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Dubol, M., Stiernman, L., Sundström-Poromaa, I., Bixo, M. & Comasco, E. (2024). Cortical morphology variations during the menstrual cycle in individuals with and without premenstrual dysphoric disorder. Journal of Affective Disorders, 355, 470-477
Open this publication in new window or tab >>Cortical morphology variations during the menstrual cycle in individuals with and without premenstrual dysphoric disorder
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2024 (English)In: Journal of Affective Disorders, ISSN 0165-0327, E-ISSN 1573-2517, Vol. 355, p. 470-477Article in journal (Refereed) Published
Abstract [en]

Background: Premenstrual dysphoric disorder (PMDD) is hypothesized to stem from maladaptive neural sensitivity to ovarian steroid hormone fluctuations. Recently, we found thinner cortices in individuals with PMDD, compared to healthy controls, during the symptomatic phase. Here, we aimed at investigating whether such differences illustrate state-like characteristics specific to the symptomatic phase, or trait-like features defining PMDD.

Methods: Patients and controls were scanned using structural magnetic resonance imaging during the mid-follicular and late-luteal phase of the menstrual cycle. Group-by-phase interaction effects on cortical architecture metrics (cortical thickness, gyrification index, cortical complexity, and sulcal depth) were assessed using surface-based morphometry.

Results: Independently of menstrual cycle phase, a main effect of diagnostic group on surface metrics was found, primarily illustrating thinner cortices (0.3 < Cohen's d > 1.1) and lower gyrification indices (0.4 < Cohen's d > 1.0) in patients compared to controls. Furthermore, menstrual cycle-specific effects were detected across all participants, depicting a decrease in cortical thickness (0.4 < Cohen's d > 1.7) and region-dependent changes in cortical folding metrics (0.4 < Cohen's d > 2.2) from the mid-follicular to the late luteal phase.

Limitations: Small effects (d = 0.3) require a larger sample size to be accurately characterized.

Conclusions: These findings provide initial evidence of trait-like cortical characteristics of the brain of individuals with premenstrual dysphoric disorder, together with indications of menstrual cycle-related variations in cortical architecture in patients and controls. Further investigations exploring whether these differences constitute stable vulnerability markers or develop over the years may help understand PMDD etiology.

Place, publisher, year, edition, pages
Elsevier, 2024
Keywords
Premenstrual dysphoric disorder, Grey matter, Magnetic resonance imaging, Surface-based morphometry, Menstrual cycle, Mental health
National Category
Obstetrics, Gynecology and Reproductive Medicine
Identifiers
urn:nbn:se:umu:diva-223266 (URN)10.1016/j.jad.2024.03.130 (DOI)38552916 (PubMedID)2-s2.0-85189323134 (Scopus ID)
Funder
Region VästerbottenUmeå UniversitySwedish Research Council, 2015-00495Swedish Research Council, 2016-01439Swedish Research Council, 2020-01801Swedish Research Council, 2021-03089Swedish Society of Medicine, SLS-573171Swedish Society of Medicine, SLS-597211Swedish Society of Medicine, SLS-789101The Swedish Brain Foundation, 2020-0255
Available from: 2024-04-17 Created: 2024-04-17 Last updated: 2024-04-17Bibliographically approved
Dehara, M., Kullberg, S., Bixo, M., Sachs, M. C., Grunewald, J. & Arkema, E. V. (2024). Menopausal hormone therapy and risk of sarcoidosis: a population-based nested case–control study in Sweden. European Journal of Epidemiology
Open this publication in new window or tab >>Menopausal hormone therapy and risk of sarcoidosis: a population-based nested case–control study in Sweden
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2024 (English)In: European Journal of Epidemiology, ISSN 0393-2990, E-ISSN 1573-7284Article in journal (Refereed) Epub ahead of print
Abstract [en]

