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Late-onset Pompe Disease (LOPD) is a rare genetic disorder caused by the deficiency of acid alpha-glucosidase leading to progressive cellular dysfunction due to the accumulation of glycogen in the lysosome. The mechanism of relentless muscle damage - a classic manifestation of the disease - has been extensively studied by analysing the whole muscle tissue; however, little, if any, is known about transcriptional heterogeneity among nuclei within the multinucleated skeletal muscle cells. This is the first report of application of single nuclei RNA sequencing to uncover changes in the gene expression profile in muscle biopsies from eight patients with LOPD and four muscle samples from age and gender matched healthy controls. We matched these changes with histology findings using GeoMx Spatial Transcriptomics to compare the transcriptome of control myofibers from healthy individuals with non-vacuolated (histologically unaffected) and vacuolated (histologically affected) myofibers of LODP patients. We observed an increase in the proportion of slow and regenerative muscle fibers and macrophages in LOPD muscles. The expression of the genes involved in glycolysis was reduced, whereas the expression of the genes involved in the metabolism of lipids and amino acids was increased in non-vacuolated fibers, indicating early metabolic abnormalities. Additionally, we detected upregulation of autophagy genes, and downregulation of the genes involved in ribosomal and mitochondrial function leading to defective oxidative phosphorylation. The upregulation of the genes associated with inflammation, apoptosis and muscle regeneration was observed only in vacuolated fibers. Notably, enzyme replacement therapy - the only available therapy for the disease - showed a tendency to restore metabolism dysregulation, particularly within slow fibers. A combination of single nuclei RNA sequencing and spatial transcriptomics revealed the landscape of normal and the diseased muscle, and highlighted the early abnormalities associated with the disease progression. Thus, the application of these two new cutting-edge technologies provided insight into the molecular pathophysiology of muscle damage in LOPD and identified potential avenues for therapeutic intervention.
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BACKGROUND: Headache is among the most common symptoms following concussion, yet headache after concussion (HAC) remains poorly characterized. This study describes headache characteristics over the first four weeks following pediatric sport-related concussion. METHODS: This is a retrospective case series of 87 athletes (mean: 14.9 years; range: 8.4-18.8 years; 38% female) treated in a specialty sports concussion clinic within 28 days of injury. Primary outcomes of headache consistency, frequency, duration, and associated migrainous symptoms were assessed at immediate (0 to 48 h) and weekly time points over the first 28 days post-injury. Generalized mixed linear models compared headache characteristics across time points. Secondary analyses compared each outcome by as-needed analgesic use. RESULTS: During the immediate post-injury period, headache was more often constant (p = 0.002) and associated with migrainous symptoms (p < 0.001). By the third week post-injury, episodic headache was more prevalent (p < 0.001). Most patients (54%) transitioned from constant, migrainous headache to episodic, non-migrainous headache. This finding was uninfluenced by as-needed analgesic medication use. CONCLUSIONS: These findings document the trajectory of HAC. Future studies should assess relationships between initial headache characteristics and recovery.
Subject(s)
Athletic Injuries , Brain Concussion , Headache , Humans , Female , Male , Adolescent , Retrospective Studies , Brain Concussion/complications , Child , Athletic Injuries/complications , Athletic Injuries/epidemiology , Headache/etiologyABSTRACT
Narrative episodic memory of movie clips can be retroactively impaired by presenting unrelated stimuli coinciding with event boundaries. This effect has been linked with rapid hippocampal processes triggered by the offset of the event, that are alternatively related either to memory consolidation or with working memory processes. Here we tested whether this effect extended to spatial memory, the temporal specificity and extent of the interference, and its effect on working- vs long-term memory. In three computerized adaptations of the Morris Water Maze, participants learned the location of an invisible target over three trials each. A second spatial navigation task was presented either immediately after finding the target, after a 10-s delay, or no second task was presented (control condition). A recall session, in which participants indicated the learned target location with 10 'pin-drop' trials for each condition, was performed after a 1-h or a 24-h break. Spatial memory was measured by the mean distance between pins and the true location. Results indicated that the immediate presentation of the second task led to worse memory performance, for both break durations, compared to the delayed condition. There was no difference in performance between the delayed presentation and the control condition. Despite this long-term memory effect, we found no difference in the rate of performance improvement during the learning session, indicating no effect of the second task on working memory. Our findings are in line with a rapid process, linked to the offset of an event, that is involved in the early stages of memory consolidation.
