So you have read all the facts and study reviews, sounds pretty good so far doesn't it? But I know you still can't full let go because you have just seen another nutritional 'expert' on T.V say eating more regularlly is fantastic for weight loss, hunger control and controlling blood sugar.
Well that's funny because, Mr Alan Aragon (www.alanaragon.com) has done a critique (as a guest article on leangains.com) on the ISSN's position/stance on meal frequency. So I hope this closes the whole debate on needing to eat more frequently. Enjoy the article!
Link to article - http://www.leangains.com/2011/04/critique-of-issn-position-stand-on-meal.html
A Critique of the ISSN Position Stand on Meal Frequency
When International Society of Sports Nutrition (ISSN) released their position stand on the topic of meal frequency, two things stood out to me.
First of all, a number of questionable conclusions are made in the abstract. With my last article in mind, the claim that "...increasing meal frequency during periods of hypoenergetic dieting may preserve lean body mass in athletic populations" seems a bit presumptuous, wouldn't you say? An inquiring mind would like to know what conclusive data these gentlemen are sitting on.
Furthermore, given yesteryear's study on meal frequency and appetite control, the claim that "Increasing meal frequency appears to help decrease hunger and improve appetite control" is also rather interesting.
I could go on and on and give you numerous examples to counter some of the statements made in the abstract. But that is not the role I'm going to play today.
What was the second thing that stood out to me? You may recognize some names amongst the authors; the more notable ones are John Berardi - author of several diet books and articles - and Jose Antonio, CEO and co-founder of ISSN.
Is John Berardi - who, aside from making numerous scientifically unsound claims, has been one of the strongest proponents of high-meal frequency eating - unbiased enough to be allowed to participate in this publication? Berardi considers HMB a worthwhile supplement for athletes and wholeheartedly recommends it on his site. For those of you who don't know, HMB is damn near worthless. Buying it is as close to throwing your money away as you can possibly get (just like Glutamine - which Berardi also recommends). What does this say about his credibility as a scientist?
Jose Antonio? He's been the nutritional consultant to several supplement companies, among them Met-Rx, the king of meal replacements. What position do you think is most beneficial to maintain in order to keep the supplement industry spinning - that high-frequency eating is superior or that there's no difference between 3 and 6 meals a day? When people feel that the need to eat every other hour or so, what is it that they add to their diet? Protein shakes, protein bars, recovery drinks and meal replacements.
There's more here if you do some digging. Suffice to say, I was not convinced that this was the best team for an unbiased "position stand" on meal frequency. And the greatest joke of all? At the end of the paper, you'll find this: "Competing interests: The authors declare that they have no competing interests." When pigs fly, perhaps.
But never mind that for now. Let's judge this paper on its own merits and forget everything else. But I've talked myself blue in the face about the topic of meal frequency and it would be refreshing to have someone else dissect this paper for us. For that purpose, there is no one more fitting than Alan Aragon.
I've been a subscriber to Alan Aragon's Research Review since the first issue. AARR provides unbiased and critical analyses of the latest research on nutrition, exercise and supplementation. Adding to that, it also contains commentaries and analyses on the latest "hot topics" in the fitness industry and blogosphere. I'm giving it two thumbs up and recommend anyone interested in nutrition and exercise science to check it out. Download a free issue here.
A Critique of the ISSN Position Stand on Meal Frequency
By Alan Aragon
Originally Presented at Leangains.com, April 4th, 2011
Introduction
The International Society of Sports Nutrition (ISSN) is a forerunner in the movement toward providing reliable nutrition information for sports and fitness professionals. By virtue of its academically decorated staff and peer-reviewed research journal (JISSN), the ISSN is in a justifiable position to consider itself one of the world’s top authorities on sports nutrition. Thus, when they issue a position statement on any given topic, it’s frequently cited as solid evidence, and not taken lightly. For example, along with other literature reviews, I regularly cite their position paper on protein requirements for athletes [1]. However, I typically follow that up with what I do in personal practice, which isn’t always research-backed. It’s important to keep an eye on both the research and the trenches, since field knowledge can take years and sometimes decades to make it into academic publication.
