An integrated microfluidic and fluorescence platform for probing in vivo neuropharmacology.

Neurotechnologies and genetic tools for dissecting neural circuit functions have advanced rapidly over the past decade, although the development of complementary pharmacological method-ologies has comparatively lagged. Understanding the precise pharmacological mechanisms of neuroactive compounds is critical for advancing basic neurobiology and neuropharmacology, as well as for developing more effective treatments for neurological and neuropsychiatric disorders. However, integrating modern tools for assessing neural activity in large-scale neural networks with spatially localized drug delivery remains a major challenge. Here, we present a dual microfluidic-photometry platform that enables simultaneous intracranial drug delivery with neural dynamics monitoring in the rodent brain. The integrated platform combines a wireless, battery-free, miniaturized fluidic microsystem with optical probes, allowing for spatially and temporally specific drug delivery while recording activity-dependent fluorescence using genetically encoded calcium indicators (GECIs), neurotransmitter sensors GRAB NE and GRAB DA , and neuropeptide sensors. We demonstrate the performance this platform for investigating neuropharmacological mechanisms in vivo and characterize its efficacy in probing precise mechanistic actions of neuroactive compounds across several rapidly evolving neuroscience domains.

An implantable device for wireless monitoring of diverse physio-behavioral characteristics in freely behaving small animals and interacting groups.

Comprehensive, continuous quantitative monitoring of intricately orchestrated physiological processes and behavioral states in living organisms can yield essential data for elucidating the function of neural circuits under healthy and diseased conditions, for defining the effects of potential drugs and treatments, and for tracking disease progression and recovery. Here, we report a wireless, battery-free implantable device and a set of associated algorithms that enable continuous, multiparametric physio-behavioral monitoring in freely behaving small animals and interacting groups. Through advanced analytics approaches applied to mechano-acoustic signals of diverse body processes, the device yields heart rate, respiratory rate, physical activity, temperature, and behavioral states. Demonstrations in pharmacological, locomotor, and acute and social stress tests and in optogenetic studies offer unique insights into the coordination of physio-behavioral characteristics associated with healthy and perturbed states. This technology has broad utility in neuroscience, physiology, behavior, and other areas that rely on studies of freely moving, small animal models.

COPD with elevated sputum group 2 innate lymphoid cells is characterized by severe disease.

Rationale: Pulmonary innate immune cells play a central role in the initiation and perpetuation of chronic obstructive pulmonary disease (COPD), however the precise mechanisms that orchestrate the development and severity of COPD are poorly understood. Objectives: We hypothesized that the recently described family of innate lymphoid cells (ILCs) play an important role in COPD. Methods: Subjects with COPD and healthy controls were clinically evaluated, and their sputum samples were assessed by flow cytometry. A mouse model of spontaneous COPD [genetically deficient in surfactant protein-D (SP-D -/- )] and ozone (O 3 ) exposure were used to examine the mechanism by which lack of functional SP-D may skew ILC2s to produce IL-17A in combination with IL-5 and IL-13, leading to a mixed inflammatory profile and more severe disease. Measurements and Main Results: COPD was characterized by poor spirometry, sputum inflammation, and the emergence of sputum GATA3 + ILCs (ILC2s), but not T-bet + ILCs (ILC1s) nor RORγt + ILCs (ILC3s). COPD subjects with elevated sputum ILC2s (the ILC2 high group) had worse spirometry and sputum neutrophilia and eosinophilia than healthy and ILC2 low subjects. This was associated with the presence of dual-positive IL-5 + IL-17A + and IL-13 + IL-17A + ILCs and nonfunctional SP-D in the sputum in ILC2 high subjects. SP-D -/- mice showed spontaneous airway neutrophilia. Lack of SP-D in the mouse lung licensed ILC2s to produce IL-17A, which was dose-dependently inhibited by recombinant SP-D. SP-D -/- mice showed enhanced susceptibility to O 3 -induced airway neutrophilia, which was associated with the emergence of inflammatory IL-13 + IL-17A + ILCs. Conclusions: We report that the presence of sputum ILC2s predicts the severity of COPD, and unravel a novel pathway of IL-17A plasticity in lung ILC2s, prevented by the immunomodulatory protein SP-D.

Assessing the Toxicity of Benzotriazole Ultraviolet Stabilizers to Fishes: Insights into Aryl Hydrocarbon Receptor-Mediated Effects.

