Is a ketogenic diet effective against dementia?

ketogenic diet prevent dementia

A sea change is underway. Ten years ago, it was heresy to propose that a ketogenic (a.k.a low carb high fat) diet was in any way healthier than the low fat high carb diet supported by public health authorities. It was branded a “gimmick” diet. In some places, doctors who prescribed it to their patients risked having their medical licenses revoked.

The German physicist Max Planck is often misquoted as having said that “science advances one funeral at a time”. Well, the man who gave birth to the low fat high carb dogma, Ancel Keys, died in 2004. His first generation of acolytes have now joined him in oblivion. The men (they were with very few exceptions all men) who created the current dietary guidelines back in the late 70’s and early 80’s are also gone, after having presided over a massive explosion in the number of people suffering from obesity and type 2 diabetes.

The newer generations of nutrition researchers do not appear to be as wedded to the old dogma. This is visible in the increasing number of studies being published on a ketogenic diet. Some of these are even appearing in the most prestigious and conservative nutrition journals.

One such study was recently published in Advances in Nutrition, a journal owned by the American Society for Nutrition. It was a systematic review looking at randomized trials of a ketogenic diet as a treatment for Alzheimer’s disease, which is the most common cause of dementia. We’re going to get to that study in a minute, but first, a little detour.

There is some evidence to support the notion that dementia can in part be caused by a high carbohydrate diet. An observational study was published back in 2012 in The Journal of Alzheimer’s Disease in which 937 elderly people were followed for four years. The median age at the start of the study was 80 years, and at the beginning, all the participants were asked to fill in a diet questionnaire and were also evaluated for cognitive function. Four years later, 200 of the 937 participants had developed some level of cognitive impairment.

When the researchers correlated this with dietary carbohydrate intake, they found that the quartile with the highest intake had an 89% increased relative risk of developing cognitive impairment during the four years of follow-up, as compared to the group with the lowest intake. And that’s after adjusting for known confounders like gender, BMI, co-morbidities, and APOE4 status (APOE4 is a gene variant that is strongly associated with increased risk of Alzheimer disease). The difference was statistically significant (p-value 0.004).

The quartile with the highest fat intake, on the other hand, had a 56% decreased relative risk of cognitive impairment as compared to the quartile with the lowest fat intake (p-value 0.03).

Interestingly, the differences between the quartiles in terms of carbohydrate and fat consumption weren’t actually that big. The highest quartile in terms of carbohydrate consumption was getting more than 58% of calories from carbohydrates, while the lowest quartile was getting less than 47%. Not a huge difference. The same was true for fat intake. The quartile with the highest fat intake was getting more than 35% of calories from fat, while the quartile with the lowest fat intake was getting les than 27%. This would seem to suggest that even relatively modest differences in consumption of carbohydrates and fats can have big effects on cognitive function over time, and that an even bigger reduction in relative carbohydrate intake might have achieved an even bigger reduction in risk of cognitive impairment.

Of course, this was an observational study, and although the results are suggestive, it can’t prove the existence of a cause and effect relationship between carbohydrate/fat intake and dementia. The results could have been caused by residual confounders that the researchers were not able to adjust for. For proof of a cause-effect relationship you need randomized controlled trials. Which is where the recent systematic review published in Advances in Nutrition comes in. As mentioned earlier, it was looking at the randomized trials that exist of a ketogenic diet as a treatment for Alzheimer’s disease and mild cognitive impairment.

Ten trials were identified, with a total of only 456 participants, which really shows how under-researched this area is. And things get worse. Only three of the trials, with a total of only 47 participants, were actually testing a ketogenic diet (i.e. a diet in which carbohydrates are restricted to the point where the body significantly increases production of ketone bodies). The rest were testing supplements containing medium chain triglycerides (MCT’s), which the body preferentially converts to ketones. From my perspective, these are two very different interventions. A ketogenic diet has many different effects on our metabolism, and I am inclined to believe that the beneficial effects come primarily from the reduction in carbohydrates and insulin, not from the increase in ketones.

