Inefficiencies in the Cache Hierarchy: A Sensitivity Study of Cacheline Size with Mobile Workloads

With the rising number of cores in mobile devices, the cache hierarchy in mobile application processors gets deeper, and the cache size gets bigger. However, the cacheline size remained relatively constant over the last decade in mobile application processors. In this work, we investigate whether the cacheline size in mobile application processors is due for a refresh, by looking at inefficiencies in the cache hierarchy which tend to be exacerbated when increasing the cacheline size: false sharing and cacheline utilization. Firstly, we look at false sharing, which is more likely to arise at larger cacheline sizes and can severely impact performance. False sharing occurs when non-shared data structures, mapped onto the same cacheline, are being accessed by threads running on different cores, causing avoidable invalidations and subsequent misses. False sharing has been found in various places such as scientific workloads and real applications. We find that whilst increasing the cacheline size does increase false sharing, it still is negligible when compared to known cases of false sharing in scientific workloads, due to the limited level of thread-level parallelism in mobile workloads. Secondly, we look at cacheline utilization which measures the number of bytes in a cacheline actually used by the processor. This effect has been investigated under various names for a multitude of server and desktop applications. As a low cacheline utilization implies that very little of the fetched cachelines was used by the processor, this causes waste in bandwidth and energy in moving data across the memory hierarchy. The energy cost associated with data movements is much higher compared to logic operations, increasing the need for cache efficiency, especially in the case of an energy-constrained platform like a mobile device. We find that the cacheline utilization of mobile workloads is low in general, decreasing when increasing the cacheline size. When increasing the cacheline size from 64 bytes to 128 bytes, the number of misses will be reduced by 10%-30%, depending on the workload. However, because of the low cacheline utilization, this more than doubles the amount of unused traffic to the L1 caches. Using the cacheline utilization as a metric in this way, illustrates an important point. If a change in cacheline size would only be assessed on its local effects, we find that this change in cacheline size will only have advantages as the miss rate decreases. However, at system level, this change will increase the stress on the bus and increase the amount of wasted energy due to unused traffic. Using cacheline utilization as a metric underscores the need for system-level research when changing characteristics of the cache hierarchy

Association between the number of coadministered P-glycoprotein inhibitors and serum digoxin levels in patients on therapeutic drug monitoring

BACKGROUND: The ABC transporter P-glycoprotein (P-gp) is recognized as a site for drug-drug interactions and provides a mechanistic explanation for clinically relevant pharmacokinetic interactions with digoxin. The question of whether several P-gp inhibitors may have additive effects has not yet been addressed. METHODS: We evaluated the effects on serum concentrations of digoxin (S-digoxin) in 618 patients undergoing therapeutic drug monitoring. P-gp inhibitors were classified as Class I, with a known effect on digoxin kinetics, or Class II, showing inhibition in vitro but no documented effect on digoxin kinetics in humans. Mean S-digoxin values were compared between groups of patients with different numbers of coadministered P-gp inhibitors by a univariate and a multivariate model, including the potential covariates age, sex, digoxin dose and total number of prescribed drugs. RESULTS: A large proportion (47%) of the digoxin patients undergoing therapeutic drug monitoring had one or more P-gp inhibitor prescribed. In both univariate and multivariate analysis, S-digoxin increased in a stepwise fashion according to the number of coadministered P-gp inhibitors (all P values < 0.01 compared with no P-gp inhibitor). In multivariate analysis, S-digoxin levels were 1.26 ± 0.04, 1.51 ± 0.05, 1.59 ± 0.08 and 2.00 ± 0.25 nmol/L for zero, one, two and three P-gp inhibitors, respectively. The results were even more pronounced when we analyzed only Class I P-gp inhibitors (1.65 ± 0.07 for one and 1.83 ± 0.07 nmol/L for two). CONCLUSIONS: Polypharmacy may lead to multiple drug-drug interactions at the same site, in this case P-gp. The S-digoxin levels increased in a stepwise fashion with an increasing number of coadministered P-gp inhibitors in patients taking P-gp inhibitors and digoxin concomitantly. As coadministration of digoxin and P-gp inhibitors is common, it is important to increase awareness about P-gp interactions among prescribing clinicians

