From progression to progress: The future of multiple sclerosis.

Significant advances have been made in the diagnosis and treatment of multiple sclerosis in recent years yet challenges remain. The current classification of MS phenotypes according to disease activity and progression, for example, does not adequately reflect the underlying pathophysiological mechanisms that may be acting in an individual with MS at different time points. Thus, there is a need for clinicians to transition to a management approach based on the underlying pathophysiological mechanisms that drive disability in MS. A Canadian expert panel convened in January 2023 to discuss priorities for clinical discovery and scientific exploration that would help advance the field. Five key areas of focus included: identifying a mechanism-based disease classification system; developing biomarkers (imaging, fluid, digital) to identify pathologic processes; implementing a data-driven approach to integrate genetic/environmental risk factors, clinical findings, imaging and biomarker data, and patient-reported outcomes to better characterize the many factors associated with disability progression; utilizing precision-based treatment strategies to target different disease processes; and potentially preventing disease through Epstein-Barr virus (EBV) vaccination, counselling about environmental risk factors (e.g. obesity, exercise, vitamin D/sun exposure, smoking) and other measures. Many of the tools needed to meet these needs are currently available. Further work is required to validate emerging biomarkers and tailor treatment strategies to the needs of individual patients. The hope is that a more complete view of the individual's pathobiology will enable clinicians to usher in an era of truly personalized medicine, in which more informed treatment decisions throughout the disease course achieve better long-term outcomes.

Oculomotor analysis to assess brain health: preliminary findings from a longitudinal study of multiple sclerosis using novel tablet-based eye-tracking software.

A growing body of evidence supports the link between eye movement anomalies and brain health. Indeed, the oculomotor system is composed of a diverse network of cortical and subcortical structures and circuits that are susceptible to a variety of degenerative processes. Here we show preliminary findings from the baseline measurements of an ongoing longitudinal cohort study in MS participants, designed to determine if disease and cognitive status can be estimated and tracked with high accuracy based on eye movement parameters alone. Using a novel gaze-tracking technology that can reliably and accurately track eye movements with good precision without the need for infrared cameras, using only an iPad Pro embedded camera, we show in this cross-sectional study that several eye movement parameters significantly correlated with clinical outcome measures of interest. Eye movement parameters were extracted from fixation, pro-saccade, anti-saccade, and smooth pursuit visual tasks, whereas the clinical outcome measures were the scores of several disease assessment tools and standard cognitive tests such as the Expanded Disability Status Scale (EDSS), Brief International Cognitive Assessment for MS (BICAMS), the Multiple Sclerosis Functional Composite (MSFC) and the Symbol Digit Modalities Test (SDMT). Furthermore, partial least squares regression analyses show that a small set of oculomotor parameters can explain up to 84% of the variance of the clinical outcome measures. Taken together, these findings not only replicate previously known associations between eye movement parameters and clinical scores, this time using a novel mobile-based technology, but also the notion that interrogating the oculomotor system with a novel eye-tracking technology can inform us of disease severity, as well as the cognitive status of MS participants.

Cost-consequence analysis of ofatumumab for the treatment of relapsing-remitting multiple sclerosis in Canada.

Aim: The costs and consequences of initial and delayed ofatumumab treatment were evaluated in relapsing-remitting multiple sclerosis with active disease in Canada. Materials & methods: A Markov cohort model was used (10-year horizon, annual cycle length, 1.5% discounting). Scenario analyses examined ofatumumab as first-line treatment versus 3 and 5 years following switch from commonly used first-line therapies. Results: Ofatumumab resulted in improvements in clinical outcomes (relapses and disease progression) and productivity (employment and full-time work), and reduction of economic burden (administration, monitoring and non-drug costs) that were comparable to other high-efficacy therapies (ocrelizumab, cladribine and natalizumab). Switching to ofatumumab earlier in the disease course may improve these outcomes. Conclusion: Results highlight the value of a high-efficacy therapy such as ofatumumab as initial treatment (i.e., first-line) in newly diagnosed relapsing-remitting multiple sclerosis patients with active disease.

Toward a Realistic Model of Diffusion-Limited Aggregation: Rotation, Size-Dependent Diffusivities, and Settling.

In this Brownian dynamics simulation study on the formation of aggregates made of spherical particles, we build on the well-established diffusion-limited cluster aggregation (DLCA) model. We include rotational effects, allow diffusivities to be size-dependent as is physically relevant, and incorporate settling under gravity. We numerically characterize the growth dynamics of aggregates and find that their radius of gyration, R g, grows approximately as R g ∼ t 1.02 for classical DLCA but slows to an approximate growth rate of R g ∼ t 0.71 when diffusivity is size-dependent. We also analyze the fractal structure of the resulting aggregates and find that their fractal dimension, d, decreases from d ≈ 1.8 for classical DLCA to d ≈ 1.7 when size-dependent rotational diffusion is included. The addition of settling effects further reduces the fractal dimension observed to d ≈ 1.6 and appears to result in aggregates with a vertical extent marginally smaller than their horizontal extent.

Cost-Effectiveness Analysis of Ofatumumab for the Treatment of Relapsing-Remitting Multiple Sclerosis in Canada.

