scholarly journals Leptin Decreases Energy Expenditure but Increases Thyroid Hormone in Patients With Lipodystrophy

2021 ◽  
Vol 5 (Supplement_1) ◽  
pp. A19-A20
Author(s):  
Emmanuel Quaye ◽  
Andrew Grover ◽  
Robert Brychta ◽  
John Christensen ◽  
Megan S Startzell ◽  
...  
Keyword(s):  
Weight Loss ◽  
Thyroid Hormone ◽  
Energy Expenditure ◽  
De Novo ◽  
De Novo Lipogenesis ◽  
Free T4 ◽  
Free T3 ◽  
Healthy Humans ◽  
Leptin Deficiency ◽  
Period 2

Abstract Leptin is an adipokine that signals energy sufficiency. In rodents, leptin deficiency is associated with decreased body temperature and energy expenditure (EE), which is reversed with leptin replacement. Leptin’s role in EE in humans is unclear; however, one study of 10% weight-reduced healthy subjects suggested that leptin replacement to pre-weight loss levels restored the decline in EE, thyroid hormone, and catecholamines associated with weight loss. Patients with lipodystrophy (LD) are characterized by deficiency of adipose tissue and can serve as models to study effects of leptin deficiency and replacement in humans. We hypothesized that treatment with recombinant leptin (metreleptin) in patients with LD would increase EE, thyroid hormone, and catecholamines. We conducted a non-randomized crossover study of 25 patients with LD who were hospitalized for 19 days on an iso-caloric diet. The initiation cohort consisted of 17 patients with no prior exposure to metreleptin, who were first studied for 5 days without metreleptin (period 1), then were treated with metreleptin for 14 days (period 2). The withdrawal cohort consisted of 8 previously metreleptin-treated patients who were continued on metreleptin for the first 5 days of the study (period 1), then were taken off metreleptin for 14 days (period 2). At the end of each period, we measured 24-hour EE (TEE) and resting EE (REE) using indirect calorimetry and free T3, T4, epinephrine, norepinephrine and dopamine after an 8–12 hour fast. In the leptin initiation cohort, TEE and REE decreased from 2402±383 kcal/day and 1805±332 kcal/day to 2272±396 kcal/day (p=0.003) and 1688±318 kcal/day (p=0.03), respectively. Free T3 increased from median (IQR) 248 (200, 270) pg/mL to 295 (259, 315) (p=0.006). No changes in catecholamines were observed in the initiation cohort. In the withdrawal cohort, free T3 decreased from 295 (267, 331) pg/mL to 265 (237, 323) (p=0.008), free T4 decreased from 1.2 ±0.2 ng/dL to 1.0±0.2 (p=0.002), and norepinephrine decreased from 191±70 pg/mL to 112±47 (p=0.03) after metreleptin withdrawal. No changes in EE, epinephrine or dopamine were observed in the withdrawal cohort. Contrary to previous studies in rodents and healthy humans, we found that introduction of metreleptin reduced EE in patients with LD. Consistent with rodent and prior human data, patients with LD had increased thyroid hormone on metreleptin, which would be expected to increase EE. The discrepancy in EE compared to other models may be due to metreleptin-induced correction of severe metabolic derangements in LD, including reduction in energy-requiring processes such as de novo lipogenesis and gluconeogenesis. These changes may offset increases in leptin-induced mediators of increased EE, such as thyroid hormone.

scholarly journals Regular exercise potentiates energetically expensive hepatic de novo lipogenesis during early weight regain

2019 ◽  
Vol 317 (5) ◽  
pp. R684-R695
Author(s):  
David M. Presby ◽  
L. Allyson Checkley ◽  
Matthew R. Jackman ◽  
Janine A. Higgins ◽  
Kenneth L. Jones ◽  
...  
Keyword(s):  
Weight Loss ◽  
Energy Expenditure ◽  
De Novo ◽  
Energy Gap ◽  
Cholesterol Biosynthesis ◽  
Density Lipoprotein ◽  
De Novo Lipogenesis ◽  
Positive Energy ◽  
Hepatic Expression ◽  
Expression Of Genes

