D-day

The past, like the future, is unknown and largely unknowable. Just when you think you have it pinned down it wriggles free and assumes new forms. History, like science, is revisionism. 

Take D-day. One of the most amazing episodes on this most terrible of days was the ascent of a battalion of US army rangers on the Pointe du Hoc, a highpoint overlooking Omaha beach, to take a German battery. They succeeded but at terrible cost; of the 580 men 77 were killed, 38 MIA and 152 wounded.

Considered a pivotal element in the D-day invasion and a byword for bravery under fire, their story was told in the film ‘The Longest Day’ and passed into legend. Until, 15 years ago, the legend was exposed by careful research and a new truth emerged. Lt. George Klein, a self-proclaimed survivor of the ascent, made a good living touting his story around the world. Military historians discovered, however, that he was not on Pointe. On D-day, George was safely behind the lines in Ireland. 

More seriously, the Hoc was not a strategic target. The guns had been moved elsewhere and commanding officer Lt. Col. James Rudder, who was aware of this, squandered his men’s lives. He also disobeyed direct orders to knock out German artillery at Maisy and, for reasons obvious to anyone who has read Catch 22, was made a war hero for his efforts.

Now let’s consider vitamin D. Here again many unnecessary deaths have been caused by the officer class, on this occasion setting RDA values so low they left crowds dying not on the beaches but in the beds of hospitals and clinics around the world. They did this partly because of their long-standing distaste for natural medicine; and here also, history is being re-written.

As recently as the 1970’s vitamin D was all about bones, and RDA values were designed primarily to prevent rickets.

Over the last half-century a more complex picture has emerged, placing vitamin D at the centre of an extensive network of genes, enzymes, receptors and risk factors for cancers (1, 2), Type 2 diabetes (3) and infective (4), degenerative (5) and auto-immune (6) diseases.

Due to D’s anti-inflammatory, immuno-regulatory and chemo-protective properties (7-9), and the fact that we can make it ourselves, its status has shifted from vitamin to hormone. At 40-60 ng/ml, the serum levels required to achieve its endocrine benefits are considerably higher than those needed to prevent rickets (10).

Despite this, many medical authorities hold the rickety old Maginot Line of 20 ng/ml (ie 11), while regulators warn that levels higher than 50 ng/ml may trigger adverse effects (12). As a result, the standard supplement recommendations of 5-20 mcg/day (200 to 800 International Units) are far too low to achieve optimal blood levels (10, 13).

Official guidelines, together with the fact that today’s ultra-processed diet has left us depleted in derma-protective phytonutrients (14-19) and therefore too delicate to cope with direct sunlight, have contributed to wide-spread hypo-vitaminosis D. In the temperate zones, most people are depleted in vitamin D for most of the year. And this has killed many more than the 2,400 brave souls who died on Hoc, and on Omaha Beach (20).

How did we get here? How can we make our way further inland? And what does this mean for supplementers?

One reason for the overly cautious advice about vitamin D is the widespread use of well-intentioned but poorly designed D+calcium supplements, which are supposed to protect against osteoporosis but do not (21). This is unsurprising, given that osteoid and bone economics involve over 20 micro-, phyto- and other nutrients and that most of us are depleted in most of them (ie 22). 

Ca supplements do however carry a risk of adverse effects including kidney stones and, likely, vascular calcification (23). This could explain why high dose calcium supplements have been associated with increased mortality (24, 25).

When used without calcium, however, and especially when combined with K2, high dose vitamin D does not cause calcification problems (26-29). This makes biological sense, and undermines current regulatory guidelines and upper safety limits (USL’s). In the USA these are set at 4,000 IU’s day, while the more conservative UK brass hats are pinned down at 2,000 IU’s. 

If the bureaucrats were ever to leave their sunless bunkers, sally up to the front lines and look to the skies, they might find enlightenment. In the sub-tropics and in the temperate zone during summer months you can make up to 10-50,000 International Units of D in your own skin in an hour or so of sunlight (27). 

Once you check your ethnocentric attitudes at the door you find that people in vestigial cultures (such as Hadza and Maasai) have an average serum 25-hydroxyvitamin D concentration of 46 ng/mL (31). Urbanites can only achieve these levels with regular use of sunbeds (32, 33), or by supplementing with circa 10,000 IU’s day (my estimate and 29, 34).

