Approximating multiple class queueing models with loss models

Multiple class queueing models arise in situations where some flexibility is sought through pooling of demands for different services. Earlier research has shown that most of the benefits of flexibility can be obtained with only a small proportion of cross-trained operators. Predicting the performance of a system with different types of demands and operator pools with different skills is very difficult. We present an approximation method that is based on equivalent loss systems. We successively develop approximations for the waiting probability, The average waiting time and the service level. Our approximations are validated using a series of simulations. Along the way we present some interesting insights into some similarities between queueing systems and equivalent loss systems that have to our knowledge never been reported in the literature.

Scheduling Networks of Queues: Heavy Traffic Analysis of a Multistation Closed Network

We consider the problem of finding an optimal dynamic priority sequencing policy to maximize the mean throughput rate in a multistation, multiclass closed queueing network with general service time distributions and a general routing structure. Under balanced heavy loading conditions, this scheduling problem can be approximated by a control problem involving Brownian motion. Although a unique, closed form solution to the Brownian control problem is not derived, an analysis of the problem leads to an effective static sequencing policy, and to an approximate means of comparing the relative performance of arbitrary static policies. Three examples are given that illustrate the effectiveness of our procedure

Revisiting Sex Equality With Transcatheter Aortic Valve Replacement Outcomes A Collaborative, Patient-Level Meta-Analysis of 11,310 Patients

AbstractBackgroundThere has been conflicting clinical evidence as to the influence of female sex on outcomes after transcatheter aortic valve replacement.ObjectivesThe aim of this study was to evaluate the impact of sex on early and late mortality and safety end points after transcatheter aortic valve replacement using a collaborative meta-analysis of patient-level data.MethodsFrom the MEDLINE, Embase, and the Cochrane Library databases, data were obtained from 5 studies, and a database containing individual patient-level time-to-event data was generated from the registry of each selected study. The primary outcome of interest was all-cause mortality. The safety end point was the combined 30-day safety end points of major vascular complications, bleeding events, and stroke, as defined by the Valve Academic Research Consortium when available.ResultsFive studies and their ongoing registry data, comprising 11,310 patients, were included. Women constituted 48.6% of the cohort and had fewer comorbidities than men. Women had a higher rate of major vascular complications (6.3% vs. 3.4%; p < 0.001), major bleeding events (10.5% vs. 8.5%; p = 0.003), and stroke (4.4% vs. 3.6%; p = 0.029) but a lower rate of significant aortic incompetence (grade ≥2; 19.4% vs. 24.5%; p < 0.001). There were no differences in procedural and 30-day mortality between women and men (2.6 % vs. 2.2% [p = 0.24] and 6.5% vs. 6.5% [p = 0.93], respectively), but female sex was independently associated with improved survival at median follow-up of 387 days (interquartile range: 192 to 730 days) from the index procedure (adjusted hazard ratio: 0.79; 95% confidence interval: 0.73 to 0.86; p = 0.001).ConclusionsAlthough women experience more bleeding events, as well as vascular and stroke complications, female sex is an independent predictor of late survival after transcatheter aortic valve replacement. This should be taken into account during patient selection for this procedure

Genetic associations of protein-coding variants in human disease.

Genome-wide association studies (GWAS) have identified thousands of genetic variants linked to the risk of human disease. However, GWAS have so far remained largely underpowered in relation to identifying associations in the rare and low-frequency allelic spectrum and have lacked the resolution to trace causal mechanisms to underlying genes1. Here we combined whole-exome sequencing in 392,814 UK Biobank participants with imputed genotypes from 260,405 FinnGen participants (653,219 total individuals) to conduct association meta-analyses for 744 disease endpoints across the protein-coding allelic frequency spectrum, bridging the gap between common and rare variant studies. We identified 975 associations, with more than one-third being previously unreported. We demonstrate population-level relevance for mutations previously ascribed to causing single-gene disorders, map GWAS associations to likely causal genes, explain disease mechanisms, and systematically relate disease associations to levels of 117 biomarkers and clinical-stage drug targets. Combining sequencing and genotyping in two population biobanks enabled us to benefit from increased power to detect and explain disease associations, validate findings through replication and propose medical actionability for rare genetic variants. Our study provides a compendium of protein-coding variant associations for future insights into disease biology and drug discovery

A three gene DNA methylation biomarker accurately classifies early stage prostate cancer

