Human Genetics of Hypoplastic Left Heart Syndrome.

Hypoplastic left heart syndrome (HLHS) is a severe congenital cardiovascular malformation characterized by hypoplasia of the left ventricle, aorta, and other structures on the left side of the heart. The pathologic definition includes atresia or stenosis of both the aortic and mitral valves. Despite considerable progress in clinical and surgical management of HLHS, mortality and morbidity remain concerns. One barrier to progress in HLHS management is poor understanding of its cause. Several lines of evidence point to genetic origins of HLHS. First, some HLHS cases have been associated with cytogenetic abnormalities (e.g., Turner syndrome). Second, studies of family clustering of HLHS and related cardiovascular malformations have determined HLHS is heritable. Third, genomic regions that encode genes influencing the inheritance of HLHS have been identified. Taken together, these diverse studies provide strong evidence for genetic origins of HLHS and related cardiac phenotypes. However, using simple Mendelian inheritance models, identification of single genetic variants that "cause" HLHS has remained elusive, and in most cases, the genetic cause remains unknown. These results suggest that HLHS inheritance is complex rather than simple. The implication of this conclusion is that researchers must move beyond the expectation that a single disease-causing variant can be found. Utilization of complex models to analyze high-throughput genetic data requires careful consideration of study design.

New Insights into the Education of Children with Congenital Heart Disease with and without Trisomy 21.

Background and Objectives: Patients with congenital heart disease (CHD), especially as a concomitant syndromal disease of trisomy 21 (T21), are at risk for impaired neurodevelopment. This can also affect these patients' education. However, there continues to be a research gap in the educational development of CHD patients and T21 CHD patients. Materials and Methods: In total, data from 2873 patients from the German National Register for Congenital Heart Defects were analyzed. The data are based on two online education surveys conducted among patients registered in the National Register for Congenital Heart Defects (2017, 2020). Results: Of 2873 patients included (mean age: 14.1 ± 4.7 years, 50.5% female), 109 (3.8%) were identified with T21 (mean age: 12.9 ± 4.4 years, 49.5% female). T21 CHD participants had a high demand for early specific interventions (overall cohort 49.1%; T21 cohort 100%). T21 CHD children more frequently attended special schools and, compared to non-trisomy 21 (nT21) CHD patients, the probability of attending a grammar school was reduced. In total, 87.1% of nT21 CHD patients but 11% of T21 CHD patients were enrolled in a regular elementary school, and 12.8% of T21 CHD patients could transfer to a secondary school in contrast to 35.5% of nT21 CHD patients. Most of the T21 CHD patients were diagnosed with psychiatric disorders, e.g., learning, emotional, or behavioral disorders (T21 CHD patients: 82.6%; nT21 CHD patients: 31.4%; p < 0.001). Conclusions: CHD patients are at risk for impaired academic development, and the presence of T21 is an aggravating factor. Routine follow-up examinations should be established to identify developmental deficits and to provide targeted interventions.

Long-term experience using CNI-free immunosuppression in selected paediatric heart transplant recipients.

BACKGROUND: CNI-free immunosuppression with conversion to mTORi-based immunosuppression has been demonstrated to reduce CNI-toxicity and to exhibit anti-proliferative properties. However, the experience of CNI-free immunosuppression in paediatric heart transplantation is limited. METHODS: A retrospective analysis was conducted of 129 paediatric heart transplants performed between 1997 and 2015. Fifteen patients with clinically indicated conversion from CNI-based to CNI-free immunosuppression were identified. Survival data, rejection episodes, renal function, post-transplantation lymphoproliferative disorder and CAV, including examination with OCT were analysed. RESULTS: Immunosuppression conversion was successful in all patients. Fourteen of 15 patients (93%) are currently living with good graft function. Median post-transplant survival was 15 years (range, 5-23 years), and median follow-up since conversion was 6 years (range, 1-11 years). Mild (grade 1R) ACR was present in three patients after discontinuation of CNIs. The recovery of renal function with a significant increase in eGFR was observed at 1 and 3 years after conversion. No patient had angiographic signs of macroscopic CAV according to the current ISHLT classification; however, OCT showed the signs of angiographically silent CAV in all patients. CAV did not progress in any patient, implying CAV was stabilised by mTORi-based CNI-free immunosuppression. CONCLUSIONS: CNI-free immunosuppression based on mTORis is a safe and appropriate strategy for maintenance therapy in selected paediatric patients, significantly improves renal function and stabilises CAV. OCT revealed early development of angiographically silent CAV.

