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There are minimal data describing outcomes in ambulatory pediatric and young adult ventricular assist device (VAD)-supported patient populations. We performed a retrospective analysis of encounter-level data from 2006 to 2017 Nationwide Emergency Department Sample (NEDS) to compare emergency department (ED) resource utilization and outcomes for pediatric (≤18 years, n = 494) to young adult (19-29 years, n = 2,074) VAD-supported patient encounters. Pediatric encounters were more likely to have a history of congenital heart disease (11.3% vs. 4.8%). However, Pediatric encounters had lower admission/transfer rates (37.8% vs. 57.8%) and median charges ($3,334 (IQR $1,473-$19,818) vs. $13,673 ($3,331-$45,884)) (all p0.05). Multivariable logistic regression modeling revealed that age itself was not a predictor of admission, instead high acuity primary diagnoses and medical complexity were: (adjusted odds ratio; 95% confidence intervals): cardiac (3.0; 1.6-5.4), infection (3.4; 1.7-6.5), bleeding (3.9; 1.7-8.8), device complication (7.2; 2.7-18.9), and ≥1 chronic comorbidity (4.1; 2.5-6.7). In this largest study to date describing ED resource use and outcomes for pediatric and young adult VAD-supported patients, we found that, rather than age, high acuity presentations and comorbidities were primary drivers of clinical outcomes. Thus, reducing morbidity in this population should target comorbidities and early recognition of VAD-related complications.

There are minimal data describing outcomes in ambulatory pediatric and young adult ventricular assist device (VAD)-supported patient populations. We performed a retrospective analysis of encounter-level data from 2006 to 2017 Nationwide Emergency Department Sample (NEDS) to compare emergency department (ED) resource utilization and outcomes for pediatric (≤18 years, n = 494) to young adult (19-29 years, n = 2,074) VAD-supported patient encounters. Pediatric encounters were more likely to have a history of congenital heart disease (11.3% vs. 4.8%). However, Pediatric encounters had lower admission/transfer rates (37.8% vs. 57.8%) and median charges ($3,334 (IQR $1,473-$19,818) vs. $13,673 ($3,331-$45,884)) (all p < 0.05). Multivariable logistic regression modeling revealed that age itself was not a predictor of admission, instead high acuity primary diagnoses and medical complexity were: (adjusted odds ratio; 95% confidence intervals): cardiac (3.0; 1.6-5.4), infection (3.4; 1.7-6.5), bleeding (3.9; 1.7-8.8), device complication (7.2; 2.7-18.9), and ≥1 chronic comorbidity (4.1; 2.5-6.7). In this largest study to date describing ED resource use and outcomes for pediatric and young adult VAD-supported patients, we found that, rather than age, high acuity presentations and comorbidities were primary drivers of clinical outcomes. Thus, reducing morbidity in this population should target comorbidities and early recognition of VAD-related complications.

This article analyzes a 2019 poster of Minnesota Representative Ilhan Omar by setting it in the context of political memes. Extending recent work on meme rhetoric, and emphasizing the roll that con...

Visual Abstract, Highlights • Combining CHD phenotype–driven gene set enrichment and CRISPR knockdown screening in zebrafish is an effective approach to identifying novel CHD genes. • Mutations affecting genes coding for the WAVE2 protein complex and small GTPase-mediated signaling are associated with LVOTO lesions. • WAVE2 complex genes brk1, nckap1, and wasf2 and regulators of small GTPase signaling cul3a and racgap1 are critical to zebrafish heart development., Summary Genetic variants are the primary driver of congenital heart disease (CHD) pathogenesis. However, our ability to identify causative variants is limited. To identify causal CHD genes that are associated with specific molecular functions, the study used prior knowledge to filter de novo variants from 2,881 probands with sporadic severe CHD. This approach enabled the authors to identify an association between left ventricular outflow tract obstruction lesions and genes associated with the WAVE2 complex and regulation of small GTPase-mediated signal transduction. Using CRISPR zebrafish knockdowns, the study confirmed that WAVE2 complex proteins brk1, nckap1, and wasf2 and the regulators of small GTPase signaling cul3a and racgap1 are critical to cardiac development.

