Wikipedia:Featured article candidates/Beta-Hydroxy beta-methylbutyric acid/archive1

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) 22:07, 4 October 2016 [1].

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Beta-Hydroxy beta-methylbutyric acid

Nominator(s): Seppi333 (Insert 2¢) and Boghog (talk) 16:03, 12 August 2016 (UTC)

Notified WT:WikiProject Medicine, WT:WikiProject Pharmacology, WT:WikiProject Chemicals, and User talk:John.

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#Drugs, treatments, and devices. 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., <ref name="...">) defined in the source code of the HMB article.

Seppi333 (Insert 2¢) 16:03, 12 August 2016 (UTC); Updated at 05:30, 23 August 2016 (UTC)

@FAC coordinators: I'm requesting that this nomination be closed/archived a little early. After speaking to John on his talk page, he expressed interest in completing his review but indicated that he likely won't have time to work much on this over the next week or two. I feel it would be better to just get the 2 week nomination hiatus out of the way while he's busy. Since Axl is currently on vacation/holiday, Zefr is unwilling to return to his review, and Nergaal hasn't responded to my recent pings or talk page messages, I don't expect much progress to be made in this nomination between now and when it would normally be closed. Seppi333 (Insert 2¢) 19:28, 4 October 2016 (UTC)

Thanks for that Seppi, will action. Cheers, Ian Rose (talk) 22:05, 4 October 2016 (UTC)

Notes by the nominator about reference formatting

This section is mostly directed at anyone who is interested in doing a review of the article citations for FA criterion 2c.

I've attempted to standardize the formatting of all references in the article as follows:

• Page ranges are written out in an unabbreviated format (e.g., 191–194 is used in page ranges instead of 191–4) with an ndash per MOS:NDASH.
• Journal titles use the standardized pubmed abbreviations for each journal cited, provided that it is listed in the NLM Catalog. Only the abbreviated words and the last word in a journal title are followed by a period.
• All dates use the DMY format.
  • Journal citation dates include the month (if available) and year of the publication date.
  • Book citation dates include the month and year of publication.
  • Web and database citation dates include the day, month, and year of the most recent revision that was listed prior to the access date, if available.
• Book citations list the 13 digit ISBN.
• The names of the authors in all citations follows the standard pubmed author format for an author list.

  For example: "John Randomguy Doe, Bob Jeremy Frank, Jean Dumas" is written as "Doe JR, Frank BJ, Dumas J" in the author list.

Seppi333 (Insert 2¢) 01:40, 28 August 2016 (UTC)

Comments by Doc James

• The large quotes raise copyright concerns for me. IMO quotes should be keep to less than 20 words. Lawyers from a pharma company have told me 7 but I think they were just bluffing. User:Diannaa or User:Moonriddengirl your thoughts? Doc James (talk · contribs · email) 21:29, 12 August 2016 (UTC)

If there's consensus here to remove/censor the quotes, then I'm okay with this; however, I assure you that the current length of the quotes is not a copyvio concern: the Hazardous Substances Data Bank (HSDB) is a database of monographs that contains literally nothing but quotations from copyrighted academic literature, copyrighted professional textbooks, or PD government websites. E.g., their entry on delta 9-Tetrahydrocannabinol is a massive page that contains nothing but excerpts that are copied verbatim from the source which is cited beneath the excerpt. PubChem transcludes almost all of HSDB's quotations to its own monographs on chemicals as well (for comparison: PubChem THC link). A number of the academic journal article quotes in the THC entry are longer than the longest quotes included in the HMB article and there's no mention in the HSDB's FAQ about obtaining permission to source their content from copyrighted publications like this; hence, the current references in the HMB article are not copyright problems if the HSDB's and PubChem's monographs aren't. Seppi333 (Insert 2¢) 22:30, 12 August 2016 (UTC)

I know this is archived, but I'm only just now seeing it and hate to leave it without response. :) There is no legal "word count" limit on the size of quotations; it is entirely context dependent. For this reason, the lawyers that told you 7 from the pharma company, Doc James, were totally making stuff up, but we also can't take the precedent of databases of monographs or PubChem, Seppi333. We are neither of those sites, and our purposes and nature are very different. Wikipedia:Non-free_content#Text notes that "extensive quotation of copyrighted text is forbidden" - there's no specifics, because what constitutes "extensive" depends on so many factors, including the length of the source (90% of a source is "extensive" even if the quote is three sentences long), the length of the new home (90% of the article is extensive, even if the quote is a paragraph out of a 400 page book), and whether the quote is the 'heart' of the source (which is why we can't just reproduce the top 5 of creatively compiled lists, even if the list contains 100 items). There's also the larger question of whether we are building something new with the quote or using it to supersede the need to review the original - which would lend towards a finding of copyright infringement. And there are movement value questions related to the fact that we encourage broad reuse, even commercially, which is why Wikipedia has more conservative copyright attitudes than non-commercial organizations, as profit is a consideration in fair use. It's complicated and cannot be nailed down to a "We can only use X words" or even a "We can safely use X words," and we cannot use text just because some other website does. In each instance, we need to ask ourselves if our use is transformative and the minimal excerpt of the non-free content that we need to further academic advancement. (Sometimes, for instance, we don't need a quote at all and can rest with a paraphrase or summary. Sometimes, the precise quote is important.) --Moonriddengirl ^(talk) 15:02, 28 August 2016 (UTC)

Yes I am well aware that the lawyers were making it up. We still however want to be conservative as lawyers can harass an organization whether they have a case or not. Doc James (talk · contribs · email) 22:47, 28 August 2016 (UTC)

@Moonriddengirl: Ah, I stand corrected then. Anyway, this nomination won't be archived until sometime around mid-October, so there's no issues with posting here at the moment. Seppi333 (Insert 2¢) 02:06, 29 August 2016 (UTC)

Comments by Nergaal

• OpposeWeak oppose this is a chemical with absolutely 0 chemical information on it. I understand it is most relevant as a performance-enhancer, but that does not mean it has no chemical information about it outside physiological conditions. Also, the article does not explicitly say it is a performance-enhancer that is not controlled at all. Nergaal (talk) 13:17, 14 August 2016 (UTC)

@Nergaal: There's very little experimental chemical data available on this compound; it was hard enough just to find an experimental mp/bp. In any event, I'm not sure what kind of chemical information you have in mind so unless you can be more specific or give examples, this is not an actionable objection.

The article does not explicitly state "it is a performance enhancer that is not controlled at all" because that statement is not made anywhere in reliable sources. It's probably true, but if I said that without a reference it would be WP:OR. Edit: to clarify, I do know of sources that make a statement about its status in specific countries (e.g., the United States), but not globally. I can address this in a region-specific manner if you think it's worth adding. Seppi333 (Insert 2¢) 13:25, 14 August 2016 (UTC)

The fact that it is used as a performance-enhancer and is a "drug" seems a bit weird to an average reader that it is not controlled. Talking about USA and EU would suffice since they tend to be the most stringent about it. Also, WADA has a list so saying that it is not on that list would be useful. Nergaal (talk) 19:39, 14 August 2016 (UTC)

1. In relation to other performance-enhancing drugs, its regulatory status isn't really any different from caffeine or creatine. Both are drugs (by this, I mean "pharmacologically active compounds") that are sold over-the-counter and which have well established athletic performance-enhancing effects. Caffeine is more similar in the sense that it's also used clinically in some cases, but it's not an endogenous compound like creatine. In any event, I'm willing to clarify its regulatory status; is there a particular statement that you'd like to include to address this?
2. The lead does include the statement "As of 2015, HMB was not tested for or banned by any sporting organization in the United States or internationally.", but it doesn't specifically refer to WADA. In any event, I'll look for sources for adding a statement about whether or not it's banned by WADA; however, if their policy on banned substances is like the NCAA, their lists may not actually be comprehensive due to possible pharmacologically-related functional analogs of banned substances (aka designer drugs). There might not be sources that explicitly cover whether or not HMB is banned by WADA if that is the case, so I'll let you know what I find after I follow up on this.
3. I have sources on hand for its regulatory control status in the US; hopefully it won't be too hard to find a source for the EU as a whole. I'll probably include this information under the "Available forms" heading after I look for an EU reference.
4. Is there any particular information about its chemical properties that you'd like to see added? I had a difficult time finding any notable information to add from references about HMB's chemical properties. User:Boghog also mentioned that there really isn't a lot of information related to its laboratory/industrial synthesis either (see User talk:Boghog/Archive 10#Synthesis). Seppi333 (Insert 2¢) 20:11, 14 August 2016 (UTC)

• Scifinder would be the best place to search for available chemical information on this compound if any of you have access to it. I can gain access to Scifinder, but that will involve me needing to update my OS so that I can get the security software needed to connect to a VPN with the university, which I won't be able to get around to for a few days. M. A. Bruhn (talk) 01:40, 15 August 2016 (UTC)

I unfortunately don't. If you see any notable information on the the conjugate acid or the base's physical characteristics (e.g., odor, consistency/form, taste, color, etc) or a discussion/description of its chemical structure, that would be useful. Since I've seen some inconsistencies on its experimental properties between references, I also need to find a secondary source that lists its density with a reference to a primary source. Seppi333 (Insert 2¢) 18:26, 15 August 2016 (UTC)

On second thought, I just remembered that HMDB includes structural classification information on compounds listed in its database, so I'll just use this - http://www.hmdb.ca/metabolites/HMDB00754#taxonomy - for describing its structural class. Seppi333 (Insert 2¢) 18:31, 15 August 2016 (UTC)

It'll probably be a another day or two before I get around to addressing these issues. Been busy irl. Seppi333 (Insert 2¢) 19:28, 17 August 2016 (UTC)

@Nergaal: I added a description of its structural classification w/ 2 images (I had to create File:Butyric acid carbons.svg for this) and a statement about it being allowed by WADA and the NCAA to the lead/body (see special:diff/735006277/735339526). With exception for a statement about the common salt(s) of the compound, which are already described in Beta-Hydroxy beta-methylbutyric acid#Available forms, and a statement about its physical characteristics, which I can't seem to find a reference for, the content in Beta-Hydroxy beta-methylbutyric acid#Chemistry currently mirrors amphetamine#Chemistry. I'm still working on getting sources for #3 above; have my recent changes addressed your concerns coverage of WADA and HMB's chemical properties? Edit: I found a patent reference for the state and appearance of the free acid form of HMB at room temperature (I covered this in special:diff/735332484/735339526). Seppi333 (Insert 2¢) 01:17, 20 August 2016 (UTC); edited at 02:06, 20 August 2016 (UTC)

@Nergaal: After looking for about an hour, I couldn't find any statement about the regulation of HMB which was more specific than the one made by the reference to which I added the relevant quote in this diff. I'm guessing that this is simply because nutritional supplements generally don't require approval by a regulatory agency before being marketed in a given country (as noted in the dietary supplement article). I believe that I've finished addressing your comments/concerns from above (regulatory status, permitted use by NCAA/WADA, and chemistry-related information) with the addition of this material. Are you satisfied with the current changes that I've made and do you have any other comments/objections about the current article content? Seppi333 (Insert 2¢) 03:07, 23 August 2016 (UTC)

@Nergaal: Is there something that you still want me to add or have you just been busy IRL? Seppi333 (Insert 2¢) 13:41, 1 September 2016 (UTC)

Can the pic in biosynthesis be changed to also show the chemical formulas? The lead could have less refs IMO. Also, the lead says it is good for muscle grwth, but perhaps mention what biocycle is it supplicating. The history section needs to be merged or expanded. Nergaal (talk) 14:33, 1 September 2016 (UTC)

1. I could use {{AI4}} to annotate the chemical formulas as wikitext onto the image, but there isn't much room to add text for some of the compounds on the right side of the image; I'd have to expand the width of the image to add formulas to those since the only place to add an annotation to MC-CoA is on the right side. That said, the CoA compounds have pretty long chemical formulas due to the coenzyme A group (e.g., MC-CoA is C₂₆H₄₂N₇O₁₇P₃S) – are you sure you want me to add that?
2. Would you prefer that the lead refs be grouped at the end of the paragraph? I ended up doing this in amphetamine's lead and wouldn't mind doing it again here.
   • This page revision - Special:permalink/737260423 - is an example of how it would look in the 2nd and 3rd paragraphs. I didn't change the 1st lead paragraph simply for the sake of comparison. Seppi333 (Insert 2¢) 17:23, 1 September 2016 (UTC)
3. I've added a summary statement from the body about the mechanism of effects/pharmacodynamics to the lead in the 1st paragraph: "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."
4. I've removed the history section pending expansion. The content was previously only covered in the lead; Axl mentioned that it wasn't covered in the body in his section below, so I created the history section in response. I suppose this will have to be 1 of those instances where a lead statement isn't covered in the body for technical reasons unless I can find more information relevant to the historical aspects of HMB. IIRC Jytdog linked a ref below that might contain useful information about HMB-related history, but I need to read through it to be sure. Seppi333 (Insert 2¢) 15:04, 1 September 2016 (UTC)

@Nergaal: I found some relevant historical HMB-containing commercial product information in the Iowa State University FY2011 proposal that Jytdog linked to below. The relevant excerpt is located at Talk:Beta-Hydroxy_beta-methylbutyric_acid#FAC-related_references in the green quote box. If I cover this in the history section, it should end up being a 3–4 sentence paragraph - would that be sufficient for an expansion? Ideally, I'd like to mention something about who actually discovered the chemical originally in that section, but unfortunately I haven't read anything about that to date. Seppi333 (Insert 2¢) 17:06, 1 September 2016 (UTC)

I expanded the history section into a 5 sentence paragraph today – Beta-Hydroxy beta-methylbutyric acid#History. If there's any issues with the current section, let me know. Seppi333 (Insert 2¢) 08:22, 3 September 2016 (UTC)

