Humanized Rag1−/−γc−/− Mice Support Multilineage Hematopoiesis and Are Susceptible to HIV-1 Infection via Systemic and Vaginal Routes

Several new immunodeficient mouse models for human cell engraftment have recently been introduced that include the Rag2−/−γc−/−, NOD/SCID, NOD/SCIDγc−/− and NOD/SCIDβ2m−/− strains. Transplantation of these mice with CD34+ human hematopoietic stem cells leads to prolonged engraftment, multilineage hematopoiesis and the capacity to generate human immune responses against a variety of antigens. However, the various mouse strains used and different methods of engrafting human cells are beginning to illustrate strain specific variations in engraftment levels, duration and longevity of mouse life span. In these proof-of-concept studies we evaluated the Balb/c-Rag1−/−γ−/− strain for engraftment by human fetal liver derived CD34+ hematopoietic cells using the same protocol found to be effective for Balb/c-Rag2−/−γc−/− mice. We demonstrate that these mice can be efficiently engrafted and show multilineage human hematopoiesis with human cells populating different lymphoid organs. Generation of human cells continues beyond a year and production of human immunoglobulins is noted. Infection with HIV-1 leads to chronic viremia with a resultant CD4 T cell loss. To mimic the predominant sexual viral transmission, we challenged humanized Rag1−/−γc−/− mice with HIV-1 via vaginal route which also resulted in chronic viremia and helper T cell loss. Thus these mice can be further exploited for studying human pathogens that infect the human hematopoietic system in an in vivo setting

The utility of the new generation of humanized mice to study HIV-1 infection: transmission, prevention, pathogenesis, and treatment

Substantial improvements have been made in recent years in the ability to engraft human cells and tissues into immunodeficient mice. The use of human hematopoietic stem cells (HSCs) leads to multi-lineage human hematopoiesis accompanied by production of a variety of human immune cell types. Population of murine primary and secondary lymphoid organs with human cells occurs, and long-term engraftment has been achieved. Engrafted cells are capable of producing human innate and adaptive immune responses, making these models the most physiologically relevant humanized animal models to date. New models have been successfully infected by a variety of strains of Human Immunodeficiency Virus Type 1 (HIV-1), accompanied by virus replication in lymphoid and non-lymphoid organs, including the gut-associated lymphoid tissue, the male and female reproductive tracts, and the brain. Multiple forms of virus-induced pathogenesis are present, and human T cell and antibody responses to HIV-1 are detected. These humanized mice are susceptible to a high rate of rectal and vaginal transmission of HIV-1 across an intact epithelium, indicating the potential to study vaccines and microbicides. Antiviral drugs, siRNAs, and hematopoietic stem cell gene therapy strategies have all been shown to be effective at reducing viral load and preventing or reversing helper T cell loss in humanized mice, indicating that they will serve as an important preclinical model to study new therapeutic modalities. HIV-1 has also been shown to evolve in response to selective pressures in humanized mice, thus showing that the model will be useful to study and/or predict viral evolution in response to drug or immune pressures. The purpose of this review is to summarize the findings reported to date on all new humanized mouse models (those transplanted with human HSCs) in regards to HIV-1 sexual transmission, pathogenesis, anti-HIV-1 immune responses, viral evolution, pre- and post-exposure prophylaxis, and gene therapeutic strategies

Reconstruction and identification of τ lepton decays to hadrons and ντ at CMS

This paper describes the algorithms used by the CMS experiment to reconstruct and identify tau -> hadrons + nu(tau) decays during Run 1 of the LHC. The performance of the algorithms is studied in proton-proton collisions recorded at a centre-of-mass energy of 8 TeV, corresponding to an integrated luminosity of 19.7 fb(-1). The algorithms achieve an identification efficiency of 50-60%, with misidentification rates for quark and gluon jets, electrons, and muons between per mille and per cent levels

Reconstruction and identification of tau lepton decays to hadrons and tau neutrino at CMS

This paper describes the algorithms used by the CMS experiment to reconstruct and identify tau to hadrons + tau neutrino decays during Run 1 of the LHC. The performance of the algorithms is studied in proton-proton collisions recorded at a centre-of-mass energy of 8 TeV, corresponding to an integrated luminosity of 19.7 inverse femtobarns. The algorithms achieve an identification efficiency of 50-60%, with misidentification rates for quark and gluon jets, electrons, and muons between per mille and per cent levels.Comment: Replaced with published version. Added journal referenc

Improved detection of delirium, implementation and validation of the CAM-ICU in elderly Emergency Department patients

Objective To evaluate the effect of routine use of the Confusion Assessment Method for the Intensive Care Unit (CAM-ICU) on the diagnosis rate of delirium in elderly Emergency Department (ED) patients and the validity of the CAM-ICU in the ED setting. Methods This was a prospective observational study in a tertiary care academic ED. We compared the diagnosis rate of delirium before implementation of the CAM-ICU, without routine use of a screening tool, with the diagnosis rate after implementation of the CAM-ICU. All consecutive patients aged 70 years or older were enrolled. The diagnosis rate before implementation was based on chart review and after implementation on a positive CAM-ICU score. In a subsample, the presence of delirium was evaluated independently according to the Diagnostic and Statistical Manual of Mental Disorders, 4th ed., text revision (DSM-IV-TR) criteria to assess the validity of the CAM-ICU. Results The total study population included 968 patients: 490 before and 478 after implementation of the CAM-ICU. The two groups were not significantly different in patient characteristics. Before implementation of the CAM-ICU, delirium was diagnosed in 14 patients (3%) and after implementation in 48 patients (10%) (P Conclusion The diagnosis rate of delirium after implementation of the CAM-ICU was three-fold higher than before. The CAM-ICU is a reliable screening tool in the ED, with high sensitivity, specificity, and positive and negative predictive value. Copyright (c) 2017 Wolters Kluwer Health, Inc. All rights reserved