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Background Our aim was to establish if presence of circulating tumor cells (CTCs) predicted worse outcome in patients with non-metastatic esophageal cancer undergoing tri-modality therapy. Methods We prospectively collected CTC data from patients with operable non-metastatic esophageal cancer from April 2009 to November 2016 enrolled in our QUINTETT esophageal cancer randomized trial (NCT00907543). Patients were randomized to receive either neoadjuvant cisplatin and 5-fluorouracil (5-FU) plus radiotherapy followed by surgical resection (Neoadjuvant) or adjuvant cisplatin, 5-FU, and epirubicin chemotherapy with concurrent extended volume radiotherapy following surgical resection (Adjuvant). CTCs were identified with the CellSearch® system before the initiation of any treatment (surgery or chemoradiotherapy) as well as at 6-, 12-, and 24-months post-treatment. The threshold for CTC positivity was one and the findings were correlated with patient prognosis. Results CTC data were available for 74 of 96 patients and identified in 27 patients (36.5%) at a median follow-up of 13.1months (interquartile range:6.8-24.1 months). Detection of CTCs at any follow-up visit was significantly predictive of worse disease-free survival (DFS;hazard ratio [HR]: 2.44; 95% confidence interval [CI]: 1.41-4.24; p =0.002), regional control (HR: 6.18; 95% CI: 1.18-32.35; p =0.031), distant control (HR: 2.93; 95% CI: 1.52-5.65; p =0.001) and overall survival (OS;HR: 2.02; 95% CI: 1.16-3.51; p =0.013). After adjusting for receiving neoadjuvant vs. adjuvant chemoradiotherapy, the presence of CTCs at any follow-up visit remained significantly predictive of worse OS ([HR]:2.02;95% [Cl]:1.16-3.51; p =0.013) and DFS (HR: 2.49;95% Cl: 1.43-4.33; p =0.001). Similarly, any observed increase in CTCs was significantly predictive of worse OS (HR: 3.14; 95% CI: 1.56-6.34; p =0.001) and DFS (HR: 3.34; 95% CI: 1.67-6.69; p <0.001). Conclusion The presence of CTCs in patients during follow-up after tri-modality therapy was associated with significantly poorer DFS and OS regardless of timing of chemoradiotherapy.

Methicillin-resistant Staphylococcus aureus (MRSA) surgical site infections (SSIs) increase morbidity and mortality. We examined the impact of the MRSA bundle on SSIs. Data regarding the implementation of the MRSA bundle from 2007 to 2008 were obtained, including admission and discharge MRSA screenings, overall MRSA infections, and cardiac and orthopedic SSIs. Chi-square was used for all comparisons. A significant decrease in MRSA transmission from a 5.8 to 3.0 per 1,000 bed-days ( P < .05) was found after implementation of the MRSA bundle. Overall MRSA nosocomial infections decreased from 2.0 to 1.0 per 1,000 bed-days ( P = .016). There was a statistically significant decrease in overall SSIs ( P < .05), with a 65% decrease in orthopaedic MRSA SSIs and 1% decrease in cardiac MRSA SSIs. Our data demonstrate that successful implementation of the MRSA bundle significantly decreases MRSA transmission between patients, the overall number of nosocomial MRSA infections, and MRSA SSIs.

Relative equilibria of Lagrangian and Hamiltonian systems with symmetry are critical points of appropriate scalar functions parametrized by the Lie algebra (or its dual) of the symmetry group. Setting aside the structures - symplectic, Poisson, or variational - generating dynamical systems from such functions highlights the common features of their construction and analysis, and supports the construction of analogous functions in non-Hamiltonian settings. If the symmetry group is nonabelian, the functions are invariant only with respect to the isotropy subgroup of the given parameter value. Replacing the parametrized family of functions with a single function on the product manifold and extending the action using the (co)adjoint action on the algebra or its dual yields a fully invariant function. An invariant map can be used to reverse the usual perspective: rather than selecting a parametrized family of functions and finding their critical points, conditions under which functions will be critical on specific orbits, typically distinguished by isotropy class, can be derived. This strategy is illustrated using several well-known mechanical systems - the Lagrange top, the double spherical pendulum, the free rigid body, and the Riemann ellipsoids - and generalizations of these systems. [ProQuest: [...] denotes formulae omitted.]

