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Revisiting Face-to-Hand Area Remapping in the Human Primary Somatosensory Cortex after a Cervical Spinal Cord Injury

Spinal cord injury (SCI) leads to profound disruptions in sensorimotor processing. Seminal research in nonhuman primates suggests this sensory deprivation causes functional remapping in the primary somatosensory cortex (S1), where somatotopic representations of deprived body parts, such as the hand in cervical SCI, become responsive to touch on intact body parts, such as the face. However, evidence for such remapping in humans remains inconclusive. We investigated face-to-hand remapping in 16 chronic cervical SCI patients (15 male, 1 female) and 21 able-bodied controls (19 male, 2 female) using two fMRI experiments. Experiment 1 employed a lip movement task, while Experiment 2 investigated the full architecture of S1 face reorganization through vibrotactile stimulation of the forehead, lips, and chin. We assessed (1) the level of face activity in the anatomical S1 hand area, (2) cortical shifts in peak face activity, (3) face-part separability in the S1 hand area, and (4) correlations with clinical characteristics that may drive face-to-hand area remapping. Our results revealed no significant evidence in favor of face-to-hand area remapping in tetraplegic patients across markers of face-to-hand remapping during either lip movement or vibrotactile stimulation of face parts. Furthermore, our markers of remapping did not correlate with clinical characteristics. Together, these findings indicate that cortical face-to-hand remapping could not be demonstrated in our cohort of chronic cervical SCI patients, highlighting the need to revisit assumptions of large-scale face-to-hand reorganization after SCI.

Working Memory Deficits in Hippocampal Amnesia are Associated with Apathy

The hippocampus is increasingly recognized for its role in working memory representations and goal-directed behavior, yet whether these functions share common neural substrates remains unclear. We investigated short-term memory performance in 27 patients (21 males and 6 females) with LGI1-antibody limbic encephalitis, a condition with predominant hippocampal involvement, compared to 27 age- and gender-matched healthy controls, using an object–location continuous report task with Bayesian mixture-modeling. Patients exhibited predominantly elevated misbinding errors—incorrectly associating objects with non-target locations—with unaltered guessing and only marginally reduced precision. Critically, apathy was positively associated with misbinding exclusively in patients, independent of depression and global cognition. Neuroimaging in a subset of patients ( n  = 12) revealed reduced hippocampal volumes and preliminary evidence for diminished hippocampal—medial prefrontal connectivity, which was associated with both higher apathy and increased misbinding at short retention intervals. These findings demonstrate that hippocampal dysfunction produces convergent deficits in memory binding and motivation, potentially reflecting disruption of a common brain mechanism linking working memory processing to goal-directed behavior.

Hypothalamic Glutamatergic/Orexinergic Neurons Attenuate Fentanyl-Induced Respiratory Depression via Medullary Pre-BöTzinger Complex Pathways

Opioid-induced respiratory depression, particularly from fentanyl, is a major contributor to overdose mortality. The hypothalamus plays a modulatory role in breathing, potentially via orexinergic and glutamatergic projections to medullary respiratory centers. Here, we investigated the role of hypothalamic neurons in counteracting fentanyl-induced respiratory depression (FIRD) in male and female mice. We found that orexin (ORX) and glutamatergic (VGlut2+) neurons are distributed in dorsal hypothalamic nuclei, mainly in the lateral hypothalamus (LH) and more sparsely in the paraventricular nucleus (PVN) and send projections to the pre-Bötzinger complex (preBötC) in the medulla. Hypercapnia activated ORX neurons in the LH, but not in the PVN. Pharmacological blockade of ORX signaling with a dual ORX receptor antagonist dose-dependently suppressed respiratory activity and exacerbated FIRD. Using chemogenetics and whole-body plethysmography, we found that activation of dorsal hypothalamic neurons projecting to the preBötC increased respiratory rate and attenuated FIRD. Activation of glutamatergic neurons in either the LH or PVN stimulated ventilation; however, this effect was independent of ORX signaling. Notably, activation of LH–glutamatergic neurons successfully reduced FIRD, whereas activation of PVN glutamatergic neurons failed to attenuate FIRD. Chemogenetic activation of LH neurons projecting to the preBötC increased respiratory rate in an ORX signaling-dependent manner and was sufficient to attenuate FIRD. In contrast, activation of PVN neurons projecting to the preBötC enhanced active movements/arousal of mice but had minimal effects on respiratory parameters. Therefore, these findings suggest that LH–ORX/glutamatergic projections to the medulla drive respiratory activity that can alleviate FIRD in mice of either sex.