There is a paucity of data regarding sex differences in the profiles and outcomes of ambulatory patients on left ventricular assist device (LVAD) support who present to the emergency department (ED).We performed a retrospective analysis of 57,200 LVAD-related ED patient encounters from the 2010 to 2018 Nationwide Emergency Department Sample. International Classification of Diseases Clinical Modification, Ninth Revision and Tenth Revision, codes identified patients aged 18 years or older with LVADs and associated primary and comorbidity diagnoses. Clinical characteristics and outcomes were stratified by sex and compared. Multivariable logistic regression was used to evaluate predictors of hospital admission and death. Female patient encounters comprised 27.2% of ED visits and occurred at younger ages and more frequently with obesity and depression (all P.01). There were no sex differences in presentation for device complication, stroke, infection, or heart failure (all P.05); however, female patient encounters were more often respiratory- and genitourinary or gynecological related (both P.01). After adjustment for age group, diabetes, depression, and hypertension, male patient encounters had a 38% increased odds of hospital admission (95% confidence interval 1.20-1.58), but there was no sex difference in the adjusted odds of death (odds ratio 1.11, 95% confidence interval 0.86-1.45).Patient encounters of females on LVAD support have significantly different comorbidities and outcomes compared with males. Further inquiry into these sex differences is imperative to improve long-term outcomes.

Introduction: We recently identified the fetal noncanonical WNT receptor ROR2 as being re-expressed in human right ventricular failure (RVF), but the myocardial role of ROR2 remains poorly described. Hypothesis: We assessed if ROR2 expression influences cardiomyocyte structure or contributes to RVF pathogenesis. Methods: ROR2 gain- and loss-of-function (ROR2 GOF and ROR2 LOF ) NRVMs were generated using adenoviral-delivered ROR2 cDNA or shRNA and cultured on nanopatterned substrates. NRVM structure was assessed by confocal microscopy (minimum n=3 replicates, >30 cells/condition). NRVM gene expression was characterized by RNAseq. The impact of ROR2 on RV structure and function was assessed using AAV9-mediated cardiac ROR2 delivery, in 4-week old C57BL/6 mice (vs GFP), and echocardiography and hemodynamics (n= 8, 50% male). Results: ROR2 GOF disrupts non-sarcomeric and sarcomeric NRVM structure, exhibiting smaller (500 vs. 711 μm 2 , p = 7.4x10 -23 ) and rounder (aspect ratio 2.1 vs. 3.1, p=1.9x10 -16 ) shape and fragmented sarcomeres (Figure). Whereas, ROR2 LOF NRVMs demonstrate a striking peripheralization of α-actinin and β-catenin. Gene-set enrichment analyses of ROR2 GOF NRVMs reveal upregulation of cytokinesis, mitosis, microtubule regulation, and insulin like growth factor receptor signaling. By 4 weeks after induction of ROR2 GOF in vivo , mice exhibit biventricular dilation and systolic dysfunction (TAPSE 0.85 vs 1.2 mm, p = 2.1x10 -5 ; right ventricular outflow dimension 2.0 vs 1.7 mm, p = 0.001, LV EDV 33.5 vs 28.6 μL, p = 0.05; LV ejection fraction 63% vs 69%, p = 0.015). RV diastolic function is reduced in ROR2 GOF (E:e’ 21.8 vs 18.6, p = 0.004 and RV EDP 2.9 vs 1.0 mmHg, p = 0.06). Conclusions: ROR2 GOF causes biventricular dilation, systolic and diastolic dysfunction in vivo . In vitro, ROR2 GOF NRVMs exhibit an immaturity phenotype with maintenance of proliferation gene program. In contrast, ROR2 LOF NRVMs form a tight monolayer with enhanced cell-cell borders.

BACKGROUND Desensitization, the process of reducing anti-human leukocyte antigen (HLA) antibodies in sensitized patients awaiting heart transplantation (HT), has unclear efficacy in pediatric HT candidates. METHODS Pediatric HT candidates listed at our institution between January 1, 2013 and June 30, 2018 were retrospectively evaluated. Sensitization was defined as the calculated panel reactive antibody (cPRA) ≥ 10% with ≥ 1 a strong positive antibody. The desensitization response was defined as a ≥ 25% reduction in the mean fluorescence intensity (MFI) for ≥ 90% of the strong positive antibodies on follow-up panel reactive antibody (PRA) testing before waitlist removal, HT, or death (data available for 13 patients). RESULTS The HT candidates were categorized as sensitized receiving desensitization therapy (ST, n = 14), sensitized not receiving therapy (SNT, n = 18), or non-sensitized (n = 55). A desensitization response was observed in 8 (62%) of the ST upon repeat PRA testing, with the ST responders receiving more doses of intravenous immunoglobulin (IVIG) (8 vs 2, p < 0.05). The anti-HLA class I antibodies were particularly resistant for non-responders (p = 1.9 × 10-4). The combination of homograft and ventricular assist device was more sensitizing than either alone (p = 3.1 × 10-4). However, these sensitization risk factors did not impact the desensitization response. The ST was associated with a higher likelihood of remaining listed and a longer waitlist time without substantially impacting the HT rate, waitlist mortality, or early post-HT outcomes. CONCLUSIONS Most ST patients had a favorable response to desensitization, with a dose-dependent response observed for IVIG. The anti-HLA class likely impacts the ST response, whereas traditional sensitization risk factors had no impact on the response.

