Top PDF Maternal LINE-1 DNA Methylation and Congenital Heart Defects in Down Syndrome

Maternal LINE-1 DNA Methylation and Congenital Heart Defects in Down Syndrome

Maternal LINE-1 DNA Methylation and Congenital Heart Defects in Down Syndrome

Congenital heart defects (CHDs) are the most common birth defects in humans, with a prevalence of 0.8% ( Dolk et al., 2011 ; Van Der Linde et al., 2011 ). The etiology of most CHDs is unknown but is thought to involve multiple genetic, epigenetic, environmental, and lifestyle factors ( Botto et al., 2003 ; Pierpont et al., 2007 ; Dolk et al., 2011 ; Van Der Linde et al., 2011 ; Sun et al., 2015 ). Only about 15 to 20% of CHDs can be attributed to known causes, with 5 to 10% of cases with CHDs showing chromosomal abnormalities ( Botto and Correa, 2003 ; Dolk et al., 2011 ). Trisomy 21 (OMIM 190685), which results in Down syndrome (DS), shows the highest association with major heart abnormalities, which are present in approximately 40 to 60% of individuals with DS. Such CHDs typically involve septal defects such as atrial septal defects, ventricular septal defects, and complete atrioventricular canal defects ( Freeman et al., 2008 ; Marder et al., 2015 ). In addition to the direct effects of the chromosomal abnormality, maternal genotype, diet, and lifestyle factors, along with environmental exposures, may be involved in the development of heart anomalies in individuals with DS. Foremost among these maternal risk factors are folic acid deficiency and genetic variations of folate pathway genes, such as the methylenetetrahydrofolate reductase gene (MTHFR) ( Brandalize et al., 2009 ; Hobbs et al., 2010 ; Coppedè, 2015 ; Asim et al., 2017 ). Altered maternal DNA methylation is suggested to be an underlying mechanism in the development of birth defects, including CHDs ( Blom et al., 2006 ; Chowdhury et al., 2011 ; Barua and Junaid, 2015 ; Serra-Juhé et al., 2015 ; Spearman, 2017 ). Some risk factors have been proposed to modulate DNA methylation, including aging, body mass index (BMI), cigarette smoking, alcohol intake, folate deficiency, MTHFR polymorphisms, and hyperhomocysteinemia patterns ( Chowdhury et al., 2011 ; Flom et al., 2011 ; Terry et al., 2011 ; Zacho et al., 2011 ; Delgado-Cruzata et al., 2015 ; Marques-Rocha et al., 2016 ; Mendelson et al., 2017 ; Wahl et al., 2017 ; Liu et al., 2018 ).
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Trends in Congenital Heart Defects in Infants With Down Syndrome

Trends in Congenital Heart Defects in Infants With Down Syndrome

Our study has several limitations. Our data lacked information on termination of pregnancies and we could not estimate rates and risks of Down syndrome–related congenital heart defects among all fetuses at risk. Consequently, we could not explore whether our findings were influenced by selection mechanisms due to antenatal screening. During the study period 1992 to 2012, the improvement of ultrasound technology could have introduced some measurement bias, increasing the likelihood of infants being diagnosed with congenital heart defects of minor clinical significance during latter years, and thus underestimating changes in risk of congenital heart defects. Furthermore, our data did not allow us to explore the impact of antenatal screening. Antenatal screening was successively introduced during the study period, but there were regional variations within Sweden. 38
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Study of Congenital Heart Defects among Down Syndrome Cases Attending A Tertiary Care Centre

Study of Congenital Heart Defects among Down Syndrome Cases Attending A Tertiary Care Centre

Parvathy U 15 et al investigated the role of cardiac surgery in the management of CHD in Down syndrome. 21 patients with Down syndrome and congenital heart defects were operated. Four (19%) patients had palliative procedures while the rest (81%) underwent primary repair. All survived the operation. The early mortality was 0, while there were 2 (9.5%) late deaths. The number of hospitalizations was markedly reduced according to the parents. Follow-up showed near normal pulmonary artery pressure in 50 percent children with large shunts and a good developmental spurt was seen in 60 percent. From a purely surgical viewpoint, the prognosis for children with Down syndrome and congenital heart disease is good.
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Original Article Screening key genes associated with congenital heart defects in Down syndrome based on differential expression network

