Patient-Derived Induced Pluripotent Stem Cell Models for Phenotypic Screening in the Neuronal Ceroid Lipofuscinoses.

Batten disease or neuronal ceroid lipofuscinosis (NCL) is a group of rare, fatal, inherited neurodegenerative lysosomal storage disorders. Numerous genes (CLN1-CLN8, CLN10-CLN14) were identified in which mutations can lead to NCL; however, the underlying pathophysiology remains elusive. Despite this, the NCLs share some of the same features and symptoms but vary in respect to severity and onset of symptoms by age. Some common symptoms include the progressive loss of vision, mental and motor deterioration, epileptic seizures, premature death, and in the rare adult-onset, dementia. Currently, all forms of NCL are fatal, and no curative treatments are available. Induced pluripotent stem cells (iPSCs) can differentiate into any cell type of the human body. Cells reprogrammed from a patient have the advantage of acquiring disease pathogenesis along with recapitulation of disease-associated phenotypes. They serve as practical model systems to shed new light on disease mechanisms and provide a phenotypic screening platform to enable drug discovery. Herein, we provide an overview of available iPSC models for a number of different NCLs. More specifically, we highlight findings in these models that may spur target identification and drug development.

Mid-term functional outcomes of patient-specific versus conventional instrumentation total knee arthroplasty: a prospective study.

INTRODUCTION: Patient-specific instrumentation (PSI) utilizes three-dimensional imaging to produce total knee arthroplasty cutting jigs which matches patient's native anatomy. However, there are limited mid- to long-term studies examining its clinical efficacy. The aim of this study was to compare functional outcomes of PSI surgery versus conventional TKA surgery at 5-year follow-up. MATERIALS AND METHODS: Sixty patients were prospectively recruited into either the MRI-based PSI or conventional TKA group. Functional outcomes were assessed using the Knee Society Function Score (KSFS), Knee Society Knee Score (KSKS) and Oxford Knee Score (OKS), while quality of life was evaluated with the Physical Component Score (PCS) and Mental Component Score (MCS) of Short-Form 36 and compared between the two groups at 5-year follow-up. RESULTS: Although the PCS was 7 ± 3 points better in the PSI group preoperatively (p = 0.017), it became 5 ± 2 points worse than the conventional group at 5-year follow-up (p = 0.025). As compared to the PSI group, the conventional group showed a significantly greater improvement in PCS at 5 years as compared to before surgery (p = 0.003). There were no significant differences in KSFS, KSKS, OKS or MCS between the two groups. CONCLUSIONS: PSI TKA did not result in improved functional outcomes or better quality of life when compared to conventional TKA. The additional costs and waiting time associated with PSI are not justifiable and therefore not recommended as an alternative to conventional TKA. LEVEL OF EVIDENCE: II.

Does the Capital Femoral Physis Bony MorphologyDiffer in Children with Symptomatic Cam-type Femoroacetabular Impingement.

