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1.
Am J Med Genet C Semin Med Genet ; : e32111, 2024 Sep 09.
Artigo em Inglês | MEDLINE | ID: mdl-39246069

RESUMO

The understanding of phenylketonuria (PKU), guidelines, and treatment landscape have evolved dramatically over the decades since newborn screen implementation. We capture this rich history from the stories and experiences of a multidisciplinary provider team from Boston Children's Hospital's PKU Clinic, who treated PKU from the early years of newborn screening and who worked together for over 40 years.

2.
Mol Genet Metab Rep ; 37: 101015, 2023 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-38053931

RESUMO

Background: Pegvaliase has allowed many adults with phenylketonuria (PKU) to achieve acceptable blood Phe control while eating an unrestricted diet. However, little is known about potential differences in nutritional status and eating behaviors after transitioning from a phenylalanine (Phe)-restricted to an unrestricted diet. Here we assessed change in nutritional status in adults with early-treated PKU who were consuming a Phe-restricted diet (intact protein ≤0.8 g/kg/day) prior to starting pegvaliase. Methods: A 15-month, prospective, longitudinal study to assess change in anthropometrics, dietary intake, laboratory indices of nutritional status, bone mineral density (BMD), body composition, measured resting energy expenditure (REE), and eating behaviors between baseline and Month 15. Results: Eleven adults (n = 7 female) aged 19.5-52.9 years completed the study. Six participants had a substantial blood Phe reduction (responders) and five participants had a modest blood Phe reduction (partial responders) by Month 15. Intact protein intake increased by an average of 49.4 g/day and 26.7 g/day in responders and partial responders, respectively. Plasma concentrations of most vitamins, minerals, and essential fatty acids assessed were normal, though micronutrient intakes decreased as participants decreased or discontinued PKU medical food(s). Responders had a more variable change in body mass index (BMI) and lean mass index (LMI) compared to partial responders, though there were no clear trends in BMD or body composition changes. Total protein intake was positively correlated with LMI. Responders, but not partial responders, self-reported increased in enjoyment of food and decreased food neophobia, uncontrolled eating, and emotional eating. Discussion: Participants transitioning to an unrestricted diet while on pegvaliase maintained adequate nutritional status overall with no clinically significant changes in cardiovascular or glycemic markers. Responders reported improvements in eating behaviors, including reduced food neophobia, uncontrolled eating, and emotional eating, and increased enjoyment of food. There were no consistent trends in BMD, body composition, or BMI changes. A larger sample size and longer follow-up period are needed to further assess potential changes.

3.
Mol Genet Metab Rep ; 33: 100938, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36420422

RESUMO

Pegvaliase, an injectable form of phenylalanine ammonia lyase, is an enzyme substitution therapy for adults with phenylketonuria (PKU). Experience with pegvaliase during lactation is scarce. Limited evidence suggests that pegvaliase does not pass into breast milk. The case presented here describes the pregnancy and lactation experience of a woman with PKU who was treated with pegvaliase prior to pregnancy, discontinued pegvaliase and was treated with a phenylalanine-restricted diet in preparation for and during pregnancy, and then reinstituted pegvaliase two weeks after giving birth and throughout lactation. No pegvaliase activity was detected in pumped breast milk samples prior to reinstituting pegvaliase, and at doses of 80, 110 and 140 mg/week during lactation. The phenylalanine content of breast milk samples collected during pegvaliase therapy were not significantly different than controls, and the infant has grown and developed normally, indicating that pegvaliase therapy during lactation is safe.

