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Administering immunotherapy in the morning seems to matter. Why?
ImHereToVote wrote 10 hours 53 min ago:
Fasted state?
yoko888 wrote 15 hours 22 min ago:
This reminded me of how my grandma always insisted on taking her meds
first thing in the morning before breakfast, before anything. She
didn’t know anything about circadian rhythms, but she’d say,
“That’s when my body feels strongest.” At the time, I thought it
was just a habit. Now, reading this, I’m wondering if she was
unknowingly syncing with her immune system’s peak time.
s1mplicissimus wrote 17 hours 11 min ago:
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
pmlnr wrote 18 hours 42 min ago:
Body meridian clock, that's why.
aitchnyu wrote 19 hours 44 min ago:
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?
Noelia- wrote 19 hours 49 min ago:
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.
OrderlyTiamat wrote 20 hours 34 min 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.
HexPhantom wrote 22 hours 57 min ago:
In a way it feels like we're scratching the surface of a new layer of
treatment optimization
EricPhy wrote 23 hours 22 min 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 wrote 20 hours 37 min 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 wrote 22 hours 44 min ago:
And not necessarily just an analog, given how there is an immune
component to stress.
Kiyo-Lynn wrote 1 day 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 wrote 1 day ago:
They do - for metastatic melanoma, the goal is before 4:30, which is
linked to higher survival rates.
Kiyo-Lynn wrote 1 day 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.
more_corn wrote 1 day ago:
Because the immune system sleeps at night and wakes up in the morning?
parsabg wrote 1 day 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.
georgeburdell wrote 1 day ago:
Not a medical doctor. Does this also have implications for other
immunotherapy like allergy shots?
owenthejumper wrote 1 day ago:
Sicker patients get emergency treatment in the hospital in the
afternoon while healthier ones in the morning in the clinic
anthuswilliams wrote 1 day ago:
The article is reporting on randomized clinical trials, which are not
subject to this dynamic.
Spooky23 wrote 1 day ago:
Cancer treatments typically don’t happen in an inpatient setting.
owenthejumper wrote 1 day ago:
Of course they do
BDGC wrote 1 day 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:
[1]: https://bioclock.ucsd.edu/
raylad wrote 1 day ago:
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.
Gravityloss wrote 8 hours 57 min ago:
I've heard similar things about fasting.
jcims wrote 16 hours 40 min ago:
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.
refulgentis wrote 7 hours 53 min ago:
? The other replies don't dismiss it...
bloqs wrote 20 hours 31 min ago:
As a younger person what are the best habits to get into to maintain
optimal long term immune health?
bregma wrote 14 hours 10 min ago:
You want to live a long time? Avoid any of the things that make it
worthwhile.
mschuster91 wrote 15 hours 17 min ago:
- 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
stronglikedan wrote 15 hours 31 min ago:
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.
kmarc wrote 14 hours 42 min ago:
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.
unshavedyak wrote 14 hours 32 min ago:
What sort of pills? Vitamins or ?
kmarc wrote 14 hours 25 min ago:
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)
webstrand wrote 15 hours 21 min ago:
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.
goda90 wrote 16 hours 30 min ago:
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
FollowingTheDao wrote 15 hours 13 min ago:
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.
pinkmuffinere wrote 12 hours 42 min ago:
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_...
throwaway290 wrote 19 hours 1 min ago:
Don't compromise it chronically. Protected sex etc.
ReptileMan wrote 19 hours 13 min ago:
Normal weight and enough sleep.
HexPhantom wrote 22 hours 55 min 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 wrote 22 hours 34 min 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.
irrational wrote 1 day 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.
sixo wrote 1 day ago:
Amazing. And shameful (for them.)
bravesoul2 wrote 1 day ago:
What's the p value? 0.5?
vkou wrote 1 day 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.
NiloCK wrote 16 hours 50 min ago:
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.
Aerroon wrote 13 hours 28 min ago:
And if the A/B test says that your intervention made the
situation worse? Now the doctor is held liable for that.
s1artibartfast wrote 10 hours 41 min ago:
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.
vidarh wrote 20 hours 32 min 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.
TeMPOraL wrote 19 hours 4 min ago:
> 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.
vidarh wrote 17 hours 56 min ago:
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.
chiefalchemist wrote 1 day 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.
vlovich123 wrote 1 day 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 wrote 1 day ago:
Its not easy to ask if it messes with staff scheduling.
raylad wrote 6 hours 33 min ago:
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.
vlovich123 wrote 1 day 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 wrote 20 hours 55 min 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.
vlovich123 wrote 15 hours 40 min ago:
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.
tilne wrote 1 day 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 wrote 1 day ago:
It is at cancer centers. Community oncologists don’t have the
resources to do it.
