Gatsky

Read the ESR1 rapid update. The methods say:

"A targeted electronic literature search was conducted to identify any additional phase III randomized controlled trials in this patient population. No additional randomized controlled trials were identified. The original guideline Expert Panels reconvened to review evidence from EMERALD and to review and approve the revised recommendations."

Where is the meta-analysis? Where is the funnel plot? What are you even arguing about? They issued an update because of one trial.

Here is another one from June 2022, a major change to how one type of breast cancer is managed, in the methods:

"A targeted electronic literature search was conducted to identify phase III clinical trials pertaining to the recommendation on immune checkpoint inhibitors in this patient population. No additional randomized trials were identified. The original Expert Panel was reconvened to review the key evidence from KEYNOTE-522 and to review and approve the revision to the recommendation."

Where is the meta-analysis? Again, what are you trying to argue? They issued an update because of one trial.

There are two updates this year, one about HER2 testing, and one about ESR1.

Sorry to hear you have suffered poor quality interactions with doctors. Being honest, if there is no trust in the relationship between patient and doctor, then nothing else matters much as the experience will be poor on both sides.

Patient can of course bring whoever they want into the circle. The problem is the intrusions that neither healthcare provider nor patient want.

Actually doctors would be universally happy to get more help and support to deliver better healthcare. That you don't talk about that is quite telling, or is that what you mean by 'regulation'?

Casting the patient doctor relationship in terms of power dynamics is a bogus sociological construct divorced from reality. The true division of power is between those who fund healthcare and those who receive it, I would start there if you think things need to be improved.

I don't think it is false. I can only speak of my experience as an oncology healthcare provider. I spend many hours each week digesting the literature, and <5% of that involves meta-analyses. In the multidisciplinary meetings I chair, we rarely discuss evidence from meta-analyses, but we are always talking about clinical trials. The NCCN guidelines were useful when I was a trainee, but otherwise they are too US-centric, and they are always out of date due to the frequency they are updated. This is why ASCO keeps issuing rapid updates in breast cancer for example (https://old-prod.asco.org/practice-patients/guidelines/breas...). There are 2 such updates this year already. If the primacy of meta-analyses were so great, why would they bother to issue rapid updates of what you class as low quality evidence?

But to give a concrete example, the problem with meta-analyses is well illustrated in the recent EBCTG meta-analysis published in the Lancet, a top tier journal. This involved over 100,000 patients, and explored concurrent chemotherapy regimens in breast cancer. The problem is that such regimens are not used anymore. The authors acknowledge in their own conclusion that this massive meta-analysis contradicts their own previous meta-analysis showing the superiority of sequential therapy. What exactly does one do with this? How does this help a patient get the right therapy? The treatment of various breast cancer subtypes has also evolved so much that the trials they meta-analyse are mostly obsolete. Hence my point, that meta-analyses are just not that useful in oncology, even truly massive well conducted ones published in prestigious journals. So it is not so simple as meta-analysis > RCT, that is merely lazy dogma. I find it hard to believe that anyone actually treating cancer patients would hold this view.

Of course most meta-analyses in oncology are not 100,000 patient behemoths conducted by consortia. They are much smaller studies, which usually don't bother to get patient level data, and just copy numbers from tables in the original papers while running through the Cochrane systematic review template.

And yet, here I am dubbed 'radical' at the bottom of a comment thread on Hacker News. Unfortunately the dogma around systematic reviews and EBM has exceeded its usefulness by quite some margin. The meta-analytic method was developed by psychologists trying to compile evidence about extra sensory perception of all things - an inauspicious beginning if there ever was one for the supposed cornerstone of medicine.

The president of Medicens sans frontieres, Rowan Gillies, gave a speech once. He had a drawing of a patient and the doctor inside a circle. His comment was 'Other people keep trying to climb into this circle. They can all fuck off.' Excuse his profanity, but I offer this response to you, who knows nothing about what I do, and understands nothing about quality healthcare.

Well you discount the most important thing in the first line. 'Cutting-edge' is a funny way of saying 'most effective', as if it were somehow irrelevant.

I didn't say most evidence is from phase III RCTs, particularly if you include everything that happens in oncology as the denominator, only that meta-analyses were not that relevant. Most of the critical patient facing interventions have the backing of good quality trials, at least where it is reasonable and possible to do a trial. Also one of your citations is seemingly casting doubt on the value of meta-analyses in oncology, so somewhat confused about your point.