Subject(s)
Memory, Long-Term , Memory, Short-Term , Spatial Memory , Humans , Memory, Short-Term/physiology , Male , Adult , Young Adult , Memory, Long-Term/physiology , Female , Spatial Memory/physiology , Mental Recall/physiology , Maze Learning/physiology , Adolescent , Virtual RealityABSTRACT
BACKGROUND AND PURPOSE: Two novel enzyme replacement therapies (ERTs), studied in phase 3 trials in late-onset Pompe patients, reached marketing authorization by the European Medicines Agency in 2022 and 2023. The European Pompe Consortium (EPOC) updates and extends the scope of the 2017 recommendations for starting, switching and stopping ERT. METHODS: The European Pompe Consortium consists of 25 neuromuscular and metabolic experts from eight European countries. This update was performed after an in-person meeting, three rounds of discussion and voting to provide a consensus recommendation. RESULTS: The patient should be symptomatic, that is, should have skeletal muscle weakness or respiratory muscle involvement. Muscle magnetic resonance imaging findings showing substantial fat replacement can support the decision to start in a patient-by-patient scenario. Limited evidence supports switching ERT if there is no indication that skeletal muscle and/or respiratory function have stabilized or improved during standard ERT of 12 months or after severe infusion-associated reactions. Switching of ERT should be discussed on a patient-by-patient shared-decision basis. If there are severe, unmanageable infusion-associated reactions and no stabilization in skeletal muscle function during the first 2 years after starting or switching treatment, stopping ERT should be considered. After stopping ERT for inefficacy, restarting ERT can be considered. Six-monthly European Pompe Consortium muscle function assessments are recommended. CONCLUSIONS: The triple-S criteria on ERT start, switch and stop include muscle magnetic resonance imaging as a supportive finding and the potential option of home infusion therapy. Six-monthly long-term monitoring of muscle function is highly recommended to cover insights into the patient's trajectory under ERT.
Subject(s)
Enzyme Replacement Therapy , Glycogen Storage Disease Type II , Glycogen Storage Disease Type II/drug therapy , Humans , Enzyme Replacement Therapy/methods , EuropeABSTRACT
Age is a primary risk factor for Parkinson's disease (PD); however, the effects of aging on the Parkinsonian brain remain poorly understood, particularly for deep brain structures. We investigated intraoperative micro-electrode recordings from the subthalamic nucleus (STN) of PD patients aged between 42 and 76 years. Age was associated with decreased oscillatory beta power and non-oscillatory high-frequency power, independent of PD-related variables. Single unit firing and burst rates were also reduced, whereas the coefficient of variation and the structure of burst activity were unchanged. Phase synchronization (debiased weighed phase lag index [dWPLI]) between sites was pronounced in the beta band between electrodes in the superficial STN but was unaffected by age. Our results show that aging is associated with reduced neuronal activity without changes to its temporal structure. We speculate that the loss of activity in the STN may mediate the relationship between PD and age.
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Purpose. To estimate the impact on mortality of nonpharmaceutical interventions (NPIs) implemented early in the COVID-19 pandemic. Methods. We implemented an agent-based modified SEIR model of COVID-19, calibrated to match death numbers reported in Pennsylvania from January 2020 to April 2021 and including representations of NPIs implemented in Pennsylvania. To investigate the impact of these strategies, we ran the calibrated model with no interventions and with varying combinations, timings, and levels of interventions. Results. The model closely replicated death outcomes data for Pennsylvania. Without NPIs, deaths in the early months of the pandemic were estimated to be much higher (67,718 deaths compared to actual 6,969). Voluntary interventions alone were relatively ineffective at decreasing mortality. Delaying implementation of interventions led to higher deaths (â¼9,000 more deaths with just a 1-week delay). School closure was insufficient as a single intervention but was an important part of a combined intervention strategy. Conclusions. NPIs were effective at reducing deaths early in the COVID-19 pandemic. Agent-based models can incorporate substantial detail on infectious disease spread and the impact of mitigations. Policy Implications. The model supports the importance and effectiveness of NPIs to decrease morbidity from respiratory pathogens. This is particularly important for emerging pathogens for which no vaccines or treatments exist, but such strategies are applicable to a variety of respiratory pathogens. Highlights: Nonpharmaceutical interventions were used extensively during the early period of the COVID-19 pandemic, but their use has remained controversial.Agent-based modeling of the impact of these mitigation strategies early in the COVID-19 pandemic supports the effectiveness of nonpharmaceutical interventions at decreasing mortality.Since such interventions are not specific to a particular pathogen, they can be used to protect against any respiratory pathogen, known or emerging. They can be applied rapidly when conditions warrant.
