tbuckley/cabot-search huggingface dataset:
Stormy weather: a retrospective analysis of demand for emergency medical services during epidemic thunderstorm asthma
Authors: Emily Andrew, Ziad Nehme, Stephen Bernard, Michael J Abramson, Ed Newbigin, Ben Piper, Justin Dunlop, Paul Holman, Karen Smith
Journal: BMJ (2017)

To describe the demand for emergency medical assistance during the largest outbreak of thunderstorm asthma reported globally, which occurred on 21 November 2016.A time series analysis was conducted of emergency medical service caseload between 1 January 2015 and 31 December 2016. Demand during the thunderstorm asthma event was compared to historical trends for the overall population and across specific subgroups.Victoria, Australia.Number of overall cases attended by emergency medical services, and within patient subgroups.On 21 November 2016, the emergency medical service received calls for 2954 cases, which was 1014 more cases than the average over the historical period. Between 6 pm and midnight, calls for 1326 cases were received, which was 2.5 times higher than expected. A total of 332 patients were assessed by paramedics as having acute respiratory distress on 21 November, compared with a daily average of 52 during the historical period. After adjustment for temporal trends, thunderstorm asthma was associated with a 42% (95% confidence interval 40% to 44%) increase in overall caseload for the emergency medical service and a 432% increase in emergency medical attendances for acute respiratory distress symptoms. Emergency transports to hospital increased by 17% (16% to 19%) and time critical referrals from general practitioners increased by 47% (21% to 80%). Large increases in demand were seen among patients with a history of asthma and bronchodilator use. The incidence of out-of-hospital cardiac arrest increased by 82% (67% to 99%) and pre-hospital deaths by 41% (29% to 55%).An unprecedented outbreak of thunderstorm asthma was associated with substantial increase in demand for emergency medical services and pre-hospital cardiac arrest. The health impact of future events may be minimised through use of preventive measures by patients and predictive early warning systems.
Multiorgan Microphysiological Systems for Drug Development: Strategies, Advances, and Challenges
Authors: Ying I. Wang, Carlos Carmona, James J. Hickman, Michael L. Shuler
Journal: Advanced Healthcare Materials (2017)

Traditional cell culture and animal models utilized for preclinical drug screening have led to high attrition rates of drug candidates in clinical trials due to their low predictive power for human response. Alternative models using human cells to build in vitro biomimetics of the human body with physiologically relevant organ-organ interactions hold great potential to act as "human surrogates" and provide more accurate prediction of drug effects in humans. This review is a comprehensive investigation into the development of tissue-engineered human cell-based microscale multiorgan models, or multiorgan microphysiological systems for drug testing. The evolution from traditional models to macro- and microscale multiorgan systems is discussed in regards to the rationale for recent global efforts in multiorgan microphysiological systems. Current advances in integrating cell culture and on-chip analytical technologies, as well as proof-of-concept applications for these multiorgan microsystems are discussed. Major challenges for the field, such as reproducibility and physiological relevance, are discussed with comparisons of the strengths and weaknesses of various systems to solve these challenges. Conclusions focus on the current development stage of multiorgan microphysiological systems and new trends in the field.
Outcomes in patients with non-small-cell lung cancer and acquired Thr790Met mutation treated with osimertinib: a genomic study
Authors: Chia-Chi Lin, Jin-Yuan Shih, Chong-Jen Yu, Chao-Chi Ho, Wei-Yu Liao, Jih-Hsing Lee, Tzu-Hsiu Tsai, Kang-Yi Su, Min-Shu Hsieh, Yih-Leong Chang, Ya-Ying Bai, Derek De-Rui Huang, Kenneth S Thress, James Chih-Hsin Yang
Journal: The Lancet Respiratory Medicine (2017)
The immunology of hypertension
Authors: Allison E. Norlander, Meena S. Madhur, David G. Harrison
Journal: The Journal of Experimental Medicine (2017)

