OMG. I'm a physician who has been deep in the keto space and all this tip toeing around LDL "might" not be dangerous just drives me crazy. LDL (which is not a "cholesterol", it is a cholesterol carrier) does NOT cause heart disease. People get confused because there is too much poor terminology of what is actually happening and if things were made more clear, everyone's understanding would be more clear. The arterial plaque is not due to an abundance of LDL, it is essentially a scab (unlike on the skin where a scab is a collection of blood cells, in the arterial wall it is a collection of cholesterol and other healing products). The scab forms because the arterial wall is damaged by turbulent blood flow which occurs at SPECIFIC REGIONS of the artery where it divides (bifurcates). Turbulent blood flow occurs when there is high blood pressure (hypertension). If the plaques/scabs were due to high LDL, as the old school, pharmaceutical driven science would have you believe, then there would be a diffuse layer of plaque/scab along the entire arterial AND venous blood vessel walls. The role of LDL is to deliver the cholesterol to the damaged arterial wall to create the scab. Stable hard scabs do not lead to heart attacks. However, if the LDL gets damaged by blood sugar (glycation) or seed oils (oxidation), then it converts to a small particle density LDL (sdLDL) and THAT LDL can get caught in the arterial wall and create a pustule (soft plaque). So pustules can form by hard plaques. If the pustule wall ruptures (ie. increased blood turbulence opens up the pustule wall) then the open pustule will cause mass clotting (thrombus). The mass clotting blocks the arterial blood flow to the heart, which leads to the heart attack (myocardial infarction) or blocks blood flow to the brain which leads to a stroke (cerebrovascular accident). Therefore, the hard plaque is associated with heart attacks because it will occur by soft plaques. Therefore, the main reason for heart disease (atherosclerosis) is not LDL (that's like blaming the house fire on the fire truck), it is high blood pressure. So what causes high blood pressure? Damage to the lining of the arterial wall (the glycocalyx). When the glycocalyx is damaged, nitric oxide cannot be released to relax the blood vessel walls and allow expansion to accommodate the blood flow. Eventually the blood vessels can stiffen. This leads to increased resistance in the vascular system which causes increased blood pressure. So what damages the glycocalyx? Most commonly, high blood sugar. So high blood sugar damages the blood vessel wall, leading to hypertension, and damages the LDL cholesterol carrier, leading to the dangerous soft plaque. And for every 4 grams of carbohydrate, the body can convert it to 1 teaspoon of sugar. The Standard American Diet has over 460 grams of carb per day (115 teaspoons of sugar per day!) while a keto diet is typically less than 10 teaspoons of sugar (or zero if your carnivore). At this point it should be clear as to how you should eat. By the way, most studies show that statins INCREASE sdLDL. Congratulations on the documentary! I look forward to it.
So your hypothesis is that high LDL is only a risk for atherosclerosis if it is coupled with high blood pressure? So if a patient came to you with high LDL levels and they were also on medication for another condition which increased blood pressure as a side effect would you say they were at a higher relative risk for CVD? And would you give advice to lower LDL via diet or medication in that case? I am on board with your point that high ldl is not sufficient as an independent factor but is necessary for CVD. Thus, necessary but not sufficient in this context is likely a correct statement. In your analogy, if there are lots of fires going on, reducing the amount of wood would limit the fire being so big it leads to events or mortality.
Me too I feel a little bit irritated by them still being afraid of the high LDL in LMHRs. I have read Dr Malcolm Kendrick's book "The Clot Thickens". LDL and cholesterol do not cause any disease!
@@michaellewis7087 He's saying that high blood pressure and consuming too much sugar and seed oils are risk factors, not high ldl-cholesterol. Cholesterol is mostly manufactured by the body because it is essential for every cell and hormones and will be naturally raised or lowered as the many millions of evolution have dictated.
LMHR getting life insurance, result is a type C rate because of the high LDL (202), despite the high HDL (132), low Triglycerides (57), A1C 5.1, all other markers normal and ideal😢. I hope one day this can be widely accepted so that we are treated the way we should be.
My cap is off to Dave... He came into a field of work he has ~zero formal training in, and *kicked the butt, sank the boats, of the leading so-called-experts, proving them wrong to a high degree, if not totally wrong and short sided in their ways of performing their very own chosen profession .* -- After working in the high tech field of software development for ~15 yrs, these engineers, managers, software developers and testers, these people in most cases were of high intelligence and overall potential. Dave is very good example of this intelligence. My cap is off to him.
