Wikipedia:Featured article candidates/Beta-Hydroxy beta-methylbutyric acid/archive2


 * The following is an archived discussion of a featured article nomination. Please do not modify it. Subsequent comments should be made on the article's talk page or in Wikipedia talk:Featured article candidates. No further edits should be made to this page.

The article was archived by Ian Rose via FACBot (talk) 04:44, 17 December 2016.

Beta-Hydroxy beta-methylbutyric acid

 * Nominator(s):  Seppi  333  (Insert 2¢) and Boghog (talk) 18:12, 18 October 2016 (UTC)

This article is about a medical food ingredient and dietary supplement that is a natural product in humans and has medical and athletic performance-enhancing applications for preventing/reversing muscle wasting and improving body composition.

This is the second pharmacology article that I've worked on for FA status. My first pharmacology FA was amphetamine, so this article's layout and formatting mirror that article. Like amphetamine, this article includes citations in the lead. I will not remove these because many of these statements are medical claims; however, I'm amenable to moving the citations into a note at the end of each paragraph as was done in the lead of amphetamine if reviewers of this nomination prefer this approach.

The labels in the section headers and their organization in the article follows MOS:PHARM and MOS:MED. The sources used to cite medical claims in this article are required to satisfy WP:MEDRS; most, if not all, of the WP:PAYWALLED medical reviews that are currently cited in the article are and will be temprorarily available in this link for viewing/downloading to allow reviewers to conduct WP:V checks for the duration of this nomination and any subsequent FAC nominations. The file names (without the .pdf extension) of the papers listed in this link reflect the reference names (i.e., ) defined in the source code of the HMB article.

 Seppi  333  (Insert 2¢) 18:12, 18 October 2016 (UTC)


 * I'm pinging you to notify you that this article has been renominated.  Seppi  333  (Insert 2¢) 18:32, 18 October 2016 (UTC)


 * Due to recent change to Wikipedia's formatting/settings, I no longer find it convenient to edit (or even view) Wikipedia. Sorry. (See here for details.) Axl ¤ [Talk]  11:05, 22 October 2016 (UTC)

Comments by Mirokado
I probably won't be able to do a full review of this, but I would like to comment that I think the ref callouts in the lead are fine as you have them: collecting them at the end of each paragraph would mean a lot of effort for each reader to decide which ref supported which statement. --Mirokado (talk) 18:39, 18 October 2016 (UTC)

Comments by Doc James
Not yet The lead is simply too complicated. This article is not written for a general audience, not even the lead. Additionally we see very large quotes remaining in the reference section. These need to be shortened significantly. Happy to see references remain in the lead. Doc James (talk · contribs · email) 20:36, 22 October 2016 (UTC) Based upon the text in Beta-Hydroxy beta-methylbutyric acid which is cited by the current reference #16, what sentences do you think should be pruned from its quote? I can't really decide.  Seppi  333  (Insert 2¢) 18:51, 26 October 2016 (UTC)
 * I don't really have a clue as to what you think is too complicated, so can you make some edits or propose some changes so that I can follow up and address this? I'll work on pruning some of the quotes sometime this coming week.  Seppi  333  (Insert 2¢) 23:41, 22 October 2016 (UTC)
 * Here is a suggestion for the first sentence of the lead that is drop dead simple:
 * β-Hydroxy β-methylbutyric acid (HMB), also known as β-hydroxy β-methylbutyrate (hydroxymethylbutyrate, HMB), is a substance naturally produced in humans that is also used as nutritional supplement.
 * Some of the remaining details in the lead (e.g., mechanism) could also be shortened and simplified. I will work on this once I have a spare moment. Boghog (talk) 20:20, 25 October 2016 (UTC)
 * I've made edits to the lead sentence per your suggestion (special:diff/745972720/746194240).  Seppi  333  (Insert 2¢) 21:02, 25 October 2016 (UTC)
 * Do you think the following highlighted clause should be deleted? "HMB produces these effects in part by stimulating myofibrillar muscle protein synthesis and inhibiting muscle protein breakdown through various mechanisms, including activation of mechanistic target of rapamycin complex 1 (mTORC1) and inhibition of proteasome-mediated proteolysis in skeletal muscles." It's the most technical statement in the lead. I only added it to give credence to the preceding clause in that sentence.  Seppi  333  (Insert 2¢) 21:18, 25 October 2016 (UTC)
 * I'm going to prune any lengthy reference quotes that make statements that are unrelated to the compound's pharmacology a little later today. Would it be alright with you if I left in the reference quotes that cover some of the more involved pharmacological information until after someone does a review of the pharmacology section? I think it would make it a lot easier on a pharmacology/molecular biology reviewer if those quotes are left in until after they've finished doing their review.  I've made a request at WT:PHARM and WT:MCB for someone to take on a review of this section to try to attract a reviewer for this section since that's the only part of the article that hasn't been thoroughly reviewed by someone with a relevant background.  Seppi  333  (Insert 2¢) 21:11, 25 October 2016 (UTC)
 * Sure sounds good. Ping me when you are done. Doc James  (talk · contribs · email) 21:36, 25 October 2016 (UTC)
 * I've censored and/or deleted parts of several reference quotes: Special:diff/746211222/746327967.
 * We want the quote to be enough to guide those looking at it to were in the source the content is supported. We do not want the quotes to be a replacement for the source and that is what might cause us problems. Doc James  (talk · contribs · email) 19:00, 26 October 2016 (UTC)
 * How's that?  Seppi  333  (Insert 2¢) 19:03, 26 October 2016 (UTC)
 * Are you ok with the current reference quotes that don't include any pharmacology information? I'm going to censor most of the pharmacology-related paragraph-long quotes after that section is reviewed.  I intend to censor most of the pharmacology-related statements in the reference quotes that currently contain both medical claims and pharmacology-related statements after the pharmacology section is reviewed.  Seppi  333  (Insert 2¢) 19:12, 26 October 2016 (UTC)

In the body
This IMO is overly detailed for the lead

"HMB produces these effects in part by stimulating myofibrillar muscle protein synthesis and inhibiting muscle protein breakdown through various mechanisms, including activation of mechanistic target of rapamycin complex 1 (mTORC1) and inhibition of proteasome-mediated proteolysis in skeletal muscles."

Doc James (talk · contribs · email) 21:19, 26 October 2016 (UTC) I'm fine with most of the changes that you made, but I made a few edits to clarify some of the existing text (Special:diff/746406984/746497057). I tried to use simple language when making these revisions, but if you think one of the statements that I added or modified in my edits needs further simplification, just let me know and I'll work on it with you.
 * Looking at the quotes and often the quote provided supports one of the uses of the ref. Wondering User:Seppi what you think of moving them to comments behind the ref in question like this ? Doc James  (talk · contribs · email) 21:26, 26 October 2016 (UTC)
 * The issue I see with that is some unknowing editor could come along, see the commented text, think it should be in the article and then uncomment it. This would introduce unattributed quotes to the article text. Sizeofint (talk) 00:50, 27 October 2016 (UTC)
 * It does say "Quote = "In conclusion, HMB treatment clearly appears to be a safe potent strategy against sarcopenia, and more generally against muscle wasting, because HMB improves muscle mass, muscle strength, and physical performance."" I have not seen people generally uncomment text but yes something one would need to keep an eye on. Doc James  (talk · contribs · email) 06:20, 27 October 2016 (UTC)
 * Ah, I missed that you kept the quote parameter. That might mitigate the issue slightly, although if the stewardship of this article changes in the future editors still may be unaware of the purpose of the the commented material. Sizeofint (talk) 18:18, 27 October 2016 (UTC)
 * I'm okay with doing this as long as the censored quote isn't removed from the reference quote, since that lets me and others know which ref a censored quote comes from.
 * Also, I added the more technical pharmacodynamics statement that you deleted to a note at the end of a simplified sentence in the lead that describes how it works/affects skeletal muscle. Are you okay with that?  Seppi  333  (Insert 2¢) 19:39, 27 October 2016 (UTC)
 * This is simplier thanks "HMB produces these effects in part by stimulating the production of proteins and inhibiting the breakdown of proteins in muscle tissue."
 * Rather than putting the more complicated details in a note that says "HMB has been shown to stimulate myofibrillarmuscle protein synthesis and inhibit muscle protein breakdown in humans through various mechanisms, including activation of mechanistic target of rapamycin complex 1 (mTORC1) and inhibition of proteasome-mediated proteolysis in skeletal muscles.[8][14][15]" this should just be dealt with in the body of the text IMO. Doc James (talk · contribs · email) 21:49, 27 October 2016 (UTC)