Taking an MCT containing supplement is obviously not the same thing as following a ketogenic diet. The seven studies of ketogenic supplements were, with only one exception, either funded by companies that sell supplements, or they failed to disclose their funding (which means they were probably funded by companies that sell supplements). Most of these studies were never registered at clinicaltrials.gov, and of the ones that were, this was done after the trials were already underway, which is highly suspect behaviour, because it means the researchers could know wether the trials were going well or not before they let the world know about them. In other words, it’s possible they were simultaneously running other trials that weren’t going so well, and that were therefore never posted on clinicaltrials.gov, which could lead to massive publication bias.

The three small studies of a ketogenic diet compared it with the traditionally recommended low fat high carb diet. One of the three ran for twelve weeks, while the other two ran for six weeks, so these were short term interventions. In terms of outcomes, there were improvements in some of the cognitive functions tested, but not in others. Overall, the results really don’t tell us anything useful, as you would expect from tiny trials run for short periods of time.

The seven studies of MCT supplements appeared to show some benefit in terms of cognitive function in Alzheimer patients, although the fact that these were mostly industry funded studies, that weren’t pre-registered at clinicaltrials.gov, makes the results hard to trust. Strangely, the systematic review only reports whether there was a “benefit” or not, but not what the size of the benefit was, or whether it was statistically or clinically significant. This feels like a rather weird omission in a systematic review. So I decided to look up the two biggest trials, with 152 and 131 participants respectively. According to the systematic review, the first showed an “improvement” in ADAS-Cog (a test of cognitive function used in Alzheimer’s disease) and MMSE (a test for dementia), while the second showed an “improvement” in ADAS-Cog .

When we look at the first of these trials, we find that the difference between the group getting MCT and the placebo group at 104 days (the longest follow-up) was less than one point on the 70 point ADAS-Cog scale. One point on a 70 point scale is not a noticeable difference. Additionally, the difference wasn’t statistically significant. In other words, there was no clinically meaningful or statistically significant difference between the groups on ADAS-Cog. If we move on to MMSE, we find no difference whatsoever between the groups. Yet this study is reported as being “positive” in the systematic review. Odd.

When I moved on and looked at the second of these trials, I immediately realized that it was just a duplicate report of the same study, with a few new analyzes of the same data set. Researchers often do this, to maximize the number of publications they can get out of one data set (since career success in research is largely determined by number of publications). How the authors of the systematic review didn’t realize this is beyond me.

So basically, one negative study was reported as two positive studies in the systematic review. And these were the two “big” studies, supposedly representing 62% of the participants in the systematic review. All the other studies were much smaller.

This weirdness really makes me wonder about the motives of the authors of the systematic review. No conflicts of interest were reported, and they reported receiving no specific funding to carry out the review. But seriously, they went through all this data in detail and didn’t realize that they were looking at the same data set twice! And then, to top it off, Advances in Nutrition, the fourth highest ranked nutrition journal, went ahead and published it, no questions asked!

This really speaks to the poor state of nutrition research more than anything else, and to the low added value provided by the process of peer review. If peer review was the rigorous process that the general public thinks it is, this nonsense would have been noticed and called out, and the article wouldn’t have been published.

What can we conclude?

Athough I am a strong proponent of a ketogenic diet as an effective therapy for metabolic syndrome, obesity and type 2 diabetes, and therefore think it’s likely that it also has beneficial effects in terms of preventing or delaying dementia (which is far more common in people suffering from these diseases), the evidence that exists today cannot prove that that is the case. Nor does the current evidence support the use of MCT supplements as a way to treat or prevent dementia.

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43 thoughts on “Is a ketogenic diet effective against dementia?”

  1. Another excellent article. You write so well and clearly in language non experts can understand. Thank you very much for your hard work.

  2. Thanks for this review. I think the better quote would be “the evil that men do lives after them”. One of the essential questions of Alzheimer’s is whether it is a disease or a syndrome. The original AD referred to a clear cut genetic alteration that resulted in dementia at a young age. Pathological examination showed globular bodies amyloid. The conclusion was drawn that this was the cause of AD. Totally misunderstanding the context a psychiatrist published a paper renaming senile dementia as a manifestation of AD as examination of the brains of these people showed the amyloid globular proteins. Association is not causation. The brain is a high energy consumer. In the modern world, the preferred energy source is glucose. More sophisticated studies show that the brain of AD patients show an inefficient utilization of glucose. This requires a different energy mechanism. This energy source can be readily supplied by ketones. From an evolutionary perspective this makes perfect sense: Prior to the modern world, food sources were scarce and humans had to go for days, weeks or months i s a semi-starvation, glucose depleted world. In that case, the only ready source of energy is fat lipolysis and release of ketones. There is a high association between T2DM and AD. It is likely that the common cause is the inefficient utilization of glucose and insensitivity to insulin and that the globular proteins are a surrogate marker rather than the cause. There is nothing more toxic in the environment to induce insulin insensitivity than a high sugared diet, especially one rich in fructose. Glucose does not appear to be an issue. It is my prediction that as long as Pharma follows the amyloid theory there will never be a treatment for AD. But there will be active or passive suppression of the ketone theory (unless there is a patentable medication that increases ketones and decreases fat).

