Single institution experience with efgartigimod in patients with myasthenia gravis: Patient selection, dosing schedules, treatment response, and adverse events.

INTRODUCTION/AIMS: Efgartigimod is a neonatal Fc receptor blocker and was the first approved medication in its class for the treatment of generalized myasthenia gravis (gMG). As a novel therapy, little is known about the use of efgartigimod in clinical practice. This study aims to describe how efgartigimod is being incorporated into the current therapeutic landscape of MG. METHODS: We reviewed the charts of 17 patients with gMG treated with efgartigimod at the University of Pennsylvania between January 2022 and June 2023. RESULTS: Efgartigimod was selected mainly for patients who were treatment refractory, had side effects to other treatments, and/or required quick improvement in their symptoms. All patients had been previously treated with at least one medication for MG and had an average baseline Myasthenia Gravis Activities of Daily Living (MG-ADL) score of 9.1. The patients treated with efgartigimod improved their MG-ADL score by an average of 5.5 points at 3 months (p < .001) and 7.1 points by 6 months (p < .001). Forty percent of patients achieved minimal symptom expression. Adverse events (AEs) were reported in 43.7% of patients on efgartigimod, the most common being mild infection (urinary tract infection and thrush). There were no serious AEs. DISCUSSION: This study found efgartigimod to be efficacious, well tolerated, and safe in patients with MG. Efgartigimod should be considered as an add-on therapy, a bridge therapy, or as a monotherapy if patients have difficulty tolerating other treatments.

Working Memory Training for Children Using the Adaptive, Self-Select, and Stepwise Approaches to Setting the Difficulty Level of Training Activities: Protocol for a Randomized Controlled Trial.

BACKGROUND: A common yet untested assumption of cognitive training in children is that activities should be adaptive, with difficulty adjusted to the individual's performance in order to maximize improvements on untrained tasks (known as transfer). Working memory training provides the ideal testbed to systematically examine this assumption as it is one of the most widely studied domains in the cognitive training literature, and is critical for children's learning, including following instructions and reasoning. OBJECTIVE: This trial aimed to examine children's outcomes of working memory training using adaptive, self-select (child selects difficulty level), and stepwise (difficulty level increases incrementally) approaches to setting the difficulty of training activities compared to an active control condition immediately and 6-month postintervention. While the aim is exploratory, we hypothesized that children allocated to a working memory training condition would show greater improvements: (1) on near transfer measures compared to intermediate and far transfer measures and (2) immediately postintervention compared to 6-month postintervention. METHODS: This double-blinded, active-controlled, parallel-group randomized trial aimed to recruit 128 children aged 7 to 11 years from 1 metropolitan primary school in Melbourne, Australia. Following baseline testing, children were randomized into 1 of 4 conditions: adaptive, self-select, or stepwise working memory training, or active control. An experimental intervention embedded in Minecraft was developed for teachers to deliver in class over 2 consecutive weeks (10 × 20-minute sessions). The working memory training comprised 2 training activities with processing demands similar to daily activities: backward span and following instructions. The control comprised creative activities. Pre- and postintervention, children completed a set of working memory tests (near and intermediate transfer) and the Raven's Standard Progressive Matrices (far transfer) to determine training outcomes, as well as motivation questionnaires to determine if motivations toward learning and the intervention were similar across conditions. Caregivers completed the ADHD-Rating Scale-5 to measure their child's attention (far transfer). Statistical analysis will include traditional null hypothesis significance testing and Bayesian methods to quantify evidence for both the null and alternative hypotheses. RESULTS: Data collection concluded in December 2022. Data are currently being processed and analyzed. CONCLUSIONS: This trial will determine whether the adaptive approach to setting the difficulty of training activities maximizes cognitive training outcomes for children. This trial has several strengths: it adopts best practices for cognitive training studies (design, methods, and analysis plan); uses a range of measures to detect discrete levels of transfer; has a 6-month postintervention assessment; is appropriately powered; and uses an experimental working memory training intervention based on our current understanding of the cognitive mechanisms of training. Findings will inform future research and design of cognitive training interventions and highlight the value of the evidence-based principles of cognitive training. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry, ACTRN12621000990820; https://www.anzctr.org.au/ACTRN12621000990820.aspx. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/47496.

Assessment of Core Surgical Skills Using a Mixed Reality Headset - The MoTOR Study.

