The effect of maternal undernutrition on the rat placental transcriptome: protein restriction up-regulates cholesterol transport

Fetal exposure to a maternal low protein diet during rat pregnancy is associated with hypertension, renal dysfunction and metabolic disturbance in adult life. These effects are present when dietary manipulations target only the first half of pregnancy. It was hypothesised that early gestation protein restriction would impact upon placental gene expression and that this may give clues to the mechanism which links maternal diet to later consequences. Pregnant rats were fed control or a low protein diet from conception to day 13 gestation. Placentas were collected and RNA Sequencing performed using the Illumina platform. Protein restriction down-regulated 67 genes and up-regulated 24 genes in the placenta. Ingenuity pathway analysis showed significant enrichment in pathways related to cholesterol and lipoprotein transport and metabolism, including atherosclerosis signalling, clathrin-mediated endocytosis, LXR/RXR and FXR/RXR activation. Genes at the centre of these processes included the apolipoproteins ApoB, ApoA2 and ApoC2, microsomal triglyceride transfer protein (Mttp), the clathrin-endocytosis receptor cubilin, the transcription factor retinol binding protein 4 (Rbp4) and transerythrin (Ttr; a retinol and thyroid hormone transporter). Real-time PCR measurements largely confirmed the findings of RNASeq and indicated that the impact of protein restriction was often striking (cubilin up-regulated 32-fold, apoC2 up-regulated 17.6-fold). The findings show that gene expression in specific pathways is modulated by maternal protein restriction in the day-13 rat placenta. Changes in cholesterol transport may contribute to altered tissue development in the fetus and hence programme risk of disease in later life

Developing the Diagnostic Adherence to Medication Scale (the DAMS) for use in clinical practice

There is a need for an adherence measure, to monitor adherence services in clinical practice, which can distinguish between different types of non-adherence and measure changes over time. In order to be inclusive of all patients it needs to be able to be administered to both patients and carers and to be suitable for patients taking multiple medications for a range of clinical conditions. A systematic review found that no adherence measure met all these criteria. We therefore wished to develop a theory based adherence scale (the DAMS) and establish its content, face and preliminary construct validity in a primary care population

A pragmatic cluster randomised trial evaluating three implementation interventions

Background Implementation research is concerned with bridging the gap between evidence and practice through the study of methods to promote the uptake of research into routine practice. Good quality evidence has been summarised into guideline recommendations to show that peri-operative fasting times could be considerably shorter than patients currently experience. The objective of this trial was to evaluate the effectiveness of three strategies for the implementation of recommendations about peri-operative fasting. Methods A pragmatic cluster randomised trial underpinned by the PARIHS framework was conducted during 2006 to 2009 with a national sample of UK hospitals using time series with mixed methods process evaluation and cost analysis. Hospitals were randomised to one of three interventions: standard dissemination (SD) of a guideline package, SD plus a web-based resource championed by an opinion leader, and SD plus plan-do-study-act (PDSA). The primary outcome was duration of fluid fast prior to induction of anaesthesia. Secondary outcomes included duration of food fast, patients' experiences, and stakeholders' experiences of implementation, including influences. ANOVA was used to test differences over time and interventions. Results Nineteen acute NHS hospitals participated. Across timepoints, 3,505 duration of fasting observations were recorded. No significant effect of the interventions was observed for either fluid or food fasting times. The effect size was 0.33 for the web-based intervention compared to SD alone for the change in fluid fasting and was 0.12 for PDSA compared to SD alone. The process evaluation showed different types of impact, including changes to practices, policies, and attitudes. A rich picture of the implementation challenges emerged, including inter-professional tensions and a lack of clarity for decision-making authority and responsibility. Conclusions This was a large, complex study and one of the first national randomised controlled trials conducted within acute care in implementation research. The evidence base for fasting practice was accepted by those participating in this study and the messages from it simple; however, implementation and practical challenges influenced the interventions' impact. A set of conditions for implementation emerges from the findings of this study, which are presented as theoretically transferable propositions that have international relevance. Trial registration ISRCTN18046709 - Peri-operative Implementation Study Evaluation (POISE

Applying the quality improvement collaborative method to process redesign: a multiple case study

