Jun/July: Issue 145

Page 6 - News by Emma Coates
OBESITY: AN EVER-INCREASING FACTOR IN HOSPITAL ADMISSIONS
1. A secondary diagnosis of obesity does not necessarily indicate obesity as a contributing factor for the admission but may instead indicate that obesity is a factor relevant to a patient's episode of care.
2. Admissions relate to inpatients only. Some (though not all) of this increase may be due to hospitals being more likely to record obesity as a secondary diagnosis than they were previously. See the Data Quality Statement for more information.
3. Taken from the Hospital Episode Statistics - https://digital.nhs.uk/data-and-information/publications/statistical/hospital-admitted-patient-care-activity/2017-18 dataset
4. As in footnote 2, a secondary diagnosis of obesity does not necessarily indicate obesity as a contributing factor for the admission but may instead indicate that obesity is a factor relevant to a patient's episode of care.
5. A finished consultant episode (FCE) is a continuous period of admitted patient care under one consultant within one healthcare provider.
6. These figures are admissions with a primary diagnosis of obesity and a main or secondary procedure of bariatric surgery.
7. This prescribing data was obtained from the electronic Prescribing Analysis and Cost tool (ePACT) system, maintained by NHS Prescription Services, a division of NHS Business Services Authority.
8. The NIC is the basic cost of a drug as listed in the Drug Tariff or price lists; it does not include discounts, dispensing costs, prescription charges or fees.
9. These figures were drawn from previously published data, 'Health Survey for England, 2017' https://digital.nhs.uk/data-and-information/publications/statistical/health-survey-for-england/2017
10. These figures were drawn from previously published data, 'National Child Measurement Programme - England 2017-18' https://digital.nhs.uk/data-and-information/publications/statistical/national-child-measurement-programme/2017-18-school-year 95% of eligible children were measured in 2017/18.
11. Based on the Index of Multiple Deprivation (IMD) which is a measure of the overall deprivation experienced by people living in a neighbourhood. IMD rankings have been split into quintiles. They are calculated by the Department for Communities and Local Government: English Indices of Deprivation 2015. www.gov.uk/government/statistics/english-indices-of-deprivation-2015

Page 11 – TELEHEALTH FOR DIET AND DIABETES by Ruth Barclay-Paterson
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2. Scottish Government. A national telehealth and telecare delivery plan for Scotland to 2015. Edinburgh: Scottish Government; 2012.
3. The King's Fund. Tackling the growing crisis in the NHS [Internet]. The King's Fund. 2016 [cited 4 March 2019]. Available from: https://www.kingsfund.org.uk/publications/articles/nhs-agenda-for-action
4. Diabetes UK. Diabetes Prevalence 2018 [Internet]. Diabetes UK. 2019 [cited 4 March 2019]. Available from: https://www.diabetes.org.uk/professionals/position-statements-reports/statistics/diabetes-prevalence-2018
5. Diabetes UK. More than 700 people a day diagnosed with diabetes [Internet]. Diabetes UK. 2014 [cited 4 March 2019]. Available from: https://www.diabetes.org.uk/about_us/news/more-than-700-a-day-diagnosed-with-diabetes
6. Diabetes UK. Diabetes UK Facts and Stats [Internet]. Diabetes.org.uk. 2019 [cited 4 March 2019]. Available from: https://www.diabetes.org.uk/resources-s3/2019-02/1362B_Facts%20and%20stats%20Update%20Jan%202019_LOW%20RES_EXTERNAL.pdf
7. 7. NHS. Type 2 diabetes [Internet]. nhs.uk. 2019 [cited 4 March 2019]. Available from: https://www.nhs.uk/conditions/type-2-diabetes/
8. Long Term Conditions Alliance Scotland. [Internet]. Alliance-scotland.org.uk. 2010 [cited 4 March 2019]. Available from: https://www.alliance-scotland.org.uk/wp-content/uploads/2018/01/ALLIANCE-annualreport-2010.pdf
9. Haas L, Maryniuk M, Beck J, Cox C, Duker P, Edwards L et al. National Standards for Diabetes Self-Management Education and Support. Diabetes Care. 2013;37(Supplement_1):S144-S153.