@Nergaal: I need your input on #1 and #2 above before proceeding on those; I believe I've addressed the other two issues on its mechanism (#3) and expanding the history section (#4) as described above. Please let me know if you'd like me to make any other changes. Seppi333 (Insert 2¢) 08:33, 3 September 2016 (UTC)
@Nergaal: Sorry to annoy you with a ping again, but I still need your input on the first two points above when you get a chance. Seppi333 (Insert 2¢) 17:49, 9 September 2016 (UTC)

• I came to take a quick look and found a bunch of problems. It is obvious no chemist has taken a stab at this article. You really need somebody with some chemical background. The melting point cannot possibly be at -30 °C, and the ref used is useless. A substance does not have a pH but a pKa. I am sure something about its lactone can be said or about some exotic synthetic ways. Anything chemistry related really. 21:20, 9 September 2016 (UTC)
  • @Nergaal: you're probably right about needing a chemist to review this; chemistry is literally the only subject area in pharmacology-related articles in which I don't have an adequate background knowledge. As for the MP/BP, I sought feedback from WP:WikiProject Chemicals at WT:CHEM#MP/BP of β-Hydroxy β-methylbutyric acid to determine what MP and BP to use. I'll request a review of this article in this FAC nomination at WT:CHEM in an attempt to address your concerns; however, I'd strongly suggest mentioning and clarifying your objection about the MP in that discussion (WT:CHEM#MP/BP of β-Hydroxy β-methylbutyric acid) in order to address the issue. Edit: just to clarify, the article and cited source indicate that the experimental least upper bound for the MP is −32 °C (i.e., it doesn't melt at that temperature), they don't say that the MP is −32 °C. Seppi333 (Insert 2¢) 21:41, 9 September 2016 (UTC)
  • As for the laboratory/industrial synthesis of HMB, @Boghog: can you comment on this? Seppi333 (Insert 2¢) 21:42, 9 September 2016 (UTC)

@Nergaal: could you comment on the first 2 issues from above about the image annotations and lead citations? I still need your feedback on those. Seppi333 (Insert 2¢) 21:52, 9 September 2016 (UTC)

Pretty much every compound has a mp. I think SciFinder sometimes lists a bunch of these numbers. Or go to Aldrich.com and put the CAS number and open the SDS document. Nergaal (talk) 22:25, 9 September 2016 (UTC)

I seem to need an account to use SciFinder; I'll ask at WP:RX and WT:CHEM sometime later tonight (I need to log off WP for now) to see if someone else can access the database entry for me. As for the Sigma Aldrich website, they list "−80 °C(lit.)" as the MP. Do you believe that this is a very reliable source for this data? As I mentioned in the WT:CHEM thread that I linked, I've found at least 3 different MPs listed for this compound in different databases, so ideally I'd like to cite a secondary source that cites primary literature. Seppi333 (Insert 2¢) 22:47, 9 September 2016 (UTC)

• Unfortunately I do not have access to SciFinder either. HMB is a liquid at room temperature and therefore by definition, it must have a melting point below room temperature and I don't think one can dismiss that the melting point could be as low as -30 °C or even lower (compare with propionic acid whose melting point is -21 °C). I do agree that we need a better source.
• Concerning HMB acid dissociation constant, the supplied source stated that the pH of HMB was less than three is clearly in error. First of all, the acidity constant should be abbreviated as pK_a, not pH. Also the pK_a of aliphatic carboxylic acids is normally in the range of 4-5 (e.g., acetic acid – 4.76). I have not been able to find an experimental value, however the ChemAxon calculated value is 4.55 which is much more reasonable. I have modified the text accordingly.
• The lactone of of HMB, 4,4-dimethyloxetan-2-one (CAS # 1823-52-5), is known, but it does not appear to be particularly notable and hence I question its relevance to this article. Boghog (talk) 07:54, 10 September 2016 (UTC)
• In re-reading the Coffman et al., JACS, 1958 citation, I now notice that this source does provide pKa values (4.42±0.02), melting point (glass at –80°C. apparently it does't crystallize), and an alternative synthesis (carboxylation of t-butanol by treatment with carbon monoxide and Fenton's reagent). I will add this. Boghog (talk) 06:40, 11 September 2016 (UTC)
• @Nergaal: Thank you for your comments that prompted me to take a second look at the chemistry section. I think I have now addressed your concerns regarding the melting point and pKa. In addition, I have added more detail about the synthesis from diacetone as well as an alternative synthesis from t-butanol. In my opinion, the synthesis section should be restricted to economically viable reactions that can be used industrially and exclude exotic synthetic routes whose notability is questionable. The originally published syntheses are simple, high yield, and cheap. Hence there has been little need for improved syntheses and as a consequence, there is not an extensive literature describing the preparation of HMB to draw on. Boghog (talk) 07:56, 11 September 2016 (UTC)

@Nergaal: When you get a chance, can you follow-up on Boghog's reply/changes to the article and/or provide further feedback on what content to add/fix in the article? I'm not really sure what you'd like me to do at this point. Seppi333 (Insert 2¢) 22:39, 16 September 2016 (UTC)

@Seppi333: I have access to SciFinder if you still need information from it. Sizeofint (talk) 18:21, 18 September 2016 (UTC)

@Sizeofint and Boghog: That would help a lot. Boghog has expressed a willingness to work on the chemistry-related content in the article (see User_talk:Boghog#trimethylamine monooxygenase and FMO3), so it would be best to correspond with him to determine what he needs. I'm not familiar with SciFinder at all. Seppi333 (Insert 2¢) 18:31, 18 September 2016 (UTC)

Hi @Sizeofint: I am trying to expand the chemistry section, but do not have access to SciFinder to find appropriate sources. I have tried searching Google Scholar, PubChem, and other free search engines and have not found much beyond the Coffman et al., JACS, 1958 citation. I just need a list of citations that describe the preparation or properties of HMB (CAS # 625-08-1) and I can take it from there. I suspect the list of citations will not be very long, but I could be wrong. Also the lactone (4,4-dimethyloxetan-2-one (CAS # 1823-52-5), PMID 11841278) was mentioned above. If there are any sources that describe the conversion of HMB into its lactone or vice versa, that would also be very useful. Boghog (talk) 19:05, 18 September 2016 (UTC)

Moved from Talk:Beta-Hydroxy beta-methylbutyric acid

With thanks to Sizeofint for supplying database searches, I have expanded the synthesis section. There are several more syntheses that could be added, but most of these are obscure reactions or reactions where HMB is a side product. Hence I question the notability of these. Also there were some early syntheses reported (and associated physical data of the synthesized HMB) based on an aldol condensation without dehydration between acetone and ethyl acetate. However I think this would be highly unlikely since the dehydration is the driving force for the reaction. As far as physical data, there is not much more that could (or should) be added. By far, the most notable aspect of HMB is that is a naturally produced metabolite and a food additive . Much less has been published about its chemistry. Hence per WP:DUE, it is appropriate that the chemistry section of this article is significantly shorter than some of the other sections. Boghog (talk) 09:35, 25 September 2016 (UTC)

@Nergaal: Boghog has been co-opted as a nominator to help address issues with the chemistry section. He has expanded the section since you last commented, so could you take a look and follow up with him? I'd appreciate it. Edit: FWIW, "Chemistry" is now the 2nd longest section in this article. Seppi333 (Insert 2¢) 17:57, 26 September 2016 (UTC)

Comments by Jytdog

First, wow, clearly a lot of work went into this. Thanks for all that work! Jytdog (talk) 22:19, 16 August 2016 (UTC)

• Support Jytdog (talk) 02:13, 28 August 2016 (UTC)

