Dietary fiber intake and mortality in a Mediterranean population: the "Seguimiento Universidad de Navarra" (SUN) project.
Cohort
Diet
Fiber
Mortality
Prospective
Vegetables
Journal
European journal of nutrition
ISSN: 1436-6215
Titre abrégé: Eur J Nutr
Pays: Germany
ID NLM: 100888704
Informations de publication
Date de publication:
Dec 2019
Dec 2019
Historique:
received:
08
02
2018
accepted:
17
10
2018
pubmed:
28
10
2018
medline:
28
4
2020
entrez:
28
10
2018
Statut:
ppublish
Résumé
To prospectively assess the association of dietary fiber intake (from different dietary sources) with all-cause mortality in a Mediterranean cohort. We assessed 19,703 participants of the SUN (Seguimiento Universidad de Navarra) cohort (mean follow-up: 10.1 years). A validated 136-item FFQ was administered at baseline. We used Cox proportional hazards models adjusted for multiple socio-demographic, anthropometric, lifestyle factors, and prevalent conditions at baseline. We observed 323 deaths during 198,341 person-years of follow-up. A significantly inverse linear trend in Cox models was observed for the association of total dietary fiber intake and all-cause mortality after adjustment for confounders (p for trend 0.017). Each additional intake of 5 g/1000 kcal of dietary fiber was associated with a 9% relative reduction in all-cause mortality risk (HR 0.91, 95% CI 0.84-0.99). Considering separate dietary sources in separate models, a significant inverse trend was apparent for fiber derived from vegetables (p for trend 0.001), but it was non-significant for fiber derived from fruit, legumes, cereals, or other sources. Soluble fiber was significantly inversely associated with all-cause mortality in the fully adjusted model (p for trend 0.007), and insoluble fiber was marginally significant (p for trend 0.08). A higher intake of total dietary fiber, and particularly fiber from vegetables, was related to a reduced all-cause mortality in our Mediterranean cohort. Dietary messages to increase the consumption of dietary patterns rich in fiber-rich foods should be broadly disseminated to decrease the alarming rate of chronic diseases and its derived mortality.
Identifiants
pubmed: 30367237
doi: 10.1007/s00394-018-1846-3
pii: 10.1007/s00394-018-1846-3
doi:
Substances chimiques
Dietary Fiber
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
3009-3022Subventions
Organisme : CIBER-OBN
ID : PI10/02658
Organisme : CIBER-OBN
ID : PI10/02293
Organisme : CIBER-OBN
ID : PI13/00615
Organisme : CIBER-OBN
ID : PI14/01668
Organisme : CIBER-OBN
ID : PI14/01798
Organisme : CIBER-OBN
ID : PI14/01764
Organisme : CIBER-OBN
ID : G03/140
Références
Burkitt DP, Walker AR, Painter NS (1974) Dietary fiber and disease. JAMA 229:1068–1074
doi: 10.1001/jama.1974.03230460018013
Bhupathiraju SN, Tobias DK, Malik VS, Pan A, Hruby A, Manson JE, Willett WC, Hu FB (2014) Glycemic index, glycemic load, and risk of type 2 diabetes: results from 3 large US cohorts and an updated meta-analysis. Am J Clin Nutr 100:218–232. https://doi.org/10.3945/ajcn.113.079533
doi: 10.3945/ajcn.113.079533
pubmed: 24787496
pmcid: 4144100
Wu Y, Qian Y, Pan Y, Li P, Yang J, Ye X, Xu G (2015) Association between dietary fiber intake and risk of coronary heart disease: a meta-analysis. Clin Nutr 34:603–611. https://doi.org/10.1016/j.clnu.2014.05.009
doi: 10.1016/j.clnu.2014.05.009
pubmed: 24929874
pmcid: 24929874
