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Background and Objective:The Residual Lesion Score is a novel tool for assessing the achievement of surgical objectives in congenital heart surgery based on widely available clinical and echocardiographic characteristics. This article describes the methodology used to develop the Residual Lesion Score from the previously developed Technical Performance Score for five common congenital cardiac procedures using the RAND Delphi methodology.Methods:A panel of 11 experts from the field of paediatric and congenital cardiology and cardiac surgery, 2 co-chairs, and a consultant were assembled to review and comment on validity and feasibility of measuring the sub-components of intraoperative and discharge Residual Lesion Score for five congenital cardiac procedures. In the first email round, the panel reviewed and commented on the Residual Lesion Score and provided validity and feasibility scores for sub-components of each of the five procedures. In the second in-person round, email comments and scores were reviewed and the Residual Lesion Score revised. The modified Residual Lesion Score was scored independently by each panellist for validity and feasibility and used to develop the “final” Residual Lesion Score.Results:The Residual Lesion Score sub-components with a median validity score of ≥7 and median feasibility score of ≥4 that were scored without disagreement and with low absolute deviation from the median were included in the “final” Residual Lesion Score.Conclusion:Using the RAND Delphi methodology, we were able to develop Residual Lesion Score modules for five important congenital cardiac procedures for the Pediatric Heart Network’s Residual Lesion Score study.

Manifestation of the properties of 3,5-diaminobenzoic acid polymer film was explored by polymerizing 3,5-diaminobenzoic acid in the presence of bromate. Depending on the initial concentration of bromate, the 3,5-diaminobenzoic acid solution was observed to transit from steady to oscillatory evolution in a batch reactor. The thus-fabricated film on Au electrodes exhibited different activities toward the electrochemical oxidation of pyrocatechol. The film synthesized at nonoscillatory conditions has a primary oxidation peak of pyrocatechol at about 0.20 V (vs Hg/Hg2SO4 electrode), as opposed to 0.0 V with the film that was prepared under oscillatory conditions. A phase diagram in the bromate–sulfuric acid phase was constructed to demonstrate the influence of each parameter on the emergence of oscillatory behavior in the 3,5-diaminobenzoic acid system. Experiments showed that an increase in the concentrations of sulfuric acid and bromate greatly increased the frequency and reduced the induction period of the...

Patient-specific in vivo ventricle material parameter determination is important for cardiovascular investigations. A new cardiac magnetic image (CMR)-based modeling approach with different zero-load diastole and systole geometries was adopted to estimate right ventricle material parameter values for healthy and patients with Tetralogy of Fallot (TOF) and seeking potential clinical applications. CMR data were obtained from 6 healthy volunteers and 16 TOF patients with consent obtained. CMR-based RV/LV models were constructed using two zero-load geometries (diastole and systole, 2G model). Material parameter values for begin-filling (BF), end-filling (EF), begin-ejection (BE), and end-ejection (EE) were recorded for analyses. Effective Young's moduli (YM) for fiber direction stress-strain curves were calculated for easy comparisons. The mean EE YM value of TOF patients was 78.6% higher than that of the healthy group (HG). The mean end-ejection YM value from worse-outcome TOF group (WG) post pulmonary valve replacement (PVR) surgery was 59.5% higher than that from the better-outcome TOF group (BG). Using begin-filling YM and end-ejection YM as predictors and the classic logistic regression model to different better-outcome group patients from worse-outcome group patients, the areas under Receiver Operating Characteristic (ROC) curves were found to be 0.797 and 0.883 for begin-filling YM and end-ejection YM, respectively. The sensitivity and specificity 0.761 and 0.755 using end-ejection YM as the predictor. This preliminary study suggests that ventricle material stiffness could be a potential parameter to be used to differentiate BG patients from WG patients with further effort and large-scale patient data validations.

Repetitive transcranial magnetic stimulation (rTMS) has become an increasingly popular tool to modulate neural excitability and induce neural plasticity in clinical and preclinical models; however, the physiological mechanisms in which it exerts these effects remain largely unknown. To date, studies have primarily focused on characterizing rTMS-induced changes occurring at the synapse, with little attention given to changes in intrinsic membrane properties. However, accumulating evidence suggests that rTMS may induce its effects, in part, via intrinsic plasticity mechanisms, suggesting a new and potentially complementary understanding of how rTMS alters neural excitability and neural plasticity. In this review, we provide an overview of several intrinsic plasticity mechanisms before reviewing the evidence for rTMS-induced intrinsic plasticity. In addition, we discuss a select number of neurological conditions where rTMS-induced intrinsic plasticity has therapeutic potential before speculating on the temporal relationship between rTMS-induced intrinsic and synaptic plasticity.