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BACKGROUND: Chronic respiratory insufficiency from progressive muscle weakness causes morbidity and mortality in late-onset Pompe disease (LOPD). Previous Pompe Registry (NCT00231400) analyses for ≤ 5 years' alglucosidase alfa treatment showed a single linear time trend of stable forced vital capacity (FVC) % predicted. METHODS: To assess longer term Pompe Registry data, piecewise linear mixed model regression analyses estimated FVC% predicted trajectories in invasive-ventilator-free patients with LOPD aged ≥ 5 years. We estimated annual FVC change 0-6 months, > 6 months-5 years, and > 5-13 years from treatment initiation, adjusting for baseline age, sex, and non-invasive ventilation. FINDINGS: Among 485 patients (4612 FVC measurements; 8.3 years median follow-up), median ages at symptom onset, diagnosis, and alglucosidase alfa initiation were 34.3, 41.1, and 44.9 years, respectively. FVC% increased during the first 6 months' treatment (slope 1.83%/year; 95% confidence interval: 0.66, 3.01; P = 0.0023), then modestly declined -0.54%/year (-0.79, -0.30; P < 0.0001) during > 6 months-5 years, and -1.00%/year (-1.36, -0.63; P < 0.0001) during > 5-13 years. The latter two periods' slopes were not significantly different from each other (Pdifference = 0.0654) and were less steep than published natural history slopes (-1% to -4.6%/year). Estimated individual slopes were ≥ 0%/year in 96.1%, 30.3%, and 13.2% of patients during the 0-6 month, > 6 month-5 year, and > 5-13 year periods, respectively. CONCLUSION: These real-world data indicate an alglucosidase alfa benefit on FVC trajectory that persists at least 13 years compared with published natural history data. Nevertheless, unmet need remains since most individuals demonstrate lung function decline 5 years after initiating treatment. Whether altered FVC trajectory impacts respiratory failure incidence remains undetermined. TRIAL REGISTRATION: This study was registered (NCT00231400) on ClinicalTrials.gov on September 30, 2005, retrospectively registered.
Subject(s)
Glycogen Storage Disease Type II , Registries , alpha-Glucosidases , Humans , Glycogen Storage Disease Type II/drug therapy , Glycogen Storage Disease Type II/physiopathology , Male , Female , alpha-Glucosidases/therapeutic use , Adult , Vital Capacity/drug effects , Vital Capacity/physiology , Middle Aged , Enzyme Replacement Therapy/methods , Young Adult , Adolescent , Child , Follow-Up Studies , Child, PreschoolABSTRACT
Concussion is a mild traumatic brain injury causing temporary neurologic dysfunction. Symptoms following concussion are variable and generally are expected to resolve within about 1 month, but some patients experience persistent and prolonged symptoms. An early return to safe, symptom-limited activity is now favored, using targeted rehabilitation and treatments. Accommodations may be needed to facilitate return-to-school and work following concussion. Athletes should not be cleared for a full return to sport until they have recovered from a concussion and completed a return-to-play progression, in addition to returning to work/school fully.
