Prediction of Shock-Refractory Ventricular Fibrillation During Resuscitation of Out-of-Hospital Cardiac Arrest.

BACKGROUND: Out-of-hospital cardiac arrest due to shock-refractory ventricular fibrillation (VF) is associated with relatively poor survival. The ability to predict refractory VF (requiring ≥3 shocks) in advance of repeated shock failure could enable preemptive targeted interventions aimed at improving outcome, such as earlier administration of antiarrhythmics, reconsideration of epinephrine use or dosage, changes in shock delivery strategy, or expedited invasive treatments. METHODS: We conducted a cohort study of VF out-of-hospital cardiac arrest to develop an ECG-based algorithm to predict patients with refractory VF. Patients with available defibrillator recordings were randomized 80%/20% into training/test groups. A random forest classifier applied to 3-s ECG segments immediately before and 1 minute after the initial shock during cardiopulmonary resuscitation was used to predict the need for ≥3 shocks based on singular value decompositions of ECG wavelet transforms. Performance was quantified by area under the receiver operating characteristic curve. RESULTS: Of 1376 patients with VF out-of-hospital cardiac arrest, 311 (23%) were female, 864 (63%) experienced refractory VF, and 591 (43%) achieved functional neurological survival. Total shock count was associated with decreasing likelihood of functional neurological survival, with a relative risk of 0.95 (95% CI, 0.93-0.97) for each successive shock (P<0.001). In the 275 test patients, the area under the receiver operating characteristic curve for predicting refractory VF was 0.85 (95% CI, 0.79-0.89), with specificity of 91%, sensitivity of 63%, and a positive likelihood ratio of 6.7. CONCLUSIONS: A machine learning algorithm using ECGs surrounding the initial shock predicts patients likely to experience refractory VF, and could enable rescuers to preemptively target interventions to potentially improve resuscitation outcome.

Machine learning identifies esophageal luminal temperature patterns associated with thermal injury in catheter ablation for atrial fibrillation.

INTRODUCTION: Luminal esophageal temperature (LET) monitoring during atrial fibrillation (AF) ablation is widely used to reduce the incidence of endoscopically detected esophageal lesion (EDEL). We sought to assess whether specific patterns of LET variation are associated with EDEL. METHODS: A high-fidelity multisensor probe was used to record LET in AF patients undergoing radiofrequency ablation (RFA) or cryoballoon ablation (CBA). Explainable machine learning and SHapley Additive exPlanations (SHAP) analysis were used to predict EDEL and assess feature importance. RESULTS: A total of 94 patients (38.3% persistent AF, 71.3% male, 72 RFA, and 22 CBA) were included. EDEL was detected in 11 patients (10 RFA and one CBA). In the RFA group, the highest LET recorded was similar between patients with and without EDEL (40.6 [40.1-41]°C vs. 40.2 [39.1-40.9]°C; p = .313), however, the rate of LET rise for the highest recorded peak was higher (0.08 [0.03-0.12]°C/s vs. 0.02 [0.01-0.05]°C/s; p = .033), and the area under the curve (AUC) for the highest peak was smaller (412.5 [206.8-634.1] vs. 588.6 [380.4-861.1]; p = .047) in patients who had EDEL. In case of CBA, the patient with EDEL had a faster LET decline (0.12 vs. 0.07 [0.02-0.14]°C/s), and a smaller AUC for the lowest trough (2491.3 vs. 2629.3 [1712.6-5283.2]). SHAP analysis revealed that a rate of LET change higher than 0.05°C/s and an AUC less than 600 were more predictive of EDEL in RFA. CONCLUSION: The rate of LET change and AUC for the recorded temperature predicted EDEL, whereas absolute peak temperatures did not.

Intra-cochlear electrode position impacts the preservation of residual hearing in an animal model of cochlear implant surgery.

