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The numbers quoted are from FDA's expanded program (as requested by patients) and as I have already noted, liability does not seem to be an issue as there have been virtually no legal challenges (an opinion share by experts). There is no mechanism for that. If a drug fails Phase I it cannot be used for anything. If it passes, the manufacturer would need to invest in Phase II anyway (at a cost of ~5 x of that of Phase I). Nothing in the bill changes that. You are also probably misunderstanding the market situation of non-approved drugs. The treatment is not mass produced at this step. Rather. the manufacturers are still developing the treatment, often with modifications based on trial results. I.e. they only have limited supply and rarely a surplus that they can push anywhere. And remember they still need sufficient supply for their trials. Plus. if they wanted to push it, they would now also invest into marketing. And that is not going to work out well as the actual customer pool is small. You cannot compare it to pain medication, as the only possible patients are the terminally ill, who cannot be registered in regular trials, are not too old to undergo treatment, etc. I.e. it is only a relatively small pool who may consider using an experimental drug. While marketing could raise the number of requests somewhat, there is an hard upper limit. What you seem to suggest is that companies are going to invest millions into Phase I, then for some reason give up on Phase II before trying (or worse, while trying, losing a few more millions on the way). Note that they cannot simply pull out of trials; only drugs in approval pipelines are eligible. Then invest more money to produce drug surplus and marketing in the hope of getting enough terminal ill patients and their doctors to sign up and make up for those investments. That sounds like a good way to lose money to me. The fact that many drugs has no bearing on it. Folks do not invest tons of money into pre-trial and early trials with the expectation that it will fail eventually. Again, the only realistic scenario is when they already got data late in the pipeline (e.g. during Phase II) that the drug is less promising and maybe leverage some funds to make up. It would be more about cutting losses than making money, though. One potential way could be to leverage successes in order to get more buy-in from investors. But it is hardly comparable to the opioid scenario you describe (unless you manage to suddenly create new terminal ill for a specific treatment).

I doubt that they did a detailed forensic analysis of everyone pinned by a tree to determine that. I.e. someone is found dead in the rubble somewhere after the storm it is almost certainly counted as direct death.

That is more in line what I was suggesting earlier. A means to leverage funds rather than a "get rich scheme". As a side note, I found a few papers that reviewed cases in states which already have right to try laws. As of 2017 there has not been a documented case where access was granted under these laws which were not already under the FDA's Expanded Access Program (some of which, such as Texas, have provisions that would prohibit manufacturers to charge patients). I.e. there is no indication that in practice these laws were little more than feel good laws with little to no actual impact. The bigger issue is, as I stated before, the intention to limit FDA's influence and, (perhaps to a lesser degree) potential endangerment of patients as the individualized oversight by the FDA is missing. Also between 2010 and 2014 5000 requests were made, so the pool for a given medication might be fairly low. Some more of the provisions of the federal act: - drug has to pass phase I trials - physician has to certify that no other options are feasible and patients is unable to participate in regular trial - access requires prescriber, manufacturer and patient's informed consent (i.e. FDA as check is eliminated) - FDA cannot use data on negative outcomes to delay or deny approval, unless the results are critical for safety reasons (a bit vague on that end) - manufacturers are protected from liability - does not create any form of entitlement for the patients There are many concerns including, but not limited to: - safety - possible diversion of patients and resources away from "proper" trials - the fact that expanded access under the FDA already works (almost all requests are approved, but FDA does provide safety suggestions that are helpful to the patients) -manufacturer's generally are already protected from liability under expanded access (historically there is a lack of legal action against them in those cases) - manufacturer would still need to divert resources and if they are indeed on track to regular approval, there is little incentive to do so (which is why I mentioned small and sketchy companies) The overall opinion in the public health community seems to range from, useless and inconsequential, a threat FDA's mission to potentially endangering. The the latter is mostly speculative at this point. Nope, it would even be bad in the short run. Here is the thing, unless they went to phase II they won't know that it won't work. If it is already there and shown to be inefficient, they would have hard time to find buyers. So that leaves mostly those that are still hopeful and also note that again, under the current rules folks can already request them and it does include investigational drugs. About 30% of them were, in fact approved later. You also forget that actually providing and administrating investigational drugs is a significant expense, which includes production and, depending on the treatment, also administration and supervision. Considering that on average per drug only ~12 request were made between 2010 and 2014, each treatment would need to be at a tremendous cost to be anywhere near profitable. Perhaps more importantly, it does divert resources from the actual trials which are run on a tight timeline and budget. That is one of the main reasons (aside from negative outcomes) why manufacturers usually limit access to their drugs, rather than expanding it. Under certain circumstances it could be more likely to happen (i.e. if the production cost is very low). Overall, I would think that it would be difficult not to run at a loss.

