tbuckley/cabot-search huggingface dataset:
Exosomal CCL2 from Tubular Epithelial Cells Is Critical for Albumin-Induced Tubulointerstitial Inflammation
Authors: Lin-Li Lv, Ye Feng, Yi Wen, Wei-Jun Wu, Hai-Feng Ni, Zuo-Lin Li, Le-Ting Zhou, Bin Wang, Jian-Dong Zhang, Steven D. Crowley, Bi-Cheng Liu
Journal: Journal of the American Society of Nephrology (2018)

Albuminuria is a key instigator of tubulointerstitial inflammation associated with CKD, but the mechanism through which filtered albumin propagates renal injury remains unclear. In this study, we explored the role in this process of exosome mRNA released from tubular epithelial cells (TECs). Compared with control mice, acute and chronic kidney injury models had more exosomes containing inflammatory cytokine mRNA, particularly the chemokine CCL2, in kidneys and urine. In vitro stimulation of TECs with BSA recapitulated this finding. Notably, the internalization of purified TEC exosomes by cultured macrophages increased if TECs were exposed to BSA. Macrophage internalization of exosomes from BSA-treated TECs led to an enhanced inflammatory response and macrophage migration, but CCL2 silencing in TECs prevented these effects. Using a GFP-CCL2 fusion mRNA construct, we observed direct transfer of CCL2 mRNA from TEC exosomes to macrophages. Mice subjected to tail vein injection of purified BSA-treated TEC exosomes developed tubular injury with renal inflammatory cell infiltration. However, injection of exosomes from BSA-treated CCL2-deficient TECs induced less severe kidney inflammation. Finally, in patients with IgA nephropathy, the increase of proteinuria correlated with augmented urinary excretion of exosomes with exaggerated expression of CCL2 mRNA. Moreover, the level of CCL2 mRNA in urinary exosomes correlated closely with levels of renal interstitial macrophage infiltration in these patients. Our studies demonstrate that the increasing release of exosomes that transfer CCL2 mRNA from TECs to macrophages constitutes a critical mechanism of albumin-induced tubulointerstitial inflammation.
Earning his stripes: a ward redesigned
Authors: Gareth Iacobucci
Journal: BMJ (2018)

Dan Weill Photography

Leading British fashion designer Paul Smith has applied his creative eye to an NHS hospital by redesigning the interior of an acute care mental health ward at St Charles Hospital in North Kensington, London.

The redesign is the latest work of the Nightingale Project (www.nightingaleproject.org), a charitable initiative that aims to …
Influenza-specific lung-resident memory T cells are proliferative and polyfunctional and maintain diverse TCR profiles
Authors: Angela Pizzolla, Thi H.O. Nguyen, Sneha Sant, Jade Jaffar, Tom Loudovaris, Stuart I. Mannering, Paul G. Thomas, Glen P. Westall, Katherine Kedzierska, Linda M. Wakim
Journal: Journal of Clinical Investigation (2018)

The human lung harbors a large population of resident memory T cells (Trm cells). These cells are perfectly positioned to mediate rapid protection against respiratory pathogens such as influenza virus, a highly contagious respiratory pathogen that continues to be a major public health burden. Animal models show that influenza-specific lung CD8+ Trm cells are indispensable for crossprotection against pulmonary infection with different influenza virus strains. However, it is not known whether influenza-specific CD8+ Trm cells present within the human lung have the same critical role in modulating the course of the disease. Here, we showed that human lung contains a population of CD8+ Trm cells that are highly proliferative and have polyfunctional progeny. We observed that different influenza virus–specific CD8+ T cell specificities differentiated into Trm cells with varying efficiencies and that the size of the influenza-specific CD8+ T cell population persisting in the lung directly correlated with the efficiency of differentiation into Trm cells. To our knowledge, we provide the first ex vivo dissection of paired T cell receptor (TCR) repertoires of human influenza–specific CD8+ Trm cells. Our data reveal diverse TCR profiles within the human lung Trm cells and a high degree of clonal sharing with other CD8+ T cell populations, a feature important for effective T cell function and protection against the generation of viral-escape mutants.
Pancreatic Juice Mutation Concentrations Can Help Predict the Grade of Dysplasia in Patients Undergoing Pancreatic Surveillance
Authors: Masaya Suenaga, Jun Yu, Koji Shindo, Koji Tamura, Jose Alejandro Almario, Christopher Zaykoski, P. Dane Witmer, Shahriar Fesharakizadeh, Michael Borges, Anne-Marie Lennon, Eun-Ji Shin, Marcia Irene Canto, Michael Goggins
Journal: Clinical Cancer Research (2018)