Dahm CC, Keogh RH, Spencer EA, Greenwood DC, Key TJ, Fentiman IS, Shipley MJ, Brunner EJ, Cade JE, Burley VJ et al (2010) Dietary fiber and colorectal cancer risk: a nested case-control study using food diaries. J Natl Cancer Inst 102:614–626. https://doi.org/10.1093/jnci/djq092
doi: 10.1093/jnci/djq092
pubmed: 20407088
Chuang SC, Norat T, Murphy N, Olsen A, Tjonneland A, Overvad K, Boutron-Ruault MC, Perquier F, Dartois L, Kaaks R et al (2012) Fiber intake and total and cause-specific mortality in the European Prospective Investigation into Cancer and Nutrition cohort. Am J Clin Nutr 96:164–174. https://doi.org/10.3945/ajcn.111.028415
doi: 10.3945/ajcn.111.028415
pubmed: 22648726
Akbaraly TN, Ferrie JE, Berr C, Brunner EJ, Head J, Marmot MG, Singh-Manoux A, Ritchie K, Shipley MJ, Kivimaki M (2011) Alternative Healthy Eating Index and mortality over 18 y of follow-up: results from the Whitehall II cohort. Am J Clin Nutr 94:247–253. https://doi.org/10.3945/ajcn.111.013128
doi: 10.3945/ajcn.111.013128
pubmed: 21613557
pmcid: 3127516
Park Y, Subar AF, Hollenbeck A, Schatzkin A (2011) Dietary fiber intake and mortality in the NIH-AARP diet and health study. Arch Intern Med 171:1061–1068. https://doi.org/10.1001/archinternmed.2011.18
doi: 10.1001/archinternmed.2011.18
pubmed: 21321288
pmcid: 3513325
Streppel MT, Ocke MC, Boshuizen HC, Kok FJ, Kromhout D (2008) Dietary fiber intake in relation to coronary heart disease and all-cause mortality over 40 y: the Zutphen Study. Am J Clin Nutr 88:1119–1125
doi: 10.1093/ajcn/88.4.1119
Lubin F, Lusky A, Chetrit A, Dankner R (2003) Lifestyle and ethnicity play a role in all-cause mortality. J Nutr 133:1180–1185
doi: 10.1093/jn/133.4.1180
Todd S, Woodward M, Tunstall-Pedoe H, Bolton-Smith C (1999) Dietary antioxidant vitamins and fiber in the etiology of cardiovascular disease and all-causes mortality: results from the Scottish Heart Health Study. Am J Epidemiol 150:1073–1080
doi: 10.1093/oxfordjournals.aje.a009931
Li S, Flint A, Pai JK, Forman JP, Hu FB, Willett WC, Rexrode KM, Mukamal KJ, Rimm EB (2014) Dietary fiber intake and mortality among survivors of myocardial infarction: prospective cohort study. BMJ 348:g2659. https://doi.org/10.1136/bmj.g2659
doi: 10.1136/bmj.g2659
pubmed: 24782515
pmcid: 4004785
Schoenaker DA, Toeller M, Chaturvedi N, Fuller JH, Soedamah-Muthu SS (2012) Dietary saturated fat and fibre and risk of cardiovascular disease and all-cause mortality among type 1 diabetic patients: the EURODIAB Prospective Complications Study. Diabetologia 55:2132–2141. https://doi.org/10.1007/s00125-012-2550-0
doi: 10.1007/s00125-012-2550-0
pubmed: 22526612
pmcid: 3390695
Buck K, Zaineddin AK, Vrieling A, Heinz J, Linseisen J, Flesch-Janys D, Chang-Claude J (2011) Estimated enterolignans, lignan-rich foods, and fibre in relation to survival after postmenopausal breast cancer. Br J Cancer 105:1151–1157. https://doi.org/10.1038/bjc.2011.374
doi: 10.1038/bjc.2011.374
pubmed: 21915130
pmcid: 3208499
McEligot AJ, Largent J, Ziogas A, Peel D, Anton-Culver H (2006) Dietary fat, fiber, vegetable, and micronutrients are associated with overall survival in postmenopausal women diagnosed with breast cancer. Nutr Cancer 55:132–140. https://doi.org/10.1207/s15327914nc5502_3
doi: 10.1207/s15327914nc5502_3
pubmed: 17044767
Krishnamurthy VM, Wei G, Baird BC, Murtaugh M, Chonchol MB, Raphael KL, Greene T, Beddhu S (2012) High dietary fiber intake is associated with decreased inflammation and all-cause mortality in patients with chronic kidney disease. Kidney Int 81:300–306. https://doi.org/10.1038/ki.2011.355
