Archive for the ‘Cholesterol’ Category
Throw away your niacin (Part II)
This part of the story surprises even me. The HPS-2 THRIVE study was stopped by Merck this past week. This was a huge study run by Oxford University in England. It utilized 14,741 patients from the United Kingdom and Scandinavia and 10,932 patients from China. Hold up! What does this say about China? Have they finally succumbed to the diseases of the West? Does any research get done in the United States anymore? After four years of follow-up, this study showed no benefit in adding niacin to a statin in reducing cardiovascular events. Further, there was a statistically significant increase in some types (not specified) of non-fatal serious side effects. The story here is even more bizarre than AIM-HIGH.
First, the background: The compound being tested was a combination drug. The two drugs in the pill were extended release niacin, known as Niaspan, and a new drug laropiprant. The drug laropiprant is a DP1 blocker and works on vascular cells to prevent flushing. The concept was that the laropiprant would block the side effect of the flushing in the niacin so that people would take the medicine. This drug has been tested before and was used for a period of time in the United States in 2008. The FDA issued a “non-approvable” letter to Merck after their first United States study, and they were forced to do further work on the compound. The compound known as Tredaptive or Cordaptive is being sold and used in Europe, but now the European regulatory bodies will look into the compound based on this study.
Still not satisfied with the answer, the naysayers (like the NRA) blame everyone and everything except the obvious. Maybe niacin just doesn’t work? Among the reasons that this study did not prove their point was because this study was all-comers. This meant that the baseline HDL was 50 mg/dl. Raising the HDL by 20% in that case would mean a HDL of 60 mg/dl. I see two points here. The first is that it says something when a group of patients who have cardiac disease have a mean HDL of 50 mg/dl. That is felt to be rather high. The risk is felt to be the greatest in low HDL like 30 mg/dl. Maybe the whole idea of HDL and raising it to prevent cardiovascular outcomes is not correct. Maybe Earth is not the center of the universe. Why didn’t Merck only enroll those that had the lowest numbers? The second – and perhaps more profound – reason that this study failed is because no one really knows what laropiprant does or what deleterious effects it might have. What if it counters the effect of Niaspan on the artery? The study should have included more tiers, one of which would have been laropiprant alone. Why did it not? As I have mentioned before, the cost of all this is astronomical and getting higher all the time. We are approaching a point where drug development may come to a grinding halt because the cost of development does not allow a company to obtain a profit.
Where do we go from here? Eat sensibly, lose weight, stop smoking and take as much statin as you can. The rest seems to be a waste of time and money. We as a society will have to wait for the next big idea. We are out of them for the time being. I only hope that when the idea comes, we will have the ability and will to test it and bring it to market.
I wish all of you a Happy Holiday season.
Throw your niacin away (Part I)
I have blogged about the uselessness of niacin in the past in a long blog piece about the AIM-HIGH study that began on May 31,2011 and ended on June 7, 2011. The point of those blogs were that niacin, when added to statin, did not provide clinical benefit. As always in medicine, and lately in every other walk of life, the naysayers come out and say that these facts don’t matter.
Let’s stop for a minute and consider why you as a patient and we as doctors give you a drug. The simplest reason is that there is a clinical benefit. When you take an antibiotic, your infection goes away. When you take an antacid, like Zantac, the burning in your stomach stops. When you take a statin, the clinical benefit is not that your LDL goes down. The LDL number is a marker for the effect of the statin. The reason you take the statin is that your clinical benefit is statistically less heart attacks, episodes of unstable angina and death. This aggregate number is significant when compared to placebo. The lower your LDL number goes, the less likely you are to have a clinical event. In spite of what your doctor likely tells you, there is no LDL number too low. 35 seems to be optimal as I have explained in other blogs.
So how did we get to this point? In the early days of trying to find a “cure” for atherosclerosis, niacin was found to increase HDL levels by up to 20%. This however was with doses of niacin that are generally intolerable: one to three grams a day. Most people have trouble taking 500 mg a day. These studies were performed before statins. They utilized relatively small numbers of subjects given the numbers of patients needed today. One reason is that in today’s work, statins are so effective that very large numbers of subjects are needed to prove the point and so the clinical benefit.
