10% Happier with Dan Harris episode 86: Gary Vaynerchuk, Media Industry Leader

In this episode of the 10% happier podcast Dan Harris discuss with Gary Vaynerchuk, an american entrepreneur and leader of a media-focused empire. He started off his career as an original wine critic by being a pioneer in the usage of platforms such as youtube or social medias. Describing himself as a business oriented person, Gary V. puts to light several concepts with respect to meditation and its financial future.

Meditation, especially the mindfulness genre, is gaining more and more traction by the day, through exposure in medias mainly. Some people that were in the meditation sphere before the hype train are nervous about its commercialization. Some people are afraid that meditation would lose its essence while other are simply bothered by the fact that the practice they love could fall under the “mainstream category”, similar to people liking an indie band but stopping to be interested in them when their popularity raises too much. On that note, Gary V says “if people truly love the impact that meditation has, wouldn’t you prefer to have 85% of humans doing this even though some people will do it just to be cool (knowing that it could still be the stepping stone for them to find the mental paradise that they are looking for) or only hardcore 4% of people doing it?”. Dan Harris was fully in line with that comment but said that in his opinion if meditation hits scale it should do it “the right way”. However, that’s not how it works. When things scale, the right people with the right intent are not necessarily the majority. Historically the biggest corporations tends to ruin the essence of something when they get involved, and it’s the push back from the community that will allow passionate and entrepreneurial people to find their way, establishing themselves as actor in that growing market.

Cost effectiveness of aspirin, clopidogrel, or both for secondary prevention of coronary heart diseases, Gaspoz et al., The New England Journal Of Medicine, Vol. 346, No 23, 2002.

The reason I chose to read and summarize this paper is that I was really interested in the way one determines how on one hand a treatment change would do on a medical level and on the other what impact in would have economically. What criterion should be used to determine if a better solution is financially attractive or not. What is the thought process to estimate how much the society should pay to extend the predicted life span of one human being. Although this study is very concise, well rounded and executed, it does only display raw numbers of how much it would cost without giving too much explanations on whether or not the authors think that cost is economically attractive and should be implemented. Estimating how much a quality-adjusted year of life is worth to certain countries will probably be one aspect that I will look further into. I would also like to add that this study was conducted in 2002 and I was unfortunately unable to find precise data on the current situation. So if any of you has a reliable source on the subject your are welcome to educate me.

Cardiovascular events and coronary heart diseases are a family of events that include angina, myocardial infarction (i.e heart attack), stroke, heart failure, heart arrhythmia and venous thrombosis. Their prevalence has increased during that last decades, in part due to increased risk factors such as sedentarity or malnutrition. After such an event, the patients that are the most at risk of a secondary coronary event are prescribed drug treatments. Both aspirin and clopidogrel are used as antiplatelet therapy, i.e for inhibition of thrombus formation by preventing platelet aggregation. This reduces by about 30 percent the risks of death from vascular causes, stroke or myocardial infarction.

The goal of this study was to determine the attractiveness of using such drugs for secondary cardiovascular event prevention, meaning prescribing a treatment only to people that already suffered such episode. At the time of the study, 85% of people eligible for aspirin treatment were prescribed one. Patients allergic to aspirin that required a treatment were given clopidogrel. Although studies have shown that clopidogrel is close to 10% more efficient to prevent secondary event, and that together aspirin and clopidogrel have a synergistic effect that lead to 20% more risk reduction, clopidogrel is not used for patients tolerant to aspirin. This is due to the higher cost of the drug, which was close to 100 times the cost of aspirin at that time. The author of the study wanted to determine the cost effectiveness of every qualified patient having such treatment (aspirin or clopidogrel alone or both together).

To answer that question, Gaspoz et al. conducted a meta analysis using data points from US population (with older than 35 years old and with a coronary disease as inclusion criterion) from various reports and surveys performed in previous years. The cost effectiveness of each treatment was estimated with all the data grouped in a computational model. Cost in $ per quality-adjusted year of life gained was calculated for the following 25 years (from 2002 to 2027). Their model allowed them to perform sensitivity analysis, a technique used to determine how different values of an independent variable impact a particular dependent variable under given set of assumptions . Also referred to as “what-if” or simulation analysis, it is a way to predict the outcome of a decision given a certain range of variables. Parameters taken into account include; percent reduction in the odds of coronary events, treatment costs, clinical data, illness incidence and cost of hospitalization. Sensitivity analysis used to find the most efficient % of patient to treat, the length of the treatment, as well as the drug pricing required for a certain treatment to be financially interesting.

If prescribed to all eligible patients, aspirin could save an estimated 6.9 million quality-adjusted year of life in 25 years. Based on the drug price at that time, each quality-adjusted life would cost $11’000 for patients taking aspirin and $31’000 by taking clopidogrel for the 5 percent of patients ineligible to aspirin. The addition of clopidogrel in the treatment of each patient would add another $130’000 per quality-adjusted year of life. Although, as described previously, the conjugate effect of aspirin and clopidogrel provide the higher risk reduction, Gaspoz and colleagues consider that it would be financially unattractive to do so.

Nevertheless, it is paramount to realize that drug pricing has a huge impact on analysis like this one. If some pharmaceutical firms decided to produce a generic form of clopidogrel and sell it at a significantly reduced price, one can imagine a scenario where clopidogrel is substituted for aspirin, or the use of both drugs in all patients. The medical world has to constantly adjust the go to treatment based on drug price variation. This often makes it an economical decision rather than a pure medical one, the main value of interest being the dollar cost per quality-adjusted year of life gained.

It is noteworthy that one has to go a step further in analyzing the total cost that such a change in treatment procedure would lead to. The author of the study described accurately how the cost of aspirin therapy was favorable but they also point out that patients who gained quality-adjusted years will survive and go through other medical conditions, increasing the health care costs. Those costs would be significantly higher than the savings done by the prevention of coronary events. To put in perspective, during the time period studied, the cost of the drug would be around 200$ million but the total cost that includes the health care would be around 8$ billion.

Except for the omission that clopidogrel IS a generic medication utilized in acute incidence and is (typically) not safe as a maintenance therapy. The longitudinal efficacy/patient safety while utilizing a maintenance dose of aspirin (baby aspirin, 81 mg) has also been called into question in recent literature/review of ethical patient care.

Isn't this study predicated on the author's assumed(?) prescriber inefficiency? This must be the case as clopidogrel and aspirin, although similar in site of action, are novel therapies and are prescribed in such a manner. Thus meaning if one was over used it is due to dangerous human error and not simply negligence, they are not wholly synonymous therapies. The author's intention seems masturbatory to me, although I recognized the publication date is 2002 (ie: written in exile of current literature). I fail to see the point of the article other than to have his name in a journal.

