Talk:Β-Hydroxy β-methylbutyric acid/GA1

GA Review
Reviewer: Tom (LT) (talk · contribs) 05:47, 28 November 2017 (UTC)

Out of sympathy for poor I will take up this review. I'll spend a few days familiarising myself with the subject matter and then post my review. --Tom (LT) (talk) 05:47, 28 November 2017 (UTC)
 *  Seppi  333  (Insert 2¢) 19:10, 28 November 2017 (UTC)
 * I forgot to mention, a lot of the paywalled reviews that are cited in this article can be viewed here: . The file names for those papers reflect the reference names that are used in the article source (i.e.,   → xyz.pdf).  Seppi  333  (Insert 2¢) 21:44, 28 November 2017 (UTC)
 * As a note, I am reviewing this article here . If this situation happens again, please ping me and I will review the article based on any changes in the interests of time. Also happy when this passes to participate at the FA if that helps. --Tom (LT) (talk) 07:37, 1 December 2017 (UTC)
 * Have made my first-pass review (and updated the table below). Will go through your replies and mark what has been addressed, and then when this is complete go through the article a second time and briefly as a second check. As stated above am happy to discuss anything below. --Tom (LT) (talk) 22:55, 8 December 2017 (UTC)

Discussion
I finished going through the points below. I just need your feedback on my responses about some of the statements in the medical and pharmacodynamics sections in order to proceed with addressing those issues.  Seppi  333  (Insert 2¢) 23:12, 21 December 2017 (UTC)
 * All right,, I will be honest here. It's clear you've put a lot of work into this article and I'm sure published in a medical journal this would be an excellent review. However, it's published here on WP and is being reviewed for "GA status" which is a different kettle of fish.
 * Firstly though, even more confusingly for me as a reviewer:
 * (a) I can't seem to find a past GA review to compare my reviews against; and
 * (b) given this has been to FA a number of times I think it will be very frustrating if I provide all sorts of specific advice to you which then needs to be rechanged in accordance with the FA reviewers' opinions; and
 * (c) some of the issues I raise are probably in response to the concerns of others.
 * That said, I've reviewed probably more than 80 articles, including some complex ones, so I think I have a fair idea of how to interpret GA criteria. So, here goes:
 * In general, I find this article very hard to read. I find this difficult for a few reasons. There are a lot of references everywhere, and a lot of wikilinks. The language is very technical. I find some of the paragraphs could be arranged in a better way. A lot of facts are presented at once without much synthesis. Systematic reviews are placed beside primary sources. Language used to describe similar issues is inconsistent. Also in some areas extraneous information provided that could be cut to make things easier to read.
 * Now, taking into account (a)-(c), I'm not quite sure what to do. I can pass this article given there doesn't seem to be many others who have commented about the readability of the article in past FA reviewers, and let FA reviewers nut out the details. I could ask for a second reviewer (not inclined to do this). I could provide specific advice which is likely to be fairly subjective. What do you think/want, ? --Tom (LT) (talk) 23:06, 2 December 2017 (UTC)
 * I'd prefer your specific advice on how to improve the readability (alternatively, feel free to make any changes you see fit it if you feel comfortable with it). If we end up rewriting the entire article in the process, that's fine with me as long as there's an improvement. Anyway, this is the first GA review for this article since I initially decided to skip the GA process and go straight to FAC.   Seppi  333  (Insert 2¢) 00:29, 3 December 2017 (UTC)
 * OK, here goes then:--Tom (LT) (talk) 22:30, 3 December 2017 (UTC)

Review of text
Happy to discuss any of the below. These suggestions are not intended to be prescriptive & only intended to illustrate my concerns about the 'well-written' point. They don't all need to be addressed for the review to pass. Hope it is helpful. --Tom (LT) (talk) 22:59, 3 December 2017 (UTC)
 * I'll address these issues as time permits. I'm not addressing these points in any systematic order, so it might appear that I've ignored some of them until I get to them.  Seppi  333  (Insert 2¢) 20:24, 4 December 2017 (UTC)

Lead

 * Too many citations. Referring to previous consensus, I have no issue with citations in the lead. However surely as a summary of text these could be whittled down to your main citations, and the lists can be provided in text.
 * If you have an alternative solution in mind, please let me know.  Seppi  333  (Insert 2¢) 19:25, 13 December 2017 (UTC)
 * : I'll work on pruning some of the citations in the lead's "sources" notes this weekend when I work on reducing the citations for content in the body. I've removed 1 so far and have identified a 2nd that I intend to remove tomorrow when I update the body of the article.  Seppi  333  (Insert 2¢) 02:34, 16 December 2017 (UTC)
 * ✅: Since 2 days ago, I cut 2 refs from the first note, which has the most refs among the 3 lead sources notes. I can't cut anymore refs without affecting the lead's verifiability.  Seppi  333  (Insert 2¢) 21:58, 17 December 2017 (UTC)
 * Thanks. --Tom (LT) (talk) 23:11, 17 December 2017 (UTC)
 * Suggest revise statement about use so that it flows in a logical order adults -> older adults and certain statements -> uncertain statements
 * All of the sentences in the lead now contain only statements of certainty; the only one that includes a clause with an a statement about effects which are uncertain is "HMB can reduce the loss of lean body mass in individuals experiencing age-related muscle loss, but more research is needed to determine how it affects muscle strength and function in older adults." The preceding sentence was recently updated with a statement of certainty about the effect on muscle strength in this age group. I could move that statement down if you still want me to; however, it should be noted that, After moving the statement you mentioned in the bullet below, the current ordering of the sentences in the 1st lead paragraph reflects the same order of content coverage as the body. I'm think Doc James might object at the next FAC to ordering medical uses after performance-enhancing uses in the lead; but, if he's okay with that, I'll put it in that order as you suggest.  Seppi  333  (Insert 2¢) 06:51, 8 December 2017 (UTC)
 * Would you mind if I reordered the statements in the 1st lead paragraph as suggested above?  Seppi  333  (Insert 2¢) 06:55, 8 December 2017 (UTC)
 * Not putting the refs behind the sentence they support IMO is not an improvement. Having them as a block of 13 makes it impossible for me to determine which part of the lead is supported by which reference.
 * I see that they are now hidden comments but I would simple show them.
 * If athletic uses are more common, I do not have an issue with that use going first in the first paragraph. Doc James  (talk · contribs · email) 18:19, 8 December 2017 (UTC)
 * It's already in the lead; my question was if you would object me be reversing the order of the sentences in the collapse tab below (these sentences summarize its medical and performance-enhancing uses) (edit: I've deleted the collapse tab and the content inside since it took up a lot of space in the source).  Seppi  333  (Insert 2¢) 19:59, 8 December 2017 (UTC); Updated 02:33, 16 December 2017 (UTC)
 * ✅: I ordered the statements on clinical effects in the lead as you suggested (healthy adults, then older adults) since Doc James didn't object following my ping (this edit was made in this diff). I removed the statement about more research being needed in an earlier edit, so there's currently no statements on uncertain effects in the lead. If you have any other suggestions for ordering the 1st lead paragraph, I'm still open to modifying it though.  Seppi  333  (Insert 2¢) 19:24, 13 December 2017 (UTC)
 * Thanks. --Tom (LT) (talk) 23:11, 17 December 2017 (UTC)
 * Suggest move statement "It is added to certain medical foods that are intended to provide nutritional support for people with muscle wasting due to cancer or HIV/AIDS and to promote wound healing." up to where you discuss clinical uses
 * ✅: it's now located immediately after the 1st lead sentence.  Seppi  333  (Insert 2¢) 19:24, 13 December 2017 (UTC)