First steps to a clinical research unit for developmental research in paediatric cardiology: conception and progress of the LEADER project (Long Term Early Development Research) in CHD.

OBJECTIVE: We developed the Long-term Early Development Research (LEADER) project to investigate the development of children with CHD and/or after cardiopulmonary resuscitation. Both populations are at risk for delays in motor, cognitive, and language development. However, few studies to date have investigated the longitudinal development in these children. METHODS: To establish a clinical research unit, we planned three studies: a cross-sectional study in children after cardiopulmonary resuscitation (LEADER-REA Pilot Study), a longitudinal study in children after cardiopulmonary resuscitation, with a focus on evaluating various biomarkers as predictors for developmental outcome (LEADER-CPR study), and a longitudinal study in children with ventricular septal defect, tetralogy of Fallot, or transposition of the great arteries after cardiac surgery (LEADER-CHD study). RESULTS: Implementation of all three LEADER studies was successful and study protocols were conducted as planned. Findings from the LEADER-REA Pilot study have been recently published and data collection for both prospective trials is ongoing. Descriptive analysis of the first 20 assessments of the LEADER-CHD study showed no severe deficits in overall cognitive, motor, and language developments in the children. CONCLUSIONS: Children with CHD and/or after cardiopulmonary resuscitation are at risk for developmental delay. Therefore, a detailed developmental assessment is necessary as a pre-requisite for individual developmental support. Our LEADER project has been shown to be feasible in a clinical setting and is the first step towards the establishment of a clinical research unit in our clinic with a focus on longitudinal research.

Developmental Outcome in Infants with Cardiovascular Disease After Cardiopulmonary Resuscitation: A Pilot Study.

Unfavorable neurological outcome in children after cardiopulmonary resuscitation in infancy is frequent. However, few studies have investigated the development of these patients using comprehensive developmental tests and the feasibility of the Bayley Scales of Infant Development, 3rd Edition (BSID-III) has not been reported for this population. In this cross-sectional pilot study, we assessed the cognitive, language, and motor development in infants after cardiopulmonary resuscitation of ≥ 5 min with the BSID-III at the age of 12 or 24 months, depending on recruitment age. For analysis, 11 patients with in-hospital (n = 8) and out-of-hospital (n = 3) cardiac arrest were included. BSID-III results could not be quantified in three patients because of visual/hearing and/or motor impairment. In patients with quantifiable scores, 50.0% scored average in composite BSID-III scores, while the other 50.0% showed developmental delays, scoring distinctly below average. We conclude that the BSID-III is feasible for developmental assessment in the majority of the study population, but the use of instruments suitable for hearing/visually impaired and/or severely disabled infants is crucial to avoid biased results. Accurate characterization of developmental deficits is important to facilitate early identification and therapy of deficits.

Dynamics in prevalence of Down syndrome in children with congenital heart disease.

We assessed the dynamics in the prevalence of children with congenital heart disease (CHD) and Down syndrome in Germany with regard to phenotype, severity, and gender. Data from patients with CHD and Down syndrome born between 1980 and 2014 were analyzed, who are registered with the German National Register for Congenital Heart Defects. One thousand six hundred eighteen CHD patients with Down syndrome were identified. The prevalence of children born with both Down syndrome and CHD was constant from 2005 to 2009 but increased from 2010 to 2014. Regarding CHD groups, complex and simple lesions have become more equal since 2005. The number of simple lesions with shunt has a peak prevalence in the period of 2010-2014. Atrioventricular septal defect was the most common CHD phenotype, but temporal changes were found within the group of CHD phenotypes over the observation period. CONCLUSION: Our findings suggest a growing number of CHD and Down syndrome, which may be the result of improved medical management and progress in educational, social, and financial support. This development is noteworthy as it adds new aspects to present discussions in the media and political settings. What is known: • Congenital heart disease is regarded to be the most important clinical phenomenon in children with Down syndrome, due to its significant impact on morbidity and mortality. • New developments in prenatal diagnostic and therapy management of congenital heart disease continue to influence the number of patients diagnosed with congenital heart disease and Down syndrome. What is New: • This study provides essential data giving the first overview of the dynamics in the prevalence of congenital heart disease and Down syndrome over an extended length of time up to 2015 in a large patient cohort, taking recent developments into account. • Our data suggest a growing prevalence of congenital heart disease and Down syndrome, which may be the result of improved medical management for Down syndrome patients and progress in educational, social, and financial support for their families; this development is noteworthy as it adds new aspects to the present discussion in the media and political settings.