Original Article Screening key genes associated with congenital heart defects in Down syndrome based on differential expression network

Down syndrome (DS) is a genetic disorder caused by trisomy of chromosome 21 [1]. It is the most commonly occurring chromosomal abnormality in live-born infants [2] and affects 1 to 2 per 1000 live births [3-5]. Despite increasing in antenatal detection, the preva- lence of babies born with DS has risen by 25% during the past 30 years and parallels the increase in advanced maternal age pregnan- cies [6]. Some of its phenotypes (e.g., cognitive impairment) are consistently present in all DS individuals, while others show incomplete pen- etrance [7-9]. The most notable phenotypes with reduced penetrance are the congenital heart defects (CHD), forty to fifty percent of newborns with DS have some form of CHD [3, 10-12]. Of those with CHD, about 80% have an atrioventricular septal defect or ventricular sep-
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Endothelial deletion of murine Jag1 leads to valve calcification and congenital heart defects associated with Alagille syndrome

Endothelial deletion of murine Jag1 leads to valve calcification and congenital heart defects associated with Alagille syndrome

The Notch signaling pathway is an important contributor to the development and homeostasis of the cardiovascular system. Not surprisingly, mutations in Notch receptors and ligands have been linked to a variety of hereditary diseases that impact both the heart and the vasculature. In particular, mutations in the gene encoding the human Notch ligand jagged 1 result in a multisystem autosomal dominant disorder called Alagille syndrome, which includes tetralogy of Fallot among its more severe cardiac pathologies. Jagged 1 is expressed throughout the developing embryo, particularly in endothelial cells. Here, we demonstrate that endothelial- specific deletion of Jag1 leads to cardiovascular defects in both embryonic and adult mice that are reminiscent of those in Alagille syndrome. Mutant mice display right ventricular hypertrophy, overriding aorta, ventricular septal defects, coronary vessel abnormalities and valve defects. Examination of mid-gestational embryos revealed that the loss of Jag1, similar to the loss of Notch1, disrupts endothelial-to-mesenchymal transition during endocardial cushion formation. Furthermore, adult mutant mice exhibit cardiac valve calcifications associated with abnormal matrix remodeling and induction of bone morphogenesis. This work shows that the endothelium is responsible for the wide spectrum of cardiac phenotypes displayed in Alagille Syndrome and it demonstrates a crucial role for Jag1 in valve morphogenesis.
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Mediating ERK1/2 signaling rescues congenital heart defects in a mouse model of Noonan syndrome

Mediating ERK1/2 signaling rescues congenital heart defects in a mouse model of Noonan syndrome

Age- and sex-matched mice (15 weeks after birth, n = 8 [4 male, 4 female]) were assessed by M-mode echo- cardiography. FS, fractional shortening; IVST, interventricular wall thickness; LVDd, left-ventricular end-dia- stolic dimension; LVDs, left-ventricular end-systolic dimension; LVPWT, left-ventricular posterior wall thick- ness; Vcfc, heart rate–corrected velocity of circumferential shortening. Data are expressed as mean ± SEM. One-way ANOVA was used for parametric comparisons, and significance of individual differences was evalu- ated using Scheffé test if ANOVA was significant. A P < 0.05 compared with Ntg. B P < 0.05 compared with
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Can folic acid protect against congenital heart defects in Down syndrome?

Can folic acid protect against congenital heart defects in Down syndrome?

