Lessons from the Pandemic: Role of Percutaneous ECMO and Balloon Atrial Septostomy in Multi-System Inflammatory Syndrome in Children.

Multi-system inflammatory syndrome in children (MIS-C) in the setting of COVID-19 can be associated with severe cardiopulmonary dysfunction. This clinical deterioration may sometimes necessitate veno-arterial extracorporeal membrane oxygenation (VA-ECMO) support. We describe an algorithmic approach including the role of balloon atrial septostomy in this cohort. This is the first reported series of percutaneous VA-ECMO in pediatric patients with MIS-C for better outcomes. The lessons from this approach can be replicated in other pediatric clinical conditions and adds to the armament of multiple pediatric specialties.

Early Reduction of Glucose Consumption Is a Biomarker of Kinase Inhibitor Efficacy Which Can Be Reversed with GLUT1 Overexpression in Lung Cancer Cells.

PURPOSE: Small molecule inhibitors that target oncogenic driver kinases are an important class of therapies for non-small cell lung cancer (NSCLC) and other malignancies. However, these therapies are not without their challenges. Each inhibitor works on only a subset of patients, the pharmacokinetics of these inhibitors is variable, and these inhibitors are associated with significant side effects. Many of these inhibitors lack non-invasive biomarkers to confirm pharmacodynamic efficacy, and our understanding of how these inhibitors block cancer cell growth remains incomplete. Limited clinical studies suggest that early (< 2 weeks after start of therapy) changes in tumor glucose consumption, measured by [18F]FDG PET imaging, can predict therapeutic efficacy, but the scope of this strategy and functional relevance of this inhibition of glucose consumption remains understudied. Here we demonstrate that early inhibition of glucose consumption as can be measured clinically with [18F]FDG PET is a consistent phenotype of efficacious targeted kinase inhibitors and is necessary for the subsequent inhibition of growth across models of NSCLC. METHODS: We tested nine NSCLC cell lines (A549, H1129, H1734, H1993, H2228, H3122, H460, HCC827, and PC9 cells) and ten targeted therapies (afatinib, buparlisib, ceritinib, cabozantinib, crizotinib, dovitinib, erlotinib, ponatinib, trametinib, and vemurafenib) across concentrations ranging from 1.6 nM to 5 µM to evaluate whether these inhibitors block glucose consumption at 24-h post-drug treatment and cell growth at 72-h post-drug treatment. We overexpressed the facilitative glucose transporter SLC2A1 (GLUT1) to test the functional connection between blocked glucose consumption and cell growth after treatment with a kinase inhibitor. A subset of these inhibitors and cell lines were studied in vivo. RESULTS: Across the nine NSCLC cell lines, ten targeted therapies, and a range of inhibitor concentrations, whether a kinase inhibitor blocked glucose consumption at 24-h post-drug treatment strongly correlated with whether that inhibitor blocked cell growth at 72-h post-drug treatment in cell culture. These results were confirmed in vivo with [18F]FDG PET imaging. GLUT1 overexpression blocked the kinase inhibitors from limiting glucose consumption and cell growth. CONCLUSIONS: Our results demonstrate that the early inhibition of lung cancer glucose consumption in response to a kinase inhibitor is a strong biomarker of and is often required for the subsequent inhibition of cell growth. Early inhibition of glucose consumption may provide complementary information to other biomarkers in determining whether a drug will effectively limit tumor growth.

High Diagnostic Yield of Endoscopic Retrograde Cholangiopancreatography Brush Cytology for Indeterminate Strictures.

Background: Endoscopic retrograde cholangiopancreatography (ERCP) brush cytology is used frequently for sampling indeterminate biliary strictures. Studies have demonstrated that the diagnostic yield of brush cytology for malignant strictures is estimated to be 6%-70%. With improved diagnostic tools, sampling techniques and specimen processing, the yield of ERCP brush cytology may be higher. This study aimed to assess the yield of brush cytology and determine factors associated with a positive diagnosis. Methods: This was a cohort study of patients who underwent ERCP brush cytology from October 2017 to May 2020. Patient demographics, clinical, procedural and pathological data were collected using chart review. Sampling data were captured up to 3 months post-index ERCP to capture repeat brushings, biopsies or surgical resections. Outcomes included the diagnostic yield, true/false positive values and true/false negative values of malignancy detection using ERCP brush cytology. Results: A total of 126 patients underwent a brush cytology, 58% were male and 79% had a stricture in the extrahepatic region. Ninety-three patients were diagnosed with a malignancy, of which 78 had positive brush cytology results and 15 had a negative brush cytology result. The diagnostic yield, sensitivity, specificity, positive predictive value, negative predictive value and accuracy were 84%, 83%, 97%, 99%, 68% and 87% respectively. Conclusion: ERCP brush cytology performed using updated sampling technique is associated with high diagnostic yield. This allows for earlier malignancy diagnosis, timely treatment and decreased need for further investigation.

