Comparative Analysis of Upper Limb Impairment Rating Processes in the AMA Guides Sixth Edition 2024 vs 2008: Impact on Stakeholders.

OBJECTIVE: To evaluate how upper limb impairment ratings are affected by updates to the AMA Guides to the Evaluation of Permanent Impairment (AMA Guides) Sixth Edition 2024 compared with the AMA Guides Sixth Edition 2008, and to investigate potential correlations with judicial, legislative, and economic factors. METHODS: Two expert evaluators reviewed 31 upper limb clinical vignettes from the 2008 and 2024 versions. The impairment ratings for each version were compared. RESULTS: After following the impairment ratings steps in each version, the results for 2024 showed no significant differences when compared with the impairment ratings generated using 2008 methods (Cohen's Kappa = 1.00). CONCLUSIONS: The updated AMA Guides Sixth Edition 2024 with improved, transparent processes and enhanced diagnosis-based impairment tables provides efficiency while retaining the accuracy, validity, and reliability of past versions of the AMA Guides.

Practical Applications and Observational Implications of Time-Based Coding for Workers' Compensation Clinical Encounters-A Follow-up to Best Practices in Documenting and Coding High-Value Care in Workers' Compensation Encounters-ACOEM Guidance Statement.

ABSTRACT: Clinical practices that provide workers' compensation care and other services related to managing work-related illnesses and injuries have long been challenged in receiving appropriate payment for their professional work. The American College of Occupational and Environmental Medicine (ACOEM) has provided excellent guidelines for coding and billing via its various documents that have been provided over the years. However, despite these guidelines, payors have been slow to adopt occupational specific coding guidelines to justify higher professional payment. With the move to a Centers for Medicare & Medicaid Services (CMS)-sponsored time-based coding option in 2011, the occupational and environmental medicine (OEM) clinics have been able to finally not only document but recoup the value of those services that go beyond the simple patient interface, being able to capture those activities that truly provide high value in the management of workers' medical issues.

Many Mickles Make a Muckle: Evidence That Gender Stereotypes Reemerge Spontaneously Via Cultural Evolution.

We explore whether societal gender stereotypes re-emerge as social information is repeatedly passed from person to person. We examined whether peoples' memories of personality attributes associated with female and male social targets became increasingly consistent with societal gender stereotypes as information was passed down social transmission chains. After passing through the memories of just four generations of participants, our initially gender-balanced micro-societies became rife with traditional gender stereotypes. While we found some evidence of the re-emergence of gender stereotypes in Experiment 1, we found the effects were stronger when targets appeared in a feminine-stereotyped occupational context (Experiment 2), and a masculine-stereotyped occupational context (Experiment 3); conversely, the re-emergence of gender stereotypes was attenuated when targets appeared in a single gender context (Experiment 4). The current findings demonstrate that gender schematic memory bias, if widely shared, might cause gender stereotypes to be maintained through cultural evolution.

Evaluation of fecal sample collection methods for feline gut microbiome profiling: fecal loop vs. litter box.

Introduction: Microbial population structures within fecal samples are vital for disease screening, diagnosis, and gut microbiome research. The two primary methods for collecting feline fecal samples are: (1) using a fecal loop, which retrieves a rectal sample using a small, looped instrument, and (2) using the litter box, which collects stool directly from the litter. Each method has its own advantages and disadvantages and is suitable for different research objectives. Methods and results: Whole-genome shotgun metagenomic sequencing were performed on the gut microbiomes of fecal samples collected using these two methods from 10 adult cats housed in the same research facility. We evaluated the influence of collection methods on feline microbiome analysis, particularly their impact on DNA extraction, metagenomic sequencing yield, microbial composition, and diversity in subsequent gut microbiome analyses. Interestingly, fecal sample collection using a fecal loop resulted in a lower yield of microbial DNA compared to the litterbox method (p = 0.004). However, there were no significant differences between the two groups in the proportion of host contamination (p = 0.106), virus contamination (p = 0.232), relative taxonomy abundance of top five phyla (Padj > 0.638), or the number of microbial genes covered (p = 0.770). Furthermore, no significant differences were observed in alpha-diversity, beta-diversity, the number of taxa identified at each taxonomic level, and the relative abundance of taxonomic units. Discussion: These two sample collection methods do not affect microbial population structures within fecal samples and collecting fecal samples directly from the litterbox within 6 hours after defecation can be considered a reliable approach for microbiome research.