There are limited data describing the prevalence of mental health disorders (MHDOs) in patients with ventricular assist devices (VADs), or associations between MHDOs and resource use or outcomes. We used the Nationwide Emergency Department Sample administrative database to analyze 44,041 ED encounters for VAD-supported adults from 2010 to 2017, to assess the relationship between MHDOs and outcomes in this population. MHDO diagnoses were present for 23% of encounters, and were associated with higher charges and rates of admission, but lower mortality.

Background With a growing population of patients supported by ventricular assist devices (VADs) and the improvement in survival of this patient population, understanding the healthcare system burden is critical to improving outcomes. Thus, we sought to examine national estimates of VAD‐related emergency department (ED) visits and characterize their demographic, clinical, and outcomes profile. Additionally, we tested the hypotheses that resource use increased and mortality improved over time. Methods and Results This retrospective database analysis uses encounter‐level data from the 2010 to 2017 Nationwide Emergency Department Sample. The primary outcome was mortality. From 2010 to 2017, >880 million ED visits were evaluated, with 44 042 VAD‐related ED visits identified. The annual mean visits were 5505 (SD 4258), but increased 16‐fold from 2010 to 2017 (824 versus 13 155). VAD‐related ED visits frequently resulted in admission (72%) and/or death (3.0%). Median inflation‐adjusted charges were $25 679 (interquartile range, $7450, $63 119) per encounter. The most common primary diagnoses were cardiac (22%), and almost 30% of encounters were because of bleeding, stroke, or device complications. From 2010 to 2017, admission and mortality decreased from 82% to 71% and 3.4% to 2.4%, respectively ( P for trends Conclusions We present the first study using national‐level data to characterize the growing ED resource use and financial burden of patients supported by VAD. During the past decade, admission and mortality rates decreased but remain substantial; in 2017 ≈1 in every 40 VAD ED encounters resulted in death, making it critical that clinical decision–making be optimized for patients with VAD to maximize good outcomes.

Cardiac disease in pediatric patients due to coronavirus SARS-CoV-2 disease (COVID-19) includes myocarditis and multisystem inflammatory syndrome, both of which can present with a broad range in severity. Here we describe an infant with COVID-19 causing fulminant myocarditis with inotrope-resistant acute heart failure requiring extracorporeal membrane oxygenation. The patient demonstrated an atypical finding of localized septal thickening suggestive of hypertrophic cardiomyopathy, but the diagnosis of myocarditis was confirmed by cardiac MRI. Serial echocardiography illustrated complete resolution of septal hypertrophy and normalized cardiac function. The current report highlights the potential severity of COVID-19 associated myocarditis, the potential for recovery, and the utility of cardiac MRI in confirming the mechanism.

Introduction: The past decade has seen tremendous growth in ambulatory ventricular assist device (VAD) patients. We sought to identify patients that present to the emergency department (ED) who are at the highest risk of death. Methods: We performed a retrospective analysis of ED encounters of VAD patients using data from the Nationwide Emergency Department Sample (NEDS) from 2010-2017. Demographic and clinical variables significantly associated with mortality (p < 0.2) in a univariate analysis were evaluated in a multivariate model. Using a random sampling of patient encounters, 80% were assigned to development and 20% to validation cohorts. A risk model was derived from independent predictors of mortality, which were weighted using integer-normalized beta coefficients. Each patient encounter was assigned to one of three groups based on risk score. Results: A total of 44,042 ED encounters of VAD patients were included in the study. The majority of patients were male (73.6%), Conclusions: We present a novel risk score and its validation for predicting mortality of VAD patients who present to the ED, which can serve as useful tool for clinicians caring for this high-risk, and growing, population.