Methods: Women with liveborn DS children participating in the Slone Epidemiology Center Birth Defects Study between 1976 and 1997 were included. We performed case-control analyses using DS with heart anomalies as cases and DS without heart anomalies as controls. Subanalyses were performed for defects that have been associated with FA in non- DS populations (conotruncal , ventricular septum (VSD)) and for those that are associated with DS (ostium secundum type atrial septal defects (ASD), and endocardial cushion defects (ECD)). Exposure was defined as the use of any FA-containing product for an average of at least 4 days per week during the first 12 weeks of pregnancy, whereas no exposure was defined as no use of folic acid in these 12 weeks.
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Sociodemographic Factors and Survival of Infants With Congenital Heart Defects

Sociodemographic Factors and Survival of Infants With Congenital Heart Defects

right ventricle (DORV), Ebstein anomaly (EA), hypoplastic left heart syndrome (HLHS), interrupted aortic arch (IAA), pulmonary atresia (PA), single ventricle (SV), tricuspid atresia (TA), total anomalous pulmonary venous return (TAPVR), dextro- transposition of the great arteries (TGA), tetralogy of Fallot (TOF), and persistent truncus arteriosus (PTA). An additional, exclusive 3-level severity classification was applied to all infants with a CHD. Those levels were as follows: CCHDs with univentricular function (high severity: HLHS, SV, TA) and CCHDs typically with biventricular function (moderate severity: COA, TGA, DORV, EA, IAA, TOF, TAPVR, PTA), and all other CHDs were classified as noncritical biventricular heart defects (low severity). Severity classifications were hierarchical and exclusive (ie, an infant with multiple CHDs would be assigned a severity classification of the defect with the highest severity and would only be included in that group). Because of the high variability in severity of PA defects with intact ventricular septum, 10 these defects
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Neurologic Status of Newborns With Congenital Heart Defects Before Open Heart Surgery

Neurologic Status of Newborns With Congenital Heart Defects Before Open Heart Surgery

Of 135 newborns who presented in the neonatal period to Cardiology and required cardiovascular surgery for a CHD, 57 were excluded because of prematurity (35); “closed” surgical procedures not requiring CPB (9); language barrier (5); CNS anom- alies (3); hypoplastic left heart syndrome (3); and syndromes (2). Of the remaining 78 newborns, 60 families were approached for consent and 56 (93.3%) agreed to participate in the study. Eighteen families were not approached for consent because of lack of availability of the caregivers or investigators. Of the 56 subjects recruited, 33 (58.9%) were males. All sub- jects were full-term, and birth weights were appro- priate for gestational age in all subjects. Apgar scores at 5 minutes ranged from 7 to 10 in all but 1 subject, whose score was 4 (this subject’s 10-minute Apgar score was 7) (Table 1). Nine of 56 (16.1%) subjects were evaluated as outpatients, whereas the remain- der were assessed in the NICU. Subjects fell into one of the following diagnostic categories of CHD: trans- position of the great arteries (12), complex (6), tetral-
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Could congenital heart defects be related to a genetic condition?

Could congenital heart defects be related to a genetic condition?

One genetic condition that can affect the heart and other parts of the body is 22q11.2 Deletion Syndrome or 22q11.2DS. People with 22q11.2DS are missing a tiny piece of one chromosome in each cell of their body. This can cause a wide range of health problems. 22q11.2DS is the second most common cause of heart defects.

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Congenital heart defects through 30 years

