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Introduction Acute stroke accounts for significant morbidity and mortality globally. The role of troponin for risk stratification in stroke is unclear. Purpose The aims of this study were to assess the relationship between peak troponin and mortality in patients with ischaemic stroke, haemorrhagic stroke, or subarachnoid haemorrhage and to compare this with the predictive value of first troponin or dynamic troponin change. Methods A retrospective cohort study was carried out using the National Institute for Health Research Health Informatics Collaborative Cardiovascular dataset of all consecutive patients who had a troponin measured at five hospitals between 2010 and 2017. Patients with at least one troponin measurement and a primary diagnosis of ischaemic stroke, haemorrhagic stroke or subarachnoid haemorrhage during a hospital admission were included. The main exposure variables were first and peak troponin, and dynamic troponin change, and the main outcome was all-cause mortality. Results were analysed using multivariable adjusted restricted cubic spline Cox regression. Survival analyses were adjusted for troponin assay, assay sensitivity (standard or highly sensitive), number of troponin measurements, age, sex, C-reactive protein level, white blood cell count, platelet count, haemoglobin, estimated glomerular filtration rate, angiography during admission, acute coronary syndrome during admission, and cardiovascular history (history of diabetes mellitus, myocardial infarction, heart failure, hypertension, stroke or atrial fibrillation). Receiver Operator Characteristic (ROC) curves were used to assess the predictive value of each exposure variable. Results 4,712 patients were included in the analysis (ischaemic stroke: 3,346; haemorrhagic stroke: 718; subarachnoid haemorrhage: 648). Peak troponin was above the upper limit of normal in 47.4% of ischaemic stroke patients, 52.8% of haemorrhagic stroke patients, and 57.1% of subarachnoid haemorrhage patients. Patients with elevated peak troponin were older and had more cardiovascular risk factors. A direct positive relationship was seen between peak troponin level and mortality hazard ratio in all three stroke subtypes (Figure 1). This relationship was consistent when considering dynamic troponin fold change for ischaemic or haemorrhagic stroke. For all three stroke subtypes, there was no added predictive value of peak troponin or dynamic troponin change over first troponin in predicting mortality (Figure 2). Conclusions A positive peak troponin was associated with increased mortality in patients presenting with ischaemic stroke, haemorrhagic stroke, or subarachnoid haemorrhage. Overall, serial troponin measurements may not improve mortality prediction beyond a single measurement. These findings may have implications for risk stratification of patients with acute stroke syndromes. Funding Acknowledgement Type of funding sources: Public grant(s) – National budget only. Main funding source(s): NIHR Imperial Biomedical Research Centre, as part of the NIHR Health Informatics Collaborative, and 2) British Heart Foundation

Prevention of infection and propagation of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a high priority in the Coronavirus Disease 2019 (COVID-19) pandemic. Here we describe S-nitrosylation of multiple proteins involved in SARS-CoV-2 infection, including angiotensin-converting enzyme 2 (ACE2), the receptor for viral entry. This reaction prevents binding of ACE2 to the SARS-CoV-2 spike protein, thereby inhibiting viral entry, infectivity and cytotoxicity. Aminoadamantane compounds also inhibit coronavirus ion channels formed by envelope (E) protein. Accordingly, we developed dual-mechanism aminoadamantane nitrate compounds that inhibit viral entry and, thus, the spread of infection by S-nitrosylating ACE2 via targeted delivery of the drug after E protein channel blockade. These non-toxic compounds are active in vitro and in vivo in the Syrian hamster COVID-19 model and, thus, provide a novel avenue to pursue therapy.

Kisspeptins (KP), encoded by Kiss1 , are reported to play a role in early-onset preeclampsia (ePE), a life-threatening hypertensive disorder of pregnancy. KP is higher in term ePE placentae than in normal pregnancies. However, the role of KP in PE has not been confirmed. The Blood Pressure High Subline 5 (BPH/5) mouse model spontaneously develops the main features of ePE, including impaired placental expansion and maternal hypertension. We have shown that Kiss1 is higher at the BPH/5 maternal-fetal interface on embryonic days (e) 4.5 and 7.5. BPH/5 females have abnormal circulating sex steroid hormones (SSH) during early gestation (e2.5), with lower estradiol-17ß (E2) and higher progesterone (P4). Since E2 and P4 may modulate uterine Kiss1 , we aimed to investigate the effects of artificial synchronization of SSH (AS-SSH) in BPH/5 uteroplacental KP signaling and placental development. We hypothesized that AS-SSH would prevent BPH/5 uteroplacental Kiss1 upregulation and normalize KP downstream expression of tissue inhibitor of metalloproteinase (TIMP) 2 and placental defects. AS-SSH was performed after ovariectomy of pregnant BPH/5 and C57 females (n = 8/strain) at e2.5 with one dose of E2 (25 ng/mouse, subcutaneously), and daily subcutaneous injections of P4 (1ng/mouse) until embryonic implantation sites (eIS) were collected 3 days post-surgery (n = 8/group). Contrary to natural (Nat) BPH/5 pregnancies, eIS Kiss1 and TIMP2 expression was not different between AS-SSH BPH/5 and C57 (p > 0.05). Nat and AS-SSH pregnant mice were anesthetized at e12.5 to assess umbilical cord blood flow via ultrasound and uteroplacental units were harvested for placental morphometry (n = 4-6/group). Placental expansion into the maternal decidua was measured and expressed as the ratio of the placenta depth in relation to the placenta + decidua. Nat BPH/5 had lower placental expansion and umbilical blood flow than Nat C57, whereas AS-SSH BPH/5 had higher placental expansion and umbilical blood flow than Nat BPH/5 (p < 0.05). In conclusion, synchronization of the E2 and P4 profile in the BPH/5 mouse early gestation mitigated Kiss1 and TIMP2 upregulation at the maternal-fetal interface and ameliorated the placental defects previously reported in this model.

Empathy is an innate ability to understand the emotional states of others along with the motivation to improve it. It has evolved over time into highly complex behaviors, the basis of which can be described using the Perception Action Model (PAM), where shared affect promotes an action that eliminates the distress of both the passive “Target” and, by extension, the active “Observer.” There are myriad biological variables that may modulate empathic behavior, including sex, sensory modalities, and neural activity. In the following studies, using our lab’s model of social contact-independent targeted helping, we first tested whether sex differences exist in helping behavior. Next, we explored sex differences in sensory and affective signaling, including the impact of direct visualization of a distressed conspecific and the type of ultrasonic vocalizations (USV) made between animal pairs during the task. Finally, we examined the neural activity of multiple cortical and subcortical regions of interest across time during targeted helping between males and females. We show both sexes exhibit similar helping behavior, but sensory and affective signaling differs between sexes. Further, changes in neural activity exhibited distinct sex-specific patterns across time. Our results indicate sex differences are not a ubiquitous presence in targeted helping. Instead, it is likely sex differences may be a convergent phenomenon in which the behavior is similar, but the underlying biological mechanisms are distinct. These results lay the groundwork for future studies to explore the similarities and differences that drive empathic behavior in both males and females.

