Resilience in Adult Coeliac Patients on a Gluten-Free Diet: A Cross-Sectional Multicentre Italian Study
Abstract
:1. Introduction
2. Patients and Methods
2.1. Study Design and Setting
2.2. Study Population
2.3. Development of the Survey Questionnaire
2.4. Data Collection
2.5. Statistics
2.6. Ethics
3. Results
3.1. Correlation between Clinical Features, Resilience, Quality of Life, Anxiety, and Depression
3.2. Resilience (CD-RISC)
3.3. Anxiety (STAI-Y 1 and STAI-Y 2)
3.4. Depression (BDI)
3.5. Quality of Life (CD-QOL)
3.6. Adherence to a Gluten-Free Diet
3.7. Correlation Analysis
3.8. Linear Regression Analysis
4. Discussion
5. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
- Lebwohl, B.; Sanders, D.S.; Green, P.H.R. Coeliac disease. Lancet 2018, 391, 70–81. [Google Scholar] [CrossRef] [PubMed]
- Ludvigsson, J.F.; Bai, J.C.; Biagi, F.; Card, T.R.; Ciacci, C.; Ciclitira, P.J.; Green, P.H.R.; Hadjivassiliou, M.; Holdoway, A.; van Heel, D.A.; et al. Diagnosis and management of adult coeliac disease: Guidelines from the British Society of Gastroenterology. Gut 2014, 63, 1210–1228. [Google Scholar] [CrossRef]
- Al-Toma, A.; Volta, U.; Auricchio, R.; Castillejo, G.; Sanders, D.S.; Cellier, C.; Mulder, C.J.; Lundin, K.E.A. European Society for the Study of Coeliac Disease (ESsCD) guideline for coeliac disease and other gluten-related disorders. United Eur. Gastroenterol. J. 2019, 7, 583–613. [Google Scholar] [CrossRef]
- Rubio-Tapia, A.; Hill, I.D.; Semrad, C.; Kelly, C.P.; Greer, K.B.; Limketkai, B.N.; Lebwohl, B. American College of Gastroenterology Guidelines Update: Diagnosis and Management of Celiac Disease. Am. J. Gastroenterol. 2023, 118, 59–76. [Google Scholar] [CrossRef]
- Zingone, F.; Maimaris, S.; Auricchio, R.; Caio, G.P.I.; Carroccio, A.; Elli, L.; Galliani, E.; Montagnani, M.; Valiante, F.; Biagi, F. Guidelines of the Italian societies of gastroenterology on the diagnosis and management of coeliac disease and dermatitis herpetiformis. Dig. Liver Dis. 2022, 54, 1304–1319. [Google Scholar] [CrossRef] [PubMed]
- Hall, N.J.; Rubin, G.; Charnock, A. Systematic review: Adherence to a gluten-free diet in adult patients with coeliac disease. Aliment. Pharmacol. Ther. 2009, 30, 315–330. [Google Scholar] [CrossRef]
- Schiepatti, A.; Maimaris, S.; Nicolardi, M.L.; Alimenti, E.; Vernero, M.; Costetti, M.; Costa, S.; Biagi, F. Determinants and Trends of Adherence to a Gluten-Free Diet in Adult Celiac Patients on a Long-term Follow-up (2000–2020). Clin. Gastroenterol. Hepatol. 2022, 20, e741–e749. [Google Scholar] [CrossRef] [PubMed]
- See, J.A.; Kaukinen, K.; Makharia, G.K.; Gibson, P.R.; Murray, J.A. Practical insights into gluten-free diets. Nat. Rev. Gastroenterol. Hepatol. 2015, 12, 580–591. [Google Scholar] [CrossRef]
- Zingone, F.; Swift, G.L.; Card, T.R.; Sanders, D.S.; Ludvigsson, J.F.; Bai, J.C. Psychological morbidity of celiac disease: A review of the literature. United Eur. Gastroenterol. J. 2015, 3, 136–145. [Google Scholar] [CrossRef]