Congenital heart defects through 30 years

Aim: To assess basic trends in epidemiology of con- genital heart defects (CHDs). Method: Population based prospective observational study. Material: CHDs in infants born alive in a Norwegian county 1982-2011. Results: In 828/71 217 infants (12 per 1000) a CHD was diagnosed. The prevalence increased from 8 to 12 per 1000 after introduction of early echocardiography in newborns with suspected CHD from 1986 (p = 0.0001). Ventricular septal defect (VSD) was the dominating CHD (474; 57%). In 222 (27%) the CHDs were missed and diagnosed after discharge from hospital after birth. Twelve critical CHDs (causing death or requiring invasive proce- dures before 28 days of life) were missed. Prenatal diagnosis of critical CHDs increased from 4/67 (6%) born 1997-2006 to 4/11 (36%) born 2007-11 (p = 0.01). In 177 (21%) a syndrome or extracardial defect oc- curred. The occurrence of CHDs associated with chromosomal disorders (60/73 (82%) trisomies) more than doubled from the cohort born in the first 10-year period 1982-91 (0.6 per 1000) to the last 2002-11 (1.4 per 1000) (p < 0.0001) in parallel with increasing births in women ≥ 35 years old in the population. 237 (29%) underwent therapeutic proce- dures (203 (86%) surgery, of whom 16 after initial catheter intervention, and 34 (14%) catheter inter- vention alone). 39/237 (16%) died, 101 (43%) were repaired and 97 (41%) had some minor residual de- fect. The death rate declined significantly from 65/532 (12%) born 1982-2001 to 11/296 (4%) born 2002-11 (p = 0.0001). 37/76 (49%) deaths occurred within 28 days after birth. Conclusions: The rate of detection of CHDs increased substantially after introduction of echocardiography in newborns with suspected CHD, especially VSDs. Some critical CHDs were overlooked. The prenatal detection rate of such defects increased. The prevalence of CHDs with associated chromoso- mal disorders increased in parallel with increasing
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Genetic aspects of congenital heart disease in down syndrome

Genetic aspects of congenital heart disease in down syndrome

Congenital heart defects are the most common of all birth defects, which is found to affect nearly 1% of newborns, and their frequency in spontaneously aborted pregnancies is et al., 2000). The categorized into three major groups such as, chromosomal, single gene disorders (10- 15%) and ., 1995). Congenital anomalies having a chromosomal cause, besides causing gross g cause of mental ., 1973). So far, more than 100 chromosomal disorders have been reported however, trisomy 21 remains the commonest with its incidence 1:650-1:1000 live births (Hassold and Sherman 2000). The clinical lled Down’s syndrome is due to three copies of chromosome 21 instead of only two in all or most of the cells of the body. The extra copy usually arises during the formation of the parental germ cell when two 21 chromosomes stick d of moving apart and taking a place individually in separate cells. This is called non-disjunction. disjunction causing trisomy 21 is of maternal origin in 88% of cases, paternal in 9%, and mitotic in 3 % (Sherman nally derived trisomy 21 is disjunction at the first meiotic division in the female embryo, though recent work has suggested that non- disjunction occurring in the second meiotic division may
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Maternal lifestyle factors in pregnancy and congenital heart defects in offspring: review of the current evidence

Maternal lifestyle factors in pregnancy and congenital heart defects in offspring: review of the current evidence

Nowadays, obesity rates have an increasing tendency, since the incidence of obesity in both developed and de- veloping countries is still rising over the years. Epidemi- ologic data from the National Health and Nutrition Examination Survey described that, from 2007–2008, 28-32% of childbearing-aged women were obese and that 7.2-8.4% of them were morbidly obese (BMI ≥ 40 kg/m 2 ) [35]. From a public health perspective, recent studies have highlighted the increased risks that are associated with obesity in pregnancy and have appealed for optimal treatment of the pre gravid obese women. Numerous studies have shown that obese women appear to be at a higher risk of pregnancy complications, such as pre- eclampsia, gestational diabetes mellitus, preterm deliv- ery, and cesarean delivery [36-39], as well as adverse fetal and neonatal outcomes, such as congenital heart defect. A meta-analysis of 18 studies published between 1966 and 2008 found an association of maternal obesity with an increased risk of cardiovascular anomalies (OR, 1.30; 95% CI, 1.12-1.51) and septal anomalies (OR, 1.20; 95% CI, 1.09-1.31) [26]. A recent meta-analysis of 14 epidemiological studies [27] demonstrated an association between overweight, moderate obesity, and severe obes- ity and all CHD combined (OR, 1.08, 95% CI, 1.02-1.15; OR, 1.15, 95% CI, 1.11-1.20; and OR, 1.39, 95% CI, 1.31- 1.47, respectively) as well as some individual defects such as pulmonary valve stenosis, hypoplastic left heart syndrome, and outflow tract defects, with the highest risk of tetralogy of Fallot for obese mothers for (OR, 1.94; 95% CI, 1.49-2.51). Being underweight did not Table 1 Maternal lifestyle factors and the risk of offspring with congenital heart defects (Continued)
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Maternal Smoking and Congenital Heart Defects in the Baltimore-Washington Infant Study

