tbuckley/cabot-search huggingface dataset:
Abstract 10213: Digoxin Use and Risk of Mortality in Hypertensive Patients With Atrial Fibrillation: The LIFE Study
Authors: Peter M Okin, Darcy A Hille, Kristian Wachtell, Sverre E Kjeldsen, Bjorn Dahlof, Richard B Devereux
Journal: Circulation (2013)

Background:  Digoxin (dig) is widely used for rate control of atrial fibrillation (AF). However, recent studies have reported conflicting results on the association of dig use in AF with mortality. Moreover, the relationship of dig use to mortality in hypertensive patients with AF has not been examined.   Methods:  Risk of all-cause mortality was examined in relation to in-treatment use of dig in 937 hypertensive patients in AF at baseline (n=134) or who developed AF during follow-up (n=803) with data on dig use at baseline and during treatment, randomly assigned to losartan- or atenolol-based treatment.   Results:  During 4.7±1.1 years follow-up, 167 patients died (17.8%) and 372 (39.7%) were on dig at some time. In univariate Cox analyses, in-treatment dig use, entered as a time-varying covariate, was associated with a 61% higher risk of death (95% CI 18-119%). After adjusting for other univariate predictors of death in this population, including age, diabetes, history of ischemic heart disease, stroke or heart failure, baseline Cornell product, QRS duration, heart rate, serum glucose, creatinine and HDL, and a propensity score for dig use entered as standard covariates, and for in-treatment heart rate, systolic pressure and Sokolow-Lyon voltage treated as time-varying covariates, dig use was no longer a significant predictor of mortality (HR 1.06, 95% CI 0.75-1.51, p=0.745). In parallel analyses excluding the 175 patients on dig at baseline, in-treatment dig use was no longer a univariate (HR 1.10, 95% CI 0.71-1.68) or multivariate (HR 0.85, 95% CI 0.54-1.34) predictor of death. Similarly, if the 45 patients with a history of heart failure were excluded, in-treatment dig use was of borderline significance in univariate analyses (HR 1.38, 95% CI 0.99-1.93) but was not a significant predictor of death in multivariate Cox analyses (HR 0.97, 95% CI 0.67-1.41).   Conclusions:  In hypertensive patients with existing or new AF, dig use is not associated with a significantly increased risk of all-cause mortality after adjusting for other independent predictors of death and for the factors associated with the propensity to use dig in this population. These findings suggest that factors other than dig use may account for the increased mortality found with dig use in some studies.
Linezolid in drug-resistant tuberculosis: haste makes waste
Authors: Jennifer Hughes, Petros Isaakidis, Aristomo Andries, Homa Mansoor, Vivian Cox, Graeme Meintjes, Helen Cox
Journal: European Respiratory Journal (2015)

We thank Bhuniya and colleagues for highlighting these common concerns regarding the use of linezolid in drug-resistant tuberculosis (DR-TB). We confirm that patients in our cohort were initially started on treatment with standardised regimens following diagnosis of rifampicin and isoniazid resistance (multidrug-resistant tuberculosis (MDR-TB)). We did have access to drug susceptibility testing (DST) for first- and second-line drugs (rifampicin, isoniazid, ethionamide, fluoroquinolones and injectable agents) and regimens were only individualised following detection of second-line drug (SLD) resistance or failure of standardised regimens. Collaboration is needed to encourage and optimise use of effective drugs and their impact on overall DR-TB treatment <http://ow.ly/TRkcu>
New data on the safety of IV iron—but why the discrepancy with FIND-CKD?
Authors: Iain C. Macdougall, Simon D. Roger
Journal: Kidney International (2015)