That may be true, but again, a multi-million dollar investment with the hopes to scam people is rather risky. In fact, I would argue that if you have the financial backing to do Phase I (plus all the additional investment prior to that), you already got more money than you could likely get out of that kind of scheme. I.e. while there is room for abuse, the get rich part does not strike me as the most likely scenario.

This is mostly an issue with smaller, sketchy companies or startup that use it to leverage funding in the short-term. It would not be a sustainable model. The provision does say that it has to go through Phase I which costs a few millions in investment. It would need to be quite an elaborate scam just to recuperate that cost.

Note that this is also possible without the law. I.e. the FDA was even able to approve individual use of investigational drugs (i.e. which has not passed an trialsyet). What is needed is only tox study on safety using animal testing and be at a stage in which it could reasonably enter Phase I trials. The new law would only allow access after Phase I but does not need FDA review anymore, which is one of the issues with it.

The official death toll in Puerto Rico due to Hurricane Maria was 64. This number only included direct effects. Kishone et al. investigated whether the hurricane could have contributed to overall change in mortality e.g. due to displacement, loss of infrastructure or interrupted health care. Based on a survey from 3299 household they calculated an excess moratlity of 4645 excess deaths caused by the Hurricane Maria. The authors also asserted that due to survivor bias this number is on the conservative side. Kischone et al "Mortality in Puerto Rico after Hurricane Maria", JAMA, 2018, DOI: 10.1056/NEJMsa1803972

Just to add information: there are ways to for individuals to request access, but the regulation is that the FDA has to sign off of them. Nonetheless, quite often they are denied by manufacturers for a number of reasons including a) it may jeopardize the approval of the drug (e.g. if the terminal ill have some adverse effects not found in healthy), b) they have limited availability, c) it would disrupt their development pipeline. One of the biggest thing that folks are wary about the bill is that it basically cuts the FDA off from that process. To be clear, there are pathways to access drugs prior to approval, it is not that they become available for the first time. However, limiting liability of the manufacturer and hiding the data from the approval process could make it more attractive for the manufacturer to agree. However many may still decline on grounds of cost and time investment, for example.

The law is problematic, but not for these specific concerns, but rather because it is not quite clear what changes it would actually bring. There are no provision to provide patients with the drugs nor is it made clear who is going to pay for it. There is no clear pathway that would make it easier or cheaper for companies to conduct trials (i.e. there is no indication that the Feds would pay for it, nor is it clear that people could pay out of pocket, nor are companies compelled to accept them). The biggest risk are probably smaller companies (or subsidaries from larger ones) that could close down when things blow up in their face. I suspect that many pharms would rather not provide medication to terminally ill patients outside of trials (for which they have to pay anyway). Additional deaths can skew the results and make a drug appear less valuable than it might be. Otoh the FDA already has provisions for compassionate access to drugs still in trials (or even investigative drugs). All it really does is muddy the water regarding FDA regulations. In the long run that could seriously impact FDA's mission (which I suspect is the main political goal). That being said, those laws are already in place in many states, so one could check whether there are any indications of what may or may not have happened as a consequence. Edit: I just glimpsed at the text and would need to read it in more depth, but there is one provision that states that adverse outcomes under these rules would not be used in the approval process unless it is critical for the evaluation. So at least that part of my argument does not hold.

It basically counts as a public disclosure and in the US (and Canada, I think) you have got a 1 year grace period. I think in the EU you don't have that provision. However, it requires that you produced the IP (i.e. are the inventor). As stranger pointed out, you could only use the information from someone else's public disclosure to create a similar, but distinct invention and patent that.

In the US there is a year grace time between public use and filing the patent. I.e. you could describe a method, use it for a paper and publish it. But you'd have to file the patent within a year.

Ok, I think we are to hung up on a specific examples, and I am indeed unsure about clownfishes in the wild. But the fact that they can survive implies that their relationship is beneficial but not essential. With regard to hermit crabs, it is actually described as a classic facultative symbiosis (specifically, facultative mutualism) in lit (read e.g. Patzner et al 2004 . Ophelia 58:1–11 for a review). Cleaning symbioses can be both. In non-fishes it is (AFAIK) entirely facultative. Note that increase in fitness for both species cannot be seen as something other than what you describe as "choice" in direct opposition to "evolution". After all, the result of cooperation behaviour is the mutual increase in fitness, too. Otherwise why engage in that behaviour? But again, that does not address the situation in the OP. What, do you think does the cooperation outlined in OP make it entirely different from all the other symbiotic behaviours we have observed. Perhaps maybe define where you see the dichotomy?