Maternal Smoking and Congenital Heart Defects in the Baltimore-Washington Infant Study

confidence interval (CI): 1.04 –3.45]), levo-transposition of the great arteries (l-TGA) (congenitally corrected TGA) (OR: 1.79 [95% CI: 1.04 –3.10]), RVOTO defects (OR: 1.32 [95% CI: 1.06 –1.65]), pulmonary valve stenosis (a subgroup of RVOTO defects) (OR: 1.35 [95% CI: 1.05–1.74]), and secundum-type atrial septal defect (OR: 1.36 [95% CI: 1.04 – 1.78]) (Table 3). Many of these associ- ations were supported by the indicator variables model as well, although be- cause of the small number of exposed case infants at the highest exposure levels, many estimates from this model had wide 95% CIs. For example, a secundum-type atrial septal defect displayed a positive dose-response re- lationship with increasing cigarette consumption, although all 3 of the 95% CIs from the indicator variables model included the null value. Conversely, the association with cigarette consump- tion and l-TGA seemed to be driven pre- dominantly by the association at the highest exposure level. This pattern was similar for laterality and looping defects (of which l-TGA is a subtype). We also observed a suggestive dose- response pattern for AVSDs without Down syndrome, although the CI from the ordinal model contained the null value (OR: 1.50 [95% CI: 0.99 –2.29]). DISCUSSION
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Association Between Congenital Heart Defects and Small for Gestational Age

Association Between Congenital Heart Defects and Small for Gestational Age

based on the complexity of the lesion. Cardiac defects were classified into 4 categories based on the anatomic lesion: (1) conotruncal, including transposition of the great arteries, tetralogy of Fallot, truncus arteriosus, double outlet right ventricle, malaligned ventricular sep- tal defect, and interrupted aortic arch type B; (2) septal, including atrial, ventricular, and atrioventricular septal defects; (3) right-sided obstructive, including pulmonary valve stenosis, pulmonary atresia, and tricuspid atresia; and (4) left-sided obstructive, including aortic valve ste- nosis, hypoplastic left heart syndrome and variants, co- arctation of the aorta, and interrupted aortic arch types A and C lesions. Complex CHD lesions, which included total and partial pulmonary venous connection, double inlet left ventricle, and other lesions with ⱖ 3 cardiac defects, were excluded from this analysis.
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Down-Klinefelter syndrome (48,XXY,+21) in a neonate associated with congenital heart disease.

Down-Klinefelter syndrome (48,XXY,+21) in a neonate associated with congenital heart disease.

This article describes a case of double trisomy 48,XXY,+21, with severe heart disease. According to the literature, the types of heart disease in Down-Klinefelter syndrome are varied. There seem to be differences between the incidence rate of congenital heart defects among patients with Down-Klinefelter and DS. More case studies are needed to establish better genotype-phenotype correlations. Early cytogenetic analysis proved to be an important tool for better diagnosis and management of Down-Klinefelter patients.

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Congenital heart defects and placental dysfunction

Congenital heart defects and placental dysfunction

The presence of an unbalanced angiogenic status in fetuses with a CHD is also supported by histological findings from placenta tissue in newborns with hypoplastic left heart syndrome (HLHS): they documented a reduction in the numbers of terminal villi and reduced villous vasculature (p=0.001), lower expression of PlGF RNA (p<0.05), increased in Syncityal Nuclear Aggregates (SNAs) (p<0.01) and overall reduced placental weight (p=0.02) compared to controls (Jones et al, 2015). Therefore, in fetuses with CHDs, placenta fails to expand its villous tree and to develop terminal villi. Stanek found similar findings on a group of fetuses affected by what he calls “postplacental hypoxia”: in these cases, normal perfusion is provided on maternal side but the fetus does not have enough oxygen due to the presence of specific malformation like cardiac defects, umbilical knots, etc. He found thinner and longer villi due to poor branching on the placental side as a reflection of a compromised fetal circulation (Stanek 2015). Another larger study on 120 placental histology of 120 fetuses with CHD showed that the placental weight-to-birth weight ratio was significantly reduced in CHDs than in controls and histological findings of villous hypomaturity, thrombosis, chorioangiosis and placental infarction (Rychick et al., 2018).
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Noninherited Risk Factors of Congenital Heart Defects in Offspring: A Revi