INTRODUCTION: Surgical skill assessment utilises direct observation and feedback by an expert which is potentially subjective, therefore obtaining objective data for hand and eye tracking is essential. Our aim was to evaluate a wearable mixed reality (MR) headset in these domains. METHODS: Participants with differing levels of surgical expertise [novice (N), intermediate (I) & expert (E)] performed 4 simulated surgical tasks; 2 general dexterity (tasks 1&2) and 2 surgical skills (tasks 3&4) wearing the MR headset capturing their hand and eye movements (median & range). Metrics included hand path length and the speed of each index or thumb tip. Gaze data were also captured. Participant demographics, prior expertise and current experience were captured with an electronic survey. Data were analysed with a Shapiro-Wilk test or ANOVA as appropriate. A p-value of < 0.05 was significant. RESULTS: Thirty-six participants were analysed (N = 18, I = 8, E = 8). Tasks 1&2 revealed 2 speed outcomes (left index and left-hand speed) which were significant. For tasks 3&4, various outcomes were significant: path length for left hand (N:45 cm vs. I:31 cm vs. E:27 cm, p = 0.03) and right hand (N:48 cm vs. I:29 cm vs. E:28 cm, p = 0.01) and total time (N:456s vs. I:292 vs. E: 245, p = 0.0002). With left-hand-tying, average path length (N:61 cm vs. I:39 vs. E:36, p = 0.04), average speed (N:11 cm/s vs. I:23 vs. E:24, p = 0.03), and total time (N:156s vs. I:43 vs. E:37, p = 0.003) were significant. The gaze-tracking was not statistically significant. CONCLUSION: The MR headset can be utilised as a valid tool for surgical performance assessment. Outcomes including path length and speed can be valuable metrics captured by the MR Headset during the task completion for detecting surgical proficiency.

New Insights into Gastrointestinal Involvement in Late-Onset Pompe Disease: Lessons Learned from Bench and Bedside.

BACKGROUND: There are new emerging phenotypes in Pompe disease, and studies on smooth muscle pathology are limited. Gastrointestinal (GI) manifestations are poorly understood and underreported in Pompe disease. METHODS: To understand the extent and the effects of enzyme replacement therapy (ERT; alglucosidase alfa) in Pompe disease, we studied the histopathology (entire GI tract) in Pompe mice (GAAKO 6neo/6neo). To determine the disease burden in patients with late-onset Pompe disease (LOPD), we used Patient-Reported Outcomes Measurements Information System (PROMIS)-GI symptom scales and a GI-focused medical history. RESULTS: Pompe mice showed early, extensive, and progressive glycogen accumulation throughout the GI tract. Long-term ERT (6 months) was more effective to clear the glycogen accumulation than short-term ERT (5 weeks). GI manifestations were highly prevalent and severe, presented early in life, and were not fully amenable to ERT in patients with LOPD (n = 58; age range: 18-79 years, median age: 51.55 years; 35 females; 53 on ERT). CONCLUSION: GI manifestations cause a significant disease burden on adults with LOPD, and should be evaluated during routine clinical visits, using quantitative tools (PROMIS-GI measures). The study also highlights the need for next generation therapies for Pompe disease that target the smooth muscles.

Neuroimaging findings in infantile Pompe patients treated with enzyme replacement therapy.

BACKGROUND: Recombinant human acid α-glucosidase (rhGAA) enzyme replacement therapy (ERT) has prolonged survival in infantile Pompe disease (IPD), but has unmasked central nervous system (CNS) changes. METHODS: Brain imaging, consisting of computed tomography (CT) and/or magnetic resonance imaging (MRI), was performed on 23 patients with IPD (17 CRIM-positive, 6 CRIM-negative) aged 2-38months. Most patients had baseline neuroimaging performed prior to the initiation of ERT. Follow-up neuroimaging was performed in eight. RESULTS: Sixteen patients (70%) had neuroimaging abnormalities consisting of ventricular enlargement (VE) and/or extra-axial cerebrospinal fluid accumulation (EACSF) at baseline, with delayed myelination in two. Follow-up neuroimaging (n=8) after 6-153months showed marked improvement, with normalization of VE and EACSF in seven patients. Two of three patients imaged after age 10years demonstrated white matter changes, with one noted to have a basilar artery aneurysm. CONCLUSIONS: Mild abnormalities on brain imaging in untreated or newly treated patients with IPD tend to resolve with time, in conjunction with ERT. However, white matter changes are emerging as seen in Patients 1 and 3 which included abnormal periventricular white matter changes with subtle signal abnormalities in the basal ganglia and minimal, symmetric signal abnormalities involving the deep frontoparietal cerebral white matter, respectively. The role of neuroimaging as part of the clinical evaluation of IPD needs to be considered to assess for white matter changes and cerebral aneurysms.

Three cases of multi-generational Pompe disease: Are current practices missing diagnostic and treatment opportunities?

