The objective of this study is to determine the prevalence of certain autoimmune diseases in transgender and gender diverse (TGD) youth.
Methods:
A multicenter, retrospective analysis was conducted from January 2013 to January 2019 of youth ≤26 years of age with concurrent diagnoses of gender dysphoria (GD) and at least one of the studied autoimmune diseases. Prevalence rates were calculated and compared to previously reported rates. Statistical significance was determined using second generation p-values as pooled estimates of prevalence rates across study sites compared to a range of rates reported in the literature.
Results:
During the study period, 128 of 3812 (3.4%) youth evaluated for GD had a concurrent diagnosis of at least one of the studied autoimmune diseases. Three autoimmune diseases had prevalence rates significantly higher than those previously documented in the literature (second generation p-value=0.000): type 1 diabetes mellitus (112.8/10,000, 95% confidence interval [CI]: 83.8–151.8), systemic lupus erythematosus (13.1/10,000, 95% CI: 5.5–31.5), and Graves' disease (12.3/10,000, 95% CI: 4.0–38.4).
Conclusion:
There is an increased prevalence of certain autoimmune diseases in youth who identify as TGD presenting for subspecialty care. Limitations such as retrospective study design, selection bias, and reliance on electronic medical records make it difficult to draw wide-reaching conclusions about these findings. This study highlights the need for more research to delineate the impacts of unrecognized or untreated GD on autoimmune disease development and control.
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References
1.
HayterSM, CookMC. Updated assessment of the prevalence, spectrum and case definition of autoimmune disease. Autoimmun Rev, 2012; 11(10):754–765; doi: 10.1016/j.autrev.2012.02.001
2.
DefreyneJ, De BacquerD, ShadidS, et al.Is type 1 diabetes mellitus more prevalent than expected in transgender persons? A local observation. Sex Med, 2017; 5(3):e215–e218; doi: 10.1016/j.esxm.2017.06.004
3.
LogelSN, BekxMT, RehmJL. Potential association between type 1 diabetes mellitus and gender dysphoria. Pediatr Diabetes, 2020; 21(2):266–270; doi: 10.1111/pedi.12947
4.
MaruJ, MillingtonK, CarswellJ. Greater than expected prevalence of type 1 diabetes mellitus found in an urban gender program. Transgend Health, 2021; 6(1):57–60; doi: 10.1089/trgh.2020.0027
5.
American Psychiatric Association. Diagnostic and statistical manual of mental disorders. American Psychiatric Association Publishing: Arlington, VA; 2013.
6.
DabeleaD, Mayer-DavisEJ, SaydahS, et al.Prevalence of type 1 and type 2 diabetes among children and adolescents from 2001 to 2009. JAMA, 2014; 311(17):1778–1786; doi: 10.1001/jama.2014.3201
7.
MenkeA, OrchardTJ, ImperatoreG, et al.The prevalence of type 1 diabetes in the United States. Epidemiology, 2013; 24(5):773–774; doi: 10.1097/EDE.0b013e31829ef01a
8.
MinelliR, GaianiF, KayaliS, et al.Thyroid and celiac disease in pediatric age: A literature review. Acta Biomed, 2018; 89(Suppl 9):11–16; doi: 10.23750/abm.v89i9-S.7872
9.
AokiY, BelinRM, ClicknerR, et al.Serum TSH and total T4 in the United States population and their association with participant characteristics: National Health and Nutrition Examination Survey (NHANES 1999–2002). Thyroid, 2007; 17(12):1211–1223; doi: 10.1089/thy.2006.0235
HollowellJG, StaehlingNW, FlandersWD, et al.Serum TSH, T(4), and thyroid antibodies in the United States population (1988 to 1994): National Health and Nutrition Examination Survey (NHANES III). J Clin Endocrinol Metab, 2002; 87(2):489–499; doi: 10.1210/jcem.87.2.8182
12.
LafranchiS. Thyroiditis and acquired hypothyroidism. Pediatr Ann, 1992; 21(1):29–39; doi: 10.3928/0090-4481-19920101-07
13.
PinelesD, ValenteA, WarrenB, et al.Worldwide incidence and prevalence of pediatric onset systemic lupus erythematosus. Lupus, 2011; 20(11):1187–1192; doi: 10.1177/0961203311412096
14.