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11. NHS Scotland. The Healthcare Quality Strategy for NHSScotland [Internet]. Gov.scot. 2010 [cited 4 March 2019]. Available from: https://www.gov.scot/resource/doc/311667/0098354.pdf/
12. McLean S, Protti D, Sheikh A. Telehealthcare for long term conditions. BMJ. 2011;342(feb03 2):d120-d120.
13. VanWormer J, Boucher J, Pronk N. Telephone-Based Counseling Improves Dietary Fat, Fruit, and Vegetable Consumption: A Best-Evidence Synthesis. Journal of the American Dietetic Association. 2006;106(9):1434-1444.
14. Goode A, Reeves M, Eakin E. Telephone-Delivered Interventions for Physical Activity and Dietary Behavior Change. American Journal of Preventive Medicine. 2012;42(1):81-88.
15. Kohl L, Crutzen R, de Vries N. Online Prevention Aimed at Lifestyle Behaviours: A Systematic Review of Reviews. Journal of Medical Internet Research. 2013;15(7):e146.
16. NHS Scotland. Scottish Diabetes Survey 2017 [Internet]. 2017. Available from: http://www.diabetesinscotland.org.uk/Publications/SDS%202017.pdf
17. PEN: Practice-based Evidence in Nutrition. PEN: Practice-based Evidence in Nutrition [Internet]. Pennutrition.com. 2017 [cited 3 May 2019]. Available from: http://www.pennutrition.com/KnowledgePathway.aspx?kpid=18478
18. Scottish Public Health Observatory. Data introduction - ScotPHO [Internet]. Scotpho.org.uk. 2018 [cited 7 April 2019]. Available from: https://www.scotpho.org.uk/health-wellbeing-and-disease/diabetes/data/data-introduction/
19. Beck J, Greenwood D, Blanton L, Bollinger S, Butcher M, Condon J et al. 2017 National Standards for Diabetes Self-Management Education and Support. Diabetes Care. 2017;40(10):1409-1419.

Page 15 - HEALTHY EATING AND LIFESTYLE TO REDUCE THE RISK OF DEMENTIA by Gill Hooper
References
All web links accessed 11.04.19
1. www.dementiastatistics.org/statistics-about-dementia/
2. https://newsroom.saga.co.uk/news/dementia-more-feared-than-cancer-new-saga-survey-reveals
3. www.dementiastatistics.org/statistics-about-dementia/
4. www.joindementiaresearch.nihr.ac.uk/content/about
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7. www.dashdiet.org
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11. Livingston G et al. Dementia prevention, intervention and care. The Lancet. July 2017
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Page 19 - UNDERSTANDING COW’S MILK PROTEIN ALLERGY IN INFANTS by Olivia Chaffey
1. Kneepkens C and Meijer Y (2009). Clinical practice. Diagnosis and treatment of cow’s milk allergy. European Journal of Paediatrics, 168(8), p 891-896
2. ACT on Cow’s Milk Allergy (2019). Cow’s Milk Allergy can be difficult to spot (online) available from www.cowsmilkallergy.co.uk/ (accessed 15/03/2019)
3. Cow’s milk protein allergy in children: identification and treatment (2018). The Pharmaceutical Journal, 300 (7913)
4. Greer F, Sicherer S and Burks A (2008). Effects of Early Nutritional Interventions on the development of Atopic Disease in Infants and Children: The Role of Maternal Dietary Restriction, Breastfeeding, Timing of Introduction and Complementary Foods, and Hydrolysed Formulas. PEDIATRICS, 121(1), p 183-191
5. Allergy UK (2017). Does my child have a Cow’s Milk Allergy? (online) available from https://www.allergyuk.org/assets/000/000/791/CMA_6_Page_original.pdf?1501583691(accessed 02/04/2019)
6. Gandy J (2014). Manual of dietetic practice. 5th ed. John Wiley & Sons, p 727
7. Allergy UK (2019). CMA Awareness (online) available from https://www.allergyuk.org/cma-campaign > (accessed 15/03/2019)
8. National Institute for Health and Care Excellence (2011). Food allergy in under 19s: assessment and diagnosis (online) available from www.nice.org.uk/guidance/cg116/chapter/1-Guidance#non-ige-mediated-food-allergy (accessed 05/04/2019
