Daedalus and Gasz recruit Armitage to mitochondria, bringing piRNA precursors to the biogenesis machinery.

The Piwi-interacting RNA (piRNA) pathway is a small RNA-based immune system that silences mobile genetic elements in animal germlines. piRNA biogenesis requires a specialized machinery that converts long single-stranded precursors into small RNAs of ∼25-nucleotides in length. This process involves factors that operate in two different subcellular compartments: the nuage/Yb body and mitochondria. How these two sites communicate to achieve accurate substrate selection and efficient processing remains unclear. Here, we investigate a previously uncharacterized piRNA biogenesis factor, Daedalus (Daed), that is located on the outer mitochondrial membrane. Daed is essential for Zucchini-mediated piRNA production and the correct localization of the indispensable piRNA biogenesis factor Armitage (Armi). We found that Gasz and Daed interact with each other and likely provide a mitochondrial "anchoring platform" to ensure that Armi is held in place, proximal to Zucchini, during piRNA processing. Our data suggest that Armi initially identifies piRNA precursors in nuage/Yb bodies in a manner that depends on Piwi and then moves to mitochondria to present precursors to the mitochondrial biogenesis machinery. These results represent a significant step in understanding a critical aspect of transposon silencing; namely, how RNAs are chosen to instruct the piRNA machinery in the nature of its silencing targets.

A genome-wide RNAi screen identifies factors required for distinct stages of C. elegans piRNA biogenesis.

In animals, piRNAs and their associated Piwi proteins guard germ cell genomes against mobile genetic elements via an RNAi-like mechanism. In Caenorhabditis elegans, 21U-RNAs comprise the piRNA class, and these collaborate with 22G RNAs via unclear mechanisms to discriminate self from nonself and selectively and heritably silence the latter. Recent work indicates that 21U-RNAs are post-transcriptional processing products of individual transcription units that produce ∼ 26-nucleotide capped precursors. However, nothing is known of how the expression of precursors is controlled or how primary transcripts give rise to mature small RNAs. We conducted a genome-wide RNAi screen to identify components of the 21U biogenesis machinery. Screening by direct, quantitative PCR (qPCR)-based measurements of mature 21U-RNA levels, we identified 22 genes important for 21U-RNA production, termed TOFUs (Twenty-One-u Fouled Ups). We also identified seven genes that normally repress 21U production. By measuring mature 21U-RNA and precursor levels for the seven strongest hits from the screen, we assigned factors to discrete stages of 21U-RNA production. Our work identifies for the first time factors separately required for the transcription of 21U precursors and the processing of these precursors into mature 21U-RNAs, thereby providing a resource for studying the biogenesis of this important small RNA class.

National analysis of sepsis hospitalizations and factors contributing to sepsis in-hospital mortality in Canada.

Sepsis is one of the leading causes of in-hospital mortality in Canada. Patient safety is an important component of sepsis prevention and control. The Canadian Institute for Health Information recently released a report that examines a national picture of sepsis hospitalizations and mortality. This article highlights and expands some of the key findings from this report. Specifically, we look here more closely at patients admitted through the emergency departments (ED) in order to determine if earlier recognition of sepsis in the ED would lead to improved patient outcomes.

Evaluation of AAP guidelines for cholesterol screening in youth: Project HeartBeat!

BACKGROUND: The American Academy of Pediatrics (AAP) criterion for screening for hypercholesterolemia in children is family history of hypercholesterolemia or cardiovascular disease or BMI > or =85th percentile. This paper aims to determine the sensitivity, specificity, and positive predictive value (PPV) of dyslipidemia screening using AAP criteria along with either family history or BMI. METHODS: Height, weight, plasma total cholesterol, low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), triglycerides, and family history were obtained for 678 children aged 8, 11, and 14 years, enrolled from 1991 to 1993 in Project HeartBeat!. Sensitivity, specificity, and PPV screening of each lipid component using family history alone, BMI > or =85th percentile alone, or family history and/or BMI > or =85th percentile, were calculated using 2008 AAP criteria (total cholesterol, LDL-C, and triglycerides > or =90th percentile; HDL-C <10th percentile). RESULTS: Sensitivity of detecting abnormal total cholesterol, LDL-C, HDL-C, and triglycerides using family history alone ranged from 38% to 43% and significantly increased to 54%-66% using family history and/or BMI. Specificity significantly decreased from approximately 65% to 52%, and there were no notable changes in PPV. In black children, cholesterol screening using the BMI > or =85th percentile criterion had higher sensitivity than when using the family history criterion. In nonblacks, family history and/or BMI > or =85th percentile had greater sensitivity than family history alone. CONCLUSIONS: When the BMI screening criterion was used along with the family history criterion, sensitivity increased, specificity decreased, and PPV changed trivially for detection of dyslipidemia. Despite increased screening sensitivity by adding the BMI criterion, a clinically significant number of children still may be misclassified.