I would like to see the science behind this. Keto only made me sick and raised my cholesterol to 240. It didn't work for me. I found that the Mediterranean diet is best.
@@bethd5049 We're all different. There never was and there never will be "the perfect diet for EVERY human"...(as some highly persuasive, charismatic RUclipsrs would have us believe!)
I eat a keto diet, walk a lot, eat low processed diet, yoga, weight lift, meditate, and manage my type 1 diabetes well. 0 cac score. but that LDL freaks out my pcm. My endo doesn't bat an eye because trig/hdl is excellent as well as with my lifestyle being anti inflammatory. I will recommend this documentary next pcm visit.
I'm still not sure if the term "Lean Mass Hyper-responder" refers exclusively to those individuals who choose to adopt a low-carb ketogenic diet, or whether it can also apply to others (eg Omnivores) who happen to be lean, with high LDL, high HDL and low Triglycerides. Please clarify...because I think there is some general confusion about this. And many thanks for your continuing brilliant work.
Good question. The term arose mostly from those following a ketogenic diet because part of the proposed mechanism for elevated LDL is the need for greater triglyceride/fatty acid delivery as an energy source. But even if the mechanism is different, the same concept could apply to someone who is truly metabolically healthy and not on a keto diet, although that hasn't been studied as of yet.
@@metabolicmind I noticed that people with MODY look like LMHRs: higher glycemia, lower ketones, lean. Have you looked into this? I wonder if LMHRs have low insulin production like MODY or maybe do have the MODY gene modification?
It is worth noting that when these LMHR ‘s are given 50-100 gm carbs they no longer have high LDL. So if you have high LDL while consuming significant carbs then I’d think something else is going on and you are not a LMHR. It is keto specific because of this as I understand it. But who knows really? 🤷♂️
Luckily here in France (and all Europe I think) insurance companies are not allowed to see our medical files. So no problem being LMHR with HDL 85 , LDL 350, TG 60. I am not worried. I believe dr Malcolm Kendrick's theory about LDL and cholesterol not causing any disease.
I'm afraid to tell you that LDL has shown causality for atherosclerosis since the 2017 with one of the biggest meta analysis in cardiology. There is no question already. LMHR only applies to a very low subset of extremely lean people on very deep ketosis. And we do not know the long term effects of this. It will take decades to know that
I think I might be one of these people. I am 68 years old, 5'6", 125 pounds. I am totally metabolically healthy - high HDL, low triglycerides, but high LDL ( for which I finally went on statins about 2 years ago). I recently had an A1C test show a level of 6.1, prediabetic. This was a shock to me, because I thought I was eating a very healthful vegetarian diet. Now, with my CGM informing me, I have gone low carb - less than 100 grams per day. I feel great, and it remains to be seen what has happened with my numbers. I am really looking forward to the documentary and hope doctors will become familiar with LMHRs and find out whether our high LDL actually harms us.
Ehm ... vegetarian is very unhealthy and has many carbs. We were misled about it. I recently predicted to my husband that there will be so many diabetics that ate vegetarian for many years.
I am LMHR and my LDL 335 is causing my PCP to go crazy. He’s referred me to a cardiologist and he is freaking out too. I’m holding strong, but they want me on statins badly.
Ask them to show you the random study that makes them react that way. Or any study, that has a statically significate absolute level of risk. Neither of those things exist. Then ask them why they are so concerned. Their concern is based on nothing but belief. In fact, Dr Hampton recently posted a video about a study that shows higher ldl is actually protective of stroke, CVD, and atherosclerosis. He doesn't mention it, but it's the RCT that he mentions.
yes same here , both sides family seem to hive high LDL but live forever. Mine is high, i went on statins for two weeks, felt as sick as a dog, went off them and will stick with my research and family history.