The Hadza and Maasai show no signs of vitamin D toxicity, and indeed have better renal health into old age than we do (35). Given their higher intake of organ meats, fermented foods and prebiotic fibers they consume (36) and produce (37, 38), via their microbiota (39, 40), significantly more vitamin K than we do. This helps to explain their near-freedom from cardiovascular disease (41), and should provide guidance for supplement manufacturers everywhere; raise D, lose Ca, add K2.

Recent research indicates the true USL of vitamin D is above 10,000 IU’s (42, 43). Further context comes from clinical studies in which far higher doses of vitamin D were used therapeutically, and without toxicity.  Hyperparathyroidism has been successfully managed with 50,000 to 200,000 IU of vitamin D daily (44), while rickets may require a daily dosage of 50,000 to as much as 300,000 IU in resistant cases (45). 

It’s fortunate that vitamin D has a wide therapeutic index, because high-dose D has lately become very fashionable. A recent paper by Borsche et al (46) put the D in Covid and the cat among the pigeons with data suggesting that D has dose-related protective effects. The authors predicted that Covid mortality should fall to zero when plasma levels of D reach 50 ng/mL … which if true, would make the Maasai and Hadza almost totally immune and raises the question, can hunter-gatherers catch Covid? 

It would be ironic if cultures once devastated by microbes imported by European colonisers were now resistant to a new, man-made virus which kills only modern consumers made sick, fat and malnourished by the Western food industry. This would be a potentially watershed study but it will never be done while Fauci, a latter-day George Klein, reigns. Rather than keeping the home fires burning (47) he is in fact paid handsomely for burning down the house (48, 49).

So is D really a cure for Covid? Well, it certainly has history. Sunbathing for tubercular patients is as old as Hippocrates, and was being used to treat TB well into the 20^th century (50). Then came the antibiotics, of course, and the sun set on heliotherapy until 21^st century science re-discovered the relevance of D to disease.

The many defects in the immune system caused by D deficiency clearly make people more prone to TB infection and to disease progression (51-56).

It seemed logical to monotherapy-minded researchers that D supplementation would find a role in TB treatment, but when prospective clinical trials were set up to look at this the results were disappointing (57, 58). 

Not surprising. Immunosuppression makes infection more likely, but why would anyone think that repairing a very few components in a person with multiple nutritional and metabolomic problems, and a generally degraded immune system, could possibly be effective? 

I believe it is the same with Covid. If you are D-deficient some of your defences are down, and your risks are up. But as the immune system has multiple nutrient requirements, and most people are depleted in most nutrients, how could one reasonably expect D to be the cure?

The authors of the cat ‘n pigeon paper (46) make the case that vitamin D3 depletion and deficiency is one of the main reasons for severe SARS-CoV-2 infections. They point out that fatality rates are higher in elderly people, black people, and people with comorbidities, who tend to have very low vitamin D3 levels (59-62). They could have added – but didn’t – that Covid fatality rates are also higher in the obese (63), in schizophrenics (64), and in those who wear the niqab or hijab (65); all of whom have low D status (66-68).

It doesn’t matter. None of this proves a causative relationship between D and Covid, and it certainly does not show that high D doses will reduce the risk of Covid death, except perhaps in the D-deficient. There are many variables at play here, and I believe the authors are making the same mistake that the earlier TB triallists did (69).

Nutritional status in Covid is critical but highly complex, and does not lend itself to monotherapy. That is a pharmaco-centric error of thought; and D is very far from being a panacea (70-72). D is important for immune function, at up to 10,000 IU/day, but so are many other dietary components. These range from vitamins A, B and C to Fe, Cu and Zn, via omega 3 PUFA’s, polyphenols, prebiotics, cyanogens and 1-3, 1-6 beta glucans.

While Borsche and his colleagues correctly flagged up nutrition, they did not go far enough. They took the Hoc, perhaps, but for those who want to go further inland I recommend the Health Protocol. The HP is not the end. It is not even the beginning of the end. But it is, perhaps, the end of the beginning.

I cannot finish this post without mentioning a strangely wonderful controlled randomised trial which reported that D supplements fail to reduce the adverse effects of earthquakes (73). I am shaken by this news, but not stirred.

Next week: Borderline Personalities and edible passports.