Exercise is a potent facilitator of long-term weight loss maintenance (WLM), whereby it decreases appetite and increases energy expenditure beyond the cost of the exercise bout. We have previously shown that exercise may amplify energy expenditure through energetically expensive nutrient deposition. Therefore, we investigated the effect of exercise on hepatic de novo lipogenesis (DNL) during WLM and relapse to obesity. Obese rats were calorically restricted with (EX) or without (SED) treadmill exercise (1 h/day, 6 days/wk, 15 m/min) to induce and maintain weight loss. After 6 wk of WLM, subsets of WLM-SED and WLM-EX rats were allowed ad libitum access to food for 1 day to promote relapse (REL). An energy gap-matched group of sedentary, relapsing rats (REL-GM) were provided a diet matched to the positive energy imbalance of the REL-EX rats. During relapse, exercise increased enrichment of hepatic DN-derived lipids and induced hepatic molecular adaptations favoring DNL compared with the gap-matched controls. In the liver, compared with both REL-SED and REL-GM rats, REL-EX rats had lower hepatic expression of genes required for cholesterol biosynthesis; greater hepatic expression of genes that mediate very low-density lipoprotein synthesis and secretion; and greater mRNA expression of Cyp27a1, which encodes an enzyme involved in the biosynthesis of bile acids. Altogether, these data provide compelling evidence that the liver has an active role in exercise-mediated potentiation of energy expenditure during early relapse.

Leptin Decreases Energy Expenditure Despite Increased Thyroid Hormone in Patients with Lipodystrophy

2021 ◽  
Author(s):  
Andrew Grover ◽  
Emmanuel Quaye ◽  
Robert J Brychta ◽  
John Christensen ◽  
Megan S Startzell ◽  
...  
Keyword(s):  
Thyroid Hormone ◽  
Energy Expenditure ◽  
Resting Energy Expenditure ◽  
Free T4 ◽  
Autonomic Nervous System Activity ◽  
Free T3 ◽  
Mediated Effects ◽  
Nervous System Activity ◽  
Before And After ◽  
Randomized Crossover Study

Abstract Context Leptin is an adipokine that signals energy sufficiency. In rodents, leptin deficiency decreases energy expenditure (EE), which is corrected following leptin replacement. In humans, data are mixed regarding leptin-mediated effects on EE. Objective To determine the effects of metreleptin on EE in patients with lipodystrophy. Design, setting, and patients Non-randomized crossover study of 25 patients with lipodystrophy (NIH, 2013-2018). Intervention The initiation cohort consisted of 17 patients without prior exposure to metreleptin, studied before and after 14 days of metreleptin. The withdrawal cohort consisted of 8 previously metreleptin-treated patients, studied before and after 14 days of metreleptin withdrawal. Main outcomes 24-hour energy expenditure (TEE), resting energy expenditure (REE), autonomic nervous system activity (heart rate variability, HrV), plasma free T3, free T4, epinephrine, norepinephrine, and dopamine. Results In the initiation cohort, TEE and REE decreased by 5.0% (121±152 kcal/day; p=0.006) and 5.9% (120±175 kcal/day; p=0.02). Free T3 increased by 19.4% (40±49 pg/dL; p=0.01). No changes in catecholamines or HrV were observed. In the withdrawal cohort, free T3 decreased by 8.0% (p=0.04), free T4 decreased by 11.9% (p=0.002), and norepinephrine decreased by 34.2% (p=0.03), but no changes in EE, epinephrine, dopamine, or HrV were observed. Conclusions Metreleptin initiation decreased EE in patients with lipodystrophy, but no changes were observed after metreleptin withdrawal. Thyroid hormone was higher on metreleptin in both initiation and withdrawal cohorts. Decreased EE after metreleptin in lipodystrophy may result from reductions in energy-requiring metabolic processes that counteract increases in EE via adipose tissue-specific neuroendocrine and adrenergic signaling.

scholarly journals Rescue pre-operative treatment with Lugol’s solution in uncontrolled Graves’ disease

2017 ◽  
Vol 6 (4) ◽  
pp. 200-205 ◽  
Author(s):  
Jan Calissendorff ◽  
Henrik Falhammar
Keyword(s):  
Heart Rate ◽  
Thyroid Hormone ◽  
Side Effects ◽  
Definitive Treatment ◽  
Graves Disease ◽  
Free T4 ◽  
Hormone Levels ◽  
Free T3 ◽  
Adherence To Medication ◽  
Thyroid Hormone Levels

