3D Echocardiogram Visualization: A New Method Based on "Focus + Context".

3D echocardiography (3DE) is the standard modality for visualizing heart valves and their surrounding anatomical structures. Commercial cardiovascular ultrasound systems commonly offer a set of parameters that allow clinical users to modify, in real time, visual aspects of the information contained in the echocardiogram. To our knowledge, there is currently no work that demonstrates if the methods currently used by commercial platforms are optimal. In addition, current platforms have limitations in adjusting the visibility of anatomical structures, such as reducing information that obstructs anatomical structures without removing essential clinical information. To overcome this, the present work proposes a new method for 3DE visualization based on "focus + context" (F+C), a concept which aims to present a detailed region of interest while preserving a less detailed overview of the surrounding context. The new method is intended to allow clinical users to modify parameter values differently within a certain region of interest, independently from the adjustment of contextual information. To validate this new method, a user study was conducted amongst clinical experts. As part of the user study, clinical experts adjusted parameters for five echocardiograms of patients with complete atrioventricular canal defect (CAVC) using both the method conventionally used by commercial platforms and the proposed method based on F+C. The results showed relevance for the F+C-based method to visualize 3DE of CAVC patients, where users chose significantly different parameter values with the F+C-based method.

Production of Ochratoxin A and Citrinin and the Expression of Their Biosynthetic Genes from Penicillium verrucosum in Liquid Culture.

Penicillium verrucosum is a fungal pathogen capable of producing two mycotoxins of concern, ochratoxin A (OTA) and citrinin (CIT). The production profile of these two mycotoxins is not well understood but could help mitigate co-contamination in the food supply. As such, the production of OTA and CIT from P. verrucosum DAOMC 242724 was investigated under different growing conditions in liquid culture. We found that among the different liquid media chosen, liquid YES (yeast extract sucrose) medium induced the highest production of both OTA and CIT, when P. verrucosum DAOMC 242724 was cultured in stationary mode. Shake culture significantly reduced the amounts of OTA and CIT produced. Among all culture conditions tested, far greater amounts of CIT were produced compared to OTA. Consequently, upon transcriptomic data analysis, a statistically significant increase in the expression of CIT biosynthetic genes was easier to detect than the expression of OTA biosynthetic genes. Our study also revealed that the putative biosynthetic gene clusters of OTA and CIT in P. verrusocum DAOMC 242724 are likely distinct from each other. It appears that despite sharing a highly similar structure, the isocoumarin rings of OTA and CIT are each assembled by a specialized polyketide synthase enzyme. Our data identified a putative nonreducing polyketide synthase responsible for assembling the carbo-skeleton of CIT. In contrast, a highly reducing polyketide synthase appears to be involved in the biosynthesis of OTA.

Genetic Factors and Long-term Treatment-Related Neurocognitive Deficits, Anxiety, and Depression in Childhood Leukemia Survivors: An Exome-Wide Association Study.

BACKGROUND: An increased risk of neurocognitive deficits, anxiety, and depression has been reported in childhood cancer survivors. METHODS: We analyzed associations of neurocognitive deficits, as well as anxiety and depression, with common and rare genetic variants derived from whole-exome sequencing data of acute lymphoblastic leukemia (ALL) survivors from the PETALE cohort. In addition, significant associations were assessed using stratified and multivariable analyses. Next, top-ranking common associations were analyzed in an independent SJLIFE replication cohort of ALL survivors. RESULTS: Significant associations were identified in the entire discovery cohort (N = 229) between the AK8 gene and changes in neurocognitive function, whereas PTPRZ1, MUC16, TNRC6C-AS1 were associated with anxiety. Following stratification according to sex, the ZNF382 gene was linked to a neurocognitive deficit in males, whereas APOL2 and C6orf165 were associated with anxiety and EXO5 with depression. Following stratification according to prognostic risk groups, the modulatory effect of rare variants on depression was additionally found in the CYP2W1 and PCMTD1 genes. In the replication SJLIFE cohort (N = 688), the male-specific association in the ZNF382 gene was not significant; however, a P value<0.05 was observed when the entire SJLIFE cohort was analyzed. ZNF382 was significant in males in the combined cohorts as shown by meta-analyses as well as the depression-associated gene EXO5. CONCLUSIONS: Further research is needed to confirm whether the current findings, along with other known risk factors, may be valuable in identifying patients at increased risk of these long-term complications. IMPACT: Our results suggest that specific genes may be related to increased neuropsychological consequences.