INTRODUCTION: Preservation of residual hearing after cochlear implantation remains challenging. There are several approaches to preserve residual hearing, but the configuration of the implant electrode array seems to play a major role. Lateral wall electrode arrays are seemingly more favorable in this context. To date, there are no experimental data available which correlate the spatial electrode position in the scala tympani with the extent of hearing preservation. METHODS: Based on µCT imaging data, this study analyses the exact position of a pure- silicone electrode array inserted into the cochlea of four guinea pigs. Array position data were correlated with the extent of hearing loss after implantation, measured using auditory brainstem measurements in the frequency range of the area occupied by the electrode array area as well as apical to the array. RESULTS: The use of pure-silicone arrays without electrodes resulted in artifact-free, high-resolution µCT images that allowed precise determination of the arrays' positions within the scala tympani. The electrode arrays' locations ranged from peri-modiolar to an anti-modiolar. These revealed a correlation of a lower postoperative hearing loss with a higher spatial proximity to the lateral wall. This correlation was found in the low-frequency range only. A significant correlation between the interindividual differences in the diameter of the scala tympani and the postoperative hearing loss could not be observed. CONCLUSION: This study demonstrates the importance of the intra-cochlear electrode array's position for the preservation of residual hearing. The advantage of such an electrode array's position approximated to the lateral wall suggests, at least for this type of electrode array applied in the guinea pig, would be advantageous in the preservation of residual hearing for the apical part of the cochlea, beyond the area occupied by the electrode array.

Electrocardiographic predictors of response to sacubitril/valsartan therapy in heart failure with reduced ejection fraction.

BACKGROUND: Sacubitril/valsartan (SV) is currently recommended as a first-line therapy in patients with heart failure and reduced ejection fraction (HFrEF) due to its significant clinical and prognostic benefit; however, not all patients respond to therapy and predictors of clinical response to SV remain under-studied. AIMS: To identify electrocardiographic (ECG) predictors of response to SV therapy in HFrEF patients. METHODS: A retrospective analysis of a hospital heart failure registry was undertaken. Consecutive HFrEF patients (New York Heart Association class II-III) on maximal-dose SV were studied. Response to SV was defined as ≥10% relative improvement in left ventricular ejection fraction (LVEF) at 3-months post-maximal-dose therapy. Pre-therapy ECGs were retrospectively analyzed for axes and standard wave and interval durations. Logistic regression was used to estimate odds ratios and 95% confidence intervals for associations between predictors and therapeutic response. Backward stepwise regression was employed to develop a parsimonious model. RESULTS: P-wave duration (PWD) 100-120 ms, PWD >120 ms, and QTc >460 ms were associated with response to SV on univariate analysis: OR 18.00 (4.45-122.90), 5.00 (1.47-20.42), and 3.10 (1.18-9.22), respectively. The preferred model that included the former two predictors in combination with pre-therapy creatinine, mineralocorticoid receptor antagonist use, and LVEF was highly selective (area under the ROC curve = 0.868). CONCLUSIONS: Prolongation of both PWD and QTc interval on baseline ECG in HFrEF patients is predictive of therapeutic response to maximal-dose SV therapy and may indicate early cardiac remodeling that is highly amenable to reversal.

The effect of photobiomodulation on hearing loss: A systematic review.

OBJECTIVES: To assess outcomes associated with photobiomodulation therapy (PBMT) for hearing loss in human and animal studies. DESIGN: Systematic review and narrative synthesis in accordance with PRISMA guidelines. SETTING: Data bases searched: MEDLINE, EMBASE, CENTRAL, ClinicalTrials.gov and Web of Science. No limits were placed on language or year of publication. Review conducted in accordance with the PRISMA 2020 statement. PARTICIPANTS: All human and animal subjects treated with PBMT for hearing loss. MAIN OUTCOME MEASURES: Pre- and post-PBMT audio metric outcomes. RESULTS: Searches identified 122 abstracts and 49 full text articles. Of these, 17 studies met the inclusion criteria, reporting outcomes in 327 animals (11 studies), 30 humans (1 study), and 40 animal specimens (5 studies). PBMT parameters included 6 different wavelengths: 908 nm (1 study), 810 nm (1 study), 532 & 635 nm (1 study), 830 nm (3 studies), 808 nm (11 studies). The duration ranged from 4 to 60 minutes in a session, and the follow-up ranged from 5-28 days. Outcomes improved significantly when wavelengths within the range of 800-830 nm were used, and with greater duration of PBMT exposure. Included studies predominantly consisted of non-randomized controlled trials (10 studies). CONCLUSIONS: Hearing outcomes following PBMT appear to be superior to no PBMT for subjects with hearing loss, although higher level evidence is required to verify this. PBMT enables concentrated, focused delivery of light therapy to the inner ear through a non-invasive manner with minimal side effects. As a result of heterogeneity in reporting PBMT parameters and outcomes across the included studies, direct comparison is challenging.