Purpose: The measurement of mutations in pancreatic juice samples collected from the duodenum during endoscopic ultrasound (EUS) may improve the diagnostic evaluation of patients undergoing pancreatic surveillance. Our aim was to evaluate the accuracy of using pancreatic juice mutation concentrations to predict the presence and histologic grade of neoplasia in the pancreas.Experimental Design: Digital next-generation sequencing (NGS) of pancreatic juice DNA using a targeted 12-gene panel was performed on 67 patients undergoing pancreatic evaluation during EUS, including patients with pancreatic ductal adenocarcinoma, patients who subsequently underwent pancreatic resection for precursor lesions, patients undergoing surveillance for their familial/inherited susceptibility to pancreatic cancer, and normal pancreas disease controls.Results: Patients with pancreatic cancer or high-grade dysplasia as their highest grade lesion had significantly higher pancreatic juice mutation concentrations than all other subjects (mean/SD digital NGS score; 46.6 ± 69.7 vs. 6.2 ± 11.6, P = 0.02). Pancreatic juice mutation concentrations distinguished patients with pancreatic cancer or high-grade dysplasia in their resection specimen from all other subjects with 72.2% sensitivity and 89.4% specificity [area under the curve (AUC) = 0.872]. Mutant TP53/SMAD4 concentrations could distinguish patients with pancreatic cancer or high-grade dysplasia in their resection specimen from all other subjects with 61.1% sensitivity and 95.7% specificity (AUC = 0.819). Among 31 high-risk individuals under surveillance, 2 of the 3 individuals with most abnormal pancreatic juice mutation profiles also had the most abnormalities on pancreatic imaging.Conclusions: Pancreatic juice mutation analysis using digital NGS has potential diagnostic utility in the evaluation of patients undergoing pancreatic surveillance. Clin Cancer Res; 24(12); 2963-74. ©2018 AACRSee related commentary by Lipner and Yeh, p. 2713.
Renal-clearable quaternary chalcogenide nanocrystal for photoacoustic/magnetic resonance imaging guided tumor photothermal therapy
Authors: Longfei Tan, Jing Wan, Weisheng Guo, Caizhang Ou, Tianlong Liu, Changhui Fu, Qiang Zhang, Xiangling Ren, Xing-Jie Liang, Jun Ren, Laifeng Li, Xianwei Meng
Journal: Biomaterials (2018)
Abstract 19152: Increased Extracellular Nucleosome Levels, Biomarkers of Cell Death, in Atrial Fibrillation Patients Compared to the Normal Population
Authors: Debra Hoppensteadt, Sallu Jabati, Trung Phan, Jeffrey Liles, Timothy Rowe, Jawed Fareed, Mushabar Syed
Journal: Circulation (2016)

