Auditory cortical regions show resting-state functional connectivity with the default mode-like network in echolocating bats.

Echolocating bats are among the most social and vocal of all mammals. These animals are ideal subjects for functional MRI (fMRI) studies of auditory social communication given their relatively hypertrophic limbic and auditory neural structures and their reduced ability to hear MRI gradient noise. Yet, no resting-state networks relevant to social cognition (e.g., default mode-like networks or DMLNs) have been identified in bats since there are few, if any, fMRI studies in the chiropteran order. Here, we acquired fMRI data at 7 Tesla from nine lightly anesthetized pale spear-nosed bats (Phyllostomus discolor). We applied independent components analysis (ICA) to reveal resting-state networks and measured neural activity elicited by noise ripples (on: 10 ms; off: 10 ms) that span this species' ultrasonic hearing range (20 to 130 kHz). Resting-state networks pervaded auditory, parietal, and occipital cortices, along with the hippocampus, cerebellum, basal ganglia, and auditory brainstem. Two midline networks formed an apparent DMLN. Additionally, we found four predominantly auditory/parietal cortical networks, of which two were left-lateralized and two right-lateralized. Regions within four auditory/parietal cortical networks are known to respond to social calls. Along with the auditory brainstem, regions within these four cortical networks responded to ultrasonic noise ripples. Iterative analyses revealed consistent, significant functional connectivity between the left, but not right, auditory/parietal cortical networks and DMLN nodes, especially the anterior-most cingulate cortex. Thus, a resting-state network implicated in social cognition displays more distributed functional connectivity across left, relative to right, hemispheric cortical substrates of audition and communication in this highly social and vocal species.

KRAGEN: a knowledge graph-enhanced RAG framework for biomedical problem solving using large language models.

MOTIVATION: Answering and solving complex problems using a large language model (LLM) given a certain domain such as biomedicine is a challenging task that requires both factual consistency and logic, and LLMs often suffer from some major limitations, such as hallucinating false or irrelevant information, or being influenced by noisy data. These issues can compromise the trustworthiness, accuracy, and compliance of LLM-generated text and insights. RESULTS: Knowledge Retrieval Augmented Generation ENgine (KRAGEN) is a new tool that combines knowledge graphs, Retrieval Augmented Generation (RAG), and advanced prompting techniques to solve complex problems with natural language. KRAGEN converts knowledge graphs into a vector database and uses RAG to retrieve relevant facts from it. KRAGEN uses advanced prompting techniques: namely graph-of-thoughts (GoT), to dynamically break down a complex problem into smaller subproblems, and proceeds to solve each subproblem by using the relevant knowledge through the RAG framework, which limits the hallucinations, and finally, consolidates the subproblems and provides a solution. KRAGEN's graph visualization allows the user to interact with and evaluate the quality of the solution's GoT structure and logic. AVAILABILITY AND IMPLEMENTATION: KRAGEN is deployed by running its custom Docker containers. KRAGEN is available as open-source from GitHub at: https://github.com/EpistasisLab/KRAGEN.

Subthreshold firing in Mott nanodevices.

Resistive switching, a phenomenon in which the resistance of a device can be modified by applying an electric field1-5, is at the core of emerging technologies such as neuromorphic computing and resistive memories6-9. Among the different types of resistive switching, threshold firing10-14 is one of the most promising, as it may enable the implementation of artificial spiking neurons7,13,14. Threshold firing is observed in Mott insulators featuring an insulator-to-metal transition15,16, which can be triggered by applying an external voltage: the material becomes conducting ('fires') if a threshold voltage is exceeded7,10-12. The dynamics of this induced transition have been thoroughly studied, and its underlying mechanism and characteristic time are well documented10,12,17,18. By contrast, there is little knowledge regarding the opposite transition: the process by which the system returns to the insulating state after the voltage is removed. Here we show that Mott nanodevices retain a memory of previous resistive switching events long after the insulating resistance has recovered. We demonstrate that, although the device returns to its insulating state within 50 to 150 nanoseconds, it is possible to re-trigger the insulator-to-metal transition by using subthreshold voltages for a much longer time (up to several milliseconds). We find that the intrinsic metastability of first-order phase transitions is the origin of this phenomenon, and so it is potentially present in all Mott systems. This effect constitutes a new type of volatile memory in Mott-based devices, with potential applications in resistive memories, solid-state frequency discriminators and neuromorphic circuits.