It’s clear that the focus of their latest position stand is meal frequency’s effect on body composition. Right from the start, the authors illustrate the importance of this topic by citing the obesity epidemic in the United States. Setting the tone as such implies that weight/fat loss is the most pressing concern of the position stand, more so than other aspects such as muscle gain and exercise performance. This focus is justified, given the prevalence of obesity in industrialized nations, not just the United States. This justification is bolstered by the myriad health complications that accompany a chronic state of excess body fat. The next question becomes, how well does the ISSN support their meal frequency assertions to this end? I encourage you to have the ISSN’s position stand open while you read through this critique of the evidence used to support their key claims. The full text of the paper is freely available, see the reference list [2].
Body Weight & Body Composition
The authors begin the above-titled section by discussing uncontrolled/observational studies, including animal data. We can safely skip those, since the threats to their validity are numerous & obvious. They then move on to discuss experimental studies in humans. They correctly note that on the whole, the evidence in this area fails to indicate the superiority of increased meal frequency for improving weight loss. An interesting and important detail is the authors’ point that the minority of studies that did show improvements as a result of increased meal frequency happened to be in athletic subjects, whereas the ones that did not examined overweight/obese subjects. Three studies were provided to support this, which I’ll discuss next.
First up is Benardot et al, who compared the effects of three 250 kcal between-meal snacks with a noncaloric placebo [3]. A significant increase in anaerobic power and lean mass was seen in the snacking group, with no such improvements seen in the placebo group. Obviously, it’s impossible to credit the superior results to a higher meal frequency since this was also accompanied by a higher overall energy intake. The next study cited was by Deutz et al, which was not a controlled comparison of the isolated effects of different meal frequencies [4]. Instead, it merely drew correlations between body composition and the results of a 24-hour recall of diet and physical activity variables. The final study was by Iwao et al, who found that boxers consuming 6 meals a day lost less lean body mass (LBM) and showed lower molecular measures of muscle catabolism than the same diet consumed in 2 meals per day [5].
Of the three aforementioned studies, one was correlational. Of these two studies that demonstrated causation, only one of them (the boxer study) equally matched the intakes of each group. However, its design flaws compromise its relevance. Aside from flaws common to studies on both sides of the fence (short trial duration, subpar assessment methods, small sample size), the total energy intake at 1200 kcal was artificially low compared to what this population would typically carry out in the long-term. It’s also important to note that the protein intake, at 20% of total kcals, amounted to a paltry 60g/day. This translated to slightly under 1.0g/kg. To illustrate the inadequacy of this dose, recent research by Mettler et al showing that protein as high as 2.3g/kg and energy intake averaging 2022 kcal was still not enough to completely prevent LBM loss in athletes under hypocaloric conditions [6]. Therefore, the ISSN’s claim that increased meal frequency in athletic populations may improve body composition is based on a single study with questionable applicability.
Missing Research on Body Composition
In addition to the aforementioned limitation, the authors failed to mention research that runs contrary to their assertion that, “Interestingly, when improvements in body composition are reported as a result of increasing meal frequency, the population studied was an athletic cohort.” Introducing the topic of comparative drops in LBM opens up a can of worms that does not support the ISSN’s claims. A recent review by Farady concluded that although daily caloric restriction (DCR) and intermittent calorie restriction (ICR) have similar effects on total bodyweight reduction, ICR has thus far been more effective for retaining lean mass [7]. The results of 11 DCR studies 7 ICR studies were clearly laid out. Here are a couple of key stats that contributed to Farady’s conclusion:
- 3 of the ICR studies showed no significant decrease in LBM, while all of the DCR studies showed decreases in LBM.
- In studies lasting 8-12 weeks, average LBM loss was 1.25% in ICR and 4% in DCR.
Adding to the body of contrary data to the ISSN’s position, there are two more studies showing the superior effects on LBM status via lower meal frequency. An 8-week trial by Stote et al found the group consuming one meal per day gained lean mass and lost body fat, while the group consuming 3 meals per day showed no improvements in body composition [8]. It should be noted that just like the study by Iwao et al, Stote et al’s results are limited by the use of BIA to assess body composition. Oyvind et al compared the 12-week effects of eating 3 versus 6 meals per day in subjects on a resistance training program, and the lower-frequency group gained significantly more LBM [9].
Collectively, this body of research refutes the ISSN’s claim that superior effects on body composition have only been seen in athletic subjects with higher meal frequencies.