Background We compared the health‐related quality of life (HRQOL) in patients undergoing trimodality therapy for resectable stage I‐III esophageal cancer. Methods A total of 96 patients were randomized to standard neoadjuvant cisplatin and 5‐fluorouracil chemotherapy plus radiotherapy (neoadjuvant) followed by surgical resection or adjuvant cisplatin, 5‐fluorouracil, and epirubicin chemotherapy with concurrent extended volume radiotherapy (adjuvant) following surgical resection. Results There was no significant difference in the functional assessment of cancer therapy‐esophageal (FACT‐E) total scores between arms at 1 year (p = 0.759) with 36% versus 41% (neoadjuvant vs. adjuvant), respectively, showing an increase of ≥15 points compared to pre‐treatment (p = 0.638). The HRQOL was significantly inferior at 2 months in the neoadjuvant arm for FACT‐E, European Organization for Research and Treatment of Cancer quality of life questionnaire (EORTC QLQ‐OG25), and EuroQol 5‐D‐3 L in the dysphagia, reflux, pain, taste, and coughing domains (p < 0.05). Half of patients were able to complete the prescribed neoadjuvant arm chemotherapy without modification compared to only 14% in the adjuvant arm (p < 0.001). Chemotherapy related adverse events of grade ≥2 occurred significantly more frequently in the neoadjuvant arm (100% vs. 69%, p < 0.001). Surgery related adverse events of grade ≥2 were similar in both arms (72% vs. 86%, p = 0.107). There were no 30‐day mortalities and 2% vs. 10% 90‐day mortalities (p = 0.204). There were no significant differences in either overall survival (OS) (5‐year: 35% vs. 32%, p = 0.409) or disease‐free survival (DFS) (5‐year: 31% vs. 30%, p = 0.710). Conclusion Trimodality therapy is challenging for patients with resectable esophageal cancer regardless of whether it is given before or after surgery. Newer and less toxic protocols are needed. This randomized trial assessed the health related quality of life in esophageal cancer patients undergoing neoadjuvant versus adjuvant trimodality therapy. Every patient experienced at least one adverse event. The quality of life was worse for patients undergoing neoadjuvant compared to adjuvant chemoradiation with no significant difference in either overall survival or disease‐free survival. More effective therapy is needed.

Biological and biophysical factors have been shown to play an important role in the initiation, progression, and rupture of intracranial aneurysms. The purpose of this study was to evaluate the association between hemodynamic forces and markers of vascular remodeling in elastase-induced saccular aneurysms in rabbits. Elastase-induced aneurysms were created at the origin of the right common carotid artery in rabbits. Hemodynamic parameters were estimated using computational fluid dynamic simulations based on 3-D-reconstructed models of the vasculature. Expression of matrix metalloproteinases (MMPs), their inhibitors (TIMPs) and markers of vascular remodeling were measured in different spatial regions within the aneurysms. Altered expression of biological markers relative to controls was correlated with the locations of subnormal time-averaged wall shear stress (WSS) but not with the magnitude of pressure. In the aneurysms, WSS was low and expression of biological markers was significantly altered in a time-dependent fashion. At 2 weeks, an upregulation of active-MMP-2, downregulation of TIMP-1 and TIMP-2, and intact endothelium were found in aneurysm cavities. However, by 12 weeks, endothelial cells were absent or scattered, and levels of pro- and active-MMP-2 were not different from those in control arteries, but pro-MMP-9 and both TIMPs were upregulated. These results reveal a strong, spatially localized correlation between diminished WSS and differential expression of biological markers of vascular remodeling in elastase-induced saccular aneurysms. The ability of the wall to function and maintain a healthy endothelium in a low shear environment appears to be significantly impaired by chronic exposure to low WSS.