I question because you seem to have put a lot of time and effort into this well thought out summary. I appreciate the effort and I have enjoyed your previous reviews. This one however, is hampered by being outdated and suspect in author intention (ie: obviously prevention>treatment, but this is North American healthcare. This assertion seems ignorant). I am aware that a large part of your benefit comes from the exercise of writing/surmising irrespective of content. I still think you owe it to yourself to provide additional benefit to this exercise by consuming actionable and intelligible sources of information. Just my opinion, but I really appreciate your thread.

First of all, thank you for your extremely well put together input. I really appreciate the feedback and am glad you are enjoying reading some of the content I produce.

You are correct, clopidogrel is a generic drug already. I made a mistake by using that term. I wrote “generic” having in mind something like “drastically cheaper”. I am aware that the term generic is not limited to the price of the drug but I did not pick up that mistake when I did a proofreading. I only wanted to highlight that if the price were to go down it would dramatically affect the outlook described in that study.

Concerning the risks that those drugs present when used as a maintenance therapy I was not aware of it. I thought about doing some further research, to see what the state of the art is today but decided to limit myself to the paper instead. I now realize that it could impede my ability to understand the full scope and the relevance of the conclusions presented in a study and thus criticize the paper as you did. This is even more relevant for old papers and putting to light concepts that have been controversial or completely dismissed is of limited use. Consuming “actionable and intelligible source of information” is a perfect way to put it and I should strive to look for such papers.

As far as the author’s intentions goes, I would tend to agree with your assessment of his assumption. Scientific research is often dominated by the “publish or perish” mentality and doing something purely to have your name in a journal is sadly quite common practice. To me this paper looks a clever way to display how a computational model can provide a detailed analysis of treatment cost-effectiveness using meta-analysis data. I am unaware of how common such analyses were at the time but I surely doubt it would be enough today to appear in a respected journal like The New England Journal of Medicine.

By the way, are you involved in the medical field? Your post is extremely eloquent and full of insight, thanks again for posting in the thread.

Thank you for your thorough reply. I agree, your review/explanation makes a lot of sense to me. In no way do you have to explain yourself and your breadth of knowledge as I respect the fact that you know more than makes sense to share for the purposes of this exercise. I hope it was clear that my critique was of the article and the author and not of you and your review of said article.

I work cursory to health care in an allied health profession. I am not an M.D., pharmacist, or Ph.D. I did undergrad in physiology and am working as a physiologist largely involved with musculoskeletal injury with a cursory understanding of cardiac rehab and an array of chronic health conditions. I am no expert, that's for sure.

One thing I didn't realize I would value so much from school is an appreciation of critical review regarding my consumption of educative material regarding my profession. This is because upon entering the workforce I found that a large chasm existed between my theoretical and practical knowledge and this severely hampered my ability to be effective in my role during the early stages of my career. That is why I emphasized the actionable information being important in my opinion. So much of the theoretical information that was parlayed to me in school was difficult to put into practice in a live scenario that wasn't a mere hypothetical circumstance. I do recognize that for someone not intending to supplement their understanding of standards of practice with certain information then the consideration for actionable information is weighted far less significantly. In that case, a more academic thought experiment is merited more credit, in my opinion. There are certainly many areas I would take this approach. I just wanted to chime in this time since as I mentioned I really enjoy your thread and have read every posting thus far. This is the first time I thought I could add something of potential value to help contribute to your exercise. I look forward to future postings.

Why to-do lists should be done differently

To-do lists are commonplace for a lot of active people. You are working on something and suddenly you realize that you should do this or that, you write that thing on a post-it and slam it on the side of your computer screen, or wherever. The dark side of to-do lists is that, depending on the surveys, close to 40% of those items never gets done (source). I tend to think that to do lists are often done wrong, I am no stranger to to-dos put aside and forgotten. Nevertheless, I am confident that by asking yourself a few key questions when deciding to put an item on a to-do list you could do them more efficiently and extract more value from it. Let’s see a couple of concepts that would limit the risks that this happens to you.


1) Couldn’t you do that thing right away?

Do not use a to-do list as a “chore storage”. It can get very tempting to write something as “to-do” even though it could be done right away. Putting things on a to-do list feels like a relief in the beginning as you believe it’s one less thing to do right at that moment. But often what ends up happening is that those to-dos accumulate up to a rupture point, too many things on the list and you feel overwhelmed. What ends up happening is that you do not control your to-do list anymore but it controls you. This temporary relief that you felt now turned into a depressing sight of boring things that will take you ages to do.

If you can, do it right now. Do not postpone without a good reason.

2) Are you sure that you have to do those things?

“If your to-do list contains everything, then it’s probably taking everywhere but where you really want to go”
Gary Keller in “The One Thing”.

People tend to put too many things on a to-do list. Putting every single thing that passes through your mind, even if it’s an idea that you are not sure you want to dedicate time to do it, is a recipe for disaster. Lots of people agree on the notion that success is achieved by big goals reached by small goals that you achieve ONE at the time.

If it doesn’t HAVE to be done, forget it and dedicate your energy to more meaningful goals.


3) Are all of those things of equal importance?

The lack of prioritization is a common mistake. You can be tempted to do the easiest things first, just to be able to cross it. Doing that will make you feel like you accomplished a lot, whereas in the grand scheme of things they weren’t necessarily important for you to progress towards your big goals.

Realize that every items on to-do lists are not equally important and do not shy away from the more critical ones solely because they are difficult tasks.

4) Can those things be done in a recent future?

Stuffing you to-do list with things that can only be done month later won’t do you any good. It will only crowd your list and add to your perceived workload. If something really needs to be done in a distant future, refer to point 5 of this post.

To-do lists should be used for tasks that can be performed in the short term. If you have a big goal that requires to be done on the long run, split it into small actionable goals that you will do one at the time.

5) Couldn’t you directly allocate a time slot at which you will do that?

A to-do list won’t do you any good if you have no idea of when you will take action. If possible, try scheduling what you want to accomplish at the most adequate time slot. Having a set timetable prevents the temptation to do something else. That approach also allows you to planify things for the longer term, having reminders popping on your calendar only in due time, not clouding your mind with tasks that are irrelevant for the moment.