Blood Markers of Health
As an obligatory introduction, the authors begin their above-titled section by discussing observational/uncontrolled studies. Again, there’s no need to wade through this, given the availability of controlled studies. The first controlled intervention discussed is by Stote et al, where blood pressure and total cholesterol (both HDL & LDL) were higher in the group consuming 1 meal per day compared to the 3-a-day group [8]. However, Stote et al noted that the difference in blood pressure may have been due to differences in circadian rhythm since it was measured in the late afternoon in the 1-meal group, and in the early morning in the 3-meal group. No speculations were made over what might have caused the cholesterol increase in the 1-meal group.
Another concern of the ISSN was the potentially adverse effect of lower meal frequency on glucose homeostasis. In support, they cited work published in the 1960’s. They also cited subsequent work done in the same proximity with contrary outcomes. Notably, they discussed a study by Jenkins et al, which compared 3 versus 17 feedings per day and found no difference in mean blood glucose levels [10]. Although the latter failed to show improvements in blood glucose levels, benefits from the (unrealistically) high meal frequency improved insulin levels and blood lipid profile. Although the data in this area is equivocal, the ISSN recommends increasing meal frequency for the purpose of improving health markers.
Missing Research on Glucose Control
An 8-week trial by Carlson et al found that subjects consuming 3 meals instead of 1 meal per day had more favorable results on an oral glucose tolerance test (OGTT) [11]. However, the authors of this study acknowledge that this may have been due to a much larger consumption of food in closer proximity to the OGTT in the single-meal group. Testing was first thing in the morning, and the single-meal group consumed their day’s intake in a 4-hour window before bed.
A very recent study adds to the evidence contrary to this idea, and was likely unavailable at the time of the ISSN position stand was written. Holmstrup et al found that glucose levels remained elevated throughout the day with frequent 6 meals compared to 3 meals, and no differences in insulin levels were seen [12]. The key design strengths this study has over predecessors were the frequent sampling used to track blood glucose and insulin levels, and the use of healthy non-obese subjects with normal glucose tolerance. These aspects make it more relevant to active & athletic populations, to whom the ISSN’s position stand is directed in the first place. Another trial too recently published to make it into the position stand was by Harvie et al, who found that intermittent energy restriction was as effective as continuous energy restriction for decreasing bodyweight and increasing insulin sensitivity [13].
In sum, due to the inconsistency of the data, it appears that increasing meal frequency for the purpose of improving health-related biomarkers is a premature recommendation.
Metabolism
The aspects of metabolism discussed in this section are diet-induced thermogenesis (DIT – also called the thermic effect of food), resting metabolic rate, and protein metabolism. As for DIT, differences between varying meal distributions across several studies are negligible. The same lack of difference was also seen in several studies, including tightly controlled designs involving metabolic chambers to measure resting metabolic rate and total energy expenditure. These data further serve to invalidate the dying cliché of stoking the metabolic fire with frequent small feedings.
The discussion of protein metabolism mainly involved the effects of meal frequency on nitrogen retention. The ISSN duly notes that most studies discussed in this section used nitrogen status as a proxy for muscle protein status, which is not always reliable. The nitrogen balance technique measures whole-body (systemic) nitrogen flux, rather than directly measuring protein turnover within skeletal muscle. Although the nitrogen balance method has limited applicability, it provides clues & hypotheses to test through more rigorous & direct means. The literature on meal frequency and nitrogen retention is reviewed, and the bulk of the data shows no differences despite meal frequencies ranging from one to six meals per day.
The discussion of effects on protein metabolism begins by citing work by Garrow et al, who saw less nitrogen loss in obese subjects in hypocaloric conditions consuming 5 meals per day, compared to consuming 1 meal per day, and lean mass preservation was more pronounced in the higher protein treatments [14]. However, the extrapolability of this research to real-world scenarios in non-sedentary & athletic populations is highly questionable. Total energy of the diets was 800 kcal, and the protein levels tested ranged from 10-15% of total kcals, amounting to 20-30g of protein per day. This amount represents about a tenth of the protein typically consumed by adult male athletes. The limitations of this study’s design are obvious.