Subject(s)
Athletic Injuries , Brain Concussion , Return to Sport , Humans , Athletic Injuries/therapy , Athletic Injuries/diagnosis , Brain Concussion/therapy , Brain Concussion/diagnosis , Primary Health Care , Recovery of Function , Return to WorkABSTRACT
The phase III double-blind PROPEL study compared the novel two-component therapy cipaglucosidase alfa + miglustat (cipa + mig) with alglucosidase alfa + placebo (alg + pbo) in adults with late-onset Pompe disease (LOPD). This ongoing open-label extension (OLE; NCT04138277) evaluates long-term safety and efficacy of cipa + mig. Outcomes include 6-min walk distance (6MWD), forced vital capacity (FVC), creatine kinase (CK) and hexose tetrasaccharide (Hex4) levels, patient-reported outcomes and safety. Data are reported as change from PROPEL baseline to OLE week 52 (104 weeks post-PROPEL baseline). Of 118 patients treated in the OLE, 81 continued cipa + mig treatment from PROPEL (cipa + mig group; 61 enzyme replacement therapy [ERT] experienced prior to PROPEL; 20 ERT naïve) and 37 switched from alg + pbo to cipa + mig (switch group; 29 ERT experienced; 8 ERT naive). Mean (standard deviation [SD]) change in % predicted 6MWD from baseline to week 104 was + 3.1 (8.1) for cipa + mig and - 0.5 (7.8) for the ERT-experienced switch group, and + 8.6 (8.6) for cipa + mig and + 8.9 (11.7) for the ERT-naïve switch group. Mean (SD) change in % predicted FVC was - 0.6 (7.5) for cipa + mig and - 3.8 (6.2) for the ERT-experienced switch group, and - 4.8 (6.5) and - 3.1 (6.7), respectively, in ERT-naïve patients. CK and Hex4 levels improved in both treatment groups by week 104 with cipa + mig treatment. Three patients discontinued the OLE due to infusion-associated reactions. No new safety signals were identified. Cipa + mig treatment up to 104 weeks was associated with overall maintained improvements (6MWD, biomarkers) or stabilization (FVC) from baseline with continued durability, and was well tolerated, supporting long-term benefits for patients with LOPD.Trial registration number: NCT04138277; trial start date: December 18, 2019.
Subject(s)
1-Deoxynojirimycin , 1-Deoxynojirimycin/analogs & derivatives , Enzyme Replacement Therapy , Glycogen Storage Disease Type II , Humans , Male , Female , Glycogen Storage Disease Type II/drug therapy , Middle Aged , Adult , 1-Deoxynojirimycin/administration & dosage , 1-Deoxynojirimycin/adverse effects , 1-Deoxynojirimycin/therapeutic use , Double-Blind Method , Enzyme Replacement Therapy/methods , alpha-Glucosidases/adverse effects , alpha-Glucosidases/administration & dosage , alpha-Glucosidases/therapeutic use , Drug Therapy, Combination , Treatment Outcome , Aged , Enzyme Inhibitors/administration & dosage , Enzyme Inhibitors/adverse effectsABSTRACT
Cipaglucosidase alfa plus miglustat (cipa + mig) is a novel, two-component therapy for Pompe disease. We report data from the Phase I/II ATB200-02 study for up to 48 months of treatment. Four adult cohorts, including one non-ambulatory ERT-experienced (n = 6) and three ambulatory cohorts, (two enzyme replacement therapy [ERT]-experienced cohorts [2-6 years (n = 11) and ≥ 7 years (n = 6)]), one ERT-naïve cohort (n = 6), received 20 mg/kg intravenous-infused cipa plus 260 mg oral mig biweekly. Change from baseline (CFBL) for multiple efficacy endpoints at 12, 24, 36, and 48 months, pharmacodynamics, pharmacokinetics, safety, and immunogenicity data were assessed. Six-minute walking distance (% predicted) improved at 12, 24, 36, and 48 months: pooled ambulatory ERT-experienced cohorts, mean(± standard deviation [SD]) CFBL: 6.1(± 7.84), n = 16; 5.4(± 10.56), n = 13; 3.4(± 14.66), n = 12; 5.9(± 17.36), n = 9, respectively; ERT-naïve cohort: 10.7(± 3.93), n = 6; 11.0(± 5.06), n = 6; 9.0(± 7.98), n = 5; 11.7(± 7.69), n = 4, respectively. Percent predicted forced vital capacity was generally stable in ERT-experienced cohorts, mean(± SD) CFBL - 1.2(± 5.95), n = 16; 1.0(± 7.96), n = 13; - 0.3(± 6.68), n = 10; 1.0(± 6.42), n = 6, respectively, and improved in the ERT-naïve cohort: 3.2(± 8.42), n = 6; 4.7(± 5.09), n = 6; 6.2(± 3.35), n = 5; 8.3(± 4.50), n = 4, respectively. Over 48 months, CK and Hex4 biomarkers improved in ambulatory cohorts. Overall, cipa + mig was well tolerated with a safety profile like alglucosidase alfa. ATB200-02 results show the potential benefits of cipa + mig as a long-term treatment option for Pompe disease. Trial registration number: NCT02675465 January 26, 2016.
