Pediatric ECG-Based Deep Learning to Predict Left Ventricular Dysfunction and Remodeling.

BACKGROUND: Artificial intelligence-enhanced ECG analysis shows promise to detect ventricular dysfunction and remodeling in adult populations. However, its application to pediatric populations remains underexplored. METHODS: A convolutional neural network was trained on paired ECG-echocardiograms (≤2 days apart) from patients ≤18 years of age without major congenital heart disease to detect human expert-classified greater than mild left ventricular (LV) dysfunction, hypertrophy, and dilation (individually and as a composite outcome). Model performance was evaluated on single ECG-echocardiogram pairs per patient at Boston Children's Hospital and externally at Mount Sinai Hospital using area under the receiver operating characteristic curve (AUROC) and area under the precision-recall curve (AUPRC). RESULTS: The training cohort comprised 92 377 ECG-echocardiogram pairs (46 261 patients; median age, 8.2 years). Test groups included internal testing (12 631 patients; median age, 8.8 years; 4.6% composite outcomes), emergency department (2830 patients; median age, 7.7 years; 10.0% composite outcomes), and external validation (5088 patients; median age, 4.3 years; 6.1% composite outcomes) cohorts. Model performance was similar on internal test and emergency department cohorts, with model predictions of LV hypertrophy outperforming the pediatric cardiologist expert benchmark. Adding age and sex to the model added no benefit to model performance. When using quantitative outcome cutoffs, model performance was similar between internal testing (composite outcome: AUROC, 0.88, AUPRC, 0.43; LV dysfunction: AUROC, 0.92, AUPRC, 0.23; LV hypertrophy: AUROC, 0.88, AUPRC, 0.28; LV dilation: AUROC, 0.91, AUPRC, 0.47) and external validation (composite outcome: AUROC, 0.86, AUPRC, 0.39; LV dysfunction: AUROC, 0.94, AUPRC, 0.32; LV hypertrophy: AUROC, 0.84, AUPRC, 0.25; LV dilation: AUROC, 0.87, AUPRC, 0.33), with composite outcome negative predictive values of 99.0% and 99.2%, respectively. Saliency mapping highlighted ECG components that influenced model predictions (precordial QRS complexes for all outcomes; T waves for LV dysfunction). High-risk ECG features include lateral T-wave inversion (LV dysfunction), deep S waves in V1 and V2 and tall R waves in V6 (LV hypertrophy), and tall R waves in V4 through V6 (LV dilation). CONCLUSIONS: This externally validated algorithm shows promise to inexpensively screen for LV dysfunction and remodeling in children, which may facilitate improved access to care by democratizing the expertise of pediatric cardiologists.

Identifying high-risk Fontan phenotypes using K-means clustering of cardiac magnetic resonance-based dyssynchrony metrics.

BACKGROUND: Individuals with a Fontan circulation encompass a heterogeneous group with adverse outcomes linked to ventricular dilation, dysfunction, and dyssynchrony. The purpose of this study was to assess if unsupervised machine learning cluster analysis of cardiovascular magnetic resonance (CMR)-derived dyssynchrony metrics can separate ventricles in the Fontan circulation from normal control left ventricles and identify prognostically distinct subgroups within the Fontan cohort. METHODS: This single-center, retrospective study used 503 CMR studies from Fontan patients (median age 15 y) and 42 from age-matched controls from January 2005 to May 2011. Feature tracking on short-axis cine stacks assessed radial and circumferential strain, strain rate, and displacement. Unsupervised K-means clustering was applied to 24 mechanical dyssynchrony metrics derived from these deformation measurements. Clusters were compared for demographic, anatomical, and composite outcomes of death, or heart transplantation. RESULTS: Four distinct phenotypic clusters were identified. Over a median follow-up of 4.2 y (interquartile ranges 1.7-8.8 y), 58 (11.5%) patients met the composite outcome. The highest-risk cluster (largely comprised of right or mixed ventricular morphology and dilated, dyssynchronous ventricles) exhibited a higher hazard for the composite outcome compared to the lowest-risk cluster while controlling for ventricular morphology (hazard ratio [HR] 6.4; 95% confidence interval [CI] 2.1-19.3; P value 0.001) and higher indexed end-diastolic volume (HR 3.2; 95% CI 1.04-10.0; P value 0.043) per 10 mL/m2. CONCLUSION: Unsupervised machine learning using CMR-derived dyssynchrony metrics identified four distinct clusters of patients with Fontan circulation and healthy controls with varying clinical characteristics and risk profiles. This technique can be used to guide future studies and identify more homogeneous subsets of patients from an overall heterogeneous population.