  3. Thanks. Unfortunately a not too uncommon tale of failure of the medical research ‘community’ at every level.

    1. Unfortunately, yes. And for the life of me, I can’t figure out why Dr. Rush would insert MCT into this. I’ve been on a ketogenic diet (religiously… meaning I don’t cheat) for over 25 years (before it became popular). After 1 year I had lost over 80 pounds and lost ALL of my health problems. I’ve continued that to this very day (no need for health insurance) and have NEVER used MCT oil nor any other supplements. Of course this doesn’t prove anything since it’s a single example, but I can tell you that my whole life changed after one year on the keto diet. Perhaps I’m lucky because I LIKE all the foods (yes, FOODS, not supplements) allowed on the keto diet and I DON’T like any of the verboten foods on this diet. For me, the keto diet is PERFECT! So much more energy than before, and throughout the 25 years I’ve never been ill. For me, that’s all the convincing I need.

      1. I agree 100% with your comments. I think thousands if not tens of thousands or hundreds of thousands will agree with you. The only one who will not agree are the ADA, American Diabetic Association (and its affiliate, Endocrine societies) and all major medical organizations. The ketogenic diet changed my life (albeit I am not as strict as I should be). MCT supplementation adds butyrate. Butyrate is a natural MCT made by gut bacteria (when not exposed to sugar). It is proffered that butyrate is one of the mechanisms by which the ketogenic diet works. As a full disclosure, I take butyrate supplements with the diet. My irritable bowel has gone away. Clearer thinking. More energy.

  4. Hi Dr Rushworth, there are carbs and carbs. Sugar for instance, if it was not for industry lobby and groupthink of the medical profession, would be a controlled substance by now. Very different from sugar naturally found in fruits and most veggies. So a low fat diet based based on plenty of fresh fruits and vegetables, a few whole grains, and proteins and fats from plants, including pulses, healthy fish and with zero sugar and zero refined flour seems pretty healthy to me. And am told it is also easier on the kidneys than a meat based diet. What do you think?

    1. (Although not Dr. Rush responding anyway): There are two types of carbohydrates. Sugar (and related sugar alcohols) and starches.

      The difference is that sugar is composed on fructose and glucose. Starches are only composed of glucose. The body can handle immense amounts of glucose (although it will make you fat; it is a healthy fat; fat on the outside; thin on the inside).

      Natural sugar is about 50% glucose/50% fructose. High fructose corn syrup is about 55% fructose/45% but comes in many variations.

      The body can only handle a small amount of fructose (about 5 grams per day or half of an average sized apple). Fructose is the sugar of fruits. In the natural form, the amount of fructose is limited by water and non-digestible carbohydrates and other nutrients.

      Fructose metabolism is similar to alcohol and so is a toxin. But the dose is the toxin. In excessive amounts it induces dysmetabolic syndrome by inducing liver insulin resistance initially. But it does more: it alters the bacterial composition, with loss of butyrate production (a form of MCT), resulting in all the syndromes of a leaky gut. It is the favored energy source of cancer cells. It also initiates the scavenger pathway in the brain, along with the reward pathways, so that people eat more.

      The Western diet is now excessively rich in sugars in general; and since the introduction of high fructose corn syrup, even more fructose. it is deficient in complex carbohydrates. We are seeing the results in the first generation raised on these excessively high sugar diets: Colo-rectal cancer at a young age; obesity as an epidemic; diabetes type 2 and pre-diabetes type 2 as an epidemic; cardiovascular disease and dementia.

      All the advantages of a plant based diet are related to the decrease in sugar consumption.