Advancements in AMA Guides Musculoskeletal Impairment Evaluations: Improved Reliability and Ease of Use.

OBJECTIVE: Describe and evaluate methodological improvements in AMA Guides to the Evaluation of Permanent Impairment (Guides) Sixth Edition 2024, including an updated sequential method and enhanced diagnosis-based impairment tables, compared to the Guides Sixth 2008. METHODS: Three physician experts and three pre-medical students, respectively, completed two rounds of impairment ratings using the AMA Guides Sixth 2008 vs. 2024 methods. Impairment values and completion times using each method were compared for both groups. RESULTS: Time to complete an impairment rating by experts averaged 3.5 minutes using Guides 2024 compared with 13.9 minutes using Guides 2008, with 100% accuracy and reliability for both. Students' time averaged 5.3 minutes and 15.9 minutes, respectively, with increased accuracy and reliability with Guides 2024. CONCLUSIONS: The Guides Sixth 2024 allowed more-efficient impairment ratings while retaining accuracy, consistency, reliability, and reproducibility.

Intergroup processes and the happy face advantage: How social categories influence emotion categorization.

There is abundant evidence that emotion categorization is influenced by the social category membership of target faces, with target sex and target race modulating the ease with which perceivers can categorize happy and angry emotional expressions. However, theoretical interpretation of these findings is constrained by gender and race imbalances in both the participant samples and target faces typically used when demonstrating these effects (e.g., most participants have been White women and most Black targets have been men). Across seven experiments, the current research used gender-matched samples (Experiments 1a and 1b), gender- and racial identity-matched samples (Experiments 2a and 2b), and manipulations of social context (Experiments 3a, 3b, and 4) to establish whether emotion categorization is influenced by interactions between the social category membership of perceivers and target faces. Supporting this idea, we found the presence and size of the happy face advantage were influenced by interactions between perceivers and target social categories, with reliable happy face advantages in reaction times for ingroup targets but not necessarily for outgroup targets. White targets and female targets were the only categories associated with a reliable happy face advantage that was independent of perceiver category. The interactions between perceiver and target social category were eliminated when targets were blocked by social category (e.g., a block of all White female targets; Experiments 3a and 3b) and accentuated when targets were associated with additional category information (i.e., ingroup/outgroup nationality; Experiment 4). These findings support the possibility that contextually sensitive intergroup processes influence emotion categorization. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

The Characteristics and Function of Small Extracellular Vesicles Derived from Human Bone Marrow and Umbilical Cord Mesenchymal Stromal Cells Are Influenced by Cell Culture Conditions.

Extracellular vesicles (EVs) derived from mesenchymal stromal cells (MSC-EVs) have been proposed as a novel therapeutic tool with numerous clinically related advantages. However, their characteristics and functionality are dependent on the source of MSCs and their cell culture conditions. Fetal bovine serum (FBS) provides a source of nutrients and growth factors to the cultured cells. However, certain pitfalls are associated with its supplementation to the culture media, including introduction of exogenous FBS-derived EVs to the cultured cells. Thus, recent practices recommend utilization of serum-free (SF) media or EV-depleted FBS. On the contrary, evidence suggests that the immunomodulatory ability of MSC-EVs can be improved by exposing MSCs to an inflammatory (IF) environment. The objective of this study was to (1) compare EVs isolated from two tissue sources of MSCs that were exposed to various cell culture conditions and (2) to evaluate their anti-inflammatory effects. Bone marrow-derived mesenchymal stromal cells (BM-MSCs) and umbilical cord-derived mesenchymal stromal cells (UC-MSCs) were exposed to either a SF media environment, an IF environment, or media supplemented with 5% EV-depleted FBS. Following isolation of MSC-EVs, the isolates were quantified and evaluated for particle size, phenotypic changes, and their immunomodulatory potential. A statistically significant difference was not identified on the yield and protein concentration of different isolates of EVs from BM-MSCs and UC-MSCs, and all isolates had a circular appearance as evaluated via electron microscopy. A significant difference was identified on the phenotype of different EVs isolates; however, all isolates expressed classical markers such as CD9, CD63, and CD81. The addition of BM-derived MSC-EVs from FBS environment or UC-derived MSC-EVs from IF environment resulted in statistically significant downregulation of IL-6 messenger RNA (mRNA) in stimulated leukocytes. This study confirms that EVs produced by different MSC sources and cell culture conditions affect their phenotype and their immunomodulatory capacities.

