Detection of toxic industrial chemicals in water supplies using surface-enhanced Raman spectroscopy

NASA Astrophysics Data System (ADS)

Spencer, Kevin M.; Sylvia, James M.; Spencer, Sarah A.; Clauson, Susan L.

2010-04-01

An effective method to create fear in the populace is to endanger the water supply. Homeland Security places significant importance on ensuring drinking water integrity. Beyond terrorism, accidental supply contamination from a spill or chemical residual increases is a concern. A prominent class of toxic industrial chemicals (TICs) is pesticides, which are prevalent in agricultural use and can be very toxic in minute concentrations. Detection of TICs or warfare agents must be aggressive; the contaminant needs to be rapidly detected and identified to enable isolation and remediation of the contaminated water while continuing a clean water supply for the population. Awaiting laboratory analysis is unacceptable as delay in identification and remediation increases the likelihood of infection. Therefore, a portable or online water quality sensor is required that can produce rapid results. In this presentation, Surface-Enhanced Raman Spectroscopy (SERS) is discussed as a viable fieldable sensor that can be immersed directly into the water supply and can provide results in <5 minutes from the time the instrument is turned on until analysis is complete. The ability of SERS to detect several chemical warfare agent degradation products, simulants and toxic industrial chemicals in distilled water, tap water and untreated water will be shown. In addition, results for chemical warfare agent degradation products and simulants will be presented. Receiver operator characteristic (ROC) curves will also be presented.

Multi-parameter optimization of aza-follow-ups to BI 207524, a thumb pocket 1 HCV NS5B polymerase inhibitor. Part 2: Impact of lipophilicity on promiscuity and in vivo toxicity.

PubMed

Beaulieu, Pierre L; Bolger, Gordon; Deon, Dan; Duplessis, Martin; Fazal, Gulrez; Gagnon, Alexandre; Garneau, Michel; LaPlante, Steven; Stammers, Timothy; Kukolj, George; Duan, Jianmin

2015-03-01

We describe our efforts to identify analogs of thumb pocket 1 HCV NS5B inhibitor 1 (aza-analog of BI 207524) with improved plasma to liver partitioning and a predicted human half-life consistent with achieving a strong antiviral effect at a reasonable dose in HCV-infected patients. Compounds 3 and 7 were identified that met these criteria but exhibited off-target promiscuity in an in vitro pharmacology screen and in vivo toxicity in rats. High lipophilicity in this class was found to correlate with increased probability for promiscuous behavior and toxicity. The synthesis of an 8×11 matrix of analogs allowed the identification of C3, an inhibitor that displayed comparable potency to 1, improved partitioning to the liver and reduced lipophilicity. Although C3 displayed reduced propensity for in vitro off-target inhibition and the toxicity profile in rats was improved, the predicted human half-life of this compound was short, resulting in unacceptable dosing requirements to maintain a strong antiviral effect in patients. Copyright © 2015 Elsevier Ltd. All rights reserved.

ABCB1-1Delta polymorphism can predict hematologic toxicity in dogs treated with vincristine.

PubMed

Mealey, K L; Fidel, J; Gay, J M; Impellizeri, J A; Clifford, C A; Bergman, P J

2008-01-01

Dogs that harbor the naturally occurring ABCB1-1Delta polymorphism experience increased susceptibility to avermectin-induced neurological toxicosis as a result of deficient P-glycoprotein function. Whether or not the ABCB1-1Delta polymorphism affects susceptibility to toxicity of other P-glycoprotein substrate drugs has not been studied. Dogs that possess the ABCB1-1Delta mutation are more likely to develop hematologic toxicity associated with vincristine than ABCB1 wild-type dogs. Thirty-four dogs diagnosed with lymphoma were included in this study. Cheek swab samples were obtained from dogs diagnosed with lymphoma that were to be treated with vincristine. DNA was extracted from cheek swabs and the ABCB1 genotype was determined. Hematologic adverse drug reactions were recorded for each dog and graded according to the Veterinary Comparative Oncology Group's criteria for adverse event reporting (Consensus Document). In order to avoid possible bias, ABCB1 genotype results for a particular patient were not disclosed to oncologists until an initial adverse event report had been submitted. Dogs heterozygous or homozygous for the ABCB1-1Delta mutation were significantly more likely to develop hematologic toxicity, specifically neutropenia (P= .0005) and thrombocytopenia (P= .0001), after treatment with vincristine than ABCB1 wild-type dogs. At currently recommended dosages (0.5-0.7 mg/M(2)), vincristine is likely to cause hematologic toxicity in dogs with the ABCB1-1Delta mutation, resulting in treatment delays and unacceptable morbidity and mortality. Assessing the ABCB1-1Delta genotype before vincristine administration and decreasing the dosage may prevent toxicity and treatment delays resulting from neutropenia or thrombocytopenia.

Docetaxel-induced skin toxicities in breast cancer patients subsequent to paclitaxel shortage: a case series and literature review

PubMed Central

Poi, Ming J.; Berger, Michael; Lustberg, Maryam; Layman, Rachel; Shapiro, Charles L.; Ramaswamy, Bhuvaneswari; Mrozek, Ewa; Olson, Erin

2013-01-01

Purpose As the result of a recent national shortage in paclitaxel, some patients who were receiving or scheduled to receive weekly paclitaxel were converted to every 3-week (q3w) docetaxel with granulocyte colony-stimulating factor support. Our institution noted higher than expected incidence of severe skin toxicity events attributable to docetaxel during the shortage period among our breast cancer patients. In this report, we summarize the clinical course of the first five cases, review the literature surrounding docetaxel-induced skin toxicity, and offer possible prevention and treatment strategies to improve docetaxel tolerability. Methods The observation period for this case series was August 1 through October 21, 2011. All patients treated with docetaxel were identified from our electronic medical record. Operable stage I–III breast cancer patients who received ≥1 dose of docetaxel monotherapy at 75–100 mg/m2 q3w were included in this study. The cases of grade 3–4 docetaxel-induced skin toxicities identified by the treating oncologists were then contacted and signed an informed consent through an Institutional Review Board-approved protocol. Results Thirty-four patients met the inclusion criteria. Five patients (14.7 %) experienced grade 3 skin toxicity events attributable to docetaxel, a significantly higher rate than previously reported for docetaxel dosed at 75–100 mg/m2. Conclusions Docetaxel-induced dermatologic toxicity is well characterized; nonetheless, its etiology is largely unknown and evidence-based prevention and management strategies are lacking. This report shows that the use of docetaxel 75–100 mg/m2 q3w subsequent to dose-dense doxorubicin and cyclophosphamide regimen can lead to unacceptable rate of severe skin toxicity. PMID:23686402

Monitoring late-onset toxicities in phase I trials using predicted risks

PubMed Central

Bekele, B. Nebiyou; Ji, Yuan; Shen, Yu; Thall, Peter F.

2008-01-01

Late-onset (LO) toxicities are a serious concern in many phase I trials. Since most dose-limiting toxicities occur soon after therapy begins, most dose-finding methods use a binary indicator of toxicity occurring within a short initial time period. If an agent causes LO toxicities, however, an undesirably large number of patients may be treated at toxic doses before any toxicities are observed. A method addressing this problem is the time-to-event continual reassessment method (TITE-CRM, Cheung and Chappell, 2000). We propose a Bayesian dose-finding method similar to the TITE-CRM in which doses are chosen using time-to-toxicity data. The new aspect of our method is a set of rules, based on predictive probabilities, that temporarily suspend accrual if the risk of toxicity at prospective doses for future patients is unacceptably high. If additional follow-up data reduce the predicted risk of toxicity to an acceptable level, then accrual is restarted, and this process may be repeated several times during the trial. A simulation study shows that the proposed method provides a greater degree of safety than the TITE-CRM, while still reliably choosing the preferred dose. This advantage increases with accrual rate, but the price of this additional safety is that the trial takes longer to complete on average. PMID:18084008

A Portable Electronic Nose for Toxic Vapor Detection, Identification, and Quantification

NASA Technical Reports Server (NTRS)

Linnell, B. R.; Young, R. C.; Griffin, T. P.; Meneghelli, B. J.; Peterson, B. V.; Brooks, K. B.

2005-01-01

The Space Program and military use large quantities of hydrazine and monomethyl hydrazine as rocket propellant, which are very toxic and suspected human carcinogens. Current off-the-shelf portable instruments require 10 to 20 minutes of exposure to detect these compounds at the minimum required concentrations and are prone to false positives, making them unacceptable for many operations. In addition, post-mission analyses of grab bag air samples from the Shuttle have confirmed the occasional presence of on-board volatile organic contaminants, which also need to be monitored to ensure crew safety. A new prototype instrument based on electronic nose (e-nose) technology has demonstrated the ability to qualify (identify) and quantify many of these vapors at their minimum required concentrations, and may easily be adapted to detect many other toxic vapors. To do this, it was necessary to develop algorithms to classify unknown vapors, recognize when a vapor is not any of the vapors of interest, and estimate the concentrations of the contaminants. This paper describes the design of the portable e-nose instrument, test equipment setup, test protocols, pattern recognition algorithms, concentration estimation methods, and laboratory test results.

Efficacy and safety evaluation of icotinib in patients with advanced non-small cell lung cancer.

PubMed

Gu, Aiqin; Shi, Chunlei; Xiong, Liwen; Chu, Tianqing; Pei, Jun; Han, Baohui

2013-02-01

To evaluate the efficacy and safety of icotinib hydrochloride in patients with advanced non-small cell lung cancer (NSCLC). A total of 89 patients with stage IIIB or IV NSCLC received icotinib at a dose of 125 mg administered 3 times a day. Icotinib treatment was continued until disease progression or development of unacceptable toxicity. A total of 89 patients were assessable. In patients treated with icotinib, the overall response rate (RR) was 36.0% (32/89), and the disease control rate (DCR) was 69.7% (62/89). RR and DCR were significantly improved in patients with adenocarcinoma versus non-adenocarcinoma (P<0.05). The symptom improvement rate was 57.3% (51/89), and the main symptoms improved were cough, pain, chest distress, dyspnea, and Eastern Cooperative Oncology Group performance status. The main toxic effects were rash [30/89 (33.7%)] and diarrhea [15/89 (16.9%)]. The level of toxicity was typically low. The use of icotinib hydrochloride in the treatment of advanced NSCLC is efficacious and safe, and its toxic effects are tolerable.

The characteristics of unacceptable/taboo thoughts in obsessive-compulsive disorder.

PubMed

Brakoulias, Vlasios; Starcevic, Vladan; Berle, David; Milicevic, Denise; Moses, Karen; Hannan, Anthony; Sammut, Peter; Martin, Andrew

2013-10-01

In the quest to unravel the heterogeneity of obsessive-compulsive disorder (OCD), an increasing number of factor analytic studies are recognising unacceptable/taboo thoughts as one of the symptom dimensions of OCD. This study aims to examine the characteristics associated with unacceptable/taboo thoughts. Using the Yale-Brown Obsessive-Compulsive Scale Symptom Checklist (YBOCS-SC) with 154 individuals with OCD, obsessive-compulsive symptoms were subjected to principal components analysis. The characteristics associated with the resulting symptom dimensions were then assessed using logistic and linear regression techniques. Unacceptable/taboo thoughts comprised of sexual, religious and impulsive aggressive obsessions, and mental rituals. Higher scores on an unacceptable/taboo thoughts symptom dimension were predicted by higher Y-BOCS obsession subscores, Y-BOCS time preoccupied by obsessions scores, Y-BOCS distress due to obsessions scores, importance of control of thought ratings, male gender, and having had treatment prior to entering into the study. Unacceptable/taboo thoughts were also predicted by greater levels of hostility, and a past history of non-alcohol substance dependence. An unacceptable/taboo thought symptom dimension of OCD is supported by a unique set of associated characteristics that should be considered in the assessment and treatment of individuals with these symptoms. Crown Copyright © 2013. Published by Elsevier Inc. All rights reserved.

Unacceptable "occupational" exposure to toxic agents among children in Ecuador.

PubMed

Harari, R; Forastiere, F; Axelson, O

1997-09-01

To document the problem of child labor as a health issue, we report here three case-studies in Ecuador: exposure to mercury among gold washers, exposure to organophosphates and carbamates in the fruit-growing industry, and exposure to solvents among shoe cleaners. We measured the relevant biological indicators of exposure (mercury in urine, urinary levels of phenols, and acetylcholine esterase in erythrocytes) among selected samples of 10 children for each working place. In all the case studies, the values of the biological indicators showed elevated exposure to well-known toxicants, which are now rare in developed countries, even among adult workers. The findings meld with a previously reported case study of intoxication from inorganic lead among children employed in the manufacture of roof tiles in Ecuador. This study highlights the need to properly evaluate and control the potential health effects due to exposure to toxic substances among children employed in different occupations in several parts of the world.

NRG Oncology-Radiation Therapy Oncology Group Study 1014: 1-Year Toxicity Report From a Phase 2 Study of Repeat Breast-Preserving Surgery and 3-Dimensional Conformal Partial-Breast Reirradiation for In-Breast Recurrence.

PubMed

Arthur, Douglas W; Winter, Kathryn A; Kuerer, Henry M; Haffty, Bruce G; Cuttino, Laurie W; Todor, Dorin A; Simone, Nicole L; Hayes, Shelly B; Woodward, Wendy A; McCormick, Beryl; Cohen, Randi J; Sahijdak, Walter M; Canaday, Daniel J; Brown, Doris R; Currey, Adam D; Fisher, Christine M; Jagsi, Reshma; White, Julia

2017-08-01

To determine the associated toxicity, tolerance, and safety of partial-breast reirradiation. Eligibility criteria included in-breast recurrence occurring >1 year after whole-breast irradiation, <3 cm, unifocal, and resected with negative margins. Partial-breast reirradiation was targeted to the surgical cavity plus 1.5 cm; a prescription dose of 45 Gy in 1.5 Gy twice daily for 30 treatments was used. The primary objective was to evaluate the rate of grade ≥3 treatment-related skin, fibrosis, and/or breast pain adverse events (AEs), occurring ≤1 year from re-treatment completion. A rate of ≥13% for these AEs in a cohort of 55 patients was determined to be unacceptable (86% power, 1-sided α = 0.07). Between 2010 and 2013, 65 patients were accrued, and the first 55 eligible and with 1 year follow-up were analyzed. Median age was 68 years. Twenty-two patients had ductal carcinoma in situ, and 33 had invasive disease: 19 ≤1 cm, 13 >1 to ≤2 cm, and 1 >2 cm. All patients were clinically node negative. Systemic therapy was delivered in 51%. All treatment plans underwent quality review for contouring accuracy and dosimetric compliance. All treatment plans scored acceptable for tumor volume contouring and tumor volume dose-volume analysis. Only 4 (7%) scored unacceptable for organs at risk contouring and organs at risk dose-volume analysis. Treatment-related skin, fibrosis, and/or breast pain AEs were recorded as grade 1 in 64% and grade 2 in 7%, with only 1 (<2%) grade ≥3 and identified as grade 3 fibrosis of deep connective tissue. Partial-breast reirradiation with 3-dimensional conformal radiation therapy after second lumpectomy for patients experiencing in-breast failures after whole-breast irradiation is safe and feasible, with acceptable treatment quality achieved. Skin, fibrosis, and breast pain toxicity was acceptable, and grade 3 toxicity was rare. Copyright © 2017 Elsevier Inc. All rights reserved.

Metastatic renal cell carcinoma: CT-guided immunotherapy as a technically feasible and safe approach to delivery of gene therapy for treatment.

PubMed

Suh, Robert D; Goldin, Jonathan G; Wallace, Amanda B; Sheehan, Ramon E; Heinze, Stefan B; Gitlitz, Barbara J; Figlin, Robert A

2004-05-01

To assess the technical feasibility and safety of weekly outpatient percutaneous computed tomographic (CT)-guided intratumoral injections of interleukin-2 (IL-2) plasmid DNA in a wide variety of superficial and deep tumor sites. Twenty-nine patients with metastatic renal cell carcinoma and a total of 30 lesions measuring 1.0 cm(2) or greater in accessible thoracic (n = 15) or abdominal (n = 15) locations underwent up to three cycles of six weekly intratumoral IL-2 plasmid DNA injections. CT was used to guide needle placement and injection. After injection cycle 1, patients whose tumors demonstrated stable (< or =25% increase and < or =50% decrease in product of lesion diameters) or decreased size (>50% decrease in product of lesion diameters) advanced to injection cycle 2. Patients whose lesions decreased in size by more than 50% over the course of injection cycle 2 were eligible to begin injection cycle 3. An acceptable safety and technical feasibility profile for this technique was deemed to be (a) a safety and feasibility profile similar to that of single-needle biopsy and (b) an absence of serious adverse events (as defined in Title 21 of the Code of Federal Regulations) and/or unacceptable toxicities (as graded according to the National Cancer Institute Common Toxicity Criteria). A total of 284 intratumoral injections were performed, with a mean of 9.8 injections (range, 6-18 injections) received by each patient. Technical success (needle placement and injection of gene therapy agent) was achieved in all cases. Complications were experienced after 42 (14.8%) of the 284 injections. The most common complication was pneumothorax (at 32 [28.6%] of 112 intrathoracic injections), for which only one patient required catheter drainage. Complications occurred randomly throughout injection cycles and did not appear to increase as patients received more injections (P =.532). No patient experienced serious adverse events or unacceptable toxicities. Percutaneous CT-guided intratumoral immunotherapy injections are technically feasible and can be safely performed.

40 CFR 231.2 - Definitions.

Code of Federal Regulations, 2013 CFR

2013-07-01

... Protection of Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED) OCEAN DUMPING SECTION 404(c) PROCEDURES...) Unacceptable adverse effect means impact on an aquatic or wetland ecosystem which is likely to result in... unacceptability of such impacts, consideration should be given to the relevant portions of the section 404(b)(1...

40 CFR 231.2 - Definitions.

Code of Federal Regulations, 2012 CFR

2012-07-01

... Protection of Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED) OCEAN DUMPING SECTION 404(c) PROCEDURES...) Unacceptable adverse effect means impact on an aquatic or wetland ecosystem which is likely to result in... unacceptability of such impacts, consideration should be given to the relevant portions of the section 404(b)(1...

Investigations into the origin of the molecular recognition of several adenosine deaminase inhibitors.

PubMed

Gillerman, Irina; Fischer, Bilha

2011-01-13

Inhibitors of adenosine deaminase (ADA, EC 3.5.4.4) are potential therapeutic agents for the treatment of various health disorders. Several highly potent inhibitors were previously identified, yet they exhibit unacceptable toxicities. We performed a SAR study involving a series of C2 or C8 substituted purine-riboside analogues with a view to discover less potent inhibitors with a lesser toxicity. We found that any substitution at C8 position of nebularine resulted in total loss of activity toward calf intestinal ADA. However, several 2-substituted-adenosine, 8-aza-adenosine, and nebularine analogues exhibited inhibitory activity. Specifically, 2-Cl-purine riboside, 8-aza-2-thiohexyl adenosine, 2-thiohexyl adenosine, and 2-MeS-purine riboside were found to be competitive inhibitors of ADA with K(i) values of 25, 22, 6, and 3 μM, respectively. We concluded that electronic parameters are not major recognition determinants of ADA but rather steric parameters. A C2 substituent which fits ADA hydrophobic pocket and improves H-bonding with the enzyme makes a good inhibitor. In addition, a gg rotamer about C4'-C5' bond is apparently an important recognition determinant.

Maintenance therapy in colon cancer.

PubMed

Giuliani, F; De Vita, F; Colucci, G; Pisconti, S

2010-11-01

In the last decade dramatic improvements have been obtained in the treatment of metastatic colorectal cancer. Thanks to the introduction in the clinical practice of new drugs such as Irinotecan and Oxaliplatin, and modern biological drugs such as Bevacizumab and Cetuximab, the response rate, progression-free and overall survival are about 50-60%, 9-11 and 20-24 months respectively. Despite this progress, many questions remain unsolved especially those related to the optimal duration of treatment and the role of maintenance therapy. To treat until progression (or unacceptable toxicity) is the classical way but in the common clinical practice is frequent to perform an induction therapy (until the maximum response is obtained) followed by a complete stop and restart on progression, or by a maintenance without the drug/s responsible of the major cumulative toxicities. The following report focus on the role of different strategies respect to the classic "treatment until progression". Copyright © 2010 Elsevier Ltd. All rights reserved.

Relating (Un)acceptability to Interpretation. Experimental Investigations on Negation

PubMed Central

Etxeberria, Urtzi; Tubau, Susagna; Deprez, Viviane; Borràs-Comes, Joan; Espinal, M. Teresa

2018-01-01

Although contemporary linguistic studies routinely use unacceptable sentences to determine the boundary of what falls outside the scope of grammar, investigations far more rarely take into consideration the possible interpretations of such sentences, perhaps because these interpretations are commonly prejudged as irrelevant or unreliable across speakers. In this paper we provide the results of two experiments in which participants had to make parallel acceptability and interpretation judgments of sentences presenting various types of negative dependencies in Basque and in two varieties of Spanish (Castilian Spanish and Basque Country Spanish). Our results show that acceptable sentences are uniformly assigned a single negation reading in the two languages. However, while unacceptable sentences consistently convey single negation in Basque, they are interpreted at chance in both varieties of Spanish. These results confirm that judgment data that distinguish between acceptable and unacceptable negative utterances can inform us not only about an adult’s grammar of his/her particular language but also about interesting cross-linguistic differences. We conclude that the acceptability and interpretation of (un)grammatical negative sentences can serve linguistic theory construction by helping to disentangle basic assumptions about the nature of various negative dependencies. PMID:29456515

Safety, resource use, and quality of life in paramount: a phase III study of maintenance pemetrexed versus placebo after induction pemetrexed plus cisplatin for advanced nonsquamous non-small-cell lung cancer.

PubMed

Gridelli, Cesare; de Marinis, Filippo; Pujol, Jean-Louis; Reck, Martin; Ramlau, Rodryg; Parente, Barbara; Pieters, Thierry; Middleton, Gary; Corral, Jesus; Winfree, Katherine; Melemed, Symantha; Zimmermann, Anna; John, William; Beyrer, Julie; Chouaki, Nadia; Visseren-Grul, Carla; Paz-Ares, Luis G

2012-11-01

In a phase III, randomized, double-blind study (PARAMOUNT), maintenance pemetrexed demonstrated significant benefit in advanced non-small-cell lung cancer (NSCLC). We present safety, resource use, and quality of life (QoL) results. After four 21-day cycles of pemetrexed-cisplatin (N = 939), patients with advanced nonsquamous NSCLC, whose disease had not progressed and who had a performance status of 0/1, were randomized 2:1 (N = 539) to maintenance pemetrexed 500 mg/m plus best supportive care or placebo plus best supportive care every 21 days until disease progression or unacceptable toxicity. QoL was measured using the EuroQol 5-dimensional questionnaire (EQ-5D). Frequently reported grade 3 to 4 drug-related toxicities with maintenance pemetrexed versus placebo were anemia (4.5% versus 0.6%; p = 0.016), fatigue (4.2% versus 0.6%; p = 0.016), and neutropenia (3.6% versus 0.0%; p < 0.006). No significant differences in drug-related grade 3 to 5 toxicities were observed with long-term pemetrexed exposure (>6 cycles), except grade 3 to 4 neutropenia, which did not result in increased infections. Patients on maintenance pemetrexed required more transfusions (13.4% versus 5.0%; p = 0.003), granulocyte colony- or granulocyte-macrophage colony-stimulating factors (5.3% versus 0.0%; p <0.001), anti-infectives (25.3% versus 16.7%; p = 0.028), and hospitalizations because of study drug (8.4% versus 3.3%, p = 0.028) than placebo-treated patients did. No significant treatment-by-time interactions, overall treatment differences, or clinically relevant changes from baseline were observed in EQ-5D scores during treatment. Long-term use of continuation maintenance pemetrexed was well tolerated; resource use was low, corresponding with known pemetrexed toxicities. The EQ-5D results demonstrate that patients tolerate long-term maintenance pemetrexed without worsening QoL.

Editor's Highlight: Transgenic Zebrafish Reporter Lines as Alternative In Vivo Organ Toxicity Models.

PubMed

Poon, Kar Lai; Wang, Xingang; Lee, Serene G P; Ng, Ashley S; Goh, Wei Huang; Zhao, Zhonghua; Al-Haddawi, Muthafar; Wang, Haishan; Mathavan, Sinnakaruppan; Ingham, Philip W; McGinnis, Claudia; Carney, Tom J

2017-03-01

Organ toxicity, particularly liver toxicity, remains one of the major reasons for the termination of drug candidates in the development pipeline as well as withdrawal or restrictions of marketed drugs. A screening-amenable alternative in vivo model such as zebrafish would, therefore, find immediate application in the early prediction of unacceptable organ toxicity. To identify highly upregulated genes as biomarkers of toxic responses in the zebrafish model, a set of well-characterized reference drugs that cause drug-induced liver injury (DILI) in the clinic were applied to zebrafish larvae and adults. Transcriptome microarray analysis was performed on whole larvae or dissected adult livers. Integration of data sets from different drug treatments at different stages identified common upregulated detoxification pathways. Within these were candidate biomarkers which recurred in multiple treatments. We prioritized 4 highly upregulated genes encoding enzymes acting in distinct phases of the drug metabolism pathway. Through promoter isolation and fosmid recombineering, eGFP reporter transgenic zebrafish lines were generated and evaluated for their response to DILI drugs. Three of the 4 generated reporter lines showed a dose and time-dependent induction in endodermal organs to reference drugs and an expanded drug set. In conclusion, through integrated transcriptomics and transgenic approaches, we have developed parallel independent zebrafish in vivo screening platforms able to predict organ toxicities of preclinical drugs. © The Author 2017. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

Vaginal microbicides: detecting toxicities in vivo that paradoxically increase pathogen transmission

PubMed Central

Cone, Richard A; Hoen, Timothy; Wong, XiXi; Abusuwwa, Raed; Anderson, Deborah J; Moench, Thomas R

2006-01-01

Background Microbicides must protect against STD pathogens without causing unacceptable toxic effects. Microbicides based on nonoxynol-9 (N9) and other detergents disrupt sperm, HSV and HIV membranes, and these agents are effective contraceptives. But paradoxically N9 fails to protect women against HIV and other STD pathogens, most likely because it causes toxic effects that increase susceptibility. The mouse HSV-2 vaginal transmission model reported here: (a) Directly tests for toxic effects that increase susceptibility to HSV-2, (b) Determines in vivo whether a microbicide can protect against HSV-2 transmission without causing toxicities that increase susceptibility, and (c) Identifies those toxic effects that best correlate with the increased HSV susceptibility. Methods Susceptibility was evaluated in progestin-treated mice by delivering a low-dose viral inoculum (0.1 ID50) at various times after delivering the candidate microbicide to detect whether the candidate increased the fraction of mice infected. Ten agents were tested – five detergents: nonionic (N9), cationic (benzalkonium chloride, BZK), anionic (sodium dodecylsulfate, SDS), the pair of detergents in C31G (C14AO and C16B); one surface active agent (chlorhexidine); two non-detergents (BufferGel®, and sulfonated polystyrene, SPS); and HEC placebo gel (hydroxyethylcellulose). Toxic effects were evaluated by histology, uptake of a 'dead cell' dye, colposcopy, enumeration of vaginal macrophages, and measurement of inflammatory cytokines. Results A single dose of N9 protected against HSV-2 for a few minutes but then rapidly increased susceptibility, which reached maximum at 12 hours. When applied at the minimal concentration needed for brief partial protection, all five detergents caused a subsequent increase in susceptibility at 12 hours of ~20–30-fold. Surprisingly, colposcopy failed to detect visible signs of the N9 toxic effect that increased susceptibility at 12 hours. Toxic effects that occurred contemporaneously with increased susceptibility were rapid exfoliation and re-growth of epithelial cell layers, entry of macrophages into the vaginal lumen, and release of one or more inflammatory cytokines (Il-1β, KC, MIP 1α, RANTES). The non-detergent microbicides and HEC placebo caused no significant increase in susceptibility or toxic effects. Conclusion This mouse HSV-2 model provides a sensitive method to detect microbicide-induced toxicities that increase susceptibility to infection. In this model, there was no concentration at which detergents provided protection without significantly increasing susceptibility. PMID:16740164

Site-specific probabilistic ecological risk assessment of a volatile chlorinated hydrocarbon-contaminated tidal estuary.

PubMed

Hunt, James; Birch, Gavin; Warne, Michael St J

2010-05-01

Groundwater contaminated with volatile chlorinated hydrocarbons (VCHs) was identified as discharging to Penrhyn Estuary, an intertidal embayment of Botany Bay, New South Wales, Australia. A screening-level hazard assessment of surface water in Penrhyn Estuary identified an unacceptable hazard to marine organisms posed by VCHs. Given the limitations of hazard assessments, the present study conducted a higher-tier, quantitative probabilistic risk assessment using the joint probability curve (JPC) method that accounted for variability in exposure and toxicity profiles to quantify risk (delta). Risk was assessed for 24 scenarios, including four areas of the estuary based on three exposure scenarios (low tide, high tide, and both low and high tides) and two toxicity scenarios (chronic no-observed-effect concentrations [NOEC] and 50% effect concentrations [EC50]). Risk (delta) was greater at low tide than at high tide and varied throughout the tidal cycle. Spatial distributions of risk in the estuary were similar using both NOEC and EC50 data. The exposure scenario including data combined from both tides was considered the most accurate representation of the ecological risk in the estuary. When assessing risk using data across both tides, the greatest risk was identified in the Springvale tributary (delta=25%)-closest to the source area-followed by the inner estuary (delta=4%) and the Floodvale tributary (delta=2%), with the lowest risk in the outer estuary (delta=0.1%), farthest from the source area. Going from the screening level ecological risk assessment (ERA) to the probabilistic ERA changed the risk from unacceptable to acceptable in 50% of exposure scenarios in two of the four areas within the estuary. The probabilistic ERA provided a more realistic assessment of risk than the screening-level hazard assessment. Copyright (c) 2010 SETAC.

5 CFR 432.105 - Proposing and taking action based on unacceptable performance.

Code of Federal Regulations, 2010 CFR

2010-01-01

... unacceptable performance. 432.105 Section 432.105 Administrative Personnel OFFICE OF PERSONNEL MANAGEMENT CIVIL SERVICE REGULATIONS PERFORMANCE BASED REDUCTION IN GRADE AND REMOVAL ACTIONS § 432.105 Proposing and taking action based on unacceptable performance. (a) Proposing action based on unacceptable performance...

The Perfect Place to Work? Australian Academic Libraries and Unacceptable Behaviour

ERIC Educational Resources Information Center

Moorcroft, Heather

2009-01-01

Despite the stereotype of libraries as peaceful retreats, unacceptable behaviour is a reality that desk staff have to deal with. This paper outlines the results of two surveys conducted at Charles Darwin University Library to investigate the extent to which this is a problem in Australian academic libraries. The first survey went to CAUL (Council…

Treatment of Gram-negative bacterial infections by potentiation of antibiotics.

PubMed

Zabawa, Thomas P; Pucci, Michael J; Parr, Thomas R; Lister, Troy

2016-10-01

Infections caused by antibiotic-resistant pathogens, particularly Gram-negative bacteria, represent significant treatment challenges for physicians resulting in high rates of morbidity and mortality. The outer membrane of Gram-negative bacteria acts as a permeability barrier to many compounds that would otherwise be effective antibacterial agents, including those effective against Gram-positive pathogens. Potentiator molecules disrupt this barrier allowing entry of otherwise impermeant molecules, thus providing a strategy to render multi-drug resistant pathogens susceptible to a broader range of antibiotics. Potentiator molecules are cationic and the mechanism of disruption involves interaction with the negatively charged outer membrane. This physical attribute, along with an often high degree of lipophilicity typically endears these molecules with unacceptable toxicity. Presented herein are examples of advanced potentiator molecules being evaluated for use in combination therapy for the treatment of resistant Gram-negative infections. Copyright © 2016 Elsevier Ltd. All rights reserved.

Milan Army Ammunition Plant remedial investigation report: Volume 1. Final report 89-91

DOE Office of Scientific and Technical Information (OSTI.GOV)

Okusu, N.; Hall, H.; Orndorff, A.

1991-12-09

A Remedial Investigation at the Milan Army Ammunition Plant, TN, was conducted for the US Army Toxic and Hazardous Materials Agency, under the terms of an Interagency Agreement with the State of Tennessee and the US Environmental Protection Agency. The study focused on the CERCLA site and selected RCRA regulated units identified by previous studies as potential sources of contamination. A broad range of chemicals including metals, explosives, and other organic compounds were found in source areas and in groundwater. The results of a risk assessment indicate that unacceptable levels of human health risks potentially exist. Conceptual models of sitemore » and unit characteristics were formulated to explain major findings, and areas not contributing to the problem were identified. For many source areas, major unknowns exist regarding hydrology, extent of contamination, and current and future impacts to groundwater quality.« less

Environmental Health

NASA Technical Reports Server (NTRS)

Pierson, Duane; James, John; Russo, Dane; Limero, Thomas; Beck, Steve; Groves, Theron

1999-01-01

The Environmental Health activity for the Extended Duration Orbiter Medical Project (EDOMP) was formed to develop an overall strategy for safeguarding crew members from potential airborne hazards anticipated on missions of extended duration. These efforts were necessary because of major modifications to the air revitalization system of the U.S. Space Shuttle and an increased potential for environmental health risks associated with longer space flights. Degradation of air quality in the Shuttle during a space flight mission has the potential to affect the performance of the crew not only during piloting, landing, or egress, but also during space flight. It was anticipated that the risk of significant deterioration in air quality would increase with extended mission lengths and could result from: (1) a major chemical contamination incident, such as a thermodegradation event or toxic leak, (2) continual accumulation of volatile organic compounds to unacceptable levels, (3) excessive levels of airborne particles, (4) excessive levels of microorganisms, or (5) accumulation of airborne pathogens.

Toward optimizing patient-specific IMRT QA techniques in the accurate detection of dosimetrically acceptable and unacceptable patient plans

PubMed Central

McKenzie, Elizabeth M.; Balter, Peter A.; Stingo, Francesco C.; Jones, Jimmy; Followill, David S.; Kry, Stephen F.

2014-01-01

Purpose: The authors investigated the performance of several patient-specific intensity-modulated radiation therapy (IMRT) quality assurance (QA) dosimeters in terms of their ability to correctly identify dosimetrically acceptable and unacceptable IMRT patient plans, as determined by an in-house-designed multiple ion chamber phantom used as the gold standard. A further goal was to examine optimal threshold criteria that were consistent and based on the same criteria among the various dosimeters. Methods: The authors used receiver operating characteristic (ROC) curves to determine the sensitivity and specificity of (1) a 2D diode array undergoing anterior irradiation with field-by-field evaluation, (2) a 2D diode array undergoing anterior irradiation with composite evaluation, (3) a 2D diode array using planned irradiation angles with composite evaluation, (4) a helical diode array, (5) radiographic film, and (6) an ion chamber. This was done with a variety of evaluation criteria for a set of 15 dosimetrically unacceptable and 9 acceptable clinical IMRT patient plans, where acceptability was defined on the basis of multiple ion chamber measurements using independent ion chambers and a phantom. The area under the curve (AUC) on the ROC curves was used to compare dosimeter performance across all thresholds. Optimal threshold values were obtained from the ROC curves while incorporating considerations for cost and prevalence of unacceptable plans. Results: Using common clinical acceptance thresholds, most devices performed very poorly in terms of identifying unacceptable plans. Grouping the detector performance based on AUC showed two significantly different groups. The ion chamber, radiographic film, helical diode array, and anterior-delivered composite 2D diode array were in the better-performing group, whereas the anterior-delivered field-by-field and planned gantry angle delivery using the 2D diode array performed less well. Additionally, based on the AUCs, there was no significant difference in the performance of any device between gamma criteria of 2%/2 mm, 3%/3 mm, and 5%/3 mm. Finally, optimal cutoffs (e.g., percent of pixels passing gamma) were determined for each device and while clinical practice commonly uses a threshold of 90% of pixels passing for most cases, these results showed variability in the optimal cutoff among devices. Conclusions: IMRT QA devices have differences in their ability to accurately detect dosimetrically acceptable and unacceptable plans. Field-by-field analysis with a MapCheck device and use of the MapCheck with a MapPhan phantom while delivering at planned rotational gantry angles resulted in a significantly poorer ability to accurately sort acceptable and unacceptable plans compared with the other techniques examined. Patient-specific IMRT QA techniques in general should be thoroughly evaluated for their ability to correctly differentiate acceptable and unacceptable plans. Additionally, optimal agreement thresholds should be identified and used as common clinical thresholds typically worked very poorly to identify unacceptable plans. PMID:25471949

Effect of storage temperature on the activity of submitochondrial particles.

PubMed

Doherty, Francis G

2008-12-01

The submitochondrial particle (SMP) assay employs processed mammalian mitchondria to assess the toxicity of chemical contaminants in aqueous solutions. Particles and associated reagents are commercially available to support two individual procedures, the electron transfer (ETr) and reverse electron transfer (RET) assays. The objective of the present study was to assess the effect of storage temperature on SMP activity. One RET and one ETr assay were conducted with sodium dodecylsulfate on each of two vials of particles stored at -20 and -80 degrees C at periodic intervals over a six-month span. Results demonstrated that SMP could remain active in either assay through six months of storage at either temperature. However, there were isolated vials of particles stored at -20 degrees C that exhibited unacceptable reductions in activity for both the ETr and the RET assays that were not related to storage duration. These results were used to develop guidance in assessing the acceptability of particle activity in SMP assays.

Efficacy of Letrozole as First-Line Treatment of Postmenopausal Women with Hormone Receptor-Positive Metastatic Breast Cancer in Korea.

PubMed

Beom, Seung Hoon; Oh, Jisu; Kim, Tae-Yong; Lee, Kyung-Hun; Yang, Yaewon; Suh, Koung Jin; Moon, Hyeong-Gon; Han, Sae-Won; Oh, Do-Youn; Han, Wonshik; Kim, Tae-You; Noh, Dong-Young; Im, Seock-Ah

2017-04-01

Letrozole showed efficacy and generally favorable toxicities, along with the convenience of oral administration in postmenopausal patients with hormone receptor (HR)-positive metastatic breast cancer (MBC). To the best of our knowledge, there have been no reports of the clinical outcomes in Korean patients, although letrozole is widely used in practice. Therefore, this studywas conducted to affirm the efficacy and toxicities of letrozole in Korean patients. This study retrospectively analyzed 84 HR-positive MBC patients who had been treated with letrozole from January 2001 to December 2012. Clinicopathological characteristics and treatment history were extracted from medicalrecords. All patients received 2.5 mg letrozole once a day until there were disease progressions or unacceptable toxicity. Progression-free survival (PFS) was the primary endpoint, and secondary endpoints were overall survival (OS), objective response rate (ORR), and toxicity. The median age of the subjects was 59.3 years. Letrozole treatment resulted in a median PFS of 16.8 months (95% confidence interval [CI], 9.8 to 23.8) and a median OS of 56.4 months (95% CI, 38.1 to 74.7). The ORR was 36.9% for the 84 patients with measurable lesions. Multivariate analysis revealed symptomatic visceral disease (hazard ratio, 3.437; 95% CI, 1.576 to 7.495; p=0.002) and a disease-free interval ≤ 2 years (hazard ratio, 2.697; 95% CI, 1.262 to 5.762; p=0.010) were independently associated with shorter PFS. However, sensitivity to adjuvant hormone treatment was not related to PFS. Letrozole was generally well tolerated. Letrozole showed considerable efficacy and tolerability as a first-line treatment in postmenopausal patients with HR-positive MBC.

Fire Detection Tradeoffs as a Function of Vehicle Parameters

NASA Technical Reports Server (NTRS)

Urban, David L.; Dietrich, Daniel L.; Brooker, John E.; Meyer, Marit E.; Ruff, Gary A.

2016-01-01

Fire survivability depends on the detection of and response to a fire before it has produced an unacceptable environment in the vehicle. This detection time is the result of interplay between the fire burning and growth rates; the vehicle size; the detection system design; the transport time to the detector (controlled by the level of mixing in the vehicle); and the rate at which the life support system filters the atmosphere, potentially removing the detected species or particles. Given the large differences in critical vehicle parameters (volume, mixing rate and filtration rate) the detection approach that works for a large vehicle (e.g. the ISS) may not be the best choice for a smaller crew capsule. This paper examines the impact of vehicle size and environmental control and life support system parameters on the detectability of fires in comparison to the hazard they present. A lumped element model was developed that considers smoke, heat, and toxic product release rates in comparison to mixing and filtration rates in the vehicle. Recent work has quantified the production rate of smoke and several hazardous species from overheated spacecraft polymers. These results are used as the input data set in the lumped element model in combination with the transport behavior of major toxic products released by overheating spacecraft materials to evaluate the necessary alarm thresholds to enable appropriate response to the fire hazard.

40 CFR Appendix M to Subpart G - Unacceptable Substitutes Listed in the September 30, 2004 Final Rule, Effective November 29, 2004

Code of Federal Regulations, 2010 CFR

2010-07-01

... —Rigid polyurethane slabstock and other foams —Polystyrene extruded insulation boardstock and billet...—Unacceptable Substitutes Listed in the September 30, 2004 Final Rule, Effective November 29, 2004 Foam Blowing—Unacceptable Substitutes End-use Substitute Decision Comments All foam end-uses: HCFC-141b Unacceptable...

40 CFR Appendix M to Subpart G - Unacceptable Substitutes Listed in the September 30, 2004 Final Rule, Effective November 29, 2004

Code of Federal Regulations, 2012 CFR

2012-07-01

... —Rigid polyurethane slabstock and other foams —Polystyrene extruded insulation boardstock and billet...—Unacceptable Substitutes Listed in the September 30, 2004 Final Rule, Effective November 29, 2004 Foam Blowing—Unacceptable Substitutes End-use Substitute Decision Comments All foam end-uses: HCFC-141b Unacceptable...

40 CFR Appendix M to Subpart G - Unacceptable Substitutes Listed in the September 30, 2004 Final Rule, Effective November 29, 2004

Code of Federal Regulations, 2011 CFR

2011-07-01

... —Rigid polyurethane slabstock and other foams —Polystyrene extruded insulation boardstock and billet...—Unacceptable Substitutes Listed in the September 30, 2004 Final Rule, Effective November 29, 2004 Foam Blowing—Unacceptable Substitutes End-use Substitute Decision Comments All foam end-uses: HCFC-141b Unacceptable...

Evaluation of triclosan in Minnesota lakes and rivers: Part I - ecological risk assessment.

PubMed

Lyndall, Jennifer; Barber, Timothy; Mahaney, Wendy; Bock, Michael; Capdevielle, Marie

2017-08-01

Triclosan, an antimicrobial compound found in consumer products, may be introduced into the aquatic environment via residual concentrations in municipal wastewater treatment effluent. We conducted an aquatic risk assessment that incorporated the available measured triclosan data from Minnesota lakes and rivers. Although only data reported from Minnesota were considered in the risk assessment, the developed toxicity benchmarks can be applied to other environments. The data were evaluated using a series of environmental fate models to ensure the data were internally consistent and to fill any data gaps. Triclosan was not detected in over 75% of the 567 surface water and sediment samples. Measured environmental data were used to model the predicted environmental exposures to triclosan in surface water, surface sediment, and biota tissues. Toxicity benchmarks based on fatty acid synthesis inhibition and narcosis were determined for aquatic organisms based, in part, on a species sensitivity distribution of chronic toxicity thresholds from the available literature. Predicted and measured environmental concentrations for surface water, sediment, and tissue were below the effects benchmarks, indicating that exposure to triclosan in Minnesota lakes and rivers would not pose an unacceptable risk to aquatic organisms. Copyright © 2017 Elsevier Inc. All rights reserved.

Efficacy of BGJ398, a Fibroblast Growth Factor Receptor 1-3 Inhibitor, in Patients with Previously Treated Advanced Urothelial Carcinoma with FGFR3 Alterations.

PubMed

Pal, Sumanta K; Rosenberg, Jonathan E; Hoffman-Censits, Jean H; Berger, Raanan; Quinn, David I; Galsky, Matthew D; Wolf, Juergen; Dittrich, Christian; Keam, Bhumsuk; Delord, Jean-Pierre; Schellens, Jan H M; Gravis, Gwenaelle; Medioni, Jacques; Maroto, Pablo; Sriuranpong, Virote; Charoentum, Chaiyut; Burris, Howard A; Grünwald, Viktor; Petrylak, Daniel; Vaishampayan, Ulka; Gez, Eliahu; De Giorgi, Ugo; Lee, Jae-Lyun; Voortman, Jens; Gupta, Sumati; Sharma, Sunil; Mortazavi, Amir; Vaughn, David J; Isaacs, Randi; Parker, Katie; Chen, Xueying; Yu, Kun; Porter, Dale; Graus Porta, Diana; Bajorin, Dean F

2018-05-30

BGJ398, a potent and selective pan-FGFR antagonist, was prospectively evaluated in patients with metastatic urothelial carcinoma bearing a diverse array of FGFR3 alterations. Patients ( N = 67) who were unable to receive platinum chemotherapy were enrolled. The majority (70.1%) had received two or more prior antineoplastic therapies. BGJ398 was administered orally at 125 mg/day on a 3 weeks on, 1 week off schedule until unacceptable toxicity or progression. The primary endpoint was the response rate. Among 67 patients treated, an overall response rate of 25.4% was observed and an additional 38.8% of patients had disease stabilization, translating to a disease control rate of 64.2%. The most common treatment-emergent toxicities were hyperphosphatemia, elevated creatinine, fatigue, constipation, and decreased appetite. Further examination of BGJ398 in this disease setting is warranted. SIGNIFICANCE: BJG398 is active in patients with alterations in FGFR3 , resulting in both reductions in tumor volume and stabilization of disease. Our data highlight putative mechanisms of resistance to the agent, which may be useful in following disease status. Cancer Discov; 8(7); 1-10. ©2018 AACR. ©2018 American Association for Cancer Research.