Activation of PDGF pathway links LMNA mutation to dilated cardiomyopathy.

Lamin A/C (LMNA) is one of the most frequently mutated genes associated with dilated cardiomyopathy (DCM). DCM related to mutations in LMNA is a common inherited cardiomyopathy that is associated with systolic dysfunction and cardiac arrhythmias. Here we modelled the LMNA-related DCM in vitro using patient-specific induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs). Electrophysiological studies showed that the mutant iPSC-CMs displayed aberrant calcium homeostasis that led to arrhythmias at the single-cell level. Mechanistically, we show that the platelet-derived growth factor (PDGF) signalling pathway is activated in mutant iPSC-CMs compared to isogenic control iPSC-CMs. Conversely, pharmacological and molecular inhibition of the PDGF signalling pathway ameliorated the arrhythmic phenotypes of mutant iPSC-CMs in vitro. Taken together, our findings suggest that the activation of the PDGF pathway contributes to the pathogenesis of LMNA-related DCM and point to PDGF receptor-ß (PDGFRB) as a potential therapeutic target.

Who are we missing? Language exclusivity of patient-reported outcomes in atrial fibrillation clinical trials.

INTRODUCTION: Patient-reported outcomes (PROs) are increasingly used to evaluate quality of life (QoL) in Atrial Fibrillation (AF) patients, providing crucial insights in clinical trials. This study examines the frequency of PRO use in AF trials and the linguistic accessibility of AF-specific PROs. BACKGROUND: As the United States becomes more multilingual, ensuring PROs are available in various languages is vital. The number of people speaking a language other than English at home has tripled from 23.1 million in 1980 to 67.8 million in 2019. This diversity necessitates the availability of PROs in multiple languages for inclusive clinical assessments. METHODS: We queried ClinicalTrials.gov for all US interventional AF trials up to November 28, 2023, reviewing each for PRO usage as primary or secondary outcomes. We identified the five most common AF-specific and generic PROs, extracting their available translations and original languages from published sources. RESULTS: Of 233 identified trials, 191 had associated publications, with 180 (94.2%) conducted solely in English. Only one trial (0.4%) used an AF-specific PRO as a primary outcome, compared to four (1.7%) with a generic PRO. Ten trials (4.3%) used AF-specific PROs as secondary endpoints, versus 22 (9.4%) using generic PROs. AF-specific PROs had significantly fewer translations than generic PROs (11.2 vs. 148.8; p < .001). The AF Effect on Quality-of-Life (AFEQT) was available in 24 languages, with limited translations in commonly spoken US languages like Arabic and Asian languages. CONCLUSION: The limited availability of AF-specific PRO translations highlights a barrier to inclusive AF clinical trials. Expanding translations for AF-specific PROs is crucial for equitable QoL assessments.

Fast spin-echo approach for accelerated B1 gradient-based MRI.

PURPOSE: To expand on the previously developed B 1 + $$ {\mathrm{B}}_1^{+} $$ -encoding technique, frequency-modulated Rabi-encoded echoes (FREE), to perform accelerated image acquisition by collecting multiple lines of k-space in an echo train. METHODS: FREE uses adiabatic full-passage pulses and a spatially varying RF field to encode unique spatial information without the use of traditional B0 gradients. The original implementation relied on acquiring single lines of k-space, leading to long acquisitions. In this work, an acceleration scheme is presented in which multiple echoes are acquired in a single shot, analogous to conventional fast spin-echo sequences. Theoretical analysis and computer simulations investigated the feasibility of this approach and presented a framework to analyze important imaging parameters of FREE-based sequences. Experimentally, the multi-echo approach was compared with conventional phase-encoded images of the human visual cortex using a simple surface transceiver coil. Finally, different contrasts demonstrated the clinical versatility of the new accelerated sequence. RESULTS: Images were acquired with an acceleration factor of 3.9, compared with the previous implementation of FREE, without exceeding specific absorption rate limits. Different contrasts can easily be acquired without major modifications, including inversion recovery-type images. CONCLUSION: FREE initially illustrated the feasibility of performing slice-selective 2D imaging of the human brain without the need for a B0 gradient along the y-direction. The multi-echo version maintains the advantages that B 1 + $$ {\mathrm{B}}_1^{+} $$ encoding provides but represents an important step toward improving the clinical feasibility of such sequences. Additional acceleration and more advanced reconstruction techniques could further improve the clinical viability of FREE-based techniques.

