Athena in 2013 and Beyond

TRISA, the U.S. Army TRADOC G2 Intelligence Support Activity, received Athena 1 in 2009. They first used Athena 3 to support studies in 2011. This paper describes Athena 4, which they started using in October 2012. A final section discusses issues that are being considered for incorporation into Athena 5 and later. Athena's objective is to help skilled intelligence analysts anticipate the likely consequences of complex courses of action that use our country's entire power base, not just our military capabilities, for operations in troubled regions of the world. Measures of effectiveness emphasize who is in control and the effects of our actions on the attitudes and well-being of civilians. The planning horizon encompasses not weeks or months, but years. Athena is a scalable, laptop-based simulation with weekly resolution. Up to three months of simulated time can pass between game turns that require user interaction. Athena's geographic scope is nominally a country, but can be a region within a county. Geographic resolution is "neighborhoods", which are defined by the user and may be actual neighborhoods, provinces, or anything in between. Models encompass phenomena whose effects are expected to be relevant over a medium-term planning horizon-three months to three years. The scope and intrinsic complexity of the problem dictate a spiral development process. That is, the model is used during development and lessons learned are used to improve the model. Even more important is that while every version must consider the "big picture" at some level of detail, development priority is given to those issues that are most relevant to currently anticipated studies. For example, models of the delivery and effectiveness of information operations messaging were among the additions in Athena 4

Athena

The Athena simulation software supports an analyst from DoD or other federal agency in making stability and reconstruction projections for operational analyses in areas like Iraq or Afghanistan. It encompasses the use of all elements of national power: diplomatic, information, military, and economic (DIME), and anticipates their effects on political, military, economic, social, information, and infrastructure (PMESII) variables in real-world battle space environments. Athena is a stand-alone model that provides analysts with insights into the effectiveness of complex operations by anticipating second-, third-, and higher-order effects. For example, the first-order effect of executing a curfew may be to reduce insurgent activity, but it may also reduce consumer spending and keep workers home as second-order effects. Reduced spending and reduced labor may reduce the gross domestic product (GDP) as a third-order effect. Damage to the economy will have further consequences. The Athena approach has also been considered for application in studies related to climate change and the smart grid. It can be applied to any project where the impacts on the population and their perceptions are important, and where population perception is important to the success of the project

Pediatric multiple sclerosis: update on diagnostic criteria, imaging, histopathology and treatment choices

Pediatric multiple sclerosis (MS) represents less than 5% of the MS population, but patients with pediatric-onset disease reach permanent disability at a younger age than adult onset patients. Accurate diagnosis at presentation and optimal long-term treatment is vital to mitigate ongoing neuroinflammation and irreversible neurodegeneration. However, it may be difficult to early differentiate pediatric MS from acute disseminated encephalomyelitis (ADEM) and neuromyelitis optica spectrum disorders (NMOSD) as they often have atypical presentation that differs from that of adult-onset MS. The purpose of this review is to summarize the updated views on diagnostic criteria, imaging, histopathology and treatment choices

Natalizumab treatment shows low cumulative probabilities of confirmed disability worsening to EDSS milestones in the long-term setting.

Abstract Background Though the Expanded Disability Status Scale (EDSS) is commonly used to assess disability level in relapsing-remitting multiple sclerosis (RRMS), the criteria defining disability progression are used for patients with a wide range of baseline levels of disability in relatively short-term trials. As a result, not all EDSS changes carry the same weight in terms of future disability, and treatment benefits such as decreased risk of reaching particular disability milestones may not be reliably captured. The objectives of this analysis are to assess the probability of confirmed disability worsening to specific EDSS milestones (i.e., EDSS scores ≥3.0, ≥4.0, or ≥6.0) at 288 weeks in the Tysabri Observational Program (TOP) and to examine the impact of relapses occurring during natalizumab therapy in TOP patients who had received natalizumab for ≥24 months. Methods TOP is an ongoing, open-label, observational, prospective study of patients with RRMS in clinical practice. Enrolled patients were naive to natalizumab at treatment initiation or had received ≤3 doses at the time of enrollment. Intravenous natalizumab (300 mg) infusions were given every 4 weeks, and the EDSS was assessed at baseline and every 24 weeks during treatment. Results Of the 4161 patients enrolled in TOP with follow-up of at least 24 months, 3253 patients with available baseline EDSS scores had continued natalizumab treatment and 908 had discontinued (5.4% due to a reported lack of efficacy and 16.4% for other reasons) at the 24-month time point. Those who discontinued due to lack of efficacy had higher baseline EDSS scores (median 4.5 vs. 3.5), higher on-treatment relapse rates (0.82 vs. 0.23), and higher cumulative probabilities of EDSS worsening (16% vs. 9%) at 24 months than those completing therapy. Among 24-month completers, after approximately 5.5 years of natalizumab treatment, the cumulative probabilities of confirmed EDSS worsening by 1.0 and 2.0 points were 18.5% and 7.9%, respectively (24-week confirmation), and 13.5% and 5.3%, respectively (48-week confirmation). The risks of 24- and 48-week confirmed EDSS worsening were significantly higher in patients with on-treatment relapses than in those without relapses. An analysis of time to specific EDSS milestones showed that the probabilities of 48-week confirmed transition from EDSS scores of 0.0–2.0 to ≥3.0, 2.0–3.0 to ≥4.0, and 4.0–5.0 to ≥6.0 at week 288 in TOP were 11.1%, 11.8%, and 9.5%, respectively, with lower probabilities observed among patients without on-treatment relapses (8.1%, 8.4%, and 5.7%, respectively). Conclusions In TOP patients with a median (range) baseline EDSS score of 3.5 (0.0–9.5) who completed 24 months of natalizumab treatment, the rate of 48-week confirmed disability worsening events was below 15%; after approximately 5.5 years of natalizumab treatment, 86.5% and 94.7% of patients did not have EDSS score increases of ≥1.0 or ≥2.0 points, respectively. The presence of relapses was associated with higher rates of overall disability worsening. These results were confirmed by assessing transition to EDSS milestones. Lower rates of overall 48-week confirmed EDSS worsening and of transitioning from EDSS score 4.0–5.0 to ≥6.0 in the absence of relapses suggest that relapses remain a significant driver of disability worsening and that on-treatment relapses in natalizumab-treated patients are of prognostic importance