Roles of Skeletal Muscle in Development: A Bioinformatics and Systems Biology Overview.

The ability to assess various cellular events consequent to perturbations, such as genetic mutations, disease states and therapies, has been recently revolutionized by technological advances in multiple "omics" fields. The resulting deluge of information has enabled and necessitated the development of tools required to both process and interpret the data. While of tremendous value to basic researchers, the amount and complexity of the data has made it extremely difficult to manually draw inference and identify factors key to the study objectives. The challenges of data reduction and interpretation are being met by the development of increasingly complex tools that integrate disparate knowledge bases and synthesize coherent models based on current biological understanding. This chapter presents an example of how genomics data can be integrated with biological network analyses to gain further insight into the developmental consequences of genetic perturbations. State of the art methods for conducting similar studies are discussed along with modern methods used to analyze and interpret the data.

Genome-wide CRISPR screens identify ferroptosis as a novel therapeutic vulnerability in acute lymphoblastic leukemia.

Acute lymphoblastic leukemia (ALL) is the most frequent cancer diagnosed in children. Despite the great progress achieved over the last 40 years, with cure rates now exceeding 85%, refractory or relapsed ALL still exhibit a dismal prognosis. This poor outcome reflects the lack of treatment options specifically targeting relapsed or refractory ALL. In order to address this gap, we performed whole-genome CRISPR/Cas drop-out screens on a panel of seven B-ALL cell lines. Our results demonstrate that while there was a significant overlap in gene essentiality between ALL cell lines and other cancer types survival of ALL cell lines was dependent on several unique metabolic pathways, including an exquisite sensitivity to GPX4 depletion and ferroptosis induction. Detailed molecular analysis of B-ALL cells suggest that they are primed to undergo ferroptosis as they exhibit high steady-state oxidative stress potential, a low buffering capacity, and a disabled GPX4-independent secondary lipid peroxidation detoxification pathway. Finally, we validated the sensitivity of BALL to ferroptosis induction using patient-derived B-ALL samples.

SlicerHeart: An open-source computing platform for cardiac image analysis and modeling.

Cardiovascular disease is a significant cause of morbidity and mortality in the developed world. 3D imaging of the heart's structure is critical to the understanding and treatment of cardiovascular disease. However, open-source tools for image analysis of cardiac images, particularly 3D echocardiographic (3DE) data, are limited. We describe the rationale, development, implementation, and application of SlicerHeart, a cardiac-focused toolkit for image analysis built upon 3D Slicer, an open-source image computing platform. We designed and implemented multiple Python scripted modules within 3D Slicer to import, register, and view 3DE data, including new code to volume render and crop 3DE. In addition, we developed dedicated workflows for the modeling and quantitative analysis of multi-modality image-derived heart models, including heart valves. Finally, we created and integrated new functionality to facilitate the planning of cardiac interventions and surgery. We demonstrate application of SlicerHeart to a diverse range of cardiovascular modeling and simulation including volume rendering of 3DE images, mitral valve modeling, transcatheter device modeling, and planning of complex surgical intervention such as cardiac baffle creation. SlicerHeart is an evolving open-source image processing platform based on 3D Slicer initiated to support the investigation and treatment of congenital heart disease. The technology in SlicerHeart provides a robust foundation for 3D image-based investigation in cardiovascular medicine.

Screening for distress in pediatric cancer survivors: A systematic comparison of one-step and two-step strategies to minimize detection errors.