- Ciacci, C.; Zingone, F. The Perceived Social Burden in Celiac Disease. Diseases 2015, 3, 102–110. [Google Scholar] [CrossRef]
- Halmos, E.P.; Deng, M.; Knowles, S.R.; Sainsbury, K.; Mullan, B.; Tye-Din, J.A. Food knowledge and psychological state predict adherence to a gluten-free diet in a survey of 5310 Australians and New Zealanders with coeliac disease. Aliment. Pharmacol. Ther. 2018, 48, 78–86. [Google Scholar] [CrossRef]
- Canova, C.; Rosato, I.; Marsilio, I.; Valiante, F.; Zorzetto, V.; Cataudella, G.; D’odorico, A.; Zingone, F. Quality of Life and Psychological Disorders in Coeliac Disease: A Prospective Multicentre Study. Nutrients 2021, 13, 3233. [Google Scholar] [CrossRef]
- Zingone, F.; Secchettin, E.; Marsilio, I.; Valiante, F.; Zorzetto, V.; Cataudella, G.; D’Odorico, A.; Canova, C. Clinical features and psychological impact of celiac disease at diagnosis. Dig. Liver Dis. 2021, 53, 1565–1570. [Google Scholar] [CrossRef]
- Marsilio, I.; Canova, C.; D’odorico, A.; Ghisa, M.; Zingone, L.; Lorenzon, G.; Savarino, E.V.; Zingone, F. Quality-of-Life Evaluation in Coeliac Patients on a Gluten-Free Diet. Nutrients 2020, 12, 2981. [Google Scholar] [CrossRef] [PubMed]
- Sisto, A.; Vicinanza, F.; Campanozzi, L.L.; Ricci, G.; Tartaglini, D.; Tambone, V. Towards a Transversal Definition of Psychological Resilience: A Literature Review. Medicina 2019, 55, 745. [Google Scholar] [CrossRef] [PubMed]
- Connor, K.M.; Davidson, J.R.T. Development of a new resilience scale: The Connor-Davidson Resilience Scale (CD-RISC). Depress. Anxiety 2003, 18, 76–82. [Google Scholar] [CrossRef] [PubMed]
- Luthar, S.S.; Cicchetti, D.; Becker, B. The Construct of Resilience: A Critical Evaluation and Guidelines for Future Work. Child Dev. 2000, 71, 543–562. [Google Scholar] [CrossRef]
- McAllister, S.J.; Vincent, A.; Hassett, A.L.; Whipple, M.O.; Oh, T.H.; Benzo, R.P.; Toussaint, L.L. Psychological Resilience, Affective Mechanisms and Symptom Burden in a Tertiary-care Sample of Patients with Fibromyalgia. Stress Health 2015, 31, 299–305. [Google Scholar] [CrossRef]
- Min, J.-A.; Jung, Y.-E.; Kim, D.-J.; Yim, H.-W.; Kim, J.-J.; Kim, T.-S.; Lee, C.-U.; Lee, C.; Chae, J.-H. Characteristics associated with low resilience in patients with depression and/or anxiety disorders. Qual. Life Res. 2013, 22, 231–241. [Google Scholar] [CrossRef]
- Parker, C.H.; Naliboff, B.D.; Shih, W.; Presson, A.P.; Kilpatrick, L.; Gupta, A.; Liu, C.; Keefer, L.A.; Sauk, J.S.; Hirten, R.; et al. The Role of Resilience in Irritable Bowel Syndrome, Other Chronic Gastrointestinal Conditions, and the General Population. Clin. Gastroenterol. Hepatol. 2021, 19, 2541–2550.e1. [Google Scholar] [CrossRef]
- Philippou, A.; Sehgal, P.; Ungaro, R.C.; Wang, K.; Bagiella, E.; Dubinsky, M.C.; Keefer, L. High Levels of Psychological Resilience Are Associated With Decreased Anxiety in Inflammatory Bowel Disease. Inflamm. Bowel Dis. 2022, 28, 888–894. [Google Scholar] [CrossRef] [PubMed]
