tbuckley/cabot-search huggingface dataset:
Evidence suggests that germline <i>RNF43</i> mutations are a rare cause of serrated polyposis
Authors: Isabel Quintana, Raquel Mejías-Luque, Mariona Terradas, Matilde Navarro, Virginia Piñol, Pilar Mur, Sami Belhadj, Elia Grau, Esther Darder, Ares Solanes, Joan Brunet, Gabriel Capellá, Markus Gerhard, Laura Valle
Journal: Gut (2018)

We read with interest the work by Yan et al published in Gut .1 The serrated (hyperplastic) polyposis syndrome (SPS) is a heterogeneous disease defined by the presence of multiple serrated polyps throughout the colon,2 causing an increased risk (16%) of colorectal cancer (CRC).3 By performing whole-exome sequencing in 20 SPS families, Gala et al identified a germline mutation, c.338C>A (p.R113*), in the RING-type E3 ubiquitin ligase RNF43, an inhibitor of the Wnt pathway, in two independent families.4 The c.394C>T (p.R132*) mutation was subsequently identified in two SPS-affected members of one family, supporting a causal role in SPS.5 In the study by Yan et al whole-exome sequence analysis of four SPS families identified a deleterious germline mutation, c.953–1G>A (p.E318fs), in six members of one family, five fulfilling the WHO criteria for SPS.1 Buchanan et al assessed the mutation status of RNF43 in 74 selected SPS families, identifying two rare missense variants, c.443C>G (p.A148G) and c.640C>G (p.L214V), predicted deleterious by in silico algorithms, in two families. No carriers of p.R113* or p.R132* were detected in 221 additional patients with SPS.6

Mutation screening of RNF43 was carried out by Sanger sequencing in …
Effect of outpatient antibiotics for urinary tract infections on antimicrobial resistance among commensal Enterobacteriaceae: a multinational prospective cohort study
Authors: A.J. Stewardson, J. Vervoort, N. Adriaenssens, S. Coenen, M. Godycki-Cwirko, A. Kowalczyk, B.D. Huttner, C. Lammens, S. Malhotra-Kumar, H. Goossens, S. Harbarth, Jascha Vervoort, Christine Lammens, Surbhi Malhotra-Kumar, Herman Goossens, Niels Adriaenssens, Samuel Coenen, Anna Kowalczyk, Maciek Godycki-Cwirko, Andrew J. Stewardson, Benedikt Huttner, Stephan Harbarth, Caroline Brossier, Cécile Delémont, Begoña Martinez de Tejada, Gesuele Renzi, Jacques Schrenzel, Sylvie Van Bylen, Jonathan Vanbergen, Philip Koeck, Peter Leysen, Kim Vandercam, Jacques Kluijtmans, Agnieszka Borkiewicz, Frank Heyvaert, Nele Michels, Gerd Deswaef, Tine Beckx, Hadewijch Declerck, Katy Embrechts, Nina Verheyen, Tine Bauwens, Josefien Béghin, Liesbeth Verpooten, Katrien Bombeke, Tine Vandenabeele, Magdalena Muras, Joanna Świstak, Anna Wesołowska, Ewa Sterniczuk, Lidia Brzozowska, Krystyna Cichowska, Jolanta Szewczyk, Grażyna Krupińska, Honorata Błaszczyk, Urszula Stawińska, Maria Szyler, Marek Kasielski, Rafał Rydz, Agata Myszkowska, Lilianna Żebrowska
Journal: Clinical Microbiology and Infection (2018)
Post-Treatment Mortality After Surgery and Stereotactic Body Radiotherapy for Early-Stage Non–Small-Cell Lung Cancer
Authors: William A. Stokes, Michael R. Bronsert, Robert A. Meguid, Matthew G. Blum, Bernard L. Jones, Matthew Koshy, David J. Sher, Alexander V. Louie, David A. Palma, Suresh Senan, Laurie E. Gaspar, Brian D. Kavanagh, Chad G. Rusthoven
Journal: Journal of Clinical Oncology (2018)

