tbuckley/cabot-search huggingface dataset:
THU0022 Analysis of 47 non-mhc ankylosing spondylitis susceptibility loci reveals shared associated variants across caucasians and chinese han
Authors: X. Zheng, Q. Li, X. Li, Y. Zhang, X. Wu, Q. Wei, S. Cao, M. Yang, Z. Lin, Z. Liao, J. Qi, Q. Lv, L. Wang, J. Liu, J. Gu
Journal: Annals of the Rheumatic Diseases (2018)

<h3>Background</h3> Genetic factors play a prominent role in AS pathogenesis. So far over 40 non-MHC Ankylosing Spondylitis(AS) susceptibility loci with genome-wide or suggestive significance have been initially reported in Caucasians, however, lack of association evidence of most loci was seen in Chinese Han and some results seemed controversial. <h3>Objectives</h3> Here, we present a systematic evaluation of 47 non-MHC AS susceptibility loci using GWAS datasets in Chinese Han. <h3>Methods</h3> Totally 1853 AS cases and 4048 newly matched controls in 4 cohorts were obtained, after imputation meta-analysis results of 93 589 variants within 47 reported loci were extracted. Best-guess genotype data were used for interaction analysis and weighted genetic risk score model construction which was then assessed by receiver operator characteristic analysis. Functional annotation was conducted using HaploReg, RegulomeDB and rVarBase Database. <h3>Results</h3> We revealed 14 AS-associated variants with nominal evidence in Chinese Han, including rs10865331(p=2.96E-9), rs10050860 (p=1.84E-4) and rs8070463(p=2.81E-4) and found potential associated variants within these loci. We then extracted variants in ERAP1 as well as HLA-B27 tag snp rs13202464 for HLA-B27-ERAP1 interaction analysis (figure 1). Epistatic association between ERAP1 (rs30187, rs10045403) and HLA-B27 (rs13202464) was confirmed. Among those 14 variants, rs30187 showed weaker risk effect in Chinese while rs10050860 and rs12504282 seemed to attribute more risk (Table 1). Genetic prediction model combining 14 variants in 11 loci with HLA-B27 achieved better discrimination ability(AUC=0.884, 95%CI=0.873~0.895) than HLA-B27 alone(p=2.17E-6). We also identified some likely functional variants at these loci. <h3>Conclusions</h3> Our results provided a detailed spectrum of non-MHC AS susceptibility loci in Chinese Han and highlighted 2 p15, ERAP1 and TBKBP1 may play a critical role in AS pathogenesis. <h3>References</h3> [1] IGAS, Cortes A, Hadler J, et al. Nature genetics. 2013Jul; 45(7):730–738. [2] Ellinghaus D, Jostins L, Spain SL, et al. Nature genetics. 2016May; 48(5):510–518. <h3>Disclosure of Interest</h3> None declared
Abstract 19167: Ultra-high Sensitive Cardiac Troponin I Baseline Levels are Affected by Age and Sex
Authors: Mitra Mastali, Qin Fu, Kimia Sobhani, Noel Bairey Merz, Jennifer Van Eyk
Journal: Circulation (2017)

Introduction and Hypothesis: Relations between elevated circulating cardiac troponin I (cTnI) levels and adverse cardiac outcomes were established prior to the advent of methods to measure extremel...
Abstract 19665: Impact of Socioeconomic Factors on Heart Failure
Authors: Khansa Ahmad, Tisha Suboc, Kara Nitti, Umair Nazir, Ambar Andrade, William Cotts
Journal: Circulation (2017)

