Cognitive and physical impairment and the risk of stroke - A prospective cohort study

The manifestation of cognitive and physical impairment in stroke patients before the acute event suggests accumulating subclinical vascular pathology in the brain. We investigated whether impairments in cognitive and physical functioning were associated with an increased stroke risk. Between 2002 and 2008, 8,519 stroke-free non-demented participants from the population-based Rotterdam Study underwent cognition and physical assessments including Mini-Mental State Examination, 15-word learning test, Stroop test, letter-digit substitution test, verbal fluency test, Purdue pegboard test and questionnaires on basic and instrumental activities of daily living (BADL; IADL). Principal component analysis was used to derive global cognition (G-factor). Incident stroke was assessed through continuous monitoring of medical records until 2016. Among 8,519 persons (mean age 66.0 years; 57.8% wome

Exploiting Inter- and Intra-Memory Asymmetries for Data Mapping in Hybrid Tiered-Memories

Modern computing systems are embracing hybrid memory comprising of DRAM and non-volatile memory (NVM) to combine the best properties of both memory technologies, achieving low latency, high reliability, and high density. A prominent characteristic of DRAM-NVM hybrid memory is that it has NVM access latency much higher than DRAM access latency. We call this inter-memory asymmetry. We observe that parasitic components on a long bitline are a major source of high latency in both DRAM and NVM, and a significant factor contributing to high-voltage operations in NVM, which impact their reliability. We propose an architectural change, where each long bitline in DRAM and NVM is split into two segments by an isolation transistor. One segment can be accessed with lower latency and operating voltage than the other. By introducing tiers, we enable non-uniform accesses within each memory type (which we call intra-memory asymmetry), leading to performance and reliability trade-offs in DRAM-NVM hybrid memory. We extend existing NVM-DRAM OS in three ways. First, we exploit both inter- and intra-memory asymmetries to allocate and migrate memory pages between the tiers in DRAM and NVM. Second, we improve the OS's page allocation decisions by predicting the access intensity of a newly-referenced memory page in a program and placing it to a matching tier during its initial allocation. This minimizes page migrations during program execution, lowering the performance overhead. Third, we propose a solution to migrate pages between the tiers of the same memory without transferring data over the memory channel, minimizing channel occupancy and improving performance. Our overall approach, which we call MNEME, to enable and exploit asymmetries in DRAM-NVM hybrid tiered memory improves both performance and reliability for both single-core and multi-programmed workloads.Comment: 15 pages, 29 figures, accepted at ACM SIGPLAN International Symposium on Memory Managemen

Unspecified Strokes: Time Trends, Determinants, and Long-Term Prognosis in the General Population

Introduction: In the absence of neuroimaging, a stroke is typically labelled as unspecified. While the majority of clinic-based stroke research focuses on hemorrhagic or ischemic stroke, in the general population, a substantial proportion of strokes remains unspecified. Objective: To investigate time trends in the occurrence and determinants of unspecified strokes and differences in patient characteristics and survival compared to ischemic or hemorrhagic stroke. Methods: We included 1,546 participants from the population-based Rotterdam Study who suffered a first-ever stroke during follow-up (1990-2016). We calculated the proportion of unspecified strokes per year and compared their characteristics between 3 time periods (1990-1999, 2000-2009, and 2010-2016) using a chi-square test, and furthermore investigated differences between unspecified, ischemic, and hemorrhagic stroke in patient characteristics and survival using age- and sex-adjusted survival curves. Results: The occurrence of unspecified stroke among all strokes decreased from 75% in 1990 to 16% in 2016. Compared to the first time period (1991-1999), diagnosis of unspecified strokes was more often done by nursing home physicians (13 vs. 40%) and unspecified stroke patients had more often dementia (30 vs. 43%) in the last time period (2010-2016). Compared to patients with ischemic or hemorrhagic stroke, patients with unspecified stroke were on average older (84.3 vs. 78.5 years) and had more often physical impairments and dementia. Furthermore, patients with unspecified stroke had a lower survival probability up to 10 years after stroke than those with ischemic stroke. Conclusions: The proportion of unspecified strokes decreased drastically from 75 to 16% in the last decades. Patients who do not undergo neuroimaging and therefore are classified as unspecified stroke represent an older, more frail patient group that suffers more often from multimorbidities and poor long-term prognosis than those who do undergo neuroimaging and are thus classified as ischemic or hemorrhagic stroke

