Extraction of Indirectly Captured Information for Use in a Comparison of Offline pH Measurement Technologies

Understanding the causes of discrepancies in pH readings of a sample can allow more robust pH control strategies to be implemented. It was found that 59.4% of differences between two offline pH measurement technologies for an historical dataset lay outside an expected instrument error range of ± 0.02pH. A new variable, OsmoRes, was created using multiple linear regression (MLR) to extract information indirectly captured in the recorded measurements for osmolality. Principal component analysis and time series analysis were used to validate the expansion of the historical dataset with the new variable OsmoRes. MLR was used to identify variables strongly correlated (p <0.05) with differences in pH readings by the two offline pH measurement technologies. These included concentrations of specific chemicals (e.g. glucose) and OsmoRes, indicating culture medium and bolus feed additions as possible causes of discrepancies between the offline pH measurement technologies. Temperature was also identified as statistically significant. It is suggested that this was a result of differences in pH-temperature compensations employed by the pH measurement technologies. In summary, a method for extracting indirectly captured information has been demonstrated, and it has been shown that competing pH measurement technologies were not necessarily interchangeable at the desired level of control (±0.02pH)

Genetic variation in the HLA region is associated with susceptibility to herpes zoster.

Herpes zoster, commonly referred to as shingles, is caused by the varicella zoster virus (VZV). VZV initially manifests as chicken pox, most commonly in childhood, can remain asymptomatically latent in nerve tissues for many years and often re-emerges as shingles. Although reactivation may be related to immune suppression, aging and female sex, most inter-individual variability in re-emergence risk has not been explained to date. We performed a genome-wide association analyses in 22,981 participants (2280 shingles cases) from the electronic Medical Records and Genomics Network. Using Cox survival and logistic regression, we identified a genomic region in the combined and European ancestry groups that has an age of onset effect reaching genome-wide significance (P&gt;1.0 × 10(-8)). This region tags the non-coding gene HCP5 (HLA Complex P5) in the major histocompatibility complex. This gene is an endogenous retrovirus and likely influences viral activity through regulatory functions. Variants in this genetic region are known to be associated with delay in development of AIDS in people infected by HIV. Our study provides further suggestion that this region may have a critical role in viral suppression and could potentially harbor a clinically actionable variant for the shingles vaccine

The eMERGE Network: A consortium of biorepositories linked to electronic medical records data for conducting genomic studies

<p>Abstract</p> <p>Introduction</p> <p>The eMERGE (electronic MEdical Records and GEnomics) Network is an NHGRI-supported consortium of five institutions to explore the utility of DNA repositories coupled to Electronic Medical Record (EMR) systems for advancing discovery in genome science. eMERGE also includes a special emphasis on the ethical, legal and social issues related to these endeavors.</p> <p>Organization</p> <p>The five sites are supported by an Administrative Coordinating Center. Setting of network goals is initiated by working groups: (1) Genomics, (2) Informatics, and (3) Consent & Community Consultation, which also includes active participation by investigators outside the eMERGE funded sites, and (4) Return of Results Oversight Committee. The Steering Committee, comprised of site PIs and representatives and NHGRI staff, meet three times per year, once per year with the External Scientific Panel.</p> <p>Current progress</p> <p>The primary site-specific phenotypes for which samples have undergone genome-wide association study (GWAS) genotyping are cataract and HDL, dementia, electrocardiographic QRS duration, peripheral arterial disease, and type 2 diabetes. A GWAS is also being undertaken for resistant hypertension in ≈2,000 additional samples identified across the network sites, to be added to data available for samples already genotyped. Funded by ARRA supplements, secondary phenotypes have been added at all sites to leverage the genotyping data, and hypothyroidism is being analyzed as a cross-network phenotype. Results are being posted in dbGaP. Other key eMERGE activities include evaluation of the issues associated with cross-site deployment of common algorithms to identify cases and controls in EMRs, data privacy of genomic and clinically-derived data, developing approaches for large-scale meta-analysis of GWAS data across five sites, and a community consultation and consent initiative at each site.</p> <p>Future activities</p> <p>Plans are underway to expand the network in diversity of populations and incorporation of GWAS findings into clinical care.</p> <p>Summary</p> <p>By combining advanced clinical informatics, genome science, and community consultation, eMERGE represents a first step in the development of data-driven approaches to incorporate genomic information into routine healthcare delivery.</p