Scheduling also allows you to be precise. Be honest with the amount of time that something should take you. Do not hesitate to push yourself and set shorter time slots. You will be surprised at how quick you can do things if you have to. As Parkinson’s law puts it “work expands so as to fill the time available for its completion".

When scheduling, take into account the complexity of the task at hand. Boring stuff or things that you can do semi-automatically should rather be placed at the end of your day, when you are running out of decision power and brain energy.

Efficient planning will lead to more productivity.

6) Did you ever think about the fact that a “to-stop-doing list” could be even more beneficial for you?

When you think about it, there is probably even more things that you do although you shouldn’t than things that you don’t do when you should. Writing a “to-stop-doing list” down could be of good use. This list could encompass;

- Stop checking your phone so damn much
- Stop letting incoming mails distract you from your current task
- Stop going on Facebook and get lost in the news feed

You probably get the point. This will spare you a bunch of time and you will feel like you finally will have sufficient time to do the tasks that you really have to do. Nah, let’s get real, you won’t feel that way, but you will surely have more time.

Think and Grow Rich

Think and grow rich is a book published in 1937 by the self-help author Oliver Napoleon Hill (1883-1970). The premise of the book is clear and hammered over and over in the text, it contains the magical secret that, once the reader discovers it, will enable anyone to accumulate humongous sums of money. This blueprint on how to make your wealth grow beyond what you could fantasize before has been put together based on the advices that Hill received from several of the most successful people at the time, such as the behemoth of the steel industry, Andrew Carnegie. The point of the book is that thoughts can be transformed in their physical counterpart. Although this book is oriented toward getting richer money wise, some of those concepts can be used to enrich your personal experience in any other way. Thoughts are basically the seedling of your concrete reality. As long as one places faith and desire in his thoughts, anyone can become wealthy.

Although this is one of the most popular self-help book of all time, it got very polarizing reviews over the years and it appears clear why after only a few pages. Think and grow rich consists of a few key principles that are lost in a sea of woo woo crap and pseudoscience. There is reasons to strongly resent the way the content is presented in the book. Some sentences have 3-5 words in all caps, like, really? This could be independant of what Napoleon Hill wished and got imposed to him by editors, but it’s a disgrace. This makes it look like a e-book that you get for free after giving your e-mail address.

You will find yourself rolling your eyes and skimming through some passages on a regular basis. The chapter on the mystery of sex-transmutation (idea that to be successful you got to canalize and redirect your sexual energy into your work, that the most successful people all have a very big sexual appetite) and on the sixth-sense are possibly the worst piece of literature ever written.

Even the suggestions that still hold true today are impaired by the author pushing it a nudge too far. One can picture the author as one of those motivational speaker gurus acting on stage, rehearsing the same thing over and over in front of a crowd that paid way too much to see that.


Nevertheless still contain some interesting take home message that are worth keeping in mind;


Desire, Faith , Auto-Suggestion & The Subconscious Mind

Hill describes the importance of desire and faith as the “eternal elixir which gives life, power, and action to the impulse of thought”. The first step to riches is to adopt a definite purpose and believe in it until it turns into a burning desire, an obsession even. This will directly influence the subconscious mind, helping thought-energy be turned into material things. Believing in your purpose and the plans that you draw to achieve them is paramount, but believing in yourself is at least as important. The author wrote a self-confidence formula that he asks the reader to read out loud, twice a day. This will force out negative emotions and replenish your mind with positive vibes. It is upon you to decide which emotions constitute the dominating influence of your mind.
positive and negative emotions cannot occupy the mind at the same time,


Imagination, Organized planning and Outwit Indecision

Before taking any action, one has to imagine what he wants from life. This could be a monetary amount or anything else, but Hill points out that you have to inject emotions into what you are picturing. Following that process you will have to write down what you are willing to give to achieve that (time, energy, …) and put down on paper how to intend to go about it.

But “wishes will not bring riches”. The knowledge that you should seek to acquire during your whole life should be used to establish your plan. The decisions that you will have to take during that process must be reached promptly and you should stick to it unless there's clear evidence that it is not the way to go forward. Indecision would crystallize into doubt and lead to fear. Based on the principles that you assimilated your “impulse of thought will be transmuted into its physical counterpart”.

Persistence

Being defeated is most of the time a state of mind, as long as defeat has not been accepted as a reality, you can keep going and move closer and closer to your goal. Obstacles and setbacks can be seen through a different lense and used as stepping stones paving the way to your goal. Don’t follow the majority that uses hard times as alibis.

Power of the master mind

The importance of mentors is also highlighted in the book. “Men take on the nature and the habits and the POWER OF THOUGHT of those with whom they associate in a spirit of sympathy and harmony”. It is honestly quite difficult to disagree on that, as Tim Ferris often puts it “your network is your net worth”. Nevertheless, sometimes you find yourself agreeing with what is written and then the author pushes the envelope. A perfect example of that is when the notion of “invisible counselors” was addressed. Hill advises readers to picture yourself with successful people such as Abraham Lincoln and Thomas Edison having an imaginary meeting discussing the process of making money.

My opinion of the book is clear cut. Think and Grow Rich is not worth the hype that it still gets today, the few good concepts are too diluted into poorly written ridiculous statements. Books either backed by science or that give you a more precise methodology to achieve success have been published since then. If you are a down to earth analytical person, this book is simply not worth your time.

The Demonization of Gluten, Freakonomics Radio, 19/10/2017
(http://freakonomics.com/podcast/demonization-gluten/)


Who doesn’t know someone that is on a gluten free diet? Media are joining forces in an attempt to scare the public from this devil product that gluten is portrayed as. Gluten-free foods are put in evidence in every close to every grocery store. But taking a step back and analyze this frenzy. Is gluten so terrible? In short, it’s not as bad for most of the population as you would think.



Let's start off by defining what gluten really is. Gluten is a composite of the proteins gliadin and glutenin. These proteins are found in the endosperms of some grass-like grains such as wheat, rye, and barley. Gluten make up about 80% of the protein contained in wheat seed.

In this podcast, Steven Dubner and the rest of the Freakonomics crew started by retracing the roots of the discovery that gluten intolerance was a thing. Going back to World War II, the Netherland went through a period called the hunger winter. Arising after a strike by the railway workers organized to support the allies, food replenishment ended up being cut off as a sanction assigned by the german army. This dutch famine was awful, but as a surprising consequence some young patients treated in an pediatric hospital began to recuperate and become more healthy. This was followed by allied planes dropping bread to help the population. But, surprisingly, for children in the hospital that had an improved situation, things got bad again, reverting to their initial stage. Doctors proceeded to investigate what change could be the root of the problem. They realised that the most significant change during that time was the patients diet. The food that was the more severely limited during that time was grains, so practitioners focused their research around that. They did put kids presenting those problems through a gluten free diet and the symptoms disappeared, coming back as soon as gluten was added to the diet again.