issues raised and worked through below Jytdog (talk) 02:13, 28 August 2016 (UTC)
The following discussion has been closed. Please do not modify it.
This is a difficult case where we have something marketed as a dietary supplement that may have actual medical use for conditions like sarcopenia. Nissen (the inventor) started a company (see here) that sells/licenses it as a nutritional ingredient (see here) - not as a drug - to other companies that include it in their dietary supplement products - they have done well and the list of the many companies that actually sell it is here. It is marketed for example by Abbott Nutrition as "nutritional therapy" (a purely fluff marketing term for "dietary supplement") that "helps build and maintain lean body mass" per this) (None of that business stuff is in the article really, and I will circle back around and add that later unless someone else does it first; I like that stuff) Anyway, for a dietary supplement, that is what it is and is par for the course. But I am very uncomfortable with descriptions of medical use. There is no evidence in the sources that HMB is actually used as a treatment for anything in medicine. Reviews claiming efficacy and safety based on (small) clinical studies, and authors of papers recommending its medical use (and one of those papers had "medical writing assistance" from Abbott Nutrition) do not read on actual medical use. Also, language in the medical section like "it is recommended...." needs to go. I strongly oppose FA and even GA while this medical stuff is in the article in this way. If this were all moved to research I could live with it. Jytdog (talk) 22:19, 16 August 2016 (UTC) @Jytdog: Thanks! It was a lot of work to research and write the existing content. Seppi333 (Insert 2¢) 20:11, 17 August 2016 (UTC) I've been a little busy over the past 2 days, so my apologies for the late reply. If you have a secondary source for the stuff you linked to on the HMB page, I'd be happy to see that included. I was already aware of it since I read through that page about a month ago, but I could not find a WP:RS-quality secondary source covering what was included there. We shouldn't be censoring information that comes from reviews, such as the recommendation of an author, but we can change the language as to how we describe the conclusions however. I don't understand your assertion that there's not evidence that it's not used as a treatment though. The papers cover reviews of clinical trials where it's used as a treatment. It doesn't need to be Rxed, so it's readily accessible outside of clinical trials as well. Are you asking for a paper asserting that it is used outside clinical trials or do you want to see something more like a paper studying the epidemiology of HMB use outside clinical trials? You've raised issues with study sizes in the past and I clarified the relevance of study size to statistical conclusions while you were away on WT:MED. I'd ask you to read my statement in this section here -Wikipedia_talk:WikiProject_Medicine/Archive_85#Comments. Seppi333 (Insert 2¢) 18:47, 17 August 2016 (UTC) Yes I read the stuff you wrote about trial size (thanks for taking that time) - I was blowing steam when I mentioned that; the bottom line is that the sources comply with MEDRS and say what they say and it is not my place as an editor to contradict them. I am not at all interested in censoring - it is more about the language used in the medical section. The core of my criticism in the medical section is the claims you made that this stuff is used as medicine on day to day basis, like say aspirin is, or maybe better, like statins are. Clinical trials are not medicine, they are research; their goal is not to treat or prevent a disease/disorder/condition or to promote wellness (which would be medicine) but rather to figure out if X does Y (science). With regard to what treatments are actually used, in my view we generally rely on treatment guidelines issued by major medical bodies or on reviews of disease X that discuss what treatments are actually given. So something like PMID 20627179.... this disease review doesn't mention HMB for example. Jytdog (talk) 23:34, 17 August 2016 (UTC) That's a fair point. I guess I just wrote it that way because that's the language that the exposition in that section of amphetamine uses; however, unlike amphetamine, HMB isn't FDA-approved and indicated for sarcopenia because it's not currently sold as a prescription or OTC drug. HMB's current medical "status" is sort of analogous to St. John's wort in the sense that SJW is used for depression, but not approved for depression, in spite of its efficacy which has been established in systematic reviews and meta-analyses. I imagine that if HMB ever goes through the FDA approval process, it will just end up being an OTC drug (as opposed to OTC supplement) with a specific medical indication (e.g., tylenol for pain or nyquil for cold/flu or cough relief) due to its safety profile. In any event, I'm completely open to revising the language in that section and I'd be happy to work on this with you. I took a stab at addressing some of your concerns; how do you feel about this language: special:diff/734956675/735006277? Side note: AFAIK the newest treatment guideline for sarcopenia which mentioms HMB is this one, but it doesn't recommend it. The two reviews that recommended its use in sarcopenia are both more recent, but they're not treatment guidelines. Seppi333 (Insert 2¢) 03:02, 18 August 2016 (UTC) Thanks, I feel like you heard me. Yes St Johns Wort is a very useful analogy - it is mentioned in treatment guidelines but is not a drug. (a venture capitalist said to me the other day "What's a drug?" And I started talking about "a substance that is used to..." and he cut me off and said "it's a piece of paper from the FDA that says how you can market something" there is a whole world of stuff wrapped up in that. ) Jytdog (talk) 03:41, 18 August 2016 (UTC) @Jytdog: Are there any other concerns/changes you'd like me to address/make in the article? Seppi333 (Insert 2¢) 01:19, 20 August 2016 (UTC) It still says "As a treatment for muscle wasting, it is usually taken as a single 3 gram dose, once per day.[4]" like this is actually taken like medicine. That also goes against MEDMOS which says we don't advise on dosing. In my view without a source showing actual medical use, this section should be moved to a Research section; which is appropriate since what it discusses are clinical trial results. I am kind of curious (really I am) what WAID would say about discussing this as "medicine" based on the sources we have. Shall we ask her? Jytdog (talk) 02:15, 20 August 2016 (UTC) User:Seppi333 - I would happily agree with [this version] for FA status. Jytdog (talk) 02:53, 20 August 2016 (UTC) @Jytdog and WhatamIdoing: Yes, I think it would be a good idea to get WAID's input; the more the better. I've tweaked the heading in the uses section in an attempt to address your concerns about putting it in a research section. I'll likely add a 2nd subsection titled "Emergency medicine" (or something along those lines) under the "Clinical research" heading to cover the clinical research that was mentioned in the following review's quote parameter - https://en.wikipedia.org/wiki/Talk:Beta-Hydroxy_beta-methylbutyric_acid#cite_note-HMB_clinical_evidence_2016_review-13 - once it's covered in a 2nd review. I could add it right now since the review satisfies MEDRS, but I'd like to include more than a single sentence about that topic when I add it (i.e., I'm hoping to find more comprehensive coverage of the clinical trial in another review). I'm not really comfortable with adding this information under a level 2 heading titled "Research" at the end of the article for the same reason that I was opposed to adding information on biomarkers under that heading in the ADHD article (my reasoning is covered at talk:ADHD). Excerpt from Talk:ADHD It is research, as is what is covered in the vast majority of the article. My concern is that what ends up going in sections that are titled "Research" in medical articles is nearly always preclinical research involving animals, in vitro, ex vivo, etc, since there's basically a section for any relevant material elsewhere in the article (assuming it follows MOS:MED). Moreover, if any preclinical research ends up being added to the article, it is going to end up in that section right next to a section involving clinical research on biomarkers. That juxtaposition creates a problem. I would actually be fine with calling the level 2 section "Biomarker research" instead of just "Research" since this would address both concerns. Seppi333 (Insert 2¢) (Insert 2¢) 03:17, 14 August 2016 (UTC) As for the dosing info, the reason I added this to that section is because that sort of information isn't be readily available in something like a drug's prescribing information or on supplement labels/bottles for that use. I also think it's necessary for comprehensive coverage of the topic in this particular circumstance. Hence, this is one of the cases where I think an exception to strict adherence to the letter of MOS:MED is appropriate (for comparison, the only dosing info in amphetamine is a sentence in Amphetamine#Overdose which states that some individuals have used 5 grams, or roughly 100 times the maximum recommended therapeutic dose [which is 60 mg], in a single day; I included this statement because I thought it was notable). It's worth noting that I also included pricing information in the article which doesn't strictly conform to the MOS either, but I included it anyway since it's a convention in other drug articles. Seppi333 (Insert 2¢) 02:58, 20 August 2016 (UTC) How's this language work for the statement in the lead? Seppi333 (Insert 2¢) 03:03, 20 August 2016 (UTC) @Jytdog: I also included the language you used to describe the recommendation of HMB use for sarcopenia, but copyedited the statement slightly since both cited reviews recommended this (see special:diff/735344844/735345697). Seppi333 (Insert 2¢) 03:14, 20 August 2016 (UTC) I am fine with these changes to the lead and to the language about recommendations. I struggle with a "use" as clinical research. I see your effort to compromise but that is just a weird use! To me the content you formerly had as "medicine" needs to be under a Research section until we have sources showing some actual medical use.... Thanks for pinging WAID - she has interesting perspectives on just this question. I have no idea what she is going to say. Jytdog (talk) 03:21, 20 August 2016 (UTC) The way I read the current Uses section and its subheadings is "Uses in clinical research for muscle wasting". IMO that doesn't sound odd, but maybe that's just me. I'm amenable to change though. Anyway, I intend to add a Research section and cover the material in Talk:Beta-Hydroxy beta-methylbutyric acid#Recent preclinical research as soon as it's covered in a review; so, if I moved the content on clinical research to a level 2 "Research" section, it will inevitably result in the juxtaposition problem that I described in the tab above. Seppi333 (Insert 2¢) 03:33, 20 August 2016 (UTC) A few comments, just from reading this section (i.e., not from reading the article itself, which is in the next tab): User:Jytdog, your investor is wrong. The drug is the thing that the paper lets you sell. And that's a remarkably bureaucratic POV. Outside of his bubble, a drug is a chemical that you use with intent to treat or cure (the definition that I assume you were starting before you were interrupted) – a definition that includes water for treating headaches on hot days. However, your conception of clinical trials is narrow. Some clinical trials, such as this one, exist for the main purpose of providing treatment. The problems addressed by that trial are regulatory, not scientific. User:Seppi333, what's DUE weight looking like? If I go to, say, an investment magazine or an old-fashioned housewives' magazine, what's the overall balance between articles about performance enhancement vs frailty syndrome? And do I understand correctly that there is very little market-share information, which makes it difficult to source claims that it is being bought by non-athletes? I don't like ===Clinical research=== being a ==Use==. I'd rather have it say something useful, such as ===Muscle loss=== (or whatever phrase you like). I'm unlikely to finish reading the article today. (Please ping if you want my attention.) WhatamIdoing (talk) 14:21, 21 August 2016 (UTC) User:WhatamIdoing - The current "Clinical research" section was formerly called "Medical use" and the sources are reviews of clinical trials that say it is safe and effective for that and recommend it for that. (see both the lead and the Medical use section in this version for example) The content said it is used medically. Is that valid? How do we know if HMB is actually being used to treat sarcopenia (doctors recommending their patients go buy the supplement or people who have sarcopenia just self-treating)? Jytdog (talk) 16:18, 21 August 2016 (UTC) @Jytdog: How would you feel about removing the "Clinical research" heading and moving "Muscle wasting" from a level 4 to a level 3 heading under "Uses"? The content in that section makes it abundantly clear in the first sentence that it's discussing HMB in the context of clinical research as opposed to an FDA-approved medical indication. It seems more apt to put content under a heading that lists the condition for which it's been studied/used rather than the evidence level supporting its use in specific conditions. "Medical" was probably too broad of a header and I suppose it probably implied that the content in that section covered medical indications; however, IMO the heading "Muscle wasting" only implies that the content contained in that section covers some sort of relationship between HMB use and muscle wasting. Seppi333 (Insert 2¢) 21:49, 21 August 2016 (UTC) @Jytdog: This is the Bloomberg company profile of the company that grants licenses for the use of HMB in dietary supplements. I can add something about this, citing this and possibly other references, if you think it's notable. Also, I'm not sure if you received my last ping - are you ok with the sectioning changes I've described above? This reflects both WAID's section preference and the current subheadings under "Uses" in the article: Special:Permalink/735661654#Uses. Seppi333 (Insert 2¢) 02:52, 23 August 2016 (UTC) @WhatamIdoing: I haven't looked at primary sources, but at the moment there's ~2x as many MEDRS-quality reviews from the past 5 years that focus HMB+sarcopenia/muscle wasting relative to reviews that cover HMB+athletic/bodybuilding uses. This is probably just due to the fact that its clinical applications is a newer, more active area of research relative to its use by and effects on athletes though. I have absolutely no idea about how it's advertised or how commonly it is mentioned in the context of muscle wasting vs athletics/sports outside of medical literature. I haven't actually seen an ad or magazine article about this compound, but that's mainly because I don't read magazines. Your assumption about the lack of research on HMB consumer demographics is correct; I haven't read any literature that discussed this topic. Seppi333 (Insert 2¢) 21:49, 21 August 2016 (UTC) User:Seppi333 I am all excited jumping and down. First, Abbott markets the product, Juven (arginine, glutamine, and HMB) as a medical food for AIDS, cancer-cachexia, and wound healing. It is medical!! Abbott describes Juven as medical food here (the exact phrase, and the "use under doctor's care" notice); see also this Nature Medicine News piece (search for Juven). Here is the press release with which Abbott launched Juven in 2004. If you search through this document you will see that MTI sold (not licensed, but sold) Juven to Abbott in 2003. You will also see that MTI sold the rights to something it called "Re-Vigor" to Abbott in 2008; Re-Vigor is arginine, lysine, and HMB, and is intended to slow down muscle wasting in the elderly. Abbott launched "Ensure Enlive" (the newest part of their Ensure line) in March 2016 (press release here) Product pages are here and here - this one is the medical food. I don't know if Ensure Enlive = Re-Vigor but it seems that way. Anyway it seems that MTI sold off "medical" rights to Abbott, allowed Abbott to use HMB for dietary supplement (the non-medical food Ensure Enlive) and have retained dietary supplement rights. So that is what I learned. Jytdog (talk) 04:16, 23 August 2016 (UTC) @Jytdog: I didn't receive a WP:ECHO notification from your ping... how odd. Anyway, that's neat! I knew that arginine/glutamine/HMB was used in hospital settings based upon reviews of a specific subset of clinical trials that involved HMB supplementation for muscle wasting, but wasn't aware that there were actual meal replacement/nutritional products that were marketed clinically for that purpose. Revigor is Abbott's registered trademark for an HMB-containing mixture; I actually first encountered HMB in the form of a ready-to-drink Myoplex formulation (this is a liquid, high-protein product marketed by Abbott which IMO doesn't taste like ass) which includes Revigor (e.g., see ASIN B00CU8JD80; the image that appears first lists "REVIGOR® HMB" in large print on the front). Per a reference cited in the HMB article, Revigor is also included in other Ensure products (e.g., in the image File:Ensure product line up June 2012.jpg, on the purple bottle labeled "muscle health" in the front and the tan "clinical strength" bottle immediately behind it on the right, you can see the word "REVIGOR" immediately beneath the phrase "muscle health" and "clinical strength" on those bottles - it's somewhat blurry because this is a low-quality non-free image for the Ensure article). Anyway, do you want me to update the wording in the article to reflect what you've found/mentioned here about its clinical use, or would you prefer that I leave the language as is? I'm likely going to include some of the links that you provided above as citations for new or existing text in the "Available forms" section. Seppi333 (Insert 2¢) 04:51, 23 August 2016 (UTC) User:Seppi333 yes medical food is an actual category recognized by the FDA and other regulatory agencies for treating conditions (with nutrition, under the care of a doctor). I am very, very comfortable with the original "medical use" heading now, as long as the medical food thing is clearly baked in (heh) and it is not discussed as a drug. I can do that if you like! Jytdog (talk) 04:58, 23 August 2016 (UTC) @Jytdog: Sure, go ahead. Seppi333 (Insert 2¢) 05:01, 23 August 2016 (UTC) OK, done here. I apologize for not formatting correctly; i have no patience for that but i know people get finnicky about citation format for FA. If you are OK with the content, all my objections are withdrawn. Jytdog (talk) 05:25, 23 August 2016 (UTC) No problem, I'll go through and tweak the citations a little later when I have more time. Seppi333 (Insert 2¢) 08:08, 23 August 2016 (UTC) @Jytdog: I think what I'm going to end up doing is cover the marketing/clinical use of HMB in medical foods and clinical research involving the isolated compound as a dietary supplement in separate paragraphs in the section on muscle wasting. Juven includes 2 additional bioactive dietary compounds relative to the supplement form, so this is worth mentioning IMO. The research that supports the associated health claims of the medical food (specifically Juven) is relatively old compared to the clinical research involving supplemental HMB alone for sarcopenia, which is what most of the current reviews of clinical research with HMB discuss. I only remember seeing one or two passing mentions of clinical research involving the use of HMB for treating muscle wasting in AIDS patients. IIRC, only about a third of the recent clinical reviews on muscle wasting that I've read have discussed the broader use of HMB for the treatment of muscle wasting in general; those reviews are the generally the ones that cite/discuss the older clinical research with HMB. For context, PMID 15080599 (from 2004; this isn't cited in the article) appears to be the most recent meta-analysis of trials involving glutamine/arginine/HMB for AIDS/cancer (note: I haven't looked at any reviews outside the of the 5 year MEDRS filter), whereas PMID 26169182 (from 2015) is the most recent meta-analysis of trials involving HMB for sarcopenia. There was a more recent phase 3 clinical trial involving the Juven formulation (PMID 18293016 - from 2008) for cancer cachexia, but it apparently had a low rate of compliance and only showed a trend (p=.08) increase in lean body mass, as measured via bioelectrical impedance analysis (this is a fairly "noisy" method for estimating lean body mass). The RCT did make a rather interesting supposition about the contribution of HMB relative to the other 2 compounds in Juven's bioactivity though: "Although arginine has been shown to promote wound healing [15], and glutamine is also a regulator of muscle turnover, HMB, a leucine metabolite, is probably the most active agent in the mixture". I need to do a little more research to find medical reviews that support the claims associated with the 2 medical food formulations before I add anything, because I'd like to ensure that I'm using the best medical sources about Ensure ... and Juven. I'll probably get around to adding coverage of the clinical research supporting the claims of these products by sometime tomorrow night. Also, I hope you don't mind that I switched the section headers back to how they were originally ("Medical" and "Enhancing performance") - I'd like to keep the section headings in amphetamine and HMB consistent whenever possible since their layout will set a precedent for other pharmacology articles once this article is promoted. Seppi333 (Insert 2¢) 15:40, 23 August 2016 (UTC) I hear that. Jytdog (talk) 15:45, 23 August 2016 (UTC) I can't really find any primary research or reviews that specifically mention "Ensure", but I imagine that's because it's basically just HMB + a meal replacement product. There's a lot of research and reviews on Juven or Juven's ARG+GLN+HMB formulation (e.g., see Talk:beta-Hydroxy beta-methylbutyric acid#FAC-related references). I've only looked through a few of the reviews that have already been cited in the article; so, after I'm done going through the rest of the reviews to see if Juven or its formulation is mentioned, I'll use what I've found to expand the 1st paragraph under beta-Hydroxy beta-methylbutyric acid#Medical. Seppi333 (Insert 2¢) 03:06, 25 August 2016 (UTC) @Jytdog: Meant to ping you in my last reply. Seppi333 (Insert 2¢) 03:07, 25 August 2016 (UTC) Sounds reasonable. Jytdog (talk) 03:55, 25 August 2016 (UTC) @Jytdog: I've expanded the paragraph about Juven under 3-Hydroxyisovaleric acid#Medical with these edits: Special:diff/736368306/736376503. I didn't add any article content about wound healing, but if you want, I can add this review - PMID 25215468 - if you think it's worth covering the clinical evidence that supports the use of Juven to promote wound healing. I still need to look through about 10 more reviews to see if they say anything notable that I haven't already covered, so I might end up adding another sentence or two in that section over the next day or so. Lastly, I didn't add anything about this study - PMID 17215743 (a trial involving Juven vs HMB alone vs placebo, where HMB alone significantly improved nitrogen balance relative to both Juven and placebo) - which I think is interesting and is covered in two reviews that I've cited in the article. Should I add coverage of that study as well? Seppi333 (Insert 2¢) 02:14, 27 August 2016 (UTC)  Done User:Seppi333 all of my concerns are addressed. There is now a proper medical product to hang the medical claims on, and the content is sound and well sourced. This can be FA as far as I am concerned. Thanks so much for working with me to address my concerns, and good luck on the rest of the work to get over the hump! Jytdog (talk) 02:21, 27 August 2016 (UTC) @Jytdog: Thanks for taking the time to do a review of the medicine-related content in the article. I appreciate it. If you have any more suggestions to improve the article or constructive criticism in the future, please feel free to let me know. Seppi333 (Insert 2¢) 08:47, 27 August 2016 (UTC) References

