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.
This was around 1995.
irrational 8 hours ago [-]
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.
bloqs 27 minutes ago [-]
As a younger person what are the best habits to get into to maintain optimal long term immune health?
sixo 14 hours ago [-]
Amazing. And shameful (for them.)
ch4s3 14 hours ago [-]
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.
teekert 3 hours ago [-]
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.
AbrahamParangi 11 hours ago [-]
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.
raverbashing 3 hours ago [-]
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"
wyldfire 13 hours ago [-]
Though it could certainly inspire such a study.
ch4s3 13 hours ago [-]
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.
vlovich123 13 hours ago [-]
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.
_qua 12 hours ago [-]
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.
vlovich123 6 hours ago [-]
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.
dotancohen 2 hours ago [-]
> the process has become more important than the problem you’re trying to solve.
This holds true in almost every professional field for which life is on the line. Medicine, class 3 electronics, aviation.
We have a word for this, which roughly translates to "rule of paperwork". Bureaucracy.
darkwater 23 minutes ago [-]
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.
renewiltord 4 hours ago [-]
Indeed, as any ethicist worth his salt would argue: we don’t want anyone saving lives without proper approval.
vkou 48 minutes ago [-]
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.
echelon 10 hours ago [-]
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.
_qua 9 hours ago [-]
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.
xvector 8 hours ago [-]
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.
_qua 8 hours ago [-]
I don’t disagree but the guy below you wants to grow human shells and try head transplants.
tomcam 6 hours ago [-]
Transplant a few heads and suddenly you never get invited to another Christmas party
echelon 9 hours ago [-]
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.
nothrabannosir 3 hours ago [-]
This comment, more than any other, has sold me on the value of red tape in medical research.
echelon 2 hours ago [-]
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.
willguest 1 hours ago [-]
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.
cannonpr 8 hours ago [-]
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.
echelon 2 hours ago [-]
We're not at all trying.
If you toss out the old rule book and provide unlimited funding, it can be made to work.
darkwater 19 minutes ago [-]
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!
daveguy 9 hours ago [-]
That's why doctors publish case studies all the time -- to inspire larger scale and statistically sound studies.
more_corn 11 hours ago [-]
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.
echelon 10 hours ago [-]
> 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.
calf 5 hours ago [-]
"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.
vkou 14 hours ago [-]
> 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.
vidarh 27 minutes ago [-]
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.
tilne 13 hours ago [-]
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.
Spooky23 8 hours ago [-]
It is at cancer centers. Community oncologists don’t have the resources to do it.
But cost is also important to patients. Or it would be in any universe that made sense.
vlovich123 13 hours ago [-]
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.
vkou 11 hours ago [-]
Its not easy to ask if it messes with staff scheduling.
vlovich123 6 hours ago [-]
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.
vkou 50 minutes ago [-]
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.
chiefalchemist 11 hours ago [-]
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.
bravesoul2 9 hours ago [-]
What's the p value? 0.5?
HexPhantom 3 hours ago [-]
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
taneliv 2 hours ago [-]
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.
unnamed76ri 16 hours ago [-]
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.
HexPhantom 3 hours ago [-]
How many side effects people just accept because no one thought to tweak the schedule
tomcam 16 hours ago [-]
Thanks for sharing, and I’m very glad you are here to discuss it.
OrderlyTiamat 29 minutes ago [-]
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.
levocardia 15 hours ago [-]
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.
trhway 14 hours ago [-]
>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) .
levocardia 7 hours ago [-]
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.
trhway 58 minutes ago [-]
i'd think the local acidity (build up of lactic acid resulting from glucose over-consumption by the cancer cells) would take a bit to build back up once glucose ups after the night.
EricPhy 3 hours ago [-]
“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.
agumonkey 33 minutes ago [-]
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.
cluckindan 3 hours ago [-]
And not necessarily just an analog, given how there is an immune component to stress.
jmward01 16 hours ago [-]
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.
HexPhantom 3 hours ago [-]
We tend to treat the body like a static system when it's actually dynamic across the day
rendaw 16 hours ago [-]
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...
iamtheworstdev 16 hours ago [-]
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?
rendaw 1 hours ago [-]
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.
tomcam 16 hours ago [-]
Where did they say they’re mad?
bjornasm 15 hours ago [-]
They explicitly fault the doctor for not acting on research that wasn't available.
unaindz 15 hours ago [-]
The last paragraph heavily implies it
Nevermark 15 hours ago [-]
> 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.
detourdog 16 hours ago [-]
I looked up CedarCure and what I found is that it is a pesticide. What is the treatment about?
iamtheworstdev 16 hours ago [-]
looks like a sublingual immunotherapy treatment for allergies to japanese cedar pollen.
rendaw 16 hours ago [-]
It's an immunotherapy drug for cedar pollen allergy.
Yeah, that tension between convenience and protocol is so real and frustrating
mjevans 15 hours ago [-]
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.
justsomehnguy 16 hours ago [-]
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.
tialaramex 16 hours ago [-]
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.
pbhjpbhj 15 hours ago [-]
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?