      1. Food/pharma industries related. Lab produced food creating sick people needing drugs….
        Back in the day, there was an expression GIGO….garbage in, garbage out. This is a life principle. You reap what you sow.
        Been a joyful low carb, intermittent faster and exerciser my whole life. I am now in what I call “the autumn of life”, no health concerns ever…never had the flu (or the jab). Always questioned these “studies”….it was laughable when “margarine” was being promoted as better than “butter”. Now they want me to believe lab-produced “meat” is better for me than grass-fed/finished beef. Simply ridiculous.
        If, after this last year, anyone believes these studies….well, get prepared ..get some great medical insurance cause you’re gonna need it.

  5. Thank you Sebastian. I had thought that real science died in 2020, but due to your efforts (& those of others like Malcolm Kendrick) a few embers are still glowing in an ever darkening world. Your blogs keep me almost sane.

    The ketogenic diet rang a bell. My son, born in 1979, suffered slightly from nocturnal epilepsy as a boy. In the 1980s it was harder to research things than now, but I found the keto diet was being tried (mostly in the US) on epileptic patients & some success had been reported. My wife was highly sceptical (didn’t approve because it went against prevailing ‘official’ dietary advice) & so I cannot say that I was very scientific in my approach. I did give Richard my approximation of a keto diet whenever possible for several years. He hasn’t had a seizure (AFAIK) for well over 25 years, is very fit & eats a balanced (‘healthy’) diet as far as I can see.

    Most of the vegetarians & vegans I know have a list of health issues as long as your arm. Mostly these seem to be kept at bay by using supplements & pharmeceuticals. In the same way that an anorexic believes food is bad for them, so those veggies insist that eating meat would make their conditions worse. I’m finding Zoe Harcombe’s blog a good pointer on diet – she wrangles various studies without mercy.

  6. Another excellent article Sebastian.
    I am 73, feel great, slim and very healthy on a carnivore diet, and my lipid profile is excellent.

  7. Slightly at a tangent, but related… the grasp of basic nutrition by members of the medical profession in the U.K. seems to be at its nadir. A stay in hospital invariably involves scant or inedible food, in the very place where healing – strongly linked with appropriate nutrition – might be expected. The studies you cite seem to typify the obfuscation of truth, ( ..how, for example, is the effect of multiple applications of herbicide and pesticide on fruit and vegetables still glossed over…?) and the skewing of ‘data’ in favour of giant food corporations’ marketing success. One of my burning questions relates to the eternal success of the so-called ‘soft drinks’ global industry, which, of course, is predicated upon corn syrup. Needless to say, there will never be a reliable assay of the real effects of these dubious confections upon the increase of dementia type conditions.

  8. You use “ketogenic” properly unlike many advocates of high fat consumption. Ketogenesis occurs when insulin signalling is low and lipolysis occurs. A ketogenic diet is a low insulin signalling diet, not a high fat diet.

    But, as you note there is little difference in the macronutrient composition of any of the popular diets. Having looked at the scatter plots of individual dietary intakes of dieters myself (a seldom done exercise) I found the overlaps are so large you could scarcely tell what diet any of the subjects were on. The variance within the dietary intakes of the subjects was immense; you could not separate an Atkins diet from an Ornish diet for many subjects because of the overlap in the individual plots.

    By the way, having been on many tenure committees I found self-plagerism to be very common. Not only did the “scientists” recycle their data among their publications, they also used chunks of the same paragraphs over and over again without attribution, which is a higher and more contemptible level of plagerism. They got away with it because few of us read all their publications as you did to find the recycled negative results. Refereeing is almost dead.

  9. Hi Sebastian,
    again, thanks for the evidence based review, very good.
    “So basically, one negative study was reported as two positive studies in the systematic review. And these were the two “big” studies”.
    Unfortunately, many of the public, and many doctors even, do not understand the failure of most current published “research”.
    Thanks again.

    1. If you are a newcomer to Dr Rushworth you will know that most of his readers/supporters are very familiar with Dr John Ioannidis and his stellar work regarding published, peer-reviewed studies.
      I was lead to Dr Rushworth from Ivor Cummins who I have read/supported for years due to his great work re: heart disease/insulin/keto etc.

