Search

The objective is to demonstrate feasibility of separating magnetic sources in quantitative susceptibility mapping (QSM) by incorporating magnitude decay ratesmml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"mml:semanticsmml:msubsupmml:miR/mml:mimml:mn2/mml:mnmml:mo∗/mml:mo/mml:msubsupmml:annotation$R_2^{\rm{*}}$/mml:annotation/mml:semantics/mml:mathin gradient echo (GRE) MRI.Magnetic susceptibility source separation was developed usingmml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"mml:semanticsmml:msubsupmml:miR/mml:mimml:mn2/mml:mnmml:mo∗/mml:mo/mml:msubsupmml:annotation$R_2^{\rm{*}}$/mml:annotation/mml:semantics/mml:mathand compared with a prior method usingmml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"mml:semanticsmml:mrowmml:msubsupmml:miR/mml:mimml:mn2/mml:mnmml:mo'/mml:mo/mml:msubsupmml:mo=/mml:momml:msubsupmml:miR/mml:mimml:mn2/mml:mnmml:mo∗/mml:mo/mml:msubsupmml:mo-/mml:momml:msubmml:miR/mml:mimml:mn2/mml:mn/mml:msub/mml:mrowmml:annotation${R^{\prime}_2} = R_2^* - {R_2}$/mml:annotation/mml:semantics/mml:maththat required an additional sequence to measure the transverse relaxation rate Rsub2/sub. Both susceptibility separation methods were compared in multiple sclerosis (MS) patients (n = 17). Susceptibility values of negative sources estimated withmml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"mml:semanticsmml:msubsupmml:miR/mml:mimml:mn2/mml:mnmml:mo∗/mml:mo/mml:msubsupmml:annotation$R_2^{\rm{*}}$/mml:annotation/mml:semantics/mml:math-based source separation in a set of enhancing MS lesions (n = 44) were correlated against longitudinal myelin water fraction (MWF) changes.In in vivo data, linear regression of the estimatedmml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"mml:semanticsmml:msupmml:miχ/mml:mimml:mo+/mml:mo/mml:msupmml:annotation${\chi}^{+}$/mml:annotation/mml:semantics/mml:mathandmml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"mml:semanticsmml:msupmml:miχ/mml:mimml:mo-/mml:mo/mml:msupmml:annotation${\chi}^{-}$/mml:annotation/mml:semantics/mml:mathsusceptibility values between themml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"mml:semanticsmml:msubsupmml:miR/mml:mimml:mn2/mml:mnmml:mo∗/mml:mo/mml:msubsupmml:annotation$R_2^*$/mml:annotation/mml:semantics/mml:math- and themml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"mml:semanticsmml:msubsupmml:miR/mml:mimml:mn2/mml:mnmml:mo'/mml:mo/mml:msubsupmml:annotation${R^{\prime}_2}$/mml:annotation/mml:semantics/mml:math-based separation methods performed across 182 segmented lesions revealed correlation coefficient r = .96 and slope close .99. Correlation analysis in enhancing lesions revealed a significant positive association between themml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"mml:semanticsmml:msupmml:miχ/mml:mimml:mo-/mml:mo/mml:msupmml:annotation${\chi}^{-}$/mml:annotation/mml:semantics/mml:mathincrease at 1-year post-onset relative to 0 year and the MWF increase at 1 year relative to 0 year (β = -0.144, 95% confidence interval: [-0.199, -0.1], p = .0008) and good agreement betweenmml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"mml:semanticsmml:msubsupmml:miR/mml:mimml:mn2/mml:mnmml:mo'/mml:mo/mml:msubsupmml:annotation${R^{\prime}_2}$/mml:annotation/mml:semantics/mml:mathandmml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"mml:semanticsmml:msubsupmml:miR/mml:mimml:mn2/mml:mnmml:mo∗/mml:mo/mml:msubsupmml:annotation$R_2^*$/mml:annotation/mml:semantics/mml:mathmethods (r = .79, slope = .95).Separation of magnetic sources based solely on GRE complex data is feasible by combining magnitude decay rate modeling and phase-based QSM andmml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"mml:semanticsmml:msupmml:miχ/mml:mimml:mo-/mml:mo/mml:msupmml:annotation${\chi}^{-}$/mml:annotation/mml:semantics/mml:mathchange may serve as a biomarker for myelin recovery or damage in acute MS lesions.