Introduction: There are minimal data describing the prevalence of mental health disorders (MHDO) in VAD-supported patients, or the association between MHDO and resource use or outcomes. Methods: This retrospective analysis utilizes all emergency department (ED) encounter-level data from the 2010-2017 Nationwide Emergency Department Sample (NEDS). Patients with VADs were identified using ICD-9/10 codes, as were associated MHDO diagnoses, which were categorized as depression/anxiety, suicide/self harm, bipolar/psychoses, and substance abuse. Outcomes and characteristics were compared for patients with and without a MHDO via descriptive statistics. Hospital admission and mortality occurring in ED or inpatient was investigated with logistic multivariable regression models adjusted for demographic and clinical characteristics. Results: Of the 47,543 encounters with VADs during the study period, 23% (n=11,103) had at least one MHDO. Depression/anxiety (82%) and substance abuse (22%) were the most prevalent MHDOs. Suicide attempt or self harm was the primary diagnosis for 20 (0.2%) encounters. Patients with MHDOs were more likely to be female (31% vs. 26%), younger (median age 59 vs. 61 years), and to have a non-MHDO chronic condition (77% vs 70%, P Discussion: 1 in 5 VAD-supported ED patient encounters also have a MHDO diagnosis. VAD-supported patients with a MHDO had higher resource use but lower mortality. These data underscore the need for greater attention to how MHDO may impact outcomes in VAD-supported patients.

Background: Drivers of adaptive and pathologic human right ventricular (RV) remodeling are poorly defined, but there is some evidence that WNT signaling contributes to these processes. Methods: Using a candidate gene approach, we sought to identify genes specifically expressed in RV failure by assessing the expression of 28 WNT-related genes in the RVs of three groups: human explanted nonfailing donor hearts (NF, n = 29), pre-transplant cardiomyopathy hearts with preserved RV function (pRV, n = 78), and pre-transplant cardiomyopathy hearts with RV failure (RVF, n = 35). Results: We identified the noncanonical WNT receptor ROR2 as transcriptionally strongly upregulated in RVF compared to pRV and NF (p < 0.05, adjusted for multiple hypothesis testing using Benjamin-Hochberg). By western blot, ROR2 protein expression correlated to mRNA expression (R 2 = 0.41, p = 8.1 x 10-18) and increased linearly with higher right atrial to pulmonary capillary wedge ratio in RVF (R 2 =0.40, p = 3.0 x 10-5). Using trichrome, immunohistochemistry, and RNAscope, we identified preferential ROR2 mRNA and protein expression in fibrotic regions by both cardiomyocytes and noncardiomyocytes. High ROR2 expression correlated with increased expression of a known ROR2 target, the WNT/Ca2+ responsive protease calpain and its target FLNA (R 2 0.25 and 0.67, respectively, p < 0.05), as well as with increased relative phosphorylation of FLNA (R 2 0.62, p < 0.05), a marker of its activation by ROR2. Finally, mice with a range of RVF severity, generated by pulmonary artery constriction, demonstrated a robust increase in ROR2 and FLNA expression compared to sham-treated animals, and ROR2 and FLNA expression correlated strongly with each other (R 2 0.89, p = 6.9 x 10-5) and with increasing RV weight normalized to body weight (R 2 ~0.8, p < 0.001, both). Conclusion: ROR2 expression in the RV is dramatically increased in humans and mice with severe RVF, and ROR2 expression correlates with worsening RV hemodynamics, calpain expression, FLNA cleavage, and FLNA phosphorylation. Taken together, the data reveal the robust activation of noncanonical WNT signaling in human RVF, and identify ROR2-mediated cytoskeleton protein cleavage as a potential novel target of human pathologic RV remodeling.

Background: No medical therapies exist to treat right ventricular (RV) remodeling and RV failure (RVF), in large part because molecular pathways that are specifically activated in pathologic human RV remodeling remain poorly defined. Murine models have suggested involvement of Wnt signaling, but this has not been well-defined in human RVF. Methods: Using a candidate gene approach, we sought to identify genes specifically expressed in human pathologic RV remodeling by assessing the expression of 28 WNT-related genes in the RVs of three groups: explanted nonfailing donors (NF, n = 29), explanted dilated and ischemic cardiomyopathy, obtained at the time of cardiac transplantation, either with preserved RV function (pRV, n = 78) or with RVF (n = 35). Results: We identified the noncanonical WNT receptor ROR2 as transcriptionally strongly upregulated in RVF compared to pRV and NF (Benjamini-Hochberg adjusted P < 0.05). ROR2 protein expression correlated linearly to mRNA expression (R 2 = 0.41, P = 8.1 × 10-18) among all RVs, and to higher right atrial to pulmonary capillary wedge ratio in RVF (R 2 = 0.40, P = 3.0 × 10-5). Utilizing Masson's trichrome and ROR2 immunohistochemistry, we identified preferential ROR2 protein expression in fibrotic regions by both cardiomyocytes and noncardiomyocytes. We compared RVF with high and low ROR2 expression, and found that high ROR2 expression was associated with increased expression of the WNT5A/ROR2/Ca2+ responsive protease calpain-μ, cleavage of its target FLNA, and FLNA phosphorylation, another marker of activation downstream of ROR2. ROR2 protein expression as a continuous variable, correlated strongly to expression of calpain-μ (R 2 = 0.25), total FLNA (R 2 = 0.67), calpain cleaved FLNA (R 2 = 0.32) and FLNA phosphorylation (R 2 = 0.62, P < 0.05 for all). Conclusion: We demonstrate robust reactivation of a fetal WNT gene program, specifically its noncanonical arm, in human RVF characterized by activation of ROR2/calpain mediated cytoskeleton protein cleavage.