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.

Accentuate the positive: Evidence that context dependent self-reference drives self-bias.

There is abundant evidence of a self-bias in cognition, with prioritised processing of information that is self-relevant. There is also abundant evidence of a positivity-bias in cognition, with prioritised processing of information that is positively valenced (e.g., positive emotional expressions, rewards). While the effects of self-bias and positivity-bias have been well documented in isolation, they have seldom been examined in parallel, so it is unclear whether one or other of these stimulus classes is prioritised or whether they interact. Addressing this gap, the current research aimed to establish the relative primacy of self-bias and positivity-bias using a classification task that paired self-relevant information with emotional expressions (i.e., Expt. 1) or reward information (i.e., Expt. 2). When the self was paired with relatively more positive information (i.e., smiling faces or high reward) we found evidence of a self-bias but no evidence of a positivity-bias. Whereas when the self was paired with relatively less positive information (i.e., neutral faces or low reward) we found evidence of a positivity-bias but no evidence of a self-bias. These results suggest the relative primacy of prioritised processing is flexible, context dependent and might be caused by a drive towards self-enhancement and the self-positivity bias.

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.

BACKGROUND: A noninvasive and sensitive imaging tool is needed to assess the fast-evolving baby brain. However, using MRI to study non-sedated babies faces roadblocks, including high scan failure rates due to subjects motion and the lack of quantitative measures for assessing potential developmental delays. This feasibility study explores whether MR Fingerprinting scans can provide motion-robust and quantitative brain tissue measurements for non-sedated infants with prenatal opioid exposure, presenting a viable alternative to clinical MR scans. ASSESSMENT: MRF image quality was compared to pediatric MRI scans using a fully crossed, multiple reader multiple case study. The quantitative T1 and T2 values were used to assess brain tissue changes between babies younger than one month and babies between one and two months. STATISTICAL TESTS: Generalized estimating equations (GEE) model was performed to test the significant difference of the T1 and T2 values from eight white matter regions of babies under one month and those are older. MRI and MRF image quality were assessed using Gwets second order auto-correlation coefficient (AC2) with its confidence levels. We used the Cochran-Mantel-Haenszel test to assess the difference in proportions between MRF and MRI for all features and stratified by the type of features. RESULTS: In infants under one month of age, the T1 and T2 values are significantly higher (p<0.005) compared to those between one and two months. A multiple-reader and multiple-case study showed superior image quality ratings in anatomical features from the MRF images than the MRI images. CONCLUSIONS: This study suggested that the MR Fingerprinting scans offer a motion-robust and efficient method for non-sedated infants, delivering superior image quality than clinical MRI scans and additionally providing quantitative measures to assess brain development.

A pentasaccharide for monitoring pharmacodynamic response to gene therapy in GM1 gangliosidosis.

BACKGROUND: GM1 gangliosidosis is a rare, fatal, neurodegenerative disease caused by mutations in the GLB1 gene and deficiency in ß-galactosidase. Delay of symptom onset and increase in lifespan in a GM1 gangliosidosis cat model after adeno-associated viral (AAV) gene therapy treatment provide the basis for AAV gene therapy trials. The availability of validated biomarkers would greatly improve assessment of therapeutic efficacy. METHODS: The liquid chromatography-tandem mass spectrometry (LC-MS/MS) was used to screen oligosaccharides as potential biomarkers for GM1 gangliosidosis. The structures of pentasaccharide biomarkers were determined with mass spectrometry, as well as chemical and enzymatic degradations. Comparison of LC-MS/MS data of endogenous and synthetic compounds confirmed the identification. The study samples were analyzed with fully validated LC-MS/MS methods. FINDINGS: We identified two pentasaccharide biomarkers, H3N2a and H3N2b, that were elevated more than 18-fold in patient plasma, cerebrospinal fluid (CSF), and urine. Only H3N2b was detectable in the cat model, and it was negatively correlated with ß-galactosidase activity. Following intravenous (IV) AAV9 gene therapy treatment, reduction of H3N2b was observed in central nervous system, urine, plasma, and CSF samples from the cat model and in urine, plasma, and CSF samples from a patient. Reduction of H3N2b accurately reflected normalization of neuropathology in the cat model and improvement of clinical outcomes in the patient. INTERPRETATIONS: These results demonstrate that H3N2b is a useful pharmacodynamic biomarker to evaluate the efficacy of gene therapy for GM1 gangliosidosis. H3N2b will facilitate the translation of gene therapy from animal models to patients. FUNDING: This work was supported by grants U01NS114156, R01HD060576, ZIAHG200409, and P30 DK020579 from the National Institutes of Health (NIH) and a grant from National Tay-Sachs and Allied Diseases Association Inc.

