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Spinal muscular atrophy (SMA) is a devastating rare disease that affects individuals regardless of ethnicity, gender, and age. The first-approved disease-modifying therapy for SMA, nusinursen, was approved by Health Canada, as well as by American and European regulatory agencies following positive clinical trial outcomes. The trials were conducted in a narrow pediatric population defined by age, severity, and genotype. Broad approval of therapy necessitates close follow-up of potential rare adverse events and effectiveness in the larger real-world population.
The Canadian Neuromuscular Disease Registry (CNDR) undertook an iterative multi-stakeholder process to expand the existing SMA dataset to capture items relevant to patient outcomes in a post-marketing environment. The CNDR SMA expanded registry is a longitudinal, prospective, observational study of patients with SMA in Canada designed to evaluate the safety and effectiveness of novel therapies and provide practical information unattainable in trials.
The consensus expanded dataset includes items that address therapy effectiveness and safety and is collected in a multicenter, prospective, observational study, including SMA patients regardless of therapeutic status. The expanded dataset is aligned with global datasets to facilitate collaboration. Additionally, consensus dataset development aimed to standardize appropriate outcome measures across the network and broader Canadian community. Prospective outcome studies, data use, and analyses are independent of the funding partner.
Prospective outcome data collected will provide results on safety and effectiveness in a post-therapy approval era. These data are essential to inform improvements in care and access to therapy for all SMA patients.
We describe an ultra-wide-bandwidth, low-frequency receiver recently installed on the Parkes radio telescope. The receiver system provides continuous frequency coverage from 704 to 4032 MHz. For much of the band (
), the system temperature is approximately 22 K and the receiver system remains in a linear regime even in the presence of strong mobile phone transmissions. We discuss the scientific and technical aspects of the new receiver, including its astronomical objectives, as well as the feed, receiver, digitiser, and signal processor design. We describe the pipeline routines that form the archive-ready data products and how those data files can be accessed from the archives. The system performance is quantified, including the system noise and linearity, beam shape, antenna efficiency, polarisation calibration, and timing stability.
Adam Smith has acquired the reputation as the father of economics, but he was not alone among the thinkers of the Scottish Enlightenment in his interest in the emerging discipline of political economy. This chapter examines the broader context of the political economy of the Scottish Enlightenment and relates it to the general move from the mercantile attitudes behind the great disaster of the Darien project to the critique of them developed by Smith in the Wealth of Nations. The economic thinking of David Hume and Sir James Steuart and others is examined in order to illustrate the breadth of the Scottish contribution to the development of thinking about the economy.
The second edition of this Companion presents a philosophical perspective on an eighteenth-century phenomenon that has had a profound influence on Western culture. A distinguished team of contributors examines the writings of David Hume, Adam Smith, Thomas Reid, Adam Ferguson and other Scottish thinkers. Their subjects range across philosophy, natural theology, economics, anthropology, natural science, and law and the arts, and in addition, they relate the Scottish Enlightenment to its historical context and assess its impact and legacy. The result is a comprehensive and accessible volume that illuminates the richness, the intellectual variety and the underlying unity of this important movement. This volume contains five entirely new chapters on morality, the human mind, aesthetics, sentimentalism and political economy, and eleven other chapters have been significantly revised and updated. The book will be of interest to a wide range of readers in philosophy, theology, literature and the history of ideas.
This chapter examines the Shareholder Primacy Norm (SPN) as a widely acknowledged impediment to corporate social responsibility (CSR), including how this relates to Stakeholder Theory. We start by explaining the SPN and then review its status under US and UK law and show that it is not a legal requirement, at least under the guise of shareholder value maximization. This is in contrast to the common assertion that managers are legally constrained from addressing CSR issues if doing so would be inconsistent with the economic interests of shareholders. Nonetheless, while the SPN might be muted as a legal norm, we show that it is certainly evident as a powerful social norm among managers and in business schools— reflective, in part, of the sole voting rights of shareholders on corporate boards and of the dominance of Shareholder Theory. We argue that this view of CSR is misguided, not least when associated with claims of a purported legally enforceable requirement to maximize shareholder value. We propose two ways by which the influence of the SPN among managers might be attenuated: extending voting rights to non-shareholder stakeholders or extending fiduciary duties of executives to non-shareholder stakeholders.
