Talk:Vitamin D/Archive 7

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D3 in plants? Yep

While there is no doubt thar fungi and yeasts use ergosterol for structure and thus make D2 when exposed to UV, yet at the same time it is also true that a few plants make 7-dehydrocholesterol, perhaps as a dedicated light sensor, and thus make D3 with the aid of UV-- just to show nature is complicated [1].

The following chapter link probably can be got to, by googling "vitamin d3 from plants", as it has internal brackets in it that keep it from being used directly:

http://www.dtu.dk/upload/fødevareinstituttet/food.dtu.dk/publikationer/2012/phd-thesis-rie_japelt[1].pdf

Bottom line: some soreheads need to work this out in their worldviews. Sorry! SBHarris 20:50, 11 February 2013 (UTC)

Milk

Milk is listed as a source in both the Vitamin D and Forms sections, but not in the sources section. Is this a deliberate omission (and if so why?) or an oversight? AFAIK milk provides around 400IU/litre, but I have no reliable source. Can someone help me out here? 87.115.6.214 (talk) 14:45, 12 November 2012 (UTC)

Milk has amounts of D that are extremely variable unless radiated with UV or fortified with D3 to some uniform number. It depends on what the cows ate, how much UV they got, and so on. That's why neat little figures can't be given. SBHarris 04:06, 12 February 2013 (UTC)

Second heading paragraph - original content??

There is only one citation in the second paragraph, and I just finished reading the entire paper by George Wolf. The majority of the second paragraph is content that is not found in this paper. 64.207.224.18 (talk) 16:37, 15 March 2013 (UTC)

I think you mean the second paragraph of the lead (the text at the top of the article). If so, please remember that the lead is just an intro that summarizes what is in the body of the article. You should find everything sourced in the body of the article. (sometimes we do ask that statements in the lead be sourced, if they are controversial or are summaries that amount to "original research" and cannot stand without sourcing. If you don't find sources in the body, then it is reasonable to complain, or better, put a "citation needed" tag in the body of the article, or even better, see if you can find sources and add them... Jytdog (talk) 17:16, 15 March 2013 (UTC)

Sorry about that, yes, the lead. Got it. Thanks! 64.207.224.18 (talk) 19:34, 15 March 2013 (UTC)

Subscript?

In this article the various forms of vitamin D are sometimes written subscript (D₂, D₃) and sometimes not (D2, D3). I can't help but wonder: does this donote different compounds or is it just a typo? Project Osprey (talk) 11:22, 25 April 2013 (UTC)

Resources

I feel that this article needs incorportation of the information on oral and intravenous Vitamin D supplementation during its deficiency. The role of a single dose of Vitamin D intramuscular depot preparation needs to be included. The following reference would prove useful in this regard.

• Einarsdóttir K, Preen DB, Clay TD, Kiely L, Holman CD, Cohen LD. "Effect of a single 'megadose' intramuscular vitamin D (600,000 IU) injection on vitamin D concentrations and bone mineral density following biliopancreatic diversion surgery". doi:10.1007/s11695-009-0024-3. PMID 19949888. {{cite journal}}: Cite journal requires |journal= (help)CS1 maint: multiple names: authors list (link)

Diptanshu^Talk 17:37, 29 June 2013 (UTC)

That source is subpar under MEDRS - you should find a review in the medical literature that discusses this. If you do use it (and you should not), whatever content you add to the article must be strictly limited to what the article says, and go no further. Jytdog (talk) 17:59, 29 June 2013 (UTC)

Vitamin D and hypersensitivity reactions

This article mentions the connection between vitamin D deficiency and asthma and MS. The type 1 diabetes article has similar speculation as to vitamin D deficiency being a probable risk factor, since type 1 diabetes occurs most frequently in Scandinavia. I wonder if that could be included here, or if these 3 related disorders should be mentioned together, since they are all autoimmune diseases and there may be a common link. Alázhlis (talk) 18:35, 17 August 2013 (UTC)

Vitamin D Is Not At All A Vitamin But A Hormone

So I was listening to a lecture on the history and function of Vitamin D on Youtube and the lecturer said that Vitamin D is not a vitamin, but it was thought that it was because mushroom sourced D2 cured rickets. However, Vitamin D has no nutritional value and functions solely as a hormone. Nowhere in the article it is specifically mentioned. Its kind of "beaten around the bush". Would anyone have any objections to changing the article to reflect that Vit D is not a vitamin but a hormone?173.180.7.3 (talk) 12:53, 25 July 2013 (UTC)BeeCier

Vitamin D is a hormone that when light exposure is limiting also becomes a vitamin because insufficient quantities are synthesized. So Vitamin D is both hormone and under certain conditions, also a vitamin. Boghog (talk) 17:07, 25 July 2013 (UTC)

Ok, I am not sure if you made a mistake in your grammar or its something else. But from what I understood about Vitamin D and even from the wiki vitamin article you linked to, a vitamin has to have a nutritional function and Vitamin D has none. Its just a hormone controlling calcium and phosphate ion concentrations. Therefore Vitamin D is not at all a vitamin.173.180.7.3 (talk) 10:41, 14 September 2013 (UTC)BeeCier

There is no mistake. Vitamin D under certain conditions is a vitamin. Please keep in mind that vitamin D does a lot more than control calcium and phosphate ion concentrations. Large numbers of genes are regulated by vitamin D acting through the vitamin D receptor. Furthermore vitamin D is essential in human development (and not just bones, other tissues as well). It is also essential for proper functioning of the immune system. A nutrient is defined as any chemical that is required for an organism to live and grow. When light is limiting, humans cannot synthesize enough vitamin D for their needs, and hence vitamin D becomes an essential nutrient and therefore by definition, a vitamin. Boghog (talk) 12:05, 14 September 2013 (UTC)

This definition of a vitamin is somewhat clearer:

Vitamins: organic substances that are required in small amounts for maintenance and growth, but which cannot be manufactured by the human body.
— Medical Subject Headings

Vitamin D, when light is limiting, clearly fits the above definition of a vitamin. Boghog (talk) 12:18, 14 September 2013 (UTC)

Just to be absolutely clear, with sunlight, the human body can manufacture vitamin D and under these conditions, vitamin D is not a vitamin. Without sunlight, the human body cannot manufacture vitamin D and under these conditions, vitamin D becomes a vitamin. Boghog (talk) 18:22, 14 September 2013 (UTC)

summary content on supplementation

User:‎Rayabhari noticed that we had duplicate text in the lead of the Effects section and below, in the Supplementation section. He/she deleted it from the lede of the Effects section with an edit note saying "https://wiki.riteme.site/w/index.php?title=Vitamin_D&curid=24998247&diff=577720952&oldid=577317087" in this dif. I am not sure how the duplication happened, but the content is indeed (and i think originally was written as) the lede for the effects section -- the effects being discussed are exactly the effects of taking supplements - I am not sure how the separate Supplements section came to be. So, I made an edit that chose the other route -- I put the content into the lede of the Effects section and deleted the Supplement section, with edit note explaining that. We do agree that the content should appear only once! Let's discuss where? Jytdog (talk) 15:38, 18 October 2013 (UTC)

animals appear to NOT obtain vitamin D through grooming

according to this study here: http://www.ncbi.nlm.nih.gov/pubmed/20412916 the section that mentions that "In {...} fur-bearing mammals, vitamin D is generated from the oily secretions of the skin deposited onto the feathers or fur and is obtained orally during grooming.[120]" should probably be revisited... — Preceding unsigned comment added by 96.63.2.100 (talk) 20:35, 30 August 2013 (UTC)

Agreed. I'm researching and writing about vitamin D and it appears to me that the oily secretions story for furry mammals is unsupported. Also, the reference for the oral grooming factoid in this entry is an anthropological reference. I'd want to see the actual source of the information cited. For example, as recently as 2010, researchers say they are not sure how D3 is synthesized by fur bearing mammals. http://www.ncbi.nlm.nih.gov/pubmed/20412916 Whoops! Just realized this is the same reference cited above.

Eperotao (talk) 17:35, 22 January 2014 (UTC)

Primary sources

Have removed these edits[2] as we do not refute recent high quality secondary sources with old primary sources and popular press books per WP:MEDRS. Doc James (talk · contribs · email) (if I write on your page reply on mine) 08:06, 26 January 2014 (UTC)

Role of vitamin D in reducing the risk of various cancers and increasing survival after its development

I am considering the following material as an edit/extension of this article on the role of vitamin D in relation to cancer. I would appreciate your comments on this material.

References used in support of the statements in the text are given at the end. I am a beginner in suggesting content for Wikipedia, so I have not yet put them in the format that will be needed when it is time to make the actual edit to the main document. Jag8452 (talk) 21:42, 15 January 2014 (UTC)

Autier's December 6. 2013 review article "Vitamin D status and ill health: a systematic review" in Lancet Diabetes and Endocrinology, largely does not agree. So if you have not looked at that, I recommend it.