Implementation of Lung Cancer Screening in Primary Care and Pulmonary Clinics: Pragmatic Clinical Trial of Electronic Health Record-Integrated Everyday Shared Decision-Making Tool and Clinician-Facing Prompts.

BACKGROUND: Although low-dose CT (LDCT) scan imaging lung cancer screening (LCS) can reduce lung cancer mortality, it remains underused. Shared decision-making (SDM) is recommended to assess the balance of benefits and harms for each patient. RESEARCH QUESTION: Do clinician-facing electronic health record (EHR) prompts and an EHR-integrated everyday SDM tool designed to support routine incorporation of SDM into primary care improve LDCT scan imaging ordering and completion? STUDY DESIGN AND METHODS: A preintervention and postintervention analysis was conducted in 30 primary care and four pulmonary clinics for visits with patients who met United States Preventive Services Task Force criteria for LCS. Propensity scores were used to adjust for covariates. Subgroup analyses were conducted based on the expected benefit from screening (high benefit vs intermediate benefit), pulmonologist involvement (ie, whether the patient was seen in a pulmonary clinic in addition to a primary care clinic), sex, and race and ethnicity. RESULTS: In the 12-month preintervention phase among 1,090 eligible patients, 77 patients (7.1%) had LDCT scan imaging orders and 48 patients (4.4%) completed screenings. In the 9-month intervention phase among 1,026 eligible patients, 280 patients (27.3%) had LDCT scan imaging orders and 182 patients (17.7%) completed screenings. Adjusted ORs were 4.9 (95% CI, 3.4-6.9; P < .001) and 4.7 (95% CI, 3.1-7.1; P < .001) for LDCT imaging ordering and completion, respectively. Subgroup analyses showed increases in ordering and completion for all patient subgroups. In the intervention phase, the SDM tool was used by 23 of 102 ordering providers (22.5%) and for 69 of 274 patients (25.2%) for whom LDCT scan imaging was ordered and who needed SDM at the time of ordering. INTERPRETATION: Clinician-facing EHR prompts and an EHR-integrated everyday SDM tool are promising approaches to improving LCS in the primary care setting. However, room for improvement remains. As such, further research is warranted. TRIAL REGISTRY: ClinicalTrials.gov; No.: NCT04498052; URL: www. CLINICALTRIALS: gov.

A qualitative systematic review on the application of the normalization of deviance phenomenon within high-risk industries.

INTRODUCTION: The concept of normalization of deviance describes the gradual acceptance of deviant observations and practices. It is founded upon the gradual desensitization to risk experienced by individuals or groups who recurrently deviate from standard operating procedures without encountering negative consequences. Since its inception, normalization of deviance has seen extensive, but segmented, application across numerous high-risk industrial contexts. The current paper describes a systematic review of the existing literature on the topic of normalization of deviance within high-risk industrial settings. METHOD: Four major databases were searched in order to identify relevant academic literature, with 33 academic papers meeting all inclusion criteria. Directed content analysis was used to analyze the texts. RESULTS: Based on the review, an initial conceptual framework was developed to encapsulate identified themes and their interactions; key themes linked to the normalization of deviance included risk normalization, production pressure, culture, and a lack of negative consequences. CONCLUSIONS: While preliminary, the present framework offers relevant insights into the phenomenon that may help guide future analysis using primary data sources and aid in the development of intervention methods. PRACTICAL APPLICATIONS: Normalization of deviance is an insidious phenomenon that has been noted in several high-profile disasters across a variety of industrial settings. A number of organizational factors allow for and/or propagate this process, and as such, the phenomenon should be considered as an aspect of safety evaluations and interventions.

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.

