Multiple sclerosis (MS) is characterized by focal inflammatory activity in the central nervous system and a diffuse, compartmentalized inflammation that is the primary driver of neuroaxonal damage and worsening disability. It is now recognized that higher-efficacy disease-modifying therapies (HE-DMT) are often required to treat the complex neuropathological changes that occur during the disease course and improve long-term outcomes. The optimal use of HE-DMTs in practice was addressed by a Canadian panel of 12 MS experts who used the Delphi method to develop 27 consensus recommendations. The HE-DMTs that were considered were the monoclonal antibodies (natalizumab, ocrelizumab, ofatumumab) and the immune reconstitution agents (alemtuzumab, cladribine). The issues addressed included defining aggressive/severe disease, patient selection of the most appropriate candidates for HE-DMTs, baseline investigations and efficacy monitoring, defining suboptimal treatment response, use of serum neurofilament-light chain in evaluating treatment response, safety monitoring, aging and immunosenescence and when to consider de-escalating or discontinuing treatment. The goals of the consensus recommendations were to provide guidelines to clinicians on their use of HE-DMTs in practice and to improve long-term outcomes in persons with MS.

Objectives: Patients with dementia (PWD) benefit from interdisciplinary care. Depression is a well-known risk factor for the progression of neurocognitive impairment and dementia; other psychiatric disorders (i.e. anxiety, post-traumatic stress disorder, bipolar disorder, psychotic disorders) also may confer an increased risk for dementia. PWD may also present with behaviours and psychological symptoms that overlap with psychiatric disorders. Our aim is threefold: (1) Review the current literature on managing psychiatric comorbidities in PWD. (2) Present an illustrative case series of PWD with psychiatric comorbidities. (3) Introduce a model of care on our Behavioural Neurology Unit (BNU) for treating PWD with psychiatric comorbidities.

Methods: Our BNU is a 20-bed quaternary inpatient unit for difficult-to-treat behaviours related to dementia. Psychiatric consultation is readily available to clinicians and often times for PWD with psychiatric comorbidities. We review best practices in managing these patients. We present a case series of PWD with psychiatric comorbidities predating their diagnosis of dementia who have significant behavioural and psychological symptoms and have failed other settings.

Results: Current guidelines for PWD do not discuss the management of psychiatric and neurologic comorbidities in detail. Among 26 cases, we highlight the judicious use of anticonvulsants, lithium, clozapine, and nabilone in PWD. We also demonstrate the importance of interdisciplinary care with primary care, neurology, psychiatry, and allied health support.

Conclusions: Dementia care is challenging and requires individualized attention and interdisciplinary collaboration. These challenges are augmented when dealing with psychiatric comorbidities. We advocate for increased attention and creative solutions to address these complex cases.

The synchronization hierarchy of finite permutation groups consists of classes of groups lying between $2$-transitive groups and primitive groups. This includes the class of spreading groups, which are defined in terms of sets and multisets of permuted points, and which are known to be primitive of almost simple, affine or diagonal type. In this paper, we prove that in fact no spreading group of diagonal type exists. As part of our proof, we show that all non-abelian finite simple groups, other than six sporadic groups, have a transitive action in which a proper normal subgroup of a point stabilizer is supplemented by all corresponding two-point stabilizers.

We are grateful to Kjølv Egeland, Thomas Fraise, and Hebatalla Taha for their commentary on the four editions of The Evolution of Nuclear Strategy. In addition to their critique of the book, their review was intended to offer ‘a looking glass into the broader field of nuclear security studies’. Our reply to their review therefore touches both upon their critique, as well as the more general theme of writing about the history of nuclear strategy. Although we disagree with many of their criticisms, and in some instances believe our work was misrepresented, the reviewers have nevertheless made points that deserve serious consideration by ourselves as well as other scholars working in the field. In this reply, we not only defend our work, but also use this as an opportunity to discuss how to approach the past of nuclear strategy, which in turn can allow us to better appreciate the present and future. In the first half of our reply we discuss the reviewers’ more general criticisms of our approach. In the second half we deal with some specific criticisms.

