[HN Gopher] Administering immunotherapy in the morning seems to ...
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Administering immunotherapy in the morning seems to matter. Why?
Author : abhishaike
Score : 224 points
Date : 2025-06-08 16:18 UTC (1 days ago)
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| zevets wrote:
| 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 wrote:
| 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 wrote:
| What does randomization mean in this context, and why does it
| fix those problems?
| NhanH wrote:
| Patients are assigned the time for their visits. The time
| itself is randomized
| ajkjk wrote:
| https://en.wikipedia.org/wiki/Randomized_controlled_trial
|
| The same thing it means in every context: that (with enough
| samples) you can control for confounders.
| tines wrote:
| 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 wrote:
| > _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 wrote:
| "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:
| I guess I'm asking, how do you randomize out the
| confounder in this case.
| ajkjk wrote:
| 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 wrote:
| Have every dose be observed by another doctor?
| kelnos wrote:
| 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:
| How does this control for the "alert nurses" variable? In
| that case, patients would do better in the morning,
| regardless of the patient.
| anigbrowl wrote:
| Why would you assume nurses are scheduled on a 9-5 basis?
| simmerup wrote:
| 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:
| 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 :)
| d_tr wrote:
| 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".
| leereeves wrote:
| > Yes, maybe morning nurses are fresher and more alert, but,
| again, randomization fixes that
|
| How does randomization fix that?
| finnh wrote:
| exactly. that one clause casts doubt on all the other
| reasoning; randomization controls for patient selection
| bias but not diurnal clinic performance
| phanimahesh wrote:
| It would if the clinic is a controlled setting and they
| can control when the nursing shift begins.
| gus_massa wrote:
| 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?
| vibrio wrote:
| "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).
| majormajor wrote:
| 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.
| detourdog wrote:
| I can schedule appointments whenever I want. I'm an early
| riser and prefer my appointments first thing in the morning.
| JumpCrisscross wrote:
| > _mid-day appointments as also a luxury for those doing
| well_
|
| Irrelevant to this study given randomization.
| pbhjpbhj wrote:
| 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:
| 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.
| munchler wrote:
| The appointment schedule was randomized, so your objection is
| incorrect.
| abhishaike wrote:
| 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
| rendaw wrote:
| 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...
| detourdog wrote:
| I looked up CedarCure and what I found is that it is a
| pesticide. What is the treatment about?
| rendaw wrote:
| It's an immunotherapy drug for cedar pollen allergy.
| iamtheworstdev wrote:
| looks like a sublingual immunotherapy treatment for allergies
| to japanese cedar pollen.
| tines wrote:
| OP is an insect going in for assisted suicide.
| annoyingnoob wrote:
| https://synapse.inc/medicine/9101/
| justsomehnguy wrote:
| 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:
| 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:
| 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?
| iamtheworstdev wrote:
| 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?
| tomcam wrote:
| Where did they say they're mad?
| unaindz wrote:
| The last paragraph heavily implies it
| bjornasm wrote:
| They explicitly fault the doctor for not acting on research
| that wasn't available.
| rendaw wrote:
| 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.
| mjevans wrote:
| 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.
| Nevermark wrote:
| > 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.
| HexPhantom wrote:
| Yeah, that tension between convenience and protocol is so real
| and frustrating
| aitchnyu wrote:
| 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.
| amluto wrote:
| If the reasoning in the OP is right, then one might infer that
| the evening is the right time to take it. The goal of cancer
| immunotherapy is to convince your body to treat the cancer as
| harmful. The goal of allergy immunotherapy is to convince your
| body to tolerate allergens. If you are more likely to consider
| antigens harmful in the morning and tolerable in the evening,
| then evening is better.
|
| As a giant confounding effect, it seems that allergy
| immunotherapy might work, at least in part, by convincing your
| body to make large amounts of IgG antibodies to the allergen,
| and IgG antibodies are in the "kill it but don't sneeze at it"
| category, which isn't same thing as having your T cell
| population tolerate the antigen.