IntroductionOxford Nanopore Technologies (ONT) offer sequencing with low-capital-layout sequencing options, which could assist in expanding HIV drug resistance testing to resource limited settings. However, sequence analysis remains time time-consuming and reliant on skilled personnel. Moreover, current ONT bioinformatic pipelines provide a single consensus sequence that is not equivalent to Sanger sequencing, as drug resistance is often detected in mixed populations. We have therefore investigated an integrated bioinformatic pipeline, Nano-RECall, for seamless drug resistance of low read coverage ONT sequence data from affordable Flongle or MinION flow cells.MethodsWe compared Sanger sequencing to ONT sequencing of the same HIV-1 subtype C polymerase chain reaction (PCR) amplicons, respectively using RECall and the novel Nano-RECall bioinformatics pipelines. Amplicons were from separate assays a) Applied Biosystems HIV-1 Genotyping Kit (ThermoFisher) spanning protease (PR) to reverse transcriptase (RT) (PR-RT) (n=46) and b) homebrew integrase (IN) (n=21). We investigated optimal read-depth by assessing the coefficient of variation (CV) of nucleotide proportions for various read-depths; and between replicates of 400 reads. The agreement between Sanger sequences and ONT sequences were assessed at nucleotide level, and at codon level for Stanford HIV drug resistance database mutations.ResultsThe coefficient of variation of ONT minority variants plateaued after a read depth of 400-fold implying limited benefit of additional depth and replicates of 400 reads showed a CV of ∼6 % for a representative position. The average sequence similarity between ONT and Sanger sequences was 99.3% (95% CI: 99.1-99.4%) for PR-RT and 99.6% (95% CI: 99.4-99.7%) for INT. Drug resistance mutations did not differ for 21 IN sequences; 16 mutations were detected by both ONT- and Sanger sequencing. For the 46 PR and RT sequences, 245 mutations were detected by either ONT or Sanger, of these 238 (97.1%) were detected by both.ConclusionsThe Nano-RECall pipeline, freely available as a downloadable application on a Windows computer, provides Sanger-equivalent HIV drug resistance interpretation. This novel pipeline combined with a simple workflow and multiplexing samples on ONT flow-cells would contribute to making HIV drug resistance sequencing feasible for resource limited settings.

Background Mortality after stage 1 palliation of hypoplastic left heart syndrome remains significant. Both cardiac output (CO) and systemic vascular resistance (SVR) contribute to hemodynamic vulnerability. Simultaneous measures of mean arterial pressure and somatic regional near infrared spectroscopy saturation can classify complex hemodynamics into 4 distinct states, with a low-CO state of higher risk. We sought to identify interventions associated with low-CO state occupancy and transition. Methods Perioperative data were prospectively collected in an institutional review board–approved database. Hemodynamic state was classified as high CO, high SVR, low SVR, and low CO using bivariate analysis. Associations of static and dynamic support levels and state classifications over 48 postoperative hours were tested between states and across transitions using mixed regression methods in a quasi-experimental design. Results Data from 10,272 hours in 214 patients were analyzed. A low-CO state was observed in 142 patients for 1107 hours. Both low CO and extracorporeal membrane oxygenation had increased mortality risk. The low-CO state was characterized by lower milrinone but higher catecholamine dose. Successful transition out of low CO was associated with increased milrinone dose and hemoglobin concentration. Increasing milrinone and hemoglobin levels predicted reduced risk of low CO in future states. Conclusions Bivariate classification objectively defines hemodynamic states and transitions with distinct support profiles. Maintaining or increasing inodilator and hemoglobin levels were associated with improved hemodynamic conditions and were predictive of successful future transitions from the low-CO state.

Background: Shone syndrome is characterized by coincident mitral valve stenosis and left ventricular outflow tract obstruction. Although first described in 1963, little research has expounded surgical outcomes. We sought to evaluate our experience with this cohort, emphasizing outcomes including mortality, morbidity, and cardiac function. Methods: A retrospective chart review of 46 patients who underwent operation for Shone syndrome between 1990 and May 2018 was conducted. Index operations included 32 repairs of the left ventricular outflow tract, four mitral valve repair/replacements, nine combined repairs, and one non-Shone’s repair. Median age at index procedure was 22 days (2 days-10 years). Mean follow-up was 9.1 years (2 months-21 years), and 70 additional operations (51 reoperations) were required. Three patients were lost to follow-up. Results: Overall survival was 95.7% with two late deaths. Freedom from death or transplant was 93.5%. Thirteen (28.3%) patients remained free from reoperation. Thirty-three patients required 51 reoperations of the left ventricle outflow tract (n = 12), mitral valve (n = 16), combined repairs (n = 21), and transplant (n = 1). At most recent follow-up, patients exhibited mitral stenosis (n = 21), aortic stenosis (n = 7), and diminished LV function (n = 2). Conclusion: Surgical correction of Shone’s offers excellent survival benefit, but reoperation burden is high, with >70% of patients requiring reintervention in the follow-up period. A total of 65% of patients developed recurrent obstruction of left ventricular inflow or outflow, however, ventricular function is preserved in the majority of patients. All but one patient had no functional deficits, classified as New York Heart Association I with > 60% requiring no medication.

Background and purpose The goal of this prospective study is to validate the use of periodic imaging during treatment with a fiducial marker detection algorithm using radiofrequency transponders for prostate cancer patients undergoing treatment for radiation therapy. Materials and methods Ten male patients were enrolled in this study and treated for prostate cancer with implanted electromagnetic monitoring beacons. We evaluated the accuracy and limitations of Intrafraction Motion Review (IMR) by comparing the known locations of the beacons using the electromagnetic monitoring system to the position data reported from IMR images. Results A total of 4054 images were taken during treatment. The difference in vector magnitude of the two methods is centered around zero (mean: 0.03 cm, SD: 0.16 cm) and Lin’s Concordance Correlation Coefficient (CCC) is 0.99 (95% CI: 0.98, 1) overall. The Euclidean distance between the two methods was close to zero (median: 0.09 cm, IQR: 0.06, 0.14 cm). The difference in distance between any two markers was centered around zero (mean: 0.01 cm, SD: 0.12 cm) and Lin’s CCC is 0.97 (95% CI: 0.96, 0.98) overall. Conclusion The accuracy of the algorithm for detected markers within the 2D images is comparable to electromagnetic monitoring for fiducial identification when detected. IMR could provide an alternate solution for patients with contraindications of use of an electromagnetic monitoring system and a cost effective alternative to the acquisition of an additional system for patient monitoring, but does not provide data for pre-treatment set-up verification and real-time 3D positioning during treatment.