Dynamics of Dentate Gyrus Place Cells and Dentate Spikes during Spatial and Nonspatial Changes in Environments

The dentate gyrus (DG) is thought to play a key role in the formation of dissociable memory representations for similar contexts. Neurons in the DG receive highly processed spatial and nonspatial sensory information from the medial and lateral entorhinal cortices, respectively. Changes in spatially tuned firing patterns of DG place cells occur after spatial changes to an environment, but the degree to which DG place cells respond to ethologically relevant nonspatial stimuli is largely unknown. Spatial and nonspatial information is thought to be transmitted to the DG during discrete local field potential events called dentate spikes. Here, we tested the extent to which different spatial and nonspatial stimuli modulate place cell firing patterns and dentate spike dynamics. We performed extracellular recordings of DG place cells and local field potentials in rats of both sexes exploring a familiar spatial environment, in which social stimuli and nonsocial odors of varying ethological relevance were presented, and a novel spatial environment. As expected, DG place cells exhibited different firing patterns between familiar and novel environments. Significant changes in firing were not observed, however, with any of the nonspatial stimuli. Surprisingly, the occurrence of dentate spikes associated with lateral entorhinal cortex input increased during exploration of ethologically relevant stimuli, and this increase was greater for social stimuli. Altogether, these results suggest that the DG preferentially responds to social stimuli at the network level, providing novel insights into how spatial and nonspatial information is processed in the DG.

Motor Prediction Reduces Beta-Band Power and Enhances Cerebellar–Somatosensory Connectivity before Self-Touch to Enable Its Attenuation

Motor control theories suggest that the brain uses forward models to predict self-generated tactile input during voluntary movements, thereby reducing the intensity of reafferent tactile sensations. When one's own body is the target, this phenomenon is called self-touch attenuation. Although self-touch attenuation is well documented, it remains unclear how prediction-related neural mechanisms drive attenuation before the self-touch input. We used magnetoencephalography to examine the neural correlates of self-touch prediction. Twenty-four human participants (12 females, 12 males) performed a self-touch, and two control tasks. In one control, they received externally generated touch without movement. In the other, the touch was triggered by the participant's movement, but the hands were spatially misaligned. This manipulation is known to weaken attenuation despite identical tactile input, movement, and task demands, because the sensorimotor context reduces prediction of touch at that body site. Self-touch evoked weaker somatosensory activity (M50 component) than both control conditions. A psychophysics task mirrored the pattern of neural attenuation, as the perception of self-touch was attenuated compared with the two control conditions. To isolate predictive neural mechanisms from general movement-related activity, we subtracted activity from corresponding stimulus-absent trials. Comparing self-touch with misaligned touch allowed us to refine the signal specific to predictive processing in self-touch and revealed greater prestimulus beta-band desynchronization and increased cerebellar-to-somatosensory connectivity before self-touch compared with misaligned touch. Our results provide the first evidence of predictive neural activity that shapes the sensory consequences of self-touch, offering insights into the mechanisms through which predictive models modulate somatosensory processing.

Delay Selection by Spike-Timing-Dependent Plasticity Shapes Efficient Networks for Signal Transmission

Information processing in the brain relies on efficient communication between different brain regions. Brain oscillations can control signal transmission in brain networks by modulating the timing and excitability of sender and receiver areas. For effective transmission, signals should arrive at target areas when their excitability is maximal. For reciprocally connected neural populations, this mechanism works if the transmission delay matches the period of their evoked oscillation. However, the mechanisms underlying such development of the connections with matched delays remain elusive. While transmission delays in brain networks change during development, the process by which delays are tuned for efficient transmission is unknown. Here, we demonstrate that the well-known Hebbian learning rule can provide a mechanism for selecting connections with delays that match the period of network oscillations. We consider a reciprocally connected bi-layer network of excitatory and inhibitory neurons that generate network-level oscillations spontaneously or in response to external stimuli. When exposed to spike-timing-dependent plasticity, the network self-organizes to potentiate connections with delays matching the oscillation period, while depressing those with non-matching delays. Our findings shed light on how transmission delays may evolve during learning and development to optimize the organization of brain networks for efficient signal transmission.