Fine with me. I deleted the note.  Seppi  333  (Insert 2¢) 22:51, 27 October 2016 (UTC)
 * Are you satisfied with the article lead and the citation quotes (specifically, the ones that don't cover pharmacology-related information) now, or is there something else you'd like me to work on?  Seppi  333  (Insert 2¢) 21:47, 4 November 2016 (UTC)

Number of refs
Looking at this text "Supplemental HMB is also used by athletes to increase exercise-induced gains in muscle size, muscle strength, and lean body mass, reduce exercise-induced skeletal muscle damage, and speed recovery from high-intensity exercise.[2][8][11][12][13]"

The quote supplied in this ref "Molecular Aspects of Medicine 2016 review" however does not support that text? It supports the text in the previous sentence. Do all 5 of those references support the statement in question? Can simply the best one or two be used? Doc James (talk · contribs · email) 21:53, 27 October 2016 (UTC)
 * The quote doesn't, but the ref does: . See section 6.3. I don't normally generalize statements or make inferences from references when I write article content, but I'll double-check that the other refs directly support at least part of that statement when I get home.   I'm editing on my phone at the moment.  Seppi  333  (Insert 2¢) 22:56, 27 October 2016 (UTC)
 * Based upon the body, it looks like refs 2, 11, and 13 independently support most or all 5 of the claims in that sentence. IIRC, ref 2 supports the entire sentence.  Seppi  333  (Insert 2¢) 23:25, 27 October 2016 (UTC)
 * Would be nice if there was the ability to have a quote in each so one could have a different quote associated with each sentence the ref is used for.  Doc James  (talk · contribs · email) 23:27, 27 October 2016 (UTC)
 * Sorry for not following up sooner. I'd be okay with using repeated citations to the same reference with a different quote, but I thought you wanted me to cut down the total amount of quoted text.  Are you saying you'd be okay with using a relatively long quote of like 6-8 sentences if that's broken up into 3 citations which contain 2-3 sentences of the original quote and cite different statements in the article text? Or, did you just mean I should do something like this with the current quotations?  I'm going to try to keep the quotes to a 3 sentence limit, but some references contain a number of significant medical claims about treatment effects that are spread over multiple sentences; e.g., reference 10 has an 8 sentence quote that independently and directly supports every claim made in each of the 6 sentences that it cites in this article; none of the 8 sentences in that quote are superfluous since every one of them supports at least part of a sentence in the article.


 * As for your question about the references that cite the performance-enhancing effects sentence:
 * the current reference #2 supports all of the claims in the performance-enhancement sentence in the quoted portion of the abstract in its abstract and the body of the article (in the event you decide to read this ref, it's worth noting that it uses the abbreviation FFM, for "fat free mass", when discussing the effects on lean body mass); the body of that citation elaborates on each of those claims covered in the abstract in more detail. It also mentions a few other performance-enhancing effects that were reported in a handful of studies; I chose not to include those in the article text. This is the most comprehensive reference on HMB's performance-enhancing effects.
 * as I mentioned earlier in this thread, section 6.3 in the current ref #8 supports several of the claims in the performance-enhancement sentence.
 * the current ref #9 (this ref cites the text in the body, but not the lead) supports a few of the claims in the sentence; it states: Beta-hydroxy-beta-methylbuty- rate (HMB) is a metabolite of the branched-chain amino acid leucine (Nissen & Abumrad, 1997), which has been investigated due to its potential role in improving muscle quality. Multiple studies have explored mechanisms that link HMB to muscle loss; it has been suggested that HMB can enhance protein synthesis via upregulation of anabolic signaling pathways and attenuate proteolysis via downregulation of catabolic signaling pathways (Hasselgren, 2014). Likewise, population surveys and clinical studies suggest that HMB treatment decreased muscle proteolysis (Baier et al., 2009) and muscle damage and increased fat-free mass gain both in young and older adults (Molfino, Gioia, Rossi Fanelli, & Muscaritoli, 2013). Indeed, HMB has been extensively used as an ergogenic aid, especially among bodybuilders and power athletes, who use it to promote exercise performance and skeletal muscle hypertrophy (Wilson et al., 2013a). However, not all studies have found beneficial effects of HMB supplementation.
 * the current reference #11 also independently supports most of the claims in that sentence: Despite differences in these studies, it does appear that HMB overall enhances muscular hypertrophy, strength, and power. In fact, the International Society for Sports Nutrition, in a position statement, writes that HMB can be used to enhance recovery by reducing skeletal muscle damage after exercise in athletically trained and untrained people. The utility of HMB does seem to be affected by timing of intake prior to workouts and dosage [97].
 * the current reference #12 supports several claims made in that sentence, including some claims that I didn't include in the article (e.g., endurance) HMB supplementation has shown to greatly influence the body strength and composition and also prevent muscle injury during exercise and improve muscle endurance. ... It can be concluded that creatine and HMB have clearly shown to exhibit ergogenic properties; as results from a meta-analysis mentioned before support their application in sports and exercise. In the table and in several sentences of that reference, it points out that HMB induces increases in lean body mass in the general population; it also noted in one sentence that a subset of studies which used a sample of well-conditioned resistance-trained athletes reported no significant effect on lean mass.
 * I deleted 1 of the references supporting the lead sentence since it was outside WP:MEDDATE (published in 2010) and wasn't really necessary since the other 4 citations were adequate. I suppose ref #8 could come out if you think 4 refs is still too much for 5 medical claims.  Seppi  333  (Insert 2¢) 21:19, 29 October 2016 (UTC)
 * Will look further in a bit. Doc James  (talk · contribs · email) 08:17, 5 November 2016 (UTC)

I just noticed this morning that the article no longer conformed to MOS:ABBR's requirement that all abbreviated terms be written out in full on their first instance. Since the Medical and Enhancing performance sections both include the HMB-CA and/or HMB-FA abbreviations which are covered in the Available forms section, I needed to move the Available forms section to the top of the Uses section. I did so in this edit. Are you okay with that, or would you prefer that we re-add the sentence on the free acid and conjugate base to the lead? The lead sentence originally was: HMB is sold worldwide as a dietary supplement in the free acid form (HMB-FA) and as a monohydrated calcium salt of the conjugate base, calcium β-hydroxy β-methylbutyrate monohydrate (HMB-Ca), at a cost of about US$30–50 per month when taking 3 grams per day. It currently is: HMB is sold worldwide as a dietary supplement at a cost of about US$30–50 per month when taking 3 grams per day.  Seppi  333  (Insert 2¢) 17:03, 9 November 2016 (UTC)
 * One could put the abbreviations in the infobox which would cover you. Doc James  (talk · contribs · email) 20:57, 9 November 2016 (UTC)