BACKGROUND: The epiphyseal tubercle, the corresponding metaphyseal fossa, and peripheral cupping are key stabilizers of the femoral head-neck junction. Abnormal development of these features in the setting of supraphysiologic physeal stress under high forces (for example, forces that occur during sports activity) may result in a cam morphology. Although most previous studies on cam-type femoroacetabular impingement (FAI) have mainly focused on overgrowth of the peripheral cupping, little is known about detailed morphologic changes of the epiphyseal and metaphyseal bony surfaces in patients with cam morphology. QUESTIONS/PURPOSES: (1) Does the CT-based bony morphology of the peripheral epiphyseal cupping differ between patients with a cam-type morphology and asymptomatic controls (individuals who did not have hip pain)? (2) Does the CT-based bony morphology of the epiphyseal tubercle differ between patients with a cam-type morphology and asymptomatic controls? (3) Does the CT-based bony morphology of the metaphyseal fossa differ between patients with a cam-type morphology and asymptomatic controls? METHODS: After obtaining institutional review board approval for this study, we retrospectively searched our institutional database for patients aged 8 to 15 years with a diagnosis of an idiopathic cam morphology who underwent a preoperative CT evaluation of the affected hip between 2005 and 2018 (n = 152). We excluded 96 patients with unavailable CT scans and 40 patients with prior joint diseases other than cam-type FAI. Our search resulted in 16 patients, including nine males. Six of 16 patients had a diagnosis of bilateral FAI, for whom we randomly selected one side for the analysis. Three-dimensional (3-D) models of the proximal femur were generated to quantify the size of the peripheral cupping (peripheral growth of the epiphysis around the metaphysis), epiphyseal tubercle (a beak-like prominence in the posterosuperior aspect of the epiphysis), and metaphyseal fossa (a groove on the metaphyseal surface corresponding to the epiphyseal tubercle). A general linear model was used to compare the quantified anatomic features between the FAI cohort and 80 asymptomatic hips (aged 8 to 15 years; 50% male) after adjusting for age and sex. A secondary analysis using the Wilcoxon matched-pairs signed rank test was performed to assess side-to-side differences in quantified morphological features in 10 patients with unilateral FAI. RESULTS: After adjusting for age and sex, we found that patients with FAI had larger peripheral cupping in the anterior, posterior, superior, and inferior regions than control patients who did not have hip symptoms or radiographic signs of FAI (by 1.3- to 1.7-fold; p < 0.01 for all comparisons). The epiphyseal tubercle height and length were smaller in patients with FAI than in controls (by 0.3- to 0.6-fold; p < 0.02 for all comparisons). There was no difference in tubercle width between the groups. Metaphyseal fossa depth, width, and length were larger in patients with FAI than in controls (by 1.8- to 2.3-fold; p < 0.001 for all comparisons). For patients with unilateral FAI, we saw similar peripheral cupping but smaller epiphyseal tubercle (height and length) along with larger metaphyseal fossa (depth) in the FAI side compared with the uninvolved contralateral side. CONCLUSION: Consistent with prior studies, we observed more peripheral cupping in patients with cam-type FAI than control patients without hip symptoms or radiographic signs of FAI. Interestingly, the epiphyseal tubercle height and length were smaller and the metaphyseal fossa was larger in hips with cam-type FAI, suggesting varying inner bone surface morphology of the growth plate. The docking mechanism between the epiphyseal tubercle and the metaphyseal fossa is important for epiphyseal stability, particularly at early ages when the peripheral cupping is not fully developed. An underdeveloped tubercle and a large fossa could be associated with a reduction in stability, while excessive peripheral cupping growth would be a factor related to improved physeal stability. This is further supported by observed side-to-side differences in tubercle and fossa morphology in patients with unilateral FAI. Further longitudinal studies would be worthwhile to study the causality and compensatory mechanisms related to epiphyseal and metaphyseal bony morphology in pathogenesis cam-type FAI. Such information will lay the foundation for developing imaging biomarkers to predict the risk of FAI or to monitor its progress, which are critical in clinical care planning. LEVEL OF EVIDENCE: Level III, prognostic study.

What Is the Association Among Epiphyseal Rotation, Translation, and the Morphology of the Epiphysis and Metaphysis in Slipped Capital Femoral Epiphysis?