@@pabeader1941this is false. I can give you a huge meta analysis thst shows LDL prove causality for atherosclerosis. Wich analyzed countless amount of research to conclude if it causes it or not. You have not opened the medical literature in cardiology once if you truly believe this
I've been dealing with hyperlipidemia all my adult life with a high LP a, my tri and high are within range but my LDL is 196, I don't care! a CAC showed 0 atherosclerosis! I eat low carb for the most part and walked several miles every week.. I was on a high therapy statin for 10 years for nothing! Nothing but pain and memory loss.. I'm 56 yrs old and 132 lbs and metabolically healthy❤
I'm in the same boat re reluctance to start prescribed Statins for high LDL. But do you think there may be a psychosomatic factor to this for some people? ie those like myself who have already "read up" about the possible side effects, then start taking the drug and attribute symptoms to the "feared" medication? Likewise (when they stop taking it) the same in reverse?
Can't wait for the movie. You have to go straight to the people because the cholesterol establishment is "aggressively disinterested" in the lean mass hyper-responder phenomenon.
My calcium score is zero not my doctor prescribed resuvistatin!? It made my toes and fingers numb and tingly so I stopped taking it. My doctor is clueless and prescribed another statin? Is there a risk? Should I try the new statin or be confident in my calcium score? Opinion please.
A positive calcium score means an end stage atherosclerosis diagnosis. Its basically if you have cancer. A positive CAC score it's thst it's already reaching metastasis. Soft plaque it's the issue and does not show in a CAC score. CAC shows when you are already flooded with soft plaque already
I know someone who has Kleinfelter’s syndrome and was without their Testosterone supplementation for several months, during this time he was diagnosed with high Cholesterol but when he spoke with his specialist the specialist said that his high Cholesterol was due to lack of Testosterone. Has Testosterone/ hormone levels been looked at in relation to Cholesterol?
What's your heart rate? Have you had P.O.Ts Postural orthostatic tachycardia? (When you bend down or get up quickly do you feel unsteady and or faint?) Have you had BPH Benign Prostatic Hyperplasia and are taking medication that includes Tamsulosin (for vascular relaxation) and or Dutasteride hydrochloride (for shrinking the prostate)? One brand containing both is Doubluts. Good research shows side affects are worth knowing.
@@MB-dq5enI am 76 and have been high on both cholesterols. Similar to my mother who died happy at 95 and half with heart failure caused by three bouts of flu / pneumonia at her age care hostel (killing fields due to predictable cross infections and other problems they are known for). My identical twin brother has the same highs in both cholesterols. I refused statins. I have mystified doctors. I am use to being very fit and trim. Keto suits me. Echo cardiogram good.ECG has always been good. Full spectrum blood tests always good. CT scan shows no pulmonary embolism. I had Covid -19 in early 2020. Took months to recover. Had three mRNA Covid injections in 2021. Then had P.O.Ts that is clearing. I could write a book about strange auto immune symptoms but I am lucky I found a holistically oriented doctor who is supportive and addressing problems. I have studied immunology and microbiology in depth. Three days water fast, right off refined carbs and sugar. Slowly recovering fitness. Taking Vitamins and getting sunshine. Cheers from Australia.
Your trig/HDL ratio is good. I don't know much about liver numbers. Do you know your height/waist ratio? Have you had a fasting glucose and insulin test? Coronary Calcium Score?
When I was on keto I got my lipids checked and my triglycerides were high. But usually my numbers were always good and in range. The triglycerides were really high. Any idea why that would happen. Also after going back to a regular diet they were normal again.
basic science goes out the window when research is predicated on over simplified studies with a solution always predicated on the use of a patentable drug that has to be used for a lifetime.. So many studies on heart chemistry start with biased heavily screened participants. How often are participants who show side effects screened in "pre testing" , just one example.
