Models of Models: The Symbiotic Relationship between Models and Wargames

Military planning uses wargames to model the processes and decisions of an operation. As these operations become increasingly complex, the wargames similarly become more complex. Complex wargames are difficult to design and execute. As such, computer-based modeling and simulation can aid the wargame development, ensuring smooth execution. In particular, computer-based modeling and simulation can develop and validate the processes, determine initial conditions, evaluate the rules, and aid in validation. In turn, the wargame can provide useful data that can be fed into detailed models that can provide quantitative analysis to decision-makers

Results of an international Delphi consensus in epilepsy with myoclonic atonic seizures/ Doose syndrome

OBJECTIVE: To establish a standard framework for early phenotypic diagnosis, investigations, expected findings from investigations, evolution, effective therapies and prognosis in the syndrome of Epilepsy with myoclonic atonic seizures (EMAS) / Doose syndrome. METHODS: A core study group (CSG) interested in EMAS was convened. CSG then identified and nominated 15 experts in the field of EMAS. This expert panel (EP) from English speaking nations was invited to participate in anonymous questionnaires. A literature review was provided to them (supplement 1). Three rounds of questionnaires were sent to identify areas of consensus, strength of consensus and areas of contention. RESULTS: Strong consensus was obtained regarding the clinical phenotype of EMAS: myoclonic atonic seizure was identified among others as a mandatory seizure type with typical onset of afebrile seizures between one and six years. A new term "stormy phase" (SP) was designated to delineate a characteristic phenotypic evolution in EMAS patients associated with seizure worsening. Strong consensus regarding the existence and time of onset of the SP, mandatory investigations to be performed early and later in the clinical course of EMAS, first and second tier treatment and prognostic factors for poor outcome were identified. Areas of lack of consensus included some seizure types that are necessary to diagnose EMAS, interictal EEG findings that prognosticate the course of EMAS, overall duration of SP, time to complete remission, and best approach to treat drug resistant EMAS. SIGNIFICANCE: Expert consensus on core diagnostic criteria of EMAS necessary for natural history studies, phenotype-genotype correlations, and clinical trials including comparative studies was demonstrated. Areas of disagreements (especially prognostic features; treatment options) need further research

Persistence of virus-specific immune responses in the central nervous system of mice after West Nile virus infection

<p>Abstract</p> <p>Background</p> <p>West Nile virus (WNV) persists in humans and several animal models. We previously demonstrated that WNV persists in the central nervous system (CNS) of mice for up to 6 months post-inoculation. We hypothesized that the CNS immune response is ineffective in clearing the virus.</p> <p>Results</p> <p>Immunocompetent, adult mice were inoculated subcutaneously with WNV, and the CNS immune response was examined at 1, 2, 4, 8, 12 and 16 weeks post-inoculation (wpi). Characterization of lymphocyte phenotypes in the CNS revealed elevation of CD19⁺B cells for 4 wpi, CD138 plasma cells at 12 wpi, and CD4⁺and CD8⁺T cells for at least 12 wpi. T cells recruited to the brain were activated, and regulatory T cells (Tregs) were present for at least 12 wpi. WNV-specific antibody secreting cells were detected in the brain from 2 to 16 wpi, and virus-specific CD8⁺T cells directed against an immunodominant WNV epitope were detected in the brain from 1 to 16 wpi. Furthermore, these WNV-specific immune responses occurred in mice with and without acute clinical disease.</p> <p>Conclusions</p> <p>Virus-specific immune cells persist in the CNS of mice after WNV infection for up to 16 wpi.</p

Contribution of chronic diseases to the mild and severe disability burden in Belgium

Background: Population aging accompanied by an increased longevity with disability has raised international concern, especially due to its costs to the health care systems. Chronic diseases are the main causes of physical disability and their simultaneous occurrence in the population can impact the disablement process, resulting in different severity levels. In this study, the contribution of chronic diseases to both mild and severe disability burden in Belgium was investigated. Methods: Data on 21 chronic diseases and disability from 35,799 individuals aged 15years or older who participated in the 1997, 2001, 2004, or 2008 Belgian Health Interview Surveys were analysed. Mild and severe disability were defined based on questions related to six activities of daily living and/or mobility limitations. To attribute disability by severity level to selected chronic diseases, multiple additive hazard models were fitted to each disability outcome, separately for men and women. Results: A stable prevalence of mild (5%) and severe (2-3%) disability was observed for the Belgian population aged 15years or older between 1997 and 2008. Arthritis was the most important contributor in women with mild and severe disability. In men, low back pain and chronic respiratory diseases contributed most to the mild and severe disability burden, respectively. The contribution also differed by age: for mild disability, depression and chronic respiratory diseases were important contributors among young individuals, while heart attack had a large contribution for older individuals. For severe disability, neurological diseases and stroke presented a large contribution in young and elderly individuals, respectively. Conclusions: Our results indicate that the assessment of the contribution of chronic diseases on disability is more informative if different levels of disability are taken into consideration. The identification of diseases which are related to different levels of disability - mild and severe - can assist policymakers in the definition and prioritisation of strategies to tackle disability, involving prevention, rehabilitation programs, support services, and training for disabled individuals

