Use and cost of disease-modifying therapies by Sonya Slifka Study participants: has anything really changed since 2000 and 2009?

Background:Disease-modifying therapies benefit individuals with relapsing forms of multiple sclerosis, but their utility remains unclear for those without relapses. Objective:To determine disease-modifying therapy use and costs in 2009, compare use in 2009 and 2000, and examine compliance with evidence-based guidelines. Methods:We determined the extent and characteristics of disease-modifying therapy use by participants in the Sonya Slifka Longitudinal Multiple Sclerosis Study (Slifka) in 2000 (n=2156) and 2009 (n=2361) and estimated out-of-pocket and total (payer) costs for 2009. Two multivariable logistic regressions predicted disease-modifying therapy use. Results:Disease-modifying therapy use increased from 55.3% in 2000 to 61.5% in 2009. In 2009, disease-modifying therapy use was reported by 76.5% of participants with relapsing-remitting multiple sclerosis, 73.2% with progressive-relapsing multiple sclerosis, 62.5% with secondary progressive multiple sclerosis, and 41.8% with primary progressive multiple sclerosis. Use was significantly associated with relapsing-remitting multiple sclerosis, shorter duration of illness, one to two relapses per year, non-ambulatory symptoms, using a cane, younger age, higher family income, and having health insurance. Average annual costs in 2009 were US$939-3101 for patients and US$16,302-18,928 for payers. Conclusion:Use rates were highest for individuals with relapsing-remitting multiple sclerosis, but substantial for those with progressive courses although clinical trials have not demonstrated significant benefits for them

Diffuse white matter loss in a transgenic rat model of cerebral amyloid angiopathy

Diffuse white matter (WM) disease is highly prevalent in elderly with cerebral small vessel disease (cSVD). In humans, cSVD such as cerebral amyloid angiopathy (CAA) often coexists with Alzheimer’s disease imposing a significant impediment for characterizing their distinct effects on WM. Here we studied the burden of age-related CAA pathology on WM disease in a novel transgenic rat model of CAA type 1 (rTg-DI). A cohort of rTg-DI and wild-type rats was scanned longitudinally using MRI for characterization of morphometry, cerebral microbleeds (CMB) and WM integrity. In rTg-DI rats, a distinct pattern of WM loss was observed at 9 M and 11 M. MRI also revealed manifestation of small CMB in thalamus at 6 M, which preceded WM loss and progressively enlarged until the moribund disease stage. Histology revealed myelin loss in the corpus callosum and thalamic CMB in all rTg-DI rats, the latter of which manifested in close proximity to occluded and calcified microvessels. The quantitation of CAA load in rTg-DI rats revealed that the most extensive microvascular Aβ deposition occurred in the thalamus. For the first time using in vivo MRI, we show that CAA type 1 pathology alone is associated with a distinct pattern of WM loss

High-Density Microwell Chip for Culture and Analysis of Stem Cells

With recent findings on the role of reprogramming factors on stem cells, in vitro screening assays for studying (de)-differentiation is of great interest. We developed a miniaturized stem cell screening chip that is easily accessible and provides means of rapidly studying thousands of individual stem/progenitor cell samples, using low reagent volumes. For example, screening of 700,000 substances would take less than two days, using this platform combined with a conventional bio-imaging system. The microwell chip has standard slide format and consists of 672 wells in total. Each well holds 500 nl, a volume small enough to drastically decrease reagent costs but large enough to allow utilization of standard laboratory equipment. Results presented here include weeklong culturing and differentiation assays of mouse embryonic stem cells, mouse adult neural stem cells, and human embryonic stem cells. The possibility to either maintain the cells as stem/progenitor cells or to study cell differentiation of stem/progenitor cells over time is demonstrated. Clonality is critical for stem cell research, and was accomplished in the microwell chips by isolation and clonal analysis of single mouse embryonic stem cells using flow cytometric cell-sorting. Protocols for practical handling of the microwell chips are presented, describing a rapid and user-friendly method for the simultaneous study of thousands of stem cell cultures in small microwells. This microwell chip has high potential for a wide range of applications, for example directed differentiation assays and screening of reprogramming factors, opening up considerable opportunities in the stem cell field