Not sure what you mean. Hermit crabs and clownfish can live without their respective partners (certainly the hermit crab and for clownfish at least in captivity). So it is not an physiological necessity. Also, any cooperative behaviour can be framed within the context of evolution. Why not? Animals doing the cleaning are not reliant on clients for survival. Likewise, clients do not need to tolerate the grooming. Again, I think you have a fairly narrow definition of co-evolution in your mind that creates an false dichotomy with your thoughts about "choice". Note that you are also changing goalposts where you started with a vague definition of choice (and note, OP was not talking about that, rather the ability of recognizing individuals, which has not been recognized yet) then you added temporal restrictions and finally mutal dependency. I do think that the reason is for this is poorly defined boundaries of definitions more than anything else. In my definition I make a clear distinction between obligate and facultative symbioses, where in the letter case, depending on situation a relationship may or may not form. In the obligate case, they are necessary for at least one of the partners for survival.

Actually no, I specifically picked examples in which the relationship benefits survival, but is not essential. Others, such as symbioses of various animals with protozoans for the digestion of ligning or the dependency of lichens on cyanobacteria are examples of obligate symbioses. So this is a completely different criterion. Here you seem to state that you are considering symbiotic relationship that are only short-lived. However, cleaning symbioses would fall under this group.

I think you are making an artificial distinction. After all, how would you tell the difference without projecting human experience on them? The ability to make friendship could be considered an evolutionary feature, after all there are plenty of species who are solitary for most of their lives. Specifically to the study in OP, on what basis would you categorize it as "choice" rather than "evolutionary" (and again, I think this distinction does not make a lot of sense to me in the first place)?

There many options to choose from. Famous ones are cleaning symbioses known in fish, birds and even some mammals. Defensive symbioses are also pretty common, including various species with sea anemones (hermit crabs, clownfish). Even endosymbioses can be optional (though quite a few are essential). Examples include Root nodule symbioses which typically only occurs when the plant is nitrogen limited. But again, it depends on what you define as choice in this regard. But then we would be in the area where we would need to discuss consciousness and the ability of make choices etc...

That does not make a lot of sense to me. Symbiotic relationships are not always essential, hence they are often by choice. What is different is that in this case the cooperation is on the individual level. That is not unique, but seems not to have been observed in birds before.

Symbiotic relationship are per definitionem relationships across species. Whether you wan to call those "societies" is a different matter.

Yeah, maintaining an oppressive dictatorship is actually quite difficult. I would expect that many seemingly cruel and maniacal actions or seemingly stupid actions, are the result of focusing on maintaining power, rather than governance. Ten Oz is correct in saying that Kim is quite experienced in that (as evidenced by him not being dead yet). Edit: so there is a surprise summit between NK and SK and apparently the US prep time is heading to Singapore. We are apparently in Bizarro world. The US president bumbles through high-stakes diplomatic negotiations and KJU is the steady one.

42/7 are the standard angles for dimetric projections, not sure about what is on there though. Also, it is a "Schablone" (with "e", though technically I should not complain about typos, if it was one). Edit, just checked some drawings and it seems that there are variations in dimetric projections, including 41.25/7.11.

I don't think that it is entirely accurate. Based on various articles on NK, it seems that the Kim's position is far more precarious than one might imagine. The purges and assassinations were means to strengthen his internal power and there are reported worries regarding military coups, especially when he leaves the country. Now, NK has again stated that they are open for talks any time, thus placing the blame squarely at the US. Thus Kim has effectively eased pressure on NK and made the US president look bad. These are huge wins for Kim who can use his external wins to cement his position. I suspect the wedge between SK and US is one of the biggest wins for NK, in this respect.

There are in fact several moving elements. One is the secretion system, which moves the building blocks of the flagellum outside of the cell and assembles them (which is what the paper is about) the other is the actual motor that rotates the assembled flagellum. The basic machinery is fairly well known, but some of the molecular interactions are more speculative than others.

It would help if you could frame your question a bit. I am literally not clear what you mean with "what is going on" and how it relates to the article you posted. The question is just so broad and just listing all what is known about flagella is nothing that I would be able (nor willing) to put into a single post. In short, flagella are long protein structures produced by bacteria to move around. The article that you have posted describes the the mechanism (itself consisting of proteins) involved in the production to this structure. Maybe you want to at least read the wikipedia article on the topic and if you want, ask specific questions?

Sorry, but that does not make it clearer to me. Are you wondering what a flagellum is? I am unclear why you would think it relates to complex life forms. Flagella are found many bacteria and is one very common mechanisms of locomotion.