| jmward01 wrote:
| 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:
| We tend to treat the body like a static system when it's
| actually dynamic across the day
| unnamed76ri wrote:
| 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.
| tomcam wrote:
| Thanks for sharing, and I'm very glad you are here to discuss
| it.
| HexPhantom wrote:
| How many side effects people just accept because no one thought
| to tweak the schedule
| cenamus wrote:
| 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.
| hypercube33 wrote:
| 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.
| unnamed76ri wrote:
| I did make sure to bring it up to my doctor in case the
| idea could help anyone else.
| Laaas wrote:
| Light affects us deeply. Very probably true for more than
| immunotherapy.
| NotGMan wrote:
| 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.
| levocardia wrote:
| 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:
| >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:
| 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:
| 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.
| egocodedinsol wrote:
| Here's a link to the abstract:
| https://ascopubs.org/doi/abs/10.1200/JCO.2025.43.16_suppl.85...
|
| apparently it was prospective and randomized. I'm a little
| shocked by the effect size.
| munchler wrote:
| This paper was not a retrospective analysis, it was a
| randomized clinical trial.
| egocodedinsol wrote:
| Yeah I'm checking - I saw several other oncologists
| suggesting song a separate discussion.
| raylad wrote:
| 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.
| sixo wrote:
| Amazing. And shameful (for them.)
| ch4s3 wrote:
| 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.
| wyldfire wrote:
| Though it could certainly inspire such a study.
| ch4s3 wrote:
| 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 wrote:
| 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:
| 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.
| echelon wrote:
| 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 wrote:
| 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.
| echelon wrote:
| 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.
| cannonpr wrote:
| 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:
| 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:
| 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!
| nothrabannosir wrote:
| This comment, more than any other, has sold me on the
| value of red tape in medical research.
| echelon wrote:
| 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:
| 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.
| xvector wrote:
| 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:
| I don't disagree but the guy below you wants to grow
| human shells and try head transplants.
| tomcam wrote:
| Transplant a few heads and suddenly you never get invited
| to another Christmas party
| tough wrote:
| 2017
|
| https://nationalpost.com/health/worlds-first-human-head-
| tran...
| short_sells_poo wrote:
| 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.
| lofaszvanitt wrote:
| good! old, dinosaur like systems need to be forgotten
| already.
| refurb wrote:
| 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".
| vlovich123 wrote:
| 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 wrote:
| > 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:
| 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.
| owenthejumper wrote:
| 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.
| Panzer04 wrote:
| 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.
| vlovich123 wrote:
| 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.
| renewiltord wrote:
| Indeed, as any ethicist worth his salt would argue: we
| don't want anyone saving lives without proper approval.
| vkou wrote:
| 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.
| refurb wrote:
| 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"
| more_corn wrote:
| 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.
| daveguy wrote:
| That's why doctors publish case studies all the time --
| to inspire larger scale and statistically sound studies.
| AbrahamParangi wrote:
| 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 wrote:
| 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"
| vrc wrote:
| 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.
| ch4s3 wrote:
| The opposite approach exposes people to a lot of
| unnecessary and dangerous medical treatment. The evidence
| based approach has uncovered that stenting doesn't
| work[1], yet a lot of do something proponents are still
| installing them at great risk to patients and at great
| cost to medical systems.
|
| [1] https://lowninstitute.org/stents-dont-work-a-look-
| back-at-th...
| h2782 wrote:
| > 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.
| echelon wrote:
| > 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 wrote:
| "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:
| 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?
| echelon wrote:
| Barry James Marshall
| uselesswords wrote:
| Classic HN reply. No elaboration, explanation, nothing.
| What exactly am I supposed to have read from your mind?
| uselesswords wrote:
| 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.
| teekert wrote:
| 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.
| jcims wrote:
| Well the concept is now being studied quite closely. Had
| someone taken it seriously thirty years ago it's quite
| possible that the net amount of suffering that millions of
| patients have endured since then could have been reduced.