OMG. I'm a physician who has been deep in the keto space and all this tip toeing around LDL "might" not be dangerous just drives me crazy. LDL (which is not a "cholesterol", it is a cholesterol carrier) does NOT cause heart disease. People get confused because there is too much poor terminology of what is actually happening and if things were made more clear, everyone's understanding would be more clear. The arterial plaque is not due to an abundance of LDL, it is essentially a scab (unlike on the skin where a scab is a collection of blood cells, in the arterial wall it is a collection of cholesterol and other healing products). The scab forms because the arterial wall is damaged by turbulent blood flow which occurs at SPECIFIC REGIONS of the artery where it divides (bifurcates). Turbulent blood flow occurs when there is high blood pressure (hypertension). If the plaques/scabs were due to high LDL, as the old school, pharmaceutical driven science would have you believe, then there would be a diffuse layer of plaque/scab along the entire arterial AND venous blood vessel walls. The role of LDL is to deliver the cholesterol to the damaged arterial wall to create the scab. Stable hard scabs do not lead to heart attacks. However, if the LDL gets damaged by blood sugar (glycation) or seed oils (oxidation), then it converts to a small particle density LDL (sdLDL) and THAT LDL can get caught in the arterial wall and create a pustule (soft plaque). So pustules can form by hard plaques. If the pustule wall ruptures (ie. increased blood turbulence opens up the pustule wall) then the open pustule will cause mass clotting (thrombus). The mass clotting blocks the arterial blood flow to the heart, which leads to the heart attack (myocardial infarction) or blocks blood flow to the brain which leads to a stroke (cerebrovascular accident). Therefore, the hard plaque is associated with heart attacks because it will occur by soft plaques. Therefore, the main reason for heart disease (atherosclerosis) is not LDL (that's like blaming the house fire on the fire truck), it is high blood pressure. So what causes high blood pressure? Damage to the lining of the arterial wall (the glycocalyx). When the glycocalyx is damaged, nitric oxide cannot be released to relax the blood vessel walls and allow expansion to accommodate the blood flow. Eventually the blood vessels can stiffen. This leads to increased resistance in the vascular system which causes increased blood pressure. So what damages the glycocalyx? Most commonly, high blood sugar. So high blood sugar damages the blood vessel wall, leading to hypertension, and damages the LDL cholesterol carrier, leading to the dangerous soft plaque. And for every 4 grams of carbohydrate, the body can convert it to 1 teaspoon of sugar. The Standard American Diet has over 460 grams of carb per day (115 teaspoons of sugar per day!) while a keto diet is typically less than 10 teaspoons of sugar (or zero if your carnivore). At this point it should be clear as to how you should eat. By the way, most studies show that statins INCREASE sdLDL.
Congratulations on the documentary! I look forward to it.
So your hypothesis is that high LDL is only a risk for atherosclerosis if it is coupled with high blood pressure? So if a patient came to you with high LDL levels and they were also on medication for another condition which increased blood pressure as a side effect would you say they were at a higher relative risk for CVD? And would you give advice to lower LDL via diet or medication in that case? I am on board with your point that high ldl is not sufficient as an independent factor but is necessary for CVD. Thus, necessary but not sufficient in this context is likely a correct statement. In your analogy, if there are lots of fires going on, reducing the amount of wood would limit the fire being so big it leads to events or mortality.
Thank you for this complete description!
Me too I feel a little bit irritated by them still being afraid of the high LDL in LMHRs. I have read Dr Malcolm Kendrick's book "The Clot Thickens". LDL and cholesterol do not cause any disease!
@@michaellewis7087 He's saying that high blood pressure and consuming too much sugar and seed oils are risk factors, not high ldl-cholesterol. Cholesterol is mostly manufactured by the body because it is essential for every cell and hormones and will be naturally raised or lowered as the many millions of evolution have dictated.
I've had a high LDL all my adult life, I had to get my DO to stop asking me to go back on statin, my CAC was 0!...I do low carb and exercise ❤
Been following for quite some time, and I’m very excited to see the movie!
Can't wait for the documentary. Such profound work? Kiddos!!!
LMHR getting life insurance, result is a type C rate because of the high LDL (202), despite the high HDL (132), low Triglycerides (57), A1C 5.1, all other markers normal and ideal😢. I hope one day this can be widely accepted so that we are treated the way we should be.
My cap is off to Dave... He came into a field of work he has ~zero formal training in, and *kicked the butt, sank the boats, of the leading so-called-experts, proving them wrong to a high degree, if not totally wrong and short sided in their ways of performing their very own chosen profession .*
--
After working in the high tech field of software development for ~15 yrs, these engineers, managers, software developers and testers, these people in most cases were of high intelligence and overall potential. Dave is very good example of this intelligence. My cap is off to him.
See you both in Las Vegas soon !!! Can't wait to see the film.
I would like to see the science behind this. Keto only made me sick and raised my cholesterol to 240. It didn't work for me. I found that the Mediterranean diet is best.
@@bethd5049 We're all different. There never was and there never will be "the perfect diet for EVERY human"...(as some highly persuasive, charismatic RUclipsrs would have us believe!)
