Export of RNA silencing from C. elegans tissues does not require the RNA channel SID-1

Double-stranded RNA (dsRNA) triggers RNA interference (RNAi) to silence genes of matching sequence. In some animals this experimentally induced silencing is transported between cells, and studies in the nematode Caenorhabditis elegans have shown that the dsRNA channel SID-1 is required for the import of such transported silencing signals. Gene silencing can also be triggered by endogenously expressed RNAi triggers, but it is unknown whether such silencing is transported between cells. Here, we show that, in C. elegans, SID-1 is required for efficient silencing of multicopy transgenes, indicating that mobile silencing signals contribute to transgene silencing. Further, most tissues can transport silencing initiated by the tissue-specific transgenic expression of RNAi triggers to other tissues, consistent with expressed RNAi triggers generating mobile silencing signals. Whereas the import of silencing signals requires SID-1, we found that mobile silencing signals generated by transgene-expressed RNAi triggers are exported to other tissues through a SID-1-independent mechanism. Furthermore, when RNAi triggers are expressed in ingested Escherichia coli, silencing signals can be transported to internal tissues from the gut lumen across gut cells that lack SID-1. Thus, C. elegans can transport endogenous and exogenous RNA silencing signals between many different tissues via at least 2 SID-1 independent export pathways.     

Carer Knowledge and Perceptions of Healthy Lifestyles for Adults with Intellectual Disabilities

Background Carers can have a significant impact supporting people with intellectual disabilities to make healthy lifestyle choices. This study examines carers’ training needs on diet and physical activity. Methods A cross‐sectional survey was undertaken of the knowledge and perceptions of carers supporting adults with intellectual disabilities. An interviewer administered questionnaire was used to examine carer knowledge of public health recommendations on diet and physical activity; perceptions of the benefits of healthy diets and physical activity levels; and the carer views on the barriers to change experienced by individuals with intellectual disabilities. Results Sixty‐three carers took part in the study. They generally had a low level of knowledge around public health recommendations on diet and physical activity. Greater importance was attributed to the health benefits of diet than physical activity. Carers rated intrapersonal barriers to change within the person with intellectual disabilities as more important, than interpersonal or external barriers to change, with significant differences in perceived barriers relevant to diet and physical activity. Conclusions Carers supporting adults with intellectual disabilities have significant training needs relevant to promoting healthy lifestyles. This highlights the opportunity to promote health improvement via the development, and provision, of effective training initiatives.     

Design and synthesis of deuterated boceprevir analogs with enhanced pharmacokinetic properties

As part of an ongoing effort to apply the Deuterated Chemical Entity Platform (DCE Platform?) to clinically validated drugs, the synthesis of deuterated analogs of the hepatitis C virus protease inhibitor boceprevir was carried out. The devised synthetic routes allowed for site‐selective deuterium incorporation with high levels of isotopic purity. Application of the DCE Platform? to boceprevir enabled the identification of several deuterated analogs that display marked levels of in vitro metabolic stabilization. Most notably, analog 1g exhibits a near doubling of in vitro half‐life in human liver microsomal assays. The details of the convergent synthetic route to the boceprevir isotopologs and the results of the metabolic stability assays are described herein.     

A learner‐centered curriculum in medical interviewing

Background: Recent research documents widespread deficits in the physical examination skills of practicing physicians. Purpose: This study explored physical examination skills of 3rd-year medical students after completion of a course in physical diagnosis. Methods: Standardized patient physical examination checklist data were analyzed for a cohort of 2,038 medical students for a patient presenting with classic signs and symptoms of an acute myocardial infarction. A follow-up paper case and survey explored reasons underlying omissions. Results: Students systematically omitted 3 of 10 component maneuvers critical to the evaluation of a patient with shortness of breath and chest pain. The same pattern of omissions was observed across 8 medical schools and over 2 successive years. The paper case follow-up study ruled out time constraints and performance anxiety as the cause. Survey data revealed that students may omit a maneuver due to inability to recall pertinence (blood pressure in both arms) or difficulty discriminating findings (heart sounds at different locations), or because of inadequate technical mastery (percussion of the lungs). Conclusions: These data suggest fundamental inadequacies in the current paradigm for teaching physical examination skills. Standardized patient checklist data can provide an informative window into the efficacy of teaching practices.     

The Availability and Use of Out-of-Hospital Physiologic Information to Identify High-Risk Injured Children in a Multisite,Population-Based Cohort

Objective. The validity of using adult physiologic criteria to triage injured children in the out-of-hospital setting remains unproven. Among children meeting adult field physiologic criteria, we assessed the availability of physiologic information, the incidence of death or prolonged hospitalization, and whether age-specific criteria would improve the specificity of the physiologic triage step. Methods. We analyzed a prospective, out-of-hospital cohort of injured children aged ≤14 years collected from December 2005 through February 2007 by 237 emergency medical services (EMS) agencies transporting to 207 acute care hospitals (trauma and nontrauma centers) in 11 sites across the United States and Canada. Inclusion criteria were standard adult physiologic values: systolic blood pressure (SBP) ≤90 mmHg, respiratory rate < 10 or > 29 breaths/min, Glasgow Coma Scale (GCS) score ≤12, and field intubation attempt. Seven physiologic variables (including age-specific values) and three demographic and mechanism variables were included in the analysis. “High-risk” children included those who died (field or in-hospital) or were hospitalized > 2 days. The decision tree was derived and validated using binary recursive partitioning. Results. Nine hundred fifty-five children were included in the analysis, of whom 62 (6.5%) died and 117 (12.3%) were hospitalized > 2 days. Missing values were common, ranging from 6% (respiratory rate) to 53% (pulse oximetry), and were associated with younger age and high-risk outcome. The final decision rule included four variables (assisted ventilation, GCS score < 11, pulse oximetry < 95%, and SBP > 96 mmHg), which demonstrated improved specificity (71.7% [95% confidence interval (CI) 66.7–76.6%]) at the expense of missing high-risk children (sensitivity 76.5% [95% CI 66.4–86.6%]). Conclusions. The incidence of high-risk injured children meeting adult physiologic criteria is relatively low and the findings from this sample do not support using age-specific values to better identify such children. However, the amount and pattern of missing data may compromise the value and practical use of field physiologic information in pediatric triage.