6,331 research outputs found
Healing Grief: A Commentary on Seneca's Consolatio ad Marciam
Both our view of Seneca’s philosophical thought and our approach to the ancient consolatory genre have radically changed since the latest commentary on the Consolatio ad Marciam was written in 1981. The aim of this work is to offer a new book-length commentary on the earliest of Seneca’s extant writings, along with a revision of the Latin text and a reassessment of Seneca’s intellectual program, strategies, and context.
A crucial document to penetrate Seneca’s discourse on the self in its embryonic stages, the Ad Marciam is here taken seriously as an engaging attempt to direct the persuasive power of literary models and rhetorical devices toward the fundamentally moral project of healing Marcia’s grief and correcting her cognitive distortions. Through close reading of the Latin text, this commentary shows that Seneca invariably adapts different traditions and voices – from Greek consolations to Plato’s dialogues, from the Roman discourse of gender and exemplarity to epic poetry – to a Stoic framework, so as to give his reader a lucid understanding of the limits of the self and the ineluctability of natural laws
The Forgetting of Fire: An Archaeology of Technics
This dissertation applies the methods of Bachelard and Foucault to key moments in the development of science. By analyzing the attitudes of four figures from four different centuries, it shows how epistemic attitudes have shifted from a participation in non-human, natural realities to a construction of human-centred technologies. The idea of an epistemic attitude is situated in reference to Foucault’s concept of the episteme and his method of archaeology; an attitude is the institutionally-situated and personally-enacted comportment of an epistemic agent toward an object of knowledge. This line of thought is pursued under the theme of elemental fire, which begins as a substance for early alchemical knowledge and ends up as a quantifiable branch of functions in technics. We call the attitude of Paracelsus, an alchemist of the sixteenth century, “participation,” which sheds light on the intimate goal of his alchemical practice. In the seventeenth century, Robert Boyle inaugurates the evolution of technics with the attitude of instrumentalization. Building off this, Lavoisier participates in the development of technics through his effort to construct the countable, using measuring instruments and chemical techniques. This attitude of accounting, and neither his theory of oxygen nor his basic observations in the laboratory, determines his decisive role in the development of chemistry. Finally, we discuss the attitude of employment as we find it in Sadi Carnot and the engineers of the steam engine, watching as fire for these epistemic agents becomes nothing but an employed instant of combustion
Securitisation on Blockchain: Implementation and Legal Challenges
Dissertation presented as the partial requirement for obtaining a Master's degree in Law and Financial MarketsBlockchain has disrupted the architecture of financial transactions more than any other innovation in the last decade. The tokenisation of real-life assets is explored in many corners of the capital markets, including the securitisation market. Howbeit, European Law, may not be sufficiently equipped to shelter the particularities of Distributed Ledger Technology (DLT). This paper constitutes a qualitative legal analysis of securitisation on blockchain in the Capital Markets Union. The primary question assesses European law's proclivity to accommodate securitisation on a blockchain. The focus lies herein firmly on disclosure requirements and continuous data reporting because DLT may streamline conventional channels. Potential implementations of blockchain precede the legal discussion as they lead to contrasting observations. Benefits and challenges for issuers, investors and regulators are displayed in an attempt to underline the utility of implementing blockchain.
In summary, the paper studies the implementation, the impact, and the level of harmonisation with the existing law of securitisation on a blockchain. The amalgam of securitisation and DLT is relatively new, resulting in the scarcity of legal documents to consult. Hence, most observations are derived through deductive reasoning by juxtaposing existing law and the singularities of blockchain. The Securitisation Regulation, Markets in Financial Instruments Directive, Prospectus Regulation, Anti-Money Laundering Directive, Central Security Depository Regulation and DLT Pilot Regime constitute the foundation of this analysis. In terms of implementation, the paper recognises permissioned blockchains and tokens as most suitable to comply with legal provisions. Furthermore, the paper observes that European securitisation law does not obstruct the use of blockchain as a data reporting tool for private securitisation, whereas some legal barriers are identified for public offerings. Other legal issues emanate from general questions relating to the issuance, trading, and settlement of tokenised securities.
