The structural effects of mutations can aid in differential phenotype prediction of beta-myosin heavy chain (Myosin-7) missense variants

MOTIVATION: High-throughput sequencing platforms are increasingly used to screen patients with genetic disease for pathogenic mutations, but prediction of the effects of mutations remains challenging. Previously we developed SAAPdap (Single Amino Acid Polymorphism Data Analysis Pipeline) and SAAPpred (Single Amino Acid Polymorphism Predictor) that use a combination of rule-based structural measures to predict whether a missense genetic variant is pathogenic. Here we investigate whether the same methodology can be used to develop a differential phenotype predictor, which, once a mutation has been predicted as pathogenic, is able to distinguish between phenotypes-in this case the two major clinical phenotypes (hypertrophic cardiomyopathy, HCM, and dilated cardiomyopathy, DCM) associated with mutations in the beta-myosin heavy chain (MYH7) gene product (Myosin-7). RESULTS: A random forest predictor trained on rule-based structural analyses together with structural clustering data gave a Matthews' correlation coefficient (MCC) of 0.53 (accuracy, 75%). A post hoc removal of machine learning models that performed particularly badly, increased the performance (MCC = 0.61, Acc = 79%). This proof of concept suggests that methods used for pathogenicity prediction can be extended for use in differential phenotype prediction

TREATABILITY TEST FOR REMOVING TECHNETIUM-99 FROM 200-ZP-1 GROUNDWATER HANFORD SITE

The 200-ZP-1 Groundwater Operable Unit (OU) is one of two groundwater OUs located within the 200 West groundwater aggregate area of the Hanford Site. The primary risk-driving contaminants within the 200-ZP-1 OU include carbon tetrachloride and technetium-99 (Tc-99). A pump-and-treat system for this OU was initially installed in 1995 to control the 0.002 kg/m{sup 3} (2000 {micro}g/L) contour of the carbon tetrachloride plume. Carbon tetrachloride is removed from groundwater with the assistance of an air-stripping tower. Ten extraction wells and three injection wells operate at a combined rate of approximately 0.017m{sup 3}/s (17.03 L/s). In 2005, groundwater from two of the extraction wells (299-W15-765 and 299-W15-44) began to show concentrations greater than twice the maximum contaminant level (MCL) of Tc-99 (33,309 beq/m{sup 3} or 900 pCi/L). The Tc-99 groundwater concentrations from all ten of the extraction wells when mixed were more than one-half of the MCL and were slowly increasing. If concentrations continued to rise and the water remained untreated for Tc-99, there was concern that the water re-injected into the aquifer could exceed the MCL standard. Multiple treatment technologies were reviewed for selectively removing Tc-99 from the groundwater. Of the treatment technologies, only ion exchange was determined to be highly selective, commercially available, and relatively low in cost. Through research funded by the U.S. Department of Energy, the ion-exchange resin Purolite{reg_sign} A-530E was found to successfully remove Tc-99 from groundwater, even in the presence of competing anions. For this and other reasons, Purolite{reg_sign} A-530E ion exchange resin was selected for treatability testing. The treatability test required installing resin columns on the discharge lines from extraction wells 299-W15-765 and 299-W15-44. Preliminary test results have concluded that the Purolite{reg_sign} A-530E resin is effective at removing Tc-99 from groundwater to below detection limits even in the presence of competing anions (e.g., nitrate and sulfate) at concentrations five to six magnitudes higher than Tc-99

Dietary assessment of British police force employees: A description of diet record coding procedures and cross-sectional evaluation of dietary energy intake reporting (The Airwave Health Monitoring Study)

Objectives: Dietary intake is a key aspect of occupational health. To capture the characteristics of dietary behaviour that is affected by occupational environment that may affect disease risk, a collection of prospective multiday dietary records is required. The aims of this paper are to: (1) collect multiday dietary data in the Airwave Health Monitoring Study, (2) describe the di etary coding procedures applied and (3) investigate the plausibility of dietary reporting in this occupational cohort. Design: A dietary coding protocol for this large-scale study was developed to minimise coding error rate. Participants (n 4412) who completed 7-day food records were included for cross-sectional analyses. Energy intake (EI) misreporting was estimated using the Goldberg method. Multivariate logistic regression models were applied to determine participant characteristics associated with EI misreporting. Setting: British police force employees enrolled (2007-2012) into the Airwave Health Monitoring Study. Results: The mean code error rate per food diary was 3.7% (SD 3.2%). The strongest predictors of EI under-reporting were body mass index (BMI) and physical activity. Compared with participants with BMI 30 kg/m2 had increased odds of being classified as under-reporting EI (men OR 5.20 95% CI 3.92 to 6.89; women OR 2.66 95% CI 1.85 to 3.83). Men and women in the highest physical activity category compared with the lowest were also more likely to be classified as underreporting (men OR 3.33 95% CI 2.46 to 4.50; women OR 4.34 95% CI 2.91 to 6.55). Conclusions: A reproducible dietary record coding procedure has been developed to minimise coding error in complex 7-day diet diaries. The prevalence of EI under-reporting is comparable with existing national UK cohorts and, in agreement with previous studies, classification of under-reporting was biased towards specific subgroups of participants