Purpose In early-stage non-small cell lung cancer (NSCLC), post-treatment mortality may influence the comparative effectiveness of surgery and stereotactic body radiotherapy (SBRT), with implications for shared decision making among high-risk surgical candidates. We analyzed early mortality after these interventions using the National Cancer Database. Patients and Methods We abstracted patients with cT1-T2a, N0, M0 NSCLC diagnosed between 2004 and 2013 undergoing either surgery or SBRT. Thirty-day and 90-day post-treatment mortality rates were calculated and compared using Cox regression and propensity score-matched analyses. Results We identified 76,623 patients who underwent surgery (78% lobectomy, 20% sublobar resection, 2% pneumonectomy) and 8,216 patients who received SBRT. In the unmatched cohort, mortality rates were moderately increased with surgery versus SBRT (30 days, 2.07% v 0.73% [absolute difference (Δ), 1.34%]; P < .001; 90 days, 3.59% v 2.93% [Δ, 0.66%]; P < .001). Among the 27,200 propensity score-matched patients, these differences increased (30 days, 2.41% v 0.79% [Δ, 1.62%]; P < .001; 90 days, 4.23% v 2.82% [Δ, 1.41%]; P < .001). Differences in mortality between surgery and SBRT increased with age, with interaction P < .001 at both 30 days and 90 days (71 to 75 years old: 30-day Δ, 1.87%; 90-day Δ, 2.02%; 76 to 80 years old: 30-day Δ, 2.80%; 90-day Δ, 2.59%; > 80 years old: 30-day Δ, 3.03%; 90-day Δ, 3.67%; all P ≤ .001). Compared with SBRT, surgical mortality rates were higher with increased extent of resection (30-day and 90-day multivariate hazard ratio for mortality: sublobar resection, 2.85 and 1.37; lobectomy, 3.65 and 1.60; pneumonectomy, 14.5 and 5.66; all P < 0.001). Conclusion Differences in 30- and 90-day post-treatment mortality between surgery and SBRT increased as a function of age, with the largest differences in favor of SBRT observed among patients older than 70 years. These representative mortality data may inform shared decision making among patients with early-stage NSCLC who are eligible for both interventions.
Management of Morgellons Disease With Low-Dose Trifluoperazine
Authors: Bernice Y. Yan, Joseph L. Jorizzo
Journal: JAMA Dermatology (2018)

Management of Morgellons Disease With Low-Dose TrifluoperazineMorgellons disease is a poorly understood condition characterized by delusions of cutaneous infiltration by microbes and/or inanimate materials.Current management involves building a strong therapeutic alliance, treating cutaneous lesions, and using low-dose antipsychotics. [1]2][3] Our study examines the novel use of low-dose trifluoperazine, a highpotency typical antipsychotic, in this patient population.Methods | This is a Weill Cornell Medical College institutional review board-approved retrospective medical record review of adult patients with Morgellons disease who presented to our dermatology department between September 1, 2006, to August 31, 2016.Inclusion criteria included age 18 years or older and at least 2 visits with a single investigator (J.L.J.).Patients with clinicopathological evidence of another dermatologic process were excluded.The main outcomes examined were clinical response, time to remission, and adverse effects.Partial remission was defined as patient-reported improvement, and at least 50% lesion clearance as determined by the same physician.Baseline function was defined as at least 90% lesion clearance and no patient-reported distress from perceived skin infiltrates.Patients received empathetic counseling concordant with published recommendations, 3 including using formication as a dermatologic sign.Trifluoperazine was initiated at 1 mg/d at bedtime, with uptitration of 1 mg/d every month according to the clinical picture.Patients were assessed for extrapyramidal findings and mood changes during follow-up visits.Results | Twenty-four patients met inclusion criteria (Table 1).Four patients were excluded; Table 2 provides a clinical overview.The mean (range) follow-up time was 11.2 (0.9-39.8) months.With our management approach, 7 patients (29%) returned to baseline function.Fifteen patients (63%) achieved
GW29-e1808 Cellular Basis of C-Type Natriuretic Peptide Produced Augmentation on Left Ventricular Systolic and Diastolic Functional Performance in Heart Failure
Authors: Zhi Zhang, Xiaowei Zhang, Tiankai Li, Hengjie Cheng, Peng Zhou, Qiuyan Dai, Cheping Cheng
Journal: Journal of the American College of Cardiology (2018)
Margaret McCartney: When a crisis is the predictable outcome of poor policy making
Authors: Margaret McCartney
Journal: BMJ (2018)