4.
Mol Genet Metab ; 133(4): 345-351, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34116943

RESUMO

BACKGROUND: Pegvaliase is an enzyme substitution therapy that reduces blood phenylalanine (Phe) in adults with phenylketonuria (PKU), and often allows normalization of protein intake (≥0.8 g protein/kg). Here we examine the nutrition status of adults with PKU consuming a normal protein intake without medical food after being treated with pegvaliase for ≥1 year. METHODS: A cross-sectional study evaluating nutritional intake (3-day food record and food frequency questionnaire), anthropometrics, laboratory indices of protein, micronutrient, and essential fatty acid (EFA) status, and questionnaires evaluating food neophobia and Epicurean eating pleasure. RESULTS: Participants (n = 18, 61% female) started pegvaliase 4.9 ± 2.1 years prior to enrollment and were aged 38.2 ± 8.8 years with a mean BMI of 29.2 ± 4.1 kg/m2. Participants consumed a mean of 73.2 ± 17.6 g protein/d (1.0 ± 0.3 g/kg/d). Eleven participants had low blood Phe (<30 µmol/L) with adequate protein intake and normal indices of protein status. Micronutrient and EFA concentrations were normal except for mildly low vitamin D (<30 ng/mL, n = 12). Intakes of sodium, saturated fat, and added sugars exceeded recommendations for healthy adults, though mean diet quality was comparable to a US adult reference population. Lower food neophobia scores correlated with an increased aesthetic appreciation of food. However, 53% of participants self-reported having moderate (n = 6) to high (n = 3) food neophobia. DISCUSSION: Participants treated with pegvaliase consumed an unrestricted diet with adequate dietary protein and, overall, had normal protein, micronutrient, and fatty acid status. Despite low blood Phe, protein nutriture was not compromised. While nutritional deficiencies were not identified, diet quality was suboptimal and some participants reported food neophobia. Nutrition education remains an important component of care as patients adapt to a normal diet.


Assuntos
Dieta , Estado Nutricional/efeitos dos fármacos , Fenilalanina Amônia-Liase/uso terapêutico , Fenilcetonúrias/tratamento farmacológico , Adulto , Estudos Transversais , Proteínas Alimentares/administração & dosagem , Ácidos Graxos Essenciais , Feminino , Humanos , Masculino , Micronutrientes/sangue , Pessoa de Meia-Idade , Fenilalanina/sangue , Fenilcetonúrias/fisiopatologia , Proteínas Recombinantes/uso terapêutico , Inquéritos e Questionários
5.
JIMD Rep ; 54(1): 3-8, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32685343

RESUMO

Cardiomyopathy is a frequent complication of propionic acidemia (PA). It is often fatal, and its occurrence is largely independent of classic metabolic treatment modalities. Liver transplantation (LT) is a treatment option for severe PA as the liver plays a vital role in metabolism of the precursors that accumulate in patients with PA. LT in PA is now considered to be a long-lasting and valid treatment to prevent cardiac disease. The subject of this report had severe cardiomyopathy that largely disappeared prior to undergoing a LT. Three years following the transplant, there was recurrence of cardiomyopathy following a surgery that was complicated with a postoperative aspiration pneumonia. On his last hospital admission, he was presented with pulmonary edema and heart failure. He continued with episodes of intractable hypotension, despite maximum inotropic and diuretic support. He died following redirection of care. We conclude that lethal cardiomyopathy may develop several years after successful LT in patients with PA.

6.
Mol Genet Metab Rep ; 24: 100603, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32489881

RESUMO

We present Boston Children's Hospital's clinic model for pegvaliase therapy in adults with phenylketonuria (PKU) and clinical outcomes in 46 patients over the first 1.5 years of commercial therapy. Approximately 70% (18/26) of patients starting pegvaliase achieved blood phenylalanine (Phe) <360 µmol/L, with an average of a 68 ± 24% decrease in blood Phe from baseline. All patients experienced at least minor side effects, but in most, management of the side effects allowed for treatment to continue.