Benzotriazole ultraviolet stabilizers (BUVSs) are chemicals used to mitigate UV-induced damage to manufactured goods. Their presence in aquatic environments and biota raises concerns, as certain BUVSs activate the aryl hydrocarbon receptor (AhR), which is linked to adverse effects in fish. However, potencies of BUVSs as AhR agonists and species sensitivities to AhR activation are poorly understood. This study evaluated the toxicity of three BUVSs using embryotoxicity assays. Zebrafish (Danio rerio) embryos exposed to BUVSs by microinjection suffered dose-dependent increases in mortality, with LD50 values of 4772, 11 608, and 56 292 ng/g-egg for UV-P, UV-9, and UV-090, respectively. The potencies and species sensitivities to AhR2 activation by BUVSs were assessed using a luciferase reporter gene assay with COS-7 cells transfected with the AhR2 of zebrafish and eight other fishes. The rank order of potency for activation of the AhR2 from all nine species was UV-P > UV-9 > UV-090. However, AhR2s among species differed in sensitivities to activation by up to 100-fold. An approximate reversed rank order of species sensitivity was observed compared to the rank order of sensitivity to 2,3,7,8-tetrachlorodibenzo[p]dioxin, the prototypical AhR agonist. Despite this, a pre-existing quantitative adverse outcome pathway linking AhR activation to embryo lethality could predict embryotoxicities of BUVSs in zebrafish.

Amine-Functionalized Polybutadiene Synthesis by Tunable Postpolymerization Hydroaminoalkylation.

Early transition metal-catalyzed hydroaminoalkylation is a powerful single-step method to selectively add amines to polybutadienes, offering an efficient strategy to access amine-functionalized polyolefins. Aryl and alkyl secondary amines were used with a tantalum catalyst to functionalize both 28 wt% (PBD13) and 70 wt% (PBD50) 1,2-polybutadiene polymers. The degree of amination was controlled by modifying amine and catalyst loading in both small- and multigram-scale reactions. The vinyl groups of 1,2-polybutadiene were aminated with ease, and unexpectedly the hydroaminoalkylation of challenging internal alkenes of the 1,4-polybutadiene unit was observed. This unanticipated reactivity was proposed to be due to a directing group effect. This hypothesis was supported with small-molecule model substrates, which also showed directed internal alkene amination. Increasing degrees of amination resulted in materials with dramatically higher and tunable glass transition temperature (Tg) values, due to the dynamic cross-linking accessible to hydrogen-bonding, amine-containing materials. Primary amine-functionalized polybutadiene was also prepared, demonstrating that a broad new class of amine-containing polyolefins can be accessed by postpolymerization hydroaminoalkylation.

Co-transcriptional genome surveillance by HUSH is coupled to termination machinery.

The HUSH complex recognizes and silences foreign DNA such as viruses, transposons, and transgenes without prior exposure to its targets. Here, we show that endogenous targets of the HUSH complex fall into two distinct classes based on the presence or absence of H3K9me3. These classes are further distinguished by their transposon content and differential response to the loss of HUSH. A de novo genomic rearrangement at the Sox2 locus induces a switch from H3K9me3-independent to H3K9me3-associated HUSH targeting, resulting in silencing. We further demonstrate that HUSH interacts with the termination factor WDR82 and-via its component MPP8-with nascent RNA. HUSH accumulates at sites of high RNAPII occupancy including long exons and transcription termination sites in a manner dependent on WDR82 and CPSF. Together, our results uncover the functional diversity of HUSH targets and show that this vertebrate-specific complex exploits evolutionarily ancient transcription termination machinery for co-transcriptional chromatin targeting and genome surveillance.

Halide Noninnocence and Direct Photoreduction of Ni(II) Enables Coupling of Aryl Chlorides in Dual Catalytic, Carbon-Heteroatom Bond-Forming Reactions.