Plasticity in Thoracic Paravertebral Sympathetic Postganglionic Neurons after High Spinal Cord Transection

Various presympathetic descending brain circuits recruit spinal cord preganglionic neurons to encode central sympathetic drive via their synaptic actions onto sympathetic postganglionic neurons (SPNs)—the final sympathetic output neurons. Thoracic paravertebral ganglia SPNs (tSPNs) provide distributed control over body tissue systems via functional subpopulations. High thoracic spinal cord injuries (SCIs) compromise supraspinal control of SPNs, causing dysautonomias including hypotension. In adult mice of either sex, we tested whether SCI-induced chronic loss of supraspinal control of tSPN activity leads to homeostatic increases in excitability. tSPN excitability spanned a >10-fold range in both sham and SCI populations, governed by a strong linear (ohmic) relationship between cell resistance and threshold depolarizing current (rheobase). The substantial variability obscured SCI-induced intrinsic plasticity. Dendritic length was reduced, as was measured cell capacitance in neuropeptide Y-expressing (NPY + ) tSPNs (putative vasoconstrictors), which represent >40% of tSPNs. NPY + tSPNs had changes in active membrane properties including an increased repetitive firing output gain (↑ f – I slope), which modeling attributed to reduced delayed rectifier currents ( I K ). After SCI, spontaneous quantal excitatory synaptic frequency increased overall (226%) including in the NPY + tSPN subpopulation (300%); their temporal summation recruited spiking in 10.5% of sham and 22.2% of SCI recordings. Computational modeling showed that spontaneous synaptic activity was particularly effective at recruiting spiking after SCI. Overall, tSPNs, including vasoconstrictors, appear to undergo compensatory increases in excitability following high thoracic SCI. These alterations would further contribute to observed central and peripheral changes that limit hypotension but also exaggerate hyper-reflexic responses.

Developmental Changes to the M-Current Shape the Direction of Its Neuromodulation in Zebrafish Motoneurons

Movements during development are refined through ongoing maturation of the spinal circuits that mediate them. In many vertebrates, including zebrafish, this maturation process involves neuromodulators; however, targets of this neuromodulation remain largely unknown. The noninactivating subthreshold potassium current—the M-current—is well known for being a neuromodulatory target. We asked whether neuromodulators might target the M-current in primary motoneurons during development. Our patch-clamp experiments in primary motoneurons of zebrafish (unknown sex) aged 3 to 5 d postfertilization (dpf) reveal distinct modulation of the M-current by acetylcholine and serotonin. Neuromodulation of the M-current was found to change during development with the effects of neuromodulation reflecting the relative levels of the M-current in primary motoneurons at different ages. Indeed, recent work has revealed that the M-current transiently peaks at 3 dpf and is reduced at 4 and 5 dpf in zebrafish primary motoneurons. Our data demonstrates an inhibitory influence of serotonin signaling via 5HT 1A receptors that promotes repetitive firing in primary motoneurons specifically at 3 dpf. 5HT 1A agonism also increases motor output during evoked swimming at that age. We also show that acetylcholine enhances the M-current via M2 receptors and limits repetitive firing in primary motoneurons most prominently at 4 and 5 dpf but not at 3 dpf. Pharmacological modulation of PIP 2 suggests that neuromodulation of the M-current in primary motoneurons may act through this signaling pathway. Our findings suggest that the developmental changes in the M-current shape the direction of neuromodulatory control over primary motoneuron firing and, by consequence, motor activity.

Increased Self-Grooming Gates Adult Visual Cortical Plasticity through a Ventral Pallidum–Visual Cortex Pathway

Repetitive behaviors are prominent features of multiple neurodevelopmental and psychiatric disorders, which are frequently accompanied by abnormalities in visual processing. However, whether repetitive behavioral states themselves actively regulate visual system and through what neural mechanisms remain unclear. Using a water spray paradigm that selectively increased self-grooming in male mice, we showed ocular-dominance plasticity in adult primary visual cortex (V1) was markedly enhanced. Neurons in the ventral pallidum (VP) were activated in synchrony with self-grooming behavior. VP inhibition abolished both grooming and plasticity, whereas VP activation was sufficient to boost both. Viral tracing identified a direct, predominantly GABAergic VP→V1 projection whose activity controlled V1 E/I balance and grooming-induced plasticity. In a pharmacological model of compulsive grooming induced by repeated meta-chlorophenylpiperazine administration, grooming intensity positively correlated with visual plasticity in a VP-dependent manner. Together, these findings identified the VP–V1 pathway as a critical circuit through which a grooming-associated behavioral state modulated adult visual cortical plasticity, revealing a previously unrecognized link between behavioral state and sensory cortical function.

