Multimodality Data Integration in Epilepsy

An important goal of software development in the medical field is the design of methods which are able to integrate information obtained from various imaging and nonimaging modalities into a cohesive framework in order to understand the results of qualitatively different measurements in a larger context. Moreover, it is essential to assess the various features of the data quantitatively so that relationships in anatomical and functional domains between complementing modalities can be expressed mathematically. This paper presents a clinically feasible software environment for the quantitative assessment of the relationship among biochemical functions as assessed by PET imaging and electrophysiological parameters derived from intracranial EEG. Based on the developed software tools, quantitative results obtained from individual modalities can be merged into a data structure allowing a consistent framework for advanced data mining techniques and 3D visualization. Moreover, an effort was made to derive quantitative variables (such as the spatial proximity index, SPI) characterizing the relationship between complementing modalities on a more generic level as a prerequisite for efficient data mining strategies. We describe the implementation of this software environment in twelve children (mean age 5.2 ± 4.3 years) with medically intractable partial epilepsy who underwent both high-resolution structural MR and functional PET imaging. Our experiments demonstrate that our approach will lead to a better understanding of the mechanisms of epileptogenesis and might ultimately have an impact on treatment. Moreover, our software environment holds promise to be useful in many other neurological disorders, where integration of multimodality data is crucial for a better understanding of the underlying disease mechanisms

Lack of correlation between the levels of soluble cytotoxic T-lymphocyte associated antigen-4 (CTLA-4) and the CT-60 genotypes

BACKGROUND: Cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) plays a critical role in downregulation of antigen-activated immune response and polymorphisms at the CTLA-4 gene have been shown to be associated with several autoimmune diseases including type-1 diabetes (T1D). The etiological mutation was mapped to the CT60-A/G single nucleotide polymorphism (SNP) that is believed to control the processing and production of soluble CTLA-4 (sCTLA-4). METHODS: We therefore determined sCTLA-4 protein levels in the sera from 82 T1D patients and 19 autoantibody positive (AbP) subjects and 117 autoantibody negative (AbN) controls using ELISA. The CT-60 SNP was genotyped for these samples by using PCR and restriction enzyme digestion of a 268 bp DNA segment containing the SNP. Genotyping of CT-60 SNP was confirmed by dye terminating sequencing reaction. RESULTS: Higher levels of sCTLA-4 were observed in T1D (2.24 ng/ml) and AbP (mean = 2.17 ng/ml) subjects compared to AbN controls (mean = 1.69 ng/ml) with the differences between these subjects becoming significant with age (p = 0.02). However, we found no correlation between sCTLA-4 levels and the CTLA-4 CT-60 SNP genotypes. CONCLUSION: Consistent with the higher serum sCTLA-4 levels observed in other autoimmune diseases, our results suggest that sCTLA-4 may be a risk factor for T1D. However, our results do not support the conclusion that the CT-60 SNP controls the expression of sCTLA-4

Hepcidin is elevated in mice injected with Mycoplasma arthritidis

Mycoplasma arthritidis causes arthritis in specific mouse strains. M. arthritidis mitogen (MAM), a superantigen produced by M. arthritidis, activates T cells by forming a complex between the major histocompatability complex II on antigen presenting cells and the T cell receptor on CD4+ T lymphocytes. The MAM superantigen is also known to interact with Toll-like receptors (TLR) 2 and 4. Hepcidin, an iron regulator protein, is upregulated by TLR4, IL-6, and IL-1. In this study, we evaluated serum hepcidin, transferrin saturation, ferritin, IL-6, IL-1, and hemoglobin levels in M. arthritidis injected C3H/HeJ (TLR2+/+, TLR4-/-) mice and C3H/HeSnJ (TLR2+/+, TLR4+/+) mice over a 21 day period. C3H/HeJ mice have a defective TLR4 and an inability to produce IL-6. We also measured arthritis severity in these mice and the amount of hepcidin transcripts produced by the liver and spleen. C3H/HeJ mice developed a more severe arthritis than that of C3H/HeSnJ mice. Both mice had an increase in serum hepcidin within three days after infection. Hepcidin levels were greater in C3H/HeJ mice despite a nonfunctioning TLR4 and low serum levels of IL-6. Splenic hepcidin production in C3H/HeJ mice was delayed compared to C3H/HeSnJ mice. Unlike C3H/HeSnJ mice, C3H/HeJ mice did not develop a significant rise in serum IL-6 levels but did develop a significant increase in IL-1β during the first ten days after injection. Both mice had an increase in serum ferritin but a decrease in serum transferrin saturation. In conclusion, serum hepcidin regulation in C3H/HeJ mice does not appear to be solely dependent upon TLR4 or IL-6

