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Background:Slowed processing speed impacts employment status in people with multiple sclerosis (PwMS). Studies on the Multiple Sclerosis Functional Composite (MSFC), which includes the Paced Auditory Serial Addition Test (PASAT), have demonstrated that the combined score predicts employment status. Whether PASAT performance alone is associated with employment status is less clear. In addition, no studies have yet evaluated whether cognitive fatigability (CF), as measured with the PASAT, is associated with employment status. The aim of the current study was to examine the association between PASAT performance, CF, and employment status in PwMS.Methods:Hundred and eighty-six PwMS completed the PASAT as part of a larger neuropsychological battery. ANOVAs and chi-squares analyzed group differences between employed and unemployed participants with respect to demographics, PASAT performance scores, and CF. Linear regression determined whether PASAT performance and/or CF scores were associated with employment status.Results:After controlling for demographic influences, group differences were noted between employed vs. unemployed individuals on PASAT performance scores only. Employment status was associated with PASAT performance scores but not CF.Conclusions:The current study confirmed that PASAT performance is associated with employment status in MS. Given that CF was not associated, it seems difficulties with information processing speed (IPS) and working memory have more impact on a PwMS’s ability to remain employed rather than within-task performance decline.

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Strong immunosuppression, including chemotherapy and immune-depleting antibodies followed by autologous haemopoietic stem-cell transplantation (aHSCT), has been used to treat patients with multiple sclerosis, improving control of relapsing disease. We addressed whether near-complete immunoablation followed by immune cell depleted aHSCT would result in long-term control of multiple sclerosis. We did this phase 2 single-arm trial at three hospitals in Canada. We enrolled patients with multiple sclerosis, aged 18–50 years with poor prognosis, ongoing disease activity, and an Expanded Disability Status Scale of 3·0–6·0. Autologous CD34 selected haemopoietic stem-cell grafts were collected after mobilisation with cyclophosphamide and filgrastim. Immunoablation with busulfan, cyclophosphamide, and rabbit anti-thymocyte globulin was followed by aHSCT. The primary outcome was multiple sclerosis activity-free survival (events were clinical relapse, appearance of a new or Gd-enhancing lesion on MRI, and sustained progression of Expanded Disability Status Scale score). This study was registered at ClinicalTrials.gov, NCT01099930. Between diagnosis and aHSCT, 24 patients had 167 clinical relapses over 140 patient-years with 188 Gd-enhancing lesions on 48 pre-aHSCT MRI scans. Median follow-up was 6·7 years (range 3·9–12·7). The primary outcome, multiple sclerosis activity-free survival at 3 years after transplantation was 69·6% (95% CI 46·6–84·2). With up to 13 years of follow-up after aHSCT, no relapses occurred and no Gd enhancing lesions or new T2 lesions were seen on 314 MRI sequential scans. The rate of brain atrophy decreased to that expected for healthy controls. One of 24 patients died of transplantation-related complications. 35% of patients had a sustained improvement in their Expanded Disability Status Scale score. We describe the first treatment to fully halt all detectable CNS inflammatory activity in patients with multiple sclerosis for a prolonged period in the absence of any ongoing disease-modifying drugs. Furthermore, many of the patients had substantial recovery of neurological function despite their disease's aggressive nature. Multiple Sclerosis Scientific Research Foundation.

Cognitive fatigability is an objective performance decrement that occurs over time during a task requiring sustained cognitive effort. Although cognitive fatigability is a common and debilitating symptom in multiple sclerosis (MS), there is currently no standard for its quantification. The objective of this study was to validate the Paced Auditory Serial Addition Test (PASAT) discrete and regression-based normative data for quantifying performance and cognitive fatigability in an Ontario-based sample of individuals with MS. Healthy controls and individuals with MS completed the 3″ and 2″ versions of the PASAT. PASAT performance was measured with total correct, dyad, and percent dyad scores. Cognitive fatigability scores were calculated by comparing performance on the first half (or third) of the task to the last half (or third). The results revealed that the 3″ PASAT was sufficient to detect impaired performance and cognitive fatigability in individuals with MS given the increased difficulty of the 2″ version. In addition, using halves or thirds for calculating cognitive fatigability scores were equally effective methods for detecting impairment. Finally, both the discrete and regression-based norms classified a similar proportion of individuals with MS as having impaired performance and cognitive fatigability. These newly validated discrete and regression-based PASAT norms provide a new tool for clinicians to document statistically significant cognitive fatigability in their patients.

