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GA Review

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Reviewer: Tom (LT) (talk · contribs) 05:47, 28 November 2017 (UTC)[reply]


Out of sympathy for poor Seppi333 I will take up this review. I'll spend a few days familiarising myself with the subject matter and then post my review. --Tom (LT) (talk) 05:47, 28 November 2017 (UTC)[reply]

 Thank you very much! – I really appreciate it Tom!! Seppi333 (Insert 2¢) 19:10, 28 November 2017 (UTC)[reply]
I forgot to mention, a lot of the paywalled reviews that are cited in this article can be viewed here: [1]. The file names for those papers reflect the reference names that are used in the article source (i.e., <ref name="xyz"> → xyz.pdf). Seppi333 (Insert 2¢) 21:44, 28 November 2017 (UTC)[reply]
As a note, I am reviewing this article here [2]. If this situation happens again, please ping me and I will review the article based on any changes in the interests of time. Also happy when this passes to participate at the FA if that helps. --Tom (LT) (talk) 07:37, 1 December 2017 (UTC)[reply]
Have made my first-pass review (and updated the table below). Will go through your replies and mark what has been addressed, and then when this is complete go through the article a second time and briefly as a second check. As stated above am happy to discuss anything below. --Tom (LT) (talk) 22:55, 8 December 2017 (UTC)[reply]

Assessment

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Rate Attribute Review Comment
1. Well-written:
1a. the prose is clear, concise, and understandable to an appropriately broad audience; spelling and grammar are correct. Language is very technical and needs to be standardised. Presently quite difficult to read significant work has been done to improve readability
1b. it complies with the Manual of Style guidelines for lead sections, layout, words to watch, fiction, and list incorporation.
2. Verifiable with no original research:
2a. it contains a list of all references (sources of information), presented in accordance with the layout style guideline. I am concerned that the overuse of references, as stated below, makes this article hard to verify. very well referenced
2b. reliable sources are cited inline. All content that could reasonably be challenged, except for plot summaries and that which summarizes cited content elsewhere in the article, must be cited no later than the end of the paragraph (or line if the content is not in prose). See discussion re. primary and small-scale sources below
2c. it contains no original research. All statements references
2d. it contains no copyright violations or plagiarism. None identified
3. Broad in its coverage:
3a. it addresses the main aspects of the topic.
3b. it stays focused on the topic without going into unnecessary detail (see summary style). Several instances of acronyms and tidbits could be removed to enhance focus
4. Neutral: it represents viewpoints fairly and without editorial bias, giving due weight to each. Nil issues
5. Stable: it does not change significantly from day to day because of an ongoing edit war or content dispute.
6. Illustrated, if possible, by media such as images, video, or audio:
6a. media are tagged with their copyright statuses, and valid non-free use rationales are provided for non-free content.
6b. media are relevant to the topic, and have suitable captions. In the main, yes. One image being discussed below Relevant images that add to the article
7. Overall assessment.

Discussion

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  • All right, Seppi333, I will be honest here. It's clear you've put a lot of work into this article and I'm sure published in a medical journal this would be an excellent review. However, it's published here on WP and is being reviewed for "GA status" which is a different kettle of fish.
  • Firstly though, even more confusingly for me as a reviewer:
    1. (a) I can't seem to find a past GA review to compare my reviews against; and
    2. (b) given this has been to FA a number of times I think it will be very frustrating if I provide all sorts of specific advice to you which then needs to be rechanged in accordance with the FA reviewers' opinions; and
    3. (c) some of the issues I raise are probably in response to the concerns of others.
  • That said, I've reviewed probably more than 80 articles, including some complex ones, so I think I have a fair idea of how to interpret GA criteria. So, here goes:
  • In general, I find this article very hard to read. I find this difficult for a few reasons. There are a lot of references everywhere, and a lot of wikilinks. The language is very technical. I find some of the paragraphs could be arranged in a better way. A lot of facts are presented at once without much synthesis. Systematic reviews are placed beside primary sources. Language used to describe similar issues is inconsistent. Also in some areas extraneous information provided that could be cut to make things easier to read.
  • Now, taking into account (a)-(c), I'm not quite sure what to do. I can pass this article given there doesn't seem to be many others who have commented about the readability of the article in past FA reviewers, and let FA reviewers nut out the details. I could ask for a second reviewer (not inclined to do this). I could provide specific advice which is likely to be fairly subjective. What do you think/want, Seppi333? --Tom (LT) (talk) 23:06, 2 December 2017 (UTC)[reply]
    @Tom (LT): I'd prefer your specific advice on how to improve the readability (alternatively, feel free to make any changes you see fit it if you feel comfortable with it). If we end up rewriting the entire article in the process, that's fine with me as long as there's an improvement. Anyway, this is the first GA review for this article since I initially decided to skip the GA process and go straight to FAC. Seppi333 (Insert 2¢) 00:29, 3 December 2017 (UTC)[reply]
    OK, here goes then:--Tom (LT) (talk) 22:30, 3 December 2017 (UTC)[reply]

@Tom (LT): I finished going through the points below. I just need your feedback on my responses about some of the statements in the medical and pharmacodynamics sections in order to proceed with addressing those issues. Seppi333 (Insert 2¢) 23:12, 21 December 2017 (UTC)[reply]

Review of text

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Happy to discuss any of the below. These suggestions are not intended to be prescriptive & only intended to illustrate my concerns about the 'well-written' point. They don't all need to be addressed for the review to pass. Hope it is helpful. --Tom (LT) (talk) 22:59, 3 December 2017 (UTC)[reply]

I'll address these issues as time permits. I'm not addressing these points in any systematic order, so it might appear that I've ignored some of them until I get to them. Seppi333 (Insert 2¢) 20:24, 4 December 2017 (UTC)[reply]

