The relationship between cortical lesions and periventricular NAWM abnormalities suggests a shared mechanism of injury in primary-progressive MS.

In subjects with multiple sclerosis (MS), pathology is more frequent near the inner and outer surfaces of the brain. Here, we sought to explore if in subjects with primary progressive MS (PPMS) cortical lesion load is selectively associated with the severity of periventricular normal appearing white matter (NAWM) damage, as assessed with diffusion weighted imaging. To this aim, twenty-four subjects with PPMS and twenty healthy controls were included in the study. Using diffusion data, skeletonized mean diffusivity (MD) NAWM maps were computed excluding WM lesions and a 2 mm-thick peri-lesional rim. The supra-tentorial voxels between 2 and 6 mm of distance from the lateral ventricles were included in the periventricular NAWM mask while the voxels between 6 and 10 mm from the lateral ventricles were included in the deep NAWM mask; mean MD values were then computed separately for these two masks. Lastly, cortical lesions were assessed on phase-sensitive inversion recovery (PSIR) images and cortical thickness was quantified on volumetric T1 images. Our main result was the observation in the PPMS group of a significant correlation between periventricular NAWM MD values and cortical lesion load, with a greater cortical lesion burden being associated with more abnormal periventricular NAWM MD. Conversely, there was no correlation between cortical lesion load and deep NAWM MD values or periventricular WM lesions. Our data thus suggest that a common - and relatively selective - factor plays a role in the development of both cortical lesion and periventricular NAWM abnormalities in PPMS

Transmission tree of the highly pathogenic avian influenza (H5N1) epidemic in Israel, 2015

The transmission tree of the Israeli 2015 epidemic of highly pathogenic avian influenza (H5N1) was modelled by combining the spatio-temporal distribution of the outbreaks and the genetic distance between virus isolates. The most likely successions of transmission events were determined and transmission parameters were estimated. It was found that the median infectious pressure exerted at 1 km was 1.59 times (95% CI 1.04, 6.01) and 3.54 times (95% CI 1.09, 131.75) higher than that exerted at 2 and 5 km, respectively, and that three farms were responsible for all seven transmission events. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s13567-016-0393-2) contains supplementary material, which is available to authorized users

Job Scheduling Using successive Linear Programming Approximations of a Sparse Model

EuroPar 2012In this paper we tackle the well-known problem of scheduling a collection of parallel jobs on a set of processors either in a cluster or in a multiprocessor computer. For the makespan objective, i.e., the completion time of the last job, this problem has been shown to be NP-Hard and several heuristics have already been proposed to minimize the execution time. We introduce a novel approach based on successive linear programming (LP) approximations of a sparse model. The idea is to relax an integer linear program and use lp norm-based operators to force the solver to find almost-integer solutions that can be assimilated to an integer solution. We consider the case where jobs are either rigid or moldable. A rigid parallel job is performed with a predefined number of processors while a moldable job can define the number of processors that it is using just before it starts its execution. We compare the scheduling approach with the classic Largest Task First list based algorithm and we show that our approach provides good results for small instances of the problem. The contributions of this paper are both the integration of mathematical methods in the scheduling world and the design of a promising approach which gives good results for scheduling problems with less than a hundred processors

Accounting fraud, business failure and creative auditing: A microanalysis of the strange case of the Sunbeam Corporation

This article closely examines the Sunbeam Corporation’s path to failure and explores the reasons for its singularity. From the analysis of US fraud cases included in the UCLA-LoPucki Bankruptcy Research Database, this corporate case appears as an outlier. For Sunbeam, the time-lapse between fraud disclosure and its final bankruptcy is the longest of the entire sample; it is unique because of its length. This article uses a historical microanalysis to evaluate different hypotheses about the Sunbeam Corporation’s path to failure. The relationships between acquisitions and fraud, ‘scapegoat dynamics’ and ‘creative auditing’ are identified as the most relevant issues to be examined against a changing institutional context. The resulting reconstruction of the events provides unexpected insights and recommendations for future research on auditing and accounting fraud

Increased circulating T cell reactivity to GM3 and GQ1b gangliosides in primary progressive multiple sclerosis

We have previously shown that patients with primary progressive multiple sclerosis (MS) have significantly elevated plasma levels of antibody to GM3 ganglioside compared to patients with relapsing-remitting MS, healthy subjects and patients with other neurological diseases. Anti-GM3 antibody levels were elevated also in patients with secondary progressive MS but to a lesser extent than in primary progressive MS. As gangliosides are particularly enriched in the axonal membrane, these findings suggested that antiganglioside immune responses might contribute to the axonal damage in progressive forms of MS. The present study was performed to determine whether peripheral blood T cell responses to GM3 are also increased in progressive MS. Blood was collected from 98 untreated patients with MS (40 with relapsing-remitting, 27 with secondary progressive and 31 with primary progressive MS), 50 healthy subjects and 24 patients with other disorders of the CNS, and reactivity to GM1, GM3, GD1a, GD1b, GD3, GT1b, GQ1b and sulphatide was assessed by 6-day T cell proliferation assays. Increased T cell reactivity to GM3 and GQ1b occurred significantly more often in patients with primary progressive MS than in healthy subjects and patients with other CNS diseases. These findings suggest that ganglioside-specific T cells may contribute to the axonal damage in primary progressive MS. (C) 2002 Elsevier Science Ltd. All rights reserved