7.
Mol Genet Metab ; 128(4): 415-421, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31623983

RESUMO

Phenylketonuria (PKU) is an autosomal recessive inborn error of metabolism caused by pathogenic variants in the phenylalanine hydroxylase gene (PAH). The correlation between genotype and phenotype can be complex and sometimes variable but often very useful for categorizing and predicting dietary tolerance and potential outcome. We reviewed medical records for 367 patients diagnosed with PKU or persistent mild hyperphenylalaninemia (MHP) between 1950 and 2015 who had PAH genotyping. In 351 we had the full PAH genotype as well as phenotypic characteristics such as phenylalanine (Phe) concentrations (at newborn screening, confirmation, and highest known), and dietary Phe tolerance. On 716 mutant chromosomes, including 14 in genotypes with only one identified variant, we identified 114 different pathogenic variants. The most frequent, p.R408W, was present in 15.4% of the alleles; other frequent variants were c.1315 + 1G > A (6.1%), p.I65T (5.7%), and p.R261Q (5.7%). Three variants, c.142 T > G (p.L48 V), c.615G > C (p.E205D), and c.1342_1345delCTCC, were novel. We used the phenotypic parameters of variants paired with null alleles (functional hemizygotes) to assign the variants as classic PKU, moderate PKU, mild PKU, MHP-gray zone, or MHP. We also included the phenotype association(s) for all of the full genotypes. In 103 patients, we also could assign sapropterin dihydrochloride responsiveness, which is a synthetic form of the tetrahydrobiopterin (BH4) PAH cofactor. This compilation from a single metabolic center provides further information on PAH variants in the United States and the correlations between genotype and phenotype.


Assuntos
Estudos de Associação Genética , Genótipo , Mutação , Fenótipo , Fenilalanina Hidroxilase/genética , Fenilcetonúrias/diagnóstico , Fenilcetonúrias/genética , Alelos , Substituição de Aminoácidos , Biopterinas/análogos & derivados , Biopterinas/uso terapêutico , Feminino , Humanos , Recém-Nascido , Masculino , Triagem Neonatal , Fenilalanina Hidroxilase/sangue , Fenilcetonúrias/tratamento farmacológico , Fenilcetonúrias/epidemiologia , Resultado do Tratamento , Estados Unidos/epidemiologia
8.
J Pediatr ; 198: 313-316, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29681447

RESUMO

Maple syrup urine disease (MSUD) is an inborn error of metabolism that causes elevated leucine in the setting of acute illnesses. We describe an 8-year-old boy with MSUD who developed acute pancreatitis and subsequent leucinosis. This case highlights the complexities of fluid management in patients with MSUD.


Assuntos
Doença da Urina de Xarope de Bordo/complicações , Doença da Urina de Xarope de Bordo/terapia , Pancreatite/etiologia , Pancreatite/terapia , Criança , Humanos , Masculino , Doença da Urina de Xarope de Bordo/diagnóstico , Pancreatite/diagnóstico
9.
JIMD Rep ; 40: 17-22, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-28887792

RESUMO

Ornithine transcarbamylase deficiency (OTCD) is an X-linked urea cycle disorder with variable expressivity in heterozygous females. While liver function testing is often abnormal in patients with OTCD, liver failure is uncommon on presentation. A 13-month-old female with no significant past medical history presented with irritability, right arm weakness, and decreased appetite. Initial workup revealed hepatic dysfunction with an INR of 3.4, ammonia level of 75 µmol/L, and abnormal brain MRI with gyral edema with restricted diffusion, and patchy signal abnormality in basal ganglia. The MRI findings led to a putative diagnosis of acute disseminated encephalomyelitis prompting corticosteroid treatment. As steroid treatment was begun, she developed significant hepatocellular dysfunction with ALT 2,222 U/L, AST 630 U/L, prolonged INR, and elevated ammonia (213 µmol/L). Neurologic signs resolved and her ammonia level decreased (43 µmol/L) without further intervention; however, she had ongoing acute liver failure with coagulopathy and episodic irritability, managed as seronegative autoimmune hepatitis with partial response to corticosteroid therapy. At 18 months of age she presented with severe irritability with markedly increased ammonia (417 µmol/L). Plasma amino acids obtained several days prior to this acute episode demonstrated elevation in glutamine (2,725 µmol/L) and alanine (1,459 µmol/L). Biochemical testing demonstrated elevation of urine orotic acid (>240.6 mmol/mol creatinine). Genetic testing confirmed a heterozygous nonsense mutation in the OTC gene (c.958C>T, R320X). After treatment with ammonia scavengers and a protein-restricted diet, hepatic function normalized and irritability resolved. The diagnosis of a urea cycle disorder should be considered in patients with unexplained hepatic dysfunction.