Although systemic hypertension affects a large proportion of the population, its etiology remains poorly defined. Emerging evidence supports the concept that immune cells become activated and enter target organs, including the vasculature and the kidney, in this disease. Mediators released by these cells, including reactive oxygen species, metalloproteinases, cytokines, and antibodies promote dysfunction of the target organs and cause damage. In vessels, these factors enhance constriction, remodeling, and rarefaction. In the kidney, these mediators increase expression and activation of sodium transporters, and cause interstitial fibrosis and glomerular injury. Factors common to hypertension, including oxidative stress, increased interstitial sodium, cytokine production, and inflammasome activation promote immune activation in hypertension. Recent data suggest that isolevuglandin-modified self-proteins in antigen-presenting cells are immunogenic, promoting cytokine production by the cells in which they are formed and T cell activation. Efforts to prevent and reverse immune activation may prove beneficial in preventing the long-term sequelae of hypertension and its related cardiovascular diseases.
European Cohort Reveals Liver Fibrosis and Steatosis in Adults with Homozygous Alpha1-antitrypsin Deficiency (PiZZ Genotype)
Authors: K. Hamesch, C.V. Heimes, L.S. Moller, M. Mandorfer, M.C. Reichert, A. Arslanow, M. Wetzel, V. Woditsch, J. Voss, T. Bretag, I. Spivak, E. Yagmur, J. Stolk, R. Bals, S. Janciauskiene, B. Siegmund, F. Lammert, A. Krag, M.H. Trauner, C. Trautwein, P. Strnad
Journal: Hepatology (2017)
Abstract 18319: Virtual Mitral Valve Repair for Improved Pre-surgical Planning: Quantitative Evaluation of Neochordoplasty versus Leaflet Resection
Authors: Ahnryul Choi, Tom C Nguyen, David D McPherson, Hyunggun Kim
Journal: Circulation (2015)

Background: Neochordoplasty and/or leaflet resection are reliable and reproducible mitral valve (MV) repair techniques for the treatment of chordal rupture with severe mitral regurgitation (MR). We developed a novel computational evaluation strategy to determine the biomechanical and physiologic characteristics of MV dynamics prior to and following potential MV repair techniques to optimize surgical planning for neochordoplasty or leaflet resection. Methods: Virtual MV models from patients with P2 chordal rupture and severe MR were created using 3D echocardiographic data (N=5). Virtual neochordoplasty was designed by adding six neochordae between the papillary muscles and the P2 scallop. Virtual resection was performed by removing a pre-defined quadrangular shaped leaflet portion in the P2 scallop and merging the excised leaflet edges. Computational simulations of MV function (pre- and post-repair) were performed using dynamic finite element methods. Coaptation lengths and leaflet stress distributions were evaluated. Results: The MVs with P2 chordal rupture demonstrated severe P2 prolapse, leaflet malcoaptation, and large stress concentrations. Both repair techniques markedly reduced posterior leaflet prolapse and restored sufficient leaflet coaptation. Virtual neochordoplasty showed larger coaptation lengths (A2-P2) compared to virtual resection. Excessive stress concentrations in the P2 scallop disappeared and peak stress values decreased by up to 85% following both repair techniques. Conclusion: We have quantitatively evaluated patient-specific MV function before and after potential MV repair using a novel virtual MV repair protocol. Both virtual neochordoplasty and leaflet resection techniques decreased posterior leaflet prolapse, lessened stress concentration, and restored leaflet coaptation. This virtual simulation strategy has the potential for improved pre-surgical planning to optimize post-repair MV function.
Do innate stereotypies serve as a basis for swallowing and learned speech movements?
Authors: Connor Mayer, Francois Roewer-Despres, Ian Stavness, Bryan Gick
Journal: Behavioral and Brain Sciences (2017)

Abstract Keven &amp; Akins suggest that innate stereotypies like TP/R may participate in the acquisition of tongue control. This commentary examines this claim in the context of speech motor learning and biomechanics, proposing that stereotypies could provide a basis for both swallowing and speech movements, and provides biomechanical simulation results to supplement neurological evidence for similarities between the two behaviors.
Trans-esophageal endobronchial ultrasound-guided needle aspiration (EUS-B-NA): A road map for the chest physician
Authors: A. Bugalho, M. de Santis, A. Szlubowski, A. Rozman, R. Eberhardt
Journal: Pulmonology (2017)

The endobronchial ultrasound (EBUS) scope has been increasingly used in the gastrointestinal tract (EUS-B). Scientific data proves its efficacy and safety to provide a complete lung cancer staging, when combined with EBUS-TBNA, and in the diagnosis of para-esophageal lesions. There are multiple barriers to start performing EUS-B but probably the most important ones are related to knowledge and training, so new operators should follow a structured training curriculum. This review aims to reflect the best current knowledge regarding EUS-B and provide a road map to assist those who are incorporating the technique into their clinical practice.
London hospital boss resigns over financial pressure as trust is placed in special measures
Authors: Abi Rimmer
Journal: BMJ (2017)

The chair of one of the biggest NHS hospital trusts in the UK has resigned over concerns about the organisation’s financial future.