I apologize for not getting back to this. I never managed to finish reading the article. I'm satisfied with the issues discussed in this section, though. WhatamIdoing (talk) 18:32, 22 September 2016 (UTC)

Comments by Zefr

Oppose: --Zefr (talk) 17:07, 21 August 2016 (UTC)

Collapsed pending an actionable response from Zefr -- Seppi333 (Insert 2¢) 13:37, 1 September 2016 (UTC)

Although adequately written and structured, the article doesn't meet the criteria for GA/FA status. Author/nominator (A/N) User:Seppi333 has worked diligently to produce a scholarly article, but there are numerous concerns and disqualifiers for GA/FA. Mainly, the topic is given WP:UNDUE weight, and is not notable in any FA portal: publicly, HMB is simply a dietary supplement with unproven effect, so does not qualify for Medicine, Sports or Science FA portals. HMB is a natural metabolite and dietary nutraceutical only, and is not a topic sufficiently notable for GA/FA attention. The section on Clinical research underlies two problems: firstly, the evidence to date for efficacy in treating sarcopenia or for muscle enhancement is far from adequate for regulatory approval, and therefore also is weak or absent of WP:MEDRS sourcing. All the research on HMB cited is WP:PRIMARY and published in non-clinical journals, so has not been subjected to sufficient scientific rigor. HMB is not approved as a drug for treating sarcopenia and is not physiologically or pharmacologically proven to have have any effect, consequently rendering it inadequately tested by scientific rigor. Secondly, A/N appears to be a user of the product and promotes its efficacy, suggesting bias in content emphasized and sources selected. Conclusion with comments for FA administrators: 1) included among the criteria for GA/FA status should be that the topic is notable. HMB is not notable, is not approved by regulatory agencies as an effective, safe drug for use in humans, and is little more than a nutraceutical fad for would-be athletes like innumerable other dietary supplements; 2) included among the GA/FA criteria should be that an article cannot be promoted for evaluation by the same person who wrote most of the article. In other words, only an independent editor who has not worked substantially on the article, but who has expertise, should nominate for GA/FA review. In the case of HMB, all the pushing for FA approval is being done by the article's main author who is also a promotional user of the supplement. Comments on content (A/N, author and nominator are the same) 1. A/N has accounted for > 95% of the content and is alone in promoting it for rapid consent first as a GA candidate, but then without due process and few signs of interest or confirmation by fellow editors, promoted it alone to FA review. 2. in the HMB article itself, there has been little/no cross-fertilization of content, sources and interpretation. Possible reasons for this isolation of editor input are 1) the topic is not generally of interest and/or 2) A/N has a history of aggressively defending and warring over one particular view, discouraging collaboration. Signs of non-collaborative behavior are here and here. 3. A/N is an advocate of using HMB for performance-enhancement and admits bias, indicating underlying WP:SOAP and WP:PLUG which should disqualify a GA/FA candidate. 4. the article has imbalance and verges on WP:OR, particularly in the Clinical research section. There are no counter-intuitive discussions about why HMB has no value. A likely reason is that negative outcomes from research on nutraceuticals are unpublishable, and the only remaining evidence for non-effect comes from personal accounts that are not WP:SCIRS. Publication of zero-effect results on true drug candidates is a critical part of winnowing candidate human therapies. The same standards should apply to supplements of questionable value like HMB. 5. even for the literature cited, there is too much falling within WP:PRIMARY. The reviews cited are mainly of poor quality having been published in non-clinical journals. There is overuse of sports journals which are infamously unscientific and poorly edited, or nutrition journals which may be an outlet of marginal credibility for nutraceuticals. On balance, there is little if any WP:MEDRS quality in the topic or sources. 6. Accordingly, the section on Pharmacology really isn't of a high quality pertaining to human mechanisms. 7. The lede is a burden to wade through for the general user. It is heavily over-cited and over-quoted per WP:OVERCITE. GA/FA criteria: 1. well-written: Generally, yes. Major caveats are that the lede is laborious as not concise with obsessive/excessive use of quotes throughout which may discourage encyclopedic review by a general reader. 2. verifiable: dubious, as negative/counter-intuitive results are not reported or are unavailable. Emphasis on the topic is WP:UNDUE. The content reflects bias and the sources are not of MEDRS standard. 3. broad in coverage. Generally yes, but counter-intuitive arguments are absent and negative analyses are not provided. 4. NPOV. No, as only one perspective that is favorable and detectably promotional is provided. The "clinical evidence" purported for use of HMB to treat sarcopenia is overstated, under-supported by WP:MEDRS, not accepted by any regulatory agency as an approved drug, and is not in common practice. 5. stable. The article appears to be stable largely because there has been one major contributor, A/N, writing more than 95% of the content. Controversial or contested editing has been aggressively reverted by A/N, discouraging collaboration. 6. media. Appear to be ok. To conclude, A/N should be commended for the hard work of assembling information on HMB. Relevant advice, however, is here. The article and its topic are not notable and the sourcing quality falls far short of GA status, so is certainly not FA. --Zefr (talk) 17:07, 21 August 2016 (UTC) @Zefr: Many of the concerns you've raised, as described, are a bit too vague for me to act on at the moment; can you be more specific as to what text/references in the article are problematic (i.e., quote the problematic statement or link the reference(s) to which you're referring) so that we can start to address the issues here? W.r.t. your concern about potential NPOV/UNDUE content in the article, I'm not really sure what particular viewpoint from medical literature that you believe is missing or underrepresented in the article; however, if you can link me to a medical source with the viewpoint which you're asserting isn't being given WP:DUE weight, I'd be happy to cover it in the article. W.r.t. your concerns about MEDRS-compliance with the sources in the section on clinical research: the pubmed ID numbers of the medical literature which is cited in the section on muscle wasting are PMID 27106402 PMID 26169182 PMID 27324808 PMID 26010896 and PMID 24336486; Pubmed indicates that every one of these papers is a "Review", as listed under the heading titled "Publication types", on the associated pubmed pages for these articles. The oldest of these reviews was published in 2014, so I'm not sure which MEDRS criterion you're referring to when you say these sources aren't MEDRS-compliant. Could you link me to the MEDRS section/criterion (e.g., a link like WP:MEDDATE) that you believe there is an issue with for each source so that we can discuss/address the problem with these sources? If you feel there's issues with any of the other sources in the article, can you link it/them here and indicate the specific problem with it/them so that we can discuss and address the problem with those references as well? W.r.t. lead citations, as I mentioned in my comment at the very beginning of this nomination, I'd be happy to move the citations into end-of-paragraph citation notes. Would you like me to do this? W.r.t. the other objections you've raised, can you be a little more specific and indicate a particular statement and/or reference when you mention an issue with a policy/guideline or FAC criterion? I'm not really sure how to begin going about addressing any of your other concerns that involve a policy/guideline/criterion because they're nonspecific. Your statements about my editing behavior and alleged bias aren't relevant to this nomination, so I'm not going to address those comments. Seppi333 (Insert 2¢) 23:10, 21 August 2016 (UTC) I would think the notability requirement simply means the subject must meet WP:N. The subject clearly does (otherwise we'd have to purge most of our chemical articles). Sizeofint (talk) 00:31, 22 August 2016 (UTC) @Sizeofint: Zefr and I don't like one another, which is why the above blob of text is a really long-winded WP:JDL statement about the article and diatribe about me. Objections at FAC are supposed to be specific enough to be actionable so that the nominator can attempt to address the objection (this is stated in bold text in the instructions for reviewers at WP:FAC), but his objections are so vague/non-specific that it's not possible to identify specific sentences or references that he claims fail to satisfy WP:MEDRS, WP:NPOV, WP:DUE, WP:OR, etc or identify the content/references that are supposedly missing from the article. For example, an actionable objection for NPOV would be something like "the statements in section 'X' are NPOV because they do not cover the alternate viewpoint 'Y' in source 'Z'. I need to know all 3 of those things to act on an objection on the grounds of NPOV. Even if the FAC coordinators don't ignore this section, which seems extremely unlikely unless he engages in a discussion and replies with more specific objections, one outstanding oppose won't prevent this article from being promoted (e.g., amphetamine had 2). So, I wouldn't bother trying to explain to him why some of his assertions (like "All the research on HMB cited is WP:PRIMARY" or "the topic [(HMB)] is given WP:UNDUE weight, and is not notable") are completely asinine or nonsensical; he's just trying to be a dick, but isn't doing a particularly good job at it. @Zefr: Since this appears to be your very first involvement in a FAC nomination, either as nominator or reviewer, you should probably read my reply to Sizeofint. Also, FAC reviews are not simply support/oppose votes; they're dialogues between reviewer and nominator. If you oppose the nomination, your rationale should be composed of objections that I can directly address. You are also expected to respond to me and vice versa so that I can work on addressing those objections until the problems are resolved and the nomination merits support. If you actually care enough to give this article a real review, you'll need to read the instructions at WP:FAC for reviewers and should probably also read User:Nikkimaria/Reviewing featured article candidates before responding here so that you know what is expected of you. You don't have to respond to me, but if you don't I will leave a note for the FAC coordinators at the top of this section to let them know about this. Seppi333 (Insert 2¢) 06:59, 22 August 2016 (UTC) @Zefr: I have to agree with Seppi that your review is too harsh; I hope you reconsider. Jytdog (talk) 03:06, 23 August 2016 (UTC) agree w/ Jytdog(as an individual who has taken article to GA [2](and considering FA)--Ozzie10aaaa (talk) 12:48, 23 August 2016 (UTC) I do not intend to give stepwise revisions of the HMB article because 1) as simply a dietary supplement among hundreds of similar agents with dubious qualities, HMB is a minor, low-notability topic not deserving of GA/FA review. Unless there is a content issue worthy of further evaluation, I will not be returning to this discussion. 2) it is unpleasant to interact with the author/nominator of the HMB article, User:Seppi333, who seems incapable of constructively dealing with criticism, e.g., saying firstly (and fairly) in response to my review: "Your statements about my editing behavior and alleged bias aren't relevant to this nomination, so I'm not going to address those comments." then later addressing my critique: "he's just trying to be a dick." WP:EQ, WP:NPA. Secondary comments further supporting opposition: 1. Lede overciting and overquoting: MOS:LEADCITE and throughout the article, WP:CITEKILL 2. Sources on muscle wasting and performance enhancement. The supporting publications in the HMB article are in non-clinical or low-quality journals, filled with speculation, exaggeration and lack of rigorous scientific evidence (a characteristic commonly applied in the marketing of many dietary supplements), and are not MEDRS quality because they do not satisfy the same requirements for proof of efficacy that a drug must meet. An enteral agent producing a change in human disease or physiology is defined as a drug by the FDA. HMB is not a drug; it is simply a supplement with unproven effects like all supplements, and is subject to labeling restrictions defined here. HMB is not a nutrient, not an antioxidant vitamin, does not have a structure/function claim, and does not have any FDA-approved health claims, so by regulatory definition does not have any proven physiological effects in humans. Existing literature for HMB does not meet good-quality MEDRS standards. 3. MEDRS qualification. Sources in the HMB article do not meet good MEDRS qualities by definition under WP:MEDASSESS which says: "When writing about treatment efficacy, knowledge about the quality of the evidence helps distinguish between minor and major views, determine due weight, and identify accepted evidence-based information." HMB literature doesn't qualify by this definition, and leads to WP:UNDUE and the qualifications of WP:MEDINDY. All of the 5 statements in MEDINDY apply to the scientific vagueness about HMB, most appropriately "If independent sources discussing a medical subject are of low quality, then it is likely that the subject itself is not notable enough to have its own article or relevant for mention in other articles." When using a flowchart for choosing MEDRS quality sources under "Biomedical journals", those sources in the HMB article for "medical" and "performance enhancement" fall under "Other", i.e., low quality, further demonstrating the overall weakness and low notability of HMB as a topic. 4. Not "medical" and not a medical food. This new revision in the HMB article entered on 23 Aug is wrong and misleading to a Wikipedia user. HMB is simply an ingredient in a supplement product not proved as an effective medicine or medical food. HMB itself is not independently proven to be effective for this purpose, and is neither a medical food nor a drug ("medicine"); it is one among many ingredients in dietary supplement products not proven individually to be effective for muscle wasting (hence none is defined as a drug). "Medical food" is a specific FDA designation here, not applicable to HMB itself. Such references to the use of HMB as a medicine or as having any physiological effect should be removed from the article as unproven, misleading, not FDA approved and not MEDRS compliant. --Zefr (talk) 17:19, 23 August 2016 (UTC) Zefr what are you talking about on the medical food thing? There are at least two products that are medical food and HMB is the ingredient driving the claims. What exactly is your issue with that? And there is nothing in the GA or FA standards about how "important" something is - we have FAs on silly video games and TV shows. Jytdog (talk) 18:32, 23 August 2016 (UTC) "The article and its topic are not notable." Seriously? Good luck at AfD... Axl ¤ [Talk] 22:55, 23 August 2016 (UTC) @Zefr: I asked for you to give me specific actionable feedback associated with your objections three times. I didn't ask for "stepwise revisions of the HMB article". Your response is simply a restatement of the feedback you've already given me. Your objection about the lead citations is something that I can act upon; I asked you a question in my response above about addressing this. I'm still waiting for an answer. I don't see HMB covered in any of the FDA links that you provided; what statement would you use them to cite in the article? The article doesn't include or cite any manufacturing labeling claims, make an assertion about any form of regulatory approval by any governmental agency, or even call the compound a "drug". As for the statement "existing literature for HMB does not meet good-quality MEDRS standards", I disagree. The literature cited in the article clearly surpasses MEDRS standards. You've repeatedly claimed that everything cited in the article in relation to clinical uses and effects is WP:UNDUE and therefore some form of minority viewpoint. And yet, you haven't cited a single source supporting some mysterious "majority perspective" which I somehow can't find in medical literature that supports your assertion that the scientific consensus on the clinical effects of HMB are different than what is stated in the article. The USFDA doesn't wave around a wand and magically grant biological effects to or remove them from a compound based upon outcomes in its approval process. Moreover, neither WP:MEDRS nor MOS:MED/MOS:PHARM mention the USFDA even once, so I don't see where you're getting the idea that the USFDA is somehow the highest-quality source for medical statements (MEDRS explicitly states that meta-analyses of RCTs are the best medical sources for statements about treatment efficacy) or that the USFDA should be cited to support medical claims; frankly, there's really no reason for the USFDA to be cited at all in this article because they don't host any literature about the compound on their website. If HMB had some form of regulatory approval in the United States, then I'd probably cite the USFDA to make a statement about that. A few of the sources that Jytdog provided above in his review - the same ones he used to add a sentence on this to the article yesterday - do indeed assert that two products which contain HMB are medical foods. Your FDA source doesn't appear to mention HMB anywhere, so I don't see where you get the idea that the FDA makes a contradictory assertion. Anyway, it's not possible for me to address any of your concerns with exception for the one about lead citations because your FAC review is not a MEDRS-quality source which I can cite in the article and you haven't provided any sources about HMB that I can use to cite content in the article that supports your assertions about its clinical efficacy. If your intent is to have me delete any/all the content to which you object, my answer is no; I won't do anything like that without a consensus among several editors. I am, however, willing to add content that you specify provided that you give me a source which directly supports the statement and satisfies the appropriate reliable sources guideline(s) for that content. I'll revisit these objections if you link me to a source that I can use to cite new article content which supports your assertions. There's really nothing that I can do otherwise. As for the lead citations, if you'd like me to change the citation formatting as I've described in my initial response, let me know. I'm still willing to make that change. Lastly, I think it might help this review go more smoothly if you read and follow the advice in the essay titled WP:DONTBEADICK. Seppi333 (Insert 2¢) 23:33, 23 August 2016 (UTC) Question is this oppose actually valid? IMO if something passes AFD then can definitely be FA. An obscure metabolite is in no way less notable than an obscure 10-km highway. Nergaal (talk) 13:28, 29 August 2016 (UTC) @Nergaal: It's really for the coordinators alone to decide, but my guess is no. I don't expect to receive a fair FAC review from Zefr due to the fact that he and I dislike one another as a result of past confrontations. I don't think that this compound is really that obscure relative to some of the related more recognizable biological compounds though; e.g., this search on google scholar using 8 common synonyms of the HMB acid/base finds about 15% of the total number of publications found from a search using 9 common synonyms of beta-hydroxybutyric acid and its conjugate base - the latter compound is quite notable for its biological role in ketosis and ketoacidosis. Seppi333 (Insert 2¢) 14:38, 29 August 2016 (UTC) Edit: That comparison to the number of publications on beta-hydroxybutyric acid probably wasn't a good example; the latter search seems to include a lot of structural derivatives of beta-hydroxybutyrate in the search results. Seppi333 (Insert 2¢) 14:41, 29 August 2016 (UTC)