Correcting image distortions from a nonlinear B 1 + $$ {\boldsymbol{B}}_{\mathbf{1}}

PURPOSE: To correct image distortions that result from nonlinear spatial variation in the transmit RF field amplitude ( B 1 + $$ {B}_1^{+} $$ ) when performing spatial encoding with the method called frequency-modulated Rabi encoded echoes (FREE). THEORY AND METHODS: An algorithm developed to correct image distortion resulting from the use of nonlinear static field (B0 ) gradients in standard MRI is adapted herein to correct image distortion arising from a nonlinear B 1 + $$ {B}_1^{+} $$ -gradient field in FREE. From a B 1 + $$ {B}_1^{+} $$ -map, the algorithm performs linear interpolation and intensity scaling to correct the image. The quality of the distortion correction is evaluated in 1.5T images of a grid phantom and human occipital lobe. RESULTS: An expanded theoretical description of FREE revealed the symmetry between this B 1 + $$ {B}_1^{+} $$ -gradient field spatial-encoding and standard B0 -gradient field spatial-encoding. The adapted distortion-correction algorithm substantially reduced image distortions arising in the spatial dimension that was encoded by the nonlinear B 1 + $$ {B}_1^{+} $$ gradient of a circular surface coil. CONCLUSION: Image processing based on straightforward linear interpolation and intensity scaling, as previously applied in conventional MRI, can effectively reduce distortions in FREE images acquired with nonlinear B 1 + $$ {B}_1^{+} $$ -gradient fields.

Ambient circulation surrounding an ablation catheter tip affects ablation lesion characteristics.

INTRODUCTION: The association between ambient circulating environments (CEs) and ablation lesions has been largely underexplored. METHODS: Viable bovine myocardium was placed in a saline bath in an ex vivo endocardial model. Radiofrequency (RF) ablation was performed using three different ablation catheters: 3.5 mm open irrigated (OI), 4, and 8 mm. Variable flow rates of surrounding bath fluids were applied to simulate standard flow, high flow, and no flow. For in vivo epicardial ablation, 24 rats underwent a single OI ablation and performed with circulating saline (30 ml/min; n = 12), versus those immersed in saline without circulation (n = 12). RESULTS: High flow reduced ablation lesion volumes for all three catheters. In no-flow endocardial CE, both 4 mm and OI catheters produced smaller lesions compared with standard flow. However, the 8 mm catheter produced the largest lesions in a no-flow CE. Ablation performed in an in vivo model with CE resulted in smaller lesions compared with ablation performed in a no-flow environment. No statistically significant differences in steam pops were found among the groups. CONCLUSION: A higher endocardial CE flow can decrease RF effectiveness. Cardiac tissue subjected to no endocardial CE flow may also limit RF for 4 mm catheters, but not for OI catheters; these findings may have implications for RF ablation safety and efficacy, especially in the epicardial space without circulating fluid or in the endocardium under varying flow conditions.

Atrial fibrillation ablation outcome prediction with a machine learning fusion framework incorporating cardiac computed tomography.

