tbuckley/cabot-search huggingface dataset:
P159Vascular endothelial growth factor receptor 2 inhibition improves endothelial function in type 2 diabetic rats: a link to purinergic signalling?
Authors: A Mahdi, Y Tratsiakovich, J Yang, C-G Ostenson, JAH Danser, J Pernow, Z Zhou
Journal: Cardiovascular Research (2018)

antagonist SR59203A (100nM).The role of the adipokine, adiponectin, was examined using exogenous adiponectin (5mg/ml) and a blocking peptide for adiponectin receptor 1 (5mg/ml).Immunohistochemistry was used to examine b3-adrenoceptor expression.Results: During EFS PVAT elicited a reproducible anti-contractile effect, which was lost in obesity.Solution transfer from stimulated exogenous PVAT to a -PVAT vessel significantly reduced contraction, confirming that stimulated healthy PVAT releases a transferable anti-contractile factor.Pharmacological denervation using 6-hydroxydopamine abolished the anti-contractile effect.In health, the b3-adrenoceptor antagonist SR59203A reduced the anti-contractile effect; however b3-adrenoceptor agonist CL-316,243 could not restore function in obesity.Using immunohistochemistry, expression of b3-adrenoceptors was reduced in obesity.Exogenous application of adiponectin induced vasodilation of healthy vessels, and a blocking peptide for adiponectin receptor-1 significantly reduced the anti-contractile effect of PVAT in health.However, in obese vessels exogenous adiponectin no longer exerted a vasodilator effect.In obese exercised mice, the PVAT anticontractile was restored, and the development of hypertension and type-II diabetes was reversed, although the mice remained obese.Exercise increased b3-adrenoceptor expression, and restored the vasodilator effects of adiponectin.Conclusions: In conclusion, sympathetic nerve stimulation elicits an anti-contractile effect via activation b3-adrenoreceptors and release of adiponectin.This effect was lost in obesity, which may contribute to development of hypertension and type-II diabetes.Exercise restored PVAT dysfunction in obesity, and normalised glucose, insulin, and blood pressure independent of weight loss. P158Red blood cells from patients with type 2 diabetes mellitus induce endothelial dysfunction through NADPH oxidase-derived reactive oxygen species
The use of MRI-detected synovitis to determine the number of involved joints for the 2010 ACR/EULAR classification criteria for Rheumatoid Arthritis – is it of additional benefit?
Authors: Aleid C Boer, Debbie M Boeters, Annette H M van der Helm-van Mil
Journal: Annals of the Rheumatic Diseases (2018)

<h3>Objective</h3> To assess the value of MRI-detected synovitis to determine the number of involved joints on the performance of the 2010-ACR/EULAR classification criteria for rheumatoid arthritis (RA). <h3>Methods</h3> 277 patients with a clinical suspicion of RA consecutively included in the Leiden Early Arthritis Clinic (EAC)-cohort underwent 1.5T MRI of MCP-, wrist- and MTP-joints. Test characteristics of the 2010-criteria were calculated when the number of involved joints was determined with and without including MRI-detected synovitis. Two outcomes were studied: disease modifying anti-rheumatic drug (DMARD)-initiation and 1987-criteria fulfilment during the first year. <h3>Results</h3> At baseline, 143 patients were classified as RA. When MRI-detected synovitis was considered, 14 patients additionally fulfilled the 2010-criteria. Of these, 64% (9/14) started DMARDs. When MRI-detected synovitis was also used to determine the number of involved joints the sensitivity changed from 62% to 67%, the specificity from 90% to 84% and the AUC from 0.76 to 0.75. The net reclassification index was −2.4%. When fulfilling the 1987-criteria was used as outcome, results were similar. <h3>Conclusion</h3> We found no scientific support that the use of MRI-detected synovitis is of additional benefit for the performance of the 2010 classification criteria.
MC4R agonism promotes durable weight loss in patients with leptin receptor deficiency
Authors: Karine Clément, Heike Biebermann, I. Sadaf Farooqi, Lex Van der Ploeg, Barbara Wolters, Christine Poitou, Lia Puder, Fred Fiedorek, Keith Gottesdiener, Gunnar Kleinau, Nicolas Heyder, Patrick Scheerer, Ulrike Blume-Peytavi, Irina Jahnke, Shubh Sharma, Jacek Mokrosinski, Susanna Wiegand, Anne Müller, Katja Weiß, Knut Mai, Joachim Spranger, Annette Grüters, Oliver Blankenstein, Heiko Krude, Peter Kühnen
Journal: Nature Medicine (2018)
Gates Foundation challenges researchers to create universal flu vaccine with $12m offer
Authors: Owen Dyer
Journal: BMJ (2018)