Enhanced risk monitoring and standardisation are expected advantages of implementing DLT as a data layer for securitisation. Apart from legal issues, the nascency of DLT and interoperability with traditional software are considered significant challenges for large-scale adoption. Thus, the most vital catalyst may be trusting the integrity of the technology
Development and characterisation of phage display-derived antibodies for synovial specific drug delivery in Rheumatoid Arthritis
OBJECTIVE: Rheumatoid Arthritis (RA) is a systemic autoimmune disease with a prevalence of 0.5-1% worldwide. In the last two decades we observed the rapid evolution of RA therapeutics, and currently, a wide range of anti-rheumatic drugs is available. In particular, the discovery of anti-Tumor Necrosis Factor-α (TNF-α) antibodies has significantly improved disease management. However, the lack of therapeutic efficacy in a significant proportion of patients and the potential systemic implications (e.g. risk of serious infections) still represent an unmet need in RA therapy. Developing novel agents with synovial targeting specificity might increase the therapeutic index while reducing systemic side effects of RA therapeutics. This project aims to design, construct and evaluate in vitro and ex vivo the targeting and anti-inflammatory capability of a novel bispecific tandem single-chain variable fragment (scFv)-Fc antibody combining synovium specificity with anti-TNFα activity. The potential advantage of this construct, called F7-TNF scFv-Fc, is a reduced systemic TNF-binding activity and increased delivery and activation of TNF-neutralizing capacity at the inflamed joints. METHODS: The first part of this work focuses on the optimisation of synovium specific scFv domains previously identified by in vivo phage display using a SCID mouse model transplanted with human synovium, A7 scFv and F7 scFv. The second part of this project moves to the generation and evaluation of a tandem bispecific scFv-Fc antibody comprising F7 scFv external arms with synovium specific targeting ability linked through a metalloproteinase (MMP) cleavable linker to the anti-TNFα variable regions of Adalimumab fused to Fc domain of human IgG1. RESULTS: F7 scFv-Fc and the tandem bispecific F7/TNF scFv-Fc antibodies proved to satisfy the essential properties as joint-targeted agents showing specific reactivity to human arthritic synovium and no reactivity to normal tissues and other chronic diseases. In addition, F7/TNF scFv-Fc demonstrated ex vivo specific synovium targeting ability and intended reduced anti-TNFα activity in its intact form prior to reaching the joint tested by ELISA and NF-Kb reporter cell assay. Human synovial fluid and recombinant human MMP-1 showed efficient cleavage of the external arms of the antibody, releasing anti-TNF scFv-Fc with same TNF inhibitory capacity/potency as Adalimumab. CONCLUSION: Overall, F7-TNF scFv-Fc has the potential of decreasing the anti-TNFα off-site activity and consequently, reduce systemic toxicity while maintaining high on-site activity. Also, the presence of a synovium targeting domain has the advantage of increasing the delivery and retention within the inflamed synovium and possibly increase the therapeutic index of anti-TNF therapeutics
More Than Machines?
We know that robots are just machines. Why then do we often talk about them as if they were alive? Laura Voss explores this fascinating phenomenon, providing a rich insight into practices of animacy (and inanimacy) attribution to robot technology: from science-fiction to robotics R&D, from science communication to media discourse, and from the theoretical perspectives of STS to the cognitive sciences. Taking an interdisciplinary perspective, and backed by a wealth of empirical material, Voss shows how scientists, engineers, journalists - and everyone else - can face the challenge of robot technology appearing »a little bit alive« with a reflexive and yet pragmatic stance
BestFLR. Randomized controlled clinical trial comparing preoperative portal embolization with polyvinyl alcohol particles (PVA) and coils versus N-butyl cyanoacrylate (NBCA)
Liver surgery offers the most effective long-term oncological outcome for the treatment of metastatic liver disease (e.g. colorectal liver metastasis) and primary liver cancer (e.g. Hepatocarcinoma, Cholangiocarcinoma). Furthermore, advancements in surgical techniques combined with better postoperative care have decreased hepatectomy mortality rates to around 4 to 3% in high-volume centres. Unfortunately, approximately less than 25% of liver cancer patients are suited for surgical treatment, being the small size of the non-tumoral part of the liver - the future liver remnant (FLR) – the main limiting factor. Techniques to increase the FLR, known as liver regenerative strategies such as portal vein embolization (PVE), will increase the FLR volume and consequently allow otherwise non-operable patients to undergo this potentially curative treatment. PVE was introduced decades ago by Japanese groups and is currently accepted as the standard of care for liver regenerative techniques due to its benefit in preventing postoperative liver failure and improving overall survival. The rationale of PVE is related to the occlusion of the portal vein branches that irrigate the tumoral liver and redirecting all portal flow to the contralateral side, the FLR. This process succumbs in the increase of the FLR after two to six weeks.