Re: The lead references – Do you want me to use the same referencing style that was used in the lead of amphetamine?  Seppi  333  (Insert 2¢) 20:51, 4 December 2017 (UTC)
 * Nevermind, I went ahead and did redid the lead sources analogous to amphetamine's lead. I'm going to group the sources in the body in the same manner as is done in the amphetamine article (sentences with 4+ references have their references placed in a sources note). Do you approve of that approach?  Seppi  333  (Insert 2¢) 04:38, 8 December 2017 (UTC)
 * @, . No bright suggestions for references in lead other than to (1) restate the lead is very difficult to read with so many references interspersed between text and (2) agree with you Doc James that large groups of references are hard to verify.--Tom (LT) (talk) 22:57, 8 December 2017 (UTC)
 * I'm not really sure how else to address this problem without using the [sources #] notes and censored refs for the sentences. Most of the lead sentences are either summaries of 2+ sentences in the body that are supported piece-wise by different references or exact duplicates of sentences in the body that (IMO) require multiple refs for making significant medical claims on efficacy/safety.  Seppi  333  (Insert 2¢) 19:31, 13 December 2017 (UTC)
 * We've done what we can, I won't push this point further. Thanks for responding to my concerns --Tom (LT) (talk) 23:11, 17 December 2017 (UTC)


 * Suggest remove unnecesssary acronyms, including WADA and NCAA which are only used once ✅

Medical

 * Does this article ("Elderly persons with ICU-acquired weakness: the potential role for β-hydroxy-β-methylbutyrate (HMB) supplementation") really comment on HIV immune function? (it is used here "Clinical trials with Juven for AIDS")
 * Yes. From : In patients with human immunodeficiency virus (HIV), Clark et al46 have demonstrated that HMB supplementation in addition to arginine and glutamine not only increased lean body mass by 2.6 kg but also increased CD3, CD4, and CD5 cell counts. As noted above, the full-text of paywalled citations in this article can be accessed via this link: .  The file names of the pdf files are the same as the reference names that are used in the article source (i.e.,   → xyz.pdf).  Seppi  333  (Insert 2¢) 05:30, 8 December 2017 (UTC)
 * Right. This study is just referencing another primary source. I strongly advocate we remove this. I don't think it's responsible to insert a statement like this without a stronger source. --Tom (LT) (talk) 22:00, 12 December 2017 (UTC)
 * I'm confused.  is marked as a review on Pubmed; the quote from above is just a summary of 1 of the primary sources it reviewed.  I can check whether or not that primary source is covered in one of the other medical reviews I've cited if that's what you're asking about though.  Seppi  333  (Insert 2¢) 22:48, 12 December 2017 (UTC)
 * The source that this statement is derived from is a primary source. I really don't think we should be including something like this, which is a medical claim unless there is a stronger source (WP:MEDRS). It is in my mind misleading to state that HMB has a role in HIV/AIDS management without stronger evidence. --Tom (LT) (talk) 02:36, 15 December 2017 (UTC)
 * Like I was saying before, that statement is cited and supported by and, both of which are classified as a medical reviews on Pubmed (follow the PMID links and click/expand the tab titled "Publication type, MeSH terms, Substances" – doing this will display "Publication type: Review"). The quoted sentence above in my initial reply to this bullet – "In patients with human immunodeficiency virus (HIV), Clark et al46 have demonstrated that HMB supplementation in addition to arginine and glutamine not only increased lean body mass by 2.6 kg but also increased CD3, CD4, and CD5 cell counts" – is from the 2nd review that I've listed (i.e., ), not the primary source it was reviewing.  In other words, that statement isn't cited or supported by a primary source; rather, it's cited and supported by 2 medical reviews which covered the findings of , which is a primary source that you seem to be confusing the review with. That primary source is not currently and has never been cited in this article.  In any event, if you'd prefer that I use a newer review instead, I can cite a medical review from 2017 ( - see Table 6 from this review) which includes 2 clinical trials with HMB for AIDS. On a slightly tangential note, HMB is currently included in medical foods that are used to provide nutritional support in individuals with AIDS/HIV (NB: medical foods are intended to be taken under medical supervision in the United States – see pages 3–6 of this FDA guidance document for further information on their regulatory/labeling requirements).  Seppi  333  (Insert 2¢) 01:03, 16 December 2017 (UTC)
 * Sorry, it just occurred to me that you seem to be taking issue with covering the findings from reviews that included that particular clinical trial in the article, not the reviews themselves. If I'm correct about that being the issue here, then when you say "a stronger source", do you mean we should wait until a 2nd clinical trial that examines those parameters is published and subsequently reviewed?  Right now, there's 3 reviews that cover 2 clinical trials of HMB for AIDS, but only 1 of those trials examined CD3 and CD8 counts. In the event you'd like to read about what clinical parameters the 2nd trial examined, this is a link to its full text:  .  If you can clarify what the issue is, I'd appreciate it, since I'm not sure if you're asking for a replacement review of that trial (re: my previous reply) or a review of a corroborating trial/primary source (re: this reply).  Seppi  333  (Insert 2¢) 01:21, 16 December 2017 (UTC)
 * The two issues are: the sentence states "Clinical trials with Juven for AIDS have also demonstrated improvements in immune status, as measured by a reduced HIV viral load relative to controls and higher CD3+ and CD8+ cell counts". (a) Here it states "trialS" yet there as you say there is only one trial showing reduced HIV viral load. (b) given that there is only one trial, it really is just included, not supported, by the reviews. I would be happy if this was rephrased in a more general way, or if the second clause was removed. --Tom (LT) (talk) 01:23, 19 December 2017 (UTC)
 * I've changed the plural to singular to accurately reflect this (diff). I don't think it would be wise to delete this sentence.  While these findings are from 1 study which was included in these reviews, these endpoints were specifically mentioned in the text of the review articles despite not being the primary endpoint (which was a change in lean mass) in the study itself.  I.e., the authors probably discussed these secondary endpoints because they are notable in their own right. In any event, what phrasing did you have it mind for this sentence?  Seppi  333  (Insert 2¢) 01:26, 20 December 2017 (UTC)