Kiyo-Lynn 8 hours ago [-]
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.
Spooky23 8 hours ago [-]
They do - for metastatic melanoma, the goal is before 4:30, which is linked to higher survival rates.
Kiyo-Lynn 8 hours ago [-]
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.
HexPhantom 3 hours ago [-]
In a way it feels like we're scratching the surface of a new layer of treatment optimization
BDGC 14 hours ago [-]
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/
apparently it was prospective and randomized. I’m a little shocked by the effect size.
munchler 15 hours ago [-]
This paper was not a retrospective analysis, it was a randomized clinical trial.
egocodedinsol 15 hours ago [-]
Yeah I’m checking - I saw several other oncologists suggesting song a separate discussion.
parsabg 11 hours ago [-]
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.
Laaas 16 hours ago [-]
Light affects us deeply. Very probably true for more than immunotherapy.
georgeburdell 12 hours ago [-]
Not a medical doctor. Does this also have implications for other immunotherapy like allergy shots?
owenthejumper 13 hours ago [-]
Sicker patients get emergency treatment in the hospital in the afternoon while healthier ones in the morning in the clinic
anthuswilliams 7 hours ago [-]
The article is reporting on randomized clinical trials, which are not subject to this dynamic.
Spooky23 8 hours ago [-]
Cancer treatments typically don’t happen in an inpatient setting.
owenthejumper 7 hours ago [-]
Of course they do
NotGMan 16 hours ago [-]
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.
more_corn 11 hours ago [-]
Because the immune system sleeps at night and wakes up in the morning?
zevets 16 hours ago [-]
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.
vhanda 16 hours ago [-]
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.
tines 16 hours ago [-]
What does randomization mean in this context, and why does it fix those problems?
The same thing it means in every context: that (with enough samples) you can control for confounders.
tines 16 hours ago [-]
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?
JumpCrisscross 16 hours ago [-]
> 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.
ajkjk 14 hours ago [-]
"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.
tines 14 hours ago [-]
I guess I'm asking, how do you randomize out the confounder in this case.
ajkjk 14 hours ago [-]
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.
bravesoul2 9 hours ago [-]
Have every dose be observed by another doctor?
kelnos 16 hours ago [-]
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.
tines 16 hours ago [-]
How does this control for the "alert nurses" variable? In that case, patients would do better in the morning, regardless of the patient.
d_tr 15 hours ago [-]
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".
anigbrowl 16 hours ago [-]
Why would you assume nurses are scheduled on a 9-5 basis?
simmerup 15 hours ago [-]
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
tines 15 hours ago [-]
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 :)
NhanH 16 hours ago [-]
Patients are assigned the time for their visits. The time itself is randomized
gus_massa 14 hours ago [-]
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?
leereeves 16 hours ago [-]
> Yes, maybe morning nurses are fresher and more alert, but, again, randomization fixes that
How does randomization fix that?
finnh 16 hours ago [-]
exactly. that one clause casts doubt on all the other reasoning; randomization controls for patient selection bias but not diurnal clinic performance
phanimahesh 6 hours ago [-]
It would if the clinic is a controlled setting and they can control when the nursing shift begins.
16 hours ago [-]
abhishaike 15 hours ago [-]
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
1 hours ago [-]
majormajor 16 hours ago [-]
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.
pbhjpbhj 15 hours ago [-]
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??
mjevans 15 hours ago [-]
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.
JumpCrisscross 16 hours ago [-]
> mid-day appointments as also a luxury for those doing well
Irrelevant to this study given randomization.
detourdog 16 hours ago [-]
I can schedule appointments whenever I want. I'm an early riser and prefer my appointments first thing in the morning.
munchler 15 hours ago [-]
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.
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.
There are many things that are simply uncertain and “untrue until proven otherwise” isn’t an exclusively optimal policy.
We have a word for this, which roughly translates to "rule of paperwork". Bureaucracy.
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.
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.
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.
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.
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.
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.
If you toss out the old rule book and provide unlimited funding, it can be made to work.
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.
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.
Since they clearly could alter the schedule, offering a limited number of later slots and comparing results would seem like the prudent response.
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.
Example: https://www.medicalnewstoday.com/articles/cancer-time-of-day...
But cost is also important to patients. Or it would be in any universe that made sense.
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 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 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.
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) .
That’s a powerful analog for depression and burnout in humans.
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...
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?
> 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.
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.
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.
Always remember what you are just an another patient with your own quirks.
apparently it was prospective and randomized. I’m a little shocked by the effect size.
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.
> 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.
The same thing it means in every context: that (with enough samples) you can control for confounders.
I think you're correct that randomising patient assignments doesn't control for provider-side confounders. Curious if the study also randomised nursing assignments.
Whether or not they controlled for nurse-alertness is something you'd have to read the paper (or assume the researchers are intelligent) for.
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.
How many patients dropped out? (Or requested a schedule change) Do they count like live or dead?
How does randomization fix that?
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
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.
Believe they are being treated like robots. Maybe even literally like gears rented by the hour, not even robots.
Irrelevant to this study given randomization.