Eperotao (talk)

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There is considerable evidence that vitamin D reduces the risk and increases survival after development of many types of cancer. The ultraviolet-B (UVB)-vitamin D-cancer hypothesis was initially proposed by the brothers Cedric and Frank Garland after they saw the map of colon cancer mortality rates in the United States in 1974 as beginning graduate students at the Johns Hopkins School of Public Health [Garland, 1980]. Rates were lowest in the Southwest and highest in the Northeast. Annual solar radiation doses are highest in the Southwest and lowest in the Northeast. They chose vitamin D to explain the link since vitamin D production is the most important physiological effect of UVB irradiance. Since then, numerous geographical ecological studies have found strong inverse correlations between solar UVB doses and incidence and/or mortality rates for many types of cancer including bladder, breast, colon, endometrial, esophageal, gallbladder, lung, ovarian, pancreatic, rectal, stomach, vulvar cancer, Hodgkin’s lymphoma, non-Hodgkin’s lymphoma, and leukemia [Grant and Garland, 2006; Moukayed and Grant, 2013]. A cohort study confirmed that solar UVB is protective against several types of cancer [Lin, 2012], and solar UVB is the primary source of vitamin D for most people [Hypponen, 2007], so these ecological studies can be considered good evidence that vitamin D reduces risk of cancer.

Observational studies of cancer incidence with respect to serum 25-hydroxyvitamin D [25(OH)D] levels also support the role of vitamin D in reducing risk of cancer. 25(OH)D is the vitamin D metabolite used to determine vitamin D blood level. The strongest evidence from observational studies is for colorectal cancer [Grant, 2011]. Strong evidence has also been found for breast cancer from case-control studies (blood drawn at time of cancer diagnosis) [Grant, 2011, 2012].

Observational studies have also found that those with higher serum 25(OH)D levels at time of cancer diagnosis live longer than those with lower serum 25(OH)D levels [Grant and Peiris, 2012].

The mechanisms whereby vitamin D reduces the risk of cancer are well known and include such effects as controlling cellular differentiation, proliferation and apoptosis, angiogenesis around tumors, and metastasis [Moukayed and Grant, 2013].

Whether some agent can be considered causally linked to a health outcome can be evaluated using Hill’s criteria for causality in a biological system. The criteria important for vitamin D and cancer include strength of association, consistent findings in different populations, temporality, biological gradient (dose-response relation, in this case the 25(OH)D level-cancer incidence rate), plausibility (mechanisms), experiment [e.g., randomized controlled trials (RCTs)], and analogy [Hill, 1965]. Several types of cancer satisfy Hill’s criteria for vitamin D [Moukayed and Grant, 2013].

However, as noted, the weakest criterion is that of experiment. There have been, however, two vitamin D RCTs that found a beneficial effect on cancer incidence and one vitamin D supplementation trial that found a beneficial effect on diagnosed prostate cancer. The first RCT found a 77% reduction in all-cancer incidence rates between the ends of the first and fourth year for postmenopausal women with initial serum 25(OH)D levels of 30 ng/ml taking 1100 IU/d vitamin D3 and 1500 mg/d calcium [Lappe, 2007]. Those taking 1500 mg/d calcium had a 44% reduced risk of all-cancer incidence, so nearly half of the effect of vitamin D3 plus calcium could be attributed to vitamin D. The second study was a reanalysis of the Women’s Health Initiative. It found “In 15,646 women (43%) who were not taking personal calcium or vitamin D supplements at randomization, CaD significantly decreased the risk of total, breast, and invasive breast cancers by 14-20% and nonsignificantly reduced the risk of colorectal cancer by 17%. In women taking personal calcium or vitamin D supplements, CaD did not alter cancer risk (HR: 1.06-1.26).” [Bolland, 2011]. The reason why there have been so few successful vitamin D RCTs for cancer or other health outcomes for that matter is that most such RCTs have been based on the pharmaceutical drug model, not the nutritional model. In the pharmaceutical drug model, it is assumed that the trial provides the only source of the agent and that there is a linear dose-response relation. However, there are other sources of vitamin D and the range of beneficial effect is limited so that if those representing the average population are given 400-1000 IU/d vitamin D3, little effect can be expected [Lappe, 2012]. New guidelines on how to conduct nutritional compound RCTs have been proposed [Heaney 2014].

Bolland MJ, Grey A, Gamble GD, Reid IR. Calcium and vitamin D supplements and health outcomes: a reanalysis of the Women's Health Initiative (WHI) limited-access data set. Am J Clin Nutr. 2011 Oct;94(4):1144-9.

Garland CF, Garland FC. Do sunlight and vitamin D reduce the likelihood of colon cancer? Int J Epidemiol. 1980 Sep;9(3):227-31.

Grant WB, Garland CF. The association of solar ultraviolet B (UVB) with reducing risk of cancer: multifactorial ecologic analysis of geographic variation in age-adjusted cancer mortality rates. Anticancer Res. 2006 Jul-Aug;26(4A):2687-99.

Grant WB, Peiris AN. Differences in vitamin D status may account for unexplained disparities in cancer survival rates between African and White Americans. Dermatoendocrinol. 2012;4(2):85-94.

Grant WB. A review of the evidence regarding the solar ultraviolet-B–vitamin D–cancer hypothesis. Standardy Medyczne/Pediatria. 2012;9:610-9. http://www.vitamindwiki.com/A+review+of+the+evidence+regarding+the+solar+ultraviolet-B-vitamin+D-cancer+hypothesis+-+Oct+2012

Grant WB. Effect of interval between serum draw and follow-up period on relative risk of cancer incidence with respect to 25-hydroxyvitamin D level; implications for meta-analyses and setting vitamin D guidelines. Dermatoendocrinol. 2011;3(3):199-204.

Heaney RP. Guidelines for optimizing design and analysis of clinical studies of nutrient effects. Nutr Rev. 2014 Jan;72(1):48-54.

Hill AB. The environment and disease: Association or causation? Proc R Soc Med. 1965 May;58:295-300. Hyppönen E, Power C. Hypovitaminosis D in British adults at age 45 y: nationwide cohort study of dietary and lifestyle predictors. Am J Clin Nutr. 2007 Mar;85(3):860-8.

Lappe JM, Heaney RP. Why randomized controlled trials of calcium and vitamin D sometimes fail. Dermatoendocrin. 2012;4(2):95-100.

Lappe JM, Travers-Gustafson D, Davies KM, Recker RR, Heaney RP. Vitamin D and calcium supplementation reduces cancer risk: results of a randomized trial. Am J Clin Nutr. 2007 Jun;85(6):1586-91.

Lin SW, Wheeler DC, Park Y, Cahoon EK, Hollenbeck AR, Freedman DM, Abnet CC. Prospective study of ultraviolet radiation exposure and risk of cancer in the U.S. Int J Cancer. 2012 Sep 15;131(6):E1015-23.

Moukayed M, Grant WB. Molecular link between vitamin D and cancer prevention. Nutrients. 2013;5(10):3993-4023. Jag8452 (talk) 21:42, 15 January 2014 (UTC)

Our biomedical content needs to be in line with the guidance at WP:MEDRS; we can't use old and/or primary studies but need to try and use recent secondary ones. At the moment we're citing PMID 24308073, a 2013 systematic evidence review, which concludes vitamin D supplementation is not likely to have any effect on cancer. An earlier 2011 review (PMID 21835895) found that serious deficiency might be bad, but there was not enough evidence to recommend supplementation. Are there any strong secondary sources which complicate this picture? Alexbrn ^{talk|contribs|COI} 22:02, 15 January 2014 (UTC)

Response. Here are the guidelines.

“The best evidence comes primarily from meta-analyses of randomized controlled trials (RCTs).[2] Systematic reviews of bodies of literature of overall good quality and consistency addressing the specific recommendation have less reliability when they include non-randomized studies.[3] Narrative reviews can help establish the context of evidence quality. Roughly in descending order of quality, lower-quality evidence in medical research comes from individual RCTs; other controlled studies; quasi-experimental studies; non-experimental, observational studies, such as cohort studies and case control studies, followed by cross-sectional studies (surveys), and other correlation studies such as ecological studies; and non-evidence-based expert opinion or clinical experience. Case reports, whether in the popular press or a peer reviewed medical journal, are a form of anecdote and generally fall below the minimum requirements of reliable medical sources.”

Thus, there are many types of evidence that are permitted. In fact, for vitamin D and both immune system and multiple sclerosis, both ecological and observational studies were cited.

Furthermore, the issues regarding vitamin D can be considered under two categories: health and medicine. Under health is what is known about disease conditions with respect to sources of vitamin D such as solar UVB as well as serum 25(OH)D levels. Under medicine is whether vitamin D supplementation can reduce the risk of disease or more importantly treat disease. All types of studies can be used for health; randomized controlled trials are preferred for medicine.Jag8452 (talk) 17:23, 29 January 2014 (UTC)

Likewise, check out this very recent review article. http://www.ncbi.nlm.nih.gov/pubmed/22701014

Eperotao (talk)

Response: these two papers reviewed vitamin D RCTs and found them lacking.

Autier P, Boniol M, Pizot C, Mullie, P. Vitamin D status and ill health: a systematic review. Lancet Diabetes & Endocrinology. Jan. 2014;2(1):76-89.

Bolland MJ, Grey A, Gamble GD, Reid IR. The effect of vitamin D supplementation on skeletal, vascular, or cancer outcomes: a trial sequential meta-analysis. Lancet Diabetes & Endocrinology, Early Online Publication 24 January 2014. doi:10.1016/S2213-8587(13)70212-2. http://download.thelancet.com/pdfs/journals/landia/PIIS2213858713702122.pdf

The problem with such RCTs is that they were designed on the pharmaceutical drug model in which the trial provides the only source of the agent and there is a linear dose-response relation. These papers discuss the problems with that approach and show how to conduct nutritional RCTs properly.

Biesalski HK, Aggett PJ, Anton R, Bernstein PS, Blumberg J, Heaney RP, Henry J, Nolan JM, Richardson DP, van Ommen B, Witkamp RF, Rijkers GT, Zöllner I. 26th Hohenheim Consensus Conference, September 11, 2010 Scientific substantiation of health claims: evidence-based nutrition. Nutrition. 2011 Oct;27(10 Suppl):S1-20.

