Characterization of early disease status in treatment-naive male paediatric patients with Fabry disease enrolled in a randomized clinical trial.

Trial designThis analysis characterizes the degree of early organ involvement in a cohort of oligo-symptomatic untreated young patients with Fabry disease enrolled in an ongoing randomized, open-label, parallel-group, phase 3B clinical trial.MethodsMales aged 5-18 years with complete α-galactosidase A deficiency, without symptoms of major organ damage, were enrolled in a phase 3B trial evaluating two doses of agalsidase beta. Baseline disease characteristics of 31 eligible patients (median age 12 years) were studied, including cellular globotriaosylceramide (GL-3) accumulation in skin (n = 31) and kidney biopsy (n = 6; median age 15 years; range 13-17 years), renal function, and glycolipid levels (plasma, urine).ResultsPlasma and urinary GL-3 levels were abnormal in 25 of 30 and 31 of 31 patients, respectively. Plasma lyso-GL-3 was elevated in all patients. GL-3 accumulation was documented in superficial skin capillary endothelial cells (23/31 patients) and deep vessel endothelial cells (23/29 patients). The mean glomerular filtration rate (GFR), measured by plasma disappearance of iohexol, was 118.1 mL/min/1.73 m(2) (range 90.4-161.0 mL/min/1.73 m(2)) and the median urinary albumin/creatinine ratio was 10 mg/g (range 4.0-27.0 mg/g). On electron microscopy, renal biopsy revealed GL-3 accumulation in all glomerular cell types (podocytes and parietal, endothelial, and mesangial cells), as well as in peritubular capillary and non-capillary endothelial, interstitial, vascular smooth muscle, and distal tubules/collecting duct cells. Lesions indicative of early Fabry arteriopathy and segmental effacement of podocyte foot processes were found in all 6 patients.ConclusionsThese data reveal that in this small cohort of children with Fabry disease, histological evidence of GL-3 accumulation, and cellular and vascular injury are present in renal tissues at very early stages of the disease, and are noted before onset of microalbuminuria and development of clinically significant renal events (e.g. reduced GFR). These data give additional support to the consideration of early initiation of enzyme replacement therapy, potentially improving long-term outcome.Trial registrationClinicalTrials.gov NCT00701415

Untersuchungen zur Modulation der prädiabetischen Inselentzündung im Tiermodell der NOD-Maus