BACKGROUND: Structural changes in the left atrium (LA) modestly predict outcomes in patients undergoing catheter ablation for atrial fibrillation (AF). Machine learning (ML) is a promising approach to personalize AF management strategies and improve predictive risk models after catheter ablation by integrating atrial geometry from cardiac computed tomography (CT) scans and patient-specific clinical data. We hypothesized that ML approaches based on a patient's specific data can identify responders to AF ablation. METHODS: Consecutive patients undergoing AF ablation, who had preprocedural CT scans, demographics, and 1-year follow-up data, were included in the study for a retrospective analysis. The inputs of models were CT-derived morphological features from left atrial segmentation (including the shape, volume of the LA, LA appendage, and pulmonary vein ostia) along with deep features learned directly from raw CT images, and clinical data. These were merged intelligently in a framework to learn their individual importance and produce the optimal classification. RESULTS: Three hundred twenty-one patients (64.2 ± 10.6 years, 69% male, 40% paroxysmal AF) were analyzed. Post 10-fold nested cross-validation, the model trained to intelligently merge and learn appropriate weights for clinical, morphological, and imaging data (AUC 0.821) outperformed those trained solely on clinical data (AUC 0.626), morphological (AUC 0.659), or imaging data (AUC 0.764). CONCLUSION: Our ML approach provides an end-to-end automated technique to predict AF ablation outcomes using deep learning from CT images, derived structural properties of LA, augmented by incorporation of clinical data in a merged ML framework. This can help develop personalized strategies for patient selection in invasive management of AF.

Impact of additional genetic abnormalities at diagnosis of chronic myeloid leukemia for first-line imatinib-treated patients receiving proactive treatment intervention.

The BCR::ABL1 gene fusion initiates chronic myeloid leukemia (CML); however, evidence has accumulated from studies of highly selected cohorts that variants in other cancer-related genes are associated with treatment failure. Nevertheless, the true incidence and impact of additional genetic abnormalities (AGA) at diagnosis of chronic phase (CP)-CML is unknown. We sought to determine whether AGA at diagnosis in a consecutive imatinib-treated cohort of 210 patients enrolled in the TIDEL-II trial influenced outcome despite a highly proactive treatment intervention strategy. Survival outcomes including overall survival, progression-free survival, failure-free survival, and BCR::ABL1 kinase domain mutation acquisition were evaluated. Molecular outcomes were measured at a central laboratory and included major molecular response (MMR, BCR::ABL1 ≤0.1%IS), MR4 (BCR::ABL1 ≤0.01%IS), and MR4.5 (BCR::ABL1 ≤0.0032%IS). AGA included variants in known cancer genes and novel rearrangements involving the formation of the Philadelphia chromosome. Clinical outcomes and molecular response were assessed based on the patient's genetic profile and other baseline factors. AGA were identified in 31% of patients. Potentially pathogenic variants in cancer-related genes were detected in 16% of patients at diagnosis (including gene fusions and deletions) and structural rearrangements involving the Philadelphia chromosome (Ph-associated rearrangements) were detected in 18%. Multivariable analysis demonstrated that the combined genetic abnormalities plus the EUTOS long-term survival clinical risk score were independent predictors of lower molecular response rates and higher treatment failure. Despite a highly proactive treatment intervention strategy, first-line imatinib-treated patients with AGA had poorer response rates. These data provide evidence for the incorporation of genomically-based risk assessment for CML.

Machine Learned Cellular Phenotypes in Cardiomyopathy Predict Sudden Death.

RATIONALE: Susceptibility to VT/VF (ventricular tachycardia/fibrillation) is difficult to predict in patients with ischemic cardiomyopathy either by clinical tools or by attempting to translate cellular mechanisms to the bedside. OBJECTIVE: To develop computational phenotypes of patients with ischemic cardiomyopathy, by training then interpreting machine learning of ventricular monophasic action potentials (MAPs) to reveal phenotypes that predict long-term outcomes. METHODS AND RESULTS: We recorded 5706 ventricular MAPs in 42 patients with coronary artery disease and left ventricular ejection fraction ≤40% during steady-state pacing. Patients were randomly allocated to independent training and testing cohorts in a 70:30 ratio, repeated K=10-fold. Support vector machines and convolutional neural networks were trained to 2 end points: (1) sustained VT/VF or (2) mortality at 3 years. Support vector machines provided superior classification. For patient-level predictions, we computed personalized MAP scores as the proportion of MAP beats predicting each end point. Patient-level predictions in independent test cohorts yielded c-statistics of 0.90 for sustained VT/VF (95% CI, 0.76-1.00) and 0.91 for mortality (95% CI, 0.83-1.00) and were the most significant multivariate predictors. Interpreting trained support vector machine revealed MAP morphologies that, using in silico modeling, revealed higher L-type calcium current or sodium-calcium exchanger as predominant phenotypes for VT/VF. CONCLUSIONS: Machine learning of action potential recordings in patients revealed novel phenotypes for long-term outcomes in ischemic cardiomyopathy. Such computational phenotypes provide an approach which may reveal cellular mechanisms for clinical outcomes and could be applied to other conditions.