BACKGROUND: Contemporary studies have described the rotational mechanism in patients with slipped capital femoral epiphysis (SCFE). However, there have been limited patient imaging data and information to quantify the rotation. Determining whether the epiphysis is rotated or translated and measuring the epiphyseal displacement in all planes may facilitate planning for surgical reorientation of the epiphysis. QUESTIONS/PURPOSES: (1) How does epiphyseal rotation and translation differ among mild, moderate, and severe SCFE? (2) Is there a correlation between epiphyseal rotation and posterior or inferior translation in hips with SCFE? (3) Does epiphyseal rotation correlate with the size of the epiphyseal tubercle or the metaphyseal fossa or with epiphyseal cupping? METHODS: We identified 51 patients (55% boys [28 of 51]; mean age 13 ± 2 years) with stable SCFE who underwent preoperative CT of the pelvis before definitive treatment. Stable SCFE was selected because unstable SCFE would not allow for accurate assessment of rotation given the complete displacement of the femoral head in relation to the neck. The epiphysis and metaphysis were segmented and reconstructed in three-dimensions (3-D) for analysis in this retrospective study. One observer (a second-year orthopaedic resident) performed the image segmentation and measurements of epiphyseal rotation and translation relative to the metaphysis, epiphyseal tubercle, metaphyseal fossa, and the epiphysis extension onto the metaphysis defined as epiphyseal cupping. To assess the reliability of the measurements, a randomly selected subset of 15 hips was remeasured by the primary examiner and by the two experienced examiners independently. We used ANOVA to calculate the intraclass and interclass correlation coefficients (ICCs) for intraobserver and interobserver reliability of rotational and translational measurements. The ICC values for rotation were 0.91 (intraobserver) and 0.87 (interobserver) and the ICC values for translation were 0.92 (intraobserver) and 0.87 (intraobserver). After adjusting for age and sex, we compared the degree of rotation and translation among mild, moderate, and severe SCFE. Pearson correlation analysis was used to assess the associations between rotation and translation and between rotation and tubercle, fossa, and cupping measurements. RESULTS: Hips with severe SCFE had greater epiphyseal rotation than hips with mild SCFE (adjusted mean difference 21° [95% CI 11° to 31°]; p < 0.001) and hips with moderate SCFE (adjusted mean difference 13° [95% CI 3° to 23°]; p = 0.007). Epiphyseal rotation was positively correlated with posterior translation (r = 0.33 [95% CI 0.06 to 0.55]; p = 0.02) but not with inferior translation (r = 0.16 [95% CI -0.12 to 0.41]; p = 0.27). There was a positive correlation between rotation and metaphyseal fossa depth (r = 0.35 [95% CI 0.08 to 0.57]; p = 0.01), width (r = 0.41 [95% CI 0.15 to 0.61]; p = 0.003), and length (r = 0.56 [95% CI 0.38 to 0.75]; p < 0.001). CONCLUSION: This study supports a rotational mechanism for the pathogenesis of SCFE. Increased rotation is associated with more severe slips, posterior epiphyseal translation, and enlargement of the metaphyseal fossa. The rotational nature of the deformity, with the center of rotation at the epiphyseal tubercle, should be considered when planning in situ fixation and realignment surgery. Avoiding placing a screw through the epiphyseal tubercle-the pivot point of rotation- may increase the stability of the epiphysis. The realignment of the epiphysis through rotation rather than simple translation is recommended during the open subcapital realignment procedure. Enlargement of the metaphyseal fossa disrupts the interlocking mechanism with the tubercle and increases epiphyseal instability. Even in the setting of a stable SCFE, an increased fossa enlargement may indicate using two screws instead of one screw, given the severity of epiphyseal rotation and the risk of instability. Further biomechanical studies should investigate the number and position of in situ fixation screws in relation to the epiphyseal tubercle and metaphyseal fossa. LEVEL OF EVIDENCE: Level III, prognostic study.

Marginal structural models for repeated measures where intercept and slope are correlated: An application exploring the benefit of nutritional supplements on weight gain in HIV-infected children initiating antiretroviral therapy.

BACKGROUND: The impact of nutritional supplements on weight gain in HIV-infected children on antiretroviral treatment (ART) remains uncertain. Starting supplements depends upon current weight-for-age or other acute malnutrition indicators, producing time-dependent confounding. However, weight-for-age at ART initiation may affect subsequent weight gain, independent of supplement use. Implications for marginal structural models (MSMs) with inverse probability of treatment weights (IPTW) are unclear. METHODS: In the ARROW trial, non-randomised supplement use and weight-for-age were recorded monthly from ART initiation. The effect of supplements on weight-for-age over the first year was estimated using generalised estimating equation MSMs with IPTW, both with and without interaction terms between baseline weight-for-age and time. Separately, data were simulated assuming no supplement effect, with use depending on current weight-for-age, and weight-for-age trajectory depending on baseline weight-for-age to investigate potential bias associated with different MSM specifications. RESULTS: In simulations, despite correctly specifying IPTW, omitting an interaction in the MSM between baseline weight-for-age and time produced increasingly biased estimates as associations between baseline weight-for-age and subsequent weight trajectory increased. Estimates were unbiased when the interaction between baseline weight-for-age and time was included, even if the data were simulated with no such interaction. In ARROW, without an interaction the estimated effect was +0.09 (95%CI +0.02,+0.16) greater weight-for-age gain per month's supplement use; this reduced to +0.03 (-0.04,+0.10) including the interaction. DISCUSSION: This study highlights a specific situation in which MSM model misspecification can occur and impact the resulting estimate. Since an interaction in the MSM (outcome) model does not bias the estimate of effect if the interaction does not exist, it may be advisable to include such a term when fitting MSMs for repeated measures.

A pharmacodynamic model of clinical synergy in multiple myeloma.