  10. Just one last comment if I may.
    I am not at all convinced that the ketogenic diet ( greater than 70%of caloric intake as fat, no carbs) is at all healthy, especially long term
    A smallish amount of good quality carbs is essential for health, and moderate amounts of protein, nuts, legumes etc.
    I wouldn’t go crazy with the high fat intake.
    What do you think of the study below?

    Viewpoint
    July 15, 2019
    Shivam Joshi, MD1,2; Robert J. Ostfeld, MD, MSc3; Michelle McMacken, MD1,2
    Author Affiliations
    JAMA Intern Med. Published online July 15, 2019. doi:10.1001/jamainternmed.2019.2633

    1. My personal take is that the evidence is strong enough that a ketogenic diet should be the first line intervention for obesity and type 2 diabetes. I agree that protein is also an important part of the equation, and I think most people eating a standard western diet are consuming too little protein for optimal health.

      1. The standard western diet is something like 50% carbs, 40% fat, and 10% protein. I think a better breakdown, if the goal is to avoid chronic disease, would be 10% carbs, 70% fat, and 20% protein.

      2. Chimpanzees are the most genetically close biological species to humans. Interestingly, chimpanzees eat ~ 50-70 g of dietary fat per day, mostly polyunsaturated ω-3 and ω-6 fatty acids, which they extract from plants. And they get the same amount of fats “in situ” as a result of the enzymatic activity of the bacteria in the colon. But this time already in the form of short-chain fatty acids, mostly butyric acid (butyrate). At the same time, people in “rich” (health problematic) countries eat 120-160 g of dietary fat per day, mostly saturated fatty acids, getting only ~ 20 g of short-chain fatty acids from intestinal bacteria. I think the problem is not so much in the amount of fat consumed as in its quality. Supermarket edible fat is a poor substitute for butyrate.

      3. Great article Sebastian, we talk of little else in our family these days, what with 2 dementing octogenarians to cope with, and the rest of us working very hard to make our very own special contribution to the obesity epidemic …

        “I think a better breakdown, if the goal is to avoid chronic disease, would be 10% carbs, 70% fat, and 20% protein.” Implementation being the only substantive issue, what is the path to this ketogenic heaven please? Hitherto I’ve always thought of finding the narrow way in terms of morality rather than waistline.

        Keep up the good work!

    1. Well, in fairness, neither was his non-dementia predecessor. I was always astonished that he could function that well on a diet of Big Macs and Diet Cola. Must have the constitution of a horse.

      1. No alcohol or tobacco….and prob no THC….just a thought…. 🙂

  11. Several things:

    Weight loss can be due to loss of fat, loss of muscle, loss of bone density, or all 3.
    People speak of weight loss but what the mean is fat loss.
    The ketogenic diet (or better insulin sensitizing diet/lipolytic diet) results when there is a decrease in carbohydrate intake (either sugar or starch).
    Dysmetabolic syndrome results from excessive sugar, due to its fructose content.
    Excessive protein intake may increase glucose and increase fat; but the fat is healthy fat.
    Definition of excessive protein intake is difficult. The accepted level of protein intake is insufficient for any active person, including older individuals. Older individuals actually need more protein than younger individuals. In reality it is very difficult to achieve excessive protein intake.
    The best guideline is simple if you want to lose fat, avoid simple carbohydrate intake (either in the form of high fructose corn syrup, table sugar or its variations, and starchy vegetables).
    As a rule, there is little difference between the various ketogenic/lipolytic type diets; they are all variations of a theme.

  12. The descriptions of all three clinical studies (NCT03860792, NCT02912936, NCT03472664) did not indicate that the compared diets are isocaloric. In the reports of these studies, I saw the pattern of food intake, but did not see the total calorie intake. IMHO, it would be wrong to consider the first in isolation from the second. Excess daily calories above the physiological minimum has a negative impact on health regardless of the consumption pattern, as was rightly noted in Abstract https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3494735/. Because of these embarrassing ambiguities, the results of the first three studies cannot be accepted as conclusive.
    In a study by Dr. Roberts, “Among 937 subjects who were cognitively normal at baseline, 200 developed incident MCI or dementia”. However, the trials were conducted in a very high-risk group; and a crossover study design would probably be more convincing.
    Finally, I dare to suggest that the most important nutritional factor is not only the amount of fat, but also the ratio of the different classes of fat absorbed by the body. We are well aware of the beneficial omega-6:omega-3 ratio (3: 1), but we pay little attention to the SPA:LFA ratio. The classic recommendations to consume more fiber and less dietary fat are nothing more than a recommendation to shift the balance of fats: from exogenous long-chain to endogenous short-chain, right?