The authors then proceed down a slippery slope by discussing the potential benefit of maximizing muscle protein synthesis (MPS) on a per-meal basis. In acute (short-term or immediate-effect) studies on individuals of average body weight, the protein dose that tops out MPS is roughly 20-30g of high-quality protein, or about 10-15g of essential amino acids (EAA). Given this, the authors make a logical leap by presuming that more frequent occasions of maxing-out MPS would ultimately lead to faster rates of muscle gain. To support this idea, they cite rodent research by Wilson et al [15] and short-term human research by Paddon-Jones et al [16]. I’ll comment on the latter since rat data pales in relevance when there’s human data available to examine.
Paddon Jones et al found that MPS was greater when an EAA + carbohydrate liquid supplement was consumed between the 3 regular-sized solid meals [16]. As a result, this study is often cited to support both the idea of increasing protein feedings as well as the benefits of dosing EAA between meals. The problem is, the group receiving the inter-meal supplementation ended up with 45g EAA + 90g carbs more than the control group by the end of the 16-hour test period. This treatment imbalance in both total calories and macronutrition is compounded by low protein intakes, averaging 23g per meal, totaling 64g per day. The experimental group’s supplemental intake boosted protein intake to 109g. So, not only was there the confounding element of unmatched macronutrition between groups, it essentially was a comparison of insufficient protein intake versus barely adequate intake.
After examining the literature on protein metabolism/nitrogen retention, the ISSN concluded that, “…it appears as if the protein content provided in each meal may be more important than the frequency of the meals ingested, particularly during hypoenergetic intakes.” Still, this statement is collectively based on the Garrow study involving 20-30g protein per day, the Wilson rodent study, and the Paddon-Jones study, all of whose limitations are critical. Nevertheless, the ISSN made the redeeming point that increasing meal frequency isn’t likely to increase metabolic rate. To their credit, they repeatedly acknowledged that there’s a lack of research on the effect of meal frequency on various aspects of metabolism in athletic & physically active subjects.
Missing Research on Markers of Protein Metabolism
Missing from this section of the paper was any mention of recent work by Soeters et al, who saw no difference in glucose, lipid, or protein metabolism between an intermittent fasting treatment (involving 20-hour fasting cycles) and a standard diet [17]. Similarly, Arnal et al saw no significant difference in body composition & nitrogen retention in subjects consuming most of their daily calories in 1 meal versus 4 evenly-spread meals throughout the day [18]. In older subjects, the same research team actually found better nitrogen retention with most of the day’s calories from 1 meal instead of 4 meals [19].
Although the ISSN isn’t firm with it, there’s an underlying implication that increasing the frequency of protein dosing at the threshold known to max-out MPS (20-30g protein or 10-15g EAA) would optimize the rate of net muscle protein gains. If this were true, then more muscle would be lost in lower-frequency treatments. Conversely, greater gains would be seen in higher-frequency treatments over time. The majority of the research thus far has simply not supported either one of these phenomena [7-9, 17-19, 21, 22].
Hunger and Satiety
This section begins by discussing short-term (within-day) effects of meal frequency on hunger and satiety. These designs involved the pre-loads of varying meal distributions, and measuring subsequent ad libitum food intake. Unanimously, the higher-frequency meal preloads resulted in better appetite control, evidenced by lesser subsequent intakes. Additionally, a study by Smeets et al found higher satiety ratings over a 24-hour period in subjects consuming 3 meals instead of 2 [20].
The important question is whether the hunger-controlling effects of higher meal frequency persist beyond a single day. The ISSN only mentions 2 such studies, and they happen to have conflicting outcomes. Stote et al’s 8-week trial reported greater hunger levels in subjects consuming 1 versus 3 meals per day [8]. A more recent trial by Cameron et al compared 6 meals per day (technically 3 meals + 3 snacks) with 3 meals per day, and found no significant differences in appetite ratings [21]. Additionally, there were no trends suggesting a significant effect of increased meal frequency on the levels of the appetite-regulating peptides ghrelin and peptide YY (PYY). As seen consistently in other research, there were no differences bodyweight decrease or body composition change. Curiously, despite the equivocal results of these two trials, the ISSN concluded that increasing meal frequency is likely to decrease hunger and control intake in subsequent meals. But as we’ll see, more recent data continues to challenge this idea.
