tbuckley/cabot-search huggingface dataset:
Phase 1 Dose-Escalation Study of the Folic Acid-Tubulysin Small-Molecule Drug Conjugate Ec1456 in Patients (Pts) with Advanced Solid Tumors
Authors: E.A. Sausville, W.A. Harb, R.K. Ramanathan, C.P. Leamon, J.A. Reddy, R. Clark, D.E. Matei
Journal: Annals of Oncology (2014)
White middle class death rate rise is linked to common diseases
Authors: Michael McCarthy
Journal: BMJ (2016)

The rise in death rates among middle aged white people in the United States may be linked to a failure to make progress in reducing mortality from common causes of death in this population, such as heart disease, and to changes to their socioeconomic status, a report by the Commonwealth Fund suggests.

Last November the Princeton University economists Anne Case and Angus Deaton reported that death rates among white people between the ages of 45 and 64—which had been falling by an average of 1.8% a year since the 1970s—had begun to rise in the late 1990s by about a half a percent a …
A Randomized Trial of Hyperglycemic Control in Pediatric Intensive Care
Authors: Duncan Macrae, Richard Grieve, Elizabeth Allen, Zia Sadique, Kevin Morris, John Pappachan, Roger Parslow, Robert C. Tasker, Diana Elbourne
Journal: New England Journal of Medicine (2014)

Whether an insulin infusion should be used for tight control of hyperglycemia in critically ill children remains unclear.We randomly assigned children (≤16 years of age) who were admitted to the pediatric intensive care unit (ICU) and were expected to require mechanical ventilation and vasoactive drugs for at least 12 hours to either tight glycemic control, with a target blood glucose range of 72 to 126 mg per deciliter (4.0 to 7.0 mmol per liter), or conventional glycemic control, with a target level below 216 mg per deciliter (12.0 mmol per liter). The primary outcome was the number of days alive and free from mechanical ventilation at 30 days after randomization. The main prespecified subgroup analysis compared children who had undergone cardiac surgery with those who had not. We also assessed costs of hospital and community health services.A total of 1369 patients at 13 centers in England underwent randomization: 694 to tight glycemic control and 675 to conventional glycemic control; 60% had undergone cardiac surgery. The mean between-group difference in the number of days alive and free from mechanical ventilation at 30 days was 0.36 days (95% confidence interval [CI], -0.42 to 1.14); the effects did not differ according to subgroup. Severe hypoglycemia (blood glucose, <36 mg per deciliter [2.0 mmol per liter]) occurred in a higher proportion of children in the tight-glycemic-control group than in the conventional-glycemic-control group (7.3% vs. 1.5%, P<0.001). Overall, the mean 12-month costs were lower in the tight-glycemic-control group than in the conventional-glycemic-control group. The mean 12-month costs were similar in the two groups in the cardiac-surgery subgroup, but in the subgroup that had not undergone cardiac surgery, the mean cost was significantly lower in the tight-glycemic-control group than in the conventional-glycemic-control group: -$13,120 (95% CI, -$24,682 to -$1,559).This multicenter, randomized trial showed that tight glycemic control in critically ill children had no significant effect on major clinical outcomes, although the incidence of hypoglycemia was higher with tight glucose control than with conventional glucose control. (Funded by the National Institute for Health Research, Health Technology Assessment Program, U.K. National Health Service; CHiP Current Controlled Trials number, ISRCTN61735247.).
A Comparative Effectiveness Analysis of the Implementation of Surgical Safety Checklists in a Tertiary Care Hospital
Authors: Matthias Bock, Antonio Fanolla, Isabelle Segur-Cabanac, Franco Auricchio, Carla Melani, Flavio Girardi, Horand Meier, Armin Pycha
Journal: JAMA Surgery (2016)

