tbuckley/cabot-search huggingface dataset:
Abstract 18101: Predictors of Mortality in Takotsubo Cardiomyopathy: Analysis From the National Inpatient Sample 2014 Database
Authors: Chayakrit Krittanawong, Bing Yue, Hafeez Ul Hassan Virk, Edgar Argulian
Journal: Circulation (2017)

Introduction: Takotsubo cardiomyopathy (TC) causes acute, reversible systolic dysfunction. Clinical variables that predict in-hospital mortality have not been well characterized. Hypothesis: The aim of this study was to determine the in-hospital mortality and clinical predictors of mortality in TC. Methods: Data for this retrospective cohort study were extracted from the Nationwide Inpatient Sample for 2014 using the 9th revision of the International Classification of Diseases (ICD) 429.83 (takotsubo cardiomyopathy). Demographics, in-hospital mortality, conventional risk factors (diabetes, hypertension, hyperlipidemia, alcohol and tobacco abuse), acute illnesses (sepsis, septic shock, stroke, acute respiratory insufficiency, acute renal failure, atrial fibrillation) and chronic conditions (anxiety, depression, malignancy and metastatic diseases) were studied. Univariate and multivariate logistic regression was used to determine predictors associated with inpatient mortality. All analyses were conducted us...
Transcriptomic Microarray Profile Analysis between Blastic Plasmacytoid Dendritic Cell Neoplasm (BPDCN) and TET2-Mutated Acute Myeloid Leukemia (AML)
Authors: Hannah Beird, Maliha Khan, Feng Wang, Mansour Alfayez, Tianyu Cai, Li Zhao, Andy Futreal, Marina Y. Konopleva, Naveen Pemmaraju
Journal: Blood (2018)
Endoscopic features of submucosal invasion in undifferentiated type early gastric cancer sized less than 2 cm without ulceration.
Authors: Su Jin Kim, Cheol Woong Choi, Dae Hwan Kang
Journal: Journal of Clinical Oncology (2019)

76 Background: The prediction of invasion depth is important to decide the treatment modality for the undifferentiated type early gastric cancer (EGC) when size is less than 2 cm and had no ulceration. We aimed to identify the endoscopic features associated with submucosal invasion in the undifferentiated type EGC that meet the criteria of size and status of ulcer in the endoscopic submucosal dissection (ESD). Methods: A total of 120 patients with undifferentiated type EGC who received ESD or operation from August 2008 to December 2017 were enrolled in this study. All lesions met the ESD criteria except the invasion depth. We retrospectively reviewed endoscopic features of tumor before the resection and depth of invasion after resection. Results: In 120 undifferentiated EGCs, the mucosal and submucosal cancer were 97 and 23 lesions, respectively, In univariable analysis, discolor change, upper third location, the presence of deep/wide erosion were associated with submucosal invasion. Multivariable analysis revealed that upper/middle third location (odds ratio [OR] 8.0, 95% confidence interval [CI] 1.2-55.0; OR 7.9, 95% CI 1.8-35.1), erosion or polypoid (OR 41.8, 95% CI 4.1-427.9), and elevated type (OR 20.9, 95% CI 2.5-173.8) were significant risk factors. In 112 patients received gastrectomy with lymph nodes dissection, lymph node metastases were found in four cases (three mucosal cancer and one submucosal cancer). However, there was no lymph node metastasis in the lesions meeting the expanded ESD indication. Conclusions: The careful decision of treatment modality is needed for undifferentiated type EGC with erosion or elevated gross type located on the upper/middle third, although the tumor size and ulcer status meet the ESD indication.
Number of FY2 doctors moving straight into specialty training falls again
Authors: Abi Rimmer
Journal: BMJ (2019)

Only just over a third of doctors who have successfully completed the foundation training programme now choose to go straight into specialty training.