 * "The efficacy of Juven for the treatment of cancer cachexia was also examined in a phase 3 clinical trial which found a strong trend (i.e., p=.08) for an improvement in lean body mass relative to controls;[14][30][33] however, according to the authors of the trial itself and a systematic review that included it, the trial did not adequately test the ability of Juven to prevent or reverse the loss of lean body mass in individuals with cancer cachexia since the majority of participants did not complete the study" I do not believe a phase 3 study meets WP:MEDRS. Surely it is a primary source. You then even include criticism by a systematic review. Should this be included at all?
 * The assertion which was made in the systematic review about the clinical trial is identical to the assertion made by the authors of clinical trial publication. In other words, the clinical trial source and systematic review draw the same conclusion about the clinical trial. I'll remove that primary source if you think it detracts from the article; I only added it because I thought it helped to show consensus.  Seppi  333  (Insert 2¢) 05:30, 8 December 2017 (UTC)  + rephrased sentence
 * I think that, guided by our local policy WP:MEDRS, we treat the secondary source as having more weight and should remove the primary phase three trial. --Tom (LT) (talk) 22:00, 12 December 2017 (UTC)
 * Sorry, I should've clarified that the thing I removed earlier was that primary source - it's no longer cited in the article (diff of removal). I rephrased the sentence after I removed it because the sentence stated something along the lines of: "the authors of the trial and a systematic review that included it stated..."  Seppi  333  (Insert 2¢) 22:48, 12 December 2017 (UTC)
 * Thanks. The line at issue is still present? "The efficacy of Juven for the treatment of cancer cachexia was also examined in a phase 3 clinical trial which found a strong trend (i.e., p=.08) for an improvement in lean body mass relative to controls" --Tom (LT) (talk) 23:31, 17 December 2017 (UTC)
 * What's wrong with that sentence?  Seppi  333  (Insert 2¢) 01:07, 20 December 2017 (UTC)
 * NB: The only reason I've included any primary medical sources in this article is to support existing medical reviews or to supplement medical reviews which don't cover specific details that are only covered in the primary source. E.g., the specific mechanisms of action that give rise to HMB's mode of action aren't covered in most medical reviews, and those that do mention mechanisms of action gloss over the details; in contrast, HMB's mode of action (increased protein biosynthesis and reduced protein catabolism) is covered in almost every medical review about the compound.  Seppi  333  (Insert 2¢) 05:30, 8 December 2017 (UTC)


 * So many citations. Are all of these needed??
 * For statements that contain clinically significant medical claims, yes. I don't think it's adequate to support a statement of a dietary supplement's clinical efficacy with a single citation since many claims about the efficacy of dietary supplements for any particular condition or effect are dubious. One can probably find a source to support a statement of efficacy for most dietary supplements for a particular purpose, so showing that there's scientific consensus across multiple reviews by citing more than one is, IMO, both appropriate and necessary in this context.  This approach is followed for statements about this compound's safety profile as well. Moreover, for a number of sentences in the article, the statement requires multiple sources because it makes multiple non-medical claims that are only individually supported by the cited references (i.e., a sentences with 3 claims might be supported by 3 sources, where each source supports only 1 of the claims).  Seppi  333  (Insert 2¢) 05:30, 8 December 2017 (UTC)
 * As I see below, sometimes what may be seen as one point is in fact two or three. On the other hand, if at all possible for a noncontroversial statement, it is adequate to use a reliable secondary source. The large number of references shows how much effort has been put into this article but also makes it harder to read and verify. So trimming if possible would be appreciated. --Tom (LT) (talk) 22:00, 12 December 2017 (UTC)
 * : I'll work on cutting down the number where possible and appropriate. I'll work on pruning the refs in this section and any corresponding ones in the lead sometime this weekend.  Seppi  333  (Insert 2¢) 03:19, 16 December 2017 (UTC)
 * ✅: I removed a review that wasn't really necessary in this diff. As of now, I've cut at least 2 references (that I remember) from this section: this review and the phase 3 clinical trial. I'm not sure it would be wise to cut reviews on the efficacy statements, which are the only statements in the text which still have multiple (i.e., 2 or 3) citations for the same content.  Seppi  333  (Insert 2¢) 23:05, 21 December 2017 (UTC)
 * Thanks. --Tom (LT) (talk) 22:21, 25 December 2017 (UTC)
 * Second paragraph is confusing because it alternates rapidly between sarcopenia, muscle mass, lean muscle mass, muscle weight, muscle atrophy, muscle wasting... if possible it would be good if these terms could be standardised into more consistent terms for ease of reading (eg "sarcopenia -> skeletal muscle mass; muscle weight/mass -> muscle mass; muscle atrophy/wasting -> loss of muscle mass")
 * I've revised it slightly. I'll try reworking it a little more later.  I agree that it does alternate a bit too much.  Seppi  333  (Insert 2¢) 07:04, 8 December 2017 (UTC)
 * ✅: I went back through it and added links to bed rest and muscle atrophy. I don't think it would be wise to change sarcopenia and/or muscle atrophy to "the loss of skeletal muscle mass" because these two terms specify a cause for this effect: sarcopenia is a medical condition involving the loss of muscle mass due to old age, whereas muscle atrophy is a condition involving the loss of muscle mass use to disuse of a muscle. If you think it should be further modified, let me know.  Seppi  333  (Insert 2¢) 22:57, 21 December 2017 (UTC)
 * Thanks, your changes are noted :) --Tom (LT) (talk) 22:21, 25 December 2017 (UTC)
 * Suggest that the whole section be reworded and possibly split up into the following: (1) preserving muscle mass in hypercatabolic states (2) preserving muscle mass in aging (3) other uses; and restrucrigin paragraphs so that the proceed as in (a) findings followed by (b) details at end of paragraph.
 * : I'll look into doing this tomorrow soon and follow up then.  Seppi  333  (Insert 2¢) 07:09, 8 December 2017 (UTC)
 * : I grouped the material as follows in this diff: statements about HMB for sarcopenia; statements about HMB for muscle atrophy from bed rest; statements about HMB for hypercatabolic disease states; and, recommendations from reviews on the treatment of all of the aforementioned conditions. If you think I should further revise it, let me know.  Seppi  333  (Insert 2¢) 22:57, 21 December 2017 (UTC)
 * Thanks, the paragraph is much easier to read. --Tom (LT) (talk) 22:21, 25 December 2017 (UTC)