Lead

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 Addressed
  • Too many citations. Referring to previous consensus, I have no issue with citations in the lead. However surely as a summary of text these could be whittled down to your main citations, and the lists can be provided in text.
  • Suggest revise statement about use so that it flows in a logical order adults -> older adults and certain statements -> uncertain statements
    • All of the sentences in the lead now contain only statements of certainty; the only one that includes a clause with an a statement about effects which are uncertain is "HMB can reduce the loss of lean body mass in individuals experiencing age-related muscle loss, but more research is needed to determine how it affects muscle strength and function in older adults." The preceding sentence was recently updated with a statement of certainty about the effect on muscle strength in this age group. I could move that statement down if you still want me to; however, it should be noted that, After moving the statement you mentioned in the bullet below, the current ordering of the sentences in the 1st lead paragraph reflects the same order of content coverage as the body. I'm think Doc James might object at the next FAC to ordering medical uses after performance-enhancing uses in the lead; but, if he's okay with that, I'll put it in that order as you suggest. Seppi333 (Insert 2¢) 06:51, 8 December 2017 (UTC)[reply]
      • @Doc James: Would you mind if I reordered the statements in the 1st lead paragraph as suggested above? Seppi333 (Insert 2¢) 06:55, 8 December 2017 (UTC)[reply]
        • Not putting the refs behind the sentence they support IMO is not an improvement. Having them as a block of 13 makes it impossible for me to determine which part of the lead is supported by which reference.
        • I see that they are now hidden comments but I would simple show them.
        • If athletic uses are more common, I do not have an issue with that use going first in the first paragraph. Doc James (talk · contribs · email) 18:19, 8 December 2017 (UTC)[reply]
          • @Doc James: It's already in the lead; my question was if you would object me be reversing the order of the sentences in the collapse tab below (these sentences summarize its medical and performance-enhancing uses) (edit: I've deleted the collapse tab and the content inside since it took up a lot of space in the source). Seppi333 (Insert 2¢) 19:59, 8 December 2017 (UTC); Updated 02:33, 16 December 2017 (UTC)[reply]
            • @Tom (LT):  Done: I ordered the statements on clinical effects in the lead as you suggested (healthy adults, then older adults) since Doc James didn't object following my ping (this edit was made in this diff). I removed the statement about more research being needed in an earlier edit, so there's currently no statements on uncertain effects in the lead. If you have any other suggestions for ordering the 1st lead paragraph, I'm still open to modifying it though. Seppi333 (Insert 2¢) 19:24, 13 December 2017 (UTC)[reply]
  • Suggest move statement "It is added to certain medical foods that are intended to provide nutritional support for people with muscle wasting due to cancer or HIV/AIDS and to promote wound healing." up to where you discuss clinical uses

@Tom (LT): Re: The lead references – Do you want me to use the same referencing style that was used in the lead of amphetamine? Seppi333 (Insert 2¢) 20:51, 4 December 2017 (UTC)[reply]

@Tom (LT): Nevermind, I went ahead and did redid the lead sources analogous to amphetamine's lead. I'm going to group the sources in the body in the same manner as is done in the amphetamine article (sentences with 4+ references have their references placed in a sources note). Do you approve of that approach? Seppi333 (Insert 2¢) 04:38, 8 December 2017 (UTC)[reply]
@Seppi333, Doc James. No bright suggestions for references in lead other than to (1) restate the lead is very difficult to read with so many references interspersed between text and (2) agree with you Doc James that large groups of references are hard to verify.--Tom (LT) (talk) 22:57, 8 December 2017 (UTC)[reply]
I'm not really sure how else to address this problem without using the [sources #] notes and censored refs for the sentences. Most of the lead sentences are either summaries of 2+ sentences in the body that are supported piece-wise by different references or exact duplicates of sentences in the body that (IMO) require multiple refs for making significant medical claims on efficacy/safety. Seppi333 (Insert 2¢) 19:31, 13 December 2017 (UTC)[reply]
We've done what we can, I won't push this point further. Thanks for responding to my concerns --Tom (LT) (talk) 23:11, 17 December 2017 (UTC)[reply]
  • Suggest remove unnecesssary acronyms, including WADA and NCAA which are only used once  Done