References

1. Feldman D, Krishnan AV, Swami S, Giovannucci E, Feldman BJ. The role of vitamin D in reducing cancer risk and progression. Nat. Rev. Cancer 2014, 14, 342. 
2. Jeon S-M, Shin E-A. Exploring vitamin D metabolism and function in cancer. Exp. Mol. Med. 2018, 50, 389. 
3. Berridge MJ. Vitamin D deficiency and diabetes. Biochem. J. 2017, 474, 1321.
4. Martineau AR, Jolliffe DA, Greenberg L, Aloia JF, Bergman P, Dubnov-Raz G. Vitamin D supplementation to prevent acute respiratory infections: Individual participant data meta-analysis. Health Technol. Assess. 2019, 23, 23020.
5. Agrawal D, Yin K. Vitamin D and inflammatory diseases. J. Inflamm Res. 2014, 12, 63898.
6. Hayes CE, Ntambi JM. Multiple Sclerosis: Lipids, Lymphocytes, and Vitamin D. Immunometabolism 2020, 10, 19.
7. Institute of Medicine, Food and Nutrition Board. Dietary Reference Intakes for Calcium and Vitamin D. Washington, DC: National Academy Press, 2010.
8. Norman AW, Henry HH. Vitamin D. In: Erdman JW, Macdonald IA, Zeisel SH, eds. Present Knowledge in Nutrition, 10th ed. Washington DC: Wiley-Blackwell, 2012.
9. Jones G. Vitamin D. In: Ross AC, Caballero B, Cousins RJ, Tucker KL, Ziegler TR, eds. Modern Nutrition in Health and Disease, 11th ed. Philadelphia: Lippincott Williams & Wilkins, 2014.
10. Charoenngam N, Holick MF. Immunologic Effects of Vitamin D on Human Health and Disease. Nutrients 2020, 12, 2097.
11. Michigami T. Rickets/Osteomalacia. Consensus on Vitamin D Deficiency and Insufficiency in Children. Clin. Calcium 2018, 28, 1307–1311.
12. National Institutes of Health. Vitamin D Factsheet for Health Professionals. https://ods.od.nih.gov/factsheets/VitaminD-HealthProfessional/
13. Grant W, Lahore H, McDonnell S, Baggerly C, French C, Aliano J. Evidence that Vitamin D Supplementation Could Reduce Risk of Influenza and COVID-19 Infections and Deaths. Nutrients 2020, 12, 988.
14. Evans JA, Johnson EJ. The role of phytonutrients in skin health. Nutrients. 2010 Aug;2(8):903-28.
15. Mintie CA, Singh CK, Ahmad N. Whole Fruit Phytochemicals Combating Skin Damage and Carcinogenesis. Transl Oncol. 2020 Feb;13(2):146-156.
16. Islam SU, Ahmed MB, Ahsan H, Islam M, Shehzad A, Sonn JK, Lee YS. An Update on the Role of Dietary Phytochemicals in Human Skin Cancer: New Insights into Molecular Mechanisms. Antioxidants (Basel). 2020 Sep 25;9(10):916.
17. Schagen SK, Zampeli VA, Makrantonaki E, Zouboulis CC. Discovering the link between nutrition and skin aging. Dermatoendocrinol. 2012 Jul 1;4(3):298-307.
18. Jacczak B, Rubiś B, Totoń E. Potential of Naturally Derived Compounds in Telomerase and Telomere Modulation in Skin Senescence and Aging. Int J Mol Sci. 2021 Jun 15;22(12):6381.
19. Solway J, McBride M, Haq F, Abdul W, Miller R. Diet and Dermatology: The Role of a Whole-food, Plant-based Diet in Preventing and Reversing Skin Aging-A Review. J Clin Aesthet Dermatol. 2020 May;13(5):38-43.
20. Grant WB, Schwalfenberg GK, Genuis SJ, Whiting SJ. An estimate of the economic burden and premature deaths due to vitamin D deficiency in Canada. Molecular Nutrition & Food Research 2010 Aug;54(8):1172-81. 
21. Reid IR. Should we prescribe calcium supplements for osteoporosis prevention? J Bone Metab. 2014 Feb;21(1):21-8.
22. Fulgoni VL, 3rd, Keast DR, Bailey RL, Dwyer J. Foods, fortificants, and supplements: Where do Americans get their nutrients? J Nutr. 2011;141(10):1847-1854.