Graft-host coupling changes can lead to engraftment arrhythmia: a computational study.

After myocardial infarction (MI), a significant portion of heart muscle is replaced with scar tissue, progressively leading to heart failure. Human pluripotent stem cell-derived cardiomyocytes (hPSC-CM) offer a promising option for improving cardiac function after MI. However, hPSC-CM transplantation can lead to engraftment arrhythmia (EA). EA is a transient phenomenon arising shortly after transplantation then spontaneously resolving after a few weeks. The underlying mechanism of EA is unknown. We hypothesize that EA may be explained partially by time-varying, spatially heterogeneous, graft-host electrical coupling. Here, we created computational slice models derived from histological images that reflect different configuration of grafts in the infarcted ventricle. We ran simulations with varying degrees of connection imposed upon the graft-host perimeter to assess how heterogeneous electrical coupling affected EA with non-conductive scar, slow-conducting scar and scar replaced by host myocardium. We also quantified the effect of variation in intrinsic graft conductivity. Susceptibility to EA initially increased and subsequently decreased with increasing graft-host coupling, suggesting the waxing and waning of EA is regulated by progressive increases in graft-host coupling. Different spatial distributions of graft, host and scar yielded markedly different susceptibility curves. Computationally replacing non-conductive scar with host myocardium or slow-conducting scar, and increasing intrinsic graft conductivity both demonstrated potential means to blunt EA vulnerability. These data show how graft location, especially relative to scar, along with its dynamic electrical coupling to host, can influence EA burden; moreover, they offer a rational base for further studies aimed to define the optimal delivery of hPSC-CM injection. KEY POINTS: Human pluripotent stem cell-derived cardiomyocytes (hPSC-CM) hold great cardiac regenerative potential but can also cause engraftment arrhythmias (EA). Spatiotemporal evolution in the pattern of electrical coupling between injected hPSC-CMs and surrounding host myocardium may explain the dynamics of EA observed in large animal models. We conducted simulations in histology-derived 2D slice computational models to assess the effects of heterogeneous graft-host electrical coupling on EA propensity, with or without scar tissue. Our findings suggest spatiotemporally heterogeneous graft-host coupling can create an electrophysiological milieu that favours graft-initiated host excitation, a surrogate metric of EA susceptibility. Removing scar from our models reduced but did not abolish the propensity for this phenomenon. Conversely, reduced intra-graft electrical connectedness increased the incidence of graft-initiated host excitation. The computational framework created for this study can be used to generate new hypotheses, targeted delivery of hPSC-CMs.

Elevated fibrosis burden as assessed by MRI predicts cryoballoon ablation failure.