Reproducibility over a 1-month period of 1H-MR spectroscopic imaging NAA/Cr ratios in clinically stable multiple sclerosis patients

N-acetylaspartate/creatine (NAA/Cr) ratios, assessed with proton magnetic resonance spectroscopy, are increasingly used as a surrogate marker for axonal dysfunction and degeneration in multiple sclerosis (MS). The purpose of this study was to test short-time reproducibility of NAA/Cr ratios in patients with clinically stable MS. In 35 MS patients we analysed NAA/Cr ratios obtained with 1H-MR spectroscopic imaging at the centrum semiovale either with lateral ventricles partially included (group 1; n=15) or more cranially with no ventricles included (group 2; n=20). To test short-term reproducibility of the NAA/Cr measurements, patients were scanned twice 4 weeks apart. We determined mean NAA/Cr and Cho/Cr ratios of 12 grey matter and 24 white matter voxels. Mean NAA/Cr ratios of both the white and grey matter did not change after 4 weeks. Overall 4-week reproducibility of the NAA/Cr ratio, expressed as coefficient of variation, was 4.8% for grey matter and 3.5% for white matter. Reproducibility of cranial scanning of the ventricles was slightly better than with cerebrospinal fluid included. Our study shows good short-term reproducibility of NAA/Cr ratio measurements in the centrum semiovale, which supports the reliability of this technique for longitudinal studies

HLA-class I markers and multiple sclerosis susceptibility in the Italian population

Previous studies reported an association with multiple sclerosis (MS) of distinct HLA-class I markers, namely HLA-A*02, HLA-Cw*05 and MOG-142L. In this work, we tested the association with MS of A*02 and Cw*05 in 1273 Italian MS patients and 1075 matched controls, which were previously analyzed for MOG-142, and explored the relationship among these three markers in modulating MS risk. HLA-A*02 conferred a statistically robust MS protection (odds ratio, OR=0.61; 95% confidence intervals, CI=0.51–0.72, P<10−9), which was independent of DRB1*15 and of any other DRB1* allele and remained similar after accounting for the other two analyzed class I markers. Conversely, the protective effect we previously observed for MOG-142L was secondary to its linkage disequilibrium with A*02. Cw*05 was not associated considering the whole sample, but its presence significantly enhanced the protection in the HLA-A*02-positive group, independently of DRB1: the OR conferred by A*02 in Cw*05-positive individuals (0.22, 95% CI=0.13–0.38) was significantly lower than in Cw*05-negative individuals (0.69, 95% CI=0.58–0.83) with a significant (P=4.94 × 10−5) multiplicative interaction between the two markers. In the absence of A*02, Cw*05 behaved as a risk factor, particularly in combination with DRB1*03 (OR=3.89, P=0.0006), indicating that Cw*05 might be a marker of protective or risk haplotypes, respectively

Patient-orientated longitudinal study of multiple sclerosis in south west England (The South West Impact of Multiple Sclerosis Project, SWIMS) 1: protocol and baseline characteristics of cohort

<p>Abstract</p> <p>Background</p> <p>There is a need for greater understanding of the impact of multiple sclerosis (MS) from the perspective of individuals with the condition. The South West Impact of MS Project (SWIMS) has been designed to improve understanding of disease impact using a patient-centred approach. The purpose is to (1) develop improved measurement instruments for clinical trials, (2) evaluate longitudinal performance of a variety of patient-reported outcome measures, (3) develop prognostic predictors for use in individualising drug treatment for patients, particularly early on in the disease course.</p> <p>Methods</p> <p>This is a patient-centred, prospective, longitudinal study of multiple sclerosis and clinically isolated syndrome (CIS) in south west England. The study area comprises two counties with a population of approximately 1.7 million and an estimated 1,800 cases of MS. Self-completion questionnaires are administered to participants every six months (for people with MS) or 12 months (CIS). Here we present descriptive statistics of the baseline data provided by 967 participants with MS.</p> <p>Results</p> <p>Seventy-five percent of those approached consented to participate. The male:female ratio was 1.00:3.01 (n = 967). Average (standard deviation) age at time of entry to SWIMS was 51.6 (11.5) years (n = 961) and median (interquartile range) time since first symptom was 13.3 (6.8 to 24.5) years (n = 934). Fatigue was the most commonly reported symptom, with 80% of participants experiencing fatigue at baseline. Although medication use for symptom control was common, there was little evidence of effectiveness, particularly for fatigue. Nineteen percent of participants were unable to classify their subtype of MS. When patient-reported subtype was compared to neurologist assessment for a sample of participants (n = 396), agreement in disease sub-type was achieved in 63% of cases. There were 836 relapses, reported by 931 participants, in the twelve months prior to baseline. Twenty-three percent of the relapsing-remitting group and 12% of the total sample were receiving disease-modifying therapy at baseline.</p> <p>Conclusions</p> <p>Demographics of this sample were similar to published data for the UK. Overall, the results broadly reflect clinical experience in confirming high symptom prevalence, with relatively little complete symptom relief. Participants often had difficulty in defining MS relapses and their own MS type.</p