QTc Prolongation in Poison Center Exposures to CredibleMeds List of Substances with "Known Risk of Torsades de Pointes".

Many drugs carry some risk of QT interval prolongation, which can lead to life-threatening dysrhythmias including Torsades de Pointes (TdP). CredibleMeds.org identifies medications categorized as "Known Risk of TdP" but does not stratify risk in acute supratherapeutic ingestions. We sought to determine the proportion of cases exhibiting QTc prolongation and life-threatening dysrhythmias including ventricular tachycardia (VT)/ventricular fibrillation (VF), TdP, and asystole in patients exposed to these substances. Retrospective chart review of cases reported to our Regional Poison Center from 2014 to 2019 of exposures to one or more of the "Known Risk" substances was performed. Demographics, therapies, clinical effects, and medical outcome for each case were analyzed. There were 1125 exposures, of which 760 had a documented QTc interval. QTc ≥ 500 ms was reported in 138 (18.2%) of the 760 cases. The most common "Known Risk" substances were citalopram, escitalopram and cocaine. Although not in the "Known Risk" category, mirtazapine, amitriptyline, diphenhydramine, and trazodone had a statistically significant association with QTc > 500 ms. Life-threatening dysrhythmias occurred in 13 cases, with VT/VF in 6 of the 760 (0.8%) cases, and one case of TdP. Flecainide (OR 11.1, 95% CI 2.2-55.8) and methadone (OR 7.1, 95% CI 2.1-23.4) were associated with increased risk of all life-threatening dysrhythmias. Exposures to medications on the Credible Meds list of "Known Risk of TdP" QTc prolongation is common, but life-threatening dysrhythmias are rare. Mirtazapine, amitriptyline, diphenhydramine, and trazodone were associated with prolonged QTc. Flecainide and methadone had the highest associated risk of life-threatening dysrhythmias.

Pediatric Cardio-Oncology Medicine: A New Approach in Cardiovascular Care.

Survival for pediatric patients diagnosed with cancer has improved significantly. This achievement has been made possible due to new treatment modalities and the incorporation of a systematic multidisciplinary approach for supportive care. Understanding the distinctive cardiovascular characteristics of children undergoing cancer therapies has set the underpinnings to provide comprehensive care before, during, and after the management of cancer. Nonetheless, we acknowledge the challenge to understand the rapid expansion of oncology disciplines. The limited guidelines in pediatric cardio-oncology have motivated us to develop risk-stratification systems to institute surveillance and therapeutic support for this patient population. Here, we describe a collaborative approach to provide wide-ranging cardiovascular care to children and young adults with oncology diseases. Promoting collaboration in pediatric cardio-oncology medicine will ultimately provide excellent quality of care for future generations of patients.

Review of Insulin Resistance in Dilated Cardiomyopathy and Implications for the Pediatric Patient Short Title: Insulin Resistance DCM and Pediatrics.

Energy metabolism in the heart is affected during states of dysfunction. Understanding how the heart utilizes substrates in cardiomyopathy may be key to the development of alternative treatment modalities. Myocardial insulin resistance has been proposed as a possible barrier to effective glucose metabolism in the heart. Extensive literature on the topic in adult individuals exists; however, review in the pediatric population is sparse. The pathophysiology of disease in children and adolescents is unique. The aim of this paper is to review the current knowledge on insulin resistance in dilated cardiomyopathy while also filling the gap when considering care in the pediatric population.

Association of persistent tachycardia with early myocardial dysfunction in children undergoing allogeneic hematopoietic cell transplantation.