Background Graves’ disease is a common cause of hyperthyroidism. Three therapies have been used for decades: pharmacologic therapy, surgery and radioiodine. In case of adverse events, especially agranulocytosis or hepatotoxicity, pre-treatment with Lugol’s solution containing iodine/potassium iodide to induce euthyroidism before surgery could be advocated, but this has rarely been reported. Methods All patients hospitalised due to uncontrolled hyperthyroidism at the Karolinska University Hospital 2005–2015 and treated with Lugol’s solution were included. All electronic files were carefully reviewed manually, with focus on the cause of treatment and admission, demographic data, and effects of iodine on thyroid hormone levels and pulse frequency. Results Twenty-seven patients were included. Lugol’s solution had been chosen due to agranulocytosis in 9 (33%), hepatotoxicity in 2 (7%), other side effects in 11 (41%) and poor adherence to medication in 5 (19%). Levels of free T4, free T3 and heart rate decreased significantly after 5–9 days of iodine therapy (free T4 53–20 pmol/L, P = 0.0002; free T3 20–6.5 pmol/L, P = 0.04; heart rate 87–76 beats/min P = 0.0007), whereas TSH remained unchanged. Side effects were noted in 4 (15%) (rash n = 2, rash and vomiting n = 1, swelling of fingers n = 1). Thyroidectomy was performed in 26 patients (96%) and one was treated with radioiodine; all treatments were without serious complications. Conclusion Treatment of uncontrolled hyperthyroidism with Lugol’s solution before definitive treatment is safe and it decreases thyroid hormone levels and heart rate. Side effects were limited. Lugol’s solution could be recommended pre-operatively in Graves’ disease with failed medical treatment, especially if side effects to anti-thyroid drugs have occurred.

scholarly journals Resting Energy Expenditure and Cold Induced Thermogenesis in Patients with Overt Hyperthyroidism

2021 ◽  
Author(s):  
Claudia Irene Maushart ◽  
Jaël Rut Senn ◽  
Rahel Catherina Loeliger ◽  
Judith Siegenthaler ◽  
Fabienne Bur ◽  
...  
Keyword(s):  
Body Composition ◽  
Energy Expenditure ◽  
Skin Temperature ◽  
Cold Exposure ◽  
Resting Energy Expenditure ◽  
Free T4 ◽  
Free T3 ◽  
Euthyroid State ◽  
Overt Hyperthyroidism ◽  
Resting Energy

Abstract Context Thyroid hormone is crucial for the adaptation to cold. Objective To evaluate the effect of hyperthyroidism on resting energy expenditure (REE), cold-induced thermogenesis (CIT) and changes in body composition and weight. Design Prospective cohort study. Setting Endocrine outpatient clinic at tertiary referral center. Patients Eighteen patients with overt hyperthyroidism. Main Outcome Measures We measured REE during hyperthyroidism, after restoring euthyroid TH levels and after 3 months of normal thyroid function. In fourteen patients energy expenditure (EE) was measured before and after a mild cold exposure of two hours and CIT was the difference between EEcold and EEwarm. Skin temperatures at eight positions were recorded during the study visits. Body composition was assessed by dual X-ray absorption. Results Free T4 (fT4) and free T3 (fT3) decreased significantly over time (fT4, p=0.0003; fT3, p=0.0001). REE corrected for lean body mass (LBM) decreased from 42 ± 6.7 kcal/24h/kg LBM in the hyperthyroid to 33±4.4 kcal/24h/kg LBM (-21%, p<0.0001 vs hyperthyroid) in the euthyroid state and three months later to 33 ± 5.2 kcal/24h/kg LBM (-21%, p=0.0022 vs. hyperthyroid, overall p<0.0001). Free T4 (p=0.0001) and free T3 (p<0.0001) were predictors of REE. CIT did not change from the hyperthyroid to the euthyroid state (p=0.96). Hyperthyroidism led to increased skin temperature at warm ambient conditions but did not alter core body temperature, nor skin temperature after cold exposure. Weight regain and body composition were not influenced by REE and CIT during the hyperthyroid state. Conclusions CIT is not increased in patients with overt hyperthyroidism.

scholarly journals Dissociation between adipose tissue fluxes and lipogenic gene expression in ob/ob mice