Comments by Sizeofint

• Support on Media
  • Acceptable copyright status - Images from scientific journals have appropriate CC-BY licenses. Other images are appropriately licensed original works by editors. All images appear to have relevant author and publication date information.
  • Captions - Images are succinctly and descriptively captioned. Perhaps change "(i.e., the number of micromoles in a liter of blood plasma)" to "(in units of micromoles per liter of blood plasma)" or similar. I don't think the "i.e." is necessary. Image captions are referenced when needed.
  • Images used where appropriate - Is there a appropriately licensed image of HMB as a salt, free-acid, or one of its available forms?
  • Image layout - Image placement is logical and doesn't cause unsightly collisions.

Sizeofint (talk) 06:05, 27 August 2016 (UTC)

@Sizeofint: Thanks for taking on an image review.

"HMB free acid" refers to the compound "beta-hydroxy beta-methylbutyric acid" (i.e., the acid w/o any inactive moieties attached to the molecule), so File:Beta-Hydroxy beta-methylbutyric acid.svg is an image of HMB free acid. This image is currently used in the drugbox and a similar PNG image is used in Beta-Hydroxy beta-methylbutyric acid#Chemistry. There is an image of the calcium salt form on commons (File:Calcium hydroxymethylbutyrate skeletal.svg), but it uses a different convention for illustrating the location of the beta-hydroxy group on the compound relative to how it's illustrated throughout the article; this is why I decided not to use it. I could probably get someone to redraw the image using the convention used throughout the article if you think it's worth adding an image of the calcium salt. I'm not familiar with the programs specified in MOS:CHEM/Structure for creating structure drawings, otherwise I'd do this myself. Seppi333 (Insert 2¢) 08:47, 27 August 2016 (UTC)

Forgot to mention: I've edited that image caption per your suggestion. Seppi333 (Insert 2¢) 08:50, 27 August 2016 (UTC)

@Seppi333: I am more referring to the physical form of HMB, not so much structure diagrams. The article describes HMB-FA as a "transparent, colorless to light yellow liquid" at room temperature. I am curious if there is an image of this physical form or its calcium salt available anywhere. Sizeofint (talk) 16:28, 27 August 2016 (UTC)

@Sizeofint: Oh. I don't think there's any images of the pure free acid or calcium salt forms available anywhere online. While it would be easy enough to just take a picture of a commercial product as a tablet or after emptying a capsule or gel cap, they include a lot of fillers and bindings agents so that probably wouldn't be too informative for the "Chemistry" section. If you thought something like this might be useful for the "Available forms" section, I could take a picture of a commercially available formulation containing the calcium salt easily enough. Seppi333 (Insert 2¢) 22:44, 27 August 2016 (UTC)

Yes, I think that would be worthwhile. It's not anything that will hold up my support though. Sizeofint (talk) 23:51, 27 August 2016 (UTC)

@Sizeofint: Alright, I can do that. I'll take a picture of a few of the capsules and a pile of the powderized contents of this formulation - ASIN B000GIPJ16 - in natural lighting sometime during daylight hours tomorrow. I'll ping you again after I've uploaded the image and added it to the article. Seppi333 (Insert 2¢) 00:40, 28 August 2016 (UTC)

My bad for not getting around to this yet; I'll have it uploaded by saturday at the latest. Seppi333 (Insert 2¢) 21:05, 31 August 2016 (UTC)

---

@Sizeofint: I've uploaded an image and placed it halfway into the beta-Hydroxy beta-methylbutyric acid#Enhancing performance section so that it spans the part of the "Available forms" section, hopefully without breaking the page-spanning line under the "Side effects" heading (like the one above here) on most browsers. Does the image and its placement look ok to you? Seppi333 (Insert 2¢) 09:16, 3 September 2016 (UTC)

@Seppi333: Looks great! Sizeofint (talk) 00:25, 4 September 2016 (UTC)

Comments by John

Just a beginning here. I have skim-read the article and the previous comments. I understand that a couple of reviewers have had qualms about over-quoting and NPOV. Have these concerns been addressed at all? I will be reading the article and the review more closely now. As I work through I will make a light copyedit with the reviews already made in mind. I will also make comments, recommendations and ask questions here. Does that sound ok? --John (talk) 19:26, 31 August 2016 (UTC)

Sounds good.

W.r.t. NPOV: Only Zefr has claimed that there's an NPOV issue in the article, but he won't point me to a source that supports his claim about there being some form of contradictory research that isn't mentioned in the article. I'm not really sure how to address his objections given the circumstances; he's being so vague that my only possible option is to delete large swaths of article text, which I won't do without a consensus among several editors.

W.r.t. the quotes: Doc James mentioned his concern about potential copyright problems associated with the lengthy quotes in the article. He asked Moonriddengirl to comment and she mentioned that there's a number of factors that determine whether text quotations are fair use or not. Neither of them have asked me to remove the quotes as of yet; however, as I mentioned in that section, I'm perfectly willing to prune the quotes down or even remove/censor them entirely if they or others genuinely believe that the quotations present a problem. Seppi333 (Insert 2¢) 20:59, 31 August 2016 (UTC)

Thank you, I will keep those comments in mind as I now begin to read the article properly. --John (talk) 21:04, 31 August 2016 (UTC)

Lead

• Medical reviews of randomized controlled trials indicate that there are no issues with safety from long-term use as a dietary supplement in adults.[2][10][15] Is this NPOV?
  • The relevant text in the citations that support that statement are currently quoted in the each reference which supports it. The statement is a summary of the text in the body, where "long-term use" is used in place of the phrase "chronic use" from 1 of the references. In clinical trials, it has been used daily for up to a year w/o any reported adverse effects. To my knowledge, there have been no adverse effects reported from the daily use of the compound at any dose in any clinical trials in humans. This is why there's no "Overdose" section in the article. In any event, it's probably best to have someone else from WP:MED who has read the article to comment about its neutrality. @Jytdog, M. A. Bruhn, and Doc James: do the three of you think that the summary of the safety profile in the lead and the section on adverse effects are neutrally worded and accurately reflect the cited reviews? Seppi333 (Insert 2¢) 23:44, 1 September 2016 (UTC)
  • Yes, that is NPOV. I've looked through those sources and over a dozen others; HMB appears to be remarkably safe for chronic usage by adults. M. A. Bruhn (talk) 23:58, 1 September 2016 (UTC)
  • I would suggest adding an "as of" date to the beginning of the statement, and maybe replace "indicate that there are" with "have found" . That is a pretty good catch, actually. Jytdog (talk) 00:18, 2 September 2016 (UTC)

    I've edited the statement accordingly. [3] Seppi333 (Insert 2¢) 00:36, 2 September 2016 (UTC)

    • I would suggest against this. It is definitely more technically true, but it is over-qualified to the point of violating NPOV by under-representing its safety. It has been really well studied. Look at these statements from reviews: "The safety profile of HMB is unequivocal", "Chronic consumption of HMB is safe in both young and old populations", "Further, chronic consumption of HMB appears safe ... No serious adverse effects from HMB consumption have been reported". You can't really "prove" safety, but the extensive trials on it which haven't turned up a single report of serious harm, and only an occasional whiff of irreproducible, very mild adverse effects, at least "indicate" that there are no issues with safety. M. A. Bruhn (talk) 01:02, 2 September 2016 (UTC)
      • while i hear that, a) none of the trials were very big and b) even with things that were tested in thousands of people, sometimes things only emerge when something has been in millions of people (vioxx, avandia, etc). The statement in the reference... "chronic consumption of HMB appears safe ... No serious adverse effects from HMB consumption have been reported" is wise and good. Jytdog (talk) 01:10, 2 September 2016 (UTC)

        After looking at the statement again, I think using an "As of" is somewhat problematic here since it's unusual to date statements about side effects (e.g., "As of June 2014, the known side effects of XYZ are..." or "As of December 2015, the side effects of ABC that have been found in clinical trials are...") in drug articles. I don't think there's anything wrong with the "have found" wording, but I'm going to cut the "As of" template because it doesn't seem to set a good precedent for writing about side effects in other WP:PHARM articles. The publication date of the most recently published reference which cites that sentence is what I used to date the statement, so I don't think there's really any loss of information by removing it. Seppi333 (Insert 2¢) 02:31, 2 September 2016 (UTC)

Off-topic

@Jytdog: HMB has been in millions of people, it's been a common supplement for decades. The article doesn't indicate this though, I agree with the discussion down below about adding a brief history section. Also you have to consider that the safety of supplements are judged with very different standards as those used for pharmaceuticals, they're just usually (of course there are plenty of exceptions) much less biologically active. The statement by those authors is fine, but we need our own wording. M. A. Bruhn (talk) 02:47, 2 September 2016 (UTC) Your claim that it is has been in millions of people is without a source so means nothing (other than raising concerns for me about how you work here in Wikipedia). With regard to your argument about dietary supplements: a) It is marketed as a medical food and a dietary supplement. b) A statement of whether something is safe or not, is a statement of whether something is safe or not. Be it flying or a drug or acupuncture. c) A lot of dietary supplements have potent activity eg St Johns Wort; HMB does apparently as well. But in any case there is nothing to your argument either.Jytdog (talk) 03:06, 2 September 2016 (UTC) What a petty cheap shot. It's been a popular supplement since the 90s, that should be enough to realize that millions have taken it over the years. Why should I look up a source estimating the number of people worldwide who have taken it, you probably can't find that on any supplement except a few like multivitamins. A) What's your point? Replace "supplements" with "medical food" and my statement is still completely correct, medical foods require no clinical trials, no proof of safety, their ingredients have to be GRAS like any other food, B) How we determine if flying is safe is very different from how we determine if a drug is safe. We don't use large RCTs to determine safety in flying just like how we don't use them in supplements either, C) "of course there are plenty of exceptions", and relative to performance-enhancing drugs HMB is not nearly as potent. M. A. Bruhn (talk) 04:10, 2 September 2016 (UTC) You may be right about the "millions" but none of us here have any source to back that up, and I have little patience for people who make shit up and none for people who stick to their guns when called on it. I have no more to say here. Seppi you have my feedback on the safety language. Good luck as the FAR unfolds! Jytdog (talk) 05:47, 2 September 2016 (UTC) Before I ever posted that I looked at: stats concerning supplement use in general, sales figures of body building supplements and a $50-60 million dollar number for sales of HMB in the US in 1998, a 2006 study by the NCAA looking at % of college athletes using HMB (and I looked at number of NCAA athletes in 2006), various literature sources giving subjective descriptions of HMB as popular supplement at various times, various articles describing prevalence of HMB usage in various specific sports disciplines (primarily bodybuilding), tried to gauge what percentage of HMB products are just pure HMB or a combination of HMB with other things, I did various back-on-the-envelope calculations from a variety of angle to try and justify a "millions" order of magnitude, and much, much more. I did all of this to counter your stupid, lazy assumption that HMB hadn't been taken by millions. Why do you think it took me an hour and 37 minutes to respond to you? I was certainly not going to write up all of my thoughts and link all of my sources just so I could be condescendingly dismissed by someone who has done zero research on HMB and who has no expertise yet think their opinions are superior to the relevant literature. M. A. Bruhn (talk) 06:09, 2 September 2016 (UTC) You still have no source for the number (by "source" I mean anything useful in a WP discussion). Jytdog (talk) 15:00, 6 September 2016 (UTC) I didn't write all of the above to try and support there being millions of people who have taken it (this you can convince yourself of if you want to), I wrote that to counter you stating that I "make shit up". The only thing I've made up was this statement "Why should I look up a source estimating the number of people worldwide who have taken it, you probably can't find that on any supplement except a few like multivitamins", which is really code for "I don't want to admit to how much time I spent looking for a source to support an obvious and uncontroversial claim, and also there is a ton of research about multivitamin usage prevalence." I brought up the fact that it has been used by millions, not to "win" some sort of "WP discussion", but because I perceived that you had no idea this was an extremely common supplement, and I wanted to indirectly confront this perception without calling you out on it and embarrassing you. I intentionally stated "The article doesn't indicate this though, I agree with the discussion down below about adding a brief history section" to try and excuse any ignorance about this supplement's prevalence. All I've gotten though is shit from you in return. M. A. Bruhn (talk) 04:28, 7 September 2016 (UTC) There is no point continuing this, which distracts from Seppi's effort to get this article to FA. You had no source for the "millions" of people having took this, and you still don't have one. This is doing nothing to improve the article. Jytdog (talk) 04:38, 7 September 2016 (UTC)