INTRODUCTION: Late-gadolinium enhancement magnetic resonance (LGE-MRI) imaging is increasingly used in management of atrial fibrillation (AFib) patients. Here, we assess the usefulness of LGE-MRI-based fibrosis quantification to predict arrhythmia recurrence in patients undergoing cryoballoon ablation. Our secondary goal was to compare two widely used fibrosis quantification methods. METHODS: In 102 AF patients undergoing LGE-MRI and cryoballoon ablation (mean age 62 years; 64% male; 59% paroxysmal AFib), atrial fibrosis was quantified using the pixel intensity histogram (PIH) and image intensity ratio (IIR) methods. PIH segmentations were completed by a third-party provider as part of the standard of care at our hospital; Image intensity ratio (IIR) segmentations of the same scans were carried out in our lab using a commercially available software package. Fibrosis burdens and spatial distributions for the two methods were compared. Patients were followed prospectively for recurrent arrhythmia following ablation. RESULTS: Average PIH fibrosis was 15.6 ± 5.8% of the left atrial (LA) volume. Depending on threshold (IIRthr ), the average IIR fibrosis (% of LA wall surface area) ranged from 5.0 ± 7.2% (IIRthr = 1.2) to 37.4 ± 10.9% (IIRthr = 0.97). An IIRthr of 1.03 demonstrated the greatest agreement between the methods, but spatial overlap of fibrotic areas delineated by the two methods was modest (Sorenson Dice coefficient: 0.49). Fourty-two patients (41.2%) had recurrent arrhythmia. PIH fibrosis successfully predicted recurrence (HR 1.07; p = .02) over a follow-up period of 362 ± 149 days; regardless of IIRthr , IIR fibrosis did not predict recurrence. CONCLUSIONS: PIH-based volumetric assessment of atrial fibrosis was modestly predictive of arrhythmia recurrence following cryoballoon ablation in this cohort. IIR-based fibrosis was not predictive of recurrence for any of the IIRthr values tested, and the overlap in designated areas of fibrosis between the PIH and IIR methods was modest. Caution must therefore be exercised when interpreting LA fibrosis from LGE-MRI, since the values and spatial pattern are methodology-dependent.

Critical appraisal of technologies to assess electrical activity during atrial fibrillation: a position paper from the European Heart Rhythm Association and European Society of Cardiology Working Group on eCardiology in collaboration with the Heart Rhythm Society, Asia Pacific Heart Rhythm Society, Latin American Heart Rhythm Society and Computing in Cardiology.

We aim to provide a critical appraisal of basic concepts underlying signal recording and processing technologies applied for (i) atrial fibrillation (AF) mapping to unravel AF mechanisms and/or identifying target sites for AF therapy and (ii) AF detection, to optimize usage of technologies, stimulate research aimed at closing knowledge gaps, and developing ideal AF recording and processing technologies. Recording and processing techniques for assessment of electrical activity during AF essential for diagnosis and guiding ablative therapy including body surface electrocardiograms (ECG) and endo- or epicardial electrograms (EGM) are evaluated. Discussion of (i) differences in uni-, bi-, and multi-polar (omnipolar/Laplacian) recording modes, (ii) impact of recording technologies on EGM morphology, (iii) global or local mapping using various types of EGM involving signal processing techniques including isochronal-, voltage- fractionation-, dipole density-, and rotor mapping, enabling derivation of parameters like atrial rate, entropy, conduction velocity/direction, (iv) value of epicardial and optical mapping, (v) AF detection by cardiac implantable electronic devices containing various detection algorithms applicable to stored EGMs, (vi) contribution of machine learning (ML) to further improvement of signals processing technologies. Recording and processing of EGM (or ECG) are the cornerstones of (body surface) mapping of AF. Currently available AF recording and processing technologies are mainly restricted to specific applications or have technological limitations. Improvements in AF mapping by obtaining highest fidelity source signals (e.g. catheter-electrode combinations) for signal processing (e.g. filtering, digitization, and noise elimination) is of utmost importance. Novel acquisition instruments (multi-polar catheters combined with improved physical modelling and ML techniques) will enable enhanced and automated interpretation of EGM recordings in the near future.

An observational comparison of FACT and ACT in the Netherlands and the US.

BACKGROUND: Assertive Community Treatment (ACT) is a well-defined service delivery model for the care and treatment of the most severely mentally ill in the community with American origins. The Dutch have adapted the model in order to accommodate a broader range of needs and allow more flexible implementation. Functional Assertive Community Treatment (FACT) provides the intensity of care needed to help participants sustain life in the community as well as continuity of care over time for many vulnerable client populations.

Post-stenting fractional flow reserve vs coronary angiography for optimization of percutaneous coronary intervention (TARGET-FFR).