Educational level and employment status in adults with congenital heart disease.

Purpose Through this study we aimed to assess the educational level and employment status of adults with CHD in Germany. METHODS: Data were acquired from an online survey carried out in 2015 by the German National Register for Congenital Heart Defects. A total of 1458 adults with CHD participated in the survey (response rate: 37.6%). For 1198 participants, detailed medical information, such as main cardiac diagnosis and information from medical reports, was available. RESULTS: Of the participants surveyed (n=1198), 54.5% (n=653) were female, and the mean age was 30 years. The majority of respondents (59.4%) stated that they had high education levels and that they were currently employed (51.1%). Patients with simple CHD had significantly higher levels of education (p<0.001) and were more likely to be employed (p=0.01) than were patients with complex CHD. CONCLUSIONS: More than half of the participants had high education levels and the majority were employed. The association between CHD and its severity and individuals' educational attainment should be investigated more closely in future studies.

Association between self-reported questionnaire data on fertility and results of hormone analyses in women after childhood cancer: a cross-sectional study.

AIM: The aim of this study was to compare self-reported questionnaire-based information on fertility impairment with results from hormone analyses in women who underwent chemoradiotherapy during childhood and adolescence. MATERIAL AND METHODS: In a cross-sectional study, questionnaires and hormone analyses (anti-Müllerian hormone [AMH], follicle-stimulating hormone, luteinizing hormone, estradiol, progesterone) were evaluated in 86 female former pediatric oncology patients in Berlin in 2009. RESULTS: Eighty-six women (median age 23 years, range 19-41) participated in the study with a median follow up of 14 years (range 2-30) after diagnosis. Among women with information on permanent and transient amenorrhea, 9% (5/55) of the women stated that they were permanently amenorrheic. Among women not taking oral contraceptives and giving information on the regularity of their menstrual cycle, 18% (4/22) had an irregular menstrual cycle and 82% (18/22) had a regular menstrual cycle. The median AMH values for women who were categorized as infertile by questionnaire-based information were significantly lower than the AMH values of women who were categorized as fertile by questionnaire (0.05 vs 2.2 ng/mL, P = 0.004). Questionnaire-based categories on the regularity of the menstrual cycle and categories based on AMH values showed a satisfying percentage agreement (66.7%) and were moderately correlated (r = 0.42, P = 0.002). CONCLUSION: Self-reported questionnaire data used to detect fertility impairment has limited correspondence with objectively measured AMH values.

Outcomes in very low birthweight infants with severe congenital heart defect following cardiac surgery within the first year of life.

OBJECTIVES: Very low birthweight (<1500 g, VLBW) infants with severe congenital heart defect (CHD) are at increased risk for perinatal and operative mortality. This study aims to describe morbidity, long-term mortality and neuro-developmental outcome in early childhood in VLBW infants who received cardiac surgery for severe CHD within 1 year after birth. METHODS: Monocentric observational study on VLBW infants with severe CHD born between 2008 and 2017. Neurodevelopmental impairment at 2 years corrected age was defined as cognitive deficit, cerebral palsy or major neurosensory deficit. RESULTS: A total of 24 patients were included. Twenty-one (87.5%) infants underwent cardiac surgery with hypothermia during cardiopulmonary bypass (median temperature 30.3°C, interquartile range 27.0-32.0°C) at a median age of 96 (40-188) days. Seven (29.2%, 95% confidence interval 14.9-49.2%) patients died within the first year after cardiac surgery. Survival rates decreased with increasing STAT mortality category of the surgical procedure. Neurodevelopmental impairment at 2 years of corrected age was found in 9 out of 17 (52.9%) surviving infants, with 8 infants (47.1%) presenting with a cognitive deficit or delay and 4 infants (23.5%) being diagnosed with cerebral palsy. Survival without neuro-developmental impairment was 29.2% (n = 7, 95% confidence interval 14.9-49.2%) in the entire study cohort. Eighty percent of the newborns with dextro-transposition of the great arteries, but no patient with univentricular anatomy, survived without neuro-developmental impairment. CONCLUSIONS: Individual VLBW infants with severe CHD may develop well despite the high combined risk for adverse outcomes. The type of cardiac malformation may affect early- and long-term outcomes.