<p>Abstract</p> <p>Background</p> <p>Despite the widespread use of quality improvement collaboratives (QICs), evidence underlying this method is limited. A QIC is a method for testing and implementing evidence-based changes quickly across organisations. To extend the knowledge about conditions under which QICs can be used, we explored in this study the applicability of the QIC method for process redesign.</p> <p>Methods</p> <p>We evaluated a Dutch process redesign collaborative of seventeen project teams using a multiple case study design. The goals of this collaborative were to reduce the time between the first visit to the outpatient's clinic and the start of treatment and to reduce the in-hospital length of stay by 30% for involved patient groups. Data were gathered using qualitative methods, such as document analysis, questionnaires, semi-structured interviews and participation in collaborative meetings.</p> <p>Results</p> <p>Application of the QIC method to process redesign proved to be difficult. First, project teams did not use the provided standard change ideas, because of their need for customised solutions that fitted with context-specific causes of waiting times and delays. Second, project teams were not capable of testing change ideas within short time frames due to: the need for tailoring changes ideas and the complexity of aligning interests of involved departments; small volumes of involved patient groups; and inadequate information and communication technology (ICT) support. Third, project teams did not experience peer stimulus because they saw few similarities between their projects, rarely shared experiences, and did not demonstrate competitive behaviour. Besides, a number of project teams reported that organisational and external change agent support was limited.</p> <p>Conclusions</p> <p>This study showed that the perceived need for tailoring standard change ideas to local contexts and the complexity of aligning interests of involved departments hampered the use of the QIC method for process redesign. We cannot determine whether the QIC method would have been appropriate for process redesign. Peer stimulus was non-optimal as a result of the selection process for participation of project teams by the external change agent. In conclusion, project teams felt that necessary preconditions for successful use of the QIC method were lacking.</p

Quantitative data management in quality improvement collaboratives

<p>Abstract</p> <p>Background</p> <p>Collaborative approaches in quality improvement have been promoted since the introduction of the Breakthrough method. The effectiveness of this method is inconclusive and further independent evaluation of the method has been called for. For any evaluation to succeed, data collection on interventions performed within the collaborative and outcomes of those interventions is crucial. Getting enough data from Quality Improvement Collaboratives (QICs) for evaluation purposes, however, has proved to be difficult. This paper provides a retrospective analysis on the process of data management in a Dutch Quality Improvement Collaborative. From this analysis general failure and success factors are identified.</p> <p>Discussion</p> <p>This paper discusses complications and dilemma's observed in the set-up of data management for QICs. An overview is presented of signals that were picked up by the data management team. These signals were used to improve the strategies for data management during the program and have, as far as possible, been translated into practical solutions that have been successfully implemented.</p> <p>The recommendations coming from this study are:</p> <p>From our experience it is clear that quality improvement programs deviate from experimental research in many ways. It is not only impossible, but also undesirable to control processes and standardize data streams. QIC's need to be clear of data protocols that do not allow for change. It is therefore minimally important that when quantitative results are gathered, these results are accompanied by qualitative results that can be used to correctly interpret them.</p> <p>Monitoring and data acquisition interfere with routine. This makes a database collecting data in a QIC an intervention in itself. It is very important to be aware of this in reporting the results. Using existing databases when possible can overcome some of these problems but is often not possible given the change objective of QICs.</p> <p>Introducing a standardized spreadsheet to the teams is a very practical and helpful tool in collecting standardized data within a QIC. It is vital that the spreadsheets are handed out before baseline measurements start.</p