Prostate brachytherapy utilization in the COVID-19 era: A cross-sectional study of radiation oncologists in the United States.

PURPOSE: Despite advantages such as abbreviated treatment course, brachytherapy (BT) utilization rates for prostate cancer (PC) in the United States (US) are declining. We surveyed practicing US radiation oncologists (ROs) to determine the proportion who offer BT for PC and whether the COVID-19 pandemic influenced practice patterns. MATERIALS AND METHODS: From July-October 2021, we surveyed practicing US ROs. Provider demographic and practice characteristics were collected. Questions assessing utilization of BT and external beam (EBRT) for patients of varying risk groups and the effect of the pandemic on practice patterns were administered. Descriptive statistics were reported. The bivariate relationships between provider characteristics and likelihood of offering BT were assessed using the Chi-square test (α < 0.05). RESULTS: Six percent of surveyed ROs responded, with 203 meeting inclusion criteria (72% male, 72% white, 53% non-academic, 69% >10 years in practice) and 156 (77%) treating PC. For low-risk, fewer providers offered BT (41% total; 25% low dose rate [LDR], 10% high dose rate [HDR], 6% both) than stereotactic body (SBRT) (54%) and moderately hypofractionated radiation therapy (MHFRT) (83%). For favorable intermediate risk, fewer offered BT (37% total; 21% LDR, 10% HDR, 6% both) than SBRT (48%), MHFRT (87%), and conventionally fractionated EBRT (38%). For high (44%) and very-high (37%) risk, fewer offered EBRT+BT than EBRT alone. For every risk group, academic ROs were significantly more likely to offer BT (all p-values<0.05). <1% of respondents reported increased pandemic-related BT usage. CONCLUSIONS: US ROs, particularly in non-academic settings, do not routinely offer BT monotherapy or boost (<50%). Practice patterns were unaffected by COVID-19. Retraining may be critical to increasing utilization.

Rabies: who should care?

Rabies is the deadliest viral infection known, with no reliable treatment, and although it is entirely preventable, rabies continues to kill more than 60,000 people every year, mostly children in countries where dog rabies is endemic. America is only 1 generation away from the time when rabies killed more than 10,000 animals and 50 Americans every year, but 3 to 5 Americans continue to die annually from rabies. Distressingly, > 50,000 Americans undergo rabies prevention therapy every year after exposure to potentially rabid animals. While enormous progress has been made, more must be done to defeat this ancient but persistent, fatal zoonosis. In the US, lack of public awareness and ambivalence are the greatest dangers imposed by rabies, resulting in unnecessary exposures, anxiety, and risk. Veterinarians have a special role in informing and reassuring the public about prevention and protection from rabies. This summary of current facts and future advances about rabies will assist veterinarians in informing their clients about the disease.

AAVrh10 vector corrects pathology in animal models of GM1 gangliosidosis and achieves widespread distribution in the CNS of nonhuman primates.

GM1 gangliosidosis is a rare, inherited neurodegenerative disorder caused by mutations in the GLB1 gene, which encodes the lysosomal hydrolase acid ß-galactosidase (ß-gal). ß-gal deficiency leads to toxic accumulation of GM1 ganglioside, predominantly in the central nervous system (CNS), resulting in progressive neurodegeneration. LYS-GM101 is an AAVrh.10-based gene therapy vector carrying the human GLB1 cDNA. The efficacy of intra-cerebrospinal fluid injection of LYS-GM101 analogs was demonstrated in GM1 mouse and cat models with widespread diffusion of ß-gal and correction of GM1 ganglioside accumulation in the CNS without observable adverse effects. Clinical dose selection was performed, based on a good-laboratory-practice study, in nonhuman primates (NHPs) using the clinical LYS-GM101 vector. A broadly distributed increase of ß-gal activity was observed in NHP brain 3 months after intra-cisterna magna injection of LYS-GM101 at 1.0 × 1012 vg/mL CSF and 4.0 × 1012 vg/mL CSF, with 20% and 60% increases compared with vehicle-treated animals, respectively. Histopathologic examination revealed asymptomatic adverse changes in the sensory pathways of the spinal cord and dorsal root ganglia in both sexes and at both doses. Taken as a whole, these pre-clinical data support the initiation of a clinical study with LYS-GM101 for the treatment of GM1 gangliosidosis.