This research investigated responses of the Belousov–Zhabotinsky (BZ) reaction to the presence of a chemically inert Pt wire in solution. Experiments showed that connecting the Pt wire to a neutral ground caused a spontaneous drastic shift in the redox potential and might even induce complex behavior. Characterizations using an unstirred ferriin solution demonstrated the formation of a red colored propagating front at the grounded Pt wire, suggesting the reduction of ferriin to ferroin. Measurements with different combinations of electrodes in both stirred and reaction-diffusion media further confirmed the reduction of BZ metal catalysts at the Pt wire and the accompanying oxidation reaction at the reference electrode. The observed drastic change in redox potential and oscillation waveform can be understood based on the passive reduction reaction at the indicator electrode that is connected to the reference electrode through a potential meter. The obtained influence can be further manipulated by adding a resistor between the Pt wire and the neutral ground, making this convenient perturbation method attractive for the study of redox chemical reaction dynamics.

Foodborne pathogens cause thousands of illnesses across the US each year. However, these pathogens gain resistance to the antimicrobials that are commonly used to treat them. Typically, antimicrobial resistance is caused by mechanisms encoded by multiple antimicrobial-resistance genes. These are carried through pathogens found in foods such as meats. It is, thus, important to study the genes that are most related to antimicrobial resistance, the pathogens, and the meats carrying antimicrobial-resistance genes. This information can be further used to correlate the antimicrobial-resistance genes found in humans for improving human health. Therefore, we perform the first multivariate statistical analysis of the antimicrobial-resistance gene data provided in the NCBI Pathogen Detection Isolates Browser database, covering six states that are geographically either in close proximity to one another (i.e., Pennsylvania (PA), Maryland (MD), and New York (NY)) or far (i.e., New Mexico (NM), Minnesota (MN), and California (CA)). Hundreds of multidimensional data points were projected onto a two-dimensional space that was specified by the first and second principal components, which were then categorized with a hierarchical clustering approach. It turns out that aadA, aph(3&rsquo, &rsquo, ), aph(3&rsquo, )-Ib, aph(6)-I, aph(6)-Id, bla, blaCMY, tet, tet(A), and sul2 constructed the assembly of ten genes that were most commonly involved in antimicrobial resistance in these six states. While geographically close states like PA, MD and NY share more similar antimicrobial-resistance genes, geographically far states like NM, MN, and CA also contain most of these common antimicrobial-resistance genes. One potential reason for this spread of antimicrobial-resistance genes beyond the geographic limitation is that animal meats like chicken and turkey act as the carriers for the nationwide spread of these genes.

Patient-specific in vivo ventricle material parameter determination is important for cardiovascular investigations. A new cardiac magnetic image (CMR)-based modeling approach with different zero-load diastole and systole geometries was adopted to estimate right ventricle material parameter values for healthy and patients with Tetralogy of Fallot (TOF) and seeking potential clinical applications. CMR data were obtained from 6 healthy volunteers and 16 TOF patients with consent obtained. CMR-based RV/LV models were constructed using two zero-load geometries (diastole and systole, 2G model). Material parameter values for begin-filling (BF), end-filling (EF), begin-ejection (BE), and end-ejection (EE) were recorded for analyses. Effective Young's moduli (YM) for fiber direction stress-strain curves were calculated for easy comparisons. The mean EE YM value of TOF patients was 78.6% higher than that of the healthy group (HG). The mean end-ejection YM value from worse-outcome TOF group (WG) post pulmonary valve replacement (PVR) surgery was 59.5% higher than that from the better-outcome TOF group (BG). Using begin-filling YM and end-ejection YM as predictors and the classic logistic regression model to different better-outcome group patients from worse-outcome group patients, the areas under Receiver Operating Characteristic (ROC) curves were found to be 0.797 and 0.883 for begin-filling YM and end-ejection YM, respectively. The sensitivity and specificity 0.761 and 0.755 using end-ejection YM as the predictor. This preliminary study suggests that ventricle material stiffness could be a potential parameter to be used to differentiate BG patients from WG patients with further effort and large-scale patient data validations.