About one-third of college students drop out before finishing their degree. The majority of those remaining will take longer than 4 years to complete their degree at “4-year” institutions. This problem emphasizes the need to identify students who may benefit from support to encourage timely graduation. Here we empirically develop machine learning algorithms, specifically Random Forest, to accurately predict if and when first-time-in-college undergraduates will graduate based on admissions, academic, and financial aid records two to six semesters after matriculation. Credit hours earned, college and high school grade point averages, estimated family (financial) contribution, and enrollment and grades in required gateway courses within a student’s major were all important predictors of graduation outcome. We predicted students’ graduation outcomes with an overall accuracy of 79%. Applying the machine learning algorithms to currently enrolled students allowed identification of those who could benefit from added support. Identified students included many who may be missed by established university protocols, such as students with high financial need who are making adequate but not strong degree progress.

Cytolethal distending toxins (Cdt) are produced by a diverse group of pathogens. One Cdt-producing organism, Aggregatibacter actinomycetemcomitans, plays a critical role in the pathogenesis of a unique form of periodontitis, formerly referred to as localized aggressive periodontitis. The active Cdt subunit, CdtB, is a potent phosphatidylinositol (PI) 3,4,5-triphosphate phosphatase capable of inducing PI-3-kinase signaling blockade, a requisite for Cdt-induced toxicity in lymphocytes. In this study, we extended our observations to include the oral keratinocyte response to AaCdt using cell lines and primary gingival keratinocytes. All three exhibited G2/M arrest when exposed to AaCdt toxin within 24 h. Toxin-treated cells exhibited reduced levels of pAkt and pGSK3β within 6 h. Pre-treatment with GSK3β kinase inhibitors, LY2090314, CHIR99021 and Tideglusib, abrogated Cdt-induced G2/M arrest. None of the oral epithelial cells exhibited evidence of apoptosis. Cells remained arrested in the G2/M phase for at least 72 h without evidence of DNA damage response activation (H2AX phosphorylation). Cdt-treated cells displayed increased phosphorylation of the cyclin dependent kinase 1 (CDK1); moreover, the GSK3 inhibitors blocked this increase and reduced total CDK1 levels. This study further clarifies the potential mechanism(s) contributing to Cdt toxicity and toxin-mediated pathogenesis.

Using the domicile itself as a metaphor, she equated traditional marriage with an old house: \"[I]t's old fashioned, its drafty, it's leaky, the roof sags, the timbers shake, there's no modern plumbing, no hardwood floors, no steam heat. The main characters prize their careers but also mourn the loss of conventional mother-child and husband-wife relationships and, more significant, the social legitimacy associated with the roles of mother and wife.3 In what follows I offer a queer reading of Imitation of life by foregrounding the Marbury/de Wolfe/Morgan domiciles as source material that illuminates the queer underpinnings of Hurst's ambivalent critique of traditional, heteronormative domesticity. Bea designs a chain of homey waffle shops that exploit Delilahs recipes and brand her the nations mammy; the subsequent meteoric rise of her restaurant career rescues Bea's family from poverty. [...]Bea exemplifies how culture redirects female desire and domestic energy toward objects and spaces that can be read as queer in their accommodation of extra-domestic and normative of female eros.

