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Quality of Life Research

, Volume 27, Issue 1, pp 195–204 | Cite as

Perceived medication adherence barriers mediating effects between gastrointestinal symptoms and health-related quality of life in pediatric inflammatory bowel disease

  • James W. VarniEmail author
  • Robert J. Shulman
  • Mariella M. Self
  • Shehzad A. Saeed
  • George M. Zacur
  • Ashish S. Patel
  • Samuel Nurko
  • Deborah A. Neigut
  • James P. Franciosi
  • Miguel Saps
  • Jolanda M. Denham
  • Chelsea Vaughan Dark
  • Cristiane B. Bendo
  • John F. Pohl
  • On Behalf of the Pediatric Quality of Life Inventory™ Gastrointestinal Symptoms Module Testing Study Consortium
Article

Abstract

Objectives

The primary objective was to investigate the mediating effects of patient-perceived medication adherence barriers in the relationship between gastrointestinal symptoms and generic health-related quality of life (HRQOL) in adolescents with inflammatory bowel disease (IBD). The secondary objective explored patient health communication and gastrointestinal worry as additional mediators with medication adherence barriers in a serial multiple mediator model.

Methods

The Pediatric Quality of Life Inventory™ Gastrointestinal Symptoms, Medicines, Communication, Gastrointestinal Worry, and Generic Core Scales were completed in a 9-site study by 172 adolescents with IBD. Gastrointestinal Symptoms Scales measuring stomach pain, constipation, or diarrhea and perceived medication adherence barriers were tested for bivariate and multivariate linear associations with HRQOL. Mediational analyses were conducted to test the hypothesized mediating effects of perceived medication adherence barriers as an intervening variable between gastrointestinal symptoms and HRQOL.

Results

The predictive effects of gastrointestinal symptoms on HRQOL were mediated in part by perceived medication adherence barriers. Patient health communication was a significant additional mediator. In predictive analytics models utilizing multiple regression analyses, demographic variables, gastrointestinal symptoms (stomach pain, constipation, or diarrhea), and perceived medication adherence barriers significantly accounted for 45, 38, and 29 percent of the variance in HRQOL (all Ps < 0.001), respectively, demonstrating large effect sizes.

Conclusions

Perceived medication adherence barriers explain in part the effects of gastrointestinal symptoms on HRQOL in adolescents with IBD. Patient health communication to healthcare providers and significant others further explain the mechanism in the relationship between gastrointestinal symptoms, perceived medication adherence barriers, and HRQOL.

Keywords

Inflammatory bowel disease Crohn’s disease Ulcerative colitis Gastrointestinal symptoms Medication adherence barriers Patient communication PedsQL 

Abbreviations

HRQOL

Health-related quality of life

IBD

Inflammatory bowel disease

PedsQL™

Pediatric Quality of Life Inventory™

Notes

Acknowledgements

Investigators for the Pediatric Quality of Life Inventory™ Gastrointestinal Symptoms Module Testing Study Consortium

The PedsQL™ Gastrointestinal Symptoms Module Testing Study Consortium sites include a Network and Statistical Center at the Center for Health Systems & Design, Colleges of Architecture and Medicine, Texas A&M University, College Station, TX (PI: James W. Varni, PhD), and 9 primary research data collection sites: Division of Pediatric Gastroenterology, Nationwide Children’s Hospital, Ohio State University School of Medicine, Columbus, OH (PI: Jolanda Denham, MD); Department of Pediatrics, Baylor College of Medicine, Children’s Nutrition Research Center, Texas Children’s Hospital, Houston, TX (PIs: Robert J. Shulman, MD and Mariella M. Self, PhD); Division of Gastroenterology, Hepatology and Nutrition, Children’s Hospital Colorado, Aurora, CO (PI: Deborah A. Neigut, MD); Center for Motility and Functional Gastrointestinal Disorders, Boston Children’s Hospital, Harvard Medical School, Boston, MA (PI: Samuel Nurko, MD); Division of Pediatric Gastroenterology, Children’s Medical Center of Dallas, University of Texas Southwestern Medical School, Dallas, TX (PI: Ashish S. Patel, MD); Division of Gastroenterology, Hepatology and Nutrition, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH (PIs: James P. Franciosi, MD, Shehzad Saeed, MD, and George M. Zacur, MD); Division of Gastroenterology, Hepatology and Nutrition, Lurie Children’s Hospital of Chicago, Northwestern University Feinberg School of Medicine, Chicago, IL (PI: Miguel Saps, MD); Division of Pediatric Gastroenterology, Hepatology and Nutrition, Goryeb Children’s Hospital, Morristown Medical Center, Morristown, NJ (PI: Barbara Verga, MD); Department of Pediatric Gastroenterology, Primary Children’s Hospital, University of Utah, Salt Lake City, UT (PI: John F. Pohl, MD)