IMPORTANCE: American Heart Association guidelines recommend echocardiography in Kawasaki disease at baseline, 1 to 2 weeks, and 4 to 6 weeks after treatment to detect coronary artery abnormalities. However, these examinations are expensive and may require sedation in young children, which is burdensome and carries some risk. OBJECTIVE: To assess the benefit of additional echocardiographic imaging at 6 weeks in patients with uncomplicated Kawasaki disease who had previously normal coronary arteries. DESIGN, SETTING, AND PARTICIPANTS: This is a retrospective review of patients with Kawasaki disease who were cared for between 1995 and 2014 in 2 academic pediatric referral practices Eligibility criteria included receiving intravenous immunoglobulin treatment for acute Kawasaki disease at a center; the absence of significant congenital heart disease; available echocardiographic measurements of both the right and left anterior descending coronary arteries at 10 days or less after diagnosis (baseline), 2 (±1) weeks, and 6 (±3) weeks of illness; and normal coronary arteries at baseline and 2 weeks, defined as maximum coronary artery z scores less than 2.0 and no distal aneurysms. Data analysis was completed from March 2015 to November 2015. MAIN OUTCOMES AND MEASURES: The number of patients with right coronary artery or left anterior descending coronary artery z scores of 2.0 or more at 6 weeks. RESULTS: The median age of the 464 included patients was 3.3 years (interquartile range, 1.8-5.4 years); 264 (56.9%) were male, 351 of 414 for whom data were available (84.8%) had complete Kawasaki disease, and 66 (14.2%) received additional intravenous immunoglobulin treatment. At 6 weeks of illness, 456 patients (98.3%) who had had normal coronary artery z scores at baseline and 2 weeks continued to have normal z scores. Of the remaining 8 patients (1.7%), the maximum z score within 6 weeks was 2.0 to 2.4 in 5 patients (1.2%), 2.5 to 2.9 in 1 patient (0.2%), and 3.0 or more in 2 patients (0.4% [95% CI, 0.1%-1.5%]). Coronary artery dimensions ultimately normalized in all but 1 patient, who had minimal dilation at 6 weeks (right coronary artery z score, 2.1). Sensitivity analyses using less restrictive cut points (eg, a maximum z score

The bromate-phenolsulfonate reaction was found to exhibit spontaneous oscillations in a batch reactor, where the addition of small amounts of ferroin would result in nonoscillatory behavior. As the ferroin concentration was increased, the system produced very rich nonlinear behavior, including three isolated oscillatory regimes that were separated by as long as 48 h nonoscillatory period. The long-lasting nonlinear behavior may be attributed to the slow desulfonation of phenolsulfonate in an acidic solution, forming phenol-like intermediates. However, unlike the bromate-phenol oscillator, oxygen was found to greatly influence the reaction, and various complex oscillations could be observed by tuning the oxygen concentration. Mechanistic studies performed through employing 1H NMR spectroscopy and mass spectrometry to measure intermediate species at different stages of the reaction were able to identify 1,4-benzoquinone, 2-bromo-1,4-benzoquinone, 2,6-dibromo-1,4-benzoquinone, and 2,4,6-tribromophenol as major components during the reaction.

Patients with repaired tetralogy of Fallot (TOF) account for the majority of cases with late onset right ventricle failure. Comparing TOF patients with healthy people may provide information to address this challenge. Cardiac magnetic resonance (CMR) data were obtained from 16 TOF patients (patient group, PG) and 6 healthy volunteers (healthy group, HG). At begin-of-ejection, better patient group (n=5, BPG) stress was very close to HG stress (54.7±38.4 kPa vs. 51.2±55.7 kPa, p=0.6889) while worse patient group (n=11, WPG) stress was 84% higher than HG stress (p=0.0418). Stress may be used as an indicator to differentiate BPG patients from WPG patients, with further validations.

Background Accurate risk prediction of coronary artery aneurysms ( CAAs ) in North American children with Kawasaki disease remains a clinical challenge. We sought to determine the predictive utility of baseline coronary dimensions adjusted for body surface area ( z scores) for future CAAs in Kawasaki disease and explored the extent to which addition of established Japanese risk scores to baseline coronary artery z scores improved discrimination for CAA development. Methods and Results We explored the relationships of CAA with baseline z scores; with Kobayashi, Sano, Egami, and Harada risk scores; and with the combination of baseline z scores and risk scores. We defined CAA as a maximum z score (zMax) ≥2.5 of the left anterior descending or right coronary artery at 4 to 8 weeks of illness. Of 261 patients, 77 patients (29%) had a baseline zMax ≥2.0. CAAs occurred in 15 patients (6%). CAAs were strongly associated with baseline zMax ≥2.0 versus P Conclusions In a North American center, baseline zMax ≥2.0 in children with Kawasaki disease demonstrated high predictive utility for later development of CAA . Future studies should validate the utility of our findings.

Patients with repaired tetralogy of Fallot account for the majority of cases with late onset right ventricle (RV) failure. A new surgical procedure placing an elastic band in the right ventricle is proposed to improve RV function measured by ejection fraction. A multiphysics modeling approach is developed to combine cardiac magnetic resonance imaging, modeling, tissue engineering and mechanical testing to demonstrate feasibility of the new surgical procedure. Our modeling results indicated that the new surgical procedure has the potential to improve right ventricle ejection fraction by 2-7% which compared favorably with recently published drug trials to treat LV heart failure.