The effect of smoking on the duration of life with and without disability, Belgium 1997-2011

Background: Smoking is the single most important health threat yet there is no consistency as to whether non-smokers experience a compression of years lived with disability compared to (ex-)smokers. The objectives of the manuscript are (1) to assess the effect of smoking on the average years lived without disability (Disability Free Life Expectancy (DFLE)) and with disability (Disability Life Expectancy (DLE)) and (2) to estimate the extent to which these effects are due to better survival or reduced disability in never smokers. Methods. Data on disability and mortality were provided by the Belgian Health Interview Survey 1997 and 2001 and a 10 years mortality follow-up of the survey participants. Disability was defined as difficulties in activities of daily living (ADL), in mobility, in continence or in sensory (vision, hearing) functions. Poisson and multinomial logistic regression models were fitted to estimate the probabilities of death and the prevalence of disability by age, gender and smoking status adjusted for socioeconomic position. The Sullivan method was used to estimate DFLE and DLE at age 30. The contribution of mortality and of disability to smoking related differences in DFLE and DLE was assessed using decomposition methods. Results: Compared to never smokers, ex-smokers have a shorter life expectancy (LE) and DFLE but the number of years lived with disability is somewhat larger. For both sexes, the higher disability prevalence is the main contributing factor to the difference in DFLE and DLE. Smokers have a shorter LE, DFLE and DLE compared to never smokers. Both higher mortality and higher disability prevalence contribute to the difference in DFLE, but mortality is more important among males. Although both male and female smokers experience higher disability prevalence, their higher mortality outweighs their disability disadvantage resulting in a shorter DLE. Conclusion: Smoking kills and shortens both life without and life with disability. Smoking related disability can however not be ignored, given its contribution to the excess years with disability especially in younger age groups

Systems Analysis Implicates WAVE2&nbsp;Complex in the Pathogenesis of&nbsp;Developmental Left-Sided Obstructive&nbsp;Heart Defects.

Genetic variants are the primary driver of congenital heart disease (CHD) pathogenesis. However, our ability to identify causative variants is limited. To identify causal CHD genes that are associated with specific molecular functions, the study used prior knowledge to filter de novo variants from 2,881 probands with sporadic severe CHD. This approach enabled the authors to identify an association between left ventricular outflow tract obstruction lesions and genes associated with the WAVE2 complex and regulation of small GTPase-mediated signal transduction. Using CRISPR zebrafish knockdowns, the study confirmed that WAVE2 complex proteins brk1, nckap1, and wasf2 and the regulators of small GTPase signaling cul3a and racgap1 are critical to cardiac development

Effects of ganaxolone on non-seizure outcomes in CDKL5 Deficiency Disorder: Double-blind placebo-controlled randomized trial.

CDKL5 deficiency disorder (CDD) is a rare developmental and epileptic encephalopathy. Ganaxolone, a neuroactive steroid, reduces the frequency of major motor seizures in children with CDD. This analysis explored the effect of ganaxolone on non-seizure outcomes. Children (2-19 years) with genetically confirmed CDD and&nbsp;≥&nbsp;16 major motor seizures per month were enrolled in a double-blind randomized placebo-controlled trial. Ganaxolone or placebo was administered three times daily for 17 weeks. Behaviour was measured with the Anxiety, Depression and Mood Scale (ADAMS), daytime sleepiness with the Child Health Sleep Questionnaire, and quality of life with the Quality of Life Inventory-Disability (QI-Disability) scale. Scores were compared using ANOVA, adjusted for age, sex, number of anti-seizure mediations, baseline 28-day major motor seizure frequency, baseline developmental skills, and behaviour, sleep or quality of life scores. 101 children with CDD (39 clinical sites, 8 countries) were randomized. Median (IQR) age was 6 (3-10) years, 79.2&nbsp;% were female, and 50 received ganaxolone. After 17 weeks of treatment, Manic/Hyperactive scores (mean difference 1.27, 95%CI -2.38,-0.16) and Compulsive Behaviour scores (mean difference 0.58, 95%CI -1.14,-0.01) were lower (improved) in the ganaxolone group compared with the placebo group. Daytime sleepiness scores were similar between groups. The total change in QOL score for children in the ganaxolone group was 2.6 points (95%CI -1.74,7.02) higher (improved) than in the placebo group but without statistical significance. Along with better seizure control, children who received ganaxolone had improved behavioural scores in select domains compared to placebo

PHIL photoinjector test line

LAL is now equiped with its own platform for photoinjectors tests and Research and Developement, named PHIL (PHotoInjectors at LAL). This facility has two main purposes: push the limits of the photoinjectors performances working on both the design and the associated technology and provide a low energy (MeV) short pulses (ps) electron beam for the interested users. Another very important goal of this machine will be to provide an opportunity to form accelerator physics students, working in a high technology environment. To achieve this goal a test line was realised equipped with an RF source, magnets and beam diagnostics. In this article we will desrcibe the PHIL beamline and its characteristics together with the description of the first two photoinjector realised in LAL and tested: the ALPHAX and the PHIN RF Guns