Ensuring Digital Accessibility through Process and Policy provides readers with a must-have resource to digital accessibility from both a technical and policy perspective. Inaccessible digital ...interfaces and content often lead to forms of societal discrimination that may be illegal under various laws. This book is unique in that it provides a multi-disciplinary understanding of digital accessibility. The book discusses the history of accessible computing, an understanding of why digital accessibility is socially and legally important, and provides both technical details (interface standards, evaluation methods) and legal details (laws, lawsuits, and regulations). The book provides real-world examples throughout, highlighting organizations that are doing an effective job with providing equal access to digital information for people with disabilities. This isn't a book strictly about interface design, nor is it a book strictly about law. For people who are charged with implementing accessible technology and content, this book will serve as a one- stop guide to understanding digital accessibility, offering an overview of current laws, regulations, technical standards, evaluation techniques, as well as best practices and suggestions for implementing solutions and monitoring for compliance. This combination of skills from the three authors—law, technical, and research, with experience in both corporate, government, and educational settings, is unique to this book, and does not exist in any other book about any aspect of IT accessibility. The authors' combination of skills marks a unique and valuable perspective, and provides insider knowledge on current best practices, corporate policies, and technical instructions. Together, we can ensure that the world of digital information is open to all users. * Learn about the societal and organizational benefits of making information technology accessible for people with disabilities * Understand the interface guidelines, accessibility evaluation methods, and compliance monitoring techniques, needed to ensure accessible content and technology * Understand the various laws and regulations that require accessible technology * Learn from case studies of organizations that are successfully implementing accessibility in their technologies and digital content
Hepatocellular carcinoma (HCC) is one of the leading causes of cancer related deaths. Patients with advanced HCC are treated with sorafenib. A recent randomized controlled trial demonstrated a ...survival benefit for regorafenib treatment in patients with advanced HCC who had progressed on sorafenib. We aimed to evaluate the cost-effectiveness of this approach.
To evaluate the cost effectiveness of regorafenib, we used a Markov model that incorporates health outcomes, measured by life-years and quality-adjusted life-years (QALYs). Drug costs were based on 2017 discounted prices. Model robustness was validated by probabilistic sensitivity analyses using Monte Carlo simulations.
The use of regorafenib results in a gain of 19.76 weeks of life (0.38 Life Years) as compared to placebo. When adjusted for quality of life, using regorafenib produced a gain of 0.25 quality adjusted life years (QALYs). The incremental cost-effectiveness ratio for regorafenib compared with best supportive care was between $201,797 and $268,506 per QALY.
The modest incremental benefit at a relatively high incremental cost of regorafenib treatment suggests that it is not cost-effective at commonly accepted willingness to pay thresholds.
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Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Graft inflammation impairs the induction of solid organ transplant tolerance and enhances acute and chronic rejection. Elucidating the mechanisms by which inflammation is induced after organ ...transplantation could lead to novel therapeutics to improve transplant outcomes. In this Review we describe endogenous substances--damage-associated molecular patterns (DAMPs)--that are released after allograft reperfusion and induce inflammation. We also describe innate immune signalling pathways that are activated after solid organ transplantation, with a focus on Toll-like receptors (TLRs) and their signal adaptor, MYD88. Experimental and clinical studies have yielded a large body of evidence that TLRs and MYD88 are instrumental in initiating allograft inflammation and promoting the development of acute and chronic rejection. Ongoing clinical studies are testing TLR inhibition strategies in solid organ transplantation, although avoiding compromising host defence to pathogens is a key challenge. Further elucidation of the mechanisms by which sterile inflammation is induced, maintained and amplified within the allograft has the potential to lead to novel anti-inflammatory treatments that could improve outcomes for solid organ transplant recipients.
RATIONALE:Aging is one of the strongest risk factors for atherosclerosis. Yet whether aging increases the risk of atherosclerosis independently of chronic hyperlipidemia is not known.
OBJECTIVE:To ...determine if vascular aging before the induction of hyperlipidemia enhances atherogenesis.