Decoding Orientation Serial Dependence from V1/V2 Population Responses Using a Cross-Attention Transformer

Perception of visual orientation is shaped by not only the current stimulus but also the recent history, showing repulsive biases or attractive serial dependence biases. Although repulsion is often assumed to arise in the early visual cortex, the neural origin of attraction remains debated: Does it reflect top–down modulation embedded in early cortical activity, or does it emerge only from downstream circuits that reverse repulsion? Here we combined two-photon calcium imaging in awake, fixating male macaques with a cross-attention transformer decoder to examine whether V1/V2 population activity contains signals that can support separate readouts of repulsive and attractive biases. We simultaneously recorded large samples of V1/V2 neurons responding to sequential oriented stimuli embedded in white noise. Despite average responses showing only repulsion, the cross-attention transformer, which was designed to model interactions between preceding and current stimulus responses, successfully decoded both repulsive and attractive biases from the same population activity. Attention-map analyses further revealed distinct readout patterns for the two biases, and a constrained shared-representation control with only final-stage output transformation performed substantially worse than the independently trained decoders. These findings indicate that V1/V2 population activity can support different readouts of history-dependent orientation bias.

Occupational Radiation Safety in Electrophysiology During Pregnancy: Evaluating Uterine Radiation Doses During Catheter Ablations and Device Implantations

Response by Rogers et al to Letter Regarding, “Deep Learning-Based Continuous QT Monitoring to Identify High-Risk Prolongation Events After Class III Antiarrhythmic Initiation”

Clinical Cardiology at the Crossroads: Perspectives on the Next Era at <i>Circulation</i>

ABHD11-Mediated mtDNA Transcription Restored Mitochondrial Function to Attenuate Cardiomyocyte Ferroptosis After Myocardial Infarction

BACKGROUND: Cardiomyocytes exhibit marked susceptibility to ferroptosis after myocardial infarction (MI), rendering ferroptosis inhibition a promising therapeutic strategy to mitigate ischemic myocardial injury. Although mitochondrial dysfunction is recognized as a core driver of ferroptosis, the potential role of mitochondrial DNA transcription in regulating cardiomyocyte ferroptosis remains unexplored. METHODS: To clarify the temporal role of the various modes of cell death in MI progression, we performed time-course echocardiography in MI models treated with various cell death inhibitors. To characterize the crucial process and molecular regulator in cardiomyocyte ferroptosis, we integrated RNA sequencing and single-nucleus RNA sequencing data from murine post-MI hearts and performed functional rescue experiments using mitochondrial protective agents. To determine the role of ABHD11 (αβ-hydrolase domain-containing protein 11) in cardiomyocyte ferroptosis and cardiac repair after MI, we used loss- and gain-of-function approaches. To elucidate the underlying mechanisms, we conducted transcriptomics, nontargeted lipidomics, site-specific mutagenesis, molecular docking, coimmunoprecipitation, native gel electrophoresis, proximity ligation assay, methylation-specific polymerase chain reaction, and chromatin immunoprecipitation assay. RESULTS: We found that cardiac ferroptosis peaked at day 7 after MI and was enriched in peri-infarct cardiomyocytes. Mitochondrial dysfunction was a key driver of cardiomyocyte ferroptosis after MI, and the lipid enzyme ABHD11 was identified as a potential regulator of both processes. ABHD11 expression was consistently reduced in mouse and human MI hearts, and its transcription was repressed by DNMT1 (DNA methyltransferase 1)–mediated promoter hypermethylation. Functionally, cardiac-specific overexpression of ABHD11 markedly alleviated cardiomyocyte ferroptosis and improved cardiac function after MI. Conversely, loss of ABHD11 in adult mice exacerbated pathological cardiac remodeling and heart failure. Mechanistically, independent of its canonical enzymatic activities, ABHD11 acted as a mitochondrial DNA transcription coactivator by enhancing the TEFM (mitochondrial transcription elongation factor)–POLRMT (mitochondrial RNA polymerase) interaction. This promoted mitochondrial DNA transcription, restored mitochondrial function, and reduced reactive oxygen species/PUFA-PLs (polyunsaturated fatty acid-containing glycerophospholipids)–driven lipid peroxidation and 4-hydroxynonenal generation. The reduction in 4-hydroxynonenal stabilized YY1 (Yin Yang 1), which subsequently regulated key ferroptosis-driving genes governing iron deposition, reactive oxygen species production, and polyunsaturated fatty acid lipids accumulation, further inhibiting lipid peroxidation and ferroptosis, and ultimately promoting cardiac recovery after MI. CONCLUSIONS: This study revealed that ABHD11-mediated mitochondrial DNA transcription attenuated cardiomyocyte ferroptosis after MI by orchestrating a mitochondrial-nuclear crosstalk, offering a novel therapeutic strategy for ischemic myocardial injury.