23. Bazarbashi N, Kapadia SR, Nicholls SJ, Carlo J, Gad MM, Kaur M, Karrthik A, Sammour YM, Diab M, Ahuja KR, Tuzcu EM, Nissen SE, Puri R. Oral Calcium Supplements Associate With Serial Coronary Calcification: Insights From Intravascular Ultrasound. JACC Cardiovasc Imaging. 2021 Jan;14(1):259-268.
24. Kassis N, Hariri EH, Karrthik AK, Ahuja KR, Layoun H, Saad AM, Gad MM, Kaur M, Bazarbashi N, Griffin BP, Popovic ZB, Harb SC, Desai MY, Kapadia SR. Supplemental calcium and vitamin D and long-term mortality in aortic stenosis. Heart. 2022 Apr 25:heartjnl-2021-320215.
25. Michaëlsson K, Melhus H, Warensjö Lemming E, Wolk A, Byberg L. Long term calcium intake and rates of all cause and cardiovascular mortality: community based prospective longitudinal cohort study. BMJ. 2013 Feb 12;346:f228. 
26. van Ballegooijen AJ, Pilz S, Tomaschitz A, Grübler MR, Verheyen N. The Synergistic Interplay between Vitamins D and K for Bone and Cardiovascular Health: A Narrative Review. Int. J. Endocrinol. 2017, 2017, 4376.
27. Maresz K. Proper calcium use: Vitamin K2 as a promoter of bone and cardiovascular health. Integr. Med. A Clin. J. InnoVision Media 2015, 14, 34. 
28. Mandatori, D, Pelusi L, Schiavone V, Pipino C, Pietro ND, Pandolfi A. The Dual Role of Vitamin K2 in “Bone-Vascular Crosstalk”: Opposite Effects on Bone Loss and Vascular Calcification. Nutrients 2021, 13, 1222.
29. McCullough PJ, Lehrer DS, Amend J. Daily oral dosing of vitamin D3 using 5000 TO 50,000 international units a day in long-term hospitalized patients: Insights from a seven year experience. J Steroid Biochem Mol Biol. 2019 May;189:228-239.
30. Adams JS, Clemens TL, Parrish JA, Holick MF. Vitamin-D synthesis and metabolism after ultraviolet irradiation of normal and vitamin-D-deficient subjects. N Engl J Med.1982 Mar 25;306(12):722-5
31. Luxwolda MF, Kuipers RS, Kema IP, Dijck-Brouwer DA, Muskiet FA. Traditionally living populations in East Africa have a mean serum 25-hydroxyvitamin D concentration of 115 nmol/l. Br J Nutr. 2012 Nov 14;108(9):1557-61.
32. Singh P, Trivedi N. Tanning beds and hypervitaminosis D: A case report. Ann Intern Med 2014;160:810-1.
33. Laurent MR, Gielen E, Pauwels S, Vanderschueren D, Bouillon R. Hypervitaminosis D associated with tanning bed use: A case report. Ann Intern Med 2017;166:155-6.
34. Diamond T, Wong YK, Golombick T. Effect of oral cholecalciferol 2,000 versus 5,000 IU on serum vitamin D, PTH, bone and muscle strength in patients with vitamin D deficiency. Osteoporos Int. 2013 Mar;24(3):1101-5.
35. Rosinger AY, Pontzer H, Raichlen DA, Wood BM, Tanner SN, Sands JM. Age-related decline in urine concentration may not be universal: Comparative study from the U.S. and two small-scale societies. Am J Phys Anthropol. 2019 Apr;168(4):705-716.
36. Liu Y, van Bennekom EO, Zhang Y, Abee T, Smid EJ. Long-chain vitamin K2 production in Lactococcus lactis is influenced by temperature, carbon source, aeration and mode of energy metabolism. Microb Cell Fact 18, 129 (2019).
37. Walther B, Karl JP, Booth SL, Boyaval P. Menaquinones, bacteria, and the food supply: the relevance of dairy and fermented food products to vitamin K requirements. Adv Nutr. 2013;4:463–73.
38. Fu X, Harshman SG, Shen X, Haytowitz DB, Karl JP, Wolfe BE, Booth SL. Multiple vitamin K forms exist in dairy foods. Curr Dev Nutr. 2017;1:e000638.