I eat a keto diet, walk a lot, eat low processed diet, yoga, weight lift, meditate, and manage my type 1 diabetes well. 0 cac score. but that LDL freaks out my pcm. My endo doesn't bat an eye because trig/hdl is excellent as well as with my lifestyle being anti inflammatory. I will recommend this documentary next pcm visit.
I remember giving you some cash at Low-Carb Breckenridge. I think you call that seed money. You have made it grow!
Thanks Dave
I'm still not sure if the term "Lean Mass Hyper-responder" refers exclusively to those individuals who choose to adopt a low-carb ketogenic diet, or whether it can also apply to others (eg Omnivores) who happen to be lean, with high LDL, high HDL and low Triglycerides. Please clarify...because I think there is some general confusion about this. And many thanks for your continuing brilliant work.
Good question. The term arose mostly from those following a ketogenic diet because part of the proposed mechanism for elevated LDL is the need for greater triglyceride/fatty acid delivery as an energy source. But even if the mechanism is different, the same concept could apply to someone who is truly metabolically healthy and not on a keto diet, although that hasn't been studied as of yet.
@@metabolicmind Many thanks👍
IBELIEVED that LMHR was a metabolic genetic condition, not a diet outcome
@@metabolicmind I noticed that people with MODY look like LMHRs: higher glycemia, lower ketones, lean. Have you looked into this? I wonder if LMHRs have low insulin production like MODY or maybe do have the MODY gene modification?
It is worth noting that when these LMHR ‘s are given 50-100 gm carbs they no longer have high LDL. So if you have high LDL while consuming significant carbs then I’d think something else is going on and you are not a LMHR. It is keto specific because of this as I understand it. But who knows really? 🤷♂️
Thank you!
Luckily here in France (and all Europe I think) insurance companies are not allowed to see our medical files. So no problem being LMHR with HDL 85 , LDL 350, TG 60. I am not worried. I believe dr Malcolm Kendrick's theory about LDL and cholesterol not causing any disease.
I'm afraid to tell you that LDL has shown causality for atherosclerosis since the 2017 with one of the biggest meta analysis in cardiology.
There is no question already. LMHR only applies to a very low subset of extremely lean people on very deep ketosis. And we do not know the long term effects of this. It will take decades to know that
I think I might be one of these people. I am 68 years old, 5'6", 125 pounds. I am totally metabolically healthy - high HDL, low triglycerides, but high LDL ( for which I finally went on statins about 2 years ago). I recently had an A1C test show a level of 6.1, prediabetic. This was a shock to me, because I thought I was eating a very healthful vegetarian diet. Now, with my CGM informing me, I have gone low carb - less than 100 grams per day. I feel great, and it remains to be seen what has happened with my numbers. I am really looking forward to the documentary and hope doctors will become familiar with LMHRs and find out whether our high LDL actually harms us.
Those statins can be a real killer 😳
Ehm ... vegetarian is very unhealthy and has many carbs. We were misled about it. I recently predicted to my husband that there will be so many diabetics that ate vegetarian for many years.
statins are directly linked to Diabetes!!!!! read the label.
Statins did not keep me from having a high CAC score, but they did cause my hgA1c sky rocket.
@@GlennGuthrie I was wondering about that in my own case!
I am LMHR and my LDL 335 is causing my PCP to go crazy. He’s referred me to a cardiologist and he is freaking out too. I’m holding strong, but they want me on statins badly.
@@tserevenad My ldl is 426dL and all other markers are acceptable. No Statins. Scary!
Ask them to show you the random study that makes them react that way. Or any study, that has a statically significate absolute level of risk. Neither of those things exist. Then ask them why they are so concerned. Their concern is based on nothing but belief. In fact, Dr Hampton recently posted a video about a study that shows higher ldl is actually protective of stroke, CVD, and atherosclerosis. He doesn't mention it, but it's the RCT that he mentions.
yes same here , both sides family seem to hive high LDL but live forever. Mine is high, i went on statins for two weeks, felt as sick as a dog, went off them and will stick with my research and family history.
Ask one of the commenters above (@goliathonscave9834) about this issue. He says he's a physician and apparently knows this subject very well.
@@pabeader1941this is false. I can give you a huge meta analysis thst shows LDL prove causality for atherosclerosis. Wich analyzed countless amount of research to conclude if it causes it or not.