Objective:Multiple sclerosis (MS) is associated with cognitive and social cognitive deficits. Social cognition impairments may include difficulty with facial expression and emotion recognition. People with MS (PwMS) may also not be aware of their cognitive challenges as demonstrated through discrepant objective and subjective assessments. Research recently conducted in demyelinated mouse models demonstrated that metformin, a drug typically used to treat type II diabetes mellitus (DMII), promotes remyelination and reverses existent social cognition impairment by repressing the monoacylglycerol lipase (MgII) enzyme in the brain. We aim to translate this basic science research and are conducting a pilot study to determine if metformin improves social cognition in PwMS. This project will compare social cognition in those with MS and comorbid DMII who are treated with metformin and those who are not. For the purposes of this interim data analysis, we collapse across both MS groups who are, and who are not, treated with metformin. The current objective is to evaluate the relationship between subjective (i.e., perceived empathy), objective social cognition and information processing speed (IPS) in PwMS and co-morbid diabetes.Participants and Methods:Preliminary data on 15 PwMS are included. Participants completed a demographic questionnaire, a cognitive assessment battery, an objective social cognition assessment and self-report questionnaires. These questionnaires assessed subjective social cognition, fatigue, mood, and disability level.Results:Preliminary results showed that IPS was positively correlated with the affective empathy domain of social cognition, r = .53, p = .04. Additionally, IPS was positively correlated with objective social cognition, r = .71, p = 003. Follow-up regression analyses demonstrated that IPS predicted objective social cognition, R2 = .71, SE = 3.04, F(1,13) = 13.36, p = .003 and subjective social cognition, R2 = .53, SE = 5.39, F(1,13) = 4.97, p = .04. However, subjective and objective measures of social cognition were not correlated, p > .05 and remained uncorrelated when IPS was controlled for, p > .05.Conclusions:A majority of the variance in social perception is explained by IPS, suggesting that how quickly one can think may be a fundamental cognitive process to allow optimal functioning in social situations. While the reason for the relationship between IPS and subjective social cognition is perhaps less apparent, it may reflect a more global cognitive compromise that impacts both cognitive and social processes. This lends support to the Relative Consequence Model that suggests IPS deficits are a fundamental cognitive deficit underlying other more complex cognitive processes. The lack of correlation between subjective perception of empathy and objective social cognition requires further exploration and could potentially be related to some individuals with MS having a diminished ability to judge their own social proficiency. Further analyses with a larger sample will be conducted to assess group differences in social cognitive outcomes and MgII levels between metformin and non-metformin groups. If PwMS who take metformin have better social cognition compared to PwMS who do not take metformin, Mgll levels can be used as a biomarker to guide metformin treatment with the goal of improving social cognition.

Cognitive fatigability (CF) can be defined as an inability to maintain performance throughout a sustained cognitive task. Individuals with multiple sclerosis (MS) are more susceptible to CF than healthy controls (HCs); however, the neural correlates underlying CF are still under investigation. Arterial spin labeling (ASL) perfusion imaging provides a non-invasive method of objectively quantifying cerebral blood flow (CBF) during sustained attention tasks. To date, no study has yet evaluated CF in MS using this methodology. 10 MS and 10 HCs completed a 20-min psychomotor vigilance task (PVT). CF was evaluated by dividing the PVT into quintiles and examining performance from the 1st to the last. Mean reaction times (RTs) and number of lapses were recorded. Global and regional CBF changes were evaluated throughout the PVT as well as during pre- and post-task rest. Increased susceptibility to CF was noted in the MS group. Distinct patterns of CBF activation were observed in areas comprising fronto-parietal, cortico-striatal, cerebellar, and basal ganglia regions; however, when and how these regions were engaged differed between the MS and HC groups. In particular, dysfunction in CBF to the middle frontal gyrus may underlie the CF effects observed. In addition, individuals with MS appear to struggle with “switching off” regions of the attentional network at rest following sustained cognitive effort. Findings support the use of ASL as an appropriate methodology for evaluating CF in MS with an overall pattern of attentional network dysfunction being observed. Objectively quantifying CF in this manner can help validate patients’ subjective complaints.