tbuckley/cabot-search huggingface dataset:
FRI0519 Factors associated with prevalence of osteoarthritis in mexico.a national multilevel individual and ecological analysis
Authors: J. Rodriguez-Amado, J. Moreno-Montoya, J. Alvarez-Nemegyei, M. V. Goycochea-Robles, L. H. Sanín, R. Burgos-Vargas, M. A. Garza-Elizondo, M. Maradiaga, M. H. Cardiel, I. Peláez-Ballestas
Journal: Annals of the Rheumatic Diseases (2013)

<h3>Background</h3> An individual focus is frequently used as a key determinant of health to evaluate the behavior of different diseases with important limitations for detecting the effect exerted by social and economic factors, and policy on the health-disease process. <h3>Objectives</h3> To identify individual and ecological factors associated with the prevalence of osteoarthritis in Mexican population. <h3>Methods</h3> Our data are from a cross-sectional, community-based study performed in four regions of México using the COPCORD methodology between August 2008 and August 2009. The total sample included 17,566 individuals of which 10,666 (60.7%) were women. The prevalence of osteoarthritis (OA) was determined in this population. The relationship between individual level (age, gender, income, education, type of work, housing facilities and access to healthcare) and ecological level (Human Development Index, inequality, level of urbanization, income, health services, migration, unemployment, Marginalization Index and Social Gap Index) with OA were analyzed with a multilevel strategy. <h3>Results</h3> A total of 1,681 (62.1%) out of 2,706 individuals had OA. The prevalence of OA was 9.5% (95% CI 9.1, 10.0) and this was higher in women (6.6% vs. 2.9%, P &lt;0.01). The prevalence in individuals under 45 years was 4.8% (95% CI 4.4, 5.2); in the 46 to 65 years group, it was 14.0% (95% CI 10.0, 15.0), and in those over 66 years 21.4% (95% CI 19.7, 23.2). Multilevel analysis showed that the individual variables associated with the presence of OA were female gender (OR = 1.2, 95% CI 1.1, 1.4), age range 55-65 years (OR = 0.6, 95% CI 0.5, 0.8), musculoskeletal pain in the last 7 days (OR = 2.6 95% CI 2.2, 3.0), use of pain treatments (OR = 1.4, 95% CI 1.2, 1.7). At the regional level, the Social Gap Index was associated with the diagnosis of OA (coefficient: 0.4, 95% CI 0.1-1.1). <h3>Conclusions</h3> The Social Gap index was the only ecological variable associated with significant variance of the prevalence of OA. Female gender, pain intensity, physical limitation, and the use of pain treatments are individual variables that are associated with the presence of OA. <h3>Disclosure of Interest</h3> None Declared
Eye Signs in Hepatic Cirrhosis
Authors: William H. J. Summerskill, George D. Molnar
Journal: New England Journal of Medicine (1962)

A SURVEY was designed to test the clinical impression that lid retraction and lid lag, sometimes associated with apparent proptosis, were present with unusual frequency in patients with hepatic cirrhosis. These ocular signs are identical with those characterizing part of the noninfiltrative component of the ophthalmopathy of Graves's disease. The incidence of such ocular changes in patients with cirrhosis and in a control population, together with an evaluation of the relation of the ocular signs to hepatic and thyroid function in patients with liver disease, forms the basis of this report.MethodsThe incidence of lid retraction, lid lag or . . .
The Impact of Genomics on the Management of Myeloma
Authors: Jill Corre, Hervé Avet-Loiseau
Journal: Journal of the National Comprehensive Cancer Network (2011)

Myeloma is a complex disease, characterized by a wide heterogeneity in clinical presentation, evolution, and molecular portraits. The successive use of cytogenetics, molecular cytogenetics, expression genomics, copy number genomics, and, more recently, deep sequencing, has shown that this heterogeneity can be used to identify markers usable for not only prognostication but also therapeutic choice and, ultimately, discovery of druggable targets. The use of some of these techniques is now mandatory for the management of patients. Although risk-adapted therapy is not yet a routine practice in myeloma, these molecular changes are essential for the definition of the prognosis.
Abstract 3680: The Akt activation inhibitor TCN-P inhibits Akt phosphorylation by binding to the PH domain of Akt and blocking its recruitment to the plasma membrane
Authors: Norbert Berndt, Hua Yang, Bernard Trinczek, Ziming Zhang, Bainan Wu, Nicholas J. Lawrence, Maurizio Pellechia, Ernst Schonbrunn, Jin Q. Cheng, Said M. Sebti
Journal: Cancer Research (2010)