Quantifying a spectrum of clinical response in atrial tachyarrhythmias using spatiotemporal synchronization of electrograms.

AIMS: There is a clinical spectrum for atrial tachyarrhythmias wherein most patients with atrial tachycardia (AT) and some with atrial fibrillation (AF) respond to ablation, while others do not. It is undefined if this clinical spectrum has pathophysiological signatures. This study aims to test the hypothesis that the size of spatial regions showing repetitive synchronized electrogram (EGM) shapes over time reveals a spectrum from AT, to AF patients who respond acutely to ablation, to AF patients without acute response. METHODS AND RESULTS: We studied n = 160 patients (35% women, 65.0 ± 10.4 years) of whom (i) n = 75 had AF terminated by ablation propensity matched to (ii) n = 75 without AF termination and (iii) n = 10 with AT. All patients had mapping by 64-pole baskets to identify areas of repetitive activity (REACT) to correlate unipolar EGMs in shape over time. Synchronized regions (REACT) were largest in AT, smaller in AF termination, and smallest in non-termination cohorts (0.63 ± 0.15, 0.37 ± 0.22, and 0.22 ± 0.18, P < 0.001). Area under the curve for predicting AF termination in hold-out cohorts was 0.72 ± 0.03. Simulations showed that lower REACT represented greater variability in clinical EGM timing and shape. Unsupervised machine learning of REACT and extensive (50) clinical variables yielded four clusters of increasing risk for AF termination (P < 0.01, χ2), which were more predictive than clinical profiles alone (P < 0.001). CONCLUSION: The area of synchronized EGMs within the atrium reveals a spectrum of clinical response in atrial tachyarrhythmias. These fundamental EGM properties, which do not reflect any predetermined mechanism or mapping technology, predict outcome and offer a platform to compare mapping tools and mechanisms between AF patient groups.

Arrhythmias including atrial fibrillation and congenital heart disease in Kleefstra syndrome: a possible epigenetic link.

AIMS: Kleefstra syndrome (KS), often diagnosed in early childhood, is a rare genetic disorder due to haploinsufficiency of EHMT1 and is characterized by neuromuscular and intellectual developmental abnormalities. Although congenital heart disease (CHD) is common, the prevalence of arrhythmias and CHD subtypes in KS is unknown. METHODS AND RESULTS: Inspired by a novel case series of KS patients with atrial tachyarrhythmias in the USA, we evaluate the two largest known KS registries for arrhythmias and CHD: Radboudumc (50 patients) based on health record review at Radboud University Medical Center in the Netherlands and GenIDA (163 patients) based on worldwide surveys of patient families. Three KS patients (aged 17-25 years) presented with atrial tachyarrhythmias without manifest CHD. In the international KS registries, the median [interquartile range (IQR)] age was considerably younger: GenIDA/Radboudumc at 10/13.5 (12/13) years, respectively. Both registries had a 40% prevalence of cardiovascular abnormalities, the majority being CHD, including septal defects, vascular malformations, and valvular disease. Interestingly, 4 (8%) patients in the Radboudumc registry reported arrhythmias without CHD, including one atrial fibrillation (AF), two with supraventricular tachycardias, and one with non-sustained ventricular tachycardia. The GenIDA registry reported one patient with AF and another with chronic ectopic atrial tachycardia (AT). In total, atrial tachyarrhythmias were noted in six young KS patients (6/213 or 3%) with at least four (three AF and one AT) without structural heart disease. CONCLUSION: In addition to a high prevalence of CHD, evolving data reveal early-onset atrial tachyarrhythmias in young KS patients, including AF, even in the absence of structural heart disease.

Intrinsically stretchable electrode array enabled in vivo electrophysiological mapping of atrial fibrillation at cellular resolution.