In a recent meta-analysis published in Atherosclerosis (2010 Jun;210(2):353-61) entitled “Meta analysis of the effect of nicotinic acid alone or in combination on cardiovascular events and atherosclerosis,” the authors reviewed 11 randomized trials. In those trials combined, 2,682 active patients and 3,934 control patients were used. Nowadays, each trial would be this big. In the AIM-HIGH trial alone 3,500 patients were studied. As discussed in the blogs mentioned above, AIM-HIGH was sponsored by NIH and stopped early as it was futile. It found ”That high dose, extended-release niacin offered no benefits beyond statin therapy alone in reducing cardiovascular-related complications.” Once again I must stress that the average LDL in this trial was 71 mg/dl. That means that some patients had LDL’s in the low 50′s. This remains the gold standard.
So we have the failure of niacin, fibric acids like Lopid and unfortunately the new class of drugs know as CETP inhibitors like torcetrapib. Hope in medicine springs eternal, and at the end of all the articles about the failure of AIM-HIGH was a plea to await the results of the final trial called Heart Protection Study 2 Treatment of HDL to Reduce the Incidence of Vascular Events.
Be careful what you wait for…
A stake through the heart (Part I)
photo from ranbaxyusa.com
There appears to be no bottom to it. I have attempted to inform you, my readers, about a problem that no one has an answer to and very few people seem to care about. It’s almost as if the phrase “what I don’t know can’t hurt me” has infected our entire national psyche. The what we don’t know is what is in our drugs.
Of all the drugs that patients waited to become generic, Lipitor stood out. It was necessary for so many patients, and it was expensive. Insurance companies would wrongly point patients to other less expensive, but not as powerful, drugs like it was OK. But, as it became clear to us that those that suffer from coronary disease need LDL levels less than 70, the power of Lipitor became more apparent. Lipitor was the largest selling drug in the world year after year, after year: $16 billion a year.
How is it possible that the company that brought the generic to market could be so careless as to have it tainted? Not only does it show just how broken the system is, but now the company has completely shut down production of atorvastatin. Does no one care? Are we doomed? Is this the new normal?
How does glass get into a drug? Why can’t we document and secure our drug sources?
Let’s take a look at the company. As reported in the New York Times on November 29, 2012, Ranbaxy Pharmaceuticals was in a heap of trouble before this incident. Ranbaxy is a subsidiary of a large Japanese pharmaceutical company called Daiichi Sankyo. As an interesting factoid, Daiichi Sankyo was the company that found the substance in Red Rice Yeast that became lovasatin. Second factoid: lovasatin is also found in oyster mushrooms. Yes, all my friends who only want to take “natural” drugs, that’s what lovastatin is – natural.
Anyway, I digress. Ranbaxy is operating under a consent decree issued on January 25, 2012. I quote from the decree:
“These problems include failure to keep written records showing that drugs had been manufactured properly; failure to investigate evidence indicating that drugs did not meet their specifications; failure to adequately separate the manufacture of penicillin drugs from non-penicillin drugs in order to prevent cross-contamination; failure to have adequate procedures to prevent contamination of sterile drugs; and inadequate testing of drugs to ensure that they kept their strength and effectiveness until their expiration date.”
What did the government do?
I quote: “Among other things, the consent decree prevents Ranbaxy from manufacturing drugs for the U.S. market at certain of its facilities until those facilities can do so according to U.S. standards. To remove false data contained in Ranbaxy’s past drug applications and to prevent Ranbaxy from submitting false data to FDA in the future, the consent decree requires Ranbaxy to take actions such as: hire an outside expert to conduct a thorough internal review at the affected facilities and to audit applications containing data from those facilities; withdraw any applications found to contain false data; set up a separate office of data reliability within Ranbaxy; and hire an outside auditor to audit the affected facilities in the future.”
So…they manufactured the active drug in India at a plant that was not shuttered in India and assembled the drug here in the United States. One would think that they would be extra careful, but apparently they don’t think like one. Ranbaxy had 43% of the market in October.
Folks, as Joe Biden would say, “If this is so screwed up, we are all in trouble. Can Gdufa save us?”
Read my next blog.
Vindication
One more urban legend dies. Since I have been practicing cardiology, now 25 years, I have championed the process of drawing random lipid panels. The lipid panel is the most important non invasive test I have. Most of my patients have coronary artery disease or some other manifestation of cholesterol damage. The guidelines are now stricter than ever, and in my constant striving to practice evidence-based medicine, I require my patients with disease to have a LDL cholesterol of 70 mg/dl or less. The lower the LDL goes, the happier I am. If you do not have any evidence of cholesterol damage. the level for LDL is > 100 mg/dl.