2007 ◽  
Vol 292 (4) ◽  
pp. E1101-E1109 ◽  
Author(s):  
S. M. Turner ◽  
S. Roy ◽  
H. S. Sul ◽  
R. A. Neese ◽  
E. J. Murphy ◽  
...  
Keyword(s):  
Gene Expression ◽  
Cell Proliferation ◽  
Adipose Tissue ◽  
De Novo ◽  
De Novo Lipogenesis ◽  
Mrna Levels ◽  
Lipogenic Genes ◽  
Lipogenic Gene Expression ◽  
Leptin Deficiency ◽  
Normal Expression

Recent evidence has been presented that expression of lipogenic genes is downregulated in adipose tissue of ob/ob mice as well as in human obesity, suggesting a functionally lipoatrophic state. Using 2H2O labeling, we measured three adipose tissue biosynthetic processes concurrently: triglyceride (TG) synthesis, palmitate de novo lipogenesis (DNL), and cell proliferation (adipogenesis). To determine the effect of the ob/ob mutation (leptin deficiency) on these parameters, adipose dynamics were compared in ob/ob, leptin-treated ob/ob, food-restricted ob/ob, and lean control mice. Adipose tissue fluxes for TG synthesis, de novo lipogenesis (DNL), and adipogenesis were dramatically increased in ob/ob mice compared with lean controls. Low-dose leptin treatment (2 μg/day) via miniosmotic pump suppressed all fluxes to control levels or below. Food restriction in ob/ob mice only modestly reduced DNL, with no change in TG synthesis or adipogenesis. Measurement of mRNA levels in age-matched ob/ob mice showed generally normal expression levels for most of the selected lipid anabolic genes, and leptin treatment had, with few exceptions, only modest effects on their expression. We conclude that leptin deficiency per se results in marked elevations in flux through diverse lipid anabolic pathways in adipose tissue (DNL, TG synthesis, and cell proliferation), independent of food intake, but that gene expression fails to reflect these changes in flux.

scholarly journals Diverse Genotypes and Phenotypes of Three Novel Thyroid Hormone Receptor-α Mutations

2016 ◽  
Vol 101 (8) ◽  
pp. 2945-2954 ◽  
Author(s):  
Korcan Demir ◽  
Anja L. M. van Gucht ◽  
Muammer Büyükinan ◽  
Gönül Çatlı ◽  
Yavuz Ayhan ◽  
...  
Keyword(s):  
Thyroid Hormone ◽  
Motor Development ◽  
Thyroid Hormone Receptor ◽  
Clinical Phenotype ◽  
Case Series ◽  
Detailed Knowledge ◽  
Thyroid Function Tests ◽  
Free T4 ◽  
Serum Free ◽  
Free T3

Context: Recently several patients with resistance to thyroid hormone (RTH)-α due to T3 receptor-α (TRα) mutations were identified. The phenotype of these patients consists of varying degrees of growth impairment, delayed bone, mental and motor development, constipation, macrocephaly, and near-normal thyroid function tests. Objective: The objective of the study was to describe the clinical phenotype of three new families with RTHα and thereby gain more detailed knowledge on this novel syndrome. Design, Setting, and Participants: RTHα was suspected in three index patients from different families. Detailed clinical and biochemical assessment and imaging and genetic analyses were performed in the patients and their relatives. In addition, functional consequences of TRα mutations were investigated in vitro. Results: We studied 22 individuals from three families and identified 10 patients with heterozygous TRα mutations: C380fs387X, R384H, and A263S, respectively. The frame-shift mutation completely inactivated TRα, whereas the missense mutations produced milder defects. These mutations were associated with decreasing severity of the clinical phenotype: the patient in family 1 showed severe defects in growth, mental, and motor development, whereas the seven patients in family 3 had only mild clinical features. The most frequent abnormalities were anemia, constipation, and a delay in at least one of the developmental milestones. Serum free T3 ranged from high-normal to high and serum free T4 and rT3 from normal to low. TSH levels were normal in all patients. Conclusions: This large case series underlines the variation in the clinical phenotype of RTHα patients. RTHα should be suspected in subjects when even mild clinical and laboratory features of hypothyroidism are present along with high/high-normal free T3, low/normal free T4, and normal TSH.

scholarly journals Thyroid Autoantibodies Are Rare in Nonhuman Great Apes and Hypothyroidism Cannot Be Attributed to Thyroid Autoimmunity