Technically PVE is commonly accomplished by a liver percutaneous approach. First an ultrasound guided transhepatic access to the portal vein is obtained, followed by a vascular
sheath being placed in the main portal vein. Through the catheterization of the portal vein using angiographic catheters and microcatheters the target portal vein branches are
embolized. Nearly all types of embolic materials have been tested and reported for PVE with no real consensus on which one would induce the greatest degree of liver regeneration. No
randomized controlled trial had been performed to directly compare different embolic materials to perform PVE. The need for a well-designed, prospective, and controlled study to address this gap in the oncological literature seemed necessary and defiant. N-Butyl Cyanoacrylate (NBCA), a liquid embolic material, first used for PVE by French groups, has robust liver regenerative results reported in animal and retrospective human studies.
Besides that, this liquid embolic has other potential advantages such as fast administration, low cost, and wide availability. At our own clinical practice there was an increasing perception
of the distinct potential role of NBCA-Lipiodol for PVE, as to push us to look at our own results. This resulted in our first publication which reported a cohort of 50 consecutive patients submitted to PVE with NBCA-lipiodol published in the journal Cancer Imaging. The FLR increase (e.g., absolute liver hypertrophy) obtained at this retrospective analysis was 52% at an average 4 weeks after PVE, which was similar to previous published results for PVE when adopting this liquid embolic agent.
Beside NBCA-lipiodol, the other most frequent embolic material reported for PVE is a combination of polyvinyl alcohol (PVA) particles plus coils. For this PVE approach PVA particles are injected first for distal embolization in the portal vein branches followed by the deposition of proximal coils for definitive obstruction. This approach has been the standard procedure for PVE in Curry Cabral hospital´s interventional radiology unit for more than a decade. Although an established technique, PVE with PVA particles plus coils seemed to promote less liver regeneration and associated with more contrast usage, more fluoroscopy time and at a higher cost than PVE with NBCA plus Lipiodo. To change not only our practice but also to make scientific work useful to other centers our group decided to embrace an original, prospective project comparing NBCA-lipiodol and PVA particles plus coils for PVE before major hepatectomies, the BestFLR trial.
It also seemed reasonable and necessary to review and publish Curry Cabral interventional radiology unit experience with PVE using PVA particles plus coils. This retrospective analysis of data was published in the Journal of Oncology. Once again, results from our own retrospective cohort were similar to previously reported FLR absolute hypertrophy results for PVE with PVA particles plus coils, ranging from 25 to 40%.
We also noticed the necessity of performing an extensive review about PVE, more specifically the embolic materials reported for this procedure, their technical specifications, efficacy, complications, and clinical outcomes. This work was gathered as a detailed literature review of related publications up to August 2019 focusing on the results of each embolic agent and mixtures used for PVE, their handling, safety profiles, and liver hypertrophy regenerative results, also exemplifying with clinical cases from our own experience. This review article was published in the journal Radiology Research and Practice.
As mentioned, to build up higher levels of evidence a randomized controlled trial (RCT) was necessary to address the difference between the two most commonly used embolic materials for PVE: NBCA-Lipiodol versus PVA particles plus coils. This RCT was carried out in Curry Cabral hospital and published in Radiology in April 2021. This trial showed that PVE with NBCA-Lipiodol produced greater absolute liver hypertrophy compared to PVA particles plus coils (46% versus 30% at 14 days, p < .001 and 57% versus 37% at 28 days, p < .001,
respectively). Also, more participants in the NBCA plus Lipiodol group presented sufficient liver hypertrophy for surgery 2 weeks after PVE compared to the PVA particles plus coils group (87% vs 53%, respectively; p = .008). This latter finding meant that patients in the NBCA Lipiodol group were ready for the planned hepatectomy earlier, which might reduce tumor progression while patients are waiting for the liver to regenerate.