Purpose: Anaplastic Lymphoma Kinase (ALK) aberrations have been identified in pediatric type infant gliomas, but their occurrence across age groups, functional effects, and treatment response have not been broadly established. Experimental Design: We performed a comprehensive analysis of ALK expression and genomic aberrations in both newly-generated and retrospective data from 371 glioblastomas (156 adult, 205 infant/pediatric and 10 congenital) with in vitro and in vivo validation of aberrations. Results: ALK aberrations at the protein or genomic level were detected in 12% of gliomas (45/371) in a wide age range (0-80 years). Recurrent as well as novel ALK fusions (LRRFIP1-ALK, DCTN1-ALK, PRKD3-ALK) were present in 50% (5/10) of congenital/infant, 1.4% (3/205) of pediatric, and 1.9% (3/156) of adult GBMs. ALK fusions were present as the only candidate driver in congenital/infant GBMs, and were sometimes focally amplified. In contrast, adult ALK fusions co-occurred with other oncogenic drivers. No activating ALK mutations were identified in any age group. Novel and recurrent ALK rearrangements promoted STAT3 and ERK1/2 pathways and transformation in vitro and in vivo. ALK-fused GBM cellular and mouse models were responsive to ALK inhibitors, including in patient cells derived from a congenital GBM. Relevant to treatment of infant gliomas, we showed that ALK protein appears minimally expressed in the forebrain at perinatal stages and no gross effects on perinatal brain development was seen in pregnant mice treated with the ALK inhibitor ceritinib. Conclusions: These findings support expanded evaluation of brain-penetrant ALK inhibitors in clinical trials across infant, pediatric, and adult GBMs. Citation Format: Anne-Florence Blandin, Ross Giglio, Maya Srikanth Graham, Guadalupe Garcia, Seth Malinowski, Jared K. Woods, Shakti Ramkissoon, Lori Ramkissoon, Frank Dubois, Kate Schoolcraft, Jessica W. Tsai, Dayle K. Wang, Robert Jones, Jayne Vogelzang, Kristine Pelton, Sarah Becker, Fiona Watkinson, Claire Sinai, Elizabeth Cohen, Matthew Booker, Michael Tolstorukov, Veerle Haemels, Liliana Goumnerova, Karen Wright, Mark Kieran, Katie Fehnel, David Reardon, Arnault Tauziede-Espariat, Rishi Lulla, Benjamin Carcamo, Stanley Chaleff, Alain Charest, Frederik De Smet, Azra H. Ligon, Adrian Dubuc, Melanie Pagès, Pascale Varlet, Patrick Wen, Brian Alexander, Susan Chi, Sanda Alexandrescu, Ralf Kittler, Robert Bachoo, Rameen Beroukhim, Pratiti Bandopadhayay, Keith L. Ligon. ALK amplification and rearrangements are recurrent targetable events in congenital and adult glioblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1201.

Childhood and adolescent obesity is a serious health problem that is on the rise at the global level. Earlier, certain diseases such as Type 2 diabetes, high blood pressure, and heart disease affected only adults, but now they are being detected in young children as well. Several studies based on machine learning have been proposed to develop obesity prediction models or to determine key determinants of obesity for designing intervention tools. Despite having a rich and diverse set of literature on obesity prediction models, obesity rates are at an all-time high for both children and adolescents. There is a need of proper understanding and critical analysis of existing machine learning models in order to design effective strategies for curbing obesity at childhood and adolescent level. This paper surveys the growing body of recent literature on machine and deep learning models for obesity prediction by providing a coherent view (critical analysis) of the limitations of the existing systems. The taxonomy of the existing literature on obesity prediction into methods used, predicted outcome, factors used, type of datasets, and the associated purpose, is discussed for analysis of the state-of-the-art. This analysis revealed that a) prediction-focused models do not use variables from as many domains as predictor-focused models do, b) very few studies proposed gender-specific and race-specific obesity prediction models, c) lack of large-scale multimodal datasets and d) existing predictor-focused models obtain an accuracy range of [53.7%, 96%] with an optimum set of predictors. Further, computer vision-based methods for obesity prediction and interpretable techniques for understanding the outcome of the models are discussed as well. In addition, we have also identified novel research directions. The overall aim is to advance the state-of-the-art and improve the quality of discourse in this field.

Prevention of infection and propagation of SARS-CoV-2 is of high priority in the COVID-19 pandemic. Here, we describe S-nitrosylation of multiple proteins involved in SARS-CoV-2 infection, including angiotensin converting enzyme 2 (ACE2), the receptor for viral entry. This reaction prevents binding of ACE2 to the SARS-CoV-2 Spike protein, thereby inhibiting viral entry, infectivity, and cytotoxicity. Aminoadamantane compounds also inhibit coronavirus ion channels formed by envelope (E) protein. Accordingly, we developed dual-mechanism aminoadamantane nitrate compounds that inhibit viral entry and thus spread of infection by S-nitrosylating ACE2 via targeted delivery of the drug after E-protein channel blockade. These non-toxic compounds are active in vitro and in vivo in the Syrian hamster COVID-19 model, and thus provide a novel avenue for therapy.

Interest in integrating magnetic resonance imaging (MRI) in radiation therapy (RT) practice has increased dramatically in recent years owing to its unique advantages such as excellent soft tissue contrast and capability of measuring biological properties. Continuous real-time imaging for intrafractional motion tracking without ionizing radiation serves as a particularly attractive feature for applications in RT. Despite its many advantages, the integration of MRI in RT workflows is not straightforward, with many unmet needs. MR safety remains one of the key challenges and concerns in the clinical implementation of MR simulators and MR-guided radiation therapy systems in radiation oncology. Most RT staff are not accustomed to working in an environment with a strong magnetic field. There are specific requirements in RT that are different from diagnostic applications. A large variety of implants and devices used in routine RT practice do not have clear MR safety labels. RT-specific imaging pulse sequences focusing on fast acquisition, high spatial integrity, and continuous, real-time acquisition require additional MR safety testing and evaluation. This article provides an overview of MR safety tailored toward RT staff, followed by discussions on specific requirements and challenges associated with MR safety in the RT environment. Strategies and techniques for developing an MR safety program specific to RT are presented and discussed.