• "Since" and "while" make these sentences slightly ambiguous. Is it possible to reword?
  • Sure, I don't see why not. If you have a particular way of rephrasing it in mind, feel free to change it. Seppi333 (Insert 2¢) 23:44, 1 September 2016 (UTC)
• HMB is sold in the United States and internationally ... You mean it is sold all around the world? This looks very insular to the majority of readers, who are not Americans. Just say it is sold all around the world, if that is an important point for the lead. I am not sure that it is.
  • I changed this to "HMB is sold worldwide ..." - is this phrasing ok? Seppi333 (Insert 2¢)
• the conjugate base, calcium β-hydroxy β-methylbutyrate monohydrate (HMB-Ca) Why the italics?
  • The clause "a monohydrated calcium salt of the conjugate base" which immediately precedes "calcium β-hydroxy β-methylbutyrate monohydrate" is referring to/talking about that particular compound/phrase, so I figured MOS:WORDSASWORDS applies here. I did something similar in the lead of amphetamine when talking about what that word "amphetamine" properly refers to. If you think it shouldn't be italicized, I don't mind removing the italics. Seppi333 (Insert 2¢) 23:44, 1 September 2016 (UTC)
• both in and outside of competition I prefer to avoid "outside of"; do we need to say this at all?
  • WADA/NCAA both make a distinction between the use of certain ergogenic substances during competition vs at any time. E.g., the WADA banned substances list has 3 tabs on the left side that link to pages on substances which are banned in specific sports, at all times, and during competition. However, it probably isn't necessary to specify that. To address this and the following bullet point simultaneously, I combined both sentences into the following statement: "As of 2015, HMB has not been banned by the National Collegiate Athletic Association (NCAA), World Anti-Doping Agency (WADA), or any other athletic organization in the United States or internationally." I don't think it's really necessary to mention the lack of testing for it since that's sort of implied. Seppi333 (Insert 2¢) 23:44, 1 September 2016 (UTC)
• Close paraphrasing is a problem. The source has "The drug is not tested for nor banned by any sporting organization" and the article says "As of 2015, HMB was not tested for or banned by any athletic organization in the United States or internationally". There's that awful clunky phrase again, but the paraphrase is a more pressing concern.
  • My bad on the paraphrasing. I should have caught that. I've attempted to address the phrasing and close paraphrasing issues with the revision that I've described in the above bullet. Let me know if the wording is ok. Seppi333 (Insert 2¢) 23:44, 1 September 2016 (UTC)

Especially as I was looking at NPOV, I see potential to rewrite this into something a little less pro-HMB. I will have more comments later but if this is a fair sample of the whole article I could not support it at present. --John (talk) 21:08, 1 September 2016 (UTC)

I think the goal here should be to ensure that the existing article text is an accurate restatement of what is asserted about it in current medical reviews. If a sentence in the article includes a medical claim which is too strong relative to what is asserted in existing literature, then the statement obviously should be revised per WP:V. If an assertion which is contradictory to what is stated in the article and the cited literature exists in other current medical literature, then it should also be covered/cited in the article per WP:DUE/WP:NPOV. However, I don't think the current wording about HMB's clinical efficacy or safety is overstated since I worked with Jytdog (see his review above) and M. A. Bruhn (see the "Comments about safety" section on the HMB talk page) to ensure that the evidence which supports the statements of efficacy and safety in the "Uses" and "Side effects" sections is clearly and accurately described in the text. To my knowledge, there are no current medical reviews which make assertions that contradict any statements in the article.

Anyway, I figured the existing article text would need a little work before satisfying 1a. Your prior experience in this area is why I asked you specifically for help. Seppi333 (Insert 2¢) 23:44, 1 September 2016 (UTC)

User:John I completely hear you on the NPOV thing. Seppi is correct that this flows directly from the sources, which are pretty darn unimpeachable with regard to their type per MEDRS, and per MEDASSESS we cannot go second guessing what they say. I am dismayed by what they say - in my view they are way too definite and rosy based on the data they use - but that is my problem, not Wikipedia's. :) And I have not seen any reviews that bring a different perspective. Seppi reflected the sources accurately. So these statements are OK per NPOV in my view. Jytdog (talk) 23:58, 1 September 2016 (UTC)

You two are both looking at this article as if it is a pharmaceutical, it's not. Why are dietary supplements considered safe until proven harmful under US law whereas pharmaceuticals are considered harmful until proven safe? If you can't answer that question then you shouldn't be presuming to know better than the literature written by those that have actual expertise in the area. M. A. Bruhn (talk) 04:49, 2 September 2016 (UTC)

The answer to why they are treated differently is politics. Dietary Supplement Health and Education Act of 1994. And pharmaceuticals are not "considered harmful until proven safe" but that is offtopic. In any case please discuss content and sourcing and stop talking about other editors per se. Jytdog (talk) 19:53, 6 September 2016 (UTC)

Supplements need to be proven harmful to be taken off the market, drugs have to be proven safe to put on the market, that is what I was trying to say. If you want to dismiss this as entirely due to politics then go ahead, you can think whatever you like. As for your last comment, why don't you reflect on that yourself. M. A. Bruhn (talk) 04:28, 7 September 2016 (UTC)

General point I am going to hold off on a more detailed review until the concerns about NPOV are properly addressed. Here is what I mean, with my FAR hat on. Whether we consider this substance as a pharmaceutical, a dietary supplement or a food, an article which is universally positive looks like it breaches NPOV. A quick Google search readily yields results like these:

• Kreider RB, Ferreira M, Wilson M, Almada AL. Effects of Calcium ß-Hydroxy-ß-methylbutyrate (HMB) Supplementation During Resistance-Training on Markers of Catabolism, Body Composition and Strength. Int J Sports Med 1999; 20: 503-5091
• Journal of the International Society of Sports Nutrition
• In studies, HMB has repeatedly failed to show any solid evidence that it increases lean muscle mass, increases strength output or reduces post workout muscle soreness [1, [2], [3].], which leads to

1: Int J Sport Nutr Exerc Metab. 2001 Sep;11: Beta-hydroxy-beta-methylbutyrate (HMB) supplementation does not affect changes in strength or body composition during resistance training in trained men. 2: J Strength Cond Res. 2009 May;23(3):827-35. Effects of nine weeks of beta-hydroxy-beta- methylbutyrate supplementation on strength and body composition in resistance trained men. 3: J Strength Cond Res. 2010 Feb;24(2): Exercise-induced muscle damage is not attenuated by beta-hydroxy-beta-methylbutyrate and alpha-ketoisocaproic acid supplementation. I lack the expertise and time to trawl properly through the sources to evaluate these sources or to find more, but I think a general reader may be perplexed not to see these more nuanced critiques represented in our article. If, on the other hand, these are outdated or misguided claims which have been debunked, it would be interesting to present the claims and the counter-claims. --John (talk) 19:31, 6 September 2016 (UTC)

@John: I'm not sure that those sources even satisfy WP:RS, much much less WP:MEDRS. If you can find a MEDRS-quality source that contains "counterclaims" like the ones you've linked, I'd be happy to add them. Unfortunately, per MEDRS, I can't add anything that doesn't meet that guideline when adding and sourcing a medical claim. I don't think I'll be able to do anything to act on your objection about an alleged NPOV issue because I know of no medical sources that make the same assertions as these websites. Seppi333 (Insert 2¢) 19:45, 6 September 2016 (UTC)

(edit conflict) User:John - NPOV = accurately reflecting what reliable sources say. For content about health, WP:MEDRS defines reliable sources, and not one of the sources you cite above are OK per MEDRS. I As I noted above, here, I too was unhappy with how positive recent reviews are, and I actually raised that at WT:MED for discussion, here: Wikipedia_talk:WikiProject_Medicine/Archive_80#Question_about_a_journal. And please take the time to read that. Please do not criticize the NPOV aspect of this article based on sources that are not reliable. Thx. Jytdog (talk) 19:48, 6 September 2016 (UTC)

Those responses can cover this subject to the degree that it is considered as a medical food. Are there any sources that speak to perceptions of its efficacy as a bodybuilding supplement? As this is not a health concern but a more general human one, I am not sure that MEDRS needs to apply. --John (talk) 20:04, 6 September 2016 (UTC)

That's interesting; we don't usually have any kind of content about "popular perceptions" about any health intervention. We apply MEDRS to content about health with regard to dietary supplements etc all the time. And to bodybuilding too. That is definitely health content. Jytdog (talk) 20:17, 6 September 2016 (UTC)

You're the experts, but if the International Journal of Sports Medicine is not considered a reliable source, there are an awful lot of other articles here that need adjusted. --John (talk) 21:27, 6 September 2016 (UTC)

Here's an interesting and I think MEDRS-compliant source which seems to present a fair summary of the various studies. There seem to be conflicting results. The article should probably reflect that. --John (talk) 21:33, 6 September 2016 (UTC)

John for pete's sake. Here is what you wrote: Journal of the International Society of Sports Nutrition. The link there is to a blog. That blog is not a reliable source. That blog posting is about this paper published in the Journal of the International Society of Sports Nutrition. That paper is a PRIMARY source (see MEDRS definitions) We don't use primary sources for content about health, we use literature reviews or statements by major medical or scientific bodies. In the post just above, you link to PMC 2245953 which = PMID 18173841. This is indeed a review, but one from 2008 - eight years old. Again per MEDRS (specifically WP:MEDDATE) we use the most recent reviews that are published, generally not more than five years old for actively-researched topics, and this is indeed actively researched. As I said above, NPOV is based on reliable sources, and MEDRS defines reliable sources. Please base your comments on WP's policies and guidelines. Jytdog (talk) 21:51, 6 September 2016 (UTC)

To my knowledge, there are currently only 2 MEDRS-quality reviews which focus entirely upon the effects of HMB in athletes - PMID 25663250 and PMID 23374455 - and one which should be published within the next couple of months: [4]. I've already used these 2 reviews to source content in the article and I'm actively monitoring pubmed for when the 3rd one is published. Seppi333 (Insert 2¢) 10:43, 7 September 2016 (UTC)

@John: Are we okay on the POV issue or do you still have concerns?
If there's an issue with the current summary sentence in the "Enhancing performance" section due to its lack of specificity, I'm okay with writing another sentence or two following the summary sentence in that paragraph to specifically address why there are positive and negative findings per the 2 reviews that focus on this topic - primarily this International Society of Sports Nutrition (ISSN) review which is a comprehensive review of all HMB studies in athletes as of February 2013, but also this review (most of this is attributed to statistical design issues in certain studies) - and which subpopulations appear to benefit more from HMB (IIRC, untrained individuals "appear" to obtain more of a benefit, but I didn't think this was particularly notable because I wasn't aware of a study which compared groups composed of HMB-treated untrained individuals, HMB-treated trained individuals, placebo-treated untrained, and placebo-treated trained individuals; this study design would allow for a statistician to determine if there's a statistically significant difference between the average lean mass gains in the untrained vs trained HMB-treated groups).
If the issue is with something which isn't covered in one of the currently cited reviews, I'll probably need your help with finding a source that makes a statement supporting your POV.

So, in a nutshell, if you still think that there's still a problem, just let me know exactly what the issue is and I'll do my best to address it. Seppi333 (Insert 2¢) 18:07, 9 September 2016 (UTC)

@John: I just want to be perfectly clear about what positive clinical findings from supplemental HMB that I've chosen to cover in the article: I did not cover recent positive findings involving HMB that were covered in MEDRS-quality reviews that either have not been replicated or been supported by research on a sample which is (IMO) sufficiently large even if that finding has been replicated in 1 or more clinical trials. Some examples of positive (i.e., statistically significant) findings that I chose not to mention in the article, despite being covered in one or more MEDRS-quality reviews of placebo-controlled clinical trials with HMB on humans, include:

• a slight lowering of LDL ["bad"] cholesterol in HMB-treated individuals relative to controls
• greater improvements in nitrogen balance from the HMB-only group relative to both Juven [i.e., an HMB+arginine+glutamine mixture] and placebo groups in trauma ICU patients
• decreases in post-discharge mortality and better nutritional status in HMB+protein-treated malnourished hospitalized adults relative to placebo-treated controls (the placebo in this case was a supplement containing only carbohydrates)
• improvements in aerobic/endurance exercise performance and indices of aerobic function in HMB-treated athletes relative to controls
• greater power output during anaerobic exercise in HMB-treated athletes relative to controls

As mentioned above, all five of these positive findings are cited by at least 1 MEDRS-quality review (e.g., the review to which the statements are hyperlinked) and the latter 2 findings (i.e., improved aerobic performance and power output) are supported by multiple primary studies, so I COULD add all 5 of these findings to the article. However, I CHOSE NOT TO because I personally don't feel that the evidence base is strong enough to merit inclusion in the article. You need to realize that I am actually erring on the opposite side of NPOV that you think I am: I'm not covering all of the positive findings that are supported by the cited literature.

