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Background: Over the past decades, survival rates of children born with congenital heart disease (CHD) have increased dramatically. Progress in prenatal diagnosis, less-invasive catheter techniques and perioperative intensive care as well as surgical techniques have led to an increased focus on extracardiac comorbidities, including potential neurodevelopmental sequelae associated with CHD. A growing body of literature reports impairments in early and school-age developmental outcome; however, there is a substantial variability in the spectrum of examined CHD types, assessment ages and applied test batteries. Furthermore, little information is available on executive function impairments in this population. Therefore, the aim of this systematic review is to determine the impact of CHD on intellectual outcome and executive functioning at school age and to determine risk factors for impaired outcomes by means of a systematic search., Methods: A systematic review of literature that reports neurodevelopmental outcome in children with CHD undergoing cardiopulmonary bypass surgery. Intelligence quotient or executive function scores will be considered primary outcomes. Databases such as Cochrane, EMBASE, MEDLINE and PsycINFO will be searched., Discussion: The results of this systematic review will summarize the current evidence on intellectual and executive function outcome after cardiopulmonary bypass surgery in school-age children with CHD. This review will thus be the basis for better patient and parental counselling and the establishment of tailored follow-up programmes and interventional trials., Systematic Review Registration: In accordance with the guidelines, our systematic review protocol was registered with the International Prospective Register of Systematic Reviews (PROSPERO) on January 9, 2019 (CRD42018086568). PROSPERO CRD42019118736 .

Children with congenital heart disease (CHD) remain at risk for neurodevelopmental impairment despite improved perioperative care. Our prospective cohort study aimed to determine the relationship between perioperative brain volumes and neurodevelopmental outcome in neonates with severe CHD. Pre- and postoperative cerebral MRI was acquired in term born neonates with CHD undergoing neonatal cardiopulmonary bypass surgery. Brain volumes were measured using an atlas prior-based automated method. One-year neurodevelopmental outcome was assessed with the Bayley-III. CHD infants (n = 77) had lower pre- and postoperative total and regional brain volumes compared to controls (n = 44, all p < 0.01). CHD infants had poorer cognitive and motor outcome (p ≤ 0.0001) and a trend towards lower language composite score compared to controls (p = 0.06). Larger total and selected regional postoperative brain volumes were found to be associated with better cognitive and language outcomes (all p < 0.04) at one year. This association was independent of length of intensive care unit stay for total, cortical, temporal, frontal and cerebellar volumes. Therefore, reduced cerebral volume in CHD neonates undergoing bypass surgery may serve as a biomarker for impaired outcome.

Objective: To determine growth and its relationship to IQ in children with congenital heart disease (CHD) undergoing cardiopulmonary bypass surgery within the first year of life., Study Design: Prospective single-center cohort study on 143 children (91 males) with different types of CHD (29 univentricular). Children with recognized genetic disorders were excluded. Growth (weight, height, and head circumference [HC]) was assessed at birth, before surgery, and at 1, 4, and 6 years and compared with Swiss growth charts. IQ was assessed at 6 years using standardized tests. Univariate and multivariable linear regressions were performed to determine predictors of HC and IQ at 6 years., Results: HC at birth was in the low average range (33rd percentile, P = .03), and weight (49th percentile, P = .23) and length (47th percentile, P = .06) were normal. All growth measures declined until the first surgery, with a catch-up growth until 6 years for height (44th percentile, P = .07) but not for weight (39th percentile, P = .003) or for HC (23rd percentile, P < .001). Children undergoing univentricular palliation showed poorer height growth than other types of CHD (P = .01). Median IQ at 6 years was 95 (range 50-135). Lower IQ at 6 years was independently predicted by lower HC at birth, lower socioeconomic status, older age at first bypass surgery, and longer length of intensive care unit stay., Conclusions: Smaller HC at birth and postnatal factors are predictive of impaired intellectual abilities at school age. Early identification should alert clinicians to provide early childhood interventions to optimize developmental potential., (Copyright © 2018 Elsevier Inc. All rights reserved.)