BACKGROUND: Multiagent therapies, due to their ability to delay or overcome resistance, are a hallmark of treatment in multiple myeloma (MM). The growing number of therapeutic options in MM requires high-throughput combination screening tools to better allocate treatment, and facilitate personalized therapy. METHODS: A second-order drug response model was employed to fit patient-specific ex vivo responses of 203 MM patients to single-agent models. A novel pharmacodynamic model, developed to account for two-way combination effects, was tested with 130 two-drug combinations. We have demonstrated that this model is sufficiently parameterized by single-agent and fixed-ratio combination responses, by validating model estimates with ex vivo combination responses for different concentration ratios, using a checkerboard assay. This new model reconciles ex vivo observations from both Loewe and BLISS synergy models, by accounting for the dimension of time, as opposed to focusing on arbitrary time-points or drug effect. Clinical outcomes of patients were simulated by coupling patient-specific drug combination models with pharmacokinetic data. FINDINGS: Combination screening showed 1 in 5 combinations (21.43% by LD50, 18.42% by AUC) were synergistic ex vivo with statistical significance (P < 0.05), but clinical synergy was predicted for only 1 in 10 combinations (8.69%), which was attributed to the role of pharmacokinetics and dosing schedules. INTERPRETATION: The proposed framework can inform clinical decisions from ex vivo observations, thus providing a path toward personalized therapy using combination regimens. FUNDING: This research was funded by the H. Lee Moffitt Cancer Center Physical Sciences in Oncology (PSOC) Grant (1U54CA193489-01A1) and by H. Lee Moffitt Cancer Center's Team Science Grant. This work has been supported in part by the PSOC Pilot Project Award (5U54CA193489-04), the Translational Research Core Facility at the H. Lee Moffitt Cancer Center & Research Institute, an NCI-designated Comprehensive Cancer Center (P30-CA076292), the Pentecost Family Foundation, and Miles for Moffitt Foundation.

End-to-end semantic segmentation of personalized deep brain structures for non-invasive brain stimulation.

Electro-stimulation or modulation of deep brain regions is commonly used in clinical procedures for the treatment of several nervous system disorders. In particular, transcranial direct current stimulation (tDCS) is widely used as an affordable clinical application that is applied through electrodes attached to the scalp. However, it is difficult to determine the amount and distribution of the electric field (EF) in the different brain regions due to anatomical complexity and high inter-subject variability. Personalized tDCS is an emerging clinical procedure that is used to tolerate electrode montage for accurate targeting. This procedure is guided by computational head models generated from anatomical images such as MRI. Distribution of the EF in segmented head models can be calculated through simulation studies. Therefore, fast, accurate, and feasible segmentation of different brain structures would lead to a better adjustment for customized tDCS studies. In this study, a single-encoder multi-decoders convolutional neural network is proposed for deep brain segmentation. The proposed architecture is trained to segment seven deep brain structures using T1-weighted MRI. Network generated models are compared with a reference model constructed using a semi-automatic method, and it presents a high matching especially in Thalamus (Dice Coefficient (DC) = 94.70%), Caudate (DC = 91.98%) and Putamen (DC = 90.31%) structures. Electric field distribution during tDCS in generated and reference models matched well each other, suggesting its potential usefulness in clinical practice.

Feasibility and relevance of discrete vasculature modeling in routine hyperthermia treatment planning.

Purpose: To investigate the effect of patient specific vessel cooling on head and neck hyperthermia treatment planning (HTP). Methods and materials: Twelve patients undergoing radiotherapy were scanned using computed tomography (CT), magnetic resonance imaging (MRI) and contrast enhanced MR angiography (CEMRA). 3D patient models were constructed using the CT and MRI data. The arterial vessel tree was constructed from the MRA images using the 'graph-cut' method, combining information from Frangi vesselness filtering and region growing, and the results were validated against manually placed markers in/outside the vessels. Patient specific HTP was performed and the change in thermal distribution prediction caused by arterial cooling was evaluated by adding discrete vasculature (DIVA) modeling to the Pennes bioheat equation (PBHE). Results: Inclusion of arterial cooling showed a relevant impact, i.e., DIVA modeling predicts a decreased treatment quality by on average 0.19 °C (T90), 0.32 °C (T50) and 0.35 °C (T20) that is robust against variations in the inflow blood rate (|ΔT| < 0.01 °C). In three cases, where the major vessels transverse target volume, notable drops (|ΔT| > 0.5 °C) were observed. Conclusion: Addition of patient-specific DIVA into the thermal modeling can significantly change predicted treatment quality. In cases where clinically detectable vessels pass the heated region, we advise to perform DIVA modeling.