Heaney RP. Guidelines for optimizing design and analysis of clinical studies of nutrient effects. Nutr Rev. 2013 Dec 13. doi: 10.1111/nure.12090. [Epub ahead of print]

Lappe JM, Heaney RP. Why randomized controlled trials of calcium and vitamin D sometimes fail. Dermatoendocrin. 2012;4(2):95-100.

Michels AJ, Frei B. Myths, artifacts, and fatal flaws: identifying limitations and opportunities in vitamin C research. Nutrients. 2013 Dec 16;5(12):5161-92.

Moser U. Vitamins - wrong approaches. Int J Vitam Nutr Res. 2012 Oct;82(5):327-32. Jag8452 (talk) 17:23, 29 January 2014 (UTC)

Vitamin D supplementation has a beneficial effect on many diseases including cancer, however this is not necessarily going to show up in RCTs. It is unfortunate that negative results from RCTs are being used by the medical community to argue that vitamin D supplements do not have any effect and that this is then used to argue for low calcidiol levels of 50 nmol/l as the healthy norm. Enforcing WP:MEDRS thus has the effect of dumbing down this coverage of this subject on Wikipedia.

Any fool with half a brain should know that exercise is such a huge confounding factor that you should first study the correlations and the causal links of vitamin D supplementation and exercise performance. There is evidence that vitamin D does play a role in athletic performance, a recent study found that higher vitamin D levels in expecting mothers is positively correlated with better muscle development in babies. Assuming that there is indeed such a link, then any study that doesn't find a direct link between, say, vitamin D supplementation and heart disease cannot be used to conclude that vitamin D supplementation is of no use to prevent heart disease. Obviously, you can dramatically reduce your risk of getting heart disease by exercising a lot more. Vitamin D can then be used to help to do that (many people have tried but failed to stick to a regular exercise routine, low vitamin D levels could well be a factor here). That any reduced risk in heart disese then comes from that increased level of exercise and not from vitamin D itself is then neither here nor there. In fact, vitamin D itself could even have negative effects on the cardiovascular system and it would still be beneficial to use vitamin D supplements to improve cardiovascular health, provided that these negative effects are not too large. Count Iblis (talk) 23:33, 24 January 2014 (UTC)

We are not here to have our own opinions. We are here to simply summarize the best available evidence. If the meta analysis conclude there is no benefit we state there is no benefit.

Of course an RCT will show benefit if there is one. The person either gets a vit D pill or a placebo. If the vit D pill is no better than placebo it does not work and is a waste of time / money. This is how medical science works. An RCT deals with all the factors you mention. Doc James (talk · contribs · email) (if I write on your page reply on mine) 23:56, 24 January 2014 (UTC)

RCTs only measure effects over a few years, not decades. If someone does not get clogged arteries at age 70 because exercising outside from the age of 20 onwards led to higher calcidiol levels which fed back into his fitness levels allowing him to exercise until old age, then an intervention study at age 65 for 5 years that administers vitamin D or a placebo will not show anything significant. This does tell you something useful, i.e. that vitamin D is not a drug that will by itself prevent clogged arteries, but you can't then go on to conclude that vitamin D has no role to play in preventing heart disease. The relevant RCT to perform is to measure exercise tolerance in young healthy people as a function of calcidiol levels. Count Iblis (talk) 10:00, 25 January 2014 (UTC)

We assume something does not work until someone proves it does, not the other way around. Doc James (talk · contribs · email) (if I write on your page reply on mine) 10:31, 25 January 2014 (UTC)

There have been positive results published in the medical literature about the relation between vitamin D levels and muscle development and physical performance. Count Iblis (talk) 11:34, 25 January 2014 (UTC)

Correlation is not causation. The greater the number of churches in the town the more bars are present in the town. This does not mean that churches cause bars or vice versa. A third factor causes both (the size of the town).

The same could be the case with vit D. Doc James (talk · contribs · email) (if I write on your page reply on mine) 11:56, 25 January 2014 (UTC)

I fully agree, but vitamin D is not some newly invented medicine for which one would be justified to make the a priori assumption that it has no useful biological role to play in the body. If that were the case, then one will get good results using the traditional logic, i.e. assume the null hypothesis that the drug does not work and let the evidence prove beyond any doubt that for certain diseases you get better outcomes when using it. The null hypothesis for vitamin D should be that you need 5000 IU per day and have calcidiol levels of around 120 nmol/l, simply because indiginous people in Africa (e.g. the Maasai) have such levels. That we don't know what use it is should be irrelevant, because we lack knowledge. Had we had full knowledge about this, then not knowing what possible use vitamin D at higher levels has would count as evidence against these higher levels, but that's not the case. Count Iblis (talk) 09:53, 26 January 2014 (UTC)

No supplementation is the default. Evidence is required to justify supplementation. Doc James (talk · contribs · email) (if I write on your page reply on mine) 10:06, 26 January 2014 (UTC)

Yes, but then your recent ancestors did not sit in the office all day long. Living according to the modern lifestyle amounts to swallowing an "anti-vitamin D pill". Count Iblis (talk) 17:31, 27 January 2014 (UTC)

Comment: The understanding of the role of vitamin D in risk of disease should be understood before considering supplementation. This is where ecological and observational studies and laboratory studies of mechanisms come in to play. Jag8452 (talk) 17:23, 29 January 2014 (UTC)

Evidence is required to justify supplementation or any intervention. That is how evidence-based medicine works, which is what Wikipedia's health-related content is based on. Jytdog (talk) 17:48, 27 January 2014 (UTC)

But I guess you do see the problem here where a gradual shift in society has imposed changes in the diet, time we spend sleeping, exercise levels, UV irradiation of the skin etc. etc. Those changes were imposed on us without any evaluation based on "evidence-based medicine". Count Iblis (talk) 22:41, 27 January 2014 (UTC)

you are begging the question. there are many great theories out there, but the only way we know if an intervention works, is by testing it in a clinical trial. once we know it works, it can be recommended. Are you unaware of the SELECT trial? It was meant to show that vitamin E and selenium would prevent cancer (which many people were convinced was braindead obvious based on the antioxidant activity of these compounds and the clear relationship shown in cells and animals between oxidative damaage and cancer, and epidemeological evidence showing deficits in those compounds in cancer patients, and which was considered so low risk that the NIH funded the clinical trial) but it showed the opposite - a slight increase in cancer risk. all the great theories in the world mean nothing when it comes to human biology. we need clinical evidence to be sure of anything. 23:22, 27 January 2014 (UTC)

I agree, but in some cases you don't know what to look for. In case of vitamin E, you could have argued that large dosages were never part of the human diet, so taking large dosages is unnatural and it is therefore appropriate to demand results from clinical trials that prove that this works for certain diseases. The prior assumption that it does nothing or may be harmful is then fully justified. But if some substance X was until very recently a normal part of the diet and that substance is no longer part of the human diet (for reasons other than health reasons), then it would be unreasonable to demand that a clinical trial first prove that it works against some disease before it can be put back. We wouldn't know what to look for, if it were to work against cancer, that may not be easily measurable (clinical trials need to have well defined endpoints, you can't just start one look at the results to see what it might be possibly effective for as that would make the results worthless from a statistical point of view). For all we know, it could help to prevent depression while everyone is looking at heart disease and cancer! Count Iblis (talk) 09:59, 28 January 2014 (UTC)

Hi Count. I am glad we agree! I completely hear you on the difficulty of planning clinical trials, especially for something like fundamental like vitamin supplementation. However as I understand it we are discussing vitamin D supplementation for a specific purpose - namely to prevent cancer and improve outcomes after diagnosis. Those are testable hypotheses. Jytdog (talk) 11:41, 28 January 2014 (UTC)

Comment: A problem with the SELECT trial of vitamin E was that alpha-tocopherol was used. There are several forms of tocopherol and tocotrienol and use of only one is not effective since the body has receptors for many forms of vitamin D.

Cardenas E, Ghosh R. Vitamin E: a dark horse at the crossroad of cancer management. Biochem Pharmacol. 2013 Oct 1;86(7):845-52. http://www.ncbi.nlm.nih.gov/pubmed/23919929

There are two forms of vitamin D, D2 (ergocalciferol) and D3 (cholecalciferol). D3 is what humans make in their skin; D2 is made by fungi and mushrooms. D2 is less effective than D3, but has been used in a number of RCTs.

Nicastro HL, Dunn BK. Selenium and prostate cancer prevention: insights from the selenium and vitamin E cancer prevention trial (SELECT). Nutrients. 2013 Apr 3;5(4):1122-48. doi: 10.3390/nu5041122.

Abstract The Selenium and Vitamin E Cancer Prevention Trial (SELECT) was conducted to assess the efficacy of selenium and vitamin E alone, and in combination, on the incidence of prostate cancer. This randomized, double-blind, placebo-controlled, 2 × 2 factorial design clinical trial found that neither selenium nor vitamin E reduced the incidence of prostate cancer after seven years and that vitamin E was associated with a 17% increased risk of prostate cancer compared to placebo. The null result was surprising given the strong preclinical and clinical evidence suggesting chemopreventive activity of selenium. Potential explanations for the null findings include the agent formulation and dose, the characteristics of the cohort, and the study design. It is likely that only specific subpopulations may benefit from selenium supplementation; therefore, future studies should consider the baseline selenium status of the participants, age of the cohort, and genotype of specific selenoproteins, among other characteristics, in order to determine the activity of selenium in cancer prevention.