BackgroundLittle is known about the relationship between brain volumes and neurodevelopmental outcome at 2 years of age in children with single-ventricle congenital heart disease (CHD). We hypothesized that reduced brain volumes may be associated with adverse neurodevelopmental outcome.MethodsVolumetric segmentation of cerebral magnetic resonance imaging (MRI) scans was carried out in 44 patients without genetic comorbidities and in 8 controls. Neurodevelopmental outcome was assessed with the Bayley-III scales.ResultsGray matter (GM), deep GM, white matter (WM), and cerebrospinal fluid (CSF) volumes were 611±59, 43±4.5, 277±30, and 16.4 ml, respectively (interquartile range (IQR) 13.1, 23.3 ml). Children undergoing neonatal cardiopulmonary bypass surgery showed smaller deep GM (P=0.005) and WM (P=0.021) volumes. Brain volumes were smaller in patients compared with controls (GM: P=0.017, deep GM: P=0.012, and WM: P=0.015), whereas CSF volumes were greater (P=0.014). Of all intracranial volumes, only CSF volume was associated with neurodevelopmental outcome, accounting for 21% (P=0.011) of variability in the cognitive composite score when combined with common risk factors in a multivariable analysis.ConclusionIncreased CSF volume represents a significant risk factor for neurodevelopmental impairment in children with single-ventricle CHD. Later assessments are warranted to determine the prognostic role of intracranial volumes for long-term outcome.

Objectives: To assess 6-year neurodevelopmental outcomes in a current cohort of children with congenital heart disease (CHD) who underwent cardiopulmonary bypass surgery (CPB), and to determine risk factors for adverse outcomes., Study Design: Outcomes were examined in 233 prospectively enrolled children with CHD (including 64 with a recognized genetic disorder) who underwent CPB between 2004 and 2009. Follow-up assessment included standardized neurologic, motor, and cognitive tests. Variables were collected prospectively, and multiple regression analysis was performed to determine independent risk factors for adverse outcome., Results: The mean patient age at assessment was 6.3 years (range, 5.1-6.8 years). IQ was lower in children with a genetic disorder (median, 55; range, 17-115) compared with children without a genetic disorder (median, 95; range, 47-135; P < .001). Cognitive and motor performance also were lower in children without a genetic disorder compared with the norm (P < .01 for both). The prevalence of children without a genetic disorder performing below -2 SD (IQ 70) was higher than the norm (5.3% vs 2.3%; P = .008), and the prevalence of poor motor performance (<10th percentile) ranged from 21.2% to 41.1% (P < .01 for all). Significant independent risk factors for poor neurodevelopmental outcome included a genetic disorder, longer length of intensive care stay, lower birth weight, postoperative seizures, and lower socioeconomic status., Conclusions: Current cohorts of children with CHD undergoing CPB show favorable outcomes but remain at risk for long-term neurodevelopmental impairments, particularly those with a genetic disorder and a complicated postoperative course. Close neurodevelopmental surveillance is necessary to provide early therapeutic support., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Objectives: To determine the prevalence, spectrum and course of cerebral lesions in neonates with congenital heart disease (CHD) undergoing full flow cardiopulmonary bypass (CPB) surgery using magnetic resonance imaging (MRI) and to examine the correlation between cerebral lesions and clinical neurological abnormalities., Methods: Prospective cohort study of neonates with d-transposition of the great arteries (n = 22), univentricular heart malformation with hypoplastic aortic arch (n = 6) and aortic arch obstructions (n = 2) undergoing CPB. Neonates underwent cerebral MRI and blinded standardized neurological examination before (median day 6) and after surgery (day 13). The MRI findings were compared with those of 20 healthy controls., Results: Preoperative cerebral lesions were present in 7 of 30 patients (23%) with isolated mild or moderate white matter injury (WMI) (n = 4), isolated small cerebral stroke (n = 1) and combined WMI and stroke (n = 2). None of the healthy controls had cerebral lesions on MRI. CHD neonates with preoperative cerebral lesions had more neurological abnormalities (P = 0.01) than neonates without cerebral lesions. Low arterial oxygen saturation (P = 0.03) was a risk factor for preoperative cerebral lesions, while balloon atrioseptostomy (P = 0.19) was not. After surgery, preoperative cerebral lesions persisted in 5 of 7 neonates, and 2 neonates (7%) showed signs of additional WMI in their postoperative MRI., Conclusions: In neonates with severe CHD, WMI was the predominant preoperative finding, while cerebral strokes were less frequent. New postoperative lesions were rare. Preoperative neurological abnormalities correlated with the presence of cerebral lesions on MRI.

