There is a general understanding among ETH investors that the enhancements from ETH 2.0, EIP-1559 and L2 solutions will result in a sustainable monetary policy with near 0% issuance and the potential for Ether to become a deflationary asset. What is even more interesting is that the net return of ETH as a SoV becomes superior to BTC the moment that issuance is lower than the staking yield. In other words, even if BTC had already ceased issuance, it offers no mechanism to provide yield to long term holders with a negligible risk exposure as ETH does. There is an execution risk that Ethereum will not deliver on what is currently planned, but if it does then what I have explained will become a reality.
You cannot separate BTC/ETH's payment rails from their respective monetary policies. As you are probably aware, issuance is just a subsidy, and without it the network will need to operate as a profitable business with a cash-flow that is entirely dependent on network fees. We are observing a situation that is causing a degradation of the utility of the Bitcoin network. What I mean by that is that the incentive for users to transact directly on the network is being diminished because of the tokenization into ETH and by the introduction of custodians (like Paypal) and traditional banking services who will soon be entering this space. If these trends continue, I suspect that the only activity that will end-up happening on-chain will be done by whales sporadically transacting to hodle and the occasional settlement from institutions. Bitcoin seems fast and frictionless, but that is because you are comparing it to something in the physical world. In digital terms Bitcoin emulates the friction of operation that is found with gold: it is difficult and expensive to move it, securing it yourself is not trivial, and it does not make for a great medium of exchange. I don't think this will be a good dynamic to generate enough transaction fees. That is of course my subjective interpretation of it, but regarding this particular situation it is nearly impossible to make objective assertions at this point. It is possible to assert that, in the digital world, the expectation of frictionless money would entail near instant transactions with negligible cost and without the relative risk/paranoia of dealing with nuclear waste and having a hacker watching your every move waiting for you to make a mistake to snatch it away. Digital money would also need to interact with other digital assets, preferably defined and operated within the same ecosystem. Ethereum is steaming ahead on all ends.
Ethereum is fostering a digital economy (this is a very important part of understanding the value of Ethereum, but I will not be exploring it in this post) with DeFi at its center. It is currently generating about three times as much trx fee revenue as Bitcoin. L2 solutions are going live as we speak, and it appears that they will be much more practical and provide better UX when compared to the Lightning Network. This will help to amplify L1 block space value and push revenue even higher. That will be followed by EIP-1559, which will burn transaction fees. Mining is currently excessively profitable and the hash rate cannot keep up. This means the financial incentive can be reduced and by burning trx fees we achieve the equivalent of an issuance reduction, while stabilizing mining revenue. Eventually the transition to PoS will dramatically cut the operational cost of the network. That means that Ethereum as a business will become more profitable and less reliant on the issuance subsidy. Finally, we will see the introduction of sharding which will scale L1 by up to 1,000 times, compounding the effect of L2 solutions and making it feasible for the network to operate as a platform for new use cases. A solution to the hackenuclear waste security situation is being explored via social recovery wallets. It is still in the early stages of research and design, but it is important to realize that the Ethereum community recognizes it as a problem and is working on a solution.
There is a lot more that can be said about the BTC vs ETH debate and I am working on a full write up that explores each individual element in more detail. Regardless, it is important to pay attention to this trend: the smartest people in this space are shifting their point of view and realizing Ethereum's potential. Raoul Pal is a seasoned investor, extremely bright and open minded. He started with Bitcoin, but it did not take him long to understand the value proposition of Ethereum. Lyn Alden is a brilliant investor and mental powerhouse who initially did not think investing in Ethereum could be justified, but she is also starting to shift her view and now understands that it has a justifiable risk/reward ratio to be included in a portfolio (although she is not personally invested in Ethereum). She has plenty of negative things to say about it, however it appears that she recognizes this is not a black and white situation. I have a feeling she will be revising her analysis on Ethereum again in the future with a more optimist view, but maybe that is just wishful thinking.
The crypto space has a few analogies that have been used to describe technical/economic mechanisms that are somewhat tricky to understand: mining, Ethereum's gas, and the analogy between ether and oil. Crypto "mining" is not like real world mining. It's purpose is not to extract resources, but it is rather a decentralized mechanism to process transactions. Newly minted BTC tokens are not "mined", they are minted by the protocol and awarded to operators. Furthermore, it is impossible to change the total mining output of the network... adding/removing miners does not affect the mining output. If you are new to crypto, you can read a more detailed explanation of mining here. ETH's "gas" is not like fuel (it cannot even be stored). It is just a computational metric that is more akin to the distance a car must travel, but not what actually makes it move. The fuel is electricity and it must be paid for with ether. When you transact you are also paying for the "car" which is the use of all active mining hardware/validators for a fraction of a second. And ether is just money.
If you put too much weight on these simplified analogies, you will not understand the economic actuality behind them. This is a source confusion in the crypto space, and it is used to support false narratives. From an economic perspective, ether is money. Once you understand this, you will know that the narrative that BTC and ETH are not competing because they are different things is analogous to saying fax machines do not compete with the internet.
The beautiful thing about ether is that it is actually not "just money". It is a mixture of a scarce monetized commodity, money, bond and tech stock.

Monetized Commodity: Ether is becoming more scarce and will continue to do so with the transition to proof-of-stake and EIP-1559. Ethereum does not have a supply cap, but it does have a roadmap for a sustainable security model and if it achieves a positive cashflow then it will not only eliminate issuance, it can become deflationary. An argument can be made about potential issues with Bitcoin's sustainability in the long run.
Currency: Ether is used as a unit of account and medium of exchange to pay for every activity in Ethereum. It is also used in the same way for venture capital related to ICOs, and Ether is also used as collateral in the DEFI space and new monetary uses will continue to emerge. It is an immature form of money, just like Bitcoin is an immature form of gold. Some people prefer to say that Ether is just a utility token. However, a utility token is just a narrowly scoped form of money. Not only is Ether's scope within its digital economy growing, by next year users will be able to pay millions of merchants with Ether through Paypal. We have never seen the adoption of a new form of money grow organically. New forms of money have always been imposed by authorities. What would the organic growth of money look like? It would look like Ether.
Ethereum's digital economy: Ethereum has limitless use cases and it is already generating economic activity with real world usefulness. Ether's value will benefit from acting as the native monetary asset for Ethereum. As Ethereum's economic activity grows, the velocity and/or value of ether must also increase.
Bond: With proof-of-stake you need to lock up Ether to receive a yield in return. It is similar to how bonds work.
Tech Stock: Ethereum provides a service. That service is paid with ether. The network is controlled by holding ether that is staked. The more valuable the service provided by Ethereum becomes, the more users will be willing to pay for transactions and the more valuable the protocol and the Ether token become. Cloud based services is the entire business model of many companies. The network will be entirely operated by stakers who happen to be the recipients of transaction fees. It is not exactly the same as holding a stock, but there are a lot of parallels.
Full reserve banking model: This is a bit of a stretch, but it is a potential end-game for Ethereum. It can serve as the base infrastructure and reserve asset for a full reserve banking system. In a nutshell: a consortium of banking companies can be formed to standardize a framework to hold and stake Ether under custody in exchange for wrapped Ether. Customers deposit Ether, banks exchange it for wETH and stake the original ETH. Resting balances of wEther on customer accounts can receive a cut of the staking rewards. Banks get their profit model, customers get to spend wrapped Ether with traditional banking services and potentially receive a share of the staking yield. Customers could also have access to a yield curve based on variable reserve requirements. This would allow banks to create money (which is actually good for the economy when it is done with moderation), but for the first time ever customers would have the choice of how much risk exposure they are comfortable with. This dynamic could help to establish a form of democratic check and balances system that discourages moral hazard. Ether could become a godsend to banks in the land of negative yields. It's a pipe dream, but not entirely impossible. Don't forget that the US OCC has essentially given banks the green light to take the first steps in this direction (US banks have been approved to use the Ethereum blockchain for their operations AND they can become validators... yup this happened).

EDIT 1: Adding an analogy to explain why ether is money:
Let’s say I have a car with a 14-gallon fuel tank and I want to take it on a road trip. The car is not aware of the price of gasoline, and it would not travel any farther if the price of gas would double the next day. That’s because the intrinsic utility of oil has nothing to do with its monetary value. The car needs gas because of its particular physical properties and how the ICE is designed to utilize it. If I want to drive from point A to point B and it takes a full tank to get there, it will take that full tank no matter what happens to the monetary properties of gas/oil. This is fundamentally different from how Ethereum uses ether.
Ethereum (the network) is not trying to be money, but it utilizes ether exclusively for its monetary properties and not because it can be magically burned by an imaginary engine of sorts. It costs money to participate in the network as a miner, and their engagement is financially incentivized with ether. Block space is a scarce resource, therefore participants who wish to transact use ether to bid for it. These interactions are utilizing ether as a monetary medium of exchange. In the long run, as the price of ether goes up, the ether denomination of gas prices goes down. That happens because no one is using ether as gas/oil, and it is actually being used as money. In the short run you may see the opposite occurring because of the dynamic between the portion of block space demand that is inelastic and the demand for ether.
EDIT 2: Revisiting key concepts to explain how they will become price catalysts.

Wide adoption of L2 solutions: these will amplify the base layer block space value while encouraging further network adoption by a significant reduction of fees. A successful integration with DeFi protocols will dismiss the "Ethereum killers" theory and consolidate market confidence.
EIP-1559: reduce excessive financial incentives to miners by burning transaction fees. This will also discourage miners from attempting to artificially raise fees via spam.
Sharding: scale L1 bandwidth, compounding the effect of L2 solutions, further consolidating Ethereum's dominance in the DeFi space, making it feasible to introduce new use cases and eventually increase trx fee revenue.
The switch from PoW to PoS: discontinuing PoW will eliminate the operating costs related to mining and will allow for a reduction of issuance. Money that was previously allocated to buying mining equipment will be redirected to the acquisition of Ether. Staking Ether will remove it from circulation for extended periods of time. Operating cost will be negligible, allowing validators to withhold most of the Ether revenue. This will be the greatest bull market catalyst in the history of cryptocurrencies and it will eclipse the effect of BTC halvenings.

Bitcoin maximalists will be nay-saying all the way through and past a market cap flip. Do not get caught up in their narrative. If you are not sure, then it is better to rebalance your portfolio proportionally to market caps. If none of these things happen and Ethereum turns out to be a failure, then you would only have reduced your gains by 20%. Otherwise, ETH will be making you mountains of money.
EDIT 3: Ethereum killers
Ethereum killers remind me a lot of Tesla killers, but a lot worse. People need to understand that cryptocurrency platforms targeting financial Dapps are fighting the equivalent force of a black-hole when it comes to Ethereum’s network effect and user retention in this space.
Bigger players, with bigger money, are entering this market and they will not settle for anything other than the top dog. This pattern reinforces Ethereum's position as the premium financial system, which ends up attracting even bigger players and resulting in the black-hole effect. To make matters even more complicated, financial apps are more valuable when they are surrounded by a rich and diverse variety of digital assets and other natively defined Dapps. There is not much you can do with your money in a ghost town.
It is VERY difficult to build this type of environment up because the platform and dapps must also have established full trust from their user base. This is not to say there is no space for other networks to grow, but just don’t get your hopes high that they will be taking Ethereum’s stronghold as a financial system. There are other use cases that do not require the amount of decentralization and security offered by Ethereum, and the networks that can focus on these are the ones who will be able to coexist with in the long-run. Gaming, ERP interoperability and supply chain are good examples of such use cases. Remember that alternatives with cheap transactions have existed for a while and they have barely touched ETH's dominance (EOS, NEO, VET, QTUM, IOTA, LSK, STRAT, ARK and dare I say... TRON).
EDIT 4: Refuting critiques about dynamic monetary policy
If an argument can be made that the financial incentives to operators (miners/stakers) are excessive or insufficient then an argument can be for the implementation and execution of a dynamic monetary policy.
I don't think an arbitrarily picked issuance schedule determined during the genesis of a new highly complex system is likely to be efficient through its lifecycle. Bitcoin's monetary policy provides the certainty of stability and protection from abuse, but it sacrifices the possibility of efficiency and jeopardizes longevity. It would be like if a captain of a ship would point it in the direction of its final destination, set the throttle, then fall back to his cabin for a nice bottle of chianti and hope that the ship would arrive safely. There would be no one at the helm to navigate the seas, no one to make sure it stayed on route, no one to avoid the storms or to take advantage of currents. In my opinion it is a pretty bad approach to something as critical as monetary policy.
With respect to Ethereum's dynamic monetary policy: I don't see any evidence to suggest developers have been enriching their pockets by keeping issuance at the levels they are. Developers are stakeholders and the Ethereum fund holds a lot of ether - debasing ether is against their self interest. There is a great misunderstanding that the one's who are adjusting issuance are the recipients of the new tokens. Is there any documented case of this happening?
EDIT 5: Addressing Bitcoin's immutable monetary policy
The idea that Bitcoin's monetary policy cannot be changed is a myth. It is a false narrative that takes for granted that the issuance subsidy will no longer be necessary at some point, but there is no way to objectively assert this. There is no divine power preventing the monetary policy from being changed. If the security model for Bitcoin was jeopardized because of insufficient cash flow to miners, then Bitcoin's monetary policy would be the first thing on the chop board to go in order to remedy the situation.
EDIT 6: Five years ago naysayers were screaming about how everything that is being done TODAY in the Ethereum network would never work. Now they are calling Ethereum a scam, or that is is a platform for degenerate gamblers, or that the fees are too high and therefore it is useless, or that it can't scale, or that something else better is just around the corner to take its place.... you know... basically all the things that traditional bankers have to say about Bitcoin, maxis are saying about Ethereum.
EDIT 7: The greater the impact a new technology can have on society, the more difficult it is to comprehend its potential. Ethereum has the potential to have a dramatic impact on human civilization. It could take decades for it to be fully realized, but it would change the world in ways that we cannot possibly imagine today. If it happens, the moon will be just a pit-stop.
EDIT 8: Thank you so much for all the awards! Ethereans understand this stuff, and I could feel the frustration in the air every time someone said that Ethereum is not money, or that ETH and BTC are completely different things, or all the other bs attacks that are in great part founded on a lack of understanding of how BTC and ETH actually work. I would love to hear what guys like Raoul Pal, Pomp, Michael Saylor and Fernando Ulrich (for my Brazilian friends) would have to say about some of the things that have been written here. If you know a way to get their attention, then please do it.
EDIT 9: Clarification about Lyn Alden's opinion of Ethereum
EDIT 10: I am still working on a much more ambitious write up. It is focused on economic aspects of money, monetary systems and global asset markets. I still have not incorporated any of the information written here, but I eventually will merge it together. One of the main new ideas that I am exploring is challenging the notion that money has no intrinsic value and that scarcity is the most important attribute of money. I think I make a compelling argument to demonstrate that facilitating economic activity is more important, and how Ethereum has a big edge over Bitcoin in this regard. Here is the link to the WIP doc.
TLDR: Ethereum is not stopping at the moon... it is not stopping on Mars... it is going straight out of the Milky Way galaxy in search for alien life... but you should own some BTC just in case the spaceship malfunctions during launch.