Wording
Wondering if "An NCAA study from 2006 found that 1.9% of college student athletes used HMB as a dietary supplement" would be better as "In 2006 about 1.9% of college student athletes in the United States used HMB as a dietary supplement" as I imagine the data is US centric. Doc James (talk · contribs · email) 21:06, 9 November 2016 (UTC)
 * I updated the wording in the article to reflect your proposal a while back but apparently forgot to mention it here. Are you satisfied with the article as is?  Seppi  333  (Insert 2¢) 19:18, 5 December 2016 (UTC)
 * Is there anything else you'd like me to address, or do you believe that the article is FA-quality now?  Seppi  333  (Insert 2¢) 02:18, 9 December 2016 (UTC)

Not supported?
We have this sentence "Supplemental HMB inhibits the loss of lean body mass in muscle wasting conditions, particularly in individuals with muscle lose with age or during bed rest. It is often used in addition to resistance exercise." supported by


 * which says "Deutz et al. (2013) did not report any effect of HMB on muscle strength after 10 days of bed rest in the elderly (men and women) but showed a clear tendency to limit the decrease observed; the latter result did not reach statistical significance probably due to the small sample size."
 * which says "may be useful in the prevention of muscle atrophy induced by bed rest" The meta analysis from 2015 on HMB has 147 treatment and 140 control older adults only. The number looking at bed rest was 24 of which 19 finished (that is 11 and 8)
 * doesn't mention bed rest in relation to HMB.

If one is dealing with something as common as muscle loss with aging it concerns me some that we are making such definitive statements based on so little data. I would call the evidence poor for "during bed rest" and tentative for aging. Doc James (talk · contribs · email) 07:52, 9 December 2016 (UTC)

Other sources (I just picked the first three that came up on pubmed)
 * 2016 systematic review finds mixed results "For proteins, a combination therapy of β-hydroxy-β-methylbutyrate (HMB), arginine, and glutamine showed an increase in lean body mass after 4 weeks in a study of advanced solid tumour patients, whereas the same combination did not show a benefit on lean body mass in a large sample of advanced lung and other cancer patients after 8 weeks. In summary, the effect of the combination of HMB, arginine, and glutamine on weight gain should be investigated in further studies on cancer patients investigating time periods of several months."


 * 2015 systematic review "The HMB studies are suggestive of a beneficial effect on older adults, but larger well-controlled studies are required that measure outcomes relevant to sarcopenia, ideally in sarcopenic populations." (as most trials were in healthy people) -> when an article uses the term "may" it can equally mean "may not"


 * "Methodology and quality of studies were too varied to draw any firm conclusion. ... High-quality research is required in critical care before treatment recommendations can be made."

The three most recent sources are much less supportive than our article. Doc James (talk · contribs · email) 07:51, 9 December 2016 (UTC)
 * This general reviews from 2014 on Sarcopenia in older people states "Two other dietary supplements have been noted as having a positive effect on muscle mass and strength, especially when combined with exercise, but are subjected to further research. Creatine is a major component of muscle stores, and studies have suggested that creatine supplementation may increase the concentration of creatine in skeletal muscle, promoting an increase in strength and mass.111–113 Beta-hydroxy-beta-methylbutyrate ([beta]-HMB) is a metabolite of the EAA leucine, and early studies suggest that it might potentially increase muscle mass, as well as reduce muscle breakdown.114" Doc James  (talk · contribs · email) 22:27, 9 December 2016 (UTC)


 * Hmm. It was originally written into the article as "appears to be useful during bed rest", which I think was closer in line with the source. I'm guessing that I must've just unwittingly revised the statement since then to make the statement on potential uses more concise (assuming I'm to blame for that edit).  I agree that the language should only be tentative when referring to bed rest.  I've revised the statement accordingly: Special:diff/753806329/754135420.   for catching this!


 * Out of curiosity, what search terms/filters did you use to find these papers? I've been using the title and synonyms link with MEDRS-filters in the template on the talk page, which only provides these results: .  I probably need to expand the synonyms to show the expanded set of results that you found.


 * FWIW, since I'm assuming you don't have access to the paper, the conclusion of the ref in the 6th bullet above is Dietary manipulation with leucine enriched EAA, HMB or creatine warrants further investigation in the critically ill and may offer a supportive strategy towards minimising muscle mass loss in these vulnerable patients. Variability in quality and methodology of current evidence does not allow for formulation of any clinical recommendations. Studies in other muscle wasting illnesses with similarities to critical illness suggest that EAA mixtures may have a beneficial effect on lean body mass; however, the data for function and strength are less clear.
 * I also recently found a July 2016 review in the past week (currently linked to on the talk page, to be added to the article) which also called for longer trials with HMB. In summary, the effect of the combination of HMB, arginine, and glutamine on weight gain should be investigated in further studies on cancer patients investigating time periods of several months.


 * [W.r.t. cancer cachexia] In any event, would you like to incorporate these reviews on HMB for cancer cachexia into the article? Currently, the article does not state that there is clear efficacy for reversing muscle wasting from cancer cachexia; it simply states that there is "emerging evidence" supporting its use for this purpose.  I believe that this language is consistent with what the above reviews state (i.e., not definitive, but promising evidence of efficacy); however, do you feel that this statement should also be revised?


 * [W.r.t. critical care] Also, since the article doesn't currently make any statements about the use of HMB in a critical care setting, would you like me to add something on that? You covered this when citing the reference in the 6th bullet above.


 * [W.r.t. sarcopenia] At the moment, the main citation supporting statements about its efficacy for sarcopenia is a systematic review and meta-analysis. Would you like me to also include the reviews above that did not conduct a meta-analysis of trials?  Seppi  333  (Insert 2¢) 01:23, 11 December 2016 (UTC)


 * Edit: I've revised what I wrote about bed rest a little further in this edit. As of this moment, the only statement in the article w.r.t. bed rest is: HMB supplementation may also prevent muscle atrophy during bed rest, but more research is needed to determine its efficacy for this purpose.  Seppi  333  (Insert 2¢) 02:09, 11 December 2016 (UTC)
 * Have adjusted to make it more tentative to fit the small amount of evidence avaliable on this topic. Thoughts. Doc James  (talk · contribs · email) 00:36, 13 December 2016 (UTC)


 * The sentence in the lead on the efficacy for sarcopenia is summarizing the following statements in the body:"Based upon a meta-analysis of seven randomized controlled trials that was published in 2015, HMB supplementation can preserve lean muscle mass in older adults. HMB does not appear to significantly affect fat mass in older adults., more research is needed to determine the precise effects on muscle strength and function in this age group." We need to phrase the lead sentence which summarizes that text in a manner that is consistent with the body. Similarly, CFCF changed the sentence about the uses of HMB for aids/wound healing/etc to a statement about the efficacy of HMB for those things; statements about efficacy are not supported by the references, nor are these references suitable to cite a statement about efficacy per MEDRS.  That lead sentence is summarizing the following text in the body:"Some branded products that contain HMB (i.e., certain formulations of Ensure and Juven) are medical foods that are used for providing nutritional support under the care of a doctor in individuals with muscle wasting due to HIV/AIDS or cancer, to promote wound healing following surgery or injury, or when otherwise recommended by a medical professional." For now, I've reverted those 2 sentences to the version prior to CFCF's revisions; we need to make both the lead and body consistent with each other and with the cited references when changing these, or there will be problems with MOS:LEAD and WP:V respectively.  Seppi  333  (Insert 2¢) 02:39, 13 December 2016 (UTC)


 * HMB is believed to produce these effects in part by stimulating the production of proteins and inhibiting the breakdown of proteins in muscle tissue. - you replaced "produces" with the bolded phrase in this sentence. The third cited source is a primary source which literally demonstrated this effect in biopsied human skeletal muscle in a study conducted on living humans; that primary source is cited by and covered in the 2nd source which cites that sentence, which is a review.  Why did you change this?  Seppi  333  (Insert 2¢) 02:40, 13 December 2016 (UTC)

Arbitrary section break
I forgot to ping you when I responded yesterday. Anyway, I'm open to revising the statements that you modified; I don't mind if you be bold and modify these yourself, but please pay attention to what the cited sources say when doing so. A number of the edits that you made yesterday introduced verifiability issues. However, as mentioned above, CFCF's recent edits had already introduced a WP:V issue in the sentence on the marketed uses for HMB-containing products, before you further edited it. That sentence cannot discuss efficacy due to the fact that the sources are not MEDRS compliant.