The latest UK Foundation Programme career destinations report, which is based on a survey of 6407 foundation year 2 (FY2) doctors in 2018 (an 86.8% response rate), showed that the trend to take a break between finishing foundation training and starting a specialty post, sometimes known as the FY3 year, is growing.1

In 2018, 37.7% of FY2s immediately took up a specialty post, down from 42.6% in 2017, 50.4% in 2016, and 71.3% in …
Multicenter Pharmacokinetic Evaluation of rFVIII-Fc (Elocta) in a Real Life and Comparison with Non-Extended Half-Life FVIII Concentrates
Authors: Claire Pouplard, Laurent Sattler, Anne Ryman, Valérie Eschwege, Emmanuel De Maistre, Claire Flaujac, Jean Szymezak, François Grand, Yohann Repesse, Hubert Galinat, Magali Donnard, Catherine Ternisien, Emmanuelle Jeanpierre
Journal: Blood (2018)
Complex Relationships of Smoking, HLA–DRB1 Genes, and Serologic Profiles in Patients With Early Rheumatoid Arthritis: Update From a Swedish Population‐Based Case–Control Study
Authors: Anna Karin Hedström, Johan Rönnelid, Lars Klareskog, Lars Alfredsson
Journal: Arthritis & Rheumatology (2019)

Objective Smoking is associated with an increased risk of rheumatoid arthritis ( RA ) in subsets of patients defined according to the presence or absence of anti–citrullinated protein antibodies ( ACPA s) and rheumatoid factors ( RF s). Moreover, an interaction between smoking and the HLA – DRB 1 shared epitope ( SE ) has been demonstrated to be a risk factor for seropositive RA . The aim of this study was to investigate the interplay between smoking and the HLA – DRB 1 SE with regard to risk of RA in different patient subsets based on ACPA and RF status. Methods Incident cases of RA (3,645 cases, 5,883 matched controls) were divided into 4 subgroups based on the presence or absence of RF and anti–cyclic citrullinated peptide 2 (anti‐ CCP 2) antibodies. The influence of smoking on the risk of disease was determined in each RA subgroup, using logistic regression models with calculation of odds ratios and 95% confidence intervals (95% CIs). The potential interaction between smoking and HLA – DRB 1 SE genes was evaluated by calculating the attributable proportion due to interaction (AP). Results In the RF +/anti‐ CCP 2+ subset of RA patients, both smoking and the presence of the HLA – DRB 1 SE conferred independent disease risks, and there was a strong interaction between the 2 risk factors (AP 0.4, 95% CI 0.3, 0.5). In the RF −/anti‐ CCP 2+ patient subset, the HLA – DRB 1 SE conferred an increased risk of RA , whereas the independent influence of smoking was limited. However, there was a significant interaction between the HLA – DRB 1 SE and smoking (AP 0.2, 95% CI 0.02, 0.5). In the RF +/anti‐ CCP 2− patient subset, there was an increased risk of disease among smokers, which was only marginally affected by the presence of the HLA – DRB 1 SE , and no interaction between the 2 factors was observed (AP 0.002, 95% CI −0.3, 0.3). In the RF −/anti‐ CCP 2− patient subset, neither smoking nor the presence of the HLA – DRB 1 SE conferred an increased risk of RA . Conclusion These findings demonstrate different effects of smoking and HLA – DRB 1 in the 4 serologically defined RA subsets.
TGR5-dependent hepatoprotection through the regulation of biliary epithelium barrier function
Authors: Grégory Merlen, Nicolas Kahale, Jose Ursic-Bedoya, Valeska Bidault-Jourdainne, Hayat Simerabet, Isabelle Doignon, Zahra Tanfin, Isabelle Garcin, Noémie Péan, Julien Gautherot, Anne Davit-Spraul, Catherine Guettier, Lydie Humbert, Dominique Rainteau, Klaus Ebnet, Christoph Ullmer, Doris Cassio, Thierry Tordjmann
Journal: Gut (2019)