Funding

No funding was specifically designated for the PedsQL™ Gastrointestinal Symptoms Module field test study data collection effort or manuscript preparation.

Compliance with ethical standards

Conflict of interest

Item development for the PedsQL™ Gastrointestinal Symptoms Module was previously supported by Takeda Pharmaceuticals North America, Inc. Data collection for the healthy controls sample was supported by intramural funding from the Texas A&M University Foundation. Dr. Varni holds the copyright and the trademark for the PedsQL™ and receives financial compensation from the Mapi Research Trust, which is a nonprofit research institute that charges distribution fees to for-profit companies that use the PedsQL™. Dr. Varni received investigator-initiated funding from Takeda Pharmaceuticals North America, Inc. (Deerfield, Illinois) for the previous item generation qualitative methods study. Dr. Pohl received investigator-initiated funding from Takeda Pharmaceuticals North America, Inc. (Deerfield, Illinois) for the previous item generation qualitative methods study. Drs. Varni and Pohl did not receive funding from Takeda Pharmaceuticals North America, Inc. for the current quantitative methods field test study. Dr. Pohl has received the following funding: INSPPIRE to Study Acute Recurrent and Chronic Pancreatitis is Children, Grant #10987759, National Institutes of Health (NIH), National Institute of Diabetes and Digestive and Kidney Diseases. Dr. Pohl is on the speaker’s bureau for Medical Education Resources, Inc. Dr. Shulman is supported by NIH grants R01 NR013497 and T32 DK007664 and receives research funding from Mead-Johnson and is a consultant for Nutrinia. Dr. Nurko is supported by NIH grant K24DK082792A. Dr Saeed is on the speaker’s bureau for Abbvie, Inc. These grants are not related to the current study. The other authors report no competing interests related to this study.

Informed consent

Informed consent was obtained from all individual participants included in the study.

Research involving human subjects

The research protocol for the field test study was approved by the Institutional Review Board at each participating institution. All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional research committees.