A gene frequency model for QTL mapping using Bayesian inference

<p>Abstract</p> <p>Background</p> <p>Information for mapping of quantitative trait loci (QTL) comes from two sources: linkage disequilibrium (non-random association of allele states) and cosegregation (non-random association of allele origin). Information from LD can be captured by modeling conditional means and variances at the QTL given marker information. Similarly, information from cosegregation can be captured by modeling conditional covariances. Here, we consider a Bayesian model based on gene frequency (BGF) where both conditional means and variances are modeled as a function of the conditional gene frequencies at the QTL. The parameters in this model include these gene frequencies, additive effect of the QTL, its location, and the residual variance. Bayesian methodology was used to estimate these parameters. The priors used were: logit-normal for gene frequencies, normal for the additive effect, uniform for location, and inverse chi-square for the residual variance. Computer simulation was used to compare the power to detect and accuracy to map QTL by this method with those from least squares analysis using a regression model (LSR).</p> <p>Results</p> <p>To simplify the analysis, data from unrelated individuals in a purebred population were simulated, where only LD information contributes to map the QTL. LD was simulated in a chromosomal segment of 1 cM with one QTL by random mating in a population of size 500 for 1000 generations and in a population of size 100 for 50 generations. The comparison was studied under a range of conditions, which included SNP density of 0.1, 0.05 or 0.02 cM, sample size of 500 or 1000, and phenotypic variance explained by QTL of 2 or 5%. Both 1 and 2-SNP models were considered. Power to detect the QTL for the BGF, ranged from 0.4 to 0.99, and close or equal to the power of the regression using least squares (LSR). Precision to map QTL position of BGF, quantified by the mean absolute error, ranged from 0.11 to 0.21 cM for BGF, and was better than the precision of LSR, which ranged from 0.12 to 0.25 cM.</p> <p>Conclusions</p> <p>In conclusion given a high SNP density, the gene frequency model can be used to map QTL with considerable accuracy even within a 1 cM region.</p

A SARS-CoV-2 protein interaction map reveals targets for drug repurposing

The novel coronavirus SARS-CoV-2, the causative agent of COVID-19 respiratory disease, has infected over 2.3 million people, killed over 160,000, and caused worldwide social and economic disruption1,2. There are currently no antiviral drugs with proven clinical efficacy, nor are there vaccines for its prevention, and these efforts are hampered by limited knowledge of the molecular details of SARS-CoV-2 infection. To address this, we cloned, tagged and expressed 26 of the 29 SARS-CoV-2 proteins in human cells and identified the human proteins physically associated with each using affinity-purification mass spectrometry (AP-MS), identifying 332 high-confidence SARS-CoV-2-human protein-protein interactions (PPIs). Among these, we identify 66 druggable human proteins or host factors targeted by 69 compounds (29 FDA-approved drugs, 12 drugs in clinical trials, and 28 preclinical compounds). Screening a subset of these in multiple viral assays identified two sets of pharmacological agents that displayed antiviral activity: inhibitors of mRNA translation and predicted regulators of the Sigma1 and Sigma2 receptors. Further studies of these host factor targeting agents, including their combination with drugs that directly target viral enzymes, could lead to a therapeutic regimen to treat COVID-19

The poet as woman : shapes of experience, a study of poetic motivation and craft in twentieth century women poets incorporating a select anthology