Introduction: Heart failure(HF) afflicts 5.7 million adults in the United States with 1 in 9 deaths attributed to HF. We examine the socioeconomic contributions to this disease process. Hypothesis: Socioeconomic factors impact HF. Methods: Data for 3,142 counties of the USA, on HF hospitalization, HF mortality, diabetes, obesity, urban-rural status, poverty, population per primary care provider (PCP), lack of insurance, lack of high school education and noncompliance with hypertension (HTN) medications, was obtained from the CDC database. Urban rural status was defined by the Office of Management & Budget (OMB) 2013, with large central metro, fringe metro, medium/small metro and nonmetro regions assigned level 1,2,3 & 4 respectively. Poverty was classified into level I (highest (21.2- 52.2%)) through V (lowest (3.2-11.4%)). Other variables were subjected to univariate analysis and subdivided into quartiles. Multivariate regression analyses were performed with predictive model construction, to assess medic...
Brief history of burnout
Authors: Rajvinder Samra
Journal: BMJ (2018)

The coining of the term "burnout" in a clinical sense is typically to the psychologist Herbert Freudenberger, 1 who in 1974 described it as particularly pertinent to caring professionals. 2 More than 40 years later, burnout is still conceptualised as uniquely affecting those in emotionally demanding professional roles. 3wever, one of the first documented reports of workplace burnout referred to people without occupational caring responsibilities. 4In 1971, three years before Freudenberger's description, 2 US air traffic controllers were commonly reporting "vocational 'burn out,' a form of exhaustion, which is manifested in a decline in quantity and quality of work production." 4 Several important, and overlooked, parallels between burnout in air traffic controllers and in doctors can inform our current approaches to tackling this phenomenon.
Growth Hormone Deficiency: Health and Longevity
Authors: Manuel H Aguiar-Oliveira, Andrzej Bartke
Journal: Endocrine Reviews (2018)

Abstract The important role of GH in the control of mammalian longevity was first deduced from extended longevity of mice with genetic GH deficiency (GHD) or GH resistance. Mice with isolated GHD (IGHD) due to GHRH or GHRH receptor mutations, combined deficiency of GH, prolactin, and TSH, or global deletion of GH receptors live longer than do their normal siblings. They also exhibit multiple features of delayed and/or slower aging, accompanied by extension of healthspan. The unexpected, remarkable longevity benefit of severe endocrine defects in these animals presumably represents evolutionarily conserved trade-offs among aging, growth, maturation, fecundity, and the underlying anabolic processes. Importantly, the negative association of GH signaling with longevity extends to other mammalian species, apparently including humans. Data obtained in humans with IGHD type 1B, owing to a mutation of the GHRH receptor gene, in the Itabaianinha County, Brazil, provide a unique opportunity to study the impact of severe reduction in GH signaling on age-related characteristics, health, and functionality. Individuals with IGHD are characterized by proportional short stature, doll facies, high-pitched voices, and central obesity. They have delayed puberty but are fertile and generally healthy. Moreover, these IGHD individuals are partially protected from cancer and some of the common effects of aging and can attain extreme longevity, 103 years of age in one case. We think that low, but detectable, residual GH secretion combined with life-long reduction of circulating IGF-1 and with some tissue levels of IGF-1 and/or IGF-2 preserved may account for the normal longevity and apparent extension of healthspan in these individuals.
Abstract 13254: Cholesterol and Mortality Among 2.1 Million US Veterans Across Chronic Kidney Disease Stages
Authors: Melissa Soohoo, Taryn Benson-Hernandez, Hamid Moradi, Carola-Ellen Kleine, Maria Marroquin, Csaba P Kovesdy, Kamyar Kalantar-Zadeh, Elani Streja
Journal: Circulation (2018)

Introduction: High serum cholesterol concentration has long been associated with higher risk of morbidity and mortality in adults, yet this has been recently challenged in elderly patients. Among c...
Physicians take legal action to challenge US board’s “monopoly” on certification
Authors: Owen Dyer
Journal: BMJ (2018)

Four doctors who say that their careers were damaged when their certification was withdrawn by the American Board of Internal Medicine (ABIM) are leading a legal challenge against what they say is an unfair monopoly of the recertification process.

Almost all American internists, and physicians in many related specialties, are expected to hold a certificate from ABIM that proves maintenance of certification (MOC). For many, this has involved steep fees and a high stakes exam every 10 years. But for those who obtained their initial certification before 1990, ABIM has waived this requirement, unfairly penalising younger doctors, the suit argues.