Understanding Palliative Cancer Chemotherapy: About Shared Decisions and Shared Trajectories

Most models of patient-physician communication take decision-making as a central concept. However, we found that often the treatment course of metastatic cancer patients is not easy to describe in straightforward terms used in decision-making models but is instead frequently more erratic. Our aim was to analyse these processes as trajectories. We used a longitudinal case study of 13 patients with metastatic colorectal and pancreatic cancer for whom palliative chemotherapy was a treatment option, and analysed 65 semi-structured interviews. We analysed three characteristics of the treatment course that contributed to the ‘erraticness’ of the course: (1) The treatment (with or without chemotherapy) contained many options; (2) these options were not stable entities to be decided upon, but changed identity over the course of treatment, and (3) contrary to the closure (option X means no option Y, Z, etc.) a decision implies, the treatment course was a continuous process in which options instead remained open. When the treatment course is characterised by these many and changeable options that do not result in closure, the shared decision-making model should take these into account. More attention needs to be paid to the erratic character of the process in which the doctor has to provide continuous information that is related to the changing situation of the patient; also, flexibility in dealing with protocols is warranted, as is vigilance about the overall direction of the process

Towards the clinical implementation of pharmacogenetics in bipolar disorder.

BackgroundBipolar disorder (BD) is a psychiatric illness defined by pathological alterations between the mood states of mania and depression, causing disability, imposing healthcare costs and elevating the risk of suicide. Although effective treatments for BD exist, variability in outcomes leads to a large number of treatment failures, typically followed by a trial and error process of medication switches that can take years. Pharmacogenetic testing (PGT), by tailoring drug choice to an individual, may personalize and expedite treatment so as to identify more rapidly medications well suited to individual BD patients.DiscussionA number of associations have been made in BD between medication response phenotypes and specific genetic markers. However, to date clinical adoption of PGT has been limited, often citing questions that must be answered before it can be widely utilized. These include: What are the requirements of supporting evidence? How large is a clinically relevant effect? What degree of specificity and sensitivity are required? Does a given marker influence decision making and have clinical utility? In many cases, the answers to these questions remain unknown, and ultimately, the question of whether PGT is valid and useful must be determined empirically. Towards this aim, we have reviewed the literature and selected drug-genotype associations with the strongest evidence for utility in BD.SummaryBased upon these findings, we propose a preliminary panel for use in PGT, and a method by which the results of a PGT panel can be integrated for clinical interpretation. Finally, we argue that based on the sufficiency of accumulated evidence, PGT implementation studies are now warranted. We propose and discuss the design for a randomized clinical trial to test the use of PGT in the treatment of BD

Payer leverage and hospital compliance with a benchmark: a population-based observational study