Electrophysiological mapping of chronic atrial fibrillation (AF) at high throughput and high resolution is critical for understanding its underlying mechanism and guiding definitive treatment such as cardiac ablation, but current electrophysiological tools are limited by either low spatial resolution or electromechanical uncoupling of the beating heart. To overcome this limitation, we herein introduce a scalable method for fabricating a tissue-like, high-density, fully elastic electrode (elastrode) array capable of achieving real-time, stable, cellular level-resolution electrophysiological mapping in vivo. Testing with acute rabbit and porcine models, the device is proven to have robust and intimate tissue coupling while maintaining its chemical, mechanical, and electrical properties during the cardiac cycle. The elastrode array records epicardial atrial signals with comparable efficacy to currently available endocardial-mapping techniques but with 2 times higher atrial-to-ventricular signal ratio and >100 times higher spatial resolution and can reliably identify electrical local heterogeneity within an area of simultaneously identified rotor-like electrical patterns in a porcine model of chronic AF.

Knowledge Gaps, Challenges, and Opportunities in Health and Prevention Research for Asian Americans, Native Hawaiians, and Pacific Islanders: A Report From the 2021 National Institutes of Health Workshop.

Asian Americans (AsA), Native Hawaiians, and Pacific Islanders (NHPI) comprise 7.7% of the U.S. population, and AsA have had the fastest growth rate since 2010. Yet the National Institutes of Health (NIH) has invested only 0.17% of its budget on AsA and NHPI research between 1992 and 2018. More than 40 ethnic subgroups are included within AsA and NHPI (with no majority subpopulation), which are highly diverse culturally, demographically, linguistically, and socioeconomically. However, data for these groups are often aggregated, masking critical health disparities and their drivers. To address these issues, in March 2021, the National Heart, Lung, and Blood Institute, in partnership with 8 other NIH institutes, convened a multidisciplinary workshop to review current research, knowledge gaps, opportunities, barriers, and approaches for prevention research for AsA and NHPI populations. The workshop covered 5 domains: 1) sociocultural, environmental, psychological health, and lifestyle dimensions; 2) metabolic disorders; 3) cardiovascular and lung diseases; 4) cancer; and 5) cognitive function and healthy aging. Two recurring themes emerged: Very limited data on the epidemiology, risk factors, and outcomes for most conditions are available, and most existing data are not disaggregated by subgroup, masking variation in risk factors, disease occurrence, and trajectories. Leveraging the vast phenotypic differences among AsA and NHPI groups was identified as a key opportunity to yield novel clues into etiologic and prognostic factors to inform prevention efforts and intervention strategies. Promising approaches for future research include developing collaborations with community partners, investing in infrastructure support for cohort studies, enhancing existing data sources to enable data disaggregation, and incorporating novel technology for objective measurement. Research on AsA and NHPI subgroups is urgently needed to eliminate disparities and promote health equity in these populations.

The ENHANCE-AF clinical trial to evaluate an atrial fibrillation shared decision-making pathway: Rationale and study design.

INTRODUCTION: Shared decision making (SDM) may result in treatment plans that best reflect the goals and wishes of patients, increasing patient satisfaction with the decision-making process. There is a knowledge gap to support the use of decision aids in SDM for anticoagulation therapy in patients with atrial fibrillation (AF). We describe the development and testing of a new decision aid, including a multicenter, randomized, controlled, 2-arm, open-label ENHANCE-AF clinical trial (Engaging Patients to Help Achieve Increased Patient Choice and Engagement for AF Stroke Prevention) to evaluate its effectiveness in 1,200 participants. METHODS: Participants will be randomized to either usual care or to a SDM pathway incorporating a digital tool designed to simplify the complex concepts surrounding AF in conjunction with a clinician tool and a non-clinician navigator to guide the participants through each step of the tool. The participant-determined primary outcome for this study is the Decisional Conflict Scale, measured at 1 month after the index visit during which a decision was made regarding anticoagulation use. Secondary outcomes at both 1 and 6 months will include other decision making related scales as well as participant and clinician satisfaction, oral anticoagulation adherence, and a composite rate of major bleeding, death, stroke, or transient ischemic attack. The study will be conducted at four sites selected for their ability to enroll participants of varying racial and ethnic backgrounds, health literacy, and language skills. Participants will be followed in the study for 6 months. CONCLUSIONS: The results of the ENHANCE-AF trial will determine whether a decision aid facilitates high quality shared decision making in anticoagulation discussions for stroke reduction in AF. An improved shared decision-making experience may allow patients to make decisions better aligned with their personal values and preferences, while improving overall AF care.