Project HeartBeat! Concept, development, and design.

Major cardiovascular disease (CVD) risk factors begin development in childhood and adolescence. Project HeartBeat! studied early development of these risk factors as growth processes. Growth, body composition, sexual maturation, major CVD risk factors, and cardiac structure and function were monitored every 4 months for up to 4 years among 678 children and adolescents (49.1% girls; 20.1% blacks) aged 8, 11, or 14 years at study entry. All resided in The Woodlands or Conroe TX. Interviews were conducted at entry and annually on diet, physical activity, and health history of participants and their families. Data were collected from 1991 to 1995, and study investigators continue data analysis and reporting. Overlap in ages at examination among three cohorts (aged 8-12, 11-15, and 14-18 years at baseline) and use of multilevel modeling methods permit analysis of some 5500 observations on each principal variable for the synthetic cohort from ages 8 to 18 years. The mixed-longitudinal design provides trajectories of change with age, for total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, and triglycerides; systolic, and fourth-phase and fifth-phase diastolic blood pressure, and left ventricular mass. These trajectories are then related to concurrent measures of multiple indices of body composition and sexual maturation and adjusted for energy intake and physical activity. The data provide valuable insights into risk factor development and suggest a fresh approach to understanding influences on blood lipids, blood pressure, and left ventricular mass during the period of childhood and adolescence, a period of dynamic change in these risk factors.

Application of patient safety indicators internationally: a pilot study among seven countries.

OBJECTIVE: To explore the potential for international comparison of patient safety as part of the Health Care Quality Indicators project of the Organization for Economic Co-operation and Development (OECD) by evaluating patient safety indicators originally published by the US Agency for Healthcare Research and Quality (AHRQ). DESIGN: A retrospective cross-sectional study. SETTING: Acute care hospitals in the USA, UK, Sweden, Spain, Germany, Canada and Australia in 2004 and 2005/2006. DATA SOURCES: Routine hospitalization-related administrative data from seven countries were analyzed. Using algorithms adapted to the diagnosis and procedure coding systems in place in each country, authorities in each of the participating countries reported summaries of the distribution of hospital-level and overall (national) rates for each AHRQ Patient Safety Indicator to the OECD project secretariat. RESULTS: Each country's vector of national indicator rates and the vector of American patient safety indicators rates published by AHRQ (and re-estimated as part of this study) were highly correlated (0.821-0.966). However, there was substantial systematic variation in rates across countries. CONCLUSIONS: This pilot study reveals that AHRQ Patient Safety Indicators can be applied to international hospital data. However, the analyses suggest that certain indicators (e.g. 'birth trauma', 'complications of anesthesia') may be too unreliable for international comparisons. Data quality varies across countries; undercoding may be a systematic problem in some countries. Efforts at international harmonization of hospital discharge data sets as well as improved accuracy of documentation should facilitate future comparative analyses of routine databases.

Understanding and using the hospital standardized mortality ratio in Canada: challenges and opportunities.

In 2005, the Canadian Institute for Health Information (CIHI) began a methodological journey to develop a Canadian version of the hospital standardized mortality ratio (HSMR). For two years, CIHI worked with hospitals, regional authorities and measurement experts to define the most appropriate methodology given Canadian datasets and systems of care. In November 2007, we made the findings publicly available for regional health authorities and larger facilities. In their lead article, Penfold et al. discuss their views regarding some methodological issues and potential limitations of the HSMR to monitor quality of care and, in particular, as a patient safety indicator. Here we respond to their specific concerns and maintain that the HSMR remains an important tool in the arsenal of information hospitals can use to focus the discussion of patient safety/quality improvement, monitor the provision of care over time and identify opportunities for improvement.

Are there socio-economic differences in caesarean section rates in Canada?

Caesarean section rates have risen in recent years, sparking renewed debate about the circumstances under which such deliveries are being, and should be, performed. Some commentators suggest that increasing rates may, in part, be explained by women in higher-income brackets requesting elective caesareans (the so-called "too posh to push" hypothesis). After adjusting for maternal age, Canadian data do not support this theory. In fact, age-adjusted caesarean section rates were significantly lower in Canada's highest-income neighbourhoods than in the lowest-income areas in 2002-03.