Der insulinabhängige Diabetes Mellitus (IDDM) oder Typ 1 Diabetes resultiert aus einer immun-mediierten Zerstörung der insulinproduzierenden beta-Zellen der Langerhans-Inseln des Pankreas. Die Th1-/Th2-Immunbalance spielt dabei eine wichtige Rolle. T-Helferzellen vom Th1-Typ und deren Zytokinprodukte (z.B. INF-gamma, TNF-alpha) werden als pathogene Immunmechanismen bei der Krankheitsentstehung beschrieben, wohingegen Th-2-assoziierte Immunzellen und deren Zytokinprodukte (z.B. IL-10, TGF-beta) als kaum destruktiv oder sogar als protektiv gelten [2, 3, 25]. Die vorliegende Arbeit beschäftigte sich mit dem pathoimmunologischen Krankheitsgeschehen des Cyclophosphamid-induzierten Typ 1 Diabetes im Tiermodell der non obese diabetic (NOD) Maus. Bei der NOD-Maus kommt es durch Infiltration mit mononukleären Zellen zu einer autoimmunen Zerstörung der beta-Zellen im Pankreas. Zu den infiltrierenden Zellen zählen u.a. Lymphocyten, die in Darm-assozierten Immungeweben vorkommen [86, 87]. So konnte gezeigt werden, dass der Verlauf des IDDM über das Darmimmunsystem zu beeinflussen ist. Sowohl Nahrungsmittelantigene, diätetische Fütterung, als auch die orale Verabreichung von spezifischen Wirkstoffen auf das Darmimmunsystem konnten den Krankheitsprozess des Typ 1 Diabetes hemmen [51, 53, 56, 57]. Das Alkylanz Cyclophosphamid beschleunigt und synchronisiert im NOD-Modell schon nach einmaliger Injektion das Krankheitsgeschehen. Es kommt zu einem Übergang von einer Th2- zu einer Th-1-Immunantwort [11]. Das Aussmaß der Infiltration in den Langerhans-Inseln des Pankreas bestimmt den Grad der Inselentzündung. Die vorliegenden histologischen Untersuchungen erlaubten eine Unterteilung der Insulitis in vier Grade. Im Mausversuch kam es 10 Tage nach intraperitonealer Injektion von 250 mg/kg Cyclophosphamid bei weiblichen NOD-Mäusen zu einer massiven Infiltration der Inseln und zu einem signifikanten Anstieg der Insulitis auf durchschnittlich Grad 4 (p Ein nächster Forschungsansatz waren Zytokinmessungen von Dünndarm mRNA von NOD-Mäusen. Es wurde der Effekt des Cyclophosphamids auf die intestinale Zytokinexpression 3 bzw. 7 Tage nach Injektion gemessen. 6 bis 7 Wochen alte, weibliche NOD-Mäuse wurden mit 250 mg/kg Cyclophosphamid intraperitoneal behandelt. Der Gehalt an mRNA von TGF-beta, IFN-gamma, IL-10 und TNF-alpha wurde mittels quantitativer RT-PCR aus Dünndarm isolierter RNA bestimmt. Innerhalb von 3 Tagen zeigte sich eine sinkende Expressionsrate von IL-10, welches mit einer Th2-Immunantwort assoziiert wird. Das Ziel der Vakzinierungsstudie war eine Modulation des Immungeschehens über die Darmmukosa. In der Vergangenheit konnten durch DNA-Vakzinierung protektive Immunantworten bei infektiösen und autoimmunen Krankheitsbildern ausgelöst werden [60, 63]. Diese Induktion einer schützenden Th2-Antwort durch eine Immunisierung mit DNA könnte den Verlauf des Typ 1 Diabetes günstig beeinflussen. 70 Tage alte, weibliche NOD-Mäuse wurden mit Plasmid-DNA-Konstrukten, welche kodierend für TGF-beta, hsp60 oder lösliches ICAM-1 waren, oral behandelt. Um den Krankheitsverlauf zu synchronisieren, erhielten die Tiere 250 mg/kg Cyclophosphamid via intraperitonealer Injektion. Ein Teil der Tiere wurde ausschließlich mit Cyclophosphamid behandelt und fungierte als Kontrollgruppen. Semiquantitative histologische Untersuchungen und immunhistologische Insulinfärbungen zeigten, dass die orale Vakzinierung mit pDNA-Konstrukten das Ausmaß der Inselinfiltration, induziert durch Cyclophosphamid, nicht nachhaltig beeinflussen konnte. Quantitative RT-PCR Analysen von RNA aus dem korrespondierenden Pankreasgewebe zeigten jedoch für die Administration mit ICAM-1-Vakzine und TGF-beta-Vakzine steigende mRNA-Spiegel für IL-10. Dies spricht für eine entzündungshemmende regulatorische Immunantwort [4, 84].The insulin-dependent diabetes mellitus (IDDM) results from an immune-mediated destruction of the insulin-producing beta-cells in the pancreatic islets of Langerhans. The Th1-/Th2-immune balance is an important immunological regulator for the progression of the disease. A current hypothesis is that the pathogenic immune response is mediated by a Th1 subset of T-cells and their cytokine products (e.g. IFN-gamma, TNF-alpha), whereas the protective immune response is mediated by a Th2 subset of T-cells and their cytokine products (e.g. IL-10, TGF-beta) [2, 3, 25]. The present studies are about the patho-immunological process of type 1 diabetes in non obese diabetic (NOD) mice, induced by cyclophosphamide. The NOD-mouse model is an animal model of IDDM that shows autoimmune destruction of the pancreatic beta-cells by infiltration with mononuclear cells. Mucosa-derived lymphocytes are described to be among the early infiltrating cells [86, 87]. Attempts to modulate disease progression by targeting the gut immune system seem to be an option to interfere with the disease process. Both food antigens, diet type and oral administration of specific agents were found to exhibit inhibitory effects on the disease progression [51, 53, 56, 57]. The alkylating drug cyclophosphamide has been used to accelerate and synchronise the disease process by inducing a shift from Th2-type to Th1-type immune reactivity [10, 11, 14]. The mononuclear infiltration of pancreatic islets is an inflammatory process named insulitis. Histological examinations allowed to score the insulitis by 4 degrees. The present results showed that a single intraperitoneal injection of cyclophosphamide (250 mg/kg) in female NOD mice resulted in a rapid increase intra-islet infiltration and insulitis of degree 4 (p<0.0002 experiment 1; p<0.002 experiment 2). Cyclophosphamide induced a “destructive” intra-insulitis within 10 days. We analysed the effect of cyclophosphamide treatment on the intestinal cytokine pattern of 6 to 7 weeks old female NOD mice. Therefore, the animals were treated with a single injection of 250 mg/kg cyclophosphamide. Control mice remained untreated. The RNA was isolated on day 3 or day 10 from small intestinal tissue and the levels of TGF-beta, IFN-gamma, IL-10 and TNF-alpha mRNA were detected by quantitative RT-PCR analysis. We found decreased IL-10 mRNA expression within 3 days after cyclophosphamide injection. IL-10 is a key cytokine of the Th2-immune response. Our aim was to modulate the immune response via the enteral mucosal immune cells by oral vaccination with plasmid DNA encoding for TGF-beta, hsp60 or soluble ICAM-1, i.e., by targeting the mucosal immune system. DNA vaccination can generate protective immunity against infectious and autoimmune diseases [60, 63]. The induction of protective Th2 responses by DNA immunisation might therefore be expected to have an effect on the course of type 1 diabetes. 70 days old female NOD mice were fed with plasmid DNA and received a single injection of 250 mg/kg cyclophosphamide. One group of mice was treated with cyclophosphamide only and served as controls. Histologic sections and immunohistochemical analysis of pancreas sections showed that oral vaccination with DNA encoding immunomodulatory molecules had no inhibitory effect on the destructive islet infiltration process. Quantitative RT-PCR analysis of corresponding pancreas mRNA showed an increase of IL-10 cytokine levels for ICAM-1 and TGF-beta treated groups. This suggests the induction of an anti-inflammatory regulatory immune response [4, 84]

