Head-to-head trial of pegunigalsidase alfa versus agalsidase beta in patients with Fabry disease and deteriorating renal function: results from the 2-year randomised phase III BALANCE study

BACKGROUND: Pegunigalsidase alfa is a PEGylated α-galactosidase A enzyme replacement therapy. BALANCE (NCT02795676) assessed non-inferiority of pegunigalsidase alfa versus agalsidase beta in adults with Fabry disease with an annualised estimated glomerular filtration rate (eGFR) slope more negative than -2 mL/min/1.73 m2/year who had received agalsidase beta for ≥1 year. METHODS: Patients were randomly assigned 2:1 to receive 1 mg/kg pegunigalsidase alfa or agalsidase beta every 2 weeks for 2 years. The primary efficacy analysis assessed non-inferiority based on median annualised eGFR slope differences between treatment arms. RESULTS: Seventy-seven patients received either pegunigalsidase alfa (n=52) or agalsidase beta (n=25). At baseline, mean (range) age was 44 (18-60) years, 47 (61%) patients were male, median eGFR was 74.5 mL/min/1.73 m2 and median (range) eGFR slope was -7.3 (-30.5, 6.3) mL/min/1.73 m2/year. At 2 years, the difference between median eGFR slopes was -0.36 mL/min/1.73 m2/year, meeting the prespecified non-inferiority margin. Minimal changes were observed in lyso-Gb3 concentrations in both treatment arms at 2 years. Proportions of patients experiencing treatment-related adverse events and mild or moderate infusion-related reactions were similar in both groups, yet exposure-adjusted rates were 3.6-fold and 7.8-fold higher, respectively, with agalsidase beta than pegunigalsidase alfa. At the end of the study, neutralising antibodies were detected in 7 out of 47 (15%) pegunigalsidase alfa-treated patients and 6 out of 23 (26%) agalsidase beta-treated patients. There were no deaths. CONCLUSIONS: Based on rate of eGFR decline over 2 years, pegunigalsidase alfa was non-inferior to agalsidase beta. Pegunigalsidase alfa had lower rates of treatment-emergent adverse events and mild or moderate infusion-related reactions. TRIAL REGISTRATION NUMBER: NCT02795676

Development of a hypoallergenic recombinant parvalbumin for first-in-man subcutaneous immunotherapy of fish allergy.

To access publisher's full text version of this article, please click on the hyperlink in Additional Links field or click on the hyperlink at the top of the page marked Files. This article is open access.The FAST (food allergy-specific immunotherapy) project aims at developing safe and effective subcutaneous immunotherapy for fish allergy, using recombinant hypoallergenic carp parvalbumin, Cyp c 1.Preclinical characterization and good manufacturing practice (GMP) production of mutant Cyp (mCyp) c 1.Escherichia coli-produced mCyp c 1 was purified using standard chromatographic techniques. Physicochemical properties were investigated by gel electrophoresis, size exclusion chromatography, circular dichroism spectroscopy, reverse-phase high-performance liquid chromatography and mass spectrometry. Allergenicity was assessed by ImmunoCAP inhibition and basophil histamine release assay, immunogenicity by immunization of laboratory animals and stimulation of patients' peripheral blood mononuclear cells (PBMCs). Reference molecules were purified wild-type Cyp c 1 (natural and/or recombinant). GMP-compliant alum-adsorbed mCyp c 1 was tested for acute toxicity in mice and rabbits and for repeated-dose toxicity in mice. Accelerated and real-time protocols were used to evaluate stability of mCyp c 1 as drug substance and drug product.Purified mCyp c 1 behaves as a folded and stable molecule. Using sera of 26 double-blind placebo-controlled food-challenge-proven fish-allergic patients, reduction in allergenic activity ranged from 10- to 5,000-fold (1,000-fold on average), but with retained immunogenicity (immunization in mice/rabbits) and potency to stimulate human PBMCs. Toxicity studies revealed no toxic effects and real-time stability studies on the Al(OH)3-adsorbed drug product demonstrated at least 20 months of stability.The GMP drug product developed for treatment of fish allergy has the characteristics targeted for in FAST: i.e. hypoallergenicity with retained immunogenicity. These results have warranted first-in-man immunotherapy studies to evaluate the safety of this innovative vaccine.info:eu-repo/grantAgreement/EC/FP7/20187

withdrawn 2017 hrs ehra ecas aphrs solaece expert consensus statement on catheter and surgical ablation of atrial fibrillation