To the Editor: Agarwal et al.’s study1Agarwal R. Kusek J.W. Pappas M.K. A randomized trial of intravenous and oral iron in chronic kidney disease.Kidney Int. 2015https://doi.org/10.1038/ki.2015.163Abstract Full Text Full Text PDF Scopus (137) Google Scholar raises controversy about the safety of intravenous iron. It would appear to show highly statistically significant results, but some of the findings only become significant after adjustment for baseline variables, e.g., the incidence rate ratio for infection-related serious adverse events changed massively from P=0.17 to <0.006 after adjustment. It is not clear what is driving this, and it is questionable whether this adjustment is appropriate for a randomized controlled trial. It is also concerning why the findings of Agarwal et al. are so discrepant with those reported in the FIND-CKD study, a multicenter study conducted in 626 patients worldwide and with considerably greater patient-years of follow-up.2.Macdougall I.C. Bock A.H. Carrera F. et al.FIND-CKD Study Investigators. FIND-CKD: a randomized trial of intravenous ferric carboxymaltose versus oral iron in patients with chronic kidney disease and iron deficiency anaemia.Nephrol Dial Transplant. 2014; 29: 2075-2084Crossref PubMed Scopus (183) Google Scholar Agarwal’s study was single-center, single-investigator adjudicating all serious adverse events, and with only 99 subjects completing the trial. Despite patients being treated with much higher doses of intravenous iron in FIND-CKD, no safety signals were evident, and indeed the incidence of infections and cardiac events across all three groups was identical. Unfortunately, Agarwal et al. hardly discuss this discrepancy, but surprisingly make two dogmatic but entirely incorrect statements about the FIND-CKD study: investigators stopped reporting serious adverse events when there was a change in anemia management, and the investigators did not report repeated events in the same patient; both these statements are entirely incorrect. In conclusion, one should not completely discount Agarwal’s data, but until it is clear why the same safety signals were not seen in FIND-CKD, or there is further confirmatory evidence, caution should be exercised in overinterpreting the data from this study.
A Phase I Study of the Safety, Pharmacokinetics, and Pharmacodynamics of Combination Therapy with Refametinib plus Sorafenib in Patients with Advanced Cancer
Authors: Alex A. Adjei, Donald A. Richards, Anthony El-Khoueiry, Fadi Braiteh, Carlos H.R. Becerra, Joe J. Stephenson, Aram F. Hezel, Morris Sherman, Lawrence Garbo, Diane P. Leffingwell, Cory Iverson, Jeffrey N. Miner, Zancong Shen, Li-Tain Yeh, Sonny Gunawan, David M. Wilson, Kimberly J. Manhard, Prabhu Rajagopalan, Heiko Krissel, Neil J. Clendeninn
Journal: Clinical Cancer Research (2015)

To assess the safety and tolerability of the small-molecule allosteric MEK inhibitor refametinib combined with sorafenib, in patients with advanced solid malignancies.This phase I dose-escalation study included an expansion phase at the maximum tolerated dose (MTD). Patients received refametinib/sorafenib twice daily for 28 days, from a dose of refametinib 5 mg plus sorafenib 200 mg to a dose of refametinib 50 mg plus sorafenib 400 mg. Plasma levels of refametinib, refametinib metabolite M17, and sorafenib were measured for pharmacokinetic assessments. Tumors were biopsied at the MTD for analysis of MEK pathway mutations and ERK phosphorylation.Thirty-two patients were enrolled in the dose-escalation cohort. The MTD was refametinib 50 mg twice daily plus sorafenib 400 mg twice daily. The most common treatment-related toxicities were diarrhea and fatigue. Refametinib was readily absorbed following oral administration (plasma half-life of ∼16 hours at the MTD), and pharmacokinetic parameters displayed near-dose proportionality, with less than 2-fold accumulation after multiple dosing. Another 30 patients were enrolled in the MTD cohort; 19 had hepatocellular carcinoma. The combination was associated with significantly reduced ERK phosphorylation in 5 out of 6 patients biopsied, with the greatest reductions in those with KRAS or BRAF mutations. Disease was stabilized in approximately half of patients, and 1 patient with colorectal cancer achieved a partial response at the MTD lasting approximately 1 year.In this phase I study, refametinib plus sorafenib was well tolerated, with good oral absorption, near-dose proportionality, and target inhibition in a range of tumor types. Clin Cancer Res; 22(10); 2368-76. ©2015 AACR.
Lactation and Progression to Type 2 Diabetes Mellitus After Gestational Diabetes Mellitus
Authors: Erica P. Gunderson, Shanta R. Hurston, Xian Ning, Joan C. Lo, Yvonne Crites, David Walton, Kathryn G. Dewey, Robert A. Azevedo, Stephen Young, Gary Fox, Cathie C. Elmasian, Nora Salvador, Michael Lum, Barbara Sternfeld, Charles P. Quesenberry
Journal: Annals of Internal Medicine (2015)