Introduction:  Atrial fibrillation (AF) is currently the most common cardiac arrhythmia encountered in clinical practice and a major cause of morbidity and mortality among adults. It is estimated that atrial fibrillation affects approximately 2.7 million people in the United States. Extracellular plasma nucleosomes (PNs) are complexes of DNA and histones that are released during cell death. Histones have been shown to function as DAMPs when they are translocated from the nucleus to the extracellular space. These nucleosomes mediate inflammatory and thromobotic responses and could serve as biomarkers in atrial fibrillation.   Methods:  The concentration of PNs in plasma samples of atrial fibrillation patients (n=43), aged normals (n=35), and young normals (n=29) were measured using the Cell Death Detection ELISA PLUS assay (Roche Diagnostics, Mannheim, Germany). For this study, the baseline plasma samples of atrial fibrillation patients were analyzed.   Results:  In comparison to the plasma from aged normals (11.42 ± 9.15 Arbitrary Units (AU)) and young normals (6.42 ± 0.87 AU; p    Conclusion:  PNs were elevated in atrial fibrillation when compared to both aged and young normals, indicating an increased release of nucleosomes, suggesting increased cell death. Extracellular nucleosomes function as DAMPs by binding to receptors and triggering the activation of multiple signal pathways. Due to the involvement of inflammation and thrombosis in the pathology of atrial fibrillation, the increased circulating nucleosome level in patients with atrial fibrillation implies that PNs may activate the immune system and generate the inflammatory response. These results suggest that PNs may serve as a biomarker in atrial fibrillation.
Characterization of Chromosome 6q Deletions in MYD88 Mutant and Wild-Type Waldenström's Macroglobulinemia
Authors: Maria Luisa Guerrera, Nickolas Tsakmaklis, Lian Xu, Guang Yang, Maria Demos, Gloria Chan, Amanda Kofides, Robert Manning, Xia Liu, Jiaji Chen, Christopher Patterson, Jorge J. Castillo, Toni Dubeau, Joshua Gustine, Ruben D. Carrasco, Luca Arcaini, Marzia Varettoni, Mario Cazzola, Steven P Treon, Zachary Hunter
Journal: Blood (2017)
Abstract 16590: Sensitive, Concentration-dependent Entropy Metrics for Quantitative Ultrasound Molecular Imaging of Thrombi
Authors: Jon N Marsh, John E McCarthy, Samuel A Wickline
Journal: Circulation (2016)

Introduction:  Ligand-targeted liquid perfluorocarbon nanoparticles (PFC NP: ~200 nm) were the first described contrast agents for ultrasound molecular imaging demonstrated over 20 years ago for tissue factor imaging in atherosclerotic plaques using conventional processing of signal energy. Recently we have developed alternative analytical (entropy) approaches using information-theoretic detectors (ITD) that provide enhanced detectability for PFC NP beacons that can penetrate into targeted tissues well beyond the range of conventional microbubbles. Here we assess the relationship between targeted PFC NP accumulation and signal intensity over time with selected entropy metrics to illustrate the concentration dependence of the method for ultrasound molecular imaging.   Methods:  Human plasma clots were created in vitro and exposed to a dilute suspension of fibrin-targeted PFC NP incorporating an anti-fibrin mAb ligand. Clots were scanned every 10-min for 1 hr with a 25-MHz acoustic microscope.   Results:  A monotonic increase in clot reflectivity was observed for both conventional (energy) and ITD metrics, consistent with increasing amounts of NP targeting to fibrin. An exponential recovery model fit to the data (r 2 =0.999) yielded asymptotic values for enhancement. Shannon entropy and its continuous analog (H c ) exhibited greater initial sensitivity to NP deposition than conventional energy-based metrics as determined by slope of noise-normalized signal change (m LogE =0.146 vs. m Hs =0.161, m Hc =0.158).   Conclusions:  The monotonic rise in signal emanating from targeted substrates reflects the accumulation of PFC NP rapidly “filling in” gaps in a naturally poorly reflective clot surface to produce a progressively brighter scattering interface created by PFC NP, demonstrating the concentration dependence of the technique for imaging sparse epitopes. The early detectability of signal enhancement with ITD attests to its sensitivity at these frequencies.
The Clinical Effectiveness and Cost-Effectiveness of Lamotrigine in Borderline Personality Disorder: A Randomized Placebo-Controlled Trial
Authors: Mike J. Crawford, Rahil Sanatinia, Barbara Barrett, Gillian Cunningham, Oliver Dale, Poushali Ganguli, Geoff Lawrence-Smith, Verity Leeson, Fenella Lemonsky, Georgia Lykomitrou, Alan A. Montgomery, Richard Morriss, Jasna Munjiza, Carol Paton, Iwona Skorodzien, Vineet Singh, Wei Tan, Peter Tyrer, Joseph G. Reilly
Journal: American Journal of Psychiatry (2018)