HirakiLT, FeldmanCH, LiuJ, et al.Prevalence, incidence, and demographics of systemic lupus erythematosus and lupus nephritis from 2000 to 2004 among children in the US Medicaid beneficiary population. Arthritis Rheum, 2012; 64(8):2669–2676; doi: 10.1002/art.34472
15.
KamphuisS, SilvermanED. Prevalence and burden of pediatric-onset systemic lupus erythematosus. Nat Rev Rheumatol, 2010; 6(9):538–546; doi: 10.1038/nrrheum.2010.121
16.
HoughtonKM, PageJ, CabralDA, et al.Systemic lupus erythematosus in the pediatric North American native population of British Columbia. J Rheumatol, 2006; 33(1):161–163.
17.
SinghP, AroraA, StrandTA, et al.Global prevalence of celiac disease: Systematic review and meta-analysis. Clin Gastroenterol Hepatol, 2018; 16(6):823–836.e2; doi: 10.1016/j.cgh.2017.06.037
18.
AlmallouhiE, KingKS, PatelB, et al.Increasing incidence and altered presentation in a population-based study of pediatric celiac disease in North America. J Pediatr Gastroenterol Nutr, 2017; 65(4):432–437; doi: 10.1097/MPG.0000000000001532
19.
Unalp-AridaA, RuhlCE, ChoungRS, et al.Lower prevalence of celiac disease and gluten-related disorders in persons living in southern vs northern latitudes of the United States. Gastroenterology, 2017; 152(8):1922–1932.e2; doi: 10.1053/j.gastro.2017.02.012
20.
KrauseML, CrowsonCS, MichetCJ, et al.Juvenile idiopathic arthritis in Olmsted County, Minnesota, 1960–2013. Arthritis Rheumatol, 2016; 68(1):247–254; doi: 10.1002/art.39323
21.
ThierryS, FautrelB, LemelleI, et al.Prevalence and incidence of juvenile idiopathic arthritis: A systematic review. Joint Bone Spine, 2014; 81(2):112–117; doi: 10.1016/j.jbspin.2013.09.003
22.
MannersPJ, BowerC. Worldwide prevalence of juvenile arthritis why does it vary so much?. J Rheumatol, 2002; 29(7):1520–1530.
23.
NgSC, ShiHY, HamidiN, et al.Worldwide incidence and prevalence of inflammatory bowel disease in the 21st century: A systematic review of population-based studies. Lancet, 2017; 390(10114):2769–2778; doi: 10.1016/S0140-6736(17)32448-0
24.
KappelmanMD, MooreKR, AllenJK, et al.Recent trends in the prevalence of Crohn's disease and ulcerative colitis in a commercially insured US population. Dig Dis Sci, 2013; 58(2):519–525; doi: 10.1007/s10620-012-2371-5
25.
WangYR, LoftusEV, CangemiJR, et al.Racial/Ethnic and regional differences in the prevalence of inflammatory bowel disease in the United States. Digestion, 2013; 88(1):20–25; doi: 10.1159/000350759
26.
MolodeckyNA, SoonIS, RabiDM, et al.Increasing incidence and prevalence of the inflammatory bowel diseases with time, based on systematic review. Gastroenterology, 2012; 142(1):e30; doi: 10.1053/j.gastro.2011.10.001
27.
HerrintonLJ, LiuL, LewisJD, et al.Incidence and prevalence of inflammatory bowel disease in a Northern California managed care organization, 1996–2002. Am J Gastroenterol, 2008; 103(8):1998–2006; doi: 10.1111/j.1572-0241.2008.01960.x
28.
HerrintonLJ, LiuL, LafataJE, et al.Estimation of the period prevalence of inflammatory bowel disease among nine health plans using computerized diagnoses and outpatient pharmacy dispensings. Inflamm Bowel Dis, 2007; 13(4):451–461; doi: 10.1002/ibd.20021
29.
LoftusCG, LoftusEV, HarmsenWS, et al.Update on the incidence and prevalence of Crohn's disease and ulcerative colitis in Olmsted County, Minnesota, 1940–2000. Inflamm Bowel Dis, 2007; 13(3):254–261; doi: 10.1002/ibd.20029
30.