That paragraph from NCCN is quite interesting. It is describing medicine in general really, and belies the fact that oncology has probably one of the strongest evidence base across all medical fields. Take for example how many stents cardiologists have inserted long after contradictory evidence was available, or how many pointless back operations have been done, or how many people have sat through fruitless psychoanalysis.

Disagree. I change practice on Monday after a single quality trial. Pick up any society guideline, only a small amount of the recommendations rely on meta-analyses. Look at immunotherapy or antibody drug conjugates, revolutionary therapies that arrived one trial at a time.

Yeah, well in my field, oncology, meta-analyses are somewhat irrelevant. As you can imagine, the bar for completing a phase 3 randomised trial in oncology is pretty high. Meta-analyses are mostly there for trainees to notch up a paper.

Another fine example of the author's point is the ivermectin in covid meta-analytic nonsense (which I cannot even bring myself to link), where a bunch of small rubbish trials are meta-analysed into a 'flawless' body of evidence while double blind randomised trials are impugned.

IRBs do not evaluate the value of a research endeavour. They are in fact unable to do this due to lack of knowledge and expertise. They approve trials which fit the mold of trials they have seen before. Why does a clinical trial get done? The main reason is that someone, usually a pharmaceutical or device company, is willing to pay for it.

Some recent examples of problems with clinical trials:

1. Using a harmful or deliberately inadequate placebo. https://academic.oup.com/jnci/article/104/4/273/979399 https://www.ahajournals.org/doi/10.1161/CIRCULATIONAHA.122.0... https://pubmed.ncbi.nlm.nih.gov/34688044/

2. Starting a bunch of clinical trials using a biomarker which turned out to be invalid. https://www.nejm.org/doi/10.1056/NEJMoa1214271

3. Endless 'me-too' trials driven by pharma, with a low chance of success. https://www.statnews.com/2019/09/04/me-too-drugs-cancer-clin...

The biggest issue, IMHO, is that clinical trials are often unethical. This is both in theory and especially in practice. I say this as a physician and clinical trial investigator.

EBM deals with this by saying ‘there is no viable alternative’, a remarkable statement of epistemological nihilism that enables much low quality snd pointless research.

Some people aren't worth it. Some people are just miserable. Not depressed, just miserable. Some people are insecure, vindictive, manipulative, querulous, disagreeable. Having a relationship with them will be as much as 100x more difficult than another person. This is the hard lesson I learned after 4 years in a thoroughly depleting relationship where I tried everything to make it work. When I look at my friends in their 40s, some have great partners and some don't, and the ones that don't have a truly execrable life despite good health, jobs, income, cars, holidays etc. Choosing a good partner matters more than almost anything else.

Don't get me wrong - I am not advocating we put all the bad partners in a camp somewhere. They are fundamentally in a state of suffering, and benefit from help and support. But the way to deliver that support is not by being in a romantic relationship with them.

If you are good partner material, consider the following asymmetry: A good partner can be in a relationship with a poor partner, but two poor partners will almost never be in a relationship together. This means that being a good partner increases your chance of ending up with a poor partner.

Antivirals probably won’t help as most infections are silent, a vaccine is needed. Moderna is working on one.

I think this is a great comment, with much broader implications for living well. Unmooring the sense of self from external factors is one important aspect of spirituality.

This reference [1] tends to support what you are saying:

For this thesis, an atmospheric propagation code named ANCHOR (Atmospheric NPS Code for High Energy Laser Optical pRopagation) was developed and utilized to study the propagation of high energy lasers in various atmospheric conditions and for numerous laser configurations. The ANCHOR code accesses existing industry databases to obtain relevant optical properties for various atmospheres and then uses scaling laws to simulate laser propagation through the defined environments. ANCHOR accounts for the effects of atmospheric diffraction, turbulence, platform jitter and thermal blooming on the laser beam, and outputs on-target irradiance and power-in-the-bucket profiles for a wide range of laser wavelengths. Several known physical trends associated with laser propagation will be reproduced, and the results will be compared to the industry accepted propagation code Wavetrain. The results of ANCHOR studies will indicate that the 100 kW-class high energy laser can effectively engage slow-moving targets at ranges greater than five kilometers in clear weather by delivering enough energy to melt 0.1 liters of one millimeter-thick aluminum aircraft skin in five seconds. For hazy, turbulent, and rainy conditions, the laser can effectively engage targets from ranges closer than three kilometers, but reasonable dwell times are only achieved for ranges closer than two kilometers.

[1] https://core.ac.uk/download/pdf/36734846.pdf

There are thousands of sequenced human genomes available to access for research purposes (1000 genomes project, UK biobank etc) so one additional genome adds no marginal value.