The virtual absence of women's viewpoint from the field of poetry and its criticism can be attributed to the subordinate position of women in western culture throughout history. Aesthetic standards, though seemingly comprehensive in their authority, nevertheless reflect this absence, being largely the product of a male perception of reality. Women poets have been discouraged and discriminated against in publication, a situation still not overcome despite current popularity, a result of their achievements in this century. The poetry of women has been seen by most men as unimportant or subsidiary to theirs. A contributory factor is that women have tended to focus on intensely observed personal experience, whereas male poets have been able to identify with the governance of men in dealing with broader issues. Thus, in addition to being held back, women have had to struggle against a lack of understanding and respect for their work. In order to bring about a desired situation in which women can participate with equal freedom and authority along with men in matters pertaining to poetry, what is needed is, first, a recognition that the problem exists, and second, an appreciation of women's literary importance past and present in contributing to aesthetic human experience. This thesis is an attempt to foster such recognition by showing a) that there has always existed, albeit frequently submerged, a distinctly feminine tradition in poetry, and b) that contemporary writing bears out that tradition while carrying it further in response to twentieth-century experience. As described and documented here, this tradition has a separate existence, a viability and its own validity. Part of the problem in extending the aesthetic to include the woman's viewpoint is that dominant trends in our century's poetry reflect the unparalleled technological advances in the culture favoring formalistic concerns and innovations at the expense of women's characteristic concern for meaningful content. The Historical Introduction begins with women's songs in Biblical times, tracing a tradition as it reaches its first peak of individualistic expression in Sappho, is seen in the medieval composition of courtly lays, is manifested sporadically both prior to and towards the end of the Renaissance in Europe, and begins gathering momentum in the seventeenth century. The veritable explosion of poetic energy we are now witnessing is the result of increased activity within the last hundred or so years, during which women have produced an historically unprecedented amount of poetry of high calibre in English, sufficient to permit comparative analysis and evaluation. The Critical Commentary, the major focus for the thesis, is an examination of the quality and range of this body of work as exemplified in the appended Anthology. Consisting of 133 poems, it presents selected twentieth-century work by American, Canadian, English and Australian poets. The poems deal with being a woman, or an artist, or both, giving voice to authentic feminine experience. Because the poets seemingly emphasize content, in its fittest expression, the discussion of the poems, like their organization in the Anthology, is predicated on content-categories derived from a study of themes and subject matters. The conclusion emerging from this tracing of a woman's tradition in poetry and from the close examination of its present flowering is that the voice and perspective of half of humanity is being restored in its more equitable ancient proportion to our culture, with attendant implications in the realms of publishing, editing, criticism, standards and teaching. Findings herein demand that standards of criticism should in all justice encompass the woman's viewpoint, incorporating and giving weight to this tradition, enabling women to be recognized as full equals in all aspects of poetic endeavor.Arts, Faculty ofEnglish, Department ofGraduat

A new perspective on the relation between fear and persuasion: The application of dual-process models

Research on the relationship between fear and persuasion led to a proliferation of conflicting results. The purpose of this project was to develop and test hypotheses regarding how fear might impact the persuasion process delineated by the Elaboration Likelihood Model. Fear could direct message recipients into the central or peripheral route by motivating or distracting them from extensive message processing. Fear could also serve as a peripheral cue. It was hypothesized that fear arousal relevant to a persuasive message would motivate subjects to carefully process the message, therefore, central route processing would occur and the amount of persuasion would be based on message quality. It was further hypothesized that fear arousal irrelevant to a persuasive message would distract subjects from attending to the message so that persuasion would occur in the peripheral route and not be based on message quality. Fear arousal was also expected to act as a peripheral cue, enhancing persuasion by its mere presence. A 3 (fear arousal: relevant, irrelevant, none) x 3 (message quality: strong, weak, minimal) x 2 (topic: heart disease, peptic ulcers) design was used. A secondary goal of this study was to develop a methodology to arouse fear separate from a persuasive message to avoid the confounding variable problem present in other fear appeal research. This was successfully accomplished. As predicted, there was a marginally significant effect demonstrating that relevant fear resulted in a greater disparity between strong and weak messages than no fear arousal for one of the topics. Contrary to predictions, irrelevant fear arousal did not result in smaller differences in persuasion when compared with no fear arousal. There was a marginally significant effect that relevant fear arousal produced greater intentions than no fear arousal in the minimal message condition for one of the topics. The results provided partial support for the hypotheses that fear can motivate extensive message processing and can serve as a peripheral cue. There was no evidence that irrelevant fear distracted from extensive processing. Implications of these results and possibilities for future research are discussed