Objective: The authors examined whether lamotrigine is a clinically effective and cost-effective treatment for people with borderline personality disorder. Method: This was a multicenter, double-blind, placebo-controlled randomized trial. Between July 2013 and November 2016, the authors recruited 276 people age 18 or over who met diagnostic criteria for borderline personality disorder. Individuals with coexisting bipolar affective disorder or psychosis, those already taking a mood stabilizer, and women at risk of pregnancy were excluded. A web-based randomization service was used to allocate participants randomly in a 1:1 ratio to receive either an inert placebo or up to 400 mg/day of lamotrigine. The primary outcome measure was score on the Zanarini Rating Scale for Borderline Personality Disorder (ZAN-BPD) at 52 weeks. Secondary outcome measures included depressive symptoms, deliberate self-harm, social functioning, health-related quality of life, resource use and costs, side effects of treatment, and adverse events. Results: A total of 195 (70.6%) participants were followed up at 52 weeks, at which point 49 (36%) of those in the lamotrigine group and 58 (42%) of those in the placebo group were taking study medication. The mean ZAN-BPD score was 11.3 (SD=6.6) among those in the lamotrigine group and 11.5 (SD=7.7) among those in the placebo group (adjusted difference in means=0.1, 95% CI=−1.8, 2.0). There was no evidence of any differences in secondary outcomes. Costs of direct care were similar in the two groups. Conclusions: The results suggest that treating people with borderline personality disorder with lamotrigine is not a clinically effective or cost-effective use of resources.
Incidence of type 1 diabetes in China, 2010-13: population based study
Authors: Jianping Weng, Zhiguang Zhou, Lixin Guo, Dalong Zhu, Linong Ji, Xiaoping Luo, Yiming Mu, Weiping Jia
Journal: BMJ (2018)