When is a crisis not a crisis? The “crisis” may be felt differently in the UK’s four NHSs, but these services are being pushed beyond reasonable capacity. I’ve little doubt that the coping mechanisms—corridor care, ambulance stacking, and a month’s worth of cancelled operations and outpatient appointments—are harmful. And these will contribute to burnout, sick leave, resignation, early retirement, and the cycle of even more rota gaps.

This is not a sudden explosive “crisis” but the predictable, and predicted, result of multifactorial choices over long periods that have made a mockery of evidence based decision making. This is winter: it’s a foreseeable annual event.

Yes, the NHS needs more money. …
The Extending Spectrum of NPC1-Related Human Disorders: From Niemann–Pick C1 Disease to Obesity
Authors: Amel Lamri, Marie Pigeyre, William S Garver, David Meyre
Journal: Endocrine Reviews (2018)

The Niemann–Pick type C1 (NPC1) protein regulates the transport of cholesterol and fatty acids from late endosomes/lysosomes and has a central role in maintaining lipid homeostasis. NPC1 loss-of-function mutations in humans cause NPC1 disease, a rare autosomal-recessive lipid-storage disorder characterized by progressive and lethal neurodegeneration, as well as liver and lung failure, due to cholesterol infiltration. In humans, genome-wide association studies and post–genome-wide association studies highlight the implication of common variants in NPC1 in adult-onset obesity, body fat mass, and type 2 diabetes. Heterozygous human carriers of rare loss-of-function coding variants in NPC1 display an increased risk of morbid adult obesity. These associations have been confirmed in mice models, showing an important interaction with high-fat diet. In this review, we describe the current state of knowledge for NPC1 variants in relationship to pleiotropic effects on metabolism. We provide evidence that NPC1 gene variations may predispose to common metabolic diseases by modulating steroid hormone synthesis and/or lipid homeostasis. We also propose several important directions of research to further define the complex roles of NPC1 in metabolism. This review emphasizes the contribution of NPC1 to obesity and its metabolic complications.
Guidelines of care for the management of cutaneous squamous cell carcinoma
Authors: John Y.S. Kim, Jeffrey H. Kozlow, Bharat Mittal, Jeffrey Moyer, Thomas Olenecki, Phillip Rodgers, Murad Alam, April Armstrong, Christian Baum, Jeremy S. Bordeaux, Marc Brown, Klaus J. Busam, Daniel B. Eisen, Vivek Iyengar, Clifford Lober, David J. Margolis, Jane Messina, Alexander Miller, Stanley Miller, Eliot Mostow, Christen Mowad, Kishwer Nehal, Kristi Schmitt-Burr, Aleksandar Sekulic, Paul Storrs, Joyce Teng, Siegrid Yu, Conway Huang, Kevin Boyer, Wendy Smith Begolka, Christopher Bichakjian
Journal: Journal of the American Academy of Dermatology (2018)
Abstract 15479: Clinical and Laboratory Outcomes of Impella Microaxillary Pumps When Used in Patients With Severe Cardiogenic Shock as a Bridge to Durable Devices or Cardiac Transplantation
Authors: Richard Cheng, Rikin Tank, Danny Ramzy, Babak Azarbal, Joseph Ebinger, Fardad Esmailian, Jon Kobashigawa, Jaime Moriguchi, Francisco Arabia
Journal: Circulation (2017)