Objective: To determine the risk factors for adverse neurodevelopmental outcomes in school-age children after full flow open-heart surgery for congenital heart disease., Methods: The outcome was assessed in 117 children without a genetic comorbidity at a mean age of 10.4 ± 2.5 years. Intelligence was assessed using the Raven's Progressive Matrices and neuromotor function using the Zurich Neuromotor Assessment. Risk factors were retrieved from detailed chart review., Results: The mean intelligence score was 89 ± 16, significantly lower than the norm (P < .001). Cerebral palsy was diagnosed in 10% of patients. Poor neuromotor performance (less than p10) was present in 15% to 20% of the children, depending on the motor task (all P < .001). Pure motor and static balance performance was also significantly impaired when patients with cerebral palsy were excluded (P < .01). Intelligence was only related to socioeconomic status (P = .006), and neuromotor outcome was related to the length of hospital stay and postoperative neurologic abnormalities (P < .03). The extracorporeal circulation time was related to adaptive fine motor performance (P = .05). All other variables were not related to outcome., Conclusions: Children without a genetic comorbidity are at risk of long-term intellectual and motor impairments also after full-flow cardiac repair. Surgery-related parameters play a less important role for adverse outcomes than postoperative complications. Our findings stress the importance of specialized follow-up assessments for all children with CHD undergoing open heart surgery., (Copyright © 2012 The American Association for Thoracic Surgery. Published by Mosby, Inc. All rights reserved.)

Objective: We aimed at evaluating surgery-related posttraumatic stress disorder (PTSD) in parents of children undergoing cardiopulmonary bypass surgery. Risk factors for parental PTSD symptoms were explored., Design: A prospective cohort study was performed assessing PTSD symptoms immediately after discharge and 6 months after cardiopulmonary bypass surgery., Setting: Recruitment took place at a tertiary pediatric medical center in Switzerland., Subjects: German-speaking parents of children with congenital heart defects aged between 0 and 16 yrs undergoing cardiopulmonary bypass surgery were eligible (n = 228). After child discharge, 135 mothers and 98 fathers of 139 children (response rate 61.0%) participated. Six months after surgery, 121 mothers and 92 fathers of 128 children (response rate, 56.1%) took part in the study., Interventions: Assessment via a screening instrument and self-rating scale, and extraction of data from charts., Measurements and Main Results: The Posttraumatic Diagnostic Scale was applied to estimate self-reported symptoms of PTSD. Following discharge, 16.4% of mothers and 13.3% of fathers met diagnostic criteria for acute PTSD. Another 15.7% of mothers and 13.3% of fathers experienced significant symptoms of posttraumatic stress. Six months after surgery, PTSD rates were 14.9% and 9.5%, respectively. Mothers experienced more severe symptoms of PTSD, but gender differences were not detected with regard to the frequency of PTSD at either time. After controlling for socioeconomic status and child preoperative morbidity, PTSD symptom severity after discharge remained the only significant predictor of PTSD severity at 6 months. Pre-, peri-, and postoperative factors did not predict parental PTSD., Conclusions: Parents of children undergoing cardiopulmonary bypass surgery are at increased risk for intermediate and long-term psychological malfunctioning. Acute symptoms of PTSD in parents shortly after discharge of their child are a major risk factor for the development of chronic PTSD. Clinicians need to identify parents at risk at an early stage to provide them with systematic support.

BackgroundNeurodevelopmental disability is the most common complication for survivors of surgery for congenital heart disease (CHD).MethodsWe analyzed individual participant data from studies of children evaluated with the Bayley Scales of Infant Development, second edition, after cardiac surgery between 1996 and 2009. The primary outcome was Psychomotor Development Index (PDI), and the secondary outcome was Mental Development Index (MDI).ResultsAmong 1770 subjects from 22 institutions, assessed at age 14.5 ± 3.7 months, PDIs and MDIs (77.6 ± 18.8 and 88.2 ± 16.7, respectively) were lower than normative means (each P < .001). Later calendar year of birth was associated with an increased proportion of high-risk infants (complexity of CHD and prevalence of genetic/extracardiac anomalies). After adjustment for center and type of CHD, later year of birth was not significantly associated with better PDI or MDI. Risk factors for lower PDI were lower birth weight, white race, and presence of a genetic/extracardiac anomaly (all P ≤ .01). After adjustment for these factors, PDIs improved over time (0.39 points/year, 95% confidence interval 0.01 to 0.78; P = .045). Risk factors for lower MDI were lower birth weight, male gender, less maternal education, and presence of a genetic/extracardiac anomaly (all P < .001). After adjustment for these factors, MDIs improved over time (0.38 points/year, 95% confidence interval 0.05 to 0.71; P = .02).ConclusionsEarly neurodevelopmental outcomes for survivors of cardiac surgery in infancy have improved modestly over time, but only after adjustment for innate patient risk factors. As more high-risk CHD infants undergo cardiac surgery and survive, a growing population will require significant societal resources.