The fact that a large proportion of insurance policyholders make no claims during a one-year period highlights the importance of zero-inflated count models when analyzing the frequency of insurance claims. There is a vast literature focused on the univariate case of zero-inflated count models, while work in the area of multivariate models is considerably less advanced. Given that insurance companies write multiple lines of insurance business, where the claim counts on these lines of business are often correlated, there is a strong incentive to analyze multivariate claim count models. Motivated by the idea of Liu and Tian (Computational Statistics and Data Analysis, 83, 200–222; 2015), we develop a multivariate zero-inflated hurdle model to describe multivariate count data with extra zeros. This generalization offers more flexibility in modeling the behavior of individual claim counts while also incorporating a correlation structure between claim counts for different lines of insurance business. We develop an application of the expectation–maximization (EM) algorithm to enable the statistical inference necessary to estimate the parameters associated with our model. Our model is then applied to an automobile insurance portfolio from a major insurance company in Spain. We demonstrate that the model performance for the multivariate zero-inflated hurdle model is superior when compared to several alternatives.

The finance industry�banks, insurers, fund managers and the rest�play a pivotal role in our economy. In particular they have a profound influence on the behaviour of our corporations and the individuals that work for them. To provide its services, the finance industry has considerable powers in corporate governance. So, if we are to reconceptualise the purpose of the corporation, this article argues that we also need to do the same for the role of the finance industry. The article begins with a review of the limited literature around �the purpose of the finance industry�. It then poses the question about what that purpose should be, whether the industry�s current practices are adequately fulfilling that purpose, and how this affects corporate behaviour. The article argues that if the finance industry itself were more purposeful, that would help to promote purposeful companies. Finally, the article makes a series of recommendations on how stakeholders can create a model of change within the industry to support purposeful outcomes.

Retirement village contracts are complex, blending together financial options on real estate, life annuities and life insurance. We analyse the structure of the cash flows involved in a retirement village contract and distil the cost components into an equivalent monthly comparison rent. In general, we observe lower monthly rents when the maintenance fees and deferred management fees are lower, when higher rates of capital gain are evident, and, importantly, when retirees reside in the retirement village for a longer period. Our analysis provides a framework to meaningfully compare the relative merits of the finances incorporated into retirement village contracts.

Background Inflammation in chronic active lesions occurs behind a closed blood–brain barrier and cannot be detected with MRI. Activated microglia are highly enriched for iron and can be visualized with quantitative susceptibility mapping (QSM), an MRI technique used to delineate iron. Objective To characterize the histopathological correlates of different QSM hyperintensity patterns in MS lesions. Methods MS brain slabs were imaged with MRI and QSM, and processed for histology. Immunolabeled cells were quantified in the lesion rim, center, and adjacent normal‐appearing white matter (NAWM). Iron+ myeloid cell densities at the rims were correlated with susceptibilities. Human‐induced pluripotent stem cell (iPSC)‐derived microglia were used to determine the effect of iron on the production of reactive oxygen species (ROS) and pro‐inflammatory cytokines. Results QSM hyperintensity at the lesion perimeter correlated with activated iron+ myeloid cells in the rim and NAWM. Lesions with high punctate or homogenous QSM signal contained no or minimally activated iron− myeloid cells. In vitro, iron accumulation was highest in M1‐polarized human iPSC‐derived microglia, but it did not enhance ROS or cytokine production. Conclusion A high QSM signal outlining the lesion rim but not punctate signal in the center is a biomarker for chronic inflammation in white matter lesions.

For the past four decades, multiple sclerosis (MS) has been a focus for clinical trial development and execution. Advances in translational neuroimmunology have led to the development of effective disease-modifying therapies (DMTs) that greatly benefit patients with MS and mitigate their burden of disease. These achievements also stem from continued progress made in the definition and discovery of sensitive disease diagnostic criteria, objective disability assessment scales, precise imaging techniques, and disease-specific biomarkers. As a result, our knowledge of MS pathophysiology is more mature; the established clinical practice for the diagnosis and management of MS could serve as a roadmap to guide the development of more disease-specific interventions. In this article we briefly review the main achievements in the evolution of clinical trials for MS, and discuss opportunities for improvements.

