BACKGROUNDUnplanned catheter-based or surgical reinterventions after congenital heart operations are independently associated with operative mortality and increased postoperative length of stay. ...OBJECTIVESThis study assessed the long-term outcomes of transplant-free survivors of hospital discharge requiring predischarge reinterventions after congenital cardiac surgery. METHODSData from patients who required predischarge reinterventions in the anatomic area of repair after congenital cardiac surgery and survived to hospital discharge at a quaternary referral center from January 2011 to December 2019 were retrospectively reviewed. Previously published echocardiographic criteria were used to assess the severity of persistent residual lesions at discharge (Grade 1, no residua; Grade 2, minor residua; and Grade 3, major residua). Outcomes included postdischarge (late) mortality or transplant and unplanned reintervention. Associations between predischarge residual lesion severity and outcomes were assessed by using Cox or competing risk models, adjusting for baseline patient characteristics, case complexity, and preoperative risk factors. RESULTSAmong the 408 patients who met entry criteria, there were 58 (14.2%) postdischarge deaths or transplants and 208 (51.0%) late reinterventions at a median follow-up of 3.0 years (IQR: 1.1-6.8 years). Greater predischarge residual lesion severity was associated with worse transplant-free survival and freedom from reintervention (both, P < 0.05). On multivariable analyses, Grade 3 patients had an increased risk of postdischarge mortality or transplant (HR: 4.8; 95% CI: 2.0-11; P < 0.001) and late reintervention (subdistribution HR: 2.1; 95% CI: 1.4-3.1; P < 0.001) vs Grade 1 patients. CONCLUSIONSAmong transplant-free survivors requiring predischarge reinterventions after congenital cardiac surgery, those with persistent major residua have significantly worse long-term outcomes. These high-risk patients warrant closer surveillance.
The genetic architecture of sporadic congenital heart disease (CHD) is characterized by enrichment in damaging de novo variants in chromatin-modifying genes. To test the hypothesis that gene pathways ...contributing to de novo forms of CHD are distinct from those for recessive forms, we analyze 2391 whole-exome trios from the Pediatric Cardiac Genomics Consortium. We deploy a permutation-based gene-burden analysis to identify damaging recessive and compound heterozygous genotypes and disease genes, controlling for confounding effects, such as background mutation rate and ancestry. Cilia-related genes are significantly enriched for damaging rare recessive genotypes, but comparatively depleted for de novo variants. The opposite trend is observed for chromatin-modifying genes. Other cardiac developmental gene classes have less stratification by mode of inheritance than cilia and chromatin-modifying gene classes. Our analyses reveal dominant and recessive CHD are associated with distinct gene functions, with cilia-related genes providing a reservoir of rare segregating variation leading to CHD.
Although DNA methylation is the best characterized epigenetic mark, the mechanism by which it is targeted to specific regions in the genome remains unclear. Recent studies have revealed that local ...DNA methylation profiles might be dictated by cis-regulatory DNA sequences that mainly operate via DNA-binding factors. Consistent with this finding, we have recently shown that disruption of CTCF-binding sites by rare single nucleotide variants (SNVs) can underlie cis-linked DNA methylation changes in patients with congenital anomalies. These data raise the hypothesis that rare genetic variation at transcription factor binding sites (TFBSs) might contribute to local DNA methylation patterning. In this work, by combining blood genome-wide DNA methylation profiles, whole genome sequencing-derived SNVs from 247 unrelated individuals along with 133 predicted TFBS motifs derived from ENCODE ChIP-Seq data, we observed an association between the disruption of binding sites for multiple TFs by rare SNVs and extreme DNA methylation values at both local and, to a lesser extent, distant CpGs. While the majority of these changes affected only single CpGs, 24% were associated with multiple outlier CpGs within ±1kb of the disrupted TFBS. Interestingly, disruption of functionally constrained sites within TF motifs lead to larger DNA methylation changes at nearby CpG sites. Altogether, these findings suggest that rare SNVs at TFBS negatively influence TF-DNA binding, which can lead to an altered local DNA methylation profile. Furthermore, subsequent integration of DNA methylation and RNA-Seq profiles from cardiac tissues enabled us to observe an association between rare SNV-directed DNA methylation and outlier expression of nearby genes. In conclusion, our findings not only provide insights into the effect of rare genetic variation at TFBS on shaping local DNA methylation and its consequences on genome regulation, but also provide a rationale to incorporate DNA methylation data to interpret the functional role of rare variants.