10.
BMC Pediatr ; 16(1): 142, 2016 08 22.
Artigo em Inglês | MEDLINE | ID: mdl-27549856

RESUMO

BACKGROUND: Argininemia is rare inborn error of metabolism which, when untreated, presents in late infancy with growth delay and developmental regression. In developed countries, argininemia is diagnosed early by newborn screening and is treated immediately with a protein-restricted diet. In developing countries, diagnosis may be delayed by the assumption that stunting is related to malnutrition alone. CASE PRESENTATION: We describe the diagnosis and treatment of argininemia in a 60-month-old Kaqchikel Maya girl in rural Guatemala. The patient initially presented with severe stunting and developmental regression. The initial diagnosis of argininemia was made by a screening test in dried blood spots and confirmed with urine and serum amino acid profiles. The patient was treated with a low-protein diet using locally available foods, leading to significant improvement in her growth and development. CONCLUSIONS: This case demonstrates that the identification, diagnosis and treatment of IEM in developing countries are increasingly feasible, as well as ethically imperative. Providers working with malnourished children in developing countries should suspect IEM in malnourished children who do not respond to standard therapies.


Assuntos
Transtornos do Crescimento/etiologia , Hiperargininemia/diagnóstico , Pré-Escolar , Doença Crônica , Diagnóstico Tardio , Países em Desenvolvimento , Feminino , Guatemala , Humanos , Hiperargininemia/complicações
11.
Mol Genet Metab ; 118(2): 72-83, 2016 06.
Artigo em Inglês | MEDLINE | ID: mdl-27211276

RESUMO

BACKGROUND: In 2014, recommendations for the nutrition management of phenylalanine hydroxylase deficiency were published as a companion to the concurrently published American College of Medical Genetics and Genomics guideline for the medical treatment of phenylketonuria (PKU). These were developed primarily from a summary of findings from the PKU scientific review conference sponsored by the National Institutes of Health and Agency for Healthcare Research & Quality along with additional systematic literature review. Since that time, the Genetic Metabolic Dietitians International and the Southeast Regional Newborn Screening and Genetics Collaborative have partnered to create a web-based technology platform for the update and development of nutrition management guidelines for inherited metabolic disorders. OBJECTIVE: The purpose of this PKU guideline is to establish harmonization in treatment and monitoring, to guide the integration of nutrition therapy in the medical management of PKU, and to improve outcomes (nutritional, cognitive, and developmental) for individuals with PKU in all life stages while reducing associated medical, educational, and social costs. METHODS: Six research questions critical to PKU nutrition management were formulated to support guideline development: Review, critical appraisal, and abstraction of peer-reviewed studies and unpublished practice literature, along with expert Delphi survey feedback, nominal group process, and external review from metabolic physicians and dietitians were utilized for development of recommendations relevant to each question. Recommendations address nutrient intake, including updated protein requirements, optimal blood phenylalanine concentrations, nutrition interventions, monitoring parameters specific to life stages, adjunct therapies, and pregnancy and lactation. Recommendations were graded using a rigorous system derived from the Academy of Nutrition and Dietetics. RESULTS AND CONCLUSION: These guidelines, updated utilizing a thorough and systematic approach to literature analysis and national consensus process, are now easily accessible to the global community via the newly developed digital platform. For additional details on specific topics, readers are encouraged to review materials on the online portal: https://GMDI.org/.


Assuntos
Medicina Baseada em Evidências/métodos , Política Nutricional , Terapia Nutricional/métodos , Fenilcetonúrias/dietoterapia , Guias de Prática Clínica como Assunto , Adulto , Consenso , Feminino , Humanos , Recém-Nascido , Fenilalanina/sangue , Gravidez , Recomendações Nutricionais
12.
JPEN J Parenter Enteral Nutr ; 39(7): 875-9, 2015 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-24618664

RESUMO

Maple syrup urine disease (MSUD) is an inherited disorder of metabolism of the branched-chain amino acids leucine, isoleucine, and valine. Complications of acute elevation in plasma leucine include ketoacidosis and risk of cerebral edema, which can be fatal. Individuals with MSUD are at risk of metabolic crisis throughout life, especially at times of physiological stress. We present a case of successful management of a woman with MSUD through pregnancy, delivery, postpartum, and lactation, including nutrition therapy using modified parenteral nutrition.