In this paper, we explore the use of an extensive list of Archimedean copulas in general and life insurance modelling. We consider not only the usual choices like the Clayton, Gumbel–Hougaard, and Frank copulas but also several others which have not drawn much attention in previous applications. First, we apply different copula functions to two general insurance data sets, co-modelling losses and allocated loss adjustment expenses, and also losses to building and contents. Second, we adopt these copulas for modelling the mortality trends of two neighbouring countries and calculate the market price of a mortality bond. Our results clearly show that the diversity of Archimedean copula structures gives much flexibility for modelling different kinds of data sets and that the copula and tail dependence assumption can have a significant impact on pricing and valuation. Moreover, we conduct a large simulation exercise to investigate further the caveats in copula selection. Finally, we examine a number of other estimation methods which have not been tested in previous insurance applications.

The classification of multiple sclerosis (MS) has been established by Lublin in 1996 and revised in 2013. The revision includes clinically isolated syndrome, relapsing-remitting, primary progressive and secondary progressive MS, and has added activity (i.e., formation of white matter lesions or clinical relapses) as a qualifier. This allows for the distinction between active and nonactive progression, which has been shown to be of clinical importance. We propose that a logical extension of this classification is the incorporation of additional key pathological processes, such as chronic perilesional inflammation, neuroaxonal degeneration, and remyelination. This will distinguish MS phenotypes that may present as clinically identical but are driven by different combinations of pathological processes. A more precise description of MS phenotypes will improve prognostication and personalized care as well as clinical trial design. Thus, our proposal provides an expanded framework for conceptualizing MS and for guiding development of biomarkers for monitoring activity along the main pathological axes in MS. Published version Study Funding: Supported in part by NIH grants R01 NS102267 and R01 NS112907 (D.P.) and a career transition fellowship from the Consortium of Multiple Sclerosis Centers and the National Multiple Sclerosis Society (M.R.L.). The Article Processing Charge was funded by the authors.

BACKGROUND AND OBJECTIVES: To determine the effects of dimethyl fumarate (DMF) and glatiramer acetate on iron content in chronic active lesions in patients with multiple sclerosis (MS) and in human microglia in vitro. METHODS: This was a retrospective observational study of 34 patients with relapsing-remitting MS and clinically isolated syndrome treated with DMF or glatiramer acetate. Patients had lesions with hyperintense rims on quantitative susceptibility mapping, were treated with DMF or glatiramer acetate (GA), and had a minimum of 2 on-treatment scans. Changes in susceptibility in rim lesions were compared among treatment groups in a linear mixed effects model. In a separate in vitro study, induced pluripotent stem cell-derived human microglia were treated with DMF or GA, and treatment-induced changes in iron content and activation state of microglia were compared. RESULTS: Rim lesions in patients treated with DMF had on average a 2.77-unit reduction in susceptibility per year over rim lesions in patients treated with GA (bootstrapped 95% CI -5.87 to -0.01), holding all other variables constant. Moreover, DMF but not GA reduced inflammatory activation and concomitantly iron content in human microglia in vitro. DISCUSSION: Together, our data indicate that DMF-induced reduction of susceptibility in MS lesions is associated with a decreased activation state in microglial cells. We have demonstrated that a specific disease modifying therapy, DMF, decreases glial activity in chronic active lesions. Susceptibility changes in rim lesions provide an in vivo biomarker for the effect of DMF on microglial activity. CLASSIFICATION OF EVIDENCE: This study provided Class III evidence that DMF is superior to GA in the presence of iron as a marker of inflammation as measured by MRI quantitative susceptibility mapping. Published version Study Funding: This study was supported by NINDS/NIH RO1 NS102267, an investigator-initiated Clinical Trial/US-BGT-13-10516 (Biogen), BI-2007-36725 (NMSS), and by grant number UL1 TR 002384 from the National Center for Advancing Translational Sciences (NCATS) of the NIH. The Article Processing Charge was funded by the authors.