The Bill and Melinda Gates Foundation and Google founder Larry Page have announced a $12m (£8.76m; €9.97m) “grand challenge” aimed at stimulating research into a universal flu vaccine that would eliminate the need for yearly shots tailored to prevalent strains.

Gates’ announcement, at this year’s Shattuck Lecture hosted by the Massachusetts Medical Society, came soon after research in Clinical Infectious Diseases predicted that next year’s vaccine will only be 20% effective against the prevalent H3N2 strain, largely because of flaws inherent in the egg based manufacturing process.1

There are signs that the US government agencies tasked with confronting the influenza threat are losing faith in the current system …
Real world adherence to Direct-Acting Antivirals in a cohort of drug users in Rome, Italy
Authors: E. Teti, L. Foroghi, V. Malagnino, V. Cento, C. Stingone, M. Compagno, G. Malerba, A. Gentile, R.A. Cavasio, L. Coppola, E. Rossi, D. Masci, P. Sammarco, B. Coladarce, G. Rodoquino, M. Patti, C. Sarrecchia, C.F. Perno, F.C. Silberstein, M. Barra, L. Sarmati, M. Andreoni
Journal: Journal of Hepatology (2018)
Features, Treatment, and Outcomes of Macrophage Activation Syndrome in Childhood‐Onset Systemic Lupus Erythematosus
Authors: R. Ezequiel Borgia, Maya Gerstein, Deborah M. Levy, Earl D. Silverman, Linda T. Hiraki
Journal: Arthritis & Rheumatology (2018)

To describe the features and treatment of macrophage activation syndrome (MAS) in a single-center cohort of patients with childhood-onset systemic lupus erythematosus (SLE), and to compare childhood-onset SLE manifestations and outcomes between those with and those without MAS.We included all patients with childhood-onset SLE followed up at The Hospital for Sick Children from 2002 to 2012, and identified those also diagnosed as having MAS. Demographic, clinical, and laboratory features of MAS and SLE, medication use, hospital and pediatric intensive care unit (PICU) admissions, as well as damage indices and mortality data were extracted from the Lupus database. Student's t-tests and Fisher's exact tests were used to compare continuous and categorical variables, respectively. We calculated incidence rate ratios of hospital and PICU admissions comparing patients with and those without MAS, using Poisson models. Kaplan-Meier survival analysis was used to examine the time to disease damage accrual.Of the 403 patients with childhood-onset SLE, 38 (9%) had MAS. The majority (68%) had concomitant MAS and SLE diagnoses. Fever was the most common MAS clinical feature. The frequency of renal and central nervous system disease, hospital admissions, the average daily dose of steroids, and time to disease damage were similar between those with and those without MAS. We observed a higher mortality rate among those with MAS (5%) than those without MAS (0.2%) (P = 0.02).MAS was most likely to develop concomitantly with childhood-onset SLE diagnosis. The majority of the MAS patients were successfully treated with corticosteroids with no MAS relapses. Although the numbers were small, there was a higher risk of death associated with MAS compared to SLE without MAS.
Oropharyngeal and nasopharyngeal decontamination with chlorhexidine gluconate in lung cancer surgery: a randomized clinical trial
Authors: Xavier Benoit D’Journo, Pierre-Emmanuel Falcoz, Marco Alifano, Jean-Philippe Le Rochais, Thomas D’Annoville, Gilbert Massard, Jean Francois Regnard, Philippe Icard, Charles Marty-Ane, Delphine Trousse, Christophe Doddoli, Bastien Orsini, Sophie Edouard, Matthieu Million, Nathalie Lesavre, Anderson Loundou, Karine Baumstarck, Florence Peyron, Stephane Honoré, Stéphanie Dizier, Aude Charvet, Marc Leone, Didier Raoult, Laurent Papazian, Pascal Alexandre Thomas
Journal: Intensive Care Medicine (2018)
Post-fabrication QAC-functionalized thermoplastic polyurethane for contact-killing catheter applications
Authors: Zachary K. Zander, Peiru Chen, Yen-Hao Hsu, Nathan Z. Dreger, Laura Savariau, Willie C. McRoy, Alec E. Cerchiari, Sean D. Chambers, Hazel A. Barton, Matthew L. Becker
Journal: Biomaterials (2018)
Conversion Disorder Diagnosis and Medically Unexplained Symptoms
Authors: Michael James Redinger, Parker Crutchfield, Tyler S. Gibb, Peter Longstreet, Robert Strung
Journal: The American Journal of Bioethics (2018)