Concurrently, in the beginning of the year of 2021, with the publication of the results from the BestFLR, two systematic reviews with meta-analysis regarding liver regeneration predictive factors for PVE were also reported. Ali et al investigated PVE accomplished with different embolic materials for effectiveness in inducing future FLR hypertrophy and other outcomes. This review included 2896 patients from 51 different studies. Liver regeneration results and growth success rate were statistically superior for NBCA-Lipiodol when compared to PVA particles plus coils. Also, PVE with NBCA-Lipiodol promoted shorter procedures and reduced fluoroscopy time (p < .001), lower radiation exposure (p = .01), and lower material costs (p < .001) than PVA plus coils. The second systematic review with meta-analysis identified two predictive factors for accomplishing higher FLR hypertrophy results, and, once again, NBCA-Lipiodol was found to be superior to PVA plus coils in promoting liver regeneration (significant difference of degree of hypertrophy - DH in favor of NBCA-lipiodol). Our own group was invited to write a commentary about this relevant publication.
Pointing out to future perspectives, new regenerative techniques need to be addressed. With PVE, although highly effective, up to 20% of patients will not undergo the planned hepatectomy, due mainly to liver tumor progression during the regeneration waiting period after PVE or insufficient FLR hypertrophy. To accelerate liver regeneration and overcome insufficient FLR hypertrophy after PVE different strategies, such as biembolization, liver venous deprivation (LVD) and associating liver partition and portal vein ligation (ALPPS) have been reported. Biembolization refers to concomitantly performing PVE and proximal hepatic vein embolization. LVD, reported as proximal hepatic vein embolization, as in biembolization, and distal hepatic vein embolization with concomitantly PVE, has encouraging liver hypertrophy results, superior to PVE. ALPPS, which stands for associating liver partition with portal vein ligation in staged hepatectomy, promotes robust and rapid liver regeneration but is associated with high morbidity and mortality. Our own group commented upon two recent publications regarding these future perspectives
The Failure of Market Efficiency
Recent years have witnessed the near total triumph of market efficiency as a regulatory goal. Policymakers regularly proclaim their devotion to ensuring efficient capital markets. Courts use market efficiency as a guiding light for crafting legal doctrine. And scholars have explored in great depth the mechanisms of market efficiency and the role of law in promoting it. There is strong evidence that, at least on some metrics, our capital markets are indeed more efficient than they have ever been. But the pursuit of efficiency has come at a cost. By focusing our attention narrowly on economic efficiency concerns—such as competition, friction, and transaction costs—we have lost sight of other, deeper values within our economic system, including wider conceptions of duty, fairness, and morality. And while regulators sometimes pay lip service to these values, they often treat them as merely a subset of efficiency: the best way to treat investors fairly, to promote equality, and to prevent immoral, exploitative behavior, in this view, is simply to create an efficient market. We have seen the consequences of this emphasis play out in spectacular fashion in the last decade. New market structures and technologies—from special purpose acquisition companies to social-media oriented trading apps to cryptocurrencies—have emerged to eliminate barriers to trade and compete with institutional incumbents. These strategies may well lead to more efficient markets insomuch as they facilitate access to capital, but they also have the side effect of placing unsophisticated individuals into complex contractual arrangements with sophisticated market actors. The result is an “efficient” market, but one with steep moral and social costs. This Article examines the limits of market efficiency as a regulatory goal and suggests a set of structural and substantive reforms aimed at better balancing efficiency with the other goals of markets. It concludes that regulators, courts, and scholars alike need to adopt a more comprehensive understanding of the proper ends of market regulation, one that emphasizes the purpose and spirit of finance over the false promise of efficiency
Essays in сomputational macroeconomics and public finance
This dissertation applies advanced and novel computational tools to two major classes of economic simulations – large-scale, multi-region overlapping generations (OLG) models and models of lifetime consumption optimization. Chapters one and two develop large-scale, global OLG models to simulate, respectively, the future of automation and consequences of major corporate tax reform. Chapters three and four utilize The Fiscal Analyzer (TFA), a lifetime consumption smoothing algorithm, to estimate lifetime marginal tax rates of American workers and evaluate the impact of the Tax Cuts and Job Act (TCJA) on residents of red and blue states
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