Survival Analysis for the Association between Anti-hypertensive Medication and Time to Dementia with Competing Risk

Indiana University-Purdue University Indianapolis (IUPUI)Background: High blood pressure (HBP) is a common risk factor for dementia in elder population. Anti-hypertensive medications have been reported to associate with lower incidence rate of dementia in elder African Americans. The Apolipoprotein E (ApoE) epsilon 4 allele has been shown to be associated with both increased dementia and hypertension risk. However, previous studies had not examined the association between anti-hypertensive medications by ApoE status accounting for the competing risk from death. Methods: This is a prospective observational cohort study in 1236 community-dwelling hypertensive African Americans aged 65 years and older without dementia at baseline, with follow-up cognitive assessment and clinical evaluation for dementia diagnosis. Dementia-free mortality was considered as the competing risk. Of these, 707 participants were genotyped for ApoE status. Anti-hypertensive medication use was obtained from prescription records in the electronic medical records of the Indiana Network for Patient Care (INPC). Cox proportional cause-specific hazard (CSH) regression models were applied to assess the association between anti-hypertensive medication use and CSHs for dementia and death in ApoE epsilon 4 carriers and non-carriers separately. Key results: In ApoE epsilon 4 carriers, participants using anti-hypertensive medications had lower CSH of dementia compared to those not on anti-hypertensive medications before adjusting for blood pressure (BP) (hazard ratio (HR), 0.365; 95% CI, 0.170 – 0.785; p = 0.0099). The HR was no longer significant once BP control was adjusted (HR, 0.784; 95% CI, 0.197 – 3.123; p = 0.7303). Anti-hypertensive medications were not associated with dementia rate in non-carriers. In ApoE epsilon 4 non-carriers, participants on anti-hypertensive treatment showed significantly lower CSH of death compared to those not on mediations adjusting for covariates and BP control (HR, 0.237; 95% CI, 0.149 – 0.375; p < 0.0001). There was no significant association between anti-hypertensive medication use and death in ApoE epsilon 4 carriers. Conclusions: Anti-hypertensive medication was associated with lower dementia rate in ApoE epsilon 4 carriers and that rate was primarily mediated through BP control. In non-carriers, anti-hypertensive medication was significantly associated with lower mortality rate and this association appears to be independent of BP control

Mechanism evolution mechanism of active support process of two-leg shield

In view of the unclear mechanism evolution of the two-leg shield during the active support process, the planar kinematic model of two-leg shield is established, the necessary conditions for the mechanism evolution of the shield are obtained, and the active cooperative control strategy of the stabilizing ram and the leg is proposed. Theoretical analysis and experimental studies show that whether mechanism evolution occurs in the active support process of the two-leg shield depends on the state of the canopy in contact with the roof and the state of the stabilizing ram; The canopy is in contact with the roof in an elevation, the canopy evolves from a rocker to a "rocker + slider", and the base evolves from a rack to a rocker when the stabilizing ram is a rigid body; When the stabilizing ram is a rigid body, with the leg elongation, the motion form of the canopy is the slide along the roof toward the coal wall and the rotation toward the roof, and the motion form of the base is the rotation around the front toe of the base toward the coal wall, and the motion trajectories of the canopy and the base show a quadratic function, and the larger the elevation angle of the canopy, the greater the distance of the slip of the canopy and the height of the lift of the base; When the stabilizing ram is a floating body, with the leg elongation, the motion form of the canopy is the slide along the roof and the rotation toward the roof, the base does not move, the length of the stabilizing ram changes as a quadratic function, while the trajectory of the canopy shows a cubic function, and the slip distance is very small, as well as reciprocating motion may occur. The proposed active cooperative control strategy of stabilizing ram and the leg can effectively avoid the suction air of stabilizing ram and the mechanism evolution of the shield. The research results reasonably explain the interference phenomenon between shearer and canopy of the shield in Pingdingshan mining area, which provides a new idea for studying the active cooperative control of leg and stabilizing ram

A Two-Stage Queue Model to Optimize Layout of Urban Drainage System considering Extreme Rainstorms