The heart consumes circulating nutrients to fuel lifelong contraction, but a comprehensive mapping of human cardiac fuel use is lacking. We used metabolomics on blood from artery, coronary sinus, and femoral vein in 110 patients with or without heart failure to quantify the uptake and release of 277 metabolites, including all major nutrients, by the human heart and leg. The heart primarily consumed fatty acids and, unexpectedly, little glucose; secreted glutamine and other nitrogen-rich amino acids, indicating active protein breakdown, at a rate ~10 times that of the leg; and released intermediates of the tricarboxylic acid cycle, balancing anaplerosis from amino acid breakdown. Both heart and leg consumed ketones, glutamate, and acetate in direct proportionality to circulating levels, indicating that availability is a key driver for consumption of these substrates. The failing heart consumed more ketones and lactate and had higher rates of proteolysis. These data provide a comprehensive and quantitative picture of human cardiac fuel use.

Background: A greater understanding of the gene programs that drive adaptive and pathologic right ventricle (RV) remodeling are needed given the poor response of the RV to standard reverse remodeling agents and the absence of RV-specific therapies. Left ventricular failure (LVF) provides an ideal model to study human RV remodeling given the spectrum of secondary RV involvement. Methods: Dilated (DCM) and ischemic cardiomyopathy (ICM) hearts in the Penn Human Heart Tissue Bank were identified as having preserved RV function (pRV) or RVF using preexplant right atrial to wedge pressure ratio. Using RT-PCR and a candidate gene approach, we assessed RV differential expression of 28 WNT -related genes and NPPA/NPPB as positive controls between nonfailing (NF, n= 29), DCM-pRV (n = 47), DCM-RVF (n = 26), ICM-pRV (n = 31), and ICM-RVF (n = 10). Genes which met significance for differential expression between NF, pRV, and RVF for both DCM and ICM using Kruskal-Wallis were further assessed by Mann Whitney U comparing pRV to RVF after combining ICM and DCM groups (Benjamini-Hochberg p < 0.05 for significance). Results: Most (20/28) WNT -related genes were differentially expressed in at least one cardiomyopathy group, but only 13, as well as NPPA, were significant for both DCM and ICM. Only, CREBBP, NFATC2, and ROR2 were differentially expressed between pRV and RVF (Table). Discussion: WNT -related genes show significant DGE in RV remodeling. But, of those tested, only CREBBP, NFATC2, and ROR2 appear to be implicated in the progression from adaptive to pathologic RV remodeling. Additional studies are underway to confirm differential protein expression.

Introduction Studies regarding sex differences in patients with LVADs have demonstrated variable characteristics and outcomes in terms of frequency of adverse events and mortality by sex. There are limited data regarding differences in LVAD-related emergency department (ED) visits between women and men. Hypothesis Comorbidity burden and clinical outcomes of LVAD patients vary by sex. Methods We performed a retrospective analysis of 44,042 LVAD-related ED encounters from the 2010-2017 Nationwide Emergency Department Sample (NEDS). ICD-9/10 codes were used to identify patients with LVADs and their associated primary and comorbidity diagnoses. Demographics, clinical characteristics, and outcomes (death, hospital admission, and rates of LVAD-related procedures) were compared via Chi-square tests. Results Women comprised 26% (n=11654) of LVAD-related ED visits. Compared to men, women were younger (58.1 years [IQR 46.59, 67.13] vs. 61.5 [IQR 51.66, 69.31]; p 0.05). Women underwent endoscopy less frequently than men (5.1% vs. 6.8%, p = 0.006), but there were no differences in blood transfusion, catheterization, device exchange, and heart transplantation (p for all ≥ 0.05). Despite being less likely than men to be admitted to the hospital (61.6% vs. 67.6%, p Conclusions Compared to men, the comorbidity profiles and clinical outcomes of women with LVADs who seek ED evaluation significantly differ. Future analyses will further explore the disparity in hospital admission by sex despite similar mortality rates. Understanding these sex differences among VAD patients is a critical step in the effort to improve long-term outcomes. Figure 1. Comorbidities (A), Primary Diagnosis (B), ED or Hospital Procedures Performed (C), and Outcomes (D) of LVAD-related ED Encounters by Sex