Thoracic duct drainage patterns in heterotaxy.

BACKGROUND: Disordered lymphatic drainage is common in congenital heart diseases (CHD), but thoracic duct (TD) drainage patterns in heterotaxy have not been described in detail. This study sought to describe terminal TD sidedness in heterotaxy and its associations with other anatomic variables. METHODS: This was a retrospective, single-center study of patients with heterotaxy who underwent cardiovascular magnetic resonance imaging at a single center between July 1, 2019 and May 15, 2023. Patients with (1) asplenia (right isomerism), (2) polysplenia (left isomerism) and (3) pulmonary/abdominal situs inversus (PASI) plus CHD were included. Terminal TD sidedness was described as left-sided, right-sided, or bilateral. RESULTS: Of 115 eligible patients, the terminal TD was visualized in 56 (49 %). The terminal TD was left-sided in 25 patients, right-sided in 29, and bilateral in two. On univariate analysis, terminal TD sidedness was associated with atrial situs (p = 0.006), abdominal situs (p = 0.042), type of heterotaxy (p = 0.036), the presence of pulmonary obstruction (p = 0.041), superior vena cava sidedness (p = 0.005), and arch sidedness (p < 0.001). On multivariable analysis, only superior vena cava and aortic arch sidedness were independently associated with terminal TD sidedness. CONCLUSIONS: Terminal TD sidedness is highly variable in patients with heterotaxy. Superior vena cava and arch sidedness are independently associated with terminal TD sidedness. Type of heterotaxy was not independently associated with terminal TD sidedness. This data improves the understanding of anatomic variation in patients with heterotaxy and may be useful for planning for lymphatic interventions.

Pediatric Electrocardiogram-Based Deep Learning to Predict Secundum Atrial Septal Defects.

Secundum atrial septal defect (ASD2) detection is often delayed, with the potential for late diagnosis complications. Recent work demonstrated artificial intelligence-enhanced ECG analysis shows promise to detect ASD2 in adults. However, its application to pediatric populations remains underexplored. In this study, we trained a convolutional neural network (AI-pECG) on paired ECG-echocardiograms (≤ 2 days apart) to detect ASD2 from patients ≤ 18 years old without major congenital heart disease. Model performance was evaluated on the first ECG-echocardiogram pair per patient for Boston Children's Hospital internal testing and emergency department cohorts using area under the receiver operating (AUROC) and precision-recall (AUPRC) curves. The training cohort comprised of 92,377 ECG-echocardiogram pairs (46,261 patients; median age 8.2 years) with an ASD2 prevalence of 6.7%. Test groups included internal testing (12,631 patients; median age 7.4 years; 6.9% prevalence) and emergency department (2,830 patients; median age 7.5 years; 4.9% prevalence) cohorts. Model performance was higher in the internal test (AUROC 0.84, AUPRC 0.46) cohort than the emergency department cohort (AUROC 0.80, AUPRC 0.30). In both cohorts, AI-pECG outperformed ECG findings of incomplete right bundle branch block. Model explainability analyses suggest high-risk limb lead features include greater amplitude P waves (suggestive of right atrial enlargement) and V1 RSR' (suggestive of RBBB). Our findings demonstrate the promise of AI-pECG to inexpensively screen and/or detect ASD2 in pediatric patients. Future multicenter validation and prospective trials to inform clinical decision making are warranted.

Morphology, Clinical Associations, and Pathologic Follow-up of Quadricuspid Aortic Valves in Children.

While quadricuspid morphology is commonly observed in truncal valves, quadricuspid aortic valves (QAV) are rare and their natural history is not well described. This retrospective study of 37 patients describes the diagnostic associations and morphologic variability of QAVs in children (median age at diagnosis 4.3 y IQR 0-12 y). Associated congenital heart diseases were present in 54% (most commonly tetralogy of Fallot (TOF) and valvar pulmonary stenosis). Among patients with isolated QAV, 11 had genetic syndrome and 5 had skeletal anomalies. Valve morphology was most commonly type B (41%) and A (35%; Hurvitz and Roberts). Dilated aortic root (Z ≥ 2) was present in 5 and dilated ascending aorta in 9 patients at diagnosis. All patients with type C (n = 3) and G (n = 1) had aortic dilation. At diagnosis, >mild AR was rare (n = 1), mild regurgitation was common (n = 12, 32%), >mild AS was rare (n = 2), and mild AS was uncommon (n = 4). Over a median follow-up of 3.3y (IQR 0.9-11y), progression of AR was seen in 2 patients and progression of aortic root or ascending aorta dilation (increase in Z score by ≥ 2) was seen in 5 patients. In conclusion, QAV is a rare congenital anomaly and about half of the cases are found in hearts that are otherwise structurally normal. A relatively high prevalence is seen in patients with TOF, pulmonary stenosis, skeletal deformities, and genetic syndromes. Meticulous evaluation of aortic valve morphology should be conducted on echocardiograms performed for these indications.

