Precise n-gram Probabilities from Stochastic Context-free Grammars

We present an algorithm for computing n-gram probabilities from stochastic context-free grammars, a procedure that can alleviate some of the standard problems associated with n-grams (estimation from sparse data, lack of linguistic structure, among others). The method operates via the computation of substring expectations, which in turn is accomplished by solving systems of linear equations derived from the grammar. We discuss efficient implementation of the algorithm and report our practical experience with it.Comment: 12 pages, to appear in ACL-9

Optimising the medical management of ileoanal pouch related complications and discovering novel therapeutic avenues through metabonomic profiling

Restorative proctocolectomy is considered a quality of life surgical procedure in patients with ulcerative colitis who fail to respond to conventional medical therapies and in some patients with Familial Adenomatous Polyposis. This thesis explores the current management of chronic primary idiopathic pouchitis through a systematic review and meta-analysis. Following this review I have explored the clinical utility of antibiotics and biologics in a cohort of patients with both chronic primary idiopathic pouchitis and pre-pouch ileitis. I have found that the treatment options for chronic pouchitis and pre-pouch ileitis are limited and that long-term treatments such as antibiotics and biologics are ineffective in a significant proportion of patients often leading to a permanent ileostomy. I have also explored the effect of some non-medical therapies including biofeedback and the Renew® anal insert for incontinence and evacuatory problems and have shown that they may be a useful adjunct in the treatment of these pouch related complications. The second focus of the thesis is to try and understand the mechanisms that drive the development of pouchitis. I undertook a systematic review to explore what was already known about the gut microbiota and its role in health and disease of the pouch. I then utilised next generation sequencing technologies to include metataxonomics, nuclear magnetic resonance and mass-spectrometry gas chromatography to link the gut microbiota with the metabolic signatures in serum, urine, faeces and mucosal tissue. I used these techniques to compare patients with pouchitis against healthy controls and patients with Familial Adenomatous Polyposis. These studies have highlighted the importance of the Firmicutes phylum and their role in the production of short chain fatty acids. I have found that a depletion in short chain fatty acids may contribute to the development of pouchitis. Future work may build on methods to increase short chain fatty acid delivery to the pouch through methods such as dietary interventions, distal feeding prior to continuity surgery or direct short chain fatty acid supplementation delivered topically to the pouch.Open Acces

Prevention of Peritonitis in Peritoneal Dialysis

Reducing the frequency of peritonitis for patients undergoing peritoneal dialysis ( PD ) continues to be a challenge. This review focuses on recent updates in catheter care and other patient factors that influence infection rates. An experienced nursing staff plays an important role in teaching proper PD technique to new patients, but nursing staff must be cognizant of each patient's unique educational needs. Over time, many patients become less adherent to proper dialysis technique, such as washing hands or wearing a mask. This behavior is associated with higher risk of peritonitis and is modifiable with re‐training. Prophylactic antibiotics before PD catheter placement can decrease the infection risk immediately after catheter placement. In addition, some studies suggest that prophylaxis against fungal superinfection after antibiotic exposure is effective in reducing fungal peritonitis, although larger randomized studies are needed before this practice can be recommended for all patients. Over time, exit site and nasal colonization with pathogenic organisms can lead to exit‐site infections and peritonitis. For patients with S taphylococcus aureus colonization, exit‐site prophylaxis with either mupirocin or gentamicin cream reduces clinical infection with this organism. Although there are limited data for support, antibiotic prophylaxis before gastrointestinal, gynecologic, or dental procedures may also help reduce the risk of peritonitis.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/99100/1/sdi12114.pd

Healthcare Web Accessibility: Litigation Avoidance or Strategic Opportunity?

In 2006, the National Federation of the Blind (NFB) sued Target Corporation alleging that the retailer’s website was inaccessible to the blind, in violation of the Americans with Disability Act (ADA) and various California statutes. Target eventually settled the case for US$9.7 million. The Target case presents an interesting dilemma to private sector healthcare providers. What corporate strategy is appropriate in the case of web accessibility? US Federal and state laws do not specifically require a private company to make its website accessible to customers with disabilities. However, the adverse media exposure from a private class action suit by a disability group can significantly damage a company’s reputation for corporate social responsibility (CSR). We develop a model of corporate web accessibility behavior based on literature linking CSR activities to corporate financial performance. We test its use within the healthcare industry focusing on private-sector companies that deliver online healthcare information. We compare our sample to a group of non-healthcare companies with a reputation for corporate social responsibility for the years before and after the onset of the Target litigation. Results reveal significant differences in the way healthcare corporations choose to address web accessibility