Introduction Previous studies have noted formation of saccular aneurysms along the distal basilar artery/P1 segments after carotid ligation in rabbits. In this prospective study we employed MICROFIL®, a polymer, which was used to fill the entire arterial tree, to examine the incidence of microaneurysm formation following right common carotid artery (RCCA) ligation in rabbits. Methods RCCA ligation was performed in 18 New Zealand White rabbits for 0 day ( n  = 2), 3 weeks ( n  = 6), or 16 weeks ( n  = 10). Three control rabbits without carotid surgery were sacrificed at 4 weeks. At the time of sacrifice, MICROFIL® MV-122 yellow was injected through left CCA to fill cerebral vasculature. After gross photographs were taken, specimens were embedded, sectioned, and stained for histopathological evaluation. Tissue and sections were carefully evaluated for microaneurysm formation, defined as a localized dilatation of the vessel wall, associated with fragmentation or complete loss of the internal elastic lamina (IEL), and/or medial degeneration. Results Gross examination with MICROFIL® opacification demonstrated no evidence of saccular aneurysm formation, but prominent perforating vessels were present in all 19 cases at, or adjacent to, the basilar terminus. Branches noted upon gross examination corresponded histologically to small, saccular contour defects, which demonstrated apparent loss of the IEL and apparent medial thinning. These observations, however, were a consequence of sectioning through the bases of perforating arteries, which simulated microaneurysm formation. Conclusions Unilateral carotid ligation does not induce microaneurysm formation at the basilar terminus in rabbits. Prominent perforating arteries as well as tissue injury from the processing may simulate “aneurysms” histologically.

Abstract BACKGROUND Morphologic features are thought to play a critical role in the rupture of intracranial, saccular aneurysms. OBJECTIVE The objective of this study was to investigate the gene expression pattern of saccular aneurysms with distinct morphologic patterns. METHODS Elastase-induced saccular aneurysms with high (≥ 2.4) and low (≤ 1.6) aspect ratios (ARs) (height to neck width) were created in 15 rabbits (n = 9 for high AR and n = 6 for low AR). RNA was isolated from the aneurysms and analyzed using a microarray containing 294 rabbit genes of interest. Genes with a statistically significant difference between low and high AR (P < .05) and a fold change of ≥ 1.5 and ≤ 0.75 to represent up- and down-regulation in high AR compared with low AR were used to identify pathways for further investigation. RESULTS Fourteen genes (4.8%) were differentially expressed in high-AR aneurysms compared with low-AR aneurysms. The expression of osteopontin, tissue inhibitor of matrix metalloproteinase, haptoglobin, cathepsin L, collagen VIII, fibronectin, galectin 3, secreted frizzled-related protein 2, CD14, decorin, and annexin I were up-regulated, whereas the expression of myosin light chain kinase, Fas antigen, and CD34 were down-regulated in high-AR aneurysms. CONCLUSION In a rabbit model of saccular aneurysm, high AR was associated with differential expression of inflammatory/immunomodulatory genes, structural genes, genes related to proteolytic enzymes and extracellular matrix–related genes. These findings may focus efforts on targets aimed at avoiding spontaneous rupture of intracranial, saccular aneurysms.