Thus, the SELECT trial underscores the difficulty of conducting randomized controlled trials, which supports the idea that ecological, observational, and laboratory studies should also be considered.

Comment: An alternate approach to ascertaining causality is through consideration of Hill’s criteria for causality.Jag8452 (talk) 19:07, 29 January 2014 (UTC)

It seems to me that the role of Wikipedia is to present the best information on any topic, not just that information that satisfies some narrow criteria. Readers of Wikipedia should be considered intelligent enough that they can evaluate the information provided. Thus, if they are told that randomized controlled trials are considered the strongest evidence but that strong trials have not yet been conducted although strong evidence is available from ecological, observational, and laboratory studies, they should be able to weigh the evidence and act accordingly.Jag8452 (talk) 17:23, 29 January 2014 (UTC)

Kinda... kinda not, some definitely not. Hard to understand exactly what you mean. If the "strong evidence" judgement you cite is the editor's own judgement, that would be "original research" which we do not allow here under WP:OR and see especially WP:SYN. If the consensus in the field, as expressed in a high-quality review article, is that "evidence from ecological etc studies is that X may be effective for Y, but RCTs have not shown efficacy and have shown increased risk; further trials would be necessary to prove safety and efficacy" that is absolutely fine to say, citing that review. The "definitely not" part, is the last bit you wrote...Wikipedia does not give medical advice and we explictly advise people NOT to act on what they read here. See WP:MEDICAL and also WP:NOTMANUAL. That said, people do come here looking for information and we have an obligation to provide readers with information based on the consensus in the given field. Jytdog (talk) 16:09, 30 January 2014 (UTC)

Wording

These changes add to much detail to some of the points. For example we do not need "of 17 studies published in English from 1966 to July 2009)" [3] Also we typically list newer reviews first. We do not add the statement generally that "more studies are ongoing". Also none significant changes or no change in English. Doc James (talk · contribs · email) (if I write on your page reply on mine) 05:19, 1 February 2014 (UTC)

So can you work on that instead of just reverting to that state that we all agree is unacceptable? Dicklyon (talk) 05:31, 1 February 2014 (UTC)

Was going to but we had a number of edit conflicts. Doc James (talk · contribs · email) (if I write on your page reply on mine) 05:39, 1 February 2014 (UTC)

NPOV

Why do people have such a hard time realizing that WP:NPOV is the relevant guideline about including multiple points of view with appropriate amounts of weight? ("Editing from a neutral point of view (NPOV) means representing fairly, proportionately, and, as far as possible, without bias, all of the significant views that have been published by reliable sources on a topic.") The squabbles above, and the revert of my attempt to improve coverage, suggest a child-like side-taking behavior that will not get us to a reasonable resolution. Dicklyon (talk) 18:02, 30 January 2014 (UTC)

We do not use old studies to refute new one. We use evidence from the last 3-5 years when avaliable per WP:MEDRS. Doc James (talk · contribs · email) (if I write on your page reply on mine) 18:22, 30 January 2014 (UTC)

Dick I know you have been around a long time but health-related articles are different from other wikipedia content in two ways: the basic science (biology) is much less well understood than the science underlying the IT industry and so the technology (in this case medicine and diagnostics) is much messier; 2) a lot of people have a lot of opinions, many of which are flakey. We therefore very much rely on WP:MEDRS to guide us on what sources are appropriate and how to build content with them - without MEDRS every quack treatment out there could claim a place in wikipedia on equal par with the medical consensus. The strong element in NPOV concerning WP:WEIGHT (appropriate weight does not mean equal weight and sometimes means no presence at all) becomes very important for keeping pseudoscience out of Wikipedia's health content. Claims that dietary supplements have any health effect (outside of avoiding deficiency diseases like rickets) are generally pretty quacky (there are a few very clear exceptions to that, like the benefit of folic acid during pregnancy). But nothing childish is going on here. Jytdog (talk) 19:02, 30 January 2014 (UTC)

There's certainly nothing in what I restored that purports to refute any newer study. It pretty much says that the newer study does not support the ones from a few years ago. This censoring of a complex debate by one recent publication, and shortening the section to be content free, is ridiculous. Dicklyon (talk) 21:06, 30 January 2014 (UTC)

You're edit warring very bad information into the article. The newer source is very strong, and notes it is in agreement with another strong source. That is the state of knowledge we should be relaying and not complicating the issue with lesser sources, especially flaming quackery (the Hollick book). It it also bad to say "the current medical consensus is that ..." as this implies it is provisional. Alexbrn ^{talk|contribs|COI} 21:15, 30 January 2014 (UTC)

Dick, do you know what is complex? Trying to have an authentic conversation with somebody who is calling you ridiculous and a "censor". If you don't come to Talk with an open mind, the "D" in BRD is pretty pointless (or one could say "content-free" :) ). Can we really talk, or do you just want to insult people? Real question. If the answer is that you want to talk, would you please address what I wrote above? Thanks. 21:20, 30 January 2014 (UTC)

I didn't call anyone ridiculous or a censor. I said the censoring ridiculous. It's about the edits, not the editors. The WP:MEDRS guideline is written to support the kind of censorship, to some extent; I get that. But it's still ridiculous to replace a section about a range of possibilities with one that says nothing here, move along. Dicklyon (talk) 00:12, 31 January 2014 (UTC)

Besides that, the conclusion quoted from the source is ridiculous on its face: "The simplest overall interpretation of the vitamin D and calcium results is that there is likely no effect on CVD or cancer. Wang and colleagues, in another systematic review of this topic, came to the same conclusion." How can any set of experimental evidence support a conclusion that there is "likely no effect" of any chemical, much less one so closely related to the cholesterol that is generally accepted as having important effects? Did they really expect anyone to take that seriously? Couldn't they find a more plausible way to say that whatever the effect is, it's probably too small to show up in studies? When Einstein said theories should be as simple as possible, but no simpler, I expect he meant to exclude this sort of "simplest" interpretation. It may be simple, but it is almost certainly not true that there is "no effect", and for us to be repeating it is sort of nutty when there are other ways to consider the range of possible effects. Dicklyon (talk) 00:23, 31 January 2014 (UTC)

In addition, note how the quoted source mischaracterizes the Wang et al paper that they reference, which concludes "Evidence from limited data suggests that vitamin D supplements at moderate to high doses may reduce CVD risk." Dicklyon (talk) 00:33, 31 January 2014 (UTC)

I have no particular knowledge of vitamin D, and no axe to grind here, but the trivialization of the sources that I see is appalling. I started reading the Fortmann reference that's being used to say that there's "no effect". It's actually quite good, and this out-of-context quote completely misrepresents it. Has anyone read it? Or tried to report what it found? Is it not relevant that the medical community see the effect of vitamin D as very much an open question, and that there are numerous ongoing studies to try to pin down whether it has good or bad effects on CVD and cancer? Seems relevant to me. I can understand why people don't want to use a popular book as a source, but to not both the acknowledge the discussion of the ideas behind it is just nuts. Cut it out. Dicklyon (talk) 02:16, 31 January 2014 (UTC)

Hi Dick. Can you please stop asking questions that are slathered with assumptions of bad faith? That is a real request. In any case, please see figure 2 of the Wang study - they did find that calcium and Vitamin D had no effect, and this is exactly what the authors of the 2013 review say when they mention their own work and Wang's: "The simplest overall interpretation of the vitamin D and calcium results is that there is likely no effect on CVD or cancer. Wang and colleagues, in another systematic review of this topic, came to the same conclusion." You are right that Wang finds "Evidence from limited data suggests that vitamin D supplements at moderate to high doses may reduce CVD risk," (note that is Vitamin D alone) and the 2013 study agrees, saying (continuation of paragraph I just quoted) "The data suggest, however, that the effects of calcium on these endpoints may be different than the effects of vitamin D. Figure 4 shows the pooled analyses for all-cause mortality. There are only two vitamin D studies to pool, but together they show a trend toward lower mortality in the supplement groups (unadjusted RR, 0.94 [95% CI, 0.88 to 1.01]). In contrast, the point estimates for calcium are all greater than 1, though with large CIs. The lack of statistical significance makes this comparison speculative, but it does support the wisdom of conducting separate studies of calcium and vitamin D for the endpoints examined here." I think it reasonable to say something along the lines of: "Vitamin D supplementation may be useful in lowering the risk of death from cardiovascular disease but high quality clinical evidence is lacking and further study is needed." which it seems (to me) accords with both reviews Would you be satisfied with that? Jytdog (talk) 03:22, 31 January 2014 (UTC)

That would be a good start. What people have been putting has been a gross misrepresentation. I'm not saying it was for a bad-faith reason, just that it's ridiculous to defend something like that the way numerous editors have, while not allowing even a sentence to say that there might be an effect. You are right that the quoted bit was about the "and" of two things, but it was not presented here that way; it was a gross error that people were defending. Thanks for working on a start to a fix. Dicklyon (talk) 07:14, 31 January 2014 (UTC)

I don't think the new wording is good (especially if that is all there is), as it seems speculative - emphasizing the possibility while the source itself goes the other way by saying an effect is "unlikely" (not "no effect" as Dick keeps asserting it says), and also stating "Vitamin D and/or calcium supplementation also showed no overall effect on CVD, cancer, and mortality". It would be quite wrong to draw different conclusions based on our interpretation of the underlying data. We should not include meh wording like "further study is needed". Alexbrn ^{talk|contribs|COI} 07:51, 31 January 2014 (UTC)