Background: We identify and validate accurate diagnostic biomarkers for prostate cancer through a systematic evaluation of DNA methylation alterations. Materials and methods: We assembled three early prostate cancer cohorts (total patients = 699) from which we collected and processed over 1300 prostatectomy tissue samples for DNA extraction. Using real-time methylation-specific PCR, we measured normalized methylation levels at 15 frequently methylated loci. After partitioning sample sets into independent training and validation cohorts, classifiers were developed using logistic regression, analyzed, and validated. Results: In the training dataset, DNA methylation levels at 7 of 15 genomic loci (glutathione S-transferase Pi 1 [GSTP1], CCDC181, hyaluronan, and proteoglycan link protein 3 [HAPLN3], GSTM2, growth arrest-specific 6 [GAS6], RASSF1, and APC) showed large differences between cancer and benign samples. The best binary classifier was the GAS6/GSTP1/HAPLN3 logistic regression model, with an area under these curves of 0.97, which showed a sensitivity of 94%, and a specificity of 93% after external validation. Conclusion: We created and validated a multigene model for the classification of benign and malignant prostate tissue. With false positive and negative rates below 7%, this three-gene biomarker represents a promising basis for more accurate prostate cancer diagnosis

Marriage, Migration, and Urban Demographic Structure: a Case From France in the Belle Epoque

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/67248/2/10.1177_036319908100600109.pd

FtsK-Dependent Dimer Resolution on Multiple Chromosomes in the Pathogen Vibrio cholerae

Unlike most bacteria, Vibrio cholerae harbors two distinct, nonhomologous circular chromosomes (chromosome I and II). Many features of chromosome II are plasmid-like, which raised questions concerning its chromosomal nature. Plasmid replication and segregation are generally not coordinated with the bacterial cell cycle, further calling into question the mechanisms ensuring the synchronous management of chromosome I and II. Maintenance of circular replicons requires the resolution of dimers created by homologous recombination events. In Escherichia coli, chromosome dimers are resolved by the addition of a crossover at a specific site, dif, by two tyrosine recombinases, XerC and XerD. The process is coordinated with cell division through the activity of a DNA translocase, FtsK. Many E. coli plasmids also use XerCD for dimer resolution. However, the process is FtsK-independent. The two chromosomes of the V. cholerae N16961 strain carry divergent dimer resolution sites, dif1 and dif2. Here, we show that V. cholerae FtsK controls the addition of a crossover at dif1 and dif2 by a common pair of Xer recombinases. In addition, we show that specific DNA motifs dictate its orientation of translocation, the distribution of these motifs on chromosome I and chromosome II supporting the idea that FtsK translocation serves to bring together the resolution sites carried by a dimer at the time of cell division. Taken together, these results suggest that the same FtsK-dependent mechanism coordinates dimer resolution with cell division for each of the two V. cholerae chromosomes. Chromosome II dimer resolution thus stands as a bona fide chromosomal process

Evidence of a causal and modifiable relationship between kidney function and circulating trimethylamine N-oxide

The host-microbiota co-metabolite trimethylamine N-oxide (TMAO) is linked to increased cardiovascular risk but how its circulating levels are regulated remains unclear. We applied "explainable" machine learning, univariate, multivariate and mediation analyses of fasting plasma TMAO concentration and a multitude of phenotypes in 1,741 adult Europeans of the MetaCardis study. Here we show that next to age, kidney function is the primary variable predicting circulating TMAO, with microbiota composition and diet playing minor, albeit significant, roles. Mediation analysis suggests a causal relationship between TMAO and kidney function that we corroborate in preclinical models where TMAO exposure increases kidney scarring. Consistent with our findings, patients receiving glucose-lowering drugs with reno-protective properties have significantly lower circulating TMAO when compared to propensity-score matched control individuals. Our analyses uncover a bidirectional relationship between kidney function and TMAO that can potentially be modified by reno-protective anti-diabetic drugs and suggest a clinically actionable intervention for decreasing TMAO-associated excess cardiovascular risk

The Staphylococcus aureus RNome and Its Commitment to Virulence

Staphylococcus aureus is a major human pathogen causing a wide spectrum of nosocomial and community-associated infections with high morbidity and mortality. S. aureus generates a large number of virulence factors whose timing and expression levels are precisely tuned by regulatory proteins and RNAs. The aptitude of bacteria to use RNAs to rapidly modify gene expression, including virulence factors in response to stress or environmental changes, and to survive in a host is an evolving concept. Here, we focus on the recently inventoried S. aureus regulatory RNAs, with emphasis on those with identified functions, two of which are directly involved in pathogenicity