Objective We explored the hypothesis that TGR5, the bile acid (BA) G-protein-coupled receptor highly expressed in biliary epithelial cells, protects the liver against BA overload through the regulation of biliary epithelium permeability. Design Experiments were performed under basal and TGR5 agonist treatment. In vitro transepithelial electric resistance (TER) and FITC-dextran diffusion were measured in different cell lines. In vivo FITC-dextran was injected in the gallbladder (GB) lumen and traced in plasma. Tight junction proteins and TGR5-induced signalling were investigated in vitro and in vivo (wild-type [WT] and TGR5-KO livers and GB). WT and TGR5-KO mice were submitted to bile duct ligation or alpha-naphtylisothiocyanate intoxication under vehicle or TGR5 agonist treatment, and liver injury was studied. Results In vitro TGR5 stimulation increased TER and reduced paracellular permeability for dextran. In vivo dextran diffusion after GB injection was increased in TGR5-knock-out (KO) as compared with WT mice and decreased on TGR5 stimulation. In TGR5-KO bile ducts and GB, junctional adhesion molecule A (JAM-A) was hypophosphorylated and selectively downregulated among TJP analysed. TGR5 stimulation induced JAM-A phosphorylation and stabilisation both in vitro and in vivo, associated with protein kinase C-ζ activation. TGR5 agonist-induced TER increase as well as JAM-A protein stabilisation was dependent on JAM-A Ser285 phosphorylation. TGR5 agonist-treated mice were protected from cholestasis-induced liver injury, and this protection was significantly impaired in JAM-A-KO mice. Conclusion The BA receptor TGR5 regulates biliary epithelial barrier function in vitro and in vivo through an impact on JAM-A expression and phosphorylation, thereby protecting liver parenchyma against bile leakage.
Overall survival and updated progression-free survival outcomes in a randomized phase II study of combination cediranib and olaparib versus olaparib in relapsed platinum-sensitive ovarian cancer
Authors: J.F. Liu, W.T. Barry, M. Birrer, J.-M. Lee, R.J. Buckanovich, G.F. Fleming, B.J. Rimel, M.K. Buss, S.R. Nattam, J. Hurteau, W. Luo, J. Curtis, C. Whalen, E.C. Kohn, S.P. Ivy, U.A. Matulonis
Journal: Annals of Oncology (2019)

BackgroundOlaparib is a poly(ADP-ribose) polymerase inhibitor and cediranib is an oral anti-angiogenic. In the primary analysis of this phase II study, combination cediranib/olaparib improved progression-free survival (PFS) compared with olaparib alone in relapsed platinum-sensitive ovarian cancer. This updated analysis was conducted to characterize overall survival (OS) and update PFS outcomes.Patients and methodsNinety patients were enrolled to this randomized, open-label, phase II study between October 2011 and June 2013 across nine United States-based academic centers. Data cut-off was 21 December 2016, with a median follow-up of 46 months. Participants had relapsed platinum-sensitive ovarian cancer of high-grade serous or endometrioid histology or had a deleterious germline BRCA1/2 mutation (gBRCAm). Participants were randomized to receive olaparib capsules 400 mg twice daily or cediranib 30 mg daily and olaparib capsules 200 mg twice daily until disease progression.ResultsIn this updated analysis, median PFS remained significantly longer with cediranib/olaparib compared with olaparib alone (16.5 versus 8.2 months, hazard ratio 0.50; P = 0.007). Subset analyses within stratum defined by BRCA status demonstrated statistically significant improvement in PFS (23.7 versus 5.7 months, P = 0.002) and OS (37.8 versus 23.0 months, P = 0.047) in gBRCA wild-type/unknown patients, although OS was not statistically different in the overall study population (44.2 versus 33.3 months, hazard ratio 0.64; P = 0.11). PFS and OS appeared similar between the two arms in gBRCAm patients. The most common CTCAE grade 3/4 adverse events with cediranib/olaparib remained fatigue, diarrhea, and hypertension.ConclusionsCombination cediranib/olaparib significantly extends PFS compared with olaparib alone in relapsed platinum-sensitive ovarian cancer. Subset analyses suggest this margin of benefit is driven by PFS prolongation in patients without gBRCAm. OS was also significantly increased by the cediranib/olaparib combination in this subset of patients. Additional studies of this combination are ongoing and should incorporate analyses based upon BRCA status.Trial RegistrationClinicaltrials.gov Identifier NCT0111648
Abstract 21277: Galectin 3 Predicts New Onset Heart Failure: Systematic Review and Meta Analysis of Prospective Studies
Authors: Usama Nasir, Waqas T Qureshi, Hania Shahid, Abhishek Dutta, Mouaz Al-Mallah
Journal: Circulation (2017)