I think it would be best to discuss how to phrase the other sentences that you modified in the lead, as well as the corresponding sentences in the body, in this section before modifying the statements in the article. I've made an attempt to modify some of these sentences as noted in the points below.


 * The sentence about there being "tentative evidence" for reducing muscle wasting in sarcopenia doesn't appear to be supported by the conclusion of the cited meta-analysis of clinical trials. However, I've removed the clause about HMB inhibiting lean mass loss in muscle wasting conditions in general because that portion of the sentence is a little overgeneralized, despite being directly supported by one of the cited references.  The efficacy of HMB for other muscle wasting conditions is covered more adequately in the body and I believe that this change to the lead makes it more consistent with the text in the body.


 * In this edit, I added coverage of the review on cancer cachexia that you linked in one of the bullet points above. The clinical trial which this review referred to in the statement you quoted is the same trial that was already covered in the article. I added the reference to the statement about the trial and added a sentence explicitly stating that more research is needed for determining treatment efficacy for cancer cachexia - both systematic reviews support that statement.
 * Note: I further revised the sentence about more research being needed in this edit.  Seppi  333  (Insert 2¢) 01:41, 14 December 2016 (UTC)


 * Athletes use supplemental HMB in the hope of increasing gains in ... - the underlined phrase in the preceding clause isn't directly supported by its references because they do not discuss the reasons that motivate healthy individuals to use HMB; they only discuss efficacy in clinical trials, so we should only be discussing efficacy in this sentence if we cite the current references.


 * I don't understand why you changed "HMB produces these effects..." to "HMB is believed to produce these effects..." in this edit. If there's a reason to make this change in the lead, we should also change the relevant statement in the body, which is currently: HMB produces these effects in part by stimulating myofibrillar muscle protein synthesis and inhibiting muscle protein breakdown through various mechanisms, including activation of mechanistic target of rapamycin complex 1 (mTORC1) and inhibition of proteasome-mediated proteolysis in skeletal muscles.


 * Lastly, do you want me to cover the research involving HMB in critically ill patients from the review you linked or add material from the review you linked on sarcopenia ?

 Seppi  333  (Insert 2¢) 00:15, 14 December 2016 (UTC)
 * What was wrong with "Certain medical foods claim it lessens muscle wasting in cancer and HIV/AIDS and promotes wound healing."? The source are claims from the manufacturer. We should call them claims. One reference supported the whole thing, why add 4? Doc James (talk · contribs · email) 02:38, 14 December 2016 (UTC)
 * You make it sound definitive "HMB inhibits the loss of lean body mass in individuals experiencing age-related muscle loss." The evidence is not there to make such a strong claim and ignores the reviews I provided above. Doc James  (talk · contribs · email) 02:39, 14 December 2016 (UTC)
 * you only provided one review on sarcopenia; the other 2 are about critically ill patients and cancer cachexia. I've added the cachexia review already, as previously noted.  WP:MEDRS states "The best evidence for treatment efficacy is mainly from meta-analyses of randomized controlled trials (RCTs).". Systematic reviews that do not use meta-analytic statistics to aggregate study results are like RCTs that report the treatment outcomes for each patient individually, without conducting any statistical analysis.  Meta-analysis is a way of aggregating the results of multiple studies into one aggregate quantitative measure of effect size, exactly analogous to how regression analysis is used to aggregate the results from multiple individuals into one aggregate quantitative measure of effect size.
 * With that in mind, if you really want me to state the number of medical reviews of individual trials that conclude that there's efficacy, then state there's a dissenting review of individual trials, and then state that the only meta-analysis of all trials concluded that there is efficacy for sarcopenia with such-and-such effect size, I'll do that despite the fact that we're giving undue weight to literature reviews over the only systematic review that conducted a meta-analysis of clinical trials.


 * As for the statement about medical foods, the sentence you wrote isn't suitable as is because food doesn't make medical claims. The intent behind this sentence was to answer the questions "in the real world, what do doctors currently use HMB-containing medical foods for?" - not "what do manufacturers claim that HMB-containing products have efficacy for?"  These two questions have the same answer simply because what a medical food is marketed for IS what it's used for; however, when we discuss efficacy in the body, we do not cite manufacturer claims - we cite medical reviews of RCTs which assert that more evidence is needed to adequately establish efficacy for some of those uses.  Most importantly, as I've stated twice before, claims about treatment efficacy made by anyone - even the manufacturer - are medical claims. Since the references for that sentence aren't MEDRS compliant, we can't use those sources to cite the sentence that you wrote.
 * Do you have any thoughts on this? Covering the medical uses like this was your idea after all.   Seppi  333  (Insert 2¢) 06:23, 14 December 2016 (UTC)


 * How do you want me to proceed?  Seppi  333  (Insert 2¢) 21:38, 16 December 2016 (UTC)
 * With respect to the sentence "provide nutritional support" agree it is not a medical claim. In fact it basically has no meaning (it is more or less a marketing statement that sounds good to get by the FDA regulations). Any food can also be said to provide nutritional support. We should simply remove it. Doc James  (talk · contribs · email) 02:57, 17 December 2016 (UTC)

These were the first three reviews on pubmed
 * 2016 systematic review finds mixed results "For proteins, a combination therapy of β-hydroxy-β-methylbutyrate (HMB), arginine, and glutamine showed an increase in lean body mass after 4 weeks in a study of advanced solid tumour patients, whereas the same combination did not show a benefit on lean body mass in a large sample of advanced lung and other cancer patients after 8 weeks. In summary, the effect of the combination of HMB, arginine, and glutamine on weight gain should be investigated in further studies on cancer patients investigating time periods of several months." Agree it is just looking at cancer. Yet is this about cancer but provides more useful info than the current statement about cancer in the lead.


 * 2015 systematic review "The HMB studies are suggestive of a beneficial effect on older adults, but larger well-controlled studies are required that measure outcomes relevant to sarcopenia, ideally in sarcopenic populations." (as most trials were in healthy people) -> when an article uses the term "may" it can equally mean "may not" Looking at the three refs you have provided, they state that HMB prevents I am not seeing where they state treat sarcopenea.


 * "Methodology and quality of studies were too varied to draw any firm conclusion. ... High-quality research is required in critical care before treatment recommendations can be made." Yes this one was in critical care.

I think what we have would support "HMB may inhibit the loss of lean body mass as individuals age." Thoughts? Doc James (talk · contribs · email) 02:57, 17 December 2016 (UTC)

Arbitrary section break2
The review you are using comes to three sentences of conclusions

"HMB contributed to preservation of muscle mass in older adults." which says it help keep mm mass, does not comment on those with sarcopenea.

