A cluster randomised controlled trial of educational prompts in diabetes care: study protocol

<p>Abstract</p> <p>Background</p> <p>Laboratory services have a central role in supporting screening, diagnosis, and management of patients. The increase in chronic disease management in primary care for conditions such as diabetes mellitus requires regular monitoring of patients' biochemical parameters. This process offers a route for improving the quality of care that patients receive by using test results as a vehicle for delivering educational messages as well as the test result itself.</p> <p>Aim</p> <p>To develop and evaluate the effectiveness of a quality improvement initiative to improve the care of patients with diabetes using test report reminders.</p> <p>Design</p> <p>A programme of four cluster randomised controlled trials within one population of general practices.</p> <p>Participants</p> <p>General practices in Newcastle-upon-Tyne, UK.</p> <p>Intervention</p> <p>Brief educational messages added to paper and electronic general practice laboratory test reports introduced over two phases. Phase One messages, attached to Haemoglobin A1c (HbA1c) reports, targeted glycaemic and cholesterol control. Phase Two messages, attached to albumin:creatinine ratio (ACR) reports, targeted blood pressure (BP) control and foot inspection.</p> <p>Outcomes</p> <p>General practice mean levels of HbA1c and cholesterol (Phase One) and diastolic and systolic BP and proportions of patients having undergone foot inspections (Phase Two); number of tests requested.</p> <p>Trial registration</p> <p>Current Controlled Trial ISRCTN2186314.</p

Ser649 and Ser650 Are the Major Determinants of Protein Kinase A-Mediated Activation of Human Hormone-Sensitive Lipase against Lipid Substrates

BACKGROUND: Hormone-sensitive lipase (HSL) is a key enzyme in the mobilization of fatty acids from stored triacylglycerols. Its activity is regulated by reversible protein phosphorylation. In rat HSL Ser563, Ser659 and Ser660 have been shown to be phosphorylated by protein kinase A (PKA) in vitro as well as in vivo. METHODOLOGY/PRINCIPAL FINDINGS: In this study we employed site-directed mutagenesis, in vitro phosphorylation and mass spectrometry to show that in vitro phosphorylation of human HSL by PKA occurs primarily on Ser649 and Ser650 (Ser659 and Ser660 in rat HSL). The wild type enzyme and four mutants were expressed in C-terminally His-tagged form in Sf9 insect cells and purified to homogeneity. HSL variants in which Ser552 and/or Ser554 were mutated to Ala or Glu retained both lipolytic and non-lipolytic activity and were phosphorylated by PKA and activated to a similar extent as the wild type enzyme. (32)P-labeling studies revealed that the bulk of the phosphorylation was on the Ser649/Ser650 site, with only a minor phosphorylation of Ser552 and Ser554. MS/MS analysis demonstrated that the peptide containing Ser649 and Ser650 was primarily phosphorylated on Ser650. The mutant lacking all four serines had severely reduced lipolytic activity, but a lesser reduction in non-lipolytic activity, had S(0.5) values for p-nitrophenol butyrate and triolein comparable to those of wild type HSL and was not phosphorylated by PKA. PKA phosphorylation of the wild type enzyme resulted in an increase in both the maximum turnover and S(0,5) using the TO substrate. CONCLUSIONS: Our results demonstrate that PKA activates human HSL against lipid substrates in vitro primarily through phosphorylation of Ser649 and Ser650. In addition the results suggest that Ser649 and Ser650 are located in the vicinity of a lipid binding region and that PKA phosphorylation controls the accessibility of this region

Charged-Higgs phenomenology in the Aligned two-Higgs-doublet model

The alignment in flavour space of the Yukawa matrices of a general two-Higgs-doublet model results in the absence of tree-level flavour-changing neutral currents. In addition to the usual fermion masses and mixings, the aligned Yukawa structure only contains three complex parameters, which are potential new sources of CP violation. For particular values of these three parameters all known specific implementations of the model based on discrete Z_2 symmetries are recovered. One of the most distinctive features of the two-Higgs-doublet model is the presence of a charged scalar. In this work, we discuss its main phenomenological consequences in flavour-changing processes at low energies and derive the corresponding constraints on the parameters of the aligned two-Higgs-doublet model.Comment: 46 pages, 19 figures. Version accepted for publication in JHEP. References added. Discussion slightly extended. Conclusions unchange