This has allowed me for 25 years to have the same discussion over and over again. The discussion goes like this: I want to draw your lipid panel. You tell me that you have eaten, and I tell you that I don’t care. The reason I don’t care is that I’m not interested in your “best” fasting number. I’m interested in your worst number. You don’t fast all day, so why would I care about the fasting level? The only real use of the fasting tests are in a research setting because the sampling needs to be uniform. Having to go to the doctor’s office is a hassle in itself. Having to go twice for a fasting specimen is unfair.
Also, for the millionth time, what you eat is not responsible for your cholesterol level. Your parents are. Your triglyceride level is more associated with fasting. This does affect the LDL level at times since the standard LDL level is inexact anyway since it is calculated not measured. We have a way to measure LDL known as Direct LDL, but it is more expensive and generally not necessary. All the “gobbledygook” on the special cholesterol panels is interesting, but why get it if you can’t do anything about it? After you get the advanced panel, the answer is still take more statin. These panels are a waste of money and just produce noise.
I usually prevail in my discussion, and I get the test.
Now an article has been published supporting what I have said all along. Published in the Archives of Internal Medicine is an article entitled “Fasting time and lipid levels in a community based population” (Arch Intern Med 2012;DOI:10.1001/archinternmed.20122.370). This article used 209,180 specimens. Fasting times ranged from one hour to 16 hours. The difference between the fasting and non fasting specimens were less than 10% for LDL. The sample is so large that it doesn’t matter if you are on statins or not. The differences in the entire population wash out.
So, it maybe possible to eventually eliminate the practice of obtaining fasting specimens. I am usually “whistling in the wind” when I try to explain things to my peers, but I will keep trying. I am going to hand out copies of this blog to my patients so that maybe I can save my voice for some of my other favorite conversations.
Whoops! (Part II)
The study of diet is difficult in humans. It has been done on mice, and as I have blogged about in the past, the whole concept of the hormones known as Sertins arise from the partial starvation of mice, which makes them live 30% longer.
Humans however are like herding cats. Particularly if you are talking about food. I have blogged before about how difficult it is to lose weight and that the weight comes gleefully back as soon as one’s concentration let’s up, and the Ice Cream returns. It seems our bodies are programmed with hormones that we are just learning about which provide us with a strong support of the highest weight we have achieved. Lose 20, gain 25 is the constant refrain.
Unfortunately, what that means is that the best way to stay skinny is to always be skinny. For most of us, it is already too late. The investigators used 21 obese young adults and starved them until they lost 10-15% of their body weight. This process primed them to then be fed 3 different diets. The whole process took seven months which is a long amount of time to have a special eating pattern unless you are in the “graybar hotel” and getting all your meals handed to you with a spork.
The three diets were a low fat diet (20% fat/ 60% carbohydrate/ 20% protein), a low-glycemic diet and a very low carbohydrate diet (10%carbohydrate/ 60% fat/ 30% protein). All the diets had the same amount of calories. All the participants participated in exercise. The primary outcome was the resting energy expenditure.
So, is a calorie a calorie? The answer seems to be that it is not. Some calories are worse to eat than others. The low carb diet subjects burned 350 calories more than the low fat diet. The low-glycemic diet lost 150 calories more than the low fat diet.
Here is the kicker. The low carb diet increased the participants’ CRP and the 24 hour cortisol levels, which are both thought to be detrimental. The low fat diet had the least energy expenditure and resulted in insulin resistance and elevations in triglyceride levels. HDL levels fell. Whoops this is the diet recommendation of the American Heart Association.
What is a person to do? How do you navigate all this? The unfortunate truth is the fewer calories you eat, the more exercise you do, the closer the calories that you do eat come from the original source (i.e.are not processed), and the less carbohydrate you eat, the leaner you will be. As I have pointed out before, and as Tara Pope has written extensively on in “the Fat Trap” (the article that I blogged about in the past), you then have a long and demanding challenge ahead of you if you want to keep it off.