"HMB supplementation may be useful in the prevention of muscle atrophy induced by bed rest or other factors." A decrease of uncertainty

"Further studies are needed to determine the precise effects of HMB on muscle strength and physical function in older adults." Means it is unclear if HMB affects str or function. Doc James (talk · contribs · email) 03:04, 17 December 2016 (UTC)
 * IMO before we should be uneqivacally recommending this stuff in WP's voice I would like to see (1) government sources supporting benefit (2) specific reviews supporting benefit (which we have some of) and (3) general reviews supporting benefit. I do not see us as having either 1 or 3. Doc James  (talk · contribs · email) 03:09, 17 December 2016 (UTC)
 * 2017 general review on sarcopinea says "A recent meta-analysis revealed some benefit of using a combined approach of dietary supplements and exercise, but the findings were inconsistent among various populations." PMID:27886695
 * Based on this 2015 review "The main message is that enhanced benefits of exercise training, when combined with dietary supplementation, have been shown in some trials – indicating potential for future interventions, but that existing evidence is inconsistent."  Doc James  (talk · contribs · email) 03:30, 17 December 2016 (UTC)

Sentence above
This sentence is supported by three references "It is added to certain medical foods to help provide nutritional support for people with muscle wasting due to cancer or HIV/AIDS and to promote wound healing."

The first refs do not make that claim? Does not mention cancer.

The second ref appears to be a conference invite Not a realiable medical source. Does not mention cancer.

The third ref is a news peice also not a sufficient medical support. Does not mention cancer.

I am unable to find in any of the four sources the mention of cancer?

Doc James (talk · contribs · email) 08:15, 9 December 2016 (UTC)


 * This sentence isn't stating or intended to suggest that HMB has efficacy for these conditions; it's intended to state its uses on the basis of what medical conditions that HMB-based medical products (specifically Juven and Ensure) are marketed to doctors/patients for in order to help to provide "nutritional support" while being used under the supervision of a doctor (@Jytdog: please correct me if I'm wrong about this). Jytdog and I decided on that wording during the first FAC (Featured article candidates/Beta-Hydroxy beta-methylbutyric acid/archive1) for describing its current medical uses.
 * In any event, I'm open to revising the wording. A statement about what HMB is marketed for doesn't require MEDRS because it's not a medical claim; it's a business-related marketing claim.  In any event, I suppose we could use a MEDRS source to support a statement about what Juven and Ensure are marketed for if we can find one, although I'm not aware of one at the moment. How do you and Jytdog propose that we modify the language so that it's agreeable to everyone?
 * Also, w.r.t. cancer, Jytdog provided this reference about the marketing of Juven for cancer-related nutritional support during the first FAC; I forgot to add that to support that part of the sentence. I'll add this reference in for now to address that issue, but we still need to iron out the wording so that the statement is acceptable to everyone.  Seppi  333  (Insert 2¢) 01:56, 11 December 2016 (UTC)
 * The medical food stuff is very hard to write about with our usual standards. The FDA lets people market medical food if they have good studies showing that nutritional support with X for Y actually helps Y and that there is some underlying biological mechanism that makes sense of that.  That's it.   We do need to be careful not to make efficacy claims in this context without good sources for that.  so this is use not efficacy. Jytdog (talk) 02:01, 11 December 2016 (UTC)
 * I've added the missing ref in this edit: Special:diff/754135420/754140460.  Seppi  333  (Insert 2¢) 02:02, 11 December 2016 (UTC)

The news peice does not mention HMB? Doc James (talk · contribs · email) 00:46, 13 December 2016 (UTC)
 * See the quote for that citation in the HMB article. It mentions Juven = HMB + other amino acids.  Seppi  333  (Insert 2¢) 01:27, 13 December 2016 (UTC)

Safety
Safety is tentatively established in people who are otherwise healthy. The evidence is not enough to state it is well established. With respect to side effects one would imagine it would be toxic to people with maple syrup urine disease and possibly alcoholics and others with liver failure who have trouble handling a high protein load. Doc James (talk · contribs · email) 00:52, 13 December 2016 (UTC)
 * Safety is tentatively established in people who are otherwise healthy. The evidence is not enough to state it is well established. - what review do you have in mind for using to cite this statement?  Seppi  333  (Insert 2¢) 02:13, 13 December 2016 (UTC)
 * Edit: Nevermind, I think that the language you used to describe safety in your recent revision is fine. Since you edited that statement in the article, is this no longer an issue?  Seppi  333  (Insert 2¢) 00:22, 14 December 2016 (UTC)
 * This is an interesting statement "although no studies have tested HMB toxicity in humans" from a 2016 review Doc James  (talk · contribs · email) 03:19, 17 December 2016 (UTC)

Comments by John
I still oppose on prose; there are three instances of "United States and/or internationally", which is very clumsy and does not belong in a FA. There will be other infelicities as well. I will take a proper look later today, but I am not pleased that this sort of thing has not yet been addressed. --John (talk) 14:30, 23 October 2016 (UTC)
 * In relation to athletic organization bans, the reason that those two sentences were written in that manner is that the phrase "in the United States and internationally" is the absolute most that could be attributed directly to the refs; the United States was the only country which the refs mentioned when discussing national athletic organizations that have not banned HMB use in competitive sports. However, since you feel that the sentences are really poorly worded, I've revised it to a statement that could be potentially be inferred from the refs:, HMB has not been banned by the NCAA, WADA, or any other prominent national or international athletic organization. It should be noted that none of the refs state that no national organization outside the US has banned HMB; however, given that no national organization with an HMB ban has been reported in any of the refs and given the blanket statements about the lack of a ban internationally, I figure it's not really a stretch to make this inference.
 * As for the third clause, "HMB is available in the United States and internationally...", I've deleted it and made it consistent with the wording used in the lead ("HMB is sold worldwide...").
 * These edits are the changes that I made. If you'd prefer that these sentences be phrased differently, please let me know or feel free to change them yourself.  Seppi  333  (Insert 2¢) 14:27, 24 October 2016 (UTC)
 * I'm working with Doc James to simplify the lead at the moment, so if you've got time to go through the prose this week, it'd probably be best to start on the body first and then go through the lead once you've finished reviewing that part. On a related note, did my edits in this diff address the concerns that you noted above?  Seppi  333  (Insert 2¢) 19:58, 26 October 2016 (UTC)
 * I think the lead has been simplified to Doc James' satisfaction, based upon our dialogue on the article talk page. Feel free to review the lead at your leisure.  Seppi  333  (Insert 2¢) 18:37, 14 November 2016 (UTC)
 * There's only about 2 weeks left before this nomination closes. Are you still willing/interested to do a prose review for this FAC?  Seppi  333  (Insert 2¢) 18:48, 5 December 2016 (UTC)
 * I will try to look. I am sorry I have been so slow to get going on this, I have been busy in my day job. One other reason I have been slow to take this up is that I had some concerns about NPOV and promotional tone the last time round and I have not yet looked to see if they have been addressed. When I looked in late October it was still failing for me. If this is still the case it will need more than a prose copyedit. I'll see when I take a look, I guess. --John (talk) 19:24, 5 December 2016 (UTC)
 * I remember that you mentioned something about that, but I'm not aware of what particular portions of the text that you see issues with. Can you clarify?  Seppi  333  (Insert 2¢) 18:56, 6 December 2016 (UTC)