Background: Lactation improves glucose metabolism, but its role in preventing type 2 diabetes mellitus (DM) after gestational diabetes mellitus (GDM) remains uncertain. Objective: To evaluate lactation and the 2-year incidence of DM after GDM pregnancy. Design: Prospective, observational cohort of women with recent GDM. (ClinicalTrials.gov: NCT01967030) Setting: Integrated health care system. Participants: 1035 women diagnosed with GDM who delivered singletons at 35 weeks' gestation or later and enrolled in the Study of Women, Infant Feeding and Type 2 Diabetes After GDM Pregnancy from 2008 to 2011. Measurements: Three in-person research examinations from 6 to 9 weeks after delivery (baseline) and annual follow-up for 2 years that included 2-hour, 75-g oral glucose tolerance testing; anthropometry; and interviews. Multivariable Weibull regression models evaluated independent associations of lactation measures with incident DM adjusted for potential confounders. Results: Of 1010 women without diabetes at baseline, 959 (95%) were evaluated up to 2 years later; 113 (11.8%) developed incident DM. There were graded inverse associations for lactation intensity at baseline with incident DM and adjusted hazard ratios of 0.64, 0.54, and 0.46 for mostly formula or mixed/inconsistent, mostly lactation, and exclusive lactation versus exclusive formula feeding, respectively ( P trend = 0.016). Time-dependent lactation duration showed graded inverse associations with incident DM and adjusted hazard ratios of 0.55, 0.50, and 0.43 for greater than 2 to 5 months, greater than 5 to 10 months, and greater than 10 months, respectively, versus 0 to 2 months (P trend = 0.007). Weight change slightly attenuated hazard ratios. Limitation: Randomized design is not feasible or desirable for clinical studies of lactation. Conclusion: Higher lactation intensity and longer duration were independently associated with lower 2-year incidences of DM after GDM pregnancy. Lactation may prevent DM after GDM delivery. Primary Funding Source: National Institute of Child Health and Human Development.
Leadership in Mammalian Societies: Emergence, Distribution, Power, and Payoff
Authors: Jennifer E. Smith, Sergey Gavrilets, Monique Borgerhoff Mulder, Paul L. Hooper, Claire El Mouden, Daniel Nettle, Christoph Hauert, Kim Hill, Susan Perry, Anne E. Pusey, Mark van Vugt, Eric Alden Smith
Journal: Trends in Ecology & Evolution (2015)
Abstract 3538: Quorum-sensing Salmonella selectively trigger protein expression within tumors
Authors: Charles A. Swofford, Nele Van Dessel, Neil S. Forbes
Journal: Cancer Research (2015)