ABIM’s certification is needed for several specialties to obtain hospital privileges and join insurers’ networks. Losing it typically forces doctors to take less prestigious jobs for lower pay.

ABIM’s actions are an unreasonable restraint of trade that …
Maladaptive Pulmonary vascular responses to chronic intermittent and sustained hypoxia in a rat hypertension model
Authors: Asuncion Rocher, Jesus Prieto-Lloret, Inmaculada Docio, Elena Olea, Maria Llanos Bravo, Ana Obeso, Angela Gomez-Niño
Journal: European Respiratory Journal (2018)

Resumen del trabajo presentado al European Respiratory Society (ERS) International Congress, celebrado en Paris (Francia) del 15 al 19 de septiembre de 2018.
A Randomized, Double-Blind, Placebo-Controlled Phase 1 Study of the Pharmacokinetics and Pharmacodynamics of REGN3918, a Human Antibody Against Complement Factor C5, in Healthy Volunteers
Authors: Jonathan Weyne, Yan Ni, Richard DelGizzi, Stephen Godin, Lori Morton, Srinivasa Prasad, Andrew J Rankin, Melissa Simek-Lemos, ming-Dauh Wang, Ronda Rippley, Olivier Harari
Journal: Blood (2018)
Abstract 17113: Transaortic Edge-to-edge Mitral Valve Repair for Functional Mitral Regurgitation in Patients Undergoing Aortic Valve Replacement: A 13-year Experience
Authors: Christos G Mihos, Maiteder Laurrari-Reyes, Judy Hung, Orlando Santana
Journal: Circulation (2015)

Objective: The study aim was to evaluate the safety and efficacy of a transaortic edge-to-edge mitral valve repair (Alfieri stitch) for moderate or greater (≥2+) functional mitral regurgitation (MR) in patients undergoing aortic valve replacement, who were deemed to be high risk for conventional double valve surgery. Methods: We retrospectively evaluated all patients who underwent aortic valve replacement combined with a transaortic edge-to-edge mitral valve repair for ≥2+ functional MR, between February 2002 and April 2015. The MR was graded as 0 (trace/none), mild (1+), moderate (2+), moderate-to-severe (3+), or severe (4+). Results: There were 40 consecutive patients identified; 32 had aortic stenosis and 8 aortic regurgitation. The mean age was 77.5 ± 5 years, and 34 (85%) were male. Coronary artery disease was present in 26 (65%) patients, while 14 (35%) had no or non-obstructive disease. Sixteen (40%) patients had a prior history of cardiac surgery, and the mean EuroSCORE II was 14.3% ± 12.9. Nine patients (22.5%) underwent concomitant coronary artery bypass grafting. At a median of 1 month (IQR 0.75-10) follow-up, there were significant improvements in preoperative versus postoperative median MR grade (3 versus 1, p&lt;0.001), and mean left ventricular ejection fraction (34% versus 41%, p=0.018), left ventricular end-diastolic dimension (54mm versus 49mm, p=0.005), and pulmonary artery systolic pressure (49mmHg versus 35mmHg, p&lt;0.001). Persistent 3-4+ MR occurred in 2 (5%) patients. In 12 patients with at least 6 month echocardiographic follow-up (mean = 18 ± 11 months), a sustained improvement in median MR grade (4 versus 1, p&lt;0.001), and mean left ventricular ejection fraction (40% versus 53%, p=0.003), left ventricular end-diastolic dimension (53mm versus 41mm, p=0.005), and pulmonary artery systolic pressure (46mmHg versus 33mmHg, p&lt;0.039) was observed, with persistent 3-4+ MR occurring in 1 (8.3%) patient. Actuarial survival at 1, 3, and 4.5-years was 82% ± 6, 71% ± 8, and 65% ± 10, respectively. Conclusions: A transaortic edge-to-edge repair for ≥2+ functional MR can be safely performed during aortic valve replacement, and confers early and mid-term improvements in MR grade, left ventricular remodeling, and pulmonary hemodynamics.
Neuronal PAS domain protein 2 (NPAS2) and human cancers: evidence of circadian gene hypothesis
Authors: Yong Zhu, Carly Guss, Derek Leaderer, Heather Brown, Yawei Zhang, Peter Boyle, Richard Stevens, Xusong Han, Tongzhang Zheng
Journal: Cancer Research (2006)