The resignation of Bob Kerslake, chair of King’s College Hospital NHS Foundation Trust, came as the regulator NHS Improvement placed the trust in special measures because of a growing deficit that had doubled within months.

Kerslake, who is a member of the House of Lords and the former head of the civil service, publicly set out his reasons for resigning in an article for the Guardian newspaper.1 He said that the trust had been struggling financially since 2013 and was still in difficulty despite making savings.

Kerslake, who had been in the post since 2015, wrote, “After two years of delivering or getting close to the deficit target agreed with …
A sirolimus-eluting bioabsorbable polymer-coated stent (MiStent) versus an everolimus-eluting durable polymer stent (Xience) after percutaneous coronary intervention (DESSOLVE III): a randomised, single-blind, multicentre, non-inferiority, phase 3 trial
Authors: Robbert J de Winter, Yuki Katagiri, Taku Asano, Krzysztof P Milewski, Philipp Lurz, Pawel Buszman, Gillian A J Jessurun, Karel T Koch, Roland P T Troquay, Bas J B Hamer, Ton Oude Ophuis, Jochen Wöhrle, Rafał Wyderka, Guillaume Cayla, Sjoerd H Hofma, Sébastien Levesque, Aleksander Żurakowski, Dieter Fischer, Maciej Kośmider, Pascal Goube, E Karin Arkenbout, Michel Noutsias, Markus W Ferrari, Yoshinobu Onuma, William Wijns, Patrick W Serruys
Journal: The Lancet (2017)
Most m6A RNA Modifications in Protein-Coding Regions Are Evolutionarily Unconserved and Likely Nonfunctional
Authors: Zhen Liu, Jianzhi Zhang
Journal: Molecular Biology and Evolution (2017)

Methylation of the adenosine base at the nitrogen-6 position (m6A) is the most prevalent internal posttranscriptional modification of mRNAs in many eukaryotes. Despite the rapid progress in the transcriptome-wide mapping of m6As, identification of proteins responsible for writing, reading, and erasing m6As, and elucidation of m6A functions in splicing, RNA stability, translation, and other processes, it is unknown whether most observed m6A modifications are functional. To address this question, we respectively analyze the evolutionary conservation of yeast and human m6As in protein-coding regions. Relative to comparable unmethylated As, m6As are overall no more conserved in yeasts and only slightly more conserved in mammals. Furthermore, yeast m6As and comparable unmethylated As have no significant difference in single nucleotide polymorphism (SNP) density or SNP site frequency spectrum. The same is true in human. The methylation status of a gene, not necessarily the specific sites methylated in the gene, is subject to purifying selection for no more than ∼20% of m6A-modified genes. These observations suggest that most m6A modifications in protein-coding regions are nonfunctional and nonadaptive, probably resulting from off-target activities of m6A methyltransferases. In addition, our reanalysis invalidates the recent claim of positive selection for newly acquired m6A modifications in human evolution. Regarding the small number of evolutionarily conserved m6As, evidence suggests that a large proportion of them are likely functional; they should be prioritized in future functional characterizations of m6As. Together, these findings have important implications for understanding the biological significance of m6A and other posttranscriptional modifications.
Abstract 15929: Blocking Osteochondrogenic Differentiation of Activated Valve Interstitial Cells Improves Aortic Valve Function in Diabetic Ldlr-/- Mice
Authors: Mei Y Speer, Mary Wallingford, Elizabeth Soberg, Mu-En Lin, Shunsuke Yamada, Marta Scatena, Cecilia M Giachelli
Journal: Circulation (2017)