Purpose Although the risk of bleeding complications is well known for patients with ventricular assist devices (VADs), there is minimal data describing how bleeding events impacts the ambulatory VAD population's emergency department (ED) resource utilization or outcomes. Methods We utilized ED-encounter level data from the Nationwide Emergency Department Sample (NEDS). Patients age ≥19 years with VADs from 2006 to 2014 were identified via ICD-9 diagnoses. Primary diagnoses were queried for bleeding events. Encounters were also queried for ED and inpatient bleeding driven procedures. Overall inpatient and ED charges and mortality were assessed. Results Over a nine-year period, 17,356 VAD-related ED visits were identified, of which bleeding events were the second most common primary diagnosis (25%). Bleeding events were less common in young adults (19 to 44 years) compared to middle (45 to 64 years) and older (≥65 years) adults (16% vs. 25% vs. 29%, p Conclusion This is the largest study to date investigating resource utilization and outcomes among ambulatory VAD patients presenting to the ED with a bleeding event. A bleeding event was the primary diagnosis for 1 in 4 ED encounters, representing the second most common primary diagnosis in this population. Bleeding events were associated with older age, frequent procedures, trend towards higher charges, and—when requiring a blood transfusion—higher mortality.

Purpose Data related to the epidemiology and resource utilization of ventricular assist device (VAD) related emergency department (ED) visits are limited. However, an improved understanding of the burden of VADs on the healthcare system is critical to designing interventions that improve outcomes. We examined national estimates of VAD-related ED visits and described medical complexity, admissions, resource utilization, and mortality. Methods This study utilizes data from ED encounter-level data via the 2006-2014 Nationwide Emergency Department Sample (NEDS). ICD-9 codes were used to identify patient-encounters with VADs. Demographic and clinical factors are reported via descriptive statistics. The primary outcome was death; secondary outcomes included median inflation-adjusted charge and hospital admission. Results From 2006 to 2014, over 900 million ED visits were evaluated, of which 17,356 (.002%) VAD-related ED visits were identified, for a median of 1,028 (SD 1,489) visits per year. Most VAD ED encounters were represented by patients that were male (74%), ≥ 45 years old (73%), and living in an urban environment (85%). 73% of VAD related ED visits resulted in inpatient admission and the median inflation-adjusted charge was $23,862 (IQR 7,129; 58,265) per visit. Mortality, either in the ED or during an associated admission, was 4.7%. The most common primary diagnoses were cardiac (32%) followed by bleeding (25%) and infection (18%). More than half of the encounters were with patients with ≥1 chronic medical condition, with diabetes (34%) and hypertension (31%) the most prevalent. Conclusion This is the first study to use national level data to describe the clinical characteristics and outcomes of patients with VADs who present to the ED. With nearly 1 in 20 VAD ED encounters resulting in death, strategies to reduce mortality are urgently needed.

Purpose There are minimal data on emergency department (ED) resource utilization for pediatric patients with ventricular assist devices (VADs), and it is unclear if adult data can be extrapolated to children. Methods This analysis of national estimates of ED-visit level encounters uses the Nationwide Emergency Department Sample (NEDS). Patients from 2006 to 2014 with VADs were identified using ICD-9 codes and categorized as pediatric (≤18y), young adult (19-44y), middle adult (45-64y) and older adult (≥65y). The primary outcome was death; secondary outcomes included median inflation adjusted charge, admission/transfer rate, and primary encounter diagnoses. Results Over the 9 years studied, a total of 254 (95% CI 190-318) pediatric, 3,003 (95% CI 2424-3582) young adult, 7,590 (95% CI 6220-8961) middle adult, and 6,857 (95% CI 5604-8110) older adult ED encounters were identified. Compared to all other age groups, the pediatric VAD ED encounters were more likely to occur at a non-teaching or non-metropolitan ED, to have private insurance as a primary payer, and have a higher proportion of female patients (p ≤ 0.0003 for all). The two most frequent primary encounter diagnoses in pediatric patients were acute gastrointestinal (19%) and respiratory complaints (14%), both of which were uncommon in all adult age groups (p 0.2 for all). Conclusion In this study evaluating ED resource utilization of VAD patients, pediatric patients had much lower admission rate and charges compared to their adult counterparts—likely reflecting generally lower acuity complaints or potentially less medical complexity. Still, high mortality rates across all ages highlights the ubiquitous fragility of patients with VADs presenting to the ED and the need for strategies to reduce morbidity and mortality.