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Mutual of Omaha Mortgage: First Time Homebuyers

The 2021-2022 Mutual of Omaha Mortgage project is focused on innovating across the home search process by providing a video-first home search experience for potential application users. Mutual of Omaha Mortgage’s goal is to provide a seamless process for homebuyers to find homes on their application and direct them to apply for a mortgage with the company. By organizing both processes on the same application, they can compete with home search platforms such as Zillow and Redfin. Additionally, with users having the capacity to list their own homes for sale in-app, this reduces the need to rely on a real estate agent and provides more savings for the homebuyer and home seller. Through development of this application, Mutual of Omaha Mortgage will lay the foundation for the creation of an application ecosystem that will be the all-in-one platform for helping users manage their finances and their home owning experience

Simplifying Warehouse Organization

The 2020-2021 DMSi Design Studio project is focused on onboarding client warehouses onto their custom enterprise resource planning tool Agility. DMSi’s goal is to create a holistic, standalone warehouse management system for their clients. One crucial step towards this main goal is to allow clients to set up locations within their warehouses digitally. While some clients have taken advantage of Agility location management, others are still on their outdated, paper systems for supply chain management. The final solution uses a mobile application to create locations within a warehouse on the fly, providing a seamless way for customers to onboard onto Agility and use it to its fullest potential

Rationale and design of the TRICHAMPION trial: Triple Chamber Pacing in Hypertrophic Obstructive Cardiomyopathy Patients

PURPOSE Dual-chamber (DDD) pacing has been used for treatment of patients with hypertrophic obstructive cardiomyopathy (HOCM). Due to inconclusive results in prior trials, current guidelines assign DDD pacing a class IIb indication in selected patients. Prior observations indicate that lack of clinical improvement may result from suboptimal effect of DDD pacing with non-physiological AV intervals due to fusion of intrinsic and paced QRS complex. METHODS he Triple Chamber Pacing in Hypertrophic Obstructive Cardiomyopathy Patients (TRICHAMPION) trial is a prospective, randomized, single-blinded, multicenter study to investigate the benefit of atrial synchronous biventricular pacing (CRT-P) in highly symptomatic HOCM patients with severe left ventricular outflow tract (LVOT) obstruction who are not candidates for ablative therapies. AV node ablation is used as key tool to optimize AV intervals in patients with QRS fusion. The primary endpoint is the percentage of patients with symptomatic improvement at 12 months, defined as improvement of New York Heart Association functional class, in the Minnesota Living with Heart Failure Questionnaire score and increased cardiopulmonary exercise endurance. CONCLUSIONS The aim of the TRICHAMPION trial is to investigate the benefit of optimized atrial synchronous biventricular pacing in absence of QRS fusion in highly symptomatic HOCM patients with severe LVOT obstruction who are not candidates for ablative therapies

Automatic Detection of Slow Conducting Channels during Substrate Ablation of Scar-Related Ventricular Arrhythmias.