Confidence Intervals, P-values, and Statistical Significance

[Q] Relationship between Confidence Intervals and P-values

Investor Insight | Synairgen: An Investment Brief by Rupert Marlow

Please read the disclaimer at the end of this note
Rupert Marlow – 25 January 2021

Summary

Synairgen, with little apparent external support, has developed what could be one of the most effective drugs for tackling the Covid-19 pandemic, SNG001. Originally intended as a broad-spectrum, respiratory anti-viral, it is now in various Covid-19 trials awaiting results. For a company of its size - at the end of 2019 it employed only 14 people - to have made the progress it has is an astonishing achievement.
In short, there are four Covid-19 trials or sub-trials involving SNG001 that are currently in progress or awaiting results. There is the second part of SG016, the at-home trial in the UK; there is the main part of SG018, an international phase III trial for patients in hospital; there is a second leg to SG018 looking at Long Covid-19; and there is the US ACTIV-2 trial for out-patients. All of these are likely to report results in the coming months, and these will be absolutely crucial for determining Synairgen’s future. For the moment, therefore, the company is in something of a waiting game.
This note suggests a target share price of £12, but essentially SNG001 is likely to be either a comparative failure or an emphatic success. There are sound reasons for thinking the latter is more probable, but the risks are unusually high.

Background

Synairgen was established in 2003 by three professors from Southampton University, and its shares were listed on AIM in June 2005. The first project was to assemble a BioBank of samples in order to build models of respiratory diseases, particularly asthma and COPD (chronic obstructive pulmonary disease), and research how these might be treated.
In time this led to the development of a broad-spectrum, respiratory anti-viral, SNG001, the active ingredient of which is interferon beta-1a. This is inhaled directly into the lungs, in a formulation that is pH neutral, once a day for 14 days, by means of an Aerogen Solo/Ultra nebuliser. SNG001 is therefore simple to administer and, in the context of respiratory infection, more efficient than other methods of delivery, such as intravenous or subcutaneous. As a result, the dosage can be considerably lower than it would be with those other methods.
Synairgen owns a number of patents protecting SNG001, both as to its mode of delivery and its pH neutral formulation. The most significant initial patents were lodged between 2009 and 2011, while in July 2020 an application was made to cover the use of inhaled interferon beta in Covid-19 patients, and in September 2020 a further application was made to cover its use in COPD patients being treated with corticosteroids.
Beyond SNG001, Synairgen’s has an approximately 17% entitlement to the net licence receipts or royalties earned by an Australian company, Pharmaxis, from an antifibrotic LOXL2 inhibitor. Pharmaxis is currently searching for a partner to carry out a phase II trial.

Interferon beta-1a

Interferon beta-1a is one of a number of interferons, which belong to a family of naturally occurring proteins known as cytokines, which play the essential role of stimulating and regulating the innate immune response. As reverse evidence of the importance of cytokines, Covid-19 can result in, often fatally, a cytokine storm, when a compromised immune system runs out of control and the body is swamped with cytokines. As a result, the immune system starts to attack the body’s own organs.
Normally, there are many pathways by which interferons, which do not themselves attack the virus, orchestrate the innate immune system. When, for example, a cell is infected by a virus, it releases interferons, which stimulate the production, within neighbouring cells, of a particular enzyme that inhibits protein synthesis, thereby making it more difficult for the virus to replicate. They activate white blood cells, such as natural killer cells, which (as their name suggests) kill infected cells, and macrophages, which remove those dead cells. They initiate the removal of virus particles within an infected cell to its surface, so that the T cells of the adaptive immune system can bind on to them.
Evidence suggests that, of all interferons, interferon beta-1a produces the strongest respiratory anti-viral response in humans, hence its selection as the active ingredient of SNG001. It has also been used as an injected therapy for multiple sclerosis for 20 years, so there is considerable experience of its impact on the human body. Patients can experience side effects, but since SNG001 is delivered directly into the lungs, the blood concentration level is roughly one-tenth of that seen in MS patients, so any possible side effects are materially diluted. In any case, trials to date show that SNG001 is well tolerated.
There is a growing body of evidence that interferon beta-1a is especially critical in protecting patients exposed to Covid-19. Although the virus is believed to suppress the production of interferon, most people, once infected, still generate the interferon they need and experience only mild symptoms, if any. There are, however, two groups of people to whom this does not apply. Some people, notably those with comorbidities and older people in a process known as immunosenescence, simply do not produce enough interferon, so their immune response is compromised. There is also a small number of people, interestingly most often male, who have a genetic mutation that has the effect of destroying the interferon that their bodies generate. Both groups are more likely to experience severe symptoms when exposed to Covid-19, and SNG001 works by giving those people the interferon beta-1a that they fail to provide naturally for themselves.
The theory has been that, since interferon is most critical in the early stages of infection, SNG001 should also be administered early. Viruses enter a cell via a surface enzyme known as an ACE2 receptor, and one concern was that, since the presence of interferon tends to increase the number of these ACE2 receptors, the cell could be more easily penetrated. It has, however, been realised only recently (https://www.nature.com/articles/s41588-020-00759-x) that the ACE2 receptors upregulated by interferon are a short version, which Coronavirus cannot bind on to as a means of entry. This opens up the possibility (see SG016 below) that SNG001 may, after all, be effective at a late stage in disease progression. In this context, it is worth noting that the Aerogen nebuliser can be used in conjunction with a ventilator.

SGO015

The initial objective for SNG001 was to prove its effectiveness as anti-viral therapy for patients with asthma or COPD, and during 2019, in the year before Covid-19 arrived, Synairgen was running the second part of a trial, SG015, to observe how COPD patients with viral infections responded to being dosed with SNG001.
The intention had been to recruit 120 patients, but with 109 recruited, the trial was paused in September 2020 to minimise the risk of infecting patients with Covid-19. Nevertheless, it showed that SNG001 was well tolerated and that it resulted in a significantly enhanced anti-viral response against placebo. One further and significant result was that, unlike intravenous or subcutaneous delivery, the benefits of SNG001 were not compromised by the use of corticosteroids, such as dexamethasone, which many patients need to control inflammation.
A full report on SG015 can be found here.
It is unclear whether, in due course, SG015 will be resumed and formally completed with a further 11 patients recruited or whether the plan, supported by evidence from the pandemic, will be to move directly to a phase III COPD trial.

COVID-19 and SG016

The arrival of Covid-19 changed Synairgen’s immediate priorities. Could SNG001 be re-purposed as an early-stage therapy?
As a result, Synairgen initiated a double-blind, placebo-controlled, phase II trial, SG016, involving 221 Covid-19 patients divided into two groups - 101 newly hospitalised and 120 at home. The hospital part of the trial began in late March 2020 and has been completed, while the at home part has finished recruiting patients, so we are waiting for the results.
The main findings of the hospital part of SG016 were announced on 20 July 2020. SNG001 was, once again, well tolerated and reduced the likelihood of developing severe disease by an impressive 79% against placebo. On admission, nearly all patients had an OSCI (Ordinal Scale for Clinical Improvement) score of 3 or, more commonly, 4, while severe disease was defined as an OSCI score of 5 (non-invasive ventilation or high-flow oxygen) or more.
The only patients to die during the trial, three in number, were all on placebo, but this was not statistically significant. One interesting result was that there was no apparent relationship between the benefits of treatment with SNG001 and the prior duration of Covid-19 symptoms. Overall, the results were not only highly encouraging, but also far better than anyone had dared to hope. The peer review, which was published inThe Lancet Respiratory Medicine30511-7/) on 13 November 2020.
The at-home, and ongoing, part of SG016 involved patients within seven days of the onset of Covid-19, before severe lower respiratory tract symptoms had developed. Patients had to be over 65 or over 50 with a recognised comorbidity. The completion of enrolment demonstrates that home treatment is a viable route for treatment. As to the trial results, we have been told to expect these during the second quarter of 2021.

SG018

In view of the encouraging results from SG016, and following discussions with the US Food and Drug Administration, Synairgen has launched SG018, a Phase III randomised, placebo-controlled trial of hospitalised Covid-19 patients. The first dose was administered in the UK on 12 January 2021, and the trial is taking place in some 20 countries, involving 610 patients with an OSCI score of 4 (mild disease - oxygen by mask or nasal prongs), compared with OSCI scores of 3 (no oxygen) and 4 for SG016. This slightly later dosing means that SG018 is arguably a little more ambitious than SG016.
Following a revision to the trial announced on 18 December 2020, there are two arms – c.300 patients to be dosed with two syringes of SNG001, and c.300 patients to be dosed with placebo. Synairgen has appointed Paraxel Biotech to conduct the trial, and the details are set out on page 18 of the placing circular dated 14 October 2020, as revised by the press release dated 18 December 2020,
Patients will be dosed once daily for 14 days, and the primary endpoints will be time to recovery (i.e. no limitation of activities) and, secondly, time to hospital discharge. In SG016 the comparable hazard ratios for these (per protocol) were 2.29 and 1.53 respectively. The secondary endpoints will be based on progression to severe disease or death, as well as a safety assessment. Finally, there will be additional assessments on days 60 and 90, by then unblinded, for symptoms of Long Covid-19.
On the basis of the science and the results from SG016, there must be a good chance that the results will be positive. Since the hospitalised arm of SG016 was run, the use of effective treatments, such as blood thinners and dexamethasone, has become more widespread, so those on placebo should do better in SG018 than they did in SG016. The headline results from SG018 may not, therefore, be quite so spectacular as they were for SG016.
The UK has recognised SG018 as a matter of Urgent Public Health and given it National Priority status. In the US, the IND (Investigational New Drug) application for SNG001 has been cleared, and the FDA has awarded it Fast Track status. Allowing for recruitment, dosing and post-treatment assessment, preliminary results should be available around May 2021. Given, however, the urgency of the situation, it is possible that the regulators will ask for an interim view of the results before then.

ACTIV-2

The US has established ACTIV-2 (Accelerating COVID-19 Therapeutic Interventions and Vaccines, and the 2 refers to outpatients) to investigate the most promising treatments and vaccines. On 25 January 2021, Synairgen announced that SNG001 would enter a phase II/III, ACTIV-2 trial in Covid-19 patients not yet requiring hospitalisation. The phase II part of this randomised, placebo-controlled trial will involve up to 220 at-home patients across the US. It will be blinded, not double-blinded, so Synairgen and the regulators can monitor progress as the trial proceeds and, if appropriate, initiate phase III.

Other trials

SNG001 was initially on the Recovery trial sponsored by the University of Oxford that has been looking at existing treatments to see how effective they might be against Covid-19. In April 2020, SNG001 was, however, removed from the trial. Why is not entirely clear, but it does not appear to have been a scientific reason.
The World Health Organisation has been running its own Solidarity trial with the aim of doing much the same thing. On 15 October 2020, they announced that interferon beta-1a, along with remdesivir, hydroxychloroquine and lopinavir, had little or no effect on overall mortality, initiation of ventilation or duration of hospital stay. The interferon beta-1a was, however, delivered by subcutaneous injection, while SNG001 is delivered via a nebuliser directly into the lungs, which is critical to its effectiveness.
Finally, Synairgen, in conjunction with Clinigen Group, has launched a Managed Access Program. This is, of course, not a trial, but it does mean that patients can apply to be treated with SNG001 as an emergency.