Open in new tab Download slide Open in new tab Download slide OBJECTIVES Neurodevelopmental disability is the most common complication among congenital heart surgery survivors. The Bayley scales are standardized instruments to assess neurodevelopment. The most recent edition (Bayley Scales of Infant and Toddler Development 3rd Edition, Bayley-III) yields better-than-expected scores in typically developing and high-risk infants than the second edition (Bayley Scales of Infant Development 2nd Edition, BSID-II). We compared BSID-II and Bayley-III scores in infants undergoing cardiac surgery. METHODS We evaluated 2198 infants who underwent operations with cardiopulmonary bypass between 1996 and 2009 at 26 institutions. We used propensity score matching to limit confounding by indication in a subset of patients (n  = 705). RESULTS Overall, unadjusted Bayley-III motor scores were higher than BSID-II Psychomotor Development Index scores (90.7 ± 17.2 vs 77.6 ± 18.8, P  < 0.001), and unadjusted Bayley-III composite cognitive and language scores were higher than BSID-II Mental Development Index scores (92.0 ± 15.4 vs 88.2 ± 16.7, P  < 0.001). In the propensity-matched analysis, Bayley-III motor scores were higher than BSID-II Psychomotor Development Index scores [absolute difference 14.1, 95% confidence interval (CI) 11.7–17.6; P  < 0.001] and the Bayley-III classified fewer children as having severe [odds ratio (OR) 0.24; 95% CI 0.14–0.42] or mild-to-moderate impairment (OR 0.21; 95% CI 0.14–0.32). The composite of Bayley-III cognitive and language scores was higher than BSID-II Mental Development Index scores (absolute difference 4.0, 95% CI 1.4–6.7; P  = 0.003), but there was no difference between Bayley editions in the proportion of children classified as having severe cognitive and language impairment. CONCLUSIONS The Bayley-III yielded higher scores than the BSID-II and classified fewer children as severely impaired. The systematic bias towards higher scores with the Bayley-III precludes valid comparisons between early and contemporary cardiac surgery cohorts. [ABSTRACT FROM AUTHOR]

Patients with complex congenital heart disease are at risk for neurodevelopmental impairments. Evidence suggests that brain maturation can be delayed and pre- and postoperative brain injury may occur, and there is limited information on the long-term effect of congenital heart disease on brain development and function in adolescent patients. At a mean age of 13.8 years, 39 adolescent survivors of childhood cardiopulmonary bypass surgery with no structural brain lesions evident through conventional cerebral magnetic resonance imaging and 32 healthy control subjects underwent extensive neurodevelopmental assessment and cerebral magnetic resonance imaging. Cerebral scans were analysed quantitatively using surface-based and voxel-based morphometry. Compared with control subjects, patients had lower total brain (P = 0.003), white matter (P = 0.004) and cortical grey matter (P = 0.005) volumes, whereas cerebrospinal fluid volumes were not different. Regional brain volume reduction ranged from 5.3% (cortical grey matter) to 11% (corpus callosum). Adolescents with cyanotic heart disease showed more brain volume loss than those with acyanotic heart disease, particularly in the white matter, thalami, hippocampi and corpus callosum (all P-values < 0.05). Brain volume reduction correlated significantly with cognitive, motor and executive functions (grey matter: P < 0.05, white matter: P < 0.01). Our findings suggest that there are long-lasting cerebral changes in adolescent survivors of cardiopulmonary bypass surgery for congenital heart disease and that these changes are associated with functional outcome. [ABSTRACT FROM PUBLISHER]