<p>Abstract</p> <p>Background</p> <p>Since 1976, Medicare has linked reimbursement for hospitals performing organ transplants to the attainment of certain benchmarks, including transplant volume. While Medicare is a stakeholder in all transplant services, its role in renal transplantation is likely greater, given its coverage of end-stage renal disease. Thus, Medicare's transplant experience allows us to examine the role of payer leverage in motivating hospital benchmark compliance.</p> <p>Methods</p> <p>Nationally representative discharge data for kidney (<it>n </it>= 29,272), liver (<it>n </it>= 7,988), heart (<it>n </it>= 3,530), and lung (<it>n </it>= 1,880) transplants from the Nationwide Inpatient Sample (1993 – 2003) were employed. Logistic regression techniques with robust variance estimators were used to examine the relationship between hospital volume compliance and Medicare market share; generalized estimating equations were used to explore the association between patient-level operative mortality and hospital volume compliance.</p> <p>Results</p> <p>Medicare's transplant market share varied by organ [57%, 28%, 27%, and 18% for kidney, lung, heart, and liver transplants, respectively (<it>P </it>< 0.001)]. Volume-based benchmark compliance varied by transplant type [85%, 75%, 44%, and 39% for kidney, liver, heart, and lung transplants, respectively (<it>P </it>< 0.001)], despite a lower odds of operative mortality at compliant hospitals. Adjusting for organ supply, high market leverage was independently associated with compliance at hospitals transplanting kidneys (OR, 143.00; 95% CI, 18.53 – 1103.49), hearts (OR, 2.84; 95% CI, 1.51 – 5.34), and lungs (OR, 3.24; 95% CI, 1.57 – 6.67).</p> <p>Conclusion</p> <p>These data highlight the influence of payer leverage–an important contextual factor in value-based purchasing initiatives. For uncommon diagnoses, these data suggest that at least 30% of a provider's patients might need to be "at risk" for an incentive to motivate compliance.</p

Lettuce Cultivar Mediates Both Phyllosphere and Rhizosphere Activity of Escherichia coli O157:H7

Plant roots and leaves can be colonized by human pathogenic bacteria, and accordingly some of the largest outbreaks of foodborne illness have been associated with salad leaves contaminated by E. coli O157. Integrated disease management strategies often exploit cultivar resistance to provide a level of protection from economically important plant pathogens; however, there is limited evidence of whether the genotype of the plant can also influence the extent of E. coli O157 colonization. To determine cultivar-specific effects on colonization by E. coli O157, we used 12 different cultivars of lettuce inoculated with a chromosomally lux-marked strain of E. coli O157:H7. Lettuce seedlings grown gnotobiotically in vitro did exhibit a differential cultivar-specific response to E. coli O157 colonization, although importantly there was no relationship between metabolic activity (measured as bioluminescence) and cell numbers. Metabolic activity was highest and lowest on the cultivars Vaila-winter gem and Dazzle respectively, and much higher in endophytic and tightly bound cells than in epiphytic and loosely bound cells. The cultivar effect was also evident in the rhizosphere of plants grown in compost, which suggests that cultivar-specific root exudate influences E. coli O157 activity. However, the influence of cultivar in the rhizosphere was the opposite to that in the phyllosphere, and the higher number and activity of E. coli O157 cells in the rhizosphere may be a consequence of them not being able to gain entry to the plant as effectively. If metabolic activity in the phyllosphere corresponds to a more prepared state of infectivity during human consumption, leaf internalization of E. coli O157 may pose more of a public health risk than leaf surface contamination alone

Protein docking by Rotation-Based Uniform Sampling (RotBUS) with fast computing of intermolecular contact distance and residue desolvation

<p>Abstract</p> <p>Background</p> <p>Protein-protein interactions are fundamental for the majority of cellular processes and their study is of enormous biotechnological and therapeutic interest. In recent years, a variety of computational approaches to the protein-protein docking problem have been reported, with encouraging results. Most of the currently available protein-protein docking algorithms are composed of two clearly defined parts: the sampling of the rotational and translational space of the interacting molecules, and the scoring and clustering of the resulting orientations. Although this kind of strategy has shown some of the most successful results in the CAPRI blind test <url>http://www.ebi.ac.uk/msd-srv/capri</url>, more efforts need to be applied. Thus, the sampling protocol should generate a pool of conformations that include a sufficient number of near-native ones, while the scoring function should discriminate between near-native and non-near-native proposed conformations. On the other hand, protocols to efficiently include full flexibility on the protein structures are increasingly needed.</p> <p>Results</p> <p>In these work we present new computational tools for protein-protein docking. We describe here the RotBUS (Rotation-Based Uniform Sampling) method to generate uniformly distributed sets of rigid-body docking poses, with a new fast calculation of the optimal contacting distance between molecules. We have tested the method on a standard benchmark of unbound structures and we can find near-native solutions in 100% of the cases. After applying a new fast filtering scheme based on residue-based desolvation, in combination with FTDock plus pyDock scoring, near-native solutions are found with rank ≤ 50 in 39% of the cases. Knowledge-based experimental restraints can be easily included to reduce computational times during sampling and improve success rates, and the method can be extended in the future to include flexibility of the side-chains.</p> <p>Conclusions</p> <p>This new sampling algorithm has the advantage of its high speed achieved by fast computing of the intermolecular distance based on a coarse representation of the interacting surfaces. In addition, a fast desolvation scoring permits the screening of millions of conformations at low computational cost, without compromising accuracy. The protocol presented here can be used as a framework to include restraints, flexibility and ensemble docking approaches.</p