B1 -gradient-based MRI using frequency-modulated Rabi-encoded echoes.

PURPOSE: Reduce expense and increase accessibility of MRI by eliminating pulsed field (B0 ) gradient hardware. METHODS: A radiofrequency imaging method is described that enables spatial encoding without B0 gradients. This method, herein referred to as frequency-modulated Rabi-encoded echoes (FREE), utilizes adiabatic full passage pulses and a gradient in the RF field (B1 ) to produce spatially dependent phase modulation, equivalent to conventional phase encoding. In this work, Cartesian phase encoding was accomplished using FREE in a multi-shot double spin-echo sequence. Theoretical analysis and computer simulations investigated the influence of resonance offset and B1 -gradient steepness and magnitude on reconstruction quality, which limit other radiofrequency imaging methodologies. Experimentally, FREE was compared to conventional phase-encoded MRI on human visual cortex using a simple surface transceiver coil. RESULTS: Image distortions occurred in FREE when using nonlinear B1 fields where the phase dependence becomes nonlinear, but with minimal change in signal intensity. Resonance offset effects were minimal for Larmor frequencies within the adiabatic full-passage pulse bandwidth. CONCLUSION: For the first time, FREE enabled slice-selective 2D imaging of the human brain without a B0 gradient in the y-direction. FREE achieved high resolution in regions where the B1 gradient was steepest, whereas images were distorted in regions where nonlinearity in the B1 gradient was significant. Given that FREE experiences no significant signal loss due to B1 nonlinearities and resonance offset, image distortions shown in this work might be corrected in the future based on B1 and B0 maps.

Perpendicular catheter orientation during papillary muscle ablation results in larger, deeper lesions.

INTRODUCTION: Ablation of papillary muscles (PMs) for refractory ventricular arrhythmias can often be challenging. The catheter approach and orientation during ablation may affect optimal radiofrequency (RF) delivery. Yet, no previous study investigated the association between catheter orientation and PM lesion size. We evaluated ablation lesion characteristics with various catheter orientations relative to the PM tissue during open irrigated ablation, using a standardized, experimental setting. METHODS: Viable bovine PM was positioned on a load cell in a circulating saline bath. RF ablation was performed over PM tissue at 50 W, with the open irrigated catheter positioned either perpendicular or parallel to the PM surface. Applied force was 10 g. Ablation lesions were sectioned and underwent quantitative morphometric analysis. RESULTS: A catheter position oriented directly perpendicular to the PM tissue resulted in the largest ablation lesion volumes and depths compared with ablation with the catheter parallel to PM tissue (75.26 ± 8.40 mm3 vs. 34.04 ± 2.91 mm3 , p < .001) and (3.33 ± 0.18 mm vs. 2.24 ± 0.10 mm, p < .001), respectively. There were no significant differences in initial impedance, peak voltage, peak current, or overall decrease in impedance among groups. Parallel catheter orientation resulted in higher peak temperature (41.33 ± 0.28°C vs. 40.28 ± 0.24°C, p = .003), yet, there were no steam pops in either group. CONCLUSION: For PM ablation, catheter orientation perpendicular to the PM tissue achieves more effective and larger ablation lesions, with greater lesion depth. This may have implications for the chosen ventricular access approach, the type of catheter used, consideration for remote navigation, and steerable sheaths.

The unique rectus extraocular muscles of cetaceans: Homologies and possible functions.