Lastly, one review published in July 2014 cited 2 other reviews (neither of which was the comprehensive ISSN review) to make the assertion that more than 20 primary publications showed positive results on body composition and muscle function/strength. As of today, about 50 pubmed-indexed clinical trials with HMB in humans have been published (this assertion is verifiable in this link), however only a fraction of those specifically examined the effect of daily HMB use on lean body mass and muscle strength/function in athletes. E.g., some of those 50 studies only examined unrelated outcomes, like the effects of long-term HMB supplementation on cardiovascular system and endothelial function in older adults, the immediate cellular effects of HMB in the skeletal muscle tissue of living humans, the effects on aerobic performance, post-discharge mortality in trauma ICU patients, etc.. Hopefully what I've mentioned here and the medical reviews that I've cited/linked will give you an idea of the current state of evidence supporting the assertions in the "Medical" and "Enhancing performance" sections in the article. Seppi333 (Insert 2¢) 19:59, 9 September 2016 (UTC)

Thanks Seppi333 for the considered response. It isn't so much that I have a POV that I want to see represented, it is more that my knowledge and experience make me suspicious of products that virtually claim to be elixirs, with perfect efficacy and no side effects, as I know and you know that in the medium to long term there is no such thing. In addition to the qualms I feel about the very positive gloss that is being given to this product in Wikipedia's voice (remember we had a similar conversation with regard to Adderall at the amphetamine FAR which we resolved amicably?), I have the additional sense of potential charlatanism and snake-oil salesmen at work, given my suspicion of bodybuilding supplements and the accusations of conflict of interest in some of the positive studies. I am not advocating for a particular POV here, but for NPOV which is policy. I would suggest, again, that a more sober wording of some of the article may answer this point. Let's pretend it is a car, or a movie. We report the rave reviews, the stars at the premiere, the awards it won, but we also report the complaints that it was over-rated. Obviously we have to go with the sources, and I hear what you say about MEDRS; this sourcing works for claims about its safety for sure, inasmuch as the subject of this article is a medicine or medical food. But I don't see anything wrong in covering it as a commercial product as well; it's possible that the majority of people reading this article will be interested in finding out about it for this reason, and if there are adverse consumer experiences out there, people reporting it didn't particularly work for them, we might profitably consider adding them to the article if they are well-sourced. Honestly, the article will read better with a more balanced approach. Incidentally, both of you, there are no strong feelings about this on my side, I am just doing my best to help you to review this article as requested, and Jytdog I am doing my best to "base [my] comments on WP's policies and guidelines." as I understand them. The relevant one here is WP:NPOV which reads in part Neutrality requires that each article or other page in the mainspace fairly represent all significant viewpoints that have been published by reliable sources, in proportion to the prominence of each viewpoint in the published, reliable sources. I'll have more to say later, and some specific recommendations. I am working at quite a slow pace as I have a lot of other things going on but rest assured I will not forget the work we are doing here. --John (talk) 00:10, 10 September 2016 (UTC)

• A couple of weeks have now passed and I should have a bit more time to put into this. If nobody objects I will have a hack at the prose; I'll do some specific recommendations. Before I do that I will read the article in detail again, to take account of the changes, which I see as a modest improvement. The pH looked awfully low, and I am glad that was picked up! --John (talk) 22:04, 17 September 2016 (UTC)

Thanks John - I appreciate your willingness to take on a review of the prose. Seppi333 (Insert 2¢) 14:35, 18 September 2016 (UTC)

@John: Since Boghog has been co-opted as a nominator to work on the chemistry content in the article to address Nergaal's concerns, I should be able to devote the majority of my time to addressing any concerns that you and Axl have about the wording and illustrations in the article. There should only be about two weeks remaining before this nomination is either archived or promoted though, so do you think you'd be able to read through the article and provide a list of issues for me to work on before then? I should be able to promptly address any concerns involving how the prose is written; finding appropriate sources for new article content or revising any of the diagrams might take me a bit longer, but I should be able to make any of those changes within a day or two provided that the an objection involving either of those is sufficiently specific.
FWIW, I didn't say this before, but I'm completely okay with revising any of the statements in the article to address potential NPOV concerns provided that the revised statement still satisfies WP:V. Seppi333 (Insert 2¢) 03:27, 25 September 2016 (UTC)

Thank you. I haven't forgotten about this. I will get to this in the next day or two, I promise. --John (talk) 20:08, 25 September 2016 (UTC)

References

Notes

Comments by Axl

• In the lead section, paragraph 2, is it necessary to include grapefruit as an example of a citrus fruit in the last sentence? Axl ¤ [Talk] 11:29, 1 September 2016 (UTC)

Grapefruit is mentioned in more sources than citrus fruit, so I went ahead and removed the latter and kept the former in the lead. Seppi333 (Insert 2¢) 11:44, 1 September 2016 (UTC)

Thanks. Axl ¤ [Talk] 12:00, 1 September 2016 (UTC)

• From the lead section, paragraph 3: "The effects of HMB on human skeletal muscle were first discovered by Steven L. Nissen at Iowa State University in the mid-1990s." Is Steven L. Nissen really a notable person who should be mentioned in the lead section? The lead is supposed to be a summary of the whole article. However neither Steven L. Nissen nor Iowa State University are mentioned in the rest of the article. Axl ¤ [Talk] 11:34, 1 September 2016 (UTC)

I'm aware that it isn't mentioned in the body, but the only place to put it would be in a History section which would contain a single sentence. I didn't think anyone would really care, but since this issue has come up I've created that section to address it. Steven Nissen is the founder of Metabolic Technologies, which jointly owns all the patents on HMB with the Iowa State University. Seppi333 (Insert 2¢) 11:44, 1 September 2016 (UTC)

Since Nergaal objected to the 1 sentence section, I'll recreate the history section if I can find some information to expand it with. Seppi333 (Insert 2¢) 14:51, 1 September 2016 (UTC)

As mentioned in Nergaal's section above, I could expand the history section to a 3–4 sentence paragraph. Is that sufficient? Seppi333 (Insert 2¢) 17:34, 1 September 2016 (UTC)

A short "History" section would be great. Axl ¤ [Talk] 19:11, 1 September 2016 (UTC)

Alright, I'll expand the section by sometime tomorrow and ping you when I'm done. Seppi333 (Insert 2¢) 19:37, 1 September 2016 (UTC)

@Axl: I've finished expanding the "History" section. Does it look ok to you? Seppi333 (Insert 2¢) 08:16, 3 September 2016 (UTC)

Yes, thanks. Axl ¤ [Talk] 10:04, 3 September 2016 (UTC)

• In "Pharmacology", is is possible to add HMB (and perhaps L-leucine) alongside amino acids in the first diagram? Axl ¤ [Talk] 12:02, 1 September 2016 (UTC)

Sure, I can do that. The font won't be a perfect match with the one used in the rest of the image though - is that ok? Seppi333 (Insert 2¢) 12:10, 1 September 2016 (UTC)

I've updated the image from [5] to [6]. If you're okay with that change, let me know and I'll update the captions in the articles where that image is used. Otherwise, I need to revert the image. Seppi333 (Insert 2¢) 12:32, 1 September 2016 (UTC)

The adjustment looks good. The new diagram also looks appropriate for the other two articles where it is used—as long as leucine and HMB are the primary mediators rather than other amino acids. Please go ahead and change the caption. Axl ¤ [Talk] 19:15, 1 September 2016 (UTC)

According to the review that the image is from (not the caption, but the article text itself), leucine and its metabolites, specifically HMB, are the most significant modulators of MPS, which they affect through the illustrated mTOR signaling pathway.

Crucially, this negative protein balance is transiently reversed (MPS > MPB) after food intake (contingent on sufficient high‐quality protein), such that net protein balance is neutral on a daily basis (MPS = MPB). The mechanisms underlying the anabolic effects of food intake involve both the stimulation of MPS (Rennie et al. 1982) and suppression of MPB (Wilkes et al. 2009). The potent increase in MPS is driven almost entirely by essential amino acids (EAAs) (Smith et al. 1992), with the branched chain AA (BCAA: leucine, isoleucine and valine), in particular leucine [and its metabolite(s), e.g. β‐hydroxy β‐methylbutyric acid (HMB) (Van Koevering & Nissen 1992)] being central to these effects (Wilkinson et al. 2013). Although the mechanisms underlying the unique anabolic properties of leucine are incompletely defined, recent work in yeast and cultured mammalians cells has demonstrated that leucyl tRNA synthetase is upstream of activating the hitherto ‘cellular AA sensor’, the mechanistic target of rapamycin complex 1 (mTORC1) in response to leucine (Bonfils et al. 2012, Han et al. 2012).
– the review linked above

The reference that they cite (Wilkinson et al. 2013) demonstrated that both leucine and HMB induce pronounced activation/phosphorylation of mTOR in humans, leading to increased myofibrillar MPS in skeletal muscle in vivo. Other amino acids also affect mTOR activity and myofibrillar MPS, but generally to a much lesser extent than leucine. Anyway, I'll go ahead and update the captions a little later today. Seppi333 (Insert 2¢) 19:37, 1 September 2016 (UTC)

I just noticed that "AA" is used twice in the graph at the bottom, so I need to revise the image to add something like "and HMB" beneath "amino acids (AA)" tomorrow when I have more time. I've reverted my change to the image for now. Seppi333 (Insert 2¢) 02:55, 2 September 2016 (UTC)

I've reuploaded the image with "Amino Acids (AA) or HMB" as the replacement text (Link to current version). I don't think the current captions need to be changed with this text replacement. Is this change ok with you? Seppi333 (Insert 2¢) 06:23, 3 September 2016 (UTC)

Yes, thank you. Axl ¤ [Talk] 10:08, 3 September 2016 (UTC)

• In "Pharmacology", subsection "Pharmacodynamics", paragraph 1: "Chronic supplementation with HMB for one month in rats." I am not convinced that one month is "chronic". (The word "chronic" usually refers to longterm diseases.) Axl ¤ [Talk] 11:34, 2 September 2016 (UTC)

Removing that word is fine with me. I've cut it. Seppi333 (Insert 2¢) 05:43, 3 September 2016 (UTC)

Thanks. Axl ¤ [Talk] 10:14, 3 September 2016 (UTC)

@Axl: The sentence "The signaling cascade that mediates the HMB-induced increase in human skeletal muscle protein synthesis has been identified in vivo." isn't entirely correct. HMB's immediate biomolecular target isn't mTOR (mTOR does function as an energy and amino acid sensor, but I'm not sure that HMB is "sensed" by mTOR analogous to how most proteinogenic amino acids do, which modulate mTOR activity through its capacity to "sense" protein precursor availability via amino acid signaling through the Rag family of GTPases (Rag GTPases) [see diagram – top left box]) - HMB would need to bind to a receptor or a different enzyme which induces mTOR phosphorylation as a downstream effect in its signaling cascade. HMB's proximal biomolecular target(s) in humans aren't currently known (this is why I included information on potential upstream targets in the pharmacodynamics section based upon in vitro and animal studies with HMB which detected signaling events involving IGF-1, Akt, and mitogen activated protein kinases), but components of its signaling cascade downstream have been identified in humans in vivo - namely mTOR phosphorylation, mTORC1 activation, p70S6 kinase phosphorylation, and 4EBP1 phosphorylation. Would you mind if I changed this sentence back to how it was or if we revised it to reflect the fact that it's immediate biomolecular target isn't known? Seppi333 (Insert 2¢) 06:23, 3 September 2016 (UTC)

The original sentence was: "As of May 2016, components of the signaling cascade that mediate the HMB-induced increase in human skeletal muscle protein synthesis have been identified in vivo." It certainly was not clear to me that some aspects of the cascade are still unknown. You might assert that omission of the definite article (i.e. stating just "components" rather than "the components") implies that not necessarily all components are known.

How about "many components", "most components" or "some components"? Axl ¤ [Talk] 10:34, 3 September 2016 (UTC)

"Many" would probably be best out of those 3. Personally, I'd probably go with "several", but I'll leave it up to you. In case you want to read the relevant literature, this primary source was the basis for that statement - it's cited by and covered in the 3 reviews which support that or the following sentence. One of the reviews is authored by many of the same individuals who authored that primary source, so I figured citing it in that section along with the reviews would be reasonable. Seppi333 (Insert 2¢) 10:48, 3 September 2016 (UTC)

That source is heavy going, especially as I have no expertise in this field. While it is clear that HMB's (insulin-independent) prevention of muscle protein breakdown is not fully understood, its effect on muscle protein synthesis seems to be better elucidated. Anyway, "several" would be fine. Axl ¤ [Talk] 12:55, 3 September 2016 (UTC)

I've updated the wording in that sentence accordingly. Seppi333 (Insert 2¢) 13:38, 3 September 2016 (UTC)

Okay, thanks. Axl ¤ [Talk] 11:42, 5 September 2016 (UTC)

• "Pharmacology", subsection "Pharmacodynamics", paragraph 1. The first half of the paragraph is about human skeletal muscle, while the second half is about the less-well understood non-muscle protein. Would you consider splitting the paragraph into two distinct paragraphs? I realise that this would leave each with only two sentences. Axl ¤ [Talk] 11:49, 5 September 2016 (UTC)

The reason that I grouped them together is that the sources discussed the latter effect (IGF-1 signaling) in the context of increased mTOR phosphorylation. I could split the paragraph if you really think it's necessary, but it is discussing the phenomenon in context of same context as the former sentences (mTOR signaling). This is why I grouped the sentences together. Are you sure you want me to split it into 2 paragraphs in light of this? Seppi333 (Insert 2¢) 09:36, 6 September 2016 (UTC)

Well, I asked you to consider it. You have done so, and you still think that a single paragraph is better. Let's leave it as it is. Axl ¤ [Talk] 10:14, 6 September 2016 (UTC)

• From "Pharmacology", subsection "Pharmacokinetics", paragraph 1: "The plasma clearance of HMB-FA, which reflects tissue uptake and utilization, is roughly 25–40% higher than the clearance of HMB-Ca as well." I am unconvinced that plasma clearance reflects tissue uptake and utilization. Actually the phrase "plasma clearance" is somewhat vague. Is this the same as "clearance (pharmacology)"? (Have a look at this reference.) It is very peculiar that HMB-FA has a higher "plasma clearance" while also having a longer elimination half-life (as indicated by the preceding sentence). I am aware that the source (Wilson) states: "Perhaps the most intriguing findings were that plasma clearance, indicative of tissue uptake and utilization, was 25% greater with HMB-FA consumption compared with an equivalent HMB-CA consumption." Axl ¤ [Talk] 12:21, 5 September 2016 (UTC)

That statement ("... which reflects tissue uptake and utilization") comes from both of the cited sources (a primary study on HMB pharmacokinetics and a review). From my reading into the sources, I believe it's referring to the plasma clearance into body tissues, primarily skeletal muscle wherein it is metabolized, not clearance into urine by the kidneys. I don't entirely understand the mechanics that mediate this effect. Do you have a proposed rewording? Seppi333 (Insert 2¢) 09:36, 6 September 2016 (UTC)

Both papers misuse the term "[plasma] clearance". This makes me uneasy about accepting them as references for the claim about tissue uptake.