Introduction: Outcomes with Impella devices used to salvage severe shock for pts otherwise eligible for durable mechanical circulatory support (MCS) or transplant (OHT) are not well established. Hy...
Safety and efficacy of concurrent administration of influenza vaccine in patients undergoing anti-PD-1 immunotherapy.
Authors: Dimitra Konstantinos Kanaloupitis, Anjana Chandran, Alyssa Ralph, Ryan Thompson, Jon M. Richards, Sigrun Hallmeyer
Journal: Journal of Clinical Oncology (2017)

e14607 Background: Concerns have been raised over administration of influenza vaccination concurrent with immune checkpoint inhibitor therapy, specifically, implication in induction of Guillain-Barre syndrome. The aim of this study is to assess the safety and efficacy of influenza vaccination in patients undergoing anti-PD1 therapy. Methods: This is a prospective observational study evaluating the safety and efficacy of Afluria (Seqirus) in patients receiving anti-PD1 therapy. Antibody titers against common influenza A and B antigens were measured by a semi-quantitative ELISA on days 0, 45 and 90+ post vaccine administration to confirm anti-PD1 therapy did not interfere with anti-influenza humoral responses. Influenza infection, confirmed by rapid antigen testing, and influenza-related hospitalizations were reported among vaccinated patients. Safety was assessed using the FDA toxicity grading scale for clinical trials. Results: The acute humoral responses and subsequent IgG responses of the 28 patients included in this study are as follows in the table. IgM responses at 45 days to both influenza A and B common antigens were statistically significant (all P&lt;0.05*). IgG response to common influenza B antigens was increased at day 45 ( P=0.001*). One of 28 patients contracted influenza B infection, confirmed by rapid antigen testing. There were no influenza-related hospitalizations. One patient had a grade 2 local adverse event (AE). A second patient had both a grade 2 local and a grade 2 systemic AE (myalgia). No grade 3/4 local or systemic AEs were reported. Conclusions: Administration of influenza vaccination concurrent with anti-PD1 therapy appeared safe in our study. No grade 3/4 local or systemic AEs were noted. Anti-PD1 therapy did not adversely affect anti-influenza humoral responses. Our data demonstrate that the increase in IgM reactivity to common influenza A and B antigens appears to be an immediate reaction to revaccination. Seroprotection can be inferred by documented infection in only one patient and absence of influenza related-hospitalizations. [Table: see text]
Pulmonary rehabilitation for patients with COPD during and after an exacerbation-related hospitalisation: back to the future?
Authors: Martijn A. Spruit, Sally J. Singh, Carolyn L. Rochester, Neil J. Greening, Frits M.E. Franssen, Fabio Pitta, Thierry Troosters, Claire Nolan, Ioannis Vogiatzis, Enrico M. Clini, William D-C. Man, Chris Burtin, Roger S. Goldstein, Lowie E.G.W. Vanfleteren, Klaus Kenn, Linda Nici, Daisy J.A. Janssen, Richard Casaburi, Takanobu Shioya, Chris Garvey, Brian W. Carlin, Richard L. ZuWallack, Michael Steiner, Emiel F.M. Wouters, Milo A. Puhan
Journal: European Respiratory Journal (2018)