Haas, the pediatrician who undertook those trials is credited as being the one linking gluten to a disease discovered long ago by a Greek physician called Aretaeus of Cappadocia, the celiac disease. The etymology of that name informs us on the nature of the problem. From the greek language, it means sickness from the belly (source). Celiac disease symptoms are not limited to the gut but can include anemia, joint pain, skin rash, behavioural changes, infertility or weight loss. This is an autoimmune disease, meaning that the immune system attacks its own tissues. This disease is triggered when genetic predispositions are met with environmental trigger, the gluten in this case. As of today, the diagnostic consists of 6 to 7 weeks of gluten rich diet follow by an endoscopic biopsy. The prevalence is around 1/300 based on current estimations. As opposed to most of the autoimmune diseases, the causative agent of health problems is known and the treatment is clear cut, the elimination of gluten into one's diet. Although this allows the eradication of symptoms in the majority of the cases, make a complete break on foods containing gluten is a significant mental challenge that leads to a drastic change in lifestyle.


In addition, cases of non-celiac gluten sensitivity have been observed. For those people the symptoms are real but are driven by biological mechanisms that remain unknown today. Although this is a real thing, it must be stated that many individuals going on a gluten free diet do not truly have that condition and are doing that without any good reason other than following the trend and listening what celebrities have to say on the matter, disregarding what science shows. Truth is, people often think it’s the right thing to do, they have heard somewhere that it’s healthier but do not dig deeper.

On the show Freakonimics radio takes a bit from this video, which is quite funny but sadly pretty representative of the situation ; YouTube link


The most interesting point presented in that podcast is that when all things considered, a gluten free diet is not synonym with an healthier one. “Gluten free substitute food often have more calories, higher fat content, are low in whole grains [which has been shown to increase risks of heart attacks ] and are low in fiber" (Benjamin Lebwohl)


On top of that, getting on such diet is extremely costly. Gluten free groceries regularly sell for two to four times the price. And, let’s be honest, you should not aim to spend money when there is no necessity at all, quoting the great Woody Allen “Money is better than poverty, if only for financial reasons”, so keep it or use it more wisely.

Cryotherapy impairs knee joint position sense and balance
Surenkok et al., Isokinetics and Exercise Science, 2008

1. Goal

This study was conducted to assess the effect of cryotherapy on knee joint position (JPS) and static balance.


2. Context

Cryotherapy (use of low temperature in medical therapy) is frequently used after sport injuries of all kind. Mostly by applying ice packs directly on the injured zone or cold spray. If the injury is not too severe and once pain level stable and tolerable athletes often get back to their sport practice. However, based on previous studies, it is known that cryotherapy can have a significant impact on processes such as muscle force production or nerve conduction velocity.


3. Hypothesis

Based on the literature available at the time, the authors emitted the hypothesis that the processes negatively affected by cryotherapy could have significant consequences on JPS, static balance and pain threshold, leading to increased risks of reinjury.


4. Material and methods

The study was performed in a laboratory in a controlled environment on 15 healthy basketball players. Each subject had to go through several sets of three test before and after cryotherapy;

1-legged balance test:



using a machine composed of a moving platform supported on its center by a pivot. The platform is tilting when the subject is losing his balance. The score is the total movement of the platform compared to a reference point. The higher the score, the worst the balance capability. Subjects had to stand 30 second one their dominant leg looking straight ahead of them.


Sense of joint position (JPS) was measured using an isokinetic dynamometer:

Illustrative youtube video

With the subject sitting with his legs at a 90° angle, the machine extended the knee at a constant speed and the subject had to press a button when he felt his knee reached a 45° angle. The same process was used from complete extension to flexion. The score was calculated as a deviation from the optimal degree of 45°. The farther it is from 45, the worst the knee JPS is. To cut out the visual and cutaneous outputs in an attempt to focus on joint position perception the subjects were blindfolded and their leg were wrapped in a pneumatic boot.

Pressure pain measurements using a pressure algometer;
Illustrative youtube video

Pain detection thresholds were determined by applying constantly increasing pressure on the surface of the knee. When the subject indicated that the pressure became painful the test immediately stopped.


5. Data analysis

Pre- and post-exercise values were compared to determine if there was a statistically significant difference. Statistically significant doesn’t mean big difference! It means that the probability that we observe a difference between two group that we compare is due to chance is small. With a big enough sample size (amount of data compared) one can obtain a statistically significant difference even if the absolute difference is <1%. The degree of confidence at which two means are statistically significantly different is represented by the p-value. The lower the p-value, the smaller the chances are that those differences are due to pure randomness. The p-value depend on the mean of the group, the standard-deviation (how much each data differ from the mean) and the sample size. The threshold commonly used is a p-value smaller than 0.05, which indicates that there is less than 5% chance that the difference observed is due to stochasticity. But it is in any case just a statistic, nothing is ever 100% certain. The statistical test used for the analysis is a student test (t-test) for paired samples. This test is universally used to compare two data groups following a normal distribution (more data are close to the medium and less are extreme values).


6. Results

After both cold pack or cold spray application the knee JPS was significantly negatively affected from flexion to extension and from extension to flexion.
However, only after applying a cold pack and not a cold spray was the one-leg static balance was significantly negatively affected. Subjects had more difficulties maintaining their balance, resulting in a higher mean value. The researchers went on and repeated the 1-leg balance test 5 minutes after the cryotherapy application and after that time delay no significant differences were observed compared to pretreatment values.


7. Key points highlighted in the discussion

- The physiological processes leading to an impairment of knee JPS could not be established with the protocols performed during that study. Is it only superficial receptors that were touched or were deeper structures also affected. Without taking temperature measurements it is not possible to draw conclusions.

- One-leg static balance was not affected by the cold spray, which could be due to the fact that it’s more superficial and evaporates quickly.

- These results taken together may indicate a disruption of neuromuscular control mechanisms.

- However, when repeating the test after 5 minutes, the score reverse to initial values. That result may be due to superficial receptor feedback returning to normal level.

The takeaway from that paper is that, even if there is not enough good measurements and data to have definitive conclusions, it is better to be on the cautious side and wait at least 5 minutes before sending an athlete back to physical activities.