Example:
[1]: https://www.medicalnewstoday.com/articles/cancer-time-...
raylad wrote 6 hours 34 min ago:
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.
vkou wrote 1 day ago:
Yes, it should.
But cost is also important to patients. Or it would be in any
universe that made sense.
ch4s3 wrote 1 day 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.
jcims wrote 16 hours 36 min ago:
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. [1] 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.
[1]: https://pmc.ncbi.nlm.nih.gov/articles/PMC9599830/
refurb wrote 12 hours 45 min ago:
> 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".
ch4s3 wrote 14 hours 26 min ago:
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.
JamesSwift wrote 13 hours 34 min ago:
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.
teekert wrote 23 hours 20 min 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.
raylad wrote 6 hours 36 min ago:
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.
echelon wrote 1 day 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.
uselesswords wrote 18 hours 1 min ago:
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.
calf wrote 1 day 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.
uselesswords wrote 17 hours 56 min ago:
So if one person injects themselves with honey and wakes up
tomorrow cured from Covid, we should inject everyone with
honey? That’s the exact opposite of a scientific process.
Evidence-based medicine is the scientific process. Love
seeing the grandstanding on this thread against EBM without a
single practical alternate proposal. Instead of complaining,
what do you propose instead?
calf wrote 4 hours 56 min ago:
The other commenter already said, ought not to let the
information wither on the vine. That's a reasonable take.
Second, "evidence-based X" is largely a euphemism and
increased usage under political austerity. In Western
society especially in academia by "medicine" we already
assume some semblance of applied science, and so
"evidence-based medicine" has been well critiqued in
medical and other scientific literature, in relation to how
institutions like hospital administrators and (austerity)
state policies might misuse the term, etc. You are not
aware of this issue, so just read some of the literature.
echelon wrote 16 hours 50 min ago:
Barry James Marshall
uselesswords wrote 12 hours 17 min ago:
Classic HN reply. No elaboration, explanation, nothing.
What exactly am I supposed to have read from your mind?
AbrahamParangi wrote 1 day 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.
h2782 wrote 18 hours 37 min 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.
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.
raverbashing wrote 23 hours 24 min 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"
ch4s3 wrote 14 hours 28 min ago:
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-ba...
vrc wrote 17 hours 7 min ago:
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.
wyldfire wrote 1 day ago:
Though it could certainly inspire such a study.
ch4s3 wrote 1 day 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.
daveguy wrote 1 day ago:
That's why doctors publish case studies all the time -- to
inspire larger scale and statistically sound studies.
more_corn wrote 1 day 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.
vlovich123 wrote 1 day 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 wrote 1 day 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.
renewiltord wrote 23 hours 46 min ago:
Indeed, as any ethicist worth his salt would argue: we
don’t want anyone saving lives without proper approval.
refurb wrote 12 hours 43 min ago:
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"
southernplaces7 wrote 3 hours 47 min ago:
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.
vkou wrote 20 hours 52 min 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.
vlovich123 wrote 1 day 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.
owenthejumper wrote 17 hours 5 min ago:
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.
vlovich123 wrote 15 hours 34 min ago:
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.
owenthejumper wrote 5 hours 9 min ago:
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.
Panzer04 wrote 16 hours 20 min ago:
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.
dotancohen wrote 21 hours 54 min 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 wrote 20 hours 28 min 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.
echelon wrote 1 day 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.
refurb wrote 12 hours 41 min ago:
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".
_qua wrote 1 day 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 wrote 1 day 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 wrote 1 day ago:
I don’t disagree but the guy below you wants to
grow human shells and try head transplants.
lofaszvanitt wrote 17 hours 46 min ago:
good! old, dinosaur like systems need to be
forgotten already.
short_sells_poo wrote 19 hours 12 min ago:
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.
tomcam wrote 1 day ago:
Transplant a few heads and suddenly you never get
invited to another Christmas party
tough wrote 18 hours 51 min ago:
2017
[1]: https://nationalpost.com/health/worlds...
echelon wrote 1 day 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 wrote 22 hours 57 min ago:
This comment, more than any other, has sold me on
the value of red tape in medical research.
echelon wrote 22 hours 17 min 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 wrote 21 hours 13 min 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 wrote 1 day 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 wrote 22 hours 15 min 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 wrote 20 hours 24 min 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!
egocodedinsol wrote 1 day ago:
Here’s a link to the abstract: [1] apparently it was prospective and
randomized. I’m a little shocked by the effect size.
