Life-Limiting Peripheral Organ Dysfunction in Feline Sandhoff Disease Emerges after Effective CNS Gene Therapy.

OBJECTIVE: GM2 gangliosidosis is usually fatal by 5 years of age in its 2 major subtypes, Tay-Sachs and Sandhoff disease. First reported in 1881, GM2 gangliosidosis has no effective treatment today, and children succumb to the disease after a protracted neurodegenerative course and semi-vegetative state. This study seeks to further develop adeno-associated virus (AAV) gene therapy for human translation. METHODS: Cats with Sandhoff disease were treated by intracranial injection of vectors expressing feline ß-N-acetylhexosaminidase, the enzyme deficient in GM2 gangliosidosis. RESULTS: Hexosaminidase activity throughout the brain and spinal cord was above normal after treatment, with highest activities at the injection sites (thalamus and deep cerebellar nuclei). Ganglioside storage was reduced throughout the brain and spinal cord, with near complete clearance in many regions. While untreated cats with Sandhoff disease lived for 4.4 ± 0.6 months, AAV-treated cats lived to 19.1 ± 8.6 months, and 3 of 9 cats lived >21 months. Correction of the central nervous system was so effective that significant increases in lifespan led to the emergence of otherwise subclinical peripheral disease, including megacolon, enlarged stomach and urinary bladder, soft tissue spinal cord compression, and patellar luxation. Throughout the gastrointestinal tract, neurons of the myenteric and submucosal plexuses developed profound pathology, demonstrating that the enteric nervous system was inadequately treated. INTERPRETATION: The vector formulation in the current study effectively treats neuropathology in feline Sandhoff disease, but whole-body targeting will be an important consideration in next-generation approaches. ANN NEUROL 2023;94:969-986.

Motion Robust MR Fingerprinting Scan to Image Neonates With Prenatal Opioid Exposure.

PURPOSE: To explore whether MR fingerprinting (MRF) scans provide motion-robust and quantitative brain tissue measurements for non-sedated infants with prenatal opioid exposure (POE). STUDY TYPE: Prospective. POPULATION: 13 infants with POE (3 male; 12 newborns (age 7-65 days) and 1 infant aged 9-months). FIELD STRENGTH/SEQUENCE: 3T, 3D T1-weighted MPRAGE, 3D T2-weighted TSE and MRF sequences. ASSESSMENT: The image quality of MRF and MRI was assessed in a fully crossed, multiple-reader, multiple-case study. Sixteen image quality features in three types-image artifacts, structure and myelination visualization-were ranked by four neuroradiologists (8, 7, 5, and 8 years of experience respectively), using a 3-point scale. MRF T1 and T2 values in 8 white matter brain regions were compared between babies younger than 1 month and babies between 1 and 2 months. STATISTICAL TESTS: Generalized estimating equations model to test the significance of differences of regional T1 and T2 values of babies under 1 month and those older. MRI and MRF image quality was assessed using Gwet's second order auto-correlation coefficient (AC2) with confidence levels. The Cochran-Mantel-Haenszel test was used to assess the difference in proportions between MRF and MRI for all features and stratified by the type of features. A P value <0.05 was considered statistically significant. RESULTS: The MRF of two infants were excluded in T1 and T2 value analysis due to severe motion artifact but were included in the image quality assessment. In infants under 1 month of age (N = 6), the T1 and T2 values were significantly higher compared to those between 1 and 2 months of age (N = 4). MRF images showed significantly higher image quality ratings in all three feature types compared to MRI images. CONCLUSIONS: MR Fingerprinting scans have potential to be a motion-robust and efficient method for nonsedated infants. LEVEL OF EVIDENCE: 2 TECHNICAL EFFICACY STAGE: 1.

Intravenous delivery of adeno-associated viral gene therapy in feline GM1 gangliosidosis.