Noninherited Risk Factors of Congenital Heart Defects in Offspring: A Revi

Ever since the first description of the fetal alcohol syndrome by Jones and Smith in 1973, many observational studies have been published on the topic of alcohol consumption in pregnant women and the effects on the development of their fetus and child, including cardiac defects. Recently, several studies investigate the association between maternal alcohol consumption during the pregnancy and CHDs. A population-based Case-control study of California births indicated that compared with nonconsumers, women who consumed alcohol less than once a week had a 1.3 fold higher risk of having infants with a conotruncal heart defect (95% CI, 1.00- 1.90), and women who consumed alcohol once a week or more had a 1.9 fold increase in risk (95% CI, 1.00- 3.40). 65
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Maternal Smoking and Congenital Heart Defects

Maternal Smoking and Congenital Heart Defects

Cardiac defects were classified into major categories based on the anatomic lesion: (1) conotruncal, including transposition of the great arteries, tetralogy of Fallot, trun- cus arteriosus, double-outlet right ventricle, malaligned ventricular septal defects (VSDs), and interrupted aortic arch type B; (2) septal, including ASDs and VSDs; (3) right-sided obstructive, including pulmonary valve ste- nosis, pulmonary atresia, tricuspid atresia, and Ebstein anomaly; (4) left-sided obstructive, including aortic valve stenosis, hypoplastic left heart syndrome and vari- ants, coarctation of the aorta, and interrupted aortic arch types A and C; (5) anomalous pulmonary venous return, including total and partial anomalous pulmonary ve- nous return; and (6) atrioventricular septal defects. All of the centers collected data on eligible defects through- out the entire study period, with 2 exceptions. First, case infants of isolated muscular VSDs were only enrolled between October 1, 1997, and December 31, 1998, after which no additional enrollment of muscular VSDs oc- curred at any center. They were, therefore, excluded from our analyses. Also, one center enrolled case infants with pulmonary valve stenosis or septal defects only during part of the study period; these CHD subtypes from this center were not included in this analysis. In addition, case infants were excluded from this study if they had an additional extracardiac birth defect or were not singleton births.
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CITED2 Mutation and methylation in children with congenital heart disease

CITED2 Mutation and methylation in children with congenital heart disease

CREB-binding protein (CBP)/P300-interacting transac- tivator 2 is a protein with ED-rich tail that in human is encoded by the CITED2 gene. CITED2 expression is reg- ulated by a variety of factors such as hypoxia, cytokines, oxidative stress, etc. [9]. There are a plurality of tran- scription factor binding sites in the promoter region of CITED2 gene, such as HIF-1, AP-2, SP1 etc., which play a vital role in CITED2 expression. Three consecutive sequence of "ACGTG" in CITED2 promoter region can maintain the stability of the combination between CITED2 and HIF-1 [10,11]. HIF-1 consists of α, β two subtypes, in which HIF-1α is degraded under normal oxygen conditions and cannot be detected. However, HIF- 1α can be detected in hypoxic conditions [12]. CITED2 blockes HIF-1α transcriptional activity by competitively inhibiting the interaction between HIF-1α and CBP/P300, Dysfunction of HIF-1α in CITED2 − / − mice may cause the cardiac malformation [13,14]. CITED2 also functions as a transcriptional co-activator by recruiting the combination of CBP/P300 and TFAP2. Deficiencies in TFAP2 co-
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