References

  1. 1.
    Benchimol, E. I., Fortinsky, K. J., Gozdyra, P., Van den Heuvel, M., Van Limbergen, J., & Griffiths, A. M. (2011). Epidemiology of pediatric inflammatory bowel disease: A systematic review of international trends. Inflammatory Bowel Diseases, 17, 423–439.CrossRefPubMedGoogle Scholar
  2. 2.
    Malaty, H. M., Fan, X., Opekun, A. R., Thibodeaux, C., & Ferry, G. D. (2010). Rising incidence of inflammatory bowel disease among children: A 12-year study. Journal of Pediatric Gastroenterology and Nutrition, 50, 27–31.CrossRefPubMedGoogle Scholar
  3. 3.
    Varni, J. W., Bendo, C. B., Nurko, S., Shulman, R. J., Self, M. M., Franciosi, J. P., et al. (2015). Health-related quality of life in pediatric patients with functional and organic gastrointestinal diseases. Journal of Pediatrics, 166, 85–90.CrossRefPubMedGoogle Scholar
  4. 4.
    Kunz, J. H., Hommel, K. A., & Greenley, R. N. (2010). Health-related quality of life of youth with inflammatory bowel disease: A comparison with published data using the PedsQL 4.0 Generic Core Scales. Inflammatory Bowel Diseases, 16, 939–946.CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Otley, A. R., Griffiths, A. M., Hale, S., Kugathasan, S., Pfefferkorn, M., Mezoff, A., et al. (2006). Health-related quality of life in the first year after a diagnosis of pediatric inflammatory bowel disease. Inflammatory Bowel Diseases, 12, 684–691.CrossRefPubMedGoogle Scholar
  6. 6.
    Jackson, C. A., Clatworthy, J., Robinson, A., & Horne, R. (2010). Factors associated with non-adherence to oral medication for inflammatory bowel disease: A systematic review. American Journal of Gastroenterology, 105, 525–539.CrossRefPubMedGoogle Scholar
  7. 7.
    Bernstein, C. N. (2015). Treatment of IBD: Where we are and where we are going. American Journal of Gastroenterology, 110, 114–126.CrossRefPubMedGoogle Scholar
  8. 8.
    Campos, S., Portela, F., Sousa, P., & Sofia, C. (2016). Inflammatory bowel disease: Adherence to immunomodulators in a biological therapy era. European Journal of Gastroenterology and Hepatology, 28, 1313–1319.CrossRefPubMedGoogle Scholar
  9. 9.
    Melesse, D. Y., Targownik, L. E., Singh, H., Blanchard, J. F., & Bernstein, C. N. (2015). Patterns and predictors of long-term nonuse of medical therapy among persons with inflammatory bowel disease. Inflammatory Bowel Diseases, 21, 1615–1622.CrossRefPubMedGoogle Scholar
  10. 10.
    Prosberg, M. V., Vester-Andersen, M. K., Andersson, M., Jess, T., Andersen, J. T., Vind, I., et al. (2016). Long-term compliance with oral 5-aminosalicylic acid therapy and risk of disease recurrence in patients with ulcerative colitis: A population-based cohort study. Inflammatory Bowel Diseases, 22, 925–932.CrossRefPubMedGoogle Scholar
  11. 11.
    Bhasin, S., Singh, H., Targownik, L. E., Israeli, E., & Bernstein, C. N. (2016). Rates and reasons for nonuse of prescription medication for inflammatory bowel disease in a referral clinic. Inflammatory Bowel Diseases, 22, 919–924.CrossRefPubMedGoogle Scholar
  12. 12.
    Spekhorst, L. M., Hummel, T. Z., Benninga, M. A., van Rheenen, P. F., & Kindermann, A. (2016). Adherence to oral maintenance treatment in adolescents with inflammatory bowel disease. Journal of Pediatric Gastroenterology and Nutrition, 62, 264–270.CrossRefPubMedGoogle Scholar
  13. 13.
    Hommel, K. A., Davis, C. M., & Baldassano, R. N. (2009). Objective versus subjective assessment of oral medication adherence in pediatric inflammatory bowel disease. Inflammatory Bowel Diseases, 15, 589–593.CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Shi, L., Liu, J., Fonseca, V., Walker, P., Kalsekar, A., & Pawaskar, M. (2010). Correlation between adherence rates measured by MEMS and self-reported questionnaires: A meta-analysis. Health and Quality of Life Outcomes, 8, 99.CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Varni, J. W., Kay, M. T., Limbers, C. A., Franciosi, J. P., & Pohl, J. F. (2012). PedsQL™ Gastrointestinal Symptoms Module item development: Qualitative methods. Journal of Pediatric Gastroenterology and Nutrition, 54, 664–671.CrossRefPubMedGoogle Scholar
  16. 16.
    Ingerski, L. M., Baldassano, R. N., Denson, L. A., & Hommel, K. A. (2010). Barriers to oral medication adherence for adolescents with inflammatory bowel disease. Journal of Pediatric Psychology, 35, 683–691.CrossRefPubMedGoogle Scholar
  17. 17.
    Gray, W. N., Denson, L. A., Baldassano, R. N., & Hommel, K. A. (2012). Treatment adherence in adolescents with inflammatory bowel disease: The collective impact of barriers to adherence and anxiety/depressive symptoms. Journal of Pediatric Psychology, 37, 282–291.CrossRefPubMedGoogle Scholar
