tbuckley/cabot-search huggingface dataset:
Junior doctor contract talks are extended “to improve chance of success”
Authors: Gareth Iacobucci
Journal: BMJ (2016)

Talks between the BMA and the government over a new contract for junior doctors in England are to continue until Wednesday 18 May, after both sides agreed to an extension requested by the arbitration body Acas (the Advisory, Conciliation and Arbitration Service).

The talks between BMA leaders and the health secretary, Jeremy Hunt, which are taking place in a hotel in Lincolnshire, have been continuing since Monday 9 May after the government agreed to pause the introduction of the new contract for five days.1

Acas said that “real progress” had …
Chemical Carcinogen-Induced Transplantable Fibrosarcomas in Histocompatible Chickens. I. Incidence of Tumor Induction in Normal and Bursectomized Chickens 2
Authors: S. P. Lerman, M. A. Palladino, G. J. Thorbecke
Journal: JNCI Journal of the National Cancer Institute (1976)

Journal Article Chemical Carcinogen-Induced Transplantable Fibrosarcomas in Histocompatible Chickens. I. Incidence of Tumor Induction in Normal and Bursectomized Chickens Get access S. P. Lerman, S. P. Lerman Search for other works by this author on: Oxford Academic PubMed Google Scholar M. A. Palladino, M. A. Palladino Search for other works by this author on: Oxford Academic PubMed Google Scholar G. J. Thorbecke G. J. Thorbecke Search for other works by this author on: Oxford Academic PubMed Google Scholar JNCI: Journal of the National Cancer Institute, Volume 57, Issue 2, August 1976, Pages 295–301, https://doi.org/10.1093/jnci/57.2.295 Published: 01 August 1976 Article history Received: 15 August 1975 Revision received: 12 February 1976 Accepted: 20 February 1976 Published: 01 August 1976
Nurses versus physician-led interhospital critical care transport: a randomized non-inferiority trial
Authors: Erik Jan van Lieshout, Jan Binnekade, Elmer Reussien, Dave Dongelmans, Nicole P. Juffermans, Rob J. de Haan, Marcus J. Schultz, Margreeth B. Vroom
Journal: Intensive Care Medicine (2016)

Regionalization and concentration of critical care increases the need for interhospital transport. However, optimal staffing of ground critical care transport has not been evaluated. In this prospective, randomized, open-label, blinded-endpoint non-inferiority trial, critically ill patients on mechanical ventilation transported by interhospital ground critical care transport were randomized between transport staffed by a dedicated team comprising a critical care nurse and paramedic (nurses group) or a dedicated team including a critical care physician (nurses + physician group). The primary outcome was the number of patients with critical events, both clinical and technical, during transport. Clinical events included decrease in blood pressure, oxygen saturation, or temperature, blood loss, new cardiac arrhythmias, or death. Non-inferiority was assumed if the upper limit of the two-sided 90 % confidence interval (CI) for the between-group difference lies below the non-inferiority margin of 3 %. Of 618 eligible transported critically ill patients, 298 could be analyzed after randomization and allocation to the nurses group (n = 147) or nurses + physician group (n = 151). The percentages of patients with critical events were 16.3 % (24 incidents in 147 transports) in the nurses group and 15.2 % (23 incidents in 151 transports) in the nurses + physician group (difference 1.1 %, two-sided 90 % CI [−5.9 to 8.1]). Critical events occurred in both groups at a higher than the expected (0–1 %) rate. In the nurses group consultations for physician assistance were requested in 8.2 % (12 in 147 transports), all of which were performed prior to transport. The number of patients with critical events did not markedly differ between critical care transports staffed by a critical care nurse and paramedic compared to a team including a critical care physician. However, as a result of an unexpected higher rate of critical events in both groups recorded by an electronic health record, non-inferiority of nurse-led interhospital critical transport could not be established ( http://www.controlled-trials.com/ISRCTN39701540 ).
Bioengineered human acellular vessels for dialysis access in patients with end-stage renal disease: two phase 2 single-arm trials
Authors: Jeffrey H Lawson, Marc H Glickman, Marek Ilzecki, Tomasz Jakimowicz, Andrzej Jaroszynski, Eric K Peden, Alison J Pilgrim, Heather L Prichard, Malgorzata Guziewicz, Stanisław Przywara, Jacek Szmidt, Jakub Turek, Wojciech Witkiewicz, Norbert Zapotoczny, Tomasz Zubilewicz, Laura E Niklason
Journal: The Lancet (2016)
High incidence of <i>FLT3 </i>mutations in adults with Acute Promyelocytic Leukemia (APL): Correlation with diagnostic features and treatment outcome (CALGB 9710)
Authors: W. Stock, K. Najib, B. K. Moser, B. L. Powell, N. Holowka, K. Gulati, C. D. Bloomfield, R. A. Larson, D. Sher
Journal: Journal of Clinical Oncology (2008)