Microcephaly is associated with impaired educational development in children with congenital heart disease.

Objectives: This study aims to evaluate the school careers of patients with congenital heart disease (CHD) and microcephaly. Methods: An exploratory online survey was conducted on patients from a previous study on somatic development in children with CHD in 2018 (n = 2818). A total of 750 patients participated in the online survey (26.6%). This publication focuses on 91 patients (12.1%) diagnosed with CHD and microcephaly who participated in the new online survey. Results: Microcephaly was significantly associated with CHD severity (p < 0.001). Microcephalic patients suffered from psychiatric comorbidity two times as often (67.0%) as non-microcephalic patients (29.8%). In particular, the percentage of patients with developmental delay, intellectual debility, social disability, learning disorder, or language disorder was significantly increased in microcephalic CHD patients (p < 0.001). A total of 85.7% of microcephalic patients and 47.6% of non-microcephalic patients received early interventions to foster their development. The school enrollment of both groups was similar at approximately six years of age. However, 89.9% of non-microcephalic but only 51.6% of microcephalic patients were enrolled in a regular elementary school. Regarding secondary school, only half as many microcephalic patients (14.3%) went to grammar school, while the proportion of pupils at special schools was eight times higher. Supportive interventions, e.g., for specific learning disabilities, were used by 52.7% of microcephalic patients and 21.6% of non-microcephalic patients. Conclusion: Patients with CHD and microcephaly are at high risk for impaired educational development. Early identification should alert clinicians to provide targeted interventions to optimize the developmental potential.

SARS-CoV-2 in Pediatric Inpatient Care: Management, Clinical Presentation and Utilization of Healthcare Capacity.

This study scrutinizes management and clinical presentation of severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) in pediatric inpatient care and evaluates the utilization of pediatric healthcare capacity during the pandemic. Within this retrospective cohort study, we systematically reviewed data of all 16,785 pediatric patients (<18 years admitted to our clinical center between January 2018 and June 2021). Data on SARS-CoV-2 test numbers, hospital admissions and clinical characteristics of infected patients were collected. Since January 2020, a total of 2513 SARS-CoV-2 tests were performed. In total, 36 patients had a positive test result. In total, 25 out of 36 SARS-CoV-2 positive children showed at least mild clinical symptoms while 11 were asymptomatic. Most common clinical symptoms were fever (60%), cough (60%) and rhinitis (20%). In parallel with the rising slope of SARS-CoV-2 in spring and fall 2020, we observed a slight decrease in the number of patients admitted to the pediatric department while the median duration of hospital treatment and intensive care occupancy remained unchanged. This study underlines that SARS-CoV-2 infected children most frequently exhibit an asymptomatic or mild clinical course. Noteworthy, the number of hospital admissions went down during the pandemic. The health and economic consequences need to be discussed within health care society and politics.

Family-Centered Care at Pediatric Cardiac Intensive Care Units in Germany and the Relationship With Parent and Infant Well-Being: A Study Protocol.

Rationale and Aim: Infants with Congenital Heart Disease (CHD) are at risk for neurodevelopmental delays, emotional, social and behavioral difficulties. Hospitalization early in life and associated stressors may contribute to these challenges. Family-centered Care (FCC) is a health care approach that is respectful of and responsive to the needs and values of a family and has shown to be effective in improving health outcomes of premature infants, as well as the mental well-being of their parents. However, there is limited empirical data available on FCC practices in pediatric cardiology and associations with parent and infant outcomes. Methods and Analysis: In this cross-sectional study, we will explore FCC practices at two pediatric cardiac intensive care units in Germany, assess parent satisfaction with FCC, and investigate associations with parental mental well-being and parenting stress, as well as infant physical and mental well-being. We will collect data of 280 infants with CHD and their families. Data will be analyzed using multivariate statistics and multilevel modeling. Implications and Dissemination: The study protocol was approved by the medical ethics committees of both partner sites and registered with the German registry for clinical trials (NR DRKS00023964). This study serves as a first step to investigate FCC practices in a pediatric cardiology setting, providing insight into the relationship between FCC and parent and infant outcomes in a population of infants with CHD. Results will be disseminated in peer-reviewed journals.