Physicians often infer psychogenic causation when confronted with medically unexplained symptoms (MUS). The inference to the best explanation is unjustifiable because it fails to meet the specific ...
High risk of esophageal varices in patients with Fontan surgery: The VALDIG FONLIVER study
Authors: L. Téllez, E. Rodríguez-Santiago, E. Garrido, A. Baiges, V.L. Mura, E. Garrido-Lestache, R. Romera, J. Martinez, A. Clemente, L. Aguilera, E. Llop, D. Rincón, M.A. Fuente, I. Sánchez, F. Gea, D.M.J. Del Cerro, R. Bañares, G.P.J. Carlos, A. Albillos
Journal: Journal of Hepatology (2018)
Association of Vasopressin Plus Catecholamine Vasopressors vs Catecholamines Alone With Atrial Fibrillation in Patients With Distributive Shock
Authors: William F. McIntyre, Kevin J. Um, Waleed Alhazzani, Alexandra P. Lengyel, Ludhmila Hajjar, Anthony C. Gordon, François Lamontagne, Jeff S. Healey, Richard P. Whitlock, Emilie P. Belley-Côté
Journal: JAMA (2018)

<h3>Importance</h3> Vasopressin is an alternative to catecholamine vasopressors for patients with distributive shock—a condition due to excessive vasodilation, most frequently from severe infection. Blood pressure support with a noncatecholamine vasopressor may reduce stimulation of adrenergic receptors and decrease myocardial oxygen demand. Atrial fibrillation is common with catecholamines and is associated with adverse events, including mortality and increased length of stay (LOS). <h3>Objectives</h3> To determine whether treatment with vasopressin + catecholamine vasopressors compared with catecholamine vasopressors alone was associated with reductions in the risk of adverse events. <h3>Data Sources</h3> MEDLINE, EMBASE, and CENTRAL were searched from inception to February 2018. Experts were asked and meta-registries searched to identify ongoing trials. <h3>Study Selection</h3> Pairs of reviewers identified randomized clinical trials comparing vasopressin in combination with catecholamine vasopressors to catecholamines alone for patients with distributive shock. <h3>Data Extraction and Synthesis</h3> Two reviewers abstracted data independently. A random-effects model was used to combine data. <h3>Main Outcomes and Measures</h3> The primary outcome was atrial fibrillation. Other outcomes included mortality, requirement for renal replacement therapy (RRT), myocardial injury, ventricular arrhythmia, stroke, and LOS in the intensive care unit and hospital. Measures of association are reported as risk ratios (RRs) for clinical outcomes and mean differences for LOS. <h3>Results</h3> Twenty-three randomized clinical trials were identified (3088 patients; mean age, 61.1 years [14.2]; women, 45.3%). High-quality evidence supported a lower risk of atrial fibrillation associated with vasopressin treatment (RR, 0.77 [95% CI, 0.67 to 0.88]; risk difference [RD], −0.06 [95% CI, −0.13 to 0.01]). For mortality, the overall RR estimate was 0.89 (95% CI, 0.82 to 0.97; RD, −0.04 [95% CI, −0.07 to 0.00]); however, when limited to trials at low risk of bias, the RR estimate was 0.96 (95% CI, 0.84 to 1.11). The overall RR estimate for RRT was 0.74 (95% CI, 0.51 to 1.08; RD, −0.07 [95% CI, −0.12 to −0.01]). However, in an analysis limited to trials at low risk of bias, RR was 0.70 (95% CI, 0.53 to 0.92,<i>P</i>for interaction = .77). There were no significant differences in the pooled risks for other outcomes. <h3>Conclusions and Relevance</h3> In this systematic review and meta-analysis, the addition of vasopressin to catecholamine vasopressors compared with catecholamines alone was associated with a lower risk of atrial fibrillation. Findings for secondary outcomes varied.
Cost-effectiveness of Electroconvulsive Therapy vs Pharmacotherapy/Psychotherapy for Treatment-Resistant Depression in the United States
Authors: Eric L. Ross, Kara Zivin, Daniel F. Maixner
Journal: JAMA Psychiatry (2018)