  18. 18.
    Chang, L., Toner, B. B., Fukudo, S., Guthrie, E., Locke, G. R., Norton, N. J., et al. (2006). Gender, age, society, culture, and the patient’s perspective in the functional gastrointestinal disorders. Gastroenterology, 130, 1435–1446.CrossRefPubMedGoogle Scholar
  19. 19.
    Muris, P., Roelofs, J., Rassin, E., Franken, I., & Mayer, B. (2005). Mediating effects of rumination and worry on the links between neuroticism, anxiety and depression. Personality and Individual Differences, 39, 1105–1111.CrossRefGoogle Scholar
  20. 20.
    de Jong-Meyer, R., Beck, B., & Riede, K. (2009). Relationships between rumination, worry, intolerance of uncertainty and metacognitive beliefs. Personality and Individual Differences, 46, 547–551.CrossRefGoogle Scholar
  21. 21.
    Barned, C., Stinzi, A., Mack, D., & O’Doherty, K. C. (2016). To tell or not to tell: A qualitative interview study on disclosure decisions among children with inflammatory bowel disease. Social Science and Medicine, 162, 115–123.CrossRefPubMedGoogle Scholar
  22. 22.
    Varni, J. W., Shulman, R. J., Self, M. M., Saeed, S. A., Patel, A. S., Nurko, S., et al. (2017). Patient health communication mediating effects between gastrointestinal symptoms and gastrointestinal worry in pediatric inflammatory bowel disease. Inflammatory Bowel Diseases, 23, 704–711.CrossRefPubMedGoogle Scholar
  23. 23.
    Varni, J. W., Bendo, C. B., Denham, J., Shulman, R. J., Self, M. M., Neigut, D. A., et al. (2014). PedsQL™ Gastrointestinal Symptoms Module: Feasibility, reliability, and validity. Journal of Pediatric Gastroenterology and Nutrition, 59, 347–355.CrossRefPubMedGoogle Scholar
  24. 24.
    Varni, J. W., Bendo, C. B., Denham, J., Shulman, R. J., Self, M. M., Neigut, D. A., et al. (2015). PedsQL™ Gastrointestinal Symptoms Scales and Gastrointestinal Worry Scales in pediatric patients with functional and organic gastrointestinal diseases in comparison to healthy controls. Quality of Life Research, 24, 363–378.CrossRefPubMedGoogle Scholar
  25. 25.
    Varni, J. W., Franciosi, J. P., Shulman, R. J., Saeed, S., Nurko, S., Neigut, D. A., et al. (2015). PedsQL™ Gastrointestinal Symptoms Scales and Gastrointestinal Worry Scales in pediatric patients with inflammatory bowel disease in comparison to healthy controls. Inflammatory Bowel Diseases, 21, 1115–1124.CrossRefPubMedGoogle Scholar
  26. 26.
    Varni, J. W., Bendo, C. B., Shulman, R. J., Self, M. M., Nurko, S., Franciosi, J. P., et al. (2015). Interpretability of the PedsQL™ Gastrointestinal Symptoms Scales and Gastrointestinal Worry Scales in pediatric patients with functional and organic gastrointestinal diseases. Journal of Pediatric Psychology, 40, 591–601.CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Varni, J. W., Shulman, R. J., Self, M. M., Nurko, S., Saps, M., Saeed, S., et al. (2015). Symptom profiles in patients with irritable bowel syndrome or functional abdominal pain compared to healthy controls. Journal of Pediatric Gastroenterology and Nutrition, 61, 323–329.CrossRefPubMedGoogle Scholar
  28. 28.
    Varni, J. W., Nurko, S., Shulman, R. J., Self, M. M., Saps, M., Bendo, C. B., et al. (2015). Pediatric functional constipation gastrointestinal symptom profile compared to healthy controls. Journal of Pediatric Gastroenterology and Nutrition, 61, 424–430.CrossRefPubMedGoogle Scholar
  29. 29.
    Varni, J. W., Shulman, R. J., Self, M. M., Saeed, S. A., Patel, A. S., Nurko, S., et al. (2016). Gastrointestinal symptoms predictors of health-related quality of life in patients with inflammatory bowel disease. Journal of Pediatric Gastroenterology and Nutrition, 63, e186–e192.CrossRefPubMedGoogle Scholar
  30. 30.
    Varni, J. W., Shulman, R. J., Self, M. M., Nurko, S., Saps, M., Saeed, S. A., et al. (2017). Gastrointestinal symptoms predictors of health-related quality of life in pediatric patients with functional gastrointestinal disorders. Quality of Life Research, 26, 1015–1025.CrossRefPubMedGoogle Scholar
  31. 31.
    Varni, J. W., Seid, M., & Kurtin, P. S. (2001). PedsQL™ 4.0: Reliability and validity of the Pediatric Quality of Life Inventory™ Version 4.0 Generic Core Scales in healthy and patient populations. Medical Care, 39, 800–812.CrossRefPubMedGoogle Scholar
  32. 32.
    Cohen, J. (1988). Statistical power analysis for the behavioral sciences (2nd ed.). Hillsdale, NJ: Erlbaum.Google Scholar
  33. 33.
    Cohen, J., Cohen, P., West, S. G., & Aiken, L. S. (2003). Applied multiple regression/correlation analysis for the behavioral sciences (3rd ed.). Mahwah, NJ: Erlbaum.Google Scholar
  34. 34.