  13. That is correct. Supplementation by butyrate (a short chain fatty acid) yields similar benefits as a ketogenic diet, at least from a GI tract point of view. The level of ignorance in the medical community masquerading as knowledge is one of the biggest scams of the modern world.

    1. I am very glad to see a like-minded person.
      You said: Supplementation by butyrate (a short chain fatty acid) yields similar benefits as a ketogenic diet.
      So isn’t it better to go for healthy fiber and probiotics instead of the toxic supermarket fats used in the ketogenic diet?

      1. Yes. My advice is this: avoid any processed food. Only eat natural foods that are unprocessed. I don’t think it matters whether it is GMO or not. Animal fats are healthy (contrary to the popular literature and much healthier than most plant oils). You can get all the healthy fat you need by eating marbled meats.

        The problem with most probiotics is that they are destroyed in stomach acid. As long as diets are low in sugar, and fructose in particular, I believe your gut microbiome will repair itself. Personally I take butyrate supplements.

  14. I really appreciate your balanced views on science. Another wonderful, sain perspective rarely seen in today’s world of Global company dominance.

    I agree with your views on AD, however ater watching this video;

    https://youtu.be/Aw16LPVnNco
    By Dr Zach Bush chemical farming and the loss of human health

    regarding the 1992 watershed of cognitive disease increases, I suggest that other factors may be involved.

    Keep up the good work

    Michael

    1. Cognitive mental decline is due to loss of neuronal activity of the hippocampus. This is due to microvasculature disruption. This is due to increased massive sugar consumption; and in particular, fructose consumption, through its metabolic effect that causes inflammation of the vasculature.

      1. Do you think the annual flu jabs have anything to do with this? I’ve never had one but (mysteriously) American kids are soooo unhealthy. The school nurses’ cabinet is loaded with epipens….so many epipens.

    1. Between Alzheimer’s and good old-fashioned senility, Dr. Rushworth, is there any real, significant difference?

  15. Did this study account for statin drugs as a factor? My hunch is it didn’t and that skewed the results of the study. There is a clear correlation between the rise in statin drugs and the rise in dementia and Alzheimer’s. When you reduce the amount of cholesterol the body produces, given the brain’s chemistry, it will certainly be one of the first things affected.

    Anyway, IMO, if a high percentage of the subjects were taking cholesterol lowering drugs, I would disregard the study.

  16. Heads up for men. Watch out for soybean oil.

    “Japanese Researchers Use Soybean Compound to Turn Male Fish Into Females”

    https://summit.news/2021/06/01/japanese-researchers-use-soybean-compound-to-turn-male-fish-female/

    The researchers actually used isoflavone, which is found in soybeans. I think it’s a good idea to avoid soy protein, although soy sauce is fine due to fermentation or hydrolysis.

    I’ve read that soybean oil contains phytoestrogens and I try to avoid it, but research about the impact looks mixed. Still, it’s a processed food, so that’s a reason to avoid it.

  17. I think one major element of the sea change Dr. Rushworth points out was the trial of Professor Tim Noakes for alleged professional misconduct by the Health Professions Council of South Africa (HPCSA). For a 2014 tweet in which he opined that LCHF was a healthy diet to wean babies from breastfeeding, he was accused of professional misconduct, but eventually exonerated. Here is a summary of what transpired by Zoe Harcombe, a public health nutritionist who was a witness for the defense at Noakes’ trial:
    https://www.zoeharcombe.com/2018/06/the-hpcsa-vs-professor-noakes-tim-wins-again/

    With four years and presumably a much larger budget to work with than Noakes (who needed to get pro bono legal services), it should have been child’s play for the prosecution to secure a verdict of guilty if LCHF were really dangerous even to adults, let alone babies. Instead, they lost, then appealed the appealed the decision, then lost again. They shot themselves in the foot, their actions in effect vindicating LCHF rather than refuting it. They didn’t have a scientific leg to stand on. I applaud Professor Noakes’ courage under such adversity.

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