The birth of airplane stability theory

Airplane stability theory was born at the end of the XIX century and matured around 100 years ago, when airplanes were hardly controllable yet. The success and safety of flights in the pioneer years depended upon largely unknown stability and control characteristics. Understanding the modes of airplane motion has been of paramount importance for the development of aviation. The contributions made by a few scientists in the decades preceding and following the first flight by the Wright brothers set the concepts and equations that, with minor notation aspects, have remained almost unchanged till present day.Magraner Rullan, JP.; Martinez-Val, R. (2014). The birth of airplane stability theory. Proceedings of the Institution of Mechanical Engineers, Part G: Journal of Aerospace Engineering. 228(9):1498-1506. doi:10.1177/0954410013494139S149815062289PERKINS, C. D. (1970). Development of airplane stability and control technology /1970 Von Karman Lecture/. Journal of Aircraft, 7(4), 290-301. doi:10.2514/3.44167Abzug, M. J., & Larrabee, E. E. (2002). Airplane Stability and Control, Second Edition. doi:10.1017/cbo9780511607141Graham, W. R. (1999). Asymptotic analysis of the classical aircraft stability equations. The Aeronautical Journal, 103(1020), 95-103. doi:10.1017/s0001924000027792Bryan, G. H., & Williams, W. E. (1904). The Longitudinal Stability of Aerial Gliders. Proceedings of the Royal Society of London, 73(488-496), 100-116. doi:10.1098/rspl.1904.0017Wegener, P. P. (1997). What Makes Airplanes Fly? doi:10.1007/978-1-4612-2254-5Pradeep, S., & Kamesh, S. (1999). Does the Phugoid Frequency Depend on Speed? Journal of Guidance, Control, and Dynamics, 22(2), 372-373. doi:10.2514/2.4391Phillips, W. F. (2000). Phugoid Approximation for Conventional Airplanes. Journal of Aircraft, 37(1), 30-36. doi:10.2514/2.2586Pamadi, B. N. (2004). Performance, Stability, Dynamics, and Control of Airplanes, Second Edition. doi:10.2514/4.862274Ananthkrishnan, N., & Ramadevi, P. (2002). Consistent Approximations to Aircraft Longitudinal Modes. Journal of Guidance, Control, and Dynamics, 25(4), 820-824. doi:10.2514/2.4952McRuer, D. T., Graham, D., & Ashkenas, I. (1990). Aircraft Dynamics and Automatic Control. doi:10.1515/978140085598

Ribonucleoprotein Particles Containing Non-Coding Y RNAs, Ro60, La and Nucleolin Are Not Required for Y RNA Function in DNA Replication

BACKGROUND: Ro ribonucleoprotein particles (Ro RNPs) consist of a non-coding Y RNA bound by Ro60, La and possibly other proteins. The physiological function of Ro RNPs is controversial as divergent functions have been reported for its different constituents. We have recently shown that Y RNAs are essential for the initiation of mammalian chromosomal DNA replication, whereas Ro RNPs are implicated in RNA stability and RNA quality control. Therefore, we investigate here the functional consequences of RNP formation between Ro60, La and nucleolin proteins with hY RNAs for human chromosomal DNA replication. METHODOLOGY/PRINCIPAL FINDINGS: We first immunoprecipitated Ro60, La and nucleolin together with associated hY RNAs from HeLa cytosolic cell extract, and analysed the protein and RNA compositions of these precipitated RNPs by Western blotting and quantitative RT-PCR. We found that Y RNAs exist in several RNP complexes. One RNP comprises Ro60, La and hY RNA, and a different RNP comprises nucleolin and hY RNA. In addition about 50% of the Y RNAs in the extract are present outside of these two RNPs. Next, we immunodepleted these RNP complexes from the cytosolic extract and tested the ability of the depleted extracts to reconstitute DNA replication in a human cell-free system. We found that depletion of these RNP complexes from the cytosolic extract does not inhibit DNA replication in vitro. Finally, we tested if an excess of recombinant pure Ro or La protein inhibits Y RNA-dependent DNA replication in this cell-free system. We found that Ro60 and La proteins do not inhibit DNA replication in vitro. CONCLUSIONS/SIGNIFICANCE: We conclude that RNPs containing hY RNAs and Ro60, La or nucleolin are not required for the function of hY RNAs in chromosomal DNA replication in a human cell-free system, which can be mediated by Y RNAs outside of these RNPs. These data suggest that Y RNAs can support different cellular functions depending on associated proteins

Can a quality improvement project impact maternal and child health outcomes at scale in northern Ghana?