Re WGS there are a lot of well established tool chains that are FLOSS (eg https://github.com/bcbio/bcbio-nextgen). You could run alignment and variant calling on a beefy workstation. A laptop would potentially work. Easy to test this with publicly available raw data. Another option: The sequencing provider often will run alignment and some default variant calling for you. Annotating and analysing these variants can be done on pretty much any computer, all with open source software. A SNP chip is even easier to deal with as the computational requirements are less.

Interpreting the results is a more manual process. Really depends on what you are interested in.

Such as? I’ve worked in genomics labs, they would be quite happy to delete stuff.

Yes, find a local sequencing provider and arrange to do a SNP chip or whole genome sequencing. In the contract ask that they delete your data after delivering it to you. This will be:

1. Expensive - probably at least 2 - 3 thousand dollars.

2. Require you to do your own analysis.

Obviously you can't be 100% sure they will delete your genomic data, but they have no incentive to keep it.

Viewers will be able to "order up" films—for example, "I want a film about a panda and a unicorn who save the world in a rocket ship. And put Bill Murray in it."

From there I believe viewers will be given the ability to be digitally scanned themselves, and pay extra to have themselves inserted in these custom films. You'll also start to see licensing deals made with studios, so that viewers can order up older films like "Star Wars" and put their face on Luke Skywalker's body, and their ex-wife's face on Darth Vader's body, and so on.

This is pretty far from what most people want, I think. How are you going to chat about your AI generated custom personal vendetta movie around the watercooler?

Although quite uncharitable, I can believe this has some truth to it. She underwent a visible transformation for the trial, wearing her hair down and changing her entire mien. Quite a contrast to her appearance during the Theranos years.

I feel that alignment is not just hard but impossible, at least if you want something truly useful. Maybe the only thing you can do is let an AI develop and observe its nature from a distance, say in a simulated world running at high speed which it does not know is simulated. You can hope it will develop principles that do align with your own, that its essential nature will be good. Sometimes I wonder if that is what a greater intelligence is doing to us.

Reading this makes you realise how much of what makes Seinfeld good is in the skillful delivery. I wonder how much they would have to rehearse to get it spot on.

The NYT death announcements have this tone. It says at the bottom that a formal obituary will be forthcoming.

Very interesting. The increase in Coeliac disease will mostly be due to the advent of a useful blood test to detect it. The lack of association between other autoimmune diseases and multiple sclerosis fits with the recent identification of Epstein-Barr virus as a probable causative agent. The reduction in pernicious anaemia could be explained by reductions in the prevalence of Helicobacter pylori (due to effective treatment and improvements in food handling).

Yeah this doesn’t quite sit right. It lacks any detail about what Google is actually doing.

Just came to say that this is a wonderful comment, and that people voluntarily playing with/remixing your creation is one sign of great art.

A technical feat, strengthening the notion that ageing is not inevitable.

At the same time, I don’t think it is particularly controversial to say that if we start modifying our own genetics we could eliminate most diseases, including many aspects of ageing. The ‘problem’ if you like is that 1) there seems to be no ethical/careful way to do this that doesn’t amount to experimenting on children; 2) we will cease to be a homogeneous species. Intermediate solutions are post-germline genetic manipulation… but how feasible is it to gene edit a majority of adult neurons, for example?

The point still stands, there are thousands of papers demonstrating preclinical utility of nanoparticles for many applications, and extremely few actual medicines.

I was listening to a talk from a leading nanoparticle researcher. He basically said that making new nanoparticles and characterising them is great for writing papers but they all fail actual testing as therapeutic delivery devices. In oncology there are kinda only two nanoparticle therapies - Abraxane, which is a well known chemotherapy drug bound to albumin; liposomal doxorubicin, an encapsulated form of another well known chemotherapy drug. They have been around a while and they are not exactly game changing, extending survival a modest amount at best. Nanoparticles are overrated from where I sit, as are University press releases.

On the other hand, antibody based therapies are amazing revolutionary drugs in oncology. Chief among them is Keytruda which has improved the lives of so many patients and has $2billion in sales every month and rising. Most recently, sticking chemotherapy drugs or radioisotopes on the end of antibodies (or smaller antibody like proteins) has shown great results as a delivery vehicle. Are these ‘nanoparticles’? No, just actual drugs that work.

My thoughts about this are that youtube is great if you have a specific learning task/interest, but if you don’t then it will lead you astray.

There is no doubt however that it has pulled off the magic trick of incentivizing thoughtful and knowledgeable people to produce good videos. This seems as close as we’ll get to a mutually beneficial arrangement in the attention economy.