Preoperative Echocardiographically Derived Mean dP/dTic Predicts Early Post-operative Dysfunction in Children Undergoing Mitral Valve Surgery.

Mean dP/dtic is a quantitative measurement of ventricular function that can be obtained noninvasively by echocardiography. In adults with mitral regurgitation (MR), it has been shown to be a more sensitive predictor of postoperative left ventricular ejection fraction (EF). The utility of dP/dtic in pediatric congenital heart diseases with MR has been underexplored. Patients (0 to ≤ 19 years) with MR who underwent mitral valve (MV) repair or replacement from 2015 to 2021 were included. Echocardiographically derived mean dP/dtic, Tei index, and EF were used to assess and compare ventricular function prior to, shortly after, and late after MV surgery. Study cohort included 61 patients (age 4.5 [IQR 0.14, 18.7] years, 89% MV repair, 11% MV replacement). Median time intervals between surgery and preoperative, early postoperative, and late postoperative echocardiograms were 6 days, 6 days, and 350 days, respectively. Median EF was 62% (z-score - 0.40) preoperatively, 56% (z-score - 1.40) early postoperatively, and 61% (z-score - 0.60) late postoperatively. Median dP/dtic was 1393 (IQR 1029, 1775) mmHg/s preoperatively, 1178 (IQR 886, 1946) mmHg/s early postoperatively, and 1270 (IQR 791, 1765) mmHg/s late postoperatively. Preoperative median dP/dtic correlated with early and late postoperative EF. Preoperative EF was not significantly correlated with early postoperative EF, but was correlated with late postoperative EF. Mitral valve intervention in pediatric patients is associated with an initial decline but subsequent recovery of systolic function. Non-invasively derived mean dP/dtic may offer advantages over other preoperative echocardiographic indices to predict postoperative systolic function.

Self-Assembled Lanthanum Oxide Nanoflakes by Electrodeposition Technique for Resistive Switching Memory and Artificial Synaptic Devices.

In recent years, many metal oxides have been rigorously studied to be employed as solid electrolytes for resistive switching (RS) devices. Among these solid electrolytes, lanthanum oxide (La2 O3 ) is comparatively less explored for RS applications. Given this, the present work focuses on the electrodeposition of La2 O3 switching layers and the investigation of their RS properties for memory and neuromorphic computing applications. Initially, the electrodeposited La2 O3 switching layers are thoroughly characterized by various analytical techniques. The electrochemical impedance spectroscopy (EIS) and Mott-Schottky techniques are probed to understand the in situ electrodeposition, RS mechanism, and n-type semiconducting nature of the fabricated La2 O3 switching layers. All the fabricated devices exhibit bipolar RS characteristics with excellent endurance and stable retention. Moreover, the device mimics the various bio-synaptic properties such as potentiation-depression, excitatory post-synaptic currents, and paired-pulse facilitation. It is demonstrated that the fabricated devices are non-ideal memristors based on double-valued charge-flux characteristics. The switching variation of the device is studied using the Weibull distribution technique and modeled and predicted by the time series analysis technique. Based on electrical and EIS results, a possible filamentary-based RS mechanism is suggested. The present results assert that La2 O3 is a promising solid electrolyte for memory and brain-inspired applications.

Expectant management of patent ductus arteriosus for preterm infants: A meta-analysis of randomized controlled trials.

We conducted this meta-analysis to compare expectant management of patent ductus arteriosus (PDA) with active treatment for PDA closure in preterm infants. Data from 7 randomized controlled trials (RCTs) showed that all-cause mortality and other clinical adverse outcomes did not differ between expectant management of PDA and active treatment. Future large-scale and double-blinded RCTs with a consistent definition for hemodynamically significant PDA, and focusing on clearly delineated high-risk subgroups or later selective treatment are needed to further evaluate the role of expectant management.

Perioperative prophylactic corticosteroids for cardiac surgery in children: A systematic review and meta-analysis.