Real-Time Pretreatment Review Limits Unacceptable Deviations on a Cooperative Group Radiation Therapy Technique Trial: Quality Assurance Results of RTOG 0933

DOE Office of Scientific and Technical Information (OSTI.GOV)

Gondi, Vinai, E-mail: vgondi@chicagocancer.org; University of Wisconsin School of Medicine & Public Health, Madison, Wisconsin; Cui, Yunfeng

2015-03-01

Purpose: RTOG 0933 was a phase II trial of hippocampal avoidance during whole brain radiation therapy for patients with brain metastases. The results demonstrated improvement in short-term memory decline, as compared with historical control individuals, and preservation of quality of life. Integral to the conduct of this trial were quality assurance processes inclusive of pre-enrollment credentialing and pretreatment centralized review of enrolled patients. Methods and Materials: Before enrolling patients, all treating physicians and sites were required to successfully complete a “dry-run” credentialing test. The treating physicians were credentialed based on accuracy of magnetic resonance imaging–computed tomography image fusion and hippocampal andmore » normal tissue contouring, and the sites were credentialed based on protocol-specified dosimetric criteria. Using the same criteria, pretreatment centralized review of enrolled patients was conducted. Physicians enrolling 3 consecutive patients without unacceptable deviations were permitted to enroll further patients without pretreatment review, although their cases were reviewed after treatment. Results: In all, 113 physicians and 84 sites were credentialed. Eight physicians (6.8%) failed hippocampal contouring on the first attempt; 3 were approved on the second attempt. Eight sites (9.5%) failed intensity modulated radiation therapy planning on the first attempt; all were approved on the second attempt. One hundred thirteen patients were enrolled in RTOG 0933; 100 were analyzable. Eighty-seven cases were reviewed before treatment; 5 (5.7%) violated the eligibility criteria, and 21 (24%) had unacceptable deviations. With feedback, 18 cases were approved on the second attempt and 2 cases on the third attempt. One patient was treated off protocol. Twenty-two cases were reviewed after treatment; 1 (4.5%) violated the eligibility criteria, and 5 (23%) had unacceptable deviations. Conclusions: Although >95% of the cases passed the pre-enrollment credentialing, the pretreatment centralized review disqualified 5.7% of reviewed cases, prevented unacceptable deviations in 24% of reviewed cases, and limited the final unacceptable deviation rate to 5%. Thus, pretreatment review is deemed necessary in future hippocampal avoidance trials and is potentially useful in other similarly challenging radiation therapy technique trials.« less

A North Central Cancer Treatment Group Phase II trial of 9-aminocamptothecin in previously untreated patients with measurable metastatic colorectal carcinoma.

PubMed

Pitot, H C; Knost, J A; Mahoney, M R; Kugler, J; Krook, J E; Hatfield, A K; Sargent, D J; Goldberg, R M

2000-10-15

Topoisomerase I inhibitors have demonstrated clinical activity in patients with metastatic colorectal carcinoma. The authors performed a Phase II study to evaluate the objective tumor response rate of 2 different doses and schedules of 9-aminocamptothecin (9-AC) in previously untreated patients with measurable recurrent metastatic colorectal carcinoma. Fifty-one patients were registered. One schedule evaluated 9-AC given at 1100 microgram/m(2)/24 hours by continuous infusion for 72 hours along with granulocyte-colony stimulating factor at 5 microgram/kg/day on Days 5 through 12. Another schedule involved 9-AC at 480 microgram/m(2)/24 hours by continuous infusion for 120 hours on Days 1, 8, and 15 given every 4 weeks. Forty-eight of 51 patients (94%) were evaluable (28 patients who received 72-hour infusion and 20 patients who received 120-hour infusion) for response and toxicity. Significant hematologic toxicities were encountered, especially with the 72-hour infusion schedule, in which 43% (12 of 28) and 28% (8 of 28) experienced Grade 4 (National Cancer Institute Common Toxicity Criteria) leukopenia and thrombocytopenia, respectively. Grade 4 neutropenia was encountered in 61% (17 of 28) and 11% (2 of 19) of patients on the 72-hour and 120-hour infusion schedules, respectively. Diarrhea, nausea, vomiting, and hepatotoxicity were troublesome nonhematologic toxicities. Seventy-nine percent (11 of 14) and 57% (4 of 7) of the patients experiencing Grade 3 or 4 nonhematologic toxicity were on the 72-hour infusion schedule. Three patients died of chemotherapy-related toxicity. One response was observed in 48 evaluable patients (2%). 9-AC did not demonstrate sufficient antitumor activity and had unacceptable toxicity in previously untreated patients with metastatic colorectal carcinoma. Copyright 2000 American Cancer Society.

A Multicenter Phase II Trial of S-1 With Concurrent Radiation Therapy for Locally Advanced Pancreatic Cancer

DOE Office of Scientific and Technical Information (OSTI.GOV)

Ikeda, Masafumi, E-mail: masikeda@east.ncc.go.jp; Ioka, Tatsuya; Ito, Yoshinori

2013-01-01

Purpose: The aim of this trial was to evaluate the efficacy and toxicity of S-1 and concurrent radiation therapy for locally advanced pancreatic cancer (PC). Methods and Materials: Locally advanced PC patients with histologically or cytologically confirmed adenocarcinoma or adenosquamous carcinoma, who had no previous therapy were enrolled. Radiation therapy was delivered through 3 or more fields at a total dose of 50.4 Gy in 28 fractions over 5.5 weeks. S-1 was administered orally at a dose of 80 mg/m{sup 2} twice daily on the day of irradiation during radiation therapy. After a 2- to 8-week break, patients received amore » maintenance dose of S-1 (80 mg/m{sup 2}/day for 28 consecutive days, followed by a 14-day rest period) was then administered until the appearance of disease progression or unacceptable toxicity. The primary efficacy endpoint was survival, and the secondary efficacy endpoints were progression-free survival, response rate, and serum carbohydrate antigen 19-9 (CA19-9) response; the safety endpoint was toxicity. Results: Of the 60 evaluable patients, 16 patients achieved a partial response (27%; 95% confidence interval [CI], 16%-40%). The median progression-free survival period, overall survival period, and 1-year survival rate of the evaluable patients were 9.7 months (95% CI, 6.9-11.6 months), 16.2 months (95% CI, 13.5-21.3 months), and 72% (95%CI, 59%-82%), respectively. Of the 42 patients with a pretreatment serum CA19-9 level of {>=}100 U/ml, 34 (81%) patients showed a decrease of greater than 50%. Leukopenia (6 patients, 10%) and anorexia (4 patients, 7%) were the major grade 3-4 toxicities with chemoradiation therapy. Conclusions: The effect of S-1 with concurrent radiation therapy in patients with locally advanced PC was found to be very favorable, with only mild toxicity.« less

Phase out persistent, bioaccumulative or highly toxic chemicals.

PubMed

Easthope, Tracey; Valeriano, Laurie

2007-01-01

Chemicals such as lindane, lead compounds, and some brominated flame retardants and organophosphate pesticides are examples of persistent, bio-accumulative, and/or highly toxic chemicals that continue to be used in commerce, although strong evidence exists that they pose threats to human and ecosystem health. These and other chemicals, by virtue of their characteristics, are very difficult to manage without unacceptable threats to workers, the environment, or ecosystems. Chemicals that cannot be safely managed should be prioritized for phase out. A transparent process to further identify and prioritize the list of chemicals for phase out is needed. With few exceptions, the U.S. government lacks the authority or an efficient policy instrument to prevent these high-priority chemicals from being used in products and processes or released to the environment. It also has been very difficult for state and local governments to restrict these chemicals. Policy instruments to efficiently and effectively phase out problematic chemicals are needed at all levels of government.

Peptide vaccines and peptidomimetics targeting HER and VEGF proteins may offer a potentially new paradigm in cancer immunotherapy

PubMed Central

Kaumaya, Pravin TP; Foy, Kevin Chu

2013-01-01

The ErbB family (HER-1, HER-2, HER-3 and HER-4) of receptor tyrosine kinases has been the focus of cancer immunotherapeutic strategies while antiangiogenic therapies have focused on VEGF and its receptors VEGFR-1 and VEGFR-2. Agents targeting receptor tyrosine kinases in oncology include therapeutic antibodies to receptor tyrosine kinase ligands or the receptors themselves, and small-molecule inhibitors. Many of the US FDA-approved therapies targeting HER-2 and VEGF exhibit unacceptable toxicities, and show problems of efficacy, development of resistance and unacceptable safety profiles that continue to hamper their clinical progress. The combination of dif ferent peptide vaccines and peptidomimetics targeting specific molecular pathways that are dysregulated in tumors may potentiate anticancer immune responses, bypass immune tolerance and circumvent resistance mechanisms. The focus of this review is to discuss efforts in our laboratory spanning two decades of rationally developing peptide vaccines and therapeutics for breast cancer. This review highlights the prospective benefit of a new, untapped category of therapies biologically targeted to EGF receptor (HER-1), HER-2 and VEGF with potential peptide ‘blockbusters‘ that could lay the foundation of a new paradigm in cancer immunotherapy by creating clinical breakthroughs for safe and efficacious cancer cures. PMID:22894670

Toward optimizing patient-specific IMRT QA techniques in the accurate detection of dosimetrically acceptable and unacceptable patient plans.

PubMed

McKenzie, Elizabeth M; Balter, Peter A; Stingo, Francesco C; Jones, Jimmy; Followill, David S; Kry, Stephen F

2014-12-01

The authors investigated the performance of several patient-specific intensity-modulated radiation therapy (IMRT) quality assurance (QA) dosimeters in terms of their ability to correctly identify dosimetrically acceptable and unacceptable IMRT patient plans, as determined by an in-house-designed multiple ion chamber phantom used as the gold standard. A further goal was to examine optimal threshold criteria that were consistent and based on the same criteria among the various dosimeters. The authors used receiver operating characteristic (ROC) curves to determine the sensitivity and specificity of (1) a 2D diode array undergoing anterior irradiation with field-by-field evaluation, (2) a 2D diode array undergoing anterior irradiation with composite evaluation, (3) a 2D diode array using planned irradiation angles with composite evaluation, (4) a helical diode array, (5) radiographic film, and (6) an ion chamber. This was done with a variety of evaluation criteria for a set of 15 dosimetrically unacceptable and 9 acceptable clinical IMRT patient plans, where acceptability was defined on the basis of multiple ion chamber measurements using independent ion chambers and a phantom. The area under the curve (AUC) on the ROC curves was used to compare dosimeter performance across all thresholds. Optimal threshold values were obtained from the ROC curves while incorporating considerations for cost and prevalence of unacceptable plans. Using common clinical acceptance thresholds, most devices performed very poorly in terms of identifying unacceptable plans. Grouping the detector performance based on AUC showed two significantly different groups. The ion chamber, radiographic film, helical diode array, and anterior-delivered composite 2D diode array were in the better-performing group, whereas the anterior-delivered field-by-field and planned gantry angle delivery using the 2D diode array performed less well. Additionally, based on the AUCs, there was no significant difference in the performance of any device between gamma criteria of 2%/2 mm, 3%/3 mm, and 5%/3 mm. Finally, optimal cutoffs (e.g., percent of pixels passing gamma) were determined for each device and while clinical practice commonly uses a threshold of 90% of pixels passing for most cases, these results showed variability in the optimal cutoff among devices. IMRT QA devices have differences in their ability to accurately detect dosimetrically acceptable and unacceptable plans. Field-by-field analysis with a MapCheck device and use of the MapCheck with a MapPhan phantom while delivering at planned rotational gantry angles resulted in a significantly poorer ability to accurately sort acceptable and unacceptable plans compared with the other techniques examined. Patient-specific IMRT QA techniques in general should be thoroughly evaluated for their ability to correctly differentiate acceptable and unacceptable plans. Additionally, optimal agreement thresholds should be identified and used as common clinical thresholds typically worked very poorly to identify unacceptable plans.

A phase II trial of imatinib mesylate in patients with biochemical relapse of prostate cancer after definitive local therapy.

PubMed

Lin, Amy M; Rini, Brian I; Weinberg, Vivian; Fong, Kristen; Ryan, Charles J; Rosenberg, Jonathan E; Fong, Lawrence; Small, Eric J

2006-10-01

To determine the biological effects of imatinib mesylate (STI-571, Gleevec; Novartis Pharmaceuticals, Inc., East Hanover, NJ, USA), as measured by prostate-specific antigen (PSA) kinetics in men with biochemical relapse of prostate cancer after definitive local therapy. Men with prostate cancer, who had had definitive local therapy, with nonmetastatic recurrent disease as manifested by a rising PSA level, were enrolled on this phase II trial. Men received 400 mg of imatinib mesylate orally twice daily and continuously until disease progression or unacceptable toxicity. The PSA level was measured monthly. In all, 20 men with biochemically relapsed prostate cancer were treated. The median pretreatment PSA level was 5.4 ng/mL. Of the 19 evaluable men, one achieved a >or= 50% reduction in PSA level and two had decreases of <50%. For the 16 men in whom the on-treatment PSA doubling time (PSADT) could be calculated (those with increasing PSA level) the median PSADT did not increase significantly (5.8 vs 7.2 months, P = 0.64). Eleven of 20 men discontinued therapy due to toxicity and the trial was stopped early due to toxicity. Based on the lack of PSA modulation and pronounced toxicities leading to early closure of this trial, further study of single-agent imatinib mesylate at this dose (400 mg twice daily) cannot be recommended in this patient population.

Dual Inhibition of the Epidermal Growth Factor Receptor Pathway with Cetuximab and Erlotinib: A Phase I Study in Patients with Advanced Solid Malignancies

PubMed Central

Guarino, Michael J.; Schneider, Charles J.; Hosford, Martha A.; Brahmer, Julie R.; Rudin, Charles M.; Finckenstein, Friedrich Graf; Philip-Norton, Robyn E.; Lu, Haolan; Weber, Martin R.; Ettinger, David S.

2017-01-01

Purpose To determine the optimal dose of the antiepidermal growth factor receptor (EGFR) monoclonal antibody cetuximab that can be safely administered in combination with a standard daily dose of erlotinib in patients with advanced solid malignancies. Patients and Methods Patients with advanced solid malignancies who had failed standard chemotherapies received escalating doses of cetuximab without a loading dose (100, 200, 250 mg/m2 i.v. weekly) in combination with a fixed dose of erlotinib (150 mg daily orally) until disease progression or unacceptable toxicity. Results Twenty-two patients were treated, including 14 patients (64%) with non-small cell lung cancer. Twenty patients received combination treatment at the highest dose level for a median of 5.5 weeks (range, 1–31 weeks). One dose-limiting toxicity was observed: grade 3 skin rash. Overall, the most common adverse events (any grade, grade 3/4) were consistent with the safety profiles of the individual drugs: acneform rash (100%, 9%), diarrhea (77%, 5%), and hypomagnesemia (59%, 12%). Seven of 18 evaluable patients (38.9%) had stable disease lasting for a median of 16.6 weeks (range, 6.1–25.1 weeks). Conclusion Dual EGFR inhibition with cetuximab and erlotinib is feasible; the observed toxicities were manageable and consistent with the safety profiles of the individual drugs. The recommended doses for phase II studies are 250 mg/m2 i.v. weekly for cetuximab and 150 mg daily orally for erlotinib. PMID:19182243

A prospective pilot study on early toxicity from a simultaneously integrated boost technique for canine sinonasal tumours using image-guided intensity-modulated radiation therapy.

PubMed

Soukup, A; Meier, V; Pot, S; Voelter, K; Rohrer Bley, C

2018-05-14

In order to overcome the common local treatment failure of canine sinonasal tumours, integrated boost techniques were tried in the cobalt/orthovoltage era, but dismissed because of unacceptable early (acute) toxicity. Intriguingly, a recent calculation study of a simultaneously integrated boost (SIB) technique for sinonasal irradiation using intensity-modulated radiation therapy (IMRT) predicted theoretical feasibility. In this prospective pilot study we applied a commonly used protocol of 10 × 4.2 Gy to the planning target volume (PTV) with a 20%-SIB dose to the gross tumour volume (GTV). Our hypothesis expected this dose escalation to be clinically tolerable if applied with image-guided IMRT. We included 9 dogs diagnosed with sinonasal tumours without local/distant metastases. For treatment planning, organs at risk were contoured according to strict anatomical guidelines. Planning volume extensions (GTV/CTV/PTV) were standardized to minimize interplanner variability. Treatments were applied with rigid patient positioning and verified daily with image guidance. After radiation therapy, we set focus on early ophthalmologic complications as well as mucosal and cutaneous toxicity. Early toxicity was evaluated at week 1, 2, 3, 8 and 12 after radiotherapy. Only mild ophthalmologic complications were found. Three patients (33%) had self-limiting moderate to severe early toxicity (grade 3 mucositis) which was managed medically. No patient developed ulcerations/haemorrhage/necrosis of skin/mucosa. The SIB protocol applied with image-guided IMRT to treat canine sinonasal tumours led to clinically acceptable side effects. The suspected increased tumour control probability and the risk of late toxicity with the used dose escalation of 20% has to be further investigated. © 2018 John Wiley & Sons Ltd.

A phase II study of high-dose celecoxib and metronomic 'low-dose' cyclophosphamide and methotrexate in patients with relapsed and refractory lymphoma.

PubMed

El Bary, Naser Abd; Hashem, Tarek; Metwally, Hasan; Ghany, Ashraf Abd; El Mageed, Hager Abd

2010-01-01

Relapsed, histologically aggressive non-Hodgkin lymphoma (NHL) has a poor prognosis; relapsed patients who do not respond to second line therapy or are unfit for BMT have a worse prognosis. Angiogenesis is increased in aggressive NHL and could be targeted by selective cyclooxygenase-2 inhibition and metronomic chemotherapy. We assessed the toxicity of metronomic chemotherapy and the response and progression-free survival in patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL). We prospectively studied 41 patients with a diagnosis of relapsed and/or refractory DLBCL who may have received any number of preceding therapies (as long as one included an anthracycline) and were not candidates for bone marrow transplantation. They received oral cyclophosphamide (50 mg every day), oral methotrexate (2.5 mg 4 times/week) and high-dose oral celecoxib (400 mg twice daily) until there was disease progression or unacceptable toxicity. All 41 patients (median age, 56 years) were evaluable for toxicity and response, with a median follow up of 9.1 months (range, 4-35 months). At relapse, 51.2% had a high international prognostic index. The treatment protocol was well tolerated with no major toxicities. The most common toxicities were fatigue (61%), nausea (22%), neutropenia (19.5%), and anemia (22%). In 31.7% there was a partial response and 48.8% had stable disease. Progression-free survival was 12 months. The median response duration was 10 months. We conclude that metronomic chemotherapy can be used for patients with relapsed and or refractory DLBCL with reasonable outcome and acceptable toxicity. Standard approaches such as hematopoietic stem cell transplantation and chemo-immunotherapy combinations should be explored prior to a decision on metronomic chemotherapy.

40 CFR Appendix E to Subpart G of... - Unacceptable Substitutes Listed in the January 26, 1999 Final Rule, Effective January 26, 1999

Code of Federal Regulations, 2011 CFR

2011-07-01

... Refrigeration and Air-Conditioning Sector Unacceptable Substitutes End-use Substitute Decision Comments All refrigeration and air-conditioning end uses MT-31 Unacceptable Chemical contained in this blend presents...

40 CFR Appendix F to Subpart G of... - Unacceptable Substitutes Listed in the January 26, 1999 Final Rule, Effective January 26, 1999

Code of Federal Regulations, 2010 CFR

2010-07-01

... Refrigeration and Air-Conditioning Sector UnacceptabLe Substitutes End-use Substitute Decision Comments All refrigeration and air-conditioning end uses Hexafluoropropylene (HFP) and all HFP-containing blends Unacceptable...

40 CFR Appendix E to Subpart G of... - Unacceptable Substitutes Listed in the January 26, 1999 Final Rule, Effective January 26, 1999

Code of Federal Regulations, 2013 CFR

2013-07-01

... Refrigeration and Air-Conditioning Sector Unacceptable Substitutes End-use Substitute Decision Comments All refrigeration and air-conditioning end uses MT-31 Unacceptable Chemical contained in this blend presents...

40 CFR Appendix E to Subpart G of... - Unacceptable Substitutes Listed in the January 26, 1999 Final Rule, Effective January 26, 1999

Code of Federal Regulations, 2012 CFR

2012-07-01

... Refrigeration and Air-Conditioning Sector Unacceptable Substitutes End-use Substitute Decision Comments All refrigeration and air-conditioning end uses MT-31 Unacceptable Chemical contained in this blend presents...

40 CFR Appendix E to Subpart G of... - Unacceptable Substitutes Listed in the January 26, 1999 Final Rule, Effective January 26, 1999

Code of Federal Regulations, 2010 CFR

2010-07-01

... Refrigeration and Air-Conditioning Sector Unacceptable Substitutes End-use Substitute Decision Comments All refrigeration and air-conditioning end uses MT-31 Unacceptable Chemical contained in this blend presents...

40 CFR Appendix F to Subpart G of... - Unacceptable Substitutes Listed in the January 26, 1999 Final Rule, Effective January 26, 1999

Code of Federal Regulations, 2012 CFR

2012-07-01

... Refrigeration and Air-Conditioning Sector UnacceptabLe Substitutes End-use Substitute Decision Comments All refrigeration and air-conditioning end uses Hexafluoropropylene (HFP) and all HFP-containing blends Unacceptable...

40 CFR Appendix F to Subpart G of... - Unacceptable Substitutes Listed in the January 26, 1999 Final Rule, Effective January 26, 1999

Code of Federal Regulations, 2013 CFR

2013-07-01

... Refrigeration and Air-Conditioning Sector UnacceptabLe Substitutes End-use Substitute Decision Comments All refrigeration and air-conditioning end uses Hexafluoropropylene (HFP) and all HFP-containing blends Unacceptable...

40 CFR Appendix F to Subpart G of... - Unacceptable Substitutes Listed in the January 26, 1999 Final Rule, Effective January 26, 1999

Code of Federal Regulations, 2011 CFR

2011-07-01

... Refrigeration and Air-Conditioning Sector UnacceptabLe Substitutes End-use Substitute Decision Comments All refrigeration and air-conditioning end uses Hexafluoropropylene (HFP) and all HFP-containing blends Unacceptable...

40 CFR Appendix E to Subpart G of... - Unacceptable Substitutes Listed in the January 26, 1999 Final Rule, Effective January 26, 1999

Code of Federal Regulations, 2014 CFR

2014-07-01

... Refrigeration and Air-Conditioning Sector Unacceptable Substitutes End-use Substitute Decision Comments All refrigeration and air-conditioning end uses MT-31 Unacceptable Chemical contained in this blend presents...

40 CFR Appendix F to Subpart G of... - Unacceptable Substitutes Listed in the January 26, 1999 Final Rule, Effective January 26, 1999

Code of Federal Regulations, 2014 CFR

2014-07-01

... Refrigeration and Air-Conditioning Sector UnacceptabLe Substitutes End-use Substitute Decision Comments All refrigeration and air-conditioning end uses Hexafluoropropylene (HFP) and all HFP-containing blends Unacceptable...

Comparative Evaluation of Biological Performance, Biosecurity, and Availability of Cellulose-Based Absorbable Hemostats.

PubMed

Wu, Yadong; Wang, Fang; Huang, Yudong

2018-05-01

Hemorrhage remains a leading cause of death after trauma, and developing a hemostat with excellent performance and good biosecurity is an extremely active area of research and commercial product development. Although oxidized regenerated cellulose (ORC) has been developed to address these problems, it is not always efficient and its biosecurity is not perfect. We aimed to refine ORC via a simple and mild neutralization method. The prepared neutralized oxidized regenerated cellulose (NORC) showed a superior gel property due to its chemical structure. The biological performance of both ORC and NORC was systematically evaluated; the results showed that ORC would induce erythema and edema in the irritation test, whereas NORC did not cause any adverse inflammation, indicating NORC had desirable biocompatibility. We further demonstrated that NORC confirmed to the toxicity requirements of International Organization for Standardization (ISO) standards; however, ORC showed an unacceptable cytotoxicity. The rabbit hepatic defect model stated that NORC exhibited better ability of hemostasis, which was attributed to its significant gel performance in physiological environment.

19 CFR 152.108 - Unacceptable bases of appraisement.

Code of Federal Regulations, 2013 CFR

2013-04-01

... 19 Customs Duties 2 2013-04-01 2013-04-01 false Unacceptable bases of appraisement. 152.108 Section 152.108 Customs Duties U.S. CUSTOMS AND BORDER PROTECTION, DEPARTMENT OF HOMELAND SECURITY... Merchandise § 152.108 Unacceptable bases of appraisement. For the purposes of this subpart, imported...

19 CFR 152.108 - Unacceptable bases of appraisement.

Code of Federal Regulations, 2011 CFR

2011-04-01

... 19 Customs Duties 2 2011-04-01 2011-04-01 false Unacceptable bases of appraisement. 152.108 Section 152.108 Customs Duties U.S. CUSTOMS AND BORDER PROTECTION, DEPARTMENT OF HOMELAND SECURITY... Merchandise § 152.108 Unacceptable bases of appraisement. For the purposes of this subpart, imported...

19 CFR 152.108 - Unacceptable bases of appraisement.

Code of Federal Regulations, 2012 CFR

2012-04-01

... 19 Customs Duties 2 2012-04-01 2012-04-01 false Unacceptable bases of appraisement. 152.108 Section 152.108 Customs Duties U.S. CUSTOMS AND BORDER PROTECTION, DEPARTMENT OF HOMELAND SECURITY... Merchandise § 152.108 Unacceptable bases of appraisement. For the purposes of this subpart, imported...

19 CFR 152.108 - Unacceptable bases of appraisement.

Code of Federal Regulations, 2010 CFR

2010-04-01

... 19 Customs Duties 2 2010-04-01 2010-04-01 false Unacceptable bases of appraisement. 152.108 Section 152.108 Customs Duties U.S. CUSTOMS AND BORDER PROTECTION, DEPARTMENT OF HOMELAND SECURITY... Merchandise § 152.108 Unacceptable bases of appraisement. For the purposes of this subpart, imported...

Continuation maintenance therapy with S-1 in chemotherapy-naïve patients with advanced squamous cell lung cancer.

PubMed

Suzuki, Seiichiro; Karayama, Masato; Inui, Naoki; Fujisawa, Tomoyuki; Enomoto, Noriyuki; Nakamura, Yutaro; Kuroishi, Shigeki; Matsuda, Hiroyuki; Yokomura, Koshi; Koshimizu, Naoki; Toyoshima, Mikio; Imokawa, Shiro; Asada, Kazuhiro; Masuda, Masafumi; Yamada, Takashi; Watanabe, Hiroshi; Suda, Takafumi

2016-08-01

Objectives Maintenance therapy is a standard therapeutic strategy in non-squamous non-small-cell lung cancer. However, there is no consensus regarding the benefit of maintenance therapy for patients with squamous cell lung cancer. We assessed maintenance therapy with S-1, an oral fluoropyrimidine agent, following induction therapy with carboplatin and S-1 in patients with squamous cell lung cancer. Methods In this phase II trial, chemotherapy-naïve patients with squamous cell lung cancer were enrolled to induction therapy with four cycles of carboplatin (at an area under the curve of 5 on day 1) and S-1 (80 mg/m(2)/day on days 1-14) in a 28-day cycle. Patients who achieved disease control after induction therapy received maintenance therapy with S-1 in a 21-day cycle until disease progression or unacceptable toxicity. The primary endpoint was progression-free survival after administration of maintenance therapy. Results Fifty-one patients were enrolled in the study. The median progression-free survival from the start of maintenance therapy was 3.0 months (95 % confidence interval, 2.5-3.5). The most common toxicities associated with maintenance therapy were anemia, thrombocytopenia, and fatigue, but they were not severe. Conclusion S-1 maintenance therapy might be a feasible treatment option in patients with squamous cell lung cancer.

21 CFR 1305.25 - Unaccepted and defective electronic orders.

Code of Federal Regulations, 2010 CFR

2010-04-01

... 21 Food and Drugs 9 2010-04-01 2010-04-01 false Unaccepted and defective electronic orders. 1305... SCHEDULE I AND II CONTROLLED SUBSTANCES Electronic Orders § 1305.25 Unaccepted and defective electronic orders. (a) No electronic order may be filled if: (1) The required data fields have not been completed...

21 CFR 1305.25 - Unaccepted and defective electronic orders.

Code of Federal Regulations, 2014 CFR

2014-04-01

... 21 Food and Drugs 9 2014-04-01 2014-04-01 false Unaccepted and defective electronic orders. 1305... SCHEDULE I AND II CONTROLLED SUBSTANCES Electronic Orders § 1305.25 Unaccepted and defective electronic orders. (a) No electronic order may be filled if: (1) The required data fields have not been completed...

The Effect of Distinguished Educators on Academic Gain of Louisiana Academically Unacceptable Schools

ERIC Educational Resources Information Center

Scroggins, Ruby C.

2012-01-01

The purpose of this study was to examine the degree of academic growth of Academically Unacceptable schools in Louisiana which have been assigned a Distinguished Educator. Distinguished Educators are external change agents who are placed in Academically Unacceptable schools in Louisiana. The data were generated from the Louisiana Department of…

Successful African-American Mathematics Students in Academically Unacceptable High Schools

ERIC Educational Resources Information Center

Sheppard, Peter A., IV

2005-01-01

The objectives of this study were to determine (1) the reasons why successful mathematics students have been able to thrive in schools labeled academically unacceptable and (2) why they have chosen to stay in these academically unacceptable schools despite having the option to leave for a better performing school. Qualitative methods including…

Silencing Receptor EphA2 Enhanced Sensitivity to Lipoplatin™ in Lung Tumor and MPM Cells.

PubMed

Lee, Hung-Yen; Mohammed, Kamal A; Goldberg, Eugene P; Kaye, Frederic; Najmunnisa, Nasreen

2016-08-08

Receptor EphA2 is overexpressed in lung cancer and malignant pleural mesothelioma (MPM) which promote tumorogenesis. Lipoplatin™, a new liposomal cisplatin formulation, is used against resistant tumors. Use of cisplatin-based drugs leads to unacceptable toxicities. To improve the effectiveness of Lipoplatin, enhancing the cellular sensitivity of lung tumor and MPM cells is critical. Therefore, we targeted receptor EphA2 by silencing interference RNA (siRNA) and treated tumor cells with Lipoplatin. The combined effects of siRNA-EphA2 and Lipoplatin were determined. We report that silencing EphA2 significantly enhanced the cellular sensitivity of lung tumor and MPM cells to Lipoplatin and maybe a potential therapy for lung cancer.

Brownfields and health risks--air dispersion modeling and health risk assessment at landfill redevelopment sites.

PubMed

Ofungwu, Joseph; Eget, Steven

2006-07-01

Redevelopment of landfill sites in the New Jersey-New York metropolitan area for recreational (golf courses), commercial, and even residential purposes seems to be gaining acceptance among municipal planners and developers. Landfill gas generation, which includes methane and potentially toxic nonmethane compounds usually continues long after closure of the landfill exercise phase. It is therefore prudent to evaluate potential health risks associated with exposure to gas emissions before redevelopment of the landfill sites as recreational, commercial, and, especially, residential properties. Unacceptably high health risks would call for risk management measures such as limiting the development to commercial/recreational rather than residential uses, stringent gas control mechanisms, interior air filtration, etc. A methodology is presented for applying existing models to estimate residual landfill hazardous compounds emissions and to quantify associated health risks. Besides the toxic gas constituents of landfill emissions, other risk-related issues concerning buried waste, landfill leachate, and explosive gases were qualitatively evaluated. Five contiguously located landfill sites in New Jersey intended for residential and recreational redevelopment were used to exemplify the approach.

PGLa-H tandem-repeat peptides active against multidrug resistant clinical bacterial isolates.

PubMed

Rončević, Tomislav; Gajski, Goran; Ilić, Nada; Goić-Barišić, Ivana; Tonkić, Marija; Zoranić, Larisa; Simunić, Juraj; Benincasa, Monica; Mijaković, Marijana; Tossi, Alessandro; Juretić, Davor

2017-02-01

Antimicrobial peptides (AMPs) are promising candidates for new antibiotic classes but often display an unacceptably high toxicity towards human cells. A naturally produced C-terminal fragment of PGLa, named PGLa-H, has been reported to have a very low haemolytic activity while maintaining a moderate antibacterial activity. A sequential tandem repeat of this fragment, diPGLa-H, was designed, as well as an analogue with a Val to Gly substitution at a key position. These peptides showed markedly improved in vitro bacteriostatic and bactericidal activity against both reference strains and multidrug resistant clinical isolates of Gram-negative and Gram-positive pathogens, with generally low toxicity for human cells as assessed by haemolysis, cell viability, and DNA damage assays. The glycine substitution analogue, kiadin, had a slightly better antibacterial activity and reduced haemolytic activity, which may correlate with an increased flexibility of its helical structure, as deduced using molecular dynamics simulations. These peptides may serve as useful lead compounds for developing anti-infective agents against resistant Gram-negative and Gram-positive species. Copyright © 2016 Elsevier B.V. All rights reserved.

Verification of Dose Distribution in Carbon Ion Radiation Therapy for Stage I Lung Cancer

DOE Office of Scientific and Technical Information (OSTI.GOV)

Irie, Daisuke; Saitoh, Jun-ichi, E-mail: junsaito@gunma-u.ac.jp; Shirai, Katsuyuki

Purpose: To evaluate robustness of dose distribution of carbon-ion radiation therapy (C-ion RT) in non-small cell lung cancer (NSCLC) and to identify factors affecting the dose distribution by simulated dose distribution. Methods and Materials: Eighty irradiation fields for delivery of C-ion RT were analyzed in 20 patients with stage I NSCLC. Computed tomography images were obtained twice before treatment initiation. Simulated dose distribution was reconstructed on computed tomography for confirmation under the same settings as actual treatment with respiratory gating and bony structure matching. Dose-volume histogram parameters, such as %D95 (percentage of D95 relative to the prescribed dose), were calculated.more » Patients with any field for which the %D95 of gross tumor volume (GTV) was below 90% were classified as unacceptable for treatment, and the optimal target margin for such cases was examined. Results: Five patients with a total of 8 fields (10% of total number of fields analyzed) were classified as unacceptable according to %D95 of GTV, although most patients showed no remarkable change in the dose-volume histogram parameters. Receiver operating characteristic curve analysis showed that tumor displacement and change in water-equivalent pathlength were significant predictive factors of unacceptable cases (P<.001 and P=.002, respectively). The main cause of degradation of the dose distribution was tumor displacement in 7 of the 8 unacceptable fields. A 6-mm planning target volume margin ensured a GTV %D95 of >90%, except in 1 extremely unacceptable field. Conclusions: According to this simulation analysis of C-ion RT for stage I NSCLC, a few fields were reported as unacceptable and required resetting of body position and reconfirmation. In addition, tumor displacement and change in water-equivalent pathlength (bone shift and/or chest wall thickness) were identified as factors influencing the robustness of dose distribution. Such uncertainties should be regarded in planning.« less

Biweekly cetuximab in combination with FOLFOX-4 in the first-line treatment of wild-type KRAS metastatic colorectal cancer: final results of a phase II, open-label, clinical trial (OPTIMIX-ACROSS Study).

PubMed

Fernandez-Plana, Julen; Pericay, Carlos; Quintero, Guillermo; Alonso, Vicente; Salud, Antonieta; Mendez, Miguel; Salgado, Mercedes; Saigi, Eugeni; Cirera, Luis

2014-11-22

This phase II study aims to evaluate the efficacy and safety of biweekly cetuximab in combination with oxaliplatin, leucovorin, and fluorouracil (FOLFOX-4) as first-line treatment of metastatic wild-type KRAS colorectal cancer. Previously untreated patients with wild-type KRAS tumours received biweekly cetuximab (500 mg/m2 on day 1) plus FOLFOX-4 (oxaliplatin 85 mg/m2 on day 1, leucovorin 200 mg/m2 on days 1 and 2, and fluorouracil as a 400 mg/m2 bolus followed by a 22-hour 600 mg/m2 infusion on day 1 and 2). Treatment was continued until disease progression, onset of unacceptable toxicities, metastases surgery, or discontinuation request. The primary endpoint was ORR. The intention-to-treat population included 99 patients with a median age of 64.1 years (range, 34-82). The ORR was 60.6% (95% CI, 50.3% to 70.3%). The median follow-up was 17.8 months; the median OS and PFS were 20.8 and 10.1 months, respectively. Metastases from colorectal cancer were surgically resected in 26 (26.3%) patients, with complete resection achieved in 18 (69.2%) patients. Median PFS and OS in patients undergoing metastatic resection were 12.6 and 29.5 months, respectively. The most common grade 3-4 toxicities were neutropenia (32.3%), acne-like rash (15.2%) and diarrhoea (11.1%). The efficacy of the biweekly combination of cetuximab with FOLFOX-4 in patients with wild-type KRAS tumours supports the administration of cetuximab in a dosing regimen more convenient for patients and healthcare providers. The activity of the biweekly administration is similar to what has been reported for the weekly regimen. Reported toxicity was also consistent with the known toxicity profile of weekly cetuximab. EudraCT Number 200800690916.

Approach to study of Cu, Ni and Zn content in soil for ecotoxicological risk assessment

NASA Astrophysics Data System (ADS)

Boluda, R.; Marimon, L.; Gil, C.; Roca-Pérez, L.

2009-04-01

Current Spanish legislation on contaminated soils defines contaminated soil as "that whose characteristics have been negatively altered by the presence of dangerous human-derived chemical components whose concentration is such that it is an unacceptable risk for human health or the environment and has been expressly declared as such by legal ruling". Regarding heavy metals, the Spanish Autonomous Communities will promote measures to obtain generic reference values to declare a soil to be contaminated. In the Valencian Community, these reference values still do not exist. So if the protection of ecosystems is considered a priority to declare a soil to be contaminated and to assess the level of risk, emergency toxicity tests and seed growth in land plants are resorted to, or tests with aquatic organisms or other experiments with leached soils obtained by standard procedures are carried out. We studied the toxic effects of calcareous contaminated soils by Cu, Ni and Zn on marine bacterium Vibrio fisheri (MicrotoxR test assay) (1) and on barley (Hordeum vulgare L.) in plate (germination index) (2) and pot (UNE 77301) (3) experiments for the purpose of establishing the Cu, Ni and Zn concentrations in soil which may lead to toxicity in order to observe, therefore, whether there is any likelihood of these pollutants coming into contact with any receptor and if adverse effects exist for living beings and the environment. The results showed significant differences among the three types of tests done but, in all cases, the concentrations needed to reflect toxicity effect on organisms were around 20 -70 (Cu and Ni) to 1000 (Zn) times higher than the levels of the control soils. The sensitivity order of the bio-assay was: (1) < (3) < (2). We would like to thank Spanish government-MICINN for partial funding and support (MICINN, project CGL2006-09776).

Phase II Evaluation of Pemetrexed in the Treatment of Recurrent or Persistent Platinum-Resistant Ovarian or Primary Peritoneal Carcinoma: A Study of the Gynecologic Oncology Group

PubMed Central

Miller, David S.; Blessing, John A.; Krasner, Carolyn N.; Mannel, Robert S.; Hanjani, Parviz; Pearl, Michael L.; Waggoner, Steven E.; Boardman, Cecelia H.

2009-01-01

Purpose To estimate the antitumor activity of pemetrexed in patients with persistent or recurrent platinum-resistant epithelial ovarian or primary peritoneal cancer and to determine the nature and degree of toxicities. Patients and Methods A phase II trial was conducted by the Gynecologic Oncology Group. Patients must have had cancer that had progressed on platinum-based primary chemotherapy or recurred within 6 months. Pemetrexed at a dose of 900 mg/m2 was to be administered as an intravenous infusion over 10 minutes every 21 days. Dose delay and adjustment was permitted for toxicity. Treatment was continued until disease progression or unacceptable adverse effects. Results From July 6, 2004, to August 23, 2006, 51 patients were entered. A total of 259 cycles (median, four; range one to 19 cycles) of pemetrexed were administered, with 40% of patients receiving six or more cycles. Overall, the treatment was well tolerated. More serious toxicities (grade 3 and 4) included neutropenia in 42%, leukopenia in 25%, anemia in 15%, and constitutional in 15% of patients. No treatment-related deaths were reported. One patient (2%) had a complete and nine patients (19%) had partial responses, with a median duration response of 8.4 months. Seventeen patients (35%) had stable disease for a median of 4.1 months. Eighteen patients (38%) had increasing disease. Three patients (6%) were not assessable. Median progression-free survival was 2.9 months, and overall survival was 11.4 months. Conclusion Pemetrexed has sufficient activity in the treatment of recurrent platinum-resistant ovarian cancer at the dose and schedule tested to warrant further investigation. PMID:19332726

Apatinib plus icotinib in treating advanced non-small cell lung cancer after icotinib treatment failure: a retrospective study

PubMed Central

Xu, Jianping; Liu, Xiaoyan; Yang, Sheng; Zhang, Xiangru; Shi, Yuankai

2017-01-01

Background Treatment failure frequently occurs in patients with epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer (NSCLC) who respond to EGFR tyrosine kinase inhibitors initially. This retrospective study tried to investigate the efficacy and safety of apatinib plus icotinib in patients with advanced NSCLC after icotinib treatment failure. Patients and methods This study comprised 27 patients with advanced NSCLC who had progressed after icotinib monotherapy. Initially, patients received oral icotinib (125 mg, tid) alone. When the disease progressed, they received icotinib plus apatinib (500 mg, qd, orally). Treatment was continued until disease progression, unacceptable toxicity or consent withdrawal. Results Followed up to December 2016, the median time of combined therapy was 7.47 months, and eight of 27 patients were dead. The median overall survival was not reached, and median progression-free survival (PFS) was 5.33 months (95% CI, 3.63–7.03 months). Moreover, the objective response rate (ORR) was 11.1%, and the disease control rate (DCR) was 81.5%. A total of 14 patients received combined therapy as the second-line treatment, and the ORR and DCR were 7.1% and 78.6%, respectively; 13 patients received drugs as the third- or later-line treatment, with an ORR and a DCR of 15.4% and 84.6%, respectively. In addition, 11 patients experienced icotinib monotherapy failure within 6 months with median PFS of 7.37 months, and 16 patients had progression after 6 months with median PFS of 2.60 months. The common drug-related toxic effects were hypertension (44.4%) and fatigue (37.0%). Conclusion Apatinib plus icotinib is efficacious in treating patients with advanced NSCLC after icotinib treatment failure, with acceptable toxic effects. PMID:29075129

40 CFR Appendix M to Subpart G of... - Unacceptable Substitutes Listed in the September 30, 2004 Final Rule, Effective November 29, 2004

Code of Federal Regulations, 2014 CFR

2014-07-01

... refrigeration, and sandwich panels —Rigid polyurethane slabstock and other foams —Polystyrene extruded... 29, 2004 Foam Blowing—Unacceptable Substitutes End-use Substitute Decision Comments All foam end-uses: HCFC-141b Unacceptable Alternatives exist with lower or zero = ODP. —Rigid polyurethane and...

40 CFR Appendix M to Subpart G of... - Unacceptable Substitutes Listed in the September 30, 2004 Final Rule, Effective November 29, 2004

Code of Federal Regulations, 2013 CFR

2013-07-01

... refrigeration, and sandwich panels —Rigid polyurethane slabstock and other foams —Polystyrene extruded... 29, 2004 Foam Blowing—Unacceptable Substitutes End-use Substitute Decision Comments All foam end-uses: HCFC-141b Unacceptable Alternatives exist with lower or zero = ODP. —Rigid polyurethane and...

Phase II Study of Concomitant Thalidomide During Radiotherapy for Hepatocellular Carcinoma

DOE Office of Scientific and Technical Information (OSTI.GOV)

Ch'ang, Hui-Ju, E-mail: hjmc@nhri.org.tw; Department of Radiation Oncology, National Cheng Kung University Hospital, Tainan, Taiwan; Hsu, Chiun

2012-02-01

Purpose: Thalidomide has been demonstrated to possess antitumor activity in patients with advanced hepatocellular carcinoma (HCC). The objective of the present study was to determine whether the combined treatment of thalidomide with radiotherapy (RT) is associated with acceptable toxicity and an improved clinical outcome in HCC patients. Methods and Materials: A total of 24 patients were enrolled to receive RT combined with thalidomide. A total dose of 50 Gy was delivered in 2-Gy fractions within 5 weeks. Thalidomide was administered 100 mg twice daily starting 3 days before RT until the development of unacceptable toxicity or disease progression. Blood samplesmore » were collected before, during, and after treatment to measure the levels of angiogenic factors and cytokines. The results of patients receiving the combined therapy were compared with those from 18 HCC patients receiving RT only. Results: No significant difference in the clinical parameters was noted between the two groups, except for the baseline interleukin-6 level, which was greater in the concomitant group (p = .05). The most common toxicities related to thalidomide use were skin rash (54.2%), somnolence (37.5%), and constipation (33.3%). No significant differences were seen in the response rate (55.6% vs. 58.3%, p = .48), median progression-free survival (182 {+-} 48.9 vs. 148 {+-} 6.2 days, p = .15), or median overall survival (258 {+-} 45.6 vs. 241 {+-} 38.6, p = .16) between those who received concomitant therapy and those who received RT alone. Thalidomide suppressed the serum basic fibroblast growth factor level significantly during RT (p = .03) and, to a lesser extent, the interleukin-6 and tumor necrosis factor-{alpha} levels. After adjusting for other potential prognostic factors in the multivariate analysis, only the baseline interleukin-6 level and stem cell-derived factor-1 during RT independently predicted the progression-free survival. A decreased serum stem cell-derived factor-1 level 1 month after RT completion was a significant predictor of the overall survival of HCC patients receiving RT. Conclusions: Despite the acceptable toxicity, thalidomide provided no additional benefit for HCC patients undergoing RT.« less

NRG Oncology Radiation Therapy Oncology Group 0822: A Phase 2 Study of Preoperative Chemoradiation Therapy Using Intensity Modulated Radiation Therapy in Combination With Capecitabine and Oxaliplatin for Patients With Locally Advanced Rectal Cancer

DOE Office of Scientific and Technical Information (OSTI.GOV)

Hong, Theodore S., E-mail: tshong1@mgh.harvard.edu; Moughan, Jennifer; Garofalo, Michael C.