Sarcoidosis incidence peaks in women between 50 and 60 years old, which coincides with menopause, suggesting that certain sex hormones, mainly estrogen, may play a role in disease development. We investigated whether menopausal hormone therapy (MHT) was associated with sarcoidosis risk in women and whether the risk varied by treatment type. We performed a nested case–control study (2007–2020) including incident sarcoidosis cases from the Swedish National Patient Register (n = 2593) and matched (1:10) to general population controls (n = 20,003) on birth year, county, and living in Sweden at the time of sarcoidosis diagnosis. Dispensations of MHT were obtained from the Swedish Prescribed Drug Register before sarcoidosis diagnosis/matching. Adjusted odds ratios (aOR) of sarcoidosis were estimated using conditional logistic regression. Ever MHT use was associated with a 25% higher risk of sarcoidosis compared with never use (aOR 1.25, 95% CI 1.13–1.38). When MHT type and route of administration were considered together, systemic estrogen was associated with the highest risk of sarcoidosis (aOR 1.51, 95% CI 1.23–1.85), followed by local estrogen (aOR 1.25, 95% CI 1.11–1.42), while systemic estrogen-progestogen combined was associated with the lowest risk compared to never users (aOR 1.12, 95% CI 0.96–1.31). The aOR of sarcoidosis did not differ greatly by duration of MHT use. Our findings suggest that a history of MHT use is associated with increased risk of sarcoidosis, with women receiving estrogen administered systemically having the highest risk.

Place, publisher, year, edition, pages
Springer Nature, 2024
Keywords
Case–control studies, Estrogen, Menopausal hormone therapy, Risk factors, Sarcoidosis, Women
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:umu:diva-219819 (URN)10.1007/s10654-023-01084-3 (DOI)001140264300001 ()38212490 (PubMedID)2-s2.0-85182203174 (Scopus ID)
Funder
Swedish Heart Lung Foundation, 2020-0452Swedish Heart Lung Foundation, 2020-0163Swedish Heart Lung Foundation, o. 2019-0478Swedish Research Council, 2019-01034Swedish Research Council, 2017-01548Swedish Research Council, 2019 -00227Konung Gustaf V:s och Drottning Victorias Frimurarestiftelse
Available from: 2024-01-22 Created: 2024-01-22 Last updated: 2024-01-22
Molin, J., Domellöf, M., Häggström, C., Vanky, E., Zamir, I., Östlund, E. & Bixo, M. (2024). Neonatal outcome following metformin-treated gestational diabetes mellitus: a population-based cohort study. Acta Obstetricia et Gynecologica Scandinavica
Open this publication in new window or tab >>Neonatal outcome following metformin-treated gestational diabetes mellitus: a population-based cohort study
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2024 (English)In: Acta Obstetricia et Gynecologica Scandinavica, ISSN 0001-6349, E-ISSN 1600-0412Article in journal (Refereed) Epub ahead of print
Abstract [en]

Introduction: Neonatal hypoglycemia is a common complication associated with gestational diabetes and therefore relevant to consider in evaluations of maternal treatment. We aimed to investigate the risk of neonatal hypoglycemia in offspring exposed to metformin treatment alone (MT) or combined with insulin (MIT) in comparison with nutrition therapy alone (NT), and insulin treatment alone (IT). In addition, we investigated MT in comparison with MIT. Secondary outcomes included neonatal anthropometrics, respiratory morbidity, hyperbilirubinemia, 5-min Apgar score, and preterm birth.

Material and methods: This Swedish population-based cohort included 16 181 women diagnosed with gestational diabetes, and their singleton offspring born in 2019–2021. We estimated risk as adjusted odds ratio (aOR) with 95% confidence interval (CI), using individual-level, linkage register-data in multivariable logistic regression models.

Results: In the main analysis, MT was associated with a lower risk of neonatal hypoglycemia versus NT (aOR 0.85, 95% CI: 0.74–0.96), versus MIT (0.74 [0.64–0.87]), and versus IT (0.47 [0.40–0.55]), whereas MIT was associated with a similar risk of neonatal hypoglycemia versus NT (1.14 [0.99–1.30]) and with lower risk versus IT (0.63 [0.53–0.75]). However, supplemental feeding rates were lower for NT versus pharmacological treatments (p < 0.001). In post hoc subgroup analyses including only exclusively breastfed offspring, the risk of neonatal hypoglycemia was modified and similar among MT and NT, and higher in MIT versus NT. Insulin exposure, alone or combined with metformin, was associated with increased risk of being large for gestational age. Compared with NT, exposure to any pharmacological treatment was associated with significantly lower risk of 5-min Apgar score < 4. All other secondary outcomes were comparable among the treatment categories.