BACKGROUND: Childhood cancer survivors should be routinely screened for psychological distress. However, existing screening tools promoted by cancer care institutions, such as the Distress Thermometer (DT) generate high rates of errors. The aim of this study is to help refining strategies of screening psychological distress in this population by exploring two-step methods combining the DT on step #1 with one question on step #2. PROCEDURE: Data from 255 survivors of childhood acute lymphoblastic leukemia aged 13-40 years were analyzed (38% 13-18 years, 62% 19+ years, 53% females). We used the DT on step #1 and the individual emotion items from the Pediatric Quality of Life Questionnaire (PedsQL) on step #2, to detect distress, depression and anxiety as measured by standard instruments. We compared sensitivity, specificity, negative and positive predictive values, Youden index, and clinical utility indices, in newly developed two-step strategies. RESULTS: The best two-step strategies to screen anxious-depressive distress were DT ≥ 2 on step #1, with the item of Sadness on step #2, and DT ≥ 2 combined with the item of Concerns. Two-step strategies outperformed the DT alone on the correct identification of distressed survivors. However, two-step strategies did not outperform the DT used alone on the correct detection of no distressed survivors. Results were similar when predicting depression or anxiety alone. CONCLUSION: Completing the DT with one single question on emotions from the PedsQL may minimize the number of participants falsely identified as distressed, which could be particularly pertinent in resource-limited clinics.

Genetic factors in treatment-related cardiovascular complications in survivors of childhood acute lymphoblastic leukemia.

Aim: Cardiovascular disease represents one of the main causes of secondary morbidity and mortality in patients with childhood cancer. Patients & methods: To further address this issue, we analyzed cardiovascular complications in relation to common and rare genetic variants derived through whole-exome sequencing from childhood acute lymphoblastic leukemia survivors (PETALE cohort). Results: Significant associations were detected among common variants in the TTN gene, left ventricular ejection fraction (p ≤ 0.0005), and fractional shortening (p ≤ 0.001). Rare variants enrichment in the NOS1, ABCG2 and NOD2 was observed in relation to left ventricular ejection fraction, and in NOD2 and ZNF267 genes in relation to fractional shortening. Following stratification according to risk groups, the modulatory effect of rare variants was additionally found in the CBR1, ABCC5 and AKR1C3 genes. None of the associations was replicated in St-Jude Lifetime Cohort Study. Conclusion: Further studies are needed to confirm whether the described genetic markers may be useful in identifying patients at increased risk of these complications.

Solid-State Overview of R-Baclofen: Relative Stability of Forms A, B and C and Characterization of a New Heterosolvate.

A new polymorphic form (Form C) of enantiopure Baclofen was isolated and characterized. Crystal structures of R-Baclofen Form A and Form C were resolved from powder diffraction data, and cell parameters by profile matching for Form B. The relative stability of these three forms is proposed based on structural data, thermal analyses and solvent-mediated conversions. The experiments highlight the stability order A < C < B at 25 °C (A is the most stable form), whereas above 180 °C it would likely be: C < A < B (C being the stable modification). Moreover, a new heterosolvate of the molecule is observed in N,N-DMF/water mixture. This heterosolvate offers a new pathway to isolate pure R-Baclofen Form B provided the lactam impurity does not exceed 3%. Upon mechanical stress Form B tends to evolve to Form C.

Maximal cardiopulmonary exercise testing in childhood acute lymphoblastic leukemia survivors exposed to chemotherapy.

PURPOSE: The purpose of this study was to demonstrate if childhood acute lymphoblastic leukemia (ALL) survivors exposed to chemotherapy (i.e., doxorubicin) are able to achieve a safe maximal cardiopulmonary exercise test (CPET). METHODS: A total of 250 childhood ALL survivors were eligible to undergo a CPET on ergocycle. Analyses were performed in 216 survivors and stratified in regard to their prognostic risk groups: 99 survivors (55 males and 44 females) at standard risk and 117 survivors (56 males and 61 females) at high risk. RESULTS: Results showed that 100% (n = 216) of survivors completed a maximal CPET confirmed by the achievement of two out of three of the following criteria: 197 survivors (91.2%) reached a peak RER value of ≥ 1.15, 197 survivors (91.2%) reached a RPE score > 7, and 210 survivors (97.2%) reached a maximal heart rate ≥ 85% of the predicted value. Linear regression analysis showed a significant association between the survivors' cumulative dose of doxorubicin and their VO2 peak measured. Two non-fatal adverse events were observed and reported at the end of the maximal CPET, while non-fatal adverse events were reported in 5 survivors during the recovery period. None of these events resulted in a long-term complication. CONCLUSION: Childhood ALL survivors with prior exposure to chemotherapy can achieve a safe maximal CPET. They were able of achieving a maximal exercise test without being limited by symptoms, potential overprotection, or musculoskeletal issues. Thus, it should be the norm to realize a CPET prior a physical activity program to propose an optimal prescription. This study provides important information regarding the maximal physiological parameters that childhood ALL survivors are able to reach and have important clinical implications in the exercise and oncology field for this population of survivors.