7002 Background: Studies have associated activating mutations of FLT3 (FLT3+) with adverse outcomes in patients (pts) with APL, but little is known about the impact of adding Arsenic Trioxide (As2O3) to frontline APL treatment on the clinical outcome of pts harboring these mutations. Methods: We examined the incidence of FLT3+ in a subset of 78 adults with newly diagnosed APL entered onto CALGB 9710, a North American Intergroup phase III randomized trial that demonstrated a significant survival benefit from adding two 25-day courses of As2O3 to post-remission consolidation therapy (Powell, et al. ASCO 2007). FLT3 internal tandem duplications (ITD) and activation loop point mutations (D835) were identified using standard methods (InVivoScribe, San Diego). FLT3+ was correlated with other diagnostic/prognostic features including PML-RARA isoform type, initial white blood cell (WBC) count, and pt age, and with treatment response. Results: FLT3+ was identified in 42 pts (54%); 28 (36%) had an ITD, 17 (22%) had a D835, and 3 (4%) had both. FLT3+ was not associated with increasing age; 55% of FLT3+ pts were male. There was a strong association of FLT3+ with high initial WBC count > 10K/μl (p= 0.0002), and with the S-isoform of PML-RARA (p < 0.0001). Overall, FLT3+ was not associated with early deaths during induction, lower CR rate, or inferior disease free survival (DFS) or survival (S). However, when analyzed by treatment arm, relapses occurred in only 2/21 (10%) FLT3+ pts who received As2O3 compared to a very high relapse rate of 13/21 (62%) among FLT3+ pts who did not receive As2O3 (p = 0.0004). Conclusions: FLT3+ occurs with high frequency (54%) in our APL cohort and is very strongly associated with high initial WBC count and S-isoform, both of which correlated with adverse outcomes for pts on CALGB 9710 (Stock et al, ASCO 07). In contrast to previous reports, we did not find an association of FLT3+ with high induction death rates, DFS, or S. Treatment with As2O3 appeared to decrease markedly the relapse rate in FLT3+ pts. These results will be examined in a larger cohort of 9710 pts. Given the high frequency of FLT3+ APL, targeted therapy with FLT3 inhibitors is an attractive strategy to further improve relapse-free survival for pts with FLT3+ APL. No significant financial relationships to disclose.
Targeted next-generation sequencing (NGS) of carcinoma of unknown primary site (CUP): Actionable genomic alterations (GA) and new routes to targeted therapies.
Authors: Jeffrey S. Ross, Kai Wang, Geoff Otto, Gary A. Palmer, Roman Yelensky, Doron Lipson, Juliann Chmielecki, Siraj M. Ali, Deborah Morosini, Vincent A. Miller, Phil Stephens
Journal: Journal of Clinical Oncology (2014)