Recent mechanistic studies of dual photoredox/Ni-catalyzed, light-driven cross-coupling reactions have found that the photocatalyst (PC) operates through either reductive quenching or energy transfer cycles. To date, reports invoking oxidative quenching cycles are comparatively rare and direct observation of such a quenching event has not been reported. However, when PCs with highly reducing excited states are used (e.g., Ir(ppy)3), photoreduction of Ni(II) to Ni(I) is thermodynamically feasible. Recently, a unified reaction system using Ir(ppy)3 was developed for forming C-O, C-N, and C-S bonds under the same conditions, a prospect that is challenging with PCs that can photooxidize these nucleophiles. Herein, in a detailed mechanistic study of this system, we observe oxidative quenching of the PC (Ir(ppy)3 or a phenoxazine) via nanosecond transient absorption spectroscopy. Speciation studies support that a mixture of Ni-bipyridine complexes forms under the reaction conditions, and the rate constant for photoreduction increases when more than one ligand is bound. Oxidative addition of an aryl iodide was observed indirectly via oxidation of the resulting iodide by Ir(IV)(ppy)3. Intriguingly, the persistence of the Ir(IV)/Ni(I) ion pair formed in the oxidative quenching step was found to be necessary to simulate the observed kinetics. Both bromide and iodide anions were found to reduce the oxidized form of the PC back to its neutral state. These mechanistic insights inspired the addition of a chloride salt additive, which was found to alter Ni speciation, leading to a 36-fold increase in the initial turnover frequency, enabling the coupling of aryl chlorides.

A wireless and battery-less implant for multimodal closed-loop neuromodulation in small animals.

Fully implantable wireless systems for the recording and modulation of neural circuits that do not require physical tethers or batteries allow for studies that demand the use of unconstrained and freely behaving animals in isolation or in social groups. Moreover, feedback-control algorithms that can be executed within such devices without the need for remote computing eliminate virtual tethers and any associated latencies. Here we report a wireless and battery-less technology of this type, implanted subdermally along the back of freely moving small animals, for the autonomous recording of electroencephalograms, electromyograms and body temperature, and for closed-loop neuromodulation via optogenetics and pharmacology. The device incorporates a system-on-a-chip with Bluetooth Low Energy for data transmission and a compressed deep-learning module for autonomous operation, that offers neurorecording capabilities matching those of gold-standard wired systems. We also show the use of the implant in studies of sleep-wake regulation and for the programmable closed-loop pharmacological suppression of epileptic seizures via feedback from electroencephalography. The technology can support a broader range of applications in neuroscience and in biomedical research with small animals.

A tool for monitoring cell type-specific focused ultrasound neuromodulation and control of chronic epilepsy.

Focused ultrasound (FUS) is a powerful tool for noninvasive modulation of deep brain activity with promising therapeutic potential for refractory epilepsy; however, tools for examining FUS effects on specific cell types within the deep brain do not yet exist. Consequently, how cell types within heterogeneous networks can be modulated and whether parameters can be identified to bias these networks in the context of complex behaviors remains unknown. To address this, we developed a fiber Photometry Coupled focused Ultrasound System (PhoCUS) for simultaneously monitoring FUS effects on neural activity of subcortical genetically targeted cell types in freely behaving animals. We identified a parameter set that selectively increases activity of parvalbumin interneurons while suppressing excitatory neurons in the hippocampus. A net inhibitory effect localized to the hippocampus was further confirmed through whole brain metabolic imaging. Finally, these inhibitory selective parameters achieved significant spike suppression in the kainate model of chronic temporal lobe epilepsy, opening the door for future noninvasive therapies.

Nanoparticles for vaccine and gene therapy: Overcoming the barriers to nucleic acid delivery.

Nucleic acid therapeutics can be used to control virtually every aspect of cell behavior and therefore have significant potential to treat genetic disorders, infectious diseases, and cancer. However, while clinically approved to treat a small number of diseases, the full potential of nucleic acid therapeutics is hampered by inefficient delivery. Nucleic acids are large, highly charged biomolecules that are sensitive to degradation and so the approaches to deliver these molecules differ significantly from traditional small molecule drugs. Current studies suggest less than 1% of the injected nucleic acid dose is delivered to the target cell in an active form. This inefficient delivery increases costs and limits their use to applications where a small amount of nucleic acid is sufficient. In this review, we focus on two of the major barriers to efficient nucleic acid delivery: (1) delivery to the target cell and (2) transport to the subcellular compartment where the nucleic acids are therapeutically active. We explore how nanoparticles can be modified with targeting ligands to increase accumulation in specific cells, and how the composition of the nanoparticle can be engineered to manipulate or disrupt cellular membranes and facilitate delivery to the optimal subcellular compartments. Finally, we highlight how with intelligent material design, nanoparticle delivery systems have been developed to deliver nucleic acids that silence aberrant genes, correct genetic mutations, and act as both therapeutic and prophylactic vaccines. This article is categorized under: Nanotechnology Approaches to Biology > Cells at the Nanoscale Therapeutic Approaches and Drug Discovery > Nanomedicine for Infectious Disease Biology-Inspired Nanomaterials > Lipid-Based Structures.