KappelmanMD, Rifas-ShimanSL, KleinmanK, et al.The prevalence and geographic distribution of Crohn's disease and ulcerative colitis in the United States. Clin Gastroenterol Hepatol, 2007; 5(12):1424–1429; doi: 10.1016/j.cgh.2007.07.012
31.
AbramsonO, DurantM, MowW, et al.Incidence, prevalence, and time trends of pediatric inflammatory bowel disease in Northern California, 1996 to 2006. J Pediatr, 2010; 157(2):233–239.e1; doi: 10.1016/j.jpeds.2010.02.024
32.
LoftusEV, SchoenfeldP, SandbornWJ. The epidemiology and natural history of Crohn's disease in population-based patient cohorts from North America: A systematic review. Aliment Pharmacol Ther, 2002; 16(1):51–60; doi: 10.1046/j.1365-2036.2002.01140.x
33.
NyagaVN, ArbynM, AertsM. Metaprop: A Stata command to perform meta-analysis of binomial data. Arch Public Health, 2014; 72(1):39; doi: 10.1186/2049-3258-72-39.
StojanovichL, MarisavljevichD. Stress as a trigger of autoimmune disease. Autoimmun Rev, 2008; 7(3):209–213; doi: 10.1016/j.autrev.2007.11.007
36.
StojanovichL. Stress and autoimmunity. Autoimmun Rev, 2010; 9(5):A271–A276; doi: 10.1016/j.autrev.2009.11.014
37.
MasonA, CroweE, HaraganB, et al.Gender dysphoria in young people: A model of chronic stress. Horm Res Paediatr, 2023; 96(1):65–65; doi: 10.1159/000520361
38.
FaresjöM. The link between psychological stress and autoimmune response in children. Crit Rev Immunol, 2015; 35(2):117–134; doi: 10.1615/critrevimmunol.2015013255
39.
KaravanakiK, TsokaE, LiacopoulouM, et al.Psychological stress as a factor potentially contributing to the pathogenesis of type 1 diabetes mellitus. J Endocrinol Invest, 2008; 31(5):406–415; doi: 10.1007/BF03346384
40.
RobinsonN, FullerJH. Role of life events and difficulties in the onset of diabetes mellitus. J Psychosom Res, 1985; 29(6):583–591; doi: 10.1016/0022-3999(85)90067-4
41.
RobinsonN, LloydCE, FullerJH, et al.Psychosocial factors and the onset of type 1 diabetes. Diabet Med, 1989; 6(1):53–58; doi: 10.1111/j.1464-5491.1989.tb01139.x
42.
SepaA, LudvigssonJ. Psychological stress and the risk of diabetes-related autoimmunity: A review article. Neuroimmunomodulation, 2006; 13(5–6):301–308; doi: 10.1159/000104858
43.
SepaA, WahlbergJ, VaaralaO, et al.Psychological stress may induce diabetes-related autoimmunity in infancy. Diabetes Care, 2005; 28(2):290–295; doi: 10.2337/diacare.28.2.290
44.
SipetićSB, VlajinacHD, KocevNI, et al.The Belgrade childhood diabetes study: A multivariate analysis of risk determinants for diabetes. Eur J Public Health, 2005; 15(2):117–122; doi: 10.1093/eurpub/cki074
45.
VitaR, LapaD, TrimarchiF, et al.Stress triggers the onset and the recurrences of hyperthyroidism in patients with Graves' disease. Endocrine, 2015; 48(1):254–263; doi: 10.1007/s12020-014-0289-8
46.
WilcoxG. Insulin and insulin resistance. Clin Biochem Rev, 2005; 26(2):19–39.
47.
SharifK, WatadA, CoplanL, et al.The role of stress in the mosaic of autoimmunity: An overlooked association. Autoimmun Rev, 2018; 17(10):967–983; doi: 10.1016/j.autrev.2018.04.005
48.
FalgaroneG, HeshmatiHM, CohenR, et al.Mechanisms in endocrinology. Role of emotional stress in the pathophysiology of Graves' disease. Eur J Endocrinol, 2013; 168(1):R13–R18; doi: 10.1530/EJE-12-0539
49.
TsatsoulisA. The role of stress in the clinical expression of thyroid autoimmunity. Ann N Y Acad Sci, 2006; 1088:382–395; doi: 10.1196/annals.1366.015
50.