Missing Longer-Term Research on Hunger & Satiety
An important study is missing from the ISSN’s review. In fairness, it’s likely because it wasn’t yet available at the time it was written. Leidy et al compared varying protein levels consumed across either 3 or 6 meals per day [22]. Predictably, the higher-protein level (25% vs. 14%) promoted greater satiety. Interestingly, the higher meal frequency led to lower daily fullness ratings regardless of protein level. Meal frequency had no significant impact on ghrelin levels, regardless of protein intake. PYY, which is associated with satiety, was 9% lower in the higher meal frequency.
When focusing mainly on the short-term (within-day) studies, increasing meal frequency appears to have beneficial effects on appetite control. However, these results for the most part have not been supported by longer-term research. Thus, the blanket recommendation to increase meal frequency in order to decrease hunger is not based on the weight of the evidence.
Athletic Populations
This section of the position paper was basically a reiteration of the outcomes of 3 studies discussed earlier, in attempt to emphasize the point that more is potentially better when it comes to meal frequency. In response, I’ll briefly review my contentions with the applicability of this data. Deutz et al was a retrospective correlational study, not a controlled intervention capable of demonstrating causation [4]. Iwao et al’s study on boxers used a protocol that was artificially low in total kcals and unrealistically low in protein compared to what athletes typically consume [5]. Benardot et al’s design did not match total energy and macronutrition between groups, so it’s not surprising that the greater performance and lean mass gains occurred in the group with the higher fuel consumption [6]. In addition to the crucial limitations of these studies, research with contrary results (and equal or better design quality) is missing from this position stand [7-9].
The authors go on to assert that data on the eating habits of competitive athletes (in primarily endurance-based sports) shows a range of roughly 5-10 eating occasions per day. They suggest that this is optimal because it enables athletes to consume a culturally normal meal pattern in addition to meals proximal to the training bout. In response to this, I’d say that this range of frequencies is fine for this population. But, I’d also contend that the energy needs of competitive athletes in endurance-based sports can be 2-4 times greater than that of recreationally active individuals (who make up the bulk of the nonsedentary adult population). Therefore, applying the meal frequency of competitive athletes to less active populations is unnecessary & impractical, at best. In my private practice, I’ve seen recreational athletes succeed long-term with as little as 2 meals per day. The most common meal frequency range I’ve observed in physically active clients with long-term success is rather broad (3-6 meals per day). Whether individuals choose the higher or lower end of that range is based solely on personal preference and tolerance.
Boiling Things Down: The Position Statements
Credit is due to the ISSN for preemptively stressing that the research on physiological & morphological effects of meal frequency in physically active and athletic populations is scarce. They responsibly state that this prevents definitive conclusions from being made. The following are the exact statements that comprise the ISSN position stand on meal frequency, which I’ll follow with my comments & conclusion.
- Increasing meal frequency does not appear to favorably change body composition in sedentary populations.
- If protein levels are adequate, increasing meal frequency during periods of hypoenergetic dieting may preserve lean body mass in athletic populations.
- Increased meal frequency appears to have a positive effect on various blood markers of health, particularly LDL cholesterol, total cholesterol, and insulin.
- Increased meal frequency does not appear to significantly enhance diet induced thermogenesis, total energy expenditure or resting metabolic rate.
- Increasing meal frequency appears to help decrease hunger and improve appetite control.
When examining the above points, 1 & 4 have a substantive, cohesive, and adequately-designed body of research backing them. Thus, they possess the strongest evidence basis of the bunch. Number 3 sits right on the fence, since it’s a particularly complex and delicate area with much conflicting data. It’s my hunch that the differential effects of varying meal frequencies on blood markers of health would greatly diminish in the presence of a formal exercise program. Again, the potentially profound impact of training that’s missing from the current meal frequency research leaves big questions unanswered. Points 2 & 5 have the least scientific support, and the largest leaps of faith and bias from the ISSN.
In Closing
I’d advise everyone with enough motivation to dig into the references and question the conclusions of all parties involved. It’s clear that position stands of authoritative organizations are far from being completely accurate, complete, and bias-free. With that said, the ISSN provides plenty of food for thought. Again, read the full text of their paper in order to get the most out of my critique of it [2]. Meal frequency research is becoming increasingly more active, so it’s safe to predict that in the coming years, more relevant designs will narrow the gap between the questions and answers. Something I can wholeheartedly agree with is the paper’s closing quote: “Nonetheless, more well-designed research studies involving various meal frequencies, particularly in physically active/athletic populations are warranted.”