<h3>Importance</h3> The appropriately coached implementation of surgical safety checklists (SSCs) reduces the incidence of perioperative complications and 30-day mortality of patients undergoing surgery. The association of the introduction of SSCs with 90-day mortality remains unclear. <h3>Objective</h3> To assess the association between the implementation of SSCs and all-cause 90- and 30-day mortality rates. <h3>Design, Setting, and Participants</h3> Evaluation of the outcomes of surgical procedures performed during the 6 months before (January 1 to June 30, 2010) and after (January 1 to June 30, 2013) the introduction of SSCs by retrospective analysis of administrative databases. The study was conducted in a public, regional, university-affiliated hospital in Italy. Data were collected from October 23, 2013, to November 12, 2014, including 90-day all-cause mortality, 30-day all-cause mortality, length of hospital stay, and 30-day readmission rate among patients undergoing noncardiac surgery. Patients undergoing surgery during the 6-month periods before and after the implementation of SSCs were compared. Data were analyzed from September 17, 2014, to July 31, 2015. <h3>Main Outcomes and Measures</h3> Risk-adjusted rates of 90- and 30-day mortality, readmission rate, and length of stay. <h3>Results</h3> The total study sample of 10 741 patients included 5444 preintervention and 5297 postintervention patients (5093 [47.4%] male and 5648 [52.6%] female patients; mean [SD] age, 53.0 [23.0] years). Ninety-day all-cause mortality was 2.4% (129 patients) before compared with 2.2% (118 patients) after the SSC implementation, for an adjusted odds ratio (AOR) of 0.73 (95% CI, 0.56-0.96;<i>P</i> = .02). Thirty-day all-cause mortality was 1.36% (74 patients) before compared with 1.32% (70 patients) after the SSC implementation, for an AOR of 0.79 (95% CI, 0.56-1.11;<i>P</i> = .17). Thirty-day readmission occurred in 797 patients (14.6%) in the preimplementation group vs 766 patients (14.5%) in the postimplementation group, for an AOR of 0.90 (95% CI, 0.81-1.01;<i>P</i> = .79). The adjusted length of stay was 10.4 (95% CI, 10.3-10.6) days in the preimplementation group compared with 9.6 (95% CI, 9.4-9.7) days in the postimplementation group (<i>P</i> &lt; .001). <h3>Conclusions and Relevance</h3> The data cannot prove causality owing to the study design. The implementation of SSCs was associated with a 27% reduction of the adjusted risk for all-cause death within 90 days but not within 30 days. The adjusted length of stay was reduced after implementation of SSCs.
Serum CD44 levels and response to selenium-based therapy in patients with gynecologic cancers
Authors: L. Rodriguez-Rodriguez, N. Muthukumaran, S. Goodin, G. Frenkel, P. Caffrey, D. G. Gibbon, W. Nieves-Neira, A. Vaidya, W. J. Shih, E. H. Rubin
Journal: Journal of Clinical Oncology (2008)

2544 Background: Selenium inhibits the development of carboplatin drug resistance in a mouse ovarian cancer xenograft model and in tissue culture. Selenium inhibits the binding of ovarian cancer cells to hyaluronic acid (HA). HA is the main ligand of the CD44 receptor that is a transmembrane protein implicated in metastases and drug resistance. Based on this data we designed a phase I trial to determine MTD/DLT and any effects of selenium in carboplatin pharmacokinetics (PK) using the combination of selenious acid (Se), carboplatin (C) and paclitaxel (P) in the treatment of chemo-naive women with gynecologic malignancies. A secondary end-point was to test serum CD44 as a surrogate marker of Se effect on in vivo drug resistance. Methods: Based on the doses given on the mouse model, we administered Se intravenously (IV) on day 1, over 5 hours. On day 3, P was given at 175mg/m2 IV over 3 hours, followed by C AUC 5 (Calvert method) for 30 min every 21 days. During the first cycle C was given at an AUC of 5 and in subsequent cycles the dose was escalated to AUC of 6. Se was escalated in cohorts of 3 patients: 50, 100, 200, 400, 800, 1,000, 1,200, 2,000 and 5,000 mcg. Serum was collected prior to each treatment during the first 6 cycles of chemotherpay. Serum CD44 was analyzed by ELISA. Results: We tested whether there is a correlation between Se treatment, serum CD44 levels and treatment response. We tested the serum from 20 patients for CD44 levels. For analysis the patients were grouped according to disease status and time to progression into 3 different groups. Group 1: Complete Responders (CR) that remain without evidence of disease at the time of this submission (N=7). Group 2: CR or PR with repsonse duration longer than a year but eventually recured (n=6). Group 3: PR/CR with response duration of less than 12 months from best response (n=7). Mann-Whitney U-test was used for statistical analysis. We found that there was a significant increase of serum CD44 levels in Group 1 pts (p<0.01) that was evident since treatment cycle #2 and persisted until the last cycle analyzed (Cycle #6). Conclusions: CD44 serum levels are an early surrogate marker of drug sensitivity and prolonged response to therapy with S/C/T. No significant financial relationships to disclose.
Adjuvant chemotherapy in completely resected stage III-N2 non-small cell lung cancer
Authors: S. Wang, W. Ou, H. Sun, H. Yang, X. Ye, Q. Fang
Journal: Journal of Clinical Oncology (2009)