|
| https://pmc.ncbi.nlm.nih.gov/articles/PMC9599830/
|
| I'm comfortable calling that shameful. Not on any one in
| particular, it's a systemic problem that could be reduced
| with sufficient tenacity and courage to take risks.
| ch4s3 wrote:
| 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:
| 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.
| refurb wrote:
| > 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".
| vkou wrote:
| > 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.
| tilne wrote:
| 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.
| vkou wrote:
| Yes, it should.
|
| But cost is also important to patients. Or it would be in
| any universe that made sense.
| Spooky23 wrote:
| It is at cancer centers. Community oncologists don't have
| the resources to do it.
|
| Example:
| https://www.medicalnewstoday.com/articles/cancer-time-of-
| day...
| vlovich123 wrote:
| 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:
| Its not easy to ask if it messes with staff scheduling.
| vlovich123 wrote:
| 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:
| 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:
| 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.
| chiefalchemist wrote:
| 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.
| vidarh wrote:
| 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:
| > _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:
| 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.
| NiloCK wrote:
| 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:
| And if the A/B test says that your intervention made the
| situation worse? Now the doctor is held liable for that.
| s1artibartfast wrote:
| 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.
| bravesoul2 wrote:
| What's the p value? 0.5?
| irrational wrote:
| 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.
| HexPhantom wrote:
| 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:
| 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.
| bloqs wrote:
| As a younger person what are the best habits to get into to
| maintain optimal long term immune health?
| ReptileMan wrote:
| Normal weight and enough sleep.
| throwaway290 wrote:
| Don't compromise it chronically. Protected sex etc.
| goda90 wrote:
| 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:
| 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:
| The states known for "hippie"/"granola" attitudes, which
| largely align with the advice given here, tend to live
| longer than the states that don't (scroll through the
| list in [1] to see this). Usually I would insist on a
| study, but the effect is so striking, and the mechanism
| by which it would work is so obvious, that I think this
| simple list is enough. And I'm sure there are studies
| too, I'm just too lazy to find and link one.
|
| [1] https://en.wikipedia.org/wiki/List_of_U.S._states_and
| _territ...
| stronglikedan wrote:
| 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.
| webstrand wrote:
| 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.
| kmarc wrote:
| 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:
| What sort of pills? Vitamins or ?
| kmarc wrote:
| 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)
| mschuster91 wrote:
| - 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
| bregma wrote:
| You want to live a long time? Avoid any of the things that
| make it worthwhile.
| jcims wrote:
| 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:
| ? The other replies don't dismiss it...
| Gravityloss wrote:
| I've heard similar things about fasting.
| BDGC wrote:
| 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/
| owenthejumper wrote:
| Sicker patients get emergency treatment in the hospital in the
| afternoon while healthier ones in the morning in the clinic
| Spooky23 wrote:
| Cancer treatments typically don't happen in an inpatient
| setting.
| owenthejumper wrote:
| Of course they do
| anthuswilliams wrote:
| The article is reporting on randomized clinical trials, which
| are not subject to this dynamic.
| georgeburdell wrote:
| Not a medical doctor. Does this also have implications for other
| immunotherapy like allergy shots?
| parsabg wrote:
| 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.
| more_corn wrote:
| Because the immune system sleeps at night and wakes up in the
| morning?
| Kiyo-Lynn wrote:
| 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:
| They do - for metastatic melanoma, the goal is before 4:30,
| which is linked to higher survival rates.
| Kiyo-Lynn wrote:
| 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.
| EricPhy wrote:
| "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.
| cluckindan wrote:
| And not necessarily just an analog, given how there is an
| immune component to stress.
| agumonkey wrote:
| 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.
| HexPhantom wrote:
| In a way it feels like we're scratching the surface of a new
| layer of treatment optimization
| OrderlyTiamat wrote:
| 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.
| Noelia- wrote:
| 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.
| aitchnyu wrote:
| 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?
| pmlnr wrote:
| Body meridian clock, that's why.
| s1mplicissimus wrote:
| 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
| yoko888 wrote:
| 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.
| ImHereToVote wrote:
| Fasted state?
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