Computer simulation of syringomyelia in dogs

Syringomyelia is a pathological condition in which fluid-filled cavities (syringes) form and expand in the spinal cord. Syringomyelia is often linked with obstruction of the craniocervical junction and a Chiari malformation, which is similar in both humans and animals. Some brachycephalic toy breed dogs such as Cavalier King Charles Spaniels (CKCS) are particularly predisposed. The exact mechanism of the formation of syringomyelia is undetermined and consequently with the lack of clinical explanation, engineers and mathematicians have resorted to computer models to identify possible physical mechanisms that can lead to syringes. We developed a computer model of the spinal cavity of a CKCS suffering from a large syrinx. The model was excited at the cranial end to simulate the movement of the cerebrospinal fluid (CSF) and the spinal cord due to the shift of blood volume in the cranium related to the cardiac cycle. To simulate the normal condition, the movement was prescribed to the CSF. To simulate the pathological condition, the movement of CSF was blocked

Predicting erythropoietin resistance in hemodialysis patients with type 2 diabetes

<p>Background: Resistance to ESAs (erythropoietin stimulating agents) is highly prevalent in hemodialysis patients with diabetes and associated with an increased mortality. The aim of this study was to identify predictors for ESA resistance and to develop a prediction model for the risk stratification in these patients.</p> <p>Methods: A post-hoc analysis was conducted of the 4D study, including 1015 patients with type 2 diabetes undergoing hemodialysis. Determinants of ESA resistance were identified by univariate logistic regression analyses. Subsequently, multivariate models were performed with stepwise inclusion of significant predictors from clinical parameters, routine laboratory and specific biomarkers.</p> <p>Results: In the model restricted to clinical parameters, male sex, shorter dialysis vintage, lower BMI, history of CHF, use of ACE-inhibitors and a higher heart rate were identified as independent predictors of ESA resistance. In regard to routine laboratory markers, lower albumin, lower iron saturation, higher creatinine and higher potassium levels were independently associated with ESA resistance. With respect to specific biomarkers, higher ADMA and CRP levels as well as lower Osteocalcin levels were predictors of ESA resistance.</p> <p>Conclusions: Easily obtainable clinical parameters and routine laboratory parameters can predict ESA resistance in diabetic hemodialysis patients with good discrimination. Specific biomarkers did not meaningfully further improve the risk prediction of ESA resistance. Routinely assessed data can be used in clinical practice to stratify patients according to the risk of ESA resistance, which may help to assign appropriate treatment strategies.</p&gt

Untargeted metabolomic analysis investigating links between unprocessed red meat intake and markers of inflammation.

BACKGROUND: Whether red meat consumption is associated with higher inflammation or confounded by increased adiposity remains unclear. Plasma metabolites capture the effects of diet after food is processed, digested, and absorbed, and correlate with markers of inflammation, so they can help clarify diet-health relationships. OBJECTIVE: To identify whether any metabolites associated with red meat intake are also associated with inflammation. METHODS: A cross-sectional analysis of observational data from older adults (52.84% women, mean age 63 ± 0.3 y) participating in the Multi-Ethnic Study of Atherosclerosis (MESA). Dietary intake was assessed by food-frequency questionnaire, alongside C-reactive protein (CRP), interleukin-2, interleukin-6, fibrinogen, homocysteine, and tumor necrosis factor alpha, and untargeted proton nuclear magnetic resonance (1H NMR) metabolomic features. Associations between these variables were examined using linear regression models, adjusted for demographic factors, lifestyle behaviors, and body mass index (BMI). RESULTS: In analyses that adjust for BMI, neither processed nor unprocessed forms of red meat were associated with any markers of inflammation (all P > 0.01). However, when adjusting for BMI, unprocessed red meat was inversely associated with spectral features representing the metabolite glutamine (sentinel hit: β = -0.09 ± 0.02, P = 2.0 × 10-5), an amino acid which was also inversely associated with CRP level (β = -0.11 ± 0.01, P = 3.3 × 10-10). CONCLUSIONS: Our analyses were unable to support a relationship between either processed or unprocessed red meat and inflammation, over and above any confounding by BMI. Glutamine, a plasma correlate of lower unprocessed red meat intake, was associated with lower CRP levels. The differences in diet-inflammation associations, compared with diet metabolite-inflammation associations, warrant further investigation to understand the extent that these arise from the following: 1) a reduction in measurement error with metabolite measures; 2) the extent that which factors other than unprocessed red meat intake contribute to glutamine levels; and 3) the ability of plasma metabolites to capture individual differences in how food intake is metabolized

