A cost-effectiveness analysis of endoscopic eradication therapy for management of dysplasia arising in patients with Barrett's oesophagus in the United Kingdom

BACKGROUND AND AIMS: Endoscopic eradication therapy (EET) is the first line approach for treating Barrett's Esophagus (BE) related neoplasia globally. The British Society of Gastroenterology (BSG) recommend EET with combined endoscopic resection (ER) for visible dysplasia followed by endoscopic ablation in patients with both low and high grade dysplasia (LGD and HGD). The aim of this study is to perform a cost-effectiveness analysis for EET for treatment of all grades of dysplasia in BE patients. METHODS: A Markov cohort model with a lifetime time horizon was used to undertake a cost effectiveness analysis. A hypothetical cohort of United Kingdom (UK) patients diagnosed with BE entered the model. Patients in the treatment arm with LGD and HGD received EET and patients with non-dysplastic BE (NDBE) received endoscopic surveillance only. In the comparator arm, patients with LGD, HGD and NDBE received endoscopic surveillance only. A UK National Health Service (NHS) perspective was adopted and the incremental cost effectiveness ratio (ICER) was calculated. Sensitivity analysis was conducted on key input parameters. RESULTS: EET for patients with LGD and HGD arising in BE is cost-effective compared to endoscopic surveillance alone (lifetime ICER £3,006 per QALY gained). The results show that as the time horizon increases, the treatment becomes more cost-effective. The five year financial impact to the UK NHS of introducing EET is £7.1m. CONCLUSIONS: EET for patients with low and high grade BE dysplasia, following updated guidelines from the BSG has been shown to be cost-effective for patients with BE in the UK

Development of a generic activities model of command and control

This paper reports on five different models of command and control. Four different models are reviewed: a process model, a contextual control model, a decision ladder model and a functional model. Further to this, command and control activities are analysed in three distinct domains: armed forces, emergency services and civilian services. From this analysis, taxonomies of command and control activities are developed that give rise to an activities model of command and control. This model will be used to guide further research into technological support of command and control activities

Ultradian Cortisol Pulsatility Encodes a Distinct, Biologically Important Signal

Cortisol is released in ultradian pulses. The biological relevance of the resulting fluctuating cortisol concentration has not been explored.Determination of the biological consequences of ultradian cortisol pulsatility.A novel flow through cell culture system was developed to deliver ultradian pulsed or continuous cortisol to cells. The effects of cortisol dynamics on cell proliferation and survival, and on gene expression were determined. In addition, effects on glucocorticoid receptor (GR) expression levels and phosphorylation, as a potential mediator, were measured.Pulsatile cortisol caused a significant reduction in cell survival compared to continuous exposure of the same cumulative dose, due to increased apoptosis. Comprehensive analysis of the transcriptome response by microarray identified genes with a differential response to pulsatile versus continuous glucocorticoid delivery. These were confirmed with qRT-PCR. Several transcription factor binding sites were enriched in these differentially regulated target genes, including CCAAT-displacement protein (CDP). A CDP regulated reporter gene (MMTV-luc) was, as predicted, also differentially regulated by pulsatile compared to continuous cortisol delivery. Importantly there was no effect of cortisol delivery kinetics on either GR expression, or activation (GR phosphoSer(211)).Cortisol oscillations exert important effects on target cell gene expression, and phenotype. This is not due to differences in cumulative cortisol exposure, or either expression, or activation of the GR. This suggests a novel means to regulate GR function

Surgical and conservative treatment of patients with congenital scoliosis: α search for long-term results

<p>Abstract</p> <p>Background</p> <p>In view of the limited data available on the conservative treatment of patients with congenital scoliosis (CS), early surgery is suggested in mild cases with formation failures. Patients with segmentation failures will not benefit from conservative treatment. The purpose of this review is to identify the mid- or long-term results of spinal fusion surgery in patients with congenital scoliosis.</p> <p>Methods</p> <p>Retrospective and prospective studies were included, reporting on the outcome of surgery in patients with congenital scoliosis. Studies concerning a small numbers of cases treated conservatively were included too. We analyzed mid-term (5 to 7 years) and long-term results (7 years or more), both as regards the maintenance of the correction of scoliosis and the safety of instrumentation, the early and late complications of surgery and their effect on quality of life.</p> <p>Results</p> <p>A small number of studies of surgically treated patients were found, contained follow-up periods of 4-6 years that in the most cases, skeletal maturity was not yet reached, and few with follow-up of 36-44 years. The results of bracing in children with congenital scoliosis, mainly in cases with failure of formation, were also studied.</p> <p>Discussion</p> <p>Spinal surgery in patients with congenital scoliosis is regarded in short as a safe procedure and should be performed. On the other hand, early and late complications are also described, concerning not only intraoperative and immediate postoperative problems, but also the safety and efficacy of the spinal instrumentation and the possibility of developing neurological disorders and the long-term effect these may have on both lung function and the quality of life of children.</p> <p>Conclusions</p> <p>Few cases indicate the long-term results of surgical techniques, in the natural progression of scoliosis. Similarly, few cases have been reported on the influence of conservative treatment.</p> <p>In conclusion, patients with segmentation failures should be treated surgically early, according to the rate of deformity formation and certainly before the pubertal growth spurt to try to avoid cor- pulmonale, even though there is lack of evidence for that in the long-term. Furthermore, in patients with formation failures, further investigation is needed to document where a conservative approach would be necessary.</p