I didn't "assert" that they said "no effect"; I merely reported that we quoted them saying "likely no effect", when "no effect" is actually a very unlikely possibility (and this on a question that was the wrong question to be talking about, as it turns out, which was vitamin d + calcium, but it was nevertheless a lame way for them to report that no effect was found). There's a huge difference between not finding any effect and concluding "likely no effect", which they seemed (in that line) to have missed; the rest of the paper was better, so why did we quote its most lame line? Dicklyon (talk) 22:36, 31 January 2014 (UTC)

Hi Alexbrn, please show where the 2013 review says "It is unlikely that taking vitamin D supplements has any effect on cardiovascular disease" (this is a statement about Vitamin D alone). I don't think you will find it. Would you please propose language that you are comfortable with, focused on Vitamin D alone? I am a big fan of being clear where there is ambiguity. As far as I can tell the 2013 review did not look at any additional studies on CV outcomes compared to the Wang study and I think both reviews found that Vitamin D may have an effect but further study is needed. Both found a weak positive signal in suboptimal studies, as far as I can see. Hence my proposed statement. I am interested in seeing yours. Thanks! Jytdog (talk) 14:03, 31 January 2014 (UTC)

We have "The simplest overall interpretation of the vitamin D and calcium results is that there is likely no effect on CVD or cancer" which, granted, is ambiguous; yet the "Results" section of the abstract has "Vitamin D and/or calcium supplementation also showed no overall effect on CVD, cancer, and mortality" (my bold) which clarifies; I'd be uneasy about leaning in the "positive" direction here when the article's narrative seems to be leaning quite hard the other way. I'm comfortable with the current wording. Perhaps appending "... even though some limited evidence has suggested otherwise" might be okay ... Alexbrn ^{talk|contribs|COI} 14:22, 31 January 2014 (UTC)

You don't have to "lean" if you report the findings faithfully. It may take more than one sentence. But the fact that some studies find positive results and that more studies are ongoing to find out more definitely needs to be in there. Dicklyon (talk) 22:36, 31 January 2014 (UTC)

Alexbrn you write ""The simplest overall interpretation of the vitamin D and calcium results is that there is likely no effect on CVD or cancer" which, granted, is ambiguous". This is not ambiguous. It is a very clear statement on the efficacy of Vitamin D and calcium, which is not under discussion. Please stop bringing it up. I just re-read the discussion section of the 2013 review. They very clearly say, more than once, that Vitamin D and calcium are very likely to have different effects and need to be studied separately to tease them apart. They specifically point readers to figure 4 ("The data suggest, however, that the effects of calcium on these endpoints may be different than the effects of vitamin D. Figure 4 shows the pooled analyses for all-cause mortality.") If you look at figure 4, you see very clearly that the vitamin D alone studies fall to the left of the effect line, the calcium-alone studies fall to the right, and the calcium + vitamin D studies fall to the left. They go on to say "There are only two vitamin D studies to pool, but together they show a trend toward lower mortality in the supplement groups (unadjusted RR, 0.94 [95% CI, 0.88 to 1.01]). In contrast, the point estimates for calcium are all greater than 1, though with large CIs. The lack of statistical significance makes this comparison speculative, but it does support the wisdom of conducting separate studies of calcium and vitamin D for the endpoints examined here." The problem with the 2013, is that they say nothing explicitly about Vitamin D and CVD. You are right that they say, in the abstract, "Vitamin D and/or calcium supplementation also showed no overall effect on CVD, cancer, and mortality." Anyway so here is where I end up. The 2013 review is very broad, and focuses on supplementation with multivitamins and with various individual supplements. The Wang study, on the other hand, is focused on "Vitamin D and calcium supplementation in prevention of cardiovascular events" as per its title. Since the 2013 study doesn't examine studies additional to those in 2013 review, I think it is reasonable to give the two articles at least equal weight -- I don't want to judge which set of authors is more important. That is why I came up with a statement between the two. I don't understand your rationale for giving more weight to the 2013 study, when it doesn't examine a different set of studies. Can you please justify that? Jytdog (talk) 03:07, 1 February 2014 (UTC)

Jytdog, the reason why I'm assigning the 2013 paper more weight is mostly because it's more recent and because the authors have evidently considered Wang. Since we have expert published conclusions based on Wang, we don't need to come up with our own. Alexbrn ^{talk|contribs|COI} 07:08, 1 February 2014 (UTC)

It's also important to examine what this "very clear statement" means. The ambiguity was in what the "and" meant; on looking at the source, it's not hard to figure out. But the statement about "likely no effect" is a perversion of the what the usual methods of statistical hypothesis testing is telling them. When they want to assess the evidence as to whether there is an effect, they make a "null hypothesis" that there is no effect. Then they run their stats, and conclude that there is not enough evidence to reject the null hypothesis, at their predetermined level of significant. This is all good and standard. But not being able to reject the null hypothesis is nowhere near supporting the claim that there is "likely no effect", which they say is the "simplest possible interpretation." This is just wrong. The simplest interpretation is actually that we don't have enough data to see what the effect is, if any. That's all one can ever say. So quoting this mistake was a real bad idea. Dicklyon (talk) 03:44, 1 February 2014 (UTC)

User:Jmh649 in today's round of edit warring among parties, why are you using the "calcium and vitamin D" content in this article? Real question. Thanks! Jytdog (talk) 05:21, 1 February 2014 (UTC)

Diff please. Doc James (talk · contribs · email) (if I write on your page reply on mine) 05:24, 1 February 2014 (UTC)

I think the problem is not so much the ref as it is your revert to the state that mischaracterizes the ref. Dicklyon (talk) 05:29, 1 February 2014 (UTC)

Bone health

I made some more fixes here. Based on this diff and this, I think we'll need to send Doc James (User:Jmh649) back to statistics class to learn how to interpret statements about hypothesis tests and statistical significance. In a sequence of edits he turns a reasonable characterization of what the source said into the gross misinterpretation "In those with osteoporosis there does not appear to be a decreased risk of fractures from vitamin D except maybe among those in care homes..." I changed it and quoted the source to back up the change. Dicklyon (talk) 05:29, 1 February 2014 (UTC)

Ref says "Vitamin D alone appears unlikely to be effective in preventing hip fracture (nine trials, 24,749 participants, RR 1.15, 95% CI 0.99 to 1.33), vertebral fracture (five trials, 9138 participants, RR 0.90, 95% CI 0.42 to 1.92) or any new fracture (10 trials, 25,016 participants, RR 1.01, 95% CI 0.93 to 1.09)." Content I added said "In those with osteoporosis there does not appear to be a decrease in fractures from vitamin D." [4] Overall summary of the paper is "Frail older people confined to institutions may sustain fewer hip fractures if given vitamin D with calcium. Vitamin D alone is unlikely to prevent fracture." And? Doc James (talk · contribs · email) (if I write on your page reply on mine) 05:35, 1 February 2014 (UTC)

Agree we need to also add a summary of "Vitamin D with calcium reduces hip fractures (eight trials, 46,658 participants, RR 0.84, 95% CI 0.73 to 0.96)." Doc James (talk · contribs · email) (if I write on your page reply on mine) 05:36, 1 February 2014 (UTC)

Anyway so in this edit you removed the bit about vit D alone. Modest is also greater than slightly.[5] Doc James (talk · contribs · email) (if I write on your page reply on mine) 05:41, 1 February 2014 (UTC)

OK, so maybe you can improve the language. I'm not a doctor and don't know your lingo. But I know that "except maybe among those in care homes" is not supported by the source, which consider only a two-way living arrangement split and specifically said, "Although subgroup analysis by residential status showed a significant reduction in hip fractures in people in institutional care, the difference between this and the community-dwelling subgroup was not significant (P = 0.15)." Dicklyon (talk) 05:50, 1 February 2014 (UTC)

What do you think "Although subgroup analysis by residential status showed a significant reduction in hip fractures in people in institutional care" means? Institutional care is a care home.Doc James (talk · contribs · email) (if I write on your page reply on mine) 05:52, 1 February 2014 (UTC)

Just because the institutional care showed a benefit and the difference with community-dwelling subgroup was no significant does not mean the community-dwelling subgroup also showed a benefit. Doc James (talk · contribs · email) (if I write on your page reply on mine) 06:22, 1 February 2014 (UTC)

Re-add

Propose we re-add "In those with osteoporosis, vitamin D alone, does not appear to decreased the risk of fractures" based on this 2009 Cochrane review [6] which states "Vitamin D alone appears unlikely to be effective in preventing hip fracture (nine trials, 24,749 participants, RR 1.15, 95% CI 0.99 to 1.33), vertebral fracture (five trials, 9138 participants, RR 0.90, 95% CI 0.42 to 1.92) or any new fracture (10 trials, 25,016 participants, RR 1.01, 95% CI 0.93 to 1.09)." Doc James (talk · contribs · email) (if I write on your page reply on mine) 07:28, 1 February 2014 (UTC)

Vit D and CVD

The 2010 Wang ref states "Results of secondary analyses in 8 randomized trials showed a slight but statistically nonsignificant reduction in CVD risk (pooled relative risk, 0.90 [95% CI, 0.77 to 1.05])"[7] So this is turned into " concluded that vitamin D supplements at moderate to high doses may reduce CVD risk" No significant change is why the 2013 review states that the 2010 review agrees. Doc James (talk · contribs · email) (if I write on your page reply on mine) 05:49, 1 February 2014 (UTC)