    Baron, R. M., & Kenny, D. A. (1986). The moderator-mediator variable distinction in social psychological research: Conceptual, strategic, and statistical considerations. Journal of Personality and Social Psychology, 51, 1173–1182.CrossRefPubMedGoogle Scholar
  35. 35.
    Preacher, K. J., & Hayes, A. F. (2008). Asymptotic and resampling strategies for assessing and comparing indirect effects in multiple mediator models. Behavior Research Methods, 40, 879–891.CrossRefPubMedGoogle Scholar
  36. 36.
    Sobel, M. E. (1982). Asymptotic confidence intervals for indirect effects in structural equation models. Sociological Methodology, 13, 290–312.CrossRefGoogle Scholar
  37. 37.
    Hayes, A. F., & Rockwood, N. J. (2016). Regression-based statistical mediation and moderation analysis in clinical research: Observations, recommendations, and implementation. Behaviour Research and Therapy. doi: 10.1016/j.brat.2016.11.001.PubMedCentralGoogle Scholar
  38. 38.
    Hayes, A. F. (2013). Introduction to mediation, moderation, and conditional process analysis: A regression-based approach. New York, NY: Guilford.Google Scholar
  39. 39.
    Jonefjäll, B., Öhman, L., Simrén, M., & Strid, H. (2016). IBS-like symptoms in patients with ulcerative colitis in deep remission are associated with increased levels of serum cytokines and poor psychological well-being. Inflammatory Bowel Diseases, 22, 2630–2640.CrossRefPubMedGoogle Scholar
  40. 40.
    Gracie, D. J., Williams, C. J., Sood, R., Mumtaz, S., Bholah, M. H., Hamlin, P. J., et al. (2017). Negative effects on psychological health and quality of life of genuine irritable bowel syndrome-type symptoms in patients with inflammatory bowel disease. Clinical Gastroenterology and Hepatology, 15, 376–384.CrossRefPubMedGoogle Scholar
  41. 41.
    Diederen, K., Hoekman, D. R., Hummel, T. Z., de Meij, T. G., Koot, B. G. P., Tabbers, M. M., et al. (2016). The prevalence of irritable bowel syndrome-type symptoms in paediatric inflammatory bowel disease, and the relationship with biochemical markers of disease activity. Alimentary Pharmacology & Therapeutics, 44, 181–188.CrossRefGoogle Scholar
  42. 42.
    Greenley, R. N., Gumidyala, A. P., Nguyen, E., Plevinsky, J. M., Poulopoulos, N., Thomason, M. M., et al. (2015). Can you teach a teen new tricks? Problem solving skills training improves oral medication adherence in pediatric patients with inflammatory bowel disease participating in a randomized trial. Inflammatory Bowel Diseases, 21, 2649–2657.CrossRefPubMedGoogle Scholar
  43. 43.
    Lönnfors, S., Vermeire, S., Greco, M., Hommes, D., Bell, C., & Avedano, L. (2014). IBD and health-related quality of life: Discovering the true impact. Journal of Crohn’s and Colitis, 8, 1281–1286.CrossRefPubMedGoogle Scholar
  44. 44.
    Linn, A. J., van Dijk, L., Smit, E. G., Jansen, J., & van Weert, J. C. (2013). May you never forget what is worth remembering: The relation between recall of medical information and medication adherence in patients with inflammatory bowel disease. Journal of Crohn’s and Colitis, 7, e543–550.CrossRefPubMedGoogle Scholar
  45. 45.
    Szigethy, E., Bujoreanu, S. I., Youk, A. O., Weisz, J., Benhayon, D., Fairclough, D., et al. (2014). Randomized efficacy trial of two psychotherapies for depression in youth with inflammatory bowel disease. Journal of the American Academy of Child and Adolescent Psychiatry, 53, 726–735.CrossRefPubMedPubMedCentralGoogle Scholar
  46. 46.
    Reigada, L. C., Hoogendoorn, C. J., Walsh, L. C., Lai, J., Szigethy, E., Cohen, B. H., et al. (2015). Anxiety symptoms and disease severity in children and adolescents with Crohn disease. Journal of Pediatric Gastroenterology and Nutrition, 60, 30–35.CrossRefPubMedGoogle Scholar
  47. 47.
    Brooks, A. J., Rowse, G., Ryder, A., Peach, E. J., Corfe, B. M., & Lobo, A. J. (2016). Systematic review: Psychological morbidity in young people with inflammatory bowel disease—Risk factors and impacts. Alimentary Pharmacology & Therapeutics, 44, 3–15.CrossRefGoogle Scholar
  48. 48.
    Fresco, D. M., Frankel, A. N., Mennin, D. S., Turk, C. L., & Heimberg, R. G. (2002). Distinct and overlapping features of rumination and worry: The relationship of cognitive production to negative affective states. Cognitive Therapy and Research, 26, 179–188.CrossRefGoogle Scholar
  49. 49.
    Fialko, L., Bolton, D., & Perrin, S. (2012). Applicability of a cognitive model of worry to children and adolescents. Behaviour Research and Therapy, 50, 341–349.CrossRefPubMedGoogle Scholar
  50. 50.
    Keeton, R. L., Mikocka-Walus, A., & Andrews, J. M. (2015). Concerns and worries in people living with inflammatory bowel disease (IBD): A mixed methods study. Journal of Psychosomatic Research, 78, 573–578.CrossRefPubMedGoogle Scholar