Is it worth it? Everyone has to answer that for themselves. What is true is that the heavier you become, the more likely it is that you will develop some medical or degenerative problem, and then it is more difficult to treat because of your weight. You would not be surprised at the number of patients I clear for orthopedic surgery because of weight related knee and hip problems.
We baby boomers will live forever. God help the country and our healthcare expenditures if we don’t start losing weight.
Goodbye Lipitor. So long Plavix.
Photo from webmd.com
It is the end of one age and the beginning of another. Two drugs that accounted for the number one and number two selling drugs in the world are now both generic. The two drugs together had roughly $25 billion in sales…a year. In the United States in 2010, Lipitor sold $5,272,576,000 and Plavix sold $4,675,483,000. You are not seeing things the numbers are correct. Insane right?
Should we be sorry they are gone? Let’s start with Lipitor. I have never seen the amount of money that Lipitor saved by preventing myocardial infarctions and death. I’m sure it dwarfs the money spent on it. In 2011, we spent $273 billion on just cardiovascular healthcare, and that number does not include the lost wages and social costs which can never have a price put on them. By 2030, the estimate is $818 billion in cardiovascular costs, but frankly, it is a ridiculous number since we can’t figure out what we are doing tomorrow. As published in The American Journal of Cardiology (2011 Jun 1;107(11):1662-6), the more adherent patients were with statin drugs, the lower their total healthcare costs were.
According to the Pfizer web site, they will have “branded” Lipitor at least until December 31, 2014. I guess they will decide at that time whether to keep manufacturing it. They are also preparing to manufacture an “authorized generic” atorvastatin. I have no idea why they will make a “branded Lipitor” and an “authorized generic.”
Does all of this make a difference? A generic drug can have between 80-125% of the active drug. I have no idea why that’s allowed, but it is. It doesn’t seem to matter. In tests at the FDA, the difference in the absorption and drug levels between the generics tested and the branded product was 3.7%. I will come back to this point in a minute. Theoretically, if you take Lipitor and have an LDL of 70, you might have a higher LDL with the generic. LDL varies so much it will be hard to say.
There is not much choice in all of this. Your insurance company will force this unless you want to pay for it yourself. This may or may not be important or possible.
Now let’s take Plavix. This is much more problematic and possibly a big problem. If you have adequate platelet suppression, at 100% of the dose, will you have adequate platelet suppression at 80%? No one knows. It’s all a big experiment. My suspicion is, however, that it won’t matter for several reasons. The first is that in Canada, they have been using generic Plavix for some time, and patients have not been dropping like flies from generic Plavix. The second is that we in the United States had generic Plavix available for one brief shining moment until the Feds stopped it. I am not aware that during that time anything dire happened. We don’t know how to measure the effect of full strength pills let alone 80% strength pills.
I have been telling my patients to try the generics, and we will all be part of this experiment together. Most prescriptions at this time are generic. Last year, 69% of all prescriptions were generic. This will only increase as the pressure on healthcare continues to rise. In fact, this one point has been highlighted as a way to obtain a quick drop in healthcare costs.
We are all in this together. It’s time to get closer together in the lifeboat.
And now for LDL (Part II)
The article in question that I have cited in my last blog reviews the work of a group of researchers known as the Cholesterol Treatment Trialists’ Collaboration. These researchers are the ones who have done the major work on the approving of the statin drugs, and they form the basis for the theory of statin used in cardiovascular disease.
As I have blogged about before, even though many patients take statins, not every patient receives a benefit. In other words, these drugs are not like antibiotics. If you give the right antibiotic for the right organism, it is almost always successful. If you give a statin, not every patient gets the benefit. Why is that? I have never understood it, but this paper points to a possible answer.
Although the LDL level is lowered by statins, most of the effect is attributed to the magical “pleiotrophic” effect. Pleiotrophic is defined as having more than one effect. However, the exact effect/effects is/are not clear to us. The reason for this is that we cannot access the material. We have no lab model of atherosclerosis, and the only chance we get to look at it is in autopsy material. There is at this time no practical way to study human atherosclerotic disease. So, we basically guess at it. Generally we guess wrong. This is not a criticism, it’s just a fact. That is why the failure rate is so high for drugs.
This article proposes that everyone should take statins. It would add 64 million patients to the ranks of patients exposed to the drugs. What the study really seemed to show, however, was that if your LDL did not drop by 40 points from the baseline number, you would not achieve a benefit. By extension, if you are taking a statin and don’t get this drop from baseline, you need more of the statin you are taking or a different statin. If you get to 40 mg of Crestor and you still don’t get the 40 point drop in LDL from baseline, I guess you give up.