8. Limitation of the study explicitly expressed by the authors

Every subject had healthy knees. In case of injury, the process of inflammation kicks off right away and could influence the effect and outcome of a cryotherapy. In a real life situation where cold is applied it is not guaranteed that the obtained results would be replicated.
No temperature change was measured. Neither the skin or deeper tissues. The authors do not have any information on how much the cold lowered the temperature and how deep the effect could be observed. Application of cold was limited to a specific duration and not a variation of temperature. It well may be that duration is the most important factor but that needs to be further determined.
Although the p-value for significant differences were clear cut, the sample size remains small and one should be careful when inferring and drawing conclusions from the data set.
No mention of what could be done as follow-up experiments, no direction on where the research should go and how it should proceed.


9. Critics

- Yes the p-value indicate a significant statistic difference but to absolute difference between the means remains extremely small. It should be a matter of honesty to comment on the magnitude of the effect observed.

- The authors briefly comment about the values of 1-leg static balance test being higher after cold spray application but the p-value being above the significativity threshold. This boils down to commenting on a pseudo-tendency that could be due to stochasticity and not a real effect.

- The description of the methods use lack several key components and do a poor job describing exactly how they implemented their protocols. One of several example is that for the pain threshold tests they took measurements at two different spots but don’t they were, or if there was a difference.

- The biggest malpractice is to reference that pain threshold is significantly different before and after cryotherapy, but putting no numeric values showing that it’s indeed the case in the text nor in the tables.


All in all it is a very descriptive paper, without mechanistic explanations. Although it could have been formulated more clearly and rigorously, experiments like that are interesting gateways to decide in which area the following studies should focus.

The Kevin Rose Show: Bitcoin true potential, with Andreas M. Antonopoulos
Link to podcast

The future is already here — it's just not very evenly distributed
William Gibson


Introduction of the intervenant

From his website:
Andreas M. Antonopoulos (https://antonopoulos.com/) is a technologist and serial entrepreneur who has become one of the most well-known and well-respected figures in bitcoin. He is the author of three books: “Mastering Bitcoin”, published by O’Reilly Media and considered the best technical guide to bitcoin and “The Internet of Money”, volumes 1 & 2 a collection of talks about why bitcoin matters.
As an engaging public speaker, teacher and writer, Andreas makes complex subjects accessible and easy to understand. As an advisor, he helps startups recognize, evaluate, and navigate security and business risks. Andreas was also one of the first to use the phrase “The Internet of Money”, as early as 2013, to describe bitcoin as part of his speaking business.
As a bitcoin entrepreneur, Andreas has founded a number of bitcoin businesses and launched several community open-source projects. He is a widely published author of articles and blog posts on bitcoin, is a permanent host on the popular Let’s Talk Bitcoin Podcast, and a frequent speaker at technology and security conferences worldwide.
Andreas offers strategic consulting to a small number of crypto-currency companies that are aligned with his interests. He also offers expert witness testimony as an expert in the security, technical details and use of crypto-currencies, worldwide.

This video is a nice introduction to Bitcoin, however it is presented in its ideal form which has not been reached yet
Youtube link

Introduction on bitcoin and cryptocurrency. Possible paradigm shift?

Disclaimers

Nothing written in that post is investment advice. Bitcoin is an amazing technology, however it is more flawed than the ideal situation portrayed by Andreas Antonopoulos in this podcast. For the moment there are serious limit of real world use. With the hype the system is currently saturated. Transaction are back loaded and fees are getting higher and higher making it less attractive for businesses to implement as a mode of payment. With a growing interest and being intensively covered in the media the price action of Bitcoin is hectic. The ideal would be that Bitcoin volatility and velocity gets to points of mainstream currency. It has to be low enough. This requisite is not limited to Bitcoin. In countries where the currency is very weak they often price in USD. Low volatility: a few percentage points up and down every year. Currently it is best described as a store of value, being regularly qualified as digital gold. An aspect not treated in that podcast but that is of real interest and worth taking the time to understand.

Bitcoin is not yet fully decentralized because mining takes a lot of computing and electrical power. Which, by extension, costs a lot of money. Those constraints gave raise to mining businesses, mainly based in China, that are pooling all the hardware required together to mine Bitcoins. Although no mining entity has close to 51% of the mining network, a few key mining players colluding is not an impossible scenario. Proof of work, the system allowing a miner to vote in the blockchain evolution and validate the blockchain transaction log, in its current form is not ideal for complete decentralization. Alternative solutions are currently researched and tried but reaching a gold standard is far stretched based on the current situation.

It is also worth noting that although Bitcoin is the most well known and the granddaddy of them all, it is not the only cryptocurrency. There are different developers teams, taking different approaches, road maps and end goals, working on project generally called “altcoins”. There are tons of them, the vast majority are surfing on the hype wave are utter crap but it is worth taking a look and spot projects that have a lot of potential and plan to use the blockchain technology in an innovative and efficient manner.


For Andreas Antonopoulos, Bitcoin strength is its ability to allow people to implement trust as an internet protocol. Anyone can do trusted transactions with people they don’t trust. No need of trust in a third party, often motivated by something that is not your freedom, self-expression, or things that you care about.

To fully grasp the potential breakthroughs that cryptocurrencies offer and the real world problems that it could solve, it is important to take a step back and look at the big picture. When living in the western world, one doesn’t realize that a lot of people are still unbanked or can’t manage their money as they wish due to outrageous state regulation or down right dictatorship.

The case for decentralization

In his plea for decentralization, Antonopoulos leads with an interesting point that for centuries church and state were operating really closely together if not by the same people.

It’s now fairly clear to the people that church and state should be separated. When together they corrupt each other, they get perverted. How about separation of state and money? Because for similar reason, money should not be used as a tool for exercising power. Or at least should follow neutral rules that don’t follow politics. Money should purely serve the role of commerce and now surveillance and control.

He then went on and illustrated how financial service provider are often using money as a system of law enforcement. States are able to put direct pressure on citizens with a looming threat of freezing their account if they do not behave as expected. One well known example is the financial blockade that was imposed by the US government on Wikileaks that was denied access to traditional financial system without due trial. An important point worth flagging is the fact that when an individual trust a financial institution, like Paypal for example, he is not only trusting this service but also all the authorities that can put pressure on this platform.

In addition, a centralized financial service can potentially be subject to drastic regulation changes, go bankrupt or even get hacked and stolen from. With a decentralized cryptocurrency like Bitcoin, a whole country could hypothetically be taken out of the grid and the system would still work.

Bitcoin is decentralized in its ideal form. Its controlled by a balance between participation and competition.