Consumer Complaints and Company Market Value

Consumer complaints affect company market value and common sense suggests that a negative impact is expected. However, do complaints always negatively impact company market value? We hypothesize in this study that complaints may have a non-linear effect on market value. Positive (e.g. avoiding high costs to solve complaints) and negative (e.g. speedy and intense diffusion) tradeoffs may occur given the level of complaints. To test our non-linear hypothesis, a panel data was collected from cell phone service providers from 2005 to 2013. The results supported our tradeoff rationale. Low levels of complaints allow for companies to increase market value, while high levels of complaints cause increasing harm to market value. The sample, model and period considered in this study, indicates a level of 0.49 complaints per thousand consumers as the threshold for a shift in tradeoffs. The effects on market value become increasingly negative when trying to make reductions to move below this level, due to negative tradeoffs

A Discourse Analysis of Pilgrimage Reviews

This paper is the first to provide an account of the discursive features of online consumer reviews of pilgrimage sites. Drawing from pilgrimage studies and narrativity theory in consumer research, we explore how consumers communicate the spiritual and material aspects of pilgrimage experiences by examining a corpus of 833 consumer reviews on TripAdvisor of the most sacred pilgrimage sites of the world’s major five faith groups. Pilgrims include analytical discursive features to communicate the material aspect of their consumption experience. They reserve narration for spiritual transformation and the experience of strong emotions. Moreover, review ratings are only reflective of the spiritual aspect of their consumption experience. As such, our research complements previous studies by highlighting the material, physical aspect of this extraordinary consumption experience

In silico modeling indicates the development of HIV-1 resistance to multiple shRNA gene therapy differs to standard antiretroviral therapy

<p>Abstract</p> <p>Background</p> <p>Gene therapy has the potential to counter problems that still hamper standard HIV antiretroviral therapy, such as toxicity, patient adherence and the development of resistance. RNA interference can suppress HIV replication as a gene therapeutic via expressed short hairpin RNAs (shRNAs). It is now clear that multiple shRNAs will likely be required to suppress infection and prevent the emergence of resistant virus.</p> <p>Results</p> <p>We have developed the first biologically relevant stochastic model in which multiple shRNAs are introduced into CD34+ hematopoietic stem cells. This model has been used to track the production of gene-containing CD4+ T cells, the degree of HIV infection, and the development of HIV resistance in lymphoid tissue for 13 years. In this model, we found that at least four active shRNAs were required to suppress HIV infection/replication effectively and prevent the development of resistance. The inhibition of incoming virus was shown to be critical for effective treatment. The low potential for resistance development that we found is largely due to a pool of replicating wild-type HIV that is maintained in non-gene containing CD4+ T cells. This wild-type HIV effectively out-competes emerging viral strains, maintaining the viral <it>status quo</it>.</p> <p>Conclusions</p> <p>The presence of a group of cells that lack the gene therapeutic and is available for infection by wild-type virus appears to mitigate the development of resistance observed with systemic antiretroviral therapy.</p

Loss-of-function mutations in the X-linked biglycan gene cause a severe syndromic form of thoracic aortic aneurysms and dissections.

Thoracic aortic aneurysm and dissection (TAAD) is typically inherited in an autosomal dominant manner, but rare X-linked families have been described. So far, the only known X-linked gene is FLNA, which is associated with the periventricular nodular heterotopia type of Ehlers-Danlos syndrome. However, mutations in this gene explain only a small number of X-linked TAAD families. We performed targeted resequencing of 368 candidate genes in a cohort of 11 molecularly unexplained Marfan probands. Subsequently, Sanger sequencing of BGN in 360 male and 155 female molecularly unexplained TAAD probands was performed. We found five individuals with loss-of-function mutations in BGN encoding the small leucine-rich proteoglycan biglycan. The clinical phenotype is characterized by early-onset aortic aneurysm and dissection. Other recurrent findings include hypertelorism, pectus deformity, joint hypermobility, contractures, and mild skeletal dysplasia. Fluorescent staining revealed an increase in TGF-β signaling, evidenced by an increase in nuclear pSMAD2 in the aortic wall. Our results are in line with those of prior reports demonstrating that Bgn-deficient male BALB/cA mice die from aortic rupture. In conclusion, BGN gene defects in humans cause an X-linked syndromic form of severe TAAD that is associated with preservation of elastic fibers and increased TGF-β signaling.Genet Med 19 4, 386-395

Global wealth disparities drive adherence to COVID-safe pathways in head and neck cancer surgery

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