GM1 gangliosidosis is a fatal neurodegenerative disease caused by a deficiency of lysosomal ß-galactosidase. In its most severe form, GM1 gangliosidosis causes death by 4 years of age, and no effective treatments exist. Previous work has shown that injection of the brain parenchyma with an adeno-associated viral (AAV) vector provides pronounced therapeutic benefit in a feline GM1 model. To develop a less invasive treatment for the brain and increase systemic biodistribution, intravenous injection of AAV9 was evaluated. AAV9 expressing feline ß-galactosidase was intravenously administered at 1.5×1013 vector genomes/kg body weight to six GM1 cats at ∼1 month of age. The animals were divided into two cohorts: (i) a long-term group, which was followed to humane end point; and (ii) a short-term group, which was analysed 16 weeks post-treatment. Clinical assessments included neurological exams, CSF and urine biomarkers, and 7 T MRI and magentic resonance spectroscopy (MRS). Post-mortem analysis included ß-galactosidase and virus distribution, histological analysis and ganglioside content. Untreated GM1 animals survived 8.0 ± 0.6 months while intravenous treatment increased survival to an average of 3.5 years (n = 2) with substantial improvements in quality of life and neurological function. Neurological abnormalities, which in untreated animals progress to the inability to stand and debilitating neurological disease by 8 months of age, were mild in all treated animals. CSF biomarkers were normalized, indicating decreased CNS cell damage in the treated animals. Urinary glycosaminoglycans decreased to normal levels in the long-term cohort. MRI and MRS showed partial preservation of the brain in treated animals, which was supported by post-mortem histological evaluation. ß-Galactosidase activity was increased throughout the CNS, reaching carrier levels in much of the cerebrum and normal levels in the cerebellum, spinal cord and CSF. Ganglioside accumulation was significantly reduced by treatment. Peripheral tissues such as heart, skeletal muscle, and sciatic nerve also had normal ß-galactosidase activity in treated GM1 cats. GM1 histopathology was largely corrected with treatment. There was no evidence of tumorigenesis or toxicity. Restoration of ß-galactosidase activity in the CNS and peripheral organs by intravenous gene therapy led to profound increases in lifespan and quality of life in GM1 cats. These data support the promise of intravenous gene therapy as a safe, effective treatment for GM1 gangliosidosis.

PEA15 loss of function and defective cerebral development in the domestic cat.

Cerebral cortical size and organization are critical features of neurodevelopment and human evolution, for which genetic investigation in model organisms can provide insight into developmental mechanisms and the causes of cerebral malformations. However, some abnormalities in cerebral cortical proliferation and folding are challenging to study in laboratory mice due to the absence of gyri and sulci in rodents. We report an autosomal recessive allele in domestic cats associated with impaired cerebral cortical expansion and folding, giving rise to a smooth, lissencephalic brain, and that appears to be caused by homozygosity for a frameshift in PEA15 (phosphoprotein expressed in astrocytes-15). Notably, previous studies of a Pea15 targeted mutation in mice did not reveal structural brain abnormalities. Affected cats, however, present with a non-progressive hypermetric gait and tremors, develop dissociative behavioral defects and aggression with age, and exhibit profound malformation of the cerebrum, with a 45% average decrease in overall brain weight, and reduction or absence of the ectosylvian, sylvian and anterior cingulate gyrus. Histologically, the cerebral cortical layers are disorganized, there is substantial loss of white matter in tracts such as the corona radiata and internal capsule, but the cerebellum is relatively spared. RNA-seq and immunohistochemical analysis reveal astrocytosis. Fibroblasts cultured from affected cats exhibit increased TNFα-mediated apoptosis, and increased FGFb-induced proliferation, consistent with previous studies implicating PEA15 as an intracellular adapter protein, and suggesting an underlying pathophysiology in which increased death of neurons accompanied by increased proliferation of astrocytes gives rise to abnormal organization of neuronal layers and loss of white matter. Taken together, our work points to a new role for PEA15 in development of a complex cerebral cortex that is only apparent in gyrencephalic species.

Diffusion-Weighted Imaging of the Orbit: A Case Series and Systematic Review.