9. Allergy UK (2016). The iMAP Milk Allergy Guideline – Initial Fact Sheet for Parents (online) available from www.allergyuk.org/assets/000/001/299/iMAP_Patient_Factsheet_original.pdf?1502805714 (accessed 03/03/2019)
10. Australasian Society of Clinical Immunology and Allergy (2015). Dietary avoidance – cow’s milk protein (dairy) allergy (online) available from www.allergy.org.au/images/pcc/ASCIA_PCC_Dietary_avoidance_cows_milk_2015.pdf (accessed 03/04/2019)
11. National Institute for Health and Care Excellence (2015). Cow’s milk protein allergy in children (online) available from https://cks.nice.org.uk/cows-milk-protein-allergy-in-children > (accessed 17/03/2019)
12. The Association of UK Dietitians (2019). Food Allergy Diet Sheets (online) available from www.bda.uk.com/regionsgroups/groups/foodallergy/diet_sheets (accessed 19/03/2019)
13. Allergy UK (2017). Cow’s Milk free Diet Information for Babies and Children (online) available from https://www.allergyuk.org/assets/000/001/207/Cow's_Milk_Free_Diet_Information_for_Babies_and_Children_original.pdf?1501228993 (accessed 03/04/2019)
14. Allergy UK (2019). Healthcare Professional Factsheet – on the use of iMAP (online) available from www.allergyuk.org/assets/000/001/601/iMAP-Additional_Tool_for_HCPs-5RM_-TB_original.pdf?1516359334 (accessed 01/04/2019)
15. NHS (2018). Your pregnancy and baby guide (online) available from www.nhs.uk/conditions/pregnancy-and-baby/drinks-and-cups-children/ (accessed 02/04/2019)
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17. Venter C, Brown T, Meyer R, Walsh J, Shah N, Nowak-Wegrzyn A, Chen T, Fleischer D, Heine R, Levin M, Vieira M and Fox A (2017). Better recognition, diagnosis and management of non-IgE-mediated cow’s milk allergy in infancy: iMAP - an international interpretation of the MAP (Milk Allergy in Primary Care) guideline. Clinical and Translational Allergy, 7(1)
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Page 27 - IRRITABLE BOWEL SYNDROME by Jessica English RD
1. Canavan C et al. The epidemiology of irritable bowel syndrome. Clin Epidemiol. 2014; 6: 71-80
2. NICE Clinical Knowledge Summaries: Guidelines for IBS. Available online at: https://cks.nice.org.uk/irritable-bowel-syndrome#!backgroundSub (accessed online 04/05/2019)
3. NICE Clinical Knowledge Summaries: Guidelines for IBS. Available online at: https://cks.nice.org.uk/irritable-bowel-syndrome#!diagnosisSub:1 (accessed online 03/05/2019)
4. Lovell RM and Ford AC (2012). Global prevalence of and risk factors for irritable bowel syndrome: a meta-analysis. Clin Gastroenterol Hepatol 10, e4
5. Bonfiglio F et al. Female-specific Association between Variants on Chromosome 9 and Self-reported Diagnosis of Irritable Bowel Syndrome. Gastroenterology, 2018
6. Hoi Leong Xavier Wong et al. Early life stress disrupts intestinal homeostasis via NGF-TrkA signalling. Nat Commun 2019 04 15; 10(1): 1745. Epub 2019 Apr 15
7. Hayes PA, Fraher MH and Quigley EM (2014). Irritable bowel syndrome: the role of food in pathogenesis and management. Gastroenterol Hepatol 10, 164-174
8. Lacy BE, Weiser K and De Lee R (2009). The treatment of irritable bowel syndrome. Ther Adv Gastroenterol 2, 221-238
9. McKenzie YA et al. British Dietetic Association systematic review and evidence-based practice guidelines for the dietary management of irritable bowel syndrome in adults (2016 update). J Hum Nutr Diet, 2016. 29(5): p 549-75
10. Rossi M et al. Volatile Organic Compounds in Faeces Associated with Response to Dietary Intervention in Patients with Irritable Bowel Syndrome. Clinical Gastroenterology and Hepatology, Vol 16, Issue 3, March 2018, p 385-391.e1
11. Diduch BK. Gastrointestinal Conditions in the Female Athlete. Clin Sports Med. 2017 Oct; 36(4): 655-669