Contributing Factors of Unmet Needs Among Young Adult Survivors of Childhood Acute Lymphoblastic Leukemia with Comorbidities.

Purpose: This study aimed to: (1) describe the domains and levels of unmet needs of young adult survivors of childhood acute lymphoblastic leukemia (cALL) with comorbidities, and (2) to explore the factors associated with higher levels of unmet needs. Unmet need was considered as supportive care needs not met. Methods: The most vulnerable cALL survivors from the PETALE study cohort completed the Short-Form Survivor Unmet Needs Survey, the Brief Pain Inventory and the 15D instrument of health-related quality of life. Demographic and clinical information, including comorbidities, were obtained from medical records or self-reporting. The participants' needs and contributing factors to their needs were evaluated using nonparametric tests. Results: Of the 72 participants, 9 (13%) reported moderate/high levels of overall unmet needs. "Worry about earning money" (56%) and "Dealing with feeling tired" (51%) were the most frequent unmet needs (all levels combined). The factors associated significantly with any domain of unmet needs were: having a comorbidity, reporting altered functional health status, high ALL risk status, pain, age (<26 years), and having previously received psychological support. Conclusion: A minority of young adult survivors of cALL with comorbidities interviewed reported moderate/high levels of unmet needs. However, financial concerns and emotional health and relationship are the two domains of greatest need. Survivors with altered health condition are most at risk of experiencing moderate/high levels of unmet needs. If confirmed in larger samples, interventions should target modifiable contributors of unmet needs such as physical health and comfort, fatigue, and emotional health.

Developing and validating equations to predict V˙O2 peak from the 6MWT in Childhood ALL Survivors.

INTRODUCTION: The 6-Minute Walking Test (6MWT) is a safe, standardized and well utilized method to assess the functional capacity. Recently, it was reported that the published prediction equations cannot accurately predict a valid maximal oxygen consumption (V̇O2 peak) value in cancer survivors. Thus, the aim of this study was to establish and to validate a new equation based on the 6MWT to predict V̇O2 peak in childhood acute lymphoblastic leukemia (ALL) survivors. METHODS: A total of 200 childhood ALL survivors were enrolled in this study, among which 168 participants underwent a cardiopulmonary exercise test and a 6MWT to assess their functional capacity and their cardiorespiratory fitness. In addition, participants completed a physical activity questionnaire. Participants were randomly divided in two groups to establish the equations (n = 118 (70%)) and to validate it (n = 50 (30%)). Multiple linear regression analyses were used to determine a new prediction equation for V̇O2 peak from 6MWT using clinical and specific variables related to the disease. The accuracy in between V̇O2 peak measured and V̇O2 peak predicted were assessed using the Bland and Altman method. RESULTS: The new establish clinical V̇O2 peak equation is: V̇O2 peak (mL.kg-1.min-1) = (-0.283*age(years)) - (0.099*weight(kg)) + (0.071*6MWD(meters)) -(0.135*HR end(bpm)) + 22.789 with a mean bias of 2.67 mL.kg-1.min-1 (95% CI (-9.64 to 14.98)). The new establish disease-specific V̇O2 peak equation is: V̇O2 peak (mL.kg-1.min-1) = (-0.236*age(years)) - (0.094*weight(kg)) -(0.120*HR end(bpm)) + (0.067*6MWD(meters)) + (0.065*MVLPA(min/day)) - (0.204*DT(years)) + 25.145 with a mean bias of 2.51 mL.kg-1.min-1 (95% CI (-9.98 to 15.01)). CONCLUSION: This is the first study that predicted V̇O2 peak from a 6MWT using clinical and specific variables related to the disease of childhood ALL survivors. The availability of these newly established V̇O2 peak equations makes them an accurate tool to provide a better follow-up and better adapted physical training for survivors. We invite researchers to use our assessment procedures for their further studies.IMPLICATIONS FOR REHABILITATIONIt is critical to understand the cardiorespiratory fitness of the childhood ALL survivorsThe maximal oxygen consumption (i.e., V̇O2 peak) is recognized as the gold standard to measure the patient's cardiorespiratory fitness in the field of exercise physiologyThis study is novel and reports the validation of two new VO2 peak equations, from 6MWT, by using clinical and disease-specific variables of childhood ALL survivorsThe availability of such validated equations can better facilitate the follow-up of survivors' cardiorespiratory fitness, by relevant health care professionals and exercise physiologists.