NanbaT, WatanabeM, InoueN, et al.Increases of the Th1/Th2 cell ratio in severe Hashimoto's disease and in the proportion of Th17 cells in intractable Graves' disease. Thyroid, 2009; 19(5):495–501; doi: 10.1089/thy.2008.0423
51.
MaoC, WangS, XiaoY, et al.Impairment of regulatory capacity of CD4+CD25+ regulatory T cells mediated by dendritic cell polarization and hyperthyroidism in Graves' disease. J Immunol, 2011; 186(8):4734–4743; doi: 10.4049/jimmunol.0904135
52.
BocktingWO, MinerMH, Swinburne RomineRE, et al.Stigma, mental health, and resilience in an online sample of the US transgender population. Am J Public Health, 2013; 103(5):943–951; doi: 10.2105/AJPH.2013.301241
53.
MarshallE, ClaesL, BoumanWP, et al.Non-suicidal self-injury and suicidality in trans people: A systematic review of the literature. Int Rev Psychiatry, 2016; 28(1):58–69; doi: 10.3109/09540261.2015.1073143
54.
Olson-KennedyJ, Cohen-KettenisPT, KreukelsBP, et al.Research priorities for gender nonconforming/transgender youth: Gender identity development and biopsychosocial outcomes. Curr Opin Endocrinol Diabetes Obes, 2016; 23(2):172–179; doi: 10.1097/MED.0000000000000236
55.
PetersonCM, MatthewsA, Copps-SmithE, et al.Suicidality, self-harm, and body dissatisfaction in transgender adolescents and emerging adults with gender dysphoria. Suicide Life Threat Behav, 2017; 47(4):475–482; doi: 10.1111/sltb.12289
56.
ReisnerSL, GreytakEA, ParsonsJT, et al.Gender minority social stress in adolescence: Disparities in adolescent bullying and substance use by gender identity. J Sex Res, 2015; 52(3):243–256; doi: 10.1080/00224499.2014.886321
NuttbrockL, HwahngS, BocktingW, et al.Psychiatric impact of gender-related abuse across the life course of male-to-female transgender persons. J Sex Res, 2010; 47(1):12–23; doi: 10.1080/00224490903062258
59.
JamesSE, HermanJL, RankinS, et al.The Report of the 2015 US Transgender Survey. National Center for Transgender Equality: Washington, DC; 2016.
DuBoisLZ, PowersS, EverettBG, et al.Stigma and diurnal cortisol among transitioning transgender men. Psychoneuroendocrinology, 2017; 82:59–66; doi: 10.1016/j.psyneuen.2017.05.008
62.
DuboisLZ. Associations between transition-specific stress experience, nocturnal decline in ambulatory blood pressure, and C-reactive protein levels among transgender men. Am J Hum Biol, 2012; 24(1):52–61; doi: 10.1002/ajhb.22203
63.
McQuillanMT, KuhnsLM, MillerAA, et al.Gender minority stress, support, and inflammation in transgender and gender-nonconforming youth. Transgend Health, 2021; 6(2):91–100; doi: 10.1089/trgh.2020.0019
64.
EffraimidisG, TijssenJG, BrosschotJF, et al.Involvement of stress in the pathogenesis of autoimmune thyroid disease: A prospective study. Psychoneuroendocrinology, 2012; 37(8):1191–1198; doi: 10.1016/j.psyneuen.2011.12.009
65.
VitaR, CernaroV, BenvengaS. Stress-induced hashitoxicosis: Case report and relative HLA serotype and genotype. Rev Assoc Med Bras, 2019; 65(6):830–833; doi: 10.1590/1806-9282.65.6.830
66.
CiacciC, SiniscalchiM, BucciC, et al.Life events and the onset of celiac disease from a patient's perspective. Nutrients, 2013; 5(9):3388–3398; doi: 10.3390/nu5093388
67.
MårildK, FrostellAS, LudvigssonJF. Psychological stress and coeliac disease in childhood: A cohort study. BMC Gastroenterol, 2010; 10:106; doi: 10.1186/1471-230X-10-106
68.
SgambatoD, MirandaA, RanaldoR, et al.The role of stress in inflammatory bowel diseases. Curr Pharm Des, 2017; 23(27):3997–4002; doi: 10.2174/1381612823666170228123357
69.
