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Pompe disease results from lysosomal acid α-glucosidase deficiency, which leads to cardiomyopathy in all infantile-onset and occasional late-onset patients. Cardiac assessment is important for its diagnosis and management. This article presents unpublished cardiac findings, concomitant medications, and cardiac efficacy and safety outcomes from the ADVANCE study; trajectories of patients with abnormal left ventricular mass z score at enrolment; and post hoc analyses of on-treatment left ventricular mass and systolic blood pressure z scores by disease phenotype, GAA genotype, and “fraction of life” (defined as the fraction of life on pre-study 160 L production-scale alglucosidase alfa). ADVANCE evaluated 52 weeks’ treatment with 4000 L production-scale alglucosidase alfa in ≥1-year-old United States of America patients with Pompe disease previously receiving 160 L production-scale alglucosidase alfa. M-mode echocardiography and 12-lead electrocardiography were performed at enrolment and Week 52. Sixty-seven patients had complete left ventricular mass z scores, decreasing at Week 52 (infantile-onset patients, change −0.8 ± 1.83; 95% confidence interval −1.3 to −0.2; all patients, change −0.5 ± 1.71; 95% confidence interval −1.0 to −0.1). Patients with “fraction of life” <0.79 had left ventricular mass z score decreasing (enrolment: +0.1 ± 3.0; Week 52: −1.1 ± 2.0); those with “fraction of life” ≥0.79 remained stable (enrolment: −0.9 ± 1.5; Week 52: −0.9 ± 1.4). Systolic blood pressure z scores were stable from enrolment to Week 52, and no cohort developed systemic hypertension. Eight patients had Wolff–Parkinson–White syndrome. Cardiac hypertrophy and dysrhythmia in ADVANCE patients at or before enrolment were typical of Pompe disease. Four-thousand L alglucosidase alfa therapy maintained fractional shortening, left ventricular posterior and septal end-diastolic thicknesses, and improved left ventricular mass z score.
Social Media Statement: Post hoc analyses of the ADVANCE study cohort of 113 children support ongoing cardiac monitoring and concomitant management of children with Pompe disease on long-term alglucosidase alfa to functionally improve cardiomyopathy and/or dysrhythmia.
Pneumatically activated systems enable myriad types of highly functional inflatables employing a wide range of architectural approaches affecting their form and function, making systematic conceptual design difficult. A new architectural class of pneumatically activated systems, constrained layer inflatable systems, consists of hierarchically architected flat layers of thin airtight bladders that are internally and/or externally constrained to generate a variety of functionalities. The highly hierarchical architectural structure of constrained layer inflatable systems coincides with the hierarchy of produced functions, providing an opportunity for the development of a functional architectural decomposition, capturing the inherent relationship between architectural and functional hierarchies. The basis of the approach is conveyed through the design of an example constrained layer inflatable system. This approach empowers the systematic understanding of the interrelated architectural and functional breakdown of constrained layer inflatable systems, enabling designers to iteratively analyze, synthesize, and re-synthesize the components of the system improving existing designs and exploring new concepts.
The eighteenth century was a period of dramatic change in political and legal thought. Much of the way in which we currently conceive of democratic institutions and the responsibilities and rights attached to citizenship can be traced back to concepts that dominated eighteenth-century thought. The social contract was debated by figures such as John Locke, Algernon Sidney, David Hume, Edmund Burke, and Mary Wollstonecraft. Among the many issues under deliberation were the validity of consent, the will of individuals, the role of virtue, and the rights of self-governance. Legal thought was very closely tied to political thought because law was a foundation of political authority. Natural law, which was associated with divinity, rose in importance because it protected inalienable rights, such as self-preservation. Positive law, that is, laws of civil society such as common law and statute law, could be reformed and updated as civil society evolved. This flexibility was praised by jurists such as Lord Mansfield, but it also drew attempts to clarify and systematize law by Sir William Blackstone and Jeremy Bentham, as they prepared the citizenry for a growing engagement with the law.
In a span of just over ten years, the reception of Mary Wollstonecraft’s work moved from temperate admiration to heightened political controversy, emotional sympathy, and personal condemnation. When Wollstonecraft wrote about female education, her ideas were generally well received. At times her thoughts were dismissed as trite or she was admonished for encouraging young women to be too independent. But she was in safe territory. Predictably, when Wollstonecraft entered into political and cultural controversies, her thoughts were either embraced because they aligned with theories of the rights of man, or they were thought to be revolutionary and a challenge to British stability. Most controversial was Wollstonecraft’s suggestion that women actively participate in civil society. In this case, she drew censorious responses from parties at both ends of the political spectrum. Her later publications, including posthumous work published by her husband, William Godwin, elicited starkly personal reactions, ranging from sympathy for her emotional turmoil, and pity because her husband made her intimate life public, to outrage over her sexual behavior and condemnation of her dubious moral conduct. Wollstonecraft’s early reception was charged with the controversies of the 1790s and marked by the uncertainty surrounding the place of women in the transformation of civil society.