Abstract Persistently activated hyper-phosphorylated Akt contributes to human oncogenesis and tumor resistance. TCN-P, the active metabolite of the Akt phosphorylation inhibitor triciribine (TCN), is in clinical trials in patients whose tumors contain hyper-phosphorylated Akt, but the mechanism by which TCN-P, inhibits Akt phosphorylation is not known. In this manuscript, we show that in vitro, TCN-P inhibits neither Akt kinase activity nor the phosphorylation of Akt S473 and T308 by mTOR or PDK1, respectively. However, in intact cells, immunofluorescence and subcellular fractionation experiments demonstrate that TCN inhibits EGF-stimulated Akt recruitment to the plasma membrane and subsequent phosphorylation of Akt on Ser473 and Thr308. Surface plasmon resonance (SPR) demonstrates that TCN-P, but not TCN, binds to full-length, non-phosphorylated (inactive) Akt. However, neither TCN-P nor TCN interacts with full-length, phosphorylated (active) Akt. Furthermore, TCN-P, but not TCN, binds Akt-derived pleckstrin homology (PH) domain with KD values of 690 nM and 1.4 µM as demonstrated by SPR and isothermal calorimetry (ITC), respectively. Consistent with these data, nuclear magnetic resonance (NMR) spectroscopy shows that TCN-P, but not TCN, binds to the PH domain engaging amino acid residues in the vicinity of the PIP3 binding pocket. Thus, SPR, NMR, as well as biochemical studies indicate that the anti-cancer drug TCN-P inhibits Akt function by binding to the PH domain of Akt, blocking its recruitment to the plasma membrane and subsequent phosphorylation, suggesting that this drug may be beneficial to patients whose tumors express persistently activated Akt. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3680.
P718A novel TGF beta-dependent signalling pathway regulating vascular smooth muscle cell differentiation
Authors: C Pagiatakis, D Sun, S Wales, JC Mcdermott
Journal: Cardiovascular Research (2014)

Purpose: Vascular smooth muscle cells (VSMCs) do not terminally differentiate; they fluctuate between a proliferative and differentiated state in response to various extracellular signals. This phenotypic modulation is a major factor that contributes to vascular diseases such as atherosclerosis and post-angioplasty restenosis. Thus, the mechanisms regulating VSMC phenotype are of great interest. TGFβ has been implicated in inducing VSMC differentiation via RhoA/ROCK signalling, whereby it induces a contractile phenotype in neural crest stem cells by up-regulating smooth muscle structural genes. Previous work in our lab showed that RhoA is involved in regulating contractile genes via regulation of myocardin expression. Therefore, we hypothesized that TGFβ is involved in regulating smooth muscle cell differentiation via downstream targets of RhoA/ROCK and components of the canonical TGFβ pathway.
Appointments later in week are less likely to be missed, finds study
Authors: G. Iacobucci
Journal: BMJ (2012)

Medical appointments scheduled at the beginning of the week are more likely to be missed than those later in the week, a study shows.

Researchers from the University of Glasgow found that the proportions of “did not attend” for GP and hospital appointments were highest on Mondays (6.2%) and lowest on Fridays (4.2%), with the proportion decreasing noticeably as …
Abstract 3573: Urine and serum biomarkers as early detection tools for ovarian cancer
Authors: Brian M. Nolen, Aleksey Lomakin, Robert Bast, Karen Lu, Adele Marrangoni, Anna E. Lokshin
Journal: Cancer Research (2012)