Highly efficient and sensitive patient-specific quality assurance for spot-scanned proton therapy.

The purpose of this work was to develop an end-to-end patient-specific quality assurance (QA) technique for spot-scanned proton therapy that is more sensitive and efficient than traditional approaches. The patient-specific methodology relies on independently verifying the accuracy of the delivered proton fluence and the dose calculation in the heterogeneous patient volume. A Monte Carlo dose calculation engine, which was developed in-house, recalculates a planned dose distribution on the patient CT data set to verify the dose distribution represented by the treatment planning system. The plan is then delivered in a pre-treatment setting and logs of spot position and dose monitors, which are integrated into the treatment nozzle, are recorded. A computational routine compares the delivery log to the DICOM spot map used by the Monte Carlo calculation to ensure that the delivered parameters at the machine match the calculated plan. Measurements of dose planes using independent detector arrays, which historically are the standard approach to patient-specific QA, are not performed for every patient. The nozzle-integrated detectors are rigorously validated using independent detectors in regular QA intervals. The measured data are compared to the expected delivery patterns. The dose monitor reading deviations are reported in a histogram, while the spot position discrepancies are plotted vs. spot number to facilitate independent analysis of both random and systematic deviations. Action thresholds are linked to accuracy of the commissioned delivery system. Even when plan delivery is acceptable, the Monte Carlo second check system has identified dose calculation issues which would not have been illuminated using traditional, phantom-based measurement techniques. The efficiency and sensitivity of our patient-specific QA program has been improved by implementing a procedure which independently verifies patient dose calculation accuracy and plan delivery fidelity. Such an approach to QA requires holistic integration and maintenance of patient-specific and patient-independent QA.

Fast personalized electrophysiological models from computed tomography images for ventricular tachycardia ablation planning.

AIMS: Clinical application of patient-specific cardiac computer models requires fast and robust processing pipelines that can be seamlessly integrated into clinical workflows. We aim at building such a pipeline from computed tomography (CT) images to personalized cardiac electrophysiology (EP) model. The simulation output could be useful in the context of post-infarct ventricular tachycardia (VT) radiofrequency ablation (RFA) planning for pre-operative targets prediction. METHODS AND RESULTS: The support for model personalization is a patient-specific virtual three-dimensional heart obtained from CT images. Here, the scar is identified as thinning of the myocardial wall on automatically computed thickness maps. We then use an Eikonal model of wave front propagation with reduced velocity in the damaged areas. An image-based vessel enhancement algorithm can automatically identify VT isthmuses. The personalized model is used for virtual pacing. We obtained a very fast pipeline that enables simulations in only a few minutes. It is fully automated starting from the semi-automated image segmentation phase. The computational time frame is compatible with the construction of a virtual pacing tool. In this tool, onset points and an optional directional block could be interactively selected. The directional block is a simple way to model tissue refractoriness. Output activation maps are compared with EP data acquired pre-operatively. We show that this framework allows the reproduction of recorded re-entrant VT activation patterns. CONCLUSION: Our simulation framework has an application in VT RFA intervention planning. It could be used to guide EP explorations and even predict ablation targets pre-operatively. This could reduce intervention duration and improve success rate.

Estrategias de guía e ingredientes dietéticos de precisión para enfermedades crónicas en población pre-sénior y sénior / Precision dietary guidelines and ingredients for chronic diseases in pre-senior and senior populations

El envejecimiento de la población supone un importante reto, económico y cualitativo, para el sistema de salud orientándolo hacia una atención de tipo preventivo, en la que la nutrición de precisión (NP) y la prescripción de hábitos saludables adquieren relevancia capital. El fin de la NP es procurar una nutrición adaptada a cada individuo, entendiendo que la prevención o el tratamiento de trastornos crónicos (obesidad, diabetes, enfermedad cardiovascular, etc.) deben abordarse de un modo integral, considerando información personal y clínica relevante, edad y características feno- y genotípicas. La elaboración de la presente guía surge de la necesidad de desarrollar modelos nutricionales de precisión que permitan la individualización del tratamiento nutricional, con énfasis en el adulto mayor. Las necesidades nutricionales, las recomendaciones dietéticas y los ingredientes para una NP en las personas pre-sénior y sénior quedan resumidas en realizar al menos 3 comidas diarias, reducir las calorías totales, optar por una alimentación variada y equilibrada con alimentos frescos y de alta densidad nutricional, incorporar verduras, legumbres y pescado, consumir productos lácteos y fibra, preferir carnes blancas en lugar de rojas, evitar frituras, embutidos y alimentos procesados, moderar el consumo de sal, café y alcohol, e hidratarse adecuadamente