The Catalytic Synthesis of N-Aryl Indoles Featuring an Alternative Disconnection. Hydroaminoalkylation for a Telescoped Reaction Sequence.

A tricatalytic telescoped synthesis toward C3-methyl-N-aryl indoline and indole products is reported. An in situ generated tantalum(V) ureate catalyst is used for the hydroaminoalkylation of o-chlorostyrene with N-methylaniline to first make a Csp3─Csp3 bond. Subsequent nickel-catalyzed C-N coupling forms N-aryl indolines, and if desired, subsequent oxidation to N-aryl indoles can be achieved using catalytic [Cu(MeCN)4]BF4 and tert-butylperoxy-2-ethylhexyl carbonate as the terminal oxidant. This strategy highlights an alternative C-C bond disconnection for the synthesis of indoles, which is enabled by the atom-economic hydroaminoalkylation reaction. The method was streamlined using a three-step, two-pot approach to afford up to 73% overall isolated yield of variously substituted C3-methyl-N-aryl indoles.

MicroRNA-like snoRNA-Derived RNAs (sdRNAs) Promote Castration-Resistant Prostate Cancer.

We have identified 38 specifically excised, differentially expressed snoRNA fragments (sdRNAs) in TCGA prostate cancer (PCa) patient samples as compared to normal prostate controls. SnoRNA-derived fragments sdRNA-D19b and -A24 emerged among the most differentially expressed and were selected for further experimentation. We found that the overexpression of either sdRNA significantly increased PC3 (a well-established model of castration-resistant prostate cancer (CRPC)) cell proliferation, and that sdRNA-D19b overexpression also markedly increased the rate of PC3 cell migration. In addition, both sdRNAs provided drug-specific resistances with sdRNA-D19b levels correlating with paclitaxel resistance and sdRNA-24A conferring dasatinib resistance. In silico and in vitro analyses revealed that two established PCa tumor suppressor genes, CD44 and CDK12, represent targets for sdRNA-D19b and sdRNA-A24, respectively. This outlines a biologically coherent mechanism by which sdRNAs downregulate tumor suppressors in AR-PCa to enhance proliferative and metastatic capabilities and to encourage chemotherapeutic resistance. Aggressive proliferation, rampant metastasis, and recalcitrance to chemotherapy are core characteristics of CRPC that synergize to produce a pathology that ranks second in cancer-related deaths for men. This study defines sdRNA-D19b and -A24 as contributors to AR-PCa, potentially providing novel biomarkers and therapeutic targets of use in PCa clinical intervention.

Altered sleep during spontaneous cannabinoid withdrawal in male mice.

Cessation of cannabinoid use in humans often leads to a withdrawal state that includes sleep disruption. Despite important health implications, little is known about how cannabinoid abstention affects sleep architecture, in part because spontaneous cannabinoid withdrawal is difficult to model in animals. In concurrent work we report that repeated administration of the high-efficacy cannabinoid 1 (CB1) receptor agonist AM2389 to mice for 5 days led to heightened locomotor activity and paw tremor following treatment discontinuation, potentially indicative of spontaneous cannabinoid withdrawal. Here, we performed parallel studies to examine effects on sleep. Using implantable electroencephalography (EEG) and electromyography (EMG) telemetry we examined sleep and neurophysiological measures before, during, and after 5 days of twice-daily AM2389 injections. We report that AM2389 produces decreases in locomotor activity that wane with repeated treatment, whereas discontinuation produces rebound increases in activity that persist for several days. Likewise, AM2389 initially produces profound increases in slow-wave sleep (SWS) and decreases in rapid eye movement (REM) sleep, as well as consolidation of sleep. By the third AM2389 treatment, this pattern transitions to decreases in SWS and total time sleeping. This pattern persists following AM2389 discontinuation and is accompanied by emergence of sleep fragmentation. Double-labeling immunohistochemistry for hypocretin/orexin (a sleep-regulating peptide) and c-Fos (a neuronal activity marker) in lateral hypothalamus revealed decreases in c-Fos/orexin+ cells following acute AM2389 and increases following discontinuation, aligning with the sleep changes. These findings indicate that AM2389 profoundly alters sleep in mice and suggest that sleep disruption following treatment cessation reflects spontaneous cannabinoid withdrawal.