OBJECTIVES/GOALS: This study aimed to investigate the mechanistic effects of fish oil (âμ-3 fatty acids) or evening primrose oil (âμ-6 fatty acids) supplementation on platelet reactivity in postmenopausal women. METHODS/STUDY POPULATION: Postmenopausal women were recruited from the Ann Arbor community and the University of Michigan Medicine Center. All subjects were recruited under study protocols approved by the University of Michigan IRB between November 2015 and March 2017. We conducted a randomized, double-blind, two-period crossover trial, consisting of a 60-day supplementation period followed by a 14-day washout period in between and at the end of the study. Subjects were treated daily in random order with 2g of fish oil supplement and 2g of evening primrose oil. Blood was drawn at baseline, post-supplementation, and after washout. The effects of fatty acid supplementation on platelet aggregation, dense granule secretion and activation of basal integrin âºIIbÎ23 were assessed following supplementation and washout period. RESULTS/ANTICIPATED RESULTS: The study started with 90 postmenopausal women. A total of 78 subjects completed the study, with 12 subjects dropping out due to non-compliance and medical reasons. Supplementation with fish oil attenuated the thrombin receptor PAR4-induced platelet aggregation, whereas primrose oil supplementation attenuated aggregation mediated by PAR4 or collagen. Supplementation with âμ-3 or âμ-6 fatty acids decreased platelet dense granule secretion and attenuated basal levels of integrin âºIIbÎ23 activation. Post-washout following supplementation with primrose oil, the thrombin receptor PAR1-induced platelet aggregation was similarly attenuated. For either treatment, the observed effects post supplementation on dense granule secretion and basal integrin activation were sustained after the washout. DISCUSSION/SIGNIFICANCE: Postmenopausal women are at increased risk for a cardiovascular event due to platelet hyperactivity. This study indicates that supplementation with âμ-3 and âμ-6 fatty acids may offer significant protection for postmenopausal women against cardiovascular diseases and occlusive thrombotic events by reducing platelet reactivity.

Although covert warfare does not readily lend itself to scientific inquiry, new technologies are increasingly providing scholars with tools that enable such research. In this note, we examine the effects of drone strikes on patterns of communication in Yemen using big data and anomaly detection methods. The combination of these analytic tools allows us to not only quantify some of the effects of drone strikes, but also to compare them to other shocks. We find that on average drone strikes leave a footprint in their aftermath, spurring significant but localized spikes in communication. This suggests that drone strikes are not a purely surgical intervention, but rather have a disruptive impact on the local population.

The Canadian Multiple Sclerosis Working Group has updated its treatment optimization recommendations (TORs) on the optimal use of disease-modifying therapies for patients with all forms of multiple sclerosis (MS). Recommendations provide guidance on initiating effective treatment early in the course of disease, monitoring response to therapy, and modifying or switching therapies to optimize disease control. The current TORs also address the treatment of pediatric MS, progressive MS and the identification and treatment of aggressive forms of the disease. Newer therapies offer improved efficacy, but also have potential safety concerns that must be adequately balanced, notably when treatment sequencing is considered. There are added discussions regarding the management of pregnancy, the future potential of biomarkers and consideration as to when it may be prudent to stop therapy. These TORs are meant to be used and interpreted by all neurologists with a special interest in the management of MS.

Because individuals develop dementia as a manifestation of neurodegenerative or neurovascular disorder, there is a need to develop reliable approaches to their identification. We are undertaking an observational study (Ontario Neurodegenerative Disease Research Initiative [ONDRI]) that includes genomics, neuroimaging, and assessments of cognition as well as language, speech, gait, retinal imaging, and eye tracking. Disorders studied include Alzheimer’s disease, amyotrophic lateral sclerosis, frontotemporal dementia, Parkinson’s disease, and vascular cognitive impairment. Data from ONDRI will be collected into the Brain-CODE database to facilitate correlative analysis. ONDRI will provide a repertoire of endophenotyped individuals that will be a unique, publicly available resource.

We give two applications of the 2-Engel relation, classically studied in finite and Lie groups, to the 4-dimensional (4D) topological surgery conjecture. The A–B slice problem, a reformulation of the surgery conjecture for free groups, is shown to admit a homotopy solution. We also exhibit a new collection of universal surgery problems, defined using ramifications of homotopically trivial links. More generally we show how $n$ -Engel relations arise from higher-order double points of surfaces in 4-space.

Background : The Canadian GILENYA® Go ProgramTM provides education and support to people with relapsing-remitting multiple sclerosis during fingolimod treatment. Methods : Data were collected and analyzed from the time of the first individual enrolled in March 2011 to March 31, 2014. Individuals were excluded if they withdrew from the program prior to receiving the first dose, or had not completed the first dose observation (FDO) at the time of data cut-off. Reports of adverse effects were validated with a database of adverse events reported to Novartis Pharmaceuticals Canada Inc. Results : A total of 2,399 individuals had completed FDO at the end of the three-year observation period. Mean age was 41.2 years; 75.2% were female. The most recent prior therapies reported were interferon-β agents (50.2%), glatiramer acetate (31.1%), natalizumab (14.2%), no prior therapy (3.3%), and other agent (1.1%). Reasons for switching to fingolimod were lack of efficacy (34.9%), side effects (34.6%), and dissatisfaction with injections/infusion (30.4%). Continuation rates with fingolimod at 12, 24 and 30 months were 80.7%, 76.6% and 76.0%, respectively. The discontinuation rate due to reported lack of efficacy during the three-year period was 1.3%. There was 94.4% adherence to the scheduled ophthalmic examination. Conclusions: The GILENYA® Go ProgramTM captures data for virtually all fingolimod-treated patients in Canada, enabling the evaluation of fingolimod use in routine practice. Ongoing patient support and reminders to take the medication, in conjunction with physicians’ and/or patients’ perception of the efficacy and tolerability of fingolimod, resulted in a high rate of continuation during longer-term therapy.