Background The natural history of coronary artery aneurysms ( CAA ) after intravenous immunoglobulin ( IVIG ) treatment in the United States is not well described. We describe the natural history of CAA in US Kawasaki disease ( KD ) patients and identify factors associated with major adverse cardiac events ( MACE ) and CAA regression. Methods and Results We evaluated all KD patients with CAA at 2 centers from 1979 to 2014. Factors associated with CAA regression, maximum CA z ‐score over time ( z Max), and MACE were analyzed. We performed a matched analysis of treatment effect on likelihood of CAA regression. Of 2860 KD patients, 500 (17%) had CAA , including 90 with CAA z ‐score >10. Most (91%) received IVIG within 10 days of illness, 32% received >1 IVIG , and 27% received adjunctive anti‐inflammatory medications. CAA regression occurred in 75%. Lack of CAA regression and higher CAA z Max were associated with earlier era, larger CAA z ‐score at diagnosis, and bilateral CAA in univariate and multivariable analyses. MACE occurred in 24 (5%) patients and was associated with higher CAA z ‐score at diagnosis and lack of IVIG treatment. In a subset of patients (n=132) matched by age at KD and baseline CAA z ‐score, those receiving IVIG plus adjunctive medication had a CAA regression rate of 91% compared with 68% for the 3 other groups ( IVIG alone, IVIG ≥2 doses, or IVIG ≥2 doses plus adjunctive medication). Conclusions CAA regression occurred in 75% of patients. CAA z ‐score at diagnosis was highly predictive of outcomes, which may be improved by early IVIG treatment and adjunctive therapies.

Psychotropic medications are often used to treat problem behaviours in people with intellectual disability which not only occur frequently but also tend to persist over time. This study examined the pattern of prescription of such medications to manage problem behaviours for adults with intellectual disabilities in a specialist psychiatric unit in Hong Kong. Individuals aged 18 or above with problem behaviours and receiving psychotropic medication for treatment in hospital, outpatient and community settings were studied. Their demographic and clinical information was collected. The type and dosage of medications were retrieved from the computer database and analysed. Those with psychotic disorder and mood (affective disorder) were excluded. After screening, 236 patients met the inclusion criteria. People with moderate intellectual disability accounted for most of the cohort (46%). Autism spectrum disorder was the commonest psychiatric diagnosis (35%) and aggression the commonest problem behaviour (52%). Antipsychotics, mood stabilisers and antidepressants were prescribed to 96%, 20% and 13% of the subjects respectively. The profile of problem behaviour in the Chinese population with intellectual disability is consistent with the findings reported in the world literature. Antipsychotic drugs are the most commonly prescribed class of psychotropic medication used to treat such behaviours. Although the current evidence is not strong enough to support a clear‐cut recommendation on the use of medications, the dichotomous notion of ‘prescription’ or ‘no prescription’ for problem behaviours may be simplistic.

Background Accurate calculation of ventricular stress and strain is critical for cardiovascular investigations. Sarcomere shortening in active contraction leads to change of ventricular zero-stress configurations during the cardiac cycle. A new model using different zero-load diastole and systole geometries was introduced to provide more accurate cardiac stress/strain calculations with potential to predict post pulmonary valve replacement (PVR) surgical outcome. Methods Cardiac magnetic resonance (CMR) data were obtained from 16 patients with repaired tetralogy of Fallot prior to and 6 months after pulmonary valve replacement (8 male, 8 female, mean age 34.5 years). Patients were divided into Group 1 (n = 8) with better post PVR outcome and Group 2 (n = 8) with worse post PVR outcome based on their change in RV ejection fraction (EF). CMR-based patient-specific computational RV/LV models using one zero-load geometry (1G model) and two zero-load geometries (diastole and systole, 2G model) were constructed and RV wall thickness, volume, circumferential and longitudinal curvatures, mechanical stress and strain were obtained for analysis. Pairwise T-test and Linear Mixed Effect (LME) model were used to determine if the differences from the 1G and 2G models were statistically significant, with the dependence of the pair-wise observations and the patient-slice clustering effects being taken into consideration. For group comparisons, continuous variables (RV volumes, WT, C- and L- curvatures, and stress and strain values) were summarized as mean ± SD and compared between the outcome groups by using an unpaired Student t-test. Logistic regression analysis was used to identify potential morphological and mechanical predictors for post PVR surgical outcome. Results Based on results from the 16 patients, mean begin-ejection stress and strain from the 2G model were 28% and 40% higher than that from the 1G model, respectively. Using the 2G model results, RV EF changes correlated negatively with stress (r = -0.609, P = 0.012) and with pre-PVR RV end-diastole volume (r = -0.60, P = 0.015), but did not correlate with WT, C-curvature, L-curvature, or strain. At begin-ejection, mean RV stress of Group 2 was 57.4% higher than that of Group 1 (130.1±60.7 vs. 82.7±38.8 kPa, P = 0.0042). Stress was the only parameter that showed significant differences between the two groups. The combination of circumferential curvature, RV volume and the difference between begin-ejection stress and end-ejection stress was the best predictor for post PVR outcome with an area under the ROC curve of 0.855. The begin-ejection stress was the best single predictor among the 8 individual parameters with an area under the ROC curve of 0.782. Conclusion The new 2G model may be able to provide more accurate ventricular stress and strain calculations for potential clinical applications. Combining morphological and mechanical parameters may provide better predictions for post PVR outcome.