Uses

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Medical
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  • Does this article ("Elderly persons with ICU-acquired weakness: the potential role for β-hydroxy-β-methylbutyrate (HMB) supplementation") really comment on HIV immune function? (it is used here "Clinical trials with Juven for AIDS")
    • Yes. From [3]: In patients with human immunodeficiency virus (HIV), Clark et al46 have demonstrated that HMB supplementation in addition to arginine and glutamine not only increased lean body mass by 2.6 kg but also increased CD3, CD4, and CD5 cell counts. As noted above, the full-text of paywalled citations in this article can be accessed via this link: [4]. The file names of the pdf files are the same as the reference names that are used in the article source (i.e., <ref name="xyz"> → xyz.pdf). Seppi333 (Insert 2¢) 05:30, 8 December 2017 (UTC)[reply]
      • Right. This study is just referencing another primary source. I strongly advocate we remove this. I don't think it's responsible to insert a statement like this without a stronger source. --Tom (LT) (talk) 22:00, 12 December 2017 (UTC)[reply]
        • I'm confused. PMID 24072740 is marked as a review on Pubmed; the quote from above is just a summary of 1 of the primary sources it reviewed. I can check whether or not that primary source is covered in one of the other medical reviews I've cited if that's what you're asking about though. Seppi333 (Insert 2¢) 22:48, 12 December 2017 (UTC)[reply]
          • The source that this statement is derived from is a primary source. I really don't think we should be including something like this, which is a medical claim unless there is a stronger source (WP:MEDRS). It is in my mind misleading to state that HMB has a role in HIV/AIDS management without stronger evidence. --Tom (LT) (talk) 02:36, 15 December 2017 (UTC)[reply]
Like I was saying before, that statement is cited and supported by PMID 24057808 and PMID 24072740, both of which are classified as a medical reviews on Pubmed (follow the PMID links and click/expand the tab titled "Publication type, MeSH terms, Substances" – doing this will display "Publication type: Review"). The quoted sentence above in my initial reply to this bullet – "In patients with human immunodeficiency virus (HIV), Clark et al46 have demonstrated that HMB supplementation in addition to arginine and glutamine not only increased lean body mass by 2.6 kg but also increased CD3, CD4, and CD5 cell counts" – is from the 2nd review that I've listed (i.e., PMID 24072740), not the primary source it was reviewing. In other words, that statement isn't cited or supported by a primary source; rather, it's cited and supported by 2 medical reviews which covered the findings of PMID 10850936, which is a primary source that you seem to be confusing the review with. That primary source is not currently and has never been cited in this article. In any event, if you'd prefer that I use a newer review instead, I can cite a medical review from 2017 (PMID 28493406 - see Table 6 from this review) which includes 2 clinical trials with HMB for AIDS. On a slightly tangential note, HMB is currently included in medical foods that are used to provide nutritional support in individuals with AIDS/HIV (NB: medical foods are intended to be taken under medical supervision in the United States – see pages 3–6 of this FDA guidance document for further information on their regulatory/labeling requirements). Seppi333 (Insert 2¢) 01:03, 16 December 2017 (UTC)[reply]
@Tom (LT): Sorry, it just occurred to me that you seem to be taking issue with covering the findings from reviews that included that particular clinical trial in the article, not the reviews themselves. If I'm correct about that being the issue here, then when you say "a stronger source", do you mean we should wait until a 2nd clinical trial that examines those parameters is published and subsequently reviewed? Right now, there's 3 reviews that cover 2 clinical trials of HMB for AIDS, but only 1 of those trials examined CD3 and CD8 counts. In the event you'd like to read about what clinical parameters the 2nd trial examined, this is a link to its full text: {{DOI|10.1177/014860710402800265}}. If you can clarify what the issue is, I'd appreciate it, since I'm not sure if you're asking for a replacement review of that trial (re: my previous reply) or a review of a corroborating trial/primary source (re: this reply). Seppi333 (Insert 2¢) 01:21, 16 December 2017 (UTC)[reply]
  • The two issues are: the sentence states "Clinical trials with Juven for AIDS have also demonstrated improvements in immune status, as measured by a reduced HIV viral load relative to controls and higher CD3+ and CD8+ cell counts". (a) Here it states "trialS" yet there as you say there is only one trial showing reduced HIV viral load. (b) given that there is only one trial, it really is just included, not supported, by the reviews. I would be happy if this was rephrased in a more general way, or if the second clause was removed. --Tom (LT) (talk) 01:23, 19 December 2017 (UTC)[reply]
    • I've changed the plural to singular to accurately reflect this (diff). I don't think it would be wise to delete this sentence. While these findings are from 1 study which was included in these reviews, these endpoints were specifically mentioned in the text of the review articles despite not being the primary endpoint (which was a change in lean mass) in the study itself. I.e., the authors probably discussed these secondary endpoints because they are notable in their own right. In any event, what phrasing did you have it mind for this sentence? Seppi333 (Insert 2¢) 01:26, 20 December 2017 (UTC)[reply]
  • "The efficacy of Juven for the treatment of cancer cachexia was also examined in a phase 3 clinical trial which found a strong trend (i.e., p=.08) for an improvement in lean body mass relative to controls;[14][30][33] however, according to the authors of the trial itself and a systematic review that included it, the trial did not adequately test the ability of Juven to prevent or reverse the loss of lean body mass in individuals with cancer cachexia since the majority of participants did not complete the study" I do not believe a phase 3 study meets WP:MEDRS. Surely it is a primary source. You then even include criticism by a systematic review. Should this be included at all?
    • The assertion which was made in the systematic review about the clinical trial is identical to the assertion made by the authors of clinical trial publication. In other words, the clinical trial source and systematic review draw the same conclusion about the clinical trial. I'll remove that primary source if you think it detracts from the article; I only added it because I thought it helped to show consensus. Seppi333 (Insert 2¢) 05:30, 8 December 2017 (UTC) minus Removed + rephrased sentence[reply]
      NB: The only reason I've included any primary medical sources in this article is to support existing medical reviews or to supplement medical reviews which don't cover specific details that are only covered in the primary source. E.g., the specific mechanisms of action that give rise to HMB's mode of action aren't covered in most medical reviews, and those that do mention mechanisms of action gloss over the details; in contrast, HMB's mode of action (increased protein biosynthesis and reduced protein catabolism) is covered in almost every medical review about the compound. Seppi333 (Insert 2¢) 05:30, 8 December 2017 (UTC)[reply]
 Addressed