Purpose: To evaluate the rate of gastrointestinal (GI) toxicity of neoadjuvant chemoradiation with capecitabine, oxaliplatin, and intensity modulated radiation therapy (IMRT) in cT3-4 rectal cancer. Methods and Materials: Patients with localized, nonmetastatic T3 or T4 rectal cancer <12 cm from the anal verge were enrolled in a prospective, multi-institutional, single-arm study of preoperative chemoradiation. Patients received 45 Gy with IMRT in 25 fractions, followed by a 3-dimensional conformal boost of 5.4 Gy in 3 fractions with concurrent capecitabine/oxaliplatin (CAPOX). Surgery was performed 4 to 8 weeks after the completion of therapy. Patients were recommended to receive FOLFOX chemotherapy after surgery. The primary endpoint ofmore » the study was acute grade 2 to 5 GI toxicity. Seventy-one patients provided 80% probability to detect at least a 12% reduction in the specified GI toxicity with the treatment of CAPOX and IMRT, at a significance level of .10 (1-sided). Results: Seventy-nine patients were accrued, of whom 68 were evaluable. Sixty-one patients (89.7%) had cT3 disease, and 37 (54.4%) had cN (+) disease. Postoperative chemotherapy was given to 42 of 68 patients. Fifty-eight patients had target contours drawn per protocol, 5 patients with acceptable variation, and 5 patients with unacceptable variations. Thirty-five patients (51.5%) experienced grade ≥2 GI toxicity, 12 patients (17.6%) experienced grade 3 or 4 diarrhea, and pCR was achieved in 10 patients (14.7%). With a median follow-up time of 3.98 years, the 4-year rate of locoregional failure was 7.4% (95% confidence interval [CI]: 1.0%-13.7%). The 4-year rates of OS and DFS were 82.9% (95% CI: 70.1%-90.6%) and 60.6% (95% CI: 47.5%-71.4%), respectively. Conclusion: The use of IMRT in neoadjuvant chemoradiation for rectal cancer did not reduce the rate of GI toxicity.« less

Phase I clinical and pharmacokinetic study of kahalalide F administered weekly as a 1-hour infusion to patients with advanced solid tumors.

PubMed

Pardo, Beatriz; Paz-Ares, Luis; Tabernero, Josep; Ciruelos, Eva; García, Margarita; Salazar, Ramón; López, Ana; Blanco, María; Nieto, Antonio; Jimeno, José; Izquierdo, Miguel Angel; Trigo, José Manuel

2008-02-15

A dose-escalation, phase I study evaluated the safety, pharmacokinetics, and efficacy of a weekly 1-h regimen of kahalalide F, a cyclic depsipeptide isolated from the marine mollusk Elysia rufescens, in adult patients with advanced solid tumors and no standard treatment available. Patients received an i.v. 1-h infusion of kahalalide F once weekly until disease progression or unacceptable toxicity. The starting kahalalide F dose was 266 microg/m(2), and dose escalation proceeded based on the worst toxicity found in the previous cohort. Thirty-eight patients were enrolled at three Spanish institutions and received once-weekly kahalalide F 1-h infusions at doses between 266 and 1,200 microg/m(2). Dose-limiting toxicities consisted of transient grade 3/4 increases in transaminase blood levels. The maximum tolerated dose for this kahalalide F schedule was 800 microg/m(2), and the recommended dose for phase II studies was 650 microg/m(2). No accumulated toxicity was found. One patient with malignant melanoma had unconfirmed partial response, one patient with metastatic lung adenocarcinoma had minor response, and six patients with different types of metastatic solid tumors had stable disease for 2.8 to 12.7 months. The noncompartmental pharmacokinetics of this kahalalide F schedule was linear and showed a narrow distribution and short body residence. The transaminitis associated with kahalalide F was dose dependent. The maximum tolerated dose was 800 microg/m(2). Dose-limiting toxicities with weekly kahalalide F 1-h i.v. infusions were transient grade 3/4 increases in blood transaminase levels, and 650 microg/m(2) was declared the recommended dose for phase II studies. This schedule showed a favorable safety profile and hints of antitumor activity.

21 CFR 1305.15 - Unaccepted and defective DEA Forms 222.

Code of Federal Regulations, 2011 CFR

2011-04-01

... 21 Food and Drugs 9 2011-04-01 2011-04-01 false Unaccepted and defective DEA Forms 222. 1305.15... I AND II CONTROLLED SUBSTANCES DEA Form 222 § 1305.15 Unaccepted and defective DEA Forms 222. (a) A DEA Form 222 must not be filled if either of the following apply: (1) The order is not complete...

21 CFR 1305.15 - Unaccepted and defective DEA Forms 222.

Code of Federal Regulations, 2010 CFR

2010-04-01

... 21 Food and Drugs 9 2010-04-01 2010-04-01 false Unaccepted and defective DEA Forms 222. 1305.15... I AND II CONTROLLED SUBSTANCES DEA Form 222 § 1305.15 Unaccepted and defective DEA Forms 222. (a) A DEA Form 222 must not be filled if either of the following apply: (1) The order is not complete...

The severity of toxic reactions to ephedra: comparisons to other botanical products and national trends from 1993-2002.

PubMed

Woolf, Alan D; Watson, William A; Smolinske, Susan; Litovitz, Toby

2005-01-01

Ephedra is a botanical product widely used to enhance alertness, as a weight loss aide, and as a decongestant. Its reported adverse effects led the Food and Drug Administration (FDA) to ban ephedra-containing products in the United States in 2004. This study's purpose was to compare toxicity from botanical products containing ephedra to nonephedra products. The Toxic Exposure Surveillance System (TESS), a national poison center database, was utilized to determine the number and outcomes of cases involving botanical products reported from 1993-2002. Cases listing both a botanical product and any other drugs or chemicals were excluded a priori. Ten-year hazard rates (moderate outcomes + major outcomes + deaths per 1000 exposures) were used to compare botanical product categories. There were 21,533 toxic exposures with definitive medical outcomes reported over the 10 yrs where a botanical product was the only substance involved. Of these, 4306 (19.9%) had moderate or major medical outcomes and there were two deaths, for an overall hazard score of 200 per 1000 exposures. The number of ephedra reports to poison centers increased 150-fold over the 10-yr period. The hazard rate for products that contained only ephedra was 250 per 1000 exposures and 267 per 1000 exposures for products that contained ephedra and additional ingredients; whereas the hazard score for only nonephedra botanical products was 96 per 1000 exposures. The rate ratios for multibotanical products with ephedra (RR 1.33; 95% C.I. 1.27-1.40) and for single-ingredient ephedra products (RR 1.25; 95% C.I. 1.11-1.40) were both two to six times higher than those of other common botanical products. Yohimbe-containing products had the highest hazard score (417) and rate ratio (2.08; 95% C.I. 1.59-2.80). Ephedra-containing botanical products accounted for a significant number of toxic exposures with severe medical outcomes reported to poison centers. Hazard rate analysis suggests poison center-reported events involving ephedra-containing botanical products were much more likely to result in severe medical outcomes than those involving nonephedra-containing botanical products. These data support recommendations by policymakers that the sale of ephedra should be prohibited to protect consumers. Our data suggest that the botanical product, yohimbe, may also be associated with unacceptably high risks of toxicity and should receive close scrutiny from health policymakers.

The Bruton tyrosine kinase inhibitor ibrutinib with chemoimmunotherapy in patients with chronic lymphocytic leukemia

PubMed Central

Barrientos, Jacqueline C.; Barr, Paul M.; Flinn, Ian W.; Burger, Jan A.; Tran, Anh; Clow, Fong; James, Danelle F.; Graef, Thorsten; Friedberg, Jonathan W.; Rai, Kanti; O’Brien, Susan

2015-01-01

The safety and efficacy of ibrutinib, an oral inhibitor of Bruton tyrosine kinase, were evaluated with chemoimmunotherapy (CIT) in a multicenter phase 1b study. Patients with relapsed/refractory chronic lymphocytic leukemia received bendamustine and rituximab (BR) or fludarabine, cyclophosphamide, and rituximab (FCR) for up to 6 cycles with daily ibrutinib (420 mg) until progressive disease or unacceptable toxicity. Enrollment to FCR-ibrutinib closed early due to a lack of fludarabine-naïve previously treated patients. No patients treated with BR-ibrutinib (n = 30) or FCR-ibrutinib (n = 3) experienced prolonged hematologic toxicity in cycle 1 (primary end point). Tolerability was as expected with either CIT or single-agent ibrutinib. The overall response rate (ORR) with BR-ibrutinib was 93.3%, including 16.7% complete responses (CRs) initially, which increased to 40% with the extension period. Including 1 patient with partial response with lymphocytosis, the best ORR was 96.7%. Sixteen of 21 patients with baseline cytopenias had sustained hematologic improvement. At 12 and 36 months, 86.3% and 70.3% remained progression-free, respectively. All 3 patients treated with ibrutinib-FCR achieved CR. Ibrutinib may enhance CIT efficacy without additive toxicities, providing the rationale for studying this combination in an ongoing phase 3 trial. The study is registered to www.clinicaltrials.gov as #NCT01292135. PMID:25755291

The Bruton tyrosine kinase inhibitor ibrutinib with chemoimmunotherapy in patients with chronic lymphocytic leukemia.

PubMed

Brown, Jennifer R; Barrientos, Jacqueline C; Barr, Paul M; Flinn, Ian W; Burger, Jan A; Tran, Anh; Clow, Fong; James, Danelle F; Graef, Thorsten; Friedberg, Jonathan W; Rai, Kanti; O'Brien, Susan

2015-05-07

The safety and efficacy of ibrutinib, an oral inhibitor of Bruton tyrosine kinase, were evaluated with chemoimmunotherapy (CIT) in a multicenter phase 1b study. Patients with relapsed/refractory chronic lymphocytic leukemia received bendamustine and rituximab (BR) or fludarabine, cyclophosphamide, and rituximab (FCR) for up to 6 cycles with daily ibrutinib (420 mg) until progressive disease or unacceptable toxicity. Enrollment to FCR-ibrutinib closed early due to a lack of fludarabine-naïve previously treated patients. No patients treated with BR-ibrutinib (n = 30) or FCR-ibrutinib (n = 3) experienced prolonged hematologic toxicity in cycle 1 (primary end point). Tolerability was as expected with either CIT or single-agent ibrutinib. The overall response rate (ORR) with BR-ibrutinib was 93.3%, including 16.7% complete responses (CRs) initially, which increased to 40% with the extension period. Including 1 patient with partial response with lymphocytosis, the best ORR was 96.7%. Sixteen of 21 patients with baseline cytopenias had sustained hematologic improvement. At 12 and 36 months, 86.3% and 70.3% remained progression-free, respectively. All 3 patients treated with ibrutinib-FCR achieved CR. Ibrutinib may enhance CIT efficacy without additive toxicities, providing the rationale for studying this combination in an ongoing phase 3 trial. The study is registered to www.clinicaltrials.gov as #NCT01292135. © 2015 by The American Society of Hematology.

Home administration of maintenance pemetrexed for patients with advanced non-squamous non-small cell lung cancer: rationale, practicalities and phase II feasibility study design.

PubMed

Lal, Rohit; Bourayou, Nawel; Hillerdal, Gunnar; Nicolson, Marianne; Vikstrom, Anders; Lorenzo, Maria; D'yachkova, Yulia; Barriga, Susana; Visseren-Grul, Carla

2013-10-03

Home-based care in oncology is mainly reserved for patients at the end of life. Regulations regarding home delivery of cytotoxics differ across Europe, with a notable lack of practice guidelines in most countries. This has led to a lack of data addressing the feasibility of home-based administration of cytotoxic chemotherapy. In advanced non-squamous non-small cell lung cancer, pemetrexed is approved as maintenance therapy after first-line chemotherapy. In this setting, patients have the potential to be treated long-term with maintenance therapy, which, in the absence of unacceptable toxicity, is continued until disease progression. The favourable safety profile of pemetrexed and the ease of its administration by 10-minute intravenous infusion every 3 weeks make this drug a suitable candidate for administration in a home setting. Literature and regulations relevant to the home-based delivery of cytotoxic therapy were reviewed, and a phase II feasibility study of home administration of pemetrexed maintenance therapy was designed. At least 50 patients with advanced non-squamous non-small cell lung cancer, Eastern Cooperative Oncology Group performance status 0-1 and no progressive disease after four cycles of platinum-based first-line therapy are required to allow investigation of the feasibility of home-based administration of pemetrexed maintenance therapy (500 mg/m(2) every 3 weeks until progressive disease or unacceptable toxicity). Feasibility is being assessed as adherence to the home-based administration process (primary endpoint), patient safety, impact on patients' quality of life, patient and physician satisfaction with home care, and healthcare resource use and costs. Enrolment of patients from the UK and Sweden, where home-based care is relatively well developed, commenced in December 2011. This feasibility study addresses an important aspect of maintenance therapy, that is, patient comfort during protracted home-based chemotherapy. The study design requires unusual methodology and specific logistics to address outcomes relevant to the home-delivery approach. This article presents a study design that offers a novel and reproducible model for home-based chemotherapy, and provides an up-to-date overview of the literature regarding this type of treatment. ClinicalTrials.gov: NCT01473563.

Project TENDR: Targeting Environmental Neuro-Developmental Risks The TENDR Consensus Statement

PubMed Central

Bennett, Deborah; Bellinger, David C.; Birnbaum, Linda S.; Bradman, Asa; Chen, Aimin; Cory-Slechta, Deborah A.; Engel, Stephanie M.; Fallin, M. Daniele; Halladay, Alycia; Hauser, Russ; Hertz-Picciotto, Irva; Kwiatkowski, Carol F.; Lanphear, Bruce P.; Marquez, Emily; Marty, Melanie; McPartland, Jennifer; Newschaffer, Craig J.; Payne-Sturges, Devon; Patisaul, Heather B.; Perera, Frederica P.; Ritz, Beate; Sass, Jennifer; Schantz, Susan L.; Webster, Thomas F.; Whyatt, Robin M.; Woodruff, Tracey J.; Zoeller, R. Thomas; Anderko, Laura; Campbell, Carla; Conry, Jeanne A.; DeNicola, Nathaniel; Gould, Robert M.; Hirtz, Deborah; Huffling, Katie; Landrigan, Philip J.; Lavin, Arthur; Miller, Mark; Mitchell, Mark A.; Rubin, Leslie; Schettler, Ted; Tran, Ho Luong; Acosta, Annie; Brody, Charlotte; Miller, Elise; Miller, Pamela; Swanson, Maureen; Witherspoon, Nsedu Obot

2016-01-01

Summary: Children in America today are at an unacceptably high risk of developing neurodevelopmental disorders that affect the brain and nervous system including autism, attention deficit hyperactivity disorder, intellectual disabilities, and other learning and behavioral disabilities. These are complex disorders with multiple causes—genetic, social, and environmental. The contribution of toxic chemicals to these disorders can be prevented. Approach: Leading scientific and medical experts, along with children’s health advocates, came together in 2015 under the auspices of Project TENDR: Targeting Environmental Neuro-Developmental Risks to issue a call to action to reduce widespread exposures to chemicals that interfere with fetal and children’s brain development. Based on the available scientific evidence, the TENDR authors have identified prime examples of toxic chemicals and pollutants that increase children’s risks for neurodevelopmental disorders. These include chemicals that are used extensively in consumer products and that have become widespread in the environment. Some are chemicals to which children and pregnant women are regularly exposed, and they are detected in the bodies of virtually all Americans in national surveys conducted by the U.S. Centers for Disease Control and Prevention. The vast majority of chemicals in industrial and consumer products undergo almost no testing for developmental neurotoxicity or other health effects. Conclusion: Based on these findings, we assert that the current system in the United States for evaluating scientific evidence and making health-based decisions about environmental chemicals is fundamentally broken. To help reduce the unacceptably high prevalence of neurodevelopmental disorders in our children, we must eliminate or significantly reduce exposures to chemicals that contribute to these conditions. We must adopt a new framework for assessing chemicals that have the potential to disrupt brain development and prevent the use of those that may pose a risk. This consensus statement lays the foundation for developing recommendations to monitor, assess, and reduce exposures to neurotoxic chemicals. These measures are urgently needed if we are to protect healthy brain development so that current and future generations can reach their fullest potential. PMID:27479987

Ground hardness and injury in community level Australian football.

PubMed

Twomey, Dara M; Finch, Caroline F; Lloyd, David G; Elliott, Bruce C; Doyle, Tim L A

2012-07-01

To describe the risk and details of injuries associated with ground hardness in community level Australian football (AF). Prospective injury surveillance with periodic objective ground hardness measurement. 112 ground hardness assessments were undertaken using a Clegg hammer at nine locations across 20 grounds, over the 2007 and 2008 AF seasons. Details of 352 injuries sustained by community level players on those grounds were prospectively collected as part of a large randomised controlled trial. The ground location of the injury was matched to the nearest corresponding ground hardness Clegg hammer readings, in gravities (g), which were classified from unacceptably low (<30 g) to unacceptably high hardness (>120 g). Clegg hammer readings ranged from 25 to 301 g. Clegg hammer hardness categories from low/normal to high/normal were associated with the majority of injuries, with only 3.7% (13 injuries) on unacceptably high hardness and 0.3% (1 injury) on the unacceptably low hardness locations. Relative to the preferred range of hardness, the risk of sustaining an injury on low/normal hardness locations was 1.31 (95%CI: 1.06-1.62) times higher and 1.82 (95%CI: 1.17-2.85) times higher on locations with unacceptably high hardness. The more severe injuries occurred with low/normal ground hardness. Despite the low number of injuries, the risk of sustaining an injury on low/normal and unacceptably hard grounds was significantly greater than on the preferred range of hardness. Notably, the severity of the injuries sustained on unacceptably hard grounds was lower than for other categories of hardness. Copyright © 2012 Sports Medicine Australia. Published by Elsevier Ltd. All rights reserved.

Phase II trial of everolimus in patients with previously treated recurrent or metastatic head and neck squamous cell carcinoma.

PubMed

Geiger, Jessica L; Bauman, Julie E; Gibson, Michael K; Gooding, William E; Varadarajan, Prakash; Kotsakis, Athanasios; Martin, Daniel; Gutkind, Jorge Silvio; Hedberg, Matthew L; Grandis, Jennifer R; Argiris, Athanassios

2016-12-01

Patients with recurrent/metastatic head and neck squamous cell carcinoma (HNSCC) demonstrate aberrant activation of the phosphotidylinositol-3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathway. We examined the efficacy of everolimus, an mTOR inhibitor, in patients with recurrent or metastatic HNSCC. This single-arm phase II study enrolled biomarker-unselected patients with recurrent or metastatic HNSCC who failed at least 1 prior therapy. Everolimus was administered until progressive disease or unacceptable toxicity. Primary endpoint was clinical benefit rate (CBR). Secondary endpoints included progression-free survival (PFS), overall survival (OS), and evaluation of tissue and serum biomarkers related to the PIK3CA pathway. Seven of 9 patients treated in the first stage were evaluable. No objective responses were seen; CBR was 28%. Three patients discontinued everolimus because of toxicity. Median PFS and OS were 1.5 and 4.5 months, respectively. No activating PI3K mutations were identified in available tumor tissue. Everolimus was not active as monotherapy in unselected patients with recurrent/metastatic HNSCC. © 2016 Wiley Periodicals, Inc. Head Neck 38: 1759-1764, 2016. © 2016 Wiley Periodicals, Inc.

Improving Public Health through Innovations in Exposure ...

EPA Pesticide Factsheets

In the traditional risk assessment paradigm, exposure science is relegated to a supporting role, providing an exposure estimate for comparison with hazard-based guidance values to determine whether there may be an unacceptable risk to public health. More recently, exposure science has transformed into a distinct discipline that complements toxicology as a means to understand the relationship between exposures to chemical mixtures and multiple health effects. This transformation is driven by advances in, for example, analytical methods, biomarker discovery, computational capabilities and algorithms, remote and on-person sensors, and geographic information systems. These major innovations in exposure science provide novel data streams that can revolutionize toxicity testing strategies and conventional risk assessment. For example, large numbers of chemicals are being detected at ever-lower concentrations in environmental and biological samples, providing relevant exposure information to be integrated into toxicity testing strategies. Novel biomarkers are being developed to expand our understanding of exposures, early biological effects, and susceptibility, and to allow for the exploration of contributions from both chemical and non-chemical stressors to adverse health outcomes. This workshop will introduce numerous innovative tools to enable better characterization of human exposures to mixtures of chemicals, including 1) a non-targeted approach to identify

Microbiological examination of cold ready-to-eat sliced meats from catering establishments in the United Kingdom.

PubMed

Gillespie, I; Little, C; Mitchell, R

2000-03-01

A microbiological study of cold, ready-to-eat sliced meats from 2579 catering establishments (public houses, hotels, cafés, restaurants, residential homes and other catering premises) found that 2587 of 3494 samples (74%) were of acceptable quality, 892 (26%) were of unsatisfactory quality and 15 (<1%) were of unacceptable quality. Unacceptable results were due to high levels of Escherichia coli, Staphylococcus aureus, Listeria species and/or Clostridium perfringens. Unsatisfactory results were mostly due to high Aerobic Plate Counts. The microbiological quality of cold, ready-to-eat meats was associated with meat type, premises type, management training, hygienic practices, meat supplier and length of storage. The relationship between food hygiene training and microbiological quality is discussed.

Risk assessment of soils contaminated by mercury mining, Northern Spain.

PubMed

Ordóñez, A; Alvarez, R; Charlesworth, S; De Miguel, E; Loredo, J

2011-01-01

Analytical results of soil samples taken in three different mercury mining sites in Northern Spain are studied to assess the potential adverse health effects of the exposure to trace elements associated with the mining process. Doses contacted through ingestion and inhalation and the dose absorbed through the skin were calculated using USEPA's exposure parameters and the US Department of Energy's toxicity values. The results of the risk assessment indicate that the highest risk is associated with ingestion of soil particles and that the trace element of major concern is arsenic, the exposure to which results in a high cancer risk value for all the sites ranging from 3.3 × 10(-5) to 3.6 × 10(-3), well above the 1 × 10(-5) probability level deemed unacceptable by most regulatory agencies. Regarding non-cancer effects, exposure to polluted soils yields an aggregate hazard index above the threshold value of 1 for all three sites, with As and Hg as the main contributors. Risk assessment has proven to be a very useful tool to identify the contaminants and exposure pathways of most concern in the soils from metal mining sites, as well as to categorize them in terms of action priority to ensure fitness for use.

Flow-through bioassay for measuring bioaccumulation of toxic substances from sediment

USGS Publications Warehouse

Mac, Michael J.; Edsall, Carol C.; Hesselberg, Robert J.; Sayers, Richard E.

1984-01-01

Over 10 million cubic meters of sediment are dredged annually from Great Lakes waterways. Because much of this material is taken from harbors, connecting channels, and other nearshore areas that often are contaminated with toxic substances, the sediments proposed for dredging need to be evaluated for the presence of bioavailable contaminants and the potential for toxicity to the biota. Sound decisions on the appropriate disposal of the dredged material can be made only after such an evaluation. Presently, no standardized procedure exists for evaluating dredged material in freshwater systems although current criteria for discharge of dredged material into marine water have been developed (USEPA/CE 1977). In the ocean discharge guideline, it is recommended that bioassays be conducted on liquid, solid, and suspended particulate phases of dredged material. because it appears that the solid phase has the greatest potential for environmental damage and because measurement of bioaccumulation must be made to evaluate sediments for disposal (USEPA/CE 1977, Seeyle and Mac 1983), we developed a bioassay for testing the solid phase of dredged material that measures the survival of organisms and, perhaps more important, the bioaccumulation of toxic substances by aquatic organisms from naturally contaminated sediments (Peddicord et al. 1980; Rubinstein et al. 1980, 1983; Seeyle st al. 1982), several have used testing methods that result in unacceptable mortality to control organisms (Bahnick et al. 1981, Prater et al. 1983). Our bioassay is intended to estimate the potential for bioaccumlation of contaminants from sediments that are not acutely toxic to test organisms, but are suspected of containing persistent contaminants. By using test organisms that are not highly susceptible to toxic compounds, the bioaccumulation test allows estimation of the potential food-chain accumulation of contaminants that may occur in local biota from surficial sediments. In practice, bioaccumulation observed in this bioassay by organisms exposed to test sediments (sediments to be dredged) would be compared to bioaccumulation observed from sediments collected from a reference site (e.g. a disposal site or open lake), and also from control sediments (relatively clean sediment). Decisions could then be based on a comparison of results between tests and reference sediments to determine if disposal would cause dehydration to the habitat, and between reference and control sediment to determine if even the reference material is seriously contaminated. Although the test is not intended to be a toxicity test per se, use of test, reference, and control sediments enables interpretation of any mortality of organisms that may occur during the bioassays. High mortality in bioassays with test or reference sediment would indicate acute toxicity of sediments in the project area. However if high mortality occurs in all three sediments, it can be assumed that the organisms were not in a healthy state at the time of testing. We describe the results of 10-day sediment bioassays in which both mortality and bioaccumulation were measured in four aquatic organisms. We exposed two infaunal organisms and two species of fish to test and control sediments in the laboratory.

Effects of the neonicotinoids acetamiprid and thiacloprid in their commercial formulations on soil fauna.

PubMed

Renaud, Mathieu; Akeju, Tolutope; Natal-da-Luz, Tiago; Leston, Sara; Rosa, João; Ramos, Fernando; Sousa, José Paulo; Azevedo-Pereira, Henrique M V S

2018-03-01

Neonicotinoids are the most prominent group of insecticides in the world and are commercialized in over 120 countries for the control of agricultural pests mainly due to their broad-spectrum activity and versatility in application. Though non-target soil organisms are likely to be exposed during application, there is paucity of information in scientific literature regarding their sensitivity to neonicotinoids. This study attempts to fill this gap by evaluating, under laboratory conditions, the chronic toxicity of the neonicotinoids thiacloprid and acetamiprid, through their commercial formulations (CF), to the soil invertebrates Folsomia candida, Eisenia andrei and Enchytraeus crypticus. Results obtained indicate that the relative reproductive sensitivity of the test organisms can be expressed as: F. candida = E. andrei > E. crypticus (for acetamiprid CF) and E. andrei > F. candida > E. crypticus (for thiacloprid CF). To extrapolate from laboratory test results to field conditions, predicted environmental concentrations (PECs) and predicted no-effect concentrations were derived. Calculated toxicity-exposure ratios (TER = EC10/PEC) were below trigger values for acetamiprid and thiacloprid, when estimated with initial PEC. While estimated hazard quotients (HQ = PEC/PNEC), were greater than the European Commission trigger value. Therefore, with the current data under standard environmental risk assessment schemes it can be considered that the risk of thiacloprid and acetamiprid to the soil compartment is unacceptable. However, further research into the effects of these substances on different organisms is required to increase the confidence in the risk assessment estimates for instance, by calculating hazardous concentrations using species sensitivity distribution curves. Copyright © 2017 Elsevier Ltd. All rights reserved.

Phase II study of sunitinib in recurrent or metastatic squamous cell carcinoma of the head and neck: GORTEC 2006-01.

PubMed

Machiels, Jean-Pascal H; Henry, Stéphanie; Zanetta, Sylvie; Kaminsky, Marie-Christine; Michoux, Nicolas; Rommel, Denis; Schmitz, Sandra; Bompas, Emmanuelle; Dillies, Anne-Françoise; Faivre, Sandrine; Moxhon, Anne; Duprez, Thierry; Guigay, Joel

2010-01-01

PURPOSE To assess the efficacy and toxicity of sunitinib monotherapy in palliative squamous cell carcinoma of the head and neck (SCCHN). PATIENTS AND METHODS Thirty-eight patients with SCCHN having evidence of progressive disease (PD) were treated with sunitinib 37.5 mg/d given continuously until PD or unacceptable toxicity. The primary end point was the rate of disease control, defined as stable disease (SD) or partial response (PR) at 6 to 8 weeks after treatment initiation (two-stage design, Simon). Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) was performed in a subset of patients before and 6 to 8 weeks after treatment. The volume transfer constant of the contrast agent (K(trans)) was used to measure changes in the microcirculation blood flow and endothelial permeability of the tumor. Results A PR was observed in one patient, SD in 18, and PD in 19 (Response Evaluation Criteria in Solid Tumors [RECIST]), resulting in a disease control rate of 50%. Among the 18 patients with SD, there were five unconfirmed PRs and six additional minor responses. A significant decrease in K(trans) was seen in three of the four patients who received DCE-MRI monitoring. Grade 5 head and neck bleeds occurred in four patients. Local complications, including the appearance or worsening of tumor skin ulceration or tumor fistula, were recorded in 15 patients. CONCLUSION Sunitinib demonstrated modest activity in palliative SSCHN. The severity of some of the complications highlights the importance of improved patient selection for future studies with sunitinib in head and neck cancer. Sunitinib should not be used outside clinical trials in SSCHN.

TAK-264 (MLN0264) in Previously Treated Asian Patients with Advanced Gastrointestinal Carcinoma Expressing Guanylyl Cyclase C: Results from an Open-Label, Non-randomized Phase 1 Study

PubMed Central

Bang, Yung-Jue; Takano, Toshimi; Lin, Chia-Chi; Fasanmade, Adedigbo; Yang, Huyuan; Danaee, Hadi; Asato, Takayuki; Kalebic, Thea; Wang, Hui; Doi, Toshihiko

2018-01-01

Purpose This phase 1 dose-escalation portion of the study evaluated the safety, pharmacokinetics (PK), and antitumor activity of TAK-264 in Asian patients with advanced gastrointestinal (GI) carcinoma or metastatic or recurrent gastric or gastroesophageal junction adenocarcinoma expressing guanylyl cyclase C (GCC). Materials and Methods Adult patients with advanced GI malignancies expressing GCC (H-score ≥ 10) received TAK-264 on day 1 of 3-week cycles as 30-minute intravenous infusions for up to 1 year or until disease progression or unacceptable toxicity. The primary objectives were to evaluate the safety profile including dose-limiting toxicities (DLTs) during cycle 1, determine the maximum tolerated dose (MTD), and characterize the PK profile of TAK-264. Results Twelve patients were enrolled and treated with 1.2 mg/kg (n=3), 1.5 mg/kg (n=3), or 1.8 mg/kg TAK-264 (n=6). Median number of treatment cycles received was two (range, 1 to 10). None of the patients experienced a DLT and the MTD was not determined. Ten patients (83%) experienced adverse events (AEs). The most common were neutropenia, anorexia, and nausea (each reported by four patients). Five patients (42%) experienced grade ≥ 3 AEs consisting of tumor hemorrhage and hypertension, ascites, adrenal insufficiency, neutropenia and asthenia. Serum exposure to TAK-264 increased proportionally with the dose and the median half-life was approximately 5.5-6.6 days. No patients experienced an objective response. Conclusion TAK-264 demonstrated a manageable safety profile with limited antitumor activity consistent with studies conducted in Western patients with advanced GI malignancies. TAK-264 exposure increased proportionally with the dose. PMID:28494535

Vinorelbine and paclitaxel for locoregional advanced or metastatic non-small-cell lung cancer.

PubMed

Pérez, Juan E; Machiavelli, Mario R; Romero, Alberto O; Romero Acuña, Luis A; Domínguez, María E; Fasce, Hebe; Flores Acosta, Luis; Marrone, Nora; Romero Acuña, Juan M; Langhi, Mario J; Amato, Sonia; Bologna, Fabrina; Ortiz, Eduardo H; Leone, Bernardo A; Lacava, Juan A; Vallejo, Carlos T

2002-08-01

A phase II trial was performed to evaluate the efficacy and toxicity of the novel combination of vinorelbine and paclitaxel as first-line chemotherapy in patients with stages IIIB and IV non-small-cell lung cancer. From January 1997 to September 1999, 34 patients (9 stage IIIB and 25 stage IV) received a regimen consisting of the following: vinorelbine 30 mg/m2 20 minutes intravenous (i.v.) infusion, days 1 and 8; and paclitaxel 135 mg/m2 3-hour i.v. (starting 1 hour after vinorelbine) on day 1. Cycles were repeated every 28 days until progression of disease or unacceptable toxicity development. The median age was 57 years (range 41-70 years); median performance status was 1. Histology was as follows: squamous cell in 24 (71%), large cell in 1 (3%), and adenocarcinoma in 9 (26%). All patients are evaluable for toxicity, whereas 30 are evaluable for response (4 patients refused treatment). Objective response was recorded in 4 of 30 patients (13%, 95% CI 1-25%). No complete response was observed. Partial response was recorded in 4 patients (13%), no change in 10 patients (34%), and progressive disease in 16 patients (53%). The median time to treatment failure was 4 months and median survival was 9 months. The limiting toxicity was myelosuppression: leukopenia in 23 patients (68%), whereas neutropenia was observed in 25 patients (78%). Peripheral neurotoxicity developed in 14 patients (41%) (without G3 or G4 episodes), and constipation (G1-G2: 10 patients), myalgia (G1-G2: 11 patients), diarrhea (G1-G2: 7 patients), and stomatitis were observed in 7 patients. Vinorelbine-paclitaxel combination showed only modest activity against locoregionally advanced or metastatic NSCLC.

Toxicity of six insecticides to predatory mite Amblyseius cucumeris (Oudemans) (Acari: Phytoseiidae) in- and off-field.

PubMed

Cheng, Shenhang; Lin, Ronghua; Zhang, Nan; Yuan, Shankui; Zhou, Xinxin; Huang, Jian; Ren, Xiaodong; Wang, Shoushan; Jiang, Hui; Yu, Caihong

2018-06-22

Amblyseius cucumeris (Oudemans) is a beneficial non-target arthropod (NTA) and a key predator of tetranychid mites in integrated pest management (IPM) programs across China. Evaluating the toxic effects of insecticides on such predatory mites is essential for the success and development of IPM. We tested six insecticides to determine the risk of neonicotinoid insecticide toxicity to predatory mites, using the 'open glass plate method' and adult female A. cucumeris in a "worst case laboratory exposure" scenario. A 48-h toxicity test was performed using the hazard quotient (HQ) approach to evaluate the risk of each insecticide. The LR 50 values (application rate that caused 50% mortality) of acetamiprid, thiamethoxam, imidacloprid, and dinotefuran were 76.4, 104.5, 84.9, and 224.6 g active ingredient (a.i.) ha -1 , respectively, with in-field HQ values of 0.40, 1.28, 0.49, and 0.82, respectively. The HQ values were lower than the trigger value of 2, and were consistent with off-field values. The risks of the four neonicotinoid insecticides to adult female A. cucumeris were acceptable in two exposure scenarios in field and off field. The 48-h LR 50 values for bifenthrin and malathion were 0.008 and 0.062 g. a.i. ha -1 , respectively, which were much lower than the recommended field application rates. The HQ values were much higher than the trigger values for both in- and off-field, indicating that the risks of these two insecticides were unacceptable. Bifenthrin and malathion posed an extremely high risk to the test species, and their use should be restricted to reduce risks to the field with augmentative releases of A. cucumeris. Copyright © 2018 Elsevier Inc. All rights reserved.

40 CFR Appendix B to Subpart G of... - Substitutes Subject to Use Restrictions and Unacceptable Substitutes

Code of Federal Regulations, 2010 CFR

2010-07-01

... Use Conditions Substitutes Application Substitute Decision Conditions Comments Electronics Cleaning w.... Electronics cleaning w/CFC-113 Dibromomethane Unacceptable High ODP; other alternatives exist. Electronics...

Failure analysis of blistered gold plating on spot welded electrical relays

NASA Technical Reports Server (NTRS)

Sokolowski, Witold; O'Donnell, Tim

1989-01-01

Gold-plated stainless-steel sideplates, part of a JPL Galileo spacecraft electronic-relay assembly, exhibited blistering after resistance spot welding. Unacceptable relays had heavy nonuniform gold electrodeposited layers with thicknesses 4.5-11.5 microns. SEM and metallographic investigations indicated much higher heat input generated during the resistance spot welding in unacceptable relays. The attributes of acceptable welded relays are contrasted with unacceptable relays; the possible mechanism of laminar formation of polymeric material in the gold plating is discussed; and some recommendations are provided to prevent similar problems.

Capecitabine/cisplatin doublet in anthracycline and taxane pretreated and HER-2 negative metastatic breast carcinoma patients.

PubMed

Ozdemir, N; Aksoy, S; Sendur, M A; Akinci, M B; Yazici, O; Budakoglu, B; Abali, H; Oksuzoglu, B; Zengin, N

2013-01-01

To evaluate the activity and toxicity of the combination of capecitabine and cisplatin (CapCisp) in anthracycline- and taxane-pretreated HER-2 negative metastatic breast carcinoma (MBC) female patients. Patients with HER-2 negative MBC pretreated with anthracycline and taxane and who were then treated with CapCisp combination were retrospectively evaluated. All patients received Cap 1000 mg/m(2) on days 1-14, and Cisp 60 mg/m(2) on day 1, repeated every 3 weeks. In case of disease control without severe toxicity, single agent Cap was continued until progression or unacceptable toxicities after Cisp cessation. Sixty-four MBC patients with median age 43 years (range 20-66) were included the study. Infiltrative ductal carcinoma prevailed (85.9%). Ten percent of the patients had grade I, 42% grade II, and 48.0% grade III tumors. Estrogen receptor (ER) and progesterone receptor (PR) were positive in 48.4 and 51.6% of the patients, respectively. Twenty-eight percent of the patients had triple negative tumors. Almost the entire patient group had this regimen as a third-line treatment. The median combination chemotherapy cycles were 6 (range 2-8). Twenty-seven non-progressive patients continued treatment with single-agent Cap. Median single-agent Cap cycles after the combination chemotherapy were 4 (range 1-38). Disease control rate was 81.3% (complete response 6.3%; partial response 48.4%, stable disease 26.6%, progressive disease 18.8%). Median follow-up time was 10.6 months. Median time to disease progression was 7 months, median overall survival (OS) was 17 months (95% CI, 6.9-16.1) measured from the start of CapCisp chemotherapy. There were no treatment-related deaths. The most frequent grade 3-4 toxicities were neutropenia (8.1%), nausea - vomiting (7.8%) and thrombocytopenia (6.3%). CapCisp doublet has an encouraging antitumor activity with acceptable and manageable toxicity in anthracycline- and taxane-pretreated HER-2 negative metastatic breast carcinoma patients.

A phase I trial of gefitinib and nimotuzumab in patients with advanced non-small cell lung cancer (NSCLC).

PubMed

Kim, Se Hyun; Shim, Hyo Sup; Cho, Jaeho; Jeong, Jae Heon; Kim, Sun Mi; Hong, Yun Kyoung; Sung, Ji Hee; Ha, Sang-Jun; Kim, Hye Ryun; Chang, Hyun; Kim, Joo Hang; Tania, Crombet; Cho, Byoung Chul

2013-03-01

Nimotuzumab (TheraCIM®) is a humanized anti-epidermal growth factor receptor (EGFR) monoclonal antibody (mAb) with minimal skin toxicity. Combining a different class of anti-EGFR drug with gefitinib is a new strategy to overcome intrinsic and acquired resistance to gefitinib. The aim of this phase I trial was to determine recommended phase II dose (RPIID) and the safety of gefitinib and nimotuzumab combination treatment. Patients with advanced/metastatic NSCLC were treated with escalating doses of weekly nimotuzumab (100mg or 200mg, IV) and fixed doses of daily gefitinib (250 mg/day, PO) until disease progression or unacceptable toxicity. We planned to enroll 10 additional patients at RPIID to ascertain the safety of treatment. EGFR mutations and KRAS mutations were analyzed from available tumor samples. A total of 16 patients were enrolled (3 in 100mg cohort, 13 in 200mg cohort). Six patients (37.5%) were female, and 5 (31.3%) were never smokers. Adenocarcinoma was the major histologic type (13 patients, 81.3%). Treatment was well-tolerated without dose-limiting toxicity (DLT). Four patients (25.0%) experienced grade 2 skin toxicity (1 in 100mg cohorts, 3 in 200mg cohort). Other common grade 1/2 toxicities were fatigue (37.5%) and diarrhea (25.0%). Among 16 evaluable patients, four patients (25.0%) achieved partial response and 7 patients (43.8%) had stable disease. Two of 4 responders had EGFR mutation (exon 19 deletion). Dual agent molecular targeting of EGFR with nimotuzumab and gefitinib in patients with advanced NSCLC is well-tolerated. The RPIID for nimotuzumab is 200mg weekly IV and for gefitinib 250 mg/day PO. Based upon this phase I trial, we are planning to conduct a randomized phase II trial comparing gefitinib and nimotuzumab with gefitinib alone in patients with advanced NSCLC. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

A spatially-dynamic preliminary risk assessment of the American peregrine falcon at the Los Alamos National Laboratory (version 1)

DOE Office of Scientific and Technical Information (OSTI.GOV)

Gallegos, A.F.; Gonzales, G.J.; Bennett, K.D.

1997-06-01

The Endangered Species Act and the Record of Decision on the Dual Axis Radiographic Hydrodynamic Test Facility at the Los Alamos National Laboratory require protection of the American peregrine falcon. A preliminary risk assessment of the peregrine was performed using a custom FORTRAN model and a geographical information system. Estimated doses to the falcon were compared against toxicity reference values to generate hazard indices. Hazard index results indicated no unacceptable risk to the falcon from the soil ingestion pathway, including a measure of cumulative effects from multiple contaminants that assumes a linear additive toxicity type. Scaling home ranges on themore » basis of maximizing falcon height for viewing prey decreased estimated risk by 69% in a canyons-based home range and increased estimated risk by 40% in a river-based home range. Improving model realism by weighting simulated falcon foraging based on distance from potential nest sites decreased risk by 93% in one exposure unit and by 82% in a second exposure unit. It was demonstrated that choice of toxicity reference values can have a substantial impact on risk estimates. Adding bioaccumulation factors for several organics increased partial hazard quotients by a factor of 110, but increased the mean hazard index by only 0.02 units. Adding a food consumption exposure pathway in the form of biomagnification factors for 15 contaminants of potential ecological concern increased the mean hazard index to 1.16 ({+-} 1.0), which is above the level of acceptability (1.0). Aroclor-1254, dichlorodiphenyltrichlorethane (DDT) and dichlorodiphenylethelyne (DDE) accounted for 81% of the estimated risk that includes soil ingestion and food consumption Contaminant pathways and a biomagnification component. Information on risk by specific geographical location was generated, which can be used to manage contaminated areas, falcon habitat, facility siting, and/or facility operations. 123 refs., 10 figs., 2 tabs.« less

Phase Ib study of the mitochondrial inhibitor ME-344 plus topotecan in patients with previously treated, locally advanced or metastatic small cell lung, ovarian and cervical cancers.

PubMed

Diamond, Jennifer R; Goff, Barbara; Forster, Martin D; Bendell, Johanna C; Britten, Carolyn D; Gordon, Michael S; Gabra, Hani; Waterhouse, David M; Poole, Mark; Ross Camidge, D; Hamilton, Erika; Moore, Kathleen M

2017-10-01

Background This multicenter, open-label, phase Ib study was designed to assess the safety, pharmacokinetics and preliminary efficacy of ME-344, a mitochondrial inhibitor, administered in combination with the topoisomerase I inhibitor, topotecan, in patients with previously treated, locally advanced or metastatic small cell lung (SCLC), ovarian and cervical cancers. Patients and methods In Part 1, patients received ME-344 10 mg/kg intravenously weekly on days 1, 8, 15 and 22 in combination with topotecan 4 mg/m 2 on days 1, 8, and 15 of a 28 day cycle. Cycles were repeated until disease progression or unacceptable toxicity. Patients were evaluated for dose-limiting toxicity (DLT) in cycle 1 and ME-344 pharmacokinetic samples were obtained. In Part 2, patients with locally advanced or metastatic SCLC and ovarian cancer were enrolled in expansion cohorts treated at the recommended phase II dose (RP2D) determined in Part 1. Results Fourteen patients were enrolled in Part 1 and no DLTs were observed. The RP2D of ME-344 in combination with topotecan was established as 10 mg/kg. In Part 2, 32 patients were enrolled. The most common treatment-emergent all-grade and grade 3/4 toxicities included fatigue (65.2%, 6.5%), neutropenia (56.5%, 43.5%) and thrombocytopenia (50%, 23.9%). One patient with recurrent ovarian cancer experienced a partial response by RECIST 1.1 and 21 patients achieved stable disease as best response. Conclusions The combination of ME-344 10 mg/kg weekly and topotecan 4 mg/m 2 was tolerable, however, the degree of anti-cancer activity does not support further investigation of the combination in unselected patients with SCLC, ovarian and cervical cancers.

Safety and efficacy of nivolumab and standard chemotherapy drug combination in patients with advanced non-small-cell lung cancer: a four arms phase Ib study

PubMed Central

Kanda, S.; Goto, K.; Shiraishi, H.; Kubo, E.; Tanaka, A.; Utsumi, H.; Sunami, K.; Kitazono, S.; Mizugaki, H.; Horinouchi, H.; Fujiwara, Y.; Nokihara, H.; Yamamoto, N.; Hozumi, H.; Tamura, T.

2016-01-01

Background The human IgG4 monoclonal antibody nivolumab targets programmed cell death-1 (PD-1) and promotes antitumor response by blocking the interaction of PD-1 with its ligands. This single-center phase Ib study investigated the tolerability, safety, and pharmacokinetics of nivolumab combined with standard chemotherapy in patients with advanced non-small-cell lung cancer (NSCLC). Patients and methods Patients who had stage IIIB without indication for definitive radiotherapy, stage IV, or recurrent NSCLC were eligible. Regimens were nivolumab 10 mg/kg + gemcitabine/cisplatin (arm A), pemetrexed/cisplatin (arm B), paclitaxel/carboplatin/bevacizumab (arm C), or docetaxel (arm D). Regimens A, B, and D were repeated every 3 weeks for up to four cycles and regimen C was repeated for up to six cycles; nivolumab alone (arm A), with pemetrexed (arm B), bevacizumab (arm C), or docetaxel (arm D) was continued every 3 weeks as maintenance therapy until disease progression or unacceptable toxicity. Dose-limiting toxicity (DLT) was evaluated during the first treatment cycle. Results As of March 2014, six patients were enrolled in each arm. The combination of nivolumab 10 mg/kg and chemotherapy was well tolerated. DLT was observed in only one patient in arm A (alanine aminotransferase increased). Select adverse events (those with a potential immunologic cause) of any grade were observed in six, four, six, and five patients in arms A, B, C, and D, respectively. Three, three, six, and one patient achieved partial response while median progression-free survival was 6.28, 9.63 months, not reached, and 3.15 months in arms A, B, C, and D, respectively. Conclusions Combination of nivolumab 10 mg/kg and chemotherapy showed an acceptable toxicity profile and encouraging antitumor activity in patients with advanced NSCLC. Clinical trials number Japanese Pharmaceutical Information Center Clinical Trials Information (JapicCTI)-132071. PMID:27765756

77 FR 20639 - Shashikant Shah: Debarment Order

Federal Register 2010, 2011, 2012, 2013, 2014

2012-04-05

... investigate, log, and archive questionable, aberrant, and unacceptable laboratory results so that Able could... maintaining false, fraudulent, and inaccurate data and records to obtain FDA approval to market new product...