Purpose With advances in mechanical circulatory support and orthotopic heart transplants (OHT) remaining a limited resource, there has been a dramatic increase in Ventricular Assist Device (VAD) implantation. There is minimal data comparing emergency department (ED) resource utilization and outcomes between these populations. We examined national estimates of VAD and OHT-related ED visits and evaluated admissions, resource utilization, and mortality. Methods This study is an epidemiological analysis comparing national estimates of ED visit-level data from the 2006-2014 Nationwide Emergency Department Sample (NEDS) in patients with VADs vs OHT, identified using ICD-9 codes. The primary outcome was death; secondary outcomes included median inflation-adjusted charge and hospital admission. We tested the hypothesis that resource utilization and mortality are higher in ED visits for VAD patients compared to OHT patients. Results 17,356 VAD-related ED, and 138,133 OHT-related visits were identified. Patients with VADs were more likely to be male (74% vs 70%, p=0.001) and ≥ 65 yo (39% vs 38%, p=0.0004). VADs were more likely to have a primary diagnosis of bleeding (25% vs 2%) and less likely to have acute respiratory disease (6% vs 20%, p Conclusion Patients with VADs presenting to the ED represent a population with greater morbidity, mortality and resource utilization compared to OHT. A more developed understanding of those factors that drive mortality and resource use is imperative for improving outcomes in this high-risk population.

With the increase in the number of patients with ventricular assist devices (VADs), understanding the burden of VADs on the healthcare system is imperative to designing interventions which improve outcomes. We examined national estimates of VAD-related emergency department (ED) visits and evaluated

This essay focuses on the language of domestic radicalization as it has been invoked in recent debates regarding homeland security and the specter of homegrown Islamic terrorism. The language of radicalization is not new. However, beginning in 2004 and 2005 this language began to be appropriated into legislative and law enforcement discussions of domestic terrorism and national security. Using the rhetorical figure of polyptoton as a critical frame, this essay explores how the language of radicalization has evolved and how it has come to shape available arguments and define the legitimacy of participants (and non-participants) within recent congressional hearings and legislation.

Christian fundamentalism is a doctrinal system and an argumentative frame, but it also functions as a “countermovement” whose members advocate resistance from a purported place of ecclesial and political marginalization. This article explores the roots of early fundamentalist resistance rhetoric as it manifested through a series of “countersymbols”—oppositional condensation symbols that invoke the corruption of an idealized community by its other to rhetorically justify resistance as necessary response.

Dilated cardiomyopathy (DCM) is a highly heterogeneous trait with sarcomeric gene mutations predominating. The cause of a substantial percentage of DCMs remains unknown, and no gene-specific therapy is available. On the basis of resequencing of 513 DCM cases and 1,150 matched controls from various cohorts of distinct ancestry, we discovered rare, functional RAF1 mutations in 3 of the cohorts (South Indian, North Indian and Japanese). The prevalence of RAF1 mutations was ~9% in childhood-onset DCM cases in these three cohorts. Biochemical studies showed that DCM-associated RAF1 mutants had altered kinase activity, resulting in largely unaltered ERK activation but in AKT that was hyperactivated in a BRAF-dependent manner. Constitutive expression of these mutants in zebrafish embryos resulted in a heart failure phenotype with AKT hyperactivation that was rescued by treatment with rapamycin. These findings provide new mechanistic insights and potential therapeutic targets for RAF1-associated DCM and further expand the clinical spectrum of RAF1-related human disorders.

Background— Human genomes harbor copy number variants (CNVs), which are regions of DNA gains or losses. Although pathogenic CNVs are associated with congenital heart disease (CHD), their effect on clinical outcomes is unknown. This study sought to determine whether pathogenic CNVs among infants with single ventricle physiology were associated with inferior neurocognitive and somatic growth outcomes. Methods and Results— Genomic DNAs from 223 subjects of 2 National Heart, Lung, and Blood Institute–sponsored randomized clinical trials in infants with single ventricle CHD and 270 controls from The Cancer Genome Atlas project were analyzed for rare CNVs >300 kb using array comparative genomic hybridization. Neurocognitive and growth outcomes at 14 months from the CHD trials were compared among subjects with and without pathogenic CNVs. Putatively pathogenic CNVs, comprising 25 duplications and 6 deletions, had a prevalence of 13.9%, significantly greater than the 4.4% rate of such CNVs among controls. CNVs associated with genomic disorders were found in 13 cases but not in controls. Several CNVs likely to be causative of single ventricle CHD were observed, including aberrations altering the dosage of GATA4 , MYH11 , and GJA5 . Subjects with pathogenic CNVs had worse linear growth, and those with CNVs associated with known genomic disorders had the poorest neurocognitive and growth outcomes. A minority of children with pathogenic CNVs were noted to be dysmorphic on clinical genetics examination. Conclusions— Pathogenic CNVs seem to contribute to the cause of single ventricle forms of CHD in ≥10% of cases and are clinically subtle but adversely affect outcomes in children harboring them.