OBJECTIVE: Perioperative corticosteroids have been used for pediatric cardiac surgery for decades, but the underlying evidence is conflicting. We aimed to investigate the efficacy and safety of perioperative prophylactic corticosteroids in pediatric heart surgeries. METHODS: We searched electronic databases until March 2023 to retrieve all randomized controlled trials (RCTs) that administered perioperative prophylactic corticosteroids to children undergoing heart surgery. We used RevMan 5.4 to pool risk ratios (RRs) and mean differences (MDs). RESULTS: A total of 12 RCTs (2,209 patients) were included in our review. Corticosteroids administration was associated with a nonsignificant reduction in all-cause mortality (RR 0.62; 95% CI: 0.37-1.02, I2 = 0%; moderate certainty); however, it was associated with a lower duration of mechanical ventilation (MV) (MD -0.63 days; 95% CI: -1.16 to -0.09 days, I2 = 41%; high certainty). Corticosteroids did not affect the length of ICU and hospital stay but significantly reduced the incidence of postoperative low cardiac output syndrome (LCOS) (RR 0.76; 95% CI: 0.60-0.96, I2 = 0%; moderate certainty) and reoperation (RR 0.37; 95% CI: 0.19-0.74, I2 = 0%; moderate certainty). There was no increase in adverse events except a higher risk of hyperglycemia and postoperative insulin use. CONCLUSIONS: The use of perioperative corticosteroids in pediatric heart surgeries is associated with a trend toward reduced all-cause mortality without attaining statistical significance. Corticosteroids reduced MV duration, and probably decrease the incidence of LCOS, and reoperations. The choice of corticosteroid agent and dose is highly variable and further larger studies may help determine the ideal agent, dose, and patient population for this prophylactic therapy.

Cardiac magnetic resonance parameters associated with successful conversion from a single ventricular to a one-and-a-half or biventricular circulation in patients with a hypoplastic right ventricle.

BACKGROUND: Some patients with pulmonary atresia with an intact ventricular septum (PA/IVS) or a left ventricle dominant atrioventricular canal defect (LDAVC) with a hypoplastic right ventricle (RV) and univentricular (1 V) circulation may be candidates for conversion to either a complete biventricular (2 V) repair or a one-and-a-half ventricle repair (1.5 V). We sought to identify pre-operative cardiovascular magnetic resonance (CMR) findings associated with successful conversion from 1V to 1.5V or 2V circulation. METHODS: In this single center retrospective study, subjects with PA/IVS or LDAVC and no conotruncal abnormalities were included if they had a 1 V circulation at the time of CMR followed by a surgical intervention intended to convert them to a 1.5 V or 2 V circulation. Conversion failure was defined as any of the following: (1) oxygen saturation < 90% at the most recent follow-up, (2) conversion back to a 1.5 V or 1 V circulation, or (3) death. RESULTS: In the PA/IVS cohort (n = 15, median age 1.32 years), 10 patients underwent surgical conversion to a 1.5 V circulation and 5 to a 2 V circulation. In the attempted 1.5 V group, there were 2 failures, and these cases had a lower RV mass (p = 0.04). In the attempted 2 V group, there was 1 failure, and no CMR parameters were significantly different compared to the successes. Among the successful 2 V group patients, the minimum RV end-diastolic volume (EDV) was 27 ml/m2. In the LDAVC cohort (n = 15, median age 1.0 years), 1 patient underwent surgical conversion to a 1.5 V circulation and 14 patients to a 2 V circulation. In the attempted 1.5 V group, the 1 conversion was a failure and had an RV EDV of 15 ml/m2. In the attempted 2 V group, there were 2 failures, and these cases had a smaller RV:LV stroke volume ratio (p = 0.05) and a lower RV ejection fraction (p = 0.05) compared to the successes. Among the successful 2 V group patients, the minimum RV EDV was 22 ml/m2. CONCLUSIONS: We identified multiple CMR parameters associated with successful conversion from 1 V circulation to 1.5 V or 2 V circulation in patients with PA/IVS and LDAVC. This information may improve patient selection for conversion procedures and encourage larger studies to better define the role of CMR.

Ventricular dyssynchrony late after the Fontan operation is associated with decreased survival.