Biomarkers of cardiometabolic complications in survivors of childhood acute lymphoblastic leukemia.

Survivors of childhood acute lymphoblastic leukemia (cALL) are at higher risk of developing cardiometabolic complications. We aimed at exploring the associations between biomarkers of inflammation, oxidative stress, endothelial function, endotoxemia and cardiometabolic risk factors. We conducted a cross-sectional analysis in 246 cALL survivors (mean age, 22.1 ± 6.3 years; mean time since diagnosis, 15.5 ± 5.2 years) and evaluated the associations using a series of logistic regressions. Using structural equation models, we also tested if the relationship between endotoxemia and cardiometabolic complications was mediated by the latent (unobserved) variable inflammation inferred from the observed biomarkers CRP, TNF-α and IL-6. High leptin-adiponectin ratio was associated with obesity [adjusted OR = 15.7; 95% CI (6.2-39.7)], insulin resistance [20.6 (5.2-82.1)] and the metabolic syndrome [11.2 (2.6-48.7)]. Higher levels of plasminogen activator inhibitor-1 and tumor necrosis factor-α were associated with obesity [3.37 (1.6-7.1) and 2.34 (1.3-4.2), respectively] whereas high C-reactive protein levels were associated with insulin resistance [3.3 (1.6-6.8)], dyslipidemia [2.6 (1.4-4.9)] and MetS [6.5 (2.4-17.9)]. Our analyses provided evidence for a directional relationship between lipopolysaccharide binding protein, related to metabolic endotoxemia, inflammation and cardiometabolic outcomes. Identification of biomarkers and biological mechanisms could open new avenues for prevention strategies to minimize the long-term sequelae, improve follow-up and optimize the quality of life of this high-risk population.

The effect of cardiorespiratory fitness and physical activity levels on cognitive functions in survivors of childhood acute lymphoblastic leukemia.

Introduction. Most childhood acute lymphoblastic leukemia (ALL) survivors develop chronic treatment-related adverse effects several years after the end of the treatment. Regular physical activity and a good cardiorespiratory fitness can decrease the risks of neurological disturbances and increase cognitive function scores. The aim of this study was to examine the effect of good cardiorespiratory fitness and physical activity levels on cognitive functions.Methods. We enrolled 219 survivors of childhood ALL. The participants underwent a cardiopulmonary exercise test, neuropsychological tests of executive functions (i.e. verbal fluency, cognitive flexibility, working memory, processing speed) and completed a physical activity questionnaire. We calculated the odds ratio to obtain the preventive fraction of physical activity and cardiorespiratory fitness levels on cognitive functions.Results. The cohort is 52% male and 48% female. A total of 182 survivors (83%) have a cardiorespiratory fitness below their predicted (<100%). Our analyses show that there is an association between good cardiorespiratory fitness and processing speed (preventive fraction of 70% for dominant hand (p < 0.01) and 65% for non-dominant hand (p < 0.01)) and with cognitive flexibility identified as the category switching measure of the D-KEFS verbal fluency (preventive fraction of 61%; p < 0.05).Conclusion. Good cardiorespiratory fitness and good levels of physical activity were associated to a preventive fraction for most cognitive function parameters measured. Good cardiorespiratory fitness levels were significantly associated with a lower prevalence of deficits in processing speed (i.e., dominant hand and non-dominant hand) and in cognitive flexibility (i.e., category switching) in childhood acute lymphoblastic leukemia survivors.