 * Available forms
 * Ensure and Juven aren't linked ✅


 * "Investigation of the presence of β-hydroxy-β-methylbutyric acid and α-hydroxyisocaproic acid in bovine whole milk and fermented dairy products by a validated liquid chromatography-mass spectrometry method" - does not seem like a secondary source
 * It's a primary source; however, the statement "[HMB] is present in insignificant quantities in certain foods, such as alfalfa, asparagus, avocados, cauliflower, grapefruit, catfish, and milk" is not a medical statement. That primary source supports only its presence in bovine milk. HMB is also present in human breast milk, but that wasn't mentioned in that sentence.  It is, however, covered more in depth in the "Detection in body fluids" section: In the breast milk of healthy lactating women, HMB and l-leucine have been quantified in ranges of 42–164 μg/L and 2.1–88.5 mg/L.[15] In comparison, HMB has been detected and quantified in the milk of healthy cows at a concentration of <20–29 μg/L.[22] This concentration is far too low to be an adequate dietary source of HMB, but milk products could be fortified with HMB to confer benefits to skeletal muscle.[22] If you think that I should remove the mention of milk and the primary source from sentence anyway, I'm ok with doing that.  Seppi  333  (Insert 2¢) 20:48, 4 December 2017 (UTC)
 * Thanks for your reply, I understand that. I also note that the non MEDMOS (WP:SECONDARY) also states it is not ideal to use a primary source. I would be inclined to remove it or replace it with a better source. --Tom (LT) (talk) 22:00, 12 December 2017 (UTC)
 * Alright, I'll look for an alternative reference.  Seppi  333  (Insert 2¢) 22:48, 12 December 2017 (UTC)
 * I couldn't find an alternative one, so I deleted the ref and mention of milk in the lead and available forms section (diff). Do you want me to delete the reference and the 2 sentences that it cites in the Beta-Hydroxy beta-methylbutyric acid section as well (1st paragraph - last 2 sentences)? That's the only section where that the reference is cited at the moment.  Seppi  333  (Insert 2¢) 07:19, 13 December 2017 (UTC)
 * Thanks. Am happy with the new arrangement. --Tom (LT) (talk) 23:22, 17 December 2017 (UTC)
 * Number of citations here is even less for the same statements than the lead
 * (see point below for this) --Tom (LT) (talk) 22:00, 12 December 2017 (UTC)
 * "when taken in doses of 3 grams per day" you say "3-6 grams" in the lead
 * The listed dollar amount and citation applies to 3 grams/day; the reader can probably figure out how much 6 grams would cost from the listed range though  Seppi  333  (Insert 2¢) 20:13, 4 December 2017 (UTC)
 * Heh, I realise that. I just mean that the lead seems to be more than just a summary of the body in this instance ("Apart from basic facts, significant information should not appear in the lead if it is not covered in the remainder of the article.", WP:LEAD), so I think this information should be included in the body too. --Tom (LT) (talk) 22:00, 12 December 2017 (UTC)
 * : Oh, haha. Ok, I can add it. Will do it the next time I work on the article.  Seppi  333  (Insert 2¢) 22:48, 12 December 2017 (UTC)
 * in this diff.  Seppi  333  (Insert 2¢) 06:57, 13 December 2017 (UTC)
 * Thanks. --Tom (LT) (talk) 23:22, 17 December 2017 (UTC)


 * Medical
 * "More research is needed." Does this need to be stated? This can surely be stated about almost everything.
 * This is stated twice; are you referring to one or both statements? The reason it was included w.r.t. the sarcopenia statement is that it was stated as a conclusion of the meta-analysis.  Seppi  333  (Insert 2¢) 07:04, 8 December 2017 (UTC)
 * The reason it was stated in the bed rest-associated muscle atrophy sentence is that there is preliminary evidence from clinical trials with small sample sized for efficacy, but its treatment efficacy hasn't been well-established based upon phase 3 randomized controlled trials (i.e., clinical trials with rather large sample sizes), as is required for FDA-approved medications.  Seppi  333  (Insert 2¢) 20:35, 4 December 2017 (UTC)
 * both instances where "more research is needed" was stated in this section. The first instance of that statement in the sentence about muscle strength in sarcopenic adults was removed when I updated the text with a medical review from 2017; that review made a conclusive statement about HMB's effect on muscle strength in sarcopenic adults based upon more recent primary research. The second instance of that statement in the sentence on bed rest was removed when I rephrased the sentence as: Preliminary clinical evidence suggests that HMB supplementation may also prevent muscle atrophy during bed rest (diff).  I think that wording conveys the same meaning as the original wording about more research being needed to establish efficacy.  Seppi  333  (Insert 2¢) 01:32, 16 December 2017 (UTC)


 * Enhancing performance
 * Are four citations really needed for this sentence "HMB produces these effects..."?
 * No, all of it is supported by just 1 reference, but it is a significant medical claim since it states a mechanism responsible for the clinical effects. I placed the references supporting that sentence into a sources note since there were 4, but do you want me to prune it down anyway?  Seppi  333  (Insert 2¢) 22:27, 12 December 2017 (UTC)
 * I think if possible, for ease of verification, and I do not think that this is particularly controversial, you could include the best of these references, or at the most 2. 4 is excessive. --Tom (LT) (talk) 02:36, 15 December 2017 (UTC)
 * : Alright, I'll reduce it to 2 the next time I update the article. That should cut at least 1 ref from the first lead paragraph's "sources" note. I removed 1 ref from the 1st lead paragraph's sources note earlier when I updated the safety profile statement as well.  Seppi  333  (Insert 2¢) 02:41, 16 December 2017 (UTC)
 * ✅: it's now cited by only 2 of the 4 refs.  Seppi  333  (Insert 2¢) 20:45, 17 December 2017 (UTC)
 * Thanks. --Tom (LT) (talk) 23:09, 17 December 2017 (UTC)
 * "Untrained individuals and trained athletes" seems to cover the whole spectrum of people doing exercise?
 * I've modified to the clause to specify untrained individuals and athletes who perform high intensity resistance or aerobic exercise. Moderate exercise causes high levels of muscular stress in untrained individuals, but that typically only occur at high intensities in trained individuals.  Seppi  333  (Insert 2¢) 22:27, 12 December 2017 (UTC)
 * Thanks. This sentence seems to have only two factual statements. Does it need three references? --Tom (LT) (talk) 02:36, 15 December 2017 (UTC)
 * The phrase "these effects" refers to the 8 effects of HMB (muscle hypertrophy/strength/power, lean mass, muscle damage, exercise recovery, aerobic exercise performance, and aerobic fitness) that were stated in the 2 sentences which preceded this sentence. Those 2 sentences were supported by 6 reviews.  This statement could be fully supported by 2 reviews if I deleted the preceding sentence on HMB's effects on aerobic exercise performance and aerobic fitness, but I don't think it would be wise to do so. The third review is necessary for supporting that part.  Do you want me to cut the preceding sentence and remove the third review from this sentence, or should I clarify that the phrase "these effects" refers to the aforementioned effects on skeletal muscle and aerobic performance/fitness?  Seppi  333  (Insert 2¢) 01:56, 16 December 2017 (UTC)
 * OK, fair enough. No issues there. --Tom (LT) (talk) 23:09, 17 December 2017 (UTC)
 * "The inhibition of exercise-induced skeletal muscle damage by HMB is affected by the time that it is used relative to exercise" (1) does this need two references? (2) I have no bright ideas but I'm sure this sentence could be written in a simpler manner
 * I'll think about how to rephrase the sentence.
 * ✅ – rephrased as "The efficacy of HMB supplementation for reducing skeletal muscle damage from prolonged or high-intensity exercise is affected by the time that it is used relative to exercise." Let me you if you think it needs further revision.  Seppi  333  (Insert 2¢) 07:16, 14 December 2017 (UTC)
 * Reads much better, thanks. --Tom (LT) (talk) 02:36, 15 December 2017 (UTC)
 * It doesn't need two references. Should it have only 1? Actually, since this sentence is discussing efficacy, I think it would be better to leave it as is.  Seppi  333  (Insert 2¢) 22:27, 12 December 2017 (UTC)
 * I think for ease of verification, and given that this does not seem to be a particularly controversial statement, the better of the two references should be included only. (but happy to compromise on this - I will flag it in the FA review if you want to leave it) --Tom (LT) (talk) 02:36, 15 December 2017 (UTC)
 * (see this diff for the removal).  Seppi  333  (Insert 2¢) 01:39, 16 December 2017 (UTC)
 * Thanks. --Tom (LT) (talk) 23:09, 17 December 2017 (UTC)
 * Suggest move "dose dependently" to a separate sentence
 * I deleted "dose-dependently" and indicated a specific dose that the vast majority of HMB studies have used instead ("3 grams of HMB per day").  Seppi  333  (Insert 2¢) 22:27, 12 December 2017 (UTC)
 * In this sentence "When combined with" there are only 4 references used more than 10 times. I suggest either trim, move to end of sentence, or hide the references mid sentence using comments
 * ✅ – I moved the refs to the end of the sentence and placed them in a sources note; I also hid them where they were to support WP:V.  Seppi  333  (Insert 2¢) 18:31, 12 December 2017 (UTC)
 * Thanks. --Tom (LT) (talk) 22:00, 12 December 2017 (UTC)
 * Is quite technical to read. Suggest some changes such as "When combined with" -> "With", "augments" -> "adds to"; "expedite" -> "speed up" ✅