The system rewards miners that play by the rules. Those that do not play by the rule loose the investment that they made in security (i.e. the money they had to put down for power and hardware allowing to mine). Tens of thousands of people are doing that in parallel, verifying all the transactions. In an ideal decentralized network everybody can look at what transactions have been registered on the blockchain and provide computing power to help the verification process.

Regarding transaction speed

The major knock against Bitcoin preventing a mass adoption is the amount of transactions that the network can process in a given amount of time. Visa is currently 5 orders of magnitude faster. But Andreas Antonopoulos points out that with traditional debit/credit card the clearing speed is close to 30 days, meaning that a merchant will receive his money much later than with a cryptocurrency payment.

In any case, a lot of cryptocurrency projects are working on solutions to increase the efficiency of the blockchain and allow more transactions per second while keeping a decentralized network. Improvement ideas include side chains, additional layers and lightning network. The technicality of each proposition is not treated in the podcast but the main idea is to find safe and efficient ways to resolve transactions without having to send every single one on the blockchain. Here is a direct quote from the podcast;

Not all those transactions are recorded on the blockchain. What happens is that you have a trust platform underpinning the network which allows to resolve disputes. If you do a contract with someone, you don’t expect to take it to court in most of the cases. In case of a dispute you take that partial transaction to the Bitcoin network and he resolves it as a neutral mathematical judge and resolve it in favor of the people that didn’t cheat.

Productivity boosting

Get rid of time losers


In the age of constant connectivity, temptations to continually check your devices are manifold. This include refreshing your facebook feed, looking at what someone recently posted on instagram, checking for new emails or texts. What can appear as taking small breaks here and there is in fact more time consuming and can amount to serious lost time, preventing you to go forward and accomplish big things. You have to also consider the time that is required for you to get back in the flow. Concretely, realising that there is an opportunity cost associated to every single time your attention drift to something meaningless is paramount. Is giving up productivity time for quasi-constant connection worth the price?

Concretely, what is causing you to give in to those distractions? This desire is often rooted deeper than it appears. This process most of the time goes beyond fighting boredom. You could be looking for validation or be afraid of missing out. At that point, checking your emails, instant messages or social networks can be equated to a form of addiction. Seeking that excitement boost that you get from a notification, a response, or someone showing interest in what you just posted. You keep coming back to it hoping that something will be there for you to be excited, even if in most cases there is nothing.

In any case, this is a perfect occasion to pause and realize that what you are doing mechanically is not a necessity. Take full control of those opportunities to do something fun and purposeful.


Gift you some unplugged time

Although commitment and self-control can be developed and improved with diligent practice, trying to resist a temptation that is so convenient to access will cost you a lot of mental energy. Removing the possibility to be distracted altogether will help your mind get over it since it doesn’t have to constantly battle the possibility to give in. For your personal computer, there are numerous softwares designed to help your control your browsing habits. Some offer a very diverse set of features (goal setting, activity reports, …) whereas others allow you to block or limit the daily time allowed on specific websites giving you the option to modulate your web browsing experience to increase your productivity. Take a look at the options available and determine what would suite your aspirations better. Leechblock (https://addons.mozilla.org/en-US/fir...don/leechblock) for Mozilla users or Stayfocusd (https://chrome.google.com/webstore/d...lahlfoji?hl=fr) for Google Chrome users are free options that should be sufficient to crack down on your tendency to get lost on social media or other websites. After being configured, those plugins will display a message on your screen indicating you that you blocked this website or that you reached the daily duration that you set.

Same goes for your phone. If you keep it in your pocket after commiting to look at it only once per hour, you’ll probably spend your energy for self-talk motivating you not to take a sneak peek. To reduce that temptation, simply put your phone away. Even if it’s in a drawer near you, the process to go and get it can be sufficient to take a step back and wonder if you really have to check it. You won’t maximize your productivity by communicating non stop with people, like e-mails, bunch that up.

“The heroes of the next generation will be those who can calm the buzzing and jigging of outside distractions long enough to listen to the sound of their own heart, those who will follow their own path until they know how to walk erect.” From James Victore


The downsides of constant connection

Being constantly connected can be perceived by your brain as a deluge of information that, if kept uncontrolled, will reduce your mind capability dedicated to thinking to critically low levels. You are constantly assailed by your devices, reminding you of what you still have to do or bombarding you with a flow of information about what has happened recently, disregarding what your fundamental interests are. The design of those media or devices is so made that it prevents you to tune in the moment.

The importance of unplugged, non-stimulated windows in your daily schedule should be emphasized. It effectively creates an environment that allows you to follow your thoughts and explore the possibilities that your mind is able to come up with. Weather if it is a new approach to the way you work, an idea that will improve your lifestyle, a revelation that could transform your business, the list of possibilities is endless. Once the seed of a creative idea or purposeful thought is planted it requires quiet and disconnected time. It can be boosted if you embrace the great surprises that serendipity can provide. Being on autopilot and acting like a zombie do not set you up to explore the potential of your own mind. Not to mention the sentiment of well being that will increase.

Taking your distance from the constant storm and tune in the moment can put you at a distinct advantage compared to the horde of people that cannot unplug even for an instant. It allows you to think in general terms, not narrowing your field of view, explore the possibilities that you can take advantage of.

The importance of unplugged time to foster creativity is well illustrated when thinking about this process as a network. As eloquently described by Steven Johnson in his book Where Good Ideas Come From: The Natural History of Innovation;

“A specific constellation of neurons -thousands of them- fire in sync with each other for the first time in your brain, and an idea pops into your consciousness. A new idea is a network of cells exploring the adjacent possible of connections that they can make in your mind.”

The Mental Game of Baseball, A Guide to Peak Performance is presented as a written display of the skills required to elevate your game to new heights. The book consists of a blend of applied psychology, anecdotes and insight from major and minor league players that realised the importance of a strong mental game. It arised from a collaboration between H. A. Dorfman, who was a recognized sport psychologist, author of several other books on the subject and Karl Kuehl, a former baseball scout, coach and manager.
Although the book puts a clear focus on baseball, most of the concepts can be generalized to other sports or activities in life. This book report is aiming to highlight the big lessons and ideas presented throughout the text.

The importance of a strong mental game

You, as many athletes or other high performers, probably often put more mind energy into trying to control external factors, which you can’t, and neglect internal control, which can be influenced constantly. Not only it’s a big misuse of energy and time, but, as a physical act stems from a thought, it can impede your physical performance.
You can easily get overwhelmed by your thoughts and literally be controlled by them. A strong mental game will allow you to retake control of those thoughts. By expanding your mental toolbox you can control your reaction to adversity, the effect it has on you, and the way you go about solving problems you are facing. Investing time to work and reflect on it can be a difference maker and put you ahead of the competition.