The aging of the population underlines an important challenge for the health system not only from sanitary and economic reasons but also by quality perspectives concerning preventive care, where precision nutrition (PN) and the prescription or advice on healthy habits becomes relevant. PN focuses on provide nutrition adapted to each individual, understanding that the prevention or treatment of chronic disorders (obesity, diabetes, cardiovascular disease, etc.) must be addressed in a comprehensive way, considering not only relevant personal and clinical information, but also healthy aging and phenotypical and genotypical features. This guide was prepared due to the need to develop precision nutritional models that allow individualized nutritional treatment for each subject and physiopathological particularities with emphasis on the elderly. Therefore, the requirements of the Spanish pre-senior and senior populations, dietary recommendations and precision foods are reviewed in this document: have at least three daily meals, reduce total calories, choose a varied and balanced diet with fresh foods and high nutritional density, add vegetables, legumes and fish, consume dairy products and fiber, prefer white meat instead of red, avoid fried foods, sausages and processed foods, moderate the consumption of salt, coffee and alcohol, and get hydrated

Spatial Resolution Requirements for Accurate Identification of Drivers of Atrial Fibrillation.

BACKGROUND: Recent studies have demonstrated conflicting mechanisms underlying atrial fibrillation (AF), with the spatial resolution of data often cited as a potential reason for the disagreement. The purpose of this study was to investigate whether the variation in spatial resolution of mapping may lead to misinterpretation of the underlying mechanism in persistent AF. METHODS AND RESULTS: Simulations of rotors and focal sources were performed to estimate the minimum number of recording points required to correctly identify the underlying AF mechanism. The effects of different data types (action potentials and unipolar or bipolar electrograms) and rotor stability on resolution requirements were investigated. We also determined the ability of clinically used endocardial catheters to identify AF mechanisms using clinically recorded and simulated data. The spatial resolution required for correct identification of rotors and focal sources is a linear function of spatial wavelength (the distance between wavefronts) of the arrhythmia. Rotor localization errors are larger for electrogram data than for action potential data. Stationary rotors are more reliably identified compared with meandering trajectories, for any given spatial resolution. All clinical high-resolution multipolar catheters are of sufficient resolution to accurately detect and track rotors when placed over the rotor core although the low-resolution basket catheter is prone to false detections and may incorrectly identify rotors that are not present. CONCLUSIONS: The spatial resolution of AF data can significantly affect the interpretation of the underlying AF mechanism. Therefore, the interpretation of human AF data must be taken in the context of the spatial resolution of the recordings.

Highest dominant frequency and rotor positions are robust markers of driver location during noninvasive mapping of atrial fibrillation: A computational study.

BACKGROUND: Dominant frequency (DF) and rotor mapping have been proposed as noninvasive techniques to guide localization of drivers maintaining atrial fibrillation (AF). OBJECTIVE: The purpose of this study was to evaluate the robustness of both techniques in identifying atrial drivers noninvasively under the effect of electrical noise or model uncertainties. METHODS: Inverse-computed DFs and phase maps were obtained from 30 different mathematical AF simulations. Epicardial highest dominant frequency (HDF) regions and rotor location were compared with the same inverse-computed measurements after addition of noise to the ECG, size variations of the atria, and linear or angular deviations in the atrial location inside the thorax. RESULTS: Inverse-computed electrograms (EGMs) individually correlated poorly with the original EGMs in the absence of induced uncertainties (0.45 ± 0.12) and were worse with 10-dB noise (0.22 ± 0.11), 3-cm displacement (0.01 ± 0.02), or 36° rotation (0.02 ± 0.03). However, inverse-computed HDF regions showed robustness against induced uncertainties: from 82% ± 18% match for the best conditions, down to 73% ± 23% for 10-dB noise, 77% ± 21% for 5-cm displacement, and 60% ± 22% for 36° rotation. The distance from the inverse-computed rotor to the original rotor was also affected by uncertainties: 0.8 ± 1.61 cm for the best conditions, 2.4 ± 3.6 cm for 10-dB noise, 4.3 ± 3.2 cm for 4-cm displacement, and 4.0 ± 2.1 cm for 36° rotation. Restriction of rotor detections to the HDF area increased rotor detection accuracy from 4.5 ± 4.5 cm to 3.2 ± 3.1 cm (P <.05) with 0-dB noise. CONCLUSION: The combination of frequency and phase-derived measurements increases the accuracy of noninvasive localization of atrial rotors driving AF in the presence of noise and uncertainties in atrial location or size.