AIMS: A fractional flow reserve (FFR) value ≥0.90 after percutaneous coronary intervention (PCI) is associated with a reduced risk of adverse cardiovascular events. TARGET-FFR is an investigator-initiated, single-centre, randomized controlled trial to determine the feasibility and efficacy of a post-PCI FFR-guided optimization strategy vs. standard coronary angiography in achieving final post-PCI FFR values ≥0.90. METHODS AND RESULTS: After angiographically guided PCI, patients were randomized 1:1 to receive a physiology-guided incremental optimization strategy (PIOS) or a blinded coronary physiology assessment (control group). The primary outcome was the proportion of patients with a final post-PCI FFR ≥0.90. Final FFR ≤0.80 was a prioritized secondary outcome. A total of 260 patients were randomized (131 to PIOS, 129 to control) and 68.1% of patients had an initial post-PCI FFR <0.90. In the PIOS group, 30.5% underwent further intervention (stent post-dilation and/or additional stenting). There was no significant difference in the primary endpoint of the proportion of patients with final post-PCI FFR ≥0.90 between groups (PIOS minus control 10%, 95% confidence interval -1.84 to 21.91, P = 0.099). The proportion of patients with a final FFR ≤0.80 was significantly reduced when compared with the angiography-guided control group (-11.2%, 95% confidence interval -21.87 to -0.35], P = 0.045). CONCLUSION: Over two-thirds of patients had a physiologically suboptimal result after angiography-guided PCI. An FFR-guided optimization strategy did not significantly increase the proportion of patients with a final FFR ≥0.90, but did reduce the proportion of patients with a final FFR ≤0.80.

Music perception and speech intelligibility in noise performance by Italian-speaking cochlear implant users.

OBJECTIVE: The goal of this study was to investigate the performance correlations between music perception and speech intelligibility in noise by Italian-speaking cochlear implant (CI) users. MATERIALS AND METHODS: Twenty postlingually deafened adults with unilateral CIs (mean age 65 years, range 46-92 years) were tested with a music quality questionnaire using three passages of music from Classical Music, Jazz, and Soul. Speech recognition in noise was assessed using two newly developed adaptive tests in Italian: The Sentence Test with Adaptive Randomized Roving levels (STARR) and Matrix tests. RESULTS: Median quality ratings for Classical, Jazz and Soul music were 63%, 58% and 58%, respectively. Median SRTs for the STARR and Matrix tests were 14.3 dB and 7.6 dB, respectively. STARR performance was significantly correlated with Classical music ratings (rs = - 0.49, p = 0.029), whereas Matrix performance was significantly correlated with both Classical (rs = - 0.48, p = 0.031) and Jazz music ratings (rs = - 0.56, p = 0.011). CONCLUSION: Speech with competitive noise and music are naturally present in everyday listening environments. Recent speech perception tests based on an adaptive paradigm and sentence materials in relation with music quality measures might be representative of everyday performance in CI users. The present data contribute to cross-language studies and suggest that improving music perception in CI users may yield everyday benefit in speech perception in noise and may hence enhance the quality of listening for CI users.

Clinical outcomes for pediatric patients receiving radiotherapy for solid tumor central nervous system metastases.

Central nervous system (CNS) metastases are rare, but devastating complications of pediatric solid tumors. Radiotherapy alone or postresection serves as an important treatment; however, data on the use of whole-brain radiotherapy (WBRT) versus focal radiotherapy, including stereotactic radiosurgery or stereotactic radiotherapy, for these indications are limited. We report a single institution experience of 26 pediatric patients treated with radiotherapy for solid tumor CNS metastases without leptomeningeal disease. Focal radiotherapy (n = 10) was well tolerated and survival outcomes did not differ between patients treated with WBRT (n = 16) versus focal radiation, suggesting that focal radiotherapy may be considered for patients with limited CNS metastases.

Characterizing the arrhythmogenic substrate in personalized models of atrial fibrillation: sensitivity to mesh resolution and pacing protocol in AF models.