The Pediatric Asthma Risk Score: A New Gold Standard for Asthma Prediction

Rationale: Early prediction of asthma is critical to identify potential primary prevention strategies. The Pediatric Asthma Risk Score (PARS) is a continuous score to predict early-life asthma but was developed and validated in relatively homogenous populations. We compared PARS directly to the Asthma Predictive Index (API) and validated in 10 cohorts with varying race, ethnicity, sex, cohort type, missing data and birth decades, and perform a meta-analysis across all 10 cohorts. Methods: We utilized data from 5674 children participating in the Children’s Respiratory and Environmental Workgroup. We applied both PARS and the API in each cohort, as well as harmonized across all cohorts, and directly compared the ability of each tool to predict asthma development at ages 5-10. Results: The PARS area under the curve (AUC) was significantly higher than the AUC of the API in 9 cohorts (p-value range 0.01 - \u3c0.001). The PARS AUC did not differ by cohort type (high risk or general population), decade of enrollment, race, sex, ethnicity, missing PARS factors or polysensitization definition (skin prick test vs. specific IgE). The weights of the 6 PARS factors in the meta-analysis were very similar to the original weights, validating the original PARS scoring. Conclusions: This multi-cohort study makes the PARS the most validated model of asthma prediction in children to date, not only with respect to the number of cohorts used but also with regards to capturing the diversity of asthma in the United States. Future studies may consider PARS the new gold standard in pediatric asthma risk prediction

Ligelizumab for Chronic Spontaneous Urticaria

Background: In the majority of patients with chronic spontaneous urticaria, most currently available therapies do not result in complete symptom control. Ligelizumab is a next-generation high-affinity humanized monoclonal anti-IgE antibody. Data are limited regarding the dose–response relationship of ligelizumab and the efficacy and safety of ligelizumab as compared with omalizumab and placebo in patients who have moderate-to-severe chronic spontaneous urticaria that is inadequately controlled with H1-antihistamines at approved or increased doses, alone or in combination with H2-antihistamines or leukotriene-receptor antagonists. Methods: In a phase 2b dose-finding trial, we randomly assigned patients to receive ligelizumab at a dose of 24 mg, 72 mg, or 240 mg, omalizumab at a dose of 300 mg, or placebo, administered subcutaneously every 4 weeks for a period of 20 weeks, or a single 120-mg dose of ligelizumab. Disease symptoms of hives, itch, and angioedema were monitored by means of weekly activity scores. The main objective was to determine a dose–response relationship for the complete control of hives (indicated by a weekly hives-severity score of 0, on a scale from 0 to 21, with higher scores indicating greater severity); the primary end point of this response was assessed at week 12. Complete symptom control was indicated by a weekly urticaria activity score of 0 (on a scale from 0 to 42, with higher scores indicating greater severity). Safety was analyzed throughout the trial. Results: A total of 382 patients underwent randomization. At week 12, a total of 30%, 51%, and 42% of the patients treated with 24 mg, 72 mg, and 240 mg, respectively, of ligelizumab had complete control of hives, as compared with 26% of the patients in the omalizumab group and no patients in the placebo group. A dose–response relationship was established. At week 12, a total of 30%, 44%, and 40% of the patients treated with 24 mg, 72 mg, and 240 mg, respectively, of ligelizumab had complete control of symptoms, as compared with 26% of the patients in the omalizumab group and no patients in the placebo group. In this small and short trial, no safety concerns regarding ligelizumab or omalizumab emerged. Conclusions: A higher percentage of patients had complete control of symptoms of chronic spontaneous urticaria with ligelizumab therapy of 72 mg or 240 mg than with omalizumab or placebo. (Funded by Novartis Pharma; ClinicalTrials.gov number, NCT02477332. opens in new tab.