- Lenti, M.V.; Cococcia, S.; Ghorayeb, J.; Di Sabatino, A.; Selinger, C.P. Stigmatisation and resilience in inflammatory bowel disease. Intern. Emerg. Med. 2020, 15, 211–223. [Google Scholar] [CrossRef] [PubMed]
- Dorn, S.D.; Hernandez, L.; Minaya, M.T.; Morris, C.B.; Hu, Y.; Leserman, J.; Lewis, S.; Lee, A.; Bangdiwala, S.I.; Green, P.H.R.; et al. The development and validation of a new coeliac disease quality of life survey (CD-QOL). Aliment. Pharmacol. Ther. 2010, 31, 666–675. [Google Scholar] [CrossRef] [PubMed]
- Zingone, F.; Iavarone, A.; Tortora, R.; Imperatore, N.; Pellegrini, L.; Russo, T.; Dorn, S.D.; Ciacci, C. The Italian translation of the Celiac Disease-specific Quality of Life Scale in celiac patients on gluten free diet. Dig. Liver Dis. 2013, 45, 115–118. [Google Scholar] [CrossRef] [PubMed]
- Spielberger, C.D.; Gorsuch, R.L.; Lushene, R.; Vagg, P.R.; Jacobs, G.A. Manual for the State-Trait Anxiety Inventory; Consulting Psychologists Press: Palo Alto, CA, USA, 1983. [Google Scholar]
- Beck, A.T.; Ward, C.H.; Mendelson, M.; Mock, J.; Erbaugh, J. An Inventory for Measuring Depression. Arch. Gen. Psychiatry 1961, 4, 561–571. [Google Scholar] [CrossRef] [PubMed]
- Biagi, F.; Andrealli, A.; Bianchi, P.I.; Marchese, A.; Klersy, C.; Corazza, G.R. A gluten-free diet score to evaluate dietary compliance in patients with coeliac disease. Br. J. Nutr. 2009, 102, 882–887. [Google Scholar] [CrossRef] [PubMed]
- Ludvigsson, J.F.; Leffler, D.A.; Bai, J.C.; Biagi, F.; Fasano, A.; Green, P.H.R.; Hadjivassiliou, M.; Kaukinen, K.; Kelly, C.P.; Leonard, J.N.; et al. The Oslo definitions for coeliac disease and related terms. Gut 2013, 62, 43–52. [Google Scholar] [CrossRef]
- Shiha, M.G.; Aziz, I. Review article: Physical and psychological comorbidities associated with irritable bowel syndrome. Aliment. Pharmacol. Ther. 2021, 54 (Suppl. S1), S12–S23. [Google Scholar] [CrossRef] [PubMed]
- Bisgaard, T.H.; Allin, K.H.; Keefer, L.; Ananthakrishnan, A.N.; Jess, T. Depression and anxiety in inflammatory bowel disease: Epidemiology, mechanisms and treatment. Nat. Rev. Gastroenterol. Hepatol. 2022, 19, 717–726. [Google Scholar] [CrossRef]
- Person, H.; Keefer, L. Psychological comorbidity in gastrointestinal diseases: Update on the brain-gut-microbiome axis. Prog. Neuro-Psychopharmacol. Biol. Psychiatry 2021, 107, 110209. [Google Scholar] [CrossRef]
- Fadgyas Stanculete, M.; Ismaiel, A.; Popa, S.L.; Capatina, O.O. Irritable Bowel Syndrome and Resilience. J. Clin. Med. 2023, 12, 4220. [Google Scholar] [CrossRef]
- Kilpatrick, L.A.; Gupta, A.; Tillisch, K.; Labus, J.S.; Naliboff, B.D.; Mayer, E.A.; Chang, L. Neural correlates of perceived and relative resilience in male and female patients with irritable bowel syndrome. Neurogastroenterol. Motil. 2024, 36, e14710. [Google Scholar] [CrossRef] [PubMed]
- Sadeghian, A.M.; Dashti, F.; Shariati, B.; Mokhtare, M.; Sotoudeheian, M. The role of cognitive emotion regulation strategies in predicting the resilience, symptom severity, and quality of life of patients with irritable bowel syndrome. Clin. Res. Hepatol. Gastroenterol. 2024, 48, 102341. [Google Scholar] [CrossRef] [PubMed]