Side-effects

 * Could include information about what happens if more than the stated doses are taken?
 * Experiments in animals with very high doses uses didn't indicate any and to my knowledge there is no reported median lethal dose (LD50) for this compound. Clinical research in humans hasn't indicated any adverse effects from higher doses (IIRC, up to 15 grams/day has been used before without reported side effects in a small study, but I don't remember where I read that).  Based upon the hypothesized immediate targets of this compound, it seems unlikely that this compound would be capable of exerting an acute toxic from high doses via pharmacological means since, beyond a certain dose (presumably in the 3-6 gram range), its effect on signaling cascades is saturated since the activation of each protein in the cascades that it triggers is already maximal.  Most studies use 3 grams of HMB because there's little difference in clinical efficacy from taking 3 grams vs 6 grams, not because of the potential for adverse effects. It is possible that biotransformation of large amounts of HMB to HMB-CoA could produce adverse effects if, for some reason, one or both of the two other primary metabolic pathways of HMB-CoA are inhibited (HMB-CoA→MC-CoA and HMB-CoA→HMG-CoA), based upon a primary study (see reference quote); however, healthy individuals are capable of readily converting HMB-CoA to MC-CoA or HMG-CoA, which are subsequently metabolized into other compounds like cholesterol and ketones, among others.   Seppi  333  (Insert 2¢) 20:06, 13 December 2017 (UTC)
 * Interesting. I think it is useful in pharmacological articles to note something about overdose/ the unlikely possibility of overdose.--Tom (LT) (talk) 23:16, 14 December 2017 (UTC)
 * : I'll go back through the cited reviews in this section to see what they say about HMB overdose/toxicity; if I can, I'll add a statement about HMB overdose in the article.  Seppi  333  (Insert 2¢) 02:04, 16 December 2017 (UTC)
 * The only review that commented on fairly high dose usage was the one that reviewed animal studies involving HMB. It stated, The no-observed adverse-effect level (NOAEL) was determined to be 3.49 and 4.16 g/kg BW daily for male and female rats, respectively". I don't think this would be particularly useful to include in the article, because an equivalent dosing in humans must first be converted using a predetermined scaling metric which isn't mentioned in the review (see the USFDA's guidance on this). In other words, since a human equivalent dose is not specified by this review, stating those g/kg values in rats would be misleading since they'll probably be interpreted by some readers as applying to humans. Nevermind, the newest review that I recently added mentioned the equivalent dose for humans based upon the same study.  It stated: "One study tested the safety of HMB for long-term use in rats. Fuller et al. (50) conducted a 91-d study with the use of Sprague-Dawley rats that tested the safety of b-hydroxy-b-methylbutyric free acid (HMBFA). This new form of HMB results in higher HMB serum concentrations than CaHMB. In this study, rats were administered an HMBFA intervention of 0%, 0.8%, 1.6%, or 4% of the diet by body weight. The highest dose is the equivalent of ~400 mg * kg-1 * d-1 for humans. No adverse advents were observed for any treatment group. Similarly, blood and urine analyses were within the normal range in all groups, with no group differences. The authors concluded that HMBFA was safe for consumption in a rat model."  Seppi  333  (Insert 2¢) 01:38, 20 December 2017 (UTC); Updated/edited at 05:46, 20 December 2017 (UTC)
 * in this diff.  Seppi  333  (Insert 2¢) 06:23, 20 December 2017 (UTC)


 * In general easy to understand and well-written.
 * Glad to hear. This section was the subject of a lot of editorial feedback/revision in an earlier talk page discussion (Talk:Beta-Hydroxy beta-methylbutyric acid).  Seppi  333  (Insert 2¢) 20:06, 13 December 2017 (UTC)
 * The safety profile - four references needed for that statement?
 * It could be cited and fully supported by only 2 (1 review on clinical research in humans, 1 review on animal research), but the additional 2 references were included to demonstrate that there is scientific consensus about its safety profile across several independent medical reviews of clinical research.  Seppi  333  (Insert 2¢) 20:06, 13 December 2017 (UTC)
 * I think that for the section, or even for the inclusion of specific side-effects, these references may be needed. But to support the statement "The safety profile of HMB in adult humans is based upon evidence from clinical trials in humans and animal studies", which is almost in WP:SKYISBLUE territory, four is too many. --Tom (LT) (talk) 23:16, 14 December 2017 (UTC)
 * ✅: I've replaced 1 review with a newer one and deleted 2 reviews which supported that statement. It's now cited by only 2 reviews.  Seppi  333  (Insert 2¢) 02:13, 16 December 2017 (UTC)
 * Also, I've updated (reduced) the number of corresponding references in the lead.  Seppi  333  (Insert 2¢) 02:28, 16 December 2017 (UTC)