First, this is not the subject on which Fortmann et al claimed Wang et al agree. Second, they did not agree, as far as I can tell, but that neither here nor there since it's not the topic (that was on Vitamin D plus calcium). On the vitamin D question, Wang had "Evidence from limited data suggests that vitamin D supplements at moderate to high doses may reduce CVD risk, whereas calcium supplements seem to have minimal cardiovascular effects. Further research is needed to elucidate the role of these supplements in CVD prevention," which is the quote that I had added to the citation so that you'd know what the statement in the article was trying to represent. If I got it not quite right, work on it. Dicklyon (talk) 05:57, 1 February 2014 (UTC)

"limited data" means that the conclusions are tentative at best. The more significant point is that the change is "non-significant" Doc James (talk · contribs · email) (if I write on your page reply on mine) 06:18, 1 February 2014 (UTC)

Exactly. "Evidence from limited data suggests that vitamin D supplements at moderate to high doses may reduce CVD risk" is a statement of a tentative finding that is not yet statistically significant. Findings like these are what motivate ongoing tests. We should write it in a way that acknowledges the way people are going and why, not pretend that the issue is settled. Dicklyon (talk) 15:55, 1 February 2014 (UTC)

In medicine the conclusion is that "their is no evidence of benefit" until a statistically significant benefit has been shown.Doc James (talk · contribs · email) (if I write on your page reply on mine) 16:15, 1 February 2014 (UTC)

There's a new meta-analysis from Lancet Diabetes Endocrinol which makes this all moot anyway. I have used it to update the article. Alexbrn ^{talk|contribs|COI} 17:06, 1 February 2014 (UTC)

The way I read WP:MEDRS, it would not be appropriate to censor all previous recent studies by a Jan 2014 study. Why not just add the info without removing other info? Dicklyon (talk) 17:36, 1 February 2014 (UTC)

User:Dicklyon in your edit note today you wrote "Alex, please restrain your censorship reflex and try to work this out on the talk page; I did not pick these refs have been in the article long before I looked at it." Please note that in areas of active research like this, older reviews are removed all the time as newer reviews come out. Jytdog (talk) 17:36, 1 February 2014 (UTC)

And Dick, if you continue making personal attacks in edit notes and in Talk, you are going to get brought to a drama board for disruptive editing. Several us have warned you, here and on your Talk page. There is no reason to make this personal. Please stop; it is just a distraction from the work. Thank you. Jytdog (talk) 17:41, 1 February 2014 (UTC)

You've got a pretty good drama board going here already. I tried to come help sort it out, but if nobody wants to help I'll give up now. Dicklyon (talk) 17:48, 1 February 2014 (UTC)

everybody is welcome to help. attacking other editors is not helping. if you decide to keep working, please comment on content, not on the contributor. thanks Jytdog (talk) 17:58, 1 February 2014 (UTC)

Article does not represent the literature correctly

This is not so much a NPOV issue, if we read the articles written by the experts on this subject who have pushed back the hardest against health claims, then the current wikipedia article still doesn't give a good overview of part of the literature that deals more with the theory.

Just read this article written by JoAnn E. Manson, who has been very vocal in defending the IOM's latest report. So, there are many (uncontroversial) theoretical reasons why vitamin D would be expected to have an effect on heart disease according to the literature. Stating that, while making it clear that this does not imply that health effects are an established fact is necessary. The subject of the article is vitamin D and therefore things that are known should be mentioned. The clinical trials that are being done are well motivated, this wiki article does a poor job inn this respect, reading this wiki article you would be led to think that these trials are random shots in the dark. Accroding to the article:

"Vitamin D may lower cardiovascular risk via several mechanisms:

Inhibiting inflammation. Vitamin D has a powerful immunomodulatory effect: laboratory studies show that it inhibits prostaglandin and cyclooxygenase 2 pathways, reduces matrix metalloproteinase 9 and several proinflammatory cytokines, and increases interleukin 10, all of which result in suppressed inflammation.1

Inhibiting vascular muscle proliferation and vascular calcification. Animal studies indicate that in moderate doses vitamin D decreases calcium cellular influx and increases matrix Gla protein, which inhibits vascular smooth muscle proliferation and vascular calcification. These protective effects contrast with the hypercalcemia associated with a high intake of vitamin D, especially in the context of renal failure or other risk factors, which may lead to increased vascular calcification.1

Regulates blood pressure. Vitamin D decreases renin gene expression and the synthesis of renin, which reduces activity of the renin-angiotensin-aldosterone system, leading to a reduction of blood pressure and a favorable effect on volume homeostasis.1

Regulates glucose metabolism. Limited evidence shows that vitamin D may increase insulin sensitivity and regulate glucose metabolism.1

Vitamin D and cardiac hypertrophy

The vitamin D receptor is present in virtually all tissues, including cardiac myocytes and endothelial cells. Animals with vitamin D deficiency have higher blood pressures, and animals genetically altered to have no vitamin D receptors (knock-out models) develop left ventricular hypertrophy and heart failure.

Animals genetically altered to have no 1-alpha-hydroxylase (so that the most active form of vitamin D is not made) also develop left ventricular hypertrophy. They can be rescued by the administration of 1,25-dihydroxy vitamin D3.1

These findings are consistent with what is observed in patients with end-stage renal disease, who produce very little 1,25-dihydroxyvitamin D3: they often develop left ventricular hypertrophy, diastolic heart failure, atherosclerosis, and vascular calcification."

Count Iblis (talk) 14:28, 1 February 2014 (UTC)

That link doesn't work. For content in an "Effects" section all we can do is relate MEDRS-backed reports of effects. The stuff you're mentioning may have a place in a "Research directions" section, but we must avoid undue weight given to anything which might imply biomedical effect in the face of (lack of) evidence. Alexbrn ^{talk|contribs|COI} 14:55, 1 February 2014 (UTC)

Alex, your anti-quackery reflex has made you into a censor. There is no problem with your statement "we must avoid undue weight given to anything which might imply biomedical effect in the face of (lack of) evidence", but here we're talking about presenting the evidence and interpretations in the literature. I think it's more important that we write it in a way that avoids implying anything, but that reports what's going on. Your reflex in reverting my changes to the CVD section, for example, left it with the quote that is least meaningful from the source, where the authors had one unsupportable interpretation, not applicable to the question we're writing about. So ease off the reflex to revert information, look at what you're writing, look at the sources, and just give a balanced representation of what they say. Dicklyon (talk) 15:48, 1 February 2014 (UTC)

This is not a sufficient source other than to say in a research section that more research is being done. Doc James (talk · contribs · email) (if I write on your page reply on mine) 15:58, 1 February 2014 (UTC)

Agreed, it's important to bear in mind here that the section in which the disputed edits have taken place is "Effects". That should contain ... well, effects. Alexbrn ^{talk|contribs|COI} 16:18, 1 February 2014 (UTC)

The bias continues unabated. Look at Jytdog's recent addition to the Immune system section. The new ref is added only for its negative result, which it contrasts with "the evidence favoring a prophylactic effect", yet the prophylactic effect is nowhere mentioned in the effects section. Why do people work so hard to make it sound like vitamin D is worthless? Dicklyon (talk) 18:00, 1 February 2014 (UTC)

This is the last time I will respond to you when you include a personal attack in a response - it is perfectly possible to discuss edits without accusing other editors of bias (for instance, dick, you could just ask "Jytdog, can you please explain why you didn't include anything about prophylaxis in the edit?". Non-rhetorical question that actually seeks an answer; no personal attack.) So please expect WP:SHUN from me going forward when you do it- the most I will probably write is "not responding". Here you ask, in a twisted, "does your mother know you beat your wife" way, why I made the edit I did. The answer to the untwisted question, is that I literally quoted the conclusion stated by the authors in the abstract and that they repeated in their conclusion section. To answer the untwisted question of why I didn't mention prophylaxis: the answer is that the authors do not mention prophylaxis in their conclusion. And to untwist the last question, the reason why the article doesn't say more positive things about supplementing with Vitamin D, is that recent, high-quality reviews of clinical studies find almost no indication where supplementation has been clearly proven to be helpful. For example, the data we have for acute pneumonia shows that giving Vitamin D to a kid with pneumonia, does nothing. Jytdog (talk) 18:33, 1 February 2014 (UTC)

OK, no good affect on acute; yes, that's what the source reports and is not in dispute. But it says it by contrast to positive results: "A recent meta-analysis of randomized controlled trials (RCTs) showed that prophylactic vitamin D supplementation in the pediatric age group reduced the rate of respiratory tract infections significantly (odds ratio (OR), 0.58; 95% CI, 0.41–0.8) [10]. Few studies have assessed the therapeutic efficacy of vitamin D supplementation as an adjunctive to antibiotics and supportive measures in treating childhood pneumonia. Unlike the evidence favoring a prophylactic effect, there is no clear evidence to support or refute the therapeutic efficacy of vitamin D in acute pneumonia. ..." So, to make the section less biased, you need to mention that, too. They link the source for you, even: this 2012 review. I'd add it, but since you reported me for edit warring against you all, I'll refrain from rocking the boat more. Dicklyon (talk) 19:54, 1 February 2014 (UTC)

not responding. my edit focused on the subject of the review - acute treatment of pediatric pneumonia; i didn't even think about prophylaxis. it is a question of scope, not bias. if you reframe your question/statement to remove the accusation of bias, i will respond to the substance. Jytdog (talk) 20:08, 1 February 2014 (UTC)

I had already phrased my comment carefully to apply the word "bias" to "the section", not to the editor. But feel free to shun my anyway. Dicklyon (talk) 20:27, 1 February 2014 (UTC)

you are carrying around a bias-detecting hammer, every edit looks like a nail. i am not dealing with that anymore. Jytdog (talk) 20:33, 1 February 2014 (UTC)