AIMS: Computationally guided persistent atrial fibrillation (PsAF) ablation has emerged as an alternative to conventional treatment planning. To make this approach scalable, computational cost and the time required to conduct simulations must be minimized while maintaining predictive accuracy. Here, we assess the sensitivity of the process to finite-element mesh resolution. We also compare methods for pacing site distribution used to evaluate inducibility arrhythmia sustained by re-entrant drivers (RDs). METHODS AND RESULTS: Simulations were conducted in low- and high-resolution models (average edge lengths: 400/350 µm) reconstructed from PsAF patients' late gadolinium enhancement magnetic resonance imaging scans. Pacing was simulated from 80 sites to assess RD inducibility. When pacing from the same site led to different outcomes in low-/high-resolution models, we characterized divergence dynamics by analysing dissimilarity index over time. Pacing site selection schemes prioritizing even spatial distribution and proximity to fibrotic tissue were evaluated. There were no RD sites observed in low-resolution models but not high-resolution models, or vice versa. Dissimilarity index analysis suggested that differences in simulation outcome arising from differences in discretization were the result of isolated conduction block incidents in one model but not the other; this never led to RD sites unique to one mesh resolution. Pacing site selection based on fibrosis proximity led to the best observed trade-off between number of stimulation locations and predictive accuracy. CONCLUSION: Simulations conducted in meshes with 400 µm average edge length and ∼40 pacing sites proximal to fibrosis are sufficient to reveal the most comprehensive possible list of RD sites, given feasibility constraints.

Neuroprotective Effect of Near-Infrared Light in an Animal Model of CI Surgery.

INTRODUCTION: The preservation of residual hearing has become an important consideration in cochlear implant (CI) recipients in recent years. It was the aim of the present animal experimental study to investigate the influence of a pretreatment with near-infrared (NIR) light on preservation of sensory hair cells and residual hearing after cochlear implantation. METHODS: NIR was applied unilaterally (15 min, 808 nm, 120 mW) to 8 guinea pigs, immediately before a bilateral scala tympani CI electrode insertion was performed. The nonirradiated (contralateral) side served as control. Twenty-eight days postoperatively, auditory brainstem responses (ABRs) were registered from both ears to screen for hearing loss. Thereafter, the animals were sacrificed and inner hair cells (IHCs) and outer hair cells (OHCs) were counted and compared between NIR-pretreated and control (contralateral) cochleae. RESULTS: There was no IHC loss upon cochlear implantation. OHC loss was most prominent on both sides at the apical part of the cochlea. NIR pretreatment led to a statistically significant reduction in OHC loss (by 39.8%). ABR recordings (across the frequencies 4-32 kHz) showed a statistically significant difference between the 2 groups and corresponds well with the apical structural damage. Hearing loss was reduced by about 20 dB on average for the NIR-pretreated group (p ≤ 0.05). DISCUSSION/CONCLUSION: A single NIR pretreatment in this animal model of CI surgery appears to be neuroprotective for residual hearing. This is in line with other studies where several NIR posttreatments have protected cochlear and other neural tissues. NIR pretreatment is an inexpensive, effective, and noninvasive approach that can complement other ways of preserving residual hearing and, hence, should deserve further clinical evaluation in CI patients.

Establishing Reproducibility and Correlation of Cochlear Microphonic Amplitude to Implant Electrode Position Using Intraoperative Electrocochleography and Postoperative Cone Beam Computed Tomography.