39. Schnorr SL, Candela M, Rampelli S, Centanni M, Consolandi C, Basaglia G, Turroni S, Biagi E, Peano C, Severgnini M, Fiori J, Gotti R, De Bellis G, Luiselli D, Brigidi P, Mabulla A, Marlowe F, Henry AG, Crittenden AN. Gut microbiome of the Hadza hunter-gatherers. Nat Commun. 2014 Apr 15;5:3654.
40. Mathers JC, Fernandez F, Hill MJ, McCarthy PT, Shearer MJ, Oxley A. Dietary modification of potential vitamin K supply from enteric bacterial menaquinones in rats. Br J Nutr. 1990 May;63(3):639-52.
41. Gurven M, Stieglitz J, Trumble B, Blackwell AD, Beheim B, Davis H, Hooper P, Kaplan H. The Tsimane Health and Life History Project: Integrating anthropology and biomedicine. Evol Anthropol. 2017 Apr;26(2):54-73.
42. Vieth R. Vitamin D supplementation, 25-hydroxyvitamin D concentrations, and safety. Am J Clin Nutr. 1999; 69(5):842-56.
43. Vieth R, Chan P-C, MacFarlane GD: Efficacy and safety of vitamin D3 intake exceeding the lowest observed adverse effect level. Am J Clin Nutr 2001;73:288–94.
44. Woodhead JS, Ghose RR, Gupta SK. Severe hypophosphataemic osteomalacia with primary hyperparathyroidism. Br Med J 1980; 281:647-648.
45. Eguchi M, Kaibara N. Treatment of hypophosphataemic vitamin D-resistant rickets and adult presenting hypophosphataemic vitamin D-resistant osteomalacia. Int Orthop 1980; 3:257-264.
46. Borsche L, Glauner B, von Mendel J. COVID-19 Mortality Risk Correlates Inversely with Vitamin D3 Status, and a Mortality Rate Close to Zero Could Theoretically Be Achieved at 50 ng/mL 25(OH)D3: Results of a Systematic Review and Meta-Analysis. Nutrients 2021, 13(10), 3596; https://doi.org/10.3390/nu13103596
47. https://en.wikipedia.org/wiki/Keep_the_Home_Fires_Burning_(Ivor_Novello_song)
48. https://www.simonandschuster.com/books/The-Real-Anthony-Fauci/Robert-F-Kennedy/Children-s-Health-Defense/9781510766808
49. https://www.zerohedge.com/political/nonprofit-watchdog-uncovers-350-million-secret-payments-fauci-collins-others-nih
50. Saleeby C. The Advance of Heliotherapy. Nature 109, 663 (1922).
51. Chan TY. Vitamin D deficiency and susceptibility to tuberculosis. Calcif Tissue Int 2000;66(6):476–8.
52. Williams B, Williams AJ, Anderson ST. Vitamin D deficiency and insufficiency in children with tuberculosis. Pediatr Infect Dis J 2008;27(10):941–2.
53. Huang S-J, Wang X-H, Liu Z-D, Cao W-L, Han Y, Ma A-G, Xu SF. Vitamin D deficiency and the risk of tuberculosis: a meta-analysis. Drug Des Devel Ther 2017;11:91.
54. Nouri-Vaskeh M, Sadeghifard S, Saleh P, Farhadi J, Amraii M, Ansarin K. Vitamin D Deficiency among Patients with Tuberculosis: a Cross-Sectional Study in Iranian-Azari Population. Tanaffos. 2019 Jan;18(1):11-17.
55. Sita-Lumsden A., Lapthorn G., Swaminathan R., Milburn H.J. Reactivation of tuberculosis and vitamin D deficiency: the contribution of diet and exposure to sunlight. Thorax. 2007;62(11):1003–1007.
56. Nnoaham K.E., Clarke A. Low serum vitamin D levels and tuberculosis: a systematic review and meta-analysis. Int J Epidemiol. 2008;37(1):113–119.
57. Sutaria N, Liu CT, Chen TC. Vitamin D Status, Receptor Gene Polymorphisms, and Supplementation on Tuberculosis: A Systematic Review of Case-Control Studies and Randomized Controlled Trials. J Clin Transl Endocrinol. 2014 Dec 1;1(4):151-160.
