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Background Pediatric cardiomyopathy is a genetically heterogeneous disease with substantial morbidity and mortality. Current guidelines recommend genetic testing in children with hypertrophic, dilated, or restrictive cardiomyopathy, but practice variations exist. Robust data on clinical testing practices and diagnostic yield in children are lacking. This study aimed to identify the genetic causes of cardiomyopathy in children and to investigate clinical genetic testing practices. Methods and Results Children with familial or idiopathic cardiomyopathy were enrolled from 14 institutions in North America. Probands underwent exome sequencing. Rare sequence variants in 37 known cardiomyopathy genes were assessed for pathogenicity using consensus clinical interpretation guidelines. Of the 152 enrolled probands, 41% had a family history of cardiomyopathy. Of 81 (53%) who had undergone clinical genetic testing for cardiomyopathy before enrollment, 39 (48%) had a positive result. Genetic testing rates varied from 0% to 97% between sites. A positive family history and hypertrophic cardiomyopathy subtype were associated with increased likelihood of genetic testing ( P =0.005 and P =0.03, respectively). A molecular cause was identified in an additional 21% of the 63 children who did not undergo clinical testing, with positive results identified in both familial and idiopathic cases and across all phenotypic subtypes. Conclusions A definitive molecular genetic diagnosis can be made in a substantial proportion of children for whom the cause and heritable nature of their cardiomyopathy was previously unknown. Practice variations in genetic testing are great and should be reduced. Improvements can be made in comprehensive cardiac screening and predictive genetic testing in first‐degree relatives. Overall, our results support use of routine genetic testing in cases of both familial and idiopathic cardiomyopathy. Registration URL: https://www.clinicaltrials.gov ; Unique identifier: NCT01873963.

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Background: Identifying genetic variants which impact the level of cell cycle reentry and establishing the degree of cell cycle progression in those variants could help guide development of therapeutic interventions aimed at effecting cardiac regeneration. We observed that C57Bl6/NCR (B6N) mice have a marked increase in cardiomyocyte S-phase activity following permanent coronary artery ligation as compared to infarcted DBA/2J (D2J) mice. Methods: Cardiomyocyte cell cycle activity post-infarction was monitored in D2J, (D2J x B6N)-F1 and [(D2J x B6N)-F1 x D2J] backcross mice via bromodeoxyuridine or 5-ethynyl-2' -deoxyuridine incorporation, using a nuclear-localized transgenic reporter to identify cardiomyocyte nuclei. Genome-wide quantitative trait locus (QTL) analysis, fine scale genetic mapping, whole exome sequencing and RNA-seq analyses of the backcross mice were performed to identify the gene responsible for the elevated cardiomyocyte S-phase phenotype. Results: (D2J x B6N)-F1 mice exhibited a 14-fold increase in cardiomyocyte S-phase activity in ventricular regions remote from infarct scar as compared to D2J mice (0.798 ± 0.09% vs. 0.056 ± 0.004%; p < 0.001). QTL analysis of [(D2J x B6N)-F1 x D2J] backcross mice revealed that the gene responsible for differential S-phase activity was located on the distal arm of Chromosome 3 (LOD score = 6.38; p < 0.001). Additional genetic and molecular analyses identified 3 potential candidates. Of these, troponin I-interacting kinase ( Tnni3k ) is expressed in B6N hearts but not in D2J hearts. Transgenic expression of Tnni3k in a D2J genetic background results in elevated cardiomyocyte S-phase activity post-injury. Cardiomyocyte S-phase activity in both TNNI3K-expressing and TNNI3K-nonexpressing mice results in the formation of polyploid nuclei. Conclusions: These data indicate that TNNI3K expression increases the level of cardiomyocyte S-phase activity following injury.

Purpose The Multinational Association for Supportive Care in Cancer (MASCC) score is used to risk stratify outpatients with febrile neutropenia (FN). However, it is rarely used in hospital settings. We aimed to describe management, use of MASCC score, and outcomes among hospitalized patients with FN. Methods We conducted a retrospective cohort study of patients with cancer and FN. We collected patient demographics, cancer characteristics, microbiological profile, MASCC score, utilization of critical care therapies, documentation of goals of care (GOC), and inpatient deaths. Outcomes associated with low-(≥ 21) versus high-risk (< 21) MASCC scores are presented as absolute differences. Results Of 193 patients, few (2%, n = 3) had MASCC scores documented, but when calculated, 52% (n = 101) had a high-risk score (< 21). GOC were discussed in 12% (n = 24) of patients. Twenty one percent (n = 40) required intermediate/ICU level of care, and 12% (n = 23) died in the hospital. Those with a low-risk score were 33% less likely to require intermediate/ICU care (95% CI 23 to 44%) and 19% less likely to die in the hospital (95% CI 10% to 27%) compared to those with high-risk score. Conclusions MASCC score was rarely used for hospitalized patients with FN, but high-risk score was associated with worse outcomes. Education efforts to incorporate MASCC score into the workflow may help identify patients at high risk for complications and help clinicians admit these patients to a higher level of care (e.g., intermediate/ICU care) or guide them to initiate earlier GOC discussions.

Dengue Fever (DF) may evolve into two life threatening forms-Dengue Hemorrhagic Fever (DHF) and Dengue Shock Syndrome (DSS). DHF is associated with increased vascular permeability and plasma leakage causing thrombocytopenia and loss of clotting factors into the third space and may result in bleeding initially due to thrombocytopenia and later due to disseminated intravascular coagulation (DIC), often as a terminal event. Prompt recognition and treatment of minor bleeds in DF children with incipient DIC with component therapy may be associated with improved survival while failure to do so is usually catastrophic. A sensitive marker for early DIC is the presence of D-dimer (DD) in the blood. To determine the correlation between the severity of thrombocytopenia and early DIC in children with DHF. The impact of additional factors like age and shock will also be evaluated. Case control prospective study of 60 DHF sero -positive children (1-15 years) with thrombocytopenia. After clinical evaluation they were divided into two equal groups based on the degree of thrombocytopenia (more than/less than 30,000/mm). PT/APTT and DD levels were estimated in all children of both groups and statistical correlation was done. There was no significant difference in the DD levels between the two groups. However, children in either group, presenting with clinical features of shock and thrombocytopenia had significantly higher DD levels. Empirical component therapy in children with DHF based purely on their low platelet counts may not be justified. However, in DHF children with thrombocytopenia and features of shock, aggressive component therapy may prevent subsequent bleeding and may be justified.

Background: Variability in the incidence and severity of bronchopulmonary dysplasia (BPD) among premature infants suggests that genetic susceptibility plays a role in pathogenesis. An assessment of copy number variants (CNV) in BPD subjects may help to identify loci that harbor genetic susceptibility factors. Methods:We conducted a retrospective analysis of clinical DNA microarray data from our institution. We identified 19 BPD subjects, and 2 controls groups (full-term and preterm) with no lung-related disease. We reanalyzed raw data from each of these subjects to identify recurrent CNV loci in BPD subjects. results: We identified three loci (at 11q13.2, 16p13.3, and 22q11.23-q12.1) with recurrent CNV in BPD subjects. The frequency of these CNV was significantly higher in BPD subjects when compared with at least one control group. We interrogated 21 genes residing within the recurrent CNV regions for development-associated changes in expression. Fifteen genes demonstrated significant changes in expression between the pseudoglandular and canalicular stage in human lungs, a time commensurate with birth at highest risk for BPD. We also identified pathways represented by the genes present within the recurrent loci. conclusion: These data identify novel loci that may harbor genes contributing to the genetic susceptibility of BPD.