Improving Phase Change Memory Performance with Data Content Aware Access

A prominent characteristic of write operation in Phase-Change Memory (PCM) is that its latency and energy are sensitive to the data to be written as well as the content that is overwritten. We observe that overwriting unknown memory content can incur significantly higher latency and energy compared to overwriting known all-zeros or all-ones content. This is because all-zeros or all-ones content is overwritten by programming the PCM cells only in one direction, i.e., using either SET or RESET operations, not both. In this paper, we propose data content aware PCM writes (DATACON), a new mechanism that reduces the latency and energy of PCM writes by redirecting these requests to overwrite memory locations containing all-zeros or all-ones. DATACON operates in three steps. First, it estimates how much a PCM write access would benefit from overwriting known content (e.g., all-zeros, or all-ones) by comprehensively considering the number of set bits in the data to be written, and the energy-latency trade-offs for SET and RESET operations in PCM. Second, it translates the write address to a physical address within memory that contains the best type of content to overwrite, and records this translation in a table for future accesses. We exploit data access locality in workloads to minimize the address translation overhead. Third, it re-initializes unused memory locations with known all-zeros or all-ones content in a manner that does not interfere with regular read and write accesses. DATACON overwrites unknown content only when it is absolutely necessary to do so. We evaluate DATACON with workloads from state-of-the-art machine learning applications, SPEC CPU2017, and NAS Parallel Benchmarks. Results demonstrate that DATACON significantly improves system performance and memory system energy consumption compared to the best of performance-oriented state-of-the-art techniques.Comment: 18 pages, 21 figures, accepted at ACM SIGPLAN International Symposium on Memory Management (ISMM

The mediating role of the venules between smoking and ischemic stroke

A potential mechanism by which smoking affects ischemic stroke is through wider venules, but this mediating role of wider venules has never been quantified. Here, we aimed to estimate to what extent the effect of smoking on ischemic stroke is possibly mediated by the venules via the recently developed four-way effect decomposition. This study was part of a population-based study including 9109 stroke-free persons participated in the study in 1990, 2004, or 2006 (mean age: 63.7 years; 58% women). Smoking behavior (smoking versus non-smoking) was identified by interview. Retinal venular calibers were measured semi-automatically on retinal photographs. Incident strokes were assessed until January 2016. A regression-based approach was used with venular calibers as mediator to decompose the total effect of smoking compared to non-smoking into four components: controlled direct effect (neither mediation nor interaction), pure indirect effect (mediation only), reference interaction effect (interaction only) and mediated interaction effect (both mediation and interaction). During a mean follow-up of 12.5 years, 665 persons suffered an ischemic stroke. Smoking increased the risk of developing ischemic stroke compared to non-smoking with an excess risk of 0.41 (95% confidence interval 0.10; 0.67). With retinal venules as a potential mediator, the excess relative risk could be decomposed into 77% controlled direct effect, 4% mediation only, 4% interaction only, and 15% mediated interaction. To conclude, in the pathophysiology of ischemic stroke, the effect of smoking on ischemic stroke may partly explained by changes in the venules, where there is both pure mediation and mediated interaction

Non-Human Primate Model of Kaposi's Sarcoma-Associated Herpesvirus Infection

Since Kaposi's sarcoma-associated herpesvirus (KSHV or human herpesvirus 8) was first identified in Kaposi's sarcoma (KS) lesions of HIV-infected individuals with AIDS, the basic biological understanding of KSHV has progressed remarkably. However, the absence of a proper animal model for KSHV continues to impede direct in vivo studies of viral replication, persistence, and pathogenesis. In response to this need for an animal model of KSHV infection, we have explored whether common marmosets can be experimentally infected with human KSHV. Here, we report the successful zoonotic transmission of KSHV into common marmosets (Callithrix jacchus, Cj), a New World primate. Marmosets infected with recombinant KSHV rapidly seroconverted and maintained a vigorous anti-KSHV antibody response. KSHV DNA and latent nuclear antigen (LANA) were readily detected in the peripheral blood mononuclear cells (PBMCs) and various tissues of infected marmosets. Remarkably, one orally infected marmoset developed a KS-like skin lesion with the characteristic infiltration of leukocytes by spindle cells positive for KSHV DNA and proteins. These results demonstrate that human KSHV infects common marmosets, establishes an efficient persistent infection, and occasionally leads to a KS-like skin lesion. This is the first animal model to significantly elaborate the important aspects of KSHV infection in humans and will aid in the future design of vaccines against KSHV and anti-viral therapies targeting KSHV coinfected tumor cells

Kaposi's Sarcoma-Associated Herpesvirus K7 Induces Viral G Protein-Coupled Receptor Degradation and Reduces Its Tumorigenicity

The Kaposi's sarcoma-associated herpesvirus (KSHV) genome encodes a G protein-coupled receptor (vGPCR). vGPCR is a ligand-independent, constitutively active signaling molecule that promotes cell growth and proliferation; however, it is not clear how vGPCR is negatively regulated. We report here that the KSHV K7 small membrane protein interacts with vGPCR and induces its degradation, thereby dampening vGPCR signaling. K7 interaction with vGPCR is readily detected in transiently transfected human cells. Mutational analyses reveal that the K7 transmembrane domain is necessary and sufficient for this interaction. Biochemical and confocal microscopy studies indicate that K7 retains vGPCR in the endoplasmic reticulum (ER) and induces vGPCR proteasomeal degradation. Indeed, the knockdown of K7 by shRNA-mediated silencing increases vGPCR protein expression in BCBL-1 cells that are induced for KSHV lytic replication. Interestingly, K7 expression significantly reduces vGPCR tumorigenicity in nude mice. These findings define a viral factor that negatively regulates vGPCR protein expression and reveal a post-translational event that modulates GPCR-dependent transformation and tumorigenicity