References
1. Campbell B, et al. International Society of Sports Nutrition position stand: protein and exercise. J Int Soc Sports Nutr. 2007 Sep 26;4:8. [Medline]
2. La Bounty PM, et al. International Society of Sports Nutrition position stand: meal frequency. J Int Soc Sports Nutr. 2011 Mar 16;8(1):4. [Epub ahead of print] [Medline] [JISSN]
3. Benardot D, et al. Between-meal energy intake effects on body composition, performance, and total caloric consumption in athletes. Med Sci Sports Exerc. 2005;37(5):S339. [MSSE]
4. Deutz RC. et al. Relationship between energy deficits and body composition in elite female gymnasts and runners. Med Sci Sports Exerc. 2000 Mar;32(3):659-68. [Medline]
5. Iwao S, et al. Effects of meal frequency on body composition during weight control in boxers. Scand J Med Sci Sports. 1996 Oct;6(5):265-72. [Medline]
6. Mettler S, et al. Increased protein intake reduces lean body mass loss during weight loss in athletes. Med Sci Sports Exerc. 2010 Feb;42(2):326-37. [Medline]
7. Varady KA. Intermittent versus daily calorie restriction: which diet regimen is more effective for weight loss? Obes Rev. 2011 Mar 17. [Epub ahead of print] [Medline]
8. Stote KS, et al. A controlled trial of reduced meal frequency without caloric restriction in healthy, normal-weight, middle-aged adults. Am J Clin Nutr. 2007 Apr;85(4):981-8.[Medline]
9. Oyvind H, et al. The effect of meal frequency on body composition during 12 weeks of strength training. 12th Annual congress of the European College of Sport Science, 2007. [ECSS]
10. Jenkins DJ, et al. Nibbling versus gorging: metabolic advantages of increased meal frequency. N Engl J Med. 1989 Oct 5;321(14):929-34. [Medline]
11. Carlson O, et al. Impact of reduced meal frequency without caloric restriction on glucose regulation in healthy, normal-weight middle-aged men and women. Metabolism. 2007 Dec;56(12):1729-34. [Medline]
12. Holmstrup ME, et al. Effect of meal frequency on glucose and insulin excursions over the course of a day. Eur e-J Clin Nutr Metab. 2010 Dec;5(6):277-80. [e-SPEN]
13. Harvie MN, et al. The effects of intermittent or continuous energy restriction on weight loss and metabolic disease risk markers: a randomized trial in young overweight women. Int J Obes (Lond). 2010 Oct 5. [Epub ahead of print] [Medline]
14. Garrow JS, et al. The effect of meal frequency and protein concentration on the composition of the weight lost by obese subjects. Br J Nutr. 1981 Jan;45(1):5-15. [Medline]
15. Wilson GJ, et al. Equal distributions of dietary protein throughout the day maximizes rat skeletal muscle mass. The FASEB Journal, 2010. 24(740.17). [FASEB J]
16. Paddon-Jones D, et al. Exogenous amino acids stimulate human muscle anabolism without interfering with the response to mixed meal ingestion. Am J Physiol Endocrinol Metab. 2005 Apr;288(4):E761-7 [Medline]
17. Soeters MR, et al. Intermittent fasting does not affect whole-body glucose, lipid, or protein metabolism. Am J Clin Nutr. 2009 Nov;90(5):1244-51. [Medline]
18. Arnal MA, et al. Protein feeding pattern does not affect protein retention in young women. J Nutr. 2000 Jul;130(7):1700-4. [Medline]
19. Arnal MA, et al. Protein pulse feeding improves protein retention in elderly women. Am J Clin Nutr. 1999 Jun;69(6):1202-8. [Medline]
20. Smeets AJ, Westerterp-Plantenga MS. Acute effects on metabolism and appetite profile of one meal difference in the lower range of meal frequency. Br J Nutr, 2008. 99(6): p. 1316-21. [Medline]
21. Cameron JD, et al. Increased meal frequency does not promote greater weight loss in subjects who were prescribed an 8-week equi-energetic energy-restricted diet. Br J Nutr. 2010 Apr;103(8):1098-101. [Medline]
22. Leidy HJ, et al. The influence of higher protein intake and greater eating frequency on appetite control in overweight and obese men. Obesity (Silver Spring). 2010 Mar 25. [Epub ahead of print] [Medline]
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