Background. Voltage mapping allows identifying the arrhythmogenic substrate during scar-related ventricular arrhythmia (VA) ablation procedures. Slow conducting channels (SCCs), defined by the presence of electrogram (EGM) signals with delayed components (EGM-DC), are responsible for sustaining VAs and constitute potential ablation targets. However, voltage mapping, as it is currently performed, is time-consuming, requiring a manual analysis of all EGMs to detect SCCs, and its accuracy is limited by electric far-field. We sought to evaluate an algorithm that automatically identifies EGM-DC, classifies mapping points, and creates new voltage maps, named "Slow Conducting Channel Maps" (SCC-Maps). Methods. Retrospective analysis of electroanatomic maps (EAM) from 20 patients (10 ischemic, 10 with arrhythmogenic right ventricular dysplasia/cardiomyopathy) was performed. EAM voltage maps were acquired during sinus rhythm and used for ablation. Preprocedural contrast-enhanced cardiac magnetic resonance (Ce-CMR) imaging was available for the ischemic population. Three mapping modalities were analysed: (i) EAM voltage maps using standard (EAM standard) or manual (EAM screening) thresholds for defining core and border zones; (ii) SCC-Maps derived from the use of the novel SCC-Mapping algorithm that automatically identify EGM-DCs measuring the voltage of the local component; and (iii) Ce-CMR maps (when available). The ability of each mapping modality in identifying SCCs and their agreement was evaluated. Results. SCC-Maps and EAM screening identified a greater number of SCC entrances than EAM standard (3.45 ± 1.61 and 2.95 ± 2.31, resp., vs. 1.05 ± 1.10; ). SCC-Maps and EAM screening highly correlate with Ce-CMR maps in the ischemic population when compared to EAM standard (Lin's correlation = 0.628 and 0.679, resp., vs. 0.212, ). Conclusion. The SCC-Mapping algorithm allows an operator-independent analysis of EGM signals showing better identification of the arrhythmogenic substrate characteristics when compared to standard voltage EAM

Automatic detection of slow conducting channels during substrate ablation of scar-related ventricular arrhythmias

Background. Voltage mapping allows identifying the arrhythmogenic substrate during scar-related ventricular arrhythmia (VA) ablation procedures. Slow conducting channels (SCCs), defined by the presence of electrogram (EGM) signals with delayed components (EGM-DC), are responsible for sustaining VAs and constitute potential ablation targets. However, voltage mapping, as it is currently performed, is time-consuming, requiring a manual analysis of all EGMs to detect SCCs, and its accuracy is limited by electric far-field. We sought to evaluate an algorithm that automatically identifies EGM-DC, classifies mapping points, and creates new voltage maps, named “Slow Conducting Channel Maps” (SCC-Maps). Methods. Retrospective analysis of electroanatomic maps (EAM) from 20 patients (10 ischemic, 10 with arrhythmogenic right ventricular dysplasia/cardiomyopathy) was performed. EAM voltage maps were acquired during sinus rhythm and used for ablation. Preprocedural contrast-enhanced cardiac magnetic resonance (Ce-CMR) imaging was available for the ischemic population. Three mapping modalities were analysed: (i) EAM voltage maps using standard (EAM standard) or manual (EAM screening) thresholds for defining core and border zones; (ii) SCC-Maps derived from the use of the novel SCC-Mapping algorithm that automatically identify EGM-DCs measuring the voltage of the local component; and (iii) Ce-CMR maps (when available). The ability of each mapping modality in identifying SCCs and their agreement was evaluated. Results. SCC-Maps and EAM screening identified a greater number of SCC entrances than EAM standard (3.45 ± 1.61 and 2.95 ± 2.31, resp., vs. 1.05 ± 1.10; ). SCC-Maps and EAM screening highly correlate with Ce-CMR maps in the ischemic population when compared to EAM standard (Lin’s correlation = 0.628 and 0.679, resp., vs. 0.212, ). Conclusion. The SCC-Mapping algorithm allows an operator-independent analysis of EGM signals showing better identification of the arrhythmogenic substrate characteristics when compared to standard voltage EAM.This study was supported by personal grants to A. Alcaine (Refs. BES-2011-046644 and EEBB-I-15-09466); by projects PID2019-104881RB-I00 from Ministerio de Ciencia e Innovación (Spain) and DPI2016-75458-R from Ministerio de Economía y Competitividad (Spain); and by Gobierno de Aragón (Grupo Referencia BSICoS ref.: T39_20R) cofounded by FEDER 2014–2020. This work was also supported in part by the project PI14/00759, integrated in the Plan Nacional de I+D+i and cofounded by the Instituto de Salud Carlos III (ISCIII)-Subdirección General de Evaluación and European Regional Development Fund (European Union). The computation was performed by the ICTS NANBIOSIS, more specifically by the High Performance Computing Unit of the CIBER in Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN) at the University of Zaragoza. The CIBER-BBN is an initiative of Instituto de Salud Carlos III