Administering immunotherapy in the morning seems to matter. Why?

239 points by abhishaike 3 weeks ago | 194 comments
  • raylad 3 weeks 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.

    • jcims 3 weeks 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 3 weeks ago
        ? The other replies don't dismiss it...
      • irrational 3 weeks ago
        Is it the time of day or how long the patient has been awake that matters? It seems like someone could change their sleep cycle to match the doctors schedule if the latter.
        • bloqs 3 weeks ago
          As a younger person what are the best habits to get into to maintain optimal long term immune health?
          • goda90 3 weeks 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

            • danbender 3 weeks ago
              Plus, fix your gut.
              • FollowingTheDao 3 weeks 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.
              • stronglikedan 3 weeks 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 3 weeks 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.

                  • webstrand 3 weeks 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.

                  • ReptileMan 3 weeks ago
                    Normal weight and enough sleep.
                    • bregma 3 weeks ago
                      You want to live a long time? Avoid any of the things that make it worthwhile.
                      • mschuster91 3 weeks 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

                        • throwaway290 3 weeks ago
                          Don't compromise it chronically. Protected sex etc.
                        • sixo 3 weeks ago
                          Amazing. And shameful (for them.)
                          • ch4s3 3 weeks 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.
                            • AbrahamParangi 3 weeks 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.

                              • teekert 3 weeks 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.

                                • jcims 3 weeks 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.

                                  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.

                                  • echelon 3 weeks 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.

                                    • wyldfire 3 weeks ago
                                      Though it could certainly inspire such a study.
                                    • vkou 3 weeks 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.

                                      • tilne 3 weeks 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.

                                        • NiloCK 3 weeks 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.

                                          • vlovich123 3 weeks 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.
                                            • vidarh 3 weeks 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.

                                              • chiefalchemist 3 weeks ago
                                                It shameful in the sense we all know there are circadian rhythms. We know the human body is not uniform from waking to shut eye. With this in mind health care therapies should be intentionally administered at various times - as wide as possible; from that perhaps outcomes will vary. You don’t need a study to look for opportunities to optimize a process.
                                              • bravesoul2 3 weeks ago
                                                What's the p value? 0.5?
                                              • Gravityloss 3 weeks ago
                                                I've heard similar things about fasting.
                                                • HexPhantom 3 weeks 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 3 weeks ago
                                                    Isn't it also quite understandable? Otherwise we risk the new way working well for half the patients and killing the other half, to exaggerate.
                                                • unnamed76ri 3 weeks 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.

                                                  • tomcam 3 weeks ago
                                                    Thanks for sharing, and I’m very glad you are here to discuss it.
                                                    • HexPhantom 3 weeks ago
                                                      How many side effects people just accept because no one thought to tweak the schedule
                                                      • cenamus 3 weeks 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.
                                                        • hypercube33 3 weeks 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.

                                                          • unnamed76ri 3 weeks ago
                                                            I did make sure to bring it up to my doctor in case the idea could help anyone else.
                                                      • levocardia 3 weeks 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 3 weeks 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 3 weeks 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.
                                                            • maherbeg 3 weeks ago
                                                              People are more insulin sensitive in the morning too which could correlate with this.
                                                              • trhway 3 weeks ago
                                                                i'd think the local acidity (build up of lactic acid resulting from glucose over-consumption by the cancer cells) would take a bit to build back up once glucose ups after the night.
                                                          • EricPhy 3 weeks 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.

                                                            • cluckindan 3 weeks ago
                                                              And not necessarily just an analog, given how there is an immune component to stress.
                                                              • agumonkey 3 weeks 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.
                                                              • jmward01 3 weeks ago
                                                                I wonder if other basic processes could be at play here like when patients go to the bathroom. If you do this in the morning they may be more likely to not need that for a while while in the evening they may do that immediately. I'm not saying this is the mechanism, just pointing out that there are a lot of timing dependent things in a person's schedule that could be a factor here. It is a great thing to point out though. I hope a lot more research goes into the idea of timing and integrating medication into a schedule most effectively.
                                                                • HexPhantom 3 weeks ago
                                                                  We tend to treat the body like a static system when it's actually dynamic across the day
                                                                • rendaw 3 weeks ago
                                                                  I'm doing CedarCure. You're required to not exercise or bath/shower for 2h after taking, which is fairly difficult in the morning, so I asked the doc if I could do it in the evening instead (despite explicit instructions to do it in the morning). The doc said it was fine, confirmed by the pharmacist.

                                                                  I should know better by now than to trust doctors to act based on research and not gut feeling, but I hope this doesn't mean the last year of taking it was a wash...

                                                                  • iamtheworstdev 3 weeks 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 3 weeks 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 3 weeks ago
                                                                        Where did they say they’re mad?
                                                                        • bjornasm 3 weeks ago
                                                                          They explicitly fault the doctor for not acting on research that wasn't available.
                                                                          • unaindz 3 weeks ago
                                                                            The last paragraph heavily implies it
                                                                        • amluto 3 weeks 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 isn’t same thing as having your T cell population tolerate the antigen.

                                                                          • Nevermark 3 weeks ago
                                                                            > I could do it in the evening instead (despite explicit instructions to do it in the morning)

                                                                            Have either you or your doctor identified the reason for the morning recommendation?

                                                                            Maybe restart consideration of timing there?

                                                                            Doctors are going to take your practical need to break one part of protocol, to maintain the rest of the protocol, seriously. They can't resolve the practicalities of patients' lives.