Abstract Background: The measurement of biomarkers present in the bodily fluids of ovarian cancer patients represents an emerging strategy for early detection. To date, a great deal of related work has been devoted to blood, given its systemic exposure and extensive availability through tissue banks. However, blood is a dynamic biofluid with a proteome under continuous metabolic and homeostatic regulation. Alternatively, urine represents a biofluid that is inherently quiescent in that all molecular and proteolytic activity is largely complete upon sampling. Additional characteristics of urine, including its high level of temperature stability and low-complexity matrix resulting from renal filtration, suggest that this biofluid may serve as an effective alternative or companion to blood in biomarker analyses. Methods: A set of urines obtained from over 700 women, including patients diagnosed with ovarian cancer, patients diagnosed with benign pelvic lesions, and healthy donors, was tested for 39 biomarkers which demonstrated previous associations with ovarian cancer. In an effort to identify additional useful biomarkers, 122 candidate biomarkers were evaluated in a separate set of 150 sera obtained from ovarian cancer patients along with benign and healthy controls. Significantly altered biomarkers were identified in each analysis and the full biomarker dataset was examined by multivariate analysis to identify multianalyte panels capable of discriminating ovarian cancer patients from controls with high accuracy. Results: Numerous significantly altered biomarkers were identified in both urine and serum. The classification performance of several biomarkers was found to differ in urine vs. serum with an overall trend in favor of urine biomarkers. Separate urine and serum biomarker panels consisting of 3-4 analytes were identified which could discriminate ovarian cancer from healthy controls at a sensitivity of 96-97% at 95% specificity. Improvement upon this classification efficiency was observed when the best urine and serum biomarkers were combined into a single panel. The combination of urine HE4 and serum CA 125 was most effective in the discrimination of ovarian cancer from benign controls. Conclusions: Urine and serum biomarkers offer complementary information regarding ovarian cancer status. Their combined use may lead to the development of effective early detection tools. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3573. doi:1538-7445.AM2012-3573
AB0774 A New Correction Method for Knee Kinematics in 3D GAIT Analysis in Healthy and Knee Osteoarthritis Patients Using Principal Component Analysis (PCA)
Authors: A. Baudet, C. Morisset, J. Maillefert, V. Gremeaux, P. Ornetti, D. Laroche
Journal: Annals of the Rheumatic Diseases (2014)

<h3>Background</h3> In 3D gait analysis, the knee joint is usually expressed using the Eulerian description. It consists in breaking down the motion between the articulating bones of the knee into three rotations around three axes: flexion/extension, abduction/adduction and internal/external rotation. However, the definition of these axes is prone to error, such as the "cross-talk" effect, due to difficult positioning of anatomical landmarks. This paper proposes a post-hoc statistical correction method by principal component analysis (PCA), based on an objective kinematic criterion for standardization, in order to improve knee joint kinematics analysis. <h3>Methods</h3> The method was applied to the 3D gait data of two different groups of three subjects (healthy and with knee osteoarthritis). Then, five indirect indicators of accuracy were computed (a) variance accorded to the 1st principal component; (b) range of motion of the varus-valgus during gait (c) Range of motion of the flexion/extension angle (d) preservation of the screw-home mechanism;(e) quantification of the symptomatic deformities in patients with knee osteoarthritis. <h3>Results</h3> The first principal component accounted for almost 90% of the total data variance. The ab/adduction range of motion (ROM) was reduced from about 25° to 30° before, to less than 5° after reorientation, and the PCA led to about 7° more knee flexion/extension ROM. Additionally, the two internal rotation peaks were still time-aligned with the flexion/extension ones, according to the screw-home mechanism. Finally, the varus/valgus angle values after correction were much closer to the performed x-ray grading than before correction. <h3>Conclusions</h3> The results showed that the correction eliminates the knee joint angle cross-talk effect, preserves the varus/valgus radiological deformation for patients with knee osteoarthritis and does not delete the knee screw mechanisms. These findings underline the fact that the proposed correction method produces new rotational axes that better fit true knee motion. <h3>Disclosure of Interest</h3> None declared <h3>DOI</h3> 10.1136/annrheumdis-2014-eular.1932
Elective Cardioversion: Influence of Paddle-Electrode Location and Size on Success Rates and Energy Requirements
Authors: Richard E. Kerber, Susan R. Jensen, Joseph Grayzel, Jeffrey Kennedy, Robert Hoyt
Journal: New England Journal of Medicine (1981)