77 FR 20641 - Jose Concepcion: Debarment Order

Federal Register 2010, 2011, 2012, 2013, 2014

2012-04-05

... investigate, log, and archive questionable, aberrant, and unacceptable laboratory results so that Able could... maintaining false, fraudulent, and inaccurate data and records to obtain FDA approval to market new product...

32 CFR 154.13 - Sensitive positions.

Code of Federal Regulations, 2013 CFR

2013-07-01

... misconduct, malfeasance, or nonfeasance of an incumbent in any such position could result in an unacceptably... the extent feasible, the Top Secret billet structure into the component Manpower Unit Manning Document...

32 CFR 154.13 - Sensitive positions.

Code of Federal Regulations, 2010 CFR

2010-07-01

... misconduct, malfeasance, or nonfeasance of an incumbent in any such position could result in an unacceptably... the extent feasible, the Top Secret billet structure into the component Manpower Unit Manning Document...

32 CFR 154.13 - Sensitive positions.

Code of Federal Regulations, 2012 CFR

2012-07-01

... misconduct, malfeasance, or nonfeasance of an incumbent in any such position could result in an unacceptably... the extent feasible, the Top Secret billet structure into the component Manpower Unit Manning Document...

32 CFR 154.13 - Sensitive positions.

Code of Federal Regulations, 2011 CFR

2011-07-01

... misconduct, malfeasance, or nonfeasance of an incumbent in any such position could result in an unacceptably... the extent feasible, the Top Secret billet structure into the component Manpower Unit Manning Document...

32 CFR 154.13 - Sensitive positions.

Code of Federal Regulations, 2014 CFR

2014-07-01

... misconduct, malfeasance, or nonfeasance of an incumbent in any such position could result in an unacceptably... the extent feasible, the Top Secret billet structure into the component Manpower Unit Manning Document...

47 CFR 22.878 - Obligation to abate unacceptable interference.

Code of Federal Regulations, 2010 CFR

2010-10-01

.... 22.878 Section 22.878 Telecommunication FEDERAL COMMUNICATIONS COMMISSION (CONTINUED) COMMON CARRIER SERVICES PUBLIC MOBILE SERVICES Air-Ground Radiotelephone Service Commercial Aviation Air-Ground Systems § 22.878 Obligation to abate unacceptable interference. This section applies only to commercial...

Successful treatment of pediatric psoriasis with Indigo naturalis composite ointment.

PubMed

Lin, Yin-Ku; Yen, Hung-Rong; Wong, Wen-Rou; Yang, Sien-Hung; Pang, Jong-Hwei Su

2006-01-01

The treatment of psoriasis in children is still an intractable problem and demands a long-term therapy with prolonged efficacy that is free from serious adverse events. Many modes of therapy are currently in use but the disease is often resistant to treatment owing to the unacceptable toxicity that leads to poor compliance. Therefore, to develop an alternative treatment is indispensable. Traditional Chinese medicine has been documented for over 1000 years to provide various effective treatments for inflammatory skin diseases. Herein, we report an 8-year-old boy with recalcitrant pediatric psoriasis who, after multiple treatment failures with conventional antipsoriatic medications, showed remarkable clinical improvement with 8 weeks of topical treatment with Indigo naturalis composite ointment. Remission has lasted for over 2 years until now. Our patient's response suggests that topical Indigo naturalis composite ointment may provide a safe and effective alternative treatment for pediatric psoriasis.

Predicting the activity and toxicity of new psychoactive substances: a pharmaceutical industry perspective.

PubMed

Leach, Andrew G

2014-01-01

Predicting the effect that new compounds might have when administered to human beings is a common desire shared by researchers in the pharmaceutical industry and those interested in psychoactive compounds (illicit or otherwise). The experience of the pharmaceutical industry is that making such predictions at a usefully accurate level is not only difficult but that even when billions of dollars are spent to ensure that only compounds likely to have a desired effect without unacceptable side-effects are dosed to humans in clinical trials, they fail in more than 90% of cases. A range of experimental and computational techniques is used and they are placed in their context in this paper. The particular roles played by computational techniques and their limitations are highlighted; these techniques are used primarily to reduce the number of experiments that must be performed but cannot replace those experiments. Copyright © 2013 John Wiley & Sons, Ltd.

Risk assessment in the management of newly diagnosed classical Hodgkin lymphoma.

PubMed

Connors, Joseph M

2015-03-12

Treatment of Hodgkin lymphoma is associated with 2 major types of risk: that the treatment may fail to cure the disease or that the treatment will prove unacceptably toxic. Careful assessment of the amount of the lymphoma (tumor burden), its behavior (extent of invasion or specific organ compromise), and host related factors (age; coincident systemic infection; and organ dysfunction, especially hematopoietic, cardiac, or pulmonary) is essential to optimize outcome. Elaborately assembled prognostic scoring systems, such as the International Prognostic Factors Project score, have lost their accuracy and value as increasingly effective chemotherapy and supportive care have been developed. Identification of specific biomarkers derived from sophisticated exploration of Hodgkin lymphoma biology is bringing promise of further improvement in targeted therapy in which effectiveness is increased at the same time off-target toxicity is diminished. Parallel developments in functional imaging are providing additional potential to evaluate the efficacy of treatment while it is being delivered, allowing dynamic assessment of risk during chemotherapy and adaptation of the therapy in real time. Risk assessment in Hodgkin lymphoma is continuously evolving, promising ever greater precision and clinical relevance. This article explores the past usefulness and the emerging potential of risk assessment for this imminently curable malignancy. © 2015 by The American Society of Hematology.

Epithelioid hemangioendothelioma of the spine treated with RapidArc volumetric-modulated radiotherapy

DOE Office of Scientific and Technical Information (OSTI.GOV)

Guy, Jean-Baptiste; Trone, Jane-Chloé; Chargari, Cyrus

2014-10-01

Radiotherapy for epithelioid hemangioendothelioma (EHE) using volumetric intensity-modulated arc radiotherapy (VMAT). A 48-year-old woman was referred for curative irradiation of a vertebral EHE after failure of surgery. A comparison between VMAT and conventional conformal tridimensional (3D) dosimetry was performed and potential advantage of VMAT for sparing critical organs from irradiation's side effects was discussed. The total delivered dose on the planning target volume was 54 Gy in 27 fractions. The patient was finally treated with VMAT. The tolerance was excellent. There was no acute toxicity, including no increase in pain. With a follow-up of 18 months, no delayed toxicity wasmore » reported. The clinical response consisted of a decrease in the dorsal pain. The D{sub max} for the spinal cord was reduced from 55 Gy (3D-radiotherapy [RT]) (which would be an unacceptable dose to the spine because of the risk of myelopathy) to 42.8 Gy (VMAT), which remains below the recommended dose threshold (45 Gy). The dose delivered to 20% of organ volume (D{sub 20}) was reduced from 47 Gy (3D-RT) to 3 Gy (VMAT) for the spinal cord. The study shows that VMAT allows the delivery of curative treatment for vertebral EHEs because of critical organ sparing.« less

Helminths and immunological tolerance.

PubMed

Johnston, Chris J C; McSorley, Henry J; Anderton, Stephen M; Wigmore, Stephen J; Maizels, Rick M

2014-01-27

Current immunosuppression regimens for solid-organ transplantation have shown disappointing efficacy in the prevention of chronic allograft rejection and carry unacceptable risks including toxicity, neoplasia, and life-threatening infection. Achievement of immunological tolerance (long-term antigen unresponsiveness in an immunocompetent host) presents the exciting prospect of freedom from immunosuppression for transplant recipients. It is now 60 years since the first demonstration of immunological tolerance in animal models of transplantation, but translation into routine clinical practice remains elusive. Helminth parasites may provide novel strategies toward achieving this goal. Helminths are remarkably successful parasites: they currently infect more than one quarter of the world's population. It is now well established that the parasites' success is the result of active immunomodulation of their hosts' immune response. Although this primarily secures ongoing survival of the parasites, helminth-induced immunomodulation can also have a number of benefits for the host. Significant reductions in the prevalence of allergy and autoimmune conditions among helminth-infected populations are well recognized and there is now a significant body of evidence to suggest that harmful immune responses to alloantigens may be abrogated as well. Here, we review all existing studies of helminth infection and transplantation, explore the mechanisms involved, and discuss possible avenues for future translation to clinical practice.

Gynecologic Oncology Group quality assurance audits: analysis and initiatives for improvement.

PubMed

Blessing, John A; Bialy, Sally A; Whitney, Charles W; Stonebraker, Bette L; Stehman, Frederick B

2010-08-01

The Gynecologic Oncology Group (GOG) is a multi-institution, multi-discipline Cooperative Group funded by the National Cancer Institute (NCI) to conduct clinical trials which investigate the treatment, prevention, control, quality of survivorship, and translational science of gynecologic malignancies. In 1982, the NCI initiated a program of on-site quality assurance audits of participating institutions. Each is required to be audited at least once every 3 years. In GOG, the audit mandate is the responsibility of the GOG Quality Assurance Audit Committee and it is centralized in the Statistical and Data Center (SDC). Each component (Regulatory, Investigational Drug Pharmacy, Patient Case Review) is classified as Acceptable, Acceptable, follow-up required, or Unacceptable. To determine frequently occurring deviations and develop focused innovative solutions to address them. A database was created to examine the deviations noted at the most recent audit conducted at 57 GOG parent institutions during 2004-2007. Cumulatively, this involved 687 patients and 306 protocols. The results documented commendable performance: Regulatory (39 Acceptable, 17 Acceptable, follow-up, 1 Unacceptable); Pharmacy (41 Acceptable, 3 Acceptable, follow-up, 1 Unacceptable, 12 N/A): Patient Case Review (31 Acceptable, 22 Acceptable, follow-up, 4 Unacceptable). The nature of major and lesser deviations was analyzed to create and enhance initiatives for improvement of the quality of clinical research. As a result, Group-wide proactive initiatives were undertaken, audit training sessions have emphasized recurring issues, and GOG Data Management Subcommittee agendas have provided targeted instruction and training. The analysis was based upon parent institutions only; affiliate institutions and Community Clinical Oncology Program participants were not included, although it is assumed their areas of difficulty are similar. The coordination of the GOG Quality Assurance Audit program in the SDC has improved data quality by enhancing our ability to identify frequently occurring deviations and develop innovative solutions to avoid or minimize their occurrence in the future.

Is chronic AhR activation by rapidly metabolized ligands safe for the treatment of immune-mediated diseases?

PubMed

Ehrlich, Allison K; Kerkvliet, Nancy I

2017-02-01

There is a long standing perception that AhR ligands are automatically disqualified from pharmaceutical development due to their induction of Cyp1a1 as well as their potential for causing "dioxin-like" toxicities. However, recent discoveries of new AhR ligands with potential therapeutic applications have been reported, inviting reconsideration of this policy. One area of exploration is focused on the activation of AhR to promote the generation of regulatory T cells, which control the intensity and duration of immune responses. Rapidly metabolized AhR ligands (RMAhRLs), which do not bioaccumulate in the same manner as 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) have been discovered that induce Tregs and display impressive therapeutic efficacy in a broad range of preclinical models of immune-mediated diseases. Given the promise of these RMAhRLs, is the bias against AhR activators still valid? Can RMAhRLs be given chronically to maintain therapeutic levels of AhR activation without producing the same toxicity profile as dioxin-like compounds? Based on our review of the data, there is little evidence to support the indiscriminate exclusion of AhR activators/Cyp1a1 inducers from early drug developmental pipelines. We also found no evidence that short-term treatment with RMAhRLs produce "dioxin-like toxicity" and, in fact, were well tolerated. However, safety testing of individual RMAhRLs under therapeutic conditions, as performed with all promising new drugs, will be needed to reveal whether or not chronic activation of AhR leads to unacceptable adverse outcomes.

Defibrotide for the treatment of severe hepatic veno-occlusive disease and multiorgan failure after stem cell transplantation: a multicenter, randomized, dose-finding trial.

PubMed

Richardson, Paul G; Soiffer, Robert J; Antin, Joseph H; Uno, Hajime; Jin, Zhezhen; Kurtzberg, Joanne; Martin, Paul L; Steinbach, Gideon; Murray, Karen F; Vogelsang, Georgia B; Chen, Allen R; Krishnan, Amrita; Kernan, Nancy A; Avigan, David E; Spitzer, Thomas R; Shulman, Howard M; Di Salvo, Donald N; Revta, Carolyn; Warren, Diane; Momtaz, Parisa; Bradwin, Gary; Wei, L J; Iacobelli, Massimo; McDonald, George B; Guinan, Eva C

2010-07-01

Therapeutic options for severe hepatic veno-occlusive disease (VOD) are limited and outcomes are dismal, but early phase I/II studies have suggested promising activity and acceptable toxicity using the novel polydisperse oligonucleotide defibrotide. This randomized phase II dose-finding trial determined the efficacy of defibrotide in patients with severe VOD following hematopoietic stem cell transplantation (HSCT) and identified an appropriate dose for future trials. Adult and pediatric patients received either lower-dose (arm A: 25 mg/kg/day; n = 75) or higher-dose (arm B: 40 mg/kg/day; n = 74) i.v. defibrotide administered in divided doses every 6 hours for > or =14 days or until complete response, VOD progression, or any unacceptable toxicity occurred. Overall complete response and day +100 post-HSCT survival rates were 46% and 42%, respectively, with no significant difference between treatment arms. The incidence of treatment-related adverse events was low (8% overall; 7% in arm A, 10% in arm B); there was no significant difference in the overall rate of adverse events between treatment arms. Early stabilization or decreased bilirubin was associated with better response and day +100 survival, and decreased plasminogen activator inhibitor type 1 (PAI-1) during treatment was associated with better outcome; changes were similar in both treatment arms. Defibrotide 25 or 40 mg/kg/day also appears effective in treating severe VOD following HSCT. In the absence of any differences in activity, toxicity or changes in PAI-1 level, defibrotide 25 mg/kg/day was selected for ongoing phase III trials in VOD.

Switch maintenance therapy with docetaxel and bevacizumab after induction therapy with cisplatin, pemetrexed, and bevacizumab in advanced non-squamous non-small cell lung cancer: a phase II study.

PubMed

Nishimoto, Koji; Karayama, Masato; Inui, Naoki; Yasui, Hideki; Hozumi, Hironao; Suzuki, Yuzo; Furuhashi, Kazuki; Fujisawa, Tomoyuki; Enomoto, Noriyuki; Nakamura, Yutaro; Inami, Nao; Matsuura, Shun; Kaida, Yusuke; Matsui, Takashi; Asada, Kazuhiro; Matsuda, Hiroyuki; Fujii, Masato; Toyoshima, Mikio; Imokawa, Shiro; Suda, Takafumi

2018-06-16

Switch maintenance therapy, using alternative agents that were not administered during induction chemotherapy, is a treatment option for advanced non-squamous non-small cell lung cancer (NSCLC). Bevacizumab is known to increase the efficacy of other chemotherapeutic agents; however, switch maintenance therapy with docetaxel and bevacizumab has not been adequately studied. The goal of this study was to evaluate the efficacy and safety of switch maintenance therapy with docetaxel and bevacizumab following induction therapy with cisplatin, pemetrexed, and bevacizumab. Chemotherapy-naïve non-squamous NSCLC patients received induction therapy of four cycles of cisplatin (75 mg/m 2 ), pemetrexed (500 mg/m 2 ), and bevacizumab (15 mg/kg). Patients who achieved disease control after induction therapy then received maintenance therapy with docetaxel (50 mg/m 2 ) and bevacizumab (15 mg/kg) until disease progression or unacceptable toxicity. The primary endpoint was progression-free survival from enrollment. This study enrolled 49 NSCLC patients, among which 38 (77.6%) completed the four cycles of induction therapy and received maintenance therapy. The median progression-free survival from enrollment was 7.8 months (95% confidence interval: 4.7-11.0 months). The most common toxicities of grade 3 or higher were neutropenia (68.4%), leukopenia (50.0%), febrile neutropenia (31.8%), and hypertension. Switch maintenance therapy with docetaxel and bevacizumab following induction therapy with cisplatin, pemetrexed, and bevacizumab demonstrated modest efficacy and frequent hematologic toxicity in non-squamous NSCLC patients.

Protocol to identify incompatible combinations of concrete materials : tech brief.

DOT National Transportation Integrated Search

2006-07-01

For this project, incompatibility of concrete materials is : defined as interactions between acceptable materials that result in unexpected or unacceptable performance. The most common problems are associated with premature stiffening (rapid sl...

Ibrutinib for patients with relapsed or refractory chronic lymphocytic leukaemia with 17p deletion (RESONATE-17): a phase 2, open-label, multicentre study.

PubMed

O'Brien, Susan; Jones, Jeffrey A; Coutre, Steven E; Mato, Anthony R; Hillmen, Peter; Tam, Constantine; Österborg, Anders; Siddiqi, Tanya; Thirman, Michael J; Furman, Richard R; Ilhan, Osman; Keating, Michael J; Call, Timothy G; Brown, Jennifer R; Stevens-Brogan, Michelle; Li, Yunfeng; Clow, Fong; James, Danelle F; Chu, Alvina D; Hallek, Michael; Stilgenbauer, Stephan

2016-10-01

The TP53 gene, encoding tumour suppressor protein p53, is located on the short arm of chromosome 17 (17p). Patients with 17p deletion (del17p) chronic lymphocytic leukaemia have poor responses and survival after chemoimmunotherapy. We assessed the activity and safety of ibrutinib, an oral covalent inhibitor of Bruton's tyrosine kinase, in relapsed or refractory patients with del17p chronic lymphocytic leukaemia or small lymphocytic lymphoma. We did a multicentre, international, open-label, single-arm study at 40 sites in the USA, Canada, Europe, Australia, and New Zealand. Patients (age ≥18 years) with previously treated del17p chronic lymphocytic leukaemia or small lymphocytic lymphoma received oral ibrutinib 420 mg once daily until progressive disease or unacceptable toxicity. The primary endpoint was overall response in the all-treated population per International Workshop on Chronic Lymphocytic Leukaemia 2008 response criteria modified for treatment-related lymphocytosis. Preplanned exploratory analyses were progression-free survival, overall survival, sustained haematological improvement, and immunological improvement. Patient enrolment is complete, but follow-up is ongoing. Treatment discontinuation owing to adverse events, unacceptable toxicity, or death were collected as a single combined category. This study is registered with ClinicalTrials.gov, number NCT01744691. Between Jan 29, 2013, and June 19, 2013, 145 patients were enrolled. The all-treated population consisted of 144 patients with del17p chronic lymphocytic leukaemia or small lymphocytic lymphoma who received at least one dose of study drug, with a median age of 64 years (IQR 57-72) and a median of two previous treatments (IQR 1-3). At the prespecified primary analysis after a median follow-up of 11·5 months (IQR 11·1-13·8), 92 (64%, 95% CI 56-71) of 144 patients had an overall response according to independent review committee assessment; 119 patients (83%, 95% CI 76-88) had an overall response according to investigator assessment. In an extended analysis with median follow-up of 27·6 months (IQR 14·6-27·7), the investigator-assessed overall response was reported in 120 patients (83%, 95% CI 76-89). 24-month progression-free survival was 63% (95% CI 54-70) and 24-month overall survival was 75% (67-81). Sustained haematological improvement was noted in 72 (79%) of 91 patients with any baseline cytopenia. No clinically relevant changes were noted from baseline to 6 months or 24 months in IgA (median 0·4 g/L at baseline, 0·6 g/L at 6 months, and 0·7 g/L at 24 months), IgG (5·0 g/L, 5·3 g/L, and 4·9 g/L), or IgM (0·3 g/L at each timepoint) concentrations. Common reasons for treatment discontinuation were progressive disease in 34 (24%) patients and adverse events, unacceptable toxicity, or death in 24 (17%) patients. Major bleeding occurred in 13 (9%) patients (11 [8%] grade 3-4). Grade 3 or worse infections occurred in 43 (30%) patients, including pneumonia in 19 (13%) patients. In the extended analysis, 38 patients died, 18 as a result of adverse events (four pneumonia, three chronic lymphocytic leukaemia, two Richter's syndrome, two sepsis, and one each of acute myocardial infarction, septic shock, encephalopathy, general deterioration in physical health, abnormal hepatic function, myocardial infarction, and renal infarction). A high proportion of patients had an overall response to ibrutinib and the risk:benefit profile was favourable, providing further evidence for use of ibrutinib in the most difficult subset of patients with chronic lymphocytic leukaemia or small lymphocytic lymphoma. Ibrutinib represents a clinical advance in the treatment of patients with del17p chronic lymphocytic leukaemia and has been incorporated into treatment algorithms as a primary treatment for these patients. Pharmacyclics LLC, an AbbVie Company. Copyright © 2016 Elsevier Ltd. All rights reserved.

40 CFR Appendix G to Subpart G of... - Substitutes Subject to Use Restrictions and Unacceptable Substitutes Listed in the March 3, 1999...

Code of Federal Regulations, 2010 CFR

2010-07-01

.... Refrigerants Unacceptable Substitutes End-use Substitute Decision Comments CFC-12, R-502, and HCFC-22 Household... gas emissions from direct release of refrigerant to the atmosphere. [64 FR 10378, Mar. 3, 1999] ...

40 CFR Appendix G to Subpart G of... - Substitutes Subject to Use Restrictions and Unacceptable Substitutes Listed in the March 3, 1999...

Code of Federal Regulations, 2011 CFR

2011-07-01

.... Refrigerants Unacceptable Substitutes End-use Substitute Decision Comments CFC-12, R-502, and HCFC-22 Household... gas emissions from direct release of refrigerant to the atmosphere. [64 FR 10378, Mar. 3, 1999] ...

Measuring Attitudes toward Acceptable and Unacceptable Parenting Practices

ERIC Educational Resources Information Center

Budd, Karen S.; Behling, Steven; Li, Yan; Parikshak, Sangeeta; Gershenson, Rachel A.; Feuer, Rachel; Danko, Christina M.

2012-01-01

This study investigated the properties of a new rating instrument, the Parenting Questionnaire (PQ), designed to measure attitudes about acceptable and unacceptable parenting practices. In Study 1, subject matter experts representing culturally diverse psychologists, parents, and college students were consulted to identify 110 items receiving high…

Home administration of maintenance pemetrexed for patients with advanced non-squamous non-small cell lung cancer: rationale, practicalities and phase II feasibility study design

PubMed Central

2013-01-01

Background Home-based care in oncology is mainly reserved for patients at the end of life. Regulations regarding home delivery of cytotoxics differ across Europe, with a notable lack of practice guidelines in most countries. This has led to a lack of data addressing the feasibility of home-based administration of cytotoxic chemotherapy. In advanced non-squamous non-small cell lung cancer, pemetrexed is approved as maintenance therapy after first-line chemotherapy. In this setting, patients have the potential to be treated long-term with maintenance therapy, which, in the absence of unacceptable toxicity, is continued until disease progression. The favourable safety profile of pemetrexed and the ease of its administration by 10-minute intravenous infusion every 3 weeks make this drug a suitable candidate for administration in a home setting. Methods Literature and regulations relevant to the home-based delivery of cytotoxic therapy were reviewed, and a phase II feasibility study of home administration of pemetrexed maintenance therapy was designed. At least 50 patients with advanced non-squamous non-small cell lung cancer, Eastern Cooperative Oncology Group performance status 0–1 and no progressive disease after four cycles of platinum-based first-line therapy are required to allow investigation of the feasibility of home-based administration of pemetrexed maintenance therapy (500 mg/m2 every 3 weeks until progressive disease or unacceptable toxicity). Feasibility is being assessed as adherence to the home-based administration process (primary endpoint), patient safety, impact on patients’ quality of life, patient and physician satisfaction with home care, and healthcare resource use and costs. Enrolment of patients from the UK and Sweden, where home-based care is relatively well developed, commenced in December 2011. Discussion This feasibility study addresses an important aspect of maintenance therapy, that is, patient comfort during protracted home-based chemotherapy. The study design requires unusual methodology and specific logistics to address outcomes relevant to the home-delivery approach. This article presents a study design that offers a novel and reproducible model for home-based chemotherapy, and provides an up-to-date overview of the literature regarding this type of treatment. Trial registration ClinicalTrials.gov: NCT01473563 PMID:24090033

Senescence sweetening of chip and fry processing potatoes

USDA-ARS?s Scientific Manuscript database

Potato storage makes the crop available over an extended time period, but increases financial risk to growers and end users. Senescence sweetening limits storage duration for chip and fry processing potatoes because it results in an unacceptable accumulation of reducing sugars that result in dark-co...

47 CFR 22.877 - Unacceptable interference to Part 90 non-cellular 800 MHz licensees from commercial aviation air...

Code of Federal Regulations, 2010 CFR

2010-10-01

...-cellular 800 MHz licensees from commercial aviation air-ground systems. 22.877 Section 22.877 Telecommunication FEDERAL COMMUNICATIONS COMMISSION (CONTINUED) COMMON CARRIER SERVICES PUBLIC MOBILE SERVICES Air-Ground Radiotelephone Service Commercial Aviation Air-Ground Systems § 22.877 Unacceptable interference...

Assignment of C1q-binding HLA antibodies as unacceptable HLA antigens avoids positive CDC-crossmatches prior to transplantation of deceased donor organs.

PubMed

Juhl, David; Marget, Matthias; Hallensleben, Michael; Görg, Siegfried; Ziemann, Malte

2017-03-01

Soon, a virtual crossmatch shall replace the complement-dependent cytotoxicity (CDC) allocation crossmatch in the Eurotransplant region. To prevent positive CDC-crossmatches in the recipient centre, careful definition of unacceptable antigens is necessary. For highly sensitized patients, this is difficult by CDC alone. Assignment of all antibodies detected by sensitive assays, however, could prevent organ allocation. To assess the usefulness of the Luminex C1q-assay to prevent positive CDC-crossmatches, all CDC-crossmatches performed prior to deceased kidney transplantation in a 16-month-period were reviewed. Sera causing positive crossmatches were investigated by the C1q-assay. 31 out of 1432 crossmatches (2.2%) were positive. Sera involved in 26 positive crossmatches were available. C1q-binding donor-specific antibodies were detected in 19 sera (73.1%). The other sera were from recipients without any HLA antibodies detectable by CDC or common solid phase assays. Three patients had known Non-HLA antibodies causing positive CDC-results. Four crossmatches were only weak positive. Therefore, avoidance of donors with HLA antigens against whom C1q-binding antibodies were detected would have prevented all positive crossmatches due to HLA antibodies. Provided that all HLA specificities against which antibodies are detected by the Luminex C1q-assay are considered as unacceptable antigens, CDC-crossmatches prior to transplantation might safely be omitted in many patients. They should be maintained in highly immunized patients, however, for whom assignment of all C1q-positive antibodies as unacceptable antigens could lead to a significant delay or even prevention of transplantation. Copyright © 2017 Elsevier B.V. All rights reserved.

Thermal immobilization of Cr, Cu and Zn of galvanizing wastes in the presence of clay and fly ash.

PubMed

Singh, I B; Chaturvedi, K; Yegneswaran, A H

2007-07-01

In the present investigation thermal treatment of galvanizing waste with clay and fly ash has been carried out to immobilize Cr, Zn, Cu and other metals of the waste at temperature range 850 degrees C to 950 degrees C. Leaching of the metals from the waste and solidified product was analyzed using toxic characteristic leaching procedure (TCLP). Results indicated that the composition of waste and clay treatment temperature are the key factors in determining the stability of solidified product. After heating at 950 degrees C, the solidified specimens of 10% waste with clay have shown comparatively a high compressive strength and less water absorption. However, a decrease in compressive strength and increase in water absorption were noticed after addition of 15% of waste with clay. The leachability of all the metals present in the waste was found to reduce considerably with the increase of treatment temperature. In the case of Cr and Zn, their leachabilty was found at unacceptable levels from the treated product obtained after heating at 850 degrees C However, their leachability was reduced significantly within an acceptable level after treatment at 950 degrees C. The thermal treatment has shown an increase of re-oxidation trend of Cr (III) to Cr (VI) up to 900 degrees C of heating and this trend became almost zero after heating at 950 degrees C. Addition of fly ash did not show any improvement in strength, durability and leachability of metals from the thermally treated product. X-ray diffraction (XRD) analysis of the product confirmed the presence of mixed phases of oxides of toxic metals.

Randomized phase II study of sequential carboplatin plus paclitaxel and gefitinib in chemotherapy-naïve patients with advanced or metastatic non-small-cell lung cancer: Long-term follow-up results.

PubMed

Kubo, Emi; Yamamoto, Noboru; Nokihara, Hiroshi; Fujiwara, Yutaka; Horinouchi, Hidehito; Kanda, Shintaro; Goto, Yasushi; Ohe, Yuichiro

2017-01-01

The epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor gefitinib was initially approved in Japan in 2002 for the treatment of advanced or metastatic non-small-cell lung cancer (NSCLC); however, the optimal order of conventional cytotoxic chemotherapy (carboplatin and paclitaxel) and gefitinib administration has not been determined. We conducted a randomized phase II study of carboplatin and paclitaxel followed by gefitinib vs. gefitinib followed by carboplatin and paclitaxel to select a candidate for further development in a phase III study of chemotherapy-naïve patients with advanced or metastatic NSCLC, regardless of their EGFR mutation status. A total of 97 patients meeting this description were randomly assigned to arm A (carboplatin and paclitaxel followed by gefitinib; n=49) or B (gefitinib followed by carboplatin and paclitaxel; n=48) from June, 2003 to October, 2005. Carboplatin and paclitaxel were administered in 4 cycles every 3 weeks; gefitinib was continued until disease progression or development of unacceptable toxicity. The primary endpoint was overall survival; the secondary endpoints were response rate and adverse event prevalence. The median overall follow-up was 65.1 months (range, 28.7-75.1 months). The major toxicities were hematological (carboplatin and paclitaxel) or skin rash, diarrhea and hepatic dysfunction (gefitinib). Interstitial lung disease was observed in 1 patient from each arm. In arms A and B, the carboplatin and paclitaxel response rate, gefitinib response rate, and median survival durations were 34.8 and 26.5%, 33.3 and 35.7%, and 18.8 and 17.2 months, respectively. Arm A was selected for a subsequent phase III study.

A Gynecologic Oncology Group phase II trial of the protein kinase C-beta inhibitor, enzastaurin and evaluation of markers with potential predictive and prognostic value in persistent or recurrent epithelial ovarian and primary peritoneal malignancies

PubMed Central

Usha, Lydia; Sill, Michael W.; Darcy, Kathleen M.; Benbrook, Doris M.; Hurteau, Jean A; Michelin, David P.; Mannel, Robert S.; Hanjani, Parviz; De Geest, Koen; Godwin, Andrew K.

2011-01-01

Purpose Protein kinase C (PKC) activation contributes to proliferation and angiogenesis in epithelial ovarian or primary peritoneal carcinoma (EOC/PPC). A multi-institutional phase II trial was conducted to evaluate the efficacy and safety of PKCβ inhibitor enzastaurin in persistent or recurrent EOC/PPC and to explore potential prognostic and predictive biomarkers. Methods Eligible women with measurable platinum-sensitive and resistant EOC/PPC were treated with continuous administration of oral enzastaurin until disease progression or unacceptable toxicity. A two-stage sequential design was used to evaluate progression-free survival (PFS) ≥ 6-months, tumor response, and toxicity. Translational studies included sequencing of the TP53, PTEN, PIK3CA and PKCβII genes for somatic mutations, quantitative PCR assays for AKT2 and PTEN copy number alterations, and measurement of circulating VEGF-A plasma levels. Results Among 27 eligible and evaluable patients, 3 women with PFS ≥ 6-months (11%) and 2 women with partial responses (7%) were observed. One of them achieved a durable response and remains on the study. No grade 4 adverse events were observed. Most common grade 3 adverse events were constitutional (4) and gastrointestinal (3). Mutations in the TP53 gene and abnormal copy number in the PTEN gene were common (56% and 48% of cases, respectively). Conclusions Enzastaurin was tolerable but had insufficient activity to proceed with the second stage of accrual. However, 1 patient has been progression-free for 44 months. No association between a biomarker and response to enzastaurin has been found. Exploratory analysis suggested an association between survival and PTEN copy number losses. PMID:21414654

A first in human, safety, pharmacokinetics, and clinical activity phase I study of once weekly administration of the Hsp90 inhibitor ganetespib (STA-9090) in patients with solid malignancies

PubMed Central

2013-01-01

Background This phase I study investigated the maximum tolerated dose (MTD), safety, pharmacokinetics and antitumor activity of ganetespib in patients with solid malignancies. Methods Patients were enrolled in cohorts of escalating ganetespib doses, given as 1 hour IV infusion, once weekly for 3 weeks, followed by a 1-week rest until disease progression or unacceptable toxicity. Endpoints included safety, pharmacokinetic and pharmacodynamic parameters and preliminary clinical activity. Results Fifty-three patients were treated at doses escalating from 7 to 259 mg/m2. The most common adverse events were Grade 1 and 2 diarrhea, fatigue, nausea or vomiting. Dose-limiting toxicities (DLT) observed were: one Grade 3 amylase elevation (150 mg/m2), one Grade 3 diarrhea and one Grade 3 and one Grade 4 asthenia (259 mg/m2). The MTD was 216 mg/m2 and the recommended phase 2 dose was established at 200 mg/m2 given IV at Days 1, 8, and 15 every 4 weeks. There was a linear relationship between dose and exposure. Plasma HSP70 protein levels remained elevated for over a week post treatment. Disease control rate (objective response and stable disease at ≥ 16 weeks) was 24.4%. Conclusions Ganetespib is well tolerated as a weekly infusion for 3 of every 4 weeks cycle. The recommended phase II dose is 200 mg/m2, and is associated with an acceptable tolerability profile. Trial registration NCT00687934 PMID:23530663

A phase II evaluation of ixabepilone in the treatment of recurrent/persistent carcinosarcom a of the uterus, an NRG Oncology/Gynecologic Oncology Group study☆

PubMed Central

McCourt, Carolyn K.; Deng, Wei; Dizon, Don S.; Lankes, Heather A.; Birrer, Michael J.; Lomme, Michele M.; Powell, Matthew A.; Kendrick, James E.; Saltzman, Joel N.; Warshal, David; Tenney, Meaghan E.; Kushner, David M.; Aghajanian, Carol

2017-01-01

Background The primary objectives were to determine the objective response rate (ORR) and safety profile of ixabepilone in women with recurrent or persistent uterine carcinosarcoma (UCS). Secondary objectives included progression-free survival (PFS) and overall survival (OS). Exploratory translational objectives included characterization of class III beta tubulin expression and its association with response, PFS, and OS. Methods Patients had measurable disease; up to two prior chemotherapeutic regimens were allowed, but must have included a taxane. Women received ixabepilone 40 mg/m2 as a 3 hour IV infusion on day 1 of a 21 day cycle. Treatment was continued until disease progression or unacceptable toxicity occurred. Results Forty-two women were enrolled, with 34 eligible and evaluable. Median age was 68 years. ECOGperformance status was 0 in 56% of women, 38% had received radiation, and 15% had received 2 lines of chemotherapy. Overall ORR was 11.8%(4/34, 90%CI 4.2–25.1%); all were partial responses. Stable disease for at least 8 weeks was achieved in 8 patients (23.5%). Median PFS and OS were 1.7 mo and 7.7 mo, respectively, with a median follow-up of 37 mo. Six month PFS was 20.6%. Major grade ≥ 3 toxicities were neutropenia (47%), fatigue (15%), dehydration (15%), hypertension (15%), and hyponatremia (15%); grade 2 peripheral neuropathy was reported in 18%. In this small sample size, class III beta tubulin expression in the primary tumor was not associated with the response to ixabepilone, PFS, or OS. Conclusion In this cohort of women, single agent ixabepilone showed modest but insufficient clinical activity. PMID:28029447

Hydroxyurea with or without imatinib in the treatment of recurrent or progressive meningiomas: a randomized phase II trial by Gruppo Italiano Cooperativo di Neuro-Oncologia (GICNO).

PubMed

Mazza, Elena; Brandes, Alba; Zanon, Silvia; Eoli, Marika; Lombardi, Giuseppe; Faedi, Marina; Franceschi, Enrico; Reni, Michele

2016-01-01

Hydroxyurea (HU) is among the most widely used salvage therapies in progressive meningiomas. Platelet-derived growth factor receptors are expressed in virtually all meningiomas. Imatinib sensitizes transformed cells to the cytotoxic effects of chemotherapeutic agents that interfere with DNA metabolism. The combination of HU with imatinib yielded intriguing results in recurrent malignant glioma. The current trial addressed the activity of this association against meningioma. Patients with recurrent or progressive WHO grade I-III meningioma, without therapeutic indication for surgery, radiotherapy, or stereotactic radiosurgery, aged 18-75 years, ECOG performance status 0-2, and not on enzyme-inducing anti-epileptic drugs were randomized to receive HU 500 mg BID ± imatinib 400 mg QD until progression, unacceptable toxicity, or patient's refusal. The primary endpoint was progression-free survival rate at 9 months (PFS-9). Between September 2009 and February 2012, 15 patients were randomized to receive HU + imatinib (N = 7; Arm A) or HU alone (N = 8; Arm B). Afterward the trial was prematurely closed due to slow enrollment rate. PFS-9 (A/B) was 0/75%, and median PFS was 4/19.5 months. Median and 2-year overall survival (A/B) rates were: 6/27.5 months; 28.5/75%, respectively. Main G3-4 toxicities were: G3 neutropenia in 1/0, G4 headache in 1/1, and G3 vomiting in 1/0. The conduction of a study in recurrent or progressive meningioma remains a challenge. Given the limited number of patients enrolled, no firm conclusions can be drawn about the combination of imatinib and HU. The optimal systemic therapy for meningioma failing surgery and radiation has yet to be identified.

Strategies for decolorization and detoxification of pulp and paper mill effluent.

PubMed

Garg, Satyendra K; Tripathi, Manikant

2011-01-01

The potential hazards associated with industrial effluents, coupled with increasing awareness of environment problems, have prompted many countries to limit the indiscriminate discharge of untreated wastewaters. The pulp and paper industry has been among the most significant of industrial polluters of the waterways, and therefore has been one of the industries of concern. The pulp and paper industry produces large quantities of brown/black effluent that primarily result from pulping, bleaching, and paper-making production stages. The dark color and toxicity of pulp-paper mill effluent comes primarily from lignin and its chlorinated derivatives (e.g., lignosulphonic acid, resins, phenols, and hydrocarbons) that are released during various processing steps of lignocellulosic materials. The color originates from pulping and pulp bleaching stages, while adsorbable organic halides (AOX) originates exclusively from chlorine bleaching. Discharge of untreated effluent results in increased BOD/COD, slime growth, thermal problems, scum formation, discoloration, loss of aesthetic quality and toxicity to the aquatic life, in the receiving waterbodies. The dark brow color of pulp-paper effluent is not only responsible for aesthetic unacceptability, but also prevents the passage of sunlight through colored waterbodies. This reduces the photosynthetic activity of aquatic flora, ultimately causing depletion of dissolved oxygen. The pulp-paper organic waste, coupled with the presence of chlorine, results in the generation of highly chlorinated organic compounds. These toxic constituents of wastewater pose a human health risk through long term exposure. via drinking water and\\or through consumption of fish that can bioaccumulate certain pollutants from the food chain. Therefore, considerable attention has been focused by many countries on decolorization of paper mill effluents , along with reduction in the contaminants that pose human health or other environmental hazards. Various physicochemical remediation treatments in the pulp-paper industry are now used, or have been suggested, but often are not implemented, because of the high cost involved. More recently, the paper and pulp industry has been investigating the use of biological remediation steps to replace or augment current treatment strategies. Certain biological treatments offer opportunities to reduce cost (both capital and operating), reduce energy consumption, and minimize environmental impact. Two primary approaches may be effective to curtail release of toxic effluents: first, development of pulping and bleaching processes that emphasize improved oxygen delignification or biopulping, plus partial or complete replacement of chlorine treatment with hydrogen peroxide or with biobleaching; second, implementation of biological processing that involves sequential two-step anaerobic-aerobic or three-step aerobic-anaerobic treatment technologies at end of pipe. The selection of the specific process will depend upon the type of pollutants/toxicants/mutagens present in the effluent. The use of environmental-friendly technologies in the pulp and paper industry is becoming more popular, partly because of increasing regulation, and partly because of the availability of new techniques that can be used to economically deal with pollutants in the effluents. Moreover, biotechnology research methods are offering promise for even greater improvements in the future. The obvious ultimate goal of the industry and the regulators should be zero emission through recycling of industrial wastewater, or discharge of the bare minimum amount of toxicants or color.

2002 Safety in Numbers Conference

DOT National Transportation Integrated Search

2002-01-09

We are all here today because there are too many people being killed as a result of : transportation incidents. In 2000, there were more than 44,000 transportation-related deaths. : That number is unacceptable and it makes the Safety Data Initiative ...

47 CFR 22.877 - Unacceptable interference to part 90 non-cellular 800 MHz licensees from commercial aviation air...

Code of Federal Regulations, 2014 CFR

2014-10-01

...-cellular 800 MHz licensees from commercial aviation air-ground systems. 22.877 Section 22.877...-Ground Radiotelephone Service Commercial Aviation Air-Ground Systems § 22.877 Unacceptable interference to part 90 non-cellular 800 MHz licensees from commercial aviation air-ground systems. The definition...

47 CFR 22.877 - Unacceptable interference to Part 90 non-cellular 800 MHz licensees from commercial aviation air...

Code of Federal Regulations, 2012 CFR

2012-10-01

...-cellular 800 MHz licensees from commercial aviation air-ground systems. 22.877 Section 22.877...-Ground Radiotelephone Service Commercial Aviation Air-Ground Systems § 22.877 Unacceptable interference to Part 90 non-cellular 800 MHz licensees from commercial aviation air-ground systems. The definition...

47 CFR 22.877 - Unacceptable interference to Part 90 non-cellular 800 MHz licensees from commercial aviation air...

Code of Federal Regulations, 2011 CFR

2011-10-01

...-cellular 800 MHz licensees from commercial aviation air-ground systems. 22.877 Section 22.877...-Ground Radiotelephone Service Commercial Aviation Air-Ground Systems § 22.877 Unacceptable interference to Part 90 non-cellular 800 MHz licensees from commercial aviation air-ground systems. The definition...

47 CFR 22.877 - Unacceptable interference to Part 90 non-cellular 800 MHz licensees from commercial aviation air...

Code of Federal Regulations, 2013 CFR

2013-10-01

...-cellular 800 MHz licensees from commercial aviation air-ground systems. 22.877 Section 22.877...-Ground Radiotelephone Service Commercial Aviation Air-Ground Systems § 22.877 Unacceptable interference to Part 90 non-cellular 800 MHz licensees from commercial aviation air-ground systems. The definition...

30 CFR 250.136 - How will MMS determine if my operating performance is unacceptable?

Code of Federal Regulations, 2010 CFR

2010-07-01

... 30 Mineral Resources 2 2010-07-01 2010-07-01 false How will MMS determine if my operating performance is unacceptable? 250.136 Section 250.136 Mineral Resources MINERALS MANAGEMENT SERVICE, DEPARTMENT...) Accidents and their nature; (b) Pollution events, environmental damages and their nature; (c) Incidents of...

Pre-Crisis Intervention Strategies for Reducing Unacceptable Behaviors by Exceptional Students in a Public Elementary School.

ERIC Educational Resources Information Center

Levine-Brown, Linda S.

This report describes the implementation of a data-based program to reduce unacceptable student behaviors and decrease the number of administrative interventions with 21 students with severe emotional disturbances. A computerized database was developed to track classroom and transportation discipline infractions. Students met monthly to review…

Influence of season and type of restaurants on sashimi microbiota.

PubMed

Miguéis, S; Moura, A T; Saraiva, C; Esteves, A

2016-10-01

In recent years, an increase in the consumption of Japanese food in European countries has been verified, including in Portugal. These specialities made with raw fish, typical Japanese meals, have been prepared in typical and on non-typical restaurants, and represent a challenge to risk analysis on HACCP plans. The aim of this study was to evaluate the influence of the type of restaurant, season and type of fish used on sashimi microbiota. Sashimi samples (n = 114) were directly collected from 23 sushi restaurants and were classified as Winter and Summer Samples. They were also categorized according to the type of restaurant where they were obtained: as typical or non-typical. The samples were processed using international standards procedures. A middling seasonality influence was observed in microbiota using mesophilic aerobic bacteria, psychrotrophic microorganisms, Lactic acid bacteria, Pseudomonas spp., H 2 S positive bacteria, mould and Bacillus cereus counts parameters. During the Summer Season, samples classified as unacceptable or potentially Hazardous were observed. Non-typical restaurants had the most cases of Unacceptable/potentially hazardous samples 83.33%. These unacceptable results were obtained as a result of high values of pathogenic bacteria like Listeria monocytogenes and Staphylococcus aureus No significant differences were observed on microbiota counts from different fish species. The need to implement more accurate food safety systems was quite evident, especially in the warmer season, as well as in restaurants where other kinds of food, apart from Japanese meals, was prepared. © Crown copyright 2016.