4589  Emerging data have demonstrated a novel role of circadian genes, responsible for a 24-hour circadian rhythm, in tumorigenesis by showing that the circadian clock may function as a tumor suppressor because of its involvement in cell proliferation, apoptosis, cell cycle control, and DNA damage response. However, few studies have tested this hypothesis in humans. The current study aimed to examine possible roles of Neuronal PAS domain protein 2 (NPAS2), a large circadian gene (∼170kb) with only one non-synonymous mutation (rs2305160, Ala394Thr) in its coding region according to public SNP databases, in human cancers. We first genotyped this missense mutation in our two recently completed case-control studies. Results from the breast cancer study (418 cases, 467 controls) showed that women with heterozygous Ala394Thr genotype had a significantly reduced risk of breast cancer compared to those with homozygous Ala394Ala (OR=0.62, 0.46-0.83, p=0.001). A similar finding was also observed in our women’s non-Hodgkin lymphoma (NHL) study (428 cases, 510 controls), in which the variant genotypes (Ala394Thr & Thr394Thr) were significantly associated with decreased risk for all NHL (OR=0.70, 0.54-0.91, p=0.008), and for B-cell lymphoma (OR=0.66, 0.50-0.88, p=0.004). These results suggest that genetic variations in NPAS2 may confer individuals’ susceptibility to breast cancer and NHL. In addition, we searched for CpG islands in NPAS2 and performed quantitative methylation-specific PCR to assess methylation changes at two CpG islands, one in promoter and another in Exon18, for blood DNA samples from 17 untreated breast cancer patients and 17 exact age-matched controls. This pilot analysis revealed an age-dependent relationship of methylation changes in Exon18 (Spearman r=-0.551, p=0.004) and a significant difference of methylation level at this locus between cases and controls (p=0.018). These findings further suggest that epigenetic changes in NPAS2 may also play a role in tumorigenesis. In summary, our study demonstrates robust associations of both genetic and epigenetic changes in NPAS2 with human cancers. Our findings support the circadian gene hypothesis that genes regulating circadian rhythms might be a novel panel of biomarkers for cancer risk and prognosis, which warrants further investigation.
Advancing Health and Health Care Using Machine Learning
Authors: Frederick P. Rivara, Stephan D. Fihn, Roy H. Perlis
Journal: JAMA Network Open (2018)