<h3>Abstract</h3> <h3>Objective</h3> To estimate the incidence of type 1 diabetes in all age groups in China during 2010-13. <h3>Design</h3> Population based, registry study using data from multiple independent sources. <h3>Setting</h3> National registration system in all 505 hospitals providing diabetes care, and communities of patients with diabetes in 13 areas across China, covering more than 133 million person years at risk, approximately 10% of the whole population. <h3>Participants</h3> 5018 people of all ages with newly diagnosed type 1 diabetes and resident in the study areas from 1 January 2010 to 31 December 2013. <h3>Main outcome measures</h3> Incidence of type 1 diabetes per 100 000 person years by age, sex, and study area. Type 1 diabetes was doctor diagnosed and further validated by onsite follow-up. Completeness of case ascertainment was assessed using the capture mark recapture method. <h3>Results</h3> 5018 cases of newly diagnosed type 1 diabetes were ascertained: 1239 participants were aged &lt;15 years, 1799 were aged 15-29 years, and 1980 were aged ≥30 years. The proportion of new onset cases in participants aged ≥20 years was 65.3%. The estimated incidence of type 1 diabetes per 100 000 persons years for all ages in China was 1.01 (95% confidence interval 0.18 to 1.84). Incidence per 100 000 persons years by age group was 1.93 (0.83 to 3.03) for 0-14 years, 1.28 (0.45 to 2.11) for 15-29 years, and 0.69 (0.00 to 1.51) for ≥30 years, with a peak in age group 10-14 years. The incidence in under 15s was positively correlated with latitude (r=0.88, P&lt;0.001), although this association was not observed in age groups 15-29 years or ≥30 years. <h3>Conclusion</h3> Most cases of new onset type 1 diabetes in China occurred among adults. The incidence of type 1 diabetes in Chinese children was among the lowest reported in the study.
Frailty Predicts Survival and Toxicity in Newly Diagnosed Multiple Myeloma Patients Ineligible for Autologous Stem Cell Transplantation; Report of the HOVON-87/Nmsg-18 Study Group
Authors: Claudia A.M. Stege, Bronno van der Holt, Ulf-Henrik Mellqvist, Mark-David Levin, Morten Salomo, Niels Abildgaard, Gerard Bos, Heleen Visser-Wisselaar, Markus Hansson, Annette van der Velden, Wendy Deenik, Astrid Gruber, Jules L.L.M. Coenen, Torben Plesner, Saskia Klein, Bea Tanis, Damian L. Szatkowski, Rolf Brouwer, Matthijs Westerman, Maria Berhardina Leijs, Harm Sinnige, Einar Haukaas, Klaas van der Hem, Marc Durian, Vera Mattijssen, Peter Gimsing, Niels Wcj Van De Donk, Marian Stevens-Kroef, Pieter Sonneveld, Anders Waage, Sonja Zweegman
Journal: Blood (2017)
Deleterious Germline Mutations in Telomere Maintenance Genes Identified in a Subset of Patients with Myelodysplastic Syndrome and Idiopathic Pulmonary Fibrosis
Authors: Kilannin Krysiak, Meagan A. Jacoby, Zachary L. Skidmore, Arpad M. Danos, Michelle O'Laughlin, Eric J. Duncavage, Matthew J. Walter, Malachi Griffith, Obi L. Griffith, Lukas D. Wartman
Journal: Blood (2016)
Nivolumab for Newly Diagnosed Advanced-Stage Classical Hodgkin Lymphoma (cHL): Results from the Phase 2 Checkmate 205 Study
Authors: Radhakrishnan Ramchandren, Michelle A. Fanale, Antonio Rueda, Philippe Armand, Marek Trněný, Tatyana A Feldman, Stephen M Ansell, Mariano Provencio, Ulrich Jaeger, Jonathon B Cohen, Kerry J Savage, Wolfgang Willenbacher, Mariana Sacchi, Anne Sumbul, Eva Domingo Domenech
Journal: Blood (2017)
Childhood Trauma and Functional Variants of 5-HTTLPR Are Independently Associated with Alexithymia in 5,283 Subjects from the General Population
Authors: Jan Terock, Sandra Van der Auwera, Deborah Janowitz, Georg Homuth, Anke Hannemann, Carsten Oliver Schmidt, Henriette Meyer zu Schwabedissen, Harald J. Freyberger, Hans Jörgen Grabe
Journal: Psychotherapy and Psychosomatics (2018)
Recurrence of Reflux After Laparoscopic Antireflux Surgery
Authors: Marco G. Patti, Francisco Schlottmann
Journal: JAMA (2018)

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Abstract 20160: Early Fluid Resuscitation of Undifferentiated Hypovolemic Hypotensive Patients in the Emergency Department: The Shock Access for Emergent Resuscitation (SAFER) Study
Authors: James H Paxton, Robert Sherwin, John Wilburn, Cheryl Courage
Journal: Circulation (2015)