A phase I study of amrubicin and fixed dose of irinotecan (CPT-11) in relapsed small cell lung cancer: Japan multinational trial organization LC0303.

PubMed

Kawahara, Masaaki; Kubo, Akihito; Komuta, Kiyoshi; Fujita, Yuka; Sasaki, Yoshiaki; Fukushima, Masanori; Daimon, Takashi; Furuse, Kiyoyuki; Mishima, Michiaki; Mio, Tadashi

2012-12-01

To determine the maximum tolerated dose of amrubicin (AMR) with a fixed dose of irinotecan (CPT-11). Patients having pathologically proven small cell lung cancer (SCLC) relapsed after one or two chemotherapies, and Eastern Cooperative Oncology Group performance status of 0 to 2 were eligible for the study. CPT-11 was delivered as 50 mg/m2 on days 1 and 8, every 21 days. AMR was delivered on day 1. Doses of AMR were level 1: 80 mg/m2, level 2: 90 mg/m2, and level 3: 100 mg/m2. Dose elevation was determined using the modified continuous reassessment method. Tolerability was assessed after the first cycle. Another two cycles were conducted when disease progression or unacceptable toxicities were not observed. Eighteen patients (mean age: 66.3 years) were enrolled. A total of 40 courses were conducted. Grade 3/4 toxicities of the first cycle were leukocytopenia: 11 (61%, grade 3/4: 8/3); neutropenia: 15 (83%, grade 3/4: 6/9); and thrombocytopenia: three (17%, grade 3/4: 2/1). Other grade 3 toxicities observed were febrile neutropenia, one; infection, three; diarrhea, one; and dyspnea, one. Dose-limiting toxicity was observed in two of six patients at level 2 (neutropenia and febrile neutropenia) and in one of six at level 3 (thrombocytopenia and infection). The maximum tolerated dose was level 3, and so, the recommended dose for phase II trials was judged to be 90 mg/m2. Objective response was obtained in four of eight patients who were able to evaluate responses. Median survival time was 13 months, with 68% at 1-year survival rate. This combination was well tolerated and showed encouraging activities in SCLC. Randomized phase II trials are being planned in chemonaive SCLC.

Assessment of variations in control of asthma over time.

PubMed

Combescure, C; Chanez, P; Saint-Pierre, P; Daurès, J P; Proudhon, H; Godard, P

2003-08-01

Control and severity of asthma are two different but complementary concepts. The severity of asthma could influence the control over time. The aim of this study was to demonstrate this relationship. A total 365 patients with persistent asthma (severity) were enrolled and followed-up prospectively. Data were analysed using a continuous time homogeneous Markov model of the natural history of asthma. Control of asthma was defined according to three health states which were qualified: optimal, suboptimal and unacceptable control (states 1, 2 and 3). Transition forces (denoted lambda(ij) from state i to state j) and transition probabilities between control states were assessed and the results stratified by asthma severity were compared. Models were validated by comparing expected and observed numbers of patients in the different states. Transition probabilities stabilised between 100-250 days and more rapidly in patients with mild-to-moderate asthma. Patients with mild-to-moderate asthma in suboptimal or unacceptable control had a high probability of transition directly to optimal control. Patients with severe asthma had a tendency to remain in unacceptable control. A Markov model is a useful tool to model the control of asthma over time. Severity modified clearly the health states. It could be used to compare the performance of different approaches to asthma management.

Student Classroom Misbehavior: An Exploratory Study Based on Teachers' Perceptions

PubMed Central

Sun, Rachel C. F.; Shek, Daniel T. L.

2012-01-01

This study aimed to examine the conceptions of junior secondary school student misbehaviors in classroom, and to identify the most common, disruptive, and unacceptable student problem behaviors from teachers' perspective. Twelve individual interviews with teachers were conducted. A list of 17 student problem behaviors was generated. Results showed that the most common and disruptive problem behavior was talking out of turn, followed by nonattentiveness, daydreaming, and idleness. The most unacceptable problem behavior was disrespecting teachers in terms of disobedience and rudeness, followed by talking out of turn and verbal aggression. The findings revealed that teachers perceived student problem behaviors as those behaviors involving rule-breaking, violating the implicit norms or expectations, being inappropriate in the classroom settings and upsetting teaching and learning, which mainly required intervention from teachers. PMID:22919297

Threats to information security of real-time disease surveillance systems.

PubMed

Henriksen, Eva; Johansen, Monika A; Baardsgaard, Anders; Bellika, Johan G

2009-01-01

This paper presents the main results from a qualitative risk assessment of information security aspects for a new real-time disease surveillance approach in general, and for the Snow surveillance system in particular. All possible security threats and acceptable solutions, and the implications these solutions had to the design of the system, were discussed. Approximately 30 threats were identified. None of these got an unacceptable high risk level originally, but two got medium risk level, of which one was concluded to be unacceptable after further investigation. Of the remaining low risk threats, some have severe consequence, thus requiring particular assessment. Since it is very important to identify and solve all security threats before real-time solutions can be used in a wide scale, additional investigations are needed.

EVALUATION OF ANTIMICROBIAL EFFICACY FOR CONTROL OF STACHYBOTRYS CHARTARUM

EPA Science Inventory

Biological contaminants in buildings are known to act as sources of indoor air pollution, discomfort, asthma and pulmonary disease to building occupants, Sick buildings are evidence of extremely problematic indoor air quality (lAO) often resulting from unacceptable concentration...

p53 activated by AND gate genetic circuit under radiation and hypoxia for targeted cancer gene therapy

PubMed Central

Ding, Miao; Li, Rong; He, Rong; Wang, Xingyong; Yi, Qijian; Wang, Weidong

2015-01-01

Radio-activated gene therapy has been developed as a novel therapeutic strategy against cancer; however, expression of therapeutic gene in peritumoral tissues will result in unacceptable toxicity to normal cells. To restrict gene expression in targeted tumor mass, we used hypoxia and radiation tolerance features of tumor cells to develop a synthetic AND gate genetic circuit through connecting radiation sensitivity promoter cArG6, heat shock response elements SNF1, HSF1 and HSE4 with retroviral vector plxsn. Their construction and dynamic activity process were identified through downstream enhanced green fluorescent protein and wtp53 expression in non-small cell lung cancer A549 cells and in a nude mice model. The result showed that AND gate genetic circuit could be activated by lower required radiation dose (6 Gy) and after activated, AND gate could induce significant apoptosis effects and growth inhibition of cancer cells in vitro and in vivo. The radiation- and hypoxia-activated AND gate genetic circuit, which could lead to more powerful target tumoricidal activity represented a promising strategy for both targeted and effective gene therapy of human lung adenocarcinoma and low dose activation character of the AND gate genetic circuit implied that this model could be further exploited to decrease side-effects of clinical radiation therapy. PMID:26177264

Screening tests for the rapid detection of diarrhetic shellfish toxins in Washington State.

PubMed

Eberhart, Bich-Thuy L; Moore, Leslie K; Harrington, Neil; Adams, Nicolaus G; Borchert, Jerry; Trainer, Vera L

2013-09-30

The illness of three people due to diarrhetic shellfish poisoning (DSP) following their ingestion of recreationally harvested mussels from Sequim Bay State Park in the summer of 2011, resulted in intensified monitoring for diarrhetic shellfish toxins (DSTs) in Washington State. Rapid testing at remote sites was proposed as a means to provide early warning of DST events in order to protect human health and allow growers to test "pre-harvest" shellfish samples, thereby preventing harvest of toxic product that would later be destroyed or recalled. Tissue homogenates from several shellfish species collected from two sites in Sequim Bay, WA in the summer 2012, as well as other sites throughout Puget Sound, were analyzed using three rapid screening methods: a lateral flow antibody-based test strip (Jellett Rapid Test), an enzyme-linked immunosorbent assay (ELISA) and a protein phosphatase 2A inhibition assay (PP2A). The results were compared to the standard regulatory method of liquid chromatography coupled with tandem mass spectroscopy (LC-MS/MS). The Jellett Rapid Test for DSP gave an unacceptable number of false negatives due to incomplete extraction of DSTs using the manufacturer's recommended method while the ELISA antibody had low cross-reactivity with dinophysistoxin-1, the major toxin isomer in shellfish from the region. The PP2A test showed the greatest promise as a screening tool for Washington State shellfish harvesters.

Screening Tests for the Rapid Detection of Diarrhetic Shellfish Toxins in Washington State

PubMed Central

Eberhart, Bich-Thuy L.; Moore, Leslie K.; Harrington, Neil; Adams, Nicolaus G.; Borchert, Jerry; Trainer, Vera L.

2013-01-01

The illness of three people due to diarrhetic shellfish poisoning (DSP) following their ingestion of recreationally harvested mussels from Sequim Bay State Park in the summer of 2011, resulted in intensified monitoring for diarrhetic shellfish toxins (DSTs) in Washington State. Rapid testing at remote sites was proposed as a means to provide early warning of DST events in order to protect human health and allow growers to test “pre-harvest” shellfish samples, thereby preventing harvest of toxic product that would later be destroyed or recalled. Tissue homogenates from several shellfish species collected from two sites in Sequim Bay, WA in the summer 2012, as well as other sites throughout Puget Sound, were analyzed using three rapid screening methods: a lateral flow antibody-based test strip (Jellett Rapid Test), an enzyme-linked immunosorbent assay (ELISA) and a protein phosphatase 2A inhibition assay (PP2A). The results were compared to the standard regulatory method of liquid chromatography coupled with tandem mass spectroscopy (LC-MS/MS). The Jellett Rapid Test for DSP gave an unacceptable number of false negatives due to incomplete extraction of DSTs using the manufacturer’s recommended method while the ELISA antibody had low cross-reactivity with dinophysistoxin-1, the major toxin isomer in shellfish from the region. The PP2A test showed the greatest promise as a screening tool for Washington State shellfish harvesters. PMID:24084788

Long Duration Space Missions: Human Subsystem Risks and Requirements

NASA Technical Reports Server (NTRS)

Kundrot, Criag E.

2011-01-01

This viewgraph presentation reviews the human health and performance risks associated with long duration space flight beyond low earth orbit. The contents include: 1) Human Research Program; 2) Human Subsystem Risks; 3) Human Exploration Framework Team (HEFT) Architecture Elements; 4) Potentially Unacceptable Risks -1; 5) Potentially Unacceptable Risks-2; and 6) Major Mission Drivers of Risk.

Fuel cell flooding detection and correction

DOEpatents

DiPierno Bosco, Andrew; Fronk, Matthew Howard

2000-08-15

Method and apparatus for monitoring an H.sub.2 -O.sub.2 PEM fuel cells to detect and correct flooding. The pressure drop across a given H.sub.2 or O.sub.2 flow field is monitored and compared to predetermined thresholds of unacceptability. If the pressure drop exists a threshold of unacceptability corrective measures are automatically initiated.

47 CFR 22.970 - Unacceptable interference to part 90 non-cellular 800 MHz licensees from cellular radiotelephone...

Code of Federal Regulations, 2011 CFR

2011-10-01

...-cellular 800 MHz licensees from cellular radiotelephone or part 90-800 MHz cellular systems. 22.970 Section... MOBILE SERVICES Cellular Radiotelephone Service § 22.970 Unacceptable interference to part 90 non-cellular 800 MHz licensees from cellular radiotelephone or part 90-800 MHz cellular systems. (a) Definition...

47 CFR 22.970 - Unacceptable interference to part 90 non-cellular 800 MHz licensees from cellular radiotelephone...

Code of Federal Regulations, 2010 CFR

2010-10-01

... 22.970 Telecommunication FEDERAL COMMUNICATIONS COMMISSION (CONTINUED) COMMON CARRIER SERVICES PUBLIC MOBILE SERVICES Cellular Radiotelephone Service § 22.970 Unacceptable interference to part 90 non... −104 dBm or higher, as measured at the R.F. input of the receiver of a mobile unit; or (B) A median...

Phase II study of biweekly plitidepsin as second-line therapy for advanced or metastatic transitional cell carcinoma of the urothelium.

PubMed

Dumez, Herlinde; Gallardo, Enrique; Culine, Stephane; Galceran, Joan Carles; Schöffski, Patrick; Droz, Jean P; Extremera, Sonia; Szyldergemajn, Sergio; Fléchon, Aude

2009-09-16

The objective of this exploratory, open-label, single-arm, phase II clinical trial was to evaluate plitidepsin (5 mg/m(2)) administered as a 3-hour continuous intravenous infusion every two weeks to patients with locally advanced/metastatic transitional cell carcinoma of the urothelium who relapsed/progressed after first-line chemotherapy. Treatment cycles were repeated for up to 12 cycles or until disease progression, unacceptable toxicity, patient refusal or treatment delay for >2 weeks. The primary efficacy endpoint was objective response rate according to RECIST. Secondary endpoints were the rate of SD lasting > or = 6 months and time-to-event variables. Toxicity was assessed using NCI-CTC v. 3.0. Twenty-one patients received 57 treatment cycles. No objective tumor responses occurred. SD lasting <6 months was observed in two of 18 evaluable patients. With a median follow-up of 4.6 months, the median PFR and the median OS were 1.4 months and 2.3 months, respectively. The most common AEs were mild to moderate nausea, fatigue, myalgia and anorexia. Anemia, lymphopenia, and increases in transaminases, alkaline phosphatase and creatinine were the most frequent laboratory abnormalities. No severe neutropenia occurred. Treatment was feasible and generally well tolerated in this patient population; however the lack of antitumor activity precludes further studies of plitidepsin in this setting.

Deriving sediment Interstitial Water Remediation Goals ...

EPA Pesticide Factsheets

Background/Objectives. Passive sampling is becoming a frequently used measurement technique at Superfund sites with contaminated sediments. Passive sampling measures the concentrations of freely dissolved chemicals (Cfrees) in the sediment interstitial water. The freely dissolved chemical is a good surrogate for and a very practical means for estimating the concentrations of bioavailable chemical in the sediments. Building from this approach, a methodology is proposed to derive sediment Interstitial Water Remediation Goals (IWRGs) for the protection of benthic organisms from direct toxicity using Cfrees measured with passive sampling.Approach/Activities. In the early 2000s, EPA developed and released Equilibrium Partitioning Sediment Benchmarks (ESBs) for a series of chemicals. ESBs are intended to be chemical concentrations below which unacceptable toxicity to benthic organisms does not occur. The ESBs (expressed with the units of ug/g OC) were derived using the equations:ESB= K_OC×FCV where K_OC=0.00028+0.983K_OWThe KOC is the organic carbon normalized sediment-water chemical partition coefficient, FCV is the Final Chronic Value from EPA’s ambient water quality criteria for the protection of aquatic life, and KOW is the n-octanol/water partition coefficient for the chemical. At a specific site, the remedial goal (CS:ESB µg/kg-dw) in sediment are then derived using the site-specific fraction of organic carbon in the sediment (fOC:SS) at the site:C_

Arsenic toxicity and accumulation in radish as affected by arsenic chemical speciation.

PubMed

Carbonell-Barrachina, A A; Burló, F; López, E; Martínez-Sánchez, F

1999-07-01

Arsenic (As) uptake by Rhapanus sativus L. (radish), cv. Nueva Orleans, growing in soil-less culture conditions was studied in relation to the chemical form and concentration of As. A 4 x 3 factorial experiment was conducted with treatments consisting of four As chemical forms [As(III), As(V), MMAA, DMAA] and three As concentrations (1.0, 2.0, and 5.0 mg As L-1). None of the As treatments were clearly phytotoxic to this radish cultivar. Arsenic phytoavailability was primarily determined by the As chemical form present in the nutrient solution and followed the trend DMAA < or = As(V) < or = As(III) < MMAA. Root and shoot As concentrations significantly increased with increasing As application rates. Monomethyl arsonic acid treatments caused the highest As accumulation in both roots and shoots, and this organic arsenical showed a higher uptake rate than the other As compounds. Inner root As concentrations were, in general, within the normal range for As contents in food crops but root skin As levels were close or above the maximum threshold set for As content in edible fruit, crops and vegetables. The statement that toxicity limits plant As uptake to safe levels was not confirmed in our study. If radish plants are exposed to a large pulse of As, as growth on contaminated nutrient solutions, they may accumulate residues which are unacceptable for animal and human consumption without exhibiting symptoms of phytotoxicity.

Dacarbazine in combination with bevacizumab for the treatment of unresectable/metastatic melanoma: a phase II study.

PubMed

Ferrucci, Pier F; Minchella, Ida; Mosconi, Massimo; Gandini, Sara; Verrecchia, Francesco; Cocorocchio, Emilia; Passoni, Claudia; Pari, Chiara; Testori, Alessandro; Coco, Paola; Munzone, Elisabetta

2015-06-01

The combined treatment of dacarbazine with an antiangiogenic drug such as bevacizumab may potentiate the therapeutic effects of dacarbazine in metastatic melanoma (MM). Preliminary antitumour activity of dacarbazine plus bevacizumab is evaluated, together with the toxicity and safety profile, in MM patients. This prospective, open-label, phase II study included patients with previously untreated MM or unresectable melanoma. Patients received dacarbazine and bevacizumab until progressive disease or unacceptable toxicity. The primary efficacy variable was the overall response rate. The secondary efficacy parameters included duration of response, duration of stable disease, time to progression/progression-free survival, time to treatment failure and overall survival. The safety analysis included recordings of adverse events and exposure to study treatment. The intention-to-treat population included 37 patients (24 men and 13 women, mean age 54.2±13.1 years). Overall response rate was 18.9% (seven patients achieved a response) and clinical benefit was 48.6%. In patients who achieved a response, the median duration of response was 16.9 months and the median duration of stable disease was 12.5 months. The median time to progression/progression-free survival and time to treatment failure were 5.5 and 3.1 months, respectively. The median overall survival was 11.4 months. Almost all patients (94.6%) experienced at least one adverse event; however, no new area of toxicity of bevacizumab emerged. The dacarbazine/bevacizumab combination provides benefits compared with dacarbazine monotherapy in historical controls, with an acceptable safety profile. This combination appears to be a valid option in specific subgroups of patients, namely, those triple negative (BRAF, C-KIT and NRAS wild type) or with a BRAF mutation who have already received, or are not eligible for, immunomodulating or targeted agents.

Defibrotide for the Treatment of Severe Hepatic Veno-Occlusive Disease and Multiorgan Failure after Stem Cell Transplantation: A Multicenter, Randomized, Dose-Finding Trial

PubMed Central

Richardson, Paul G.; Soiffer, Robert J.; Antin, Joseph H.; Uno, Hajime; Jin, Zhezhen; Kurtzberg, Joanne; Martin, Paul L.; Steinbach, Gideon; Murray, Karen F.; Vogelsang, Georgia B.; Chen, Allen R.; Krishnan, Amrita; Kernan, Nancy A.; Avigan, David E.; Spitzer, Thomas R.; Shulman, Howard M.; Di Salvo, Donald N.; Revta, Carolyn; Warren, Diane; Momtaz, Parisa; Bradwin, Gary; Wei, L. J.; Iacobelli, Massimo; McDonald, George B.; Guinan, Eva C.

2010-01-01

Therapeutic options for severe hepatic veno-occlusive disease (VOD) are limited and outcomes are dismal, but early phase I/II studies have suggested promising activity and acceptable toxicity using the novel polydisperse oligonucleotide defibrotide. This randomized phase II dose-finding trial determined the efficacy of defibrotide in patients with severe VOD following hematopoietic stem cell transplantation (HSCT) and identified an appropriate dose for future trials. Adult and pediatric patients received either lower-dose (arm A: 25 mg/kg/day; n = 75) or higher-dose (arm B: 40 mg/kg/day; n = 74) i.v. defibrotide administered in divided doses every 6 hours for ≥ 14 days or until complete response, VOD progression, or any unacceptable toxicity occurred. Overall complete response and day + 100 post-HSCT survival rates were 46% and 42%, respectively, with no significant difference between treatment arms. The incidence of treatment-related adverse events was low (8% overall; 7% in arm A, 10% in arm B); there was no significant difference in the overall rate of adverse events between treatment arms. Early stabilization or decreased bilirubin was associated with better response and day + 100 survival, and decreased plasminogen activator inhibitor type 1 (PAI-1) during treatment was associated with better outcome; changes were similar in both treatment arms. Defibrotide 25 or 40 mg/kg/day also appears effective in treating severe VOD following HSCT. In the absence of any differences in activity, toxicity or changes in PAI-1 level, defibrotide 25 mg/kg/day was selected for ongoing phase III trials in VOD. PMID:20167278

Apatinib plus icotinib in treating advanced non-small cell lung cancer after icotinib treatment failure: a retrospective study.

PubMed

Xu, Jianping; Liu, Xiaoyan; Yang, Sheng; Zhang, Xiangru; Shi, Yuankai

2017-01-01

Treatment failure frequently occurs in patients with epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer (NSCLC) who respond to EGFR tyrosine kinase inhibitors initially. This retrospective study tried to investigate the efficacy and safety of apatinib plus icotinib in patients with advanced NSCLC after icotinib treatment failure. This study comprised 27 patients with advanced NSCLC who had progressed after icotinib monotherapy. Initially, patients received oral icotinib (125 mg, tid) alone. When the disease progressed, they received icotinib plus apatinib (500 mg, qd, orally). Treatment was continued until disease progression, unacceptable toxicity or consent withdrawal. Followed up to December 2016, the median time of combined therapy was 7.47 months, and eight of 27 patients were dead. The median overall survival was not reached, and median progression-free survival (PFS) was 5.33 months (95% CI, 3.63-7.03 months). Moreover, the objective response rate (ORR) was 11.1%, and the disease control rate (DCR) was 81.5%. A total of 14 patients received combined therapy as the second-line treatment, and the ORR and DCR were 7.1% and 78.6%, respectively; 13 patients received drugs as the third- or later-line treatment, with an ORR and a DCR of 15.4% and 84.6%, respectively. In addition, 11 patients experienced icotinib monotherapy failure within 6 months with median PFS of 7.37 months, and 16 patients had progression after 6 months with median PFS of 2.60 months. The common drug-related toxic effects were hypertension (44.4%) and fatigue (37.0%). Apatinib plus icotinib is efficacious in treating patients with advanced NSCLC after icotinib treatment failure, with acceptable toxic effects.

Compliance with post-operative adjuvant chemotherapy in non-small cell lung cancer. An analysis of National Cancer Institute of Canada and intergroup trial JBR.10 and a review of the literature.

PubMed

Alam, Naveed; Shepherd, Frances A; Winton, Timothy; Graham, Barbara; Johnson, David; Livingston, Robert; Rigas, James; Whitehead, Marlo; Ding, Keyue; Seymour, Lesley

2005-03-01

Resected non-small cell lung cancer (NSCLC) has 5-years survival rates of 30-70%. The role of adjuvant chemotherapy remains unclear with poor compliance reported in most trials. The compliance with adjuvant chemotherapy (ACT) for stage IB and II NSCLC was analyzed using data from a North American multi-centre phase III study (accrual 1994-2001) that compared adjuvant chemotherapy to observation. Planned chemotherapy consisted of cisplatin (CIS) 50 mg/m2 days 1, 8 and vinorelbine (VIN) 25 mg/m2 days 1, 8, 15, 22 for four cycles; the VIN dose had been reduced from 30 mg/m2 after an initial cohort of patients experienced unacceptable toxicity. Four hundred and twenty-four patients were randomized after the amendment, 215 to the chemotherapy arm. Median age was 60 years, 64% were male and 84% had stage II disease. Thirty-seven patients completed one cycle, 14 completed two, 20 completed three and 108 patients completed all four cycles. Ten patients received no therapy. Multivariate analysis demonstrated statistically significant differences in compliance with extent of surgery, gender and age. Patients randomized in Canada were more likely to fail to complete chemotherapy due to refusal of therapy than their American counterparts. Patients who had pneumonectomies were more likely to discontinue therapy due to toxicity than those who had lesser resections. Extent of surgery may play a role in both the compliance and toxicity of ACT. Differences between nations in the perception of the risks and benefits of adjuvant chemotherapy regimens, both between physicians and patients, should be investigated further.

Corrected Panel-Reactive Antibody Positivity Rates for Hypersensitized Patients in Turkish Population With Calculated Panel-Reactive Antibody Software.

PubMed

Karadeniz, S T; Akgul, S U; Ogret, Y; Ciftci, H S; Bayraktar, A; Bakkaloglu, H; Caliskan, Y; Yelekci, K; Turkmen, A; Aydin, A E; Oguz, F S; Carin, M; Aydin, F

2017-04-01

High rates of panel-reactive antibody (PRA) may decrease the chance of kidney transplantation and may result in long waiting periods before transplantation. The calculated PRA (cPRA) is performed based on unacceptable HLA antigens. These antigens are identified by a program that was created based on the antibodies that developed against the HLA antigens circulating in serum and on the risk of binding of these antibodies to antigens. The antigen profile of the population and antigen frequencies can be measured, and more realistic cPRA positivity rates may be obtained using this method. We developed a program based on the HLA antigens of 494 blood donors in 2 European Federation for Immunogenetics-accredited Tissue Typing Laboratories in Turkey. Next-generation sequencing-based tissue typing (HLA-A, -B, -C, -DR, -DQ, 4 digits) of the samples was performed. The PRA screening test was performed on 380 patients who were waiting for organ transplant from a cadaver in Istanbul Faculty of Medicine. The single antigen bead assay testing was performed to identify the antibody profiles on 48 hypersensitized patients. The PRA testing results using the current methods were 44.6% ± 18.5%, and the cPRA rate was 86.2% ± 5.1%. The mean PRA positivity of the sensitized patients using the current methods was 44.6%; however, the rate was 86.2% using the cPRA. cPRA shows the rate of the rejected donors according to all unacceptable antigens. The need for a list of unacceptable antigens in place of the PRA positivity rate is a real change in the sensitization-dependent calculation as cPRA positivity rate. In principal, implementation of cPRA will encourage many centers and laboratories to adopt a standard measurement of sensitization in Turkey. It will increase the chances of better donor match, particularly for hypersensitized patients, by the creation of an unacceptable mismatch program using cPRA software. Copyright © 2017 Elsevier Inc. All rights reserved.

Methodology and measures for preventing unacceptable flow-accelerated corrosion thinning of pipelines and equipment of NPP power generating units

NASA Astrophysics Data System (ADS)

Tomarov, G. V.; Shipkov, A. A.; Lovchev, V. N.; Gutsev, D. F.

2016-10-01

Problems of metal flow-accelerated corrosion (FAC) in the pipelines and equipment of the condensate- feeding and wet-steam paths of NPP power-generating units (PGU) are examined. Goals, objectives, and main principles of the methodology for the implementation of an integrated program of AO Concern Rosenergoatom for the prevention of unacceptable FAC thinning and for increasing operational flow-accelerated corrosion resistance of NPP EaP are worded (further the Program). A role is determined and potentialities are shown for the use of Russian software packages in the evaluation and prediction of FAC rate upon solving practical problems for the timely detection of unacceptable FAC thinning in the elements of pipelines and equipment (EaP) of the secondary circuit of NPP PGU. Information is given concerning the structure, properties, and functions of the software systems for plant personnel support in the monitoring and planning of the inservice inspection of FAC thinning elements of pipelines and equipment of the secondary circuit of NPP PGUs, which are created and implemented at some Russian NPPs equipped with VVER-1000, VVER-440, and BN-600 reactors. It is noted that one of the most important practical results of software packages for supporting NPP personnel concerning the issue of flow-accelerated corrosion consists in revealing elements under a hazard of intense local FAC thinning. Examples are given for successful practice at some Russian NPP concerning the use of software systems for supporting the personnel in early detection of secondary-circuit pipeline elements with FAC thinning close to an unacceptable level. Intermediate results of working on the Program are presented and new tasks set in 2012 as a part of the updated program are denoted. The prospects of the developed methods and tools in the scope of the Program measures at the stages of design and construction of NPP PGU are discussed. The main directions of the work on solving the problems of flow-accelerated corrosion of pipelines and equipment in Russian NPP PGU are defined.

Phase 2 Study of Combined Sorafenib and Radiation Therapy in Patients With Advanced Hepatocellular Carcinoma

DOE Office of Scientific and Technical Information (OSTI.GOV)

Chen, Shang-Wen, E-mail: sjfchiou@gmail.com; School of Medicine, Taipei Medical University, Taipei, Taiwan; School of Medicine, China Medical University, Taichung, Taiwan

Purpose: This phase 2 study evaluated the efficacy of radiation therapy (RT) with concurrent and sequential sorafenib therapy in patients with unresectable hepatocellular carcinoma (HCC). Methods and Materials: Forty patients with unresectable HCC unfit for transarterial chemoembolization were treated with RT with concurrent and sequential sorafenib. Sorafenib was administered from the commencement of RT at a dose of 400 mg twice daily and continued to clinical or radiologic progression, unacceptable adverse events, or death. All patients had underlying Child-Pugh A cirrhosis. The maximal tumor diameter ranged from 3.0 cm to 15.5 cm. Coexisting portal vein thrombosis was found in 24 patients and wasmore » irradiated simultaneously. The cumulative RT dose ranged from 40 Gy to 60 Gy (median, 50 Gy). Image studies were done 1 month after RT and then every 3 months thereafter. Results: Thirty-three (83%) completed the allocated RT. During RT, the incidence of hand-foot skin reactions ≥ grade 2 and diarrhea were 37.5% and 25%, respectively, and 35% of patients had hepatic toxicities grade ≥2. Twenty-two (55.0%) patients achieved complete or partial remission at the initial assessment, and 18 (45%) had stable or progressive disease. The 2-year overall survival and infield progression-free survival (IFPS) were 32% and 39%, respectively. A Cancer of the Liver Italian Program (CLIP) score ≥2 was associated with an inferior outcome in overall survival. Six patients (15%) developed treatment-related hepatic toxicity grade ≥3 during the sequential phase, and 3 of them were fatal. Conclusions: When RT and sorafenib therapy were combined in patients with unresectable HCC, the initial complete or partial response rate was 55% with a 2-year IFPS of 39%. A CLIP score ≥2 was associated with an inferior outcome in overall survival. Hepatic toxicities are a major determinant of the safety; the combination should be used with caution and needs further investigation.« less

47 CFR 90.672 - Unacceptable interference to non-cellular 800 MHz licensees from 800 MHz cellular systems or part...

Code of Federal Regulations, 2010 CFR

2010-10-01

... 47 Telecommunication 5 2010-10-01 2010-10-01 false Unacceptable interference to non-cellular 800 MHz licensees from 800 MHz cellular systems or part 22 Cellular Radiotelephone systems, and within the 900 MHz Business/Industrial Land Transportation Pool. 90.672 Section 90.672 Telecommunication FEDERAL COMMUNICATIONS COMMISSION (CONTINUED) SAFETY...

Anti-HER2 Therapy Beyond Second-Line for HER2-Positive Metastatic Breast Cancer: A Short Review and Recommendations for Several Clinical Scenarios from a Spanish Expert Panel

PubMed Central

Martínez-Jañez, Noelia; Chacón, Ignacio; de Juan, Ana; Cruz-Merino, Luis; del Barco, Sònia; Fernández, Isaura; García-Teijido, Paula; Gómez-Bernal, Amalia; Plazaola, Arrate; Ponce, José; Servitja, Sonia; Zamora, Pilar

2016-01-01

Summary Background The aim of this project was to provide an expert opinion regarding anti-human epidermal growth factor receptor 2 (HER2) therapy beyond second-line treatment of metastatic breast cancer (mBC). Methods A group of experts discussed specific issues concerning anti-HER2 therapy in late-line settings in mBC. Results Trastuzumab emtansine (T-DM1) or dual HER2 blockade appeared to be good options for HER2-positive mBC after ≥ 2 HER2-targeted therapies. Once an objective response has been achieved with anti-HER2-containing therapy, the anti-HER2 agent can be continued until progression of the disease, unacceptable toxicity or patient decision. mBC treated with ≥ 3 consecutive lines of anti-HER therapy, ≥ 1 being a dual HER2 blockade and with early progression of disease during a fourth or later-line treatment, are clinically resistant to anti-HER therapy. For progression of metastasis in the brain after anti-HER2 therapy, lapatinib and chemotherapy appear to be a good alternative after best local treatment. Conclusions Further clinical trials are needed to provide valuable knowledge about the best treatment options in the later settings of mBC. PMID:27239176

Helminths and Immunological Tolerance

PubMed Central

Johnston, Chris J.C.; McSorley, Henry J.; Anderton, Stephen M.; Wigmore, Stephen J.; Maizels, Rick M.

2014-01-01

Current immunosuppression regimens for solid-organ transplantation have shown disappointing efficacy in the prevention of chronic allograft rejection and carry unacceptable risks including toxicity, neoplasia, and life-threatening infection. Achievement of immunological tolerance (long-term antigen unresponsiveness in an immunocompetent host) presents the exciting prospect of freedom from immunosuppression for transplant recipients. It is now 60 years since the first demonstration of immunological tolerance in animal models of transplantation, but translation into routine clinical practice remains elusive. Helminth parasites may provide novel strategies toward achieving this goal. Helminths are remarkably successful parasites: they currently infect more than one quarter of the world’s population. It is now well established that the parasites’ success is the result of active immunomodulation of their hosts’ immune response. Although this primarily secures ongoing survival of the parasites, helminth-induced immunomodulation can also have a number of benefits for the host. Significant reductions in the prevalence of allergy and autoimmune conditions among helminth-infected populations are well recognized and there is now a significant body of evidence to suggest that harmful immune responses to alloantigens may be abrogated as well. Here, we review all existing studies of helminth infection and transplantation, explore the mechanisms involved, and discuss possible avenues for future translation to clinical practice. PMID:24025322

[A new method for quantitative measurement of the cadmium absorbed by chick embryos].

PubMed

Gottofrey, J

1984-01-01

We attempted to determine the quantity of cadmium incorporated in hens eggs after immersion in cadmium solutions, and the cadmium concentration measured in embryos. We discussed equipment allowing simultaneous treatment of up to 42 samples, and called it " digestor ". It consisted of two gas-heated sand baths, two stands for cooling down solutions and an evacuation system for toxic vapours. Our method was based on wet mineralisation. It consisted of desintegrating experimental chick embryos in a HNO3/H2O2 mixed solution. After heating and evaporating, the quantity of cadmium in the remnant was determined by atomic absorption spectrophotometry. The reliability of such a technique was tested by studying as controls controls 17 days-old chick embryos injected with a known quantity of Cd(NO3). It showed no loss of cadmium. We also compared our procedure with a dry ashing method. The latter showed unacceptable losses and insufficient precision for the problems we wanted to investigate. Our method gave us much more precise results. The equipment we developed has functioned wholly satisfactorily and allowed us to investigate for instance cadmium distribution and concentration in embryonic organs of 17 days-old chicks. It could also be useful for researches concerning other biological samples analyzed for different heavy metals.

Potential use of CD40 ligand for immunotherapy of childhood B-cell precursor acute lymphoblastic leukaemia.

PubMed

D'Amico, Giovanna; Marin, Virna; Biondi, Andrea; Bonamino, Martin Hernán

2004-09-01

Around 20% of children affected by B-cell precursor acute lymphoblastic leukaemia (BCP-ALL) still experience a recurrence of the disease after diagnosis, despite a significant improvement in the cure rate (80%). Moreover, standard therapies have high and often unacceptable acute and chronic organ toxicity, with an increased risk for secondary malignancies. Therefore, new strategies are needed to improve overall survival and decrease treatment-associated morbidity. Recent in-vitro and in-vivo studies have demonstrated that CD40 engagement improves tumour immunogenicity and, consequently, generates a strong antitumour immune response. The CD40-CD40 ligand (CD40L) system is of pivotal importance in the immune response via interactions between T cells and antigen-presenting cells. The general aim of this chapter is to review the feasibility of developing cellular strategies to increase childhood BCP-ALL immunogenicity, and the potential use of CD40L as a new strategy to induce an antileukaemia immune response in BCP-ALL.

Carbon nanotube nanostructured hybrid materials systems for renewable energy applications

NASA Astrophysics Data System (ADS)

Marquis, Fernand D. S.

2011-01-01

Global energy demand is growing at an alarming and unsustainable rate, drawing mainly on the use of fossil fuels. These reserves are decreasing rapidly and becoming increasingly expensive. The associated emissions of greenhouse gases and other toxic pollutants are becoming environmentally unacceptable. Energy security has become a major issue as fossil fuels are confined to few areas in the world and their availability is controlled by political, economic, and ecological factors. A global coherent energy strategy that encompasses the entire energy life cycle is required in order to address all the forms of energy harvesting, storage, conversion, transmission, and distribution. Hybrid nanomaterial systems hold the key to fundamental advances in direct renewable energy and energy storage and conversion which are needed to enable renewable energy and meet the general energy challenges and associated environmental effects. This paper presents new approaches and methodologies used to design and develop carbon nanotube nanostructured hybrid nanomaterial systems incorporating structural and light-absorbing electron donor polymers, inorganic semiconductors, metallic and ceramic nanoparticles as energy harvesting and storage systems.

[In silico, in vitro, in omic experimental models and drug safety evaluation].

PubMed

Claude, Nancy; Goldfain-Blanc, Françoise; Guillouzo, André

2009-01-01

Over the last few decades, toxicology has benefited from scientific, technical, and bioinformatic developments relating to patient safety assessment during clinical and drug marketing studies. Based on this knowledge, new in silico, in vitro, and "omic" experimental models are emerging. Although these models cannot currently replace classic safety evaluations performed on laboratory animals, they allow compounds with unacceptable toxicity to be rejected in the early stages of drug development, thereby reducing the number of laboratory animals needed. In addition, because these models are particularly adapted to mechanistic studies, they can help to improve the relevance of the data obtained, thus enabling better prevention and screening of the adverse effects that may occur in humans. Much progress remains to be done, especially in the field of validation. Nevertheless, current efforts by industrial, academic laboratories, and regulatory agencies should, in coming years, significantly improve preclinical drug safety evaluation thanks to the integration of these new methods into the drug research and development process.

42 CFR 493.1445 - Standard; Laboratory director responsibilities.

Code of Federal Regulations, 2010 CFR

2010-10-01

... quality laboratory services for all aspects of test performance, which includes the preanalytic, analytic... result is found to be unacceptable or unsatisfactory; (5) Ensure that the quality control and quality assessment programs are established and maintained to assure the quality of laboratory services provided and...

LAI inversion from optical reflectance using a neural network trained with a multiple scattering model

NASA Technical Reports Server (NTRS)

Smith, James A.

1992-01-01

The inversion of the leaf area index (LAI) canopy parameter from optical spectral reflectance measurements is obtained using a backpropagation artificial neural network trained using input-output pairs generated by a multiple scattering reflectance model. The problem of LAI estimation over sparse canopies (LAI < 1.0) with varying soil reflectance backgrounds is particularly difficult. Standard multiple regression methods applied to canopies within a single homogeneous soil type yield good results but perform unacceptably when applied across soil boundaries, resulting in absolute percentage errors of >1000 percent for low LAI. Minimization methods applied to merit functions constructed from differences between measured reflectances and predicted reflectances using multiple-scattering models are unacceptably sensitive to a good initial guess for the desired parameter. In contrast, the neural network reported generally yields absolute percentage errors of <30 percent when weighting coefficients trained on one soil type were applied to predicted canopy reflectance at a different soil background.

Frequency and Acceptability of Adverse Events After Anterior Cervical Discectomy and Fusion: A Survey Study From the Cervical Spine Research Society.

PubMed

Wilson, Jefferson R; Radcliff, Kris; Schroeder, Gregory; Booth, Madison; Lucasti, Christopher; Fehlings, Michael; Ahmad, Nassr; Vaccaro, Alexander; Arnold, Paul; Sciubba, Daniel; Ching, Alex; Smith, Justin; Shaffrey, Christopher; Singh, Kern; Darden, Bruce; Daffner, Scott; Cheng, Ivan; Ghogawala, Zoher; Ludwig, Steven; Buchowski, Jacob; Brodke, Darrel; Wang, Jeffrey; Lehman, Ronald A; Hilibrand, Alan; Yoon, Tim; Grauer, Jonathan; Dailey, Andrew; Steinmetz, Michael; Harrop, James S

2018-06-01

Anterior cervical discectomy and fusion has a low but well-established profile of adverse events. The goal of this study was to gauge surgeon opinion regarding the frequency and acceptability of these events. A 2-page survey was distributed to attendees at the 2015 Cervical Spine Research Society (CSRS) meeting. Respondents were asked to categorize 18 anterior cervical discectomy and fusion-related adverse events as either: "common and acceptable," "uncommon and acceptable," "uncommon and sometimes acceptable," or "uncommon and unacceptable." Results were compiled to generate the relative frequency of these responses for each complication. Responses for each complication event were also compared between respondents based on practice location (US vs. non-US), primary specialty (orthopedics vs. neurosurgery) and years in practice. Of 150 surveys distributed, 115 responses were received (76.7% response rate), with the majority of respondents found to be US-based (71.3%) orthopedic surgeons (82.6%). Wrong level surgery, esophageal injury, retained drain, and spinal cord injury were considered by most to be unacceptable and uncommon complications. Dysphagia and adjacent segment disease occurred most often, but were deemed acceptable complications. Although surgeon experience and primary specialty had little impact on responses, practice location was found to significantly influence responses for 12 of 18 complications, with non-US surgeons found to categorize events more toward the uncommon and unacceptable end of the spectrum as compared with US surgeons. These results serve to aid communication and transparency within the field of spine surgery, and will help to inform future quality improvement and best practice initiatives.

40 CFR Appendix G to Subpart G of... - Substitutes Subject to Use Restrictions and Unacceptable Substitutes Listed in the March 3, 1999...

Code of Federal Regulations, 2012 CFR

2012-07-01

... Restrictions and Unacceptable Substitutes Listed in the March 3, 1999, Final rule, Effective April 2, 1999. G Appendix G to Subpart G of Part 82 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED... Pt. 82, Subpt. G, App. G Appendix G to Subpart G of Part 82—Substitutes Subject to Use Restrictions...

40 CFR Appendix G to Subpart G of... - Substitutes Subject to Use Restrictions and Unacceptable Substitutes Listed in the March 3, 1999...

Code of Federal Regulations, 2013 CFR

2013-07-01

... Restrictions and Unacceptable Substitutes Listed in the March 3, 1999, Final rule, Effective April 2, 1999. G Appendix G to Subpart G of Part 82 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED... Pt. 82, Subpt. G, App. G Appendix G to Subpart G of Part 82—Substitutes Subject to Use Restrictions...

40 CFR Appendix G to Subpart G of... - Substitutes Subject to Use Restrictions and Unacceptable Substitutes Listed in the March 3, 1999...

Code of Federal Regulations, 2014 CFR

2014-07-01

... Restrictions and Unacceptable Substitutes Listed in the March 3, 1999, Final rule, Effective April 2, 1999. G Appendix G to Subpart G of Part 82 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED... Pt. 82, Subpt. G, App. G Appendix G to Subpart G of Part 82—Substitutes Subject to Use Restrictions...

40 CFR Appendix K to Subpart G of... - Substitutes Subject to Use Restrictions and Unacceptable Substitutes Listed in the July 22, 2002...

Code of Federal Regulations, 2010 CFR

2010-07-01

... Restrictions and Unacceptable Substitutes Listed in the July 22, 2002, Final Rule, Effective August 21, 2002 K Appendix K to Subpart G of Part 82 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED... Pt. 82, Subpt. G, App. K Appendix K to Subpart G of Part 82—Substitutes Subject to Use Restrictions...

40 CFR Appendix K to Subpart G of... - Substitutes Subject to Use Restrictions and Unacceptable Substitutes Listed in the July 22, 2002...

Code of Federal Regulations, 2014 CFR

2014-07-01

... Restrictions and Unacceptable Substitutes Listed in the July 22, 2002, Final Rule, Effective August 21, 2002 K Appendix K to Subpart G of Part 82 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED... Pt. 82, Subpt. G, App. K Appendix K to Subpart G of Part 82—Substitutes Subject to Use Restrictions...

40 CFR Appendix K to Subpart G of... - Substitutes Subject to Use Restrictions and Unacceptable Substitutes Listed in the July 22, 2002...

Code of Federal Regulations, 2012 CFR

2012-07-01

... Restrictions and Unacceptable Substitutes Listed in the July 22, 2002, Final Rule, Effective August 21, 2002 K Appendix K to Subpart G of Part 82 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED... Pt. 82, Subpt. G, App. K Appendix K to Subpart G of Part 82—Substitutes Subject to Use Restrictions...

40 CFR Appendix K to Subpart G of... - Substitutes Subject to Use Restrictions and Unacceptable Substitutes Listed in the July 22, 2002...

Code of Federal Regulations, 2013 CFR

2013-07-01

... Restrictions and Unacceptable Substitutes Listed in the July 22, 2002, Final Rule, Effective August 21, 2002 K Appendix K to Subpart G of Part 82 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED... Pt. 82, Subpt. G, App. K Appendix K to Subpart G of Part 82—Substitutes Subject to Use Restrictions...

40 CFR Appendix K to Subpart G of... - Substitutes Subject to Use Restrictions and Unacceptable Substitutes Listed in the July 22, 2002...

Code of Federal Regulations, 2011 CFR

2011-07-01

... Restrictions and Unacceptable Substitutes Listed in the July 22, 2002, Final Rule, Effective August 21, 2002 K Appendix K to Subpart G of Part 82 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED... Pt. 82, Subpt. G, App. K Appendix K to Subpart G of Part 82—Substitutes Subject to Use Restrictions...

40 CFR Appendix C to Subpart G of... - Substitutes Subject to Use Restrictions and Unacceptable Substitutes Listed in the May 22, 1996...

Code of Federal Regulations, 2012 CFR

2012-07-01

... Restrictions and Unacceptable Substitutes Listed in the May 22, 1996 Final Rule, Effective June 21, 1996 C Appendix C to Subpart G of Part 82 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED... Pt. 82, Subpt. G, App. C Appendix C to Subpart G of Part 82—Substitutes Subject to Use Restrictions...

40 CFR Appendix C to Subpart G of... - Substitutes Subject to Use Restrictions and Unacceptable Substitutes Listed in the May 22, 1996...