Pharmacology

 * Pharmacodynamics


 * If possible would suggest "protein synthesis" -> "protein creation" or even "formation" (and standardise "biosynthesis")
 * The terms "muscle protein synthesis" (MPS) and "muscle protein breakdown" (MPB) are widely used in the literature on this compound and on muscle protein turnover in general. I'll simplify the phrase if you really think it should be rephrased; but, at the same time, I'd expect the average high school student to know what the term "synthesis" means since most high schools require students to learn chemistry and biology.  Seppi  333  (Insert 2¢) 21:45, 13 December 2017 (UTC)
 * I will demure on this point, but it is just an example of how this article could be made easier to read for the lay person. To support my assertion, I quickly calculated a Flesch Grade Level on this article using MS word, and it is 19.5, ie. suitable for reading by those with more than 6 years of university education. The average US adult reads at grade 8-9. --Tom (LT) (talk) 01:27, 19 December 2017 (UTC)
 * The pharmacodynamics and chemistry sections of a drug article are not interesting to most people who read a drug article (e.g., I've completely rewritten a few drug articles and the chemistry section still doesn't interest me that much; the synthesis section in drug articles is gibberish to me because I lack the necessary background knowledge in organic chemistry to interpret it). They're both very specialized topics that should be included in pharmacology articles, but which necessary involve a lot of fairly technical material.  If someone isn't familiar with molecular biology and pharmacology, they're not going to understand a comprehensive pharmacodynamics section – regardless of how simplistic the language is – because they lack a background knowledge of important concepts; for example, in this article, this section isn't going to make sense to anyone who isn't familiar with what signaling cascades, ribosomes, and proteasomes are and their purpose in cells.  One way of addressing this is by adding notes to sentences to clarify what is being discussed and elaborate on those concepts (e.g., like this note, this one, or this third one), but I haven't done this in this article (yet). Let me know if you think it's worth clarifying some of the concepts in this section with explanatory notes; I'm willing to do that.  Dumbing down the language in the entire section probably won't make it more readable without addressing this other issue though. If there are particular sentences that you think should be clarified in this section, please point them out!  Seppi  333  (Insert 2¢) 01:51, 20 December 2017 (UTC)
 * FWIW, the readability of this article is better than the amphetamine article based upon .  Seppi  333  (Insert 2¢) 02:00, 20 December 2017 (UTC)
 * Fair enough. On re-read after all the changes you've made, I feel the article is quite a bit more readable. --Tom (LT) (talk) 22:18, 25 December 2017 (UTC)
 * "Several components of the signaling cascade that mediate the HMB-induced increase in human skeletal muscle protein synthesis have been identified " surely doesn't need 2 references
 * The review lists the main component of the signaling cascade (mTORC1) and the secondary effects on GH/IGF-1 secretion in humans which was covered in that section (for context, GH and IGF-1 increase protein synthesis via mTORC1); the primary source lists all of the known downstream components in the signaling cascade (mTORC1, p70S6 kinase, 4EBP1) which HMB acts through.  Seppi  333  (Insert 2¢) 21:45, 13 December 2017 (UTC)
 * I won't push this particular point, but if they could be included where those respective products are listed I think it would reduce the burden of unnecessary references.To support the statement "several components... have been identified" really only needs a single source - the fact that several components have been identified by some person or group is not controversial --Tom (LT) (talk) 23:27, 14 December 2017 (UTC) for later reference
 * "Supplementation with HMB for one month in rats has also been shown to increase growth hormone and insulin-like growth factor 1 (IGF-1) signaling through their associated receptors in certain non-muscle tissues" if this is to do with non-muscles, then suggest move to the last paragraph
 * GH and IGF-1 are hormones, so they circulate in blood plasma to all tissues. I think the ref was discussing non-muscle tissues in that specific context, however I added a 2nd statement from a new clinical review of human research on GH and IGF-1 secretion in response to resistance exercise in humans after that sentence. That 2nd sentence does pertain to GH/IGF-1 signaling in skeletal muscle, so, for contextual relevance, I've deleted "non-muscle" from the first sentence; it now says "... in certain tissues".  (edited in this diff)  Seppi  333  (Insert 2¢) 21:45, 13 December 2017 (UTC)
 * Thanks. I still see this sentence as confusing. The paragraph opens with "Several components of the signaling cascade that mediate the HMB-induced increase in human skeletal muscle protein synthesis " so I am mentally expecting a paragraph about HMB and skeletal muscle, yet they we have a statement about use in other tissues. I think this should be moved to one of the other paragraphs. --Tom (LT) (talk) 23:27, 14 December 2017 (UTC)
 * GH and IGF-1 trigger protein synthesis through mTORC1 phosphorylation upon binding to their respective tyrosine receptor kinases; that's the reason I included the original sentence in that paragraph. Those two statements don't really have any relevance to the topics discussed in the last 2 paragraphs in that section (i.e., the paragraphs about intramuscular cholesterol and myosatellite cell proliferation/differentiation/fusion), but it is somewhat relevant to the muscle protein breakdown paragraph.  I've further revised the wording so that the discussion about the effect on GH/IGF-1 in rats is easier to understand, more general, and more relevant to the discussion about the effect on those substances in humans (diff). Seppi  333  (Insert 2¢) 08:40, 16 December 2017 (UTC)
 * Thanks, that makes a lot more sense. --Tom (LT) (talk) 23:20, 17 December 2017 (UTC)
 * Image two - (1) doesn't specificially mention HMB; (2) silly question, but couldn't find it answered in article. IS HMB a protein?
 * Image 2 was included to illustrate the MPS response to exercise. It was included to give the reader an idea how much the baseline MPS is in response to exercise; the futher increase in response to HMB supplementation is listed in that section.  If you think it should be removed, I'm ok with taking it out.  Seppi  333  (Insert 2¢) 20:22, 4 December 2017 (UTC)
 * HMB is not a protein since it's not an amino acid complex; its chemical classification is covered in the chemistry section: "β-Hydroxy β-methylbutyric acid is a monocarboxylic β-hydroxy acid".  Seppi  333  (Insert 2¢) 20:22, 4 December 2017 (UTC)
 * Thanks for your thoughtful reply. I think that as HMB isn't a protein and this relates to MPS in response to protein ingestion, this is one step too far away from the primary topic of the article. I think we should remove it. --Tom (LT) (talk) 22:04, 12 December 2017 (UTC)
 * (see this diff).  Seppi  333  (Insert 2¢) 22:52, 12 December 2017 (UTC)
 * "Based upon animal studies" -> could trim citations? (currently 4)
 * I was able to cut two which made slightly different claims from the 2 that I didn't remove, but weren't necessary to fully support the sentence (see this diff).  Seppi  333  (Insert 2¢) 21:45, 13 December 2017 (UTC)