Anomaly Cancelation in Field Theory and F-theory on a Circle

We study the manifestation of local gauge anomalies of four- and six-dimensional field theories in the lower-dimensional Kaluza-Klein theory obtained after circle compactification. We identify a convenient set of transformations acting on the whole tower of massless and massive states and investigate their action on the low-energy effective theories in the Coulomb branch. The maps employ higher-dimensional large gauge transformations and precisely yield the anomaly cancelation conditions when acting on the one-loop induced Chern-Simons terms in the three- and five-dimensional effective theory. The arising symmetries are argued to play a key role in the study of the M-theory to F-theory limit on Calabi-Yau manifolds. For example, using the fact that all fully resolved F-theory geometries inducing multiple Abelian gauge groups or non-Abelian groups admit a certain set of symmetries, we are able to generally show the cancelation of pure Abelian or pure non-Abelian anomalies in these models.Comment: 48 pages, 2 figures; v2: typos corrected, comments on circle fluxes adde

Knowing the enemy: ant behavior and control in a pediatric hospital of Buenos Aires

Ant control is difficult in systems even where a variety of control strategies and compounds are allowed; in sensitive places such as hospitals, where there are often restrictions on the methods and toxicants to be applied, the challenge is even greater. Here we report the methods and results of how we faced this challenge of controlling ants in a pediatric hospital using baits. Our strategy was based on identifying the species present and analyzing their behavior. On the one hand, we evaluated outdoors in the green areas of the hospital, the relative abundance of ant genera, their food preferences and the behavioral dominances. On the other hand, control treatments were performed using separately two boron compounds added to sucrose solution which was not highly concentrated to avoid constrains due to the viscosity. Most of the species in the food preference test accepted sugary food; only one species was recorded to visit it less than the protein foods. This result was consistent with the efficacy of control treatments by sugary baits within the rooms. For species that showed good acceptance of sugar solutions in the preference test outdoors, sugar bait control indoors was 100& effective. Conversely, for the only species that foraged significantly less on sugar food, the bait treatment was ineffective. This work reveals the importance of considering the behavior and feeding preferences of the species to be controlled by toxic baits.Fil: Josens, Roxana Beatriz. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Fisiología, Biología Molecular y Neurociencias. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Fisiología, Biología Molecular y Neurociencias; ArgentinaFil: Sola, Francisco Javier. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Fisiología, Biología Molecular y Neurociencias. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Fisiología, Biología Molecular y Neurociencias; ArgentinaFil: Marchisio, Nahuel Matías. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Fisiología, Biología Molecular y Neurociencias. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Fisiología, Biología Molecular y Neurociencias; ArgentinaFil: Di Renzo, María Agostina. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Biodiversidad y Biología Experimental. Laboratorio del Grupo de Estudio de Insectos Sociales; ArgentinaFil: Giacometti, Alina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Fisiología, Biología Molecular y Neurociencias. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Fisiología, Biología Molecular y Neurociencias; Argentin

Clinical, biochemical and genetic spectrum of 70 patients with ACAD9 deficiency: Is riboflavin supplementation effective?