doi: 10.1038/ki.2011.355
pubmed: 22012132
Nilsson LM, Winkvist A, Brustad M, Jansson JH, Johansson I, Lenner P, Lindahl B, Van Guelpen B (2012) A traditional Sami diet score as a determinant of mortality in a general northern Swedish population. Int J Circumpolar Health 71:1–12. https://doi.org/10.3402/ijch.v71i0.18537
doi: 10.3402/ijch.v71i0.18537
pubmed: 22584519
Bazzano LA, He J, Ogden LG, Loria CM, Whelton PK (2003) Dietary fiber intake and reduced risk of coronary heart disease in US men and women: the National Health and Nutrition Examination Survey I Epidemiologic Follow-up Study. Arch Intern Med 163:1897–1904. https://doi.org/10.1001/archinte.163.16.1897
doi: 10.1001/archinte.163.16.1897
pubmed: 12963562
Mann JI, Appleby PN, Key TJ, Thorogood M (1997) Dietary determinants of ischaemic heart disease in health conscious individuals. Heart 78:450–455
doi: 10.1136/hrt.78.5.450
Belle FN, Kampman E, McTiernan A, Bernstein L, Baumgartner K, Baumgartner R, Ambs A, Ballard-Barbash R, Neuhouser ML (2011) Dietary fiber, carbohydrates, glycemic index, and glycemic load in relation to breast cancer prognosis in the HEAL cohort. Cancer Epidemiol Biomark Prev 20:890–899. https://doi.org/10.1158/1055-9965.EPI-10-1278
doi: 10.1158/1055-9965.EPI-10-1278
Holmes MD, Stampfer MJ, Colditz GA, Rosner B, Hunter DJ, Willett WC (1999) Dietary factors and the survival of women with breast carcinoma. Cancer 86:826–835
doi: 10.1002/(SICI)1097-0142(19990901)86:5<826::AID-CNCR19>3.0.CO;2-0
Palli D, Russo A, Saieva C, Salvini S, Amorosi A, Decarli A (2000) Dietary and familial determinants of 10-year survival among patients with gastric carcinoma. Cancer 89:1205–1213
doi: 10.1002/1097-0142(20000915)89:6<1205::AID-CNCR3>3.0.CO;2-5
Yang Y, Zhao LG, Wu QJ, Ma X, Xiang YB (2015) Association between dietary fiber and lower risk of all-cause mortality: a meta-analysis of cohort studies. Am J Epidemiol 181:83–91. https://doi.org/10.1093/aje/kwu257
doi: 10.1093/aje/kwu257
pubmed: 25552267
Kim Y, Je Y (2016) Dietary fibre intake and mortality from cardiovascular disease and all cancers: a meta-analysis of prospective cohort studies. Arch Cardiovasc Dis 109:39–54. https://doi.org/10.1016/j.acvd.2015.09.005
doi: 10.1016/j.acvd.2015.09.005
pubmed: 26711548
Jessri M, Wolfinger RD, Lou WY, L’Abbe MR (2017) Identification of dietary patterns associated with obesity in a nationally representative survey of Canadian adults: application of a priori, hybrid, and simplified dietary pattern techniques. Am J Clin Nutr 105:669–684. https://doi.org/10.3945/ajcn.116.134684
doi: 10.3945/ajcn.116.134684
pubmed: 28148504
US Department of Health and Human Services; US Department of Agriculture (2015) 2015–2020 Dietary Guidelines for Americans. 8th ed. Washington, DC: US Dept of Health and Human Services. http://www.health.gov/DietaryGuidelines . Accessed 8 Nov 2017
Kimokoti RW, Millen BE (2016) Nutrition for the prevention of chronic diseases. Med Clin North Am 100:1185–1198. https://doi.org/10.1016/j.mcna.2016.06.003
doi: 10.1016/j.mcna.2016.06.003
pubmed: 27745589
Hartley L, May MD, Loveman E, Colquitt JL, Rees K (2016) Dietary fibre for the primary prevention of cardiovascular disease. Cochrane Database Syst Rev. https://doi.org/10.1002/14651858.CD011472.pub2
doi: 10.1002/14651858.CD011472.pub2
pubmed: 26758499