The profound influence of Thomas Donaldson and Thomas Dunfee’s integrative social contracts theory (ISCT) on the field of business ethics has been challenged by Andreas Scherer and Guido Palazzo’s Habermasian approach, which has achieved prominence of late with articles that expressly question the defensibility of ISCT’s hypernorms. This article builds on recent efforts by Donaldson and Scherer to bridge their accounts by providing discursive foundations to the hypernorms at the heart of the ISCT framework. Extending prior literature, we propose an ISCT* framework designed to retain ISCT’s practical virtue of managerial guidance while answering the demands of Scherer and Palazzo’s discursive account. By subscribing to a suitable portfolio of discursively justified hypernorms, we argue, companies unlock the valuable moral guidance of ISCT*, which says to treat these hypernorms as unequivocal outer bounds to the pursuit of business and as a starting point to tailor local norms through discursive stakeholder engagement.
Until recent decades, historians of modern East Asia generally considered Asianism to be an imperialistic ideology of militant Japan. Although Japanese expansionists certainly used the term and its concept in this way in the 1930s and 1940s, earlier proponents of Asianism looked upon it as a very real strategy of uniting Asian nations to defend against Western imperialism. Showing that Chinese intellectuals considered different forms of Asianism as viable alternatives in the early days of the Republic of China, this article examines a number of discussions of Asianism immediately following the 1911 Revolution. Concentrating on newspaper articles and speeches by intellectuals Ye Chucang and Sun Yat-sen, I show the international aspirations of the Guomindang elite at this crucial point in the construction of the Chinese nation. Despite the dominance of discourse on the nation state, these intellectuals advocated different Asianist programmes for strategic purposes within the first two years of the Republic, dependent on their very different relationships with Japan.
Breakthrough Listen is a 10-yr initiative to search for signatures of technologies created by extraterrestrial civilisations at radio and optical wavelengths. Here, we detail the digital data recording system deployed for Breakthrough Listen observations at the 64-m aperture CSIRO Parkes Telescope in New South Wales, Australia. The recording system currently implements two modes: a dual-polarisation, 1.125-GHz bandwidth mode for single-beam observations, and a 26-input, 308-MHz bandwidth mode for the 21-cm multibeam receiver. The system is also designed to support a 3-GHz single-beam mode for the forthcoming Parkes ultra-wideband feed. In this paper, we present details of the system architecture, provide an overview of hardware and software, and present initial performance results.
In cattle early gastrulation-stage embryos (Stage 5), four tissues can be discerned: (i) the top layer of the embryonic disc consisting of embryonic ectoderm (EmE); (ii) the bottom layer of the disc consisting of mesoderm, endoderm and visceral hypoblast (MEH); (iii) the trophoblast (TB); and (iv) the parietal hypoblast. We performed microsurgery followed by RNA-seq to analyse the transcriptome of these four tissues as well as a developmentally earlier pre-gastrulation embryonic disc. The cattle EmE transcriptome was similar at Stages 4 and 5, characterised by the OCT4/SOX2/NANOG pluripotency network. Expression of genes associated with primordial germ cells suggest their presence in the EmE tissue at these stages. Anterior visceral hypoblast genes were transcribed in the Stage 4 disc, but no longer by Stage 5. The Stage 5 MEH layer was equally similar to mouse embryonic and extraembryonic visceral endoderm. Our data suggest that the first mesoderm to invaginate in cattle embryos is fated to become extraembryonic. TGFβ, FGF, VEGF, PDGFA, IGF2, IHH and WNT signals and receptors were expressed, however the representative members of the FGF families differed from that seen in equivalent tissues of mouse embryos. The TB transcriptome was unique and differed significantly from that of mice. FGF signalling in the TB may be autocrine with both FGFR2 and FGF2 expressed. Our data revealed a range of potential inter-tissue interactions, highlighted significant differences in early development between mice and cattle and yielded insight into the developmental events occurring at the start of gastrulation.