Long-term neurodevelopmental sequelae are commonly detectable in children after open-heart surgery with cardiopulmonary bypass (CPB). The objective of the study was to determine the neurodevelopmental outcome in these children in relation to postoperative inflammatory reaction. This is a prospective, observational study on children with congenital heart defects ( n = 32) undergoing elective open-heart surgery in a tertiary pediatric cardiac center. Neurodevelopmental outcome was assessed in the median 6 months after CPB. Neurological examination was done in all children before the operation and, additionally, complete neurodevelopmental status was assessed preoperatively in 14 children. Three hours after the end of CPB, plasma concentrations of interleukin (IL)-6 and IL-8 were strongly elevated ( p < 0.001). Moreover, there was a rise of neutrophils and C-reactive protein at 24 h postoperatively ( p < 0.001). Intellectual performance after surgery was correlated with preoperative performance, r S = 0.83, p < 0.001 (mean IQ scores after CPB = 90.4 ± 18.4 and before CPB = 87.5 ± 14.5, p = 0.20). Multiple regression analysis demonstrated that preoperative IQ scores accounted for 83.8% of the variance of postoperative IQ scores ( p < 0.0001). Inflammatory variables were not significant predictors of postoperative IQ scores. The frequency of neuromotor abnormalities at 6 months after CPB was influenced by the presence of a cyanotic heart defect, duration of CPB and aortic clamp time, and plasma levels of IL-6 shortly after CPB ( R2 = 67.8%, p = 0.002). In conclusion, in the examined population, preexisting neurodevelopmental impairment is frequent and predicts postoperative outcome. The high frequency of postoperative neuromotor disabilities seems to be associated with the type of congenital heart defect but also with the procedure and possible complications of CPB. [ABSTRACT FROM AUTHOR]

Objectives: To evaluate the predictive value of pre- and postoperative amplitude-integrated electroencephalography (aEEG) on neurodevelopmental outcomes in children operated for congenital heart disease (CHD).Study Design: Prospectively enrolled cohort of 60 infants with CHD who underwent cardiac surgery with cardiopulmonary bypass in the first 3 months of life. Infants with a genetic comorbidity were excluded. aEEG was assessed for 12 hours pre- and 48 hours postoperatively. Background pattern was classified by the use of standard categories, and the presence of seizures and sleep-wake cycles (SWCs) was noted. Outcome at 1 and 4 years of age was assessed with standardized developmental tests.Results: Preoperatively, infants either showed continuous normal voltage (n = 56) or discontinuous normal voltage (n = 4). Postoperatively, abnormal background pattern (flat trace, burst suppression, or continuous low voltage) was detected in 7 (12%), discontinuous normal voltage in 37 (61%), and continuous normal voltage in 16 (27%) infants. Nineteen infants (32%) did not return to normal SWCs within the recording period. Seizures were detected in 4 infants preoperatively and in another 4 postoperatively. After we controlled for surgical and postoperative risk factors, abnormal postoperative background pattern and lack of return to SWCs independently predicted poorer intelligence quotient at 4 years (P = .03 and P = .04 respectively) but was not related to motor outcome.Conclusion: aEEG is a useful bedside tool that helps to predict outcome in infants undergoing open-heart surgery for CHD. Abnormal postoperative background pattern and lack of return to SWCs are markers for subsequent impaired cognitive development. [ABSTRACT FROM AUTHOR]

CONTEXT Cognitive function and executive function (EF) impairments contribute to the long-term burden of congenital heart disease (CHD). However, the degree and profile of impairments are insufficiently described. OBJECTIVE To systematically review and meta-analyze the evidence on cognitive function and EF outcomes in school-aged children operated for CHD and identify the risk factors for an unfavorable outcome. DATA SOURCES Cochrane, Embase, Medline, and PsycINFO. STUDY SELECTION Original peer-reviewed studies reporting cognitive or EF outcome in 5- to 17-year old children with CHD after cardiopulmonary bypass surgery. DATA EXTRACTION Results of IQ and EF assessments were extracted, and estimates were transformed to means and SE. Standardized mean differences were calculated for comparison with healthy controls. RESULTS Among 74 studies (3645 children with CHD) reporting total IQ, the summary estimate was 96.03 (95% confidence interval: 94.91 to 97.14). Hypoplastic left heart syndrome and univentricular CHD cohorts performed significantly worse than atrial and ventricular septum defect cohorts (P = .0003; P = .027). An older age at assessment was associated with lower IQ scores in cohorts with transposition of the great arteries (P = .014). Among 13 studies (774 children with CHD) reporting EF compared with controls, the standardized mean difference was -0.56 (95% confidence interval: -0.65 to -0.46) with no predilection for a specific EF domain or age effect. LIMITATIONS Heterogeneity between studies was large. CONCLUSIONS Intellectual impairments in CHD are frequent, with severity and trajectory depending on the CHD subtype. EF performance is poorer in children with CHD without a specific EF profile. The heterogeneity in studied populations and applied assessments is large. A uniform testing guideline is urgently needed. [ABSTRACT FROM AUTHOR]

