Gaussian Fluctuations of Eigenvalues in Wigner Random Matrices

We study the fluctuations of eigenvalues from a class of Wigner random matrices that generalize the Gaussian orthogonal ensemble. We begin by considering an $n \times n$ matrix from the Gaussian orthogonal ensemble (GOE) or Gaussian symplectic ensemble (GSE) and let $x_k$ denote eigenvalue number $k$. Under the condition that both $k$ and $n-k$ tend to infinity with $n$, we show that $x_k$ is normally distributed in the limit. We also consider the joint limit distribution of $m$ eigenvalues from the GOE or GSE with similar conditions on the indices. The result is an $m$-dimensional normal distribution. Using a recent universality result by Tao and Vu, we extend our results to a class of Wigner real symmetric matrices with non-Gaussian entries that have an exponentially decaying distribution and whose first four moments match the Gaussian moments.Comment: 21 pages, to appear, J. Stat. Phys. References and other corrections suggested by the referees have been incorporate

Comprehensive Evaluation of the 5XFAD Mouse Model for Preclinical Testing Applications: A MODEL-AD Study.

The ability to investigate therapeutic interventions in animal models of neurodegenerative diseases depends on extensive characterization of the model(s) being used. There are numerous models that have been generated to study Alzheimer\u27s disease (AD) and the underlying pathogenesis of the disease. While transgenic models have been instrumental in understanding AD mechanisms and risk factors, they are limited in the degree of characteristics displayed in comparison with AD in humans, and the full spectrum of AD effects has yet to be recapitulated in a single mouse model. The Model Organism Development and Evaluation for Late-Onset Alzheimer\u27s Disease (MODEL-AD) consortium was assembled by the National Institute on Aging (NIA) to develop more robust animal models of AD with increased relevance to human disease, standardize the characterization of AD mouse models, improve preclinical testing in animals, and establish clinically relevant AD biomarkers, among other aims toward enhancing the translational value of AD models in clinical drug design and treatment development. Here we have conducted a detailed characterization of the 5XFAD mouse, including transcriptomics, electroencephalogram

The Evidence Does Not Speak for Itself: The Role of Research Evidence in Shaping Policy Change for the Implementation of Publicly Funded Syringe Exchange Programs in Three US Cities

BACKGROUND: A breadth of literature exists that explores the utilization of research evidence in policy change processes. From this work, a number of studies suggest research evidence is applied to change processes by policy change stakeholders primarily through instrumental, conceptual, and/or symbolic applications, or is not used at all. Despite the expansiveness of research on policy change processes, a deficit exists in understanding the role of research evidence during change processes related to the implementation of structural interventions for HIV prevention among injection drug users (IDU). This study examined the role of research evidence in policy change processes for the implementation of publicly funded syringe exchange services in three US cities: Baltimore, MD, Philadelphia, PA, and Washington, DC. METHODS: In-depth qualitative interviews were conducted with key stakeholders (n=29) from each of the study cities. Stakeholders were asked about the historical, social, political, and scientific contexts in their city during the policy change process. Interviews were transcribed and analyzed for common themes pertaining to applications of research evidence. RESULTS: In Baltimore and Philadelphia, the typological approaches (instrumental and symbolic/conceptual, respectively) to the applications of research evidence used by harm reduction proponents contributed to the momentum for securing policy change for the implementation of syringe exchange services. Applications of research evidence were less successful in DC because policymakers had differing ideas about the implications of syringe exchange program implementation and because opponents of policy change used evidence incorrectly or not at all in policy change discussions. CONCLUSION: Typological applications of research evidence are useful for understanding policy change processes, but their efficacy falls short when sociopolitical factors complicate legislative processes. Advocates for harm reduction may benefit from understanding how to effectively integrate research evidence into policy change processes in ways that confront the myriad of factors that influence policy change

Multidrug-Resistant Tuberculosis Outbreak among US-bound Hmong Refugees, Thailand, 2005

Enhanced pre-immigration screening and program expansion decreased TB importation

Comprehensive Evaluation of the 5XFAD Mouse Model for Preclinical Testing Applications: A MODEL-AD Study