You have not opened the medical literature in cardiology once if you truly believe this
I've been dealing with hyperlipidemia all my adult life with a high LP a, my tri and high are within range but my LDL is 196, I don't care! a CAC showed 0 atherosclerosis!
I eat low carb for the most part and walked several miles every week..
I was on a high therapy statin for 10 years for nothing!
Nothing but pain and memory loss.. I'm 56 yrs old and 132 lbs and metabolically healthy❤
I'm in the same boat re reluctance to start prescribed Statins for high LDL. But do you think there may be a psychosomatic factor to this for some people? ie those like myself who have already "read up" about the possible side effects, then start taking the drug and attribute symptoms to the "feared" medication? Likewise (when they stop taking it) the same in reverse?
High LDL it's one of the primary factors for dementia and alzheimers as it has proven to cause plaque in arteries. Including the brain.
Can't wait for the movie. You have to go straight to the people because the cholesterol establishment is "aggressively disinterested" in the lean mass hyper-responder phenomenon.
Dave!
Why dont you skip X and switch to Bluesky?
My calcium score is zero not my doctor prescribed resuvistatin!? It made my toes and fingers numb and tingly so I stopped taking it.
My doctor is clueless and prescribed another statin? Is there a risk? Should I try the new statin or be confident in my calcium score?
Opinion please.
A positive calcium score means an end stage atherosclerosis diagnosis.
Its basically if you have cancer. A positive CAC score it's thst it's already reaching metastasis.
Soft plaque it's the issue and does not show in a CAC score. CAC shows when you are already flooded with soft plaque already
I know someone who has Kleinfelter’s syndrome and was without their Testosterone supplementation for several months, during this time he was diagnosed with high Cholesterol but when he spoke with his specialist the specialist said that his high Cholesterol was due to lack of Testosterone. Has Testosterone/ hormone levels been looked at in relation to Cholesterol?
Male
age. 60
Trig. 84
hdl. 63
ratio. 1.3
ldl. 428
ac1. 5.6
BMI. 23.6
alt. 31
ast. 18
ratio. 1.7
no statin
Am I high risk?
What's your heart rate? Have you had P.O.Ts
Postural orthostatic tachycardia? (When you bend down or get up quickly do you feel unsteady and or faint?)
Have you had BPH Benign Prostatic Hyperplasia and are taking medication
that includes Tamsulosin (for vascular relaxation) and or Dutasteride hydrochloride (for shrinking the prostate)? One brand containing both is Doubluts. Good research shows side affects are worth knowing.
none of this. My ldl is through the roof (426 dL)while all my other markers are acceptable. Im on a low carb diet
@@xge555Can you explain the significance of these values for POTS?
@@MB-dq5enI am 76 and have been high on both cholesterols. Similar to my mother who died happy at 95 and half with heart failure caused by three bouts of flu / pneumonia at her age care hostel (killing fields due to predictable cross infections and other problems they are known for). My identical twin brother has the same highs in both cholesterols. I refused statins. I have mystified doctors. I am use to being very fit and trim. Keto suits me. Echo cardiogram good.ECG has always been good. Full spectrum blood tests always good. CT scan shows no pulmonary embolism. I had Covid -19 in early 2020. Took months to recover. Had three mRNA Covid injections in 2021. Then had P.O.Ts
that is clearing. I could write a book about strange auto immune symptoms but I am lucky I found a holistically oriented doctor who is supportive and addressing problems.
I have studied immunology and microbiology in depth. Three days water fast, right off refined carbs and sugar. Slowly recovering fitness. Taking Vitamins and getting sunshine. Cheers from Australia.
Your trig/HDL ratio is good.
I don't know much about liver numbers.
Do you know your height/waist ratio?
Have you had a fasting glucose and insulin test?
Coronary Calcium Score?
When I was on keto I got my lipids checked and my triglycerides were high. But usually my numbers were always good and in range. The triglycerides were really high. Any idea why that would happen. Also after going back to a regular diet they were normal again.
Could be insufficient Ω3. My trigs at my last test were 36mg/dL.
Did you make sure you were fasted?
Have you tried going off coffee for a week and retesting?
basic science goes out the window when research is predicated on over simplified studies with a solution always predicated on the use of a patentable drug that has to be used for a lifetime.. So many studies on heart chemistry start with biased heavily screened participants. How often are participants who show side effects screened in "pre testing" , just one example.