Vaccination and competition from treatments

The best hope is that vaccines will lead us out of this pandemic as 2021 unfolds. Pfizer and Moderna claim an efficacy of over 90% for their respective vaccines, which both use messenger RNA that has been adapted to get the body itself to generate the distinctive coronavirus spike protein. This is distinct from conventional vaccines, such as Oxford/AstraZeneca’s, which take the form of a deactivated or otherwise inactive version of the virus that still contains the spike protein. The evidence, so far, suggests that the messenger RNA vaccines are the more effective of the two, but either way, to get these vaccines up and running within twelve months of the virus appearing is a remarkable achievement, and this should give us all some comfort in the event of further eruptions of this pandemic or an entirely new one.
Nevertheless, the task of vaccinating the whole world will be enormous, so Covid-19 will not be eliminated quickly. There are also more general questions about vaccine take-up, how long they provide protection for, the extent to which they reduce transmission of the virus and whether mutations might lower their effectiveness. While vaccination will, no doubt, be the principal route for ending the pandemic, this does suggest that treatments like SNG001 will be needed for some time to come.
But, even if its trial results are positive, SNG001 will not have the treatment field to itself. A number of drug treatments have already been approved, such as dexamethasone and, more recently, tocilizumab. As a general rule, however, these are for critically ill patients, so do not directly compete with SNG001. There are also a large number of other drug trials taking place, and some of these will undoubtedly demonstrate significant effectiveness against Covid-19. In other words, for SNG001 to be commercially successful, it may have to demonstrate not only absolute effectiveness but also superior relative effectiveness.
In this context, however, SNG001 has three strong competitive advantages. First, the evidence to date suggests that it is particularly effective, possibly unrivalled, in the early stages of disease progression. Secondly, since it works, not by recognising the virus itself, but by enabling the innate immune system to function as it should, it will work against mutant variants of Covid-19. Finally, it is easy to administer.

The possible applications for SNG001

As things stand, therefore, SNG001 has five possible applications. SG018 is designed to test its use on patients newly hospitalised with Covid-19, specifically scoring 4 on the OSCI scale (see above). The second possible use is for patients soon after they first show symptoms of Covid-19, and that is covered by the second, ongoing, at home, arm of SG016. The third possible use is for Long Covid-19, for which there are no obvious treatments at present, and that is covered by the 60 and 90 day assessments of SG018.
The other two possible applications go beyond Covid-19. Given now the awareness of the damage, both to human health and the economy, that respiratory viruses in general (and Coronaviruses in particular, of which we have experienced three in the last 20 years, SARS, MERS and Covid-19) can do, governments are being urged to stockpile effective, broad-spectrum therapies. The idea is that these would then be immediately available to provide some protection until appropriate vaccines can be developed.
The other use takes us back to Synairgen’s original plan in that, before Covid-19, SNG001 was envisaged as a broad-spectrum anti-viral for COPD patients, hence the phase II trial SG015. The COPD market as a whole is huge, causing 3.2 million deaths per year globally and at any one moment affecting c.2.4% of the world’s population. There are no treatments for COPD itself, but subject to further trials, SNG001 could have a major role in that market.

The future for SNG001

The results from SG018 may not be known until perhaps May 2021, but based on both the strong science behind SNG001 and the results from SG016, it is probable that the results will be positive. On that basis, and given the urgent need for treatments that work, there has to be a significant likelihood that SNG001 will start to receive approvals in, say, mid 2021, or perhaps earlier if the regulators make interim assessments. Given also that the trial involves over 20 countries, it is to be hoped that approval will eventually be granted by several countries.
Following the placing in October 2020, £33 million was set aside for producing 100,000 treatment courses of SNG001 per month in 2021, but in order to obtain orders once the trial results are known (assuming they are successful), Synairgen will need to show that it can increase production rapidly to a significant multiple of that figure. The company has therefore already signed up two sources of interferon beta-1a, Akron Biotechnology and Rentschler Biopharma, and two companies to handle fill and finish, Catalent Biologics and Thermo Fisher Scientific.
The pattern of sales for SNG001 as a Covid-19 therapeutic can therefore be expected to climb rapidly to a peak before falling gradually away as the pandemic is brought under control, but the scale and timing of that are almost impossible to predict. After that, there is the question of stockpiling against future pandemics or a resurgence of this one, and this could be a source of demand for many years to come. In due course, there is then the possible market for treating COPD patients.

A financial assessment

As explained, the level of sustained sales is hard to predict, but in order to arrive at some sort of financial assessment, let us use, as a long-term number, the above production figure of 100,000 treatments per month.
The question of pricing is no easier and will depend on many factors, most obviously the strength of its competitive position within the overall market. Richard Marsden, Synairgen’s CEO, has mentioned a price of $3000 for the 14-day treatment, but that may be something of a starting point in negotiations that can only take place once approvals are forthcoming, and there will, no doubt, be significant, subsequent price erosion. On the other hand, drugs that keep people out of hospital or reduce their stay are valuable. In any event, let us assume for these purposes a long-term sustainable average price of $1000. On the basis of 100,000 treatments per month, that equates to an annual revenue of $1.2 billion.
If we further assume a profit margin of 67.5%, and given an exchange rate of $1.35, that would generate a gross profit of £600 million per year. If, in view of the risks and uncertainties involved, we then apply a price to earnings ratio of 5, that suggests a target market capitalisation of c.£2.4 billion or a share price of £12, given that there are 200 million shares in issue.
Piling assumption upon assumption in this way and arriving at a single target price gives a false sense of precision. In practice, the share price is likely to remain volatile before responding to SNG001’s evident success or failure. On the one hand, the trials might not meet their endpoints, so SNG001 does not obtain any worthwhile approvals or orders. There is also the question of competition from other drugs, and post-pandemic opportunities may prove elusive.
On the other hand, both the science and the evidence so far suggest that SNG001 has enormous, broad-spectrum potential, and it is entirely possible that the above numbers are too cautious. As explained, success seems more likely than failure, but the risks are high, and in the end, investors have to decide for themselves.

Disclaimer - The writer is a shareholder in Synairgen, and the views expressed in this note are his alone. This note should not be interpreted or used as investment advice.

Children and adults should avoid consuming animal products to reduce risk for chronic disease: NO

https://academic.oup.com/ajcn/advance-article/doi/10.1093/ajcn/nqaa236/5901950

Children and adults should avoid consuming animal products to reduce risk for chronic disease: NO

Frédéric Leroy, Neal D Barnard
The American Journal of Clinical Nutrition, nqaa236, https://doi.org/10.1093/ajcn/nqaa236
Published: 05 September 2020

ABSTRACT

Excessive attention to the animal versus plant binary food choice reflects society's moral views on eating right. To claim that avoidance of animal products is required to prevent chronic disease is not supported by evidence, makes little sense from an evolutionary perspective, and distracts policy makers from common-sense approaches to achieve adequate nutrition. Animal products provide highly bioavailable nutrients, some of which are not easily obtained from plants, and can play a key role in meeting the nutritional challenges of populations in both high- and low-income countries. This role goes beyond the need for protein and relates to vitamins, minerals, and numerous often-overlooked nutrients, such as long-chain fatty acids, taurine, and choline. Restrictive dietary prescriptions that exclude animal products complicate the quest for optimal nutrition by undermining dietary diversity and flexibility, and by introducing a dependency on fortification and supplementation. Thus, a vegan diet may put the general population at increased risk of poor nutrition, a problem of particular concern for those with special nutritional requirements.
adequate essential nutrition, protein, micronutrients, nutritional needs, animal products

Main Argument (Leroy)

An evolutionary perspective argues against the need to eliminate animal-source foods

As with all animals, human nutritional requirements have been influenced by dietary composition throughout the evolution of our species (1). Reliance on substantial amounts of animal foods from both terrestrial and aquatic origin (marrow, organs, fat, meat, eggs, fish, and/or seafood) is characteristic of the human diet throughout the Pleistocene and more recent hunter-gatherers, which can—to some degree—serve as models for ancestral behavior (2). Depending on which resources are available within each habitat, the share of animal products in such diets (as a proportion of total energy) usually exceeds what is now consumed in the West, with only occasional incidences of chronic “diseases of modernity” (3). These evolutionary relationships have influenced our reproductive, digestive, and metabolic functions, fulfilling the nutritional requirements for the development of a large brain (1, 2). The consumption of (fermented) milk exerted an additional evolutionary influence since the Neolithic in populations with access to livestock. The relatively short time frame during which lactase persistence developed indicates that dairy provided strong nutritional benefits for crop-based and malnourished populations in need of protein and micronutrients. The fact that animal products have provided indispensable nutrition for at least 1.5 million years (1) is hard to reconcile with arguments for their exclusion from current diets (2, 4).

The intake of animal foods cannot be causally linked to the incidence of chronic diseases

Available epidemiological studies predominantly point toward neutral or protective associations for such animal foods as dairy, fish, and poultry (5–8). In contrast, various (but not all) observational studies have shown weak relative-risk estimates for high red- or processed-meat intake (i.e., amounts far exceeding 1 serving/d). However, the latter diminish with studies having a lower risk of bias (9) or when cross-cultural assessment is performed (4). In less-Westernized settings, associations tend to disappear or even invert, indicating strong effect modification and confounding by baseline nutritional status and healthy user bias. Regarding the latter, lifestyle characteristics of low versus high consumers of red and processed meats indicate likely bias among these associations in Western countries. Vegetarians differ from nonvegetarians with respect not only to the amount of meat consumed, but also to smoking, physical activity, alcohol consumption, and processed-food intake. Overall, evidence for a causal connection between red- or processed-meat intake and chronic diseases or mortality is inconsistent and inconclusive. Indeed, there is at most “low” to “very low” certainty evidence that higher intakes of red and processed meats result in small reductions in cancer mortality and incidence (10) or cardiometabolic outcomes and all-cause mortality (11). Similarly, there is little evidence that severe restriction of animal foods beyond a well-formulated omnivorous diet would reduce the prevalence of overweight and obesity (12).
Animal and human intervention studies of causal mechanisms typically address only short-term and intermediate surrogate outcomes, whereas markers of oxidative and inflammatory stress or cardiovascular risk fail to indicate harm (4, 13). While a modest increase in LDL cholesterol may occur, animal foods decrease apoB-to-apoA1 ratio, a strong marker of small, dense LDL particles and future cardiovascular disease. In a recent rigorous systematic review involving the use of Grading of Recommendations Assessment, Development, and Evaluation (GRADE) criteria, the quality of evidence linking red and processed meats to potential adverse health outcomes was found to be “low” to “very low,” and not sufficient to support recommendations to reduce their consumption (14).

Animal foods provide high-quality nutrition

Animal products are the best source of nutrient-rich food for children <2 y old (15), while also providing the general population with important nutrition. A key benefit of animal foods is their protein amount and anabolic superiority (8, 12, 16), an advantage that becomes evident with consideration of essential amino acids content and ileal digestibility. The “Digestible Indispensable Amino Acid Score” (DIAAS) for animal protein is usually ≥1, outperforming plant proteins (legumes: 0.6; cereals: 0.3–0.5) and only approximated by soy (0.8–0.9). With use of state-of-the-art DIAAS, rather than conventional protein scoring systems, nuts, seeds, tofu, and pulses cannot be considered good sources of dietary protein (17).
Animal foods also provide essential fatty acids, with distinct benefits related to the content of EPA and DHA. These long-chain omega-3 fatty acids, abundantly present in oily fish and some other animal foods, are critical for normal brain development in childhood, fertility, immunity, and general health. Their shorter-chain precursor, ɑ-linolenic acid (ALA, 18:3n−3; available in plants), is poorly converted in vivo (5–10% for EPA, 1–5% for DHA) (16, 18). Thus, to achieve the equivalent of the commonly recommended 250 mg/d of EPA or DHA may require many grams of ALA daily, well above the consumption level of most Western vegetarians and vegans (19).
As with EPA and DHA, vitamin A is more efficiently obtained by direct intake from animal foods than from plant precursors. The biological value of the latter depends on the dose and species of the carotenoid, genetic and ethnic variability, and dietary context. Vegan diets are often low in fat, which further compromises absorption. For β-carotene, absorption varies between 5% and 65% and conversion between 4:1 to 28:1 (20). Other vitamins that may become problematic with restriction of animal foods include vitamin D, riboflavin, and niacin. Adequate supply of vitamin B-12 is of particular concern, as vegans have lower serum vitamin B-12 concentrations and, consequently, higher plasma homocysteine than omnivores (4, 12, 16). Whereas animal foods are excellent sources of vitamin B-12 (the Recommended Daily Intake can be delivered by a 100-g serving of beef, tuna, trout, or sardines), vegan diets require supplementation to avoid adverse psychiatric, neurological, and hematologic effects of deficiency. Moreover, supplementation and fortification are not always adequate to achieve sufficiency (4, 16). With the possible exception of some foods foreign to Western cuisine (e.g., the sea vegetable nori), dietary sources of vitamin B-12 are limited to animal products. Furthermore, vitamin K-2 found in animal products (e.g., egg yolks and dairy) may play a protective role for bone and cardiovascular health, beyond the effects associated with plant-associated vitamin K-1 (21).
Animal products provide highly bioavailable minerals (4, 8). Multiple servings of vegetables are often needed to match a single portion of animal food, a problem that may be exacerbated by the presence of antinutrients such as oxalates and phytates (16). For some key minerals, it may be impractical to obtain optimal intakes from plant foods (1, 16). For example, calcium, iron, and zinc are readily absorbed from dairy, fish with edible bones, and red meat; bioavailability of these critical minerals is characteristically lower from plant foods (12). For selenium, availability in crops depends strongly on the mineral status of the soil, whereas animal products vary to a much lesser degree in this regard. In addition, iodine status is often problematic in vegans and somewhat less so in vegetarians, with dairy being a good source (4).
Thus, a plant-based food-supply system would be dependent on fortification and supplementation to avoid risk of widespread micronutrient deficiencies (16). Furthermore, plant-based diets would also lack health benefits derived from the matrix of whole animal foods, beyond macro- and micronutrients (8). For instance, animal foods contain commonly overlooked bioactive components that promote neurological health, cognitive functions, antioxidant defenses, and muscle physiology (2, 4). Relative or absolute deficiencies of choline, carnosine, anserine, creatine, taurine, carnitine, and glutathione may occur with avoidance of animal products (2, 4, 16, 22).