Indices of Change: Analysing the Indexical Properties of Data from Psychotherapy Case Work to Discern Patterns of Therapeutic Change Over Time

With reference to semiotic theory, a form of data analysis is proposed that explicitly unpacks the indexical properties of data from psychotherapy case studies. The approach is observed to happen within the therapeutic hour as a co-production between the client and their therapist. Thus analysing the data in this way seeks to address two common charges against traditional research into psychotherapy processes: that it fails to capture the true value of the therapy and lacks the sensitivity to measure outcomes. Two case vignettes will demonstrate the utility of this approach in lived context, with meaning emerging as therapy continues

A microRNA Expression Profile as Non-Invasive Biomarker in a Large Arrhythmogenic Cardiomyopathy Cohort

Arrhythmogenic Cardiomyopathy (AC) is a clinically and genetically heterogeneous myocardial disease. Half of AC patients harbour private desmosomal gene variants. Although microRNAs (miRNAs) have emerged as key regulator molecules in cardiovascular diseases and their involvement, correlated to phenotypic variability or to non-invasive biomarkers, has been advanced also in AC, no data are available in larger disease cohorts. Here, we propose the largest AC cohort unbiased by technical and biological factors. MiRNA profiling on nine right ventricular tissue, nine blood samples of AC patients, and four controls highlighted 10 differentially expressed miRNAs in common. Six of these were validated in a 90-AC patient cohort independent from genetic status: miR-122-5p, miR-133a-3p, miR-133b, miR-142-3p, miR-182-5p, and miR-183-5p. This six-miRNA set showed high discriminatory diagnostic power in AC patients when compared to controls (AUC-0.995), non-affected family members of AC probands carrying a desmosomal pathogenic variant (AUC-0.825), and other cardiomyopathy groups (Hypertrophic Cardiomyopathy: AUC-0.804, Dilated Cardiomyopathy: AUC-0.917, Brugada Syndrome: AUC-0.981, myocarditis: AUC-0.978). AC-related signalling pathways were targeted by this set of miRNAs. A unique set of six-miRNAs was found both in heart-tissue and blood samples of AC probands, supporting its involvement in disease pathogenesis and its possible role as a non-invasive AC diagnostic biomarker

Developing a digital intervention for cancer survivors: an evidence-, theory- and person-based approach

This paper illustrates a rigorous approach to developing digital interventions using an evidence-, theory- and person-based approach. Intervention planning included a rapid scoping review which identified cancer survivors’ needs, including barriers and facilitators to intervention success. Review evidence (N=49 papers) informed the intervention’s Guiding Principles, theory-based behavioural analysis and logic model. The intervention was optimised based on feedback on a prototype intervention through interviews (N=96) with cancer survivors and focus groups with NHS staff and cancer charity workers (N=31). Interviews with cancer survivors highlighted barriers to engagement, such as concerns about physical activity worsening fatigue. Focus groups highlighted concerns about support appointment length and how to support distressed participants. Feedback informed intervention modifications, to maximise acceptability, feasibility and likelihood of behaviour change. Our systematic method for understanding user views enabled us to anticipate and address important barriers to engagement. This methodology may be useful to others developing digital interventions

The effects of weather and climate change on dengue

There is much uncertainty about the future impact of climate change on vector-borne diseases. Such uncertainty reflects the difficulties in modelling the complex interactions between disease, climatic and socioeconomic determinants. We used a comprehensive panel dataset from Mexico covering 23 years of province-specific dengue reports across nine climatic regions to estimate the impact of weather on dengue, accounting for the effects of non-climatic factors