  • So many citations. Are all of these needed??
    • For statements that contain clinically significant medical claims, yes. I don't think it's adequate to support a statement of a dietary supplement's clinical efficacy with a single citation since many claims about the efficacy of dietary supplements for any particular condition or effect are dubious. One can probably find a source to support a statement of efficacy for most dietary supplements for a particular purpose, so showing that there's scientific consensus across multiple reviews by citing more than one is, IMO, both appropriate and necessary in this context. This approach is followed for statements about this compound's safety profile as well. Moreover, for a number of sentences in the article, the statement requires multiple sources because it makes multiple non-medical claims that are only individually supported by the cited references (i.e., a sentences with 3 claims might be supported by 3 sources, where each source supports only 1 of the claims). Seppi333 (Insert 2¢) 05:30, 8 December 2017 (UTC)[reply]
    • As I see below, sometimes what may be seen as one point is in fact two or three. On the other hand, if at all possible for a noncontroversial statement, it is adequate to use a reliable secondary source. The large number of references shows how much effort has been put into this article but also makes it harder to read and verify. So trimming if possible would be appreciated. --Tom (LT) (talk) 22:00, 12 December 2017 (UTC)[reply]
  • Second paragraph is confusing because it alternates rapidly between sarcopenia, muscle mass, lean muscle mass, muscle weight , muscle atrophy, muscle wasting... if possible it would be good if these terms could be standardised into more consistent terms for ease of reading (eg "sarcopenia -> skeletal muscle mass; muscle weight/mass -> muscle mass; muscle atrophy/wasting -> loss of muscle mass")
  • Suggest that the whole section be reworded and possibly split up into the following: (1) preserving muscle mass in hypercatabolic states (2) preserving muscle mass in aging (3) other uses; and restrucrigin paragraphs so that the proceed as in (a) findings followed by (b) details at end of paragraph.
Available forms
  • Ensure and Juven aren't linked  Done
  • "Investigation of the presence of β-hydroxy-β-methylbutyric acid and α-hydroxyisocaproic acid in bovine whole milk and fermented dairy products by a validated liquid chromatography-mass spectrometry method" - does not seem like a secondary source
    • It's a primary source; however, the statement "[HMB] is present in insignificant quantities in certain foods, such as alfalfa, asparagus, avocados, cauliflower, grapefruit, catfish, and milk" is not a medical statement. That primary source supports only its presence in bovine milk. HMB is also present in human breast milk, but that wasn't mentioned in that sentence. It is, however, covered more in depth in the "Detection in body fluids" section: In the breast milk of healthy lactating women, HMB and l-leucine have been quantified in ranges of 42–164 μg/L and 2.1–88.5 mg/L.[15] In comparison, HMB has been detected and quantified in the milk of healthy cows at a concentration of <20–29 μg/L.[22] This concentration is far too low to be an adequate dietary source of HMB, but milk products could be fortified with HMB to confer benefits to skeletal muscle.[22] If you think that I should remove the mention of milk and the primary source from sentence anyway, I'm ok with doing that. Seppi333 (Insert 2¢) 20:48, 4 December 2017 (UTC)[reply]
  • Number of citations here is even less for the same statements than the lead
  • "when taken in doses of 3 grams per day" you say "3-6 grams" in the lead
Medical
  • "More research is needed." Does this need to be stated? This can surely be stated about almost everything.
    • This is stated twice; are you referring to one or both statements? The reason it was included w.r.t. the sarcopenia statement is that it was stated as a conclusion of the meta-analysis. Seppi333 (Insert 2¢) 07:04, 8 December 2017 (UTC)[reply]
    • The reason it was stated in the bed rest-associated muscle atrophy sentence is that there is preliminary evidence from clinical trials with small sample sized for efficacy, but its treatment efficacy hasn't been well-established based upon phase 3 randomized controlled trials (i.e., clinical trials with rather large sample sizes), as is required for FDA-approved medications. Seppi333 (Insert 2¢) 20:35, 4 December 2017 (UTC)[reply]
    • minus I've removed both instances where "more research is needed" was stated in this section. The first instance of that statement in the sentence about muscle strength in sarcopenic adults was removed when I updated the text with a medical review from 2017; that review made a conclusive statement about HMB's effect on muscle strength in sarcopenic adults based upon more recent primary research. The second instance of that statement in the sentence on bed rest was removed when I rephrased the sentence as: Preliminary clinical evidence suggests that HMB supplementation may also prevent muscle atrophy during bed rest (diff). I think that wording conveys the same meaning as the original wording about more research being needed to establish efficacy. Seppi333 (Insert 2¢) 01:32, 16 December 2017 (UTC)[reply]
Enhancing performance
  • Are four citations really needed for this sentence "HMB produces these effects..."?
  • "Untrained individuals and trained athletes" seems to cover the whole spectrum of people doing exercise?
    • I've modified to the clause to specify untrained individuals and athletes who perform high intensity resistance or aerobic exercise. Moderate exercise causes high levels of muscular stress in untrained individuals, but that typically only occur at high intensities in trained individuals. Seppi333 (Insert 2¢) 22:27, 12 December 2017 (UTC)[reply]
      • Thanks.  Question: This sentence seems to have only two factual statements. Does it need three references? --Tom (LT) (talk) 02:36, 15 December 2017 (UTC)[reply]
        • The phrase "these effects" refers to the 8 effects of HMB (muscle hypertrophy/strength/power, lean mass, muscle damage, exercise recovery, aerobic exercise performance, and aerobic fitness) that were stated in the 2 sentences which preceded this sentence. Those 2 sentences were supported by 6 reviews. This statement could be fully supported by 2 reviews if I deleted the preceding sentence on HMB's effects on aerobic exercise performance and aerobic fitness, but I don't think it would be wise to do so. The third review is necessary for supporting that part. Do you want me to cut the preceding sentence and remove the third review from this sentence, or should I clarify that the phrase "these effects" refers to the aforementioned effects on skeletal muscle and aerobic performance/fitness? Seppi333 (Insert 2¢) 01:56, 16 December 2017 (UTC)[reply]
  • "The inhibition of exercise-induced skeletal muscle damage by HMB is affected by the time that it is used relative to exercise" (1) does this need two references? (2) I have no bright ideas but I'm sure this sentence could be written in a simpler manner
  • Suggest move "dose dependently" to a separate sentence
  • In this sentence "When combined with" there are only 4 references used more than 10 times. I suggest either trim, move to end of sentence, or hide the references mid sentence using comments
  • Is quite technical to read. Suggest some changes such as "When combined with" -> "With", "augments" -> "adds to"; "expedite" -> "speed up"  Done