OBJECTIVES: The primary objective of this study was to establish the reproducibility of cochlear microphonic (CM) recordings obtained from a cochlear implant (CI) electrode contact during and immediately after insertion. This was achieved by evaluating the insertion angle and calculating the position of the apical electrode contact during insertion, using postoperative cone beam computed tomography (CBCT). The secondary objective was to create individualized patient maps of electrode contacts located within acoustically sensitive regions by correlating the CM amplitude to the electrode position determined using CBCT. METHODS: CMs were recorded from a CI electrode contact during and immediately after insertion in 12 patients (n = 14 ears). Intraoperative recordings were made for a 0.5 kHz tone burst stimulus and were recorded from the apical electrode contact. Postinsertion recordings were made from the odd-numbered electrode contacts (1-15) along the array, using a range of stimulus frequencies (from 0.125 to 2 kHz). The time point at which each electrode contact passed through the round window was noted throughout the insertion, and the CM amplitude at this point was correlated to postoperative CBCT. This correlation was then used to estimate the CM amplitude at particular points within the cochlea, which was in turn compared with the amplitudes recorded from each electrode postoperatively to assess the reproducibility of the recordings. RESULTS: Significant correlation was shown between intraoperative insertion and postinsertion angles at two amplitude events (maximum amplitude: 29° mean absolute error, r = 0.77, p = 0.006; 10% of maximum amplitude: 52° mean absolute error, r = 0.85, p = 0.002). CONCLUSION: We have developed a novel method to demonstrate the reproducibility of the CM responses recorded from a CI electrode during insertion. By correlating the CM amplitude with the postoperative CBCT, we have also been able to create individualized maps of CM responses, categorizing the cochlea into acoustically responsive and unresponsive regions. If the electrode contacts within the acoustically sensitive regions are shown to be associated with improved loudness discrimination, it could have implications for optimal electrode mapping and placement.

Palliative radiotherapy for pediatric patients: Parental perceptions of indication, intent, and outcomes.

OBJECTIVES: Palliative radiation therapy (pRT) is often used to improve quality of life for pediatric patients. Though palliative doses are generally lower than those for cure, pRT may still introduce undesirable effects. The decision to pursue additional therapy for a child may be challenging and depends on parents' knowledge and expectations. The goal of this study was to explore parental perceptions of pRT. METHODS: Twenty-eight children referred for pRT were enrolled in our prospective study. Parents were counseled regarding the indication and expected outcomes. They then completed a series of questionnaires to assess their understanding of pRT, side effects that their child experienced, and how the outcomes compared to their expectations. RESULTS: The majority of parents listed pain relief and addressing new disease as the main indication for pRT. When asked about expectations, the majority chose improvement in quality of life and prolongation of their child's life. Interestingly, 32% of parents expected pRT to cure their child's disease. Most patients undergoing pRT did not experience any adverse symptoms. The outcomes of pRT in the majority of cases exceeded parental expectations. CONCLUSION: Improved quality of life with pRT sometimes blurs the distinction between palliation and cure. We found that most parents understand the aim to improve quality of life, although a proportion of parents perceived pRT as a cure to their child's disease. Despite this, the majority of parents reported that the outcome of the pRT course exceeded their expectations. We postulate that parents derive comfort from pursuing active treatment.

Dynamic voltage threshold adjusted substrate modification technique for complex atypical atrial flutters with varying circuits.

BACKGROUND: Atypical atrial flutter (AFL) is common in patients with postsurgical atrial scar, with macro- or microscopic channels in the scar acting as substrate for reentry. Heterogeneous atrial scarring can cause varying flutter circuits, which makes mapping and ablation challenging, and recurrences common. AIM: We hypothesize that dynamically adjusting voltage thresholds can identify heterogeneous atrial scarring, which can then be effectively homogenized to eliminate atypical AFLs. METHODS: We studied consecutive patients who presented to Electrophysiology laboratory for atypical AFL ablation with history of atriotomy and included the patients with multiple, varying flutter circuits during mapping in our study. We excluded patients with stable flutter circuit that was sustained and could be localized using traditional entrainment and activation mapping strategy. In the included patients, we performed detailed high-density voltage map of the atrium of interest. We adjusted voltage thresholds as needed to identify heterogeneity and channels in the scarred regions. A thorough scar homogenization was performed with irrigated smart-touch ablation catheter. Re-inducibility of tachycardia, and immediate and long-term outcomes were studied. RESULTS: Of five studied cases, one was female; age 66 ± 10 years. All five had prior surgical substrate. All the patients had multiple flutter morphologies, which varied as we mapped the AFL. After scar homogenization, tachycardia was not inducible in any patient. No recurrence of flutter was noted during a mean follow-up duration of 450 ± 27 days. CONCLUSION: High-density voltage mapping and homogenization of the scar can be an effective strategy in eliminating complex scar-mediated atypical AFL with multiple circuits.