Background Quality improvement (QI) interventions are becoming more common in low- and middle-income countries, yet few studies have presented impact evaluations of these approaches. In this paper, we present an impact evaluation of a scale-up phase of ‘Project Fives Alive!’, a QI intervention in Ghana that aims to improve maternal and child health outcomes. ‘Project Fives Alive!’ employed a QI methodology to recognize barriers to care-seeking and care provision at the facility level and then to identify, test and implement simple and low-cost local solutions that address the barriers. Methods A quasi-experimental design, multivariable interrupted time series analysis, with data coming from 744 health facilities and controlling for potential confounding factors, was used to study the effect of the project. The key independent variables were the change categories (interventions implemented) and implementation phase – Wave 2a (early phase) versus Wave 2b (later phase). The outcomes studied were early antenatal care (ANC), skilled delivery, facility-level under-five mortality and attendance of underweight infants at child welfare clinics. We stratified the analysis by facility type, namely health posts, health centres and hospitals. Results Several of the specific change categories were significantly associated with improved outcomes. For example, three of five change categories (early ANC, four or more ANC visits and skilled delivery/immediate postnatal care (PNC)) for health posts and two of five change categories (health education and triage) for hospitals were associated with increased skilled delivery. These change categories were associated with increases in skilled delivery varying from 28% to 58%. PNC changes for health posts and health centres were associated with greater attendance of underweight infants at child welfare clinics. The triage change category was associated with increased early antenatal care in hospitals. Intensity, the number of change categories tested, was associated with increased skilled delivery in health centres and reduced under-five mortality in hospitals. Conclusions Using an innovative evaluation technique we determined that ‘Project Fives Alive!’ demonstrated impact at scale for the outcomes studied. The QI approach used by this project should be considered by other low- and middle-income countries in their efforts to improve maternal and child health

A novel synthesis and detection method for cap-associated adenosine modifications in mouse mRNA

A method is described for the detection of certain nucleotide modifications adjacent to the 5' 7-methyl guanosine cap of mRNAs from individual genes. The method quantitatively measures the relative abundance of 2'-O-methyl and N6,2'-O-dimethyladenosine, two of the most common modifications. In order to identify and quantitatify the amounts of N6,2'-O-dimethyladenosine, a novel method for the synthesis of modified adenosine phosphoramidites was developed. This method is a one step synthesis and the product can directly be used for the production of N6,2'-O-dimethyladenosine containing RNA oligonucleotides. The nature of the cap-adjacent nucleotides were shown to be characteristic for mRNAs from individual genes transcribed in liver and testis

Developing community-driven quality improvement initiatives to enhance chronic disease care in Indigenous communities in Canada : the FORGE AHEAD program protocol

BACKGROUND: Given the dramatic rise and impact of chronic diseases and gaps in care in Indigenous peoples in Canada, a shift from the dominant episodic and responsive healthcare model most common in First Nations communities to one that places emphasis on proactive prevention and chronic disease management is urgently needed. METHODS: The Transformation of Indigenous Primary Healthcare Delivery (FORGE AHEAD) Program partners with 11 First Nations communities across six provinces in Canada to develop and evaluate community-driven quality improvement (QI) initiatives to enhance chronic disease care. FORGE AHEAD is a 5-year research program (2013-2017) that utilizes a pre-post mixed-methods observational design rooted in participatory research principles to work with communities in developing culturally relevant innovations and improved access to available services. This intensive program incorporates a series of 10 inter-related and progressive program activities designed to foster community-driven initiatives with type 2 diabetes mellitus as the action disease. Preparatory activities include a national community profile survey, best practice and policy literature review, and readiness tool development. Community-level intervention activities include community and clinical readiness consultations, development of a diabetes registry and surveillance system, and QI activities. With a focus on capacity building, all community-level activities are driven by trained community members who champion QI initiatives in their community. Program wrap-up activities include readiness tool validation, cost-analysis and process evaluation. In collaboration with Health Canada and the Aboriginal Diabetes Initiative, scale-up toolkits will be developed in order to build on lessons-learned, tools and methods, and to fuel sustainability and spread of successful innovations. DISCUSSION: The outcomes of this research program, its related cost and the subsequent policy recommendations, will have the potential to significantly affect future policy decisions pertaining to chronic disease care in First Nations communities in Canada. TRIAL REGISTRATION: Current ClinicalTrial.gov protocol ID NCT02234973 . Date of Registration: July 30, 2014