TargownikLE, SextonKA, BernsteinMT, et al.The relationship among perceived stress, symptoms, and inflammation in persons with inflammatory bowel disease. Am J Gastroenterol, 2015; 110(7):1001–1013; doi: 10.1038/ajg.2015.147
70.
MaunderRG, LevensteinS. The role of stress in the development and clinical course of inflammatory bowel disease: Epidemiological evidence. Curr Mol Med, 2008; 8(4):247–252; doi: 10.2174/156652408784533832
71.
MawdsleyJE, RamptonDS. Psychological stress in IBD: New insights into pathogenic and therapeutic implications. Gut, 2005; 54(10):1481–1491; doi: 10.1136/gut.2005.064261
72.
MaunderRG. Evidence that stress contributes to inflammatory bowel disease: Evaluation, synthesis, and future directions. Inflamm Bowel Dis, 2005; 11(6):600–608; doi: 10.1097/01.mib.0000161919.42878.a0
73.
ArakiM, ShinzakiS, YamadaT, et al.Psychologic stress and disease activity in patients with inflammatory bowel disease: A multicenter cross-sectional study. PLoS One, 2020; 15(5):e0233365; doi: 10.1371/journal.pone.0233365
74.
BernsteinCN. Psychological stress and depression: Risk factors for IBD?. Dig Dis, 2016; 34(1–2):58–63; doi: 10.1159/000442929
75.
WintjensDSJ, de JongMJ, van der Meulen-de JongAE, et al.Novel perceived stress and life events precede flares of inflammatory bowel disease: A prospective 12-month follow-up study. J Crohns Colitis, 2019; 13(4):410–416; doi: 10.1093/ecco-jcc/jjy177
76.
TriantafillidisJK, MerikasE, GikasA. Psychological factors and stress in inflammatory bowel disease. Expert Rev Gastroenterol Hepatol, 2013; 7(3):225–238; doi: 10.1586/egh.13.4
77.
MawdsleyJE, RamptonDS. The role of psychological stress in inflammatory bowel disease. Neuroimmunomodulation, 2006; 13(5–6):327–336; doi: 10.1159/000104861
78.
GreeneBR, BlanchardEB, WanCK. Long-term monitoring of psychosocial stress and symptomatology in inflammatory bowel disease. Behav Res Ther, 1994; 32(2):217–226; doi: 10.1016/0005-7967(94)90114-7
79.
LuoH, SunY, LiY, et al.Perceived stress and inappropriate coping behaviors associated with poorer quality of life and prognosis in patients with ulcerative colitis. J Psychosom Res, 2018; 113:66–71; doi: 10.1016/j.jpsychores.2018.07.013
80.
MawdsleyJE, MaceyMG, FeakinsRM, et al.The effect of acute psychologic stress on systemic and rectal mucosal measures of inflammation in ulcerative colitis. Gastroenterology, 2006; 131(2):410–419; doi: 10.1053/j.gastro.2006.05.017
81.
BittonA, SewitchMJ, PeppercornMA, et al.Psychosocial determinants of relapse in ulcerative colitis: A longitudinal study. Am J Gastroenterol, 2003; 98(10):2203–2208; doi: 10.1111/j.1572-0241.2003.07717.x
82.
LevensteinS, PranteraC, VarvoV, et al.Psychological stress and disease activity in ulcerative colitis: A multidimensional cross-sectional study. Am J Gastroenterol, 1994; 89(8):1219–1225.
83.
RussoE, TrevisiE, ZulianF, et al.Psychological profile in children and adolescents with severe course Juvenile Idiopathic Arthritis. ScientificWorldJournal, 2012; 2012:841375; doi: 10.1100/2012/841375
84.
NeufeldKM, KarunanayakeCP, MaenzLY, et al.Stressful life events antedating chronic childhood arthritis. J Rheumatol, 2013; 40(10):1756–1765; doi: 10.3899/jrheum.121505
85.
DeshpandeA. The human leukocyte antigen system … simplified. Glob J Transfus Med, 2017; 2:77–88.
86.
SallansRK. Lessons from a transgender patient for health care professionals. AMA J Ethics, 2016; 18(11):1139–1146; doi: 10.1001/journalofethics.2016.18.11.mnar1-1611
87.