Cancer survivors who have undergone hematopoietic cell transplantation (HCT) are at risk for myocardial dysfunction. Children who receive allogenic HCT encounter systemic inflammation resulting in tachycardia and hypertension. The effect of these abnormalities on myocardial function is not known. The aim of this study was to determine whether cardiac dysfunction early after HCT can be predicted by tachycardia or hypertension, within a retrospective single-center sample of pediatric HCT recipients. Early tachycardia or hypertension was defined as a majority of values taken from infusion date to 90 days post-infusion being abnormal. Ejection fraction <53% determined systolic dysfunction. A composite score of accepted pediatric diastolic abnormalities determined diastolic dysfunction. Among 80 subjects (median age 8 years), early tachycardia, systolic dysfunction, and diastolic dysfunction were present in 64%, 25%, and 48% of the sample, respectively. In multivariable models, early tachycardia was an independent predictor of early systolic dysfunction (OR = 12.6 [1.4-112.8], p = 0.024) and diastolic dysfunction (OR = 3.9 [1.3-11.5], p = 0.013). Tachycardia and cardiac dysfunction are common and associated with one another in the early period after pediatric HCT. Future studies may elucidate the role of tachycardia and myocardial dysfunction early after HCT as important predictors of future cardiovascular dysfunction.

Novel use of cangrelor in pediatrics: A pilot cohort study demonstrating use in ventricular assist devices.

Thromboembolic events and bleeding are major sources of morbidity among pediatric patients supported on a ventricular assist device (VAD). Pharmacokinetics and pharmacodynamics of enteral antiplatelet agents are affected and variable due to erratic enteral absorption in end-stage heart failure and VAD circulation. Additionally, 20%-40% of the population are poor metabolizers of clopidogrel, a prodrug, making cangrelor an alternative when antiplatelet therapy is crucial. Cangrelor has been used effectively and safely for short durations in adults during percutaneous coronary interventions, but the use of cangrelor is still under investigation in pediatrics. This case series utilized cangrelor, a novel short-acting, reversible, intravenous P2Y12 platelet inhibitor in managing pediatric patients supported with a VAD. We performed a retrospective, single-center review of patients admitted to a tertiary medical center with end-stage heart failure requiring mechanical circulatory support and concomitant cangrelor administration between January 2019 and March 2020. Platelet function testing, cangrelor dose, bleeding complications, thromboembolic events, and frequency of circuit interventions during the use of cangrelor were recorded. Optimal platelet reactivity, defined as P2Y12 < 180 platelet reaction units (PRU), was measured with serial point-of-care testing (VerifyNow). Seven patients, median age of 4.9 years, met the above criteria. Three patients had a diagnosis of complex congenital heart disease. Four patients had dilated or restrictive cardiomyopathy. All patients were on continuous flow VADs. The median VAD duration was 84.5 days (IQR 61.5-103). The median duration on cangrelor was 43 days (IQR 8-70). The median cangrelor dose to reach the therapeutic threshold was 0.75 µg/kg/min with the mean P2Y12 , while on cangrelor of 164.75 PRU. Bleeding complications included mild gastrointestinal bleeding and hematuria. There was one patient with pump thrombosis requiring intervention. There were no cerebrovascular events while on cangrelor. We report the first successful long-term use of cangrelor in pediatric patients. The reversibility and short half-life of cangrelor make it a feasible antiplatelet agent in selected patients. This data supports the use of cangrelor in children as a viable antiplatelet option; with minimal bleeding complications and no cerebrovascular events demonstrated in this cohort.

Individual differences in object recognition.

There is substantial evidence for individual differences in personality and cognitive abilities, but we lack clear intuitions about individual differences in visual abilities. Previous work on this topic has typically compared performance with only 2 categories, each measured with only 1 task. This approach is insufficient for demonstration of domain-general effects. Most previous work has used familiar object categories, for which experience may vary between participants and categories, thereby reducing correlations that would stem from a common factor. In Study 1, we adopted a latent variable approach to test for the first time whether there is a domain-general object recognition ability, o. We assessed whether shared variance between latent factors representing performance for each of 5 novel object categories could be accounted for by a single higher-order factor. On average, 89% of the variance of lower-order factors denoting performance on novel object categories could be accounted for by a higher-order factor, providing strong evidence for o. Moreover, o also accounted for a moderate proportion of variance in tests of familiar object recognition. In Study 2, we assessed whether the strong association across categories in object recognition is due to third-variable influences. We find that o has weak to moderate associations with a host of cognitive, perceptual, and personality constructs and that a clear majority of the variance in and covariance between performance on different categories is independent of fluid intelligence. This work provides the first demonstration of a reliable, specific, and domain-general object recognition ability, and suggest a rich framework for future work in this area. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

Gender differences in recognition of toy faces suggest a contribution of experience.