PURPOSE: To describe the findings of diffusion-weighted imaging (DWI) for a series of orbital lesions and provide a systematic review of relevant literature. METHODS: A retrospective review of 20 patients with orbital lesions who underwent MRI with DWI at two academic institutions between 2015 and 2020 was performed. Lesion diagnosis was histopathologically confirmed except a presumed cavernous hemangioma. Echoplanar diffusion-weighted images had been acquired using 2 or 3 b values (b=0 and 1000 or b=0, 500, and 1000) at 1.5T or 3T. Lesions with significant artifacts were excluded. DWI sequences were analyzed by neuro-radiologists blinded to the diagnosis. Mean ADC values of lesions were calculated from a single region of interest. An independent two-tailed t test was used to compare categories of lesions with p < 0.05 considered significant. A systematic review of the literature was performed. RESULTS: Our study included 21 lesions. ADC values were significantly lower for malignant lesions (0.628 ± 0.125 × 10 -3 mm 2 /s) than inflammatory lesions (1.167 ± 0.381 × 10 -3 mm 2 /s) ( p < 0.001). ADC values were significantly lower for orbital lymphoma (mean 0.621 ± 0.147 × 10 -3 mm 2 /s) than idiopathic orbital inflammation (mean 1.188 ± 0.269 × 10 -3 mm 2 /s) with no overlap ( p < 0.001). CONCLUSIONS: Orbital malignancies demonstrated lower ADC values, while inflammatory processes demonstrated higher ADC values, except IgG4-related disease. DWI and ADC values differentiated idiopathic orbital inflammation from orbital lymphoma. This study highlights the role of DWI in evaluating orbital pathology.

Impact of prostate biopsy secondary pathology review on radiotherapy management.

BACKGROUND: The Gleason scoring system is the most widely used method to assess prostate adenocarcinoma pathology however interobserver variability is significant. Gleason score, PSA level, and clinical stage comprise the NCCN risk stratification that guides treatment decision making. Given the importance of an accurate Gleason score and wide interobserver variability, referral centers routinely review outside pathology at the time of consultation. We sought to address the impact a secondary pathology review had on radiation therapy treatment recommendations in men with prostate cancer at our institution. METHODS: We retrospectively collected patient data on 342 patients seen at our institution from January 2012 to December 2018. Clinicopathologic data were used to subdivide patients into risk groups and available treatment options per NCCN criteria. Cases reviewed by our genitourinary pathologist (GUP) were compared with reports from outside pathologists. Inter-rater reliability between pathologists was assessed with weighted Cohen's kappa statistic and agreement of treatment options was determined by McNemar's exact tests. RESULTS: GUP scored more cores positive in 16.47% of cases on secondary review. Primary Gleason score was changed in 12.28% of patients and secondary score in 26.02% of cases. Total Gleason score was different in 29.24% of cases, 19.01% were downgraded and 10.23% upgraded. The weighted kappa statistic was 0.759 (95% confidence interval [CI]: 0.711, 0.807). 18.77% of patients were assigned to a different NCCN risk group following secondary review. The weighted kappa statistic comparing NCCN risk stratification was 0.802 (95% CI: 0.754, 0.850). Secondary review influenced radiation therapy recommendations pertaining to brachytherapy boost and androgen deprivation therapy in men with high risk disease (χ2 = 5.33, p = 0.0386; χ2 = 8.05, p = 0.0072, respectively). Kappa statistic was found to be highest when GUP assessed high-risk disease versus all other categories (κ = 0.823, 95% CI: 0.750, 0.895). CONCLUSIONS: We found nearly one in five men (18.7%) was assigned a different NCCN risk group and thus offered potentially different treatment options after a secondary pathology review at our institution. Given the inherent nature of prostate cancer and lung disease-specific survival associated with modern therapies, our study demonstrates the importance of a secondary pathology review and its potential impact on radiation therapy recommendations.

High-resolution hippocampal diffusion tensor imaging of mesial temporal sclerosis in refractory epilepsy.

OBJECTIVE: We explore the possibility of using diffusion tensor imaging (DTI) and neurite orientation dispersion and density imaging (NODDI) to discern microstructural abnormalities in the hippocampus indicative of mesial temporal sclerosis (MTS) at the subfield level. METHODS: We analyzed data from 57 patients with refractory epilepsy who previously underwent 3.0-T magnetic resonance imaging (MRI) including DTI as a standard part of presurgical workup. We collected information about each subject's seizure semiology, conventional electroencephalography (EEG), high-density EEG, positron emission tomography reports, surgical outcome, and available histopathological findings to assign a final diagnostic category. We also reviewed the radiology MRI report to determine the radiographic category. DTI- and NODDI-based metrics were obtained in the hippocampal subfields. RESULTS: By examining diffusion characteristics among subfields in the final diagnostic categories, we found lower orientation dispersion indices and elevated axial diffusivity in the dentate gyrus in MTS compared to no MTS. By similarly examining among subfields in the different radiographic categories, we found all diffusion metrics were abnormal in the dentate gyrus and CA1. We finally examined whether diffusion imaging would better inform a radiographic diagnosis with respect to the final diagnosis, and found that dentate diffusivity suggested subtle changes that may help confirm a positive radiologic diagnosis. SIGNIFICANCE: The results suggest that diffusion metric analysis at the subfield level, especially in dentate gyrus and CA1, maybe useful for clinical confirmation of MTS.