Dedication to work on it and get better at it

Dealing with the mind is much less straightforward than dealing with muscles. It takes considerable time and effort. Wishing will get you nowhere, you must take action. Wanting without working is a sure recipe for failure. Using the advices highlighted in this book report, schedule time for thinking about the state of your mental game. Take time to regularly review the effort you are putting in and the way it affect your thinking process during a physical performance. Be ready to recognize your flaws. Be honest, you have to hold yourself accountable, if you do it for someone else you won’t put as much energy as you could. Excuse making is just trying to be less accountable for your effort.
“Dedication and commitment are common values and uncommon practices”, say the authors.

Set goals for yourself

The authors emphasize the importance of setting well calibrated goals for yourself. When too easy to attain goals are likely to make an athlete underprepared whereas goals that are unattainable will lead to a feeling of dissatisfaction even in case of good performances. Efficient goals are used a the base for good planning of an athlete preparation. Looking for perfection will only create discomfort and tense you up.

Once the path is set up, follow it

Don’t let anything or anyone distract you from your process. Emotional swings should not impact the way you approach things. By establishing a clear plan during training or in a competition setting, you will prime your mind to be watchful for relevant cues, which will equate to an elevated level of concentration, without additional mental effort on the moment. You’ll find yourself in a zone of complete focus that is effortless.

“No one can make us feel as if we’re failures without our consent. Confident people never consent”.

Cultivate a proper mindset

Just like you make adjustments on your way of playing the sport itself, you can adjust your mindset and your approach. Effective thinking will get you a long way.

Control fear:
Nobody can prevent fear, but you can learn to cope with it or overcome it. If you do not look fear in the eyes directly, and let it control you, it can jeopardize all the work that you put prior. In the book, fire is used as an allegory for fear. If contained, it can be used to cook you a meal, but if you let it get the better of you it can burn your house down. The author later personify fear and describe it as a monster and a liar. If you listen to fear you will be deceived and you will perceive situations as harder to handle as they truly are. If you let enough leeway to fear, it will crush you under the impression that you are not capable to overcome adversity. But a good mental game can turn fear into your advantage, making you more alert, or, at the very least, be ignore and starve it.

The importance of living in the present moment

Allocating mental energy to ruminate the past or be concerned with the future won’t do you any good. Being distracted from the present will cause prejudice as it is the only time you can act on. Reflecting on past performances or future possible outcomes will only impede the work you did put to prepare.

“The successes we achieved in our past are more real than the failure we fear in our future.”

If you feel the pressure rising do not hesitate to grant yourself a moment to quiet down. Do it by focusing on your slow and controlled breathing, being mindful. When the breath is the center of your focus, the cause of the tension won’t have a place at the front of your mind anymore.
The exception to project yourself in the future is if you are visualizing yourself doing something correctly, do it with as much details as you manage. This will prime your body, from the nervous system to the muscles, to react as he is supposed to when in said situation. It is paramount to avoid visualizing things the way you do not want them to happen. A negative belief will turn into a self-fulfilling prophecy, predicting a failure will lead you to fail.

Discard external pressures

It’s hard to know how to please some people. It’s easy to know it’s impossible to please them all. But it’s essential to know the attempt should not be made.

You’ll put enough on by yourself. In the book, the mind is described in several occasions as a fortress. Letting external pressure in is like an enemy penetrating the walls of your fortress.


It’s on you to adapt

The legendary basketball coach John Wooden said, “Failure is not failure, unless it’s failure to change”. Although often scary, the prospect of change should be welcomed. This does not mean that you should try everything as soon as someone mentions it, but that you should be open to opportunities to improve, be willing to risk doing things wrong at first to find out how to do them correctly. Failures, just as successes, should be seen as opportunities to get better, and never as excuses to stay stuck. When you fail, and you will, use it as a motivation and remember that, as Dorfman and Kuehl puts it eloquently, “Failure reflects on the performance, not the performer”.

Should you read this book?

This book is a few very good advices lost in anecdotes from back in the days. Although easy to read and warmly written, it only touches the surface of the psychological elements involved and lacks actionable advices on how to work on the mental game. The target audience is mostly fans that would like to think what players experience in their mind at certain period of their careers and not avid learners that want to improve in that area. Since the book has been published, research in the field has experienced tremendous progress and books based on more up-to-date understanding of the mind-performance should be of better use for you.

Antivirulence drugs, a new paradigm?

Resistance to antibiotics, defined as the recovery of population growth after exposure to antibiotics, is spreading fast and finding new antibiotic compounds becomes harder and harder. Plus, those molecules have a clinical lifespan relatively short. All in all, although necessary, this research costs a lot and is always trailing behind the adaptive capabilities of bacteria. If the scientific community does not put effort into alternative solutions we are risking losing the arms race (for more, see reference 1).
Research in the field has been looking for new approaches to tackle the pending disaster. In their paper “Targeting virulence: a new paradigm for antimicrobial therapy”, published in the journal Nature in 2007, Clatworthy and colleagues put forward the possibility to design drugs aiming to disarm the targeted pathogen. Instead of directly killing the pathogen or cut its growing and dividing pathways like traditional antibiotics do, the concept consists of targeting virulence factors produced to facilitate the establishment of the infection and the following diseases.

In this article, discover why this alternative approach is full of promise and could play a major role in pathogen treatment going forward.

The constant arms race

Antibiotic resistance is a naturally and randomly occurring process. The is due to a single or a combination of random mutations in the genome of the pathogen, decreasing its sensitivity to a specific antibiotic or making it completely resistant. This can be achieved by numerous mechanisms, such as modification of the target of the antibiotic, antibiotic being pumped out, or production of inactivating enzymes (ref. 2). The short generation time of bacteria (time needed between each divisions) implicate that the chance of a slight mistake in the genetical code transmitted to the next generation is likely to happen.

Without increasing the mutation rate, traditional antibiotics apply a strong selective pressure by direct killing or preventing the targeted pathogen to divide. This grants a higher fitness to the subpopulation with an advantageous mutation. This fitness superiority leads to outperformance of resistant population in presence of antibiotic, outnumbering and replacing the initial population.