de Carvalho CM, de Paula TP, Viana LV, Machado VM, de Almeida JC, Azevedo MJ (2017) Plasma glucose and insulin responses after consumption of breakfasts with different sources of soluble fiber in type 2 diabetes patients: a randomized crossover clinical trial. Am J Clin Nutr 106:1238–1245. https://doi.org/10.3945/ajcn.117.157263
doi: 10.3945/ajcn.117.157263
pubmed: 28855225
Monfort-Pires M, Ferreira SRG (2016) Modification in a single meal is sufficient to provoke benefits in inflammatory responses of individuals at low-to-moderate cardiometabolic risk. Clin Nutr 35:1242–1250. https://doi.org/10.1016/j.clnu.2016.02.015
doi: 10.1016/j.clnu.2016.02.015
pubmed: 26987426
Donovan SM (2017) Introduction to the special focus issue on the impact of diet on gut microbiota composition and function and future opportunities for nutritional modulation of the gut microbiome to improve human health. Gut Microb 8:75–81. https://doi.org/10.1080/19490976.2017.1299309
doi: 10.1080/19490976.2017.1299309
Martinez-Gonzalez MA, Sanchez-Villegas A, De Irala J, Marti A, Martinez JA (2002) Mediterranean diet and stroke: objectives and design of the SUN project. Seguimiento Universidad de Navarra. Nutr Neurosci 5:65–73
doi: 10.1080/10284150290007047
Segui-Gomez M, de la Fuente C, Vazquez Z, de Irala J, Martinez-Gonzalez MA (2006) Cohort profile: the ‘Seguimiento Universidad de Navarra’ (SUN) study. Int J Epidemiol 35:1417–1422. https://doi.org/10.1093/ije/dyl223
doi: 10.1093/ije/dyl223
pubmed: 17060332
Martin-Moreno JM, Boyle P, Gorgojo L, Maisonneuve P, Fernandez-Rodriguez JC, Salvini S, Willett WC (1993) Development and validation of a food frequency questionnaire in Spain. Int J Epidemiol 22:512–519
doi: 10.1093/ije/22.3.512
Fernandez-Ballart JD, Pinol JL, Zazpe I, Corella D, Carrasco P, Toledo E, Perez-Bauer M, Martinez-Gonzalez MA, Salas-Salvado J, Martin-Moreno JM (2010) Relative validity of a semi-quantitative food-frequency questionnaire in an elderly Mediterranean population of Spain. Br J Nutr 103:1808–1816. https://doi.org/10.1017/S0007114509993837
doi: 10.1017/S0007114509993837
pubmed: 20102675
de la Fuente-Arrillaga C, Ruiz ZV, Bes-Rastrollo M, Sampson L, Martinez-Gonzalez MA (2010) Reproducibility of an FFQ validated in Spain. Public Health Nutr 13:1364–1372. https://doi.org/10.1017/S1368980009993065
doi: 10.1017/S1368980009993065
pubmed: 20105389
Mataix Verdu J (2009) Tabla de composición de alimentos [Food composition tables], 5th edn. Universidad de Granada, Granada
Moreiras O, Carbajal A, Cabrera L, Cuadrado C (2013) Tablas de composición de alimentos [Food composition tables], 16th edn. Piramide, Madrid
Trichopoulou A, Costacou T, Bamia C, Trichopoulos D (2003) Adherence to a Mediterranean diet and survival in a Greek population. N Engl J Med 348:2599–2608. https://doi.org/10.1056/NEJMoa025039
doi: 10.1056/NEJMoa025039
pubmed: 12826634
Martinez-Gonzalez MA, Lopez-Fontana C, Varo JJ, Sanchez-Villegas A, Martinez JA (2005) Validation of the Spanish version of the physical activity questionnaire used in the Nurses’ Health Study and the Health Professionals’ Follow-up Study. Public Health Nutr 8:920–927
doi: 10.1079/PHN2005745
Ainsworth BE, Haskell WL, Whitt MC, Irwin ML, Swartz AM, Strath SJ, O’Brien WL, Bassett DR Jr, Schmitz KH, Emplaincourt PO et al (2000) Compendium of physical activities: an update of activity codes and MET intensities. Med Sci Sports Exerc 32:S498–S504
doi: 10.1097/00005768-200009001-00009