The forgotten smoker: a qualitative study of attitudes towards smoking, quitting, and tobacco control policies among continuing smokers

Although research suggests that the majority of smokers want to quit smoking, the uptake of Stop Smoking Services, designed to assist smokers with quitting, remains low. Little is known about continuing smokers who do not access these services, and opportunities to influence their motivation and encourage quit attempts through the uptake of services. Using PRIME theory, this study explored differences between continuing smokers who had varying levels of motivation to quit, in terms of their plans to quit, evaluative beliefs about smoking, cigarette dependence, and attitudes towards tobacco control policies and services

CHKA and PCYT1A gene polymorphisms, choline intake and spina bifida risk in a California population

BACKGROUND: Neural tube defects (NTDs) are among the most common of all human congenital defects. Over the last two decades, accumulating evidence has made it clear that periconceptional intake of folic acid can significantly reduce the risk of NTD affected pregnancies. This beneficial effect may be related to the ability of folates to donate methyl groups for critical physiological reactions. Choline is an essential nutrient and it is also a methyl donor critical for the maintenance of cell membrane integrity and methyl metabolism. Perturbations in choline metabolism in vitro have been shown to induce NTDs in mouse embryos. METHODS: This study investigated whether single nucleotide polymorphisms (SNPs) in human choline kinase A (CHKA) gene and CTP:phosphocholine cytidylytransferase (PCYT1A) gene were risk factors for spina bifida. Fluorescence-based allelic discrimination analysis was performed for the two CHKA intronic SNPs hCV1562388 (rs7928739) and hCV1562393, and PCYT1A SNP rs939883 and rs3772109. The study population consisted of 103 infants with spina bifida and 338 non-malformed control infants who were born in selected California counties in the period 1989–1991. RESULTS: The CHKA SNP hCV1562388 genotypes with at least one C allele were associated with a reduced risk of spina bifida (odds ratio = 0.60, 95%CI = 0.38–0.94). The PCYT1A SNP rs939883 genotype AA was associated with a twofold increased risk of spina bifida (odds ratio = 1.89, 95% CI = 0.97–3.67). These gene-only effects were not substantially modified by analytic consideration to maternal periconceptional choline intake. CONCLUSION: Our analyses showed genotype effects of CHKA and PCYT1A genes on spina bifida risk, but did not show evidence of gene-nutrient interactions. The underlying mechanisms are yet to be resolved

Measurement of the Bottom-Strange Meson Mixing Phase in the Full CDF Data Set

We report a measurement of the bottom-strange meson mixing phase \beta_s using the time evolution of B0_s -> J/\psi (->\mu+\mu-) \phi (-> K+ K-) decays in which the quark-flavor content of the bottom-strange meson is identified at production. This measurement uses the full data set of proton-antiproton collisions at sqrt(s)= 1.96 TeV collected by the Collider Detector experiment at the Fermilab Tevatron, corresponding to 9.6 fb-1 of integrated luminosity. We report confidence regions in the two-dimensional space of \beta_s and the B0_s decay-width difference \Delta\Gamma_s, and measure \beta_s in [-\pi/2, -1.51] U [-0.06, 0.30] U [1.26, \pi/2] at the 68% confidence level, in agreement with the standard model expectation. Assuming the standard model value of \beta_s, we also determine \Delta\Gamma_s = 0.068 +- 0.026 (stat) +- 0.009 (syst) ps-1 and the mean B0_s lifetime, \tau_s = 1.528 +- 0.019 (stat) +- 0.009 (syst) ps, which are consistent and competitive with determinations by other experiments.Comment: 8 pages, 2 figures, Phys. Rev. Lett 109, 171802 (2012

Maternal TLR4 and NOD2 Gene Variants, Pro-Inflammatory Phenotype and Susceptibility to Early-Onset Preeclampsia and HELLP Syndrome

Background: Altered maternal inflammatory responses play a role in the development of preeclampsia and the hemolysis, elevated liver enzymes and low platelets (HELLP) syndrome. We examined whether allelic variants of the innate immune receptors toli-like receptor 4 (TLR4) and nucleotide-binding oligomerization domain (NOD2), that impair the inflammatory response to endotexin are related to preeclampsia and HELLP syndrome. Methods and Finding: We determined five common mutations in TLR4 (D299G and T399I and NOD2 (R70W, G908R and L1007fs) in 340 primiparous women with a histo

Cell Cycle Phase Regulates Glucocorticoid Receptor Function

The glucocorticoid receptor (GR) is a member of the nuclear hormone receptor superfamily of ligand-activated transcription factors. In contrast to many other nuclear receptors, GR is thought to be exclusively cytoplasmic in quiescent cells, and only translocate to the nucleus on ligand binding. We now demonstrate significant nuclear GR in the absence of ligand, which requires nuclear localisation signal 1 (NLS1). Live cell imaging reveals dramatic GR import into the nucleus through interphase and rapid exclusion of the GR from the nucleus at the onset of mitosis, which persists into early G1. This suggests that the heterogeneity in GR distribution is reflective of cell cycle phase