Conclusions: The risk of neonatal hypoglycemia appears to be comparable among offspring exposed to single metformin treatment and nutrition therapy alone, and the lower risk that we observed in favor of metformin is probably explained by a difference in supplemental feeding practices rather than metformin per se. By contrast, the lower risk favoring metformin exposure over insulin exposure was not explained by supplemental feeding. However, further investigations are required to determine whether the difference is an effect of metformin per se or mediated by other external factors.

Place, publisher, year, edition, pages
John Wiley & Sons, 2024
Keywords
gestational diabetes mellitus, metformin, neonatal hypoglycemia, neonatal outcome, population-based, register-based
National Category
Obstetrics, Gynecology and Reproductive Medicine Endocrinology and Diabetes
Identifiers
urn:nbn:se:umu:diva-220881 (URN)10.1111/aogs.14787 (DOI)001153803000001 ()38288656 (PubMedID)2-s2.0-85183895565 (Scopus ID)
Funder
Region Västerbotten, C-ALF 7004352Umeå University, 310426017
Available from: 2024-02-15 Created: 2024-02-15 Last updated: 2024-02-15
Sandström, A., Bixo, M., Bäckström, T., Möller, A. & Turkmen, S. (2023). Altered GABAA receptor function in women with endometriosis: a possible pain-related mechanism. Acta Obstetricia et Gynecologica Scandinavica, 102(10), 1316-1322
Open this publication in new window or tab >>Altered GABAA receptor function in women with endometriosis: a possible pain-related mechanism
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2023 (English)In: Acta Obstetricia et Gynecologica Scandinavica, ISSN 0001-6349, E-ISSN 1600-0412, Vol. 102, no 10, p. 1316-1322Article in journal (Refereed) Published
Abstract [en]

Introduction: The mechanism underlying endometriosis-related pain remains poorly understood. Previous studies have indicated that γ-aminobutyric acid (GABA) type A (GABAA) receptors and GABAergic substances (eg endogenous neurosteroids) play important mechanistic roles in various pain conditions. Our primary objective was to compare GABAA receptor function between women with endometriosis and healthy controls by performing a challenge test with diazepam, a GABAA receptor agonist, using the saccadic eye velocity as the main outcome. The secondary objective was to investigate the relationship between GABAA receptor function and serum levels of allopregnanolone, an endogenous positive modulator of the GABAA receptor, in the participating women.

Material and methods: 15 women with pelvic pain and laparoscopically confirmed endometriosis and 10 healthy, symptom-free, control women, aged 18–40 years, underwent the diazepam challenge test during the follicular phase of the menstrual cycle. Basal serum allopregnanolone levels were measured prior to diazepam injection.

Results: Compared with healthy controls, women with pelvic pain and confirmed endometriosis had a significantly smaller change in saccadic eye velocity after GABAA receptor stimulation with diazepam, indicating lower sensitivity to diazepam. The saccadic eye velocity response was not correlated with the serum allopregnanolone levels.

Conclusions: Women with painful endometriosis show altered GABAA receptor function, depicted as a muted response to an exogenous GABAA receptor agonist.

Place, publisher, year, edition, pages
John Wiley & Sons, 2023
Keywords
allopregnanolone, central sensitisation, endometriosis, GABA, pain
National Category
Obstetrics, Gynecology and Reproductive Medicine
Identifiers
urn:nbn:se:umu:diva-206360 (URN)10.1111/aogs.14559 (DOI)000954282800001 ()36944570 (PubMedID)2-s2.0-85150900704 (Scopus ID)
Available from: 2023-04-26 Created: 2023-04-26 Last updated: 2023-12-19Bibliographically approved
Stiernman, L., Dubol, M., Comasco, E., Sundström-Poromaa, I., Boraxbekk, C.-J., Johansson, I.-M. & Bixo, M. (2023). Emotion-induced brain activation across the menstrual cycle in individuals with premenstrual dysphoric disorder and associations to serum levels of progesterone-derived neurosteroids. Translational Psychiatry, 13(1), Article ID 124.
Open this publication in new window or tab >>Emotion-induced brain activation across the menstrual cycle in individuals with premenstrual dysphoric disorder and associations to serum levels of progesterone-derived neurosteroids
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2023 (English)In: Translational Psychiatry, E-ISSN 2158-3188, Vol. 13, no 1, article id 124Article in journal (Refereed) Published
Abstract [en]