OK, then let me know if you'd object to me adding the balancing information about a positive prophylactic effect. I don't want to provoke another revert war. Dicklyon (talk) 21:00, 1 February 2014 (UTC)

Dick, whether vitamin D has a prophylactic effect or not is a different topic from whether Vitamin D is useful in acute treatment. Something can be good for one and useless for other, good for both, or useless for both. They are independent variables, as it were. information about a prophylactic effect therefore cannot "balance" any information about a treatment effect. Do you see how your seeking "balance" of "positive" and "negative" is disrupting our ability to discuss the topics at hand? (real question) Jytdog (talk) 22:27, 1 February 2014 (UTC)

You perplex me. I'm saying the prophylaxis balances acute treatment. I'm saying that our coverage is biased toward what vitamin D is NOT good for, and terribly short on what it IS good for. You don't find that same imbalance in the reference about on effect on acute, as it acknowledges that there is a positive prophylactic effect. The topic is effects. I'm unclear on whether you are arguing that we should omit such information about positive effects, or what. The present coverage is biased toward non-effects; you're OK with that? Dicklyon (talk) 23:05, 1 February 2014 (UTC)

dick this is definition of tendentious editing. The editors working here have long experience working on health-related articles, and they have found the most recent, high quality sources, read them, and reported what they say. The medical consensus on vitamin D, and indeed most supplements, is that there there is very little evidence (outside of things like folic acid) that they are good for anything beyond avoiding the classic deficiency diseases, and in the developed world those are rare anyway. There is plenty that supplements ~may~ do but almost nothing that we know they do. For you to come to this article with a preconceived belief that they must be good for something, and to try to push "good" things into the article, is tendentious. Please stop reading every source looking for something positive to say. On the source that started this exact thread, the source was focused on treatment and that is what I wrote about. You apparently searched the article for something good to say and found something peripheral to the subject of the article and complained that I didn't mention it. Again - that is the definition of cherry-picking, tendentious editing. Please stop it already. Jytdog (talk) 15:33, 2 February 2014 (UTC)

You have decided to rely on your own conclusion that "there is very little evidence ... that they are good for anything beyond avoiding the classic deficiency diseases" while ignoring the evidence of a positive effect that is reported in the very source you're quoting! And you call me tendentious for pointing out the bias! I can see why this article is in such bad shape. Dicklyon (talk) 02:03, 4 February 2014 (UTC)

sigh. no. for the third time or so, the article was about treatment, and i wrote about treatment. i wasn't even thinking about prophylaxis - i was thinking about the subject of the article. anyway we will keep working source by source. Jytdog (talk) 02:29, 4 February 2014 (UTC)

So nobody is interested in reducing the bias in the immune system section by noting the prophylactic effect of vitamin D against respiratory infections, as reported in this recent study? Still perplexed why Jytdog rejects this as being outside the domain that he wants to write about, but surely some others who work on this article would care to improve it, no? Dicklyon (talk) 23:45, 4 February 2014 (UTC)

I have removed the addition regarding pneumonia and would not support addition of the above source either. Neither journals are indexed in MEDLINE, and therefore red flags for possible poor sources. I could find no other MEDRS compliant sources discussing Vitamin D and pneumonia; if the topic is only discussed in journals of questionable reliability, it is best to wait until it is discussed in better sources before discussing. Yobol (talk) 23:55, 4 February 2014 (UTC)

Another too-broad brush: This edit puts in "Taking vitamin D supplements has no significant effect on mortality," which both trivializes what the source says and mis-uses the statistical concept of "significant". And there are certainly subpopulations where it's not true. So someone should work on converting it to something more correct and meaningful. Dicklyon (talk) 22:04, 1 February 2014 (UTC)

You misquote. The sentence starts, crucially, "In general ... ". The subsequent paras cover non-general cases. Correction: no this is what should be there! Alexbrn ^{talk|contribs|COI} 22:16, 1 February 2014 (UTC)

Thank you for acknowledging and fixing your errors here and in the article. Dicklyon (talk) 22:25, 1 February 2014 (UTC)

And thank you for raising! Alexbrn ^{talk|contribs|COI} 22:27, 1 February 2014 (UTC)

Biological effects of vitamin D

Dear Fellow Editors. As a new player in the editing game, but with many years of studying the health effects of vitamin D, I think that much of the discussion on this talk page lately has been too narrowly focused. While one of the end goals of vitamin D research is treatment to prevent and treat disease, much of the research on vitamin D has been on its biological effects, some of which are related to health and disease. I would like to propose that we look again at the Wikipedia guidelines and reach a general agreement on how to apply them to vitamin D.

One of the major assumptions being made in the discussions regarding vitamin D is that it should be evaluated regarding the evidence that it is useful for treatment to prevent and treat disease. However, this is just one aspect of vitamin D. Vitamin D is required for life by nearly all animals. Thus, in addition to evaluating vitamin D’s role in treatment, the evidence of the effect of vitamin D on health outcomes from many types of studies should be considered. The rules for both medicine [[8]] and natural sciences [[9]] can be employed.

For medicine:

“The medical guidelines or position statements produced by nationally or internationally recognised expert bodies often contain an assessment of the evidence as part of the report.

”The best evidence comes primarily from meta-analyses of randomized controlled trials (RCTs). Systematic reviews of bodies of literature of overall good quality and consistency addressing the specific recommendation have less reliability when they include non-randomized studies. Narrative reviews can help establish the context of evidence quality. Roughly in descending order of quality, lower-quality evidence in medical research comes from individual RCTs; other controlled studies; quasi-experimental studies; non-experimental, observational studies, such as cohort studies and case control studies, followed by cross-sectional studies (surveys), and other correlation studies such as ecological studies; and non-evidence-based expert opinion or clinical experience. Case reports, whether in the popular press or a peer reviewed medical journal, are a form of anecdote and generally fall below the minimum requirements of reliable medical sources.

“Cochrane Library reviews are generally of high-quality and are routinely maintained even if their initial publication dates fall outside the above window.”

For natural sciences:

Respect secondary sources “In general, scientific information in Wikipedia articles should be based on published, reliable secondary sources, or on widely cited tertiary and primary sources. Sources that are robust in methodology, published in high quality venues, and authored by widely cited researchers are preferred. Especially for surprising or extraordinary results, the description should adhere closely to the interpretation of the data given by the authors or by reliable secondary sources (see Wikipedia:No original research).

“Primary sources should be used when discussing a particular result or recent research directions. When citing a primary source, be especially mindful of the policy on undue weight, as primary sources are more prone to misuse than secondary or tertiary sources. An individual primary source should never be cited or juxtaposed so as to "debunk" or contradict the conclusions of a reliable secondary source, unless the primary source itself directly makes such a claim (see Wikipedia:Synthesis of published material that advances a position). Primary sources favoring a minority opinion should not be aggregated or presented devoid of context in such a way as to undermine proportionate representation of expert opinion in a field.”

Respect primary sources “A primary source, such as a report of a pivotal experiment cited as evidence for a hypothesis, may be a valuable component of an article. A good article may appropriately cite primary, secondary, and tertiary sources. Use of primary sources should always conform to the No original research policy.

"Wikipedia articles must not contain original research. The phrase "original research" (OR) is used on Wikipedia to refer to material—such as facts, allegations, and ideas—for which no reliable, published sources exist.” (from http://wiki.riteme.site/wiki/Wikipedia:No_original_research)

Summarize scientific consensus “The prevailing scientific consensus should be presented as the dominant view and articles should be framed accordingly. Scientific consensus can be found in e.g. recent, authoritative review articles, high quality journal articles, or widely used postsecondary textbooks. Significant minority views should be accorded due weight and presented in the context of their acceptance by experts in the field. If mainstream secondary sources in a field do not consider a detail or opinion relevant, it may not be appropriate to cover it at that article; such details and opinions may be desirable at an article on a sub-topic or at a separate article, with linking governed by WP:SPINOUT and WP:ONEWAY.”

Assess evidence quality “Editors should be careful to avoid engaging in original research, but the quality of available evidence should be kept in mind when assessing whether a particular idea or viewpoint is well-accepted by the relevant academic community. Such evidence should include reviews of the literature including the work of several different research groups. Individual papers often disagree with each other, but there are several indicators that may be assessed even without specialist knowledge to differentiate high quality papers from low”

Thus, the guidelines do permit studies other than randomized controlled trials to be considered under the rules for medical topics. This is especially important for vitamin D studies since there are concerns that many of the vitamin D randomized controlled trials to date have not been properly conducted. The pharmaceutical model for randomized controlled trials assumes that there is no other source of the material and that there is a linear dose-response relation between agent and effect. Neither assumption is satisfied for vitamin D.

The primary failures include using too little vitamin D (400-1000 IU/d) and not measuring serum 25-hydroxyvitamin D [25(OH)D] levels of those enrolled in the studies. However, there do appear to be two types of vitamin D randomized controlled trials: those asking whether giving vitamin D supplements to healthy community-dwelling individuals yields any health benefit and those asking whether the 25(OH)D level-health outcome relations found in observational studies are correct.