                                                                            • detourdog 3 weeks ago
                                                                              I looked up CedarCure and what I found is that it is a pesticide. What is the treatment about?
                                                                            • uselesswords 3 weeks ago
                                                                              I think you are misunderstanding a couple of things. The label for Cedarcure doesn’t have timed dosing, just says take it during the day. Furthermore this research article would actually indicate it’s better to take it in the afternoon for your particular drug, if there really is any connection. Which is still a crazy connection to make because you are complaining about a specific immumotherapy regimen finding not being applied to an allergy-style medication. Why not apply this logic to every drug that interacts with the immune system (which is all of them)? Furthermore as other comments pointed out, you’re mad your doctor didn’t know about a brand-new study that didn’t exist when they made a recommendation?

                                                                              Doctor’s have a wide discretion and often get things wrong. But in your case, that’s not what happened. If anything your doctor actually got it right either by chance or intuition.

                                                                              • justsomehnguy 3 weeks 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 3 weeks 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 3 weeks 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?
                                                                                • aitchnyu 3 weeks 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.

                                                                                  • mjevans 3 weeks 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.

                                                                                    • HexPhantom 3 weeks ago
                                                                                      Yeah, that tension between convenience and protocol is so real and frustrating
                                                                                    • BDGC 3 weeks ago
                                                                                      If you’re interested in circadian biology, which underlies chronoimmunotherapy, please check out UCSD’s BioClock Studio. We create tutorial videos and other media to teach circadian biology concepts: https://bioclock.ucsd.edu/
                                                                                      • NotGMan 3 weeks 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.

                                                                                        • egocodedinsol 3 weeks ago
                                                                                          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 3 weeks ago
                                                                                            This paper was not a retrospective analysis, it was a randomized clinical trial.
                                                                                            • egocodedinsol 3 weeks ago
                                                                                              Yeah I’m checking - I saw several other oncologists suggesting song a separate discussion.
                                                                                          • aitchnyu 3 weeks 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?
                                                                                            • Kiyo-Lynn 3 weeks 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 3 weeks ago
                                                                                                They do - for metastatic melanoma, the goal is before 4:30, which is linked to higher survival rates.
                                                                                                • Kiyo-Lynn 3 weeks 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.
                                                                                              • OrderlyTiamat 3 weeks 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.

                                                                                                • parsabg 3 weeks ago
                                                                                                  I wonder if the same would also be true for immunosuppressants administered for autoimmune conditions. Given they mostly interact with the signaling pathways, I guess in theory they should also be more effective in the morning if there is more immune cell activity going on.
                                                                                                  • Laaas 3 weeks ago
                                                                                                    Light affects us deeply. Very probably true for more than immunotherapy.
                                                                                                    • more_corn 3 weeks ago
                                                                                                      Because the immune system sleeps at night and wakes up in the morning?
                                                                                                      • HexPhantom 3 weeks ago
                                                                                                        In a way it feels like we're scratching the surface of a new layer of treatment optimization
                                                                                                        • georgeburdell 3 weeks ago
                                                                                                          Not a medical doctor. Does this also have implications for other immunotherapy like allergy shots?
                                                                                                          • pmlnr 3 weeks ago
                                                                                                            Body meridian clock, that's why.
                                                                                                            • owenthejumper 3 weeks ago
                                                                                                              Sicker patients get emergency treatment in the hospital in the afternoon while healthier ones in the morning in the clinic
                                                                                                              • anthuswilliams 3 weeks ago
                                                                                                                The article is reporting on randomized clinical trials, which are not subject to this dynamic.
                                                                                                                • Spooky23 3 weeks ago
                                                                                                                  Cancer treatments typically don’t happen in an inpatient setting.
                                                                                                              • s1mplicissimus 3 weeks 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

                                                                                                                • ImHereToVote 3 weeks ago
                                                                                                                  Fasted state?
                                                                                                                  • Noelia- 3 weeks 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.
                                                                                                                    • yoko888 3 weeks ago
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                                                                                                                      • zevets 3 weeks ago
                                                                                                                        This is bad science. Patients schedule when they go to immunotherapy appointments. People who go in the morning are still working/doing things, where once you get _really_ sick, you end up scheduling mid-day, because its such a hassle to do anything at all.
                                                                                                                        • vhanda 3 weeks 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.

                                                                                                                          • leereeves 3 weeks ago
                                                                                                                            > Yes, maybe morning nurses are fresher and more alert, but, again, randomization fixes that

                                                                                                                            How does randomization fix that?

                                                                                                                            • finnh 3 weeks ago
                                                                                                                              exactly. that one clause casts doubt on all the other reasoning; randomization controls for patient selection bias but not diurnal clinic performance
                                                                                                                            • vibrio 3 weeks 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).
                                                                                                                              • tines 3 weeks ago
                                                                                                                                What does randomization mean in this context, and why does it fix those problems?
                                                                                                                                • ajkjk 3 weeks ago
                                                                                                                                  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.

                                                                                                                                  • kelnos 3 weeks 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.
                                                                                                                                    • NhanH 3 weeks ago
                                                                                                                                      Patients are assigned the time for their visits. The time itself is randomized
                                                                                                                                    • gus_massa 3 weeks 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?

                                                                                                                                      • 3 weeks ago
                                                                                                                                      • abhishaike 3 weeks 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

                                                                                                                                        • 3 weeks ago
                                                                                                                                        • majormajor 3 weeks 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 3 weeks 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 3 weeks 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 3 weeks ago
                                                                                                                                              > mid-day appointments as also a luxury for those doing well

                                                                                                                                              Irrelevant to this study given randomization.

                                                                                                                                              • detourdog 3 weeks ago
                                                                                                                                                I can schedule appointments whenever I want. I'm an early riser and prefer my appointments first thing in the morning.
                                                                                                                                              • munchler 3 weeks ago
                                                                                                                                                The appointment schedule was randomized, so your objection is incorrect.