11048 Background: CUP comprises 3% of adult malignancy in the US. Evaluation for a primary site is often unrevealing and may involve invasive studies. We performed NGS to identify potential therapeutic targets not currently tested for in routine care of CUP patients. Methods: Hybridization capture of 3,769 exons from 236 cancer-related genes and 47 introns of 19 genes commonly rearranged in cancer was applied to ≥ 50ng of DNA extracted from 200 CUP FFPE specimens and sequenced to high, uniform median coverage (756X) and assessed for all 4 classes of GAs. Elligible CUP were uniformly negative for site-specific IHC, FISH or mRNA biomarkers. Actionable alterations were defined as those for which cancer drugs on the market or in registered clinical trials could be identified. Results: 63% of CUP were adenocarcinomas (ACUP) and 37% were non-adenocarcinomas (non-ACUP). 54% were female and 46% male (median age 59). IHC workup was performed on 95% and mRNA profiling on 3%. 841 GA were identified in 121 genes for an average of 4.21 GA/CUP. 192/200 (96%) CUP had at least 1 GA. 169 (85%) CUP had at least 1 actionable GA (2.00 actionable GA/CUP). The most common actionable GA were KRAS (25% ACUP, 12% non-ACUP), CDKN2A (19% ACUP and non-ACUP), MCL1 (10% ACUP, 8% non-ACUP), PTEN (8% in both ACUP and non-ACUP), PIK3CA (8% in ACUP and 9% in non-ACUP), BRAF (6% in ACUP and 2% in non-ACUP) and NF1 (5% in ACUP and 3% in non-ACUP),. Mutations and amplifications of ERBB2 (10%), EGFR (8%) and BRAF (6%) were common in ACUP but not present in non-ACUP. 5 (3%) CUP had rearrangements involving ERBB3, FGFR1 and FGFR2. The greater frequency of actionable GA in the RTK/RAS signaling pathway observed in 90 (72%) ACUP cases compared to the 29 (39%) of non-ACUP cases was significant (p<0.0001). Conclusions: 85% CUP patients had at least one actionable GA with the potential to impact therapy selection with GA in the RTK/RAS/MAPK pathway more frequent in ACUP tumors. Given the poor prognosis of CUP, comprehensive genomic profiling may identify targeted therapeutic approaches to improve outcomes for this disease while potentially reducing the often costly and time consuming search for anatomic site of origin.
A phase 2 study of bortezomib, cyclophosphamide, pegylated liposomal doxorubicin and dexamethasone for newly diagnosed multiple myeloma
Authors: P S Becker, T A Gooley, D J Green, N Burwick, T Y Kim, K Kojouri, Y Inoue, D J Moore, E Nelli, T Dennie, W I Bensinger
Journal: Blood Cancer Journal (2016)

The goal of initial treatment for transplant eligible patients with multiple myeloma (MM) is to achieve the deepest possible response in an effort to attain prolonged event-free survival after transplant.There has been an excellent response to the threedrug regimens of agents approved for upfront use (Table 1), including bortezomib/IMiD (thalidomide or lenalidomide) dexamethasone (VTD or VRD) and bortezomib/cyclophosphamide/ dexamethasone (VCD).We had previously treated patients with three cycles each of two sequential three-drug regimens, VCD, then VTD, and reported an overall response rate of 92%, with a CR rate of 26%. 1 Another three-drug regimen, liposomal doxorubicin/ bortezomib/dexamethasone (DVD) also resulted in a good overall response rate of 71.5% ⩾ PR, and 20% CR in previously untreated patients. 2Our objective in developing the bortezomib, cyclophosphamide, pegylated liposomal doxorubicin and dexamethasone regimen was to improve the depth of response and overall response rate compared to three-drug regimens.In addition, the study was designed to improve ease of administration by use of weekly dosing rather than the typical twice weekly dosing (that is, days 1, 4, 8 and 11) of bortezomib (the standard dosing at study inception).The efficacy of this four-drug regimen was examined in newly diagnosed, transplant eligible patients, with a secondary objective of evaluating rates of successful stem cell mobilization and survival after transplant.
Pharmacological Strategies to Retard Cardiovascular Aging
Authors: Irene Alfaras, Clara Di Germanio, Michel Bernier, Anna Csiszar, Zoltan Ungvari, Edward G. Lakatta, Rafael de Cabo
Journal: Circulation Research (2016)