Aim: At a single pediatric tertiary care center, we assessed the performance of established Japanese risk scores (RS) to identify patients (pts) with Kawasaki Disease (KD) at higher risk for re-treatment (re-tx). We also sought to determine if the addition of baseline coronary Z-scores to RS could improve the prediction re-tx. Methods: We reviewed available clinical, lab and echocardiogram (echo) data for KD pts treated from 1/2006 to 5/2014. The maximum z-score (zMax) of the right coronary artery (RCA) or left anterior descending artery (LAD) at baseline was used. Abnormal coronary arteries at baseline echo were defined as zMax ≥2 in the RCA or LAD. Kobayashi, Sano, Egami and Harada scores were calculated, comparing low and high risk scores to re-tx. The zMax was incorporated into each RS with 1 point added (+1) if baseline zMax ≥2. In an alternative approach, zMax was added as a covariate in a logistic regression model. The discrimination of each model was assessed using the c statistic. Results: Of 339 pts, 214 (63%) were male, and median age was 3.2 y (range 0.1-14.1 y). At diagnosis, 29% (97/339) had ≤3 classical criteria for KD, and 25% (85/339) received IVIG re-tx. At baseline, the median zMax was 1.37 (-1.64-14.2) and 26% (88/339) had zMax ≥2. Classification as high risk by all four RS was significantly associated with re-tx (p Conclusions: Published RS for predicting IVIG resistance are associated with higher rates of re-tx in our patient population, but are not sufficient to discriminate patients at risk for re-tx. With the addition of baseline zMax as a covariate to the RS, prediction for re-tx was improved, although still modest. Further study in larger, multi-center studies are needed to validate these findings and to better understand the risk factors for re-tx in KD in North American children.

Background: The late natural history of coronary artery aneurysms (CAA) after IVIG treatment in the US is not well described. Methods: We evaluated all KD patients (pts) at 2 centers from 1984-2014. Entry criteria were: 1) IVIG treatment; 2) CAA, defined as LAD or RCA z-score ≥ 3 or Japanese Ministry of Health criteria; and 3) ≥1 follow-up (f/u) echo. Kaplan Meier curves evaluated time to CAA regression (z < 2.5) and Cox regression examined factors associated with persistent CAA and major adverse cardiac events (MACE= death, MI, CABG, PCI, occluded CA). Results: Of 2592 KD pts, 408 (15%) met entry criteria and were 72% male; 54% white, 21% Asian, 7% black, 18% other race. Median age at fever onset was 1.8 y [IQR: 0.7-4.4y], 74% had complete KD, and fever days before 1 st IVIG were 7d [IQR 6-10d]. IVIG retreatment occurred in 35% and adjunctive anti-inflammatory therapy in 37%, both increased over time (p Over median f/u of 2.6 y (0.01-29.0y), 313 (77%) had CAA regression at median of 1.1 mo (IQR =0.3-16.9mo). Univariate risk factors for CAA persistence were z ≥ 8 at diagnosis (HR 0.22, p Day 10 (HR 0.46, p8 at diagnosis (p Conclusion: Most CAA regress within the first year after treatment. Persistent CAA are more likely in pts with larger CAA, multi-vessel CAA and late IVIG treatment. In pts with large CAA, time to regression has gotten shorter in more recent eras, possibly related to greater use of adjunctive therapies.

Background: Echocardiography (echo) is recommended in patients (pts) with KD at baseline, 2 wks, and 6 wks after fever onset to detect coronary artery (CA) abnormalities. However, echo imaging is expensive and in infants and toddlers often requires sedation, which is burdensome and carries some risk. Objective: To assess the benefit of additional echo imaging in uncomplicated KD pts with normal CAs at baseline and 2 wks. Methods: In this retrospective two-center study, eligibility criteria were: 1) admission and treatment at center for acute KD; 2) no significant congenital heart disease; 3) available echo measurements of both the right (R) CA and left anterior descending (LAD) at ≤ Day 10 (baseline), 2 (±1) wks and 6 (±3) wks; and 4) normal CAs = RCA and LAD z scores [zMax] ≤2.0 and no aneurysms. Results: Of 2,600 pts treated for KD from 1976 - 2014, 457 had normal CAs at baseline and 2 wks and met other inclusion criteria. Of these, 57% were male; median age was 3.3 yrs [IQR 1.8 to 5.4 yrs]; 77% had complete KD; and 14% received IVIG retreatment. At 6 wks, 450 (98.5%) had normal CAs. Of the remaining 7 pts, zMax was 2.0-2.4 in 5 (1.1%); their z scores subsequently normalized at 1 yr. The zMax was 2.5-2.9 in 1 (0.2%) pt who remained on low dose aspirin until 6 mos, when ECHO normalized. The zMax was ≥3.0 in 1 pt (0.2%, 95% CI [0.0%, 1.2%]) with a dilated LAD, which was normal 3 wks later. Sensitivity analysis using zMax of Conclusion: New CA abnormalities are rarely detected at 6 wks in KD pts with normal CAs at baseline and 2 wks. The 6 wk echo may be unnecessary for uncomplicated KD pts with normal CAs at baseline and 2 wks. Figure - CA zMax shown as mean (+), median, 25th to 75th %tile.