DNA methylation dynamics during in vivo differentiation of blood and skin stem cells.

DNA methylation is a mechanism of epigenetic regulation that is common to all vertebrates. Functional studies underscore its relevance for tissue homeostasis, but the global dynamics of DNA methylation during in vivo differentiation remain underexplored. Here we report high-resolution DNA methylation maps of adult stem cell differentiation in mouse, focusing on 19 purified cell populations of the blood and skin lineages. DNA methylation changes were locus specific and relatively modest in magnitude. They frequently overlapped with lineage-associated transcription factors and their binding sites, suggesting that DNA methylation may protect cells from aberrant transcription factor activation. DNA methylation and gene expression provided complementary information, and combining the two enabled us to infer the cellular differentiation hierarchy of the blood lineage directly from genome-scale data. In summary, these results demonstrate that in vivo differentiation of adult stem cells is associated with small but informative changes in the genomic distribution of DNA methylation.

Synthetic memory circuits for tracking human cell fate.

A variety of biological phenomena, from disease progression to stem cell differentiation, are typified by a prolonged cellular response to a transient environmental cue. While biologically relevant, heterogeneity in these long-term responses is difficult to assess at the population level, necessitating the development of biological tools to track cell fate within subpopulations. Here we present a novel synthetic biology approach for identifying and tracking mammalian cell subpopulations. We constructed three genomically integrated circuits that use bistable autoregulatory transcriptional feedback to retain memory of exposure to brief stimuli. These "memory devices" are used to isolate and track the progeny of cells that responded differentially to doxycycline, hypoxia, or DNA-damaging agents. Following hypoxic or ultraviolet radiation exposure, strongly responding cells activate the memory device and exhibit changes in gene expression, growth rates, and viability for multiple generations after the initial stimulus. Taken together, these results indicate that a heritable memory of hypoxia and DNA damage exists in subpopulations that differ in long-term cell behavior.

New insights on the cardiac safety factor: Unraveling the relationship between conduction velocity and robustness of propagation.

Cardiac conduction disturbances are linked with arrhythmia development. The concept of safety factor (SF) has been derived to describe the robustness of conduction, but the usefulness of this metric has been constrained by several limitations. For example, due to the difficulty of measuring the necessary input variables, SF calculations have only been applied to synthetic data. Moreover, quantitative validation of SF is lacking; specifically, the practical meaning of particular SF values is unclear, aside from the fact that propagation failure (i.e., conduction block) is characterized by SF < 1. This study aims to resolve these limitations for our previously published SF formulation and explore its relationship to relevant electrophysiological properties of cardiac tissue. First, HL-1 cardiomyocyte monolayers were grown on multi-electrode arrays and the robustness of propagation was estimated using extracellular potential recordings. SF values reconstructed purely from experimental data were largely between 1 and 5 (up to 89.1% of sites characterized). This range is consistent with values derived from synthetic data, proving that the formulation is sound and its applicability is not limited to analysis of computational models. Second, for simulations conducted in 1-, 2-, and 3-dimensional tissue blocks, we calculated true SF values at locations surrounding the site of current injection for sub- and supra-threshold stimuli and found that they differed from values estimated by our SF formulation by <10%. Finally, we examined SF dynamics under conditions relevant to arrhythmia development in order to provide physiological insight. Our analysis shows that reduced conduction velocity (Θ) caused by impaired intrinsic cell-scale excitability (e.g., due to sodium current a loss-of-function mutation) is associated with less robust conduction (i.e., lower SF); however, intriguingly, Θ variability resulting from modulation of tissue scale conductivity has no effect on SF. These findings are supported by analytic derivation of the relevant relationships from first principles. We conclude that our SF formulation, which can be applied to both experimental and synthetic data, produces values that vary linearly with the excess charge needed for propagation. SF calculations can provide insights helpful in understanding the initiation and perpetuation of cardiac arrhythmia.