Avoidance of animal-source foods undermines dietary robustness and causes unnecessary risk

Considering the important benefits of animal products as nutrient-dense foods and the absence of evidence for harm, their elimination from the diet comes with unnecessary risks (12). By omitting entire food groups, veganism is a highly restrictive approach that may undermine dietary robustness (4). According to a recent analysis, the greatest food-security challenge in 2050 will be the provision of nutrient-dense foods rather than adequacy of calories or carbohydrates (23). Many of the most problematic nutrients are optimally provided by animal products, including high-quality protein, calcium, iron, zinc, and vitamins A, D, and B-12 (23), as well as choline and DHA (22).
From an international perspective, a lack of access to animal foods can exacerbate malnutrition in vulnerable populations (15). Animal foods supply many nutrients that may be lacking in the cereal-based diets in low-income regions of Asia, Africa, and South America. Provision of meat, eggs, fish, or dairy to children is an effective way to reduce stunting and promote cognitive development (1, 8, 15, 24). But even in high-income populations, vegan diets require careful planning and supplementation to avoid major health problems (4, 16). The required nutritional knowledge, dietary discipline, culinary skills (e.g., proper processing of dried legumes), and resource availability are not consistently present in the general population. Even among the most sophisticated consumers, vegan diets may not be suitable for many people, especially children (24) and those unable to convert plant-derived precursors in sufficient amounts into their bioactive forms (as considered above). In fact, suboptimal nutrient concentrations have been frequently encountered among vegan and vegetarian populations—for instance, with respect to long-chain omega-3 fatty acids, iodine, and vitamin B-12 (4, 16). Concerningly, >90% of vegans and 70% of vegetarians were reportedly deficient in vitamin B-12 (compared with ∼1 in 10 omnivores), with use of the most sensitive diagnostics (25). Moreover, vegetarian and vegan mothers often have low long-chain omega-3 fatty acid and vitamin B-12 status (24, 26, 27), putting the health of their offspring at risk, as underscored by clinical case reports describing severe pathologies (4). Although harmful dietary practices can also be found among omnivore parents, failure to thrive and serious malnutrition syndromes appear to be more strongly linked to vegan and vegetarian upbringing (28), with implications to health later in life (29).

Conclusions

Rather than being portrayed as a cause of a public health crisis, animal products should be recognized as being at the forefront of the battle against malnutrition and diet-related disease, including cardiometabolic diseases. These foods are nutrient dense, highly satiating, and provide a basis for diets aiming to restore metabolic health and prevent age-related diseases (8, 12, 30).
The excessive focus of dietary discourse on animal versus plant foods in the prevention of chronic disease is poorly supported by scientific evidence, especially with regard to calls for the total elimination of animal products. The argument against animal foods is largely based on observational studies that lack the causal data required to inform policy interventions. On the contrary, animal products offer quality nutrition, components of which cannot be easily substituted by plants. Food policies that aim to minimize animal-food consumption will expose populations to unnecessary risk, especially in the face of projected global nutritional challenges. Such narrow approaches to human diets may cause harm and distract from greater dietary priorities that find common ground at both sides of the animal versus plant foods debate, such as the importance of avoiding excessive intakes of nutrient-poor, highly processed foods in globalizing foodscapes.

Refutation (Barnard)

Dr. Leroy has recounted several common myths that merit correction. The romantic notion that hunter-gatherers have been free of “diseases of modernity” was contradicted by the extensive atherosclerosis found in autopsies of Masai individuals (31) and in ancient Inuit remains (32). Meat ingestion clearly contributes to atherosclerosis.
The effect of diet on brain size is mere conjecture. Whales, elephants, and dolphins have larger brains than humans, as did Neanderthals; shrews have a greater brain-to-body-size ratio. Meat and saturated fat consumption is associated with accelerated cognitive decline, increased risk of Alzheimer disease, and brain atrophy.
While a genetic mutation fostering lactase persistence prevents lactose-induced diarrhea, evolution provided no protection against milk's longer-term hazards, notably prostate, breast, and ovarian cancer. In 2020, the Adventist Health Study-2 reported that women with the highest (compared with the lowest) milk consumption had a 50% higher risk of incident breast cancer (33).
The benefits of vegetarian and vegan diets are not attributable to differences in smoking, physical activity, or alcohol use. These and many other confounders have been controlled for in epidemiologic studies. Randomized trials confirm that avoiding animal products reduces body weight, blood pressure, and lipids. A 2015 meta-analysis showed that vegetarian diets lowered total and LDL cholesterol by 14 mg/dL (0.36 mmol/L) and 13 mg/dL (0.34 mmol/L), respectively (34).
The risks of elevated LDL-cholesterol concentrations caused by animal product ingestion are not mitigated by particle-size differences. LDL particles are atherogenic, regardless of particle size (35). In the Women's Health Study, higher concentrations of both small and large LDL particles significantly increased the HR for incident cardiovascular disease (36).
The cited meta-analyses of observational studies that had calculated the benefits of reducing meat consumption by 3 servings/wk were described by Dr. Leroy as discounting these benefits. They actually confirm them. One (10) predicted a reduction in cancer mortality by 7%. A similar reduction in processed meat would be expected to reduce esophageal (30%), colorectal (7%), and breast (10%) cancer incidence, and overall cancer mortality (8%). The second (11) predicted a reduction in cardiovascular mortality by 10%, stroke by 6%, myocardial infarction by 7%, and type 2 diabetes by 10%, all statistically significant. The effects of avoiding meat altogether would likely be much greater.
The characterization of the evidence against meat as being of “low” or “very low” certainty was based on the highly controversial GRADE system, which is not suited to evaluating nutrition studies. It mistakenly discounts even the most rigorous prospective studies and would similarly have discounted studies demonstrating passive smoking's dangers. The benefits of avoiding animal products have been amply demonstrated in both prospective studies and controlled trials.
The idea that malnourished populations have used animal products as a hedge against malnutrition or starvation provides no guidance for individuals seeking to improve their health. Even in populations with marginal nutrition, reliance on animal products is a disastrous strategy. As meat-eating increased in China between 1990 and 2016, cardiovascular disease prevalence doubled.
Protein requirements in children and adults are easily met by a diet of legumes, vegetables, grains, and fruits. According to the WHO, "Protein deficiency is almost always accompanied by inadequate energy intake...," meaning the problem is a lack of food, not a lack of meat (37).
Regarding fatty acids, the European Prospective Investigations into Cancer and Nutrition (EPIC)–Norfolk Study found that, while long-chain fatty acid intake was lower in vegans than in fish-eaters, plasma concentrations of long-chain fatty acids were remarkably similar, suggesting better conversion from precursor fatty acids in the vegan group.
Ingesting preformed vitamin A has no advantage; it has potential toxicity not seen with β-carotene and other carotenoids.
While meat and dairy products contain vitamin B-12, absorption is often poor due to gastric atrophy, medications, and other causes, leading to marginal vitamin B-12 status in ∼20% of elderly individuals. Fortification or supplementation is more effective and cheaper.
Dr. Leroy cites iodine as one of milk's helpful attributes. However, cows do not synthesize iodine or any other element. Iodine in milk comes from iodine-containing disinfectants used to clean contaminated udders and milking equipment and from supplements fed to cattle (38). Better (and cheaper) nutritional strategies are the use of iodized salt, which greatly reduced iodine deficiency in the United States, or the use of sea vegetables, as is common in Asia. These strategies avoid the saturated fat, cholesterol, sugars, estrogens, and cancer risk associated with milk.
Similarly, animals do not synthesize iron or calcium. They obtain them from plants, as humans do. Green leafy vegetables are particularly good sources of both. Iron intakes among vegetarians are typically similar to or even slightly higher than those of omnivores (39). There is no value—and there are significant risks—of excessive iron intake. The same is true for taurine (which promotes intestinal production of genotoxic hydrogen sulfide) and choline (which is prothrombotic and promotes trimethylamine N-oxide production).
Animal products lack dietary fiber, vitamin C, and complex carbohydrate. Overall nutrient intake on an omnivorous diet is inferior to that on a healthful vegan diet. In a 2008 study, adopting a vegan diet increased total vitamin A activity, β-carotene, vitamins K and C, folate, magnesium, and potassium, while reducing intake of saturated fat and cholesterol (40).
Dr. Leroy's citation of inadequate nutrition related to “vegetarian and vegan upbringing” had nothing to do with the adequacy of vegan diets. Rather, it described a 1970s Israeli religious group that limited breastfeeding to 3 mo and then used an improper infant formula. The answer is not meat or bovine milk; it is breast milk or formula. As noted by the Academy of Nutrition and Dietetics, “…appropriately planned vegetarian, including vegan, diets are healthful, nutritionally adequate, and may provide health benefits … for all stages of the life cycle.”
To nourish a growing population, feeding plants to animals and then consuming their muscles, milk, or eggs is resource-intensive, adds unwanted cholesterol, saturated fat, and pathogenic microorganisms, and displaces healthful nutrients.

Rebuttal (Leroy)

Dr. Barnard's dismissal of the rareness of diseases of modernity in ancestral populations and the link between animal foods and _Homo sapiens_’ cognitive development as “myths” and “romantic notions” was less unexpected than his reference to George Mann (31). Being a critic of the diet–heart hypothesis, Mann precisely described the Masai as almost free of cardiovascular disease, despite intimal thickening and high intakes of animal fat. Likewise, the authors reporting on Inuit mummies not only mentioned that atherosclerosis could as well have been due to indoor fires, but also that they remained agnostic about clinical outcomes, especially as cardiovascular deaths were rare among mid-20th century Inuit (32).
The rebuttal relies heavily on nutritional epidemiology of chronic disease. As practiced in the West, the latter mostly expresses responses to cultural norms of “eating right” rather than identifying diet–chronic disease relations (41). Its limitations have been mentioned; adjustment for isolated lifestyle factors (e.g., smoking) remains inadequate to correct for the full spectrum of confounders and biases. Dr. Barnard's interpretation of the Nutritional Recommendations (NutriRECS) studies misses the point; the merit of GRADE, described as “controversial” but officially endorsed by >100 organizations worldwide, is to relate associations to quality of evidence. Statistical significance as such is not a sufficient basis for causal interpretation and guideline formulation if the evidence is low quality. Epistemologically, there is no reason nutritional sciences should settle for lower standards.
Controlled trials may strengthen observation-driven hypotheses but, as argued above, this has not been the case for animal foods. Isolating LDL cholesterol from a broader view of disease risk factors is poorly informative. The evidence disagrees with the claim that LDL particle-size differences do not mitigate risk (42, 43); and the importance of triglycerides and other components of the metabolic syndrome should not be disregarded. If anything, associations between LDL cholesterol and mortality are of a protective nature for most elderly individuals (44), the group in which most deaths occur and for which animal foods are largely beneficial in view of healthy aging (4).
The assertion that reliance on animal foods would be a “disastrous strategy,” even for populations with marginal nutrition that suffer from deficiencies and rampant stunting incidences in children, originates from a higher-income, urban, and Western-centric perspective (15). Even in the West, however, dietary restrictions driven by ideological choice (rather than income) often lead to malnourishment of infants, children, and adolescents [the list of clinical case reports is long, the pathologies severe (4, 24)]. The position paper on vegan diets by the Academy of Nutrition and Dietetics largely reflects the perspective of Seventh-Day Adventists (45) and has been contradicted by warnings issued by other authorities (e.g., the Belgian Royal Academy of Medicine and the Swiss Federal Commission for Nutrition).
Animals concentrate nutrients from plants, which make them very robust sources of nutrition. The various deficiencies at the population level in people not being able (or not willing) to access them attest to that (4). Neither the boosting of “complex carbohydrates” nor the restriction of animal fat and “unwanted” cholesterol will meet the nutritional challenges of mid-century. The provision of essential nutrition will.