Purpose: Kawasaki disease (KD) awareness and therapy have evolved since its description in 1967. We explored historical trends since 1984 in patients (pts) treated for KD at a single institution. Methods: Inclusion criteria were 1) first episode of KD, and 2) treated with IVIG within 3 weeks of illness onset. Exclusion criteria were 1) evaluation solely for a second opinion, and 2) presence of congenital heart disease. We reviewed age at diagnosis, sex, race, presence of complete vs. incomplete (fever + Results: Of 1739 pts, 1133 met eligibility criteria. Race included 61% White, 10% Black, 11% Asian: 6% other, and 12% unknown. At diagnosis, 16% were age Conclusions: At a single center over 3 decades, treatment of incomplete KD, as well as retreatment with IVIG and use of adjunctive therapies have become increasingly common. Pts who had incomplete diagnostic criteria received IVIG later in their illness. Future studies should assess whether these secular trends have improved outcomes in pts with KD.

Objective Patients with repaired tetralogy of Fallot account for a substantial proportion of cases with late-onset right ventricular failure. The current surgical approach, which includes pulmonary valve replacement/insertion, has yielded mixed results. Therefore, it may be clinically useful to identify parameters that can be used to predict right ventricular function response to pulmonary valve replacement. Methods Cardiac magnetic resonance data before and 6 months after pulmonary valve replacement were obtained from 16 patients with repaired tetralogy of Fallot (8 male, 8 female; median age, 42.75 years). Right ventricular ejection fraction change from pre- to postpulmonary valve replacement was used as the outcome. The patients were divided into group 1 (n = 8, better outcome) and group 2 (n = 8, worst outcome). Cardiac magnetic resonance–based patient-specific computational right ventricular/left ventricular models were constructed, and right ventricular mechanical stress and strain, wall thickness, curvature, and volumes were obtained for analysis. Results Our results indicated that right ventricular wall stress was the best single predictor for postpulmonary valve replacement outcome with an area under the receiver operating characteristic curve of 0.819. Mean values of stress, strain, wall thickness, and longitudinal curvature differed significantly between the 2 groups with right ventricular wall stress showing the largest difference. Mean right ventricular stress in group 2 was 103% higher than in group 1. Conclusions Computational modeling and right ventricular stress may be used as tools to identify right ventricular function response to pulmonary valve replacement. Large-scale clinical studies are needed to validate these preliminary findings.