Background: Mitochondrial acyl-CoA dehydrogenase family member 9 (ACAD9) is essential for the assembly of mitochondrial respiratory chain complex I. Disease causing biallelic variants in ACAD9 have been reported in individuals presenting with lactic acidosis and cardiomyopathy. Results: We describe the genetic, clinical and biochemical findings in a cohort of 70 patients, of whom 29 previously unpublished. We found 34 known and 18 previously unreported variants in ACAD9. No patients harbored biallelic loss of function mutations, indicating that this combination is unlikely to be compatible with life. Causal pathogenic variants were distributed throughout the entire gene, and there was no obvious genotype-phenotype correlation. Most of the patients presented in the first year of life. For this subgroup the survival was poor (50% not surviving the first 2 years) comparing to patients with a later presentation (more than 90% surviving 10 years). The most common clinical findings were cardiomyopathy (85%), muscular weakness (75%) and exercise intolerance (72%). Interestingly, severe intellectual deficits were only reported in one patient and

Efficacy of avalglucosidase alfa on forced vital capacity percent predicted in treatment-naïve patients with late-onset Pompe disease: A pooled analysis of clinical trials.

BACKGROUND: The efficacy of avalglucosidase alfa (AVA) versus alglucosidase alfa (ALG) on forced vital capacity percent predicted (FVCpp) in patients with late-onset Pompe disease (LOPD) has been assessed in the Phase 3 COMET trial (NCT02782741). Due to the rarity of LOPD and thus small sample size in COMET, additional data were analyzed to gain further insights into the efficacy of AVA versus ALG. METHODS: Data from treatment-naive patients with LOPD were pooled from COMET and Phase 1/2 NEO1/NEO-EXT (NCT01898364/NCT02032524) trials for patients treated with AVA, and Phase 3 LOTS trial (NCT00158600) for patients treated with ALG. Regression analyses using mixed models with repeated measures consistent with those pre-specified in COMET were performed post-hoc. Analyses were adjusted for trials and differences in baseline characteristics. Four models were developed: Model 1 considered all trials; Model 2 included Phase 3 trials; Model 3 included Phase 3 trials and was adjusted for baseline ventilation use; Model 4 included COMET and NEO1/NEO-EXT (i.e., AVA trials only). RESULTS: Overall, 100 randomized patients from COMET (AVA, n&nbsp;=&nbsp;51, ALG, n&nbsp;=&nbsp;49), 60 from LOTS (ALG arm only), and three patients from NEO1/NEO-EXT (who received open-label AVA only) were considered for analysis. Mean age at enrollment was similar across trials (45.3-50.3&nbsp;years); however, patients from LOTS had a longer mean duration of disease versus COMET and NEO1/NEO-EXT trials (9.0&nbsp;years and 0.5-2.2&nbsp;years, respectively) and younger mean age at diagnosis (36.2&nbsp;years and 44.7-48.6&nbsp;years, respectively). Least squares mean (95% confidence interval) improvement from baseline in FVCpp at Week 49-52 for AVA versus ALG was 2.43 (-0.13; 4.99) for COMET (n&nbsp;=&nbsp;98); 2.31 (0.06; 4.57) for Model 1 (n&nbsp;=&nbsp;160); 2.43 (0.21; 4.65) for Model 2 (n&nbsp;=&nbsp;157); 2.80 (0.54; 5.05) for Model 3 (n&nbsp;=&nbsp;154); and 2.27 (-0.30; 4.45) for Model 4 (n&nbsp;=&nbsp;101). CONCLUSIONS: Models 1 to 3, which had an increased sample size versus COMET, demonstrated a nominally significant effect on FVCpp favoring AVA versus ALG after 1&nbsp;year of treatment, consistent with results from COMET

Defining clinically meaningful thresholds for forced vital capacity in patients with neuromuscular disorders:Lessons learned from the COMET study in Pompe disease