Abstract Salmonella that secrete anti-cancer proteins have the potential to eliminate tumors, but nonspecific expression causes damage to healthy tissue. Salmonella, integrated with a density-dependent switch, would only express proteins in tightly packed colonies within tumors, reducing side-effects after the initial bacterial administration. To test this, we cloned the lux quorum-sensing (QS) system and a GFP reporter into the attenuated Salmonella strain VNP20009. Fluorescence and bacterial density were measured in culture and a tumor-on-a-chip device to determine the critical density necessary to initiate expression. QS Salmonella were injected into 4T1 tumor-bearing mice to quantify GFP expression in vivo. At densities below 0.6×1010 CFU/g in tumors, less than 3% of QS Salmonella expressed GFP. Above densities of 4.2×1010 CFU/g, QS Salmonella had similar expression levels to constitutive controls. GFP expression by QS colonies was dependent upon the distance to neighboring bacteria. No colonies expressed GFP when the average distance to neighbors was greater than 155 μm. Calculations of autoinducer concentrations showed that expression was sigmoidally dependent on density and inversely dependent on average radial distance. Based on bacterial counts from excised tissue, the liver density (0.0079×1010 CFU/g) was less than the critical density (0.11×1010 CFU/g) necessary to initiate expression, indicating that expression of a therapeutic protein would not be induced in healthy organs. Inserting the bacterial toxin S. Aureus α-hemolysin (SAH) under the control of the QS system resulted in the expression of SAH only at high bacterial dosage. In vitro, supernatant from cultures of QS-SAH Salmonella reduced cancer cell viability by 70%. When administered to the microfluidic tumor-on-a-chip, QS-SAH Salmonella killed 43% of the tissue, 12 times greater (P&amp;lt;0.05) than induced by control bacteria. QS Salmonella are a promising tool for cancer treatment that will target drugs to tumors, while preventing damage to healthy tissue. Citation Format: Charles A. Swofford, Nele Van Dessel, Neil S. Forbes. Quorum-sensing Salmonella selectively trigger protein expression within tumors. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3538. doi:10.1158/1538-7445.AM2015-3538
The decrease of plaque volume during percutaneous coronary intervention has a negative impact on coronary flow in acute myocardial infarction
Authors: Hiroshi Sato, Hidetaka Iida, Atsushi Tanaka, Hidemasa Tanaka, Shinichi Shimodouzono, Eiji Uchida, Takahiko Kawarabayashi, Junichi Yoshikawa
Journal: Journal of the American College of Cardiology (2004)
A Tumor Suppressor Function for Notch Signaling in Forebrain Tumor Subtypes
Authors: Claudio Giachino, Jean-Louis Boulay, Robert Ivanek, Alvaro Alvarado, Cristobal Tostado, Sebastian Lugert, Jan Tchorz, Mustafa Coban, Luigi Mariani, Bernhard Bettler, Justin Lathia, Stephan Frank, Stefan Pfister, Marcel Kool, Verdon Taylor
Journal: Cancer Cell (2015)
Seed filling in domesticated maize and rice depends on SWEET-mediated hexose transport
Authors: Davide Sosso, Dangping Luo, Qin-Bao Li, Joelle Sasse, Jinliang Yang, Ghislaine Gendrot, Masaharu Suzuki, Karen E Koch, Donald R McCarty, Prem S Chourey, Peter M Rogowsky, Jeffrey Ross-Ibarra, Bing Yang, Wolf B Frommer
Journal: Nature Genetics (2015)
(Ir)relevance of Metformin Treatment in Patients with Metastatic Pancreatic Cancer: An Open-Label, Randomized Phase II Trial
Authors: Michele Reni, Erica Dugnani, Stefano Cereda, Carmen Belli, Gianpaolo Balzano, Roberto Nicoletti, Daniela Liberati, Valentina Pasquale, Marina Scavini, Paola Maggiora, Valeria Sordi, Vito Lampasona, Domenica Ceraulo, Gaetano Di Terlizzi, Claudio Doglioni, Massimo Falconi, Lorenzo Piemonti
Journal: Clinical Cancer Research (2015)