The purpose of the current study was to investigate the unique effects of a commonly used skill incorporated into treatment packages for borderline personality disorder (BPD), countering emotion-driven behavioral urges. Individuals with BPD (N = 8) participated in a single-case experimental design, specifically a multiple baseline, in which they were randomly assigned to complete a baseline assessment-only phase of 2 or 4 weeks. Participants then received four sessions of the countering emotional behaviors module from the unified protocol, followed by a 4-week follow-up phase. Throughout the duration of the study, daily data capture was used to assess real-time changes in the frequency of emotionally avoidant behaviors in response to emotional experiences. Symptoms of BPD, depression, and anxiety were also assessed. By follow-up, the majority of patients demonstrated a meaningful reduction (per single-case experimental design guidelines for evaluating improvements) in their use of avoidant behaviors. There was also preliminary evidence that encouraging participants to act counter to avoidant urges is associated with decreases in BPD, depression, and anxiety symptoms, as well as negative affectivity. The countering emotional behaviors skill from the unified protocol indeed engages its putative target of emotionally avoidant behavioral coping, indicating it is an active ingredient in multicomponent treatment packages for BPD, with implications for downstream clinical endpoints such as BPD and depressive and anxiety symptoms. (PsycInfo Database Record (c) 2020 APA, all rights reserved).

Oxyntomodulin (OXM) is an intestinal peptide hormone that activates both glucagon-like peptide-1 (GLP-1) and glucagon (GCG) receptors. The natural peptide reduces body weight in obese subjects and exhibits direct acute glucoregulatory effects in patients with type II diabetes. However, the clinical utility of OXM is limited due to its lower in vitro potency and short in vivo half-life. To overcome these issues, we developed stapled, long-acting, and highly potent OXM analogs with balanced activities at both GLP-1 and GCG receptors. The lead molecule O14 exhibits potent and long-lasting effects on glucose control, body weight loss, and reduction of hepatic fat reduction in DIO mice. Importantly, O14 significantly reversed hepatic steatosis; reduced liver weight, total cholesterol, and hepatic triglycerides; and improved markers of liver function in a nonalcoholic steatohepatitis (NASH) mouse model. A symmetrical version of the peptide was also shown to be more efficacious and long-lasting in controlling glucose than semaglutide and the clinical candidate cotadutide in wild-type mice, highlighting the utility of our designs of the dual agonist as a potential new therapy for diabetes and liver diseases.

Background Mortality after stage 1 palliation of hypoplastic left heart syndrome remains significant. Hemodynamic changes result from interaction of cardiac output (CO) and systemic vascular resistance (SVR). We sought to identify time-dependent changes in postoperative hemodynamic states and their associations with mortality. Methods Perioperative data were prospectively collected in an institutional review board–approved database. Hemodynamic state was classified as high CO, high SVR, low SVR, and low CO using bivariate analysis of mean arterial pressure and somatic regional near-infrared spectroscopic oximetry saturation. State classifications over 48 postoperative hours were modelled using multinomial logistic regressions for association with mortality. Results Data from 9614 of 10,272 hours in 214 patients were analyzed. Operative survival was 91%. The predominant state was high CO (46% time). Low CO state without extracorporeal membrane oxygenation (ECMO) was found in 52% of patients for 9.7% time. ECMO was employed in 24 (11.2%) patients for 10.4% time. State stability was 33%, with high SVR the least stable (17%) and high CO the most stable (53%). Transition from high CO increased in hours 1 to 12, mainly to low SVR. Transition to low CO was 18.4%, increasing in hours 1 to 12, mainly from high SVR. The transition risk to ECMO was 0.32%, and 0.74% during hours 1 to 12, only from low CO. Both low CO and ECMO had increased mortality risk. Conclusions Bivariate classification defines hemodynamic states with distinct physiologic, transition, and mortality risk profiles. High SVR state was unstable. Transition to ECMO occurred only from low CO, while the low SVR and high CO states were safest.

BACKGROUND: Difficulty weaning from cardiopulmonary bypass (CPB) or the need to return to CPB (collectively D-CPB) may occur after the Norwood procedure. We sought to evaluate the relationship between D-CBP and survival. METHODS: This was a retrospective chart review of all patients undergoing a Norwood procedure at our institution during the interval 2005-2017. Primary outcome was survival for the Norwood procedure. Secondary outcomes included various measures of morbidity. Successful wean from CBP (S-CPB) was defined as no need to return to full flow CPB during the initial definitive wean or after separation from CPB; otherwise the classification was difficulty with wean (D-CBP). Successful rescue in the D-CPB group was defined as not requiring extracorporeal life support (ECLS) either in the operating room or within the first three postoperative days. RESULTS: Of the 196 patients in the cohort, 49 were D-CPB. Survival for S-CPB was 92.5% (136/147) vs 71.4%% (35/49) for D-CPB (p = 0.001). Major morbidity occurred in 29.9% (44/147) in S-CPB vs 69.4 % (34/49) in D-CPB (p < 0.001). With multivariable analysis, D-CPB was significantly associated with mortality (OR=8.09; CI 2.72 – 24.05; p

The surgical treatment of mitral disease in pediatrics is challenging. Managing diversity in patient anatomy, growth, and the need for long-term anticoagulation requires trade-offs between imperfect solutions. We sought to assess our approach to pediatric mitral valve surgery and identify predictors associated with mortality and recurrent mitral disease. The medical records, echocardiograms, and operative reports of all patients who underwent surgical intervention on the mitral valve from January 2000 to April 2016 were reviewed. A total of 143 patients underwent mitral valve surgery, 64 of which were neonates or infants (ages 10-355 days) and 79 of which were children (ages 1-17.8 years). Neonates and infants had a higher preoperative New York Heart Association heart failure classification in comparison to children (P0.001) with a less severe degree of mitral valve insufficiency (P = 0.007). Postoperative outcomes for primary repair patients (n = 133) demonstrated significant differences in recurrence of mitral valve disease, with 38% of neonates/infants and 21% of children affected (P = 0.028). Five-year rates of mortality or transplant were 22% (8%, 33%) in neonates and infants compared to 4% (0%, 10%) in children, P = 0.013. Mitral valve surgery in neonates and infants is particularly high risk and is associated with higher rate of recurrence and reintervention early. However, if successful early, mitral valve repair in neonates and infants can result in a durable freedom from reintervention that parallels freedom from reintervention in older children undergoing repair. Further understanding of mechanisms of failure and better matching of anatomic substrate to strategy is needed.