Background: Galectin 3, a fibrosis biomarker, has found to have significant prognostic value in predicting all cause mortality in heart failure patients. However, its role in predicting the risk for new onset heart failure is not well established. We conduct a meta-analysis to analyze the correlation of increase in serum Galectin 3 levels from baseline and development of new onset heart failure. Methods: MEDLINE, EMBASE, CINAHL, Web of Science, meeting abstracts and Cochrane central databases were searched from inception till May 2017. 6 studies were included in the study. Hazard ratio, random effects model was used to estimate the correlation of increase in Galectin 3 levels with development of new onset heart failure. Between studies heterogeneity was assessed by I 2 method. Results: Pooled patient population comprised of 24,297 patients (mean age 59.1 years, 50.6% male). 1444 (5.9%) patients develop new onset heart failure. Mean baseline Galectin 3 levels were 16.7 ug/L. Patients were followed up for mean duration of 5 years. Increase in Galectin 3 levels from baseline was associated with significant increase in risk of new onset heart failure (1.86 [1.36-2.54], p = 0.0002). We noted considerable heterogeneity 80% between studies. Conclusion: This meta analysis showed that galectin 3 levels were directly associated with risk of new onset heart failure. Therefore, galectin 3 can help in early detection of new onset heart failure and hence can help in providing preventive strategies.
NuTide:302: A phase Ib study to assess the safety, pharmacokinetics and clinical activity of the ProTide NUC-3373 when combined with standard agents used in colorectal cancer.
Authors: T.R. Jeffry Evans, Sarah Patricia Blagden, Janet Shirley Graham, Kristen Keon Ciombor, Aimery De Gramont, Josep Tabernero, Jordan Berlin
Journal: Journal of Clinical Oncology (2019)

TPS719 Background: Although 5-fluorouracil-based chemotherapies (5-FU, capecitabine, and floxuridine) remain the cornerstone of combination therapies for colorectal cancer (CRC), their clinical utility is limited by key cancer resistance mechanisms associated with breakdown, transport, and activation. These agents require intracellular conversion to the active metabolite fluorodeoxyuridine-monophosphate (FUDR-MP) before they can exert their core anti-cancer activity through inhibition of the enzyme thymidylate synthase (TS). NUC-3373 is a phosphoramidate transformation of FUDR-MP designed to bypass the key resistance mechanisms associated with 5-FU. Results from the first-in-human study of NUC-3373 (NuTide:301) in patients with advanced solid tumours demonstrated a favourable PK/PD profile for NUC-3373, with a longer plasma t 1/2 (9.7 hours) than 5-FU (8-14 minutes) and much higher levels of the active anti-cancer metabolite, FUDR-MP (Ghazaly et alESMO, 2017). TS is efficiently inhibited and sequestered into TS-ternary complexes (TS-T), depleting the pool of dTMP within 2-4 hours. Methods: NuTide:302 is a two-part, Phase Ib study in patients with CRC who have relapsed after ≥ 2 prior lines of 5-FU-containing therapies. The primary objective is to identify a recommended NUC-3373 dose when administered every 2 weeks in combination with standard agents used in CRC treatment. Secondary objectives include safety, PK/PD, and anti‐tumour activity. In Part 1, approximately 12 patients will be administered NUC-3373 with leucovorin (LV) to determine if LV is beneficial in augmenting the formation of TS-T. If so, it will be administered in Part 2. In Part 2, the following combination agents will be administered with NUC-3373 (±LV): oxaliplatin; oxaliplatin + bevacizumab; oxaliplatin + panitumumab; irinotecan; and irinotecan + cetuximab. Up to 62 patients will be enrolled in cohorts of 3-6, in a modified 3+3 design. Enrollment to Part 1 initiated in September 2018. Clinical trial information: NCT03428958.
Eltrombopag Rescue for Childhood Severe Acquired Aplastic Anemia after Poor Response to Immunosuppressive Treatment: A Nationwide Study on Behalf of the French Reference Center for Aplastic Anemia
Authors: Nimrod Buchbinder, Regis Peffault De Latour, Flore Sicre De Fontbrune, Cecile Pochon, Catherine Paillard, Elodie Gouache, Jean-Hugues Dalle, Thierry Leblanc
Journal: Blood (2018)
Error in Byline
Authors: Orrin Devinsky, Philippe Ryvlin, Daniel Friedman
Journal: JAMA Neurology (2018)