Study Objective: To describe initial emergency department (ED) efforts in obtaining adequate vascular access (AVA) and initiating appropriate fluid resuscitation for hypovolemic patients with undifferentiated hypotension within the first 3 hours following ED arrival. Background: Hypotensive hypovolemic patients require immediate AVA, to facilitate the administration of medications and fluids to restore homeostasis. Patients with septic shock must receive appropriate intravenous antibiotics within 60 minutes of sepsis diagnosis, and 30 mL/kg fluid challenge within 3 hours. Methods: Unplanned interim analysis was performed on data from the first 87 consented patients enrolled in the Shock Access For Emergent Resuscitation (SAFER) study. SAFER is an observational, prospective, multicenter study focused on the early ED management of undifferentiated hypovolemic, hypotensive adult patients triaged to the medical resuscitation bay for suspected shock. AVA was defined as any two of the following vascular access devices (VADs): 20-gauge or larger peripheral intravenous (PIV) or intraosseous (IO) catheter, or central venous catheter (CVC). Results: 87 patients were enrolled, with a mean age of 60.3 years (SD 13.7 years). Fifty patients (57.5%) were females. The median time required for successful VAD placement was 125 seconds for PIV (IQR 206-75, n=103), 371 seconds for ultrasound-PIV (IQR 409-287, n=12), 129 seconds for IO (IQR 177-107, n=7), and 876 seconds for CVC lines (IQR 1241-660, n=18). AVA was achieved within 3 hours in 57 patients (65.5%). Thirty-three patients (37.9%) were found to have severe sepsis or septic shock, with 20 patients (23.0%) requiring vasopressors. Among septic patients, the mean volume of crystalloid infused was 1361 mL (SD 1028) or 18.6 mL/kg at 1 hour, and 2461 mL (SD 1652 mL) or 34.6 mL/kg at 3 hours. Among 98 vascular access attempts in septic patients, first-attempt success rates were higher for IO (100%, n=6) and CVC (70%, n=20) than for PIV (57.4%, n=61) or US-PIV (36.4%, n=11) lines. Nineteen (57.6%) septic patients received less than the requisite 30 mL/kg fluid challenge. Conclusion: Difficulties in obtaining AVA may prevent compliance with current guidelines for the management of septic shock. Further study is needed.
OP0149 Mortality in new-onset rheumatoid arthritis - has modern rheumatology had an impact?
Authors: M Holmqvist, L Ljung, J Askling
Journal: Annals of the Rheumatic Diseases (2017)

<h3>Background</h3> A wealth of studies have linked rheumatoid arthritis (RA) with an excess mortality compared to the general population. With increasingly effective anti-rheumatic treatment strategies there is, however, considerable uncertainty whether this mortality gap still exists and, if so, how soon after RA onset it occurs. <h3>Objectives</h3> To assess the mortality in RA compared to the general population with specific focus on when during the course of the disease the risk is increased and if it also applies to patients diagnosed in recent years. <h3>Methods</h3> We performed a population-based cohort study of 17,512 patients with new-onset RA (identified from the Swedish Rheumatology Quality Register) 1997 through 2015, and 78,847 individually matched general population comparator subjects. We followed all individuals using nationwide census registers with full coverage to identify all deaths through 2015. We calculated mortality rates with 95% confidence intervals (CI) and compared the mortality in RA to that in the general population using Cox proportional hazards models adjusted for age, sex, year of diagnosis, and residential area. <h3>Results</h3> During a mean follow-up from RA diagnosis of 7 years, 2,386 RA patients and 9,850 population comparator subjects died (crude incidence: 19 per 1000 in RA and 18 per 1000 in the general population), with only a marginal decline (in the RA and in the general population cohort) during the study period. The overall HR was 0.99 (0.95–1.04), but whereas there was no increase in mortality during the first five years after RA diagnosis; the HR ≥10 years after RA onset was 40% increased. The overall pattern of HRs was similar for patients diagnosed 1997–2001, 2002–2006, and 2007–2011 (table). <h3>Conclusions</h3> The five-year mortality in RA is not increased, neither for patients diagnosed in the past nor for those diagnosed during the most recent five years. By contrast, at least in the most recent inception cohort for which ten-year mortality currently can be calculated (those diagnosed up to 2006), RA is still associated with an increased risk of death. <h3>Disclosure of Interest</h3> None declared