 * "may also facilitate the stabilization of " -> "may help stabilize" ✅
 * "It is not clear if long-term supplementation with HMB in humans produces a similar increase in growth hormone and IGF-1 " if we are comparing against rats this is difficult to interpret, because the rats were given it for a 1 month but humans were taking it long-erm
 * Re - the above bullet: since I added the material about the effect on GH/IGF-1 in humans based upon 1 small clinical trial that was included in a systematic review, I left that part in simply because it provides corroborating support from animal research for the statement in humans.  Seppi  333  (Insert 2¢) 21:45, 13 December 2017 (UTC)
 * Thanks. --Tom (LT) (talk) 23:27, 14 December 2017 (UTC)
 * "Similar to L-leucine" (1) suggest reinclude ", of which HMB is a product"; (2) I do not think you need to include the note, and if you do I suggest remove "in one study" as that would be a primary source.
 * I rephrased this as "Similar to HMB's metabolic precursor, -leucine, ..." because stating that "HMB is a (metabolic) product of X" would really only make sense if that X was an enzyme, which has a substrate (e.g., leucine) and a product (e.g., HMB). I hope that wording is ok with you (edited in this diff).  Seppi  333  (Insert 2¢) 21:45, 13 December 2017 (UTC)
 * Thanks, much better. --Tom (LT) (talk) 23:27, 14 December 2017 (UTC)
 * The "in one study" clause in that sentence provides context for the statement, so I think removing it would make the context ambiguous. If you feel strongly about removing it, I will, but I don't think it would be helpful. In any event, since the sentences in all of the notes in the pharmacology section only discuss molecular biology, pharmacodynamic mechanisms, or pharmacokinetics without making any medical claims (at least not clinically relevant ones, depending upon how broadly the phrase "medical claims" is interpreted), the primary sources for those statements only really needs to satisfy the no OR restriction in WP:SCIRS and the other WP:SCIRS requirements (e.g., independent, up-to-date, peer-reviewed journal sources).  Sourcing for similar content in articles on proteins, amino acids, and other biomolecules is typically governed by SCIRS because most endogenously synthesized compounds don't have medical uses.  Seppi  333  (Insert 2¢) 21:45, 13 December 2017 (UTC)
 * I think the note should be removed, for the following reasons: I do not think it adds particularly to the paragraph or article; it relies on a single source, which makes it unreliable; it distracts from the flow of information; and I do not think it relates strongly enough to the sentence or paragraph to which it is attached to be included. --Tom (LT) (talk) 23:27, 14 December 2017 (UTC)
 * The reliance on a single source is a valid issue, but I was actually planning on slightly expanding the note with coverage of a recently published primary source which examined the same parameters as the study which is cited in that note, but used HMB-Ca instead of HMB-FA. It found that the same effects occur with both HMB dosage forms and compared its results with the earlier primary source which is cited in the note.  The purpose of the note is to specify an effect size for the increase in skeletal muscle protein synthesis (MPS) by HMB (i.e., it answers the question "how large is this increase?") in living humans; the entire paragraph in which the note is located only discusses how HMB affects MPS, so I don't understand why you think it has little relevance.  Seppi  333  (Insert 2¢) 21:11, 17 December 2017 (UTC)
 * OK, I won't push this point. Can we move the note to the end of the sentence to improve readability? I will add a "" so that some of my ongoing concerns are noted in case somebody else mentions them in the FA. --Tom (LT) (talk) 23:20, 17 December 2017 (UTC)
 * ✅: Good idea – that's more consistent with the placement of the other notes in this section (diff).  Seppi  333  (Insert 2¢) 05:46, 18 December 2017 (UTC)

Chemistry
The comment below pertains to the discussion at FAC
 * "A variety of synthetic routes " - >"HMB has been created in a number of ways" (this applies to the image caption too)
 * Since MOS:MED/MOS:PHARM specify that "Synthesis" be used as the title of this section, it seems a bit odd to replace the word "synthesis" in the text and leave it in the section title (NB: the content/sub-sections within the chemistry section were loosely based upon MOS:CHEM/Chemicals). Also, "synthetic routes" is wikilinked in this sentence (that's a link to a redirect to chemical synthesis) and I think the topic of the target page would be somewhat ambiguous if I put a piped-link to that article on the phrase created in a number of ways.  Seppi  333  (Insert 2¢) 07:56, 18 December 2017 (UTC)
 * Happy to leave this given MOS#MED, but I do think this article could be made more readable. This would help its content be communicated to a greater audience --Tom (LT) (talk) 01:29, 19 December 2017 (UTC)
 * The first reported chemical syntheses -> "The first creation chemically..."
 * See the response to the preceding bullet.  Seppi  333  (Insert 2¢) 07:56, 18 December 2017 (UTC)
 * "β-hydroxy β-methylbutyric acid" -> Mentioned lots of times here. Isn't this HMB? It would be best if, after the first mention in the lead, every other reference in the body uses HMB. I mention this only because in the second paragraph you do use that acronym and it's confusing because it implies they might be two different things
 * In this particular section (Chemistry), using the full term for the conjugate acid (β-hydroxy β-methylbutyric acid) and conjugate base (β-hydroxy β-methylbutyrate) when discussing the properties of one or comparing the two is necessary because they're two distinct compounds (see the images to the right and their chemical formulas - the base has one less hydrogen atom than the acid and a negative charge on one oxygen atom). I believe (NB: Boghog wrote the entire subsection on synthesis; if you can comment on this, that'd be helpful) that specifying that the product is the acid matters for the synthesis subsection since a particular synthesis method might never yield the conjugate base.  Nonetheless, since the entire chemical synthesis subsection is discussing the conjugate acid, I just left the first mention of HMB as the expanded term for the acid and converted all other instances to "HMB" in that subsection (diff).  Seppi  333  (Insert 2¢) 07:56, 18 December 2017 (UTC)
 * All rightly. --Tom (LT) (talk) 01:29, 19 December 2017 (UTC)
 * Why have you used the initial acronym (which does not state "free acid form" when all the other sections use the full form of the word? I think acronyms in general tend to make things less readable
 * (assuming that you were referring to this)  Seppi  333  (Insert 2¢) 22:50, 12 December 2017 (UTC)
 * You surely do not need more than one citation for:
 * "with the chemical formula C5H10O3" the chemical formula
 * The phrase you quoted requires only 1 reference, but 2 references are required to cite the entire sentence; if I were to cite it piece-wise, it would read: β-Hydroxy β-methylbutyric acid is a monocarboxylic β-hydroxy acid and natural product with the chemical formula C5H10O3. –  Seppi  333  (Insert 2¢) 21:09, 11 December 2017 (UTC)
 * "transparent, colorless to light yellow liquid which is soluble in water"
 * This phrase requires 3 references: transparent, colorless to light yellow liquid which is soluble in water. –  Seppi  333  (Insert 2¢) 21:09, 11 December 2017 (UTC)
 * Agree - you make a good point. --Tom (LT) (talk) 22:09, 12 December 2017 (UTC)
 * Suggest remove this unnecessary tidbit "(NaOCl, more commonly known as bleach)" and "(CO)" as the paragraph is already complicated enough
 * ✅: diff.  Seppi  333  (Insert 2¢) 07:56, 18 December 2017 (UTC)
 * The whole 'chemical structure' paragraph. Why do you need two references per line for things such as what is the conjugate acid and what is the conjugate base?
 * One refs state the acid is the conjugate acid of the base, whereas the other ref states that the base is the conjugate base of the acid; hence, both refs are necessary to fully support the assertions in that sentence.  Seppi  333  (Insert 2¢) 21:17, 11 December 2017 (UTC)
 * "Synthesis" - am in favour putting on my simplification hat of renaming to "Creation" but acknowledge this may not be totally desired
 * "Synthesis" is the correct title of this section according to MOS:MED/MOS:PHARM.  Seppi  333  (Insert 2¢) 21:17, 11 December 2017 (UTC)
 * Great images by the way
 * Thanks. Credit goes to User:Boghog for those.  Seppi  333  (Insert 2¢) 21:17, 11 December 2017 (UTC)
 * Suggest move the refractive index formula into a note, I am not sure how this adds to the text
 * I don't think it's useful information to most readers, but demanded that the chemistry section be expanded at, so Boghog added it to include more information about its chemical properties. I'm not sure Nergaal would be happy with that being placed in a note at the next FAC if he chooses to comment again.  Seppi  333  (Insert 2¢) 21:17, 11 December 2017 (UTC)
 * OK. Well I will note that I don't think it's useful, is unnecessary jargon and excessively technical, and also we are not a manual (WP:NOT) and leave it at that - this can be discussed more in FA if other editors comment on it. --Tom (LT) (talk) 22:09, 12 December 2017 (UTC)