Side-effects

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 Addressed
  • Could include information about what happens if more than the stated doses are taken?
    • Experiments in animals with very high doses uses didn't indicate any and to my knowledge there is no reported median lethal dose (LD50) for this compound. Clinical research in humans hasn't indicated any adverse effects from higher doses (IIRC, up to 15 grams/day has been used before without reported side effects in a small study, but I don't remember where I read that). Based upon the hypothesized immediate targets of this compound, it seems unlikely that this compound would be capable of exerting an acute toxic from high doses via pharmacological means since, beyond a certain dose (presumably in the 3-6 gram range), its effect on signaling cascades is saturated since the activation of each protein in the cascades that it triggers is already maximal. Most studies use 3 grams of HMB because there's little difference in clinical efficacy from taking 3 grams vs 6 grams, not because of the potential for adverse effects. It is possible that biotransformation of large amounts of HMB to HMB-CoA could produce adverse effects if, for some reason, one or both of the two other primary metabolic pathways of HMB-CoA are inhibited (HMB-CoA→MC-CoA and HMB-CoA→HMG-CoA), based upon a primary study (see reference quote);[1] however, healthy individuals are capable of readily converting HMB-CoA to MC-CoA or HMG-CoA, which are subsequently metabolized into other compounds like cholesterol and ketones, among others. Seppi333 (Insert 2¢) 20:06, 13 December 2017 (UTC)[reply]
      • Interesting. I think it is useful in pharmacological articles to note something about overdose/ the unlikely possibility of overdose.--Tom (LT) (talk) 23:16, 14 December 2017 (UTC)[reply]
        •  In progress: I'll go back through the cited reviews in this section to see what they say about HMB overdose/toxicity; if I can, I'll add a statement about HMB overdose in the article. Seppi333 (Insert 2¢) 02:04, 16 December 2017 (UTC)[reply]
          • The only review that commented on fairly high dose usage was the one that reviewed animal studies involving HMB. It stated, The no-observed adverse-effect level (NOAEL) was determined to be 3.49 and 4.16 g/kg BW daily for male and female rats, respectively". I don't think this would be particularly useful to include in the article, because an equivalent dosing in humans must first be converted using a predetermined scaling metric which isn't mentioned in the review (see the USFDA's guidance on this). In other words, since a human equivalent dose is not specified by this review, stating those g/kg values in rats would be misleading since they'll probably be interpreted by some readers as applying to humans. Nevermind, the newest review that I recently added mentioned the equivalent dose for humans based upon the same study. It stated: "One study tested the safety of HMB for long-term use in rats. Fuller et al. (50) conducted a 91-d study with the use of Sprague-Dawley rats that tested the safety of b-hydroxy-b-methylbutyric free acid (HMBFA). This new form of HMB results in higher HMB serum concentrations than CaHMB. In this study, rats were administered an HMBFA intervention of 0%, 0.8%, 1.6%, or 4% of the diet by body weight. The highest dose is the equivalent of ~400 mg * kg-1 * d-1 for humans. No adverse advents were observed for any treatment group. Similarly, blood and urine analyses were within the normal range in all groups, with no group differences. The authors concluded that HMBFA was safe for consumption in a rat model." Seppi333 (Insert 2¢) 01:38, 20 December 2017 (UTC); Updated/edited at 05:46, 20 December 2017 (UTC)[reply]

References

  1. ^ Mock DM, Stratton SL, Horvath TD, Bogusiewicz A, Matthews NI, Henrich CL, Dawson AM, Spencer HJ, Owen SN, Boysen G, Moran JH (November 2011). "Urinary excretion of 3-hydroxyisovaleric acid and 3-hydroxyisovaleryl carnitine increases in response to a leucine challenge in marginally biotin-deficient humans". The Journal of Nutrition. 141 (11): 1925–1930. doi:10.3945/jn.111.146126. PMC 3192457. PMID 21918059. Reduced activity of MCC impairs catalysis of an essential step in the mitochondrial catabolism of the BCAA leucine. Metabolic impairment diverts methylcrotonyl CoA to 3-hydroxyisovaleryl CoA in a reaction catalyzed by enoyl-CoA hydratase (22, 23). 3-Hydroxyisovaleryl CoA accumulation can inhibit cellular respiration either directly or via effects on the ratios of acyl CoA:free CoA if further metabolism and detoxification of 3-hydroxyisovaleryl CoA does not occur (22). The transfer to carnitine by 4 carnitine acyl-CoA transferases distributed in subcellular compartments likely serves as an important reservoir for acyl moieties (39–41). 3-Hydroxyisovaleryl CoA is likely detoxified by carnitine acetyltransferase producing 3HIA-carnitine, which is transported across the inner mitochondrial membrane (and hence effectively out of the mitochondria) via carnitine-acylcarnitine translocase (39). 3HIA-carnitine is thought to be either directly deacylated by a hydrolase to 3HIA or to undergo a second CoA exchange to again form 3-hydroxyisovaleryl CoA followed by release of 3HIA and free CoA by a thioesterase.