We compared the success rates and energy requirements of two electrode-paddle positions (anteroposterior vs. anterolateral) and different paddle sizes in the elective cardioversion of atrial arrhythmias. We prospectively studied 173 patients — 111 in atrial fibrillation and 62 in atrial flutter. The anterolateral paddles used were either two standard-size (8.5-cm diameter) paddles or one 13-cm diameter anterior paddle with one standard-size lateral paddle. The anteroposterior paddles used were either a standard-size or a 13-cm anterior paddle with a 12-cm posterior paddle. Overall cardioversion success rates with either paddle position were similar (>90 per cent). The larger paddles did not significantly reduce energy requirements for cardioversion of either arrhythmia. We conclude that anterolateral paddles are as effective as anteroposterior paddles for the elective cardioversion of atrial arrhythmias, and that there is no demonstrable advantage to using paddles that are larger than the standard size in either position. (N Engl J Med. 1981; 305:658–62.)
PTU-031 Downregulation of the vitamin B<sub>12</sub>receptor in fibrolamellar carcinoma of the liver: the first consistent molecular abnormality
Authors: P Johnson, G Baldwin, M Teng, B O'Sullivan, J James, M-A Brundler, P Taniere
Journal: Gut (2012)

Introduction Fibrolamellar hepatocellular carcinoma (FLHCC) is a rare tumour of young adults that is characterised by the presence of large tumour cells with strongly eosinophilic cytoplasm, surrounded by fibrous lamellae, in the absence of chronic liver disease. No consistent molecular abnormalities have been detected to date but an elevation of serum vitamin B12 binding capacity has been described. Methods Up to 80% of vitamin B12 (cobalamin), is stored in the liver after endocytosis via the transcobalamin receptor (CD320). We hypothesised that disruption to the transcobalamin receptor (hereafter referred to as CD320) might render the liver locally B12 deficient and elicit a compensatory production of the serum B12 binding protein (TCN1). We sought a functional mutation of CD320 in 15 cases of FLHCC and 30 cases of conventional hepatocellular carcinoma (HCC), 10 cases with cirrhosis (C-HCC) and 20 cases with no cirrhosis (NC-HCC)) acting as control tissues. cDNA was synthesised using RNA purified from formalin fixed paraffin embedded (FFPE) tissues and primers were designed to amplify the region spanning exon2/3 across the mutation site. Results Sequencing analysis showed ∼5% (1/18) mutation in NC HCC. However, 60% (9/15) of the FLHCC cohort did not show any amplification while 80% of NC-HCC (16/20) and C-HCC (8/10) tumours tested positive. The quality of purified mRNA was verified by amplifying for two different housekeeping genes, tubulin and β-glucuronidase. To determine the reason for non-amplification of CD320exon2/3, we sequenced the promoter and promoter regulator region of CD320 using DNA purified from FFPE tissue. Comparison of the sequences of CD320 (+) and (−) representative samples showed no difference in their DNA sequence. Methylation analysis of the methylation sensitive promoter regulator region of NC-HCC, and FLHCC showed a correlation between the level of methylation and CD320 suppression in NC-HCC but not for FLHCC. To address this discrepancy, a second region of CD320, spanning exon3/4 was amplified. Interestingly, all the FLHCC samples were positive giving an amplification product for this region. Immunostaining for CD320 was in agreement with the exon 3/4 amplification data. Conclusion Taken together, these results indicate that the expression of a non-functional splice variant (variant 2), which lacks the crucial triple glutamic acid repeat within the exon 2 necessary for the receptor's function, may contribute to the increased serum Vitamin B12 binding capacity in FLHCC. Competing interests None declared.
Abstract 4265: Derivation and characterization of endometrial cancer cells resistant to phosphatidylinositol-3-kinase (PI3K) pathway inhibitors.
Authors: Samuel J. Klempner, Andrea P. Myers, Jane Li, Gordon Mills, Lewis C. Cantley
Journal: Cancer Research (2013)