Background Respiratory impairment in neuromuscular disorders (NMDs) is generally assessed using forced vital capacity (FVC). Any improvement in FVC trajectory will delay ventilatory support; however, the change required for patients to perceive a noticeable clinical benefit, the clinically meaningful threshold (CMT), has not been defined in NMDs.Objective To derive the within-person and between-group CMTs for FVC (% predicted) in patients with late-onset Pompe disease (LOPD).Methods This analysis leverages data from the Phase 3 COMET trial (NCT02782741, registered 25 May 2016), which assessed the efficacy of avalglucosidase alfa (AVA) versus alglucosidase alfa (ALG) on upright FVC (% predicted) in LOPD. Anchor- and distribution-based methods were used to estimate the within-person and between-group CMTs for FVC at Weeks 49 and 97.Results COMET enrolled 99 participants aged &gt;= 18 years (52% male; mean age 48.0 years). The within-person CMT for absolute change in FVC expressed as % predicted was estimated as 3.0% [95% confidence interval (CI) 2.3, 3.8]. The proportion of patients with a meaningful increase in FVC was higher in the AVA versus ALG group across the CI of the estimated CMT (odds ratios: 2.3-2.6; nominal p-values: 0.026-0.058). The between-group CMT, needed to evaluate differences between treatment groups, was estimated as 2.1% predicted [95% CI 1.1, 3.1].Conclusions We identified a narrow range of within-person and between-group CMTs for upright FVC (% predicted) in LOPD. Post hoc application of these thresholds to COMET showed that a greater proportion of patients in the AVA group had clinically meaningful improvement in FVC versus ALG. These findings may aid in interpretation of data from studies in other NMDs

Multi-messenger observations of a binary neutron star merger

On 2017 August 17 a binary neutron star coalescence candidate (later designated GW170817) with merger time 12:41:04 UTC was observed through gravitational waves by the Advanced LIGO and Advanced Virgo detectors. The Fermi Gamma-ray Burst Monitor independently detected a gamma-ray burst (GRB 170817A) with a time delay of ~1.7 s with respect to the merger time. From the gravitational-wave signal, the source was initially localized to a sky region of 31 deg2 at a luminosity distance of 40+8-8 Mpc and with component masses consistent with neutron stars. The component masses were later measured to be in the range 0.86 to 2.26 Mo. An extensive observing campaign was launched across the electromagnetic spectrum leading to the discovery of a bright optical transient (SSS17a, now with the IAU identification of AT 2017gfo) in NGC 4993 (at ~40 Mpc) less than 11 hours after the merger by the One- Meter, Two Hemisphere (1M2H) team using the 1 m Swope Telescope. The optical transient was independently detected by multiple teams within an hour. Subsequent observations targeted the object and its environment. Early ultraviolet observations revealed a blue transient that faded within 48 hours. Optical and infrared observations showed a redward evolution over ~10 days. Following early non-detections, X-ray and radio emission were discovered at the transient’s position ~9 and ~16 days, respectively, after the merger. Both the X-ray and radio emission likely arise from a physical process that is distinct from the one that generates the UV/optical/near-infrared emission. No ultra-high-energy gamma-rays and no neutrino candidates consistent with the source were found in follow-up searches. These observations support the hypothesis that GW170817 was produced by the merger of two neutron stars in NGC4993 followed by a short gamma-ray burst (GRB 170817A) and a kilonova/macronova powered by the radioactive decay of r-process nuclei synthesized in the ejecta

Effect of avalglucosidase alfa on disease-specific and general patient-reported outcomes in treatment-naïve adults with late-onset Pompe disease compared with alglucosidase alfa:Meaningful change analyses from the Phase 3 COMET trial