Assuntos
Lactação , Doença da Urina de Xarope de Bordo/terapia , Complicações na Gravidez/terapia , Adulto , Aminoácidos de Cadeia Ramificada/sangue , Ingestão de Energia , Feminino , Humanos , Necessidades Nutricionais , Nutrição Parenteral , Gravidez , Resultado do Tratamento
13.
Mol Genet Metab ; 114(1): 25-8, 2015 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-25467057

RESUMO

Phenylketonuria (PKU) is an inborn error in phenylalanine metabolism due to deficiency of the enzyme, phenylalanine hydroxylase (PAH). Treatment includes restriction of dietary phenylalanine, and in some individuals, supplementation with the PAH cofactor, tetrahydrobiopterin (sapropterin dihydrochloride). A survey was conducted among patients with PKU who had been prescribed sapropterin to assess reasons for continuing or discontinuing the drug. The primary reason that sapropterin responders discontinued the drug was because of side effects, followed by insufficient reduction of blood phenylalanine and insurance issues. Conversely, those who remained on therapy cited increased tolerance for dietary protein as the main reason for continuation, along with lower blood phenylalanine concentrations and feeling better. This study suggests that adherence to sapropterin therapy is mainly dependent upon the increase in dietary protein allowed when on the drug.


Assuntos
Biopterinas/análogos & derivados , Dieta , Adesão à Medicação , Fenilalanina/sangue , Fenilcetonúrias/terapia , Adolescente , Adulto , Biopterinas/efeitos adversos , Biopterinas/uso terapêutico , Criança , Pré-Escolar , Coleta de Dados , Proteínas Alimentares/administração & dosagem , Feminino , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Fenilcetonúrias/sangue , Telefone , Adulto Jovem
14.
JIMD Rep ; 17: 37-9, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-25155776

RESUMO

In the United States, and most developed nations, the newborn screening (NBS) panel covers many primary disorders of metabolism, including phenylketonuria (PKU). When an elevated phenylalanine level is identified, the infant is evaluated for PKU and should also be tested for tetrahydrobiopterin (BH4) deficiency. A neonate presented with a phenylalanine level of 254 µmol/L (reference range <138 µmol/L) on newborn screening. The infant's confirmatory phenylalanine was 118 µmol/L (reference range <77 µmol/L). Her urine pterin profile was normal, and initially she had no measurable activity of red blood cell (RBC) dihydropteridine reductase (DHPR). Subsequent study revealed normal levels of CSF tetrahydrobiopterin and neurotransmitter metabolites, and by 18 months of age, her RBC DHPR activity was detectable at 0.5 nmol/min/mgHgb (reference range 0.8-3.9). Sequencing of the QDPR gene for DHPR revealed c.1A>T nucleotide substitution in exon 3 expressed as "p.MET1?" Phenylalanine hydroxylase (PAH) gene sequencing revealed compound heterozygosity for L249F and A300S. Although initial testing suggested the child was affected with DHPR deficiency, further analysis, finding increasing levels of DHPR activity and PAH compound mutant heterozygosity, indicated that the primary disorder is mild hyperphenylalaninemia with carrier status for DHPR deficiency. This is an example of newborn screening results leading to confusing findings requiring extensive biochemical studies and genotyping in order to arrive at the appropriate diagnosis.

15.
Mol Genet Metab ; 106(4): 488-90, 2012 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-22771013

RESUMO

An 8-½ year old boy with glutaric aciduria type I (GA1) and chronic dystonia presented with severe rhabdomyolysis in association with a febrile illness. His clinical course was complicated by acute renal failure, cardiac arrest and hypoxic ischemic encephalopathy. As acute neurological decompensation is typically not seen in patients with GA1 beyond early childhood, this case report serves as an important reminder that patients with GA1 and status dystonicus may be at risk for acute life-threatening rhabdomyolysis, renal failure and further neurological injury at any age.