Calcific aortic valve disease (CAVD) is prevalent in the elderly, especially those with type II diabetes mellitus (T2DM). To explore molecular and cellular mechanisms of CAVD, a robust CAVD mouse model exhibiting >75% incidence of hemodynamically significant aortic stenosis (AS) was developed. LDLr -/- ApoB 100/100    mice fed a customized diabetogenic, procalcific diet for ~8 weeks developed hyperglycemia and obesity. A transient expression of SMA and SM22α in aortic valve leaflets and hinge areas was found, identifying the presence of activated valve interstitial cells (aVICs) during early stage CAVD in these mice. The expression of SMA and SM22α disappeared by 6-12 months on diet, and hemodynamically significant AS developed. aVIC lineage tracing studies using LDLr -/- :SM22Cre:R26R-LacZ mice fed the T2DM-inducing diet indicated that the majority of cells in the thickened aortic valve leaflets and hinge areas were β-galactosidase positive (β-gal + ) and therefore derived from aVICs. Immunohistochemical staining showed that the majority of Runx2 +  cells were also β-gal + , identifying aVICs as a key source of osteochondrogenic precursors in CAVD. Finally, Runx2 deletion in aVICs in T2DM LDLr -/- :SM22Cre:Runx2 fl/fl  mice significantly improved aortic valve function compared to the LDLr -/- :Runx2 fl/fl  counterparts. The functionally improved aortic valves also showed reduced valve thickness, decreased osteoblastic differentiation (as measured by osteocalcin expression), and decreased cartilaginous matrix deposition (as determined by type X collagen expression). To our knowledge, these data are the first to definitively show that blocking osteochondrogenic differentiation of aVICs improves valve function in CAVD.
Copy number variation meta-analysis reveals a novel duplication at 9p24 associated with multiple neurodevelopmental disorders
Authors: Joseph T. Glessner, Jin Li, Dai Wang, Michael March, Leandro Lima, Akshatha Desai, Dexter Hadley, Charlly Kao, Raquel E. Gur, Nadine Cohen, Patrick M. A. Sleiman, Qingqin Li, Hakon Hakonarson
Journal: Genome Medicine (2017)

Neurodevelopmental and neuropsychiatric disorders represent a wide spectrum of heterogeneous yet inter-related disease conditions. The overlapping clinical presentations of these diseases suggest a shared genetic etiology. We aim to identify shared structural variants spanning the spectrum of five neuropsychiatric disorders. We investigated copy number variations (CNVs) in five cohorts, including schizophrenia (SCZ), bipolar disease (BD), autism spectrum disorders (ASD), attention deficit hyperactivity disorder (ADHD), and depression, from 7849 cases and 10,799 controls. CNVs were called based on intensity data from genome-wide SNP arrays and CNV frequency was compared between cases and controls in each disease cohort separately. Meta-analysis was performed via a gene-based approach. Quantitative PCR (qPCR) was employed to validate novel significant loci. In our meta-analysis, two genes containing CNVs with exonic overlap reached genome-wide significance threshold of meta P value < 9.4 × 10−6 for deletions and 7.5 × 10−6 for duplications. We observed significant overlap between risk CNV loci across cohorts. In addition, we identified novel significant associations of DOCK8/KANK1 duplications (meta P value = 7.5 × 10−7) across all cohorts, and further validated the CNV region with qPCR. In the first large scale meta-analysis of CNVs across multiple neurodevelopmental/psychiatric diseases, we uncovered novel significant associations of structural variants in the locus of DOCK8/KANK1 shared by five diseases, suggesting common etiology of these clinically distinct neurodevelopmental conditions.
Effects of insulin-glucose infusion on left ventricular function at rest and during dynamic exercise in healthy subjects and noninsulin dependent diabetic patients
Authors: Ferdinando Carlo Sasso, Ornella Carbonara, Domenico Cozzolino, Pierfrancesco Rambaldi, Luigi Mansi, Daniele Torella, Sandro Gentile, Salvatore Turco, Roberto Torella, Teresa Salvatore
Journal: Journal of the American College of Cardiology (2000)
JAK/STAT3-Regulated Fatty Acid β-Oxidation Is Critical for Breast Cancer Stem Cell Self-Renewal and Chemoresistance
Authors: Tianyi Wang, Johannes Francois Fahrmann, Heehyoung Lee, Yi-Jia Li, Satyendra C. Tripathi, Chanyu Yue, Chunyan Zhang, Veronica Lifshitz, Jieun Song, Yuan Yuan, George Somlo, Rahul Jandial, David Ann, Samir Hanash, Richard Jove, Hua Yu
Journal: Cell Metabolism (2017)
MicroRNAs regulate key cell survival pathways and mediate chemosensitivity during progression of diffuse large B-cell lymphoma
Authors: Suvi-Katri Leivonen, Katherine Icay, Kirsi Jäntti, Ilari Siren, Chengyu Liu, Amjad Alkodsi, Alejandra Cervera, Maja Ludvigsen, Stephen Jacques Hamilton-Dutoit, Francesco d’Amore, Marja-Liisa Karjalainen-Lindsberg, Jan Delabie, Harald Holte, Rainer Lehtonen, Sampsa Hautaniemi, Sirpa Leppä
Journal: Blood Cancer Journal (2017)