Personal model-assisted identification of NAD+ and glutathione metabolism as intervention target in NAFLD.

To elucidate the molecular mechanisms underlying non-alcoholic fatty liver disease (NAFLD), we recruited 86 subjects with varying degrees of hepatic steatosis (HS). We obtained experimental data on lipoprotein fluxes and used these individual measurements as personalized constraints of a hepatocyte genome-scale metabolic model to investigate metabolic differences in liver, taking into account its interactions with other tissues. Our systems level analysis predicted an altered demand for NAD+ and glutathione (GSH) in subjects with high HS Our analysis and metabolomic measurements showed that plasma levels of glycine, serine, and associated metabolites are negatively correlated with HS, suggesting that these GSH metabolism precursors might be limiting. Quantification of the hepatic expression levels of the associated enzymes further pointed to altered de novo GSH synthesis. To assess the effect of GSH and NAD+ repletion on the development of NAFLD, we added precursors for GSH and NAD+ biosynthesis to the Western diet and demonstrated that supplementation prevents HS in mice. In a proof-of-concept human study, we found improved liver function and decreased HS after supplementation with serine (a precursor to glycine) and hereby propose a strategy for NAFLD treatment.

Left atrial model reconstruction in atrial fibrillation ablation: reliability of new mapping and complex impedance systems.

AIMS: The effectiveness of atrial fibrillation (AF) ablation relies on detailed knowledge of the anatomy of the left atrium (LA) and pulmonary veins (PVs). It is common to combine computed tomography/magnetic resonance (CT/MR) with imaging by electroanatomical (EA) mapping systems. The aim of this study was to evaluate the accuracy of LA anatomical reconstruction by 'One Model' and 'VeriSense' tools (Ensite Velocity 3.0, St Jude Medical), compared with CT/MR imaging. METHODS AND RESULTS: Seventy-two patients with AF underwent pre-procedural imaging (97% CT-scan, 3% MR imaging) and transcatheter ablation of PVs. Operators were blinded to CT/MR imaging. Electrical Coupling Index (ECI) was used to recognize venous structures when the circular catheter could not. The LA 'One Model' map was obtained without complications; all 124 main left PVs and 144 main right PVs were detected. Nine of 9 intermediate right PVs and 30 of 30 early branches were detected, whereas 1 of the 27 early branches on the right inferior PVs was missed. Comparison between LA intervein distances measured on the roof (RO) and the posterior wall (PW) showed a high correspondence between the EA model and CT/MR imaging (RO CT/MR imaging vs. EA: 32 ± 7 vs. 32 ± 7 mm; PW CT/MR imaging vs. EA: 36 ± 6 vs. 36 ± 7 mm). The EA model yielded slightly larger PV ostia diameters, owing to the distortion caused by catheter pressure. CONCLUSIONS: Recent 3D mapping tools allow outstanding anatomical rendering and are key in complex ablation procedure set-up. This study shows that 3D anatomical reconstruction of LA, PVs, and their variable branches is not only safe and fast but also accurate and reliable.

Simultaneous display of multiple three-dimensional electrophysiological datasets (dot mapping).