Assuntos
Injúria Renal Aguda/complicações , Erros Inatos do Metabolismo dos Aminoácidos/complicações , Encefalopatias Metabólicas/complicações , Distonia/complicações , Parada Cardíaca/complicações , Rabdomiólise/complicações , Criança , Imagem de Difusão por Ressonância Magnética , Seguimentos , Glutaril-CoA Desidrogenase/deficiência , Humanos , Lactente , Masculino
16.
Mol Genet Metab ; 106(3): 269-76, 2012 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-22575621

RESUMO

Phenylketonuria (PKU) is an inherited disorder of phenylalanine (Phe) metabolism. Until recently, the only treatment for PKU was a Phe-restricted diet. Increasing evidence of suboptimal outcomes in diet-treated individuals, inconsistent PKU management practices, and the recent availability of tetrahydrobiopterin (BH(4)) therapy have fueled the need for new management and treatment recommendations for this metabolic disorder. BH(4), now available as sapropterin dihydrochloride (sapropterin), may offer the potential for improved metabolic control as well as enhanced dietary Phe tolerance in some PKU patients. A group of metabolic dietitians from North America convened in June 2011 to draft recommendations for the use of sapropterin therapy in PKU. Physicians with extensive experience in PKU management were invited at a later date to contribute to the development of these recommendations. Based on extensive clinical experience and current evidence, the present recommendations provide guidance from patient selection and determination of sapropterin response to the long-term management of patients on sapropterin therapy. Target Phe levels, nutritional adequacy, neurocognitive screening and adherence to treatment are addressed to optimize patient outcomes.


Assuntos
Biopterinas/análogos & derivados , Fenilcetonúrias/tratamento farmacológico , Biopterinas/uso terapêutico , Pré-Escolar , Dieta , Humanos , Monitorização Fisiológica , América do Norte , Fenilalanina/sangue
17.
J Inherit Metab Dis ; 35(2): 279-86, 2012 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-21779791

RESUMO

BACKGROUND: Classic galactosemia is an autosomal recessive disorder due to galactose-1-phosphate uridyltransferase (GALT) deficiency. Newborn screening and early treatment do not completely prevent tremor, speech deficits, and diminished IQ in both sexes and premature ovarian insufficiency (POI) in women. Data on how individuals with galactosemia fare as adults will improve our ability to predict disease progression. METHODS: Thirty-three adults (mean age = 32.6 ± 11.7 years; range = 18-59) with classic galactosemia, confirmed by genotype and undetectable GALT enzyme activity, were evaluated. Analyses assessed associations among age, genotype, clinical features and laboratory measures. RESULTS: The sample included 17 men and 16 women. Subjects exhibited cataracts (21%), low bone density (24%), tremor (46%), ataxia (15%), dysarthria (24%), and apraxia of speech (9%). Subjects reported depression (39%) and anxiety (67%). Mean full scale IQ was 88 ± 20, (range = 55-122). All subjects followed a dairy-free diet and 75-80% reported low intake of calcium and vitamin D. Mean height, weight and body mass were within established norms. All female subjects had been diagnosed with POI. One woman and two men had had children. Logistic regression analyses revealed no associations between age, genotype or gender with IQ, tremor, ataxia, dysarthria, apraxia of speech or anxiety. Each 10- year increment of age was associated with a twofold increase in odds of depression. CONCLUSIONS: Taken together, these data do not support the hypothesis that galactosemia is a progressive neurodegenerative disease. However, greater attention to depression, anxiety, and social relationships may relieve the impact of this disorder in adults.


Assuntos
Galactosemias/diagnóstico , Adolescente , Adulto , Progressão da Doença , Feminino , Galactosemias/enzimologia , Galactosemias/genética , Genótipo , Humanos , Recém-Nascido , Masculino , Pessoa de Meia-Idade , Triagem Neonatal/métodos , Doenças Neurodegenerativas/enzimologia , Doenças Neurodegenerativas/etiologia , Doenças Neurodegenerativas/metabolismo , Fenótipo , UTP-Hexose-1-Fosfato Uridililtransferase/deficiência , UTP-Hexose-1-Fosfato Uridililtransferase/genética , Adulto Jovem
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