Comments by Graeme Bartlett
I am going to go through this with a fine tooth comb looking for misspelling, funny characters, nonstandard use, and referencing. Graeme Bartlett (talk) 00:22, 31 October 2016 (UTC)
 * 1) Firstly there are three uses of "∼" instead of "~".  The first fails to render on my terminal, showing as a hollow rectangle, So this should be changed to "~".
 * 2) † is explained in note 8, but perhaps the explanation could be placed directly under the "Abnormal HMB concentrations measured in disease states" table.
 * adding the explanation in the bottom cell as you suggest is a good idea. I like that.
 * 1) There do seem to be a lot of unneeded quotes in the references. Some of this such as ref1 also include footnote numbers. But are they foot notes from this article, or the ereferece?  If the latter I think we should remove them as adding to confusion.
 * Replacing quoted footnotes with ... is certainly better than having them there. Though I think they can be safely omitted too.
 * 1) Should "a-KIC" read "α-KIC"?
 * 2) We should be using full journal titles rather than abbreviations
 * I feel strongly about this, as although specialists will know what those journal titles mean, other academics or average readers will not know. Putting the full title will make that clear, and easier to look up in a library catalog. First use of journal names can also be linked to the article about the journal.
 * 1) Despite the title being "beta-Hydroxy beta-methylbutyric acid", this is never used in the body of the text at all, instead it switches to using β.  This is a bit inconsistent.
 * 2) Some sources use "β-hydroxy-β-methylbutyric acid" with an extra "-" before the second "β".
 * 3) calcium β-hydroxy β-methylbutyrate monohydrate  is mentioned as abbreviating to "HMB-Ca", but references call this "CaHMB" or "Ca-HMB", so those two could be listed in parenthesis too.
 * 4) Do people really use units like "μmol/mmol" for ratios?
 * 5) In the  Wilkinson DJ, Hossain T, quote there is non-formatted ml−1 which is weird without superscript.  However I think the quoting is not needed.

I changed your bulleted list to a numbered list so that I could respond to each item in a more straightforward manner. I hope that this is okay with you. If not, feel free to convert the list back to a bulleted one.
 * Thanks for taking on a review of this nomination! I really appreciate it.
 * I've replaced all the instances of the former tilde ("∼") with the latter ("~"), per your justification. Diff of changes.
 * Do you mean that it should be placed in a table cell that acts like a footer, analogous to the bottom table cell in Fluoxetine where the explanation of the meaning of the tan-colored cells is placed? I could do that pretty easily if that's what you had in mind; just let me know.
 * I've moved the content from the note to a table footer cell. This is what the table looks like now: Special:Permalink/747877200.  Seppi  333  (Insert 2¢) 22:49, 4 November 2016 (UTC)
 * Please let me know if you'd like me to make any cosmetic changes to this table footer cell or implement it differently; I'm open to revising this in the event that you're not satisfied.  Seppi  333  (Insert 2¢) 16:08, 9 November 2016 (UTC)
 * As I noted above in Doc James' section, most of the references are going to be pruned down once someone reviews the pharmacology-related article content; the pharmacology content is very technical and involved, so I figure that even someone who is knowledgeable in pharmacology and/or molecular and cell biology will benefit a lot if all of the relevant statements and contextual information from the cited references that supports the pharmacology-related article content are clearly indicated within the quote parameter. Once this content has been reviewed, the lengthy citation quotes that contain pharmacology-related information will be censored – this includes all but 1 citation that currently includes a quote of more than 3 sentences.

In regard to the citation footnotes within quotations (e.g., the superscripted numbers in the quote of the article's 1st reference), those refer to the citations that are cited by the quoted reference, not the references cited in this article. I could omit those footnotes from the quote; however, in order to keep the quotations correctly formatted and ensure that they conform to MOS:QUOTE and MOS:ELLIPSIS, I'd have to replace almost every quoted footnote with a nonbreaking space followed by an ellipsis (i.e.,  - this renders as " ..."). If one of the quotes ends at a footnote, then I wouldn't have to follow this convention; but, whenever a quote continues past the footnote, I'd need to make this replacement since I'd be omitting material from the quoted text (MOS:QUOTE states "Use ellipses to indicate omissions from quoted text). Would you prefer that I replace the footnotes with ellipses?
 * Alright, I'll go through and replace footnotes within quotations with ellipses where appropriate sometime tonight or tomorrow and follow up here when I'm done.  Seppi  333  (Insert 2¢) 22:49, 4 November 2016 (UTC)
 * I've removed the superscripted references in all reference quotes. Diff of changes. Did you want me to do the same with bracketed (e.g., a quote like "Random statement.[4]") and unbracketed, non-superscripted references (e.g., a quote like "Random statement.4")?
 * As an alternative to removing all of the superscripted (and possibly all other) references cited within the quoted references, would you be alright with me including references within quotes if all of them are hyperlinked to the article which the reference cited? That should remove any confusion for the reader about what source a quoted reference refers to (important to you) and indicate to the reader that a particular statement is supported by evidence (important to me). I prefer this solution; however, if you don't think this is a suitable compromise, I'm still willing to remove all other quoted references.  Seppi  333  (Insert 2¢) 16:08, 9 November 2016 (UTC)
 * In the article text, all abbreviated terms that refer to alpha-ketoisocaproate should be written as "α-KIC" instead of "a-KIC" for consistency and compliance with MOS:ABBR. In the citation quotes and elsewhere, this need not be the case since the use of "α-KIC" vs "a-KIC" is merely a matter of the author's personal preference.
 * I've replaced "a-KIC" with "[α-KIC]" in the quotes since this is an appropriate substitution and conforms to MOS:BRACKET. Diff of changes.  Seppi  333  (Insert 2¢) 22:49, 4 November 2016 (UTC)
 * Is this solution okay with you, or would you prefer a different approach?  Seppi  333  (Insert 2¢) 16:08, 9 November 2016 (UTC)
 * I don't mind converting the journal titles to the full title format, although the current references are all consistent with Pubmed's abbreviated journal title format at the moment. The only reason that I chose to use the abbreviated format is that it's currently pubmed's standardized format for journal titles (e.g., this pubmed abstract lists "Pharmacol Res." instead of "Pharmacological research" as the journal title and this pubmed abstract lists "J Anim Physiol Anim Nutr" instead of "Journal of animal physiology and animal nutrition" as the journal title).  If you feel strongly about using the full title instead of the abbreviated format, I am willing to change this though. Just let me know if so.
 * Okay, I'll convert the journal titles from the abbreviated format to the full format tomorrow. I'll follow up here when I'm done. Addressed by Boghog.  Seppi  333  (Insert 2¢) 22:49, 4 November 2016 (UTC); Updated 16:08, 9 November 2016 (UTC)
 * The main reason why I'm inclined to use the expanded term "beta-Hydroxy beta-methylbutyric acid" in the title is that most keyboards containing the English alphabet don't include a key for &beta; and I imagine that most people don't know how to produce that character using keyboard shortcuts. Consequently, most readers on the English Wikipedia would probably find it difficult to write out and search for an article titled "β-Hydroxy β-methylbutyric acid". Since the lowercase Greek beta is a very common symbol, I imagine that almost everyone who arrives at the article knows what it means; consequently, I don't think that "β" ≝ "lowercase beta" needs to be stated in the article either. Nonetheless, if you feel strongly about changing the title or article text so that they're consistent, I'm open to changing the article to address this issue though.
 * I'm aware of this. Most sources that mention HMB discuss the conjugate base and some of those include a hyphen (this is written as "β-hydroxy-β-methylbutyrate"); some sources also omit the hyphen when referring to the acid and/or base. There isn't a "correct" format for hyphenating the term and the use of a hyphen there really only depends upon the author's personal preference.
 * HMB-Ca, CaHMB, and Ca-HMB aren't really that notable as alternative names of "calcium β-hydroxy β-methylbutyrate monohydrate"; all three are just unofficial/nonstandardized abbreviations which various authors used as shorter synonyms to refer to the compound in their publications. The only reason any of those is included in our article is that "calcium β-hydroxy β-methylbutyrate monohydrate" is an excessively long term and, like the authors who used those abbreviations, I needed a shorter way to refer to that compound, especially in the drugbox.  I'm not opposed to using CaHMB or Ca-HMB in the article, but I'd prefer to only list 1 of the 3 terms because they're just abbreviations. Since "calcium β-hydroxy β-methylbutyrate monohydrate" has other more notable alternate names besides those abbreviations, I think that listing only the abbreviations without mentioning any of the other alt names would be problematic.
 * "μmol/mmol creatinine" is a standardized unit for urinary concentrations in the Human Metabolome Database; this entry in that database cited those units and the rest of the associated row entries in that table. Based upon a quick search of that term in quotes on google scholar (970 results) and google search  (5600 results), "μmol/mmol creatinine" appears to be a fairly common unit of measurement in other publications for referring to the concentration of a substance in urine as well.
 * Thanks for catching this. I've superscripted the −1 in both places where it was used in the quote: diff of changes.  As mentioned above, I intend to censor that quote once the pharmacology section is reviewed by an editor from WP:PHARM or WP:MCB.
 *  Seppi  333  (Insert 2¢) 21:37, 4 November 2016 (UTC)