Using the ordinal pattern concept in permutation entropy, we propose a model sufficiency test to study a given model's point prediction accuracy. Compared to some classical model sufficiency tests, such as the Broock et al.'s (1996) test, our proposal does not require a sufficient model to eliminate all structures exhibited in the estimated residuals. When the innovations in the investigated data's underlying dynamics show a certain structure, such as higher-moment serial dependence, the Broock et al.'s (1996) test can lead to erroneous conclusions about the sufficiency of point predictors. Due to the structured innovations, inconsistency between the model sufficiency tests and prediction accuracy criteria can occur. Our proposal fills in this incoherence between model and prediction evaluation approaches and remains valid when the underlying process has non-white additive innovation., 32 pages, 5 figures, to appear at the Journal of Forecasting

The emergence of single cell technologies provides the opportunity to characterize complex immune/central nervous system cell assemblies in multiple sclerosis (MS) and to study their cell population structures, network activation and dynamics at unprecedented depths. In this review, we summarize the current knowledge of astrocyte subpopulations in MS tissue and discuss the challenges associated with resolving astrocyte heterogeneity with single-nucleus RNA-sequencing (snRNA-seq). We further discuss multiplexed imaging techniques as tools for defining population clusters within a spatial context. Finally, we will provide an outlook on how these technologies may aid in answering unresolved questions in MS, such as the glial phenotypes that drive MS progression and/or neuropathological differences between different clinical MS subtypes.

The pathophysiology of progressive multiple sclerosis remains elusive, significantly limiting available disease-modifying therapies. Proton MRS (1 H-MRS) enables in vivo measurement of small molecules implicated in multiple sclerosis, but its application to key metabolites glutamate, γ-aminobutyric acid (GABA), and glutathione has been sparse. We employed, at 7 T, a previously validated 1 H-MRS protocol to measure glutamate, GABA, and glutathione, as well as glutamine, N-acetyl aspartate, choline, and myoinositol, in the frontal cortex of individuals with relapsing-remitting (N = 26) or progressive (N = 21) multiple sclerosis or healthy control adults (N = 25) in a cross-sectional analysis. Only individuals with progressive multiple sclerosis demonstrated reduced glutamate (F2,65 = 3.424, p = 0.04; 12.40 ± 0.62 mM versus control 13.17 ± 0.95 mM, p = 0.03) but not glutamine (F2,65 = 0.352, p = 0.7; 4.71 ± 0.35 mM versus control 4.84 ± 0.42 mM), reduced GABA (F2,65 = 3.89, p = 0.03; 1.29 ± 0.23 mM versus control 1.47 ± 0.25 mM, p = 0.05), and possibly reduced glutathione (F2,65 = 0.352, p = 0.056; 2.23 ± 0.46 mM versus control 2.51 ± 0.48 mM, p

The most accurate estimation of transition probabilities for a multi-state model of health status requires longitudinal data. However, for many countries such data are usually not available. Instead, population level mortality incidence and disability prevalence rates are often all that can be accessed. In this paper, for a three-state no-recovery model (with states healthy, disabled, dead), using simple mathematical derivations, we propose a framework to estimate the age- and gender-specific boundaries within which each of the transition probabilities should fall. We then provide two methods for estimating unique transition probabilities—a least squares procedure and a method based on the ‘extra mortality’ factor proposed by Rickayzen and Walsh (Br Actuarial J 8(2):341–393, 2002, https://doi.org/10.1017/s1357321700003755 ). We also show the acceptable range for the ‘extra mortality’ factor given the mortality and disability data. Furthermore, we provide a critique of the method proposed by Van der Gaag et al. (Demogr Res 32:75, 2015), as their estimates can fall outside the acceptable boundaries. Finally, we estimate life and health expectancies, as well as premium rates for a life care annuity and a disability annuity using our derived transition probabilities.

The idea of nuclear-weapon-free zones is as old as nuclear weapons. The nuclear club reaction to the recent emergence of Nuclear-free zones has been mixed and in some cases hostile, as in the French bombing of the Rainbow Warrior. Nuclear-free zones may in the ultimate analysis be successful precisely because they are a concrete and tangible way for people to show their aspirations for peace. Finland proclaimed itself nuclear-free as early as 1947. In 1961, at the United Nations, Sweden tabled the Unden Plan calling for, inter alia, the establishment of nuclear-free zones. The civil use of nuclear energy is considered a relatively easy route to an eventual acquisition. Adam Rapacki from Poland, a country often overrun by bellicose neighbours, produced a plan for an ‘atomic free’ Central Europe involving the removal of nuclear weapons from East and West Germany, Poland and Czechoslovakia.