Code of Federal Regulations, 2014 CFR

2014-07-01

... Restrictions and Unacceptable Substitutes Listed in the May 22, 1996 Final Rule, Effective June 21, 1996 C Appendix C to Subpart G of Part 82 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED... Pt. 82, Subpt. G, App. C Appendix C to Subpart G of Part 82—Substitutes Subject to Use Restrictions...

40 CFR Appendix C to Subpart G of... - Substitutes Subject to Use Restrictions and Unacceptable Substitutes Listed in the May 22, 1996...

Code of Federal Regulations, 2010 CFR

2010-07-01

... Restrictions and Unacceptable Substitutes Listed in the May 22, 1996 Final Rule, Effective June 21, 1996 C Appendix C to Subpart G of Part 82 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED... Pt. 82, Subpt. G, App. C Appendix C to Subpart G of Part 82—Substitutes Subject to Use Restrictions...

Minimally invasive brow suspension for facial paralysis.

PubMed

Costantino, Peter D; Hiltzik, David H; Moche, Jason; Preminger, Aviva

2003-01-01

To report a new technique for unilateral brow suspension for facial paralysis that is minimally invasive, limits supraciliary scar formation, does not require specialized endoscopic equipment or expertise, and has proved to be equal to direct brow suspension in durability and symmetry. Retrospective survey of a case series of 23 patients between January 1997 and December 2000. Metropolitan tertiary care center. Patients with head and neck tumors and brow ptosis caused by facial nerve paralysis. The results of the procedure were determined using the following 3-tier rating system: outstanding (excellent elevation and symmetry); acceptable (good elevation and fair symmetry); and unacceptable (loss of elevation). The results were considered outstanding in 12 patients, acceptable in 9 patients, and unacceptable in only 1 patient. One patient developed a hematoma, and 1 patient required a secondary adjustment. The technique has proved to be superior to standard brow suspension procedures with regard to scar formation and equal with respect to facial symmetry and suspension. These results have caused us to abandon direct brow suspension and to use this minimally invasive method in all cases of brow ptosis due to facial paralysis.

The Impact of Symptom Dimensions on Outcome for Exposure and Ritual Prevention Therapy in Obsessive-Compulsive Disorder

PubMed Central

Williams, Monnica T.; Farris, Samantha G.; Turkheimer, Eric N.; Franklin, Martin E.; Simpson, H. Blair; Liebowitz, Michael; Foa, Edna B.

2014-01-01

Objective Obsessive-compulsive disorder (OCD) is a severe condition with varied symptom presentations. The behavioral treatment with the most empirical support is exposure and ritual prevention (EX/RP). This study examined the impact of symptom dimensions on EX/RP outcomes in OCD patients. Method The Yale-Brown Obsessive-Compulsive Scale (Y-BOCS) was used to determine primary symptoms for each participant. An exploratory factor analysis (EFA) of 238 patients identified five dimensions: contamination/cleaning, doubts about harm/checking, hoarding, symmetry/ordering, and unacceptable/taboo thoughts (including religious/moral and somatic obsessions among others). A linear regression was conducted on those who had received EX/RP (n = 87) to examine whether scores on the five symptom dimensions predicted post-treatment Y-BOCS scores, accounting for pre-treatment Y-BOCS scores. Results The average reduction in Y-BOCS score was 43.0%, however the regression indicated that unacceptable/taboo thoughts (β = .27, p = .02) and hoarding dimensions (β = .23, p = .04) were associated with significantly poorer EX/RP treatment outcomes. Specifically, patients endorsing religious/moral obsessions, somatic concerns, and hoarding obsessions showed significantly smaller reductions in Y-BOCS severity scores. Conclusions EX/RP was effective for all symptom dimensions, however it was less effective for unacceptable/taboo thoughts and hoarding than for other dimensions. Clinical implications and directions for research are discussed. PMID:24983796

Assessment of the microbiological safety of salad vegetables and sauces from kebab take-away restaurants in the United Kingdom.

PubMed

Meldrum, R J; Little, C L; Sagoo, S; Mithani, V; McLauchlin, J; de Pinna, E

2009-09-01

The purpose of this study was to establish the microbiological safety of salad vegetables and sauces served in kebab take-away restaurants. Comparison with published microbiological guidelines revealed that 4.7% of 1213 salad vegetable samples were of unsatisfactory microbiological quality due to Escherichia coli and/or Staphylococcus aureus levels at > or =10(2) cfu g(-1). Another 0.3% of salad samples were of unacceptable quality due to S. aureus at > or =10(4) cfu g(-1) (2 samples) or the presence of Salmonella Kentucky (1 sample). Cucumber was the most contaminated salad vegetable with regards to unsatisfactory levels of E. coli (6.0%) or S. aureus (4.5%). Five percent of 1208 sauce samples were of unsatisfactory microbiological quality due to E. coli, S. aureus at > or =10(2) cfu g(-1) and/or Bacillus cereus and other Bacillus spp. at > or =10(4) cfu g(-1). A further 0.6% of sauce samples were of unacceptable quality due to Bacillus spp. (Bacillus subtilis, Bacillus pumilus, Bacillus licheniformis) at > or =10(5) cfu g(-1) or the presence of Salmonella Agbeni (1 sample). More samples of chili sauce (8.7%) were of unsatisfactory or unacceptable microbiological quality than any other sauce types. The results emphasize the need for good hygiene practices in kebab take-away restaurants handling these types of ready-to-eat products.

Developing cold-chipping potato varieties by silencing the vacuolar invertase gene

USDA-ARS?s Scientific Manuscript database

Accumulation of reducing sugars during cold storage is a persistent and costly problem for the potato processing industry. High temperature processing of potato tubers with elevated amounts of reducing sugars results in potato chips, fries and other products that are unacceptable to consumers becaus...

The Enterococcus QPCR Method for Recreational Water Quality Testing: Testing Background, Performance and Issues

EPA Science Inventory

Currently accepted culture-based monitoring methods for fecal indicator bacteria in surface waters take at least 24 hr to determine if unacceptable levels of fecal pollution have reached our recreational beaches. During this waiting period changing water conditions may result eit...

Cumulative effects of forest management activities: how might they occur?

Treesearch

R. M. Rice; R. B. Thomas

1985-01-01

Concerns are often voiced about possible environmental damage as the result of the cumulative sedimentation effects of logging and forest road construction. In response to these concerns, National Forests are developing procedures to reduce the possibility that their activities may lead to unacceptable cumulative effects

16 CFR 1209.37 - Corrective actions.

Code of Federal Regulations, 2011 CFR

2011-01-01

... 16 Commercial Practices 2 2011-01-01 2011-01-01 false Corrective actions. 1209.37 Section 1209.37... SAFETY STANDARD FOR CELLULOSE INSULATION Certification § 1209.37 Corrective actions. (a) Test failure. When any test required by § 1209.36 yields failing or unacceptable results, corrective action must be...

Diffusion of Responsibility and Extreme Behavior.

ERIC Educational Resources Information Center

Mathes, Eugene W.; Kahn, Arnold

The results of this investigation support, in part, the diffusion of responsibility hypothesis which states that antisocial behavior will occur whenever individuals are motivated to engage in socially-unacceptable behavior, and find themselves in a group of similarly motivated individuals. The mechanism by which this antisocial behavior is…

Seismic performance assessment of base-isolated safety-related nuclear structures

USGS Publications Warehouse

Huang, Y.-N.; Whittaker, A.S.; Luco, N.

2010-01-01

Seismic or base isolation is a proven technology for reducing the effects of earthquake shaking on buildings, bridges and infrastructure. The benefit of base isolation has been presented in terms of reduced accelerations and drifts on superstructure components but never quantified in terms of either a percentage reduction in seismic loss (or percentage increase in safety) or the probability of an unacceptable performance. Herein, we quantify the benefits of base isolation in terms of increased safety (or smaller loss) by comparing the safety of a sample conventional and base-isolated nuclear power plant (NPP) located in the Eastern U.S. Scenario- and time-based assessments are performed using a new methodology. Three base isolation systems are considered, namely, (1) Friction Pendulum??? bearings, (2) lead-rubber bearings and (3) low-damping rubber bearings together with linear viscous dampers. Unacceptable performance is defined by the failure of key secondary systems because these systems represent much of the investment in a new build power plant and ensure the safe operation of the plant. For the scenario-based assessments, the probability of unacceptable performance is computed for an earthquake with a magnitude of 5.3 at a distance 7.5 km from the plant. For the time-based assessments, the annual frequency of unacceptable performance is computed considering all potential earthquakes that may occur. For both assessments, the implementation of base isolation reduces the probability of unacceptable performance by approximately four orders of magnitude for the same NPP superstructure and secondary systems. The increase in NPP construction cost associated with the installation of seismic isolators can be offset by substantially reducing the required seismic strength of secondary components and systems and potentially eliminating the need to seismically qualify many secondary components and systems. ?? 2010 John Wiley & Sons, Ltd.

An evaluation of flight path management automation in transport category aircraft

NASA Technical Reports Server (NTRS)

Chandra, D.; Bussolari, S. R.

1991-01-01

A desk-top simulation of a Boeing 757/767 Electronic Flight Instrumentation System (EFIS) and Control Display Unit (CDU) was used in an experiment to compare three modes of communication for the clearance amendment process: standard voice procedures, a textual delivery method, and a graphical delivery method. Eight qualified Boeing 757/767 pilots served as subjects. Each flew nine landing scenarios with three amendments given in each scenario. Both acceptable and unacceptable clearance amendments were presented in order to assess situational awareness. Times for comprehension and execution of the amendment were recorded along with workload ratings, responses to unacceptable amendments, and subjective impressions. The graphical mode was found to be superior in terms of the time measures and subjective ratings. No difference was found between the modes in the ability to detect unacceptable clearances.

Cyclophosphamide conditioning in patients with severe aplastic anaemia given unrelated marrow transplantation: a phase 1-2 dose de-escalation study.

PubMed

Anderlini, Paolo; Wu, Juan; Gersten, Iris; Ewell, Marian; Tolar, Jakob; Antin, Joseph H; Adams, Roberta; Arai, Sally; Eames, Gretchen; Horwitz, Mitchell E; McCarty, John; Nakamura, Ryotaro; Pulsipher, Michael A; Rowley, Scott; Leifer, Eric; Carter, Shelly L; DiFronzo, Nancy L; Horowitz, Mary M; Confer, Dennis; Deeg, H Joachim; Eapen, Mary

2015-09-01

The optimum preparative regimen for unrelated donor marrow transplantation in patients with severe aplastic anaemia remains to be established. We investigated whether the combination of fludarabine, anti-thymocyte globulin, and total body irradiation (TBI) would enable reduction of the cyclophosphamide dose to less than 200 mg/kg while maintaining engraftment and having a survival similar to or better than that with standard regimens using a cyclophosphamide dose of 200 mg/kg (known to be associated with significant organ toxicity) for unrelated donor transplantation for severe aplastic anaemia. We have previously shown that cyclophosphamide at 150 mg/kg resulted in excess toxicity and its omission (0 mg/kg) resulted in unacceptable graft failure (three of three patients had secondary graft failure). Here we report results for the 50 mg/kg and 100 mg/kg cohorts. In a multicentre phase 1-2 study, patients (aged ≤65 years) with severe aplastic anaemia, adequate organ function, and an unrelated adult marrow donor HLA matched at the allele level for HLA A, B, C, and DRB1 or mismatched at a single HLA locus received bone marrow grafts from unrelated donors. All patients received anti-thymocyte globulin (rabbit derived 3 mg/kg per day, intravenously, on days -4 to -2, or equine derived 30 mg/kg per day, intravenously, on days -4 to -2), fludarabine (30 mg/m(2) per day, intravenously, on days -5 to -2), and TBI (2 Gy). Cyclophosphamide dosing started at 150 mg/kg and was de-escalated in steps of 50 mg/kg (to 100 mg/kg, 50 mg/kg, and 0 mg/kg). The primary endpoint was the selection of the optimum cyclophosphamide dose based on assessments of graft failure (primary or secondary), toxicity, and early death during 100 days of follow-up after the transplant; this is the planned final analysis for the primary endpoint. This trial is registered with ClinicalTrials.gov, number NCT00326417. 96 patients had bone marrow transplant. At day 100, 35 (92%) of 38 patients were engrafted and alive in the cyclophosphamide 50 mg/kg cohort and 35 (85%) of 41 in the 100 mg/kg cohort. Cyclophosphamide 50 mg/kg and 100 mg/kg resulted in posterior means for fatality without graft failure of 0·7% (credible interval 0-3·3) and 1·4% (0-4·9), respectively. Three patients (8%) had graft failure with cyclophosphamide 50 mg/kg and six (15%) with cyclophosphamide 100 mg/kg. Four (11%) patients had major regimen-related toxicity with cyclophosphamide 50 mg/kg and nine (22%) with cyclophosphamide 100 mg/kg. The most common organ toxicity was pulmonary (grade 3 or 4 dyspnoea or hypoxia including mechanical ventilation), and occurred in three (8%) and four (10%) patients given cyclophosphamide 50 mg/kg and 100 mg/kg, respectively. Cyclophosphamide at 50 mg/kg and 100 mg/kg with TBI 2 Gy, fludarabine, and anti-thymocyte globulin results in effective conditioning and few early deaths after unrelated donor transplantation for severe aplastic anaemia. These doses of cyclophosphamide provide a framework for further regimen optimisation strategies. US National Heart, Lung, and Blood Institute and National Cancer Institute. Copyright © 2015 Elsevier Ltd. All rights reserved.

Race Differences and Type II Errors: A Comment on Borkowski and Krause.

ERIC Educational Resources Information Center

Jensen, Arthur R.

1985-01-01

Borkowski and Krause (1983) concluded that the locus of black-white intelligence differences lies in metaprocesses not elementary cognitive processes. However, some variables were difference scores with unacceptably low reliability. Magnitude comparisons of racial differences give a different picture of results; comparable differences in measures…

Identifying Ethical Hypernorms for Accounting Educators

ERIC Educational Resources Information Center

Siegel, Philip H.; Mintz, Steven; Naser-Tavakolian, Mohsen; O'Shaughnessy, John

2012-01-01

Accounting educators have a unique role in academe because students learn about codes of ethics that will guide their actions as professionals. We identify hypernorms related to internal auditing educators that reflect unethical behaviors believed to be universally unacceptable by that community. We then compare the results to a prior survey of…

42 CFR 493.1407 - Standard; Laboratory director responsibilities.

Code of Federal Regulations, 2010 CFR

2010-10-01

... developed and used for each of the tests performed in the laboratory provide quality laboratory services for... results are found to be unacceptable or unsatisfactory; (5) Ensure that the quality control and quality assessment programs are established and maintained to assure the quality of laboratory services provided and...

A New Definition of Punishment

ERIC Educational Resources Information Center

Hall, Philip S.

2013-01-01

Punishment is a procedure in which responses are followed by either the removal of positive reinforcement or the presentation of an aversive stimulus (Skinner, 1953) that results in a decrease in the frequency and/or intensity of the response (Azrin & Holtz, 1966). By definition, punishment seeks to stop unacceptable, unwanted, and bothersome…

Image registration assessment in radiotherapy image guidance based on control chart monitoring.

PubMed

Xia, Wenyao; Breen, Stephen L

2018-04-01

Image guidance with cone beam computed tomography in radiotherapy can guarantee the precision and accuracy of patient positioning prior to treatment delivery. During the image guidance process, operators need to take great effort to evaluate the image guidance quality before correcting a patient's position. This work proposes an image registration assessment method based on control chart monitoring to reduce the effort taken by the operator. According to the control chart plotted by daily registration scores of each patient, the proposed method can quickly detect both alignment errors and image quality inconsistency. Therefore, the proposed method can provide a clear guideline for the operators to identify unacceptable image quality and unacceptable image registration with minimal effort. Experimental results demonstrate that by using control charts from a clinical database of 10 patients undergoing prostate radiotherapy, the proposed method can quickly identify out-of-control signals and find special cause of out-of-control registration events.

New algorithms for optimal reduction of technical risks

NASA Astrophysics Data System (ADS)

Todinov, M. T.

2013-06-01

The article features exact algorithms for reduction of technical risk by (1) optimal allocation of resources in the case where the total potential loss from several sources of risk is a sum of the potential losses from the individual sources; (2) optimal allocation of resources to achieve a maximum reduction of system failure; and (3) making an optimal choice among competing risky prospects. The article demonstrates that the number of activities in a risky prospect is a key consideration in selecting the risky prospect. As a result, the maximum expected profit criterion, widely used for making risk decisions, is fundamentally flawed, because it does not consider the impact of the number of risk-reward activities in the risky prospects. A popular view, that if a single risk-reward bet with positive expected profit is unacceptable then a sequence of such identical risk-reward bets is also unacceptable, has been analysed and proved incorrect.

Cyclin-Dependent Kinase Inhibitors for the Treatment of Breast Cancer: Past, Present, and Future.

PubMed

DiPippo, Adam J; Patel, Neelam K; Barnett, Chad M

2016-06-01

Treatment of metastatic breast cancer (MBC) that is resistant to endocrine therapy presents a significant clinical challenge. The well-known role of cell cycle dysregulation in these patients is partly mediated by cyclin-dependent kinase (CDK) activity. Specific cyclin and CDK complexes regulate cell cycle progression by managing the transition through the cell cycle, and inhibition of CDKs represents an important target for novel agents. First-generation CDK inhibitors (e.g., flavopiridol) were relatively nonselective and had an unacceptable toxicity profile in early trials. Second-generation CDK inhibitors were designed to target the CDK4 and CDK6 (CDK4/6) pathway and have shown promising clinical activity with an acceptable toxicity profile in patients with MBC. Palbociclib is a first-in-class CDK4/6 inhibitor that was granted accelerated U.S. Food and Drug Administration approval in combination with letrozole for the treatment of MBC in the first-line setting (February 2015) as well as in combination with fulvestrant for MBC that had progressed on previous endocrine therapy (February 2016). Other CDK4/6 inhibitors, including ribociclib and abemaciclib, are under investigation as monotherapy and in combination with endocrine or anti-human epidermal growth receptor 2 therapy for the treatment of MBC. Ongoing clinical trials should provide additional information to guide the appropriate use of these agents and identify patient populations that could derive the most benefit. © 2016 Pharmacotherapy Publications, Inc.

California Dept. of Toxic Substances Control (DTSC) Update of the Schools Naturally Occurring Asbestos Guidance

NASA Astrophysics Data System (ADS)

Malinowski, M.

2012-12-01

Prior to acquisition and/or construction of prospective school sites, the California Education Code mandates that school districts complete environmental assessments and cleanups for prospective new or expanding school sites in order to qualify for state funding. If prospective school sites are determined to have environmental contamination from hazardous materials, including naturally occurring hazardous materials such as naturally occurring asbestos (NOA), where there may be unacceptable potential health risks, the school sites must be properly mitigated prior to occupancy for protection of human health and the environment. NOA is of special concern for schools, because children who are exposed to asbestos may be at increased risk of developing asbestos-related diseases over time. In order to protect human health, the Department of Toxic Substances Control's (DTSC) goals at school sites are to: 1) identify the presence of NOA in school site soils using exposure-reducing soil thresholds; 2) manage potential NOA exposures using mitigation measures to reduce generation of airborne asbestos fibers from soils on school sites; and 3) ensure long-term monitoring and protection of mitigation measures via Operations & Maintenance activities. DTSC is currently in the process of revising its Interim Guidance Naturally Occurring Asbestos (NOA) at School Sites - September 2004. The revisions include: 1) updating the guidance to consider incremental sampling for use at NOA sites in consultation with DTSC's project manager and technical staff, and 2) documenting a tiered approach to addressing high and low activity areas on a school.

p53 activated by AND gate genetic circuit under radiation and hypoxia for targeted cancer gene therapy.

PubMed

Ding, Miao; Li, Rong; He, Rong; Wang, Xingyong; Yi, Qijian; Wang, Weidong

2015-09-01

Radio-activated gene therapy has been developed as a novel therapeutic strategy against cancer; however, expression of therapeutic gene in peritumoral tissues will result in unacceptable toxicity to normal cells. To restrict gene expression in targeted tumor mass, we used hypoxia and radiation tolerance features of tumor cells to develop a synthetic AND gate genetic circuit through connecting radiation sensitivity promoter cArG6 , heat shock response elements SNF1, HSF1 and HSE4 with retroviral vector plxsn. Their construction and dynamic activity process were identified through downstream enhanced green fluorescent protein and wtp53 expression in non-small cell lung cancer A549 cells and in a nude mice model. The result showed that AND gate genetic circuit could be activated by lower required radiation dose (6 Gy) and after activated, AND gate could induce significant apoptosis effects and growth inhibition of cancer cells in vitro and in vivo. The radiation- and hypoxia-activated AND gate genetic circuit, which could lead to more powerful target tumoricidal activity represented a promising strategy for both targeted and effective gene therapy of human lung adenocarcinoma and low dose activation character of the AND gate genetic circuit implied that this model could be further exploited to decrease side-effects of clinical radiation therapy. © 2015 The Authors. Cancer Science published by Wiley Publishing Asia Pty Ltd on behalf of Japanese Cancer Association.

Cancer Trials Ireland (ICORG) 06-34: A multi-centre clinical trial using three-dimensional conformal radiation therapy to reduce the toxicity of palliative radiation for lung cancer.

PubMed

McDermott, Ronan L; Armstrong, John G; Thirion, Pierre; Dunne, Mary; Finn, Marie; Small, Cormac; Byrne, Mary; O'Shea, Carmel; O'Sullivan, Lydia; Shannon, Aoife; Kelly, Emma; Hacking, Dayle J

2018-05-01

Cancer Trials Ireland (ICORG) 06-34: A multi-centre clinical trial using three-dimensional conformal radiation therapy to reduce the toxicity of palliative radiation for lung cancer. NCT01176487. Trials of radiation therapy for the palliation of intra-thoracic symptoms from locally advanced non-small cell lung cancer (NSCLC) have concentrated on optimising fractionation and dose schedules. In these trials, the rates of oesophagitis induced by this "palliative" therapy have been unacceptably high. In contrast, this non-randomised, single-arm trial was designed to assess if more technically advanced treatment techniques would result in equivalent symptom relief and reduce the side-effect of symptomatic oesophagitis. Thirty-five evaluable patients with symptomatic locally advanced or metastatic NSCLC were treated using a three-dimensional conformal technique (3-DCRT) and standardised dose regimens of 39 Gy in 13 fractions, 20 Gy in 5 fractions or 17 Gy in 2 fractions. Treatment plans sought to minimise oesophageal dose. Oesophagitis was recorded during treatment, at two weeks, one month and three months following radiation therapy and 3-6 monthly thereafter. Mean dose to the irradiated oesophagus was calculated for all treatment plans. Five patients (14%) had experienced grade 2 oesophagitis or dysphagia or both during treatment and 2 other patients had these side effects at the 2-week follow-up. At follow-up of one month after therapy, there was no grade two or higher oesophagitis or dysphagia reported. 22 patients were eligible for assessment of late toxicity. Five of these patients reported oesophagitis or dysphagia (one had grade 3 dysphagia, two had grade 2 oesophagitis, one of whom also had grade 2 dysphagia). Quality of Life (QoL) data at baseline and at 1-month follow up were available for 20 patients. At 1-month post radiation therapy, these patients had slightly less trouble taking a short walk, less shortness of breath, did not feel as weak, had better appetite and generally had a better overall quality of life than they did at baseline. They did report being slightly more tired. This trial is the first of its kind showing that 3-DCRT provides patients with lower rates of oesophageal toxicity whilst yielding acceptable rates of symptom control. (Sponsored by Cancer Trials Ireland (ICORG) Study number 06-34, the Friends of St. Luke's and the St. Luke's Institute of Cancer Research.). Copyright © 2018 Elsevier B.V. All rights reserved.

Folfirinox in elderly patients with pancreatic or colorectal cancer-tolerance and efficacy.

PubMed

Guion-Dusserre, Jean-Florian; Bertaut, Aurélie; Ghiringhelli, François; Vincent, Julie; Quipourt, Valérie; Marilier, Sophie; Tharin, Zoé; Bengrine-Lefevre, Leila

2016-11-14

To study the tolerance and the efficiency of FOLFIRINOX in elderly patients diagnosed with colorectal or pancreatic cancer. This retrospective study included elderly patients aged over 70 years of age treated at Georges-Francois Leclerc Center by FOLFIRINOX for histological proved colorectal or pancreatic cancer between January 2009 and January 2015. Chemotheapy regimen consisted of oxaliplatin (85 mg/m 2 in over 120 min) followed by leucovorin (400 mg/m 2 in over 120 min), with the addition, after 30 min of irinotecan (180 mg/m 2 in over 90 min) then 5 fluorouracil (5FU) (400 mg/m 2 administred intravenous bolus), followed by 5FU (2400 mg/m 2 intraveinous infusion over 46 h) repeated every 2 wk. Geriatric parameters were recorded at the beginning. Toxicities were evaluated with the Common Terminology Criteria for Adverse Events 4.03. Tumor response was evaluated by CT scan. Treatment continued until disease progression, unacceptable toxicities or patient refusal. Fifty-two patients aged from 70 to 87 years were treated by FOLFIRINOX, 34 had colorectal cancer and 18 had pancreatic cancer. Most of them were in good general condition, 82.7% had a 0-1 performance status and 61.5% had a Charlson Comorbidity Index < 10. The most frequent severe toxicities were neutropenia (17 patients, n = 32.7%) and diarrhea (35 patients n = 67.3%); 10 of the case of neutropenia and 5 of diarrhea registered a grade 4 toxicity. Thirty-nine patients (75%) initially received an adapted dose of chemotherapy. The dosage was adjusted for 26% of patients during the course of treatment. Tumor response evaluated by RECIST criteria showed a controlled disease for 25 patients (48.1%), a stable disease for 13 and a partial response for 12 patients. Time under treatment was higher for colorectal cancer with a median time of 2.44 mo (95%CI: 1.61-3.25). Overall survival was 43.88 mo for colorectal cancer and 12.51 mo for pancreatic cancer. In univariate or multivariate analysis, none of geriatric parameters were linked to overall survival. Only the type of tumor (pancreatic/colorectal) was linked in both analysis. For people over 70 years old, FOLFIRINOX regimen seems to induce manageable toxicities but similar, even higher, median survival rates compared to younger people.

[Analysis the relationship between the found ways and first diagnosis age for large vestibular aqueduct children].

PubMed

Yang, Yali; Huang, Lihui; Cheng, Xiaohua; Fu, Xinxing; Liu, Jiaxing; Ni, Tingting

2014-11-01

To explore the found ways and first diagnosis age of children with large vestibular aqueduct, and their relations with hearing loss. Medical histories of 122 cases of children diagnosed with large vestibular aqueduct by HRCT or MRI had been collected from January 2009 to April 2014 in our hospital children's hearing diagnosis center clinic. Found ways comprise of accepting universal newborn hearing screening (UNHS) group and unaccepting UNHS group. Accepting UNHS children were divided into two ears unpassing group, single ear unpassing group and passing group. The patients in unaccepting UNHS group were divided into not sensitive to sounds, speech stunting, sudden hearing loss, and other group. Analysis the relationship between the found ways and first diagnosis age and their relations with hearing loss. There are 84 cases (68.85%) accepting UNHS, the average age of first diagnosis was (17.24 ± 17.08) months; 37 cases (31.15%) are not accepting UNHS. The average age of first diagnosis was (30.92 ± 18.21) months. The average first diagnosis age of accepting UNHS group was more earlier than the unaccepting UNHS group. The difference was statistically signif- icant (P < 0.01). There were 57 cases (67.85%) whose two ears not pass UNHS; 15 cases (17.86%) single ear not pass; namely the referral rate was 85.71%; 12 cases (14.29%) pass the test. The first diagnosis age of passing UNHS group was more later than two ears unpassing group (P < 0.001). In the unaccepting UNHS group, the average first diagnosis age of not sensitive to sounds group (19.69 ± 11.16 months) was more earlier than words dysplasia group (37.13 ± 15.62 months) and sudden hearing loss group (47.40 ± 24.70 months) (P < 0.01). The difference in the degree of hearing loss between accepting UNHS and unaccepting UNHS group had no statistical significance (P > 0.05). In unaccepting UNHS group ,the average first diagnosis age of the mild-to-moderate hearing loss group was later than the very severe hearing loss group (P < 0.01). Most of large vestibular aqueduct children can be found and receive diagnosis early by UNHS. But part of these patients with late-onset or progressive hearing loss, especially these with mild-to-moderate hearing loss cannot be found early, which should arouse our attention.

Prospective randomized double-blind multicentre phase II study comparing gemcitabine and cisplatin plus sorafenib chemotherapy with gemcitabine and cisplatin plus placebo in locally advanced and/or metastasized urothelial cancer: SUSE (AUO-AB 31/05).

PubMed

Krege, Susanne; Rexer, Heidrun; vom Dorp, Frank; de Geeter, Patrick; Klotz, Theodor; Retz, Margitte; Heidenreich, Axel; Kühn, Michael; Kamradt, Joern; Feyerabend, Susan; Wülfing, Christian; Zastrow, Stefan; Albers, Peter; Hakenberg, Oliver; Roigas, Jan; Fenner, Martin; Heinzer, Hans; Schrader, Mark

2014-03-01

To evaluate the efficacy and safety of gemcitabine and cisplatin in combination with sorafenib, a tyrosine-kinase inhibitor, compared with chemotherapy alone as first-line treatment in advanced urothelial cancer. The study was a randomized phase II trial. Its primary aim was to show an improvement in progression-free survival (PFS) of 4.5 months by adding sorafenib to conventional chemotherapy. Secondary objectives were objective response rate (ORR), overall survival (OS) and toxicity. The patients included in the trial had histologically confirmed locally advanced and/or metastatic urothelial cancer of the bladder or upper urinary tract. Chemotherapy with gemcitabine (1250 mg/qm on days 1 and 8) and cisplatin (70 mg/qm on day 1) repeated every 21 days, was administered to all patients in a double-blind randomization of additional sorafenib (400 mg twice daily) vs placebo (two tablets twice daily) on days 3-21. Treatment continued until progression or unacceptable toxicity, the maximum number of cycles was limited to eight. The response assessment was repeated after every two cycles. Between October 2006 and October 2010, 98 of 132 planned patients were recruited. Nine patients were ineligible. The final analysis included 40 patients in the sorafenib and 49 patients in the placebo arm. There were no significant differences between the two arms concerning ORR (sorafenib: complete response [CR] 12.5%, partial response [PR] 40%; placebo: CR 12%, PR 35%), median PFS (sorafenib: 6.3 months, placebo: 6.1 months) or OS (sorafenib: 11.3 months, placebo: 10.6 months). Toxicity was moderately higher in the sorafenib arm. Diarrrhoea occurred significantly more often in the sorafenib arm and hand-foot syndrome occurred only in the sorafenib arm. The study was closed prematurely because of slow recruitment. Although the addition of sorafenib to standard chemotherapy showed acceptable toxicity, the trial failed to show a 4.5 months improvement in PFS. © 2013 The Authors. BJU International © 2013 BJU International.

Denver's Public Schools: Reforms, Challenges, and the Future

ERIC Educational Resources Information Center

Bray, Judy; Medler, Alex

2009-01-01

Denver is currently in the national education spotlight, largely because of its willingness to try a unique combination of major education reforms not seen in other large urban school districts. While many observers hold these reforms in high regard, a steep road lies ahead. Current student results are unacceptable by all measures. The time is…

Genetic and environmental effects on production of spontaneous tetraploids in cucumber (Cucumis sativus L.)

USDA-ARS?s Scientific Manuscript database

The appearance of spontaneous tetraploid (4x) plants is a serious problem for cucumber growers and the seed industry. These plants produce unacceptable fruits with poor quality that do not meet market standards, and result in substantial losses. A higher frequency of spontaneous 4x plants has been a...

Measuring the Outcomes of State Policies for Gifted Education: An Equity Analysis of Texas School Districts.

ERIC Educational Resources Information Center

Baker, Bruce D.

2001-01-01

This article introduces a set of policy tools for measuring outcomes of gifted education policies and applies these tools to data on the distribution of Texas gifted education spending. Results indicate continued vast inequities across school districts and unacceptable correlations among student population characteristics, community wealth, and…

76 FR 55723 - Final Supplemental Environmental Impact Statement, Sequoyah Nuclear Plant Units 1 and 2 License...

Federal Register 2010, 2011, 2012, 2013, 2014

2011-09-08

... environmentally unacceptable conditions. Following the events at the Fukushima (Japan) Daiichi Nuclear Power Plant... the Fukushima accident is unlikely to occur at any TVA plant. Nonetheless, the effort has resulted in... the Fukushima Dai-ichi Accident, concluded that continued operation and continued licensing activities...

Why We Test Students for Drugs

ERIC Educational Resources Information Center

Brady, Lisa A.

2008-01-01

Today, there is a collective national awareness that an unacceptable number of teens are involved in the use of dangerous drugs such as methamphetamine, ecstasy, and heroin, and they have access to high-grade marijuana. Alcohol use, even more pervasive, results in risky sexual behaviors, automobile accidents, and even death. To the dismay of many…

[Ethical behavioral standards of medical students on examinations and studies].

PubMed

Tolkin, Lior; Glick, Shimon

2007-06-01

In recent years the medical literature has reflected an increasing interest in the medical ethics of physicians and medical students. Studies have shown that cheating in medical school is frequent enough to cause concern, that there is a positive correlation between students' ethical attitude and their ethical behavior and between cheating in school and cheating in patient care. This study aims to examine student attitudes towards cheating, their self-reported behavior, analyze cultural and sub-cultural differences, and to reach practical conclusions that might be incorporated into the teaching of ethics in medical schools. Anonymous questionnaires were distributed to 193 first and second year students of the Israeli and American programs at Ben-Gurion University. The questionnaire consisted of fifty three multiple choice questions. The students were asked to state their opinion on various cheating practices at medical school and dishonesty in patient care, to estimate how they would resolve various ethical dilemmas and to provide some demographic information. The results were analyzed using SPSS. T-tests, Chi-Square tests, one-way analysis of variance, and Pearson and Spearman's coefficients, all used as appropriate. Completed questionnaires were returned by 141 students (73%). The majority of the students regard cheating in an exam (93%) or on a final paper (85%) to be morally unacceptable behavior. Copying during an exam is regarded as more morally unacceptable than copying a homework exercise. The majority of the students consider faking a patient's laboratory results to be morally unacceptable behavior (98%). American students regard copying a homework exercise, reconstructing exam questions for the benefit of next year students and giving answers to a fellow student during an exam to be more morally unacceptable in comparison to the Israeli students. Married students consider cheating to be more morally unacceptable than unmarried students. A positive correlation was found between religiosity and the position that cheating is a morally negative practice. There is a positive correlation between cheating in high school and the position that cheating is morally acceptable. In addition, the more often a student cheated in high school the more that student claims that he or she would cheat if they were sure that they would not be caught. Amongst Israeli students, there was a correlation between the view that the faculty did not treat them well, and the position that cheating is morally acceptable, No correlation was found between cheating and gender, age, birth country of parents, army service, or type of high school. Students' attitude toward cheating is significantly determined by the cultural and sub-cultural characteristics of each student's background. Ethical discussions in which an ethical code would be formed, moral dilemmas analyzed and cultural differences addressed, may help improve the ethical behavior of students in medical school, and thus improve their ethical practice in patient care.

Test and Evaluation Master Plan (TEMP) for the Navy Occupational Health Information Management System (NOHIMS). Appendix A through Appendix U.

DTIC Science & Technology

1985-04-24

reliability/ downtime/ communication lines/ man-machine interface/ other: 2. A noticeable (to the user) failure happens about and that number has been...improving/ steady/ getting.worse. 3. The number of failures /errors for NOHIMS is acceptable/ somewhat acceptable/ somewhat unacceptable/ unacceptable...somewhat fast/ somewhat slow/ slow. 7. When a NWHIMS failure occurs, it affects the day-to-day provision of medical care because work procedures must

Occurrence of Organic Wastewater Contaminants, Pharmaceuticals, and Personal Care Products in Selected Water Supplies, Cape Cod, Massachusetts, June 2004

DTIC Science & Technology

2005-01-01

previously detected high nitrate concen- trations. (Phenol and d- limonene , detected in equipment blanks at unacceptably high concentrations, are not...both tables, were not counted twice. (Phenol and d- limonene , detected in equipment blanks at unaccept- ably high concentrations, are not included in...The surrogate recoveries (not included in table 2) for the PPCP method were 101 and 102 percent. Three compounds, d- limonene , phenol, and

Beliefs about Emotions, Depression, Anxiety and Fatigue: A Mediational Analysis.

PubMed

Sydenham, Mia; Beardwood, Jennifer; Rimes, Katharine A

2017-01-01

Beliefs that it is unacceptable to experience or express negative emotions have been found to be associated with various clinical problems. It is unclear how such beliefs, which could be viewed as a form of unhelpful perfectionism about emotions, may contribute to symptomatology. This study investigated two hypotheses: a) greater endorsement of beliefs about the unacceptability of negative emotions will be associated with greater emotional avoidance and lower levels of support-seeking and self-compassion; b) these beliefs about emotions will be associated with higher levels of symptoms of depression, anxiety and fatigue and that this relationship will be mediated by social support-seeking, emotional avoidance and self-compassion. Online questionnaires were completed by 451 community participants. Mediational analyses were undertaken to investigate emotional avoidance, social support-seeking and self-compassion as mediators of the relationship between beliefs about emotions and symptoms of depression, anxiety and fatigue. Beliefs about the unacceptability of negative emotions were significantly associated with more emotional avoidance and less self-compassion and support-seeking. The relationships between beliefs about emotions and depression, anxiety and fatigue were significantly mediated by self-compassion and emotional avoidance but not social support-seeking. Future research should investigate whether interventions that pay particular attention to emotional avoidance and self-compassion, such as mindfulness-based therapy or modified forms of CBT, may be beneficial in reducing distress and fatigue associated with beliefs about the unacceptability of negative emotions.

The attitudes of dental students towards socially acceptable and unacceptable group working practices.

PubMed

Sisson, K; Newton, J

2007-08-01

To explore the attitudes of undergraduate dental students towards academically unacceptable behaviour. Three sets of vignettes were designed exploring; attitudes towards sharing essays which students present as their own work (set 1), attitudes towards purchasing an essay from a commercial website (set 2), and attitudes towards working in a group (set 3). Eighty-nine dental students read the vignettes, then indicated whether they felt the student depicted should engage in the behaviour, and whether any assessment of the work would be a fair assessment of the student's ability. In addition for the group working vignette, respondents were asked to indicate whether in that situation they would speak to the tutor about their own contribution to the group product. Twenty-one respondents (24%) reported that students should share essays, 11 (12%) felt that the essay would be a fair assessment; 13 (15%) felt that students should buy commercially produced essays, five (6%) felt it would be a fair assessment. For the vignettes involving group work, 31 (35%) respondents felt that group-based assessments were fair, 65 (73%) of respondents felt it unlikely that they would speak to the tutor about their individual contribution. A disturbing proportion of dental students report that cheating is acceptable, the majority feel that unacceptable academic practices are not a fair indication of students' ability. The respondents reported that they were unlikely to report the unacceptable working practices of fellow students.

Pediatric nurses' differentiations between acceptable and unacceptable parent discipline behaviors: a Q-study.

PubMed

Ho, Grace W K; Gross, Deborah A

2015-01-01

Nurses are mandated to report suspected cases of child maltreatment. However, it is unclear how nurses decide what constitutes child abuse or evidence for reporting. It is crucial to examine how nurses define various forms of child maltreatment, including child abuse and its differentiation from physical discipline, to enhance our services to families with young children. The present study examined pediatric nurses' views on acceptable versus unacceptable discipline behaviors to better understand parent behaviors that nurses are likely to deem reportable to child protective services. Using Q methodology, a convenience sample of 48 pediatric nurses from one urban medical center sorted 71 statements related to the behavior or outcome of punishing a child via the Internet application FlashQ. The statements were sorted on a predefined continuum ranging from "Most Unacceptable" to "Most Acceptable." By-person factor analysis was used to uncover groups of nurses with similar sorts and to generate a unique sort that represented the viewpoint of nurses in that group. Two distinct viewpoints were uncovered. Although there was consensus on what constitutes most acceptable and most unacceptable parent behaviors, nurses varied on their endorsement of using physical force as a form of discipline, suggesting a potential for discrepant tendencies to identify and report child abuse. Copyright © 2015 National Association of Pediatric Nurse Practitioners. Published by Elsevier Inc. All rights reserved.

Rationale and pre-clinical efficacy of a novel anti-EMP2 antibody for the treatment of invasive breast cancer

PubMed Central

Fu, Maoyong; Maresh, Erin L.; Helguera, Gustavo F.; Kiyohara, Meagan; Qin, Yu; Ashki, Negin; Daniels-Wells, Tracy R.; Aziz, Najib; Gordon, Lynn K.; Braun, Jonathan; Elshimali, Yahya; Soslow, Robert A.; Penichet, Manuel L.; Goodglick, Lee; Wadehra, Madhuri

2014-01-01

Despite significant advances in biology and medicine, the incidence and mortality due to breast cancer world-wide is still unacceptably high. Thus, there is an urgent need to discover new molecular targets. In this paper, we show evidence for a novel target in human breast cancer, the tetraspan protein epithelial membrane protein-2 (EMP2). Using tissue tumor arrays, protein expression of EMP2 was measured and found to be minimal in normal mammary tissue, but it was upregulated in 63% of invasive breast cancer tumors and in 73% of triple negative tumors tested. To test the hypothesis that EMP2 may be a suitable target for therapy, we constructed a fully human IgG1 antibody specific for a conserved domain of human and murine EMP2. Treatment of breast cancer cells with the anti-EMP2 IgG1 significantly inhibited EMP2 mediated signaling, blocked FAK/Src signaling, inhibited invasion, and promoted apoptosis in vitro. In both human xenograft and syngeneic metastatic tumor monotherapy models, anti-EMP2 IgG1 retarded tumor growth without detectable systemic toxicity. This anti-tumor effect was in part attributable to a potent ADCC response as well as direct cytotoxicity induced by the monoclonal antibody. Together, these results identify EMP2 as a novel therapeutic target for invasive breast cancer. PMID:24448822

Rationale and preclinical efficacy of a novel anti-EMP2 antibody for the treatment of invasive breast cancer.

PubMed

Fu, Maoyong; Maresh, Erin L; Helguera, Gustavo F; Kiyohara, Meagan; Qin, Yu; Ashki, Negin; Daniels-Wells, Tracy R; Aziz, Najib; Gordon, Lynn K; Braun, Jonathan; Elshimali, Yahya; Soslow, Robert A; Penichet, Manuel L; Goodglick, Lee; Wadehra, Madhuri

2014-04-01

Despite significant advances in biology and medicine, the incidence and mortality due to breast cancer worldwide is still unacceptably high. Thus, there is an urgent need to discover new molecular targets. In this article, we show evidence for a novel target in human breast cancer, the tetraspan protein epithelial membrane protein-2 (EMP2). Using tissue tumor arrays, protein expression of EMP2 was measured and found to be minimal in normal mammary tissue, but it was upregulated in 63% of invasive breast cancer tumors and in 73% of triple-negative tumors tested. To test the hypothesis that EMP2 may be a suitable target for therapy, we constructed a fully human immunoglobulin G1 (IgG1) antibody specific for a conserved domain of human and murine EMP2. Treatment of breast cancer cells with the anti-EMP2 IgG1 significantly inhibited EMP2-mediated signaling, blocked FAK/Src signaling, inhibited invasion, and promoted apoptosis in vitro. In both human xenograft and syngeneic metastatic tumor monotherapy models, anti-EMP2 IgG1 retarded tumor growth without detectable systemic toxicity. This antitumor effect was, in part, attributable to a potent antibody-dependent cell-mediated cytotoxicity response as well as direct cytotoxicity induced by the monoclonal antibody. Together, these results identify EMP2 as a novel therapeutic target for invasive breast cancer.

Phase II study of cabozantinib in patients with progressive glioblastoma: subset analysis of patients naive to antiangiogenic therapy

PubMed Central

Drappatz, Jan; de Groot, John; Prados, Michael D; Reardon, David A; Schiff, David; Chamberlain, Marc; Mikkelsen, Tom; Desjardins, Annick; Holland, Jaymes; Ping, Jerry; Weitzman, Ron; Cloughesy, Timothy F

2018-01-01

Abstract Background Cabozantinib is a tyrosine kinase inhibitor with activity against vascular endothelial growth factor receptor 2 (VEGFR2) and MET that has demonstrated clinical activity in advanced solid tumors. This open-label, phase II trial evaluated cabozantinib in patients with recurrent or refractory glioblastoma (GBM). Methods Patients were initially enrolled at a starting dose of 140 mg/day, but the starting dose was amended to 100 mg/day because of toxicity. Treatment continued until disease progression or unacceptable toxicity. The primary endpoint was objective response rate assessed by an independent radiology facility using modified Response Assessment in Neuro-Oncology criteria. Additional endpoints included duration of response, 6-month and median progression-free survival, overall survival, and safety. Results Among 152 patients naive to prior antiangiogenic therapy, the objective response rate was 17.6% and 14.5% in the 140 mg/day and 100 mg/day groups, respectively, which did not meet the predefined statistical target for success. The proportions of patients alive and progression free at 6 months were 22.3% and 27.8%, respectively. Median progression-free survival was 3.7 months in both groups, and median overall survival was 7.7 months and 10.4 months, respectively. The incidence of grade 3/4 adverse events (AEs) was 79.4% and 84.7% in the 140 mg/day and 100 mg/day groups, respectively, and dose reductions due to AEs were experienced by 61.8% and 72.0%, respectively. Common grade 3/4 AEs included fatigue, diarrhea, and palmar-plantar erythrodysesthesia syndrome. Conclusions Cabozantinib showed evidence of clinical activity in patients with recurrent GBM naive to antiangiogenic therapy, although the predefined statistical target for success was not met. At the starting doses assessed, AEs were frequently managed with dose reductions. Clinical Trials Registration Number NCT00704288 (https://www.clinicaltrials.gov/ct2/show/NCT00704288) PMID:29016998

A Pilot Study of Apatinib as Third-Line Treatment in Patients With Heavily Treated Metastatic Colorectal Cancer.