Education of Children With Cyanotic Congenital Heart Disease After Neonatal Cardiac Surgery.

BACKGROUND: The aim of the study was to evaluate the educational achievement of patients diagnosed with univentricular heart physiology (UVHP) or transposition of the great arteries (TGA) after neonatal cardiac surgery. METHODS: An exploratory online survey was performed with patients registered with the National Register for Congenital Heart Defects in Germany. For this publication, a subgroup analysis was conducted among patients diagnosed with TGA (n = 173; 36.3%) and UVHP (n = 304; 63.7%). RESULTS: Median age of the sample at school enrollment was 6 years (range, 5-8 years). The majority were enrolled at a standard elementary school (n = 368 of 477; 77.1%), although patients with UVHP were enrolled significantly more often at a special needs school (n = 52 of 304; 17.1%, TGA patients n = 11/ of 173; 6.4%, P < .001). A total of 45.8% (n = 66 of 144) of the patients graduated with a high school diploma. A substantial number of patients had been diagnosed with behavioral or learning disorders (TGA patients n = 63 of 173 [36.4%], UVHP patients n = 148 of 304 [48.7%]) and received early supportive therapy or remedial teaching before (TGA patients n = 89 of 173 [51.4%], UVHP patients n = 209 of 304 [68.8%]) and/or during their school careers (TGA patients n = 54 of 173 [31.2%], UVHP patients n = 120 of 304 [39.5%]). CONCLUSIONS: A large proportion of patients who underwent neonatal cardiac surgery graduated with a high school diploma. These results are of great importance to congenital heart defect patients, affected families, and treating physicians. Nevertheless, study participants, especially patients with UVHP, face some academic challenges. We conclude that long-term follow-up examinations and regular developmental assessments may be beneficial.

A Prospective Clinical Trial Measuring the Effects of Cardiopulmonary Bypass Under Mild Hypothermia on the Inflammatory Response and Regulation of Cold-Shock Protein RNA-Binding Motif 3.

Therapeutic hypothermia during cardiac surgery has been widely used for neuroprotection and to attenuate the systemic inflammatory response due to cardiopulmonary bypass (CPB). Experimental data suggest that cold-shock protein RNA-binding motif 3 (RBM3), which is induced in response to hypothermia, plays a key role in hypothermia-induced organ protection. To date, investigation on RBM3 has been performed exclusively in vitro or in animal models, and the detection and regulation of RBM3 in human blood has not been investigated until now. The aim of this study was to investigate the level of RBM3 protein and cytokine expression profile involved in the inflammatory response in patients with congenital heart disease undergoing cardiac surgery involving CPB and therapeutic hypothermia. A single-center prospective trial with 23 patients undergoing cardiac surgery with CPB was performed. RBM3 protein was quantified in blood serum samples collected from patients and healthy individuals employing a new developed enzyme-linked immunosorbent assay. Cytokine levels were analyzed from dry blood spot samples using a Quanterix Simoa Immunoassay. For the first time, RBM3 protein was detected in blood samples of patients with congenital heart disease undergoing cardiac surgery. Hereby, RBM3 protein concentrations were significantly elevated in patients after cardiac surgery with CPB and mild hypothermia as compared with pre-surgery levels. Moreover, a complex immune reaction with significant induction of pro-inflammatory cytokines (interleukin [IL]-1 beta, IL-6, IL-8, IL-16, IL-18, monocyte chemotactic protein 1, CC-chemokine ligand [CCL]3, CCL4, intercellular adhesion molecule-1) in response to CPB was detected. Significantly elevated vascular endothelial growth factor and matrix metallopeptidase 3 concentrations reflecting ischemia/reperfusion-induced injury were observed 24 hours after weaning from CPB. The use of CPB is still associated with a complex inflammatory response. RBM3 protein is measurable in blood samples of patients with significantly higher concentrations after cardiac surgery with CPB and mild-to-moderate hypothermia. RBM3 is a new candidate as a biomarker for therapeutic hypothermia and a possible new therapeutic target for organ protection.