β cells may participate and contribute to their own demise during Type 1 diabetes (T1D). We identified a novel role of Tet2 in regulating immune killing of β cells. Tet2 is induced in murine and human β cells with inflammation but its expression is reduced in surviving β cells. Tet2-KO mice that receive WT bone marrow transplants develop insulitis but not diabetes and islet infiltrates do not eliminate β cells even though immune cells from the mice can transfer diabetes to NOD/scid recipients. Tet2-KO β cells show reduced expression of inflammatory genes, associated with closed transcription factor binding sites. Tet2-KO recipients are protected from transfer of disease by diabetogenic immune cells. We conclude that Tet2 regulates pathologic interactions between β cells and immune cells and controls intrinsic protective pathways. Modulating TET2 may enable survival of β cells or their replacements in the setting of pathologic immune cells.

Students in many jurisdictions can study Mathematics at different levels in their final 2 years of secondary education. The levels of Mathematics range from standard (not involving calculus), through basic calculus, to more advanced treatments of calculus and algebra. In this context, some students can elect to study Mathematics at a level below their ability. We consider the situation in New South Wales (NSW), Australia, where most Year 12 students who apply to university are awarded a percentile ranking, namely the Australian Tertiary Admission Rank (ATAR). The ATAR reflects students’ results in the final 2 years of secondary education and frequently determines what they can study at university. As the study of Mathematics is often segregated by gender, it is of interest to explore how boys’ and girls’ choices about level of Mathematics study affect their ATAR. We analyze administrative data for 46,000 senior secondary students in NSW who completed their Year 12 in 2011 and the Longitudinal Survey of Australian Youth (LSAY) for the same cohort. Using two-level regressions that control for relevant student and school characteristics, we find that, for a given level of performance in Mathematics in Year 10, girls see greater improvement than boys in Year 12 for all levels of Mathematics except the most advanced course. Girls who study basic Mathematics achieve ATAR increments as high as girls in some advanced courses. We discuss how awareness of these results may influence students’ decisions on what level of Mathematics to study in Years 11 and 12.

Background The pathological processes in the first weeks of multiple sclerosis (MS) lesion formation include myelin digestion that breaks chemical bonds in myelin lipid layers. This can increase lesion magnetic susceptibility, which is a potentially useful biomarker in MS patient management, but not yet investigated. Purpose To understand and quantify the effects of myelin digestion on quantitative susceptibility mapping (QSM) of MS lesions. Study type Histological and QSM analyses on in vitro models of myelin breakdown and MS lesion formation in vivo. Population/specimens Acutely demyelinating white matter lesions from MS autopsy tissue were stained with the lipid dye oil red O. Myelin basic protein (MBP), a major membrane protein of myelin, was digested with trypsin. Purified human myelin was denatured with sodium dodecyl sulfate (SDS). QSM was performed on phantoms containing digestion products and untreated controls. In vivo QSM was performed on five MS patients with newly enhancing lesions, and then repeated within 2 weeks. Field strength/sequence 3D T 2 * -weighted spoiled multiecho gradient echo scans performed at 3T. Assessment Region of interest analyses were performed by a biochemist and a neuroradiologist to determine susceptibility changes on in vitro and in vivo QSM images. Statistical tests Not applicable. Results MBP degradation by trypsin increased the QSM measurement by an average of 112 ± 37 ppb, in excellent agreement with a theoretical estimate of 111 ppb. Degradation of human myelin by SDS increased the QSM measurement by 23 ppb. As MS lesions changed from gadolinium enhancing to nonenhancing over an average of 15.8 ± 3.7 days, their susceptibility increased by an average of 7.5 ± 6.3 ppb. Data conclusion Myelin digestion in the early stages of MS lesion formation contributes to an increase in tissue susceptibility, detectable by QSM, as a lesion evolves from gadolinium enhancing to nonenhancing. Level of evidence 1 Technical Efficacy: Stage 3 J. Magn. Reson. Imaging 2018;47:1281-1287.

We consider a modification to the Poisson common factor model and utilise a generalised linear model (GLM) framework that incorporates a smoothing process and a set of linear constraints. We extend the standard GLM model structure to adopt Lagrange methods and P-splines such that smoothing and constraints are applied simultaneously as the parameters are estimated. Our results on Australian, Canadian and Norwegian data show that this modification results in an improvement in mortality projection in terms of producing more accurate forecasts in the out-of-sample testing. At the same time, projected male-to-female ratio of death rates at each age converges to a constant and the residuals of the models are sufficiently random, indicating that the use of smoothing does not adversely affect the fit of the model. Further, the irregular patterns in the estimates of the age-specific parameters are moderated as a result of smoothing and this model can be used to produce more regular projected life tables for pricing purposes.