Cytomegaloviral determinants of CD8+ T cell programming and RhCMV/SIV vaccine efficacy

Simian immunodeficiency virus (SIV) insert-expressing, 68–1 Rhesus Cytomegalovirus (RhCMV/SIV) vectors elicit major histocompatibility complex (MHC)-E- and -II-restricted, SIV-specific CD8(+) T cell responses, but the basis of these unconventional responses and their contribution to demonstrated vaccine efficacy against SIV challenge in the rhesus monkeys (RMs) has not been characterized. We show that these unconventional responses resulted from a chance genetic rearrangement in 68–1 RhCMV that abrogated the function of eight distinct immunomodulatory gene products encoded in two RhCMV genomic regions (Rh157.5/Rh157.4 and Rh158–161), revealing three patterns of unconventional response inhibition. Differential repair of these genes with either RhCMV-derived or orthologous human CMV (HCMV)-derived sequences (UL128/UL130; UL146/UL147) leads to either of two distinct CD8(+) T cell response types – MHC-Ia-restricted-only, or a mix of MHC-II- and MHC-Ia-restricted CD8(+) T cells. Response magnitude and functional differentiation are similar to RhCMV 68–1, but neither alternative response type mediated protection against SIV challenge. These findings implicate MHC-E-restricted CD8(+) T cell responses as mediators of anti-SIV efficacy and indicate that translation of RhCMV/SIV vector efficacy to humans will likely require deletion of all genes that inhibit these responses from the HCMV/HIV vector

Dementia in Africa: Current evidence, knowledge gaps, and future directions

\ua9 2021 the Alzheimer\u27s Association. In tandem with the ever-increasing aging population in low and middle-income countries, the burden of dementia is rising on the African continent. Dementia prevalence varies from 2.3% to 20.0% and incidence rates are 13.3 per 1000 person-years with increasing mortality in parts of rapidly transforming Africa. Differences in nutrition, cardiovascular factors, comorbidities, infections, mortality, and detection likely contribute to lower incidence. Alzheimer\u27s disease, vascular dementia, and human immunodeficiency virus/acquired immunodeficiency syndrome–associated neurocognitive disorders are the most common dementia subtypes. Comprehensive longitudinal studies with robust methodology and regional coverage would provide more reliable information. The apolipoprotein E (APOE) ε4 allele is most studied but has shown differential effects within African ancestry compared to Caucasian. More candidate gene and genome-wide association studies are needed to relate to dementia phenotypes. Validated culture-sensitive cognitive tools not influenced by education and language differences are critically needed for implementation across multidisciplinary groupings such as the proposed African Dementia Consortium

Virtual Reality and 3D Imaging to Support Collaborative Decision Making for Adaptation of Long-Life Assets

European companies of today are involved in many stages of the product life cycle. There is a trend towards the view of their business as a complex industrial product-service system (IPSS). This trend shifts the business focus from a traditional product oriented one to a function oriented one. With the function in focus, the seller shares the responsibility of for example maintenance of the product with the buyer. As such IPSS has been praised for supporting sustainable practices. This shift in focus also promotes longevity of products and promotes life extending work on the products such as adaptation and upgrades. Staying competitive requires continuous improvement of manufacturing and services to make them more flexible and adaptive to external changes. The adaptation itself needs to be performed efficiently without disrupting ongoing operations and needs to result in an acceptable after state. Virtual planning models are a key technology to enable planning and design of the future operations in parallel with ongoing operations. This chapter presents an approach to combine digitalization and virtual reality (VR) technologies to create the next generation of virtual planning environments. Through incorporating digitalization techniques such as 3D imaging, the models will reach a new level of fidelity and realism which in turn makes them accessible to a broader group of users and stakeholders. Increased accessibility facilitates a collaborative decision making process that invites and includes cross functional teams. Through such involvement, a broader range of experts, their skills, operational and tacit knowledge can be leveraged towards better planning of the upgrade process. This promises to shorte

The Severity of Ischemia Determines and Predicts Malignant Brain Edema in Patients with Large Middle Cerebral Artery Infarction

In order to determine the impact of the severity of ischemia on malignant edema formation, we investigated various degrees of perfusional deficit by (11)C-flumazenil PET in patients with large middle cerebral artery (MCA) infarction.17 patients with large MCA stroke were included. Cerebral blood flow (CBF) was measured 15.9 ± 6.4 h after the ictus. Patients were divided into a malignant (n = 9) and a benign group (n = 8) as a function of their clinical courses and edema. Edema was measured as maximal midline shift on follow-up CTs. Total hypoperfusion volume was divided into different subvolumes according to the degree of CBF reduction.Subvolumes of severe ischemia relative to total ischemic area were significantly larger in the malignant group than in the benign group and were significantly correlated with edema formation. The highest correlation and best predictive values for edema formation with a sensitivity, specificity, and a positive and negative predictive value of 100% were found for subvolumes with severe ischemia. Correlation coefficients and prediction decreased for subvolumes with less severe perfusional deficit, pointing to the risk of misclassifying patients when relying on the volume of total perfusional deficit alone.Malignant MCA infarction seems to be determined more by the volume of severe perfusional deficit than that of total perfusional deficit. Assessment of severely ischemic areas allows prediction of malignant edema formation and might help to select candidates for hemicraniectomy

There is more to it than: the greater the infarction volume, the more probable is a malignant MCA infarction

© 2006 The American Heart Association, Inc