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13. Johannesson E et al. Intervention to increase physical activity in irritable bowel syndrome shows long-term positive effects, World J Gastroenterol. 2015 Jan 14; 21(2): 600-608
14. Schumann D, Langhorst J, Dobos G, Cramer H. Randomised clinical trial: yoga vs a low-FODMAP diet in patients with irritable bowel syndrome. Aliment Pharmacol Ther. 2018 Jan; 47(2): 203-211
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21. Peters SL et al. Randomised clinical trial: the efficacy of gut-directed hypnotherapy is similar to that of the low-FODMAP diet for the treatment of irritable bowel syndrome. Aliment Pharmacol Ther, 2016. 44(5): p. 447-59
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23. McKenzie YA et al. British Dietetic Association systematic review of systematic reviews and evidence-based practice guidelines for the use of probiotics in the management of irritable bowel syndrome in adults (2016 update). J Hum Nutr Diet. 2016 Oct; 29(5): 576-92
24. Jose-Walter Huaman et al. Effects of Prebiotics vs a Diet Low in FODMAPs in Patients with Functional Gut Disorders. Gastroenterology. 2018 Oct; 155(4): 1004-1007
25. Quigley BM et al. (Can't Get No) Patient Satisfaction: The Predictive Power of Demographic, GI, and Psychological Factors in IBS Patients. J Clin Gastroenterol. 2018 Aug; 52(7): 614-621

Page 31 - THE FLEXITARIAN DIET: IS IT JUST A FAD? By Tabitha Ward
1. Eating Better (2017). The future of eating is flexitarian [online]. Available from: https://www.eating-better.org/uploads/Documents/2017/Eating%20Better_The%20future%20of%20eating%20is%20flexitarian.pdf
2. Oxford English Dictionary (2014). The Definitive Record of the English Language [online]. Available from: www.oed.com
3. Streit L (2018). The Flexitarian Diet: A Detailed Beginner's Guide [online]. Healthline [viewed 14/0319]. Available from: www.healthline.com/nutrition/flexitarian-diet-guide
4. Clavijo K and Wu B (2016). Why Popular Diets Don't Work: A Systemic Review and Implications for Educators. ISBN 14994046
5. Humane Research Council (2014). Study of Current and Former Vegetarians and Vegans [online]. HRC. Available from: https://faunalytics.org/wp-content/uploads/2015/06/Faunalytics_Current-Former-Vegetarians_Full-Report.pdf
6. Crew B (2014). New Study Reveals 84% of Vegetarians Return to Meat [online]. Science Alert [viewed 14/03/19]. Available from: www.sciencealert.com/new-study-reveals-84-of-vegetarians-return-to-meat
7. Randles A. What is the flexitarian diet? [online]. Available from: https://theflexitarian.co.uk/flexitarian-diet-2/
8. Dinu M, Pagliai G, Casini A and Sofi F (2016). Vegetarian, vegan diets and multiple health outcomes: a systematic review with meta-analysis of observational studies. European Heart Journal; Eur Heart J. 37 p 549-549
9. Derbyshire EJ (2016).Flexitarian Diets and Health: A Review of the Evidence-Based Literature. ISBN 2296-861X
10. Damian Carrington (2018). Avoiding meat and dairy is 'single biggest way' to reduce your impact on earth; biggest analysis to date reveals huge footprint of livestock – it provides just 18% of calories, but takes up 83% of farmland. Guardian Newspapers ISBN 0261-3077
11. Oxford University (2018). Balanced plant-based diets improve our health and the health of the planet [online]. University of Oxford. Available from: www.ox.ac.uk/news/2018-10-12-balanced-plant-based-diets-improve-our-health-and-health-planet
12. McEvoy CT, Temple N and Woodside JV (2012). Vegetarian diets, low-meat diets and health: a review. 15(12), p 2287-2294

Page 35 - ORAL NUTRITIONAL SUPPLEMENTS: THE RANGE AVAILABLE AND HOW TO USE THEM by Evelyn Toner RD
1. National Institute for Clinical Excellence (NICE) (2006). Nutrition Support for Adults: Oral Nutrition Support, Enteral Tube Feeding and Parenteral Nutrition CG 32. Accessed 03.05.19 www.nice.org.uk/guidance/cg32