METHODS AND RESULTS:We analyzed the aortas of young and aged normolipidemic wild type, disease-free mice and found that aging led to elevated IL (interleukin)-6 levels and mitochondrial dysfunction, associated with increased mitophagy and the associated protein Parkin. In aortic tissue culture, we found evidence that with aging mitochondrial dysfunction and IL-6 exist in a positive feedback loop. We triggered acute hyperlipidemia in aged and young mice by inducing liver-specific degradation of the LDL (low-density lipoprotein) receptor combined with a 10-week western diet and found that atherogenesis was enhanced in aged wild-type mice. Hyperlipidemia further reduced mitochondrial function and increased the levels of Parkin in the aortas of aged mice but not young mice. Genetic disruption of autophagy in smooth muscle cells of young mice exposed to hyperlipidemia led to increased aortic Parkin and IL-6 levels, impaired mitochondrial function, and enhanced atherogenesis. Importantly, enhancing mitophagy in aged, hyperlipidemic mice via oral administration of spermidine prevented the increase in aortic IL-6 and Parkin, attenuated mitochondrial dysfunction, and reduced atherogenesis.
CONCLUSIONS:Before hyperlipidemia, aging elevates IL-6 and impairs mitochondrial function within the aorta, associated with enhanced mitophagy and increased Parkin levels. These age-associated changes prime the vasculature to exacerbate atherogenesis upon acute hyperlipidemia. Our work implies that novel therapeutics aimed at improving vascular mitochondrial bioenergetics or reducing inflammation before hyperlipidemia may reduce age-related atherosclerosis.
VISUAL OVERVIEW:An online visual overview is available for this article.
There are two classes of viable progenitors for normal Type Ia supernovae (SNe Ia): systems in which a white dwarf explodes at the Chandrasekhar mass ( ), and systems in which a white dwarf explodes ...below the Chandrasekhar mass (sub- ). It is not clear which of these channels is dominant; observations and light-curve modeling have provided evidence for both. Here we use an extensive grid of 4500 time-dependent, multiwavelength radiation transport simulations to show that the sub- model can reproduce the entirety of the width-luminosity relation, while the model can only produce the brighter events , implying that fast-declining SNe Ia come from sub- explosions. We do not assume a particular theoretical paradigm for the progenitor or explosion mechanism, but instead construct parameterized models that vary the mass, kinetic energy, and compositional structure of the ejecta, thereby realizing a broad range of possible outcomes of white dwarf explosions. We provide fitting functions based on our large grid of detailed simulations that map observable properties of SNe Ia, such as peak brightness and light-curve width, to physical parameters such as and total ejected mass. These can be used to estimate the physical properties of observed SNe Ia.
In a large-scale, preregistered experiment on informal political communication, we algorithmically matched participants, varying two dimensions: 1) the degree of incidental similarity on nonpolitical ...features; and 2) their stance agreement on a contentious political topic. Matched participants were first shown a computer-generated social media profile of their match highlighting all the shared nonpolitical features; then, they read a short, personal, but argumentative, essay written by their match about the reduction of inequality via redistribution of wealth by the government. We show that support for redistribution increased and polarization decreased for participants with both mild and strong views, regardless of their political leaning. We further show that feeling close to the match is associated with an 86% increase in the probability of assimilation of political views. Our analysis also uncovers an asymmetry: Interacting with someone with opposite views greatly reduced feelings of closeness; however, interacting with someone with consistent views only moderately increased them. By extending previous work about the effects of incidental similarity and shared identity on affect into the domain of political opinion change, our results bear real-world implications for the (re)-design of social media platforms. Because many people prefer to keep politics outside of their social networks, encouraging cross-cutting political communication based on nonpolitical commonalities is a potential solution for fostering consensus on potentially divisive and partisan topics.
ABSTRACT Type Ia supernovae (SNe Ia) that are multiply imaged by gravitational lensing can extend the SN Ia Hubble diagram to very high redshifts (z 2), probe potential SN Ia evolution, and deliver ...high-precision constraints on H0, w, and m via time delays. However, only one, iPTF16geu, has been found to date, and many more are needed to achieve these goals. To increase the multiply imaged SN Ia discovery rate, we present a simple algorithm for identifying gravitationally lensed SN Ia candidates in cadenced, wide-field optical imaging surveys. The technique is to look for supernovae that appear to be hosted by elliptical galaxies, but that have absolute magnitudes implied by the apparent hosts' photometric redshifts that are far brighter than the absolute magnitudes of normal SNe Ia (the brightest type of supernovae found in elliptical galaxies). Importantly, this purely photometric method does not require the ability to resolve the lensed images for discovery. Active galactic nuclei, the primary sources of contamination that affect the method, can be controlled using catalog cross-matches and color cuts. Highly magnified core-collapse SNe will also be discovered as a byproduct of the method. Using a Monte Carlo simulation, we forecast that the Large Synoptic Survey Telescope can discover up to 500 multiply imaged SNe Ia using this technique in a 10 year z-band search, more than an order of magnitude improvement over previous estimates. We also predict that the Zwicky Transient Facility should find up to 10 multiply imaged SNe Ia using this technique in a 3 year R-band search-despite the fact that this survey will not resolve a single system.