7563 Background: We evaluate effect of postoperative adjuvant chemotherapy on overall survival after complete resection of stage III-N2 non-small-cell lung cancer. Methods: From Jan.1999 to Dec. 2003, a total of 150 stage III-N2 non-small cell lung cancer patients randomly received four cycles of chemotherapy (NVB25mg/m2, D1,D5 or paclitaxel 175mg/m2, D1 / carboplatin AUC=5, D1) or observation after operation. Results: The median survival for the 150 patients was 879 days, with a 1-year survival rate of 81%, 3-year survival rate of 43%, and 5-year survival rate of 28%.There was significant difference in median survival between chemotherapy and control group (897 days vs 821 days p=0.04), and also there was significant difference in 5-year survival rate (30% vs 24% p&lt;0.05). The most common site of recurrence was brain. 26% (39/150) of patients recurred in the brain as their first site, 22% (18/79) for chemotherapy group, 29% (21/71) for control group. The median survival time for brain metastasis patients between chemotherapy and control group is no difference (812 days vs 512 days, p=0.122), but there was significant difference in 2-year survival rate (66.71% vs 37.6% p&lt;0.05). Conclusions: Postoperative adjuvant chemotherapy dose significantly improves median survival among completely resected stage III-N2 non-small-cell lung cancer patients, and significantly improves 5-year survival rate. It dose not decrease incidence of brain metastasis but postpone the time of brain metastasis in chemotherapy group. No significant financial relationships to disclose.
Abstract 180: Alcohol Consumption Negatively Competes with Estrogen-Mediated Myocardial Repair in Ovariectomized Mice: Ethanol-Mediated Suppression of Estradiol-Induced Survival Signaling in Endothelial Progenitor Cells
Authors: Alexander R Mackie, Erin Lambers, Melissa A Thal, Suresh Verma, Prasanna Krishnamurthy, Eneda Hoxha, Veronica Ramirez, Hiromichi Hamada, Douglas W Losordo, Raj Kishore
Journal: Circulation Research (2012)

Studies in post-menopausal women and ovariectomized (OVX) animals have suggested a cardio-protective (CP) role of estrogen replacement therapy. However, randomized clinical trials have not confirmed this finding with hormone replacement (HRT). Although HRT initiation and duration might explain part of this disparity, other factors that mask the CP effect of estradiol (E2) require scrutiny. We and others have reported that E2-supplementation (E2sup) with 17β-E2 pellets enhances voluntary alcohol consumption in OVX mice. In this study, we examined the effect that enhanced ethanol consumption with E2sup has on post-infarct myocardial function and repair. E2sup OVX BALB/c mice, consumed significantly more 10% ethanol for 6 weeks compared to those implanted with placebo pellets. Following acute myocardial infarction (AMI), LV functions were consistently depressed in mice consuming ethanol (E2sup+Etoh) compared to mice receiving only E2sup. Additionally, the E2sup+Etoh group also displayed a loss of the improvements in both fibrosis area and capillary density observed in the E2sup mice following AMI. E2sup+Etoh mice also displayed a diminished number of circulating endothelial progenitor cells (EPCs) as compared to the E2sup group. In vitro, exposure of EPCs to ethanol suppressed E2-induced EPC proliferation and survival. At the molecular level, estrogen response element (ERE) DNA binding activity and ERE-dependent reporter gene transcription were markedly repressed in ethanol treated EPCs. Ethanol also attenuated E2-induced eNOS expression and phosphorylation. Furthermore, ethanol blocked E2-induced activation of cell survival signaling pathways, Akt and ERK, and activated the pro-apoptotic JNK signaling via direct association with mixed lineage kinase 3. These data suggest that E2 modulation of alcohol consumption and the ensuing EC dysfunction may negatively compete with the beneficial effects of estrogen on the heart.
The statistical sins of Jeremy Hunt
Authors: David Craven
Journal: BMJ (2015)

Four things the health secretary needs to get right

The health secretary for England, Jeremy Hunt, has been criticised recently over his handling of statistics. Although it can be easy to make statistical errors, his handling of the so called “weekend effect” and new contract for junior doctors has seen some particularly egregious examples.