Low-gluten diet linked to heart attack risk

“Gluten-free diet can do more harm than good for people without coeliac disease,” The Independent reports, as a new study found that the “trendy gluten-free diets loved by Gwyneth Paltrow and Russell Crowe may increase the risk of heart disease”.
Gluten is a protein found in grains such as wheat, barley and rye. In people with coeliac disease, it damages the intestines and triggers digestive symptoms such as diarrhoea, meaning they need to follow a gluten-free diet.
Recently there has been increasing interest in the possible health benefits of avoiding gluten among people who do not have coeliac disease, though the long term evidence about its effects in this group is currently limited. Despite this, the gluten-free food market is reported to have made $3.5bn worth of global sales in 2016.
The current study followed more than 100,000 people from 1986 to 2012, assessing their diets and whether they had heart attacks during that time. These people did not have heart disease at the start of the study, and importantly did not have coeliac disease.
Overall, it found that once other risk factors were taken into account, people’s consumption of gluten was not related to their risk of heart attack. However, further analyses suggested that lower consumption of gluten specifically from whole grains (wheat, barley and rye) was associated with increased heart attack risk compared to higher consumption from these sources.
Ideally these findings would be confirmed by other studies, but this research will take time. In the meantime, if you don’t need to avoid gluten for medical reasons, this study suggests it may be beneficial to continue including whole grains in your diet for their cardiovascular benefits.
Where did the story come from? The study was carried out by researchers from Columbia University in New York, and Massachusetts General Hospital, Harvard Medical School, Brigham and Women’s Hospital, and the Harvard T. H. Chan School of Public Health in Boston. The authors were funded by grants from the American Gastroenterological Association, Massachusetts General Hospital and the National Institutes of Health.
The study was published in the peer-reviewed British Medical Journal on an open access basis so it is free to read online.
The UK media provided reasonable coverage of the study. As you would expect, most of the otherwise academic reporting was given a touch of glamour by listing celebrities associated with gluten-free dieting.
What kind of research was this? This was a prospective cohort study looking at whether how much gluten a person eats is linked to their risk of developing heart disease over a long period of time.
Gluten is a protein found in wheat, rye, and barley. It causes inflammation and damage to the intestines in people with coeliac disease. People with coeliac disease have an increased risk of heart disease, but eating a gluten-free diet helps to reduce this risk, as well as symptoms.
Eating a gluten free diet has become increasingly popular among people who do not have coeliac disease as a result of concerns that gluten may cause various digestive and other health problems. However, the impact a low gluten diet may have on risk of heart disease in people who do not have coeliac disease has not been studied in long term prospective studies. This is what the current study wanted to assess.
While a randomised controlled trial is generally the best way to test whether a particular factor causes a specific outcome, it would not be feasible to randomly allocate thousands of people to eat gluten or not for a long period of time. Therefore, a large cohort study such as this is the best way to look at this question.
The main challenge with this study type is to try and single out the effect of gluten as opposed to any other factor. Researchers do this by using statistical techniques to try and “remove” the impact of these other factors (known as confounders).
What did the research involve? The researchers analysed data from two very large cohort studies in the US called the Nurses’ Health Study and the Health Professionals Follow-up Study.
The 110,017 participants without coeliac disease who did not have heart disease in 1986 filled out detailed questionnaires about their diet at the start of the study and every four years after that, up to 2010. The researchers followed them up to see who developed heart disease over this period, and whether different levels of gluten consumption affected the likelihood of developing the condition.
The standard diet questionnaire included more than 130 questions about how often a person consumed specified portions of certain foods and drinks. The researchers used the participants’ responses to estimate how much gluten they were consuming on average over the study period using a database of nutritional contents of the foods and drinks.
They included gluten from wheat, rye and barley, but did not include the small amounts of gluten which are present in oats or condiments such as soy sauce as they felt these would be negligible. People were then split into five groups with increasing levels of gluten consumption for comparison.
Because people might change their diet as a result of illness, for people who developed diabetes, cancer, or certain heart disease events such as stroke or had surgery to treat heart disease, the researchers only considered their diet before they developed these conditions.
Participants filled out questionnaires about their health every two years, and if they reported having a heart attack their medical records were checked.
Deaths from heart attack were identified from state and national records, or reports from next of kin. Medical and post-mortem records and death certificates were also checked for these individuals. If these record checks confirmed the reported diagnosis, these people were considered as having developed heart disease.
The researchers analysed whether participants who consumed more gluten were any more or less likely to develop heart disease. They took into account many potential confounders that could be related to heart disease risk, including:

age
race
body mass index
history of diabetes, high blood pressure or high cholesterol
regular use of aspirin and non-steroidal anti-inflammatory рreparation
current use of statins
current use of a multivitamin
smoking history
physical activity
parental history of heart attack
menopausal status and menopausal hormone use
other dietary factors such as alcohol, red and processed meats, polyunsaturated and trans fats, and fruit and vegetables In addition, the researchers also looked at what happened if they took into account consumption of whole and refined grains, as these contain gluten, and have been linked to level of heart disease risk.

What were the basic results? The mean daily intake of gluten at the start of the study was:
7.5g among women and 10.0g among men in the highest consumption group 2.6g among women and 3.3g among men in the lowest consumption group People with higher gluten intake tended to have:

lower alcohol intake
smoke less
consume less fat overall
eat less unprocessed red meat
consume more whole grains and refined grains During the study 6,529 participants (5.9%) experienced a heart attack.

Before taking into account potential confounders, heart attacks were more common in the group with the lowest gluten consumption than in those with the highest consumption.
However, after taking into account known risk factors for heart disease, the difference between the groups was not statistically significant.
When the researchers looked at the impact of consumption of gluten from just refined grains they also found the difference between groups was not statistically significant.
But when they considered the impact of consumption of gluten in whole grains – they found those with highest gluten consumption were 15% less likely to develop heart attacks over follow up (hazard ratio 0.85, 95% confidence interval 0.77 to 0.93).
How did the researchers interpret the results? The researchers concluded that differences in long term dietary intake of gluten were not associated with risk of heart disease. However, their results suggested that avoiding gluten may reduce consumption of whole grains, and this may lead to increased risk of heart disease.
They recommended that “promotion of gluten-free diets among people without [coeliac] disease should not be encouraged”.
Conclusion This study has found that while overall gluten consumption in people without coeliac disease may not be related to heart disease risk, avoiding whole grains (wheat, barley and rye) in order to avoid gluten may be associated with increased heart disease risk.
This study has several strengths, including its large size, the fact that data was collected prospectively and diet assessed at several time-points, the long period of follow up, and that it took into account a wide range of potential confounders.
As with all studies of this type, it is possible that other factors may affect the results. However, the researchers took into account as many potential confounding factors as they could in their analyses. This increases confidence in the results, but it is still possible that these or other unmeasured confounding factors are having an effect.
The researchers noted that they did not specifically ask participants whether they were intentionally following a “gluten free” diet or consumption of gluten-free substitute foods.
It is important to emphasise that this study was only in people who did not have coeliac disease. People with coeliac disease need to eat a gluten free diet to control their symptoms, and it is thought that this diet may actually contribute to the reduction in risk of heart disease seen after diagnosis in this group. So people eating a gluten free diet for this purpose should not be concerned by the findings in this study.
The study collected data from 1986 to 2012. Diets over this period have changed, and avoidance of gluten is likely to be more common nowadays. It would be interesting to repeat the study now to see if the same results are found. While it would be good to have these findings confirmed by other studies, carrying out similarly large scale and long term research will take time.
Ideally, if you don’t need to avoid gluten for medical reasons, then this study suggests it may be beneficial to continue including whole grains in your diet for their cardiovascular benefits.
Find out more about common digestive problems, such as bloating and heartburn, and how to treat them.

Post your favorite bogus nutrition myths & fads

Associations of fat and carbohydrate intake with cardiovascular disease and mortality: prospective cohort study of UK Biobank participants - March 2020

A Combat Overhaul Essay, How to fix many Stellaris issues in one fell Swoop. (Port from Forum)

Hi there, this post is mostly dedicated to mods and dev that would have missed it on the Forum, for the others I guess it would make for a great reading before sleep or during long car travel I guess? Yes, it's very long.
if you want to read the clean version of the forum the link is here https://forum.paradoxplaza.com/forum/index.php?threads/a-combat-overhaul-essay.1321180/ , I didn't manage to properly paste it and it's really getting late TT.
Introduction and Disclaimers
Lately i've seen a recurrent topic on the forum, things like "Ships outdated", "Combat system improvement" or "Crisis is too easy". Those questions are delicate, and it's not rare that those topic get out of control, thus I wanted to give a try, with compelling and efficient Arguments I hope, on how we could improve current Combat system. I toke the liberty to not put this the Suggestion (it's a sub-forum, if you asked yo... Wait a minute you're from reddit? then nevermind...), as I feel those kind of post must be seen by the maximum amount of people, including potential modders, although I doubt modders could achieve to the same degree the ideas below.
Also please for the love of Steve have an open minded stance on what you're about to read, do not take everything I say for the absolute truth, tweaks and little change here and there are bound to happen, just get the general message.
( English isn't my main language... So prepare yourselves.)
Overall thoughts on current combat system
When it comes down to current Combat system, I think it's "meh", the main reason is because of how one dimensionnal it is. You make corvets, you attack, you win/loose, you unlocked Destroyers? Slap some Medium Destroyers in what you already have and you do you. Cruisers now? Go ahead. Battleship? Of course you make them. There is a problem tho, once you unlock the new hull, you have no reason to build the older ones ever again, and there is 99% of the time no reason to use different layout (Like when you have L Battleship, why bother with anything else save for PD/scoutwing?), with the exception of "Torpvets", the missile variant of corvets. To quote a friend, current late game looks like a rock-paper-scissors, with Corvets countering Battleship, Battleship countering Cruisers, and Cruisers countering Corvets and Destroyers being a meme Psionic niche (which is the only real entertaining interaction in current combat stellaris). Not only that, but this statement has a flaw, most players do not even think Cruisers are good (which is wrong btw, they're quite efficient against corvets, but only early/mid game), and they're right when it comes down to late game (way too weak to L battleship), so it's not really Rock-Paper-scissors but rather Rock-paper-scissors"that dull over time and rocks are turning into avalanche". Furthermore, the "meta" shaped around very specific Weapons, especially later on. the Neutron launcher, the X weapon, Autocanons, and Torpedoes and disruptor in niche situations. All the others weapons are only used because it just happened to be the highest weapon tier you possess. So what do we do?
Our problems are the following:

Limited efficient weaponry (beyond gameplay issues, this is very sad for a galactic scaled strategy game)
Obsolete hulls over time.
One sided snowball (if both player use the same thing but one happens to have integrated another empire before, the other empire is unlikely to have a chance).
Limited approaches to a war.