Financial toxicity is now a well established and generally accepted toxicity related to cancer care. While policy makers and politicians continue to debate about system‐wide changes, physicians and ...patients can seek ways to decrease financial toxicity and to incorporate this issue into every decision‐making process.
See also pages 1453‐63.
The Interagency Registry for Mechanically Assisted Circulatory Support (Intermacs), a joint effort among the National Heart, Lung, and Blood Institute, the Food and Drug Administration, the Centers ...for Medicare and Medicaid Services, and others, was established in 2005 at the University of Alabama at Birmingham. The registry examined clinical outcomes and quality-of-life metrics of patients who received an Food and Drug Administration-approved durable mechanical circulatory support (MCS) device to treat advanced heart failure. On January 1, 2018, the Intermacs Database became part of The Society of Thoracic Surgeons National Database, providing additional resources for quality assessment and improvement and scientific advancement.
The Intermacs Database Annual Report summarizes outcomes in patients (≥19 years of age) who underwent durable MCS implant between June 23, 2006, and December 31, 2017. Outcomes are presented for patients who underwent isolated continuous flow left ventricular assist device (CF LVAD) support, CF LVAD support with concomitant right ventricular assist device (RVAD) implant, or total artificial heart implant. Analyses of patients with CF LVADs are stratified by axial flow and centrifugal flow configurations. Because of the association of era with outcomes, the survival analyses are restricted to isolated CF LVADs implanted in the 2012 to 2016 era.
There were 25,145 adult patients with MCS reported to Intermacs, of whom 18,539 (74%) received CF LVADs, 667 (2.6%) had an RVAD with CF LVAD, 339 received a total artificial heart (1.3%), and 20 (0.07%) received an isolated RVAD. Of the CF LVADs, mean age was 57 ± 1 years, 26% were listed for transplantation, and 51% were in cardiogenic shock (profile 1 to 2) preoperatively. CF LVADs included 14,527 axial flow (78%) and 4,012 centrifugal flow (22%) devices. Intermacs patient phenotype has evolved over time to include more patients with profile 3 (26% in 2006 to 2011 versus 35% in 2012 to 2016) and fewer patients with profile 2 (40% versus 35%), patients with better markers of preoperative renal and hepatic function, and more patients who received implants for destination therapy (29% versus 48%) indication. In 2017, centrifugal flow implants (51%) approximated that of axial flow devices (49%). Mean CF LVAD support duration was 20 months (31,563 patient-years). One-year survival for isolated CF LVADs was 83% and 5-year survival was 46%. One-year survivals for centrifugal versus axial flow devices were 85% and 84%, respectively. Patients who required concomitant RVAD support had 1- and 5-year survivals of 58% and 28%, respectively. Freedom from all-cause readmission was 70% at 1 month and 20% at 1 year. At 1 year, stroke occurred in 20% of patients on centrifugal flow and 13% of patients on axial flow support (p < 0.001), gastrointestinal bleeding affected 20% of patients with centrifugal flow devices and 25% of patients with axial flow devices (p < 0.001), and pump-related infection occurred in 28% of patients with centrifugal flow devices versus 25% of patients with axial flow devices (p = 0.01). Neurologic dysfunction (19% of deaths) and multisystem organ dysfunction (15%) were the most common causes of death.
With the evolution of MCS, patient phenotype and outcomes are also changing over time. CF LVAD support is increasingly being used in the less ill patient phenotype and more patients are supported for destination therapy. Mean survival is now approaching 5 years, but adverse events, especially neurologic events, continue to have a detrimental impact on the success of CF LVAD support.
In recent years, leaders in a number of nations have undermined their public sector’s capacity to deliver on its core goals. To understand this interference, it is necessary to examine the formal and ...informal organizational dynamics at play within bureaucracies. Considering a widely applicable generalized organization, a formal model outlines how a leader may augment the career incentives of supervisors and lower-level workers, which shifts the alignment of policy with an organization’s central mission. While hierarchy may amplify disruption, organizational culture can coalesce as a norm facilitating resistance to extreme shifts, thereby stabilizing long-term mission compliance. Yet, should disruption lead to an exodus of mission-driven employees, durable reversals of an organization’s capacity to fulfill its aims may ensue. The model highlights three trajectories disrupted organizations follow: temporary reversal, erosion, and resistance. Implications are considered for public sector institutions and international organizations as well as for the study of bureaucratic and state capacities.
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