Aging is the major risk factor for cardiovascular diseases, which are the leading cause of death in the United States. Traditionally, the effort to prevent cardiovascular disease has been focused on addressing the conventional risk factors, including hypertension, hyperglycemia, hypercholesterolemia, and high circulating levels of triglycerides. However, recent preclinical studies have identified new approaches to combat cardiovascular disease. Calorie restriction has been reproducibly shown to prolong lifespan in various experimental model animals. This has led to the development of calorie restriction mimetics and other pharmacological interventions capable to delay age-related diseases. In this review, we will address the mechanistic effects of aging per se on the cardiovascular system and focus on the prolongevity benefits of various therapeutic strategies that support cardiovascular health.
Statistical controversies in clinical research: the importance of importance
Authors: A. Gleiss, R. Zeillinger, E.I. Braicu, F. Trillsch, I. Vergote, M. Schemper
Journal: Annals of Oncology (2016)

We define the notion of 'importance' of prognostic factors in studies of survival and suggest quantifying it by the Schemper–Henderson measure of explained variation. Conceptual differences to the standard approach for the statistical analysis of oncologic studies of survival are discussed and exemplified by means of a study of ovarian cancer. Explained variation permits to establish a ranking of the importance of factors, also if measured on different scales, or of different types (dichotomous, qualitative or continuous), and permits to compare groups of related factors. In practice, the importance of prognostic factors often is disappointingly low. From this, it follows that even strong and highly significant prognostic factors often do not translate into close determination of individual survival of patients.
The Impact of Individual Anthropogenic Emissions Sectors on the Global Burden of Human Mortality due to Ambient Air Pollution
Authors: Raquel A. Silva, Zachariah Adelman, Meridith M. Fry, J. Jason West
Journal: Environmental Health Perspectives (2016)

Exposure to ozone and fine particulate matter (PM2.5) can cause adverse health effects, including premature mortality due to cardiopulmonary diseases and lung cancer. Recent studies quantify global air pollution mortality but not the contribution of different emissions sectors, or they focus on a specific sector.We estimated the global mortality burden of anthropogenic ozone and PM2.5, and the impact of five emissions sectors, using a global chemical transport model at a finer horizontal resolution (0.67° × 0.5°) than previous studies.We performed simulations for 2005 using the Model for Ozone and Related Chemical Tracers, version 4 (MOZART-4), zeroing out all anthropogenic emissions and emissions from specific sectors (All Transportation, Land Transportation, Energy, Industry, and Residential and Commercial). We estimated premature mortality using a log-linear concentration-response function for ozone and an integrated exposure-response model for PM2.5.We estimated 2.23 (95% CI: 1.04, 3.33) million deaths/year related to anthropogenic PM2.5, with the highest mortality in East Asia (48%). The Residential and Commercial sector had the greatest impact globally-675 (95% CI: 428, 899) thousand deaths/year-and in most regions. Land Transportation dominated in North America (32% of total anthropogenic PM2.5 mortality), and it had nearly the same impact (24%) as Residential and Commercial (27%) in Europe. Anthropogenic ozone was associated with 493 (95% CI: 122, 989) thousand deaths/year, with the Land Transportation sector having the greatest impact globally (16%).The contributions of emissions sectors to ambient air pollution-related mortality differ among regions, suggesting region-specific air pollution control strategies. Global sector-specific actions targeting Land Transportation (ozone) and Residential and Commercial (PM2.5) sectors would particularly benefit human health. Citation: Silva RA, Adelman Z, Fry MM, West JJ. 2016. The impact of individual anthropogenic emissions sectors on the global burden of human mortality due to ambient air pollution. Environ Health Perspect 124:1776-1784; http://dx.doi.org/10.1289/EHP177.
Right Ventricular Functional Reserve in Pulmonary Arterial Hypertension
Authors: Steven Hsu, Brian A. Houston, Emmanouil Tampakakis, Anita C. Bacher, Parker S. Rhodes, Stephen C. Mathai, Rachel L. Damico, Todd M. Kolb, Laura K. Hummers, Ami A. Shah, Zsuzsanna McMahan, Celia P. Corona-Villalobos, Stefan L. Zimmerman, Fredrick M. Wigley, Paul M. Hassoun, David A. Kass, Ryan J. Tedford
Journal: Circulation (2016)