Physicians' intentions and use of three patient decision aids

<p>Abstract</p> <p>Background</p> <p>Decision aids are evidence based tools that assist patients in making informed values-based choices and supplement the patient-clinician interaction. While there is evidence to show that decision aids improve key indicators of patients' decision quality, relatively little is known about physicians' acceptance of decision aids or factors that influence their decision to use them. The purpose of this study was to describe physicians' perceptions of three decision aids, their expressed intent to use them, and their subsequent use of them.</p> <p>Methods</p> <p>We conducted a cross-sectional survey of random samples of Canadian respirologists, family physicians, and geriatricians. Three decision aids representing a range of health decisions were evaluated. The survey elicited physicians' opinions on the characteristics of the decision aid and their willingness to use it. Physicians who indicated a strong likelihood of using the decision aid were contacted three months later regarding their actual use of the decision aid.</p> <p>Results</p> <p>Of the 580 eligible physicians, 47% (n = 270) returned completed questionnaires. More than 85% of the respondents felt the decision aid was well developed and that it presented the essential information for decision making in an understandable, balanced, and unbiased manner. A majority of respondents (>80%) also felt that the decision aid would guide patients in a logical way, preparing them to participate in decision making and to reach a decision. Fewer physicians (<60%) felt the decision aid would improve the quality of patient visits or be easily implemented into practice and very few (27%) felt that the decision aid would save time. Physicians' intentions to use the decision aid were related to their comfort with offering it to patients, the decision aid topic, and the perceived ease of implementing it into practice. While 54% of the surveyed physicians indicated they would use the decision aid, less than a third followed through with this intention.</p> <p>Conclusion</p> <p>Despite strong support for the format, content, and quality of patient decision aids, and physicians' stated intentions to adopt them into clinical practice, most did not use them within three months of completing the survey. There is a wide gap between intention and behaviour. Further research is required to study the determinants of this intention-behaviour gap and to develop interventions aimed at barriers to physicians' use of decision aids.</p

Probing the charged Higgs boson at the LHC in the CP-violating type-II 2HDM

We present a phenomenological study of a CP-violating two-Higgs-doublet Model with type-II Yukawa couplings at the Large Hadron Collider (LHC). In the light of recent LHC data, we focus on the parameter space that survives the current and past experimental constraints as well as theoretical bounds on the model. Once the phenomenological scenario is set, we analyse the scope of the LHC in exploring this model through the discovery of a charged Higgs boson produced in association with a W boson, with the former decaying into the lightest neutral Higgs and a second W state, altogether yielding a b\bar b W^+W^- signature, of which we exploit the W^+W^- semileptonic decays.Comment: 37 pages, 16 figures; v2 updated treatment of LHC constraint

Central engine afterglow of Gamma-ray Bursts

Before 2004, nearly all GRB afterglow data could be understood in the context of the external shocks model. This situation has changed in the past two years, when it became clear that some afterglow components should be attributed to the activity of the central engine; i.e., the {\it central engine afterglow}. We review here the afterglow emission that is directly related to the GRB central engine. Such an interpretation proposed by Katz, Piran & Sari, peculiar in pre-{\it Swift} era, has become generally accepted now.Comment: 4 pages including 1 figure. Presented at the conference "Astrophysics of Compact Objects" (July 1-7, 2007; Huangshan, China

The VICI-trial: high frequency oscillation versus conventional mechanical ventilation in newborns with congenital diaphragmatic hernia: an international multicentre randomized controlled trial

Background: Congenital diaphragmatic hernia (CDH) is a severe congenital anomaly of the diaphragm resulting in pulmonary hypoplasia and pulmonary hypertension. It is associated with a high risk of mortality and pulmonary morbidity. Previous retrospective studies have reported high frequency oscillatory ventilation (HFO) to reduce pulmonary morbidity in infants with CDH, while others indicated HFO to be associated with worse outcome. We therefore aimed to develop a randomized controlled trial to compare initial ventilatory treatment with high-frequency oscillation and conventional ventilation in infants with CDH.Methods/design: This trial is designed as a multicentre trial in which 400 infants (200 in each arm) will be included. Primary outcome measures are BPD, described as oxygen dependency by day 28 according to the definition of Jobe and Bancalari, and/or mortality by day 28. All liveborn infants with CDH born at a gestational age of over 34 weeks and no other severe congenital anomalies are eligible for inclusion. Parental informed consent is asked antenatally and the allocated ventilation mode starts within two hours after birth. Laboratory samples of blood, urine and tracheal aspirate are taken at the first day of life, day 3, day 7, day 14 and day 28 to evaluate laboratory markers for ventilator-induced lung injury and pulmonary hypertension.Discussion: To date, randomized clinical trials are lacking in the field of CDH. The VICI-trial, as the first randomized clinical trial in the field of CDH, may provide further insight in ventilation strategies in CDH patient. This may hopefully prevent mortality and morbidity.Trial registration: Netherlands Trial Register (NTR): NTR1310