2][3][4][5] Medicine poses unique challenges compared with areas like recognizing images, driving autonomous vehicles, or gaming, for which machine learning has had remarkable success.Obstacles to successful application of machine learning in medicine include availability of large, high-quality databases to derive prediction models that are accurate and interpretable and deployment of these models in ways that improve, rather than simply complicate, medical practice.JAMA Network Open, a fully open access journal in the JAMA Network of journals with an international audience of health care clinicians and policy makers, is pleased to announce a call for papers on "advancing health and health care using machine learning."We are interested in reports of original research that describe ways in which validated applications of machine learning, artificial intelligence, and natural language processing provide the potential to advance the health of individuals or populations through improved health care and better understanding of factors that affect health.Appropriate studies include clinical research using machine learning to improve clinical diagnosis and prognosis of disease, identify high-risk individuals in a population, or provide information that can be used to most appropriately monitor risk factors and treat patients using precision medicine.Methodologic innovation in machine learning is welcome, provided that innovation is applied to a clinically meaningful problem and presented in a clinically interpretable manner.That is, we are seeking cutting-edge applications of machine learning with significant clinical validation that can move medical practice forward.][8][9][10][11] Note that JAMA Network Open does not publish narrative review articles, basic science, or animal model studies.
Combining p38MAPK Inhibitors with a Second Targeted Agent Enhances Blockade of Inflammatory Signaling-Mediated Survival in Acute Myeloid Leukemia Cells
Authors: Stephen E Kurtz, Christopher A. Eide, Narain P. Dubey, Andy Kaempf, Shannon K. McWeeney, Cristina E. Tognon, Motomi Mori, Brian J. Druker, Jeffrey W. Tyner, Anupriya Agarwal
Journal: Blood (2018)
Acid-Induced Downregulation of ASS1 Contributes to the Maintenance of Intracellular pH in Cancer
Authors: Alon Silberman, Omer Goldman, Odeya Boukobza Assayag, Adi Jacob, Shiran Rabinovich, Lital Adler, Joo Sang Lee, Rom Keshet, Alona Sarver, Julia Frug, Noa Stettner, Sivan Galai, Erez Persi, Keren Bahar Halpern, Yehudit Zaltsman-Amir, Ben Pode-Shakked, Raya Eilam, Yair Anikster, Sandesh C.S. Nagamani, Igor Ulitsky, Eytan Ruppin, Ayelet Erez
Journal: Cancer Research (2018)

Downregulation of the urea cycle enzyme argininosuccinate synthase (ASS1) by either promoter methylation or by HIF1α is associated with increased metastasis and poor prognosis in multiple cancers. We have previously shown that in normoxic conditions, ASS1 downregulation facilitates cancer cell proliferation by increasing aspartate availability for pyrimidine synthesis by the enzyme complex CAD. Here we report that in hypoxia, ASS1 expression in cancerous cells is downregulated further by HIF1α-mediated induction of miR-224-5p, making the cells more invasive and dependent on upstream substrates of ASS1 for survival. ASS1 was downregulated under acidic conditions, and ASS1-depleted cancer cells maintained a higher intracellular pH (pHi), depended less on extracellular glutamine, and displayed higher glutathione levels. Depletion of substrates of urea cycle enzymes in ASS1-deficient cancers decreased cancer cell survival. Thus, ASS1 levels in cancer are differentially regulated in various environmental conditions to metabolically benefit cancer progression. Understanding these alterations may help uncover specific context-dependent cancer vulnerabilities that may be targeted for therapeutic purposes. SIGNIFICANCE: Cancer cells in an acidic or hypoxic environment downregulate the expression of the urea cycle enzyme ASS1, which provides them with a redox and pH advantage, resulting in better survival.Graphical Abstract: http://cancerres.aacrjournals.org/content/canres/79/3/518/F1.large.jpg.
Mapping the Connectome Using Novel AAV Vectors, DNA Barcoding and Spatial Transcriptomics
Authors: Marcus Davidsson, Patrick Aldrin-Kirk, Tiago Cardoso, Morgan Hartnor, Andreas Heuer, Annelie Mollbrink, Joakim Lundeberg, Malin Parmar, Tomas Bjorklund
Journal: Molecular Therapy (2018)
Double Vs Single Autologous Stem Cell Transplantation for Newly Diagnosed Multiple Myeloma: Long-Term Follow-up (10-Years) Analysis of Randomized Phase 3 Studies
Authors: Michele Cavo, Hartmut Goldschmidt, Laura Rosinol, Lucia Pantani, Sonja Zweegman, Hans Jürgen Salwender, Juan Jose Lahuerta, Henk M. Lokhorst, Maria Teresa Petrucci, Igor Blau, Albert Oriol, Nicoletta Testoni, Katja Weisel, Rafael Rios, Francesca Patriarca, Jesús Blanchard, Luca Dozza, Maria-Victoria Mateos, Monica Galli, Jesus F San-Miguel, Mario Boccadoro, Joan Blade, Pieter Sonneveld
Journal: Blood (2018)
Abstract 14520: A Novel Paradigm and a New Drug for the Management of Ductus-dependent Congenital Heart Disease
Authors: Lincai Ye, Minghui Li, Xiuxia Ye, Xu Liu, Huiwen Chen, Chuan Jiang, Haibo Zhang, Jinfen liu, Haifa Hong
Journal: Circulation (2017)