And those problems can all be resumed by ONE : Lack of diversity.
My Reasoning
According to my experience in strategic games, the bigger a games get, the less likely you'll achieve real balance. So, again, what do you do? In such a game as stellaris, for me the best approach would be you flood the game with enough diversity, enough counter measures, enough relevant mechanics (I insist on relevant) to get the player engaged, make them transcend the "Rock-paper-scissors"that still dull over times and rocks are turning into avalanche "" for a "Rock-paper-scissors-Lizard-Spock-etc..." that relies on counters and flavor to hook the player, without discarding the obvious “more shit counter less shit” (again a quote) which is your usual defacto win condition in strategy games (4X especially)
You still following? Good let's get started then:
Introducing Crews, Empire interactions and identity, Drones, Automation, Super Shield, New Environnemental Hazard, New support slot, New "weapons" and fleet stance.
Crews
Crews are the core of a ship, a ship can not operate without a crew. Crews have their own health that decrease in 2 steps depending on the damage the armoHull suffer, there are permanent damage that requires the crew to be docked to a starbase or a special Utility slot in order to regenerate, and there are non permanent damage that can heal overtime, and could roughly be interpreted as a combination of both physical and moral injuries, and thus will affect the ship capabilities as it goes down, those 2 bar can drop at the same time. It would look roughly like this.
https://forumcontent.paradoxplaza.com/public/530521/upload_2020-2-4_15-44-3.png
You will note however that the designation "Crew" includes automated systems. Ships do not get experience by themselves anymore, it is their "crew" that improves over time.
Crews will be a great assets in order to drasticly increase the flavor and diversity of the combat overhaul, by adding a new front to look for in battles. Now I know more mechanics does not equal more overall fun in most cases, but I felt like in Stellaris this feels just right.
their specialization and traits are defined by the empire "Identity" and their respective species traits. Crew can be customized in a dedicated tabs by their composition (The 100% xenophobic crew, or the mixed xenophile crew with 40% of a specie and their 20% and 40% allies) in a pie chart composition. Crew templates are then attributed to ship designs. Depending on how the mods/dev feel like, a crew doesn't have to be dynamic, for performance sake.
Crew Traits
Species Traits will affect the ship overall capacities for exemple we could go with
Ingeneous improve the energy weapons of their ships
Industrious improve the kinetic weapons of their ships
Strong/Very Strong, Resilient and Weak complete the crew's power at deflecting Boarding parties.
Sociologist have increased efficiency with and against environnemental Hazard (Biological Boarding, Mass poisoning).
Engineer give a passive hull and Armor regeneration
Physicist have increased shields.
Fast learner and Slow learners affect the crew experience ratio.
Communal, Lithoid and Enduring Increase the crew's HP.
Agraryan and Intelligent are already strong as it is, but the former could have Crew regen while Intelligent could be soft boost to the 3 "Science trait" mentionned before.
Special Lithoid traits halves the cost of the ship special ressources.
Talented increase Tracking
But what about Machines you may Ask?
Drilling Claws makes for dreadful boarders, especially the "Shredder" version. (we'll get to that later)
Super Conductive both affect Energy Weapon and Shield, but leave the crew weak to EMP attacks (or in contrary give a bonus to Weapon/Shield if hit by energy weaponry?)
Efficient processors is an all around minor boost.
Durable have increased health
Mass-Produced and Recycled have increased regeneration
Logic engines is the Intelligent equivalent.
Enhanced Memory increase tracking by twice the amount talented would
Learning algorithm... you get the point
And the more "Exotic ones" ?
Robust would drasticly increase the health
Erudite would be a buffed up Intelligent
Cybernetic would increase range and crew damage
Synthetic would increase range further, crew damage=Cybernetic.
Psionic would keep their Evasive tendencies.
Naturally any antoganist Traits would have the reverse effect.
Crew's Identity Ethics can not be enforced on crews, unless you happen to be autoritharian or militarist. Egalitarian can not enforce crews, but their and pacifist ones make up with bonus that are situationnaly better than the other ethos. As far as "Empire Identity goes", it's just a global term to define "Ethics" and some extra Perks:
Pacifist Crew have increased retreat capabilities and Fire rate in their territory.
Militarist have increased overall fire rate, and some extra perk I suppose.
Egalitarian have an Even better fire rate than Militarist, but only in total war or Liberation war
Autoritharian would have bonuses against weaker empire or rebelling vassales.
Materialist will prefer keeping their "technological jewel" safe and thus have increased ship/armor
Xenophile will make the most uses out of a diverse crew and will enhance their traits
Xenophobic will have increased Fire rate against xenos but a criplling debuff if fighting their own kind
Spiritualist are zealous but do not give anything on their own (event based!)
Indentured Crew are both available to Xenophobic and Autoritharian depending on their policies, and makes for great fodder by having reduced War exhaustion penalities upon death.
A crew not sharing ethics with the empire it serves has an overall debuff to its stats.
A crew sharing a fanatic ethic does not have increased stats however, but they're more likely to show up without enforcement But this is where the fun begins. In additions to the regular crews, that entirely relies upon your ethic attraction (if this god damn system is fixed!) or could be enforced by Autoritharian/militarist (Maybe dictatorial and Imperial even?) empires, there are "secondary" identities that can be enforced regardless of your ethics if the conditions are required. They can either complement the ethic or act as totaly independant trait.
"Media conglomerate" crews have fire rate bonus depending on the relative war exhaustion between the 2 sides.
"Purifiers" crews have, you guessed it, an absolute hatred for everything and have the stats to back them up.
"Barbaric Despoiler" can replenish their crew lost health through abduction and by docking on ennemy starbases, they make a more open use of the
"Pirate" Fleet stance with little to no penalities. They would typically require “dynamic crews” to work, but it's unlikely anyone would go through the trouble.
"Criminal Syndicate" crew have a "smuggle" fleet stance. They can smuggle fleets in ennemy position and have them ready before war.
"Naval Contractors" crew make for slightly cheaper ships, but switching government will cost you direly.
"Feudal fleets" are a soft version of the stratapies fleets of the great khan. They build up overtime depending on the Overlord economy and belongs to the subject as long as they do not rebel. "Police state" Crews make quick work of Piracy.
"Hiveminded" Crews are cheaper in naval capacity
"Machine Empire" Crews have better tracking, and are resistent to most boarding methods.
"Warrior Culture", "Strenght of Legions" and "warbots" both affect crews boarding and defensive capabilities
"Zero Waste Protocols" are less likely to take "permanent" crew damage (one that requires healing)
"Determined Exterminators" have their genocidal bonuses.
The Following are "special crews" that do not have any link to ethics, and are either unlocked through events, Ascension perk or tech
"Brain crew" are unlocked through Autonomous drones tech, gives considerable fleet power but are weak to boarding. "Automated crew" are invulnerable to most boarding methods, and have decent bonuses. "Shrouded crew" gives the fleet a fleet stance that will make it warp in anywhere by going through the shroud, getting considerable bonuses but loosing all control upon it. All spiritualist crews have increased bonus in a system with a worshipped celestial body, but there is also a specific and limited "Guardians" one that make formidable defenders in said system. "Nihilistic Crew", gained through nihilistic acquisition, are a sad sight to behold and honestly i've no idea what bonus I would give them, so let me know if you have any ideas. "Metal head" crew would make a fine easter egg. "Arrogant" is the crew type of fallen empire, and typically rarely retreat. “Levianthan”, “Events”, every critters of the galaxy, they can all be customized through that.
Titan Dreadnough and Flagship crews
Regardless of your empire type, when it comes down to Flagship,Titan or Dreadnough. crew can be chosen for their ethics if they happen to be shared with the Empire ethics.
Why crews
After this whole section of me basicly throwing a stupid amount of ideas, one could ask "but why tho?".

Well first crew bring a whole new layer of customization and thus flavors.
Second, currently when it comes down to "late game" L battleship spam is the most dominant form of warfare, to counter this, weaknesses and counter measures must be made.

Different Boardings
Boarding could come in many form, Ships with a dedicated utility slot ( even small range teleportation device, Spore Artillery?), a new kind of missiles or hangar. They would also come in Different flavor, but most of them would cost the Crew's own health to be used “up to a certain treshold”.
"Shredder boarding" designating boarding typically done by ravaging drones, dealing damage to hull but also heavy damage to automated systems. "Regular boarding", with basicly "armies" trying to get the better of their opponent, reducing the ship capabilities while the boarding is ungoing. "Biological Boarding" with specialized Armies that would deal increased damage against Bio crews. "Psionic Boarding" Where the ship quickly become grounded as its crew "first" life bar depletes very fast. Etc
Implication of Boarding
All this might seem a bit confusing, but it could be resumed by "if as a Synthetic overlord, you see a wave of boarding pods like current torpedoes going for your battleship uncontested, you should be worried". A Ship loosing its crew to boarding can also turn on its former owner, although much weaker given the likelyhood of having a small crew manning it (unlikely to happen if you have enigmatic engineering). Following this concept, ships that failed to be taken control of would provide a better bounty of tech when reverse engineered.
Some admiral thoughts and flagships
Also let us ask ourselves one thing: “Does it makes sense that because some fancy xenos in his battleship amongst other battleship has a fleetwide bonus to fire power because he just happened to have some cybernetic implant?”. With a crew system, Admiral could be redesigned, their species trait being attributed to the crews, they could have something else instead, perhaps expanding on the amount of trait they could get?
There could also be notions like “Flagship” introduced, with hulls of Cruiser size or above could generate auras for their fleet. This could also be expanded upon quite easily aswell, scaled down version of what the incomming “Dreadnough” will achieve. “Flag ship” could have increased stats, but be empire limited aswell.
The purpose of Crew based mechanics
Back to crews, the Idea behind this mechanic, beyond just flavor, is to allow "weaker" empire to be somehow able to slow down their assailant by inflicting "True damage" to them, damage that should be avoided at all cost on a conquest war, and to provide an additionnal mean to hit hard on larger ship composition. Some may say it's too similar to the role provided by Torpedoes, and I do agree, then again didn't it came to anyone minds how the idea of torpedoes happened? They're just regular missiles but hit harder, while regular missiles themselves are not that good at dealing with smaller fleet comp. In a system involving Boarding, it is actually quite likely torpedoes no longer have their place, except for taking down real behemoth like Titans, Dreadnough, Leviathan and Colossus. It is something to take into consideration, I know some people love there devastator just as I do (Edit : I think i've an idea, more on it latter)
Overall what would this changes bring?
On their own, not much. Even if more weapons, ideas or mechanics were created, on their own those would change nothing. In stellaris there's always been a "dominant" build, one "paradoxal" (ahaha) phenomenon, and as long as every build have access to the same possibilities, creating counter measures will prove meaningless, if as long as one (or 2) of those builds would just "make more stuff". So in order for those changes to be meaningful, there should be different "path" with different "opportunities".
Stellaris old nemesis, the Alpha build(s)
^{Yeah, so this is the part when we touch a sensitive topic about the game, so keep your safebelt attached.}
In current stellaris, there are "5 build" that can be differencied, 2 of them picked at the very start, the 3 others being Ascension, and a "6th one" that is kinda special.
Those are "BIO","SYNTH","PSY","MACHINE", and "HIVEMIND", (the 6th one being regular empire that decided to not go down a path for whatever reason, mostly economic? I guess?)
When it comes down to raw "power" and how they interact with each other it currently roughly looks like this.
That cursed Image https://forumcontent.paradoxplaza.com/public/530493/upload_2020-2-4_13-50-54.png
With Machine capable of going for Conquest from the get go (which is absurd btw) with almost uncontested efficiency
Hivemind and Psi hitting peak efficiency at roughly the same time (but hivemind has more pops and
does not grant anything for Psi if a war would happen)
Bio hitting slightly latter, overall the weakest in term of power, but has a valid reason to attack a hivemind
and Synth, hitting the last, but with an absurd power peak that essentially translate into "Gg".
Wherever you like it or not, this is roughly how the game looks at this moment. The Dominant build here is "SYNTH", but "MACHINE" is not far behind. "SYNTH" have access to the flesh is weak, which on its own is almost equivalent to the entire 2 other finished Ascention path, why you ask?:
-Growth across the board (Robots + Habitability)
-Efficiency across the board (habitability)
-Can safely research Synthetics with no issue of an AI rebellion backfiring.
-it's gated by a Tier 2 (?!!) tech
Now mix that with Synth ascension and you get... Basicly all the Bonuses that makes "MACHINE" as good.. (yeah and remimber that absurd growth? It gets bigger).
Honestly, present this to any new player and they'll be "Why".
And they would be right, why in a galaxy with so many choices, so many opportunities, would it come down to "did you synth ascend" or "did you pick Machine/Mechanist/technocracy" on the empire screen?
Dev could fix this... But then you know what will happen? The next big thing will be Bio and/or Hivemind, that for the sole reason they're capable of "making more" will be able to crush the competition. And it will all start over.
How could we fix it
My Proposition is to give weaponry, utilities and other gimmicks to all of those 5 build, through the form of increased weight toward given tech, and decreased toward others, but also events.
Synth would remain "THE BIG GUN", they'd still hit hard late game
Machine would become the "Track bois", and have an edge over small/medium hull based fleets.
Psi would expand on their evasive, and dirty trickster identity
Hivemind would finally become massive swarm
Bio would be your typical dream team of race(s) striving for their survival and ennemies of the gestalt.
Thus we'd get this.
https://forumcontent.paradoxplaza.com/public/530492/upload_2020-2-4_13-49-23.png
Synth Overwhelms the Machine through gun and knoweldge over their ennemy.
Machine and Synth are straight up "better" version of their fleshy counter part and thus have an edge as "metal empire"
Hivemind overwhelm the Big guns through shear number of overall smaller fleets.
Psi are unlikely to land their deceptive tricks of the mind upon litteral Gestalt, but can easily do so on Bio and Synth, the latter who likely broke things in the shroud and thus enraged its inhabitants.
Bio do not have weaknesses exploitable by gestalt, and their more unpredictable behaviors compared to the "shroud manipulated" and "efficiency seekers" are much harder to counter than gestalt.
Back to the problem
This is the reasonment I have with this.
With current system however, several "arrows" are missing.
Hivemind do not have the edge of the number against synth.
Machine are too powerful economicly wise and will proceed to kill everyone if they so desire.
Psionic have niche usage against Synth bigger guns through usage of High evasion small fleet, which can be countered quite easily and is also heavily Rng driven, but are also left in the dust economicly wise with no other mechanic to back it up.
Bio is overall weaker to everyone, hivemind included, by being in an akward middle, unable to pull cheesy effective strat like psi, and unable to keep up with the 3 others economy, having to go the extra step to make up (like hivemind, but worse, atleast they can use conquered pops instead of livestocks).We won't talk about the various "Rush" build out there that totaly discard all the aboves statement, for our interest is more oriented towards the Mid-game combat (The introduced techs are for the most part Tier 3+, which is rarely reached by rush build)
And if as a regular empire you decided to go for neither, you'd basicly be "discount" Bio, except you loose your niche as Hivemind killer (we'll get back to that latter)
Thus most new mechanics I will explain in this second part will mainly help Bio, Psi, and Hive in order to keep them somewhat "competitive" even in a struggling situation. Naturally, Economy will have to be taken into consideration aswell, and thus the "Synth" should always be a little step ahead of everything else (because it hits late and support an overall high risk high reward playstyle).
But what about the word “Competitive”
Some people are scared of this word, but they shouldn't. Although I believe it's wrong to turn the game into a competitive mess, I believe imagining it as such can allow to think of ways to fix some crippling gameplay holes.
Right now Empire flexibility, Flavor, and “RP” are decided on the empire screen. But those choices are meaningless, if you're ultimately drawn to a single most potent build. You will always have this bad taste in the mouth “man if I went this everything could have been smoother”
I believe the alternative is to add a “second layer” of defining mechanics, and because the one I'll propose happen to be combat related, I toke the liberty to explain my point of view on the subject of empire ever since “Le guin”. I believe this second layer would finally allow “niche” empire, no matter the balance patch, to still be relevant in a game.
No one wants to play a game where your empire is set on a path despite the choices that were given to you, but look at the game now, and before aswell, we're already on said path. With this new layer, the 5 path will always remain relevant, as long as those changes were done right. Also bear in mind this is no 1v1 game, alliances, shady deals, and all this fluffy stuff are part of the deal.
How to bring diversity in a one dimensionnal combat system
Ok, let's assume it is the right thing to do for Stellaris, where do we start?
We could give each "build" technologies that would only be accessible for the others through reverse engineering or Research agreement (because of the poor associated weight). Those technologies, beyond setting those build on their own "playstyle", would prove efficient at countering the strenght of 2 of the other build, and exploiting their weaknesses. Because we're talking combat overhaul my main concern will be weapon and other space related features. Of course we could also add traditions in the mix, but that is another topic. Crew, a mechanic we introduced earlier, will play a very interesing part in this.
Hivemind
Being the nemesis of both Synth and Psi, hivemind must be helped in order to take down Big ships and evasive squads, through number and shear Damage.