Central nervous system (CNS) germ cell tumors (GCTs) represent 2-3% of all primary CNS tumors. The majority are germinomas, which are radiosensitive and have an excellent prognosis. Contrarily, CNS non-germinomatous GCTs (NGGCTs) have less favorable prognosis and require more aggressive treatment. The expression of checkpoint/immune markers in CNS GCTs, particularly NGGCTs, is unknown. We previously reported a case of a patient whose intracranial NGGCT (predominantly choriocarcinoma) responded to immune checkpoint inhibition therapy. This case led us to evaluate our archive of intracranial GCTs for expression of PD-L1 and PD-1. With IRB approval, we searched the pathology archives at our institution for CNS GCTs. Demographic, radiologic, clinical, and histologic information was extracted from the medical records. Immunohistochemistry for lymphocytic markers (CD4, CD8, CD20), PD-1, and PD-L1 was performed. PD-L1 was considered positive if greater than 1% of tumor cells were positive and PD-1 was reported as a percentage of positive inflammatory cells. Fifty cases were identified, including 28 germinomas (mean age at diagnosis: 15.5 years; 17 males, 11 females), and 22 NGGCTs (mean age at diagnosis: 12.0 years, 21 males, 1 female). Germinomas were mostly suprasellar (17/28) and NGGCTs were predominantly pineal (17/22). Twenty-two germinomas (79%) were positive for PD-L1 expression, and 13 NGGCTs (57%) were positive for PD-L1. Cases of choriocarcinoma showed the most diffuse PD-L1 expression. PD-1 expression was seen in lymphocytes among 27/28 of the germinomas and 20/23 of the NGGCTs (ranging from 1-40% of lymphocytes). As expected, larger quantities of inflammatory cells were present in cases of germinoma. We demonstrate immune activity in CNS GCTs, and our results suggest that immune checkpoint inhibitors may be efficacious in the treatment of intracranial GCTs. Among NGGCTs, cases of choriocarcinoma showed the highest expression of PD-L1 in tumor cells, suggesting that this subtype may have the greatest benefit from checkpoint blockade.

Infection with Cryptosporidium spp. can cause severe diarrhea, leading to long-term adverse impacts and even death in malnourished children and immunocompromised patients. The only FDA-approved drug for treating cryptosporidiosis, nitazoxanide, has limited efficacy in the populations impacted the most by the diarrheal disease, and safe, effective treatment options are urgently needed. Initially identified by a large-scale phenotypic screening campaign, the antimycobacterial therapeutic clofazimine demonstrated great promise in both in vitro and in vivo preclinical models of Cryptosporidium infection. Unfortunately, a phase 2a clinical trial in HIV-infected adults with cryptosporidiosis did not identify any clofazimine treatment effect on Cryptosporidium infection burden or clinical outcomes. To explore whether clofazimine’s lack of efficacy in the phase 2a trial may have been due to subtherapeutic clofazimine concentrations, a pharmacokinetic/pharmacodynamic modeling approach was undertaken to determine the relationship between clofazimine in vivo concentrations and treatment effects in multiple preclinical infection models. Exposure-response relationships were characterized using Emax and logistic models, which allowed predictions of efficacious clofazimine concentrations for the control and reduction of disease burden. After establishing exposure-response relationships for clofazimine treatment of Cryptosporidium infection in our preclinical model studies, it was unmistakable that the clofazimine levels observed in the phase 2a study participants were well below concentrations associated with anti-Cryptosporidium efficacy. Thus, despite a dosing regimen above the highest doses recommended for mycobacterial therapy, it is very likely the lack of treatment effect in the phase 2a trial was at least partially due to clofazimine concentrations below those required for efficacy against cryptosporidiosis. It is unlikely that clofazimine will provide a remedy for the large number of cryptosporidiosis patients currently without a viable treatment option unless alternative, safe clofazimine formulations with improved oral absorption are developed. (This study has been registered in ClinicalTrials.gov under identifier NCT03341767.)

Introduction: Coarctation of the aorta (CoA) severity is assessed via trans-CoA blood pressure gradient (BPG) estimated using simplified Bernoulli equation (SBE) with indices from noninvasive Doppler echocardiography (echo). However, simplifications of the SBE and inconsistent readings through a suboptimal insonation window limit diagnostic accuracy (DA). In a rabbit model mimicking human CoA (Fig. 1A), catheter vs. Doppler comparison of BPG revealed diastolic continuous-flow pressure gradient (CFPG) was independently associated with severity. We therefore hypothesized the unique properties of CFPG would improve DA in humans. Methods: SBE and CFPG were quantified using color flow Doppler in humans and rabbits with discrete non-recurrent CoA before repair (Fig. 1B). Quantifications used peak velocity proximal to (V p ) and at the CoA (V pk ), early diastolic velocity (V d ), doppler velocity index (DVI), and normalized diastolic pressure half-time (dPHT; see Fig. 1B and C for definitions). Results were compared with measured BPG in rabbits (peak-to-peak catheter BPG) and humans (upper-lower extremity BPG). There was a total of 18 human and 26 rabbit cases; significance was defined a priori as a BPG of ≥20 mmHg. A CFPG ≥4 mmHg threshold was identified by maximizing sensitivity plus specificity in receiver operative curves (ROC). Results: Accuracy measures (Fig. 1D) revealed the superior performance of CFPG vs. SBE. Although reports suggest Fig. 1- (A) MRI confirming morphological similarities between rabbit and human CoA, (B) Spectral Doppler images show diastolic continuous flow, (C) indices derived from the generalized Bernoulli equation assuming exponential diastolic pressure loss, (D) diagnostic performance for CFPG vs. conventional SBE.