Meta-Analysis of Genome-Wide Association Studies and Network Analysis-Based Integration with Gene Expression Data Identify New Suggestive Loci and Unravel a Wnt-Centric Network Associated with Dupuytren’s Disease

Dupuytren´s disease, a fibromatosis of the connective tissue in the palm, is a common complex disease with a strong genetic component. Up to date nine genetic loci have been found to be associated with the disease. Six of these loci contain genes that code for Wnt signalling proteins. In spite of this striking first insight into the genetic factors in Dupuytren´s disease, much of the inherited risk in Dupuytren´s disease still needs to be discovered. The already identified loci jointly explain ~1% of the heritability in this disease. To further elucidate the genetic basis of Dupuytren´s disease, we performed a genome-wide meta-analysis combining three genome-wide association study (GWAS) data sets, comprising 1,580 cases and 4,480 controls. We corroborated all nine previously identified loci, six of these with genome-wide significance (p-value < 5x10-8). In addition, we identified 14 new suggestive loci (p-value < 10−5). Intriguingly, several of these new loci contain genes associated with Wnt signalling and therefore represent excellent candidates for replication. Next, we compared whole-transcriptome data between patient- and control-derived tissue samples and found the Wnt/β-catenin pathway to be the top deregulated pathway in patient samples. We then conducted network and pathway analyses in order to identify protein networks that are enriched for genes highlighted in the GWAS meta-analysis and expression data sets. We found further evidence that the Wnt signalling pathways in conjunction with other pathways may play a critical role in Dupuytren´s disease

Modulation of β-Catenin Signaling by Glucagon Receptor Activation

The glucagon receptor (GCGR) is a member of the class B G protein–coupled receptor family. Activation of GCGR by glucagon leads to increased glucose production by the liver. Thus, glucagon is a key component of glucose homeostasis by counteracting the effect of insulin. In this report, we found that in addition to activation of the classic cAMP/protein kinase A (PKA) pathway, activation of GCGR also induced β-catenin stabilization and activated β-catenin–mediated transcription. Activation of β-catenin signaling was PKA-dependent, consistent with previous reports on the parathyroid hormone receptor type 1 (PTH1R) and glucagon-like peptide 1 (GLP-1R) receptors. Since low-density-lipoprotein receptor–related protein 5 (Lrp5) is an essential co-receptor required for Wnt protein mediated β-catenin signaling, we examined the role of Lrp5 in glucagon-induced β-catenin signaling. Cotransfection with Lrp5 enhanced the glucagon-induced β-catenin stabilization and TCF promoter–mediated transcription. Inhibiting Lrp5/6 function using Dickkopf-1(DKK1) or by expression of the Lrp5 extracellular domain blocked glucagon-induced β-catenin signaling. Furthermore, we showed that Lrp5 physically interacted with GCGR by immunoprecipitation and bioluminescence resonance energy transfer assays. Together, these results reveal an unexpected crosstalk between glucagon and β-catenin signaling, and may help to explain the metabolic phenotypes of Lrp5/6 mutations

Dkk1 Stabilizes Wnt Co-Receptor LRP6: Implication for Wnt Ligand-Induced LRP6 Down-Regulation

The low density lipoprotein receptor-related protein-6 (LRP6) is an essential co-receptor for canonical Wnt signaling. Dickkopf 1 (Dkk1), a major secreted Wnt signaling antagonist, binds to LRP6 with high affinity and prevents the Frizzled-Wnt-LRP6 complex formation in response to Wnts. Previous studies have demonstrated that Dkk1 promotes LRP6 internalization and degradation when it forms a ternary complex with the cell surface receptor Kremen.In the present study, we found that transfected Dkk1 induces LRP6 accumulation while inhibiting Wnt/LRP6 signaling. Treatment with Dkk1-conditioned medium or recombinant Dkk1 protein stabilized LRP6 with a prolonged half-life and induces LRP6 accumulation both at the cell surface and in endosomes. We also demonstrated that Kremen2 co-expression abrogated the effect of Dkk1 on LRP6 accumulation, indicating that the effect of Kremen2 is dominant over Dkk1 regulation of LRP6. Furthermore, we found that Wnt3A treatment induces LRP6 down-regulation, an effect paralleled with a Wnt/LRP6 signaling decay, and that Dkk1 treatment blocked Wnt3A-induced LRP6 down-regulation. Finally, we found that LRP6 turnover was blocked by an inhibitor of caveolae-mediated endocytosis.Our results reveal a novel role for Dkk1 in preventing Wnt ligand-induced LRP6 down-regulation and contribute significantly to our understanding of Dkk1 function in Wnt/LRP6 signaling