Pharmacology

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 Addressed
Pharmacodynamics
  • If possible would suggest "protein synthesis" -> "protein creation" or even "formation" (and standardise "biosynthesis")
    • The terms "muscle protein synthesis" (MPS) and "muscle protein breakdown" (MPB) are widely used in the literature on this compound and on muscle protein turnover in general. I'll simplify the phrase if you really think it should be rephrased; but, at the same time, I'd expect the average high school student to know what the term "synthesis" means since most high schools require students to learn chemistry and biology. Seppi333 (Insert 2¢) 21:45, 13 December 2017 (UTC)[reply]
      • I will demure on this point, but it is just an example of how this article could be made easier to read for the lay person. To support my assertion, I quickly calculated a Flesch Grade Level on this article using MS word, and it is 19.5, ie. suitable for reading by those with more than 6 years of university education. The average US adult reads at grade 8-9. --Tom (LT) (talk) 01:27, 19 December 2017 (UTC)[reply]
        • The pharmacodynamics and chemistry sections of a drug article are not interesting to most people who read a drug article (e.g., I've completely rewritten a few drug articles and the chemistry section still doesn't interest me that much; the synthesis section in drug articles is gibberish to me because I lack the necessary background knowledge in organic chemistry to interpret it). They're both very specialized topics that should be included in pharmacology articles, but which necessary involve a lot of fairly technical material. If someone isn't familiar with molecular biology and pharmacology, they're not going to understand a comprehensive pharmacodynamics section – regardless of how simplistic the language is – because they lack a background knowledge of important concepts; for example, in this article, this section isn't going to make sense to anyone who isn't familiar with what signaling cascades, ribosomes, and proteasomes are and their purpose in cells. One way of addressing this is by adding notes to sentences to clarify what is being discussed and elaborate on those concepts (e.g., like this note, this one, or this third one), but I haven't done this in this article (yet). Let me know if you think it's worth clarifying some of the concepts in this section with explanatory notes; I'm willing to do that. Dumbing down the language in the entire section probably won't make it more readable without addressing this other issue though. If there are particular sentences that you think should be clarified in this section, please point them out! Seppi333 (Insert 2¢) 01:51, 20 December 2017 (UTC)[reply]
        • FWIW, the readability of this article is better than the amphetamine article based upon [5][6]. Seppi333 (Insert 2¢) 02:00, 20 December 2017 (UTC)[reply]
  • "Several components of the signaling cascade that mediate the HMB-induced increase in human skeletal muscle protein synthesis have been identified " surely doesn't need 2 references
    • The review lists the main component of the signaling cascade (mTORC1) and the secondary effects on GH/IGF-1 secretion in humans which was covered in that section (for context, GH and IGF-1 increase protein synthesis via mTORC1); the primary source lists all of the known downstream components in the signaling cascade (mTORC1, p70S6 kinase, 4EBP1) which HMB acts through. Seppi333 (Insert 2¢) 21:45, 13 December 2017 (UTC)[reply]
      • I won't push this particular point, but if they could be included where those respective products are listed I think it would reduce the burden of unnecessary references.To support the statement "several components... have been identified" really only needs a single source - the fact that several components have been identified by some person or group is not controversial --Tom (LT) (talk) 23:27, 14 December 2017 (UTC) for later reference[reply]
  • "Supplementation with HMB for one month in rats has also been shown to increase growth hormone and insulin-like growth factor 1 (IGF-1) signaling through their associated receptors in certain non-muscle tissues" if this is to do with non-muscles, then suggest move to the last paragraph
    • GH and IGF-1 are hormones, so they circulate in blood plasma to all tissues. I think the ref was discussing non-muscle tissues in that specific context, however I added a 2nd statement from a new clinical review of human research on GH and IGF-1 secretion in response to resistance exercise in humans after that sentence. That 2nd sentence does pertain to GH/IGF-1 signaling in skeletal muscle, so, for contextual relevance, I've deleted "non-muscle" from the first sentence; it now says "... in certain tissues". (edited in this diff) Seppi333 (Insert 2¢) 21:45, 13 December 2017 (UTC)[reply]
      • Thanks. I still see this sentence as confusing. The paragraph opens with "Several components of the signaling cascade that mediate the HMB-induced increase in human skeletal muscle protein synthesis " so I am mentally expecting a paragraph about HMB and skeletal muscle, yet they we have a statement about use in other tissues. I think this should be moved to one of the other paragraphs. --Tom (LT) (talk) 23:27, 14 December 2017 (UTC)[reply]
        • GH and IGF-1 trigger protein synthesis through mTORC1 phosphorylation upon binding to their respective tyrosine receptor kinases; that's the reason I included the original sentence in that paragraph. Those two statements don't really have any relevance to the topics discussed in the last 2 paragraphs in that section (i.e., the paragraphs about intramuscular cholesterol and myosatellite cell proliferation/differentiation/fusion), but it is somewhat relevant to the muscle protein breakdown paragraph. I've further revised the wording so that the discussion about the effect on GH/IGF-1 in rats is easier to understand, more general, and more relevant to the discussion about the effect on those substances in humans (diff).Seppi333 (Insert 2¢) 08:40, 16 December 2017 (UTC)[reply]
  • Image two - (1) doesn't specificially mention HMB; (2) silly question, but couldn't find it answered in article. IS HMB a protein?
  • "Based upon animal studies" -> could trim citations? (currently 4)
  • "may also facilitate the stabilization of " -> "may help stabilize"  Done
  • "It is not clear if long-term supplementation with HMB in humans produces a similar increase in growth hormone and IGF-1 " if we are comparing against rats this is difficult to interpret, because the rats were given it for a 1 month but humans were taking it long-erm
  • "Similar to L-leucine" (1) suggest reinclude ", of which HMB is a product"; (2) I do not think you need to include the note, and if you do I suggest remove "in one study" as that would be a primary source.
    1. I rephrased this as "Similar to HMB's metabolic precursor, L-leucine, ..." because stating that "HMB is a (metabolic) product of X" would really only make sense if that X was an enzyme, which has a substrate (e.g., leucine) and a product (e.g., HMB). I hope that wording is ok with you (edited in this diff). Seppi333 (Insert 2¢) 21:45, 13 December 2017 (UTC)[reply]
    2. The "in one study" clause in that sentence provides context for the statement, so I think removing it would make the context ambiguous. If you feel strongly about removing it, I will, but I don't think it would be helpful. In any event, since the sentences in all of the notes in the pharmacology section only discuss molecular biology, pharmacodynamic mechanisms, or pharmacokinetics without making any medical claims (at least not clinically relevant ones, depending upon how broadly the phrase "medical claims" is interpreted), the primary sources for those statements only really needs to satisfy the no OR restriction in WP:SCIRS#Respect primary sources and the other WP:SCIRS requirements (e.g., independent, up-to-date, peer-reviewed journal sources). Sourcing for similar content in articles on proteins, amino acids, and other biomolecules is typically governed by SCIRS because most endogenously synthesized compounds don't have medical uses. Seppi333 (Insert 2¢) 21:45, 13 December 2017 (UTC)[reply]
      1. I think the note should be removed, for the following reasons: I do not think it adds particularly to the paragraph or article; it relies on a single source, which makes it unreliable; it distracts from the flow of information; and I do not think it relates strongly enough to the sentence or paragraph to which it is attached to be included. --Tom (LT) (talk) 23:27, 14 December 2017 (UTC)[reply]
        The reliance on a single source is a valid issue, but I was actually planning on slightly expanding the note with coverage of a recently published primary source which examined the same parameters as the study which is cited in that note, but used HMB-Ca instead of HMB-FA. It found that the same effects occur with both HMB dosage forms and compared its results with the earlier primary source which is cited in the note. The purpose of the note is to specify an effect size for the increase in skeletal muscle protein synthesis (MPS) by HMB (i.e., it answers the question "how large is this increase?") in living humans; the entire paragraph in which the note is located only discusses how HMB affects MPS, so I don't understand why you think it has little relevance. Seppi333 (Insert 2¢) 21:11, 17 December 2017 (UTC)[reply]
        OK, I won't push this point. Can we move the note to the end of the sentence to improve readability? I will add a "" so that some of my ongoing concerns are noted in case somebody else mentions them in the FA. --Tom (LT) (talk) 23:20, 17 December 2017 (UTC)[reply]
         Done: Good idea – that's more consistent with the placement of the other notes in this section (diff). Seppi333 (Insert 2¢) 05:46, 18 December 2017 (UTC)[reply]