Subject(s)
1-Deoxynojirimycin/analogs & derivatives , Glycogen Storage Disease Type II , Propionates , Adult , Humans , Glycogen Storage Disease Type II/therapy , Treatment Outcome , alpha-Glucosidases/therapeutic use , Indoles , Enzyme Replacement Therapy/methodsABSTRACT
Patients with neuromuscular diseases (NMD) can present to the neurologist with symptoms and signs of respiratory failure, either acutely or as an insidious process in the outpatient setting. Since the advent of non-invasive ventilation, the outcomes of patients with ventilatory failure due to NMD have dramatically improved. However, the natural history of different NMDs requires a nuanced approach to respiratory investigation and management. Respiratory failure dictates the prognosis of many NMDs and timing the most appropriate investigation and referral to ventilation services is crucial in optimising care.
Subject(s)
Neuromuscular Diseases , Noninvasive Ventilation , Respiratory Insufficiency , Humans , Respiratory Insufficiency/etiology , Respiratory Insufficiency/therapy , Prognosis , Chronic Disease , Neuromuscular Diseases/complications , Neuromuscular Diseases/diagnosis , Neuromuscular Diseases/therapyABSTRACT
Connectivity-derived 7-Tesla MRI segmentation and intraoperative microelectrode recording can both assist subthalamic nucleus targeting for deep brain stimulation in Parkinson's disease. It remains unclear whether deep brain stimulation electrodes placed in the 7-Tesla MRI segmented subdivision with predominant projections to cortical motor areas (hyperdirect pathway) achieve superior motor improvement and whether microelectrode recording can accurately distinguish the motor subdivision. In 25 patients with Parkinson's disease, deep brain stimulation electrodes were evaluated for being inside or outside the predominantly motor-connected subthalamic nucleus (motor-connected subthalamic nucleus or non-motor-connected subthalamic nucleus, respectively) based on 7-Tesla MRI connectivity segmentation. Hemi-body motor improvement (Movement Disorder Society Unified Parkinson's Disease Rating Scale, Part III) and microelectrode recording characteristics of multi- and single-unit activities were compared between groups. Deep brain stimulation electrodes placed in the motor-connected subthalamic nucleus resulted in higher hemi-body motor improvement, compared with electrodes placed in the non-motor-connected subthalamic nucleus (80% versus 52%, P < 0.0001). Multi-unit activity was found slightly higher in the motor-connected subthalamic nucleus versus the non-motor-connected subthalamic nucleus (P < 0.001, receiver operating characteristic 0.63); single-unit activity did not differ between groups. Deep brain stimulation in the connectivity-derived 7-Tesla MRI subthalamic nucleus motor segment produced a superior clinical outcome; however, microelectrode recording did not accurately distinguish this subdivision within the subthalamic nucleus.
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Chronic Hepatitis C virus (HCV) infection is a major cause of morbidity and deaths worldwide. HCV treating teams are working toward the goal of eliminating HCV by 2030. People who inject drugs (PWIDs) are at high risk of HCV but contact tracing is not routine practice. Here, we present the outcomes of a HCV 'test, trace and treat' pilot using peer workers to test contacts of individuals with HCV. PWIDs with HCV were invited to participate when they presented for treatment. For those agreeing to participate, a peer approached them to invite potential contacts for HCV testing. Data were collected on uptake, HCV test results, treatment rates and reasons for declining. Overall, 295 individuals (162 recent HCV [<1 year], 69 reinfections, 64 known chronic HCV) were invited to participate, of whom 147 (50%) agreed and 30 (20% of those agreeing) brought forward 120 contacts for testing. Of these, 44 (37%) were HCV RNA positive, including 23 who were not known to services. 34 (77%) started antiviral treatment. HCV RNA positivity was highest in contacts of reinfections (45%) compared with recent HCV (33%) and known chronic HCV (25%). The most common reason for index individuals declining participation was that they reported no longer being in contact with individuals from their injecting network (65%). In conclusion, half of PWIDs with HCV agreed to participate in the pilot, but only 20% of these brought contacts forward. The frequency of active HCV was high in the contacts and the majority started antiviral treatment.