The European Respiratory Society (ERS) and American Thoracic Society (ATS) guideline on management of chronic obstructive pulmonary disease (COPD) exacerbations was published in the March 2017 issue of the European Respiratory Journal [1]. Based on evidence syntheses, including meta-analyses, relevant evidence up to September 2015 was summarised and clinical recommendations for treatment of COPD exacerbations were formulated. These guidelines were endorsed by the ERS Executive Committee and approved by the ATS Board of Directors in December 2016. Healthcare professionals should educate COPD patients and recommend rehabilitation in the peri-exacerbation period <http://ow.ly/gaiC30eQlVE>
Single-Arm Phase II Trial of Pegylated Interferon Alpha 2a in Patients with High-Risk Essential Thrombocythemia or Polycythemia Vera Resistant or Intolerant to Hydroxyurea: MPN Symptom Impact & Quality of Life Results of the Myeloproliferative Disorders-Research Consortium (MPD-RC) Protocol 111 Global Phase II Trial
Authors: Amylou C. Dueck, John Mascarenhas, Heidi Elizabeth Kosiorek, Abdulraheem Yacoub, Josef T. Prchal, Dmitriy Berenzon, Maria R. Baer, Ellen K Ritchie, Richard T Silver, Craig M. Kessler, Elliott F. Winton, Maria Chiara Finazzi, Alessandro Rambaldi, Alessandro M. Vannucchi, David S. Leibowitz, Damiano Rondelli, Murat O. Arcasoy, Rosalind Catchatourian, Joseph Vadakara, Vittorio Rosti, Elizabeth Hexner, Marina Kremyanskaya, Alicia Orellana, Lonette Sandy, Joseph Tripodi, Vesna Najfeld, Mohamed E. Salama, Rona Singer Weinberg, Raajit K. Rampal, Ronald Hoffman, Ruben A Mesa
Journal: Blood (2017)
Sustained silencing peanut allergy by xanthopurpurin is associated with suppression of peripheral and bone marrow IgE producing B cell
Authors: Xiu-Min Li, Kamal D. Srivastava, Yujuan Chen, Patrick Yoo, Changda Liu, Serife Uzun, Hang Li, Anna H. Nowak-Wegrzyn, Nan Yang
Journal: Journal of Allergy and Clinical Immunology (2018)
Fish oil in infancy protects against food allergy in Iceland—Results from a birth cohort study
Authors: M. Clausen, K. Jonasson, T. Keil, K. Beyer, S. T. Sigurdardottir
Journal: Allergy (2018)

Abstract Background Consumption of oily fish or fish oil during pregnancy, lactation and infancy has been linked to a reduction in the development of allergic diseases in childhood. Methods In an observational study, Icelandic children (n = 1304) were prospectively followed from birth to 2.5 years with detailed questionnaires administered at birth and at 1 and 2 years of age, including questions about fish oil supplementation. Children with suspected food allergy were invited for physical examinations, allergic sensitization tests, and a double‐blind, placebo‐controlled food challenge if the allergy testing or clinical history indicated food allergy. The study investigated the development of sensitization to food and confirmed food allergy according to age and frequency of postnatal fish oil supplementation using proportional hazards modelling. Results The incidence of diagnosed food sensitization was significantly lower in children who received regular fish oil supplementation (relative risk: 0.51, 95% confidence interval: 0.32‐0.82). The incidence of challenge‐confirmed food allergy was also reduced, although not statistically significant (0.57, 0.30‐1.12). Children who began to receive fish oil in their first half year of life were significantly more protected than those who began later ( P = .045 for sensitization, P = .018 for allergy). Indicators of allergy severity decreased with increased fish oil consumption ( P = .013). Adjusting for parent education and allergic family history did not change the results. Conclusion Postnatal fish oil consumption is associated with decreased food sensitization and food allergies in infants and may provide an intervention strategy for allergy prevention.
Blockade of the Complement C5a/C5aR1 Axis Impairs Lung Cancer Bone Metastasis by CXCL16-mediated Effects
Authors: Daniel Ajona, Carolina Zandueta, Leticia Corrales, Haritz Moreno, María J. Pajares, Sergio Ortiz-Espinosa, Elena Martínez-Terroba, Naiara Perurena, Fernando J. de Miguel, Eloisa Jantus-Lewintre, Carlos Camps, Silvestre Vicent, Jackeline Agorreta, Luis M. Montuenga, Ruben Pio, Fernando Lecanda
Journal: American Journal of Respiratory and Critical Care Medicine (2018)