Letter by Li et al Regarding Article, “Deep Learning-Based Continuous QT Monitoring to Identify High-Risk Prolongation Events After Class III Antiarrhythmic Initiation”

Cell Type–Specific Targeting of Different Smooth Muscle Cell Populations by Intersectional Genetics

BACKGROUND: The Cre/loxP recombination system is the main tool for cell type–specific lineage tracing and gene targeting. Currently available smooth muscle cell (SMC)–specific Cre mouse lines show off-target activity outside the SMC lineage and are unable to distinguish among arterial SMCs (ASMCs), venous SMCs, and nonvascular SMCs (NVSMCs). These limitations prevent ASMC- and NVSMC-specific gene targeting, which is required to characterize the role of SMCs in different organs and diseases. METHODS: To achieve precise manipulation of ASMCs in vivo, we combined alleles for Cspg4-Dre and rox-Stop–containing Acta2-CreER ( Acta2-rox-CreER ), generating a mouse line with Cre activity exclusively in ASMCs. RNA sequencing of fluorescence-activated cell sorting–isolated ASMCs was used to reveal differences in ASMCs among multiple organs. To specifically target and characterize NVSMCs in different organs, a combination of Chrm2-Dre and Acta2-rox-CreER was used. Disease-specific transcriptional changes of pulmonary ASMCs and NVSMCs were determined in the Sugen 5416/hypoxia model of pulmonary arterial hypertension. Usefulness for functional studies was assessed by inactivation of the genes for the splicing factors RBPMS (RNA-binding protein with multiple splicing) and RBPMS2 (RNA-binding protein with multiple splicing 2) in ASMCs. RESULTS: Intersectional genetic approaches using Cspg4-Dre and Acta2-rox-CreER mouse lines specifically targeted ASMCs within various organs. A combination of Chrm2-Dre with Acta2-rox-CreER achieved specific targeting of NVSMCs. Transcriptomic profiling revealed distinct gene expression signatures in ASMCs of different organs, indicating organ-dependent transcriptional adaptation of ASMCs. Transcriptional differences among NVSMCs were found in the lung, intestine, and bladder. Activation of distinct pathways was uncovered in pulmonary ASMCs and bronchial SMCs after induction of pulmonary arterial hypertension. Inactivation of Rbpms and Rbpms2 in ASMCs increased thickness of the muscular layer in pulmonary arteries, whereas inactivation in all SMCs abolished the contractile phenotype of NVSMCs in the intestine. CONCLUSIONS: The successful generation of mouse lines specifically targeting different subtypes of SMCs enhances specificity, allowing distinction between vascular and nonvascular effects of diseased SMCs. The identification of vessel bed–specific gene signatures will pave the way for specific manipulation of SMCs in distinct diseased organs, such as the lung in pulmonary arterial hypertension.

Mechanical CPR Device Use and Cardiac Arrest Survival in EMS Agencies

BACKGROUND: Cardiopulmonary resuscitation (CPR) by health care responders is often suboptimal during out-of-hospital cardiac arrest (OHCA). Mechanical CPR devices have been promoted as a strategy to improve CPR quality. Whether their use in routine care is associated with improved OHCA survival at emergency medical service (EMS) agencies is unclear. METHODS: Within the Cardiac Arrest Registry to Enhance Survival, we assessed agency-level rates of OHCA survival at EMS agencies with ≥2 years of OHCA data before and after their first documented use of a mechanical CPR device from 2013 to 2019 using an observational cohort study design. Temporal trends in favorable neurological survival (without severe neurological disability) and survival to discharge were first assessed in EMS agencies that did not initiate mechanical CPR device use (control agencies) using multivariable hierarchical logistic regression. Then an interrupted time series analysis evaluated whether introduction of mechanical CPR devices at EMS agencies was associated with higher OHCA survival. RESULTS: Among 51 994 patients with OHCA at 73 control agencies, there were no temporal trends in risk-adjusted rates of favorable neurological survival (annual rates ranged between 9.6% and 10.6%; P trend =0.23) or survival to discharge (annual rates ranged between 11.1% and 12.0%; P trend =0.31). At 49 EMS agencies that introduced mechanical CPR devices (14 110 OHCAs before and 17 804 OHCAs after), the mean EMS agency risk-adjusted rate of favorable neurological survival was 8.9% ± 2.2% before mechanical CPR device introduction and 8.3% ± 1.3% after, with no change in model intercept (adjusted odds ratio, 0.94 [95% CI, 0.80–1.11]; P =0.48) or slope after introduction of mechanical CPR devices (adjusted odds ratio per year, 1.03 [95% CI, 0.96–1.12]; P =0.41). Similarly, the mean EMS agency risk-adjusted rate of survival to discharge was 11.0% ± 2.2% before and 10.0% ± 1.0% after device introduction, with no significant change in model intercept or slope after device introduction. CONCLUSIONS: In a large US registry of OHCA, EMS agency rates of favorable neurological survival and survival to discharge were not higher after the initiation of mechanical CPR device use.