The supported Ross is used to mitigate the neoaortic root dilation that has been described with the unsupported Ross. There is limited literature assessing the efficacy of the supported Ross in young patients. In this study, the fate of the neoaortic root was compared in the supported and unsupported Ross procedure in adolescent patients.A retrospective review was performed of patients who underwent the Ross procedure between 1996 and 2019. An analysis was conducted of patients aged 10 to 18 years who underwent the supported and unsupported Ross operation, without a Konno enlargement, to assess for longitudinal echocardiographic changes. Given differences in follow-up time, both regression analysis and Mann-Whitney nonparametric tests were used to correct for time from discharge to most recent follow-up.The median follow-up time for supported and unsupported Ross patients without a Konno enlargement was 2.90 years (0.21-13.03 years) and 12.13 years (2.63-19.47 years), respectively. Unsupported Ross patients experienced a higher rate of change per year in the aortic annulus (P = .003 and P = .014) and aortic sinus (P = .002 and P = .002) diameters, respectively. There was no significant difference in the rate of change of end-diastolic left ventricular internal diameter (P = .703 and P = .92) and aortic insufficiency (P = .687 and P = .215) between the supported and unsupported Ross patients.Progressive dilation of the neoaortic root in unsupported Ross patients is significantly mitigated with the supported Ross with excellent stability. The supported Ross is safe and effective and may play an increasing role in the management of children with aortic disease.

The unintended neurologic sequelae of chemotherapy contribute to significant patient morbidity. Chemotherapy-related cognitive impairment (CRCI) is observed in up to 80% of cancer patients treated with chemotherapy and involves multiple cognitive domains including executive functioning. The pathophysiology underlying CRCI and the neurotoxicity of chemotherapy is incompletely understood, but oxidative stress and DNA damage are highly plausible mechanisms based on preclinical data. Unfortunately, validating pathways relevant to CRCI in humans is limited by an absence of relevant neuropathologic studies of patient brain tissue. In the present study, we stained sections of frontal lobe autopsy tissue from cancer patients treated with chemotherapy (n = 15), cancer patients not treated with chemotherapy (n = 10), and patients without history of cancer (n = 10) for markers of oxidative stress (nitrotyrosine, 4-hydroxynonenal) and DNA damage (pH2AX, pATM). Cancer patients treated with chemotherapy had increased staining for markers of oxidative stress and DNA damage in frontal lobe cortical neurons compared to controls. We detected no statistically significant difference in oxidative stress and DNA damage by the duration between last administration of chemotherapy and death. The study highlights the potential relevance of oxidative stress and DNA damage in the pathophysiology of CRCI and the neurotoxicity of chemotherapy.

There is a growing appreciation for the idea that bacterial utilization of host-derived lipids, including cholesterol, supports Mycobacterium tuberculosis (Mtb) pathogenesis. This has generated interest in identifying novel antibiotics that can disrupt cholesterol utilization by Mtb in vivo. Here we identify a novel small molecule agonist (V-59) of the Mtb adenylyl cyclase Rv1625c, which stimulates 3’, 5’-cyclic adenosine monophosphate (cAMP) synthesis and inhibits cholesterol utilization by Mtb. Similarly, using a complementary genetic approach that induces bacterial cAMP synthesis independent of Rv1625c, we demonstrate that inducing cAMP synthesis is sufficient to inhibit cholesterol utilization in Mtb. Although the physiological roles of individual adenylyl cyclase enzymes in Mtb are largely unknown, here we demonstrate that the transmembrane region of Rv1625c is required for cholesterol metabolism. Finally, in this work the pharmacokinetic properties of Rv1625c agonists are optimized, producing an orally-available Rv1625c agonist that impairs Mtb pathogenesis in infected mice. Collectively, this work demonstrates a novel role for Rv1625c and cAMP signaling in controlling cholesterol metabolism in Mtb and establishes that cAMP signaling can be pharmacologically manipulated for the development of new antibiotic strategies.Author SummaryThe recalcitrance of Mycobacterium tuberculosis (Mtb) to conventional antibiotics has created a need to identify novel pharmacological mechanisms to inhibit Mtb pathogenesis. There is a growing understanding of the metabolic adaptations Mtb adopts during infection to support its survival and pathogenesis. This has generated interest in identifying small molecule compounds that effectively inhibit these in vivo metabolic adaptations, while overcoming challenges like poor pharmacokinetic properties or redundancy in target pathways. The Mtb cholesterol utilization pathway has repeatedly been speculated to be a desirable antibiotic target, but compounds that successfully inhibit this complex pathway and are suitable for use in vivo are lacking. Here, we establish that stimulating cAMP synthesis in Mtb is a mechanism that is sufficient to block cholesterol utilization by the bacterium, preventing the release of key metabolic intermediates that are derived from breakdown of the cholesterol molecule. For the first time, we identify small molecule agonists of the Mtb adenylyl cyclase Rv1625c that have promising pharmacological properties and are suitable for use during in vivo studies. These Rv1625c agonists increase cAMP synthesis, inhibit cholesterol utilization by Mtb, and disrupt Mtb pathogenesis in mouse models of chronic infection.

Despite the effectiveness of direct-acting antiviral agents in treating hepatitis C virus (HCV), cases of treatment failure have been associated with the emergence of resistance-associated substitutions. To better guide clinical decision-making, we developed and validated a near-whole-genome HCV genotype-independent next-generation sequencing strategy. HCV genotype 1–6 samples from direct-acting antiviral agent treatment-naïve and -treated HCV-infected individuals were included. Viral RNA was extracted using a NucliSens easyMAG and amplified using nested reverse transcription-polymerase chain reaction. Libraries were prepared using Nextera XT and sequenced on the Illumina MiSeq sequencing platform. Data were processed by an in-house pipeline (MiCall). Nucleotide consensus sequences were aligned to reference strain sequences for resistance-associated substitution identification and compared to NS3, NS5a, and NS5b sequence data obtained from a validated in-house assay optimized for HCV genotype 1. Sequencing success rates (defined as achieving &gt, 100-fold read coverage) approaching 90% were observed for most genotypes in samples with a viral load &gt, 5 log10 IU/mL. This genotype-independent sequencing method resulted in &gt, 99.8% nucleotide concordance with the genotype 1-optimized method, and 100% agreement in genotype assignment with paired line probe assay-based genotypes. The assay demonstrated high intra-run repeatability and inter-run reproducibility at detecting substitutions above 2% prevalence. This study highlights the performance of a freely available laboratory and bioinformatic approach for reliable HCV genotyping and resistance-associated substitution detection regardless of genotype.