Somewhere to go: assessing the impact of public restroom interventions on reports of open defecation in San Francisco, California from 2014 to 2020.

BACKGROUND: Open defecation due to a lack of access to sanitation facilities remains a public health issue in the United States. People experiencing homelessness face barriers to accessing sanitation facilities, and are often forced to practice open defecation on streets and sidewalks. Exposed feces may contain harmful pathogens posing a significant threat to public health, especially among unhoused persons living near open defecation sites. The City of San Francisco's Department of Public Works implemented the Pit Stop Program to provide the unhoused and the general public with improved access to sanitation with the goal of reducing fecal contamination on streets and sidewalks. The objective of this study was to assess the impact of these public restroom interventions on reports of exposed feces in San Francisco, California. METHODS: We evaluated the impact of various public restroom interventions implemented from January 1, 2014 to January 1, 2020 on reports of exposed feces, captured through a 311 municipal service. Publicly available 311 reports of exposed feces were spatially and temporally matched to 31 Pit Stop restroom interventions at 27 locations across 10 San Francisco neighborhoods. We conducted an interrupted time-series analysis to compare pre- versus post-intervention rates of feces reports near the restrooms. RESULTS: Feces reports declined by 12.47 reports per week after the installation of 13 Pit Stop restrooms (p-value = 0.0002). In the same restrooms, the rate of reports per week declined from the six-month pre-intervention period to the post-intervention period (slope change = -0.024 [95% CI = -0.033, -0.014]). In a subset of restrooms, where new installations were made (Mission and Golden Gate Park), and in another subset of restrooms where restroom attendants were provided (Mission, Castro/Upper Market, and Financial District/South Beach), feces reports also declined. CONCLUSIONS: Increased access to public toilets reduced feces reports in San Francisco, especially in neighborhoods with people experiencing homelessness. The addition of restroom attendants also appeared to have reduced feces reports in some neighborhoods with PEH. These interventions should be audited for implementation quality, observed utilization data, and user experience at the neighborhood level in order to tailor sanitation interventions to neighborhood-specific needs.

Toxic and metabolic leukoencephalopathies in emergency department patients: a primer for the radiologist.

One of the most common chief complaints in the emergency department (ED) is altered mental status (AMS). Imaging plays a critical role in triaging patients and identifying the etiology of AMS. Toxic and metabolic etiologies are one of the primary differential categories for AMS, leading to toxic leukoencephalopathies. Toxic leukoencephalopathies are white matter disorders that result from either exogenous or endogenous sources. Common exogeneous causes of toxic leukoencephalopathy include drugs of abuse (heroin and cocaine), alcohol, inhaled gases (carbon monoxide), industrial agents (pesticides, toluene, ethylene glycol), and neurotoxic medications (methotrexate, metronidazole, vigabatrine, etc.); endogenous causes include hyper- and hypoglycemia, hyperammonemia, hyponatremia, and uremia. The imaging findings of toxic leukoencephalopathies manifest through a combination of vasogenic and cytotoxic edema, resulting in white matter patterns. These white matter patterns have been found to be pathognomonic. In the ED setting, it is imperative to develop a diagnosis based off of the imaging due to the lack of history and context that is typically provided with a chief complaint of altered mental status (AMS). To offer expeditious and accurate diagnosis, we present the classic imaging features of toxic leukoencephalopathies and correlate these imaging findings with pathophysiology.

Therapeutic benefit after intracranial gene therapy delivered during the symptomatic stage in a feline model of Sandhoff disease.