Electroconvulsive therapy (ECT) is a highly effective treatment for depression but is infrequently used owing to stigma, uncertainty about indications, adverse effects, and perceived high cost.To assess the cost-effectiveness of ECT compared with pharmacotherapy/psychotherapy for treatment-resistant major depressive disorder in the United States.A decision analytic model integrating data on clinical efficacy, costs, and quality-of-life effects of ECT compared with pharmacotherapy/psychotherapy was used to simulate depression treatment during a 4-year horizon from a US health care sector perspective. Model input data were drawn from multiple meta-analyses, randomized trials, and observational studies of patients with depression. Where possible, data sources were restricted to US-based studies of nonpsychotic major depression. Data were analyzed between June 2017 and January 2018.Six alternative strategies for incorporating ECT into depression treatment (after failure of 0-5 lines of pharmacotherapy/psychotherapy) compared with no ECT.Remission, response, and nonresponse of depression; quality-adjusted life-years; costs in 2013 US dollars; and incremental cost-effectiveness ratios. Strategies with incremental cost-effectiveness ratios of $100 000 per quality-adjusted life-year or less were designated cost-effective.Based on the Sequenced Treatment Alternatives to Relieve Depression trial, we simulated a population with a mean (SD) age of 40.7 (13.2) years, and 62.2% women. Over 4 years, ECT was projected to reduce time with uncontrolled depression from 50% of life-years to 33% to 37% of life-years, with greater improvements when ECT is offered earlier. Mean health care costs were increased by $7300 to $12 000, with greater incremental costs when ECT was offered earlier. In the base case, third-line ECT was cost-effective, with an ICER of $54 000 per quality-adjusted life-year. Third-line ECT remained cost-effective in a range of univariate, scenario, and probabilistic sensitivity analyses. Incorporating all input data uncertainty, we estimate a 74% to 78% likelihood that at least 1 of the ECT strategies is cost-effective and a 56% to 58% likelihood that third-line ECT is the optimal strategy.For US patients with treatment-resistant depression, ECT may be an effective and cost-effective treatment option. Although many factors influence the decision to proceed with ECT, these data suggest that, from a health-economic standpoint, ECT should be considered after failure of 2 or more lines of pharmacotherapy/psychotherapy.
Dressings for venous leg ulcers
Authors: Sophia Tate, Annie Price, Keith Harding
Journal: BMJ (2018)

### What you need to know

A 65 year old man presents with a two month history of a wound in the gaiter area of his left leg. He has a history of a left leg deep vein thrombosis after a long flight but is otherwise fit and well. He had been self-managing with dressings bought over the counter, but the wound has gradually increased in size. The wound is not painful but is weeping serous fluid, causing irritation of the surrounding skin. Examination shows a 4×3×0.1 cm wound above the left medial malleolus. There is haemosiderin deposition, venous flare, and moderate oedema in the limb. The ankle-brachial pressure index (ABPI) is normal at 1.0. He is diagnosed with a venous leg ulcer, which is managed with dressings and compression bandaging. 