Abstract Purpose: We aimed to assess the safety and efficacy of metformin for treating patients with metastatic pancreatic cancer and to identify endocrine and metabolic phenotypic features or tumor molecular markers associated with sensitivity to metformin antineoplastic action. Experimental Design: We designed an open-label, randomized, phase II trial to assess the efficacy of adding metformin to a standard systemic therapy with cisplatin, epirubicin, capecitabine, and gemcitabine (PEXG) in patients with metastatic pancreatic cancer. Patients ages 18 years or older with metastatic pancreatic cancer were randomly assigned (1:1) to receive PEXG every 4 weeks in combination or not with 2 g oral metformin daily. The primary endpoint was 6-months progression-free survival (PFS-6) in the intention-to-treat population. Results: Between August 2010 and January 2014, we randomly assigned 60 patients to receive PEXG with (n = 31) or without metformin (n = 29). At the preplanned interim analysis, the study was ended for futility. PFS-6 was 52% [95% confidence interval (CI), 33–69] in the control group and 42% (95% CI, 24–59) in the metformin group (P = 0.61). Furthermore, there was no difference in disease-free survival and overall survival between groups. Despite endocrine metabolic modifications induced by metformin, there was no correlation with the outcome. Single-nucleotide polymorphism rs11212617 predicted glycemic response, but not tumor response to metformin. Gene expression on tumor tissue did not predict tumor response to metformin. Conclusions: Addition of metformin at the dose commonly used in diabetes did not improve outcome in patients with metastatic pancreatic cancer treated with standard systemic therapy. Clin Cancer Res; 22(5); 1076–85. ©2015 AACR. See related commentary by Yang and Rustgi, p. 1031
Myocardial Microvascular Inflammatory Endothelial Activation in Heart Failure With Preserved Ejection Fraction
Authors: Constantijn Franssen, Sophia Chen, Andreas Unger, H. Ibrahim Korkmaz, Gilles W. De Keulenaer, Carsten Tschöpe, Adelino F. Leite-Moreira, René Musters, Hans W.M. Niessen, Wolfgang A. Linke, Walter J. Paulus, Nazha Hamdani
Journal: JACC Heart Failure (2015)
Safe and Successful Implementation of CPOE for Chemotherapy at a Children's Cancer Center
Authors: James M. Hoffman, Donald K. Baker, Scott C. Howard, Joseph H. Laver, Jerry L. Shenep
Journal: Journal of the National Comprehensive Cancer Network (2011)

Computerized prescriber order entry (CPOE) for medications has been implemented in only approximately 1 in 6 United States hospitals, with CPOE for chemotherapy lagging behind that for nonchemotherapy medications. The high risks associated with chemotherapy combined with other aspects of cancer care present unique challenges for the safe and appropriate use of CPOE. This article describes the process for safe and successful implementation of CPOE for chemotherapy at a children's cancer center. A core principle throughout the development and implementation of this system was that it must be as safe (and eventually safer) as existing paper systems and processes. The history of requiring standardized, regimen-specific, preprinted paper order forms served as the foundation for safe implementation of CPOE for chemotherapy. Extensive use of electronic order sets with advanced functionality; formal process redesign and system analysis; automated clinical decision support; and a phased implementation approach were essential strategies for safe implementation of CPOE. With careful planning and adequate resources, CPOE for chemotherapy can be safely implemented.
Immune profiling in human breast cancer is predictive of 5- and 10-year survival.
Authors: Brendon Coventry, Michael J Weightman, John Bradley, John M Skinner
Journal: Journal for ImmunoTherapy of Cancer (2015)

Meeting abstracts Immunotherapy for breast cancer is now being seriously considered, despite past beliefs that this cancer type was non-immunogenic. Immune profiling has been variably associated with outcome, but standard techniques have greatly limited interpretation. These studies examine immune
To RCT or Not to RCT: How to Change Practice for Rare Cancers?
Authors: Anthony M. Brade, Laura Ann Dawson
Journal: Journal of Clinical Oncology (2015)