Sandhoff disease (SD) is an autosomal recessive lysosomal storage disease caused by defects in the ß-subunit of ß-N-acetylhexosaminidase (Hex), the enzyme that catabolizes GM2 ganglioside. Hex deficiency causes neuronal storage of GM2 and related glycoconjugates, resulting in progressive neurodegeneration and death, typically in infancy. No effective treatment exists for human patients. Adeno-associated virus (AAV) gene therapy led to improved clinical outcome and survival of SD cats treated before the onset of disease symptoms. Most human patients are diagnosed after clinical disease onset, so it is imperative to test AAV-gene therapy in symptomatic SD cats to provide a realistic indication of therapeutic benefits that can be expected in humans. In this study, AAVrh8 vectors injected into the thalamus and deep cerebellar nuclei of symptomatic SD cats resulted in widespread central nervous system enzyme distribution, although a substantial burden of storage material remained. Cats treated in the early symptomatic phase showed delayed disease progression and a significant survival increase versus untreated cats. Treatment was less effective when administered later in the disease course, although therapeutic benefit was still possible. Results are encouraging for the treatment of human patients and provide support for the development AAV-gene therapy for human SD.

Natural history of Tay-Sachs disease in sheep.

Tay-Sachs disease (TSD) is a fatal neurodegenerative disease caused by a deficiency of the enzyme ß-N-acetylhexosaminidase A (HexA). TSD naturally occurs in Jacob sheep is the only experimental model of TSD. TSD in sheep recapitulates neurologic features similar to juvenile onset and late onset TSD patients. Due to the paucity of human literature on pathology of TSD, a better natural history in the sheep TSD brain, which is on the same order of magnitude as a child's, is necessary for evaluating therapy and characterizing the pathological events that occur. To provide clinicians and researchers with a clearer understanding of longitudinal pathology in patients, we compare spectrum of clinical signs and brain pathology in mildly symptomatic (3-months), moderately symptomatic (6-months), or severely affected TSD sheep (humane endpoint at ~9-months of age). Increased GM2 ganglioside in the CSF of TSD sheep and a TSD specific biomarker on MRS (taurine) correlate with disease severity. Microglial activation and reactive astrocytes were observed globally on histopathology in TSD sheep with a widespread reduction in oligodendrocyte density. Myelination is reduced primarily in the forebrain illustrated by loss of white matter on MRI. GM2 and GM3 ganglioside were increased and distributed differently in various tissues. The study of TSD in the sheep model provides a natural history to shed light on the pathophysiology of TSD, which is of utmost importance due to novel therapeutics being assessed in human patients.

Pronounced Therapeutic Benefit of a Single Bidirectional AAV Vector Administered Systemically in Sandhoff Mice.

The GM2 gangliosidoses, Tay-Sachs disease (TSD) and Sandhoff disease (SD), are fatal lysosomal storage disorders caused by mutations in the HEXA and HEXB genes, respectively. These mutations cause dysfunction of the lysosomal enzyme ß-N-acetylhexosaminidase A (HexA) and accumulation of GM2 ganglioside (GM2) with ensuing neurodegeneration, and death by 5 years of age. Until recently, the most successful therapy was achieved by intracranial co-delivery of monocistronic adeno-associated viral (AAV) vectors encoding Hex alpha and beta-subunits in animal models of SD. The blood-brain barrier crossing properties of AAV9 enables systemic gene therapy; however, the requirement of co-delivery of two monocistronic AAV vectors to overexpress the heterodimeric HexA protein has prevented the use of this approach. To address this need, we developed multiple AAV constructs encoding simultaneously HEXA and HEXB using AAV9 and AAV-PHP.B and tested their therapeutic efficacy in 4- to 6-week-old SD mice after systemic administration. Survival and biochemical outcomes revealed superiority of the AAV vector design using a bidirectional CBA promoter with equivalent dose-dependent outcomes for both capsids. AAV-treated mice performed normally in tests of motor function, CNS GM2 ganglioside levels were significantly reduced, and survival increased by >4-fold with some animals surviving past 2 years of age.

A Safe and Reliable Technique for CNS Delivery of AAV Vectors in the Cisterna Magna.