Premenstrual dysphoric disorder (PMDD) is a debilitating disorder characterized by severe mood symptoms in the luteal phase of the menstrual cycle. PMDD symptoms are hypothesized to be linked to an altered sensitivity to normal luteal phase levels of allopregnanolone (ALLO), a GABAA-modulating progesterone metabolite. Moreover, the endogenous 3β-epimer of ALLO, isoallopregnanolone (ISO), has been shown to alleviate PMDD symptoms through its selective and dose-dependent antagonism of the ALLO effect. There is preliminary evidence showing altered recruitment of brain regions during emotion processing in PMDD, but whether this is associated to serum levels of ALLO, ISO or their relative concentration is unknown. In the present study, subjects with PMDD and asymptomatic controls underwent functional magnetic resonance imaging (fMRI) in the mid-follicular and the late-luteal phase of the menstrual cycle. Brain responses to emotional stimuli were investigated and related to serum levels of ovarian steroids, the neurosteroids ALLO, ISO, and their ratio ISO/ALLO. Participants with PMDD exhibited greater activity in brain regions which are part of emotion-processing networks during the late-luteal phase of the menstrual cycle. Furthermore, activity in key regions of emotion processing networks - the parahippocampal gyrus and amygdala - was differentially associated to the ratio of ISO/ALLO levels in PMDD subjects and controls. Specifically, a positive relationship between ISO/ALLO levels and brain activity was found in PMDD subjects, while the opposite was observed in controls. In conclusion, individuals with PMDD show altered emotion-induced brain responses in the late-luteal phase of the menstrual cycle which may be related to an abnormal response to physiological levels of GABAA-active neurosteroids.

Place, publisher, year, edition, pages
Springer Nature, 2023
National Category
Psychiatry
Identifiers
urn:nbn:se:umu:diva-206958 (URN)10.1038/s41398-023-02424-3 (DOI)000968319200001 ()37055419 (PubMedID)2-s2.0-85152386545 (Scopus ID)
Available from: 2023-04-26 Created: 2023-04-26 Last updated: 2024-05-17Bibliographically approved
Molin, J., Vanky, E. & Bixo, M. (2023). Free leptin index, excessive weight gain, and metformin treatment during pregnancy in polycystic ovary syndrome: What about inflammation? [Letter to the editor]. British Journal of Obstetrics and Gynecology, 130(7), 841-842
Open this publication in new window or tab >>Free leptin index, excessive weight gain, and metformin treatment during pregnancy in polycystic ovary syndrome: What about inflammation?
2023 (English)In: British Journal of Obstetrics and Gynecology, ISSN 1470-0328, E-ISSN 1471-0528, Vol. 130, no 7, p. 841-842Article in journal, Letter (Refereed) Published
Place, publisher, year, edition, pages
John Wiley & Sons, 2023
National Category
Obstetrics, Gynecology and Reproductive Medicine
Identifiers
urn:nbn:se:umu:diva-207695 (URN)10.1111/1471-0528.17493 (DOI)000974287800001 ()37072649 (PubMedID)2-s2.0-85152891063 (Scopus ID)
Available from: 2023-04-28 Created: 2023-04-28 Last updated: 2023-07-13Bibliographically approved
Vinnars, M.-T., Bixo, M. & Damdimopoulou, P. (2023). Pregnancy-related maternal physiological adaptations and fetal chemical exposure. Molecular and Cellular Endocrinology, 578, Article ID 112064.
Open this publication in new window or tab >>Pregnancy-related maternal physiological adaptations and fetal chemical exposure
2023 (English)In: Molecular and Cellular Endocrinology, ISSN 0303-7207, E-ISSN 1872-8057, Vol. 578, article id 112064Article in journal (Refereed) Published
Abstract [en]