I caution that this doesn’t entirely tell the story. We have seen many examples so far of adding other drugs to statins to achieve “goal” levels, and this does not seem to work. Why that is, I do not know. It is not just the LDL number. It seems to have something to do with the statin drug itself. Having said that, I am referring to the “magic” effects of the drug since we know that just lowering the number with niacin, Zetia or any other substance doesn’t seem to work.
One thing seems clear. If you do not have evidence of cardiovascular disease and want to take a statin to prevent it, you need to take one at a dose that lowers your LDL 40 points from baseline. If you don’t do that, you might as well spare the whole effort. This may not be the most satisfying answer, but at this point in time, it seems to be the most accurate.
The saga continues, and the drugs will keep coming as I have blogged about in the past. I, and most cardiologists, agree on one thing: this is a set of illnesses that are best prevented if possible. Hosing down the burning barn during a myocardial infarction is not as good as fire prevention.
We will all keep looking for an answer. Maybe in my lifetime we will succeed.
And now for LDL (Part I)
I have spent the last several blog posts discussing HDL and the apparent failure of the class of drugs known as CETP inhibitors. Also, much to my dismay, the possibility that the hypothesis of raising HDL to prevent coronary disease may be deeply flawed. One of the benefits that I get by writing this blog is that I too get to learn and expand my knowledge base.
Often when we as physicians read something, we don’t “get” the deeper meaning. When you have to distill it and rework it so that other individuals may learn from the information, the author also gains from the experience. Sometimes new insights arise, and sometimes I have clarity about a topic that I did not have before. Just such an “AH-HA!” moment occurred concerning the next article that I will bring to your attention. Perhaps the most important controversy surrounding cardiology today is whether or not we can prevent cardiovascular disease and death by lowering everyone’s cholesterol with a statin.
I have written about this before. The concept is known as primary prevention. The concept requires everyone to take a statin, and by doing so, the hope is that physicians obtain the results we want (i.e. less strokes, myocardial infarctions and death in their patients). Let me pause for one second and remind you my readers that this discussion is not about people who have carotid artery disease or coronary artery disease. Those individuals have a robust benefit from taking statin drugs. The statin drugs are one leg in the 3-legged stool. The others being antiplatelet drugs and beta blockers. This discussion is about individuals that have no evidence of atherosclerotic disease. In the future, this discussion may be more defined. With our present day technology of Coronary Computed Tomographic Angiography, we can define who does and who doesn’t have subclinical disease, and these are the people we can treat with benefit. I suspect that there are already studies going on in this manner of treatment. Further, let me remind you that a true study will never be performed. No one will pay for the thousands of patients needed to be followed and for the length of time needed to determine if treating people in their 20′s can prevent disease in their 50′s. The best we have is meta analysis of the subject.
Does giving everyone statin work? How do we prove it? Should we do it? Recently an article was published in Lancet titled “The effects of lowering LDL cholesterol with statin therapy in people at low risk of vascular disease: meta-analysis of individual data from 27 randomized trials” (doi:10.1016/S0140-6736(12)60367-5). This study used 22 randomized trials of drug versus placebo and five randomized trials of some statin vs. a large amount of statin. Those in the placebo studies were followed for a mean of 4.8 years and those in the comparison studies were followed for a mean of 5.1 years. A total of 170,000 patients were combined in the work. This study reports that there is a benefit. In doing so, they may have unearthed the answer to a question that I have always had and have shared with many of my patients. That question is why don’t all patients get a benefit from a statin? The answer in my next blog.
Maybe we are just wrong (Part II)
One of the main reasons that we are able to map the human genome is that the technology improved so rapidly. Scientists and physicians now have the ability to identify SNP or single nucleotide polymorphism. In English, we can establish when your gene doesn’t exactly match the way the gene is supposed to look. This is known as polymorphism or another look.
The identification of these gene polymorphisms in large populations can then be examined to see if the change identified leads to better or worse outcomes. Does the change cause disease or does it prevent disease? One such gene is the endothelial lipase gene. This gene was isolated in 20,913 myocardial infarction cases and 95,407 controls.