The Expression of VEGF-A Is Down Regulated in Peripheral Blood Mononuclear Cells of Patients with Secondary Progressive Multiple Sclerosis

BACKGROUND: Most patients with relapsing-remitting multiple sclerosis (RRMS) eventually enter a secondary progressive (SPMS) phase, characterized by increasing neurological disability. The mechanisms underlying transition to SPMS are unknown and effective treatments and biomarkers are lacking. Vascular endothelial growth factor-A (VEGF-A) is an angiogenic factor with neuroprotective effects that has been associated with neurodegenerative diseases. SPMS has a prominent neurodegenerative facet and we investigated a possible role for VEGF-A during transition from RRMS to SPMS. METHODOLOGY/PRINCIPAL FINDINGS: VEGF-A mRNA expression in peripheral blood mononuclear (PBMC) and cerebrospinal fluid (CSF) cells from RRMS (n = 128), SPMS (n = 55) and controls (n = 116) were analyzed using real time PCR. We demonstrate reduced expression of VEGF-A mRNA in MS CSF cells compared to controls (p<0.001) irrespective of disease course and expression levels are restored by natalizumab treatment(p<0.001). VEGF-A was primarily expressed in monocytes and our CSF findings in part may be explained by effects on relative monocyte proportions. However, VEGF-A mRNA expression was also down regulated in the peripheral compartment of SPMS (p<0.001), despite unchanged monocyte counts, demonstrating a particular phenotype differentiating SPMS from RRMS and controls. A possible association of allelic variability in the VEGF-A gene to risk of MS was also studied by genotyping for six single nucleotide polymorphisms (SNPs) in MS (n = 1114) and controls (n = 1234), which, however, did not demonstrate any significant association between VEGF-A alleles and risk of MS. CONCLUSIONS/SIGNIFICANCE: Expression of VEGF-A in CSF cells is reduced in MS patients compared to controls irrespective of disease course. In addition, SPMS patients display reduced VEGF-A mRNA expression in PBMC, which distinguish them from RRMS and controls. This indicates a possible role for VEGF-A in the mechanisms regulating transition to SPMS. Decreased levels of PBMC VEGF-A mRNA expression should be further evaluated as a biomarker for SPMS

Disability outcomes in the N-MOmentum trial of inebilizumab in neuromyelitis optica spectrum disorder

OBJECTIVE: To assess treatment effects on Expanded Disability Status Scale (EDSS) score worsening and modified Rankin Scale (mRS) scores in the N-MOmentum trial of inebilizumab, a humanized anti-CD19 monoclonal antibody, in participants with neuromyelitis optica spectrum disorder (NMOSD). METHODS: Adults (N = 230) with aquaporin-4 immunoglobulin G-seropositive NMOSD or -seronegative neuromyelitis optica and an EDSS score ≤8 were randomized (3:1) to receive inebilizumab 300 mg or placebo on days 1 and 15. The randomized controlled period (RCP) was 28 weeks or until adjudicated attack, with an option to enter the inebilizumab open-label period. Three-month EDSS-confirmed disability progression (CDP) was assessed using a Cox proportional hazard model. The effect of baseline subgroups on disability was assessed by interaction tests. mRS scores from the RCP were analyzed by the Wilcoxon-Mann-Whitney odds approach. RESULTS: Compared with placebo, inebilizumab reduced the risk of 3-month CDP (hazard ratio [HR]: 0.375; 95% CI: 0.148-0.952; p = 0.0390). Baseline disability, prestudy attack frequency, and disease duration did not affect the treatment effect observed with inebilizumab (HRs: 0.213-0.503; interaction tests: all p > 0.05, indicating no effect of baseline covariates on outcome). Mean EDSS scores improved with longer-term treatment. Inebilizumab-treated participants were more likely to have a favorable mRS outcome at the end of the RCP (OR: 1.663; 95% CI: 1.195-2.385; p = 0.0023). CONCLUSIONS: Disability outcomes were more favorable with inebilizumab vs placebo in participants with NMOSD