Summary: Transcription activator-like effector nucleases (TALENs) are a new class of engineered nucleases that are easier to design to cleave at desired sites in a genome than previous types of nucleases. We report here the use of TALENs to rapidly and efficiently generate mutant alleles of 15 genes in cultured somatic cells or human pluripotent stem cells, the latter for which we differentiated both the targeted lines and isogenic control lines into various metabolic cell types. We demonstrate cell-autonomous phenotypes directly linked to disease—dyslipidemia, insulin resistance, hypoglycemia, lipodystrophy, motor-neuron death, and hepatitis C infection. We found little evidence of TALEN off-target effects, but each clonal line nevertheless harbors a significant number of unique mutations. Given the speed and ease with which we were able to derive and characterize these cell lines, we anticipate TALEN-mediated genome editing of human cells becoming a mainstay for the investigation of human biology and disease. Highlights: ► A system for efficient and rapid genome editing with TALENs ► Generation of isogenic human cellular models of disease ► Identification of disease-associated phenotypes in multiple human cell types ► Minimal TALEN off-target effects, but significant clone-to-clone sequence variation Introduction: The study of human disease has been facilitated by the ability to identify the gene mutations responsible; at the same time, it has been hampered by the lack of an inexhaustible supply of easily accessible tissues from patients bearing those mutations. Another limitation is that many gene mutations that would be informative for disease biology if they could be studied in isolated cells are incompatible with human life (i.e., embryonic lethal). Classical gene-targeting technology via homologous recombination has proven to be an invaluable tool of experimental biology through its use in mouse embryonic stem cells for generating germline knockout and knockin mice; however, its use in mammalian systems has been limited primarily to studies in mice. In many cases, mice do not faithfully phenocopy human physiology and disease, e.g., cholesterol metabolism, coronary artery disease, and human hepatitis C virus (HCV) infection. The emergence of genome editing with engineered nucleases, as well as human pluripotent stem cell (hPSC) technology and differentiation protocols to obtain a variety of cell and tissue types in vitro, now make it possible to rapidly interrogate the effects of genetic modification in otherwise isogenic human model systems. Transcription activator-like effector nucleases (TALENs) are a new class of engineered nucleases that, due to their modular domain structure, have proven more straightforward to design and construct for performing genome editing than other types of nucleases (Bogdanove and Voytas, 2011). TALENs are typically designed as a pair that binds to genomic sequences flanking a target site and generates a double-strand break, which is repaired by the cell using either homology-directed repair (HDR) or the error-prone process of nonhomologous end-joining (NHEJ) (Christian et al., 2010; Li et al., 2011; Miller et al., 2011; Hockemeyer et al., 2011). NHEJ can be exploited to introduce small insertions or deletions (indels) resulting in frameshift mutations that effectively knock out a protein-coding gene. An exogenously introduced double-stranded DNA or single-stranded DNA oligonucleotide (ssODN) can serve as a repair template for HDR to incorporate an alteration into the genome (Soldner et al., 2011). In principle, TALEN pairs can be generated de novo with standard molecular biology techniques in a matter of days (Cermak et al., 2011; Sanjana et al., 2012). To demonstrate the utility, efficiency, and rapidity of TALEN technology in generating human cellular models with which to derive new biological insights, we created mutations in 15 genes and performed detailed phenotypic analysis of four genes for which novel roles in disease biology have emerged in recent years—APOB, SORT1, AKT2, and PLIN1. Results: Modular Assembly and Use of TALENs for Efficient and Rapid Genome Editing The DNA-binding domain of a TALEN comprises an array of 33- to 35-amino-acid monomers that are “coded” to recognize and bind specific DNA base pairs (bp) in a 1:1 fashion (Moscou and Bogdanove, 2009; Boch et al., 2009). We built upon previously described modular Golden Gate methodologies to allow assembly of multiple DNA fragments in an ordered fashion (Li et al., 2011; Cermak et al., 2011), such that a single ligation of preassembled tetramers and trimers generates TALENs that recognize any 15 bp recognition site in the genome (Figure 1; Figure S1 available online). This assembly method requires only 1–2 days for completion and is not prone to errors that complicate methods that rely on PCR amplification of monomers. Furthermore, we have developed a set of optimized vectors and methods for the delivery of TALENs into mammalian cells and, in particular, hPSCs. In brief, we transfect or electroporate TALEN pairs into cells and then subject them to fluorescence-activated cell sorting (FACS) 48 hr posttransfection based on fluorescent-marker expression. We replate the sorted cells at low density and allow them to recover and grow for 1 week, resulting in the formation of distinct single colonies. Colonies are expanded, genomic DNA purified, and mutations analyzed by PCR, agarose-gel screening, and Sanger sequencing (Figure 1 and Figure S1). The entire process from start to finish can be completed in less than one month., National Institutes of Health (U.S.) (R01-DK097768)

Patients with repaired Tetralogy of Fallot (ToF) account for the majority of cases with late onset right ventricle (RV) failure. The current surgical approach, which includes pulmonary valve replacement/insertion (PVR), has yielded mixed results [1–2]. A new surgical option placing an elastic band in the right ventricle is proposed to improve RV cardiac function measured by ejection fraction (EF).Copyright © 2012 by ASME

This randomized, double-blind study evaluated the antiemetic efficacy and the side-effects of promethazine pretreatment (0.5 mg · kg−1 IV + 0.5 mg · kg−1 IM) versus droperidol + placebo pretreatment (droperidol. 0.075 mg kg−1 IV + physiological saline, 0.02 ml · kg−1 IM). One hundred unpremeditated ASA physical status I children ranging from two to ten years, and undergoing outpatient strabismus surgery were studied. All children received inhalational anaesthesia with halothane, nitrous oxide and oxygen. Neither opioids nor muscle relaxants were used. The incidence of vomiting and/or retching and the incidence of side-effects were determined in the post-anaesthesia recovery room (PARR), in the short-stay surgical unit (SSSU), and after discharge from the hospital (including the journey and the stay at home during the first postoperative day). Promethazine and droperidol were equally effective in reducing the incidence of vomiting before discharge to two and eight per cent respectively. On the contrary, the incidences of vomiting after discharge and overall were significantly less with promethazine (ten and ten per cent) than with droperidol pretreatment (54 and 56 per cent) (P < 0.0001). Promethazine permitted the time to discharge from the hospital to be reduced to an average of three hours, without increasing the incidence of vomiting postdischarge. Promethazine pretreatment is much less expensive than droperidol pretreatment. The incidence of restlessness was significantly less with droperidol (eight per cent) than with promethazine (36 per cent) (P < 0.001). Promethazine pretreatment demands the use of an analgesic like acetaminophen in order to reduce the incidence of postoperative pain and restlessness. With the exception of restlessness, the overall incidence of side-effects was not statistically different between the two groups.