Author Correction: A systems biology approach uncovers cell-specific gene regulatory effects of genetic associations in multiple sclerosis.

An amendment to this paper has been published and can be accessed via a link at the top of the paper

Athena in 2011

No abstract availabl

Measurements of forces produced by the mitotic spindle using optical tweezers

We used a trapping laser to stop chromosome movements in Mesostoma and crane-fly spermatocytes and inward movements of spindle poles after laser cuts across Potorous tridactylus (rat kangaroo) kidney (PtK2) cell half-spindles. Mesostoma spermatocyte kinetochores execute oscillatory movements to and away from the spindle pole for 1–2 h, so we could trap kinetochores multiple times in the same spermatocyte. The trap was focused to a single point using a 63× oil immersion objective. Trap powers of 15–23 mW caused kinetochore oscillations to stop or decrease. Kinetochore oscillations resumed when the trap was released. In crane-fly spermatocytes trap powers of 56–85 mW stopped or slowed poleward chromosome movement. In PtK2 cells 8-mW trap power stopped the spindle pole from moving toward the equator. Forces in the traps were calculated using the equation F = Q′P/c, where P is the laser power and c is the speed of light. Use of appropriate Q′ coefficients gave the forces for stopping pole movements as 0.3–2.3 pN and for stopping chromosome movements in Mesostoma spermatocytes and crane-fly spermatocytes as 2–3 and 6–10 pN, respectively. These forces are close to theoretical calculations of forces causing chromosome movements but 100 times lower than the 700 pN measured previously in grasshopper spermatocytes

Author Correction: A systems biology approach uncovers cell-specific gene regulatory effects of genetic associations in multiple sclerosis (Nature Communications, (2019), 10, 1, (2236), 10.1038/s41467-019-09773-y)

The original version of this Article contained an error in the spelling of the author Nikolaos A. Patsopoulos, which was incorrectly given as Niklaos A. Patsopoulos, and author Efthimios Dardiotis, which was incorrectly given as Dardiotis Efthimios. This has now been corrected in both the PDF and HTML versions of the Article

Metabolic reprogramming of natural killer cells in obesity limits antitumor responses.

Up to 49% of certain types of cancer are attributed to obesity, and potential mechanisms include overproduction of hormones, adipokines, and insulin. Cytotoxic immune cells, including natural killer (NK) cells and CD8+ T cells, are important in tumor surveillance, but little is known about the impact of obesity on immunosurveillance. Here, we show that obesity induces robust peroxisome proliferator-activated receptor (PPAR)-driven lipid accumulation in NK cells, causing complete 'paralysis' of their cellular metabolism and trafficking. Fatty acid administration, and PPARα and PPARδ (PPARα/δ) agonists, mimicked obesity and inhibited mechanistic target of rapamycin (mTOR)-mediated glycolysis. This prevented trafficking of the cytotoxic machinery to the NK cell-tumor synapse. Inhibiting PPARα/δ or blocking the transport of lipids into mitochondria reversed NK cell metabolic paralysis and restored cytotoxicity. In vivo, NK cells had blunted antitumor responses and failed to reduce tumor growth in obesity. Our results demonstrate that the lipotoxic obese environment impairs immunosurveillance and suggest that metabolic reprogramming of NK cells may improve cancer outcomes in obesity