Each rectus extraocular muscle in cetaceans divides into two portions: a massive palpebral belly that inserts into the deep surface of the eyelids and a smaller scleral belly that inserts onto the eyeball. While the cetacean palpebral insertions have long been recognized, their homologies and functions remain unclear. To compare cetacean rectus EOM insertions with the global and orbital rectus EOM insertions of other mammals we dissected orbital contents of 20 odontocete species, 2 mysticete species and 18 non-cetacean species, both aquatic and terrestrial. Four cetacean species were also examined with magnetic resonance imaging (MRI). All four rectus muscles in cetaceans had well-developed palpebral bellies and insertions. Adjacent palpebral bellies showed varying degrees of fusion, from near independence to near complete fusion. Fusion was most complete towards palpebral insertions and less towards origins. A medial moiety of the superior rectus palpebral belly is likely the levator palpebrae superioris. Smaller but still robust scleral insertions were present on all recti, with the medial rectus (MR) being significantly more muscular than the others. All non-cetacean species examined had recti with distinct global and orbital insertions, the latter generally onto Tenon's capsule. Orbital insertions in pygmy hippopotamus and Florida manatee extended into the deep surfaces of the eyelids, hence qualifying as palpebral insertions. Our results suggest that rectus EOMs of mammals generally have both global and orbital insertions, and that palpebral bellies of cetaceans and other species are modified homologs of the orbital insertions. The presence of palpebral insertions in pygmy hippopotamus and absence in other cetartiodactyls suggests an intermediate condition between terrestrial cetartiodactyls and cetaceans. Palpebral insertions in Florida manatee and reports of their presence in some pinnipeds suggest parallel evolution in multiple aquatic lineages. Various functions of cetacean palpebral recti have been proposed, including eyelid dilators, protection during diving and thermogenesis for warming eye and brain. For further insight into their possible functions, we observed eye movements of captive bottlenose dolphins (Tursiops truncatus) at the U.S. National Aquarium. Our observations showed that in addition to rotation of the eyeball the entire surrounding palpebral region also moves during gaze changes. For example during upward gaze the globe not only rotates in supraduction but translates dorsally as well. It appears the rectus palpebral bellies are responsible for flexing the palpebral structures and thus also translating the globe, while the scleral insertions act directly for ocular rotation. Along with frequent non-conjugate eye movements, the oculomotor mechanics and repertoire of cetaceans are thus quite distinctive. Summarily, axial displacement within the orbit is a major 'eye movement' in cetaceans, with protrusion and retraction mediated by well-developed circular muscles and retractor bulbi respectively. Torsional eye movements driven by elaborate oblique EOMs are likewise significant. The roles of rectus EOMs for ocular rotation via their scleral insertions, especially the highly muscular MR, are for typical supra/infraductions and nasal/temporal ductions. The palpebral bellies accentuate these ductions by translating the globe and surrounding structures in the same direction.

Impact of Cardiopulmonary Bypass on Neurogenesis and Cortical Maturation.

OBJECTIVE: Neurodevelopmental delays and frontal lobe cortical dysmaturation are widespread among children with congenital heart disease (CHD). The subventricular zone (SVZ) is the largest pool of neural stem/progenitor cells in the postnatal brain. Our aim is to determine the effects of cardiopulmonary bypass (CPB) on neurogenesis and cortical maturation in piglets whose SVZ development is similar to human infants. METHODS: Three-week-old piglets (n = 29) were randomly assigned to control (no surgery), mild-CPB (34°C full flow for 60 minutes) and severe-CPB groups (25°C circulatory-arrest for 60 minutes). The SVZ and frontal lobe were analyzed with immunohistochemistry 3 days and 4 weeks postoperatively. MRI of the frontal lobe was used to assess cortical development. RESULTS: SVZ neurogenic activity was reduced up to 4 weeks after both mild and severe CPB-induced insults. CPB also induced decreased migration of young neurons to the frontal lobe, demonstrating that CPB impairs postnatal neurogenesis. MRI 4 weeks after CPB displayed a decrease in gyrification index and cortical volume of the frontal lobe. Cortical fractional anisotropy was increased after severe CPB injury, indicating a prolonged deleterious impact of CPB on cortical maturation. Both CPB-induced insults displayed a significant change in densities of three major inhibitory neurons, suggesting excitatory-inhibitory imbalance in the frontal cortex. In addition, different CPB insults altered different subpopulations of inhibitory neurons. INTERPRETATION: Our results provide novel insights into cellular mechanisms contributing to CHD-induced neurological impairments. Further refinement of CPB hardware and techniques is necessary to improve long-term frontal cortical dysmaturation observed in children with CHD. ANN NEUROL 2021;90:913-926.