Despite better therapeutic options and improved survival of diffuse large B-cell lymphoma (DLBCL), 30-40% of the patients experience relapse or have primary refractory disease with a dismal prognosis. To identify biological correlates for treatment resistance, we profiled microRNAs (miRNAs) of matched primary and relapsed DLBCL by next-generation sequencing. Altogether 492 miRNAs were expressed in the DLBCL samples. Thirteen miRNAs showed significant differential expression between primary and relapse specimen pairs. Integration of the differentially expressed miRNAs with matched mRNA expression profiles identified highly anti-correlated, putative targets, which were significantly enriched in cancer-associated pathways, including phosphatidylinositol (PI)), mitogen-activated protein kinase (MAPK), and B-cell receptor (BCR) signaling. Expression data suggested activation of these pathways during disease progression, and functional analyses validated that miR-370-3p, miR-381-3p, and miR-409-3p downregulate genes on the PI, MAPK, and BCR signaling pathways, and enhance chemosensitivity of DLBCL cells in vitro. High expression of selected target genes, that is, PIP5K1 and IMPA1, was found to be associated with poor survival in two independent cohorts of chemoimmunotherapy-treated patients (n = 92 and n = 233). Taken together, our results demonstrate that differentially expressed miRNAs contribute to disease progression by regulating key cell survival pathways and by mediating chemosensitivity, thus representing potential novel therapeutic targets.
Go, no-go decision making for phase 3 clinical trials: ACT IV revisited – Authors' reply
Authors: Michael Weller, Nicholas Butowski, David D Tran, Lawrence D Recht, Michael Lim, Hal Hirte, Lynn Ashby, Laszlo Mechtler, Samuel A Goldlust, Fabio Iwamoto, Jan Drappatz, Donald M O'Rourke, Mark Wong, Mark G Hamilton, Gaetano Finocchiaro, James Perry, Wolfgang Wick, Jennifer Green, Yi He, Christopher D Turner, Michael J Yellin, Tibor Keler, Thomas A Davis, Roger Stupp, John H Sampson
Journal: The Lancet Oncology (2017)
Endothelial permeability, LDL deposition, and cardiovascular risk factors—a review
Authors: Santa Mundi, Marika Massaro, Egeria Scoditti, Maria Annunziata Carluccio, Victor W M van Hinsbergh, Marial Luisa Iruela-Arispe, Raffaele De Caterina
Journal: Cardiovascular Research (2017)

Early atherosclerosis features functional and structural changes in the endothelial barrier function that affect the traffic of molecules and solutes between the vessel lumen and the vascular wall. Such changes are mechanistically related to the development of atherosclerosis. Proatherogenic stimuli and cardiovascular risk factors, such as dyslipidaemias, diabetes, obesity, and smoking, all increase endothelial permeability sharing a common signalling denominator: an imbalance in the production/disposal of reactive oxygen species (ROS), broadly termed oxidative stress. Mostly as a consequence of the activation of enzymatic systems leading to ROS overproduction, proatherogenic factors lead to a pro-inflammatory status that translates in changes in gene expression and functional rearrangements, including changes in the transendothelial transport of molecules, leading to the deposition of low-density lipoproteins (LDL) and the subsequent infiltration of circulating leucocytes in the intima. In this review, we focus on such early changes in atherogenesis and on the concept that proatherogenic stimuli and risk factors for cardiovascular disease, by altering the endothelial barrier properties, co-ordinately trigger the accumulation of LDL in the intima and ultimately plaque formation.
Abstract 19857: Genome Wide Association With Aortic Dimension in Bicuspid Aortic Valve Disease
Authors: Mahyar Heydarpour, Martin I Sigurdsson, Vanessa Montiero, Jasmine T Shahram, Jochen D Muehlschlegel, Tsuyoshi Kaneko, Prem S Shekar, Thoralf M Sundt, Simon C Body
Journal: Circulation (2016)

Introduction: Ascending aortic dilation occurs frequently in patients with a bicuspid aortic valve (BAV) and is a source of morbidity and mortality, but its causes are incompletely known. Hypothesi...
Diagnostic Value of Transluminal Attenuation Gradient for the Presence of Ischemia as Defined by Fractional Flow Reserve and Quantitative Positron Emission Tomography
Authors: Michiel J. Bom, Roel S. Driessen, Wynand J. Stuijfzand, Pieter G. Raijmakers, Cornelis C. Van Kuijk, Adriaan A. Lammertsma, Albert C. van Rossum, Niels van Royen, Juhani Knuuti, Maija Mäki, Koen Nieman, James K. Min, Jonathon A. Leipsic, Ibrahim Danad, Paul Knaapen
Journal: JACC. Cardiovascular imaging (2017)