Subject(s)
Hepatitis C, Chronic , Hepatitis C , Substance Abuse, Intravenous , Humans , Hepatitis C, Chronic/diagnosis , Hepatitis C, Chronic/drug therapy , Antiviral Agents/therapeutic use , Reinfection , RNA , Substance Abuse, Intravenous/drug therapy , Hepatitis C/diagnosis , Hepatitis C/drug therapy , Hepacivirus/geneticsABSTRACT
PURPOSE: Myasthenia gravis (MG) is a rare but life-threatening complication of immune-checkpoint inhibitor (ICI) therapy and often co-presents with myositis and myocarditis. Previous case series of ICI-related MG have reported high mortality rates. We present a series of ten patients from a tertiary oncology centre outlining outcomes of an early multi-modal immunosuppression strategy. METHODS: We reviewed The Christie Hospital database of immunotherapy-related toxicity from 2017 to 2020. Symptom severity was assessed using the Myasthenia Gravis Foundation of America (MGFA) classification. RESULTS: Ten patients with ICI-related MG were identified. All patients presented following 1 (n = 4) or 2 (n = 6) cycles of ICI. Symptom progression was rapid with a median of 3 days from onset of symptoms to admission. Concomitant myositis and myocarditis were observed in nine patients. AChR or MuSK autoantibodies were positive in six patients. All patients received urgent treatment with intravenous methylprednisolone (IVMP) and eight received intravenous immunoglobulin (IVIG). A single patient died from myasthenia-related symptoms; the remaining 9 patients were successfully discharged. CONCLUSION: In our cohort, we demonstrate good outcomes associated with early intensive immunosuppressive treatment with IVIG and IVMP. An agreed national treatment protocol or clinical discussion forum would be beneficial.
Subject(s)
Myasthenia Gravis , Myocarditis , Myositis , Humans , Immune Checkpoint Inhibitors/adverse effects , Immunoglobulins, Intravenous/therapeutic use , Immunosuppression Therapy , Myasthenia Gravis/chemically induced , Myasthenia Gravis/drug therapy , Myasthenia Gravis/complications , Myocarditis/chemically induced , Myocarditis/drug therapy , Myocarditis/complications , Myositis/chemically induced , Myositis/drug therapy , Myositis/complicationsABSTRACT
OBJECTIVE: Drug use disorder (DUD) is a worldwide problem, and strategies to reduce its incidence are central to decreasing its burden. This investigation seeks to provide a proof of concept for the ability of agent-based modeling to predict the impact of the introduction of an effective school-based intervention, the Good Behavior Game (GBG), on reducing DUD in Scania, Sweden, primarily through increasing school achievement. METHOD: We modified an existing agent-based simulation model of opioid use disorder to represent DUD in Scania County, southern Sweden. The model represents every individual in the population and is calibrated with the linked individual data from multiple sources including demographics, education, medical care, and criminal history. Risks for developing DUD were estimated from the population in Scania. Scenarios estimated the impact of introducing the GBG in schools located in disadvantaged areas. RESULTS: The model accurately reflected the growth of DUD in Scania over a multiyear period and reproduced the levels of affected individuals in various socioeconomic strata over time. The GBG was estimated to improve school achievement and lower DUD registrations over time in males residing in disadvantaged areas by 10%, reflecting a decrease of 540 cases of DUD. Effects were considerably smaller in females. CONCLUSIONS: This work provides support for the impact of improving school achievement on long-term risks of developing DUD. It also demonstrated the value of using simulation modeling calibrated with data from a real population to estimate the impact of an intervention applied at a population level.
Subject(s)
Opioid-Related Disorders , Substance-Related Disorders , Male , Female , Humans , Sweden , Substance-Related Disorders/epidemiology , SchoolsABSTRACT
The zinc iodine (ZI) redox flow battery (RFB) has emerged as a promising candidate for grid-scale electrical energy storage owing to its high energy density, low cost and environmental friendliness. In this work, ZI RFBs were made with electrodes comprising carbon nanotubes (CNT) with redox-active iron particles, yielding higher discharge voltages, power densities, and 90% lower charge transfer resistances compared to cells with inert carbon electrodes. Analysis of the polarization curves reveals that cells with iron-containing electrodes have lower mass transfer resistances and 100% increase in power density (44 mW cm-2 to 90 mW cm-2) at 110 mA cm-2 relative to cells with inert carbon electrodes.