BACKGROUND: Ventricular dyssynchrony and its relationship to clinical outcomes is not well characterized in patients following Fontan palliation. METHODS: Single-center retrospective analysis of cardiac magnetic resonance (CMR) imaging of patients with a Fontan circulation and an age-matched healthy comparison cohort as controls. Feature tracking was performed on all slices of a ventricular short-axis cine stack. Circumferential and radial strain, strain rate, and displacement were measured; and multiple dyssynchrony metrics were calculated based on timing of these measurements (including standard deviation of time-to-peak, maximum opposing wall delay, and maximum base-to-apex delay). Primary endpoint was a composite measure including time to death, heart transplant or heart transplant listing (D/HTx). RESULTS: A total of 503 cases (15 y; IQR 10, 21) and 42 controls (16 y; IQR 11, 20) were analyzed. Compared to controls, Fontan patients had increased dyssynchrony metrics, longer QRS duration, larger ventricular volumes, and worse systolic function. Dyssynchrony metrics were higher in patients with right ventricular (RV) or mixed morphology compared to those with LV morphology. At median follow-up of 4.3 years, 11% had D/HTx. Multiple risk factors for D/HTx were identified, including RV morphology, ventricular dilation, dysfunction, QRS prolongation, and dyssynchrony. Ventricular dilation and RV morphology were independently associated with D/HTx. CONCLUSIONS: Compared to control LVs, single right and mixed morphology ventricles in the Fontan circulation exhibit a higher degree of mechanical dyssynchrony as evaluated by CMR-FT. Dyssynchrony indices correlate with ventricular size and function and are associated with death or need for heart transplantation. These data add to the growing understanding regarding factors that can be used to risk-stratify patients with the Fontan circulation.

Magnetic resonance three-dimensional steady-state free precession imaging of the thoracic duct in patients with Fontan circulation and its relationship to outcomes.

BACKGROUND: Lymphatic complications are common in patients with Fontan circulation. Three-dimensional balanced steady-state free precession (3D bSSFP) angiography by cardiovascular magnetic resonance (CMR) is widely used for cardiovascular anatomical assessment. We sought to determine the frequency of thoracic duct (TD) visualization using 3D bSSFP images and assess whether TD characteristics are associated with clinical outcomes. METHODS: This was a retrospective, single-center study of patients with Fontan circulation who underwent CMR. Frequency matching of age at CMR was used to construct a comparison group of patients with repaired tetralogy of Fallot (rTOF). TD characteristics included maximum diameter and a qualitative assessment of tortuosity. Clinical outcomes included protein-losing enteropathy (PLE), plastic bronchitis, listing for heart transplantation, and death. A composite outcome was defined as presence of any of these events. RESULTS: The study included 189 Fontan patients (median age 16.1 years, IQR 11.0-23.2 years) and 36 rTOF patients (median age 15.7 years, IQR 11.1-23.7 years). The TD diameter was larger (median 2.50 vs. 1.95 mm, p = 0.002) and more often well visualized (65% vs. 22%, p < 0.001) in Fontan patients vs. rTOF patients. TD dimension increased mildly with age in Fontan patients, R = 0.19, p = 0.01. In Fontan patients, the TD diameter was larger in those with PLE vs. without PLE (age-adjusted mean 4.11 vs. 2.72, p = 0.005), and was more tortuous in those with NYHA class ≥ II vs. class I (moderate or greater tortuosity 75% vs. 28.5%, p = 0.02). Larger TD diameter was associated with a lower ventricular ejection fraction that was independent of age (partial correlation = - 0.22, p = 0.02). More tortuous TDs had a higher end-systolic volume (mean 70.0 mL/m2 vs. 57.3 mL/m2, p = 0.03), lower creatinine (mean 0.61 mg/dL vs. 0.70 mg/dL, p = 0.04), and a higher absolute lymphocyte count (mean 1.80 K cells/µL vs. 0.76 K cells/µL, p = 0.003). The composite outcome was present in 6% of Fontan patients and was not associated with TD diameter (p = 0.50) or tortuosity (p = 0.09). CONCLUSIONS: The TD is well visualized in two-thirds of patients with Fontan circulation on 3D-bSSFP images. Larger TD diameter is associated with PLE and increased TD tortuosity is associated with an NYHA class ≥ II.

Longitudinal changes in ventricular size and function are associated with death and transplantation late after the Fontan operation.