Global gene delivery to the CNS has therapeutic importance for the treatment of neurological disorders that affect the entire CNS. Due to direct contact with the CNS, cerebrospinal fluid (CSF) is an attractive route for CNS gene delivery. A safe and effective route to achieve global gene distribution in the CNS is needed, and administration of genes through the cisterna magna (CM) via a suboccipital puncture results in broad distribution in the brain and spinal cord. However, translation of this technique to clinical practice is challenging due to the risk of serious and potentially fatal complications in patients. Herein, we report development of a gene therapy delivery method to the CM through adaptation of an intravascular microcatheter, which can be safely navigated intrathecally under fluoroscopic guidance. We examined the safety, reproducibility, and distribution/transduction of this method in sheep using a self-complementary adeno-associated virus 9 (scAAV9)-GFP vector. This technique was used to treat two Tay-Sachs disease patients (30 months old and 7 months old) with AAV gene therapy. No adverse effects were observed during infusion or post-treatment. This delivery technique is a safe and minimally invasive alternative to direct infusion into the CM, achieving broad distribution of AAV gene transfer to the CNS.

ERK-Directed Phosphorylation of mGlu5 Gates Methamphetamine Reward and Reinforcement in Mouse.

Methamphetamine (MA) is a highly addictive psychomotor stimulant drug. In recent years, MA use has increased exponentially on a global scale, with the number of MA-involved deaths reaching epidemic proportions. There is no approved pharmacotherapy for treating MA use disorder, and we know relatively little regarding the neurobiological determinants of vulnerability to this disease. Extracellular signal-regulated kinase (ERK) is an important signaling molecule implicated in the long-lasting neuroadaptations purported to underlie the development of substance use disorders, but the role for this kinase in the propensity to develop addiction, particularly MA use disorder, is uncharacterized. In a previous MA-induced place-conditioning study of C57BL/6J mice, we characterized mice as MA-preferring, -neutral, or -avoiding and collected tissue from the medial prefrontal cortex (mPFC). Using immunoblotting, we determined that elevated phosphorylated ERK expression within the medial prefrontal cortex (mPFC) is a biochemical correlate of the affective valence of MA in a population of C57BL/6J mice. We confirmed the functional relevance for mPFC ERK activation for MA-induced place-preference via site-directed infusion of the MEK inhibitor U0126. By contrast, ERK inhibition did not have any effect upon MA-induced locomotion or its sensitization upon repeated MA treatment. Through studies of transgenic mice with alanine point mutations on T1123/S1126 of mGlu5 that disrupt ERK-dependent phosphorylation of the receptor, we discovered that ERK-dependent mGlu5 phosphorylation normally suppresses MA-induced conditioned place-preference (MA-CPP), but is necessary for this drug's reinforcing properties. If relevant to humans, the present results implicate individual differences in the capacity of MA-associated cues/contexts to hyper-activate ERK signaling within mPFC in MA Use Disorder vulnerability and pose mGlu5 as one ERK-directed target contributing to the propensity to seek out and take MA.

Strategies to improve communication in telementoring in acute care coordination: a scoping review.

Background: Telementoring facilitates the coordination of advanced medical care in rural, remote or austere environments. Because the interpersonal element of telementoring has been relatively underexplored, we conducted a scoping review to identify strategies to improve communication in telementoring. Methods: Two independent reviewers searched all English-language articles in MEDLINE and Scopus from 1964 to 2017, as well as reference lists of relevant articles to identify articles addressing telementored interactions between health care providers. Search results were gathered in June 2017 and updated in January 2018. Identified articles were categorized by theme. Results: We identified 144 articles, of which 56 met our inclusion criteria. Forty-one articles focused on improving dispatcher-directed cardiopulmonary resuscitation (CPR). Major themes included the importance of language in identifying out-of-hospital cardiac arrest and how to provide instructions to enable administration of effective CPR. A standardized approach with scripted questions was associated with improved detection of out-of-hospital cardiac arrest, and a concise script was associated with improved CPR quality compared to no mentoring, unscripted mentoring or more complex instructions. Six articles focused on physician-physician consultation. Use of a handover tool that highlighted critical information outperformed an unstructured approach regarding transmission of vital information. Nine articles examined telementoring in trauma resuscitation. A common theme was the need to establish an understanding between mentor and provider regarding the limitations of the provider and his or her environment. Conclusion: The available data suggest that standardization coupled with short, concise validated scripts could improve efficacy, safety and engagement. Improvements will require multidisciplinary input, practice and deliberate efforts to address barriers.