PubMed

Liang, Lijun; Wang, Lei; Zhu, Panrong; Xia, Youyou; Qiao, Yun; Wu, Jiang; Zhuang, Wei; Fei, Jiayan; Wen, Yixuan; Jiang, Xiaodong

2018-03-02

Antiangiogenic therapy has shown improved clinical outcome in metastatic colorectal cancer (mCRC). After the failure of standard treatments, regorafenib and TAS-102 would be recommended for patients with mCRC, however, they have not been approved in China during this study period. This pilot study aimed to assess the efficacy and safety of apatinib, a novel oral inhibitor targeting vascular endothelial growth factor receptor 2, as third-line treatment for patients with mCRC refractory to standard therapies. In this retrospective study, all patients received apatinib treatment until progressive disease (PD), death, unacceptable toxicity, and curative surgery. The dose or treatment schedule was modified according to the physician's discretion according to the toxicity profiles. Between March 2015 and June 2017, 36 patients were enrolled and eligible for evaluation of the safety and efficacy. One patient (2.8%) achieved complete response, 3 (8.3%) achieved partial response, 24 (66.7%) achieved stable disease, and 8 (22.2%) PD. The objective response rate and the disease control rate were 11.1% (4 of 36), and 77.8% (28 of 36), respectively. Moreover, the median overall survival (OS) since the initiation of first-line treatment was 33.2 months. The median progression-free survival (PFS) and median OS from apatinib treatment were 4.8 and 10.1 months, respectively. Intergroup analysis showed that there was no significant difference in median PFS and median OS between patients who were previously treated with and without bevacizumab. The most common Grade 3 to 4 adverse reactions were hand-foot syndrome, hypertension, and proteinuria. Our results suggested that apatinib was active as a third-line treatment of refractory mCRC with a manageable tolerability profile. In addition, preliminary data suggested that the efficacy of apatinib would not be affected by previous bevacizumab treatment. Further prospective randomized controlled clinical trials are urgently needed. Copyright © 2018 Elsevier Inc. All rights reserved.

Rational therapeutic choice for older patients with lymphoma.

PubMed

Bron, Dominique; Soubeyran, Pierre

2017-09-01

The choice for an optimal treatment in older lymphoma patients is a real challenge for hemato-oncologists. They have to treat a potentially curative lymphoma, and concomitantly protect their patients from unacceptable toxicities. Some recommendations are provided for the major subtypes of lymphomas including the antitumoral treatment and primarily the optimal supportive care. All the recent literature data converge to say that the approach of an older patient with a malignant hemopathy is a multistep procedure. This process comprises the appraisal of life expectancy of the patient with or without the disease, the prognostic factors of the tumor, the functional, physiological and cognitive functions evaluation, the socio-economical environment and the patient's expectancy in terms of quality of life. Major progresses have been achieved in the management of diffuse large B cell lymphoma and mantle cell lymphoma in patients up to 80 and above 80 years old. With all these information in hands, the hematologist will decide if the treatment's objective is the standard treatment with optimal supportive care (fit patients), tailor-made adapted chemotherapy (unfit patients) or preservation of quality of life (frail patients).

Comments on Economides and Ehlig-Economides,"Sequestering carbon dioxide in a closed underground volume," SPE 124430, October 2009

DOE Office of Scientific and Technical Information (OSTI.GOV)

Oldenburg, Curt; Pruess, Karsten; Birkholzer, Jens

The paper examines the pressure increase resulting from injection of CO2 into a 1D radial system with closed boundaries. The finding is that unacceptably high pressures are obtained when only 1% or less of the pore volume is occupied by injected CO2. These results are used to make the general conclusion that large-scale CCS is not feasible.

Safety and efficacy of nivolumab and standard chemotherapy drug combination in patients with advanced non-small-cell lung cancer: a four arms phase Ib study.

PubMed

Kanda, S; Goto, K; Shiraishi, H; Kubo, E; Tanaka, A; Utsumi, H; Sunami, K; Kitazono, S; Mizugaki, H; Horinouchi, H; Fujiwara, Y; Nokihara, H; Yamamoto, N; Hozumi, H; Tamura, T

2016-12-01

The human IgG4 monoclonal antibody nivolumab targets programmed cell death-1 (PD-1) and promotes antitumor response by blocking the interaction of PD-1 with its ligands. This single-center phase Ib study investigated the tolerability, safety, and pharmacokinetics of nivolumab combined with standard chemotherapy in patients with advanced non-small-cell lung cancer (NSCLC). Patients who had stage IIIB without indication for definitive radiotherapy, stage IV, or recurrent NSCLC were eligible. Regimens were nivolumab 10 mg/kg + gemcitabine/cisplatin (arm A), pemetrexed/cisplatin (arm B), paclitaxel/carboplatin/bevacizumab (arm C), or docetaxel (arm D). Regimens A, B, and D were repeated every 3 weeks for up to four cycles and regimen C was repeated for up to six cycles; nivolumab alone (arm A), with pemetrexed (arm B), bevacizumab (arm C), or docetaxel (arm D) was continued every 3 weeks as maintenance therapy until disease progression or unacceptable toxicity. Dose-limiting toxicity (DLT) was evaluated during the first treatment cycle. As of March 2014, six patients were enrolled in each arm. The combination of nivolumab 10 mg/kg and chemotherapy was well tolerated. DLT was observed in only one patient in arm A (alanine aminotransferase increased). Select adverse events (those with a potential immunologic cause) of any grade were observed in six, four, six, and five patients in arms A, B, C, and D, respectively. Three, three, six, and one patient achieved partial response while median progression-free survival was 6.28, 9.63 months, not reached, and 3.15 months in arms A, B, C, and D, respectively. Combination of nivolumab 10 mg/kg and chemotherapy showed an acceptable toxicity profile and encouraging antitumor activity in patients with advanced NSCLC. Japanese Pharmaceutical Information Center Clinical Trials Information (JapicCTI)-132071. © The Author 2016. Published by Oxford University Press on behalf of the European Society for Medical Oncology.

20 CFR 655.540 - Suspension or invalidation of filed attestations for locations in Alaska.

Code of Federal Regulations, 2010 CFR

2010-04-01

... employer's misrepresentation in or failure to carry out its attestation); or from a discovery by ETA that... the DHS of the violation and of the Administrator's notice to ETA. (b) Result of ETA action. If, after accepting an attestation for filing, ETA finds that the attestation is unacceptable because it falls within...

Shooting for Stars: Cross-Sector Lessons for Retaining High-Performing Educators. Building an Opportunity Culture for America's Teachers

ERIC Educational Resources Information Center

Ableidinger, Joe; Kowal, Julie

2010-01-01

As the United States continues to grapple with unacceptable education results, "a great teacher for every student" has risen to a national imperative. In response, many districts have increased retention efforts through teacher induction programs, professional development, mentoring, and other strategies. But education actually has lower…

The Addition of Saccharin to Taste Cues Affects Taste Preference Conditioning in Thirsty Rats

ERIC Educational Resources Information Center

Forestell, Catherine A.; LoLordo, Vincent M.

2004-01-01

Previous failures to condition preferences for the unacceptable taste cues sucrose octaacetate (SOA) and citric acid (CA) using a reverse-order, differential conditioning procedure (Forestell & LoLordo, 2000) may have been the result of low consumption of the taste cues in training or of their relatively low acceptability to rats that are thirsty…

40 CFR 26.1706 - Criteria and procedure for decisions to protect public health by relying on otherwise...

Code of Federal Regulations, 2011 CFR

2011-07-01

... protect public health by relying on otherwise unacceptable research. 26.1706 Section 26.1706 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY GENERAL PROTECTION OF HUMAN SUBJECTS Ethical Standards for Assessing Whether To Rely on the Results of Human Research in EPA Actions § 26.1706 Criteria and procedure...

40 CFR 26.1706 - Criteria and procedure for decisions to protect public health by relying on otherwise...

Code of Federal Regulations, 2012 CFR

2012-07-01

... protect public health by relying on otherwise unacceptable research. 26.1706 Section 26.1706 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY GENERAL PROTECTION OF HUMAN SUBJECTS Ethical Standards for Assessing Whether To Rely on the Results of Human Research in EPA Actions § 26.1706 Criteria and procedure...

40 CFR 26.1706 - Criteria and procedure for decisions to protect public health by relying on otherwise...

Code of Federal Regulations, 2010 CFR

2010-07-01

... protect public health by relying on otherwise unacceptable research. 26.1706 Section 26.1706 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY GENERAL PROTECTION OF HUMAN SUBJECTS Ethical Standards for Assessing Whether To Rely on the Results of Human Research in EPA Actions § 26.1706 Criteria and procedure...

40 CFR 26.1706 - Criteria and procedure for decisions to protect public health by relying on otherwise...

Code of Federal Regulations, 2013 CFR

2013-07-01

... protect public health by relying on otherwise unacceptable research. 26.1706 Section 26.1706 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY GENERAL PROTECTION OF HUMAN SUBJECTS Standards for Assessing Whether To Rely on the Results of Human Research in EPA Actions § 26.1706 Criteria and procedure for...

40 CFR 26.1706 - Criteria and procedure for decisions to protect public health by relying on otherwise...

Code of Federal Regulations, 2014 CFR

2014-07-01

... protect public health by relying on otherwise unacceptable research. 26.1706 Section 26.1706 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY GENERAL PROTECTION OF HUMAN SUBJECTS Standards for Assessing Whether To Rely on the Results of Human Research in EPA Actions § 26.1706 Criteria and procedure for...

Uneven-aged silviculture of longleaf pine

Treesearch

James M. Guldin

2006-01-01

The use of uneven-aged silviculture has increased markedly in the past 20 years. This is especially true in the southern United States, where the use of clearcutting and planting is often viewed as a practice whose emphasis on fiber production results in unacceptable consequences for other values, such as those that benefit from maintenance of continuous forest cover...

Nanoparticle albumin-bound paclitaxel (nab-paclitaxel) as second-line chemotherapy in HER2-negative, taxane-pretreated metastatic breast cancer patients: prospective evaluation of activity, safety, and quality of life.

PubMed

Palumbo, Raffaella; Sottotetti, Federico; Trifirò, Giuseppe; Piazza, Elena; Ferzi, Antonella; Gambaro, Anna; Spinapolice, Elena Giulia; Pozzi, Emma; Tagliaferri, Barbara; Teragni, Cristina; Bernardo, Antonio

2015-01-01

A prospective, multicenter trial was undertaken to assess the activity, safety, and quality of life of nanoparticle albumin-bound paclitaxel (nab-paclitaxel) as second-line chemotherapy in HER2-negative, taxane-pretreated metastatic breast cancer (MBC). Fifty-two women with HER2-negative MBC who were candidates for second-line chemotherapy for the metastatic disease were enrolled and treated at three centers in Northern Italy. All patients had previously received taxane-based chemotherapy in the adjuvant or first-line metastatic setting. Single-agent nab-paclitaxel was given at the dose of 260 mg/m(2) as a 30-minute intravenous infusion on day 1 each treatment cycle, which lasted 3 weeks, in the outpatient setting. No steroid or antihistamine premedication was provided. Treatment was stopped for documented disease progression, unacceptable toxicity, or patient refusal. All of the enrolled patients were evaluable for the study endpoints. The objective response rate was 48% (95% CI, 31.5%-61.3%) and included complete responses from 13.5%. Disease stabilization was obtained in 19 patients and lasted >6 months in 15 of them; the overall clinical benefit rate was 77%. The median time to response was 70 days (range 52-86 days). The median progression-free survival time was 8.9 months (95% CI, 8.0-11.6 months, range 5-21+ months). The median overall survival point has not yet been reached. Toxicities were expected and manageable with good patient compliance and preserved quality of life in patients given long-term treatment. Our results showed that single-agent nab-paclitaxel 260 mg/m(2) every 3 weeks is an effective and well tolerated regimen as second-line chemotherapy in HER2-negative, taxane-pretreated MBC patients, and that it produced interesting values of objective response rate and progression-free survival without the concern of significant toxicity. Specifically, the present study shows that such a regimen is a valid therapeutic option for that 'difficult to treat' patient population represented by women who at the time of disease relapse have already received the most active agents in the adjuvant and/or metastatic setting (ie, conventional taxanes).

Thought-action fusion and anxiety disorders symptoms in normal adolescents.

PubMed

Muris, P; Meesters, C; Rassin, E; Merckelbach, H; Campbell, J

2001-07-01

The present study examined thought-action fusion (TAF) in a large sample of normal adolescents (n=427). Participants completed the Thought-Action Fusion Questionnaire for Adolescents (TAFQ-A) and scales measuring trait anxiety, symptoms of obsessive-compulsive disorder, other anxiety disorders, and depression. Results showed that the TAFQ-A is a reliable instrument assessing two dimensions of TAF, viz. Morality (i.e., the belief that unacceptable thoughts are morally equivalent to overt actions) and Likelihood (i.e., the belief that thinking of an unacceptable or disturbing situation will increase the probability that that situation actually occurs). Furthermore, TAF was not only associated with symptoms of OCD, but also with symptoms of other anxiety disorders and depression. However, when controlling for levels of trait anxiety, most connections between TAF and anxiety disorders symptoms disappeared. Symptoms of OCD and generalised anxiety remained significantly related to TAF. Altogether, the data are supportive of the notion that TAF is involved in a broad range of anxiety disorders and in particular OCD.

'Isn't it ironic?' Beliefs about the unacceptability of emotions and emotional suppression relate to worse outcomes in fibromyalgia.

PubMed

Bowers, Hannah; Wroe, Abigail L; Pincus, Tamar

2017-05-01

Beliefs about the unacceptability of experiencing and expressing emotions have been found to be related to worse outcomes in people with persistent physical symptoms. The current study tested mediation models regarding emotional suppression, beliefs about emotions, support-seeking and global impact in fibromyalgia. One hundred eighty-two participants took part in an online questionnaire testing potential mechanisms of this relationship using mediation analysis. The model tested emotional suppression and affective distress as serial mediators of the relationship between beliefs about emotions and global impact. In parallel paths, two forms of support-seeking were tested (personal/emotional and symptom-related support-seeking) as mediators. Emotional suppression and affective distress significantly serially mediated the relationship between beliefs about emotions and global impact. Neither support-seeking variable significantly mediated this relationship. Results indicate a potential mechanism through which beliefs about emotions and global impact might relate which might provide a theoretical basis for future research on treatments for fibromyalgia.

Behavior guidance techniques in Pediatric Dentistry: attitudes of parents of children with disabilities and without disabilities.

PubMed

de Castro, Alessandra Maia; de Oliveira, Fabiana Sodré; de Paiva Novaes, Myrian Stella; Araújo Ferreira, Danielly Cunha

2013-01-01

This study compared the parental acceptance of pediatric behavior guidance techniques (BGT). Forty parents of children without disabilities (Group A) and another 40 parents of children with disabilities (Group B) were selected. Each BGT was explained by a single examiner and it was presented together with a photograph album. After that parents evaluated the acceptance in: totally unacceptable, somewhat acceptable, acceptable, and totally acceptable. Results indicated that in Group A, the BGT based on communicative guidance was accepted by most participants. In Group B, just one mother considered totally unacceptable the voice control method and other two, tell-show-do. For both groups, the general anesthesia was the less accepted BGT. There was statistically significant difference in acceptance for protective stabilization with a restrictive device in Group B. Children's parents with and without disabilities accepted behavioral guidance techniques, but basic techniques showed higher rates of acceptance than advanced techniques. ©2013 Special Care Dentistry Association and Wiley Periodicals, Inc.

Raising quality of maintenance and control of metallic structures in large-load technological machines

NASA Astrophysics Data System (ADS)

Drygin, M. Yu; Kuryshkin, N. P.

2018-01-01

Active growth of coal extraction and underinvestment of coal mining in Russia lead to the fact that technical state of more than 86% of technological machines at opencast coal mines is unacceptable. One of the most significant problems is unacceptable state of supporting metallic structures of excavators and mine dump trucks. The analysis has shown that defects in these metallic structures had been accumulated for a long time. Their removal by the existing method of repair welding was not effective - the flaws reappeared in 2-6 months of technological machines’ service. The authors detected the prime causes that did not allow to make a good repair welding joint. A new technology of repair welding had been tested and endorsed, and this allowed to reduce the number of welded joints’ flaws by 85% without additional raising welders’ qualification. As a result the number of flaws in metallic structures of the equipment had been reduced by 35 % as early as in the first year of using the new technology.

An Alternative Derivation of the Energy Levels of the "Particle on a Ring" System

NASA Astrophysics Data System (ADS)

Vincent, Alan

1996-10-01

All acceptable wave functions must be continuous mathematical functions. This criterion limits the acceptable functions for a particle in a linear 1-dimensional box to sine functions. If, however, the linear box is bent round into a ring, acceptable wave functions are those which are continuous at the 'join'. On this model some acceptable linear functions become unacceptable for the ring and some unacceptable cosine functions become acceptable. This approach can be used to produce a straightforward derivation of the energy levels and wave functions of the particle on a ring. These simple wave mechanical systems can be used as models of linear and cyclic delocalised systems such as conjugated hydrocarbons or the benzene ring. The promotion energy of an electron can then be used to calculate the wavelength of absorption of uv light. The simple model gives results of the correct order of magnitude and shows that, as the chain length increases, the uv maximum moves to longer wavelengths, as found experimentally.

Injury risk associated with ground hardness in junior cricket.

PubMed

Twomey, Dara M; White, Peta E; Finch, Caroline F

2012-03-01

To establish if there is an association between ground hardness and injury risk in junior cricket. Nested case-series of players who played matches on specific grounds with objective ground hardness measures, within a prospective cohort study of junior community club cricket players. Monitoring of injuries and playing exposure occurred during 434 matches over the 2007/2008 playing season. Objective assessment of the hardness of 38 grounds was undertaken using a Clegg hammer at 13 sites on 19 different junior cricket grounds on the match eve across the season. Hardness readings were classified from unacceptably low (<30 g) to unacceptably high (>120 g) and two independent raters assessed the likelihood of each injury being related to ground hardness. Injuries sustained on tested grounds were related to the ground hardness measures. Overall, 31 match injuries were reported; 6.5% were rated as likely to be related to ground hardness, 16.1% as possibly related and 74.2% as unlikely to be related and 3.2% unknown. The two injuries likely to be related to ground hardness were sustained whilst diving to catch a ball resulting, in a graze/laceration from contact with hard ground. Overall, 31/38 (82%) ground assessments were rated as having 'unacceptably high' hardness and all others as 'high/normal' hardness. Only one injury occurred on an objectively tested ground. It remains unclear if ground hardness is a contributing factor to the most common injury mechanism of being struck by the ball, and needs to be confirmed in future larger-scale studies. Copyright © 2011 Sports Medicine Australia. Published by Elsevier Ltd. All rights reserved.

Bias due to Preanalytical Dilution of Rodent Serum for Biochemical Analysis on the Siemens Dimension Xpand Plus

PubMed Central

Johns, Jennifer L.; Moorhead, Kaitlin A.; Hu, Jing; Moorhead, Roberta C.

2018-01-01

Clinical pathology testing of rodents is often challenging due to insufficient sample volume. One solution in clinical veterinary and exploratory research environments is dilution of samples prior to analysis. However, published information on the impact of preanalytical sample dilution on rodent biochemical data is incomplete. The objective of this study was to evaluate the effects of preanalytical sample dilution on biochemical analysis of mouse and rat serum samples utilizing the Siemens Dimension Xpand Plus. Rats were obtained from end of study research projects. Mice were obtained from sentinel testing programs. For both, whole blood was collected via terminal cardiocentesis into empty tubes and serum was harvested. Biochemical parameters were measured on fresh and thawed frozen samples run straight and at dilution factors 2–10. Dilutions were performed manually, utilizing either ultrapure water or enzyme diluent per manufacturer recommendations. All diluted samples were generated directly from the undiluted sample. Preanalytical dilution caused clinically unacceptable bias in most analytes at dilution factors four and above. Dilution-induced bias in total calcium, creatinine, total bilirubin, and uric acid was considered unacceptable with any degree of dilution, based on the more conservative of two definitions of acceptability. Dilution often caused electrolyte values to fall below assay range precluding evaluation of bias. Dilution-induced bias occurred in most biochemical parameters to varying degrees and may render dilution unacceptable in the exploratory research and clinical veterinary environments. Additionally, differences between results obtained at different dilution factors may confound statistical comparisons in research settings. Comparison of data obtained at a single dilution factor is highly recommended. PMID:29497614

T Cell Activation in South African HIV-Exposed Infants Correlates with Ochratoxin A Exposure

PubMed Central

Wood, Lianna Frances; Wood, Matthew P.; Fisher, Bridget S.; Jaspan, Heather B.; Sodora, Donald L.

2017-01-01

The introduction of non-breastmilk foods to HIV-infected infants is associated with increased levels of immune activation, which can impact the rate of HIV disease progression. This is particularly relevant in countries where mother-to-child transmission of HIV still occurs at unacceptable levels. The goal of this study was to evaluate the levels of the toxic food contaminant ochratoxin A (OTA) in HIV-exposed South African infants that are either breastfed or consuming non-breast milk foods. OTA is a common mycotoxin, found in grains and soil, which is toxic at high doses but has immunomodulatory properties at lower doses. Samples from HIV-exposed and HIV-unexposed infants enrolled in prospective observational cohort studies were collected and analyzed at birth through 14 weeks of age. We observed that infants consuming non-breast milk foods had significantly higher plasma levels of OTA at 6 weeks of age compared to breastfed infants, increasing until 8 weeks of age. The blood levels of OTA detected were comparable to levels observed in OTA-endemic communities. OTA plasma levels correlated with HIV target cell activation (CCR5 and HLADR expression on CD4+ T cells) and plasma levels of the inflammatory cytokine CXCL10. These findings provide evidence that elevated OTA levels in South African infants are associated with the consumption of non-breastmilk foods and activation of the immune system. Reducing infant OTA exposure has the potential to reduce immune activation and provide health benefits, particularly in those infants who are HIV-exposed or HIV-infected. PMID:29312338

Weekly docetaxel is safe and effective in the treatment of advanced-stage acquired immunodeficiency syndrome-related Kaposi sarcoma.

PubMed

Lim, Soon Thye; Tupule, Anil; Espina, Byron M; Levine, Alexandra M

2005-01-15

Intravenous paclitaxel, 100 mg/m(2), given over 3 hours every 2 weeks is associated with a response rate of 59% in patients with recurrent or refractory acquired immunodeficiency syndrome (AIDS)-related Kaposi sarcoma (KS). However, this regimen is associated with significant myelosuppression, and the inconvenience of a 3-hour infusion. Moreover, no effective therapies have been defined for use after treatment failure with this agent. A Phase II trial was conducted with weekly docetaxel in patients with advanced-stage KS to assess safety and antitumor activity. Docetaxel was administered at a dose of 25 mg/m(2) intravenously over 15-30 minutes weekly for 8 weeks. Thereafter, if the patient experienced stable disease or better response, treatment doses were given every other week until complete disease remission, disease progression, or unacceptable toxicity occurred. Twelve patients were accrued-9 had > 25 mucocutaneous lesions, 1 had lymphedema, and 2 had visceral involvement. Ten patients (83%) had previous systemic chemotherapy, including 4 who received previous paclitaxel. Treatment was well tolerated, with no Grade 4 toxicity of any type. Grade 3 neutropenia occurred in 33% of patients but no patient had neutropenic fever. Five patients (42%) achieved a partial response, including 1 who had previously failed to respond to paclitaxel. The median time to disease progression was 26 months (range, 5-53 months). With a median follow-up period of 45 months, the median survival point had not been reached. Weekly docetaxel is safe, with reasonable antitumor activity in patients with advanced-stage, recurrent, or refractory AIDS-related KS. (c) 2004 American Cancer Society.

Phase I dose-finding study of sorafenib with FOLFOX4 as first-line treatment in patients with unresectable locally advanced or metastatic gastric cancer.

PubMed

Chi, Yihebali; Yang, Jianliang; Yang, Sheng; Sun, Yongkun; Jia, Bo; Shi, Yuankai

2015-06-01

To determine the maximum tolerated dose (MTD), dose-limiting toxicity (DLT) and efficacy of sorafenib in combination with FOLFOX4 (oxaliplatin/leucovorin (LV)/5-fluorouracil) as first-line treatment for advanced gastric cancer, we performed a phase I dose-finding study in nine evaluable patients with unresectable locally advanced or metastatic gastric cancer or gastroesophageal junction adenocarcinoma. According to modified Fibonacci method, the design of this study was to guide elevation of the sorafenib dosage to the next level (from 200 mg twice daily to 400 mg twice daily and then, if tolerated, 600 mg twice daily). If the patient achieved complete response (CR), partial response (PR) or stable disease (SD) after eight cycles of treatment, combination chemotherapy was scheduled to be discontinued and sorafenib monotherapy continued at the original dose until either disease progression or unacceptable toxicity. In sorafenib 200 mg twice daily group, DLT was observed in 1 of 6 patients, and in 400 mg twice daily group, it was observed in 2 of 3 patients. Seven of 9 (77.8%) evaluable patients achieved PR, with a median overall survival (OS) of 11.8 [95% confidence interval (CI): 8.9-14.7] months. Common adverse effects include hand-foot syndrome, leukopenia, neutropenia, anorexia, and nausea. Twice-daily dosing of sorafenib 200 mg in combination with FOLFOX4 was proven effective and safe for the treatment of advanced gastric cancer, and could be an appropriate dosage for subsequent phase II clinical studies.

Characterizing the Benefits of Seismic Isolation for Nuclear Structures: A Framework for Risk-Based Decision Making

DOE Office of Scientific and Technical Information (OSTI.GOV)

Bolisetti, Chandrakanth; Yu, Chingching; Coleman, Justin

This report provides a framework for assessing the benefits of seismic isolation and exercises the framework on a Generic Department of Energy Nuclear Facility (GDNF). These benefits are (1) reduction in the risk of unacceptable seismic performance and a dramatic reduction in the probability of unacceptable performance at beyond-design basis shaking, and (2) a reduction in capital cost at sites with moderate to high seismic hazard. The framework includes probabilistic risk assessment and estimates of overnight capital cost for the GDNF.

Lakes and ponds recreation management: a state-wide application of the visitor impact management process

Treesearch

Jerry J. Vaske; Rodney R. Zwick; Maureen P. Donnelly

1992-01-01

The Visitor Impact Management (VIM) process is designed to identify unacceptable changes occurring as a result of visitor use and to develop management strategies to keep visitor impacts within acceptable levels. All previous attempts to apply the VIM planning framework have concentrated on specific resources. This paper expands this focus to an entire state. Based on...

Ground-based and in-flight simulator studies of low-speed handling characteristics of two supersonic cruise transport concepts

NASA Technical Reports Server (NTRS)

Grantham, W. D.; Nguyen, L. T.; Deal, P. L.; Neubauer, M. J.; Smith, P. M.; Gregory, F. D.

1978-01-01

Conventional and powered lift concepts for supersonic approach and landing tasks are considered. Results indicated that the transport concepts had unacceptable low-speed handling qualities with no augmentation, and that in order to achieve satisfactory handling qualities, considerable augmentation was required. The available roll-control power was acceptable for the powered-lift concept.

When Will Our Values Finally Result in the Creation of New Pathways for Change--Change that We Can Believe In?

ERIC Educational Resources Information Center

Rusch, Frank R.; Wolfe, Pamela

2008-01-01

Despite efforts over the past several decades to improve the delivery of transition services for youth with disabilities, outcomes continue to be unacceptably dismal for most youth, including high rates of unemployment, residential independence, and financial dependence, concurrent with low rates of enrollment in college or other postsecondary…

40 CFR Appendix B to Subpart G of... - Substitutes Subject to Use Restrictions and Unacceptable Substitutes

Code of Federal Regulations, 2011 CFR

2011-07-01

... unique fittings —must be used with detailed labels —all CFC-12 must be removed from the system prior to... potential failure of both air conditioning systems and recovery/recycling equipment. For the purposes of... use a new refrigerant includes all procedures that result in the air conditioning system using a new...

Quality of Care for Acute Myocardial Infarction in Rural and Urban US Hospitals

ERIC Educational Resources Information Center

Baldwin, Laura-Mae; MacLehose, Richard F.; Hart, L. Gary; Beaver, Shelli K.; Every,Nathan; Chan,Leighton

2004-01-01

Context: Acute myocardial infarction (AMI) is a common and important cause of admission to US rural hospitals, as transport of patients with AMI to urban settings can result in unacceptable delays in care. Purpose: To examine the quality of care for patients with AMI in rural hospitals with differing degrees of remoteness from urban centers.…

Traditional and MLC based dose compensator design for patients with hip prostheses undergoing pelvic radiation therapy.

PubMed

Alecu, R; Alecu, M; Loomis, T; Ochran, T; He, T

1999-01-01

Perturbations in the dose distribution caused by a hip prosthesis when treating pelvic malignancies can result in unacceptable dose inhomogeneities within the target volume. Our results, obtained by in vivo exit dose measurements with diodes, showed a 55% reduction in the dose at the exit dmax of a lateral 15 MV photon beam after passing through a bilateral cobalt-chrome alloy hip prosthesis. Such an inhomogeneous dose distribution may decrease the curability. Solutions such as treatment techniques to avoid the prosthesis are often not the best choice as the dose to the rectum may be unacceptably high. In this work an alternative method of dose compensator is presented. Two types of dose compensators were designed based on a 3-D treatment planning system and CT images of a pelvic phantom containing a hip prosthesis: one was fabricated from a polyethylene-lead slab in the representation of step fringes and placed on a tray in the path of the beam while the other was produced by the use of several fields shaped with a multileaf collimator. The calculation procedures developed by the authors for generating the compensators are described. Results of film measurements performed in a phantom with and without the compensators in place are discussed.

General human health issues for Moon and Mars missions: Results from the HUMEX study

NASA Astrophysics Data System (ADS)

Horneck, Gerda; Comet, Bernard

The general health issues considered in two scenarios of human long-term exploratory missions, which include a mission to a lunar base and a mission to Mars, have been analysed. Based on statistical data from occupational and normal population groups of Western countries, the following safety objectives have been chosen: individual risk of death by illness (=natural death) during the mission shall be <2 × 10-3/year, that by injury (=accidental death) <4 × 10-4/year, and that from all causes, including spacecraft failure (taken from most exposed professions) <3 × 10-2/year. Using the classical reliability requirements for human space missions, reliability objectives have been set for each mission scenario, resulting in values compatible with the mission safety objectives. The main results are as follows: (i) based of the probability of occurrence of diseases and injuries and on the constraints imposed by exploratory mission scenarios, the crew shall have a full autonomy in terms of medical and surgical diagnostics and care means and competency; (ii) the control of the toxic and biological risks in a confined environment for a so long exposure shall be carefully analyzed and the technical solutions shall master these risks; (iii) the state of the art shows that bone loss during the long stay in weightlessness, especially during missions to Mars, remains an unacceptable risk. Solutions to control and to prevent this risk shall be developed; (iv) the control of human physical capacity impairment under weightlessness shall be optimised. A roadmap in the field of health care has been elaborated for a future European participation strategy towards human exploratory missions taking into account preparatory activities, such as analogue situations and ISS opportunities, and potential terrestrial applications and benefits.

Assessing the inhalation cancer risk of particulate matter bound polycyclic aromatic hydrocarbons (PAHs) for the elderly in a retirement community of a mega city in North China.

PubMed

Han, Bin; Liu, Yating; You, Yan; Xu, Jia; Zhou, Jian; Zhang, Jiefeng; Niu, Can; Zhang, Nan; He, Fei; Ding, Xiao; Bai, Zhipeng

2016-10-01

Assessment of the health risks resulting from exposure to ambient polycyclic aromatic hydrocarbons (PAHs) is limited by the lack of environmental exposure data among different subpopulations. To assess the exposure cancer risk of particulate carcinogenic polycyclic aromatic hydrocarbon pollution for the elderly, this study conducted a personal exposure measurement campaign for particulate PAHs in a community of Tianjin, a city in northern China. Personal exposure samples were collected from the elderly in non-heating (August-September, 2009) and heating periods (November-December, 2009), and 12 PAHs individuals were analyzed for risk estimation. Questionnaire and time-activity log were also recorded for each person. The probabilistic risk assessment model was integrated with Toxic Equivalent Factors (TEFs). Considering that the estimation of the applied dose for a given air pollutant is dependent on the inhalation rate, the inhalation rate from both EPA exposure factor book was applied to calculate the carcinogenic risk in this study. Monte Carlo simulation was used as a probabilistic risk assessment model, and risk simulation results indicated that the inhalation-ILCR values for both male and female subjects followed a lognormal distribution with a mean of 4.81 × 10 -6 and 4.57 × 10 -6 , respectively. Furthermore, the 95 % probability lung cancer risks were greater than the USEPA acceptable level of 10 -6 for both men and women through the inhalation route, revealing that exposure to PAHs posed an unacceptable potential cancer risk for the elderly in this study. As a result, some measures should be taken to reduce PAHs pollution and the exposure level to decrease the cancer risk for the general population, especially for the elderly.

Audit and internal quality control in immunohistochemistry

PubMed Central

Maxwell, P; McCluggage, W

2000-01-01

Aims—Although positive and negative controls are performed and checked in surgical pathology cases undergoing immunohistochemistry, internal quality control procedures for immunohistochemistry are not well described. This study, comprising a retrospective audit, aims to describe a method of internal quality control for immunohistochemistry. A scoring system that allows comparison between cases is described. Methods—Two positive tissue controls for each month over a three year period (1996–1998) of the 10 antibodies used most frequently were evaluated. All test cases undergoing immunohistochemistry in the months of April in this three year period were also studied. When the test case was completely negative for a given antibody, the corresponding positive tissue control from that day was examined. A marking system was devised whereby each immunohistochemical slide was assessed out of a possible score of 8 to take account of staining intensity, uniformity, specificity, background, and counterstaining. Using this scoring system, cases were classified as showing optimal (7–8), borderline (5–6), or unacceptable (0–4) staining. Results—Most positive tissue controls showed either optimal or borderline staining with the exception of neurone specific enolase (NSE), where most slides were unacceptable or borderline as a result of a combination of low intensity, poor specificity, and excessive background staining. All test cases showed either optimal or borderline staining with the exception of a single case stained for NSE, which was unacceptable. Conclusions—This retrospective audit shows that immunohistochemically stained slides can be assessed using this scoring system. With most antibodies, acceptable staining was achieved in most cases. However, there were problems with staining for NSE, which needs to be reviewed. Laboratories should use a system such as this to evaluate which antibodies regularly result in poor staining so that they can be excluded from panels. Routine evaluation of immunohistochemical staining should become part of everyday internal quality control procedures. Key Words: immunohistochemistry • audit • internal quality control PMID:11265178

Defining acceptable levels for ecological indicators: an approach for considering social values.

PubMed

Smyth, Robyn L; Watzin, Mary C; Manning, Robert E

2007-03-01

Ecological indicators can facilitate an adaptive management approach, but only if acceptable levels for those indicators have been defined so that the data collected can be interpreted. Because acceptable levels are an expression of the desired state of the ecosystem, the process of establishing acceptable levels should incorporate not just ecological understanding but also societal values. The goal of this research was to explore an approach for defining acceptable levels of ecological indicators that explicitly considers social perspectives and values. We used a set of eight indicators that were related to issues of concern in the Lake Champlain Basin. Our approach was based on normative theory. Using a stakeholder survey, we measured respondent normative evaluations of varying levels of our indicators. Aggregated social norm curves were used to determine the level at which indicator values shifted from acceptable to unacceptable conditions. For seven of the eight indicators, clear preferences were interpretable from these norm curves. For example, closures of public beaches because of bacterial contamination and days of intense algae bloom went from acceptable to unacceptable at 7-10 days in a summer season. Survey respondents also indicated that the number of fish caught from Lake Champlain that could be safely consumed each month was unacceptably low and the number of streams draining into the lake that were impaired by storm water was unacceptably high. If indicators that translate ecological conditions into social consequences are carefully selected, we believe the normative approach has considerable merit for defining acceptable levels of valued ecological system components.

Defining Acceptable Levels for Ecological Indicators: An Approach for Considering Social Values

NASA Astrophysics Data System (ADS)

Smyth, Robyn L.; Watzin, Mary C.; Manning, Robert E.

2007-03-01

Ecological indicators can facilitate an adaptive management approach, but only if acceptable levels for those indicators have been defined so that the data collected can be interpreted. Because acceptable levels are an expression of the desired state of the ecosystem, the process of establishing acceptable levels should incorporate not just ecological understanding but also societal values. The goal of this research was to explore an approach for defining acceptable levels of ecological indicators that explicitly considers social perspectives and values. We used a set of eight indicators that were related to issues of concern in the Lake Champlain Basin. Our approach was based on normative theory. Using a stakeholder survey, we measured respondent normative evaluations of varying levels of our indicators. Aggregated social norm curves were used to determine the level at which indicator values shifted from acceptable to unacceptable conditions. For seven of the eight indicators, clear preferences were interpretable from these norm curves. For example, closures of public beaches because of bacterial contamination and days of intense algae bloom went from acceptable to unacceptable at 7-10 days in a summer season. Survey respondents also indicated that the number of fish caught from Lake Champlain that could be safely consumed each month was unacceptably low and the number of streams draining into the lake that were impaired by storm water was unacceptably high. If indicators that translate ecological conditions into social consequences are carefully selected, we believe the normative approach has considerable merit for defining acceptable levels of valued ecological system components.

A Framework to Evaluate Wildlife Feeding in Research, Wildlife Management, Tourism and Recreation.

PubMed

Dubois, Sara; Fraser, David

2013-10-11

Feeding of wildlife occurs in the context of research, wildlife management, tourism and in opportunistic ways. A review of examples shows that although feeding is often motivated by good intentions, it can lead to problems of public safety and conservation and be detrimental to the welfare of the animals. Examples from British Columbia illustrate the problems (nuisance animal activity, public safety risk) and consequences (culling, translocation) that often arise from uncontrolled feeding. Three features of wildlife feeding can be distinguished: the feasibility of control, the effects on conservation and the effects on animal welfare. An evaluative framework incorporating these three features was applied to examples of feeding from the literature. The cases of feeding for research and management purposes were generally found to be acceptable, while cases of feeding for tourism or opportunistic feeding were generally unacceptable. The framework should allow managers and policy-makers to distinguish acceptable from unacceptable forms of wildlife feeding as a basis for policy, public education and enforcement. Many harmful forms of wildlife feeding seem unlikely to change until they come to be seen as socially unacceptable.

Universal Health Coverage - The Critical Importance of Global Solidarity and Good Governance Comment on "Ethical Perspective: Five Unacceptable Trade-offs on the Path to Universal Health Coverage".

PubMed

Reis, Andreas A

2016-06-07

This article provides a commentary to Ole Norheim' s editorial entitled "Ethical perspective: Five unacceptable trade-offs on the path to universal health coverage." It reinforces its message that an inclusive, participatory process is essential for ethical decision-making and underlines the crucial importance of good governance in setting fair priorities in healthcare. Solidarity on both national and international levels is needed to make progress towards the goal of universal health coverage (UHC). © 2016 by Kerman University of Medical Sciences.

Deviant Behavior in Higher Educational Institutions of the Central Federal District and the Northwestern Federal District: Causes, Scale, Varieties, and Prospects of Control and Prevention

ERIC Educational Resources Information Center

Talanov, S. L.

2014-01-01

Corruption and other forms of unacceptable behavior in Russian universities frequently is the result of poor conditions of work, low salaries, and inadequate administrative and oversight structures. A thorough reform and reorganization of institutions of higher education should go a long way to reducing the incidence of this behavior. [This…

One State's Systems Change Efforts to Reduce Child Care Expulsion: Taking the Pyramid Model to Scale

ERIC Educational Resources Information Center

Vinh, Megan; Strain, Phil; Davidon, Sarah; Smith, Barbara J.

2016-01-01

This article describes the efforts funded by the state of Colorado to address unacceptably high rates of expulsion from child care. Based on the results of a 2006 survey, the state of Colorado launched two complementary policy initiatives in 2009 to impact expulsion rates and to improve the use of evidence-based practices related to challenging…

Bowel injury associated with pelvic radiotherapy

NASA Astrophysics Data System (ADS)

François, Agnès; Milliat, Fabien; Vozenin-Brotons, Marie-Catherine

2005-02-01

Radiation therapists have to deal with the difficulty to give an efficient radiation dose to the tumor without generating unacceptable normal tissue injury. Acute reactions are experienced in most of the patients and are characterized by diarrhea resulting from intestinal mucosal injury. In some cases, intestinal wall fibrosis may develop, with hazard of occlusion syndrome. The only therapeutic recourse consists of surgical resection of the injured bowel.

The microbiological safety of ready-to-eat specialty meats from markets and specialty food shops: a UK wide study with a focus on Salmonella and Listeria monocytogenes.

PubMed

Gormley, F J; Little, C L; Grant, K A; de Pinna, E; McLauchlin, J

2010-04-01

From 2359 specialty meats (continental sausages, cured/fermented, dried meats) sampled from markets and specialty food shops, 98.9% of samples were of satisfactory or acceptable microbiological quality. However, 16 (0.7%) were unsatisfactory as a result of Escherichia coli, Staphylococcus aureus or Listeria spp. contamination (>or=10(2) CFU/g), and nine (0.4%) were unacceptable due to presence of Salmonella spp. or Listeria monocytogenes (>10(2) CFU/g). Meats with unacceptable levels of L. monocytogenes were within shelf life (range: 8-143 days remaining). Nine different subtypes of L. monocytogenes were detected with sero/AFLP type 1/2c VII predominating (37%), although this subtype was not overrepresented in any particular meat type (P > 0.05). Ninety-six percent of continental sausages and cured/fermented products were stored at <8 degrees C at premises, including seven of the nine unacceptable samples. These nine meats were all pre-packed prior to supply to retail premises (OR = 0.1 P = 0.003) indicating that contamination with bacterial pathogens occurred earlier in the production chain. Most samples (72.7%, 8/11) with unsatisfactory levels of E. coli were sliced on request, suggesting cross-contamination at point of sale. This study highlights the importance of ensuring that products do not become contaminated before final packaging, that storage conditions are controlled, and that durability dates are an accurate indication of the shelf life of the product so as to minimise the potential for L. monocytogenes to be present at levels hazardous to health at the point of sale.

A Comparison of Spectacles Purchased Online and in UK Optometry Practice

PubMed Central

Alderson, Alison J.; Green, Alison; Whitaker, David; Scally, Andrew J.; Elliott, David B.

2016-01-01

ABSTRACT Purpose To compare spectacles bought online with spectacles from optometry practices. Methods Thirty-three participants consisting of single vision spectacle wearers with either a low (N = 12, mean age 34 ± 14 years) or high prescription (N = 11, mean age 28 ± 9 years) and 10 presbyopic participants (mean age 59 ± 4 years) wearing progressive addition lenses (PALs) purchased 154 pairs of spectacles online and 154 from UK optometry practices. The spectacles were compared via participant-reported preference, acceptability, and safety; the assessment of lens, frame, and fit quality; and the accuracy of the lens prescriptions to international standard ISO 21987:2009. Results Participants preferred the practice spectacles (median ranking 4th, IQR 1–6) more than online (6th, IQR 4–8; Mann-Whitney U = 7345, p < 0.001) and practice PALs (median ranking 2nd, IQR 1–4) were particularly preferred (online 6.5th, IQR 4–9, Mann-Whitney U = 455, p < 0.001). Of those deemed unacceptable and unsafe, significantly more were bought online (unacceptable: online 43/154 vs. practice 15/154, Fisher’s exact p = 0.0001; unsafe: online 14/154 vs. practice 5/154, Fisher’s exact p = 0.03). Conclusions Participants preferred spectacles from optometry practice rather than those bought online, despite lens quality and prescription accuracy being similar. A greater number of online spectacles were deemed unsafe or unacceptable because of poor spectacle frame fit, poor cosmetic appearance, and inaccurate optical centration. This seems particularly pertinent to PAL lenses, which are known to increase falls risk. Recommendations are made to improve both forms of spectacle provision. PMID:27536974

Effect of smoking regulations in local restaurants on smokers' anti‐smoking attitudes and quitting behaviours

PubMed Central

Albers, Alison B; Siegel, Michael; Cheng, Debbie M; Biener, Lois; Rigotti, Nancy A

2007-01-01

Objective To examine the effect of smoking regulations in local restaurants on anti‐smoking attitudes and quitting behaviours among adult smokers. Design Hierarchical linear modelling (HLM) was used to assess the relationship between baseline strength of town‐level restaurant smoking regulation and follow‐up (1) perceptions of the social acceptability of smoking and (2) quitting behaviours. Setting Each of the 351 Massachusetts towns was classified as having strong (complete smoking ban) or weak (all other and no smoking restrictions) restaurant smoking regulations. Subjects 1712 adult smokers of Massachusetts aged ⩾18 years at baseline who were interviewed via random‐digit‐dial telephone survey in 2001–2 and followed up 2 years later. Main outcome measures Perceived social acceptability of smoking in restaurants and bars, and making a quit attempt and quitting smoking. Results Among adult smokers who had made a quit attempt at baseline, living in a town with a strong regulation was associated with a threefold increase in the odds of making a quit attempt at follow‐up (OR = 3.12; 95% CI 1.51 to 6.44). Regulation was found to have no effect on cessation at follow‐up. A notable, although marginal, effect of regulation was observed for perceiving smoking in bars as socially unacceptable only among smokers who reported at baseline that smoking in bars was socially unacceptable. Conclusions Although local restaurant smoking regulations did not increase smoking cessation rates, they did increase the likelihood of making a quit attempt among smokers who had previously tried to quit, and seem to reinforce anti‐social smoking norms among smokers who already viewed smoking in bars as socially unacceptable. PMID:17400947

Effects of the lampricide 3-trifluoromethyl-4-nitrophenol (TFM) on pH, net oxygen production, and respiration by algae

USGS Publications Warehouse

Scholefield, Ronald J.; Fredricks, Kim T.; Slaght, Karen S.; Seelye, James G.