Preparation and use of wireless reprogrammable multilateral optogenetic devices for behavioral neuroscience.

Wireless battery-free optogenetic devices enable behavioral neuroscience studies in groups of animals with minimal interference to natural behavior. Real-time independent control of optogenetic stimulation through near-field communication dramatically expands the realm of applications of these devices in broad contexts of neuroscience research. Dissemination of these tools with advanced functionalities to the neuroscience community requires protocols for device manufacturing and experimental implementation. This protocol describes detailed procedures for fabrication, encapsulation and implantation of recently developed advanced wireless devices in head- and back-mounted forms. In addition, procedures for standard implementation of experimental systems in mice are provided. This protocol aims to facilitate the application of wireless optogenetic devices in advanced optogenetic experiments involving groups of freely moving rodents and complex environmental designs. The entire protocol lasts ~3-5 weeks.

Viscoelastic parameterization of human skin cells characterize material behavior at multiple timescales.

Countless biophysical studies have sought distinct markers in the cellular mechanical response that could be linked to morphogenesis, homeostasis, and disease. Here, an iterative-fitting methodology visualizes the time-dependent viscoelastic behavior of human skin cells under physiologically relevant conditions. Past investigations often involved parameterizing elastic relationships and assuming purely Hertzian contact mechanics, which fails to properly account for the rich temporal information available. We demonstrate the performance superiority of the proposed iterative viscoelastic characterization method over standard open-search approaches. Our viscoelastic measurements revealed that 2D adherent metastatic melanoma cells exhibit reduced elasticity compared to their normal counterparts-melanocytes and fibroblasts, and are significantly less viscous than fibroblasts over timescales spanning three orders of magnitude. The measured loss angle indicates clear differential viscoelastic responses across multiple timescales between the measured cells. This method provides insight into the complex viscoelastic behavior of metastatic melanoma cells relevant to better understanding cancer metastasis and aggression.

Sensory neurons control the functions of dendritic cells to guide allergic immunity.

Dendritic cells of the innate immune system and sensory neurons of the peripheral nervous system are embedded in barrier tissues and gather information about an organisms' environment. While the mechanisms by which dendritic cells recognize and initiate adaptive immune responses to pathogens is well defined, how they sense allergens is poorly understood. Indeed, allergens induce dendritic cell maturation and migration in vivo, but not in vitro. How are adaptive immune responses to allergens initiated if dendritic cells do not directly sense allergens? Sensory neurons release neuropeptides within minutes of allergen exposure. Recent evidence demonstrated that while neuropeptides modify dendritic cell function during pathogen responses, they are required for dendritic cell function during allergic responses. These emerging studies suggest that sensory neurons do not just pass information along to the central nervous system, but also to dendritic cells, particularly during the initiation of adaptive immunity to allergens.

No pain, no gain: Sensory neurons heal a sunburn.

In a recent issue of Nature, Hoeffel et al. describe a novel pathway of sterile tissue repair utilizing a mouse model of sunburn. This wound healing pathway is coordinated by sensory neuron-derived TAFA4 that induces IL-10 production from Tim4+ dermal macrophages to prevent sustained inflammation and the emergence of tissue fibrosis.

A decision tree model for neuroimmune guidance of allergic immunity.

The immune system defends the body from infectious and non-infectious threats. Distinct recognition strategies have evolved to generate antigen-specific immunity against pathogens or toxins versus antigen-independent tissue repair. Structural recognition, or the sensing of conserved motifs, guides the immune response to viruses, bacteria, fungi, and unicellular parasites. Functional recognition, which is sensing that is based on the activities of an input, guides antigen-independent tissue healing and antigen-specific Type 2 immunity to toxins, allergens, and helminth parasites. Damage-associated molecular patterns (DAMPs), released from damaged and dying cells, permit functional recognition by immune cells. However, the DAMP paradigm alone does not explain how functional recognition can lead to such disparate immune responses, namely wound healing and Type 2 immunity. Recent work established that sensory neurons release neuropeptides in response to a variety of toxins and allergens. These neuropeptides act on local innate immune cells, stimulating or inhibiting their activities. By integrating our knowledge on DAMP function with new information on the role of neuropeptides in innate immune activation in Type 2 immunity, we describe a decision tree model of functional recognition. In this model, neuropeptides complement or antagonize DAMPs to guide the development of antigen-specific Type 2 immunity through the activation of innate immune cells. We discuss why this decision tree system evolved and its implications to allergic diseases.