Table of contents O1 The European Social Preferences Measurement (ESPM) study project: social cost value analysis, budget impact, commercial life cycle revenue management, and the economics of biopharmaceutical Research & Development (R&D) Michael Schlander, Søren Holm, Erik Nord, Jeff Richardson, Silvio Garattini, Peter Kolominsky-Rabas, Deborah Marshall, Ulf Persson, Maarten Postma, Steven Simoens, Oriol de Solà Morales, Keith Tolley, Mondher Toumi, Harry Telser O2 Newborn Screening: the potential and the challenges James R Bonham O3 Untreatable disease outcomes - how would we measure them? Helmut Hintner, Anja Diem, Martin Laimer O4 Taking Integrated Care Forward: Experiences from Canada to inspire service provision for people living with rare disease in Europe Réjean Hébert O5 Listening to the patient’s voice: social media listening for safety and benefits in rare diseases Nabarun Dasgupta, Carrie E. Pierce, Melissa Jordan O6 Via Opta: Mobile apps making visually impaired patients’ lives easier Barbara Bori, Mohanad Fors, Emilie Prazakova O7 A report of the IRDiRC “Small Population Clinical Trial” Task Force Simon Day O8 HAE patient identification and diagnosis: An innovative, ‘game changing’ collaboration Thomas J. Croce Jr. O9 Co-creating with the community: primary packaging & administration for people with haemophilia Jonas Fransson, Philip Wood O10 Go with Gaucher, taking forward the next generation. How to involve young people to create a new generation of patient advocates Anne-Grethe Lauridsen, Joanne Higgs, Vesna Stojmirova Aleksovska P1 ODAK – Orphan Drug for Acanthamoeba Keratitis Christina Olsen, Ritchie Head, Antonio Asero, Vincenzo Papa, Christa van Kan, Loic Favennec, Silvana Venturella, Michela Salvador, Alan Krol P5 Rare Navigators help people living with rare diseases to manage the social – and healthcare systems Stephanie J. Nielsen, Birthe B. Holm P6 The eAcademy for Tay-Sachs & Sandhoff disease app Daniel Lewi, Patricia Durão P10 The role of a patient organisation in driving the research agenda in a rare disease Heather Band, Andrea West P13 Expertise for rare diseases mapped Marinda J.A. Hammann, Marije C. Effing-Boele, Hanka K. Dekker P14 The hidden costs of rare diseases: a feasibility study Amy Hunter, Amy Simpson P15 FDA’s new natural history grant program: support to build a solid foundation for development of products for rare diseases Gumei Liu, Katherine Needleman, Debra Lewis, Gayatri Rao P17 Understanding the wider impact of adrenal insufficiency: patient organisation involvement in the TAIN project Amy Simpson, Amy Hunter, Martin J Whitaker P20 Bridging the gaps between medical and social care for people living with a rare disease Raquel Castro

Background and purpose To test the hypothesis that systemic administration of vitamin C, through its action of stimulating collagen synthesis and crosslinking, would decrease the recurrence and improve the occlusion of experimental aneurysms treated with platinum coils. Methods Experimental aneurysms were created in female rabbits and were embolized with platinum coils (>30% packing density). The animals were divided into three groups: group 1 (n=6) rabbits served as controls, group 2 (n=5) rabbits were fed with a vitamin C supplemented feed and group 3 (n=8) rabbits were medicated with vitamin C pills. Digital subtraction angiography was used to evaluate stability after embolization. Subjects were euthanized at 12 weeks after coil implantation, and serum vitamin C levels were then measured. Histological samples were examined with a grading system (range 0–12) based on the neck and dome features. Masson Trichrome staining was used to evaluate collagen deposition. Parametric data were analyzed with one way analysis of variance and non-parametric data were examined using a Kruskal–Wallis test. Results There were no significant differences between groups in mean aneurysm size. Mean serum vitamin C concentration was significantly higher in group 3 and group 2 compared with group 1, while vitamin C levels between group 2 and group 3 were statistically comparable. Coil compaction was noted in one of six subjects in group 1 and in three of eight subjects in group 3. All of the remaining aneurysms in the test and control groups showed stable occlusion. There were no significant differences in histological scores or collagen deposition among groups. Conclusions Vitamin C supplementation following platinum coil embolization does not demonstrate improvement of long term occlusion rates of aneurysms.

ABSTRACT Purpose: The primary aim of this study was to evaluate the use of three nursing interventions-occlusive wrap, chemical mattress, and regulation of delivery room temperature-singly and in combination in consecutive years on thermo-regulation in six groups of low birth weight infants. Design: A quasi-experimental design was used. Prospective data were collected on 133 infants weighing <1,500 g. Interventions were tested on different groups of infants in each of three years. The control group comprised 295 infants on which retrospective chart data were available over an earlier three-year period. Sample: Infants weighing <1,500 g participated in the study. Main Outcome Variable: The main outcome variable was NICU admission temperatures of infants weighing <1,500 g. For data analysis, infants were divided into two groups: those weighing <1,000 g and those weighing between 1,000 and 1,500 g. Results: For each of the three interventions, the percentage having a normal NICU admission temperature in each intervention group exceeded the control group percentage, but the increase was not significant. Use of each intervention-occlusive wrap alone, occlusive wrap in addition to chemical mattress, and occlusive wrap in addition to chemical mattress and increased delivery room temperature-appeared to influence thermoregulation positively.