Acidogenic Potential of “Sugar-Free” Cough Drops

A patient presented with extensive marginal ditching around restorations recently placed during whole-mouth rehabilitation. The patient was not xerostomic and was otherwise normal except for the self-reported excessive use of “sugar-free” cough drops sweetened with sorbitol and Isomalt® (an equimolar mix of glucosyl-mannitol and glucosylsorbitol). This prompted an in vitro investigation to determine whether Streptococcus sobrinus 6715, a cariogenic streptococcus, could grow and produce acid in growth medium containing an aqueous extract of such “sugar-free” cough drops. The results indicate that S. sobrinus 6715 uses Isomalt® and sorbitol extensively, producing terminal culture pH as low as 4.2 when grown on medium with cough drop extract containing these sugars. This pH is sufficient to demineralize dental enamel. Patients should be cautioned against the chronic overuse of “sugar-free” cough drops and other “sugar-free” confections sweetened with a mixture of Isomalt® and sorbitol

EphB6 Receptor Modulates Micro RNA Profile of Breast Carcinoma Cells

Breast carcinoma cells have a specific pattern of expression for Eph receptors and ephrin ligands. EphB6 has previously been characterized as a signature molecule for invasive breast carcinoma cells. The transcription of EphB6 is silenced in breast carcinoma cells and its re-expression leads to decreased invasiveness of MDA-MB-231 cells. Such differences in phenotypes of native and EphB6 expressing MDA-MB-231 cells relate to an altered profile of micro RNAs. Comparative hybridization of total RNA to slides containing all known miRNAs by using locked nucleic acid (LNA) miRCURY platform yielded a significantly altered profile of miRNAs in MDA-MB-231 cells stably transfected with EphB6. After applying a threshold of change and a p-value of <0.001, the list of significantly altered miRNAs included miR-16, miR-23a, miR-24, miR-26a, miR-29a, miR-100, miRPlus-E1172 and miRPlus-E1258. The array-based changes were validated by real-time qPCR of miR-16, miR-23a, miR-24 and miR-100. Except miRPlus-E1172 and miRPlus-E1258, the remaining six miRNAs have been observed in a variety of cancers. The biological relevance of target mRNAs was predicted by using a common-target selection approach that allowed the identification of SMARCA5, SMARCC1, eIF2C2, eIF2C4, eIF4EBP2, FKABP5, FKBP1A, TRIB1, TRIB2, TRIB3, BMPR2, BMPR1A and BMPR1B as important targets of a subset of significantly altered miRNAs. Quantitative PCR revealed that the levels of SMARCC1, eIFC4, eIF4EB2, FKBP1a, FKBP5, TRIB1, TRIB3, BMPR1a and BMPR2 transcripts were significantly decreased in MDA-MB-231 cells transfected with EphB6. These observations confirm targeting of specific mRNAs by miR-100, miR-23a, miR-16 and miR-24, and suggest that the kinase-deficient EphB6 receptor is capable of initiating signal transduction from the cell surface to the nucleus resulting in the altered expression of a variety of genes involved in tumorigenesis and invasion. The alterations in miRNAs and their target mRNAs also suggest indirect involvement of EphB6 in PI3K/Akt/mTOR pathways