The cornerstone of venous leg ulcer treatment is compression therapy, which increases venous return and reduces venous hypertension.1 However, dressings are important because they can provide symptom control and optimise the local wound environment to promote healing. This article provides an overview of the dressings that may be used in venous leg ulcers and guidance on selection.

About 1% of the adult population in Westernised countries are affected by venous ulcers on the leg or foot.2 The prevalence increases with age to 1.7% in …
Pitfalls of antinuclear antibody detection in systemic lupus erythematosus: the positive experience of a national multicentre study
Authors: Francesca Pregnolato, Maria Orietta Borghi, Pier Luigi Meroni
Journal: Annals of the Rheumatic Diseases (2018)

Table 1 ANA detection Test results HEp-2 IFA CTD SPA* Anti-ENA Anti-dsDNA Manual Auto 1 † Auto 2 Auto 3 a b Positive % (n/N) 100 (91/91) 100 (91/91) 98 (89/91) 99 (90/91) 88 (80/91) 91 (83/91) 45 (40/89) 59 (54/91) Negative % (n/N) 0 (0/91) 0 (0/0) 2 (2/91) 1 (1/91) 12 (11/91) 9 (8/91) 55 (49/89) 41 (37/91) *CTD SPA, connective tissue diseases screening solid phase assay; (a) Quanta Flash CTD screen plus, INOVA Diagnostics: recombinant Scl-70, Jo-1, SSA/Ro 52, SSA/Ro 60, SSB/La, centromere A and B, RNA Pol III, Mi-2, Ku, Th/To, PCNA, native Sm and RNP, synthetic Pm/Scl and ribosomal-P peptides and synthetic dsDNA; (b) ELiA CTD screen, Thermo Fisher: dsDNA, SSA/Ro 52, SSA/Ro 60, SSB/La, U1-RNP (RNP-70, A, C), Sm, centromere B, Jo-1, Scl-70, Rib-P, fibrillarin, RNA Pol III, PM-Scl, PCNA and Mi-2, all recombinant except native purified dsDNA.†Automated reading systems: (1) AKLIDES, Medipan GMBH; (2) NOVA-View, INOVA Diagnostics; (3) G-Sight, Menarini Diagnostics.ANA, anti-nuclear antibodies; ENA, extractable nuclear antigen; HEp-2 IFA, indirect immunofluorescence on HEp-2 cells.
Estimation of the Percentage of US Patients With Cancer Who Benefit From Genome-Driven Oncology
Authors: John Marquart, Emerson Y. Chen, Vinay Prasad
Journal: JAMA Oncology (2018)