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Importance: In the previously reported Comparative Enzyme Replacement Trial With neoGAA Versus rhGAA (COMET) trial, avalglucosidase alfa treatment for 49 weeks showed clinically meaningful improvements in upright forced vital capacity (FVC) percent predicted and 6-minute walk test (6MWT) compared with alglucosidase alfa. Objective: To report avalglucosidase alfa treatment outcomes during the COMET trial extension. Design, Setting, and Participants: This phase 3 double-blind randomized clinical trial with crossover in the extension period enrolled patients 3 years and older with previously untreated late-onset Pompe disease (LOPD) between November 2, 2016, and February 10, 2021, with primary analysis after 49 weeks. Patients were treated at 55 referral centers in 20 countries. Efficacy outcomes were assessed at 97 weeks and safety outcomes to last follow-up, with data cutoff at February 10, 2021. Data were analyzed from May to June 2021. Interventions: Random assignment (1:1) to receive 20 mg/kg of avalglucosidase alfa or alglucosidase alfa by intravenous infusion every other week for 49 weeks; thereafter, all patients received 20 mg/kg of avalglucosidase alfa every other week. Main Outcomes and Measures: The primary outcome was the least squares (LS) mean change from baseline in FVC percent predicted. Secondary outcomes included the LS mean change from baseline in 6MWT, muscle strength, motor function, quality of life, and disease biomarkers. Safety and tolerability were also assessed. Results: Of 100 participants from the double-blind treatment period, 95 entered the extension period. Of these, 51 (54%) were men, and the mean (range) age was 48.3 (10-79) years. At the start of this study, mean upright FVC percent predicted was similar between treatment arms, and 6MWT distance was greater in the avalglucosidase alfa arm. From baseline to week 97, LS mean (SE) FVC percent predicted increased by 2.65 (1.05) for those who continued avalglucosidase alfa and 0.36 (1.12) for those who switched to avalglucosidase alfa. The LS mean (SE) 6MWT distance increased by 18.60 (12.01) m and 4.56 (12.44) m, respectively. For participants who switched to avalglucosidase alfa, FVC percent predicted remained stable (LS mean [SE] change from week 49 to 97, 0.09 [0.88]) and 6MWT distance improved (LS mean [SE] change from week 49 to 97, 5.33 [10.81] m). Potentially treatment-related adverse events were reported in 29 patients (56.9%) who continued avalglucosidase alfa and in 25 patients (56.8%) who switched. Conclusions and Relevance: In this randomized clinical trial extension, maintenance of positive clinical outcomes was demonstrated for patients continuing avalglucosidase alfa treatment and, to a lesser extent, patients who switched from alglucosidase alfa. No new safety concerns were observed. Trial Registration: ClinicalTrials.gov Identifier: NCT02782741.
Subject(s)
Glycogen Storage Disease Type II , Male , Humans , Middle Aged , Aged , Female , Glycogen Storage Disease Type II/drug therapy , Quality of Life , Treatment Outcome , Vital Capacity , Double-Blind MethodABSTRACT
OBJECTIVE: A small percentage of universities and colleges conducted mass SARS-CoV-2 testing. However, universal testing is resource-intensive, strains national testing capacity, and false negative tests can encourage unsafe behaviors. PARTICIPANTS: A large urban university campus. METHODS: Virus control centered on three pillars: mitigation, containment, and communication, with testing of symptomatic and a random subset of asymptomatic students. RESULTS: Random surveillance testing demonstrated a prevalence among asymptomatic students of 0.4% throughout the term. There were two surges in cases that were contained by enhanced mitigation and communication combined with targeted testing. Cumulative cases totaled 445 for the term, most resulting from unsafe undergraduate student behavior and among students living off-campus. A case rate of 232/10,000 undergraduates equaled or surpassed several peer institutions that conducted mass testing. CONCLUSIONS: An emphasis on behavioral mitigation and communication can control virus transmission on a large urban campus combined with a limited and targeted testing strategy.