The role of tortuosity in filtration efficiency: a general network model for filtration

Filters are composed of a complex network of interconnected pores each with tortuous paths. We present a general network model to describe a filter structure comprising a random network of interconnected pores, relaxing traditional assumptions made with simplified theoretical models. We use the model to examine the dependence of the filter performance on both its underlying pore structure (expressed through the pore interconnectivity and porosity gradient) and the feed composition (expressed through the size of the contaminants). We find that a simple scaling allows the performance curves over a wide range of the filter material properties to be mapped onto a single master curve. We also study the link between the tortuosity of a filter and its resulting performance, leading to further self-similarity observations. When we vary the properties of the feed, however, the performance curves are distinct from one another and do not collapse onto a single master curve. Our network model allows us to probe the behaviour of a complex and realistic filter configuration within a framework that is easy to implement and study, enabling accelerated testing and reducing experimental costs in filtration challenges

Cardiac Involvement in Fabry Disease: JACC Review Topic of the Week

Fabry disease (FD) is a rare X-linked inherited lysosomal storage disorder caused by deficient α-galactosidase A activity that leads to an accumulation of globotriasylceramide (Gb3) in affected tissues, including the heart. Cardiovascular involvement usually manifests as left ventricular hypertrophy, myocardial fibrosis, heart failure, and arrhythmias, which limit quality of life and represent the most common causes of death. Following the introduction of enzyme replacement therapy, early diagnosis and treatment have become essential to slow disease progression and prevent major cardiac complications. Recent advances in the understanding of FD pathophysiology suggest that in addition to Gb3 accumulation, other mechanisms contribute to the development of Fabry cardiomyopathy. Progress in imaging techniques have improved diagnosis and staging of FD-related cardiac disease, suggesting a central role for myocardial inflammation and setting the stage for further research. In addition, with the recent approval of oral chaperone therapy and new treatment developments, the FD-specific treatment landscape is rapidly evolving

The role of tortuosity in filtration efficiency: a general network model for filtration

Filters are composed of a complex network of interconnected pores each with tortuous paths. We present a general network model to describe a filter structure comprising a random network of interconnected pores, relaxing traditional assumptions made with simplified theoretical models. We use the model to examine the dependence of the filter performance on both its underlying pore structure (expressed through the pore interconnectivity and porosity gradient) and the feed composition (expressed through the size of the contaminants). We find that a simple scaling allows the performance curves over a wide range of the filter material properties to be mapped onto a single master curve. We also study the link between the tortuosity of a filter and its resulting performance, leading to further self-similarity observations. When we vary the properties of the feed, however, the performance curves are distinct from one another and do not collapse onto a single master curve. Our network model allows us to probe the behaviour of a complex and realistic filter configuration within a framework that is easy to implement and study, enabling accelerated testing and reducing experimental costs in filtration challenges.</br

Evaluation of the efficacy and safety of three dosing regimens of agalsidase alfa enzyme replacement therapy in adults with Fabry disease

Lubor Gol&aacute;ň,1 Ozlem Goker-Alpan,2 Myrl Holida,3 Ikka Kantola,4 Mariusz Klopotowski,5 Johanna Kuusisto,6 Ale&scaron; Linhart,1 Jacek Musial,7 Kathleen Nicholls,8 Derlis Gonzalez-Rodriguez,9 Reena Sharma,10 Bojan Vujkovac,11 Peter Chang,12 Anna Wijatyk12 1First Faculty of Medicine, Department of Cardiovascular Medicine, Charles University, Prague, Czech Republic; 2Lysosomal Research and Treatment Unit, Fairfax, VA, USA; 3Stead Family Department of Pediatrics, Division of Medical Genetics, University of Iowa Hospitals and Clinics, Iowa City, IA, USA; 4Division of Medicine, Turku University Hospital, Turku, Finland; 5Institute of Cardiology, Warsaw, Poland; 6Department of Medicine, Center for Medicine and Clinical Research, University of Eastern Finland and Kuopio University Hospital, Kuopio, Finland; 7Department of Internal Medicine, Jagiellonian University Medical College, Krakow, Poland; 8Department of Nephrology, Royal Melbourne Hospital and the University of Melbourne, VIC, Australia; 9Instituto Privado de Hematologia E Investigacion Clinica (IPHIC), Asuncion, Paraguay; 10Salford Royal NHS Foundation Trust, Salford, UK; 11General Hospital Slovenj Gradec, Slovenj Gradec, Slovenia; 12Shire, Lexington, MA, USA Purpose: Efficacy and safety of agalsidase alfa at 0.2&nbsp;mg/kg weekly were compared with 0.2&nbsp;mg/kg every other week (EOW). Exploratory analyses were performed for 0.4&nbsp;mg/kg weekly.Patients and methods: This was a 53-week, Phase III/IV, multicenter, open-label study (NCT01124643) in treatment-na&iuml;ve adults (&ge;18&nbsp;years) with Fabry disease. Inclusion criteria were left ventricular hypertrophy at baseline, defined as left ventricular mass indexed to height&nbsp;&gt;50&nbsp;g/m2.7 for males and &gt;47&nbsp;g/m2.7 for females. Primary endpoint was reduction of left ventricular mass indexed to height as assessed by echocardiography. Secondary endpoints included cardiac (peak oxygen consumption, 6-minute walk test, Minnesota Living with Heart Failure Questionnaire, New York Heart Association classification), renal (Modification of Diet in Renal Disease, estimated glomerular filtration rate), and biomarker (plasma globotriaosylceramide) assessments. Safety endpoints were adverse events and anti&ndash;agalsidase alfa antibodies.Results: Twenty patients were randomized to 0.2&nbsp;mg/kg EOW (mean age, 50.3&nbsp;years; 70% male), 19 to 0.2&nbsp;mg/kg weekly (51.8&nbsp;years; 53% male), and 5 to 0.4&nbsp;mg/kg weekly (49.4&nbsp;years; 40% male). The mean change in left ventricular mass indexed to height by Week 53 in the 0.2-mg/kg EOW and weekly groups was 3.2&nbsp;g/m2.7 and 0.5&nbsp;g/m2.7, with no significant difference between groups. No clinically meaningful changes by Week 53 were found within or between the 0.2-mg/kg groups for peak oxygen consumption, 6-minute walk test, or Minnesota Living with Heart Failure Questionnaire. Two patients in each group improved by &ge;1 New York Heart Association classi&shy;fication. No significant differences were found between 0.2&nbsp;mg/kg EOW and weekly for mean change in estimated glomerular filtration rate (-1.21&nbsp;mL/min/1.73 m2 vs -3.32&nbsp;mL/min/1.73&nbsp;m2) or plasma globotriaosylceramide (-1.05&nbsp;nmol/mL vs -2.13&nbsp;nmol/mL), respectively. Infusion-related adverse events were experienced by 25% and 21% in the 0.2-mg/kg EOW and weekly groups. Tachycardia, fatigue, and hypotension were experienced by two or more patients overall. Anti&ndash;agalsidase alfa antibodies were detected in 11.4% of patients and neutralizing antibodies in 6.8%. Infusion-related reactions did not appear to be correlated with antibody status.Conclusion: No efficacy or safety differences were found when the approved EOW dosage of agalsidase alfa was increased to weekly administration. Exploratory analyses for 0.4&nbsp;mg/kg weekly showed similar results. Keywords: adverse events, exercise tolerance, left ventricular hypertrophy, lysosomal storage disorder, quality of life, renal functio