OBJECTIVES Neonates with hypoplastic left heart syndrome (HLHS) are at risk of high mortality and neurodevelopmental morbidity. As an alternative to Norwood-type stage I palliation, the hybrid procedure has been developed. It consists of bilateral pulmonary artery banding, catheter-based stenting of the arterial duct and balloon atrioseptostomy and delays open-heart surgery. Thus, it may be associated with a better outcome. The aim of this study was to determine the mortality and neurodevelopmental outcome in patients with HLHS and other univentricular heart (UVH) defects treated with hybrid or Norwood procedures. METHODS Thirty-one children (18 males) with HLHS and other UVH defects undergoing Norwood or hybrid procedure between 2004 and 2008 were consecutively enrolled. Mortality and neurodevelopmental outcome at 1 year of age were determined. RESULTS One-year mortality was 36% (31% in the hybrid vs. 39% in the Norwood group, P = 0.71). Predictors of mortality were lower birth weight (P = 0.02), older age at first procedure (P = 0.02) and smaller size of ascending aorta (P = 0.05). Overall, median psychomotor development index (PDI) and mental development index (MDI) of the Bayley Scales of Infant Development II were lower than the norm of 100 [PDI 57 (49–99), P < 0.001; MDI 91 (65–109), P = 0.002]. No effect of surgical treatment on neurodevelopmental outcome was found. Predictors of impaired motor outcome were length of hospital stay (LOHS) (P = 0.01), lower body weight at second procedure (P = 0.004) and female sex (P = 0.01). Predictors of impaired cognitive outcome were longer mechanical ventilation time (P = 0.03), intensive care unit stay (P = 0.04) and LOHS (P < 0.001), respectively. CONCLUSIONS Mortality at 1 year of age is comparable between patients undergoing hybrid and Norwood procedures. Early neurodevelopmental outcome is significantly impaired in patients with both HLHS and other UVH defects. Multicentre randomized studies are needed to determine the long-term neurodevelopmental outcome of children treated with the hybrid procedure. [ABSTRACT FROM PUBLISHER]

Background: Children with congenital heart disease (CHD) are at risk of impaired growth.Aims: To describe height, weight, head circumference (HC), and body mass index (BMI) at 10 years and identify risk factors for altered longitudinal growth in children with CHD.Study Design: Growth parameters were evaluated from birth until 10 years using z-scores. The impact of cardiac and noncardiac factors on longitudinal growth was investigated.Subjects: A total of 135 children with different types of CHD who underwent cardiopulmonary bypass surgery, no genetic disorder.Outcome Measures: Head circumference, weight, height and BMI.Results: At 10 years, z-scores for height and BMI did not differ from the Swiss population (P > 0.1). Z-scores for weight and HC were significantly below the norm (-0.38 and - 0.71, P < 0.01). From 1 to 10 years, all growth parameters except BMI increased significantly (P ≤ 0.001, BMI: P = 0.14). Lower gestational age and longer length of hospitalization were associated with either impaired head circumference or length at 10 years, while lower socioeconomic status was associated with higher BMI and weight at 10 years (all P < 0.05).Conclusion: Despite partial catch-up, somatic growth remains impaired in children with CHD with weight and HC below the norm at 10 years. The only cardiac factor associated with impaired longitudinal growth was duration of hospital stay. Furthermore, lower socioeconomic background may pose a risk of overweight at older age. Close monitoring of growth parameters and parental counselling in all CHD children is advisable beyond early childhood to ensure optimal somatic growth. [ABSTRACT FROM AUTHOR]