Weekend mortality —In October Fiona Godlee, editor in chief of The BMJ , wrote to Hunt to pull him up on his conflation of the concepts of correlation and causation and to try to persuade him to stop making this error.1 A study in The BMJ (doi:10.1136/bmj.h4596) had shown a correlation between admission to hospital at weekends and death rates. It found that 11 000 more …
Correlation between muscular dysfunction and vascular inflammation in COPD
Authors: Anupama Gupta, Rajesh Gupta, Sushma Sood, Ankur Agarwal
Journal: European Respiratory Journal (2013)

Background: Pulse wave velocity (PWV) a marker for vascular inflammation has been correlated with EMG for myopathy in COPD.  Material & methods: 50 known COPD patients for 5 years or more, age 40 years or more and 50 controls, healthy volunteers with matched age and sex included in study. Routine investigations to r/o other illness and specific tests i.e. PWV measured in three different segments using pulse transducers simultaneous ECG recorded on four channel polygraph and EMG of Quadriceps recorded using needle electrodes, inserted at the insertion point using sweep speed of 5-10 ms/div and amplification of 50µv/division for studying spontaneous activity and 200µV/divisions for Motor Unit Potentials to correlate with each other and various determinants of COPD.  Results: The mean PWV values increased significantly in COPD group of segments AO-Rad, AO-Fem and Fem-Dp 6.244±1.168, 6.86±.990 & 8.56±1.110 than in controls 5.144±.664, 5.40±.782 and 7.10±.678 respectively. The mean EMG value of amplitude of Rectus Femoris and Vastus Medialis in COPD patients was 1278.42±840.81 and 799.90±598.635 respectively, significantly decrease to 53.54% and 66.03% of control value.  Discussions: PWV had significantly negatively correlated with the FEV1/FVC in the COPD group, more affected in AO-Fem segment increased to 27.05% compared to controls. EMG values i.e. recruitment and amplitude significantly decreased in COPD patients compared to controls. Vastus Medialis was more severely affected while amplitude represented a correlation with FVC and duration of illness.  Smoking pack years was important factors for myopathy in COPD though no correlation was seen between EMG and PWV.
Sleep Duration is Associated with Degree of Insulin Resistance in a High Risk Population: the Baptist Employee Healthy Heart Study
Authors: Shozab Ali, Ebenezer Oni, Ehimen Aneni, Lara Roberson, Janisse Post, Gagandeep Nagi, Sameer Shaharyar, Omar Jamal, Rehan Malik, Muhammad Aziz, Adnan Younus, Beatriz Rosell, Henry Guzman, Ricardo Cury, Jonathan Fialkow, Arthur Agatston, Emir Veledar, Theodore Feldman, Khurram Nasir
Journal: Circulation (2014)
Abstract 167: MicroRNA Profiles of Non--ST-Elevation Myocardial Infarction
Authors: Jeanine Ward, Rafael de la Puente, David McManus
Journal: Circulation Research (2012)

Significance: MicroRNAs (miRNAs) are short, stable, noncoding translational regulators used as early biomarkers for numerous disease processes. Although specific miRNA patterns are associated with STEMI, the profile and timecourse of miRNA release in NSTEMI is currently unknown but of potential clinical significance.Materials and Methods: With IRB approval, patients identified with chest pain were identified at the UMass Medical Center. Upon ED arrival (T0), a K2EDTA tube of whole blood was obtained with simultaneous troponin cTnI levels. After a 6 hour (T6) observation period, another additional K2EDTA tube was drawn, again contemporaneous with cTnI levels. Patients were selected based on an elevated cTnI level (greater then or equal to ≥ 0.04 ng/ml) at T6 as compared to a negative cTnI levels (&lt; 0.04 ng/ml) at T0. MiRNA was isolated from patient plasma using a Trizol extraction procedure. Real-time reverse transciptase polymerase chain reaction (QRT-PCR) was performed for 94 a priori miRNAs common to cardiovascular development or disease. Results: Of the 94 miRNAs examined, 11 demonstrated greater than 2-fold change as compared to baseline (Figure 1). A subset of this cohort, namely miRNAs 208a, 483-5p, and 601 revealed statistically significant fold difference (p&lt; 0.05). MiRNA 208a is associated with acute MI. MiRNA 601 has not been previously shown correlated with heart disease. Conclusion: This investigation reveals a novel 11 member miRNA profile, including miRNA 208a, 483-5p, and 601, which is associated with NSTEMI. Our findings suggest this miRNA profile by be used as a potential biomarker of myocardial injury.
Smoking history, drug toxicity, and survival in non-small cell lung cancer (NSCLC) patients receiving epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) drugs
Authors: M. E. Cooley, K. M. Emmons, H. Li, D. P. Harrington, D. C. Christiani, D. M. Jackman, T. Cohen, B. E. Johnson
Journal: Journal of Clinical Oncology (2008)