2. Wilson L (2017). Malnutrition Task Force: State of the Nation, Older people and malnutrition in the UK Today. Accessed 03/05/19 www.malnutritiontaskforce.org.uk/wp-content/uploads/2017/10/AW-5625-Age-UK-MTF_Report.pdf
3. Elia M and Russell C (2009). Combating malnutrition; Recommendations for Action. Accessed 03/05/19 www.bapen.org.uk/pdfs/reports/advisory_group_report.pdf
4. Elia M (2015). The cost of malnutrition in England and potential cost savings from nutritional interventions. A report on the cost of disease-related malnutrition in England and a budget impact analysis of implementing the NICE clinical guidelines/quality standard on nutritional support in adults. Accessed 03/05/19 www.bapen.org.uk/pdfs/economic-report-short.pdf
5. Ruxton C (2015). ONS and the power of taste. Dietetics Today. Accessed 07/05/19 www.bda.uk.com/dt/articles/ons_the_power_taste
6. Stratton RJ and Elia M (2007). A review of reviews: A new look at the evidence for oral nutritional supplements in clinical practice. Clinical Nutrition Supplements 2:5-23
7. Philipson TJ et al (2013). Impact of oral nutritional supplementation on hospital outcomes. Am J Manag Care 19: 121-128
8. Elia M et al (2009). The cost of disease-related malnutrition in the UK and economic considerations for the use of oral nutritional supplements (ONS) in adults. BAPEN. Accessed 03/05/19 www.bapen.org.uk/pdfs/health_econ_exec_sum.pdf
9. Lad H et al (2005). Elderly patients’ compliance and elderly patients’ and health professionals’ views, and attitudes towards prescribed sip-feed supplements. J Nutr Health Aging 9: 310-314
10. Ozcagli TG et al (2013). A study in four European countries to examine the importance of sensory attributes of oral nutritional supplements on preference and likelihood of compliance. Turk J Gastroenterol 24: 266-272
11. BAPEN (2016). Oral Nutritional Supplements (ONS). www.bapen.org.uk/nutrition-support/nutrition-by-mouth/oral-nutritional-supplements. Accessed 03/05/19

Page 40 - LOW-PROTEIN FOODS: COST-EFFECTIVE PRESCRIBING - By Catherine Kidd
1. Shaw V (eds) 2007. Clinical Paediatric Dietetics. 4th Edition. Oxford: Wiley Blackwell
2. NSPKU – the prescription of low-protein foods in PKU. Accessed at: www.NSPKU.org [Accessed on: 2nd May 2019]
3. Ford S (2018). The costs of a special diet. Network Health Digest Feb 19 issue 141; p 35-39. Available online https://issuu.com/nhpublishingltd/docs/issue_141_the_costs_of_a_special_di?e=14357770/68024599
4. NHS London Procurement Partnership. www.lpp.nhs.uk/ [Accessed on: 2nd May 2019]
5. Manual for Prescribed Specialised Services 2018/19. www.england.nhs.uk/wp-content/uploads/2017/10/prescribed-specialised-services-manual.pdf [Accessed on: 2nd May 2019]
6. Report of Responses Following the Public Consultation on Gluten-Free Prescribing: Availability of Gluten-Free Food on Prescription in Primary Care. https://assets.publishing.service.gov.uk/government/uploads/system/uploads/attachment_data/file/678181/report_of_responses_-_gluten_free_food_prescribing_consultation.pdf [Accessed on: 2nd May 2019]

Page 45 TYROSINAEMIA - By Harriet Churchill
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2. Nutricia. Guidelines for the Nutritional Management of Tyrosinaemia Type I. A Practical Guide for the use of TYR products [Internet]. [Cited 30th April 2019]. Available from: www.nutricialearningcenter.com/globalassets/pdfs/metabolics/tyr_guidelines
3. de Laet et al. Recommendations for the management of tyrosinaemia type 1. Orphanet journal of rare diseases. Orphanet J Rare Dis. 2013 Jan 11 ;8: 8. [Internet]. [Cited 30th April 2019]. Available from: www.researchgate.net/publication/234120716_Recommendations_for_the_management_of_tyrosinaemia_type_1