Right ventricular (RV) functional reserve affects functional capacity and prognosis in patients with pulmonary arterial hypertension (PAH). PAH associated with systemic sclerosis (SSc-PAH) has a substantially worse prognosis than idiopathic PAH (IPAH), even though many measures of resting RV function and pulmonary vascular load are similar. We therefore tested the hypothesis that RV functional reserve is depressed in SSc-PAH patients.RV pressure-volume relations were prospectively measured in IPAH (n=9) and SSc-PAH (n=15) patients at rest and during incremental atrial pacing or supine bicycle ergometry. Systolic and lusitropic function increased at faster heart rates in IPAH patients, but were markedly blunted in SSc-PAH. The recirculation fraction, which indexes intracellular calcium recycling, was also depressed in SSc-PAH (0.32±0.05 versus 0.50±0.05; P=0.039). At matched exercise (25 W), SSc-PAH patients did not augment contractility (end-systolic elastance) whereas IPAH did (P<0.001). RV afterload assessed by effective arterial elastance rose similarly in both groups; thus, ventricular-vascular coupling declined in SSc-PAH. Both end-systolic and end-diastolic RV volumes increased in SSc-PAH patients to offset contractile deficits, whereas chamber dilation was absent in IPAH (+37±10% versus +1±8%, P=0.004, and +19±4% versus -1±6%, P<0.001, respectively). Exercise-associated RV dilation also strongly correlated with resting ventricular-vascular coupling in a larger cohort.RV contractile reserve is depressed in SSc-PAH versus IPAH subjects, associated with reduced calcium recycling. During exercise, this results in ventricular-pulmonary vascular uncoupling and acute RV dilation. RV dilation during exercise can predict adverse ventricular-vascular coupling in PAH patients.
Long-Term Exposure to Particulate Matter and Self-Reported Hypertension: A Prospective Analysis in the Nurses’ Health Study
Authors: Zhenyu Zhang, Francine Laden, John P. Forman, Jaime E. Hart
Journal: Environmental Health Perspectives (2016)

Background:Studies have suggested associations between elevated blood pressure and short-term air pollution exposures, but the evidence is mixed regarding long-term exposures on incidence of hypertension.Objectives:We examined the association of hypertension incidence with long-term residential exposures to ambient particulate matter (PM) and residential distance to roadway.Methods:We estimated 24-month and cumulative average exposures to PM10, PM2.5, and PM2.5–10 and residential distance to road for women participating in the prospective nationwide Nurses’ Health Study. Hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated for incident hypertension from 1988 to 2008 using Cox proportional hazards models adjusted for potential confounders. We considered effect modification by age, diet, diabetes, obesity, region, and latitude.Results:Among 74,880 participants, 36,812 incident cases of hypertension were observed during 960,041 person-years. In multivariable models, 10-μg/m3 increases in 24-month average PM10, PM2.5, and PM2.5–10 were associated with small increases in the incidence of hypertension (HR: 1.02, 95% CI: 1.00, 1.04; HR: 1.04, 95% CI: 1.00, 1.07; and HR: 1.03, 95% CI: 1.00, 1.07, respectively). Associations were stronger among women &lt; 65 years of age (HR: 1.04, 95% CI: 1.01, 1.06; HR: 1.07, 95% CI: 1.02, 1.12; and HR: 1.05, 95% CI: 1.01, 1.09, respectively) and the obese (HR: 1.07, 95% CI: 1.04, 1.12; HR: 1.15, 95% CI: 1.07, 1.23; and HR: 1.13, 95% CI: 1.07, 1.19, respectively), with p-values for interaction &lt; 0.05 for all models except age and PM2.5–10. There was no association with roadway proximity.Conclusions:Long-term exposure to particulate matter was associated with small increases in risk of incident hypertension, particularly among younger women and the obese.Citation:Zhang Z, Laden F, Forman JP, Hart JE. 2016. Long-term exposure to particulate matter and self-reported hypertension: a prospective analysis in the Nurses’ Health Study. Environ Health Perspect 124:1414–1420; http://dx.doi.org/10.1289/EHP163
Enzalutamide after abiraterone in patients with metastatic castrate-resistant prostate cancer (mCRPC).
Authors: Gurprataap Singh Sandhu, Rahul Atul Parikh, Leonard Joseph Appleman, David Friedland
Journal: Journal of Clinical Oncology (2014)