The second type of studies should enroll people with low serum 25(OH)D levels. There are few such studies. Here are two:

Bolland MJ, Grey A, Gamble GD, Reid IR. Calcium and vitamin D supplements and health outcomes: a reanalysis of the Women's Health Initiative (WHI) limited-access data set. Am J Clin Nutr. 2011 Oct;94(4):1144-9, PMID 21880848

This shows 14-20% reduction in cancer incidence rates for those not taking vitamin D or calcium prior to enrolling in the study

Camargo CA Jr, Ganmaa D, Frazier AL, Kirchberg FF, Stuart JJ, Kleinman K, Sumberzul N, Rich-Edwards JW. Randomized trial of vitamin D supplementation and risk of acute respiratory infection in Mongolia. Pediatrics. 2012 Sep;130(3):e561-7, PMID 22908115

The baseline serum 25(OH)D level was 7 ng/ml and a significant benefit was found for 300 IU/d vitamin D. In contrast to the Camargo paper, the baseline 25(OH)D level was 30 ng/ml in the following study, and no beneficial effect of vitamin D supplementation was found.

Murdoch DR, Slow S, Chambers ST, Jennings LC, Stewart AW, Priest PC, Florkowski CM, Livesey JH, Camargo CA, Scragg R. Effect of vitamin D3 supplementation on upper respiratory tract infections in healthy adults: the VIDARIS randomized controlled trial. JAMA. 2012 Oct 3;308(13):1333-9, PMID 23032549

See these papers regarding the design of vitamin D randomized controlled trials:

Biesalski HK, Aggett PJ, Anton R, Bernstein PS, Blumberg J, Heaney RP, Henry J, Nolan JM, Richardson DP, van Ommen B, Witkamp RF, Rijkers GT, Zöllner I. 26th Hohenheim Consensus Conference, September 11, 2010 Scientific substantiation of health claims: evidence-based nutrition. Nutrition. 2011 Oct;27(10 Suppl):S1-20, PMID 21700425

Heaney RP. Guidelines for optimizing design and analysis of clinical studies of nutrient effects. Nutr Rev. 2014 Jan;72(1):48-54, PMID 24330136

Lappe JM, Heaney RP. Why randomized controlled trials of calcium and vitamin D sometimes fail. Dermatoendocrin. 2012;4(2):95-100, PMID 22928064

Moser U. Vitamins - wrong approaches. Int J Vitam Nutr Res. 2012 Oct;82(5):327-32, PMID 23798051

Since vitamin D is a natural compound essential for most animal life, what seems to make more sense at this stage is to consider vitamin D in terms of what is known about the relation of health outcomes with respect to solar ultraviolet-B irradiance, the primary source of vitamin D for most people, and serum 25(OH)D levels. Such information comes from ecological, laboratory, and observational studies. The information can then be assessed using Hill’s criteria for causality in a biological system

Hill AB. The environment and disease: Association or causation? Proc R Soc Med. 1965 May;58:295-300, PMID 14283879

Here is one study finding a beneficial effect of vitamin D supplementation. As it is a meta-analysis and a Cochrane report, it qualifies for inclusion as medical evidence.

“Meta-analyses of vitamin D3 supplementation found statistically significantly decreased cancer mortality (relative risk 0.88 (95% confidence interval 0.78 to 0.98); P = 0.02; I2 = 0%; 44,492 participants; 4 trials)” [Bjelakovic, 2014].

Bjelakovic G, Gluud LL, Nikolova D, Whitfield K, Wetterslev J, Simonetti RG, Bjelakovic M, Gluud C. Vitamin D supplementation for prevention of mortality in adults. Cochrane Database Syst Rev. 2014 Jan 10;1:CD007470. [Epub ahead of print] http://www.ncbi.nlm.nih.gov/pubmed/24414552 Circ Cardiovasc Qual Outcomes. 2012 Nov;5(6):819-29. doi: 10.1161/CIRCOUTCOMES.112.967604. Epub 2012 Nov 13.

Regarding CVD, here is another paper by Lu Wang et al. reviewing prospective observational studies of CVD with respect to serum 25(OH)D levels.

Wang L, Song Y, Manson JE, Pilz S, März W, Michaëlsson K, Lundqvist A, Jassal SK, Barrett-Connor E, Zhang C, Eaton CB, May HT, Anderson JL, Sesso HD, Circulating 25-hydroxy-vitamin D and risk of cardiovascular disease: a meta-analysis of prospective studies. Circ Cardiovasc Qual Outcomes. 2012 Nov;5(6):819-29. doi: 10.1161/CIRCOUTCOMES.112.967604. Epub 2012 Nov 13, PMID 23149428

Abstract

BACKGROUND:

Vitamin D status has been linked to the risk of cardiovascular disease (CVD). However, the optimal 25-hydroxy-vitamin D (25[OH]-vitamin D) levels for potential cardiovascular health benefits remain unclear.

METHODS AND RESULTS: We searched MEDLINE and EMBASE from 1966 through February 2012 for prospective studies that assessed the association of 25(OH)-vitamin D concentrations with CVD risk. A total of 24 articles met our inclusion criteria, from which 19 independent studies with 6123 CVD cases in 65 994 participants were included for a meta-analysis. In a comparison of the lowest with the highest 25(OH)-vitamin D categories, the pooled relative risk was 1.52 (95% confidence interval, 1.30-1.77) for total CVD, 1.42 (95% confidence interval, 1.19-1.71) for CVD mortality, 1.38 (95% confidence interval, 1.21-1.57) for coronary heart disease, and 1.64 (95% confidence interval, 1.27-2.10) for stroke. These associations remained strong and significant when analyses were limited to studies that excluded participants with baseline CVD and were better controlled for season and confounding. We used a fractional polynomial spline regression analysis to assess the linearity of dose-response association between continuous 25(OH)-vitamin D and CVD risk. The CVD risk increased monotonically across decreasing 25(OH)-vitamin D below ≈60 nmol/L, with a relative risk of 1.03 (95% confidence interval, 1.00-1.06) per 25-nmol/L decrement in 25(OH)-vitamin D.

CONCLUSIONS: This meta-analysis demonstrated a generally linear, inverse association between circulating 25(OH)-vitamin D ranging from 20 to 60 nmol/L and risk of CVD. Further research is needed to clarify the association of 25(OH)-vitamin D higher than 60 nmol/L with CVD risk and assess causality of the observed associations.

Here is a recent review of vitamin D and health benefits:

Hossein-Nezhad A, Holick MF. Vitamin D for health: A global perspective. Mayo Clin Proc. 2013 July;88(7):720-55 PMID 23790560

Here is a review that considers observational studies and randomized controlled trials:

Kaulgud RS, Shreyas AC, Vinay SP, Kulkarni SK, Vijayalakshmi PB, Joshi RR, Swhay M. Emerging roles of vitamin D in various spectra of diseases. Int J Biomedical Res. 2013;4(4):191-204. http://www.ijbr.ssjournals.com/index.php/journal/article/view/264

Abstract

Vitamin D has been found to be useful for a number of conditions. Various studies have found it useful in different disorders to varying degree. It is being prescribed very frequently in clinical practice. So, we decided to conduct review to clarify its role in prevention and treatment of different disorders. We found more than thousand articles and reviewed relevant literature from databases like Cochrane, Pubmed, Medline that tested role of this vitamin in various spectra of diseases. We found vitamin D to be efficacious in conditions like cardiovascular diseases, diabetes mellitus, osteoporosis; but its role in treatment of certain conditions like multiple sclerosis, cognition needs to be assessed further studies.

It is noted that vitamin D blood levels are mentioned in the Wikipedia article on Colon cancer.

Medication

Aspirin and celecoxib appear to decrease the risk of colorectal cancer in those at high risk However it is not recommended in those at average risk. There is tentative evidence for calcium supplementation but it is not sufficient to make a recommendation Vitamin D intake and blood levels are associated with a lower risk of colon cancer.

Jag8452 (talk) 02:36, 4 February 2014 (UTC)

What change are you suggesting? Doc James (talk · contribs · email) (if I write on your page reply on mine) 03:15, 4 February 2014 (UTC)

I would recommend starting with this 2014 review, and reporting what it says, as a counterpoint POV to other recent studies. Don't take sides or push conclusions, just report in a balanced way the different findings and different opinions about the potential value of more studies. I also agree that our reporting of "effects" is severely limited by focusing on narrow medical questions. There are a lot of known effects worth reporting, quite independent of the question of whether supplementation is a good medical recommendation for various subpopulations. Dicklyon (talk) 06:36, 4 February 2014 (UTC)

We already cite that article's only conclusion (that it help the institutionalized elderly). What is your specific proposal? Alexbrn ^{talk|contribs|COI} 06:42, 4 February 2014 (UTC)

We note in the lead that "The best evidence of benefit is for ... and a decrease in mortality in elderly women.[8]" But then nothing from the article is mentioned in the text. I can't see the article without paying, but I see the summary with things like "Vitamin D3 seemed to decrease mortality in elderly people living independently or in institutional care" and "further placebo-controlled randomised trials seem warranted", which either contradict or supplement other more negative outlooks presented in the text. I don't understand the reluctance to make a more balanced presentation. Dicklyon (talk) 07:06, 4 February 2014 (UTC)

It's cited in the "Mortality" section. We don't have trivial statements like "more trials are needed", as guided by WP:MEDORDER. Every paper says that pretty much. Mind you, interestingly and unusually the Lancet meta-analysis we just added says that further research into some aspects of vitamin D wuld be futile. Alexbrn ^{talk|contribs|COI} 07:21, 4 February 2014 (UTC)

Why so it is! I hadn't noticed that this one shows up as both ref 8 and ref 16. That should be fixed. And in the Mortality section, the reference needs to be clearly attached to the positive result, not only to the negative result as it is now. That's worth fixing, no? Dicklyon (talk) 23:59, 4 February 2014 (UTC)