Contexte: Le mentorat en ligne facilite la coordination des soins médicaux de pointe dans les environnements ruraux, éloignés ou rudimentaires. Toutefois, le facteur relationnel de ce type d'interaction est resté plutôt sous-exploré. C'est pourquoi nous avons réalisé une revue exploratoire pour dégager des stratégies d'amélioration de la communication en contexte de mentorat en ligne. Méthodes: Deux réviseurs indépendants ont cherché à recenser les articles portant sur les interactions de mentorat en ligne entre professionnels de la santé parmi tous les articles de langue anglaise publiés entre 1964 et 2017 indexés dans les bases de données MEDLINE et Scopus, ainsi que dans les listes bibliographiques des articles pertinents. Les résultats de recherche ont été recueillis en juin 2017 et actualisés en janvier 2018, et les articles recensés ont été regroupés par thèmes. Résultats: Nous avons retenu 144 articles, dont 56 répondant à nos critères d'inclusion. De ce total, 41 portaient sur l'amélioration de la réanimation cardiorespiratoire (RCR) dirigée par un répartiteur. Parmi les thèmes principaux, on retrouve l'importance du langage dans l'identification des arrêts cardiaques hors de l'hôpital, ainsi que la manière de fournir des instructions permettant de pratiquer une RCR efficace. Une approche normalisée avec des questions scénarisées a été associée à une meilleure détection des arrêts cardiaques hors de l'hôpital, alors qu'un scénario concis a été associé à une amélioration de la qualité de la RCR comparativement à une approche sans mentorat, avec mentorat non scénarisé ou avec des instructions plus complexes. Six des articles retenus portaient sur la consultation de type médecin­médecin. Ils ont conclu que l'utilisation d'un outil de transfert mettant en évidence l'information importante était plus efficace qu'une approche non structurée pour la transmission de renseignements vitaux. Finalement, 9 articles portaient sur le mentorat en ligne en réanimation traumatologique. Un des thèmes communs de ces articles était le besoin d'établir une compréhension mutuelle entre mentors et professionnels en ce qui concerne les restrictions de ces derniers et de leur environnement. Conclusion: Les données disponibles semblent indiquer que la normalisation associée à des scénarios courts, concis et éprouvés pourrait améliorer l'efficacité, la sécurité et l'engagement. Cependant, toute amélioration nécessitera un encadrement multidisciplinaire, de la pratique et des efforts délibérés pour surmonter les obstacles.

Effects of a Thermal Accelerant Gel on Microwave Ablation Zone Volumes in Lung: A Porcine Study.

Background Thermal ablation of cancers may be associated with high rates of local tumor progression. A thermal accelerant gel has been developed to improve the transmission of microwave energy in biologic tissues with the aim of enlarging the thermal ablation zone. Purpose To determine the effects of a thermal accelerant gel on microwave ablation zone volumes in porcine lung and to compare percutaneous and endobronchial delivery methods. Materials and Methods Thirty-two consecutive microwave lung ablations were performed in nine 12-week-old domestic male swine under general anesthesia by using fluoroscopic guidance between September 2017 and April 2018. Experimental ablations were performed following percutaneous injection of thermal accelerant into the lung (n = 16) or after endobronchial injection by using a flexible bronchoscope (n = 8). Control ablations were performed without accelerant gel (n = 8). Lung tissue was explanted after the animals were killed, and ablation zone volumes were calculated as the primary outcome measure by using triphenyltetrazolium chloride vital staining. Differences in treatment volumes were analyzed by generalized mixed modeling. Results Thermal accelerant ablation zone volumes were larger than control ablations (accelerant vs control ablation, 4.3 cm3 [95% confidence interval: 3.4, 5.5] vs 2.1 cm3 [95% confidence interval: 1.4, 2.9], respectively; P < .001). Among ablations with the thermal accelerant, those performed following percutaneous injection had a larger average ablation zone volume than those performed following endobronchial injection (percutaneous vs endobronchial, 4.8 cm3 [95% confidence interval: 3.6, 6.4] vs 3.3 cm3 [95% confidence interval: 2.9, 3.8], respectively; P = .03). Ablation zones created after endobronchial gel injection were more uniform in size distribution (standard error, percutaneous vs endobronchial: 0.13 vs 0.07, respectively; P = .03). Conclusion Use of thermal accelerant results in larger microwave ablation zone volumes in normal porcine lung tissue. Percutaneous thermal accelerant injection leads to a larger ablation zone volume compared with endobronchial injection, whereas a more homogeneous and precise ablation zone size is observed by using the endobronchial approach. © RSNA, 2019 See also the editorial by Goldberg in this issue.