Background: The Phase 3 COMET trial (NCT02782741) comparing avalglucosidase alfa and alglucosidase alfa included health-related quality of life (HRQoL) assessments in treatment-naïve patients with late-onset Pompe disease (LOPD). Here, we further characterize results from disease-specific and general patient-reported outcome (PRO) measures. Methods: Adults who participated in the COMET trial receiving avalglucosidase alfa or alglucosidase alfa (both 20 mg/kg biweekly) during the 49-week double-blind treatment period were included in the analysis. Proportions of patients exceeding meaningful change thresholds at Week 49 were compared post hoc between treatment groups. PROs and their meaningful change thresholds included: Pompe Disease Severity Scale (PDSS; decrease 1.0–1.5 points), Pompe Disease Impact Scale (PDIS; decrease 1.0–1.5 points), Rasch-built Pompe-specific Activity Scale (R-PAct; change from unable to able to complete activity), 12-item Short Form Health Survey (SF-12; physical component summary [PCS] score: increase ≥6 points, mental component summary [MCS] score: increase ≥7 points), EuroQol 5 Dimension 5 Level (EQ-5D-5L; improvement of ≥1 category), and Patient Global Impression of Change (PGIC; any improvement). Results: The analysis included 99 adult patients (avalglucosidase alfa n = 50; alglucosidase alfa n = 49). Patients who received avalglucosidase alfa had significantly greater odds of achieving a meaningful change versus alglucosidase alfa for the PDSS Shortness of Breath (OR [95% CI] 11.79 [2.24; 62.18]), Fatigue/Pain (6.24 [1.20; 32.54]), Morning Headache (13.98 [1.71; 114.18]), and Overall Fatigue (5.88 [1.37; 25.11]) domains, and were significantly more likely to meet meaningful change thresholds across multiple PDSS domains (all nominal p &lt; 0.05). A numerically greater proportion of patients in the avalglucosidase alfa group were able to complete selected activities of the R-PAct compared with the alglucosidase alfa group. Significantly greater proportions of patients who received avalglucosidase alfa achieved meaningful improvements for EQ-5D-5L usual activities dimension, EQ visual analog scale, and all four PGIC domains. The proportion of patients with improvements in SF-12 PCS and MCS was greater in the avalglucosidase alfa group versus alglucosidase alfa group, but was not significant (p &gt; 0.05). Conclusions: These analyses show that avalglucosidase alfa improves multiple symptoms and aspects of daily functioning, including breathing and mobility. This supports the clinical relevance of the effects of avalglucosidase alfa on HRQoL for patients with LOPD.</p

Effect of avalglucosidase alfa on disease-specific and general patient-reported outcomes in treatment-naïve adults with late-onset Pompe disease compared with alglucosidase alfa:Meaningful change analyses from the Phase 3 COMET trial

Background: The Phase 3 COMET trial (NCT02782741) comparing avalglucosidase alfa and alglucosidase alfa included health-related quality of life (HRQoL) assessments in treatment-naïve patients with late-onset Pompe disease (LOPD). Here, we further characterize results from disease-specific and general patient-reported outcome (PRO) measures. Methods: Adults who participated in the COMET trial receiving avalglucosidase alfa or alglucosidase alfa (both 20 mg/kg biweekly) during the 49-week double-blind treatment period were included in the analysis. Proportions of patients exceeding meaningful change thresholds at Week 49 were compared post hoc between treatment groups. PROs and their meaningful change thresholds included: Pompe Disease Severity Scale (PDSS; decrease 1.0–1.5 points), Pompe Disease Impact Scale (PDIS; decrease 1.0–1.5 points), Rasch-built Pompe-specific Activity Scale (R-PAct; change from unable to able to complete activity), 12-item Short Form Health Survey (SF-12; physical component summary [PCS] score: increase ≥6 points, mental component summary [MCS] score: increase ≥7 points), EuroQol 5 Dimension 5 Level (EQ-5D-5L; improvement of ≥1 category), and Patient Global Impression of Change (PGIC; any improvement). Results: The analysis included 99 adult patients (avalglucosidase alfa n = 50; alglucosidase alfa n = 49). Patients who received avalglucosidase alfa had significantly greater odds of achieving a meaningful change versus alglucosidase alfa for the PDSS Shortness of Breath (OR [95% CI] 11.79 [2.24; 62.18]), Fatigue/Pain (6.24 [1.20; 32.54]), Morning Headache (13.98 [1.71; 114.18]), and Overall Fatigue (5.88 [1.37; 25.11]) domains, and were significantly more likely to meet meaningful change thresholds across multiple PDSS domains (all nominal p &lt; 0.05). A numerically greater proportion of patients in the avalglucosidase alfa group were able to complete selected activities of the R-PAct compared with the alglucosidase alfa group. Significantly greater proportions of patients who received avalglucosidase alfa achieved meaningful improvements for EQ-5D-5L usual activities dimension, EQ visual analog scale, and all four PGIC domains. The proportion of patients with improvements in SF-12 PCS and MCS was greater in the avalglucosidase alfa group versus alglucosidase alfa group, but was not significant (p &gt; 0.05). Conclusions: These analyses show that avalglucosidase alfa improves multiple symptoms and aspects of daily functioning, including breathing and mobility. This supports the clinical relevance of the effects of avalglucosidase alfa on HRQoL for patients with LOPD.</p