Gastroesophageal Balloon Tamponade Simulation Training with 3D Printed Model Improves Knowledge, Skill, and Confidence.

Background: Gastroesophageal balloon tamponade (BT) tube placement is a life-saving procedure for refractory bleeding from gastroesophageal varices performed by gastroenterologists, intensivists, internists, and emergency medicine physicians. Despite a recognized need for procedural training, no standard curriculum or assessment tools exist. Given the infrequent performance of this procedure, the development of a representative and accessible simulation model would permit hands-on training to practice and maintain proficiency with BT tube placement.

Favorable Sustained Virologic Response Rates Using Direct-Acting Antiviral Therapies at a Large Safety-Net Hospital.

Background: Direct-acting antivirals (DAA) have revolutionized the treatment of chronic hepatitis C virus (HCV) infection.

Objective: To evaluate the clinical effectiveness of DAA in a safety-net population.

Methods: Retrospective cohort study including patients who received at least one dose of DAA for chronic HCV infection.

Primary intestinal lymphangiectasia diagnosed by video capsule endoscopy in a patient with immunodeficiency presenting with bacteraemia.

A 24-year-old woman with a medical history of chronic lower extremity oedema, abdominal pain, diarrhoea and recurrent pulmonary infections presented with sepsis from right lower extremity cellulitis. Blood cultures grew Laboratory evaluation revealed lymphopaenia, hypogammaglobulinaemia, a low CD4+ T-cell count and nutritional deficiencies resulting from protein-losing enteropathy (PLE). CT showed small bowel wall thickening in the jejunum and ileum.

Variant Inosine Triphosphatase Phenotypes Are Associated With Increased Ribavirin Triphosphate Levels.

Individuals with lower inosine triphosphatase (ITPA) enzyme activity have a reduced likelihood of experiencing hemolytic anemia during hepatitis C virus (HCV) treatment containing ribavirin (RBV). Because ITPA degrades purines and RBV is a purine analogue, it is conceivable that ITPA activity may affect intracellular RBV concentrations. Here we assessed the association between ITPA activity phenotype and concentrations of RBV triphosphate (RBV-TP) in red blood cells (RBCs) during HCV treatment.

Identifying practice gaps to optimize medical care for patients with nonalcoholic fatty liver disease.

Background: Nonalcoholic fatty liver disease (NAFLD) is a leading cause of chronic liver disease. Primary care providers (PCPs), in contrast to gastroenterology/hepatology (GI/Hep) providers, are the first medical contact for the majority of patients with, or at risk for, NAFLD. PCP awareness of and facility with NAFLD is critical for management of these patients.

Sorafenib therapy for hepatocellular carcinoma prior to liver transplant is associated with increased complications after transplant.

This study compared post-transplant outcomes of patients with hepatocellular carcinoma (HCC) who took sorafenib prior to orthotopic liver transplantation (OLT) with those patients who were not treated with sorafenib. Thirty-three patients with HCC who were listed for liver transplantation were studied: 10 patients were treated with sorafenib prior to transplantation in an attempt to prevent progression of HCC while awaiting transplant. The remaining 23 patients were considered controls.

Randomised controlled trial and parallel economic evaluation of conventional ventilatory support versus extracorporeal membrane oxygenation for severe adult respiratory failure (CESAR).

Objectives: To determine the comparative effectiveness and cost-effectiveness of conventional ventilatory support versus extracorporeal membrane oxygenation (ECMO) for severe adult respiratory failure.

Design: A multicentre, randomised controlled trial with two arms.

Setting: The ECMO centre at Glenfield Hospital, Leicester, and approved conventional treatment centres and referring hospitals throughout the UK.

Opposing interactions between Drosophila cut and the C/EBP encoded by slow border cells direct apical constriction and epithelial invagination.

Stage 10 of Drosophila oogenesis can be subdivided into stages 10A and 10B based on a change in the morphology of the centripetal follicle cells (FC) from a columnar to an apically constricted shape. This coordinated cell shape change drives epithelial cell sheet involution between the oocyte and nurse cell complex which patterns the operculum structure of the mature eggshell. We have shown previously that proper centripetal FC migration requires transient expression of the C/EBP encoded by slow border cells (slbo) at 10A, due in part to Notch activation followed by slbo autorepression (Levine et al.

Control of hyperglycaemia in paediatric intensive care (CHiP): study protocol.