Techs, and boon, related to the usage of Smaller hull, Hangar, Missiles and Boarding mechanics
Giving more “supressing methods” in addition to the previously mentionned Boarding, through the New fleet focus mechanic (more on that later) focusing fire on Propulsors/Weapons, respecting the following order in efficiency ( Hangar>Missiles>Small>Medium at focusing down ships component) (note that every empire would have those, hivemind just happens to have an edge on Hangar and Missiles)
Techs related to increasing the amount of ships a hivemind can muster.

Machine
Being the nemesis of both “light/medium” composition, Machine will receive boon at efficiently “removing the pest” through tracking bonus and overall utility vs Smaller Hull.

Techs, and boon, related to the usage of medium/heavy hull, medium guns, drones, missiles, and computers, resistance to most boarding methods.
Drones would be in short “Cheaper hangar” heavily focused on utility and defense, they would basicly be an expanded version of current scout wing.
Techs and Computers dedicated at taking out the “small fries”.

Synthetics
Typically the result of an empire having a lust for knoweldge/poweanything really, Synth will make an heavy usage of large weaponry and large fleets, which is exploited by Psi and Hivemind, who will attempt to bypass those issue through smallemore evasive vessels and eliminating the crew directly. They will however punch through the more regular fleet composition that Bio and Machine would offer them.

The absurd current growth and Eco casted aside, Synth would remain quite similar to how we know it, a Juggernaut of a late game, but with a rather fragile mid/early game, with their “combat” tech being unlocked quite late.
Their crew would tipically be the weakest in the game until they can get their hand on others tech.
Although I've little ideas on how to make them different to what we currently know, the best bet would be to increase the weight for new Hull.

Psi
With dominion over the mind and behaviors of single minded entities, and with the shroud backing them (willingly or not?) against the synth betrayers, Psi will elude common sense by the usage of rather light composition and will privilege cunning approaches to a conflict before dealing the finishing blow. Most of their superchery won't work on gestalt however.

With the less amount of eco related boost, Psi make up by having access to a rather large pannel of posibilities when it comes down to designing their fleets, and various ways to engage a fight.
They are much more likely to unlock “Teleport Boarding”, bypassing PD/Drones and deals significant damage to the first Bar life of ennemy crew, crippling the ship direly.
Psionic crew can man an unique assets of weapon, utility and even shield, most notably the “Super shield”.

Bio
Bio are your typical dream team of Alien leagued against a greater threat, or some twisted dominator redesigning the galaxy to their image. If any of the above would be deemed “standard”, it would be the Bio. If finding differences between machine and Synth wasn't hard enough, the one between Bio and hivemind is even worse. They should have access to their own traits, which hivemind won't have access. To be entirely honest it is hard to find them fitting mechanics, but your best bet would be enhanced PD, a large arrey of utility and access to several Gestalt disruptive mechanics, such as dedicated “Hive disruptor” weaponry for exemple.

They would typically have strong crew, while still being weaker to psi on this matter.
Their fleet composition would be Medium/Heavy.
Large utility assets for their fleets, PD included

Non-Alligned.
Non Alligned empire decided to not go down any of this path for whatever reason, perhaps because they transcended them all, but still have to fight. Maybe they uncovered relic related weaponries, perhaps they found out about a way to unite all 3 other path. To not let those empires feeling casted aside, new situationnal AP, something along the lines of “if has said relic, or if has 200 minor artefact or if has 1 Psi 1 Bio 1 synth pop” then they'd have access to different opportunities. They could be jack of all trades, master of none, or litteral unpredictable empires.
So what's new? While I had many ideas on the topic, it would take too long and probably not be relevant for a sizeable amount of them. So here is a compiled version instead.
Weapons
Beam Weapons : The following “Beams” requires target's shield to be down in order to work.
Bio Beam → Designed to focus Bio crew before the ship, does not affect shield.
Psionic Beam → Designed to quickly deplete the first health bar of a crew, effect weakened against gestalt
Purificating Beam →Designed to deal consequent damage to synth crew, reduced damage against Hivemind and 0 damage to regular crew but may swap the ethic of the crew of Bio to spiritualist (they have no effect!)
Neutron Beam → A dreadful lategame weapon that make quick work of any Bio crews.
EMP weaponry → not as efficient as Bio Beam, but get the job done vs Machine crews.
Missiles
Boarding Pods and a dedicated tech tree.
(From your “average” boarding to your “Xenomorph” boarding)
Regular Missiles will require an overall to better fit the new array of possibilities.
Biomissiles → a Direct hit on the hull and the Bio crew's health
Fix a certain bug that involves hangar and pd... you know which one...
Bigger Missile
Just like S M L is a thing
G and XG could also become a thing. Torpedoes would finally make sense, Neutron launcher could maybe fit back in there? Their purpose is to take down even bigger ships, while regular missiles will hardly matter against bigger ships than Battleship.
Hangar
Reintroducing Bombers, Strikers and add Drones. Strikers>Drones>Bombers
Strikers and Bombers are essential tools for Hivemind and Bio, (except Bio would happen to have better access at strikers while Hive would have a better access at bomber)
Strikers are better at attacking smaller hull and hangar related shenanigans, but do not have the same efficiency at taking down bigger ships and focusing fire on great hull part than Bombers.
Drones are a cost efficient mean to deal with bombers, and have additionnal utility, they're mostly machine related.
Repair Drones Shield nullifier “Scout Wing Drones” (Strikers are not meant to deal with missiles, but they're a good middle answer to either bomber or ennemy ships, drones however, can deal with missiles).
Shields
the previously mentionned “Super shield” would act as a third layer of protection for the ship. It must be manned by psionic crew and has only 1hp. Every incomming damage will be reduced to 1.
Very expensive in power, those shields would be an answer to the “Big guns”.
Fleet Orders
This one has been asked a lot. Fleet Orders as I see it would decline in 2 “orders”, a Fleet stance, and a Fleet focus.
Fleet Stance
Fleet stance could potentially replace the rather outdated “War policies” and be directly applied to fleets. Hit and Run, Defense in depht, Rapid Deployment, No Retreat would be included, but there would be others like
Holy Guardians (Significant bonus while in a system with a consecrated world, spiritualist crew only)
Search and destroy (For machine, Additionnal damages against smaller hull),
Rogue Fleet (A fleet that pretend it went rogue and ignore borders, the bigger the fleet, the more likely a negative event would happen),
Plunder fleet (for Barbaric despoiler, it's Rogue fleet but with a greater amount of allowed ships)
Smuggled, that we talked about earlier, making a fleet jumping into FTL to a location on the map until war happens. Etc...
Fleet Stance would be harder to switch in order to stay a minimum true to what “War policy” attempted to achieve.
Fleet focus
Fleet Focus on the other hand, are specialized, often combat related, commands. They can be changed at any moment, except during the beginning of a combat.
Overwhelming (The fleet will not bother stopping its course through smaller fleet (in size) composition and will just fire while passing by, dealing extra war exhaustion to the opposing side)
Full Retreat (The fleet switch all power to Shield and Drivers and will ignore fights, increasing war exhaustion upon loosing ships)
Aim for the Guns ! (The Fleet will focus fire the heavy guns of the ennemy, decreasing their ability to shoot with them. Efficiency increase according to the weapon used to do this)
Aim for the Propulsors! (Self explanatory)
Acquisition (Fleet will cease any non boarding methods)
Focus fire (Fleet will be even more likely to take down targets one by one)
stealth manoeuvers (If equipped with the “Stealth” utility slot, ships do not fight while stealthed)
Spiritualist Crews
Spiritualist has always been this weird child. In this system, it would be a perfect opportunity to give them volatile crews, ones that will gain bonuses for a while by seeing a meteor, or loose some at the sight of heresy. They do not have bonuses per say, but they have events that may trigger, and will affect all spiritualist crew in the System (for performance sake). They're also twice as weak if the empire does not have spiritualist ethic compared to the other ethics.
Utility slot
The current utility slot is quite limited. Let's fix that
Clone vats. Crew doesn't have to back up to a starbase belonging to the owner, it will instead regen on its own. (BIO and HIVE are more likely to get this)
Spawning Pool (cheaper Clone vats for HIVE)
Small Robot Bay. Robotic crew can be replaced, but the process is slower compared to clone vats, and it requires to dock on a mining Station (Alloy/minerals)/be in friendly spaced
There could be Modules for the drones to enhance them.
Anti Boarding Slots like reinforced doors or something.
The Aforementionned teleporters, that passively sends crew directly to the other ships. could also unlock building for planetary defense ?
STEALTH, Starbases dismantlers, every cunning and deviant means to deal damage vs a greater threat
Miscellaneaous
Environnemental Hazard.
Come to think of it, it would be a nice addition to the game, but i've already seen some mod out there fitting for this. Not a priority by any means, and I'm pretty sure everyone has an idea on how much environnemental hazard beyond a mere “Black hole = Less Retreat, Nebulae = no vision, etc this game could have in order to enhance combat.
About Hivemind and Machine being locked pick.
Who decreed so? What if the dev gave both of them the opportunity to “ascend” aswell, and those ascended version would fit better “BIO”, “SYNTH” or even maybe “PSI”? What if they went down the “Non aligned” path, and found Absurd precursor weaponry?
Titan and Dreadnough.
It is worth considering scaling their health up, or just increasing their overall resilience, to make better flagship.
"This is too much DLC related"
Well then make it its own DLC, and leave the people with vanilla I guess? The thing almost feels like a mod in its simplicity, but the outcome and what it could bring to the table is DLC worthy.
What this could mean for Future Crisis.
With this many possibilities open, Crisis can certainly gain in difficulty from that. Crisis could become sufficiently strong and difficult to counter in order to compel people into harnessing enough of the other builds tech to take them down, through alliance, shear tech output or reverse engineering.
A 4th crisis, one focused on crew (hmmmm hello hunters?) could also spawn from such idea.
Conclusion.
To me, this seems like killing 2 Battleship with 1 Boarding pod.

It's a perfect opportunity to introduce a wide variety of flavor related mechanics, and an insane one for modders out there to customize many aspect of warfare.
The “Counter” based mechanics will make for a great safebelt in case some build become excessively strong, and people will be safely able to play whatever they want without being “guess i'll die”. Naturally everyone will have access to most other tech eventually, but a sizeable amount of them will be under conditions of what you decided to be. It will also bring challenge in SP, as you spawn next to one empire set on the path to become your nemesis, will you take him out before he reach his "killing tools"? will you ally yourself with its own nemesis? will you directly ally him and take care of his nemesis? Truly the only limit to this is performance, if poorly executed this could get messy with a whole new crew system. But I believe it's fairly manageable, and will make for an overall healthier combat system than our current “pop based” one.

Last but not least, if I could resume this gigantic amount of words by a meme it would be
https://i.imgflip.com/3o4blc.jpg
Hoped you liked the read, if you can make a quick detour to the Megathread "The Faults in Our Stellaris" you can see a sizeable amount of "faults" are actually treated here.

Should we change the way we interpret negative studies?

All nitpicks, criticism, refutations, and discussion of new study ‘low carb increases mortality’

You know the one.
This study: KetoScience Link
The Lancet30135-X/fulltext)

Dietary carbohydrate intake and mortality: a prospective cohort study and meta-analysis

Sara B Seidelmann, MD30135-X/fulltext#)
Brian Claggett, PhD30135-X/fulltext#)
Susan Cheng, MD30135-X/fulltext#)
Mir Henglin, BA30135-X/fulltext#)
Amil Shah, MD30135-X/fulltext#)
Eric B Rimm, ScD30135-X/fulltext#)
Walter C Willett, MD30135-X/fulltext#)
Scott D Solomon, MD30135-X/fulltext#)
Show all authors30135-X/fulltext#)

Open AccessPublished:August 16, 2018
DOI:https://doi.org/10.1016/S2468-2667(18)30135-X30135-X)
Open access funded by National Institutes of Health

Summary

Background

Low carbohydrate diets, which restrict carbohydrate in favour of increased protein or fat intake, or both, are a popular weight-loss strategy. However, the long-term effect of carbohydrate restriction on mortality is ~~controversial~~ and could depend on whether dietary carbohydrate is replaced by plant-based or animal-based fat and protein. We aimed to investigate the association between carbohydrate intake and mortality.