The quinazolines CBR417 and CBR490 were previously shown to be potent anti-wolbachials that deplete Wolbachia endosymbionts of filarial nematodes and present promising pre-clinical candidates for human filarial diseases such as onchocerciasis. In the present study we tested both candidates in two models of chronic filarial infection, namely the Litomosoides sigmodontis and Brugia pahangi jird model and assessed their long-term effect on Wolbachia depletion, microfilariae counts and filarial embryogenesis 16−18 weeks after treatment initiation (wpt). Once per day (QD) oral treatment with CBR417 (50 mg/kg) for 4 days or twice per day (BID) with CBR490 (25 mg/kg) for 7 days during patent L. sigmodontis infection reduced the Wolbachia load by >99% and completely cleared peripheral microfilaremia from 10–14 wpt. Similarly, 7 days of QD treatments (40 mg/kg) with CBR417 or CBR490 cleared >99% of Wolbachia from B. pahangi and reduced peritoneal microfilariae counts by 93% in the case of CBR417 treatment. Transmission electron microscopy analysis indicated intensive damage to the B. pahangi ovaries following CBR417 treatment and in accordance filarial embryogenesis was inhibited in both models after CBR417 or CBR490 treatment. Suboptimal treatment regimens of CBR417 or CBR490 did not lead to a maintained reduction of the microfilariae and Wolbachia load. In conclusion, CBR417 or CBR490 are pre-clinical candidates for filarial diseases, which achieve long-term clearance of Wolbachia endosymbionts of filarial nematodes, inhibit filarial embryogenesis and clear microfilaremia with treatments as short as 7 days., Graphical abstract Image 1, Highlights • CBR417 and CBR490 provide long-term effects in 2 chronic filaria jird models. • CBR417 and CBR490 deplete >99% Wolbachia in B. pahangi and L. sigmodontis filariae. • CBR417 and CBR490 clear L. sigmodontis microfilariae after 10–14 weeks. • CBR417 and CBR490 inhibit filarial embryogenesis in both models. • Suboptimal doses do not maintain reduction of microfilariae and Wolbachia.

Background Arginine vasopressin is a nonapeptide hormone with effects on intracellular water transport and arterial tone that is used in distributive shock and following cardiopulmonary bypass. We sought to evaluate the safety and efficacy of vasopressin infusion on hemodynamics and fluid balance in the early postoperative period after Fontan completion. Methods We conducted a randomized, double-blinded, placebo-controlled study of vasopressin infusion for 24 hours after cardiopulmonary bypass for Fontan completion. Patient characteristics, hospital outcomes, and measures of hemodynamic parameters, urine output, chest tube drainage, fluid balance, laboratory data, and plasma arginine vasopressin concentrations were collected at baseline and for 48 postoperative hours. Data were analyzed using mixed-effect regressions. Results Twenty patients were randomized, 10 to vasopressin and 10 to placebo. Transpulmonary gradient (6.4 ± 0.5 vs 8.3 ± 0.5 mm Hg, P = .011) and chest tube drainage (23 ± 20 vs 40 ± 20 mL/kg, P = .028) for 48 hours after surgery were significantly lower in the vasopressin arm compared to placebo. Arginine vasopressin concentrations were elevated above baseline after surgery until 4 hours post cardiac intensive care unit admission in both arms, and higher in the vasopressin arm during postoperative infusion. No differences in sodium concentration, liver function, or renal function were noted between groups. Conclusions Vasopressin infusion after Fontan completion appears safe and was associated with reduced transpulmonary gradient and chest tube drainage in the early postoperative period. A larger multiinstitutional study may show further outcome benefit.

This study reports on airborne measurements of stratocumulus cloud properties under varying degrees of influence from biomass burning (BB) plumes off the California coast. Data are reported from five total airborne campaigns based in Marina, California, with two of them including influence from wildfires in different areas along the coast of the western United States. The results indicate that subcloud cloud condensation nuclei number concentration and mass concentrations of important aerosol species (organics, sulfate, nitrate) were better correlated with cloud droplet number concentration (N(d)) as compared to respective above-cloud aerosol data. Given that the majority of BB particles resided above cloud tops, this is an important consideration for future work in the region as the data indicate that the subcloud BB particles likely were entrained from the free troposphere. Lower cloud condensation nuclei activation fractions were observed for BB-impacted clouds as compared to non-BB clouds due, at least partly, to less hygroscopic aerosols. Relationships between N(d) and either droplet effective radius or drizzle rate are preserved regardless of BB influence, indicative of how parameterizations can exhibit consistent skill for varying degrees of BB influence as long as N(d) is known. Lastly, the composition of both droplet residual particles and cloud water changed significantly when clouds were impacted by BB plumes, with differences observed for different fire sources stemming largely from effects of plume aging time and dust influence.

Thrombocytopenia and platelet dysfunction induced by extracorporeal blood circulation are thought to contribute to postsurgical bleeding complications in neonates undergoing cardiac surgery with cardiopulmonary bypass (CPB). In this study, we examined how changes in platelet function relate to changes in platelet count and to excessive bleeding in neonatal CPB surgery. Platelet counts and platelet P-selectin exposure in response to agonist stimulation were measured at four times before, during, and after CPB surgery in neonates with normal versus excessive levels of postsurgical bleeding. Relative to baseline, platelet counts were reduced in patients while on CPB, as was platelet activation by the thromboxane A2 analog U46619, thrombin receptor activating peptide (TRAP), and collagen-related peptide (CRP). Platelet activation by adenosine diphosphate (ADP) was instead reduced after platelet transfusion. We provide evidence that thrombocytopenia is a likely contributor to CPB-associated defects in platelet responsiveness to U46619 and TRAP, CPB-induced collagen receptor downregulation likely contributes to defective platelet responsiveness to CRP, and platelet transfusion may contribute to defective platelet responses to ADP. Platelet transfusion restored to baseline levels platelet counts and responsiveness to all agonists except ADP but did not prevent excessive bleeding in all patients. We conclude that platelet count and function defects are characteristic of neonatal CPB surgery and that platelet transfusion corrects these defects. However, since CPB-associated coagulopathy is multifactorial, platelet transfusion alone is insufficient to treat bleeding events in all patients. Therefore, platelet transfusion must be combined with treatment of other factors that contribute to the coagulopathy to prevent excessive bleeding.