The one polymorphism of this gene occurs in 2.6% of humans and causes an increase in HDL but no change in the other components of the lipid panel. The difference in HDL levels would predict a 13% decrease in myocardial infarction. It, however, showed no difference when matched to the control group. In fact, when the SNP’s of CETP were examined, a variant was found that decreased the risk of myocardial infarction by 4%. Unbelievably but true, the variant raises HDL and also lowers LDL. Who knows which effect is more important.
The second way this group looked at the genetics of HDL was to develop a genetic score that consisted of 14 SNP’s related to HDL and 13 SNPs related to LDL. This score was then applied to 12,428 cases of myocardial infarction and 41,331 controls. From observational studies previously done, it is believed that if you increase HDL by one standard deviation (which is a certain percentage), then you decrease the risk of cardiovascular disease. This was not found to be the case when genetics changed the levels of HDL. To further enhance the unease of the study, it was found that when genetics lowered LDL, the risk of cardiovascular disease also decreased. Once again we see the power of lowering LDL. It doesn’t seem to matter how you lower your LDL, the lower your LDL goes, the fewer cardiovascular effects you have. This is powerful information which should give us all pause, doctors and patients alike. Physicians maybe attempting to proceed in the wrong fashion, and answers may be there but are being marginalized because we physicians cling to beliefs that may not be accurate.
As I have mentioned before, some patients have high HDL levels and in the past have been told that they are not at risk. This does not seem to be the case because we now know that it is not the amount of HDL but whether the HDL is actually doing what it is supposed to be doing. Your HDL needs to be “functional” and in the process do what HDL is supposed to do. In the future we physicians will not test HDL levels but whether your HDL is functional. Instead of examining the SNP’s of HDL amount we need to examine the SNP’s of function of HDL. A simple test needs to be developed, and I am certain that somewhere this is being dealt with.
Is LDL lowering the answer? Read my next blog.
Maybe we are just wrong (Part I)
As I have stated before, one of the benefits of the long view of things is to assess how “facts” change over time. What perhaps surprises me most is medicine’s reluctance to sometimes acknowledge just how wrong we are. For my entire career, now spanning 32 years, I have been taught and I have believed that raising HDL is the holy grail of medicine. If only we could crack the code, all would be right with the world, and we might stem the tide of America’s leading cause of death.
As I have shown in the last set of blog posts, this just might not be the case. To further the pain is an article published in Lancet that may in fact cause us to pause and reconsider the whole idea. It is a truly monumental article and of course was buried in the back of the paper if reported at all. Much of the silence is because of the way the study was performed, an elegant and very complicated experiment that defies easy analysis. Published online on May 17, 2012 (doi:10.1016/S0141-6736(12) 601312-2) and entitled “Plasma HDL cholesterol and the risk of myocardial infarction: a mendelian randomization study,” this study considers and performs an elegant thought experiment. I hold many things in awe, walking on the moon and genetic analysis among just two examples. In the span of 66 years, we went from the Wright brothers to Neil Armstrong. When has the pace of innovation matched that? Although genes were known since an Austrian monk named Gregor Mendel began to understand the science of genetics in the mid 1800′s, the structure of genetic material was not understood until Watson and Crick showed the way in 1953. 1962 saw the award of a Nobel Prize for the work. In 1990, work started on mapping the entire human genome, and this process was completed in 2003. Less than 10 years later, we now have studies utilizing the information and techniques and have the ability to identify exact genes and their variations.
This paper represents just such work. In simplest form, the authors asked the question, “What happens when a specific gene causes HDL to rise?” The simple answer is supposed to be that the risk of cardiovascular disease is supposed to decrease. That’s not what they found. For years we physicians were told that if you raised HDL, the risk of cardiovascular death was lowered. As we now see, these statements may not be true. HDL may go up, and the risk of death may not change. Just because two things move together does not necessarily mean that the movements are related. The past several weeks’ blog posts have reviewed the debacle of CETP inhibitors and highlight that perhaps we don’t know as much as we thought we did. The very real possibility exists that the only way CETP inhibitors work is that they lower LDL even lower than statins when combined with them. This has also been seen in niacin studies as well as other substances when that substance is added to statins. As will be seen in the following blog post, it seems — as we all know it — who your parents are seemed to be the main factor in who you become and what subsequently happens to you. This may be truer then we presently understand.
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