240 Background: Abiraterone is a 17a hydroxylase and C17,20-lyase inhibitor that blocks androgen biosynthesis and is approved for treatment in patients with mCRPC. Enzalutamide, a second-generation androgen receptor signaling inhibitor was recently approved for use in patients with mCRPC post-docetaxel. There is paucity of information regarding sequential use of enzalutamide after abiraterone. Methods: This is a single-center, retrospective analysis of 23 patients with mCRPC who received enzalutamide after progression on abiraterone. Post-treatment prostate specific antigen(PSA) response and time to PSA progression were used to determine enzalutamide efficacy. Patients were followed for 6 months post initiation of enzalutamide. Results: At the time of enzalutamide initiation, median age was 70 years, with average Gleason score of 7 at the time of diagnosis. All patients were on ongoing androgen deprivation therapy, and 15 patients had received prior docetaxel chemotherapy. Median duration of abiraterone and enzalutamide treatment was 7 and 4.5 months respectively. 12 patients had at least one declining PSA value post enzalutamide treatment, with 5 patients showing &gt;25% decline in PSA and 4 patients &gt; 50%. Median time to PSA progression in patients receiving enzalutamide following abiraterone was 2.3 months. Conclusions: Sequential enzalutamide in patients with CRPC post-abiraterone showed only modest activity, indicating that the clinical benefit of sequential use of highly potent androgen pathway inhibitors cannot be assumed, and should be measured in prospective studies.
Handling missing items in the Exacerbations of Chronic Pulmonary Disease Tool
Authors: Andrew W. Hitchings, Emma H. Baker, Paul W. Jones
Journal: European Respiratory Journal (2016)

The Exacerbations of Chronic Pulmonary Disease Tool (EXACT) is a 14-item, self-administered daily symptom diary designed to identify and characterise exacerbations of chronic obstructive pulmonary disease (COPD). It provides a reliable, valid and standardised measure of exacerbation symptoms, and is sensitive to changes during recovery [1]. Scores are expressed on a 100-point scale, with higher values indicating worse symptoms or health state. In addition, the EXACT-derived E-RS (EXACT Respiratory Symptoms) provides valid daily COPD symptom scores [2, 3]. Electronic administration is recommended and has several advantages, notably in preventing item omission [4]. However, the expense of electronic solutions may prove prohibitive, particularly in noncommercial studies, when a pen-and-paper version may be used instead. In this context, it is important to have a method to deal with missing items. This is yet to be established. Within certain limits, missing items in the EXACT instrument can be imputed from the remaining answered items <http://ow.ly/4mJQzP> We thank Nancy Kline Leidy and Elizabeth Bacci (Evidera, Bethesda, MD, USA) for their helpful comments on the first draft of this manuscript. We thank the NIHR Clinical Research Network Portfolio, Comprehensive Local Research Networks and the participating centres for their support in conducting the clinical trial from which these data were acquired.