9570 Background: An association has been identified between response to the EGFR-TKIs (erlotinib and gefitinib) and absence of a history of smoking cigarettes. Further studies are needed that examine the relationship between smoking history and cancer treatment outcomes with these drugs. This study aimed to examine the relationship between smoking history, drug toxicity and survival in patients with NSCLC treated with EGFR-TKIs and identify factors associated with survival among former smokers. Methods: A secondary analysis using data from Dana-Farber/Harvard Cancer Center Thoracic Oncology Program’s clinical research information system was done. A prospective self-report tobacco questionnaire and chart review was used to collect patient data. Toxicities were graded by the Common Toxicity Criteria. Survival information was obtained from multiple sources, including the social security death index. The primary endpoints were toxicity and survival. Survival was measured from the first day of treatment with an EGFR-TKI. Results: One hundred eighty-seven patients who were treated with EGFR-TKI drugs between 1/1/2002 and 1/1/2005 were eligible for this study. Five patients with unknown smoking status were excluded from the analysis Median survival was 13.9 months for never smokers (N=33), 6 months for former (N=106), and 4.9 months for current smokers (N=43) (P =0.06, adjusted for line of treatment). During the initial first treatment, never smokers had highest prevalence of rash (27%) followed by former (11%) and current smokers (2%) (P=0.005, Fisher’s exact test), and least shortness of breath (0%, 13%, 9%) (P=0.05). Multivariate Cox regression analysis showed that factors associated with shorter survival were number of cigarettes smoked per day (Hazard Ratio [HR]=1.03; P=0.004) and male gender (HR=1.71; P=0.04). Presence of rash was associated with longer survival (HR=0.17; P<0.001). Conclusions: The prevalence of rash and shortness of breath differed by smoking status. A marginally significant difference in overall survival was also observed. Number of cigarettes smoked per day, presence of rash and male gender were predictive factors of survival among former smokers. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration GenZyme GenZyme
In vivo activity of R1530 (R) alone and in combination with docetaxel (D) and bevacizumab (B) in a prostate carcinoma (PCa) xenograft model
Authors: K. D. Kolinsky, Y. Zhang, K. Packman, B. Higgins
Journal: Journal of Clinical Oncology (2009)

e16124 Background: R is a multikinase inhibitor currently in phase I clinical testing. Its inhibitory profile includes several kinases that play critical roles in cancer cell growth and division leading to disruption at M-phase and antiangiogenic effects. Studies were conducted to evaluate the efficacy and tolerability of R alone and in combination with D and B in the 22rv1 androgen independent PCa model. Methods: Initially TGI of optimal dose (OD) R, D and B were evaluated. Then the TGI and increased life span (ILS) of the minimum efficacious dose (MED) and 2/3 OD R ± 2/3 OD D was tested. A final study compared doublets of 2/3 OD R + 2/3 OD D, 2/3 OD D + OD B, 2/3 OD R + OD B, and triplet of 2/3 OD D + 2/3 OD R+ 2/3 OD B. Results: All treatment groups were tolerated and there was no antagonism. TGI and ILS results are listed below ( Table ). Conclusions: The OD of R B and D showed monotherapy TGI in this model. MED R + 2/3 OD D gave ILS statistically better (sb) than singlets but TGI was sb than MED R but not the D singlet. 2/3 OD R + 2/3 OD D produced sb TGI and ILS than each singlet. TGI and ILS with 2/3 OD R is sb than 2/3 OD D. TGI and ILS of 2/3 OD R + 2/3 OD D was sb than the 2/3 OD D + OD B but not the 2/3 OD R + B doublet. TGI and ILS was sb for 2/3 OD R + OD B versus 2/3 OD D + OD B. The TGI of the triplet was equivalent to the 2/3 OD R + 2/3 OD D doublet, but ILS was sb in the triplet. Also, the TGI and ILS was sb for triplet versus 2/3 OD D + OD B. TGI and ILS of the triplet was equal to 2/3 OD R + OD B. In general, the results demonstrate that the shared mechanism of mitotic disruption by R and D do not render antagonism, but in fact, allow for potentiated TGI and ILS. Also of note is the equally superior TGI and ILS provided by R + B and R + B + D. In general, the preclinical results generated support clinical testing of these agents in PCa. * p value for all. [Table: see text] [Table: see text]