Chemistry

[edit]
β-Hydroxy β-methylbutyric acid – the conjugate acid
Chemical formula: C
5H
10O
3 (PubChem entry)
β-Hydroxy β-methylbutyrate – the conjugate base
Chemical formula: C
5H
9O−
3 (PubChem entry)
 Addressed

The comment below pertains to the discussion at FAC

  • "β-hydroxy β-methylbutyric acid" -> Mentioned lots of times here. Isn't this HMB? It would be best if, after the first mention in the lead, every other reference in the body uses HMB. I mention this only because in the second paragraph you do use that acronym and it's confusing because it implies they might be two different things
    • In this particular section (Chemistry), using the full term for the conjugate acid (β-hydroxy β-methylbutyric acid) and conjugate base (β-hydroxy β-methylbutyrate) when discussing the properties of one or comparing the two is necessary because they're two distinct compounds (see the images to the right and their chemical formulas - the base has one less hydrogen atom than the acid and a negative charge on one oxygen atom). I believe (NB: Boghog wrote the entire subsection on synthesis; @Boghog: if you can comment on this, that'd be helpful) that specifying that the product is the acid matters for the synthesis subsection since a particular synthesis method might never yield the conjugate base. Nonetheless, since the entire chemical synthesis subsection is discussing the conjugate acid, I just left the first mention of HMB as the expanded term for the acid and converted all other instances to "HMB" in that subsection (diff). Seppi333 (Insert 2¢) 07:56, 18 December 2017 (UTC)[reply]
  • Why have you used the initial acronym (which does not state "free acid form" when all the other sections use the full form of the word? I think acronyms in general tend to make things less readable
  • You surely do not need more than one citation for:
  • Suggest remove this unnecessary tidbit "(NaOCl, more commonly known as bleach)" and "(CO)" as the paragraph is already complicated enough
  • The whole 'chemical structure' paragraph. Why do you need two references per line for things such as what is the conjugate acid and what is the conjugate base?
    • One refs state the acid is the conjugate acid of the base, whereas the other ref states that the base is the conjugate base of the acid; hence, both refs are necessary to fully support the assertions in that sentence. Seppi333 (Insert 2¢) 21:17, 11 December 2017 (UTC)[reply]
  • "Synthesis" - am in favour putting on my simplification hat of renaming to "Creation" but acknowledge this may not be totally desired
  • Great images by the way
  • Suggest move the refractive index formula into a note, I am not sure how this adds to the text
    • I don't think it's useful information to most readers, but Nergaal demanded that the chemistry section be expanded at [7], so Boghog added it to include more information about its chemical properties. I'm not sure Nergaal would be happy with that being placed in a note at the next FAC if he chooses to comment again. Seppi333 (Insert 2¢) 21:17, 11 December 2017 (UTC)[reply]
      • OK. Well I will note that I don't think it's useful, is unnecessary jargon and excessively technical, and also we are not a manual (WP:NOT) and leave it at that - this can be discussed more in FA if other editors comment on it. --Tom (LT) (talk) 22:09, 12 December 2017 (UTC)[reply]
Detection in body fluids
  • "Endogenously synthesized HMB has been detected and quantified in several human biofluids " -> HMB created by the body has been found and measured in several human fluids" –  Done
  • "e average molar concentration of HMB has been quantified at 4.0 micromolar (μM) -> "The average concentration has been measured at 4.0 μm (micromolar)"
    • "4.0 micromolar (μM)" is the format specified by MOS:UNITNAMES for introducing units that readers are expected to not know. (Units unfamiliar to general readers should be presented as a name–symbol pair on first use, linking the unit name (Energies were originally 2.3 megaelectronvolts (MeV), but were eventually 6 MeV).)
  • Suggest change all "quantified" -> "measured" for readability –  Done
  • Suggest remove all the acronyms, as they are all used only once (including NMR, LC-MS, GC-MS, and even potentially CSF)