58. Zhang J, Chen C, Yang J. Effectiveness of vitamin D supplementation on the outcome of pulmonary tuberculosis treatment in adults: a meta-analysis of randomized controlled trials. Chin Med J (Engl). 2019 Dec 20;132(24):2950-2959.
59. Forrest KYZ, Stuhldreher WL. Prevalence and correlates of vitamin D deficiency in US adults. Nutr. Res. 2011, 31, 48.
60. Biesalski HK. Vitamin D deficiency and co-morbidities in COVID-19 patients–A fatal relationship? NFLs J. 2020, 20, 10.
61. Gloth FM. Vitamin D Deficiency in Homebound Elderly Persons. JAMA J. Am. Med. Assoc. 1995, 274, 7027.
62. Giménez VMM, Inserra F, Ferder L, García J, Manucha W. Vitamin D deficiency in African Americans is associated with a high risk of severe disease and mortality by SARS-CoV. -J Hum Hypertens. Springer Sci. Bus. Media LLC 2020, 35, 378.
63. Kompaniyets L, Goodman AB, Belay B, Freedman DS, Sucosky MS, Lange SJ, Gundlapalli AV, Boehmer TK, Blanck HM. Body Mass Index and Risk for COVID-19-Related Hospitalization, Intensive Care Unit Admission, Invasive Mechanical Ventilation, and Death – United States, March-December 2020. MMWR Morb Mortal Wkly Rep. 2021 Mar 12;70(10):355-361.
64. Nemani K, Li C, Olfson M, Blessing EM, Razavian N, Chen J, Petkova E, Goff DC. Association of Psychiatric Disorders With Mortality Among Patients With COVID-19. JAMA Psychiatry. 2021 Apr 1;78(4):380-386.
65. Hassan SM, Ring A, Tahir N, Gabbay M. How do Muslim community members perceive Covid-19 risk reduction recommendations – a UK qualitative study? BMC Public Health 21, 449 (2021). https://doi.org/10.1186/s12889-021-10506-4
66. Walsh JS, Bowles S, Evans AL. Vitamin D in obesity. Curr Opin Endocrinol Diabetes Obes. 2017 Dec;24(6):389-394.
67. Cui X, McGrath JJ, Burne THJ, Eyles DW. Vitamin D and schizophrenia: 20 years on. Mol Psychiatry. 2021 Jul;26(7):2708-2720.
68. Mishal AA. Effects of different dress styles on vitamin D levels in healthy young Jordanian women. Osteoporos Int. 2001;12:931–935.
69. Chen J, Mei K, Xie L, Yuan P, Ma J, Yu P, Zhu W, Zheng C, Liu X. Low vitamin D levels do not aggravate COVID-19 risk or death, and vitamin D supplementation does not improve outcomes in hospitalized patients with COVID-19: a meta-analysis and GRADE assessment of cohort studies and RCTs. Nutr J. 2021 Oct 31;20(1):89.
70. Manson JE, Cook NR, Lee IM, Christen W, Bassuk SS, Mora S, Gibson H, Gordon D, Copeland T, D’Agostino D, Friedenberg G, Ridge C, Bubes V, Giovannucci EL, Willett WC, Buring JE; VITAL Research Group. Vitamin D Supplements and Prevention of Cancer and Cardiovascular Disease. N Engl J Med. 2019 Jan 3;380(1):33-44.
71. Neale RE, Baxter C, Romero BD, McLeod DSA, English DR, Armstrong BK, Ebeling PR, Hartel G, Kimlin MG, O’Connell R, van der Pols JC, Venn AJ, Webb PM, Whiteman DC, Waterhouse M. The D-Health Trial: a randomised controlled trial of the effect of vitamin D on mortality. Lancet Diabetes Endocrinol. 2022 Feb;10(2):120-128.
72. Theodoratou E, Tzoulaki I, Zgaga L, Ioannidis JP. Vitamin D and multiple health outcomes: umbrella review of systematic reviews and meta-analyses of observational studies and randomised trials. BMJ. 2014 Apr 1;348:g2035.
73. Slow S, Florkowski CM, Chambers ST, Priest PC, Stewart AW, Jennings LC, Livesey JH, Camargo CA Jr, Scragg R, Murdoch DR. Effect of monthly vitamin D3 supplementation in healthy adults on adverse effects of earthquakes: randomised controlled trial. BMJ. 2014 Dec 15;349:g7260.