In Reply We read with interest the letter by Scorza and colleagues regarding the potential use of ω-3 fatty acid supplementation to treat epilepsy.We need to systematically assess interventions to prevent sudden unexpected death in epilepsy (SUDEP), as has been done successfully in preventing sudden infant death syndrome, through the "back to sleep" and subsequent "safe to sleep" educational programs.The authors cite 3 small human trials of ω-3 fatty acids to treat epilepsy.Two of these studies were negative and 1 found a small beneficial association with seizure frequency at a low dose but no association at a higher dose of ω-3 fatty acid supplementation.A finding that is concerning for the authors' thesis is that the only SUDEP occurred in the highdose ω-3 fatty acid treatment group.A recent Cochrane review analyzed these 3 studies as well as 5 additional studies of polyunsaturated fatty acid (PUFA) supplementation in epilepsy and concluded that "supplementation with PUFA did not produce significant differences in mean frequency of seizures, quality of life, or other side effects." 1 Based on the current evidence, we do not recommend ω-3 fatty acids as either a treatment for epilepsy or a supplement to prevent SUDEP.We support well-powered randomized clinical trials to formally assess the potential efficacy of any supplement or other therapy in epilepsy care.As a cautionary note, the law of unintended consequences must always be considered.Vitamin E supplementation was once recommended to prevent heart disease and cancer, based largely on correlations that suggested a potential benefit. 2 However, larger randomized clinical trials demonstrated no benefits for cardiac health, 3 and some in fact found an increase in gastrointestinal cancers and overall mortality. 4A Cochrane review concluded that "there is no evidence to support antioxidant supplements for primary or secondary prevention.Beta-carotene and vitamin E seem to increase mortality." 4Similarly, recommendations to reduce fat or saturated fat consumption to prevent cardiac disease likely contributed to a shift to increased carbohydrate consumption, which may have contributed to a large increase in the prevalence of obesity, type 2 diabetes, hypertension, and other disorders.Finally, the use of PUFAs has been linked to higher rates of cancer deaths. 5Therefore, while "common sense" approaches may appear to have a good reward/risk ratio, without solid scientific data, unsubstantiated recommendations may have adverse and unintended consequences.First, do no harm.In conclusion, we remain eager for additional therapies that can reduce SUDEP directly or through the mediating associations of reduced seizure frequency and severity.However, it remains unclear if ω-3 fatty acid supplementation is beneficial, neutral, or harmful for seizure control and SUDEP.
ABT-165 plus FOLFIRI versus bevacizumab plus FOLFIRI in patients with metastatic colorectal cancer (mCRC) previously treated with fluoropyrimidine/oxaliplatin and bevacizumab.
Authors: Zev A. Wainberg, Lan Wang, Huibin Yue, Monica Motwani, Sreeneeranj Kasichayanula, Martha Elizabeth Blaney, Louie Naumovski, John H. Strickler
Journal: Journal of Clinical Oncology (2019)

TPS720 Background: Dual variable domain immunoglobulin ABT-165 targets human vascular endothelial growth factor (VEGF) and delta-like ligand 4 (DLL4). Combined VEGF and DLL4 blockade increased inhibition of subcutaneous xenograft growth of human colon cancer-derived cell lines versus blockade of either axis alone. In vivo, ABT-165 plus chemotherapy (CT) induced tumor regression with improved efficacy, vs anti-VEGF monoclonal antibody plus CT. In a phase 1 study, tolerable recommended phase 2 dose was identified for ABT-165 plus FOLFIRI and showed promising efficacy. This phase 2 trial in progress assesses efficacy/safety of ABT-165 plus FOLFIRI vs bevacizumab (bev) plus FOLFIRI in patients with second-line mCRC. Methods: This is an open-label, multicenter, phase 2 randomized (1:1) trial (NCT03368859) in patients (≥ 18 years; Eastern Cooperative performance status: 0–1) with histologically/cytologically confirmed mCRC who progressed after fluoropyrimidine/oxaliplatin and bev. ABT-165 (2.5 mg/kg) plus FOLFIRI (irinotecan: 180 mg/m 2 ; leucovorin: 400 mg/m 2 ; fluorouracil bolus: 400 mg/m 2 , infusion: 2400 mg/m 2 ) or bev (5 mg/kg) plus FOLFIRI are given intravenously on day 1 of each 14-day cycle, until disease progression/intolerable toxicity. Primary endpoint is progression-free survival (PFS). Secondary endpoints include overall survival (OS), objective response rate (ORR), and safety. Exploratory endpoints include biomarkers predictive for efficacy/safety, correlation of DLL4 levels with PFS, OS, and ORR, pharmacodynamic effects, and efficacy/safety-exposure relationships in ABT-165 arm. Hazard ratios of PFS and OS comparing the 2 groups are estimated using Cox proportional hazard model. Kaplan-Meier methodology is used to estimate PFS and OS curves, median PFS and OS, and their 90% confidence intervals. Safety is assessed by ABT-165 exposure, adverse events (AEs), serious AEs, all deaths, and changes in laboratory data and vital signs. Archival tissue is collected and evaluated for DLL4 expression and angiogenesis signature. Approximately 100 patients are planned to be enrolled, with recruitment initiated January 2018. Clinical trial information: NCT03368859.
Absorption and Excretion of Mercury in Man
Journal: JAMA (1963)

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