PURPOSE The thermoluminescence dosimeter (TLD) has desirable features including low cost, reusability, small size, and relatively low energy dependence. However, the commonly available poly-crystal TLDs (e.g., TLD-100) exhibit high interdetector variability that requires individual calibration for high detection accuracy. To improve individual TLD tracking robustness, we developed an optical fingerprinting method to identify the TLD-100 chips. METHODS Seven hundred and fifty-two images were initially captured using a digital microscope camera to build a feature library for both facets of 376 TLD-100 chips. A median intensity thresholding method was used to segment images into foreground and background. The affine transformation was used to register the segmented images to the same position. The fingerprint of each image was calculated from its registered image. All fingerprints were then recorded in an Elasticsearch® search database. The TLD fingerprint match was tested three times when the library was established and repeated once 20 months later. All chips were irradiated at 0, 1, 4, and 8 Gy on a calibrated clinical MV linac to establish the individual calibration curve. RESULTS The true positive rate of identifying TLDs based on their optical fingerprints was 100% at initialization of the inventory. After 20 months and multiple deployments for characterization, calibration, and dose measurement, the true positive match rate dropped to 99% with zero false-positive matches. The TLDs exhibited high self-consistency in the dose-response test with R2 between 0.988 and 1 with linear regression. CONCLUSIONS The TLD-100 chips surface textures are unique and sufficient to support accurate identification based on the optical fingerprinting. This method provides inexpensive and robust management of the TLDs for individual calibration and dosimetry.

Highlights •Many patients with adult CHD will experience a progressive decline in cardiopulmonary function leading to advanced HF. •These high-risk patients present unique anatomic and physiological challenges that may not be amenable to repair. •For highly selected patients, mechanical circulatory support and heart transplantation offer excellent short- and long-term outcomes. •Prospective registries are needed to determine optimal timing of referral, risk factors for adverse outcomes, and strategies for preservation of end-organ function.

Identifying the neural correlates of positive interactions between friendship dyads may provide insights into mechanisms associated with adolescent social development. Forty-eight 14- to 18-year old typically developing adolescents were video-recorded discussing a shared positive event with a close friend and subsequently viewed clips during an fMRI scan of that friend during the interaction and of an unfamiliar peer in a similar interaction. Adolescents also reported on their positive affect in daily life while with friends using ecological momentary assessment. We used multivariate repeated measures models to evaluate how positive affect with friends in the laboratory and in daily life was associated with neural response to friend and stranger positive and neutral clips. Adolescents who exhibited more positive affect when with friends in the laboratory showed less dorsolateral prefrontal cortex to friend positive clips. More positive affect when with friends in daily life was associated with less bilateral anterior insula response to friend positive clips, but greater left anterior insula response to stranger positive clips. Findings provide information on the role of lateral prefrontal cortex and anterior insula in enjoyment of friendships during adolescence.

Objective Children of depressed parents are at increased risk for psychopathology. One putative mechanism of risk appears to be altered processing of emotion-related stimuli. Although prior work has evaluated how adolescent offspring of depressed parents may show blunted reward processing compared to low-risk youth, there has been less attention to how young children with this familial history may differ from their peers during middle childhood, a period of critical socio-affective development Method The current study evaluated 56 emotionally healthy 6-to 8-year children who were deemed at high-risk (n = 25) or low-risk (n = 31) for depression based on maternal history of depression. Children completed a behavioral reward seeking task in the laboratory and an fMRI paradigm assessing neural response to happy faces, a social reward. Results Findings demonstrated that high-risk children showed blunted responding to happy faces in the dorsal striatum compared to low-risk children. Further, lower responding in the dorsal striatum and dorsolateral prefrontal cortex was related to lower behavioral reward seeking, but only in high-risk children. Conclusion Function within neural reward regions may be altered in high-risk offspring as young as 6- to 8-years of age. Further, neural reward responding may be linked to lower behavioral response to obtain reward in these high-risk offspring.

Purpose Gliosarcoma is a histologic variant of glioblastoma (GBM), and like GBM carries a poor prognosis. Median survival is less than one (1) year with less than 5% of patients alive after 5 years. Although there is no cure, standard treatment includes surgery, radiation and chemotherapy. While very similar to GBM, gliosarcoma exhibits several distinct differences, morphologically and molecularly. Therefore, we report a comprehensive analysis of DNA copy number changes in gliosarcoma using a cytogenomic DNA copy number (CN) microarray (OncoScan®). Methods Cytogenomic DNA copy number microarray (OncoScan®) was performed on 18 cases of gliosarcoma. MetaCore™ enrichment was applied to the array results to detect associated molecular pathways. Results The most frequent alteration was copy number loss, comprising 57% of total copy number changes. The number of losses far exceeded the number of amplifications (***

Fontan fenestration reduces chest tube duration and shortens post-operative length of stay but is not universally performed. Using a large national database, we sought to describe current use of the Fontan fenestration, including factors associated with placement. The Virtual Pediatric System database was queried to identify patients with the Society of Thoracic Surgery code for a Fontan procedure during their admission from January 2009 until June 2016. Those undergoing a fenestrated Fontan were compared to those undergoing a non-fenestrated Fontan. Of the 1695 patients, 1084 (64%) had a fenestration placed. There was variation between centers with the range of fenestration placement being 8 to 100%. Those with a fenestration placed had lower weight, despite similar age, and were more likely to have a single right ventricle. Those with a fenestration had lower systolic blood pressure and greater need for mechanical ventilation within the first hour of admission to the intensive care unit after Fontan. Most patients still have a fenestration placed at the time of Fontan but this varies markedly by center. Fenestration placement is more common in higher risk patients including those with a systemic right ventricle. Further study is necessary to determine specific patient populations that benefit from fenestration placement at the time of Fontan.

The purpose of this study was to assess the performance characteristics of commercially available US foundry consumables for use in three-dimensional sand printers. The silica sands selected were 57 grain fineness number (GFN) and 70 GFN. These sands were a high-purity round grain silica and had low trace contaminates, to reduce any possible influence from contaminates. The furan resin system was selected since it is the most widely utilized resin system for 3D printed sand in the USA. The furan resin system was from a domestic US foundry supplier. The printed samples were traditional tensile specimen and rectangle samples for the determination of density. The samples were examined for the following properties: tensile strength, loss on ignition, density, scratch hardness, and permeability. The results of this investigation confirmed that the tested domestic resin system and silica sands matched the original equipment manufacturer performance properties.

The long-term outcome of patients with corrected transposition of the great arteries and associated lesions after physiologic repair is uncertain. Anatomic correction, utilizing the morphologic left ventricle as a systemic pumping chamber and the mitral valve as the systemic atrioventricular valve, is considered the preferred method, especially for patients with either tricuspid valve regurgitation, with Ebstein's malformation of the tricuspid valve, or with right ventricular dysfunction. The double switch employs both an atrial switch and arterial switch to "correct" the atrioventricular and ventriculoarterial discordance. Associated lesions are also repaired. The best outcomes with double switch are achieved with patients in the first few years of life even if reconditioning of morphologic left ventricle is required. However, the long-term function of the conduction system, the aortic valve, and the ventricles is variable and requires close surveillance.