Novel Biomarkers of Human GM1 Gangliosidosis Reflect the Clinical Efficacy of Gene Therapy in a Feline Model.

GM1 gangliosidosis is a fatal neurodegenerative disease that affects individuals of all ages. Favorable outcomes using adeno-associated viral (AAV) gene therapy in GM1 mice and cats have prompted consideration of human clinical trials, yet there remains a paucity of objective biomarkers to track disease status. We developed a panel of biomarkers using blood, urine, cerebrospinal fluid (CSF), electrodiagnostics, 7 T MRI, and magnetic resonance spectroscopy in GM1 cats-either untreated or AAV treated for more than 5 years-and compared them to markers in human GM1 patients where possible. Significant alterations were noted in CSF and blood of GM1 humans and cats, with partial or full normalization after gene therapy in cats. Gene therapy improved the rhythmic slowing of electroencephalograms (EEGs) in GM1 cats, a phenomenon present also in GM1 patients, but nonetheless the epileptiform activity persisted. After gene therapy, MR-based analyses revealed remarkable preservation of brain architecture and correction of brain metabolites associated with microgliosis, neuroaxonal loss, and demyelination. Therapeutic benefit of AAV gene therapy in GM1 cats, many of which maintain near-normal function >5 years post-treatment, supports the strong consideration of human clinical trials, for which the biomarkers described herein will be essential for outcome assessment.

Widespread Central Nervous System Gene Transfer and Silencing After Systemic Delivery of Novel AAV-AS Vector.

Effective gene delivery to the central nervous system (CNS) is vital for development of novel gene therapies for neurological diseases. Adeno-associated virus (AAV) vectors have emerged as an effective platform for in vivo gene transfer, but overall neuronal transduction efficiency of vectors derived from naturally occurring AAV capsids after systemic administration is relatively low. Here, we investigated the possibility of improving CNS transduction of existing AAV capsids by genetically fusing peptides to the N-terminus of VP2 capsid protein. A novel vector AAV-AS, generated by the insertion of a poly-alanine peptide, is capable of extensive gene transfer throughout the CNS after systemic administration in adult mice. AAV-AS is 6- and 15-fold more efficient than AAV9 in spinal cord and cerebrum, respectively. The neuronal transduction profile varies across brain regions but is particularly high in the striatum where AAV-AS transduces 36% of striatal neurons. Widespread neuronal gene transfer was also documented in cat brain and spinal cord. A single intravenous injection of an AAV-AS vector encoding an artificial microRNA targeting huntingtin (Htt) resulted in 33-50% knockdown of Htt across multiple CNS structures in adult mice. This novel AAV-AS vector is a promising platform to develop new gene therapies for neurodegenerative disorders.

In Vivo Selection Yields AAV-B1 Capsid for Central Nervous System and Muscle Gene Therapy.

Adeno-associated viral (AAV) vectors have shown promise as a platform for gene therapy of neurological disorders. Achieving global gene delivery to the central nervous system (CNS) is key for development of effective therapies for many of these diseases. Here we report the isolation of a novel CNS tropic AAV capsid, AAV-B1, after a single round of in vivo selection from an AAV capsid library. Systemic injection of AAV-B1 vector in adult mice and cat resulted in widespread gene transfer throughout the CNS with transduction of multiple neuronal subpopulations. In addition, AAV-B1 transduces muscle, ß-cells, pulmonary alveoli, and retinal vasculature at high efficiency. This vector is more efficient than AAV9 for gene delivery to mouse brain, spinal cord, muscle, pancreas, and lung. Together with reduced sensitivity to neutralization by antibodies in pooled human sera, the broad transduction profile of AAV-B1 represents an important improvement over AAV9 for CNS gene therapy.