Bes-Rastrollo M, Perez Valdivieso JR, Sanchez-Villegas A, Alonso A, Martinez-Gonzalez MA (2005) Validación del peso e índice de masa corporal auto-declarados de los participantes de una cohorte de graduados universitarios. [Validation of self-reported weight and body mass index of participants in a cohort of university graduates]. Rev Esp Obes 3:183–189
Hu FB, Stampfer MJ, Rimm E, Ascherio A, Rosner BA, Spiegelman D, Willett WC (1999) Dietary fat and coronary heart disease: a comparison of approaches for adjusting for total energy intake and modeling repeated dietary measurements. Am J Epidemiol 149:531–540
doi: 10.1093/oxfordjournals.aje.a009849
Ros E, Hu FB (2013) Consumption of plant seeds and cardiovascular health: epidemiological and clinical trial evidence. Circulation 128:553–565. https://doi.org/10.1161/CIRCULATIONAHA.112.001119
doi: 10.1161/CIRCULATIONAHA.112.001119
pubmed: 23897849
pmcid: 3745769
Darmadi-Blackberry I, Wahlquist ML, Kouris-Blazos A, Steen B, Lukito W, Horie Y, Horie K (2004) Legumes: the most important dietary predictors of survival in older people of different ethnicities. Asia Pac J Clin Nutr 13:217–220
pubmed: 15228991
Micha R, Shulkin ML, Penalvo JL, Khatibzadeh S, Singh GM, Rao M, Fahimi S, Powles J, Mozaffarian D (2017) Etiologic effects and optimal intakes of foods and nutrients for risk of cardiovascular diseases and diabetes: systematic reviews and meta-analyses from the Nutrition and Chronic Diseases Expert Group (NutriCoDE). PLoS One 12:e0175149. https://doi.org/10.1371/journal.pone.0175149
doi: 10.1371/journal.pone.0175149
pubmed: 28448503
pmcid: 5407851
Yao B, Fang H, Xu W, Yan Y, Xu H, Liu Y, Mo M, Zhang H, Zhao Y (2014) Dietary fiber intake and risk of type 2 diabetes: a dose-response analysis of prospective studies. Eur J Epidemiol 29:79–88. https://doi.org/10.1007/s10654-013-9876-x
doi: 10.1007/s10654-013-9876-x
pubmed: 24389767
Zhang Z, Xu G, Ma M, Yang J, Liu X (2013) Dietary fiber intake reduces risk for gastric cancer: a meta-analysis. Gastroenterology 145:113–120. https://doi.org/10.1053/j.gastro.2013.04.001
doi: 10.1053/j.gastro.2013.04.001
pubmed: 23567349
Song M, Wu K, Meyerhardt JA, Ogino S, Wang M, Fuchs CS, Giovannucci EL, Chan AT (2018) Fiber intake and survival after colorectal cancer diagnosis. JAMA 4:71–79. https://doi.org/10.1001/jamaoncol.2017.3684
doi: 10.1001/jamaoncol.2017.3684
Aune D, Chan DS, Greenwood DC, Vieira AR, Rosenblatt DA, Vieira R, Norat T (2012) Dietary fiber and breast cancer risk: a systematic review and meta-analysis of prospective studies. Ann Oncol 23:1394–1402. https://doi.org/10.1093/annonc/mdr589
doi: 10.1093/annonc/mdr589
pubmed: 22234738
Gibb RD, McRorie JW Jr, Russell DA, Hasselblad V, D’Alessio DA (2015) Psyllium fiber improves glycemic control proportional to loss of glycemic control: a meta-analysis of data in euglycemic subjects, patients at risk of type 2 diabetes mellitus, and patients being treated for type 2 diabetes mellitus. Am J Clin Nutr 102:1604–1614. https://doi.org/10.3945/ajcn.115.106989
doi: 10.3945/ajcn.115.106989
pubmed: 26561625
Emilien CH, Hsu WH, Hollis JH (2017) Effect of resistant wheat starch on subjective appetite and food intake in healthy adults. Nutrition 43–44:69–74. https://doi.org/10.1016/j.nut.2017.06.020
doi: 10.1016/j.nut.2017.06.020
pubmed: 28935147
Jiao J, Xu JY, Zhang W, Han S, Qin LQ (2015) Effect of dietary fiber on circulating C-reactive protein in overweight and obese adults: a meta-analysis of randomized controlled trials. Int J Food Sci Nutr 66:114–119. https://doi.org/10.3109/09637486.2014.959898