BACKGROUND: Ofatumumab is a high-efficacy disease-modifying therapy (DMT) approved for first-line treatment of relapsing-remitting multiple sclerosis (RRMS) in Canada. OBJECTIVE: The aim of this study was to evaluate the cost effectiveness of ofatumumab from a Canadian healthcare system perspective. METHODS: A Markov cohort model was run over 65 years using annual cycles, 1.5% annual discount rate, and 100% treatment discontinuation at 10 years. The British Columbia database informed natural history transition probabilities. Treatment efficacy for DMTs were sourced from a network meta-analysis. Clinical trial data were used to estimate probabilities for treatment-related adverse events. Health utilities and costs were obtained from Canadian sources (if available) and the literature. RESULTS: Among first-line indicated therapies for RRMS, ofatumumab was dominant (more effective, lower costs) over teriflunomide, interferons, dimethyl fumarate, and ocrelizumab. Compared with glatiramer acetate and best supportive care, ofatumumab resulted in incremental cost-effectiveness ratios (ICERs) of $24,189 Canadian dollars per quality-adjusted life-year (QALY) and $28,014/QALY, respectively. At a willingness-to-pay threshold of $50,000/QALY, ofatumumab had a 64.3% probability of being cost effective. Among second-line therapies (scenario analysis), ofatumumab dominated natalizumab and fingolimod and resulted in an ICER of $50,969 versus cladribine. CONCLUSIONS: Ofatumumab is cost effective against all comparators and dominant against all currently approved and reimbursed first-line DMTs for RRMS, except glatiramer acetate.

Modeling huddling penguins.

We present a systematic and quantitative model of huddling penguins. In this mathematical model, each individual penguin in the huddle seeks only to reduce its own heat loss. Consequently, penguins on the boundary of the huddle that are most exposed to the wind move downwind to more sheltered locations along the boundary. In contrast, penguins in the interior of the huddle neither have the space to move nor experience a significant heat loss, and they therefore remain stationary. Through these individual movements, the entire huddle experiences a robust cumulative effect that we identify, describe, and quantify. This mathematical model requires a calculation of the wind flowing around the huddle and of the resulting temperature distribution. Both of these must be recomputed each time an individual penguin moves since the huddle shape changes. Using our simulation results, we find that the key parameters affecting the huddle dynamics are the number of penguins in the huddle, the wind strength, and the amount of uncertainty in the movement of the penguins. Moreover, we find that the lone assumption of individual penguins minimizing their own heat loss results in all penguins having approximately equal access to the warmth of the huddle.

Simulation of mixing within drops due to surface tension variations.

We present the results of a numerical investigation of the mixing within drops caused by surface tension variations. With microfluidic applications in mind, we simulate drops surrounded by a fluid of equal density and viscosity. We investigate both stationary coalescing drops and steadily flowing drops, and study the influence of drop size ratio, viscous effects, and surface tension variations. We measure the mixing efficiency using the variance of the concentration distribution and find that surface tension variations may result in faster mixing than geometric effects.

Force balance at the transition from selective withdrawal to viscous entrainment.

We simulate the evolution of the steady-state interface in the selective withdrawal regime. Selective withdrawal ends when the upward pull exerted by the viscous flow in the withdrawing liquid layer overcomes the downward force due to surface tension. The lower-layer dynamics are unimportant. The dominant contribution to the surface-tension force comes from the large area where the interface is weakly deflected, instead of the small area where the surface is most distorted. A scaling estimate based on this idea yields results that agree quantitatively with both simulations and previous experiments.

Flow lines and mixing within drops in microcapillaries.

We present a theoretical and numerical investigation of streamlines and mixing within drops flowing in capillaries. We first study theoretically the limit case of purely viscous flow around a drop of negligible radius, and find that, owing to geometrical constraints, recirculating regions are always present at the front and back of such drops. Using two-dimensional simulations, we visualize streamlines for larger drops, showing that the extent of these recirculating torii increases with drop size and decreases with Reynolds number. We study the mixing within drops as they are subjected to time-dependent shear, thus modeling a sinusoidal channel, and find that while cross-stream mixing is efficient, streamwise mixing is hindered by the front and back recirculating regions.

Glatiramer acetate: evidence for a dual mechanism of action.

Glatiramer acetate is a disease-modifying drug approved for the treatment of relapsing-remitting multiple sclerosis. Since its discovery almost four decades ago, and in particular since the observation of its beneficial clinical effects in the late 1980s and early 1990s, numerous data have been generated and contribute pieces of a puzzle to help explain the mechanism of action of glatiramer acetate. Two major themes have emerged, namely (i) the induction of glatiramer acetate-reactive TH2 immunoregulatory cells, and (ii) the stimulation of neurotrophin secretion in the central nervous system that may promote neuronal repair.

On the horizon: possible neuroprotective role for glatiramer acetate.

Inflammation and neurodegeneration characterize the pathogenesis of multiple sclerosis (MS). Slow axonal degeneration, rather than acute inflammation, is considered the cause of chronic disability in MS. The signs of acute axonal damage and loss have been shown to occur early in the lesion development of patients with chronic MS and often correlate with demyelination and inflammation. While immune activity in the central nervous system has traditionally been considered to be a detrimental event in MS, recent studies have found that autoimmune T cells may play an important role in protecting neurons from the ongoing spreading damage. Neuroprotection in MS is a new and evolving concept, and many questions remain with regard to potential targets for therapeutic intervention. Preliminary studies, both in animals and in humans, have suggested that glatiramer acetate (GA) may confer neuroprotective activity in addition to bystander suppression. Additional research is needed to determine if these promising neuroprotective effects correlated with the long-term effect of GA in MS.