C5aR1 (CD88), a receptor for complement anaphylatoxin C5a, is a potent immune mediator. Its impact on malignant growth and dissemination of non-small cell lung cancer cells is poorly understood.To investigate the contribution of the C5a/C5aR1 axis to the malignant phenotype of non-small cell lung cancer cells, particularly in skeletal colonization, a preferential lung metastasis site.Association between C5aR1 expression and clinical outcome was assessed in silico and validated by immunohistochemistry. Functional significance was evaluated by lentiviral gene silencing and ligand l-aptamer inhibition in in vivo models of lung cancer bone metastasis. In vitro functional assays for signaling, migration, invasion, metalloprotease activity, and osteoclastogenesis were also performed.High levels of C5aR1 in human lung tumors were significantly associated with shorter recurrence-free survival, overall survival, and bone metastasis. Silencing of C5aR1 in lung cancer cells led to a substantial reduction in skeletal metastatic burden and osteolysis in in vivo models. Furthermore, metalloproteolytic, migratory, and invasive tumor cell activities were modulated in vitro by C5aR1 stimulation or gene silencing. l-Aptamer blockade or C5aR1 silencing significantly reduced the osseous metastatic activity of lung cancer cells in vivo. This effect was associated with decreased osteoclastogenic activity in vitro and was rescued by the exogenous addition of the chemokine CXCL16.Disruption of C5aR1 signaling in lung cancer cells abrogates their tumor-associated osteoclastogenic activity, impairing osseous colonization. This study unveils the role played by the C5a/C5aR1 axis in lung cancer dissemination and supports its potential use as a novel therapeutic target.
Multifunctional Role of Chymase in Acute and Chronic Tissue Injury and Remodeling
Authors: Louis J. Dell’Italia, James F. Collawn, Carlos M. Ferrario
Journal: Circulation Research (2018)

Chymase is the most efficient Ang II (angiotensin II)–forming enzyme in the human body and has been implicated in a wide variety of human diseases that also implicate its many other protease actions. Largely thought to be the product of mast cells, the identification of other cellular sources including cardiac fibroblasts and vascular endothelial cells demonstrates a more widely dispersed production and distribution system in various tissues. Furthermore, newly emerging evidence for its intracellular presence in cardiomyocytes and smooth muscle cells opens an entirely new compartment of chymase-mediated actions that were previously thought to be limited to the extracellular space. This review illustrates how these multiple chymase-mediated mechanisms of action can explain the residual risk in clinical trials of cardiovascular disease using conventional renin–angiotensin system blockade.
Abstract 18779: Baroreflex Activation Therapy Rapidly Improves Hemodynamics and Maintains End Organ function in Volume Load Induced Heart Failure
Authors: Yasuhiro Oga, Takafumi Sakamoto, Keita Saku, Takeshi Tohyama, Takuya Nishikawa, Takuya Kishi, Hiroyuki Tsutsui, Kenji Sunagawa
Journal: Circulation (2016)

Background:  Arterial baroreflex tightly controls sympathetic nerve activity (SNA) and stabilizes hemodynamics. Baroreflex controlled SNA dynamically regulates not only vascular resistance or cardiac afterload, but also stressed blood volume, thus cardiac preload. It is also well known that acute heart failure (AHF) excessively activates SNA which in turn induces central volume shift and worsens hemodynamics (e.g. pulmonary edema). Thus, we hypothesized that electrical baroreflex activation (BA) immediately inhibits excessive SNA and improves hemodynamics while maintaining end-organ function.   Methods:  In 8 Sprague-Dawley rats, we created myocardial infarction to impair left ventricular (LV) systolic function. We attached electrodes to the unilateral aortic depressor nerve and stimulated by 5±2V (10Hz) for BA. We infused donated blood (15 ml/kg) to induce AHF and simultaneously measured parameters of SNA, hemodynamics, renal artery flow (RF) and urine flow (UF) for 30 minutes (CTL). After removing blood to restore the baseline condition, we re-infused volume with BA and compared those parameters with or without BA.   Results:  Volume infusion in CTL increased AP, while BA significantly reduced SNA (-27.7±15.0%, p   Conclusions:  In impaired LV systolic function, volume loading markedly deteriorates hemodynamics and induces AHF. BA immediately inhibits SNA and significantly improves pulmonary edema without compromising hemodynamics. Baroreflex activation therapy may serve as a new therapeutic strategy for AHF.