The goal of this review is to highlight recent discoveries in the field of genetics as it relates to congenital heart disease (CHD). Recent advancements in next generation sequencing technology and tools to interpret this growing body of data have allowed us to refine our understanding of the molecular mechanisms that result in CHD.From multiple different study designs, the genetic lesions that cause CHD are increasingly being elucidated. Of the more novel findings, a forward genetic screen in mice has implicated recessive inheritance and the ciliome broadly in CHD pathogenesis. The developmental delays frequently observed in patients with CHD appear to result from mutations affecting genes that overlap heart and brain developmental regulation. A meta-analysis has provided clarity, discriminating pathologic from incidental copy number variations and defining a critical region or gene.Recent technological advances have rapidly expanded our understanding of CHD genetics, and support the applicability to the clinical domain in both sporadic and inherited disease. Though significant gaps remain, genetic lesions remain the primary explanation for CHD pathogenesis, although the precise mechanism is likely multifactorial.

The RASopathies are a relatively common group of phenotypically similar and genetically related autosomal dominant genetic syndromes caused by missense mutations affecting genes participating in the RAS/mitogen-activated protein kinase (MAPK) pathway that include Noonan syndrome (NS) and Noonan syndrome with multiple lentigines (NSML, formerly LEOPARD syndrome). NS and NSML can be difficult to differentiate during infancy, but the presence of multiple lentigines, cafe au lait spots, and specific cardiac defects facilitate the diagnosis. Furthermore, individual PTPN11 missense mutations are highly specific to each syndrome and engender opposite biochemical alterations on the function of SHP-2, the protein product of that gene. Here, we report on a 5-year-old male with two de novo PTPN11 mutations in cis, c.1471C>T (p.Pro491Ser), and c.1492C>T (p.Arg498Trp), which are associated with NS and NSML, respectively. This boy's phenotype is intermediate between NS and NSML with facial dysmorphism, short stature, mild global developmental delay, pulmonic stenosis, and deafness but absence of cafe au lait spots or lentigines. The double-mutant SHP-2 was found to be catalytically impaired. This raises the question of whether clinical differences between NS and NSML can be ascribed solely to the relative SHP-2 catalytic activity.

A 49-year-old male recreational weight lifter suffered an isolated partial tear of the subscapularis muscle after minimal trauma. His history was atypical for development of a subscapularis tear, which made his case more difficult to evaluate and subsequently treat. His recovery was uncomplicated and was facilitated by a physical therapy program to enhance rotator cuff strength and proprioception. This report includes a brief review of the literature on the etiology and management of these tears. This case emphasizes the importance of an appropriate physical examination and judicious use of imaging techniques so that uncommon disorders, even those with unusual presentations, can be diagnosed and managed to obtain good outcomes.

Mobile ad hoc networks (MANETs) are notoriously difficult to defend against attack. In this paper we demonstrate that by optimizing a previously reported covert timing channel, it is possible to simultaneously improve the reliability of the channel and create a metric that reliably detects attacks. Using standard methods from information theory, we compute the capacity of the covert channel and show that it is reduced under wormhole attack. This result leads us to a novel application of error-correcting codes to our covert channel, where the number of errors corrected provides a measure of the likelihood that a route traverses a wormhole. This technique does not use any of the bearer-channel communications bandwidth nor does it require modifications to the protocols or hardware.

In this paper, Wireless Personal Area Network (IEEE 802.15.4) wireless channel utilization using Memsic (formerly Crossbow) IRIS Motes is measured and compared to ns2.34 simulation and theoretical models. Results show divergence between calculated, simulated and experimental results at higher throughput. Experimental results also highlight the limitations of the MoteWorks framework with regard to channel throughput measurements. A set of mitigation strategies is outlined to improve future research efforts aiming to characterize the validity of simulation models using the Memsic wireless sensor nodes.