Abstract Endometrial cancer remains the most common gynecologic malignancy in the United States with an estimated 43,000 cases annually. Limited options exist for patients with recurrent endometrial cancer after tumor progression following platinum/taxane combinations, and newer therapies are needed. Endometrial cancers have among the highest rates of oncogenic aberrations in the phosphatidylinositol-3-kinase (PI3K) pathway with frequencies approaching 75%, and clinical trials targeting components on the PI3K pathway are ongoing. Despite the clinical observation that many responses to PI3K inhibitors are short lived an understanding of the molecular mechanisms of resistance is lacking. We have derived endometrial cancer cell lines resistant to a panel of PI3K/AKT/mTOR inhibitors in clinical development in an effort to understand molecular mechanisms and signaling changes underlying resistance to PI3K-targeted therapy. All lines have previously undergone mutational analysis of the PI3K and RAS-ERK pathways. Representative compounds inhibiting each node in the canonical class I PI3K signaling cascade have been chosen. These agents have been synthesized base on the published structures and include a pan-p110 inhibitor, an allosteric AKT inhibitor, a dual p110-mTOR, and a MEK inhibitor. Using parallel high-throughput intracellular phospho-kinase and phospho-receptor tyrosine kinase (RTK) arrays for screening we have identified candidate common resistance mechanisms to inhibition of signaling nodes in the PI3K pathway. The phospho-screening approach has highlighted the interplay between PI3K/AKT/mTOR signaling and the Ras/Raf/MEK/ERK pathways in the development of resistance. We have begun to validate ERK upregulation as an activated escape pathway in patient samples from an AKT inhibitor clinical trial. Conserved resistance profiles may ultimately be used to define a subset of endometrial cancer patients unlikely to respond to PI3K/Akt/mTOR inhibitors and may inform more rational early phase combination strategies. Citation Format: Samuel J. Klempner, Andrea P. Myers, Jane Li, Gordon Mills, Lewis C. Cantley. Derivation and characterization of endometrial cancer cells resistant to phosphatidylinositol-3-kinase (PI3K) pathway inhibitors. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4265. doi:10.1158/1538-7445.AM2013-4265
THU0135 “indispensable or intolerable?” a retrospective review of methotrexate discontinuation in rheumatoid arthritis:
Authors: A.J. Badcock, A.P. Malaviya, A.J. Ostor
Journal: Annals of the Rheumatic Diseases (2013)

<h3>Background</h3> Due to its efficacy and safety methotrexate (MTX) has become the first-line disease-modifying drug for rheumatoid arthritis (RA). Its overall tolerability however has not been extensively studied. We addressed this question with real-life data from RA patients treated with MTX. <h3>Objectives</h3> To study the prevalence and causes of MTX discontinuation in RA patients in routine clinical practice. <h3>Methods</h3> As part of an audit, a retrospective review of our electronic database was undertaken to identify all patients who had received MTX for RA. In those that had stopped treatment, the reasons for this were explored. The dose and duration of MTX therapy was also recorded. <h3>Results</h3> 1551 patients on MTX were identified from our rheumatology database. MTX had been stopped in 523 patients (216 in the preceding 24 months). Of these 216 patients, 108 had RA as the primary diagnosis and thus were further analysed. The mean dose at the time of discontinuation of MTX was 14.5mg/week (dose range 2.5-25mg, SD 5.25) (missing data in 19 patients). Abnormal blood results (cytopenias and altered liver function) accounted for 25% of these patients. In approximately 50%, therapy was stopped due to unacceptable symptoms (see table 1). Approximately one in five patients reported feeling "non-specifically unwell" or fatigued. This data relates only to those who discontinued MTX and does not include patients who suffer from side-effects but elect to continue therapy. <h3>Conclusions</h3> Our study indicates that over time approximately one-third of patients discontinue MTX. Although gastrointestinal and haematological causes are common, up to one in five patients report non-specific symptoms (fatigue, tiredness) as the reason for discontinuation. Further research needs to be directed to identifying those patients who continue MTX despite side-effects, in order to optimise patient adherence and compliance. <h3>Disclosure of Interest</h3> None Declared
Improving outcomes from in-hospital cardiac arrest
Authors: Keith Couper, Gavin D Perkins
Journal: BMJ (2016)

Make sure local practice is informed by the latest guidelines Over 200 000 adults a year sustain a cardiac arrest while in hospital in the United States.1 Most trials have taken place outside hospital,2 yet the aetiology, patient characteristics, time to treatment, and outcomes are quite different to cardiac arrests occurring in inpatients.Clinical guidelines for inhospital resuscitation are therefore mainly drawn from the extrapolation of findings from out-ofhospital trials, observational studies, and consensus of expert opinion coordinated through the International Liaison Committee for Resuscitation.3