[1]: https://ascopubs.org/doi/abs/10.1200/JCO.2025.43.16_suppl.8516
munchler wrote 1 day ago:
This paper was not a retrospective analysis, it was a randomized
clinical trial.
egocodedinsol wrote 1 day ago:
Yeah I’m checking - I saw several other oncologists suggesting
song a separate discussion.
levocardia wrote 1 day 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 wrote 1 day 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 wrote 1 day 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 wrote 21 hours 2 min 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.
NotGMan wrote 1 day 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.
Laaas wrote 1 day ago:
Light affects us deeply. Very probably true for more than
immunotherapy.
unnamed76ri wrote 1 day 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 wrote 22 hours 52 min ago:
How many side effects people just accept because no one thought to
tweak the schedule
cenamus wrote 19 hours 10 min ago:
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.
unnamed76ri wrote 10 hours 54 min ago:
I did make sure to bring it up to my doctor in case the idea
could help anyone else.
hypercube33 wrote 17 hours 46 min ago:
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.
tomcam wrote 1 day ago:
Thanks for sharing, and I’m very glad you are here to discuss it.
jmward01 wrote 1 day 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 wrote 22 hours 49 min ago:
We tend to treat the body like a static system when it's actually
dynamic across the day
rendaw wrote 1 day 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...
amluto wrote 15 hours 19 min ago:
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 isnâ€�…
same thing as having your T cell population tolerate the antigen.
aitchnyu wrote 19 hours 48 min ago:
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.
HexPhantom wrote 22 hours 51 min ago:
Yeah, that tension between convenience and protocol is so real and
frustrating
Nevermark wrote 1 day 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.
mjevans wrote 1 day 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.
iamtheworstdev wrote 1 day 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 wrote 21 hours 32 min 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 wrote 1 day ago:
Where did they say they’re mad?
bjornasm wrote 1 day ago:
They explicitly fault the doctor for not acting on research that
wasn't available.
unaindz wrote 1 day ago:
The last paragraph heavily implies it
justsomehnguy wrote 1 day 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 wrote 1 day 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 wrote 1 day 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?
detourdog wrote 1 day ago:
I looked up CedarCure and what I found is that it is a pesticide.
What is the treatment about?
annoyingnoob wrote 1 day ago:
[1]: https://synapse.inc/medicine/9101/
tines wrote 1 day ago:
OP is an insect going in for assisted suicide.
iamtheworstdev wrote 1 day ago:
looks like a sublingual immunotherapy treatment for allergies to
japanese cedar pollen.
rendaw wrote 1 day ago:
It's an immunotherapy drug for cedar pollen allergy.
zevets wrote 1 day 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.
abhishaike wrote 1 day 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
munchler wrote 1 day ago:
The appointment schedule was randomized, so your objection is
incorrect.
majormajor wrote 1 day 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 wrote 1 day 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 wrote 1 day 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 wrote 1 day ago:
> mid-day appointments as also a luxury for those doing well
Irrelevant to this study given randomization.
detourdog wrote 1 day ago:
I can schedule appointments whenever I want. I'm an early riser and
prefer my appointments first thing in the morning.
vhanda wrote 1 day 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.
vibrio wrote 17 hours 14 min ago:
"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).
gus_massa wrote 1 day 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 wrote 1 day ago:
> Yes, maybe morning nurses are fresher and more alert, but, again,
randomization fixes that
How does randomization fix that?
finnh wrote 1 day ago:
exactly. that one clause casts doubt on all the other reasoning;
randomization controls for patient selection bias but not diurnal
clinic performance
phanimahesh wrote 1 day ago:
It would if the clinic is a controlled setting and they can
control when the nursing shift begins.
tines wrote 1 day ago:
What does randomization mean in this context, and why does it fix
those problems?
kelnos wrote 1 day 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 wrote 1 day 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 wrote 1 day 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".
simmerup wrote 1 day 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 wrote 1 day 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 :)
anigbrowl wrote 1 day ago:
Why would you assume nurses are scheduled on a 9-5 basis?
ajkjk wrote 1 day ago:
[1] The same thing it means in every context: that (with enough
samples) you can control for confounders.
[1]: https://en.wikipedia.org/wiki/Randomized_controlled_tria...
tines wrote 1 day 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?
ajkjk wrote 1 day 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 wrote 1 day ago:
I guess I'm asking, how do you randomize out the confounder
in this case.
bravesoul2 wrote 1 day ago:
Have every dose be observed by another doctor?
ajkjk wrote 1 day 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.
JumpCrisscross wrote 1 day 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.
NhanH wrote 1 day ago:
Patients are assigned the time for their visits. The time itself
is randomized
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