 * I have indented some of my responses above, as well as introducing a couple of other things below. I have struck off my points that are addressed satisfactorily. Graeme Bartlett (talk) 22:07, 4 November 2016 (UTC)

11. The history section fails to say who discovered or first made the acid. From references I can see it was made in 1958, but the article does not tell us.

12. If any of the authors of references are notable then author-link can be used to give them a blue link. (I have not check that yet to see if there are any) (I will check references carefully for fullness and correctness later) Graeme Bartlett (talk) 22:07, 4 November 2016 (UTC)


 * ✅ Full journal names are now used throughout. Boghog (talk) 13:45, 5 November 2016 (UTC)
 * Thanks for suggestion for expanding the history section. I cannot find any secondary sources that specifically state who first discovered or made this substance, but the earliest HMB synthetic citation in Reaxys which is based on the Beilstein database is to a paper in 1877 by Alexander Zaytsev.  I have added that citation to the article as well as later citations to what appears the first isolation from a natural source in 1941 and the first isolation as a human metabolite in 1968 (also from Reaxys searches).  (When it comes to early organic chemistry, if it is not listed in Beilstein, it probably never happened.) I hope this is sufficient.
 * I have added author-links to Alexander Zaytsev and Leopold Ružička in two citations. Boghog (talk) 08:29, 6 November 2016 (UTC)


 * Thanks Boghog. Graeme Bartlett (talk) 12:37, 6 November 2016 (UTC)


 * My bad for not following up sooner; I've been busier than expected off-wiki during the past few days. I should have some time tomorrow to make the changes that I indicated above though.   Seppi  333  (Insert 2¢) 02:05, 8 November 2016 (UTC)
 * Sorry for my long-delayed action on my proposed changes. My responses above from today on issues #2–4 are further indented and bulleted. I've removed the superscripted quoted references that you pointed out from the article; I'm willing to remove all non-superscripted quoted references as well if you'd prefer this.  I also proposed an alternative solution which I think should be mutually satisfying.
 * With respect to your concerns in #6–8, can you give me some guidance as to what you'd like me to change in the article? I'm not really sure what the particular issue or desired solution is in those cases.  Seppi  333  (Insert 2¢) 16:08, 9 November 2016 (UTC)
 * I'd be happy to address these and any other issues you find with the article; I still need a little more feedback to act on the remaining issues though. If any of my responses/revisions weren't to your liking, please let me know and I'll attempt to resolve the issue.  Seppi  333  (Insert 2¢) 18:42, 14 November 2016 (UTC)
 * For β versus beta, it probably just needs a note in the lead. 99% of readers will know it, but the few will be informed. For HMB-Ca, CaHMB, and Ca-HMB, listing the two most distinct ones in parenthesis should do (HMB-Ca, CaHMB). Graeme Bartlett (talk) 20:28, 14 November 2016 (UTC)
 * I also did check references, but found no information missing, so I suppose that deserves a "well done". Graeme Bartlett (talk) 20:28, 14 November 2016 (UTC)
 * How's this?  Seppi  333  (Insert 2¢) 23:23, 14 November 2016 (UTC)
 * Good solution, 6 and 7 considered sorted. Graeme Bartlett (talk) 23:31, 14 November 2016 (UTC)

Ah, good. I'm not sure if you saw, but in that same edit diff, I also added the CaHMB abbreviation to "(HMB-Ca, CaHMB)", as you proposed. Was there something else that you wanted me to do in order to address #8?

For #2, I added the note to the table as a footer as we discussed a while back (see the table in Beta-Hydroxy beta-methylbutyric acid). Did you want me to implement it differently, or is that issue addressed?

For #4, I replaced every instance of "a-KIC" with "[α-KIC]" in the references so that the article exclusively uses the abbreviation α-KIC now. Did this change address that issue?  Seppi  333  (Insert 2¢) 18:56, 5 December 2016 (UTC)
 * I am happy with that. Graeme Bartlett (talk) 20:47, 5 December 2016 (UTC)
 * Ah, ok. Have I addressed #2 then? In this edit, I moved the old note 8 to the table footer as we discussed.
 * For #3 (footnotes in quotes), did you want me to remove only the superscripted footnotes (which I did in this edit), or all footnotes in quotes? If you'd like, I can remove the others as well.  Seppi  333  (Insert 2¢) 02:07, 9 December 2016 (UTC)
 * It was the footnotes that you see in the quotes in the references section I was complaining about. I don't think you need the "..." but that is superior to a number with no explanation. I have struck off those complaints 2 and 3 now addressed. Perhaps there is still to much text quoted in references. But I won't hold that against FA status, and I will leave it to others to decide how much is required. Graeme Bartlett (talk) 04:34, 9 December 2016 (UTC)
 * Alright. Thanks again for taking the time to do this review of the article! Do you think that there's anything else I can do to improve the article?  Also, if you happen to notice any issues related to the FA criteria that still need to be addressed, please let me know.  In either case, I'd be happy to work on making the necessary revisions.  Seppi  333  (Insert 2¢) 03:05, 11 December 2016 (UTC)