CarlströmR, EkS, GabrielssonS. ‘Treat me with respect’: Transgender persons' experiences of encounters with healthcare staff. Scand J Caring Sci, 2021; 35(2):600–607; doi: 10.1111/scs.12876
88.
SorbaraJC, NgoHL, PalmertMR. Factors associated with age of presentation to gender-affirming medical care. Pediatrics, 2021; 147(4):e2020026674; doi: 10.1542/peds.2020-026674
89.
BilliAC, KahlenbergJM, GudjonssonJE. Sex bias in autoimmunity. Curr Opin Rheumatol, 2019; 31(1):53–61; doi: 10.1097/BOR.0000000000000564
90.
CattaliniM, SolianiM, CaparelloMC, et al.Sex differences in pediatric rheumatology. Clin Rev Allergy Immunol, 2019; 56(3):293–307; doi: 10.1007/s12016-017-8642-3
91.
HillBG, HodgeB, MisischiaR. Lupus nephritis in a transgender woman on cross-sex hormone therapy: A case for the role of oestrogen in systemic lupus erythematosus. Lupus, 2020; 29(13):1807–1810; doi: 10.1177/0961203320946372
92.
CampochiaroC, HostLV, OngVH, et al.Development of systemic sclerosis in transgender females: A case series and review of the literature. Clin Exp Rheumatol, 2018; 36Suppl 113(4):50–52.
93.
HillL, JeganathanV, ChinnasamyP, et al.Differential roles of estrogen receptors α and β in control of B-cell maturation and selection. Mol Med, 2011; 17(3–4):211–220; doi: 10.2119/molmed.2010.00172
94.
PauklinS, SernándezIV, BachmannG, et al.Estrogen directly activates AID transcription and function. J Exp Med, 2009; 206(1):99–111; doi: 10.1084/jem.20080521
95.
FishEN. The X-files in immunity: Sex-based differences predispose immune responses. Nat Rev Immunol, 2008; 8(9):737–744.
96.
ValorL, TeijeiroR, AristimuñoC, et al.Estradiol-dependent perforin expression by human regulatory T-cells. Eur J Clin Invest, 2011; 41(4):357–364; doi: 10.1038/nri2394
97.
ForestaC, ZuccarelloD, BiagioliA, et al.Oestrogen stimulates endothelial progenitor cells via oestrogen receptor-alpha. Clin Endocrinol (Oxf), 2007; 67(4):520–525; doi: 10.1111/j.1365-2265.2007.02918.x
ColizziM, CostaR, PaceV, et al.Hormonal treatment reduces psychobiological distress in gender identity disorder, independently of the attachment style. J Sex Med, 2013; 10(12):3049–3058; doi: 10.1111/jsm.12155
100.
HeylensG, VerrokenC, De CockS, et al.Effects of different steps in gender reassignment therapy on psychopathology: A prospective study of persons with a gender identity disorder. J Sex Med, 2014; 11(1):119–126; doi: 10.1111/jsm.12363
101.
RistoriJ, CocchettiC, CastelliniG, et al.Hormonal treatment effect on sexual distress in transgender persons: 2-Year follow-up data. J Sex Med, 2020; 17(1):142–151; doi: 10.1016/j.jsxm.2019.10.008
102.
LearmonthC, ViloriaR, LambertC, et al.Barriers to insurance coverage for transgender patients. Am J Obstet Gynecol, 2018; 219(3):272.e1–272.e4; doi: 10.1016/j.ajog.2018.04.046
103.
RobertsTK, FantzCR. Barriers to quality health care for the transgender population. Clin Biochem, 2014; 47(10–11):983–987; doi: 10.1016/j.clinbiochem.2014.02.009
104.
ThompsonHM. Patient perspectives on gender identity data collection in electronic health records: An analysis of disclosure, privacy, and access to care. Transgend Health, 2016; 1(1):205–215; doi: 10.1089/trgh.2016.0007
105.
McDowellA, DowshenNL. Measuring and addressing inequities in health care access for transgender and gender diverse youth in the U.S. J Adolesc Health, 2021; 68(3):431–432; doi: 10.1016/j.jadohealth.2020.12.125
106.
LernerA, JeremiasP, MatthiasT. The world incidence and prevalence of autoimmune diseases is increasing. Int J Celiac Dis, 2015; 3:151–155; doi: 10.12691/ijcd-3-4-8
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