BACKGROUND: Cross-sectional studies have reported that ventricular dilation and dysfunction are associated with adverse clinical outcome in Fontan patients; however, longitudinal changes and their relationship with outcome are not known. METHODS: This was a single-center retrospective analysis of Fontan patients with at least 2 cardiovascular magnetic resonance (CMR) scans without intervening interventions. Serial measures of end-diastolic volume index (EDVI), end-systolic volume index (ESVI), ejection fraction (EF), indexed mass (massi), mass-to-volume ratio, and end-systolic wall stress (ESWS) were used to estimate within-patient change over time. Changes were compared for those with and without a composite outcome (death, heart transplant, or transplant listing) as well as between patients with left (LV) and right ventricular (RV) dominance. RESULTS: Data from 156 patients were analyzed with a mean age at 1st CMR of 17.8 ± 9.6 years. 490 CMRs were included with median of 3 CMRs/patient (range 2-9). On regression analysis with mixed effects models, volumes and ESWS increased, while mass, mass-to-volume ratio, and EF decreased over time. With a median follow-up of 10.2 years, 14% met the composite outcome. Those with the composite outcome had a greater increase in EDVI compared to those without (4.7 vs. 0.8 ml/BSA1.3/year). Compared with LV dominance, RV dominance was associated with a greater increase in ESVI (1.4 vs. 0.5 ml/BSA1.3/year), a greater decrease in EF (- 0.61%/year vs. - 0.24%/year), and a higher rate of the composite outcome (21% vs. 8%). CONCLUSIONS: Ventricles in the Fontan circulation exhibit a steady decline in performance with an increase in EDVI, ESVI, and ESWS, and decrease in EF, mass index, and mass-to-volume ratio. Those with death or need for heart transplantation have a faster increase in EDVI. Patients with rapid increase in EDVI (> 5 ml/BSA1.3/year) may be at a higher risk of adverse outcomes and may benefit from closer surveillance. RV dominance is associated with worse clinical outcomes and remodeling compared to LV dominance.

Normative values for ureteral diameter in children.

BACKGROUND: Assessment of the ureter is a fundamental part of the radiologic evaluation of the urinary tract. Abnormal ureteral dilation warrants further investigation to assess the etiology, which includes obstruction and/or reflux. Despite this fundamental need, there are no established normative values in children based on imaging. OBJECTIVE: To provide normative values for ureteral diameter in pediatric patients with age-related ranges. MATERIALS AND METHODS: We retrospectively reviewed all magnetic resonance (MR) urography studies and chose only normal ureters for assessment. The images were analyzed on commercially available software to assess maximum internal diameter. Manual measurements were done in cases where the images were below the resolution for automated assessment. Maximum intraluminal ureteral diameters were measured in upper, mid and lower thirds and the average of the three maximum ureteral diameters was used to obtain the average widest internal ureteral diameter. Multivariable linear regression was performed to test the association between the calculated diameter and gender. Differences in sizes between the left and right ureter were assessed using paired Wilcoxon signed rank test. RESULTS: One hundred twenty-one MR urography studies were selected, which included 160 ureter units. The diameter increases progressively with age, ranging from 3.2 mm during infancy to 5.0 mm in patients older than 16 years of age. After 9 years of age, the average widest internal ureteral diameter is slightly larger in males compared to females (odds ratio [OR]=1.91, 95% confidence interval [CI] [1.63, 2.25], P<0.0001). The right ureter was slightly larger than the left (3.9 mm vs. 3.7 mm, P=0.004) among 39 patients in whom both right and left ureter units were included. The average mid ureteral diameter is widest, followed by the distal third then proximal third. CONCLUSION: We present the normative values for the average widest internal ureteral diameter based on laterality and different segments. In the pediatric population, 3.8 mm should be considered the average widest internal ureteral diameter.

Left Ventricular Outflow Tract Gradient Is Associated With Coronary Artery Obstruction in Children With Williams-Beuren Syndrome.

OBJECTIVES: Patients with Williams-Beuren syndrome are associated with a high risk of hemodynamic collapse during sedation and/or anesthesia, presumably due to occult coronary obstruction. The objective of this study was to determine the association between transthoracic echocardiogram findings and the presence of coronary obstruction to examine if coronary obstruction can be predicted by transthoracic echocardiogram before anesthesia. DESIGN: Retrospective data analysis of patients with Williams-Beuren syndrome who underwent transthoracic echocardiogram, cardiac catheterization, and/or surgical interventions to determine the correlation between echocardiogram findings and the presence of coronary obstruction determined by cardiac catheterization and/or surgery. SETTING: Single-center university teaching hospital. PARTICIPANTS: The study included 49 patients with Williams-Beuren syndrome who underwent transthoracic echocardiogram, cardiac catheterization, and/or surgical interventions. MEASUREMENTS AND MAIN RESULTS: The only variable associated with coronary artery obstruction was the maximum instantaneous gradient (MIG) across the left ventricular outflow tract (LVOT) on a transthoracic echocardiogram. LVOT MIG ≥ 75 mmHg as the optimal cutoff value was associated with coronary artery obstruction (area under the curve 0.659, odds ratio 6.71, 95% CI 1.31-34.35, p = 0.022). CONCLUSION: LVOT gradient can serve as a good predictor of the presence of coronary obstruction in patients with Williams-Beuren syndrome.

Inhibition of HDAC3 reverses Alzheimer's disease-related pathologies in vitro and in the 3xTg-AD mouse model.