Challenges in molecular dynamics simulations of heat exchange statistics

We study heat exchange in temperature-biased metal-molecule-metal molecular junctions by employing the LAMMPS atomic molecular dynamics simulator. Generating the nonequilibrium steady state with Langevin thermostats at the boundaries of the junction, we show that the {\it average} heat current across a gold-alkanedithiol-gold nanojunction behaves correctly-physically, with the thermal conductance value matching the literature. In contrast, the {\it full probability distribution function} for heat exchange, as generated by the simulator, violates the fundamental fluctuation symmetry for entropy production. We trace this failure back to the implementation of the thermostats and the expression used to calculate the heat exchange. To rectify this issue and produce the correct statistics, we introduce single-atom thermostats as an alternative to conventional many-atom thermostats. Once averaging heat exchange over the hot and cold thermostats, this approach successfully generates the correct probability distribution function, which we use to study the behavior of both the average heat current and its noise. We further examine the thermodynamic uncertainty relation in the molecular junction and show that it holds, albeit demonstrating nontrivial trends. Our study points to the need to carefully implement nonequilibrium molecular dynamics solvers in atomistic simulation software tools for future investigations of noise phenomena in thermal transport

Real-time qPCR Assay Development for Detection of Bacillus thuringiensis and Serratia marcescens DNA and the Influence of Complex Microbial Community DNA on Assay Sensitivity

Real-time quantitative polymerase chain reaction (real-time qPCR) assays are an effective technique to detect biological warfare agents and surrogate organisms. In my study, primers were designed to detect chromosomal DNA of biological warfare agent surrogates B. thuringiensis and S. marcescens (representing B. anthracis and Y. pestis, respectively) via real-time qPCR. Species-level specificity of the primers was demonstrated through comparisons with a bacterial strain panel and corroborated by qPCR data. Additionally, the primer efficacy was tested when template DNA was spiked into metagenomic DNA extracted from clinical lung microbiome samples. The results showed that while detection of B. thuringiensis or S. marcescens was still largely successful, the addition of metagenomic DNA did significantly inhibit amplification in most cases. The present study is significant not only for the design of multiple novel primer pairs able to detect bacterial agents in metagenomic DNA, but also the quantitative insight to the influence of background DNA on single species detection at low DNA concentrations

Screening large-scale association study data: exploiting interactions using random forests

BACKGROUND: Genome-wide association studies for complex diseases will produce genotypes on hundreds of thousands of single nucleotide polymorphisms (SNPs). A logical first approach to dealing with massive numbers of SNPs is to use some test to screen the SNPs, retaining only those that meet some criterion for futher study. For example, SNPs can be ranked by p-value, and those with the lowest p-values retained. When SNPs have large interaction effects but small marginal effects in a population, they are unlikely to be retained when univariate tests are used for screening. However, model-based screens that pre-specify interactions are impractical for data sets with thousands of SNPs. Random forest analysis is an alternative method that produces a single measure of importance for each predictor variable that takes into account interactions among variables without requiring model specification. Interactions increase the importance for the individual interacting variables, making them more likely to be given high importance relative to other variables. We test the performance of random forests as a screening procedure to identify small numbers of risk-associated SNPs from among large numbers of unassociated SNPs using complex disease models with up to 32 loci, incorporating both genetic heterogeneity and multi-locus interaction. RESULTS: Keeping other factors constant, if risk SNPs interact, the random forest importance measure significantly outperforms the Fisher Exact test as a screening tool. As the number of interacting SNPs increases, the improvement in performance of random forest analysis relative to Fisher Exact test for screening also increases. Random forests perform similarly to the univariate Fisher Exact test as a screening tool when SNPs in the analysis do not interact. CONCLUSIONS: In the context of large-scale genetic association studies where unknown interactions exist among true risk-associated SNPs or SNPs and environmental covariates, screening SNPs using random forest analyses can significantly reduce the number of SNPs that need to be retained for further study compared to standard univariate screening methods

Better primer design for metagenomics applications by increasing taxonomic distinguishability

Current methods of understanding microbiome composition and structure rely on accurately estimating the number of distinct species and their relative abundance. Most of these methods require an efficient PCR whose forward and reverse primers bind well to the same, large number of identifiable species, and produce amplicons that are unique. It is therefore not surprising that currently used universal primers designed many years ago are not as efficient and fail to bind to recently cataloged species. We propose an automated general method of designing PCR primer pairs that abide by primer design rules and uses current sequence database as input. Since the method is automated, primers can be designed for targeted microbial species or updated as species are added or deleted from the database. In silico experiments and laboratory experiments confirm the efficacy of the newly designed primers for metagenomics applications