Background: Although antenatal diagnostic technique has considerably improved, proper management of ductus-dependent congenital heart disease (CHD) is always a great concern to pediatricians. Curre...
ECT2/PSMD14/PTTG1 axis promotes the proliferation of glioma through stabilizing E2F1
Authors: Tongle Zhi, Kuan Jiang, Xiupeng Xu, Tianfu Yu, Fengqi Zhou, Yingyi Wang, Ning Liu, Junxia Zhang
Journal: Neuro-Oncology (2018)

Epithelial cell transformation sequence 2 (ECT2) is upregulated in glioma and promotes glioma cell proliferation. A preliminary experiment showed a positive correlation between ECT2 and pituitary tumor-transforming gene 1 (PTTG1). The aim of this study was to explore how ECT2 affects PTTG1 to influence the proliferation of glioma cells. The expression of ECT2 in glioma was detected by western blot and reverse transcription PCR. The effect of ECT2 on glioma proliferation was examined using cell proliferation–related assays and in vivo experiments. The effect of ECT2 on the stability of E2F transcription factor 1 (E2F1) and the expression of PTTG1 were examined by western blot, co-immunoprecipitation, and in vivo ubiquitination assays. ECT2 was upregulated in gliomas and was negatively correlated with prognosis; its downregulation inhibited glioma cell proliferation. Furthermore, ECT2 regulated PTTG1 expression by affecting the stability of E2F1, thereby affecting the glioma cell proliferation. In addition, the deubiquitinating enzyme proteasome 26S subunit, non-ATPase 14 (PSMD14) affected the degradation of E2F1 and regulated the stability of E2F1. Interestingly, ECT2 regulated the expression of PSMD14. In this study, we clarify a new mechanism by which ECT2 regulates the expression of PTTG1 and thus affects the proliferation of glioma cells: ECT2 influences the stability of E2F1 by regulating the expression of the deubiquitinating enzyme PSMD14, thereby affecting the expression of PTTG1. Intensive and extensive understanding of the mechanism of ECT2 in glioma proliferation may provide an opportunity for the development of new molecular therapeutic targets for glioma treatment.
The ambition of the <i>European Respiratory Journal</i>: chapter 4
Authors: Marc Humbert, Anh Tuan Dinh-Xuan, Elin L. Reeves, Matthew G. Broadhead, Neil J. Bullen
Journal: European Respiratory Journal (2015)

Already we are more than half-way through the current 5-year editorial cycle of the European Respiratory Journal ( ERJ ), and as we begin 2016 we again open our first issue of the new year with our annual round up and look to the future. The ERJ : publishing and contextualising the best in respiratory research and practice <http://ow.ly/V1Gsd>
Five-Day Versus Ten-Day Schedules of Decitabine in Older Patients with Newly Diagnosed Acute Myeloid Leukemia: Results of a Randomized Phase II Study
Authors: Nicholas J Short, Hagop M. Kantarjian, Sanam Loghavi, Xuelin Huang, Wei Qiao, Gautam Borthakur, Tapan M. Kadia, Naval G. Daver, Maro N. Ohanian, Courtney D. DiNardo, Zeev E. Estrov, Rashmi Kanagal-Shamanna, Abhishek Maiti, Christopher B. Benton, Prithviraj Bose, Yesid Alvarado, Elias J. Jabbour, Steven M. Kornblau, Naveen Pemmaraju, Nitin Jain, Yvonne Gasior, Mary Ann Richie, Sherry A. Pierce, Jorge E. Cortes, Marina Y. Konopleva, Guillermo Garcia-Manero, Farhad Ravandi
Journal: Blood (2018)