Comments by CFCF
Comments before looking into sources: More comments later. Carl Fredrik  💌 📧 21:00, 6 November 2016 (UTC) I'm waiting for this systematic review to be published before adding more detail about the HMB treatment effect sizes for muscle strength, muscle size, and lean mass in athletes - effect sizes for some of these vary by the training status and presumably also vary by the age of the individual. All of this information comes from reviews of blinded RCTs.
 * 1) Infobox includes US & UN status, is there any EU, AU, JP or other status that could go here as well?
 * 2) From lede: "Supplemental HMB is also used by athletes to increase exercise-induced gains in muscle size, muscle strength, and lean body mass, reduce exercise-induced skeletal muscle damage, and speed recovery from high-intensity exercise." How well does it work? What type of study examined this, how strong is the evidence?
 * 3) Same as above, but for the body, I want more information on the quality of the studies and whether the effect is great or barely significant.
 * 4) Did they compare to placebo, BCAA or Leucine?
 * 5) Who funded these studies? HMB-supplementation is controversial, and it is known that a number of studies are funded by the manufacturers.
 * 6) Are there meta-analyses? If no, why not? Did anyone suggest there is need for further analysis to say whether the effect is significant.
 * 7) From lede: "Small amounts of HMB are present in certain foods, such as alfalfa, asparagus, avocados, cauliflower, grapefruit, catfish, and milk." — but it also says " substance that is naturally produced in humans and used as nutritional supplement." Does that mean it's supplemented to alfalfa, asparagus etc. or is it naturally produced outside of humans as well?
 * 8) From lede:"As of 2015, HMB has not been banned by the [...]", this would sound better as "is allowed".
 * 9) The NCAA college students study, was it American?
 * 10) From lede: "Since only a small fraction of l-leucine is metabolized into HMB, pharmacologically active concentrations of the compound in blood and muscle can only be achieved by supplementing HMB directly. A healthy adult produces approximately 0.3 grams per day, while supplemental HMB is usually taken in doses of 3–6 grams per day." — Seems to imply there is a correlation between supplemented dose and blood concentrations — but not at what level. Supplemental doses could be at 3-6 grams with 0% absorbed and do nothing.
 * I haven't come across any references that make a statement about HMB's regulatory status in those countries.
 * There's 5 medical claims in that sentence; the effects on size and strength aren't covered in any more detail in the article. Lean mass changes in athletes aren't covered in the article, but the effect size from a meta-analysis on changes in lean mass in elderly subjects is covered in a note in the medical section. The inhibitory effects on exercise-induced muscle damage, as measured by changes in muscle damage biomarkers, is mentioned in a note in the sentence in the body; the capacity for it to speed recovery from high intensity exercise is essentially just a consequence of its inhibitory effect on muscle damage; it tends to decrease soreness when used at an appropriate time prior to high-intensity exercise.
 * Re-above. I intend to update the body and lead when that systematic review is published.
 * Metabolic Technologies Inc., which holds all of the current HMB patents and licenses the right to manufacture it, has funded only 12 HMB studies, based upon . Around 60 clinical trials have been conducted with HMB in humans. "HMB-supplementation is controversial" - I haven't come across a reliable source that makes an assertion like this; I don't know what you're basing that statement on.
 * There are meta-analyses. There are two current meta-analyses which examine its clinical effects in sarcopenia/muscle wasting. All the other meta-analyses, some of which examined the effect sizes in athletes, are outside WP:MEDDATE. IIRC the most recent of those is 7 years old. None of the sources that are cited in the article, which includes almost every MEDRS-quality review on the subject, assert that any of those 5 effects is equivocal. Certain sources, such as, mentioned other performance-enhancing effects (e.g., aerobic performance) that were found in a small number of clinical trials, but which do require more research to verify.  I didn't mention those effects in the article.
 * It's naturally produced in plants and animals.
 * I agree that it would improve the language; however, the NCAA and WADA don't white-list or endorse substances, so it technically wouldn't be accurate.
 * IIRC, yes.
 * I haven't come across a source that explicitly mentions the absolute bioavailability for oral administration. One can easily find the relevant information on blood concentrations in the detection in body fluids section though; based upon the data there, oral administration of 3 grams of HMB-FA increases the plasma concentration of HMB by ~100-fold above basal levels at Tmax.
 *  Seppi  333  (Insert 2¢) 03:49, 8 November 2016 (UTC)
 * is there anything in particular that you'd like me to add to or change in the article? For the most part, I'm not really sure what you'd like to see revised in the article (excluding the coverage of effect sizes - I'm still waiting on that systematic review to be published).  FWIW, the sentence on the NCAA study (you mentioned this in #8) was revised to indicate that the sampled population was American student athletes; I'm not sure if that was an issue for you though.  Seppi  333  (Insert 2¢) 18:49, 14 November 2016 (UTC)
 * Not sure if you received my last ping notification, so I'm pinging you again.  Seppi  333  (Insert 2¢) 02:08, 9 December 2016 (UTC)
 * I'm happy with the changes, and have no further comments. However compared to your earlier work this is not entirely on par with it. I would have no issue supporting GA as it is, however FA seems dubious because it is likely the knowledge on the topic will change soon. Accepting it now would require a FAR in a couple of months and I'm cautious to fully support it because of that. Carl Fredrik   💌 📧 10:34, 9 December 2016 (UTC)
 * I spent about two years working on the amphetamine article and summarizing about 80 years of clinical research and 20-30 years of pharmacological research before it was finally promoted to FA status. I've also spent a lot of time further improving the amphetamine article by adding more recent medical reviews after it was promoted in January 2015. In comparison, I've only spent 8 months working on this article to summarize 20 years of clinical/pharmacological research and 10 years of medical research.  In a nutshell, there isn't as much of a comprehensive understanding of the clinical effects and pharmacology of this compound as there is for amphetamine.
 * If the amount of coverage of these topics isn't what you meant by "not entirely on par [with my earlier work]", can you give me a general idea of what you think I should pay attention to improving in this article? I'll make a sincere effort to improve what you believe to be deficient if I can find suitable references to improve coverage of that aspect of the HMB article.  Seppi  333  (Insert 2¢) 02:17, 11 December 2016 (UTC)
 * Just because knowlege on a topic will increase in the next few years does not prevent FA status. We just have to assess this on what is already published. If our coverage is justified by that then we can count broadness and completeness satisfied.  An editor may have insider or unpublished knowlege about something important coming up on the topic, but at this point that is original research, and merely means the article should be updated later. Graeme Bartlett (talk) 12:50, 11 December 2016 (UTC)
 * I think you missunderstand Graeme. My qualms lie in the fact that the field is very much divided with as Seppi describes it "large" reviews coming up. While a lack of certainty isn't an argument against FA-status, a quickly shifting field is. In the requirements for FA an article is to be "stable", and if it covers an issue that will undoubtably change in the coming year (not couple of years) that article will be either inherently unstable or simply incomplete and outdated before even being shown on the main page. So either we promote it and demand review as soon as newer articles are released, or we accept outdated content for the main-page...  Carl Fredrik   💌 📧 13:17, 11 December 2016 (UTC)
 * There are many subjects that are controversial for which featured articles have been written. What is wrong with presenting the present state of knowledge? A featured article is only highlighted on the front page for a single day and it is unlikely the scientific consensus will change markedly between today and when the article is featured on the front page. If and when new reviews are published that support a change of consensus, then we can revisit the featured status of this article. Boghog (talk) 16:37, 11 December 2016 (UTC)


 * FWIW, based upon the title of the upcoming systematic review that I mentioned earlier ("Beta-hydroxy-beta-methylbutyrate free acid improves resistance training-induced muscle mass and function: a systematic review"), I don't expect that I'm going to end up revising any existing article text since the article currently includes the same medical claim as the statement in the title of that systematic review. More than likely (i.e., barring any unexpected findings from the most recent RCTs in athletes), what I'll end up needing to do when that review is published is add about a paragraph of new text to describe the effect sizes associated with the clinical effects in athletes that are already mentioned in the article. I have no qualms with stating that a lack of efficacy has been established for all of these clinical effects if that happens to be the conclusion of the systematic review; however, even in those circumstances, revising the article accordingly wouldn't make the article unstable – unless there's an active content dispute or edit warring – because it would only require a single edit to update the article and address this.  Seppi  333  (Insert 2¢) 02:37, 12 December 2016 (UTC)

Closing comment
After two months this review has generated a good deal of discussion but unfortunately nothing approaching consensus to promote, so I'll archive it shortly. Perhaps a Peer Review would be useful before a re-nomination at FAC. Cheers, Ian Rose (talk) 04:42, 17 December 2016 (UTC)

Ian Rose (talk) 04:44, 17 December 2016 (UTC)
 * The above discussion is preserved as an archive. Please do not modify it. No further edits should be made to this page.