Educational achievement of children with congenital heart disease: Promising results from a survey by the German National Register of Congenital Heart Defects.

BACKGROUND: Survival rates of children with congenital heart disease (CHD) have increased significantly in the decade. There is now increased interest in the long-term outcome and quality of life of these children. AIMS: To assess the educational achievement of patients with CHD in Germany. STUDY DESIGN: Cross-sectional study using an online survey. The recruitment of study participants was carried out via the database of the German National Register for Congenital Heart Defects (NRCHD). SUBJECTS: Patients born between 1992 and 2011 were enrolled in the study. For 2609 study participants (female = 1870 (71.7%); 1072 (41.1%) patients; 1537 (58.9%) parents), who participated in the survey, detailed information regarding the underlying CHD diagnosis and clinical data was available. OUTCOME MEASURES: Age at enrollment, secondary school form, school year repetition, school degree. RESULTS: The large majority of study participants were enrolled at a conventional elementary school (83.4%) and started school at the age of 6 years or below (73.3%). In total 45.7% of graduated study participants graduated with the qualification necessary to study at any university. In terms of analysis of the different CHD severity subgroups 57.3% of patients with a mild CHD, 47.5% with a moderate CHD and only 35.1% suffering from a severe CHD attained a high school diploma. CONCLUSIONS: In our study, the majority of participating CHD patients had a standard school career. These initial results are of great importance to affected families and treating physicians as they show that, in general, a normal school career is possible for all CHD patients.

Long-term early development research in congenital heart disease (LEADER-CHD): a study protocol for a prospective cohort observational study investigating the development of children after surgical correction for congenital heart defects during the first 3 years of life.

INTRODUCTION: Congenital heart disease (CHD) is the most common birth defect. Studies on the development of children with CHD point towards deficits in motoric, cognitive and language development. However, most studies are cross-sectional and there is a gap in the knowledge concerning developmental trajectories, risk and protective factors and a lack of research concerning environmental predictors. Specifically, no studies have so far considered the importance of early caregiving experiences and child temperament for the development of children with CHD. METHODS: In a single-centre prospective cohort study, cognitive, motoric and language development of 180 children after corrective surgery for a simple transposition of the great arteries (TGA), tetralogy of Fallot (TOF) or ventricular septal defect (VSD) will be assessed at ages 12, 24 and 36 months with the Bayley Scales of Infant Development 3rd Edition (BSID-III). At age 12 months, a free-play video observation will be conducted to investigate the relationship between primary caregiver and child, and child temperament will be assessed with the Infant Behavior Questionnaire-Revised Short Version. Medical information will be obtained from patient records and demographic information via questionnaires. ANALYSIS: Frequency and severity of developmental delays will be reported descriptively. Differences between groups (TGA, TOF, VSD) will be subjected to repeated-measures analysis across time points. Multiple regressions will be applied for the analysis of predictors at each time point. For the analysis of differential developmental trajectories, mixed-model analysis will be applied. ETHICS AND DISSEMINATION: The study has been approved by the local medical ethics committee. Written informed consent will be obtained from all participants. Parents have the option to be debriefed about BSID-III results after each assessment and about the study results after project completion. Results will be disseminated in peer-reviewed journals and presented at conferences. TRIAL REGISTRATION NUMBER: DRKS00011006; Pre-results.

Neuroprotection via RNA-binding protein RBM3 expression is regulated by hypothermia but not by hypoxia in human SK-N-SH neurons.