In the world of evidence-based medicine, a dogmatic hierarchy of clinical trial design 1 has conditioned us to only change practice based on randomized data and to discount observational studies. Thus, defining treatment paradigms for rare cancers (or rare subsets of cancers) remains a challenge. If a randomized controlled trial (RCT) cannot be completed, how does one establish practice-changing results? In the article that accompanies this editorial, Tao et al 2 report a retrospective analysis of 79 patients and the impact of radiation dose on outcomes for inoperable, locally advanced intrahepatic cholangiocarcinoma (IHC).Tantalizingly,patientstreatedto higher than the median radiation dose (biologic equivalent dose 80.5 Gy, equivalent to approximately 58 Gy in 15 fractions) achieved remarkable levels of long-term local control, overall survival, and progression-free survival (78%, 58%, and 39%, respectively, at 3 years) with a surprisingly low incidenceoftoxicities.Ofnote,biologicequivalentdosewastheonly variable statistically associated with outcomes on multivariable analysis. The outcomes of these patients are within reported outcomes of patients with ICH in surgical series. In contrast, the expected outcome fromstandard of caretreatmentfor these patients can be estimated from the results of the randomized ABC-02 trial, 2 which treated a mix of inoperable patients (approximately 25% locally advanced and 75% metastatic) with systemic therapy alone, 3 achieving a 3-year survival rate that was close to zero.
SOME OBSERVATIONS ON THE RELATIONSHIP BETWEEN SYPHILIS OF THE NERVOUS SYSTEM AND THE PSYCHOSES
Authors: LAWSON G. LOWREY
Journal: American Journal of Psychiatry (1917)

1. Of about 2500 cases examined in the last three years, II are sufficiently unusual to be reported on. 2. Of these, four had clinical pictures of dementia præcox; one of constitutional inferiority, and one imbecility; two organic and three paresis. 3. In two cases of dementia præcox, the serology of neurosyphilis was found early. In the other two, only after many years. In all four it was not expected. One case has tabetic symptoms, the others no symptoms of neurosyphilis. The case with tabetic symptoms also exhibits catatomic symptoms. 4. These are the only cases of dementia præecox in the hospital showing such serology, though other cases have positive blood tests. 5. One "hysterical" or "constitutionally inferior" person developed secondary syphilis five years before death. A year before death, the serology of neurosyphilis was demonstrated. Autopsy confirmed this. No clinical symptoms. 6. An "imbecile" developed genuine paresis in the hospital. Autopsy and serologytypical. 7. An "organic" case without signs of paresis gives the serology of it. 8. A case, clinically Huntington's Chorea, gives the serology of paresis, without clinical signs of it. 9. One case, clinically paresis at first, seems now like dementia præcox. Serology positive. 10. One case, clinically paresis, has run an extremely long, stationary course. Wassermann negative in blood and fluid; other tests positive. II. One case, clinically and serologically paresis, has as his most prominent symptom, and the only one at the present time, auditory hallucinations. 12. We have to do with (a) neurosyphilis in unusual causal relationships, or (b) coincident psychoses and symptomless neurosyphilis. 13. Diagnoses should be based on both clinical and laboratory findings. The neglect of either may lead to improper results.
Preliminary results from a Phase I/II study of epacadostat (incb024360) in combination with pembrolizumab in patients with selected advanced cancers
Authors: Tara C Gangadhar, Omid Hamid, David C Smith, Todd M Bauer, Jeffrey S Wasser, Jason J Luke, Ani S Balmanoukian, David R Kaufman, Yufan Zhao, Janet Maleski, Lance Leopold, Thomas F Gajewski
Journal: Journal for ImmunoTherapy of Cancer (2015)

Meeting abstracts Indoleamine 2,3-dioxygenase 1 (IDO1) is a tryptophan-catabolizing enzyme that is expressed in many cancers and induces immune tolerance by suppressing T cell responses. Epacadostat is a potent, selective oral inhibitor of IDO1. A dose-escalation study of epacadostat with