Endocrinology ◽  
2013 ◽  
Vol 154 (12) ◽  
pp. 4896-4907 ◽  
Author(s):  
Holly Aliesky ◽  
Cynthia L. Courtney ◽  
Basil Rapoport ◽  
Sandra M. McLachlan
Keyword(s):  
Thyroid Hormone ◽  
Thyroid Autoimmunity ◽  
Great Apes ◽  
Normal Serum ◽  
Thyroid Peroxidase ◽  
Thyroid Autoantibodies ◽  
Free T4 ◽  
Hormone Levels ◽  
Free T3 ◽  
Thyroid Hormone Levels

The great apes include, in addition to Homo, the genera Pongo (orangutans), Gorilla (gorillas), and Pan, the latter comprising two species, P. troglodytes (chimpanzees) and P. paniscus (bonobos). Adult-onset hypothyroidism was previously reported in 4 individual nonhuman great apes. However, there is scarce information on normal serum thyroid hormone levels and virtually no data for thyroid autoantibodies in these animals. Therefore, we examined thyroid hormone levels and TSH in all nonhuman great ape genera including adults, adolescents, and infants. Because hypothyroidism in humans is commonly the end result of thyroid autoimmunity, we also tested healthy and hypothyroid nonhuman great apes for antibodies to thyroglobulin (Tg), thyroid peroxidase (TPO), and the TSH receptor (TSHR). We established a thyroid hormone and TSH database in orangutans, gorillas, chimpanzees, and bonobos (447 individuals). The most striking differences are the greatly reduced free-T4 and free-T3 levels in orangutans and gorillas vs chimpanzees and bonobos, and conversely, elevated TSH levels in gorillas vs Pan species. Antibodies to Tg and TPO were detected in only 2.6% of adult animals vs approximately 10% in humans. No animals with Tg, TPO, or TSHR antibodies exhibited thyroid dysfunction. Conversely, hypothyroid nonhuman great apes lacked thyroid autoantibodies. Moreover, thyroid histology in necropsy tissues was similar in euthyroid and hypothyroid individuals, and lymphocytic infiltration was absent in 2 hypothyroid animals. In conclusion, free T4 and free T3 are lower in orangutans and gorillas vs chimpanzees and bonobos, the closest living human relatives. Moreover, thyroid autoantibodies are rare and hypothyroidism is unrelated to thyroid autoimmunity in nonhuman great apes.

scholarly journals The Effect of Antithyroid Drug Pretreatment on Acute Changes in Thyroid Hormone Levels after 131I Ablation for Graves’ Disease1

2001 ◽  
Vol 86 (7) ◽  
pp. 3016-3021 ◽  
Author(s):  
H. B. Burch ◽  
B. L. Solomon ◽  
D. S. Cooper ◽  
P. Ferguson ◽  
N. Walpert ◽  
...  
Keyword(s):  
Thyroid Hormone ◽  
Radioiodine Therapy ◽  
Antithyroid Drug ◽  
Antithyroid Drugs ◽  
Free T4 ◽  
Hormone Levels ◽  
Free T3 ◽  
Average Decrease ◽  
Thyroid Hormone Levels ◽  
Acute Changes