Alzheimer's disease (AD) is the leading cause of age-related dementia. Neuropathological hallmarks of AD include brain deposition of ß-amyloid (Aß) plaques and accumulation of both hyperphosphorylated and acetylated tau. RGFP-966, a brain-penetrant and selective HDAC3 inhibitor, or HDAC3 silencing, increases BDNF expression, increases histone H3 and H4 acetylation, decreases tau phosphorylation and tau acetylation at disease-associated sites, reduces ß-secretase cleavage of the amyloid precursor protein (APP), and decreases Aß1-42 accumulation in HEK-293 cells overexpressing APP with the double Swedish mutation (HEK/APPsw). In the triple transgenic AD mouse model (3xTg-AD), repeated administration of 3 and 10 mg/kg of RGFP-966 reverses pathological tau phosphorylation at Thr181, Ser202, and Ser396, increases levels of the Aß degrading enzyme Neprilysin in plasma, decreases Aß1-42 protein levels in the brain and periphery, and improves spatial learning and memory. Finally, we show that RGFP-966 decreases Aß1-42 accumulation and both tau acetylation and phosphorylation at disease residues in neurons derived from induced pluripotent stem cells obtained from APOEε4-carrying AD patients. These data indicate that HDAC3 plays an important regulatory role in the expression and regulation of proteins associated with AD pathophysiology, supporting the notion that HDAC3 may be a disease-modifying therapeutic target.

In Vitro Effect of Dovitinib (TKI258), a Multi-Target Angiokinase Inhibitor on Aggressive Meningioma Cells.

Background: Meningiomas represent ∼30% of primary central nervous system (CNS) tumors. Although advances in surgery and radiotherapy have significantly improved survival, there remains an important subset of patients whose tumors have more aggressive behavior and are refractory to conventional therapy. Recent advances in molecular genetics and epigenetics suggest that this aggressive behavior may be due to the deletion of the DNA repair and tumor suppressor gene, CHEK2, neurofibromatosis Type 2 (NF2) mutation on chromosome 22q12, and genetic abnormalities in multiple RTKs including FGFRs. Management of higher-grade meningiomas, such as anaplastic meningiomas (AM: WHO grade III), is truly challenging and there isn't an established chemotherapy option. We investigate the effect of active multi tyrosine receptor kinase inhibitor Dovitinib at stopping AM cell growth in in vitro with either frequent codeletion or mutated CHEK2 and NF2 gene.Methods: Treatment effects were assessed using MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay, western blot analysis, caspases assay, and DNA fragmentation assay.Results: Treatment of CH157MN and IOMM-Lee cells with Dovitinib suppressed multiple angiokinases-mainly FGFRs, leading to suppression of downstream signaling by RAS-RAF-MAPK molecules and PI3K-AKT molecules which are involved in cell proliferation, cell survival, and tumor invasion. Furthermore, Dovitinib induced apoptosis via downregulation of survival proteins (Bcl-XL), and over-expression of apoptotic factors (Bax and caspase-3) regardless of CHEK2 and NF2 mutation status.Conclusions: This study establishes the groundwork for the development of Dovitinib as a therapeutic agent for high-grade AM with either frequent codeletion or mutated CHEK2 and NF2, an avenue with high translational potential.

Chemical Functionalisation of 2D Materials by Batch and Continuous Hydrothermal Flow Synthesis.

2D materials are single or few layered materials consisting of one or several elements with a thickness of a few nanometres. Their unique, tuneable physical and chemical properties including ease of chemical functionalisation makes this class of materials useful in a variety of technological applications. The feasibility of 2D materials strongly depends on better synthetic approaches to improve properties, increase performance, durability and reduce costs. As such, in the synthesis of nanomaterials, hydrothermal processes are widely adopted through a precursor-product synthesis route. This method includes batch or continuous flow systems, both employing water at elevated temperatures (above boiling point) and pressures to fine-tune the physical, chemical, optical and electronic properties of the nanomaterial. Both techniques yield particles with different morphology, size and surface area due to different mechanisms of particle formation. In this Minireview, we present batch and continuous hydrothermal flow synthesis of a selection of 2D derivatives (graphene, MXene and molybdenum disulfide), their chemical functionalisation as an advantageous approach in exploring properties of these materials as well as the benefits and challenges of employing these processes, and an outlook for further research.

AMERICAN ASSOCIATION OF CLINICAL ENDOCRINOLOGISTS/AMERICAN COLLEGE OF ENDOCRINOLOGY CLINICAL PRACTICE GUIDELINES FOR THE DIAGNOSIS AND TREATMENT OF POSTMENOPAUSAL OSTEOPOROSIS-2020 UPDATE.