Inconsistencies between measures of cognitive dysfunction in childhood acute lymphoblastic leukemia survivors: Description and understanding.

OBJECTIVES: The frequency of cognitive difficulties in childhood cancer survivors varies according to the measurement strategy. The goal of this research is to (a) describe agreements and differences between measures of working memory and attention (b) identify contributors of these differences, such as emotional distress, affects, and fatigue. METHODS: We used data available for 138 adults successfully treated for childhood acute lymphoblastic leukemia (ALL) (PETALE cohort). Working memory and attention were assessed using subtests from the WAIS-IV and self-reported questionnaires (BRIEF-SR and CAARS-S:L). Potential contributors included emotional distress, anxiety, depression (BSI-18), affects (PANAS), and fatigue (PedsQL-MFS). We explored measurement agreements and differences using diagnostic indices and multivariate regression models. RESULTS: The frequencies of working memory and attention deficits were higher when using cognitive tests (15%-21%) than with self-reports (10%-11%). Self-reported questionnaires showed high specificity (median 0.87) and low sensitivity (median 0.10), suggesting they did not reliably identify positive cases on cognitive tests. We identified negative affectivity as a possible contributor to inconsistencies between self-report and test results. CONCLUSIONS: When measuring working memory and attention in childhood ALL survivors, cognitive test results and self-reports should not be considered equivalent. At best, self-report may be used for screening (high specificity), but not to assess prevalence in large samples. Self-reported difficulties are also probably influenced by the negative mood in this population.

MARIN: an open-source mobile augmented reality interactive neuronavigation system.

PURPOSE: Neuronavigation systems making use of augmented reality (AR) have been the focus of much research in the last couple of decades. In recent years, there has been considerable interest in using mobile devices for AR in the operating room (OR). We propose a complete system that performs real-time AR video augmentation on a mobile device in the context of image-guided neurosurgery. METHODS: MARIN (mobile augmented reality interactive neuronavigation system) improves upon the state of the art in terms of performance, allowing real-time augmentation, and interactivity by allowing users to interact with the displayed data. The system was tested in a user study with 17 subjects for qualitative and quantitative evaluation in the context of target localization and brought into the OR for preliminary feasibility tests, where qualitative feedback from surgeons was obtained. RESULTS: The results of the user study showed that MARIN performs significantly better in terms of both time ([Formula: see text]) and accuracy ([Formula: see text]) for the task of target localization in comparison with a traditional image-guided neurosurgery (IGNS) navigation system. Further, MARIN AR visualization was found to be more intuitive and allowed users to estimate target depth more easily. CONCLUSION: MARIN improves upon previously proposed mobile AR neuronavigation systems with its real-time performance, higher accuracy, full integration in the normal workflow and greater interactivity and customizability of the displayed information. The improvement in efficiency and usability over previous systems will facilitate bringing AR into the OR.

Three-Dimensional Modeling of Surgically Implanted Stent-Based Valves in the Mitral Position in Children.

PURPOSE: In children with a mitral annulus too small to accommodate traditional prostheses, surgical implantation of stent-based valves is a promising option. However no reliable preoperative methods exist to guide patient selection, device sizing, and positioning. We describe a novel methodology to visualize and quantify device fit in 3-dimensional echocardiogram (3DE)-derived heart models. DESCRIPTION: Heart models were created from existing preoperative 3DEs using custom software. Valve models were virtually implanted into the models, and both device fit and left ventricular outflow tract (LVOT) area were quantified. EVALUATION: The 3DEs of 3 patients who underwent Melody valve placement in the mitral position were retrospectively modeled: 1 with LVOT obstruction, 1 with perivalvar leak, and 1 without complications. In all cases 2-dimensional measurements underestimated 3D annular dimensions, and the patient with clinical LVOT obstruction had the lowest predicted LVOT area-to-aortic area ratio (0.5). CONCLUSIONS: 3DE-based preoperative modeling of surgical implantation of stent-based valves in the mitral position may improve quantification of mitral valve dimensions and inform risk stratification for potential LVOT obstruction.