Acute changes in thyroid hormone levels before and after radioiodine therapy for Graves’ disease were compared in 42 patients randomized to receive either antithyroid drug pretreatment or no pretreatment. Five patients (11.9%), including 3 in the pretreatment arm and 2 in the no pretreatment arm experienced a late exacerbation of thyrotoxicosis after radioiodine therapy. The majority (19 of 21, 90.5%) of pretreated patients experienced a transient increase in free T4 and free T3 after discontinuation of antithyroid drugs, with little further elevation after radioiodine therapy. After stopping antithyroid drugs and before radioiodine administration, mean serum free T4 values rose from 14.7 ± 6.9 to 21.6 ± 12.1 pmol/L, representing a 46.9% increase, whereas serum free T3 levels rose from 4.9± 1.7 to 8.1 ± 6.3 pmol/L, representing a 65.3% increase. The average pretreated patient experienced a 52.4% increase [95% confidence interval (CI), +26.4% to +78.5%] in free T4 and a 61.8% increase (95% CI, +23.5% to +100.0%) in free T3. Conversely, the majority (19 of 21, 90.5%) of nonpretreated patients experienced a rapid decline in thyroid hormone levels after radioiodine treatment. Over the 14 days after radioiodine therapy mean free T4 values in nonpretreated patients fell from 85.8 ± 60.4 to 58.0 ± 76.5 pmol/L, representing a 32.4% decrease, whereas mean free T3 levels fell from 16.1 ± 8.0 to 10.8 ± 11.1 pmol/L, representing a 32.9% decrease. The average nonpretreated patient experienced a 20.6% decrease (95% CI, −47.3% to +7.0%) in free T4 and a 24.3% decrease (95% CI, −1.2% to −47.4%) in free T3 during this time period. Excluding 2 patients with a late exacerbation after radioiodine, 19 nonpretreated patients experienced a decrease in mean free T4 values from 76.8 ± 46.6 to 36.6 ± 19.8 pmol/L, representing a 52.3% decrease, whereas mean free T3 levels fell from 15.5 ± 7.7 to 7.8 ± 3.6 pmol/L, representing a 49.7% decrease. The average decrease in free T4 levels among this subgroup of patients was 30.1% (95% CI, −4.6% to −55.6%), whereas the average decrease in free T3 was 34.4% (95% CI, −13.7% to −55.1%). High levels of TSH receptor autoantibodies at diagnosis were associated with an acute worsening of thyrotoxicosis after stopping antithyroid drug pretreatment. We conclude that pretreatment with antithyroid drugs does not protect against worsening thyrotoxicosis after radioiodine, but may allow such patients to start from a lower baseline level should an aggravation in thyrotoxicosis occur. The findings support the recommendation that most patients with Graves’ disease do not require antithyroid drug pretreatment before receiving radioiodine.

scholarly journals Combining metformin therapy with caloric restriction for the management of type 2 diabetes and nonalcoholic fatty liver disease in obese rats

2015 ◽  
Vol 40 (10) ◽  
pp. 1038-1047 ◽  
Author(s):  
Melissa A. Linden ◽  
Kristi T. Lopez ◽  
Justin A. Fletcher ◽  
E. Matthew Morris ◽  
Grace M. Meers ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Weight Loss ◽  
Liver Disease ◽  
Caloric Restriction ◽  
Fatty Liver Disease ◽  
De Novo ◽  
De Novo Lipogenesis ◽  
Nonalcoholic Fatty Liver ◽  
Oletf Rats

Weight loss is recommended for patients with nonalcoholic fatty liver disease (NAFLD), while metformin may lower liver enzymes in type 2 diabetics. Yet, the efficacy of the combination of weight loss and metformin in the treatment of NAFLD is unclear. We assessed the effects of metformin, caloric restriction, and their combination on NAFLD in diabetic Otsuka Long-Evans Tokushima Fatty (OLETF) rats. Male OLETF rats (age 20 weeks; n = 6–8 per group) were fed ad libitum (AL), given metformin (300 mg·kg−1·day−1; Met), calorically restricted (70% of AL; CR), or calorically restricted and given metformin (CR+Met) for 12 weeks. Met lowered adiposity compared with AL but not to the same magnitude as CR or CR+Met (p < 0.05). Although only CR improved fasting insulin and glucose, the combination of CR+Met was needed to improve post-challenge glucose tolerance. All treatments lowered hepatic triglycerides, but further improvements were observed in the CR groups (p < 0.05, Met vs. CR or CR+Met) and a further reduction in serum alanine aminotransferases was observed in CR+Met rats. CR lowered markers of hepatic de novo lipogenesis (fatty acid synthase, acetyl-CoA carboxylase (ACC), and stearoyl-CoA desaturase-1 (SCD-1)) and increased hepatic mitochondrial activity (palmitate oxidation and β-hydroxyacyl CoA dehydrogenase (β-HAD) activity). Changes were enhanced in the CR+Met group for ACC, SCD-1, β-HAD, and the mitophagy marker BNIP3. Met decreased total hepatic mTOR content and inhibited mTOR complex 1, which may have contributed to Met-induced reductions in de novo lipogenesis. These findings in the OLETF rat suggest that the combination of caloric restriction and metformin may provide a more optimal approach than either treatment alone in the management of type 2 diabetes and NAFLD.

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