Methods

We studied 15 428 adults aged 45–64 years, in four US communities, who completed a dietary questionnaire at enrolment in the Atherosclerosis Risk in Communities (ARIC) study (between 1987 and 1989), and who did not report extreme caloric intake (<600 kcal or >4200 kcal per day for men and <500 kcal or >3600 kcal per day for women). The primary outcome was all-cause mortality. We investigated the association between the percentage of energy from carbohydrate intake and all-cause mortality, accounting for possible non-linear relationships in this cohort. We further examined this association, combining ARIC data with data for carbohydrate intake reported from seven multinational prospective studies in a meta-analysis. Finally, we assessed whether the substitution of animal or plant sources of fat and protein for carbohydrate affected mortality.

Findings

During a median follow-up of 25 years there were 6283 deaths in the ARIC cohort, and there were 40 181 deaths across all cohort studies. In the ARIC cohort, after multivariable adjustment, there was a U-shaped association between the percentage of energy consumed from carbohydrate (mean 48·9%, SD 9·4) and mortality: a percentage of 50–55% energy from carbohydrate was associated with the lowest risk of mortality. In the meta-analysis of all cohorts (432 179 participants), both low carbohydrate consumption (<40%) and **high carbohydrate consumption (>70%) conferred greater mortality risk than did moderate intake, which was consistent with a U-shaped association (pooled hazard ratio **1·20, 95% CI 1·09–1·32 for low carbohydrate consumption; 1·23, 1·11–1·36 for high carbohydrate consumption). However, results varied by the source of macronutrients: mortality increased when carbohydrates were exchanged for animal-derived fat or protein (1·18, 1·08–1·29) and mortality decreased when the substitutions were plant-based (0·82, 0·78–0·87).

Interpretation

Both high and low percentages of carbohydrate diets were associated with increased mortality, with minimal risk observed at 50–55% carbohydrate intake. Low carbohydrate dietary patterns favouring animal-derived protein and fat sources, from sources such as lamb, beef, pork, and chicken, were associated with higher mortality, whereas those that favoured plant-derived protein and fat intake, from sources such as vegetables, nuts, peanut butter, and whole-grain breads, were associated with lower mortality, suggesting that the source of food notably modifies the association between carbohydrate intake and mortality.

Funding

National Institutes of Health.
Dr Sara Seidelmann, clinical and research fellow in cardiovascular medicine from Brigham and Women's Hospital in Boston, who led the research, said: "Low-carb diets that replace carbohydrates with protein or fat are gaining widespread popularity as a health and weight-loss strategy.
"However, our data suggests that animal-based low carbohydrate diets, which are prevalent in North America and Europe, might be associated with shorter overall life span and should be discouraged.
"Instead, if one chooses to follow a low carbohydrate diet, then exchanging carbohydrates for more plant-based fats and proteins might actually promote healthy ageing in the long term."

Reactions:

https://twitter.com/SBakerMD/status/1030471255495979009
https://twitter.com/ProfTimNoakes/status/1030375444527435776
https://twitter.com/Mangan150/status/1030487002276196352
https://twitter.com/CampbellMurdoch/status/1030488888534548481
https://twitter.com/ColinChampMD/status/1030489170924453888
https://twitter.com/FatEmperostatus/1030460135976710145
https://twitter.com/GrassBased/status/1030435088951996416
https://www.reddit.com/science/comments/980oxn/very_lowcarb_diet_could_shorten_life_expectancy/
https://www.bbc.com/news/health-45195474
https://cluelessdoctors.com/2018/08/17/when-bad-science-can-harm-you/
https://www.reddit.com/KetoNews/comments/9ft9t7/the_latest_attack_on_lowcarb_diets_science_o Nina Teicholz
https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(17)32252-3/abstract
http://asianwithoutrice.com/low-carb-that-kills-part-1-of-2-mischief-public-manipulation/
http://asianwithoutrice.com/making-low-carb-a-murderer-part-2-of-2-broken-from-the-start/
https://isupportgary.com/articles/fakenews-headlines-low-carb-diets-arent-dangerous
ARTICLES DISAGREEING WITH SEIDELMANN PAPER:
http://www.zoeharcombe.com/2018/08/low-carb-diets-could-shorten-life-really/ DR. ZOE HARCOMBE PhD Low carb diets could shorten life (really?!) August 23, 2018 association, carbohydrates, causation, epidemiology, Harvard, meta-analysis, relative risk
https://www.wsj.com/articles/carbs-good-for-you-fat-chance-1536705397 WALL STREET JOURNAL Carbs, Good for You? Fat Chance! Dietary dogma’s defenders continue to mislead the public and put Americans’ health at risk. By Nina TeicholzSept. 11, 2018 6:36 p.m. ET
https://anhinternational.org/2018/08/22/scientific-attack-on-low-carb-diets/ ANH (ALLIANCE FOR NATURAL HEALTH) INTERNATIONAL Scientific attack on low carb diets: Why the healthy low carb community shouldn't be swayed by the latest Lancet Public Health study 22 August 2018 Robert Verkerk PhD, scientific and executive director, ANH-Intl
https://anhinternational.org/2018/08/29/the-collapsing-edifice-of-nutritional-science/ ANH (ALLIANCE FOR NATURAL HEALTH) INTERNATIONAL The collapsing edifice of nutritional science: Could reserach be made to work in the interests of the public rather than corporations following the latest scientific attack... 29 August 2018 Robert Verkerk PhD, scientific and executive director, ANH-Intl
https://cluelessdoctors.com/2018/08/17/when-bad-science-can-harm-you/ When Bad Science Can Harm You Angela A. Stanton, PhD August 17, 2018
https://cluelessdoctors.com/2018/08/25/the-ripple-effect-of-bad-science/ The Ripple-Effect of Bad Science Angela A. Stanton, PhD August 25, 2018
https://www.linkedin.com/pulse/low-carbs-mortality-john-schoonbee LINKED IN Low carbs and mortality John Schoonbee, PhD: Global Chief Medical Officer at Swiss Re Published on August 20, 2018
https://www.docmuscles.com/will-a-low-carbohydrate-diet-kill-you/ DOC MUSCLES Will A Low-Carbohydrate Diet Kill You? Adam S. Nally, D.O. AUGUST 20, 2018
https://blog.bulletproof.com/low-carb-diet-study/ BULLETPROOF BLOG New Study Links Low-Carb Diet to Earlier Death: Here’s What It Gets Wrong By: DAVE ASPREY August 21, 2018
https://www.youtube.com/watch?v=Ce6eHcUOc4s YOUTUBE Do low-carb diets lead to early death? (The ARIC/Lancet Study Explored) Ken D Berry MD Published on Aug 19, 2018 59,732 views
https://vancouversun.com/opinion/op-ed/david-harper-keto-diet-a-healthy-alternative-to-the-standard-western-diet VANCOUVER SUN David Harper: Keto diet a healthy alternative to the standard Western diet Updated: August 23, 2018 A study published in The Lancet that concluded the ketogenic diet is associated with shorter lifespans did not consider ketogenic diets at all, but was a meta-study that incorporated decades-old research on low carb diets that did not put participants into a state of nutritional ketosis, says David Harper
https://www.psychologytoday.com/us/blog/diagnosis-diet/201809/latest-low-carb-study-all-politics-no-science Psychology Today Dr. Georgia Ede

hazard ratio interpretation risk video

d Hazard Ratio. The hazard ratio is the ratio of (chance of an event occurring in the treatment arm)/ (chance of an event occurring in the control arm) (20 ). The HR has also been defined as, the ratio of (risk of outcome in one group)/ (risk of outcome in another group), occurring at a given interval of time ( 21 ). The risk of ASCV mortality increased in a linear manner with higher free thyroxine levels (hazard ratio, 2.41; confidence interval, 1.68-3.47 per 1 ng/dL) and lower thyroid-stimulating hormone In other words, the relative reduction in risk of death is always less than the hazard ratio implies. It is also a decreasing function of the time point at which it is assessed. For instance, in the example in Figure 1, a 40% hazard reduction implies risk reductions of 25% and only 14% in the 1‐year and 2‐year mortality rates, respectively. In survival analysis, the hazard ratio (HR) is the ratio of the hazard rates corresponding to the conditions described by two levels of an explanatory variable. For example, in a drug study, the treated population may die at twice the rate per uni... Hazard Ratio (i.e. the ratio of hazards) = Hazard in the intervention group ÷ Hazard in the control group Hazard represents the instantaneous event rate, which means the probability that an individual would experience an event (e.g. death/relapse) at a particular given point in time after the intervention, assuming that this individual has survived to that particular point of time without experiencing any event. Hazard ratio. Hazard ratio is a measure of relative risk over time in circumstances where we are interested not only in the total number of events, but in their timing as well. The event of interest may be death or it may be a non-fatal event such as readmission or symptom change. This brief communication will clarify the difference between a relative hazard and a relative risk. We highlight the importance of this difference, and demonstrate in practical terms that 1 minus the hazard ratio should not be interpreted as a risk reduction in the commonly understood sense of the term. The Hazard ratio (HR) is one of the measures that in clinical research are most often difficult to interpret for students and researchers. In this post we will try to explain this measure in terms of its practical use. You should know what the Hazard Ratio is, but we will repeat it again. Let’s take […] Hazard Ratio interpretation ? a hazard ratio of 1.1 indicates that one group has 1.1 times the risk I think you are probably looking at a forest plot which compares the risk in 2 This brief communication will clarify the difference between a relative hazard and a relative risk. We highlight the importance of this difference, and demonstrate in practical terms that 1 minus the hazard ratio should not be interpreted as a risk reduction in the commonly understood sense of the term.

hazard ratio interpretation risk top

Interpreting Hazard Ratios - YouTube

This video wil help students and clinicians understand how to interpret hazard ratios. The Kaplan Meier (Kaplan-Meier) curve is frequently used to perform time-to-event analysis in the medical literature. The Kaplan Meier curve, also known as ... Kaplan Meier curve and hazard ratio tutorial (Kaplan Meier curve and hazard ratio made simple!) ... Eric McCoy 16,925 views. 52:54. Part 1 of 3 (Interpreting Odds, Risk, and Rate Ratio Results ... RR and OR are commonly used measures of association in observational studies. In this video I will discuss how to interpret them and how to apply them to pat... Discover how to use Stata to compute risk ratios from summary data. Copyright 2011-2019 StataCorp LLC. All rights reserved. This short video describes how to interpret a survival plot. Please post any comments or questions below, or at our Statistics for Citizen Scientists group: ... This video will show you how to calculate and interpret odds ratios and risk ratios with an example.For more assistance with statistics, consider this book:M... A brief conceptual introduction to hazard ratios and survival curves (also known as Kaplan Meier plots). Hopefully this gives you the information you need to... This is a short presentation on hazard ratio, its uses, interpretation, and a talk about some relevant concepts. About Press Copyright Contact us Creators Advertise Developers Terms Privacy Policy & Safety How YouTube works Test new features Press Copyright Contact us Creators ...

On the Interpretation of the Hazard Ratio and

hazard ratio interpretation risk

hazard ratio interpretation risk - win

A break down of the bull case for Ethereum and how it relates to Bitcoin

Confidence Intervals, P-values, and Statistical Significance

[Q] Relationship between Confidence Intervals and P-values

Investor Insight | Synairgen: An Investment Brief by Rupert Marlow

Summary

Background

Interferon beta-1a

SGO015

COVID-19 and SG016

SG018

ACTIV-2

Other trials

Vaccination and competition from treatments

The possible applications for SNG001

The future for SNG001

A financial assessment

Children and adults should avoid consuming animal products to reduce risk for chronic disease: NO

Children and adults should avoid consuming animal products to reduce risk for chronic disease: NO

ABSTRACT

Main Argument (Leroy)

An evolutionary perspective argues against the need to eliminate animal-source foods

The intake of animal foods cannot be causally linked to the incidence of chronic diseases

Animal foods provide high-quality nutrition

Avoidance of animal-source foods undermines dietary robustness and causes unnecessary risk

Conclusions

Refutation (Barnard)

Rebuttal (Leroy)

Low-gluten diet linked to heart attack risk

Post your favorite bogus nutrition myths & fads

Associations of fat and carbohydrate intake with cardiovascular disease and mortality: prospective cohort study of UK Biobank participants - March 2020

Abstract

Objective

Design

Setting

Participants

Main outcome measures

Results

Conclusion

Strengths and limitations of this study

A Combat Overhaul Essay, How to fix many Stellaris issues in one fell Swoop. (Port from Forum)

Should we change the way we interpret negative studies?

All nitpicks, criticism, refutations, and discussion of new study ‘low carb increases mortality’

Dietary carbohydrate intake and mortality: a prospective cohort study and meta-analysis

Summary

Background

Methods

Findings

Interpretation

Funding

Reactions:

hazard ratio interpretation risk video

hazard ratio interpretation risk top

Interpreting Hazard Ratios - YouTube