4. Hollak CEM, Lachmann R. Inherited metabolic disease in adults: a clinical guide. Section 3 Disorders of Protein Metabolism, 13. Tyrosinaemia Type 1. Oxford University Press; 2016. p 93-96
5. Chakrapani A et al. Disorders of Tyrosine Metabolism. In: Saudubray JM, et al, eds. Inborn Metabolic Diseases: Diagnosis and Treatment. 5th ed. Heidelberg, Germany: Springer; 2012: 265-76
6. Lock AE et al. From toxicological problem to therapeutic use: the discovery of the mode of action of 2-(2-nitro-4-trifluoromethylbenzoyl)-1,3-cyclohexanedione (NTBC), its toxicology and development as a drug. J Inherit Metab Dis. 1998 Aug; 21 (5): 498-506. [Internet]. [Cited 30th April 2019]. Available from: www.ncbi.nlm.nih.gov/pubmed/9728330
7. van Spronsen FJ et al. Dietary Considerations in Tyrosinaemia Type I. Adv Exp Med Biol. 2017; 959: 197-204. [Internet]. [Cited 30th April 2019]. Available from: www.ncbi.nlm.nih.gov/pubmed/28755197
8. Dixon M, Macdonald A, White F and Stafford J (2014). Disorders of Amino Acid Metabolism, Organic Acidaemias and Urea Cycle Disorders in Clinical Paediatric Dietetics Ed Shaw V, 4th Ed, Wiley Blackwell, Oxford 381-525. [Internet]. [Cited 30th April 2019]. Available from: https://onlinelibrary.wiley.com/doi/abs/10.1002/9781118915349.ch17
9 de Laet C et al. Neuropsychological outcome of NTBC-treated patients with tyrosinaemia type 1; Developmental Medicine & Child Neurology. 2011. 53; 962-964. [Internet]. [Cited 30th April 2019]. Available from: https://onlinelibrary.wiley.com/doi/full/10.1111/j.1469-8749.2011.04048.x
10 Vitaflo USA. TYR Sphere. [Internet]. [Cited 30th April 2019]. Available from: www.nestlehealthscience.us/Vitaflo-USA/inborn-errors-of-metabolism/protein-metabolism/tyrosinemia/TYR-sphere
11 Van Calcar SC, Ney DM. Food products made with glycomacropeptide, a low-phenylalanine whey protein, provide a new alternative to amino-acid-based medical foods for nutrition management of phenylketonuria. J Acad Nutr Diet. 2012 Aug; 112(8): 1201-10. [Internet]. [Cited 30th April 2019]. Available from: www.ncbi.nlm.nih.gov/pubmed/22818728
12 MacDonald A, Gokmen-Ozel H, van Rijn M et al. The reality of dietary compliance in the management of phenylketonuria. J Inherit Metab Dis. 2010. 33: 665. [Internet]. [Cited 30th April 2019]. Available from: https://doi.org/10.1007/s10545-010-9073-y
13 NSPKU. Dietary information for the treatment of Phenylketonuria (2016/2017). Revised April 2019. [Internet]. [Cited 30th April 2019]. Available from: www.nspku.org/sites/default/files/publications/Dietary%20Information%20for%20the%20Treatment%20of%20PKU%202016-2017_Revised%20April%202019.pdf
14 Schlump JU, Perot C, Ketteler K, Schiff M, Mayatepek E, Wendel U, Spiekerkoetter U. Severe neurological crisis in a patient with hereditary tyrosinaemia type I after interruption of NTBC treatment. J Inherit Metab Dis. 2008 Dec; 31 Suppl 2(): S223-5. [Internet]. [Cited 30th April 2019]. Available from: www.ncbi.nlm.nih.gov/pubmed/18500574
15 NSPKU. The prescription of low-protein foods in PKU (2017) [Internet]. [Cited 30th April 2019]. Available from: www.nspku.org/sites/default/files/publications/Prescription%20guidelines.pdf
16 Thimm E, Herebian D, Assmann B, Klee D, Mayatepek E, Spiekerkoetter U. Increase of CSF tyrosine and impaired serotonin turnover in tyrosinaemia type I. Mol Genet Metab. 2011 Feb; 102(2): 122-5. [Internet]. [Cited 30th April 2019]. Available from: www.ncbi.nlm.nih.gov/pubmed/21112803
17 Daly A, Gokmen-Ozel H, MacDonald A, Preece MA, Davies P, Chakrapani A, McKiernan P. Diurnal variation of phenylalanine concentrations in tyrosinaemia type 1: should we be concerned? J Hum Nutr Diet. 2012 Apr; 25(2): 111-6. [Internet]. [Cited 30th April 2019]. Available from: www.ncbi.nlm.nih.gov/pubmed/22168396