Genome-wide association analyses of physical activity and sedentary behavior provide insights into underlying mechanisms and roles in disease prevention

Although physical activity and sedentary behavior are moderately heritable, little is known about the mechanisms that influence these traits. Combining data for up to 703,901 individuals from 51 studies in a multi-ancestry meta-analysis of genome-wide association studies yields 99 loci that associate with self-reported moderate-to-vigorous intensity physical activity during leisure time (MVPA), leisure screen time (LST) and/or sedentary behavior at work. Loci associated with LST are enriched for genes whose expression in skeletal muscle is altered by resistance training. A missense variant in ACTN3 makes the alpha-actinin-3 filaments more flexible, resulting in lower maximal force in isolated type IIA muscle fibers, and possibly protection from exercise-induced muscle damage. Finally, Mendelian randomization analyses show that beneficial effects of lower LST and higher MVPA on several risk factors and diseases are mediated or confounded by body mass index (BMI). Our results provide insights into physical activity mechanisms and its role in disease prevention. Multi-ancestry meta-analyses of genome-wide association studies for self-reported physical activity during leisure time, leisure screen time, sedentary commuting and sedentary behavior at work identify 99 loci associated with at least one of these traits

The Large High Altitude Air Shower Observatory (LHAASO) Science White Paper

The Large High Altitude Air Shower Observatory (LHAASO) project is a new generation multi-component instrument, to be built at 4410 meters of altitude in the Sichuan province of China, with the aim to study with unprecedented sensitivity the spec trum, the composition and the anisotropy of cosmic rays in the energy range between 10$^{12}$ and 10$^{18}$ eV, as well as to act simultaneously as a wide aperture (one stereoradiant), continuously-operated gamma ray telescope in the energy range between 10$^{11}$ and $10^{15}$ eV. The experiment will be able of continuously surveying the TeV sky for steady and transient sources from 100 GeV to 1 PeV, t hus opening for the first time the 100-1000 TeV range to the direct observations of the high energy cosmic ray sources. In addition, the different observables (electronic, muonic and Cherenkov/fluorescence components) that will be measured in LHAASO will allow to investigate origin, acceleration and propagation of the radiation through a measurement of energy spec trum, elemental composition and anisotropy with unprecedented resolution. The remarkable sensitivity of LHAASO in cosmic rays physics and gamma astronomy would play a key-role in the comprehensive general program to explore the High Energy Universe. LHAASO will allow important studies of fundamental physics (such as indirect dark matter search, Lorentz invariance violation, quantum gravity) and solar and heliospheric physics. In this document we introduce the concept of LHAASO and the main science goals, providing an overview of the project.Comment: This document is a collaborative effort, 185 pages, 110 figure

Genome-Wide Association Study of White Blood Cell Count in 16,388 African Americans: the Continental Origins and Genetic Epidemiology Network (COGENT)

Total white blood cell (WBC) and neutrophil counts are lower among individuals of African descent due to the common African-derived “null” variant of the Duffy Antigen Receptor for Chemokines (DARC) gene. Additional common genetic polymorphisms were recently associated with total WBC and WBC sub-type levels in European and Japanese populations. No additional loci that account for WBC variability have been identified in African Americans. In order to address this, we performed a large genome-wide association study (GWAS) of total WBC and cell subtype counts in 16,388 African-American participants from 7 population-based cohorts available in the Continental Origins and Genetic Epidemiology Network. In addition to the DARC locus on chromosome 1q23, we identified two other regions (chromosomes 4q13 and 16q22) associated with WBC in African Americans (P<2.5×10−8). The lead SNP (rs9131) on chromosome 4q13 is located in the CXCL2 gene, which encodes a chemotactic cytokine for polymorphonuclear leukocytes. Independent evidence of the novel CXCL2 association with WBC was present in 3,551 Hispanic Americans, 14,767 Japanese, and 19,509 European Americans. The index SNP (rs12149261) on chromosome 16q22 associated with WBC count is located in a large inter-chromosomal segmental duplication encompassing part of the hydrocephalus inducing homolog (HYDIN) gene. We demonstrate that the chromosome 16q22 association finding is most likely due to a genotyping artifact as a consequence of sequence similarity between duplicated regions on chromosomes 16q22 and 1q21. Among the WBC loci recently identified in European or Japanese populations, replication was observed in our African-American meta-analysis for rs445 of CDK6 on chromosome 7q21 and rs4065321 of PSMD3-CSF3 region on chromosome 17q21. In summary, the CXCL2, CDK6, and PSMD3-CSF3 regions are associated with WBC count in African American and other populations. We also demonstrate that large inter-chromosomal duplications can result in false positive associations in GWAS