When there is a gender effect, women perform better then men in face recognition tasks. Prior work has not documented a male advantage on a face recognition task, suggesting that women may outperform men at face recognition generally either due to evolutionary reasons or the influence of social roles. Here, we question the idea that women excel at all face recognition and provide a proof of concept based on a face category for which men outperform women. We developed a test of face learning to measures individual differences with face categories for which men and women may differ in experience, using the faces of Barbie dolls and of Transformers. The results show a crossover interaction between subject gender and category, where men outperform women with Transformers' faces. We demonstrate that men can outperform women with some categories of faces, suggesting that explanations for a general face recognition advantage for women are in fact not needed.

Aortic coarctation and carotid artery aneurysm in a patient with Hardikar syndrome: Cardiovascular implications for affected individuals.

Hardikar syndrome is a multiple congenital anomaly syndrome first characterized in 1992 by Hardikar et al. to describe two individuals with cholestasis, cleft lip/palate, retinal pigmentation, intestinal abnormalities, and genitourinary anomalies. Between 1992 and 2002, four individuals with Hardikar syndrome were reported in the literature. The fourth individual [Maluf et al. (2002), Transplantation 74:1058-1061; Poley and Proud (2008) Am J Med Genet Part A 146A:2473-2479], who had progressive cholestatic liver disease ultimately requiring liver transplantation, has continued to be followed at our institution. Recently, at the age of 14 years, during an evaluation for refractory hypertension, she was found to have developed coarctation of the aorta that was treated with aortic angioplasty and stenting, dramatically improving her hypertension. Further vascular investigation also revealed a small aneurysm of her carotid artery requiring neurosurgical evaluation and anticoagulant therapy. To our knowledge, these vascular anomalies have not been reported in Hardikar syndrome and the high association of congenital heart disease in the individuals with Hardikar syndrome has not been further addressed. Herein, we discuss this additional clinical information, speculate briefly on possible molecular etiologies, and discuss potential cardiac surveillance recommendations. We hope that broadening the known phenotype of this very rare disorder will further aid clinicians in their management and surveillance for these individuals.

Item response theory analyses of the Cambridge Face Memory Test (CFMT).

We evaluated the psychometric properties of the Cambridge Face Memory Test (CFMT; Duchaine & Nakayama, 2006). First, we assessed the dimensionality of the test with a bifactor exploratory factor analysis (EFA). This EFA analysis revealed a general factor and 3 specific factors clustered by targets of CFMT. However, the 3 specific factors appeared to be minor factors that can be ignored. Second, we fit a unidimensional item response model. This item response model showed that the CFMT items could discriminate individuals at different ability levels and covered a wide range of the ability continuum. We found the CFMT to be particularly precise for a wide range of ability levels. Third, we implemented item response theory (IRT) differential item functioning (DIF) analyses for each gender group and 2 age groups (age ≤ 20 vs. age > 21). This DIF analysis suggested little evidence of consequential differential functioning on the CFMT for these groups, supporting the use of the test to compare older to younger, or male to female, individuals. Fourth, we tested for a gender difference on the latent facial recognition ability with an explanatory item response model. We found a significant but small gender difference on the latent ability for face recognition, which was higher for women than men by 0.184, at age mean 23.2, controlling for linear and quadratic age effects. Finally, we discuss the practical considerations of the use of total scores versus IRT scale scores in applications of the CFMT.

Face recognition in emotional scenes: observers remember the eye shape but forget the nose.

Face recognition is believed to be a highly specialized process that allows individuals to recognize faces faster and more accurately than ordinary objects. However, when faces are viewed in highly emotional contexts, the process becomes slower and less accurate. This suggests a change in recognition strategy compared to recognition in non-arousing contexts. Here we explore this finding by using a novel paradigm to determine which face dimensions are most important for recognizing faces that were initially encoded in highly emotional contexts. Participants were asked to recognize faces from a 3-alternative display after viewing a similar face that was embedded in either a neutral, positive, or negative emotional scene. Results showed that individuals rely on eye shape when recognizing faces that were encoded while embedded in either positive or negative emotional contexts, and ignore nose shape when recognizing faces that were encoded while embedded in negative emotional scenes. The findings suggest that, after encoding that face during heightened emotional arousal, individuals are more likely to commit errors when identifying a face on the basis of nose shape, and less likely to commit errors when identifying a face on the basis of eye shape.