The Postcardiac Arrest Inflammatory Response: Mechanisms and Therapeutic Targets

Postcardiac arrest syndrome is a complex multisystem disorder that evolves after return of spontaneous circulation and remains a major determinant of morbidity and mortality following out-of-hospital cardiac arrest. Beyond anoxic brain injury and transient myocardial dysfunction, many patients develop a systemic ischemia/reperfusion response with endothelial and microvascular dysfunction, vasoplegia, and immune dysregulation—features that contribute to shock and organ failure. Hemodynamic instability is often mixed with low systemic vascular resistance despite preserved or recovering cardiac output, but management is still largely supportive and centered on achieving a target mean arterial pressure. An increasing understanding of the central role of inflammation, including gastrointestinal barrier disruption, cytokine release, complement activation, nitric oxide–cGMP signaling, and immune phenotypic heterogeneity has prompted evaluation of targeted adjunctive therapies. However, randomized trials of immunomodulators and other vasoactive strategies have yielded mixed results, reflecting biological heterogeneity and limited phenotypic stratification. This review synthesizes contemporary understanding of the inflammatory and hemodynamic mechanisms underpinning postcardiac arrest syndrome, examines current and emerging pharmacologic strategies, and highlights priorities for future investigation, including mechanistic phenotyping, prospective biobanking, and prospective trial requirements to guide more precise management strategies in postcardiac arrest care.

Subcutaneous Defibrillator Implantation With or Without Defibrillation Test: The Primary Results of the Randomized PRAETORIAN-DFT Trial

BACKGROUND: To improve survival of patients at risk of sudden cardiac death, subcutaneous implantable cardioverter defibrillators (S-ICDs) require optimal implant positioning for effective shocks. Defibrillation (DF) testing is recommended but carries serious risks. The PRAETORIAN score predicts defibrillation outcomes on the basis of chest X-ray. The PRAETORIAN-DFT (Prospective Randomized Comparative Trial of Subcutaneous Implantable Cardioverter Defibrillator Implantation With and Without Defibrillation Testing) trial evaluated whether omission of DF testing guided by the PRAETORIAN score is noninferior for first-shock efficacy. METHODS: In this multinational trial, S-ICD patients from 37 centers were randomized to DF testing or no DF testing. In the No-DF testing group, the PRAETORIAN score was evaluated before discharge. The primary end point was failed first shock for spontaneous ventricular arrhythmias, as a surrogate for defibrillation success, tested for noninferiority with a 3% absolute risk margin. Secondary end points included mortality, potential DF testing–related complications, and S-ICD revisions. RESULTS: The included 965 patients (No-DF testing, n=483; DF testing, n=482) were followed for a median of 41 months. Failed first shock for spontaneous ventricular arrhythmia occurred in 1.7% of the No-DF testing group versus 2.3% of the DF testing group (–0.6% [95% CI, –2.6 to 1.4], P &lt;0.001). There were no significant differences in all-cause mortality (hazard ratio [HR], 0.9 [95% CI, 0.6–1.4]) or arrhythmic death (HR, 0.4 [95% CI, 0.04–3.4]). Potential DF testing–related complications occurred in 1.7% in the DF testing group. Postoperative S-ICD revisions due to inadequate positioning were identical between groups (n=2 each). CONCLUSIONS: PRAETORIAN score–guided omission of DF testing after S-ICD implantation did not increase the risk of failed first shocks for spontaneous ventricular arrhythmias and reduced procedural risk without increasing S-ICD revisions. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT03495297.

Letter by Hu et al Regarding Article, “Cell-Specific Inducible Human APOL1 Risk Variant Expression in Mice Causes Hypertension and Renal Damage”