Objective: The development of these guidelines is sponsored by the American Association of Clinical Endocrinologists (AACE) Board of Directors and American College of Endocrinology (ACE) Board of Trustees and adheres with published AACE protocols for the standardized production of clinical practice guidelines (CPGs). Methods: Recommendations are based on diligent reviews of the clinical evidence with transparent incorporation of subjective factors, according to established AACE/ACE guidelines for guidelines protocols. Results: The Executive Summary of this 2020 updated guideline contains 52 recommendations: 21 Grade A (40%), 24 Grade B (46%), 7 Grade C (14%), and no Grade D (0%). These detailed, evidence-based recommendations allow for nuance-based clinical decision-making that addresses multiple aspects of real-world care of patients. The evidence base presented in the subsequent Appendix provides relevant supporting information for the Executive Summary recommendations. This update contains 368 citations: 123 (33.5%) evidence level (EL) 1 (highest), 132 (36%) EL 2 (intermediate), 20 (5.5%) EL 3 (weak), and 93 (25%) EL 4 (lowest). New or updated topics in this CPG include: clarification of the diagnosis of osteoporosis, stratification of the patient according to high-risk and very-high-risk features, a new dual-action therapy option, and transitions from therapeutic options. Conclusion: This guideline is a practical tool for endocrinologists, physicians in general, regulatory bodies, health-related organizations, and interested laypersons regarding the diagnosis, evaluation, and treatment of post-menopausal osteoporosis. Abbreviations: 25(OH)D = 25-hydroxyvitamin D; AACE = American Association of Clinical Endocrinologists; ACE = American College of Endocrinology; AFF = atypical femoral fracture; ASBMR = American Society for Bone and Mineral Research; BEL = best evidence level; BMD = bone mineral density; BTM = bone turnover marker; CI = confidence interval; CPG = clinical practice guideline; CTX = C-terminal telopeptide type-I collagen; DXA = dual-energy X-ray absorptiometry; EL = evidence level; FDA = U.S. Food and Drug Administration; FRAX® = Fracture Risk Assessment Tool; GI = gastrointestinal; HORIZON = Health Outcomes and Reduced Incidence with Zoledronic acid ONce yearly Pivotal Fracture Trial (zoledronic acid and zoledronate are equivalent terms); ISCD = International Society for Clinical Densitometry; IU = international units; IV = intravenous; LSC = least significant change; NOF = National Osteoporosis Foundation; ONJ = osteonecrosis of the jaw; PINP = serum amino-terminal propeptide of type-I collagen; PTH = parathyroid hormone; R = recommendation; ROI = region of interest; RR = relative risk; SD = standard deviation; TBS = trabecular bone score; VFA = vertebral fracture assessment; WHO = World Health Organization.

AMERICAN ASSOCIATION OF CLINICAL ENDOCRINOLOGISTS/AMERICAN COLLEGE OF ENDOCRINOLOGY CLINICAL PRACTICE GUIDELINES FOR THE DIAGNOSIS AND TREATMENT OF POSTMENOPAUSAL OSTEOPOROSIS- 2020 UPDATE EXECUTIVE SUMMARY.

Objective: The development of these guidelines is sponsored by the American Association of Clinical Endocrinologists (AACE) Board of Directors and American College of Endocrinology (ACE) Board of Trustees and adheres with published AACE protocols for the standardized production of clinical practice guidelines (CPGs). Methods: Recommendations are based on diligent reviews of the clinical evidence with transparent incorporation of subjective factors, according to established AACE/ACE guidelines for guidelines protocols. Results: The Executive Summary of this 2020 updated guideline contains 52 recommendations: 21 Grade A (40%), 24 Grade B (46%), 7 Grade C (14%), and no Grade D (0%). These detailed, evidence-based recommendations allow for nuance-based clinical decision-making that addresses multiple aspects of real-world care of patients. The evidence base presented in the subsequent Appendix provides relevant supporting information for the Executive Summary recommendations. This update contains 368 citations: 123 (33.5%) evidence level (EL) 1 (highest), 132 (36%) EL 2 (intermediate), 20 (5.5%) EL 3 (weak), and 93 (25%) EL 4 (lowest). New or updated topics in this CPG include: clarification of the diagnosis of osteoporosis, stratification of the patient according to high-risk and very-high-risk features, a new dual-action therapy option, and transitions from therapeutic options. Conclusion: This guideline is a practical tool for endocrinologists, physicians in general, regulatory bodies, health-related organizations, and interested laypersons regarding the diagnosis, evaluation, and treatment of post-menopausal osteoporosis.