Antivirulence drug, a definition

A pathogen is considered virulent when he is able to cause a disease. To establish an infection, the pathogen is producing what is called virulence factors. Those factors present wide ranging characteristics but are ultimately designed to cause damage in the host or help the infection process. Inhibiting those virulence factors would “disarm” the pathogen (ref. 3) and either give a window of opportunity for the immune system to overcome the infection or have a synergistic effect with traditional antibiotics to fight an infection. This is what antivirulence drug are geared to do. Unlike conventional antibiotics, the viability of the pathogen is not the direct target of the therapy. It’s factors essential for the infection that are taken away by such drugs.

Although not completely “evolution-proof” as presented in some papers, you will see those drugs definitely do have strong arguments in their favor (ref 4).

A case for an antivirulence approach

Our current practice of antibiotic discovery and usage is not sustainable. Although significantly different from the traditional approach, targeting virulence factors have distinct advantages. This expands the repertoire of possible targets, giving the research field more tools to not get behind in the arms race. The biggest upside being that they lead to less drug resistance. Indeed, most of the research done in the antibiotic field aims at discovering or designing new or better compounds that have the ability to kill bacteria or prevent them to grow further. Those antibiotics are called bactericidal or bacteriostatic, respectively. This can be achieved by inhibiting bacterial function essential for growth in living organisms (in vivo). Those functions include replication of the genetic material, synthesis of proteins, or cell wall production. But this imply that commensal bacteria (defined as having no negative impact on the carrier health) can also be impacted.
As opposed to traditional antibiotics, antivirulence drugs offer the possibility to target bacterial viability in specific conditions, like the environment that a bacteria is facing in vivo, meaning in the host. And by targeting virulence factors specifically commensal bacteria will be spared, preserving the host endogenous microbiome.

Table 1: non-exhaustive list of strategies
Inhibition of toxin function:

• Masking the active
  Prevent oligomerization
  Block the downstream effects

Targeting bacterial toxin delivery:

• Prevent binding
  Inhibit bacterial secretion system

Targeting the regulation of virulence expression:

• Could prevent toxin formation altogether or reduce it by targeting regulatory steps
• Can target transcriptional regulators directly

By aiding clearance, it implies that anti-virulence drugs are detrimental to the pathogen in that specific environment, the fitness is negatively impacted, putting selective pressure for resistance. Although sometimes presented as “evolution proof”, antivirulence drug apparition can happen. Pathogens resistant to anti-virulence drugs have been isolated in the clinic or observed in laboratories (modification of target, …). However, this doesn’t mean that using that approach has no interest, what matters is: can and will this resistance spread efficiently throughout the bacterial population and create public health problems?

Granted that mechanisms of resistance exists, the mode of action of antivirulence drugs has a significant positive aspect as the selection pressure is limited to where the virulence factor are produced, i.e. the infection site. This trait will not be selected in commensal populations, often colonizing the skin or the nose. Drugs with such environmental specificity can be classified the same way as narrow-spectrum antibiotics. This is not only specie specific but also population specific. By restricting the population, the evolution of resistance will be slowed due to smaller number of bacteria (and thus smaller the mutational supply) negatively affected by the drug. The narrower and the better targeted the drug is, the slowest a resistance will be selected and spreaded.

Real life examples

One example is furanone inhibitors, that modulates the quorum sensing of bacteria such as Pseudomonas aeruginosa or Streptococcus mutans (ref. 5). Quorum sensing is a form a bacterial communication regulating processes, such as biofilm formation (agglomerate of microorganisms in a complex sugar matrix for protection) or virulence factor expression. When the bacterial population of bacteria reaches a threshold, they down regulate their toxin production. Drugs that can influence the quorum sensing cascade can trick the regulatory system, reduce biofilm formation and increase immune and antibiotic-associated clearance.
Another example of such antivirulence drug preventing virulence factor production: Staphylococcus aureus protects itself from host defense by inhibiting reactive chemical species by producing a golden pigment. The drug, called phosphonosulphonates, is able to prevent the synthesis of this pigment by inhibiting a necessary enzyme (ref. 6). Thus, the drug has no direct bactericidal effect, but is rendering the bug sensitive to the host natural defenses.

We can even imagine a scenario where production of a virulence factor would be counter selected when in presence of antivirulence drug. Toxin production is a significant energy expenditure burden for a bacteria. In presence of drug inhibiting the given toxin the toxin is rendered functionless and is only imposing metabolic cost. This present a net disadvantage compared to bacteria that lost the virulence factor. In such case toxin-negative strains will be positively selected.
Published scientific data illustrating this possibility is scarce, but a study (ref. 7) elegantly showed that a toxin-positive strain of Corynebacterium diphtheriae returned to a commensal state after targeting its high metabolic costs toxin with an antitoxin vaccine. However, observing such lasting avirulence is quite rare as evolution can allow to overcome this disadvantage and giving the advantage back to toxin producing bacteria. A straightforward way to deal with such drug the pathogen could overexpress the toxin, overwhelming the drug due to number of toxins.

Outlook, what’s still to come?

The need for further development notwithstanding, antivirulence drugs appear to be destined for a bright future. Weather used as stand alones or administered in conjunction with traditional antibiotics, an alternative approach to fight pathogen infections will extend the human armurerie, which is desperately needed.
Antivirulence drugs can be individualized and tailored for a target pathogen, but doing so requires a solid fundamental understanding of what we are facing. The narrower the spectrum, the smaller the risk of resistance dissemination. This means that research aiming at the understanding of those pathogens is crucial and should be encouraged accordingly.


Ref. 1: (Coates, A. R. M., Halls, G. & Hu, Y. Novel classes of antibiotics or more of the same? Br. J. Pharmacol. 163, 184–194 (2011)
Ref. 2: Davies, J. & Davies, D. Origins and evolution of antibiotic resistance. Microbiol. Mol. Biol. Rev. 74, 417–433 (2010)
Ref. 3: (Clatworthy, A. E., Pierson, E. & Hung, D. T. Targeting virulence: a new paradigm for antimicrobial therapy. Nature Chem. Biol. 3, 541–548 (2007)
Ref. 4:From Targeting virulence: can we make evolution-proof drugs?, Allen et al., Nature Reviews Microbiology 2014
Ref. 5: (Liu, C.-I. et al. A cholesterol biosynthesis inhibitor blocks Staphylococcus aureus virulence. Science 319, 1391–1394 (2008)
Ref. 6: Use of the quorum sensing inhibitor furanone C-30 to interfere with biofilm formation by Streptococcus mutans and its luxS mutant strain
Ref. 7: Pappenheimer, A. in Bacterial Vaccines (Ed. Germanier, R.) 1–36 (Academic Press, 1984