Evaluating the 12-Lead Electrocardiogram for Diagnosing ARVC in Young Populations: Implications for Preparticipation Screening of Athletes.

BACKGROUND: Arrhythmogenic right-ventricular cardiomyopathy (ARVC) is an identified cause of sport-related sudden cardiac arrest (SCA). Identifying athletes with ARVC and restricting them from exercise is believed to reduce the risk of SCA. The electrocardiogram (ECG) is considered to be an important component of screening for ARVC; however, the sensitivity of the 12-lead ECG to identify ARVC in young asymptomatic persons is unknown. METHODS: In this retrospective study, we identified 70 patients (49 ARVC-positive, based on Task Force Criteria, and 21 age-matched ARVC-negative persons from a paediatric arrhythmia database (<18 years of age); ECGs were analyzed for abnormalities, based on International Criteria for Interpretation of ECGs in Athletes, and ECG findings were adjudicated by group consensus. RESULTS: Of the 49 ARVC-positive patients (median age: 17 [interquartile range: 16-18], 65% male), 22% were found to have abnormal ECGs; the most common ECG findings were T-wave inversions. Patients with symptoms were more likely to have abnormal ECGs than asymptomatic patients (28% compared with 17%, respectively; P = 0.002). Of 16 gene-positive patients, 31% had abnormal ECGs. Patients with abnormal ECGs had larger right-ventricular end-diastolic volume indexes on magnetic resonance imaging than those with normal ECGs (P = 0.03). CONCLUSIONS: The ECG was insensitive for detecting ARVC in young (age <18 years), asymptomatic patients, and is unlikely to provide significant diagnostic value for identifying ARVC on routine preparticipation screening of adolescent athletes.

INTRODUCTION: La cardiomyopathie ventriculaire droite arythmogène (CVDA) est une cause établie d'arrêt cardiaque soudain (ACS) du sportif. On croit que le fait de repérer les athlètes atteints de CVDA et de limiter leur exercice réduit le risque d'ACS. On considère que l'électrocardiogramme (ECG) est une composante importante du dépistage de la CVDA. Toutefois, on ignore la sensibilité de l'ECG à 12 dérivations pour détecter la CVDA chez les jeunes personnes asymptomatiques. MÉTHODES: Dans cette étude rétrospective, nous avons repéré 70 patients (49 personnes dont les résultats sont positifs à la CVDA selon les critères de la Task Force, et 21 personnes appariées selon l'âge dont les résultats étaient positifs à la CVDA) d'une base de données sur l'arythmie en pédiatrie (< 18 ans); nous avons analysé les ECG pour détecter les anomalies selon les Critères de consensus internationaux de l'interprétation de l'ECG chez l'athlète, et nous sommes prononcés sur les résultats des ECG par consensus. RÉSULTATS: Parmi les 49 patients dont les résultats étaient positifs à la CVDA (âge médian : 17 [intervalle interquartile : 16-18], 65 % de sexe masculin), nous avons observé que 22 % d'entre eux avaient des résultats anormaux à l'ECG; les résultats les plus fréquents à l'ECG montraient des inversions de l'onde T. Les patients symptomatiques étaient plus susceptibles d'avoir des résultats anormaux à l'ECG que les patients asymptomatiques (28 % et 17 %, respectivement; P = 0,002). Parmi les 16 patients qui avaient des résultats génétiques positifs, 31 % avaient des résultats anormaux à l'ECG. Les patients qui avaient des résultats anormaux à l'ECG avaient des indices plus grands du volume télédiastolique du ventricule droit en fin de diastole à l'imagerie par résonance magnétique que ceux qui avaient des résultats normaux à l'ECG (P = 0,03). CONCLUSIONS: L'ECG n'a pas montré la sensibilité pour détecter la CVDA chez les jeunes (< 18 ans) patients asymptomatiques et n'a pas été susceptible de fournir une valeur diagnostique significative pour détecter la CVDA au dépistage systématique préalable à l'activité sportive des athlètes adolescents.