Background: There is increasing evidence that tight blood glucose (BG) control improves outcomes in critically ill adults. Children show similar hyperglycaemic responses to surgery or critical illness. However it is not known whether tight control will benefit children given maturational differences and different disease spectrum.

Efficacy and economic assessment of conventional ventilatory support versus extracorporeal membrane oxygenation for severe adult respiratory failure (CESAR): a multicentre randomised controlled trial.

Background: Severe acute respiratory failure in adults causes high mortality despite improvements in ventilation techniques and other treatments (eg, steroids, prone positioning, bronchoscopy, and inhaled nitric oxide). We aimed to delineate the safety, clinical efficacy, and cost-effectiveness of extracorporeal membrane oxygenation (ECMO) compared with conventional ventilation support.

Methods: In this UK-based multicentre trial, we used an independent central randomisation service to randomly assign 180 adults in a 1:1 ratio to receive continued conventional management or referral to consideration for treatment by ECMO.

Discovery of an inhibitor of insulin-like growth factor 1 receptor activation: implications for cellular potency and selectivity over insulin receptor.

Insulin-like growth factor 1 receptor (IGF-1R) is an attractive target for anti-cancer therapy due to its anti-apoptotic effect on tumor cells, but inhibition of insulin receptor (IR) may have undesired metabolic consequences. The primary sequences of the ATP substrate-binding sites of these receptors are identical and the crystal structures of the activated kinase domains are correspondingly similar. Thus, most small-molecule inhibitors described to date are equally potent against the activated kinase domains of IGF-1R and IR.

Thienopyrimidine-based dual EGFR/ErbB-2 inhibitors.

Two new series of potent and selective dual EGFR/ErbB-2 kinase inhibitors derived from novel thienopyrimidine cores have been identified. Isomeric thienopyrimidine cores were evaluated as isosteres for a 4-anilinoquinazoline core and several analogs containing the thieno[3,2-d]pyrimidine core showed anti-proliferative activity with IC(50) values less than 1 microM against human tumor cells in vitro.

Discovery of 5-[[4-[(2,3-dimethyl-2H-indazol-6-yl)methylamino]-2-pyrimidinyl]amino]-2-methyl-benzenesulfonamide (Pazopanib), a novel and potent vascular endothelial growth factor receptor inhibitor.

Inhibition of the vascular endothelial growth factor (VEGF) signaling pathway has emerged as one of the most promising new approaches for cancer therapy. We describe herein the key steps starting from an initial screening hit leading to the discovery of pazopanib, N(4)-(2,3-dimethyl-2H-indazol-6-yl)-N(4)-methyl-N(2)-(4-methyl-3-sulfonamidophenyl)-2,4-pyrimidinediamine, a potent pan-VEGF receptor (VEGFR) inhibitor under clinical development for renal-cell cancer and other solid tumors.

Methods of data collection and analysis for the economic evaluation alongside a national, multi-centre trial in the UK: conventional ventilation or ECMO for Severe Adult Respiratory Failure (CESAR).

Background: Extracorporeal Membrane Oxygenation (ECMO) is a technology used in treatment of patients with severe but potentially reversible respiratory failure. A multi-centre randomised controlled trial (CESAR) was funded in the UK to compare care including ECMO with conventional intensive care management. The protocol and funding for the CESAR trial included plans for economic data collection and analysis.

The INNOVO multicentre randomised controlled trial: neonatal ventilation with inhaled nitric oxide versus ventilatory support without nitric oxide for severe respiratory failure in preterm infants: follow up at 4-5 years.

Background: Trials of inhaled nitric oxide (iNO) used short term in preterm infants with severe respiratory failure have to date shown no evidence of benefit, and there have been no trials reporting follow-up to 4 years of age. The INNOVO trial recruited 108 infants (55 iNO arm and 53 controls) from 15 neonatal units. By 1 year of age 59% had died, and 84% of the survivors had signs of impairment or disability.

Impact of common epidermal growth factor receptor and HER2 variants on receptor activity and inhibition by lapatinib.

The goal of this study was to characterize the effects of non-small cell lung carcinoma (NSCLC)-associated mutations in epidermal growth factor receptor (EGFR/ErbB1) and HER2 (ErbB2) on interactions with the dual tyrosine kinase inhibitor lapatinib. Biochemical studies show that commonly observed variants of EGFR [G719C, G719S, L858R, L861Q, and Delta746-750 (del15)] are enzyme activating, increasing the tyrosine kinase V(max) and increasing the K(m)((app)) for ATP. The point mutations G719C and L861Q had minor effects on lapatinib K(i)s, whereas EGFR mutations L858R and del15 had a higher K(i) for lapatinib than wild-type EGFR.