Prenatal life represents a susceptible window of development during which chemical exposures can permanently alter fetal development, leading to an increased likelihood of disease later in life. Therefore, it is essential to assess exposure in the fetus. However, direct assessment in human fetuses is challenging, so most research measures maternal exposure. Pregnancy induces a range of significant physiological changes in women that may affect chemical metabolism and responses. Moreover, placental function, fetal sex, and pregnancy complications may further modify these exposures. The purpose of this narrative review is to give an overview of major pregnancy-related physiological changes, including placental function and impacts of pregnancy complications, to summarize existing studies assessing chemical exposure in human fetal organs, and to discuss possible interactions between physiological changes and exposures. Our review reveals major knowledge gaps in factors affecting fetal chemical exposure, highlighting the need to develop more sophisticated tools for chemical health risk assessment in fetuses.

Place, publisher, year, edition, pages
Elsevier, 2023
Keywords
Chemical exposure, Endocrine-disrupting chemical, Fetal development, Physiological adaptation, Placenta, Pregnancy complication
National Category
Obstetrics, Gynecology and Reproductive Medicine
Identifiers
urn:nbn:se:umu:diva-214608 (URN)10.1016/j.mce.2023.112064 (DOI)37683908 (PubMedID)2-s2.0-85171170072 (Scopus ID)
Funder
EU, Horizon 2020, EU952516Swedish Research Council Formas, 2018-02280Swedish Research Council Formas, 2020–01621Karolinska Institute
Available from: 2023-09-27 Created: 2023-09-27 Last updated: 2023-09-27Bibliographically approved
Dubol, M., Stiernman, L., Wikström, J., Lanzenberger, R., Neill Epperson, C., Sundström-Poromaa, I., . . . Comasco, E. (2022). Differential grey matter structure in women with premenstrual dysphoric disorder: evidence from brain morphometry and data-driven classification. Translational Psychiatry, 12(1), Article ID 250.
Open this publication in new window or tab >>Differential grey matter structure in women with premenstrual dysphoric disorder: evidence from brain morphometry and data-driven classification
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2022 (English)In: Translational Psychiatry, E-ISSN 2158-3188, Vol. 12, no 1, article id 250Article in journal (Refereed) Published
Abstract [en]

Premenstrual dysphoric disorder (PMDD) is a female-specific condition classified in the Diagnostic and Statical Manual—5th edition under depressive disorders. Alterations in grey matter volume, cortical thickness and folding metrics have been associated with a number of mood disorders, though little is known regarding brain morphological alterations in PMDD. Here, women with PMDD and healthy controls underwent magnetic resonance imaging (MRI) during the luteal phase of the menstrual cycle. Differences in grey matter structure between the groups were investigated by use of voxel- and surface-based morphometry. Machine learning and multivariate pattern analysis were performed to test whether MRI data could distinguish women with PMDD from healthy controls. Compared to controls, women with PMDD had smaller grey matter volume in ventral posterior cortices and the cerebellum (Cohen’s d = 0.45–0.76). Region-of-interest analyses further indicated smaller volume in the right amygdala and putamen of women with PMDD (Cohen’s d = 0.34–0.55). Likewise, thinner cortex was observed in women with PMDD compared to controls, particularly in the left hemisphere (Cohen’s d = 0.20–0.74). Classification analyses showed that women with PMDD can be distinguished from controls based on grey matter morphology, with an accuracy up to 74%. In line with the hypothesis of an impaired top-down inhibitory circuit involving limbic structures in PMDD, the present findings point to PMDD-specific grey matter anatomy in regions of corticolimbic networks. Furthermore, the results include widespread cortical and cerebellar regions, suggesting the involvement of distinct networks in PMDD pathophysiology.