<h3>Importance</h3> To date, the benefit of genome-driven cancer therapy has not been quantified. <h3>Objective</h3> We sought to estimate the annual percentage of patients in the United States with advanced or metastatic cancer who could be eligible for and benefit from US Food and Drug Administration (FDA)-approved genome-driven therapy from 2006 to 2018. <h3>Design, Setting, and Participants</h3> Retrospective cross-sectional study using publically available data of (1) demographic characteristics of patients with advanced or metastatic cancer; (2) FDA data on cancer drugs approved from January 2006 through January 2018; (3) measures of response and duration of response from drug labels; and (4) published reports estimating the frequency of various genomic aberrations used to estimate what percentage of patients would have been eligible for and would have benefited from genome-driven therapy during the studied period. <h3>Main Outcomes and Measures</h3> Estimated percentage of US patients with cancer eligible for and benefiting from genome-targeted and genome-informed therapy by year, response rate of genome-informed indications, and duration of response. <h3>Results</h3> A total of 31 drugs with 38 FDA-approved indications met our inclusion criteria for genome-targeted or genome-informed therapy from January 1, 2006, through January 31, 2018. The estimated number of patients eligible for genome-targeted therapy in 2006 was 28 729 of a total 564 830 patients with metastatic cancer, or 5.09% (95% CI, 5.03%-5.14%). By 2018, this number had increased to 50 811 of 609 640, or 8.33% (95% CI, 8.26%-8.40%). For genome-informed therapy in 2006, the eligible number of patients was 59 301 of 564 830, or 10.50% (95% CI, 10.42%-10.58%). In 2018, genome-informed treatment could be offered to 94 157 of 609 640, or 15.44% (95% CI, 15.35%-15.53%) of patients with metastatic cancer. The percentage of patients with cancer estimated to benefit from genome-targeted therapy in 2006 was 0.70% (95% CI, 0.68%-0.72%), and in 2018, it had increased to 4.90% (95% CI, 4.85%-4.95%). For genome-informed treatment in 2006, the percentage estimated to benefit was 1.31% (95% CI, 1.28%-1.34%), and in 2018, it had increased to 6.62% (95% CI, 6.56%-6.68%). The median overall response rate for all genome-informed drugs through January 2018 was 54%, and the median duration of response was 29.5 months. <h3>Conclusions and Relevance</h3> Although the number of patients eligible for genome-driven treatment has increased over time, these drugs have helped a minority of patients with advanced cancer. To accelerate progress in precision oncology, novel trial designs of genomic therapies should be developed, and broad portfolios of drug development, including immunotherapeutic and cytotoxic approaches, should be pursued.
P147STAT3 mediates differentiation and maintenance of human pluripotent stem-derived endothelial cells
Authors: G Foldes, K Lawlor, S E Harding, A M Randi
Journal: Cardiovascular Research (2018)

Background: High plasticity derivatives of human pluripotent stem cells (hPSC) such as embryonic stem cells (hESC) are being intensively developed for their use in endothelial replacement.Methods/Results: In this study, we found that transient addition of Activin A, followed by culture with VEGF165, BMP4 and FGF2 was an effective mechanism to induce differentiation of hESC toward the endothelial lineage.Indeed, human GeneChip microarray analysis revealed that endothelial gene regulatory networks were gradually increased during 12 days of differentiation.Isolated hESC-derived endothelial cells (hESC-EC) expressed mature endothelial-associated genes, including CD31, NRP1, VEcadherin, Tie2, VWF and ICAM2, reaching levels comparable with human umbilical cord vascular endothelial cells by day 19.We found that a network of CD31+ tubes comprising endothelial precursor cells had formed in culture from 10 days after start of differentiation of hESC.As assessed by automated high content microscopy, the alignment and tube formation of the newly formed CD31+ vascular network were markedly decreased in response to C188-9, a novel small molecule inhibitor of STAT3 transcription factor (tube length: 57%, connected tube area: 22% of those in control, both p<0.001).Human ESC-EC were capable of transdifferentiating into mesenchymal cells in long-term cultures.Endothelial-mesenchymal transition was characterised by gradual loss of endothelial marker expression and increased mesenchymal marker FSP1 expression.We found that inhibition of STAT3 tyr705 phosphorylation by C188-9 resulted in a decreased proliferation of FSP1+ mesenchymal cells (2-fold decrease in Ki67%-positive population, p<0.001), and subsequently reduced number of FSP+ cells (36% reduction, p<0.05).At the same time, C188-9 increased the number of CD31+ hESC-EC by 30% (p=0.05,n=6).Viability remained unchanged in C188-9-treated cells (Topro3 necrosis marker, p=0.32, n=3).Conclusions: These results suggest that STAT3 pathway may play a dual role in the generation and maintenance of hPSC-derived endothelial cells.Elucidation of molecular signals during endothelial differentiation of hPSC may allow specific targeting of their activities to enhance differentiation and promote vascular tissue regeneration.