Extreme rainstorm is a main factor to cause urban floods when urban drainage system cannot discharge stormwater successfully. This paper investigates distribution feature of rainstorms and draining process of urban drainage systems and uses a two-stage single-counter queue method M/M/1→M/D/1 to model urban drainage system. The model emphasizes randomness of extreme rainstorms, fuzziness of draining process, and construction and operation cost of drainage system. Its two objectives are total cost of construction and operation and overall sojourn time of stormwater. An improved genetic algorithm is redesigned to solve this complex nondeterministic problem, which incorporates with stochastic and fuzzy characteristics in whole drainage process. A numerical example in Shanghai illustrates how to implement the model, and comparisons with alternative algorithms show its performance in computational flexibility and efficiency. Discussions on sensitivity of four main parameters, that is, quantity of pump stations, drainage pipe diameter, rainstorm precipitation intensity, and confidence levels, are also presented to provide guidance for designing urban drainage system

Transcriptome and expression profiling analysis revealed changes of multiple signaling pathways involved in immunity in the large yellow croaker during Aeromonas hydrophila infection

<p>Abstract</p> <p>Background</p> <p>The large yellow croaker (<it>Pseudosciaena crocea</it>) is an economically important marine fish in China suffering from severe outbreaks of infectious disease caused by marine bacteria such as <it>Aeromonas hydrophila </it>(<it>A. hydrophila</it>), resulting in great economic losses. However, the mechanisms involved in the immune response of this fish to bacterial infection are not fully understood. To understand the molecular mechanisms underlying the immune response to such pathogenic bacteria, we used high-throughput deep sequencing technology to investigate the transcriptome and comparative expression profiles of the large yellow croaker infected with <it>A. hydrophila</it>.</p> <p>Results</p> <p>A total of 13,611,340 reads were obtained and assembled into 26,313 scaffolds in transcriptional responses of the <it>A. hydrophila</it>-infected large yellow croaker. Via annotation to the NCBI database, we obtained 8216 identified unigenes. In total, 5590 (68%) unigenes were classified into Gene Ontology, and 3094 unigenes were found in 20 KEGG categories. These genes included representatives from almost all functional categories. By using Solexa/Illumina's DeepSAGE, 1996 differentially expressed genes (P value < 0.05) were detected in comparative analysis of the expression profiles between <it>A. hydrophila</it>-infected fish and control fish, including 727 remarkably upregulated genes and 489 remarkably downregulated genes. Dramatic differences were observed in genes involved in the inflammatory response. Bacterial infection affected the gene expression of many components of signaling cascades, including the Toll-like receptor, JAK-STAT, and MAPK pathways. Genes encoding factors involved in T cell receptor (TCR) signaling were also revealed to be regulated by infection in these fish.</p> <p>Conclusion</p> <p>Based on our results, we conclude that the inflammatory response may play an important role in the early stages of infection. The signaling cascades such as the Toll-like receptor, JAK-STAT, and MAPK pathways are regulated by <it>A. hydrophila </it>infection. Interestingly, genes encoding factors involved in TCR signaling were revealed to be downregulated by infection, indicating that TCR signaling was suppressed at this early period. These results revealed changes of multiple signaling pathways involved in immunity during <it>A. hydrophila </it>infection, which will facilitate our comprehensive understanding of the mechanisms involved in the immune response to bacterial infection in the large yellow croaker.</p

Notch2 controls hepatocyte-derived cholangiocarcinoma formation in mice.

Liver cancer comprises a group of malignant tumors, among which hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC) are the most common. ICC is especially pernicious and associated with poor clinical outcome. Studies have shown that a subset of human ICCs may originate from mature hepatocytes. However, the mechanisms driving the trans-differentiation of hepatocytes into malignant cholangiocytes remain poorly defined. We adopted lineage tracing techniques and an established murine hepatocyte-derived ICC model by hydrodynamic injection of activated forms of AKT (myr-AKT) and Yap (YapS127A) proto-oncogenes. Wild-type, Notch1 flox/flox , and Notch2 flox/flox mice were used to investigate the role of canonical Notch signaling and Notch receptors in AKT/Yap-driven ICC formation. Human ICC and HCC cell lines were transfected with siRNA against Notch2 to determine whether Notch2 regulates biliary marker expression in liver tumor cells. We found that AKT/Yap-induced ICC formation is hepatocyte derived and this process is strictly dependent on the canonical Notch signaling pathway in vivo. Deletion of Notch2 in AKT/Yap-induced tumors switched the phenotype from ICC to hepatocellular adenoma-like lesions, while inactivation of Notch1 in hepatocytes did not result in significant histomorphological changes. Finally, in vitro studies revealed that Notch2 silencing in ICC and HCC cell lines down-regulates the expression of Sox9 and EpCAM biliary markers. Notch2 is the major determinant of hepatocyte-derived ICC formation in mice