The Canadian Multiple Sclerosis Working Group (CMSWG) developed practical recommendations in 2004 to assist clinicians in optimizing the use of disease-modifying therapies (DMT) in patients with relapsing multiple sclerosis. The CMSWG convened to review how disease activity is assessed, propose a more current approach for assessing suboptimal response, and to suggest a scheme for switching or escalating treatment. Practical criteria for relapses, Expanded Disability Status Scale (EDSS) progression and MRI were developed to classify the clinical level of concern as Low, Medium and High. The group concluded that a change in treatment may be considered in any RRMS patient if there is a high level of concern in any one domain (relapses, progression or MRI), a medium level of concern in any two domains, or a low level of concern in all three domains. These recommendations for assessing treatment response should assist clinicians in making more rational choices in their management of relapsing MS patients.

Bedouin Arabs in southern Israel are a traditionally semi-nomadic population undergoing the nutrition transition in a context of urbanisation. The effect of these changes on the nutritional status of pregnant women is unknown. The Dietary Exposures and Pregnancy Outcomes in a Society In Transition (DEPOSIT) study evaluated the adequacy of pregnant Bedouin women's usual dietary intake and their nutritional status. Dietary intake was assessed in a cross-sectional study design using repeat 24 h recall (24HR) questionnaires. The National Cancer Institute method was used to estimate the usual intake of selected nutrients. The Estimated Average Requirement (EAR) was used to evaluate nutrient intake adequacy. Measured weight and height data were used to calculate the participants' BMI. A total of 1109 24HR were obtained from 683 participants, of which 8 % contained no animal-source protein and an additional 43 % contained no haeme-Fe. Animal-source protein intake reached less than half of the EAR for most participants (71 %). Over 90 % had inadequate intakes of Ca, Fe, animal-source Zn, vitamin A and folate. The probability of consuming haeme-source Fe was higher among urban than rural participants (OR 1·68, 95 % CI 1·17, 2·41), and among those with employed v. unemployed husbands (OR 1·81, 95 % CI 1·27, 2·58). Only 14 % reported consuming home-produced animal products. According to pre-pregnancy BMI, 42 % were overweight or obese. The DEPOSIT study findings suggest that Bedouin Arab women are in need of interventions that address the co-existing problems of inadequate nutrient intakes and increased risk of obesity.

In an incompressible perfectly conducting fluid the Navier-Stokes equations become\[\frac{\partial v}{\partial t} + v.\nabla v = -\nabla {\rm P} - \nu\Delta v + j\times {\boldmath H},\]where j = curl H, div H = 0, div v = 0, and dH/dt = curl (v × H). The last equation follows from the Maxwell equation dH/dt = − curl E and the assumption of perfect conduction — that the electric field in the frame of the fluid vanishes, E′ = E + v × H = 0. In geometric terms, it says that the system evolves so that the time derivative of H is equal to minus its spatial Lie derivative:\[\frac{{\rm d}{\boldmath H}}{{\rm d}t} = -L_{\rm v}{\boldmath H}.\]

Thus H is equivariant with respect to the evolution (or ‘frozen in the fluid’) as long as the evolution follows these equations. Since the first equation tends to dissipate magnetic energy E = ∫ ∥H∥2 the question naturally rises whether the topology of H determines lower bounds on E. We treat this question in the general context of a divergence-free vector field H on a closed Riemannian 3-manifold M. We obtain a result bounding E from below but make no assertion on the existence of extremals. Arnol'd (1986) has defined a quadratic form for any ‘null-homologous’ H

We have obtained HST-NICMOS observations of five of M31's most metal-rich globular clusters: G1, G170, G174, G177 & G280. For the two clusters farthest from the nucleus, G1 and G280, we statistically subtract the field population and estimate metallicities using K-(J - K) color-magnitude diagrams (CMDs). Based on the slopes of their infrared giant branches we estimate [Fe/H] = −1.22 ± 0.43 dex for G1 and −0.15 ± 0.37 dex for G280. We combine our infrared observations of G1 with two epochs of optical HST-WFPC2 F-band data and identify at least one LPV based on color and variability. The location of G1's giant branch in the K, (V - K) CMD is very similar to that of M107, indicating a somewhat higher metallicity than our purely infrared CMD; [Fe/H]= −0.9 ± 0.2 dex.