doi: 10.3109/09637486.2014.959898
pubmed: 25578759
Wannamethee SG, Whincup PH, Thomas MC, Sattar N (2009) Associations between dietary fiber and inflammation, hepatic function, and risk of type 2 diabetes in older men: potential mechanisms for the benefits of fiber on diabetes risk. Diabetes Care 32:1823–1825. https://doi.org/10.2337/dc09-0477
doi: 10.2337/dc09-0477
pubmed: 19628814
pmcid: 2752933
Sonnenburg JL, Backhed F (2016) Diet-microbiota interactions as moderators of human metabolism. Nature 535:56–64. https://doi.org/10.1038/nature18846
doi: 10.1038/nature18846
pubmed: 27383980
pmcid: 5991619
Eshak ES, Iso H, Date C, Kikuchi S, Watanabe Y, Wada Y, Wakai K, Tamakoshi A (2010) Dietary fiber intake is associated with reduced risk of mortality from cardiovascular disease among Japanese men and women. J Nutr 140:1445–1453. https://doi.org/10.3945/jn.110.122358
doi: 10.3945/jn.110.122358
pubmed: 20573945
Pietinen P, Rimm EB, Korhonen P, Hartman AM, Willett WC, Albanes D, Virtamo J (1996) Intake of dietary fiber and risk of coronary heart disease in a cohort of Finnish men. The Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study. Circulation 94:2720–2727
doi: 10.1161/01.CIR.94.11.2720
Threapleton DE, Greenwood DC, Evans CE, Cleghorn CL, Nykjaer C, Woodhead C, Cade JE, Gale CP, Burley VJ (2013) Dietary fibre intake and risk of cardiovascular disease: systematic review and meta-analysis. BMJ 347:f6879. https://doi.org/10.1136/bmj.f6879
doi: 10.1136/bmj.f6879
pubmed: 24355537
pmcid: 3898422
Threapleton DE, Greenwood DC, Evans CE, Cleghorn CL, Nykjaer C, Woodhead C, Cade JE, Gale CP, Burley VJ (2013) Dietary fiber intake and risk of first stroke: a systematic review and meta-analysis. Stroke 44:1360–1368. https://doi.org/10.1161/STROKEAHA.111.000151
doi: 10.1161/STROKEAHA.111.000151
Aune D, Chan DS, Lau R, Vieira R, Greenwood DC, Kampman E, Norat T (2011) Dietary fibre, whole grains, and risk of colorectal cancer: systematic review and dose-response meta-analysis of prospective studies. BMJ 343:d6617. https://doi.org/10.1136/bmj.d6617
doi: 10.1136/bmj.d6617
pubmed: 22074852
pmcid: 3213242
U.S. Department of Health and Human Services. U.S. Food & Drug Administration (2017). https://www.fda.gov/food/ingredientspackaginglabeling/labelingnutrition/ucm528582.htm . Accessed 8 Nov 2017
Ungar PS, Sponheimer M (2011) The diets of early hominins. Science 334:190–193. https://doi.org/10.1126/science.1207701
doi: 10.1126/science.1207701
pubmed: 21998380
Tuohy KM, Gougoulias C, Shen Q, Walton G, Fava F, Ramnani P (2009) Studying the human gut microbiota in the trans-omics era—focus on metagenomics and metabonomics. Curr Pharm Des 15:1415–1427
doi: 10.2174/138161209788168182
Ryan KK, Seeley RJ (2013) Physiology. Food as a hormone. Science 339:918–919. https://doi.org/10.1126/science.1234062
doi: 10.1126/science.1234062
pubmed: 23430646
pmcid: 4240228
Tolhurst G, Heffron H, Lam YS, Parker HE, Habib AM, Diakogiannaki E, Cameron J, Grosse J, Reimann F, Gribble FM (2012) Short-chain fatty acids stimulate glucagon-like peptide-1 secretion via the G-protein-coupled receptor FFAR2. Diabetes 61:364–371. https://doi.org/10.2337/db11-1019
doi: 10.2337/db11-1019
pubmed: 22190648
pmcid: 3266401
Sun Q, Geng Z, Willett W, Hu F (2016) Re: The use of food frequency questionnaires (FFQs) is both pseudo-scientific and illogical. BMJ 355:i5796
pubmed: 27881409
pmcid: 5121105