- Shapero, B.G.; Farabaugh, A.; Terechina, O.; DeCross, S.; Cheung, J.C.; Fava, M.; Holt, D.J. Understanding the effects of emotional reactivity on depression and suicidal thoughts and behaviors: Moderating effects of childhood adversity and resilience. J. Affect. Disord. 2019, 245, 419–427. [Google Scholar] [CrossRef]
- Kalisch, R.; Baker, D.G.; Basten, U.; Boks, M.P.; Bonanno, G.A.; Brummelman, E.; Chmitorz, A.; Fernàndez, G.; Fiebach, C.J.; Galatzer-Levy, I.; et al. The resilience framework as a strategy to combat stress-related disorders. Nat. Hum. Behav. 2017, 1, 784–790. [Google Scholar] [CrossRef]
- Chmitorz, A.; Kunzler, A.; Helmreich, I.; Tüscher, O.; Kalisch, R.; Kubiak, T.; Wessa, M.; Lieb, K. Intervention studies to foster resilience—A systematic review and proposal for a resilience framework in future intervention studies. Clin. Psychol. Rev. 2018, 59, 78–100. [Google Scholar] [CrossRef] [PubMed]
- Schiepatti, A.; Maimaris, S.; Lusetti, F.; Scalvini, D.; Minerba, P.; Cincotta, M.; Fazzino, E.; Biagi, F. High Prevalence of Functional Gastrointestinal Disorders in Celiac Patients with Persistent Symptoms on a Gluten-Free Diet: A 20-Year Follow-Up Study. Dig. Dis. Sci. 2023, 68, 3374–3382. [Google Scholar] [CrossRef]
- Penny, H.A.; Baggus, E.M.R.; Rej, A.; Snowden, J.A.; Sanders, D.S. Non-Responsive Coeliac Disease: A Comprehensive Review from the NHS England National Centre for Refractory Coeliac Disease. Nutrients 2020, 12, 216. [Google Scholar] [CrossRef]
- Malamut, G.; Soderquist, C.R.; Bhagat, G.; Cerf-Bensussan, N. Advances in Nonresponsive and Refractory Celiac Disease. Gastroenterology 2024, 167, 132–147. [Google Scholar] [CrossRef]
- Nachman, F.; del Campo, M.P.; González, A.; Corzo, L.; Vázquez, H.; Sfoggia, C.; Smecuol, E.; Sánchez, M.I.P.; Niveloni, S.; Sugai, E.; et al. Long-term deterioration of quality of life in adult patients with celiac disease is associated with treatment noncompliance. Dig. Liver Dis. 2010, 42, 685–691. [Google Scholar] [CrossRef]
- Barratt, S.M.; Leeds, J.S.; Sanders, D.S. Quality of life in Coeliac Disease is determined by perceived degree of difficulty adhering to a gluten-free diet, not the level of dietary adherence ultimately achieved. J. Gastrointestin Liver Dis. 2011, 20, 241–245. [Google Scholar] [PubMed]
- Ludvigsson, J.F.; Lebwohl, B.; Chen, Q.; Bröms, G.; Wolf, R.L.; Green, P.H.R.; Emilsson, L. Anxiety after coeliac disease diagnosis predicts mucosal healing: A population-based study. Aliment. Pharmacol. Ther. 2018, 48, 1091–1098. [Google Scholar] [CrossRef] [PubMed]
Item | Total, N = 305 (%) |
---|---|
Gender, female | 221 (72%) |
Age at diagnosis (mean ± SD) | 36 ± 16 |
Age at enrolment (median, IQR) | 48 (35–60) |
<35 years | 68 (22%) |
35–55 years | 134 (44%) |
>55 years | 103 (34%) |
Clinical pattern at diagnosis [Oslo] | 182 |
Classical | 74 (41%) |
Non-classical | 95 (52%) |
Silent | 13 (7%) |