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Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Although neuroimaging advances have deepened our understanding of brain health in individuals with congenital heart disease (CHD), it is less clear how neuroimaging findings relate to ...neurodevelopmental and mental health outcomes across the lifespan. We systematically synthesized and critically evaluated evidence on associations between neuroimaging and neurodevelopmental, neurocognitive, psychiatric, or behavioral outcomes among individuals with transposition of great arteries or single-ventricle CHD (Protocol CRD42021229617). Six databases were searched and 45 papers from 25 unique studies were identified. Structural brain injury was generally linked to poorer neurodevelopment in infancy. Brain volumes and microstructural and functional brain changes appear linked to neurocognitive outcomes, including deficits in attention, learning, memory, and executive function in children and adolescents. Fetal neuroimaging studies were limited. Four papers investigated psychiatric outcomes; none found associations with neuroimaging. Multicenter, longitudinal studies incorporating functional neuroimaging and mental health outcomes are much-needed to inform early neuroprotective and therapeutic strategies in CHD.
Abstract
Venous thromboembolic (VTE) complications in children and adolescents with acute lymphoblastic leukaemia (ALL) and T or B cell lymphoblastic lymphoma (T/B cell LL) can result not only in ...life-threatening acute complications but also contribute to significant long-term sequelae. The PREVAPIX-ALL study is an open-label randomized controlled study comparing outcomes of treatment with prophylactic dose apixaban versus no anticoagulation (standard of care) in children and adolescents with ALL and T/B cell LL receiving standard induction chemotherapy with asparaginase and the presence of a central venous access device. On day 29 of induction, all patients undergo screening imaging with duplex ultrasonography and echocardiography. The primary efficacy endpoint of the study is a composite of symptomatic and asymptomatic VTE that includes deep vein thrombosis, pulmonary embolism, cerebral sinovenous thrombosis or VTE-related death. The primary safety outcome is major bleeding. Secondary outcomes are central line-associated infections, patency and line replacement, superficial thrombosis, arterial events and death. A planned sample size of 500 randomized paediatric patients enrolled over a period of 5 years is based on the estimation of VTE rates of 20 and 10% in the standard of care and apixaban groups, respectively. An optional biomarker study in 150 patients will examine predictors of increased VTE risk and study in vivo anticoagulant effects of apixaban in children by measuring specific biomarkers in the haemostatic system and inflammatory pathway. This study will provide valuable information for the safety and efficacy of apixaban in VTE prevention during induction in paediatric ALL.
An analysis of surveillance data on inpatients younger than 21 years of age who had multisystem inflammatory syndrome in children and were hospitalized between March 15 and October 31, 2020, showed ...that initial treatment with IVIG plus glucocorticoids was associated with a lower risk of cardiovascular dysfunction and a lower incidence of adjunctive therapy use than IVIG alone.
BACKGROUND—In the Single Ventricle Reconstruction (SVR) trial, 1-year transplantation-free survival was better for the Norwood procedure with right ventricle–to–pulmonary artery shunt (RVPAS) ...compared with a modified Blalock-Taussig shunt (MBTS). At 3 years, we compared transplantation-free survival, echocardiographic right ventricular ejection fraction, and unplanned interventions in the treatment groups.