AIMS: Complex ablation procedures are supported by accurate representation of an increasing variety of electrophysiological and imaging data within electroanatomic mapping systems (EMS). This study aims to develop a novel method for representing multiple complementary datasets on a single cardiac chamber model. Validation of the system and its application to both atrial and ventricular arrhythmias is examined. METHODS AND RESULTS: Dot mapping was conceived to display multiple datasets by utilizing quantitative surface shading to represent one dataset and finely spaced dots to represent others. Dot positions are randomized within triangular (surface meshes) or tetrahedral (volumetric meshes) simplices making the approach directly transferrable to contemporary EMS. Test data representing uniform electrical activation (n = 10) and focal scarring (n = 10) were used to test dot mapping data perception accuracy. User experience of dot mapping with atrial and ventricular clinical data is evaluated. Dot mapping ensured constant screen dot density for regions of uniform dataset values, regardless of user manipulation of the cardiac chamber. Perception accuracy of dot mapping was equivalent to colour mapping for both propagation direction (1.5 ± 1.8 vs. 4.8 ± 5.3°, P = 0.24) and focal source localization (1.1 ± 0.7 vs. 1.4 ± 0.5 mm, P = 0.88). User acceptance testing revealed equivalent diagnostic accuracy and display fidelity when compared with colour mapping. CONCLUSION: Dot mapping provides the unique ability to display multiple datasets from multiple sources on a single cardiac chamber model. The visual combination of multiple datasets may facilitate interpretation of complex electrophysiological and imaging data.

Three-Dimensional Electroanatomic Mapping System-Enhanced Cardiac Resynchronization Therapy Device Implantation: Results From a Multicenter Registry.

INTRODUCTION: Cardiac resynchronization therapy (CRT) device implantation guided by an electroanatomic mapping system (EAMS) is an emerging technique that may reduce fluoroscopy and angiography use and provide information on coronary sinus (CS) electrical activation. We evaluated the outcome of the EAMS-guided CRT implantation technique in a multicenter registry. METHODS: During the period 2011-2014 we enrolled 125 patients (80% males, age 74 [71-77] years) who underwent CRT implantation by using the EnSite system to create geometric models of the patient's cardiac chambers, build activation mapping of the CS, and guide leads positioning. Two hundred and fifty patients undergoing traditional CRT implantation served as controls. Success and complication rates, fluoroscopy and total procedure times in the overall study population and according to center experience were collected. Centers that performed ≥10 were defined as highly experienced. RESULTS: Left ventricular lead implantation was successful in 122 (98%) cases and 242 (97%) controls (P = 0.76). Median fluoroscopy time was 4.1 (0.3-10.4) minutes in cases versus 16 (11-26) minutes in controls (P < 0.001). Coronary sinus angiography was performed in 33 (26%) cases and 208 (83%) controls (P < 0.001). Complications occurred in 5 (4%) cases and 17 (7%) controls (P = 0.28). Median fluoroscopy time (median 11 minutes vs. 3 minutes, P < 0.001) and CS angiography rate (55% vs. 21%, P < 0.001) were significantly higher in low experienced centers, while success rate and complications rate were similar. CONCLUSIONS: EAMS-guided CRT implantation proved safe and effective in both high- and low-experienced centers and allowed to reduce fluoroscopy use by ≈75% and angiography rate by ≈70%.

Atrial fibrillation septal pacing: translation of modelling results.

AIMS: Atrial fibrillation (AF) septal pacing consists of rapid pacing from a ring of electrodes around the atrial septum, leading to local capture of both atria during AF. The present model-based study evaluated the impact of the number of stimulation electrodes in the septal ring on AF capture for different types of sustained AF dynamics. METHODS AND RESULTS: Using a biophysical model of AF based on CT scans from an AF patient, models with different AF substrates (Cholinergic AF and Meandering Wavelets) were created by varying the atrial membrane kinetics. Rapid pacing was applied from the septum area with a ring of 1, 2, 3, 4, 6, 8, or 12 electrodes during 20 seconds at a pacing cycle lengths (PCLs) in the range 60-100% of AF cycle length (AFCL), in 4% steps. Percentage of captured tissue during rapid pacing was determined using 24 sensing electrode pairs evenly distributed on the atrial surface. Results were averaged over 10 AF simulations. For Cholinergic AF, the number of stimulation electrodes on the septal ring had no significant impact on AF capture independently of AF dynamics. For Meandering Wavelets, more electrodes were needed to achieve AF capture in the presence of complex AF. CONCLUSION: Changes in AF substrate significantly impacted septal pacing outcomes and response to rapid AF pacing may similarly vary patient-to-patient. The number of stimulation electrodes had a lesser impact, suggesting that the design of a ring with 3-4 electrodes around the septum would be sufficient for most AF dynamics.