Objective Patients with repaired tetralogy of Fallot account for most cases of late-onset right ventricle failure. The current surgical approach, which includes pulmonary valve replacement/insertion, has yielded mixed results. A new surgical option of placing an elastic band in the right ventricle is proposed to improve right ventricular cardiac function as measured by the ejection fraction. Methods A total of 20 computational right ventricular/left ventricular/patch/band combination models using cardiac magnetic resonance imaging from a patient with tetralogy of Fallot were constructed to investigate the effect of band material stiffness variations, band length, and active contraction. These models included 4 different band material properties, 3 band length, 3 active contracting band materials, and models with patch and scar replaced by contracting tissue. Results Our results indicated that the band insertion, combined with active band contraction and tissue regeneration techniques that restore right ventricular myocardium, has the potential to improve right ventricular ejection fraction by 7.5% (41.63% ejection fraction from the best active band model to more than 34.10% ejection fraction from baseline passive band model) and 4.2% (41.63% from the best active band model compared with cardiac magnetic resonance imaging-measured ejection fraction of 37.45%). Conclusions The cardiac magnetic resonance imaging-based right ventricular/left ventricular/patch/band model provides a proof of concept for using elastic bands to improve right ventricular cardiac function. Band insertion, combined with myocardium regeneration techniques and right ventricular remodeling surgical procedures, has the potential to improve ventricular function in patients with repaired tetralogy of Fallot and other similar forms of right ventricular dysfunction after surgery. Additional investigations using in vitro experiments, animal models, and, finally, patient studies are warranted.

Twenty-six patients, ASA physical status 1, scheduled for elective cesarean section, were divided at random into two groups and received via an epidural catheter 20 ml of 2.2% lidocaine hydrocarbonate (17.3 mg.ml-1 lidocaine base) with 5 micrograms.ml-1 epinephrine freshly added (Group CO2 = 13 patients) or 20 ml of 2% lidocaine hydrochloride (17.3 mg.ml-1 lidocaine base) also with 5 micrograms.ml-1 epinephrine freshly added. Following clampage of the umbilical cord (at 40.1 +/- 4.9 min after the injection of lidocaine for the CO2 group and at 41.0 +/- 5.4 min for the HCl group), serum concentrations of lidocaine were measured both in the mother and in the umbilical vein. All newborns were examined by the same blinded pediatrician with Apgar scores at 1, 5 and 10 min and with Neurobehavioral Adaptive Capacity Scores (NACS) at 15 min, 2 h and 24 h. The concentrations of lidocaine in the serum were comparable in both groups: in the mothers 8.61 +/- 1.48 mumol.l-1 for the CO2 group vs 8.04 +/- 2.36 mumol.l-1 for the HCl group and in the newborns 3.86 +/- 0.84 mumol.l-1 for the CO2 group vs 3.92 +/- 0.95 mumol.l-1 for the HCl group. The ratio of umbilical vein to maternal vein concentrations of lidocaine was also similar in both groups: 0.45 +/- 0.07 for the CO2 group vs 0.54 +/- 0.24 for the HCl group. The percentage of newborns with a normal NACS (score > or = 35/40) was equal in both groups, i.e. 91% at 15 min and 2 h of life and 100% at 24 h of life.(ABSTRACT TRUNCATED AT 250 WORDS)

The pharmacokinetic variables of sufentanil were studied in 20 healthy children between two and eight years of age. The plasma concentrations of sufentanil were measured for up to 480 min after administration of a bolus of sufentanil, 1-3 micrograms.kg-1. The distribution half-life (t1/2 alpha) was 5.2 +/- 2.2 (mean +/- SD) min and the elimination half life (t1/2 beta) was 97.0 +/- 42.0 min. The volume of distribution at steady state (Vdss) was 2.9 +/- 0.6 L.kg-1 and the clearance was 30.5 +/- 8.8 ml.kg-1.min-1. The Vdss was one and a half times greater than that reported in adults when expressed as a function of body weight but similar to that of adults when expressed as a function of body surface area. According to our results, the clearance of sufentanil in normal children between two and eight years of age is twice as rapid as that described in adults and adolescents. A greater clearance of sufentanil in children suggests that they would require relatively greater maintenance doses than adults.