METHODS AND RESULTS—Vital status and medical history were ascertained from annual medical records, death indexes, and phone interviews. The cohort included 549 patients randomized and treated in the SVR trial. Transplantation-free survival for the RVPAS versus MBTS groups did not differ at 3 years (67% versus 61%; P=0.15) or with all available follow-up of 4.8±1.1 years (log-rank P=0.14). Pre-Fontan right ventricular ejection fraction was lower in the RVPAS group than in the MBTS group (41.7±5.1% versus 44.7±6.0%; P=0.007), and right ventricular ejection fraction deteriorated in RVPAS (P=0.004) but not MBTS (P=0.40) subjects (pre-Fontan minus 14-month mean, −3.25±8.24% versus 0.99±8.80%; P=0.009). The RVPAS versus MBTS treatment effect had nonproportional hazards (P=0.004); the hazard ratio favored the RVPAS before 5 months (hazard ratio=0.63; 95% confidence interval, 0.45–0.88) but the MBTS beyond 1 year (hazard ratio=2.22; 95% confidence interval, 1.07–4.62). By 3 years, RVPAS subjects had a higher incidence of catheter interventions (P<0.001) with an increasing HR over time (P=0.005)<5 months, 1.14 (95% confidence interval, 0.81–1.60); from 5 months to 1 year, 1.94 (95% confidence interval, 1.02–3.69); and >1 year, 2.48 (95% confidence interval, 1.28–4.80).
CONCLUSIONS—By 3 years, the Norwood procedure with RVPAS compared with MBTS was no longer associated with superior transplantation-free survival. Moreover, RVPAS subjects had slightly worse right ventricular ejection fraction and underwent more catheter interventions with increasing hazard ratio over time.
CLINICAL TRIAL REGISTRATION—URLhttp://www.clinicaltrials.gov. Unique identifierNCT00115934.
The goal of this statement was to review the available literature on surveillance, screening, evaluation, and management strategies and put forward a scientific statement that would comprehensively ...review the literature and create recommendations to optimize neurodevelopmental outcome in the pediatric congenital heart disease (CHD) population.
A writing group appointed by the American Heart Association and American Academy of Pediatrics reviewed the available literature addressing developmental disorder and disability and developmental delay in the CHD population, with specific attention given to surveillance, screening, evaluation, and management strategies. MEDLINE and Google Scholar database searches from 1966 to 2011 were performed for English-language articles cross-referencing CHD with pertinent search terms. The reference lists of identified articles were also searched. The American College of Cardiology/American Heart Association classification of recommendations and levels of evidence for practice guidelines were used. A management algorithm was devised that stratified children with CHD on the basis of established risk factors. For those deemed to be at high risk for developmental disorder or disabilities or for developmental delay, formal, periodic developmental and medical evaluations are recommended. A CHD algorithm for surveillance, screening, evaluation, reevaluation, and management of developmental disorder or disability has been constructed to serve as a supplement to the 2006 American Academy of Pediatrics statement on developmental surveillance and screening. The proposed algorithm is designed to be carried out within the context of the medical home. This scientific statement is meant for medical providers within the medical home who care for patients with CHD.
Children with CHD are at increased risk of developmental disorder or disabilities or developmental delay. Periodic developmental surveillance, screening, evaluation, and reevaluation throughout childhood may enhance identification of significant deficits, allowing for appropriate therapies and education to enhance later academic, behavioral, psychosocial, and adaptive functioning.
Significant disparities exist between patients of different races and with different family incomes; less is understood regarding community-level factors on outcomes.
In this study, we used linked ...data from the Pediatric Health Information System database and the US Census Bureau to examine associations between median annual household income by zip code and mortality, length of stay, inpatient standardized costs, and costs per day, over and above the effects of race and payer, first for children undergoing cardiac surgery (2005-2015) and then for all pediatric discharges (2012-2015). Median community-level income was examined as continuous and categorical (by quartile) predictors. Hierarchical logistic and censored linear regression models were constructed. To these models, patient and surgical characteristics, year, race, payer, state, urban or rural designation, and center fixed effects were added.
We identified 101 013 cardiac surgical (and 857 833 total) hospitalizations from 46 institutions. Children from the lowest-income neighborhoods who were undergoing cardiac surgery had 1.18 times the odds of mortality (95% confidence interval CI: 1.03 to 1.35), 7% longer lengths of stay (CI: 1% to 14%), and 7% higher standardized costs (CI: 1% to 14%) than children from the highest-income neighborhoods. Results for all children were similar, both with and without any major chronic conditions. The effects of neighborhood were only partially explained by differences in race, payer, or the centers at which patients received care. There were no differences in costs per day.
Children from lower-income neighborhoods are at increased risk of mortality and use more resource intensive care than children from higher-income communities, even after accounting for disparities between races, payers, and centers.
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