Disease duration (years, median, IQR) | 8 (3–17) |
<1 year | 34 (11%) |
1–5 years | 70 (23%) |
>5 years | 201 (66%) |
Educational level | |
Academic degree | 149 (49%) |
No academic degree | 156 (51%) |
Marital status | |
Stable relationship * | 196 (64%) |
No stable relationship ** | 109 (36%) |
GFD adherence [23] | 182 |
Good (Pavia score ≥3) | 162 (89%) |
Poor (Pavia score ≤2) | 20 (11%) |
Clinical response to a GFD | 305 |
Complete | 222 (73%) |
Partial/absent | 83 (27%) |
Received instruction on how to follow a GFD? | |
Yes | 281 (92%) |
No | 24 (8%) |
Membership of Italian Coeliac Association | |
Yes | 105 (34%) |
No | 149 (49%) |
Previously | 51 (17%) |
CD-RISC, median (IQR) | 69 (41–69) |
Low resilience (CD-RISC < 35), N (%) | 7 (2%) |
High resilience (CD-RISC ≥ 35), N (%) | 298 (98%) |
CD-QOL, median (IQR) | 84 (73–92) |
STAI-Y1, median (IQR) | 39 (32–50) |
STAI-Y2, median (IQR) | 40 (33–49) |
BDI II, median (IQR) | 7 (3–14) |
CD-RISC | STAI-Y1 | STAI-Y2 | BDI II | CD-QOL | ||||||
---|---|---|---|---|---|---|---|---|---|---|
Median (IQR) | p-Value | Median (IQR) | p-Value | Median (IQR) | p-Value | Median (IQR) | p-Value | Median (IQR) | p-Value | |
Gender | 0.03 | <0.01 | 0.001 | 0.001 | 0.08 | |||||
M | 73 (62–79) | 35 (29–45) | 36 (31–46) | 3 (1–10) | 87 (75–93) | |||||
F | 68 (58–76) | 41 (33–52) | 42 (35–50) | 8 (3–15) | 83 (72–90) | |||||
Clinical pattern at diagnosis | 0.68 | 0.49 | 0.18 | 0.04 | 0.71 | |||||
Classical | 67 (57–76) | 41 (30–53) | 42 (33–54) | 9 (3–17) | 83 (71–88) | |||||
Non classical | 68 (56–75) | 39 (33–49) | 42 (35–49) | 7 (3–13) | 84 (71–90) | |||||
silent | 64 (58–73) | 33 (31–46) | 36 (32–42) | 3 (1–5) | 85 (73–94) | |||||
Age at enrolment | 0.02 | 0.29 | 0.01 | 0.05 | 0.29 | |||||
<35 years | 67 (53–74) | 42 (36–53) | 44 (37–56) | 9 (4–17) | 84 (71–89) | |||||
35–55 years | 71 (59–79) | 38 (31–49) | 39 (32–47) | 6 (2–13) | 83 (71–92) | |||||
≥55 years | 70 (61–76) | 39 (32–48) | 40 (33–47) | 7 (2–13) | 85 (76–92) | |||||
Disease duration | 0.90 | 0.41 | 0.52 | 0.91 | 0.71 | |||||
< 1year | 70 (60–77) | 45 (36–51) | 43 (35–51) | 5 (3–14) | 85 (70–91) | |||||
1–5 years | 67 (59–77) | 37 (30–49) | 39 (32–47) | 8 (2–14) | 80 (71–90) | |||||
>5 years | 70 (58–76) | 39 (32–49) | 40 (33–49) | 7 (2–13) | 85 (74–92) | |||||
Educational level | 0.73 | 0.27 | 0.76 | 0.40 | 0.24 | |||||
No academic degree | 70 (59–77) | 39 (31–49) | 41 (33–49) | 8 (3–15) | 85 (76–92) | |||||
Academic degree | 68 (58–76) | 39 (33–50) | 39 (33–49) | 7 (2–13) | 82 (71–91) | |||||
Marital status | 0.03 | 0.27 | 0.02 | <0.01 | 0.34 | |||||
Stable relationship * | 70 (60–78) | 39 (32–48) | 39 (33–47) | 6 (2–13) | 84 (75–92) | |||||
No stable relationship ** | 68 (54–75) | 40 (33–51) | 43 (34–54) | 9 (4–16) | 84 (70–91) | |||||
Persistent symptoms despite a GFD | 0.30 | 0.12 | 0.03 | <0.01 | <0.001 | |||||
No | 69 (59–77) | 39 (31–49) | 39 (33–48) | 7 (2–13) | 86 (76–92) | |||||
Yes | 69 (54–76) | 41 (34–54) | 42 (35–55) | 8 (4–18) | 76 (68–86) | |||||