A suitable statement might be "Tissue uptake and utilization of HMB-FA is 25–40% higher than for HMB-Ca." Is there another source that provides this information without mentioning "clearance"? Axl ¤ [Talk] 13:07, 6 September 2016 (UTC)

I'll take a look and follow up if I can find anything. I'll probably use your suggested version either way. Seppi333 (Insert 2¢) 20:02, 6 September 2016 (UTC)

This study in rats (by Shreeram) indicates higher bioavailability for Ca-HMB. Regarding clearance, Shreeram states: "This observation is in agreement with Fuller et al. who observed a 25% increase in the systemic clearance of FAHMB compared with CaHMB." Shreeram also mentions: "Another plausible explanation for the increased clearance of FAHMB might be rapid tissue uptake and/or oxidation compared with CaHMB." Axl ¤ [Talk] 12:20, 7 September 2016 (UTC)

Compared to HMB-FA, HMB-Ca has a higher relative bioavailability in rats and a lower relative bioavailability in humans. I'm hesitant to use an animal study to cite PK info for this reason. Seppi333 (Insert 2¢) 16:20, 7 September 2016 (UTC)

@Axl: I've reworded the statement per your suggestion. Only these 2 studies with HMB in humans - PMID 21134325 & PMID 26373270 - appear to cover the difference in tissue uptake/utilization between HMB-Ca and HMB-FA. On a related note, our definition in the lead of the clearance (pharmacology) article appears to be in agreement with how PMID 15601437 (i.e., the study about plasma clearance that you linked) defines it. I don't really see any inconsistency between how the 2 cited sources (the ISSN review and PMID 26373270) and PMID 15601437 use the term "plasma clearance"; the latter article indicates that metabolism and/or excretion in organs (e.g., skeletal muscle) other than the lungs, kidneys, and liver contributes to plasma clearance. Per its abstract, "Plasma (total, systemic...) clearance is determined by all the individual metabolizing/eliminating organ clearances and involves mainly liver and kidney clearances.". Nonetheless, I now realize that the way I originally wrote that statement ("The plasma clearance of HMB-FA, which reflects tissue uptake and utilization, is roughly 25–40% higher than the clearance of HMB-Ca as well") was incorrect because it suggested that ALL of HMB's plasma clearance is due to tissue uptake and utilization (i.e., due to HMB metabolism to cholesterol, presumably mostly in skeletal muscle, or to acetyl-CoA in various body tissues). This is clearly false because its renal excretion rate is 10–40%, as stated in the article and the sources which cite that statement. Seppi333 (Insert 2¢) 20:34, 9 September 2016 (UTC)

Thank you. I am happy with the current statements. Axl ¤ [Talk] 11:44, 12 September 2016 (UTC)

• In "Pharmacology", subsection "Biosynthesis", the diagram has a misspelling: "β-methyl-gluconly-CoA" on the right should be "β-methyl-gluconyl-CoA". Axl ¤ [Talk] 12:07, 12 September 2016 (UTC)

Fixed: Before After. Seppi333 (Insert 2¢) 13:45, 13 September 2016 (UTC)

Thanks. Axl ¤ [Talk] 18:37, 13 September 2016 (UTC)

• In "Pharmacology", subsection "Biosynthesis", the diagram appears to show two pathways that re-join at the end as acetyl-CoA. However, alongside HMB-CoA, there is a (reversible) reaction to MC-CoA. Use of the abbreviation here makes the diagram less obvious that this is the same chemical as β-methyl-crotonyl-CoA. Shouldn't these two be conflated, so that there is a sort of "triangle" between HMB, HMB-CoA and MC-CoA, straddling both sides of diagram? Axl ¤ [Talk] 12:13, 12 September 2016 (UTC)

I haven't read the original source in which the image was first published (IIRC, it's a 1990 paper by Stevem Nissen), but I think the rationale for drawing the image that way was to emphasize the fact that, whenever biotin is deficient or in instances of MC-CoA carboxylase deficiency, MC-CoA metabolism is diverted away from its standard pathway and ultimately results (through unspecified mechanisms) in large urinary concentrations of HMB w/ no effect on urinary HMB-CoA concentrations; the increase in urinary HMB above the basal concentrations found in healthy adult urine appears to be about 10−100-fold and 1000-fold for biotin deficiency and MC-CoA carboxylase deficiency, respectively. The intermediate steps were probably also glossed over by the authors who drew it because the reactions involved in those circumstances aren't fully understood. I've been thinking about creating a new biosynthesis diagram to address some of the issues with the current one. Besides the fact that it illustrates a single pathway between HMB and MC-CoA in two different parts of the diagram (i.e., HMB ← HMB-CoA ← MC-CoA and HMB → HMB-CoA ↔ MC-CoA; this should really just be illustrated as HMB ↔ HMB-CoA ↔ MC-CoA, with a note that the "←" direction dominates during biotin deficiency), some of the pathways that are covered in the metabolism section aren't reflected in that image. I don't have time to draw an entirely new diagram at the moment, but it's on my to-do list. Seppi333 (Insert 2¢) 13:45, 13 September 2016 (UTC)

• If you think it's worth covering what I've mentioned in the note in the metabolism section, let me know. I didn't think HMB-carnitine to be a notable intermediate product in the metabolism of HMB because it's converted back into HMB-CoA, although it might also be directly converted to HMB. This wouldn't be the first time that I've omitted mention of an intermediate product in an FA or FA-nominated article though. I haven't done a thorough literature search on the carnitine intermediate, so I only know of a single ref - this primary source - that covers component of HMB's metabolic pathway. If you think it's worth adding to the article, I'll see if I can find a review that covers the metabolism of "3-hydroxyisovaleryl carnitine" to 3-hydroxyisovaleric acid (aka HMB).Seppi333 (Insert 2¢) 22:04, 16 September 2016 (UTC)

• In "Pharmacology", subsection "Biosynthesis", the diagram does not show that the conversion of MC-CoA and MG-CoA to HMB-CoA and HMG-CoA occur during biotin deficiency. Axl ¤ [Talk] 12:16, 12 September 2016 (UTC)

Also, the diagram does not show the conversion of HMB-CoA to HMB (during biotin deficiency) at all. Axl ¤ [Talk] 12:47, 12 September 2016 (UTC)

As noted above, I'm probably going to draw an entirely new diagram to illustrate the more comprehensive info in the 3-Hydroxyisovaleric acid#Metabolism section and address the issues with the current one. I'm hoping to get around to this within the few weeks.Seppi333 (Insert 2¢) 13:45, 13 September 2016 (UTC)

• "Pharmacology", subsection "Biosynthesis", paragraph 2 mentions β-methylcrotonoyl-CoA, while the diagram indicates β-methyl-crotonyl-CoA. Axl ¤ [Talk] 12:22, 12 September 2016 (UTC)

Added a hyphen to the text. Seppi333 (Insert 2¢) 13:45, 13 September 2016 (UTC)

Actually I was more concerned about the -oyl vs -yl suffix. Axl ¤ [Talk] 18:40, 13 September 2016 (UTC)

Oh. I didn't even notice that; I've removed the o. It's now "β-methylcrotonyl-CoA". Seppi333 (Insert 2¢) 13:23, 14 September 2016 (UTC)

lol, thanks. Axl ¤ [Talk] 10:26, 16 September 2016 (UTC)

• From "Pharmacology", subsection "Biosynthesis", paragraph 2: "During biotin deficiency, HMB can be synthesized from MC-CoA via enoyl-CoA hydratase and an unknown thioesterase enzyme, which convert MC-CoA into β-hydroxy β-methylbutyryl-CoA (HMB-CoA) and HMB-CoA into HMB respectively." Does the unknown thioesterase convert MC-CoA into HMB-CoA? (I think so, but the sentence needs to have the syntax & formatting adjusted.) Axl ¤ [Talk] 12:28, 12 September 2016 (UTC)

I don't believe that it does; the function of this "unknown thioesterase" enzyme is to cleave off the CoA group from a substrate molecule. If it were to accept MC-CoA as a substrate as well, it would probably cleave it into beta-methyl-crotonic acid and free CoA. Enoyl-CoA hydratase is responsible for HMB-CoA ↔ MC-CoA; the unknown thioesterase is responsible for HMB-CoA → HMB + free CoA. The statement is cited by the first and last sentences of this reference's quote. For context, "3HIA" is HMB and "3-hydroxyisovaleryl CoA" is HMB-CoA. Seppi333 (Insert 2¢) 13:45, 13 September 2016 (UTC)

In that case, the diagram seems to contradict the text. The diagram shows conversion of MC-CoA directly to HMB via enol-CoA hydrase [not hydratase]. There is no implication of a thioesterase at all. Axl ¤ [Talk] 10:35, 16 September 2016 (UTC)

Yep, I'm aware. This is the specific pathway that I was referring to above with the statements: "I haven't read the original source in which the image was first published (IIRC, it's a 1990 paper by Stevem Nissen), but I think the rationale for drawing the image that way was to emphasize the fact that, whenever biotin is deficient or in instances of MC-CoA carboxylase deficiency, MC-CoA metabolism is diverted away from its standard pathway and ultimately results (through unspecified mechanisms) in large urinary concentrations of HMB w/ no effect on urinary HMB-CoA concentrations ... The intermediate steps were probably also glossed over by the authors who drew it because the reactions involved in those circumstances aren't fully understood". I probably should have clarified that I was specifically referring to the somewhat misleading depiction of MC-CoA → HMB being catalyzed by enoyl-CoA hydratase alone, along with the second depiction of an HMB-CoA ↔ MC-CoA pathway, when I said this - my bad. In any event, "enol-CoA hydrase" is a less common synonym of "enoyl CoA hydratase"; if you want me to add a "y" to "enol" and a "ta" after the "hydra", I probably could make that change to the image without making it look odd. As for the thioesterase, if you'd like me to add that to the image then I'd probably delete the "enol-CoA hydrase" and use the closest font in MS Paint to the one used in the image to add "enoyl CoA hydratase + unknown thioesterase". Seppi333 (Insert 2¢) 22:04, 16 September 2016 (UTC)

Thank you for the clarification. I don't mind whether "enoyl-CoA hydratase" or "enol-CoA hydrase" is used, but the text should be consistent with the diagram. If "enoyl-CoA hydratase" is more commonly used, then this is preferable. I don't think that two enzymes should be applied to a single step in the diagram. Rather, enoyl-CoA hydratase should lead to HMB-CoA, then the thioesterase should show conversion of HMB-CoA to HMB. [Sorry for the delayed response. I am currently on holiday.] Axl ¤ [Talk] 08:03, 20 September 2016 (UTC)

Ah, alright. I'll see what I can do about adjusting the graphic accordingly. I should be able to do this over the next day or two. Seppi333 (Insert 2¢) 03:13, 25 September 2016 (UTC)

@Axl: before after - how's that look? I can't add new text to the image in paint; it ends up looking awful, but I managed to change enol CoA-hydrase to enoyl CoA-hydratase using the image text and add HMB-CoA as a product of enoyl CoA-hydratase using arrows and the same text in the iamge. Seppi333 (Insert 2¢) 17:45, 26 September 2016 (UTC)

Thanks. That's an improvement. Axl ¤ [Talk] 19:26, 26 September 2016 (UTC)

• In "Chemistry", could any information about melting point, boiling point & density be added? Axl ¤ [Talk] 11:57, 13 September 2016 (UTC)

MOS:PHARM notes that basic chem/phys properties should just be covered in the drugbox, but I don't mind adding the melting point and density if you think it's worth covering these. The BP isn't that notable since, at normal atmospheric pressure, it decomposes instead of boiling at high temperatures. Would you like me to add a sentence on the MP and density? Seppi333 (Insert 2¢) 13:45, 13 September 2016 (UTC)

Ah, okay. No need to for any change. Axl ¤ [Talk] 10:38, 16 September 2016 (UTC)

• From "Chemistry", paragraph 1: "The pKa of HMB-FA is 4.4, which is higher than the pH of gastric acid." I suppose that the implication is that in the stomach, HMB-FA exists mainly as the free acid form rather than conjugate base form. Can this be mentioned in the article? If not, it might better to remove the reference to gastric pH. Axl ¤ [Talk] 12:02, 13 September 2016 (UTC)

  Removed it. Seppi333 (Insert 2¢) 13:45, 13 September 2016 (UTC)

Okay. Axl ¤ [Talk] 10:39, 16 September 2016 (UTC)

References

Notes

• Closing note: This candidate has been withdrawn, but there may be a delay in bot processing of the close. Please see WP:FAC/ar, and leave the {{featured article candidates}} template in place on the talk page until the bot goes through. Ian Rose (talk) 22:07, 4 October 2016 (UTC)

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