Use of recombinant activated factor VII in primary postpartum hemorrhage: the Northern European registry 2000-2004.

Objective: To collect data from nine European countries for cases of obstetric hemorrhage between 2000 and 2004 in which recombinant activated factor VII (rFVIIa) was used.

Methods: The cases were identified through national surveys. Standardized case report forms included sociodemographic details, past medical and obstetric history, and details of the progress and management of labor in which the postpartum hemorrhage occurred.

Pharmacokinetic-pharmacodynamic correlation from mouse to human with pazopanib, a multikinase angiogenesis inhibitor with potent antitumor and antiangiogenic activity.

With the development of targeted therapeutics, especially for small-molecule inhibitors, it is important to understand whether the observed in vivo efficacy correlates with the modulation of desired/intended target in vivo. We have developed a small-molecule inhibitor of all three vascular endothelial growth factor (VEGF) receptors (VEGFR), platelet-derived growth factor receptor, and c-Kit tyrosine kinases, pazopanib (GW786034), which selectively inhibits VEGF-induced endothelial cell proliferation. It has good oral exposure and inhibits angiogenesis and tumor growth in mice.

Neonatal ventilation with inhaled nitric oxide vs. ventilatory support without inhaled nitric oxide for infants with severe respiratory failure born at or near term: the INNOVO multicentre randomised controlled trial.

Background: Evidence from European centres to support the use of nitric oxide (NO) in mature newborns with evidence of severe respiratory failure is sparse.

Methods: Infants of >33 weeks' gestation, <28 days old, and with severe respiratory failure requiring ventilatory support were randomised to receive or not to receive inhaled NO (iNO). The study was not blinded.

Orally active 4-amino-5-diarylurea-furo[2,3-d]pyrimidine derivatives as anti-angiogenic agent inhibiting VEGFR2 and Tie-2.

During our effort to develop dual VEGFR2 and Tie-2 inhibitors as anti-angiogenic agents for cancer therapy, we discovered 4-amino-5-(4-((2-fluoro-5-(trifluoromethyl)phenyl)- aminocarbonylamino)phenyl)furo[2,3-d]pyrimidine (8a) possessing strong inhibitory activity at both the enzyme and cellular level against VEGFR2 and Tie-2. Compound 8a demonstrated high pharmacokinetic exposure through oral administration, and showed marked tumor growth inhibition and anti-angiogenic activity in mouse HT-29 xenograft model via once-daily oral administration.

CESAR: conventional ventilatory support vs extracorporeal membrane oxygenation for severe adult respiratory failure.

Background: An estimated 350 adults develop severe, but potentially reversible respiratory failure in the UK annually. Current management uses intermittent positive pressure ventilation, but barotrauma, volutrauma and oxygen toxicity can prevent lung recovery. An alternative treatment, extracorporeal membrane oxygenation, uses cardio-pulmonary bypass technology to temporarily provide gas exchange, allowing ventilator settings to be reduced.

Design and effective synthesis of novel templates, 3,7-diphenyl-4-amino-thieno and furo-[3,2-c]pyridines as protein kinase inhibitors and in vitro evaluation targeting angiogenetic kinases.

A novel class of 3,7-diphenyl-4-amino-thieno and furo[3,2-c]pyridine has been designed based on pharmacophore models of ATP competitive kinase inhibitors. Versatile synthetic methods via double Suzuki coupling to explore SAR have been established and potent inhibitors against angiogenetic targets, VEGFR2, Tie-2, and EphB4, have been successfully discovered.

A randomised controlled trial investigating the effect of n-3 long-chain polyunsaturated fatty acid supplementation on cognitive and retinal function in cognitively healthy older people: the Older People And n-3 Long-chain polyunsaturated fatty acids (OPAL) study protocol [ISRCTN72331636].

The number of individuals with age-related cognitive impairment is rising dramatically in the UK and globally. There is considerable interest in the general hypothesis that improving the diet of older people may slow the progression of cognitive decline. To date, there has been little attention given to the possible protective role of n-3 long-chain polyunsaturated fatty acids (n-3 LCPs) most commonly found in oily fish, in age-related loss of cognitive function.