GFD adherence [23] | 0.07 | 0.11 | 0.06 | 0.048 | 0.19 | |||||
Poor (Pavia score ≤ 2) | 59 (52–70) | 48 (36–57) | 47 (38–55) | 10 (6–22) | 77 (68–87) | |||||
Good (Pavia score ≥ 3) | 68 (58–76) | 39 (32–50) | 41 (33–50) | 7 (2–14) | 84 (72–90) |
Variable | Univariate Regression Analysis Coefficient (95% CI) | p-Value * | Multivariate Analysis Coefficient (95%CI) ** | p-Value * |
---|---|---|---|---|
Gender | 0.02 | 0.59 | ||
Male | 0 (reference) | 0 (reference) | ||
Female | −4.26 (−7.80, −0.73) | −0.75 (−3.47, 1.98) | ||
Age at enrolment (years) | 0.13 (0.03–0.23) | 0.01 | 0.01 (−0.07, 0.09) | 0.79 |
Clinical pattern at diagnosis | ||||
Classical | 0 (reference) | - | ||
Non-classical | −0.32 (−4.78–4.14) | 0.89 | ||
Silent | −3.66 (−12.31–4.99) | 0.41 | ||
Disease duration (years) | 0.11 (−0.04–0.27) | 0.15 | ||
Educational level | 1.00 | |||
No academic degree | 0 (reference) | |||
Academic degree | 0.00 (−3.19–3.19) | |||
Marital status | 0.02 | 0.34 | ||
Stable relationship | 0 (reference) | 0 (reference) | ||
No stable relationship | −4.06 (−7.35, −0.76) | −1.31 (−4.05, 1.41) | ||
Persistent symptoms despite a GFD | −2.46 (−6.02–1.11) | 0.18 | ||
Membership of the Italian Coeliac Association | −1.38 (−4,73–1.97) | 0.42 | ||
Good GFD adherence | 4.09 (−2.69–10.88) | 0.24 | ||
CD-QOL | 0.35 (0.23–0.46) | <0.001 | 0.04 (−0.06, 0.15) | 0.40 |
STAI-Y1 | −0.62 (−073,−0.51) | <0.001 | −0.88 (−0.25, 0.08) | 0.31 |
STAI-Y2 | −0.83 (−0.93, −0.72) | <0.001 | −0.98 (−1.14, −0.81) | <0.001 |
BDI | −0.69 (−0.85, −0.54) | <0.001 | 0.23 (0.03–0.44) | 0.02 |
Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content. |
© 2024 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
Share and Cite
Schiepatti, A.; Maimaris, S.; Randazzo, S.; Maniero, D.; Biti, R.; Caio, G.; Lungaro, L.; Carroccio, A.; Seidita, A.; Scalvini, D.; et al. Resilience in Adult Coeliac Patients on a Gluten-Free Diet: A Cross-Sectional Multicentre Italian Study. Nutrients 2024, 16, 2595. https://doi.org/10.3390/nu16162595
Schiepatti A, Maimaris S, Randazzo S, Maniero D, Biti R, Caio G, Lungaro L, Carroccio A, Seidita A, Scalvini D, et al. Resilience in Adult Coeliac Patients on a Gluten-Free Diet: A Cross-Sectional Multicentre Italian Study. Nutrients. 2024; 16(16):2595. https://doi.org/10.3390/nu16162595
Chicago/Turabian StyleSchiepatti, Annalisa, Stiliano Maimaris, Simona Randazzo, Daria Maniero, Roland Biti, Giacomo Caio, Lisa Lungaro, Antonio Carroccio, Aurelio Seidita, Davide Scalvini, and et al. 2024. "Resilience in Adult Coeliac Patients on a Gluten-Free Diet: A Cross-Sectional Multicentre Italian Study" Nutrients 16, no. 16: 2595. https://doi.org/10.3390/nu16162595
APA StyleSchiepatti, A., Maimaris, S., Randazzo, S., Maniero, D., Biti, R., Caio, G., Lungaro, L., Carroccio, A., Seidita, A., Scalvini, D., Ciacci, C., Biagi, F., & Zingone, F. (2024). Resilience in Adult Coeliac Patients on a Gluten-Free Diet: A Cross-Sectional Multicentre Italian Study. Nutrients, 16(16), 2595. https://doi.org/10.3390/nu16162595