OBJECTIVE: Therapeutic hypothermia is an established treatment for perinatal asphyxia. Yet, many term infants continue to die or suffer from neurodevelopmental disability. Several experimental studies have demonstrated a beneficial effect of mild-to-moderate hypothermia after hypoxic injury, but the understanding of hypothermia-induced neuroprotection remains incomplete. In general, global protein synthesis is attenuated by hypothermia, but a small group of RNA-binding proteins including the RNA-binding motif 3 (RBM3) is upregulated in response to cooling. The aim of this study was to establish an in vitro model to investigate the effects of hypoxia and hypothermia on neuronal cell survival, as well as to examine the kinetics of concurrent cold-shock protein RBM3 gene expression. METHODS: Experiments were performed by using human SK-N-SH neurons exposed to different oxygen concentrations (21%, 8%, or 0.2% O2) for 24 hours followed by moderate hypothermia (33.5°C) or normothermia for 24, 48, or 72 hours. Cell death was determined by quantification of lactate dehydrogenase and neuron-specific enolase releases into the cell cultured medium, and cell morphology was assessed by using immunofluorescence staining. The regulation of RBM3 gene expression was assessed by reverse transcriptase-quantitative polymerase chain reaction and Western blot analysis. RESULTS: Exposure to hypoxia (0.2% O2) for 24 hours resulted in significantly increased cell death in SK-N-SH neurons, whereas exposure to 8% O2 had no significant impact on cell viability. Post-hypoxia treatment with moderate hypothermia for 48 or 72 hours rescued the neurons from hypoxia-induced cell death. Moreover, exposure to severe hypoxia led to observable cell swelling, which was also attenuated by moderate hypothermia. Finally, moderate hypothermia but not hypoxia led to the induction of RBM3 expression on both transcriptional and translational levels. CONCLUSION: Moderate hypothermia protects neurons from hypoxia-induced cell death. The expression of the cold-shock protein RBM3 is induced by moderate hypothermia and could be one possible mediator of hypothermia-induced neuroprotection.

Changing prevalence of severe congenital heart disease: Results from the National Register for Congenital Heart Defects in Germany.

OBJECTIVE: To assess the prevalence of congenital heart disease (CHD) in Germany in relation to phenotypes, severity and gender. DESIGN: Cross-sectional registry study. SETTING: We analyzed data from patients with CHD born between 1996 and 2015. PATIENTS: A total of 26 630 patients, registered with the NRCHD, were born between 1996 and 2015. 10 927 patients were excluded from the current analysis due to prior registration with the NRCHD under the German PAN Prevalence Study, which showed a potential bias in the inclusion of this patient population (proportion of mild cardiac lesions was comparatively high due to improved diagnostic capability for earlier identifying minor lesions). At least 15 703 patients with demographic data and detailed medical information were included in the current study. INTERVENTIONS: None. OUTCOME MEASURES: Prevalence of CHD in Germany differentiated into gender, severity, and phenotype. RESULTS: In total, 15 703 patients with CHD (47.1% female) were included in this study. The five most common phenotypes were found to be ventricular septal defect (19.2%), atrial septal defect (13.0%), Tetralogy of Fallot (9.3%), univentricular heart (9.4%), and coractation of the aortae (7.0%). The prevalence of CHD in regard to severity changed over the duration of the observation period. From 1996 to 2007, the number of simple CHD rose steadily (P < .001), whereas the number of severe CHD has grown significantly since 2008/2009 (P < .001). In regard to gender, the prevalence of simple CHD was higher in females, whereas complex lesions were more common in males (P < .001). CONCLUSIONS: Our study shows a growing number of registered severe CHD in the recent decade in Germany. This development is noteworthy as it implicates a growing demand for first intensive hospital care, expert pediatric cardiologic aftercare, and consequently higher economic impact for this patient population.

Childhood leukemia and its impact on graduation and having children: results from a national survey.

To assess the level of graduation, the wish to have children and the course of pregnancy among former patients with childhood leukemia in comparison to the general German population and depending on gender, a nationwide survey was conducted in 2008. In total 63.6% (1476/2319) of the contacted survivors of childhood leukemia participated (mean age 25.7 years, range 19-43 years). Survivors graduated at higher levels of school compared to the general population, with 48.6% (female) versus 38.0% and 52.6% (male) versus 35.8% (p < 0.001). Also, 93.3% of female and 89.3% of male survivors indicated a similar general wish to have children compared to the general population. Survivors reported parenthood less frequently compared to the general population (p < 0.001). The course of pregnancy in survivors was characterized by fewer abortions (p < 0.001). Having leukemia in childhood and adolescence impairs the likelihood of becoming a parent but reduces neither the wish to have children nor the level of graduation.