Copyright information

© Springer International Publishing AG 2017

Authors and Affiliations

  • James W. Varni
    • 1
    Email author
  • Robert J. Shulman
    • 2
  • Mariella M. Self
    • 3
  • Shehzad A. Saeed
    • 4
  • George M. Zacur
    • 4
  • Ashish S. Patel
    • 5
  • Samuel Nurko
    • 6
  • Deborah A. Neigut
    • 7
  • James P. Franciosi
    • 4
  • Miguel Saps
    • 8
  • Jolanda M. Denham
    • 9
  • Chelsea Vaughan Dark
    • 10
  • Cristiane B. Bendo
    • 11
  • John F. Pohl
    • 12
  • On Behalf of the Pediatric Quality of Life Inventory™ Gastrointestinal Symptoms Module Testing Study Consortium
  1. 1.Department of Pediatrics, College of Medicine, Department of Landscape Architecture and Urban Planning, College of ArchitectureTexas A&M UniversityCollege StationUSA
  2. 2.Department of Pediatrics, Baylor College of Medicine, Children’s Nutrition Research CenterTexas Children’s HospitalHoustonUSA
  3. 3.Departments of Psychiatry and Pediatrics, Baylor College of MedicineTexas Children’s HospitalHoustonUSA
  4. 4.Division of Gastroenterology, Hepatology and NutritionCincinnati Children’s Hospital Medical CenterCincinnatiUSA
  5. 5.Division of Pediatric Gastroenterology, Children’s Medical Center of DallasUniversity of Texas Southwestern Medical SchoolDallasUSA
  6. 6.Center for Motility and Functional Gastrointestinal Disorders, Boston Children’s HospitalHarvard Medical SchoolBostonUSA
  7. 7.Division of Gastroenterology, Hepatology and NutritionChildren’s Hospital ColoradoAuroraUSA
  8. 8.Division of Gastroenterology, Hepatology and Nutrition, Lurie Children’s Hospital of ChicagoNorthwestern University Feinberg School of MedicineChicagoUSA
  9. 9.Division of Gastroenterology, Hepatology and NutritionNationwide Children’s HospitalColumbusUSA
  10. 10.Department of PsychologyTexas A&M UniversityCollege StationUSA
  11. 11.Department of Pediatric Dentistry and Orthodontics, Faculty of DentistryFederal University of Minas GeraisBelo HorizonteBrazil
  12. 12.Department of Pediatric Gastroenterology, Primary Children’s HospitalUniversity of UtahSalt Lake CityUSA

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