The ability to investigate therapeutic interventions in animal models of neurodegenerative diseases depends on extensive characterization of the model(s) being used. There are numerous models that have been generated to study Alzheimer’s disease (AD) and the underlying pathogenesis of the disease. While transgenic models have been instrumental in understanding AD mechanisms and risk factors, they are limited in the degree of characteristics displayed in comparison with AD in humans, and the full spectrum of AD effects has yet to be recapitulated in a single mouse model. The Model Organism Development and Evaluation for Late-Onset Alzheimer’s Disease (MODEL-AD) consortium was assembled by the National Institute on Aging (NIA) to develop more robust animal models of AD with increased relevance to human disease, standardize the characterization of AD mouse models, improve preclinical testing in animals, and establish clinically relevant AD biomarkers, among other aims toward enhancing the translational value of AD models in clinical drug design and treatment development. Here we have conducted a detailed characterization of the 5XFAD mouse, including transcriptomics, electroencephalogram, in vivo imaging, biochemical characterization, and behavioral assessments. The data from this study is publicly available through the AD Knowledge Portal

Efficacy and cost-effectiveness of an outcall program to reduce carer burden and depression among carers of cancer patients (PROTECT) : rationale and design of a randomized controlled trial

Published: 6 January 2014BACKGROUND: Carers provide extended and often unrecognized support to people with cancer. The aim of this study is to test the hypothesis that excessive carer burden is modifiable through a telephone outcall intervention that includes supportive care, information and referral to appropriate psycho-social services. Secondary aims include estimation of changes in psychological health and quality of life. The study will determine whether the intervention reduces unmet needs among patient dyads. A formal economic program will also be conducted. METHODS/DESIGN: This study is a single-blind, multi-centre, randomized controlled trial to determine the efficacy and cost-efficacy of a telephone outcall program among carers of newly diagnosed cancer patients. A total of 230 carer/patient dyads will be recruited into the study; following written consent, carers will be randomly allocated to either the outcall intervention program (n = 115) or to a minimal outcall / attention control service (n = 115). Carer assessments will occur at baseline, at one and six months post-intervention. The primary outcome is change in carer burden; the secondary outcomes are change in carer depression, quality of life, health literacy and unmet needs. The trial patients will be assessed at baseline and one month post-intervention to determine depression levels and unmet needs. The economic analysis will include perspectives of both the health care sector and broader society and comprise a cost-consequences analysis where all outcomes will be compared to costs. DISCUSSION: This study will contribute to our understanding on the potential impact of a telephone outcall program on carer burden and provide new evidence on an approach for improving the wellbeing of carers.Patricia M Livingston, Richard H Osborne, Mari Botti, Cathy Mihalopoulos, Sean McGuigan, Leila Heckel, Kate Gunn, Jacquie Chirgwin, David M Ashley and Melinda William

Identification of unique neoantigen qualities in long-term survivors of pancreatic cancer

Pancreatic ductal adenocarcinoma is a lethal cancer with fewer than 7% of patients surviving past 5 years. T-cell immunity has been linked to the exceptional outcome of the few long-term survivors1,2, yet the relevant antigens remain unknown. Here we use genetic, immunohistochemical and transcriptional immunoprofiling, computational biophysics, and functional assays to identify T-cell antigens in long-term survivors of pancreatic cancer. Using whole-exome sequencing and in silico neoantigen prediction, we found that tumours with both the highest neoantigen number and the most abundant CD8+ T-cell infiltrates, but neither alone, stratified patients with the longest survival. Investigating the specific neoantigen qualities promoting T-cell activation in long-term survivors, we discovered that these individuals were enriched in neoantigen qualities defined by a fitness model, and neoantigens in the tumour antigen MUC16 (also known as CA125). A neoantigen quality fitness model conferring greater immunogenicity to neoantigens with differential presentation and homology to infectious disease-derived peptides identified long-term survivors in two independent datasets, whereas a neoantigen quantity model ascribing greater immunogenicity to increasing neoantigen number alone did not. We detected intratumoural and lasting circulating T-cell reactivity to both high-quality and MUC16 neoantigens in long-term survivors of pancreatic cancer, including clones with specificity to both high-quality neoantigens and predicted cross-reactive microbial epitopes, consistent with neoantigen molecular mimicry. Notably, we observed selective loss of high-quality and MUC16 neoantigenic clones on metastatic progression, suggesting neoantigen immunoediting. Our results identify neoantigens with unique qualities as T-cell targets in pancreatic ductal adenocarcinoma. More broadly, we identify neoantigen quality as a biomarker for immunogenic tumours that may guide the application of immunotherapies