 * Detection in body fluids
 * "Endogenously synthesized HMB has been detected and quantified in several human biofluids " -> HMB created by the body has been found and measured in several human fluids" – ✅
 * "e average molar concentration of HMB has been quantified at 4.0 micromolar (μM) -> "The average concentration has been measured at 4.0 μm (micromolar)"
 * "4.0 micromolar (μM)" is the format specified by MOS:UNITNAMES for introducing units that readers are expected to not know. (Units unfamiliar to general readers should be presented as a name–symbol pair on first use, linking the unit name (Energies were originally 2.3 megaelectronvolts (MeV), but were eventually 6 MeV).)
 * OK, fair enough. --Tom (LT) (talk) 22:09, 12 December 2017 (UTC)
 * Suggest change all "quantified" -> "measured" for readability – ✅
 * Suggest remove all the acronyms, as they are all used only once (including NMR, LC-MS, GC-MS, and even potentially CSF)
 * ✅: removed the first 3. CSF is listed in the table, so I think that's better to leave in (diff).  Seppi  333  (Insert 2¢) 05:51, 18 December 2017 (UTC)

History

 * No comments, easy to understand and fairly interesting

In general

 * Excellent article you have clearly put a lot of effort into
 * Too many references - (1) should be trimmed if at all possible, especially when single facts have multiple references; (2) lead seems to have more references than the body for some things, this should surely be reversed
 * Thank you, I can see you've tried to trim the references and appreciate this. --Tom (LT) (talk) 22:26, 25 December 2017 (UTC)
 * Some language used in the article is quite technical and could be simplified to enhance readability
 * Suggest you quickly run through the article and standardise all spellings of HMB to the acronym HMB and HMB-FA, as currently they alternate making this quite difficult to read at times
 * The only place in the article (as of today) where the expanded/full term was used, but the acronym could be used instead, was in the history section; I've updated that section accordingly (diff). The use of HMB-Ca and HMB-FA and the remaining uses of the expanded/full terms are in places where using the acronym "HMB" would not be appropriate since the text is referring specifically to one commercial formulation, the conjugate acid, or the conjugate base in those contexts. "HMB" refers to all of those collectively.  Seppi  333  (Insert 2¢) 07:18, 20 December 2017 (UTC)
 * after reconsideration, I decided to standardize HMB-Ca and HMB-FA to HMB in the side effects section as well since the difference in the dose of HMB between HMB-Ca and HMB-FA is pretty small (diff). Almost all clinical studies used 3 g of either formulation anyway.  Seppi  333  (Insert 2¢) 23:34, 21 December 2017 (UTC)
 * Thanks. The article's readability has improved (in my eyes at least) throughout the review.
 * Images are excellent
 * Won't delve in to the sources used that much other than to say for posterity's sake that they will need a closer look in FA several of them are primary sources and small scale studies

I hope this review helps. Will start working through your replies in the next day or so. Cheers --Tom (LT) (talk) 22:50, 8 December 2017 (UTC)

I combed through the references and compiled the list below that includes every primary source cited in the article which has a PMID number (the handful of other primary sources cite statements in chemistry, history, etc., so they're all covered by WP:RS).

Primary sources with a PMID # that were cited in this article – the sections in the body where these are cited are listed in parentheses:  Seppi  333  (Insert 2¢) 00:02, 9 December 2017 (UTC)
 * – included in medical section, but doesn't support a medical claim - only comments on the adequancy of the study
 * 1) – supports statements about concentrations in bovine milk and food fortification with HMB ( Available forms, Detection in body fluids)
 * 2) – supports statements about presence in human milk and its concentration range (Detection in body fluids)
 * 3) – support its commercial availability and statements about its pharmacokinetics (Available uses, Pharmacokinetics)
 * 4) – support statements about its metabolic pathway (Biosynthesis)
 * 5) – supports which protein kinases, myogenic factors, or transcription factors mediate the effects that were identified in reviews of in vitro research, but which glossed over the details (Pharmacodynamics)
 * 6) – supports only the following sentence in a reference note: Since all T cells are CD3+, a measure of CD3+ cells is used as a general estimate of total T cells. (Special:permalink/814463242)
 * 7) – supports statements about pharmacodynamics & concentration in blood plasma following oral ingestion (Pharmacodynamics, Detection in body fluids)
 * 8) * – not currently cited, but was planning to add this to the article to support statements in pharmacodynamics and detection in body fluid; this study is analogous to the one in the bullet immediately above.

COMMENT: Under the rubric of "less is more," I find it unnecessary and annoying that so many of the references include extended quotation of material from the abstracts or articles. Some exceeding 150 words and containing mention of references in the cited article. If the information is essential to the article it belongs in the article. If not, it does not belong anywhere. I've rarely seen reference bloat of this nature, and this is a particularly egregious example. David notMD (talk) 15:45, 12 December 2017 (UTC)
 * The extended quotes are there so that I don't need to constantly sift back through the refs during FAC when people challenge whether or not material is supported by a reference, which occurs at every FAC. I intend to censor all of the ref quotes to at most 5 sentences after a WP:V check is finished.  I'm not going to censor them now though.  Seppi  333  (Insert 2¢) 17:57, 12 December 2017 (UTC)
 * Appreciate the explanation. Whenever I am trying to uplift an article to GA status, my workspace is strewn with printouts of abstracts and pages from PDFs of articles. I've yet to attempt a FA. NOTE: I do agree with the too-many-refs comment from the GA reviewer, but again, some of that probably in anticipation of FA submittal. David notMD (talk) 18:08, 12 December 2017 (UTC)

Conclusion
Thanks for your patience,. This is a great article that you've put a lot of effort into. With your many changes I feel the article has improved to meet GA criteria. I have one or two concerns that I feel we are at loggerheads here with and will pop on the article's talk page, but nothing that would mean this article shouldn't become a GA. Thanks for your responsiveness; Merry Christmas! --Tom (LT) (talk) 22:26, 25 December 2017 (UTC)
 * Thanks again for doing the GA review of this article Tom! I really appreciate all the time and effort you put into reviewing it; I think it was very constructive/helpful.  Seppi  333  (Insert 2¢) 22:30, 25 December 2017 (UTC)