studies, since I haven't yet seen it being raised in any paper yet as a concern and the results seem far too strong to blame entirely on 'night nurses make more mistakes'. Fully possible that that is the case! I just am on the other side of it
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I always have seen mid-day appointments as also a luxury for those doing well (at least professionally/financially). If you have to go first thing in the morning, it's often because your boss wants you in relatively early and won't let you take time mid-day. If you're in a position where you can go in at 2PM and not have to sacrifice sleep to do so, that feels healthier.
Given the highly-evident strong circular nature of the body, a hypothesis that it has something to do with that seems highly likely, certainly worth following up on.
Given the highly-evident strong circular nature of the body, a hypothesis that it has something to do with that seems highly likely, certainly worth following up on.
Surely your boss legally has to let you attend a health appointment? Though they might not have to pay you. That seems like a very basic workers right, the sort of thing you'd have a general strike over if it didn't exist??
The most vulnerable, at least among those who have a job at least, often have the most draconian restrictions on when and what they can do.
Believe they are being treated like robots. Maybe even literally like gears rented by the hour, not even robots.
Believe they are being treated like robots. Maybe even literally like gears rented by the hour, not even robots.
> mid-day appointments as also a luxury for those doing well
Irrelevant to this study given randomization.
Irrelevant to this study given randomization.
I can schedule appointments whenever I want. I'm an early riser and prefer my appointments first thing in the morning.
The appointment schedule was randomized, so your objection is incorrect.
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.
This was around 1995.