Pompe disease (Glycogen storage disease type II, GSDII, or acid maltase deficiency) is an autosomal recessive metabolic myopathy with a broad clinical spectrum, ranging from infantile to late-onset presentations. In 2015, Pompe disease was added as a core condition to the Recommended Uniform Screening Panel for state newborn screening (NBS). The clinical importance of Pompe disease is evolving with the use of NBS, increasing awareness of the disease, and higher than previously reported disease prevalence; however, current practices miss additional diagnostic and potential treatment opportunities in close relatives of the family proband. In this report, we describe three families with multiple individuals in multiple generations affected by both infantile and late-onset clinical presentations of Pompe disease. The presence of multi-generational disease within these families highlights the importance of subsequent risk assessment through medical history and physical examination, with a low threshold for the screening of a proband's family members. We recommend enzymology (GAA activity assay) as the first screening method, as opposed to targeted mutation analysis, for at-risk family members. Given that the initial symptoms of the slowly progressive late-onset presentation of Pompe disease may be mild or non-specific, enzymatic testing of all parents of affected infants should be considered.

Durable and sustained immune tolerance to ERT in Pompe disease with entrenched immune responses.

BACKGROUND: Enzyme replacement therapy (ERT) has prolonged survival and improved clinical outcomes in patients with infantile Pompe disease (IPD), a rapidly progressive neuromuscular disorder. Yet marked interindividual variability in response to ERT, primarily attributable to the development of antibodies to ERT, remains an ongoing challenge. Immune tolerance to ongoing ERT has yet to be described in the setting of an entrenched immune response. METHODS: Three infantile Pompe patients who developed high and sustained rhGAA IgG antibody titers (HSAT) and received a bortezomib-based immune tolerance induction (ITI) regimen were included in the study and were followed longitudinally to monitor the long-term safety and efficacy. A trial to taper the ITI protocol was attempted to monitor if true immune tolerance was achieved. RESULTS: Bortezomib-based ITI protocol was safely tolerated and led to a significant decline in rhGAA antibody titers with concomitant sustained clinical improvement. Two of the 3 IPD patients were successfully weaned off all ITI protocol medications and continue to maintain low/no antibody titers. ITI protocol was significantly tapered in the third IPD patient. B cell recovery was observed in all 3 IPD patients. CONCLUSION: This is the first report to our knowledge on successful induction of long-term immune tolerance in patients with IPD and HSAT refractory to agents such as cyclophosphamide, rituximab, and methotrexate, based on an approach using the proteasome inhibitor bortezomib. As immune responses limit the efficacy and cost-effectiveness of therapy for many conditions, proteasome inhibitors may have new therapeutic applications. FUNDING: This research was supported by a grant from the Genzyme Corporation, a Sanofi Company (Cambridge, Massachusetts, USA), and in part by the Lysosomal Disease Network, a part of NIH Rare Diseases Clinical Research Network (RDCRN).

Characterization of gait in late onset Pompe disease.

The skeletal muscle manifestations of late-onset Pompe disease (LOPD) cause significant gait impairment. However, the specific temporal and spatial characteristics of abnormal gait in LOPD have not been objectively analyzed or described in the literature. This pilot study evaluated the gait of 22 individuals with LOPD using the GAITRite® temporospatial gait analysis system. The gait parameters were compared to normal reference values, and correlations were made with standard measures of disease progression. The LOPD population demonstrated significant abnormalities in temporospatial parameters of gait including a trend towards decreased velocity and cadence, a prolonged stance phase, prolonged time in double limb support, shorter step and stride length, and a wider base of support. Precise descriptions and analyses of gait abnormalities have much potential in increasing our understanding of LOPD, especially in regards to how its natural history may be modified by the use of enzyme replacement therapy (ERT) and other interventions. Gait analysis may provide a sensitive early marker of the onset of clinical symptoms and signs, offer an additional objective measure of disease progression and the impact of intervention, and serve as a potentially important clinical endpoint. The additional data from comprehensive gait analysis may personalize and optimize physical therapy management, and the clarification of specific gait patterns in neuromuscular diseases could be of clinical benefit in the ranking of a differential diagnosis.

The multi-modal Australian ScienceS Imaging and Visualization Environment (MASSIVE) high performance computing infrastructure: applications in neuroscience and neuroinformatics research.

The Multi-modal Australian ScienceS Imaging and Visualization Environment (MASSIVE) is a national imaging and visualization facility established by Monash University, the Australian Synchrotron, the Commonwealth Scientific Industrial Research Organization (CSIRO), and the Victorian Partnership for Advanced Computing (VPAC), with funding from the National Computational Infrastructure and the Victorian Government. The MASSIVE facility provides hardware, software, and expertise to drive research in the biomedical sciences, particularly advanced brain imaging research using synchrotron x-ray and infrared imaging, functional and structural magnetic resonance imaging (MRI), x-ray computer tomography (CT), electron microscopy and optical microscopy. The development of MASSIVE has been based on best practice in system integration methodologies, frameworks, and architectures. The facility has: (i) integrated multiple different neuroimaging analysis software components, (ii) enabled cross-platform and cross-modality integration of neuroinformatics tools, and (iii) brought together neuroimaging databases and analysis workflows. MASSIVE is now operational as a nationally distributed and integrated facility for neuroinfomatics and brain imaging research.