Place, publisher, year, edition, pages
Springer Nature, 2022
National Category
Psychiatry
Identifiers
urn:nbn:se:umu:diva-203604 (URN)10.1038/s41398-022-02017-6 (DOI)000811739600001 ()35705554 (PubMedID)2-s2.0-85132071288 (Scopus ID)
Available from: 2023-01-19 Created: 2023-01-19 Last updated: 2024-05-17Bibliographically approved
Molin, J., Vanky, E., Løvvik, T. S., Dehlin, E. & Bixo, M. (2022). Gestational weight gain, appetite regulating hormones, and metformin treatment in polycystic ovary syndrome: A longitudinal, placebo-controlled study. British Journal of Obstetrics and Gynecology, 129(7), 1112-1121
Open this publication in new window or tab >>Gestational weight gain, appetite regulating hormones, and metformin treatment in polycystic ovary syndrome: A longitudinal, placebo-controlled study
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2022 (English)In: British Journal of Obstetrics and Gynecology, ISSN 1470-0328, E-ISSN 1471-0528, Vol. 129, no 7, p. 1112-1121Article in journal (Refereed) Published
Abstract [en]

Objective: To explore mechanisms that modulate gestational weight gain (GWG) in women with polycystic ovary syndrome (PCOS) and healthy controls.

Design: Sub-sample of randomised controlled trials (PCOS) combined with a prospective cohort (controls).

Setting: Eleven Norwegian, Swedish, and Icelandic hospitals.

Population: Pregnant women with PCOS treated with metformin (PCOS-M, n = 36) or placebo (PCOS-P, n = 37), and healthy pregnant women (HC, n = 15).

Methods: Serum levels of the appetite regulating hormones leptin, ghrelin, allopregnanolone, and soluble leptin receptor (sOB-R) were determined in the first and third trimesters.

Main Outcome Measures: Excessive GWG (eGWG) relative to body mass index according to Institute of Medicine (IOM) guideline. Serum leptin/sOB-R ratio, or free-leptin-index (FLI), as biomarker of leptin sensitivity. Serum ghrelin and allopregnanolone levels.

Results: The overall prevalence of eGWG was 44% (38/86). Women with eGWG had higher first and third trimester FLI (< 0.001), and lower third trimester allopregnanolone levels (= 0.003) versus women with non-eGWG. The prevalence of eGWG was lower in PCOS-M versus PCOS-P (28% versus 62%, odds ratio = 0.4, 95% CI 0.2–0.8, = 0.005). FLI decreased during pregnancy in PCOS-M (= 0.01), but remained unaltered in PCOS-P and HC. Ghrelin and allopregnanolone levels were comparable in PCOS-M, PCOS-P and HC throughout pregnancy.

Conclusion: Excessive GWG is associated with enhanced leptin resistance, and attenuated physiological increase in serum allopregnanolone levels during pregnancy. Metformin reduces the risk for eGWG and improves leptin sensitivity in pregnant women with PCOS.

Place, publisher, year, edition, pages
John Wiley & Sons, 2022
National Category
Obstetrics, Gynecology and Reproductive Medicine
Identifiers
urn:nbn:se:umu:diva-191090 (URN)10.1111/1471-0528.17042 (DOI)000734689400001 ()34865304 (PubMedID)2-s2.0-85122031307 (Scopus ID)
Funder
Region Västerbotten, 310426013The Research Council of Norway, 213497
Available from: 2022-01-14 Created: 2022-01-14 Last updated: 2022-07-12Bibliographically approved
Bixo, M. (2022). Gynekologisk anamnes och undersökningsmetoder (2ed.). In: Marie Bixo; Inger Sundström Poromaa (Ed.), Problemorienterad gynekologi och obstetrik: (pp. 28-43). Stockholm: Liber
Open this publication in new window or tab >>Gynekologisk anamnes och undersökningsmetoder
2022 (Swedish)In: Problemorienterad gynekologi och obstetrik / [ed] Marie Bixo; Inger Sundström Poromaa, Stockholm: Liber, 2022, 2, p. 28-43Chapter in book (Other academic)
Place, publisher, year, edition, pages
Stockholm: Liber, 2022 Edition: 2
National Category
Obstetrics, Gynecology and Reproductive Medicine
Identifiers
urn:nbn:se:umu:diva-207843 (URN)9789147141906 (ISBN)
Available from: 2023-05-03 Created: 2023-05-03 Last updated: 2023-05-16Bibliographically approved
Organisations
Identifiers
ORCID iD: ORCID iD iconorcid.org/0000-0002-4988-1967

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