References

  1. ^ a b c "3-hydroxyisovaleric acid". Chemical Entities of Biological Interest. European Bioinformatics Institute. 23 October 2015. Retrieved 20 August 2016.
  2. ^ "3-Hydroxyisovaleric acid". HMDB Version 3.6. Human Metabolome Database. 11 February 2016. Retrieved 25 May 2016.
  3. ^ WO application 2015094925, White TO, "Stable liquid filled hard capsule comprising beta-hydroxy-beta-methylbutyric acid", published 25 June 2015, assigned to Capsugel Belgium Nv 
  4. ^ "Beta-Hydroxyisovaleric acid". ChemicalBook. Retrieved 20 August 2016.
  5. ^ 3-OH-isovaleric acid. Royal Society of Chemistry. Retrieved 10 August 2016. Experimental Boiling Point: ... 128 °C / 7 mm ...
    Experimental solubility:
    Soluble in water     {{cite encyclopedia}}: |work= ignored (help)

History

[edit]
  • No comments, easy to understand and fairly interesting

In general

[edit]
  • Excellent article you have clearly put a lot of effort into
  • Too many references - (1) should be trimmed if at all possible, especially when single facts have multiple references; (2) lead seems to have more references than the body for some things, this should surely be reversed
  • Some language used in the article is quite technical and could be simplified to enhance readability
    • Suggest you quickly run through the article and standardise all spellings of HMB to the acronym HMB and HMB-FA, as currently they alternate making this quite difficult to read at times
      • The only place in the article (as of today) where the expanded/full term was used, but the acronym could be used instead, was in the history section; I've updated that section accordingly (diff). The use of HMB-Ca and HMB-FA and the remaining uses of the expanded/full terms are in places where using the acronym "HMB" would not be appropriate since the text is referring specifically to one commercial formulation, the conjugate acid, or the conjugate base in those contexts. "HMB" refers to all of those collectively. Seppi333 (Insert 2¢) 07:18, 20 December 2017 (UTC)[reply]
        •  Edit: after reconsideration, I decided to standardize HMB-Ca and HMB-FA to HMB in the side effects section as well since the difference in the dose of HMB between HMB-Ca and HMB-FA is pretty small (diff). Almost all clinical studies used 3 g of either formulation anyway. Seppi333 (Insert 2¢) 23:34, 21 December 2017 (UTC)[reply]
          • Thanks. The article's readability has improved (in my eyes at least) throughout the review.
  • Images are excellent
  • Won't delve in to the sources used that much other than to say for posterity's sake that they will need a closer look in FA several of them are primary sources and small scale studies

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

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

Primary sources with a PMID # that were cited in this article – the sections in the body where these are cited are listed in parentheses:

  • PMID 18293016 – included in medical section, but doesn't support a medical claim - only comments on the adequancy of the study minus Removed
  1. PMID 24495238 – supports statements about concentrations in bovine milk and food fortification with HMB (Available forms, Detection in body fluids)
  2. PMID 26271627 – supports statements about presence in human milk and its concentration range (Detection in body fluids)
  3. PMID 26373270 – support its commercial availability and statements about its pharmacokinetics (Available uses, Pharmacokinetics)
  4. PMID 21918059 – support statements about its metabolic pathway (Biosynthesis)
  5. PMID 19211028 – supports which protein kinases, myogenic factors, or transcription factors mediate the effects that were identified in reviews of in vitro research, but which glossed over the details (Pharmacodynamics)
  6. PMID 27499494 – supports only the following sentence in a reference note: Since all T cells are CD3+, a measure of CD3+ cells is used as a general estimate of total T cells. (Special:permalink/814463242#cite_note-39)
  7. PMID 23551944 – supports statements about pharmacodynamics & concentration in blood plasma following oral ingestion (Pharmacodynamics, Detection in body fluids)
    • PMID 29097038 – not currently cited, but was planning to add this to the article to support statements in pharmacodynamics and detection in body fluid; this study is analogous to the one in the bullet immediately above.

Seppi333 (Insert 2¢) 00:02, 9 December 2017 (UTC)[reply]

COMMENT: Under the rubric of "less is more," I find it unnecessary and annoying that so many of the references include extended quotation of material from the abstracts or articles. Some exceeding 150 words and containing mention of references in the cited article. If the information is essential to the article it belongs in the article. If not, it does not belong anywhere. I've rarely seen reference bloat of this nature, and this is a particularly egregious example. David notMD (talk) 15:45, 12 December 2017 (UTC)[reply]

@David notMD: The extended quotes are there so that I don't need to constantly sift back through the refs during FAC when people challenge whether or not material is supported by a reference, which occurs at every FAC. I intend to censor all of the ref quotes to at most 5 sentences after a WP:V check is finished. I'm not going to censor them now though. Seppi333 (Insert 2¢) 17:57, 12 December 2017 (UTC)[reply]
Appreciate the explanation. Whenever I am trying to uplift an article to GA status, my workspace is strewn with printouts of abstracts and pages from PDFs of articles. I've yet to attempt a FA. NOTE: I do agree with the too-many-refs comment from the GA reviewer, but again, some of that probably in anticipation of FA submittal. David notMD (talk) 18:08, 12 December 2017 (UTC)[reply]

Conclusion

[edit]

Thanks for your patience, Seppi333. This is a great article that you've put a lot of effort into. With your many changes I feel the article has improved to meet GA criteria. I have one or two concerns that I feel we are at loggerheads here with and will pop on the article's talk page, but nothing that would mean this article shouldn't become a GA. Thanks for your responsiveness; Merry Christmas! --Tom (LT) (talk) 22:26, 25 December 2017 (UTC)[reply]

Thanks again for doing the GA review of this article Tom! I really appreciate all the time and effort you put into reviewing it; I think it was very constructive/helpful. Seppi333 (Insert 2¢) 22:30, 25 December 2017 (UTC)[reply]
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