1999-01-01

The lampricide 3-trifluoromethyl-4-nitrophenol (TFM) has been used in the United States and Canada for more than 35 years to control larval sea lampreys (Petromyzon marinus) in tributaries of the Great Lakes. Occasionally, during stream treatments with TFM, nontarget-fish mortality reaches unacceptable levels. These losses could be due to the presence of sensitive fish species, excess TFM, or a combination of factors that influence the toxicity of TFM, such as delays in daily stream reaeration by algae resulting in extended periods of low pH and low dissolved oxygen (DO). We determined the effects of a broad range of TFM concentrations on net DO production and respiration by two species of algae, in two culture media (high alkalinity and low alkalinity). The pH and DO in cultures of Chlorella pyrenoidosa and Selenastrum capricornutum were recorded at time zero and again after a 9-h exposure to TFM under either lighted or dark conditions. Algal cultures exposed to TFM concentrations typical of those used to control sea lampreys in streams showed only small changes in pH (<0.1) and small reductions in DO (about 8% in lighted conditions and 11% in dark conditions). Changes in pH and DO of this magnitude probably do not change the efficacy of TFM or cause nontarget fish mortality if algae are the predominant photosynthetic organisms in the stream.

Tobacco control environment: cross-sectional survey of policy implementation, social unacceptability, knowledge of tobacco health harms and relationship to quit ratio in 17 low-income, middle-income and high-income countries

PubMed Central

Corsi, Daniel J; Gilmore, Anna B; Kruger, Annamarie; Igumbor, Ehimario; Chifamba, Jephat; Yang, Wang; Wei, Li; Iqbal, Romaina; Mony, Prem; Gupta, Rajeev; Vijayakumar, Krishnapillai; Mohan, V; Kumar, Rajesh; Rahman, Omar; Yusoff, Khalid; Ismail, Noorhassim; Zatonska, Katarzyna; Altuntas, Yuksel; Rosengren, Annika; Bahonar, Ahmad; Yusufali, AfzalHussein; Dagenais, Gilles; Lear, Scott; Diaz, Rafael; Avezum, Alvaro; Lopez-Jaramillo, Patricio; Lanas, Fernando; Rangarajan, Sumathy; Teo, Koon; McKee, Martin; Yusuf, Salim

2017-01-01

Objectives This study examines in a cross-sectional study ‘the tobacco control environment’ including tobacco policy implementation and its association with quit ratio. Setting 545 communities from 17 high-income, upper-middle, low-middle and low-income countries (HIC, UMIC, LMIC, LIC) involved in the Environmental Profile of a Community's Health (EPOCH) study from 2009 to 2014. Participants Community audits and surveys of adults (35–70 years, n=12 953). Primary and secondary outcome measures Summary scores of tobacco policy implementation (cost and availability of cigarettes, tobacco advertising, antismoking signage), social unacceptability and knowledge were associated with quit ratios (former vs ever smokers) using multilevel logistic regression models. Results Average tobacco control policy score was greater in communities from HIC. Overall 56.1% (306/545) of communities had >2 outlets selling cigarettes and in 28.6% (154/539) there was access to cheap cigarettes (<5cents/cigarette) (3.2% (3/93) in HIC, 0% UMIC, 52.6% (90/171) LMIC and 40.4% (61/151) in LIC). Effective bans (no tobacco advertisements) were in 63.0% (341/541) of communities (81.7% HIC, 52.8% UMIC, 65.1% LMIC and 57.6% LIC). In 70.4% (379/538) of communities, >80% of participants disapproved youth smoking (95.7% HIC, 57.6% UMIC, 76.3% LMIC and 58.9% LIC). The average knowledge score was >80% in 48.4% of communities (94.6% HIC, 53.6% UMIC, 31.8% LMIC and 35.1% LIC). Summary scores of policy implementation, social unacceptability and knowledge were positively and significantly associated with quit ratio and the associations varied by gender, for example, communities in the highest quintile of the combined scores had 5.0 times the quit ratio in men (Odds ratio (OR) 5·0, 95% CI 3.4 to 7.4) and 4.1 times the quit ratio in women (OR 4.1, 95% CI 2.4 to 7.1). Conclusions This study suggests that more focus is needed on ensuring the tobacco control policy is actually implemented, particularly in LMICs. The gender-related differences in associations of policy, social unacceptability and knowledge suggest that different strategies to promoting quitting may need to be implemented in men compared to women. PMID:28363924

Description of an Audio-Based Paced Respiration Intervention for Vasomotor Symptoms

PubMed Central

Burns, Debra S.; Drews, Michael R.; Carpenter, Janet S.

2013-01-01

Millions of women experience menopause-related hot flashes or flushes that may have a negative effect on their quality of life. Hormone therapy is an effective treatment, however, it may be contraindicated or unacceptable for some women based on previous health complications or an undesirable risk–benefit ratio. Side effects and the unacceptability of hormone therapy have created a need for behavioral interventions to reduce hot flashes. A variety of complex, multimodal behavioral, relaxation-based interventions have been studied with women (n = 88) and showed generally favorable results. However, currently extensive resource commitments reduce the translation of these interventions into standard care. Slow, deep breathing is a common component in most interventions and may be the active ingredient leading to reduced hot flashes. This article describes the content of an audio-based program designed to teach paced breathing to reduce hot flashes. Intervention content was based on skills training theory and music entrainment. The audio intervention provides an efficient way to deliver a breathing intervention that may be beneficial to other clinical populations. PMID:23914283

[A Systematic Review to Identify Unacceptable Intake Levels of Vitamin B6 among Patients Taking Levodopa].

PubMed

Sato, Yoko; Yasumiishi, Chiaki; Chiba, Tsuyoshi; Umegaki, Keizo

2017-01-01

The interaction of levodopa and vitamin B6 is a well-known issue. This study investigated the incidence of unacceptable intake levels of vitamin B6 among levodopa users by means of a systematic review. We searched two databases (PubMed and "Igaku Chuo Zasshi") for articles about adverse events due to the interaction of levodopa and vitamin B6 published up to August 2017. Of 98 citations retrieved, 11 studies met the selection criteria. The results indicated that a vitamin B6 intake level of more than 50 mg/day could reduce the efficacy of levodopa. The recommended intake of vitamin B6 for Japanese adults is 1.4 mg/day for men and 1.2 mg/day for women. Therefore, the acceptable intake of vitamin B6 for levodopa patients would be within the range of the recommended intake level, which is also within the usual range in foods in Japan, except for dietary supplements or health foods. Levodopa users should be cautious about taking dietary supplements and over-the-counter drugs.

In vivo results of hydrogel composite pericardial substitutes.

PubMed

Blue, M A; Guilbeau, E J; Brandon, T A; Walker, A S; Bjotvedt, G; Fisk, R L

1991-01-01

In this study, two improved pericardial patches were developed and evaluated for their efficacy as pericardial substitutes. The patches are composites consisting of a hydrogel (PHEMA) that coats an underlying mesh (either ETFE or PET). Studies were conducted using subcutaneous implants in rats and pericardial patch implants in greyhound dogs. Adhesions between the substitute and pericardium and the epicardium were minimal. The ETFE composite patch caused an unacceptable epicardial reaction. The PET patch results were encouraging; the epicardium was largely unaffected by the patch.

Positive-pressure ventilation during transport: a randomized crossover study of self-inflating and flow-inflating resuscitators in a simulation model.

PubMed

Lucy, Malcolm J; Gamble, Jonathan J; Daku, Brian L; Bryce, Rhonda D; Rana, Masud

2014-12-01

Positive-pressure ventilation during transport of intubated patients is generally delivered via a hand-pressurized device. Of these devices, self-inflating resuscitators (SIR) and flow-inflating resuscitators (FIR) constitute the two major types used. Selection of a particular device for transport, however, remains largely an institutional practice. To evaluate the hypothesis that transport ventilation goals of intubated pediatric patients are better achieved using an FIR compared to an SIR. This randomized crossover simulation study compared the performance of SIR and FIR among anesthesia providers in a pediatric transport scenario. Subjects hand-ventilated a test lung while simultaneously maneuvering a stretcher bed to simulate patient transport. Hand ventilation was carried out using a Jackson-Rees circuit (FIR) and a Laerdal pediatric silicone resuscitator (SIR). The primary outcome was the proportion of total breaths delivered within the predefined target PIP/PEEP range (30+/- 3, 10+/- 3 cm H2O). Secondary outcomes included proportion of total breaths delivered with operationally defined unacceptable breath variables (PIP > 35 cm H2O or PEEP < 5 cm H2O). Overall, participants were four times more likely to deliver target breaths and one-third less likely to deliver unacceptable breaths using the FIR compared to the SIR. When comparing device performance, a 44% increase in the proportions of target breaths and a 40.4% decrease in unacceptable breaths using the FIR were observed (P < 0.0001 for both). Hand ventilation during patient transport is superior using the FIR compared to the SIR to achieve target ventilatory goals and avoid unacceptable ventilatory cycles. © 2014 John Wiley & Sons Ltd.

The normative dimension and legal meaning of endangered and recovery in the U.S. Endangered Species Act.

PubMed

Vucetich, John A; Nelson, Michael P; Phillips, Michael K

2006-10-01

The ethical, legal, and social significance of the U.S. Endangered Species Act of 1973 (ESA) is widely appreciated. Much of the significance of the act arises from the legal definitions that the act provides for the terms threatened species and endangered species. The meanings of these terms are important because they give legal meaning to the concept of a recovered species. Unfortunately, the meanings of these terms are often misapprehended and rarely subjected to formal analysis. We analyzed the legal meaning of recovered species and illustrate key points with details from "recovery" efforts for the gray wolf (Canis lupus). We focused on interpreting the phrase "significant portion of its range," which is part of the legal definition of endangered species. We argue that recovery and endangerment entail a fundamentally normative dimension (i.e., specifying conditions of endangerment) and a fundamentally scientific dimension (i.e., determining whether a species meets the conditions of endangerment). Specifying conditions for endangerment is largely normative because it judges risks of extinction to be either acceptable or unacceptable. Like many other laws that specify what is unacceptable, the ESA largely specifies the conditions that constitute unacceptable extinction risk. The ESA specifies unacceptable risks of extinction by defining endangered species in terms of the portion of a species' range over which a species is "in danger of extinction." Our analysis indicated that (1) legal recovery entails much more than the scientific notion of population viability, (2) most efforts to recover endangered species are grossly inadequate, and (3) many unlisted species meet the legal definition of an endangered or threatened species.

VAC protocol for treatment of dogs with stage III hemangiosarcoma.

PubMed

Alvarez, Francisco J; Hosoya, Kenji; Lara-Garcia, Ana; Kisseberth, William; Couto, Guillermo

2013-01-01

Hemangiosarcomas (HSAs) are aggressive tumors with a high rate of metastasis. Clinical stage has been considered a negative prognostic factor for survival. The study authors hypothesized that the median survival time (MST) of dogs with metastatic (stage III) HSA treated with a vincristine, doxorubicin, and cyclophosphamide (VAC) chemotherapy protocol would not be different than those with stage I/II HSA. Sixty-seven dogs with HSA in different anatomic locations were evaluated retrospectively. All dogs received the VAC protocol as an adjuvant to surgery (n = 50), neoadjuvant (n = 3), or as the sole treatment modality (n = 14). There was no significant difference (P = 0.97) between the MST of dogs with stage III and stage I/II HSA. For dogs presenting with splenic HSA alone, there was no significant difference between the MST of dogs with stage III and stage I/II disease (P = 0.12). The overall response rate (complete response [CR] and partial response [PR]) was 86%). No unacceptable toxicities were observed. Dogs with stage III HSA treated with the VAC protocol have a similar prognosis to dogs with stage I/II HSA. Dogs with HSA and evidence of metastases at the time of diagnosis should not be denied treatment.

Developments in the Classification and Treatment of the Juvenile Idiopathic Inflammatory Myopathies

PubMed Central

Rider, Lisa G.; Katz, James D.; Jones, Olcay Y.

2013-01-01

The juvenile idiopathic inflammatory myopathies (JIIM) are rare, heterogeneous autoimmune diseases that share chronic muscle inflammation and weakness. JIIM broadly includes three major clinicopathologic groups: juvenile dermatomyositis, juvenile polymyositis, and overlap myositis. A growing spectrum of clinicopathologic groups and serologic phenotypes defined by the presence of myositis-specific or myositis-associated autoantibodies are now recognized, each with differing demographics, clinical manifestations, laboratory findings, and prognoses. With the first multi-center collaborative studies and controlled trials using standardized preliminarily validated outcome measures, the therapy of juvenile myositis has advanced. Although daily oral corticosteroids remain the backbone of treatment, disease-modifying anti-rheumatic drugs (DMARDs) are almost always used as adjunctive therapy. Methotrexate is the conventional DMARD for the initial therapy, either alone or combined with intravenous pulse methylprednisolone, and/or intravenous immunoglobulin for patients with moderate to severe disease. Cyclosporine may be added to these or serve as an alternative to methotrexate. Other drugs and biologic therapies, including mycophenolate mofetil, tacrolimus, cyclophosphamide, rituximab, and infliximab, might benefit selected patients with recalcitrant disease, unacceptable steroid toxicity, or patients with risk factors for poor prognosis. The treatment of cutaneous disease, calcinosis, and the role for rehabilitation are also discussed. PMID:24182859

Current and Emerging Therapies for Lupus Nephritis

PubMed Central

Parikh, Samir V.

2016-01-01

The introduction of corticosteroids and later, cyclophosphamide dramatically improved survival in patients with proliferative lupus nephritis, and combined administration of these agents became the standard-of-care treatment for this disease. However, treatment failures were still common and the rate of progression to ESRD remained unacceptably high. Additionally, treatment was associated with significant morbidity. Therefore, as patient survival improved, the goals for advancing lupus nephritis treatment shifted to identifying therapies that could improve long-term renal outcomes and minimize treatment-related toxicity. Unfortunately, progress has been slow and the current approaches to the management of lupus nephritis continue to rely on high-dose corticosteroids plus a broad-spectrum immunosuppressive agent. Over the past decade, an improved understanding of lupus nephritis pathogenesis fueled several clinical trials of novel drugs, but none have been found to be superior to the combination of a cytotoxic agent and corticosteroids. Despite these trial failures, efforts to translate mechanistic advances into new treatment approaches continue. In this review, we discuss current therapeutic strategies for lupus nephritis, briefly review recent advances in understanding the pathogenesis of this disease, and describe emerging approaches developed on the basis of these advances that promise to improve upon the standard-of-care lupus nephritis treatments. PMID:27283496

Phase III randomized trial comparing 5-fluorouracil and oxaliplatin with or without docetaxel in first-line advanced gastric cancer chemotherapy (GASTFOX study).

PubMed

Zaanan, Aziz; Samalin, Emmanuelle; Aparicio, Thomas; Bouche, Olivier; Laurent-Puig, Pierre; Manfredi, Sylvain; Michel, Pierre; Monterymard, Carole; Moreau, Marie; Rougier, Philippe; Tougeron, David; Taieb, Julien; Louvet, Christophe

2018-04-01

In advanced gastric cancer, doublet regimen including platinum salts and fluoropyrimidine is considered as a standard first-line treatment. The addition of docetaxel (75 mg/m 2  q3w) to cisplatin (75 mg/m 2  q3w) and 5-fluorouracil has been shown to improve efficacy. However, this regimen (DCF) was associated with frequent severe toxicities (including more complicated neutropenia), limiting its use in clinical practice. Interesting alternative docetaxel-based regimens have been developed that need to be validated. GASTFOX study is a randomized phase III trial comparing FOLFOX alone or with docetaxel at 50 mg/m 2 (TFOX regimen) in first-line treatment for advanced gastric cancer. In both arms, cycle is repeated every 2 weeks until disease progression or unacceptable toxicity. Main eligibility criteria: histologically proven locally advanced or metastatic gastric or esogastric junction adenocarcinoma, HER negative status, measurable disease, ECOG performance status 0 or 1, and adequate renal, hepatic and bone marrow functions. The primary endpoint is radiological/clinical progression-free survival (PFS). A difference of 2 months for the median PFS in favor of TFOX is expected (HR = 0.73) Based on a two-sided α risk of 5% and a power of 90%, 454 events are required to show this difference. Secondary endpoints included overall survival, overall response rate, safety, quality of life and the therapeutic index. This study is planned to include 506 patients to demonstrate the superiority of TFOX over FOLFOX in first-line advanced gastric cancer treatment (NCT03006432). Copyright © 2018 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.

Redox-Responsive Magnetic Nanoparticle for Targeted Convection-Enhanced Delivery of O6-Benzylguanine to Brain Tumors

PubMed Central

2015-01-01

Resistance to temozolomide (TMZ) based chemotherapy in glioblastoma multiforme (GBM) has been attributed to the upregulation of the DNA repair protein O6-methylguanine-DNA methyltransferase (MGMT). Inhibition of MGMT using O6-benzylguanine (BG) has shown promise in these patients, but its clinical use is hindered by poor pharmacokinetics that leads to unacceptable toxicity. To improve BG biodistribution and efficacy, we developed superparamagnetic iron oxide nanoparticles (NP) for targeted convection-enhanced delivery (CED) of BG to GBM. The nanoparticles (NPCP-BG-CTX) consist of a magnetic core coated with a redox-responsive, cross-linked, biocompatible chitosan-PEG copolymer surface coating (NPCP). NPCP was modified through covalent attachment of BG and tumor targeting peptide chlorotoxin (CTX). Controlled, localized BG release was achieved under reductive intracellular conditions and NPCP-BG-CTX demonstrated proper trafficking of BG in human GBM cells in vitro. NPCP-BG-CTX treated cells showed a significant reduction in MGMT activity and the potentiation of TMZ toxicity. In vivo, CED of NPCP-BG-CTX produced an excellent volume of distribution (Vd) within the brain of mice bearing orthotopic human primary GBM xenografts. Significantly, concurrent treatment with NPCP-BG-CTX and TMZ showed a 3-fold increase in median overall survival in comparison to NPCP-CTX/TMZ treated and untreated animals. Furthermore, NPCP-BG-CTX mitigated the myelosuppression observed with free BG in wild-type mice when administered concurrently with TMZ. The combination of favorable physicochemical properties, tumor cell specific BG delivery, controlled BG release, and improved in vivo efficacy demonstrates the great potential of these NPs as a treatment option that could lead to improved clinical outcomes. PMID:25247850

Pulsed corona discharge for improving treatability of coking wastewater.

PubMed

Liu, Ming; Preis, Sergei; Kornev, Iakov; Hu, Yun; Wei, Chao-Hai

2018-02-01

Coking wastewater (CW) contains toxic and macromolecular substances that inhibit biological treatment. The refractory compounds remaining in biologically treated coking wastewater (BTCW) provide chemical oxygen demand (COD) and color levels that make it unacceptable for reuse or disposal. Gas-phase pulsed corona discharge (PCD) utilizing mostly hydroxyl radicals and ozone as oxidants was applied to both raw coking wastewater (RCW) and BTCW wastewater as a supplemental treatment. The energy efficiency of COD, phenol, thiocyanate and cyanide degradation by PCD was the subject of the research. The cost-effective removal of intermediate oxidation products with addition of lime was also studied. The energy efficiency of oxidation was inversely proportional to the pulse repetition frequency: lower frequency allows more effective utilization of ozone at longer treatment times. Oxidative treatment of RCW showed the removal of phenol and thiocyanate at 800 pulses per second from 611 to 227mg/L and from 348 to 86mg/L, respectively, at 42kWh/m 3 delivered energy, with substantial improvement in the BOD 5 /COD ratio (from 0.14 to 0.43). The COD and color of BTCW were removed by 30% and 93%, respectively, at 20kWh/m 3 , showing energy efficiency for the PCD treatment exceeding that of conventional ozonation by a factor of 3-4. Application of lime appeared to be an effective supplement to the PCD treatment of RCW, degrading COD by about 28% at an energy input of 28kWh/m 3 and the lime dose of 3.0kg/m 3 . The improvement of RCW treatability is attributed to the degradation of toxic substances and fragmentation of macromolecular compounds. Copyright © 2017. Published by Elsevier B.V.

A first-in-Asian phase 1 study to evaluate safety, pharmacokinetics and clinical activity of VS-6063, a focal adhesion kinase (FAK) inhibitor in Japanese patients with advanced solid tumors.

PubMed

Shimizu, Toshio; Fukuoka, Kazuya; Takeda, Masayuki; Iwasa, Tutomu; Yoshida, Takeshi; Horobin, Joanna; Keegan, Mitchell; Vaickus, Lou; Chavan, Ajit; Padval, Mahesh; Nakagawa, Kazuhiko

2016-05-01

VS-6063 (also known as defactinib or PF-04554878) is a second-generation inhibitor of focal adhesion kinase and proline-rich tyrosine kinase-2. This phase 1 study evaluated the safety and tolerability, pharmacokinetics, and clinical activity of VS-6063 in Japanese subjects with advanced solid tumor malignancies in a first-in-Asian study setting. VS-6063 was administered orally twice daily (b.i.d.) in 21-day cycles to cohorts of three subjects each with a standard 3 + 3 dose-escalation design until disease progression or unacceptable toxicity. Blood samples for pharmacokinetics were collected on Day 1 and 15. The assessments were performed using CTCAE v4.0 for adverse events (AEs), and the Response Evaluation Criteria In Solid Tumors, version v1.1 (RECIST v1.1) for tumor response. Nine patients were treated across three dose levels (200-600 mg BID). No dose-limiting toxicities were observed at any dose level. Most frequent treatment-related AEs were Grade 1/2 unconjugated hyperbilirubinemia, fatigue, decreased appetite, and diarrhea. Only one subject in the 200 mg BID cohort experienced reversible and transient Grade 3 unconjugated hyperbilirubinemia. PK analyses confirmed that the exposure at the recommended Phase 2 dose (RP2D) of 400 mg BID was comparable with exposures previously reported in non-Japanese subjects. Durable stable disease of approximately 24 weeks was confirmed in two subjects (malignant mesothelioma and rectal cancer). VS-6063 was well tolerated at all dose levels investigated in this first-in-Asian study. These data support the administration of VS-6063 to Japanese subjects at the RP2D in clinical trials involving solid tumor malignancies.

Redox-responsive magnetic nanoparticle for targeted convection-enhanced delivery of O6-benzylguanine to brain tumors.

PubMed

Stephen, Zachary R; Kievit, Forrest M; Veiseh, Omid; Chiarelli, Peter A; Fang, Chen; Wang, Kui; Hatzinger, Shelby J; Ellenbogen, Richard G; Silber, John R; Zhang, Miqin

2014-10-28

Resistance to temozolomide (TMZ) based chemotherapy in glioblastoma multiforme (GBM) has been attributed to the upregulation of the DNA repair protein O(6)-methylguanine-DNA methyltransferase (MGMT). Inhibition of MGMT using O(6)-benzylguanine (BG) has shown promise in these patients, but its clinical use is hindered by poor pharmacokinetics that leads to unacceptable toxicity. To improve BG biodistribution and efficacy, we developed superparamagnetic iron oxide nanoparticles (NP) for targeted convection-enhanced delivery (CED) of BG to GBM. The nanoparticles (NPCP-BG-CTX) consist of a magnetic core coated with a redox-responsive, cross-linked, biocompatible chitosan-PEG copolymer surface coating (NPCP). NPCP was modified through covalent attachment of BG and tumor targeting peptide chlorotoxin (CTX). Controlled, localized BG release was achieved under reductive intracellular conditions and NPCP-BG-CTX demonstrated proper trafficking of BG in human GBM cells in vitro. NPCP-BG-CTX treated cells showed a significant reduction in MGMT activity and the potentiation of TMZ toxicity. In vivo, CED of NPCP-BG-CTX produced an excellent volume of distribution (Vd) within the brain of mice bearing orthotopic human primary GBM xenografts. Significantly, concurrent treatment with NPCP-BG-CTX and TMZ showed a 3-fold increase in median overall survival in comparison to NPCP-CTX/TMZ treated and untreated animals. Furthermore, NPCP-BG-CTX mitigated the myelosuppression observed with free BG in wild-type mice when administered concurrently with TMZ. The combination of favorable physicochemical properties, tumor cell specific BG delivery, controlled BG release, and improved in vivo efficacy demonstrates the great potential of these NPs as a treatment option that could lead to improved clinical outcomes.

A phase II evaluation of ixabepilone in the treatment of recurrent/persistent carcinosarcoma of the uterus, an NRG Oncology/Gynecologic Oncology Group study.

PubMed

McCourt, Carolyn K; Deng, Wei; Dizon, Don S; Lankes, Heather A; Birrer, Michael J; Lomme, Michele M; Powell, Matthew A; Kendrick, James E; Saltzman, Joel N; Warshal, David; Tenney, Meaghan E; Kushner, David M; Aghajanian, Carol

2017-01-01

The primary objectives were to determine the objective response rate (ORR) and safety profile of ixabepilone in women with recurrent or persistent uterine carcinosarcoma (UCS). Secondary objectives included progression-free survival (PFS) and overall survival (OS). Exploratory translational objectives included characterization of class III beta tubulin expression and its association with response, PFS, and OS. Patients had measurable disease; up to two prior chemotherapeutic regimens were allowed, but must have included a taxane. Women received ixabepilone 40mg/m 2 as a 3hour IV infusion on day 1 of a 21daycycle. Treatment was continued until disease progression or unacceptable toxicity occurred. Forty-two women were enrolled, with 34 eligible and evaluable. Median age was 68years. ECOG performance status was 0 in 56% of women, 38% had received radiation, and 15% had received 2 lines of chemotherapy. Overall ORR was 11.8% (4/34, 90% CI 4.2-25.1%); all were partial responses. Stable disease for at least 8weeks was achieved in 8 patients (23.5%). Median PFS and OS were 1.7mo and 7.7mo, respectively, with a median follow-up of 37mo. Six month PFS was 20.6%. Major grade≥3 toxicities were neutropenia (47%), fatigue (15%), dehydration (15%), hypertension (15%), and hyponatremia (15%); grade 2 peripheral neuropathy was reported in 18%. In this small sample size, class III beta tubulin expression in the primary tumor was not associated with the response to ixabepilone, PFS, or OS. In this cohort of women, single agent ixabepilone showed modest but insufficient clinical activity. Copyright © 2016. Published by Elsevier Inc.

A phase II study of icotinib and whole-brain radiotherapy in Chinese patients with brain metastases from non-small cell lung cancer.

PubMed

Fan, Yun; Huang, Zhiyu; Fang, Luo; Miao, Lulu; Gong, Lei; Yu, Haifeng; Yang, Haiyan; Lei, Tao; Mao, Weimin

2015-09-01

Icotinib is a new first-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors. A phase II study was conducted to evaluate the efficacy and safety of icotinib in combination with whole-brain radiotherapy (WBRT) in Chinese NSCLC patients with brain metastases (BMs); the cerebrospinal fluid (CSF)/plasma concentrations of icotinib were also investigated. Eligible patients had BMs from NSCLC, regardless of the EGFR status. Icotinib was administered at 125 mg orally 3 times/day until tumor progression or unacceptable toxicity, concurrently with WBRT (3.0 Gy per day, 5 days per week, to 30 Gy). CSF and plasma samples were collected simultaneously from 10 patients. Icotinib concentrations in the CSF and plasma were measured by high-performance liquid chromatography coupled with tandem mass spectrometry. Twenty patients were enrolled. The median follow-up time was 20.0 months. The overall response rate was 80.0%. The median progression-free survival time was 7.0 months (95% CI 1.2-13.2 months), and the median survival time (MST) was 14.6 months (95% CI 12.5-16.7 months). Of the 18 patients with known EGFR status, the MST was 22.0 months for those with an EGFR mutation and was 7.5 months for those with wild-type EGFR (P = 0.0001). The CSF concentration and penetration rate of icotinib were 11.6 ± 9.1 ng/mL and 1.4 ± 1.1%, respectively. No patient experienced ≥grade 4 toxicity. Icotinib was well tolerated in combination with WBRT and showed efficacy in patients with BMs from NSCLC. This clinical benefit was related to the presence of activating EGFR mutations.

Randomized phase II clinical trial of chemo-immunotherapy in advanced nonsmall cell lung cancer

PubMed Central

Lasalvia-Prisco, Eduardo; Garcia-Giralt, Emilio; Vázquez, Jesús; Aghazarian, Marta; Lasalvia-Galante, Eduardo; Larrañaga, Joshemaria; Spera, Gonzalo

2008-01-01

The purpose of this study was to compare chemotherapy-naive patients with stage IV nonsmall cell lung cancer patients treated with chemotherapy or chemoimmunotherapy. We tested doxetacel plus cisplatinum as chemotherapy protocol. An immunomodulatory adjuvant system was added as chemoimmunotherapy to the previously mentioned protocol. This system contains three well-known and complementary conditioners of protective immune-responses: cyclophosphamide low-dose, granulocyte macrophage-colony stimulant factor and magnesium silicate granuloma. Eighty-eight patients were randomly assigned to receive every 3-weeks one of the treatments under comparison. Patients received four cycles of treatment unless disease progression or unacceptable toxicity was documented. The maximum follow-up was one year. In each arm, tumor response (rate,duration), median survival time, 1-year overall survival, safety, and immunity modifications were assessed. Immunity was evaluated by submitting peripheral blood mononuclear cells to laboratory tests for nonspecific immunity: a) phytohemaglutinin-induced lymphocyte proliferation, b) prevalence of T-Regulatory (CD4+CD25+) cells and for specific immunity: a) lymphocyte proliferation induced by tumor-associated antigens (TAA) contained in a previously described autologous thermostable hemoderivative. The difference (chemotherapy vs. chemoimmunotherapy) in response rate induced by the two treatments (39.0% and 35.0%) was not statistically significant. However, the response duration (22 and 31 weeks), the median survival time (32 and 44 weeks) and 1-year survival (33.3% and 39.1%) were statistically higher with chemoimmunotherapy. No difference in toxicity between both arms was demonstrated. A switch in the laboratory immunity profile, nonspecific and specific, was associated with the chemoimmunotherapy treatment: increase of proliferative lymphocyte response, decrease of tolerogenic T-regulatory cells and eliciting TAA-sensitization. PMID:19707385

Dimensions of operational stress and forms of unacceptable risk taking with small arms and munitions.

PubMed

Ben-Shalom, Uzi

2015-01-01

Accidents with small arms and munitions during deployment is a significant safety concern for leaders and safety specialists in combat units. Operational stress may lead to forms of unacceptable risk taking with small arms that may underlie some of these accidents. The present research studied the correlation between two dimensions of operational stress, two forms of risk taking with small arms among combat unit soldiers and possible mediators. The dimensions of operational threat, negative affect and personality profile from the EPQ-R-S were predictors; "exaggerated preparedness" and "risky games with small arms and munitions" were dependent variables; safety climate of the platoon served as a mediator variable. The participants were 461 compulsory service combat soldiers in 31 companies. This field study was conducted during period of top security alert. The results reveal that perceived threat is indeed correlated with exaggerated operational preparedness whereas general emotional state was correlated with risky games with small arms. Safety climate mediated only the correlation between general emotional state and risky games with small arms and munitions. Preparedness and risky games were predicted by the interaction of Psychoticism and the Lie Scale from the EPQ-R-S. The results may enhance the efforts in reducing risk taking and prevention of accidents with small arms and munitions during and following deployment.

Early maladaptive schemas and suicidal risk in an Iranian sample of patients with obsessive-compulsive disorder.

PubMed

Khosravani, Vahid; Sharifi Bastan, Farangis; Samimi Ardestani, Mehdi; Jamaati Ardakani, Razieh

2017-09-01

There are few studies on suicidal risk and its related factors in patients diagnosed with obsessive-compulsive disorder (OCD). This study investigated the associations of early maladaptive schemas, OC symptom dimensions, OCD severity, depression and anxiety with suicidality (i.e., suicidal ideation and suicide attempts) in OCD patients. Sixty OCD outpatients completed the Scale for Suicide Ideation (SSI), the Young Schema Questionnaire-Short Form (YSQ-SF), the Yale-Brown Obsessive Compulsive Scale (Y-BOCS), the Dimensional Obsessive-Compulsive Scale (DOCS) and the Depression Anxiety Stress Scales (DASS-21). 51.7% of patients had lifetime suicide attempts and 75% had suicidal ideation. OCD patients with lifetime suicide attempts exhibited significantly higher scores on early maladaptive schemas than those without such attempts. Logistic regression analysis revealed that the mistrust/abuse schema and the OC symptom dimension of unacceptable thoughts explained lifetime suicide attempts. The mistrust/abuse schema, unacceptable thoughts and depression significantly predicted suicidal ideation. These findings indicated that the mistrust/abuse schema may contribute to high suicidality in OCD patients. Also, patients suffering from unacceptable thoughts need to be assessed more carefully for warning signs of suicide. Copyright © 2017 Elsevier Ireland Ltd. All rights reserved.

Low immunisation uptake: Is the process the problem?

PubMed Central

Harrington, P.; Woodman, C.; Shannon, W.

2000-01-01

OBJECTIVE—To examine mothers' satisfaction with the process of immunisation and its possible contribution to suboptimal immunisation uptake.
DESIGN—In depth interviews with mothers.
SETTING—Two Community Care Areas, Dublin city, Ireland.
PARTICIPANTS—In depth interviews of 23 mothers of children 1-2 years old, recruited purposively from a birth cohort born in 1994.
MAIN RESULTS—Mothers preferred general practice to Health Centre immunisation (11:5) for predominantly emotional compared with practical reasons (4:1). Health Centre immunisation was seen, at times, as unacceptably rough and inhuman. Many mothers experienced severe emotional distress at the prospect of inflicting the pain of immunisation on their babies. The non-empathic stance of some immunising doctors was unacceptable to mothers. They valued attempts by health professionals to acknowledge the pain of immunisation and to engage with their baby. Adverse experiences contributed to deferral of future visits and to defaulting behaviour.
CONCLUSIONS—Low empathy mass immunisation in clinic type settings may be unacceptable to mothers in the 1990s, and may in part explain suboptimal uptake in health care systems that use such clinics.


Keywords: immunisation; health behaviour; immunisation uptake PMID:10814662

Effect of sexual excitation on testosterone and nitric oxide levels of water buffalo bulls (Bubalus bubalis) with different categories of sexual behavior and their correlation with each other.

PubMed

Swelum, Ayman Abdel-Aziz; Saadeldin, Islam M; Zaher, Hany A; Alsharifi, Sawsan A M; Alowaimer, Abdullah N

2017-06-01

We studied the effect of sexual excitation on serum testosterone and nitric oxide (NO) levels in water buffalo bulls with different categories of sexual behavior and their correlation with each other. Buffalo bulls were classified according to their sexual behavior (including reaction time, sexual aggressiveness and mating ability): acceptable (good to excellent) (n=5), fair (n=5), and unacceptable (poor) (n=5) sexual behavior. Blood samples were collected from all animals immediately before and after sexual teasing and/or mounting to estimate the testosterone and NO levels using a commercial radioimmunoassay kit and Griess reaction test, respectively. Comparisons among groups were evaluated using a mixed-design analysis of variance. Pearson's correlation coefficients were calculated to determine the relationship between testosterone and NO levels before and after sexual excitation besides sexual behavior. The level of testosterone before sexual excitation was higher (p≤0.05) in bulls with acceptable and fair sexual behavior than in bulls with unacceptable sexual behavior (0.86±0.01, 0.69±0.02, and 0.29±0.02ng/mL, respectively). The level of NO was higher (p≤0.05) in bulls with acceptable and fair sexual behavior than in bulls with unacceptable sexual behavior (8.00±0.03, 7.66±0.19, and 6.29±0.33μM, respectively). Sexual excitation significantly (p<0.05) increase testosterone and NO levels in bulls with acceptable (1.45±0.01ng/mL and 19.04±0.32μM, respectively) or fair (0.92±0.02ng/mL and 14.95±0.34μM, respectively) sexual behavior, but not in bulls with unacceptable sexual behavior. The unacceptable sexual behavior bulls had significantly lower testosterone and NO levels than the other bulls. There was a strong correlation and association between serum testosterone and NO levels besides sexual behavior of buffalo bulls. In conclusion, the alteration in the testosterone and NO levels after sexual excitation depends on the sexual behavior category of buffalo-bull. Testosterone and NO can be used to create a sexual behavior score. The testosterone and NO levels of can be predicted via evaluation of sexual behavior of buffalo bull. Copyright © 2017 Elsevier B.V. All rights reserved.

Dabrafenib and Trametinib Treatment in Patients With Locally Advanced or Metastatic BRAF V600–Mutant Anaplastic Thyroid Cancer

PubMed Central

Subbiah, Vivek; Kreitman, Robert J.; Wainberg, Zev A.; Cho, Jae Yong; Schellens, Jan H.M.; Soria, Jean Charles; Wen, Patrick Y.; Zielinski, Christoph; Cabanillas, Maria E.; Urbanowitz, Gladys; Mookerjee, Bijoyesh; Wang, Dazhe; Rangwala, Fatima

2018-01-01

Purpose We report the efficacy and safety of dabrafenib (BRAF inhibitor) and trametinib (MEK inhibitor) combination therapy in BRAF V600E–mutated anaplastic thyroid cancer, a rare, aggressive, and highly lethal malignancy with poor patient outcomes and no systemic therapies with clinical benefit. Methods In this phase II, open-label trial, patients with predefined BRAF V600E–mutated malignancies received dabrafenib 150 mg twice daily and trametinib 2 mg once daily until unacceptable toxicity, disease progression, or death. The primary end point was investigator-assessed overall response rate. Secondary end points included duration of response, progression-free survival, overall survival, and safety. Results Sixteen patients with BRAF V600E–mutated anaplastic thyroid cancer were evaluable (median follow-up, 47 weeks; range, 4 to 120 weeks). All patients had received prior radiation treatment and/or surgery, and six had received prior systemic therapy. The confirmed overall response rate was 69% (11 of 16; 95% CI, 41% to 89%), with seven ongoing responses. Median duration of response, progression-free survival, and overall survival were not reached as a result of a lack of events, with 12-month estimates of 90%, 79%, and 80%, respectively. The safety population was composed of 100 patients who were enrolled with seven rare tumor histologies. Common adverse events were fatigue (38%), pyrexia (37%), and nausea (35%). No new safety signals were detected. Conclusion Dabrafenib plus trametinib is the first regimen demonstrated to have robust clinical activity in BRAF V600E–mutated anaplastic thyroid cancer and was well tolerated. These findings represent a meaningful therapeutic advance for this orphan disease. PMID:29072975

Dabrafenib and Trametinib Treatment in Patients With Locally Advanced or Metastatic BRAF V600-Mutant Anaplastic Thyroid Cancer.

PubMed

Subbiah, Vivek; Kreitman, Robert J; Wainberg, Zev A; Cho, Jae Yong; Schellens, Jan H M; Soria, Jean Charles; Wen, Patrick Y; Zielinski, Christoph; Cabanillas, Maria E; Urbanowitz, Gladys; Mookerjee, Bijoyesh; Wang, Dazhe; Rangwala, Fatima; Keam, Bhumsuk

2018-01-01

Purpose We report the efficacy and safety of dabrafenib (BRAF inhibitor) and trametinib (MEK inhibitor) combination therapy in BRAF V600E-mutated anaplastic thyroid cancer, a rare, aggressive, and highly lethal malignancy with poor patient outcomes and no systemic therapies with clinical benefit. Methods In this phase II, open-label trial, patients with predefined BRAF V600E-mutated malignancies received dabrafenib 150 mg twice daily and trametinib 2 mg once daily until unacceptable toxicity, disease progression, or death. The primary end point was investigator-assessed overall response rate. Secondary end points included duration of response, progression-free survival, overall survival, and safety. Results Sixteen patients with BRAF V600E-mutated anaplastic thyroid cancer were evaluable (median follow-up, 47 weeks; range, 4 to 120 weeks). All patients had received prior radiation treatment and/or surgery, and six had received prior systemic therapy. The confirmed overall response rate was 69% (11 of 16; 95% CI, 41% to 89%), with seven ongoing responses. Median duration of response, progression-free survival, and overall survival were not reached as a result of a lack of events, with 12-month estimates of 90%, 79%, and 80%, respectively. The safety population was composed of 100 patients who were enrolled with seven rare tumor histologies. Common adverse events were fatigue (38%), pyrexia (37%), and nausea (35%). No new safety signals were detected. Conclusion Dabrafenib plus trametinib is the first regimen demonstrated to have robust clinical activity in BRAF V600E-mutated anaplastic thyroid cancer and was well tolerated. These findings represent a meaningful therapeutic advance for this orphan disease.

Stereotactic body radiation therapy for isolated hilar and mediastinal non-small cell lung cancers.

PubMed

Horne, Zachary D; Richman, Adam H; Dohopolski, Michael J; Clump, David A; Burton, Steven A; Heron, Dwight E

2018-01-01

The seminal phase II trial for pulmonary stereotactic body radiation therapy (SBRT) suggested that SBRT to central lesions resulted in unacceptable toxicity. Alternative dose-fractionation schemes have been proposed which may improve safety without compromise of efficacy. We report our institutional outcomes of SBRT for hilar/mediastinal non-small cell lung cancer (NSCLC). A retrospective review was conducted of patients with NSCLC in a hilar or mediastinal nodal station which was treated with SBRT. Patients presented with a lesion involving the hilum or mediastinum from primary or oligorecurrent NSCLC. Kaplan-Meier with log-rank testing and Cox analysis were utilized for outcomes analysis. From 2008-2015, 40 patients with median age of 70 were treated with SBRT for primary/oligorecurrent hilar/mediastinal NSCLC with median follow-up of 16.4 months. 85% presented with oligorecurrent disease at a median of 22.4 months following definitive therapy. The aortico-pulmonary window was the target in 40%, the hilum in 25%, lower paratracheal in 20%, subcarinal in 10%, and prevascular in 5%. The median dose was 48Gy in 4 fractions (range: 35-48Gy in 4-5 fractions). Median overall (OS) and progression-free (PFS) survivals were 22.7 and 13.1 months, respectively. Two-year local control was 87.7% and not significantly different between hilar and mediastinal targets. Median PFS was significantly improved in patients with hilar vs mediastinal nodal targets: 33.3 vs 8.4 months, respectively (p=0.031). OS was not statistically different between hilar and mediastinal targets (p=0.359). On multivariable analysis, hilar vs mediastinal target predicted for PFS (HR 3.045 95%CI [1.044-8.833], p=0.042), as did shorter time to presentation in patients with oligorecurrence (HR 0.983 [95%CI 0.967-1.000], p=0.049). Acute grade 3+ morbidity was seen in 3 patients (hemoptysis, pericardial/pleural effusion, heart failure) and late grade 3+ morbidity (hemoptysis) in 1 patient. Hilar/mediastinal SBRT appears to be a safe technique for the local control of isolated nodal disease with limited toxicity from the fractionation schemes utilized. Copyright © 2017 Elsevier B.V. All rights reserved.

Sorafenib and everolimus for patients with unresectable high-grade osteosarcoma progressing after standard treatment: a non-randomised phase 2 clinical trial.

PubMed

Grignani, Giovanni; Palmerini, Emanuela; Ferraresi, Virginia; D'Ambrosio, Lorenzo; Bertulli, Rossella; Asaftei, Sebastian Dorin; Tamburini, Angela; Pignochino, Ymera; Sangiolo, Dario; Marchesi, Emanuela; Capozzi, Federica; Biagini, Roberto; Gambarotti, Marco; Fagioli, Franca; Casali, Paolo Giovanni; Picci, Piero; Ferrari, Stefano; Aglietta, Massimo

2015-01-01

Results of previous study showed promising but short-lived activity of sorafenib in the treatment of patients with unresectable advanced and metastatic osteosarcoma. This treatment failure has been attributed to the mTOR pathway and might therefore be overcome with the addition of mTOR inhibitors. We aimed to investigate the activity of sorafenib in combination with everolimus in patients with inoperable high-grade osteosarcoma progressing after standard treatment. We did this non-randomised phase 2 trial in three Italian Sarcoma Group centres. We enrolled adults (≥18 years) with relapsed or unresectable osteosarcoma progressing after standard treatment (methotrexate, cisplatin, and doxorubicin, with or without ifosfamide). Patients received 800 mg sorafenib plus 5 mg everolimus once a day until disease progression or unacceptable toxic effects. The primary endpoint was 6 month progression-free survival (PFS). All analyses were intention-to-treat. This trial is registered with ClinicalTrials.gov, number NCT01804374. We enrolled 38 patients between June 16, 2011, and June 4, 2013. 17 (45%; 95% CI 28-61) of 38 patients were progression free at 6 months. Toxic effects led to dose reductions, or short interruptions, or both in 25 (66%) of 38 patients and permanent discontinuation for two (5%) patients. The most common grade 3-4 adverse events were lymphopenia and hypophosphataemia each in six (16%) patients, hand and foot syndrome in five (13%), thrombocytopenia in four (11%), and fatigue, oral mucositis, diarrhoea, and anaemia each in two (5%). One patient (3%) had a grade 3 pneumothorax that required trans-thoracic drainage, and that recurred at the time of disease progression. This was reported as a serious adverse event related to the study drugs in both instances. No other serious adverse events were reported during the trial. There were no treatment-related deaths. Although the combination of sorafenib and everolimus showed activity as a further-line treatment for patients with advanced or unresectable osteosarcoma, it did not attain the prespecified target of 6 month PFS of 50% or greater. Italian Sarcoma Group. Copyright © 2015 Elsevier Ltd. All rights reserved.

[Nab-Paclitaxel plus Gemcitabine Hydrochloride in Patients with Metastatic or Recurrent Pancreatic Cancer - A Single Institution Experience].

PubMed

Takeda, Yutaka; Katsura, Yoshiteru; Ohmura, Yoshiaki; Sakamoto, Takuya; Akiyama, Yasuki; Kuwahara, Ryuichi; Morimoto, Yoshihiro; Ishida, Tomo; Oneda, Yasuo; Murakami, Kouhei; Naito, Atsushi; Kagawa, Yoshinori; Takeno, Atsushi; Kato, Takeshi; Tamura, Shigeyuki

2016-11-01

Pancreatic adenocarcinoma is one of the leading causes of cancer deaths in Japan.Albumin -bound paclitaxel (nab-paclitaxel)plus gemcitabine hydrochloride(GEM)combination chemotherapy provided significant improvements in the overall and progression-free survival in a phase III trial in Europe and America and a phase II trial in Japan.As a result, this combination therapy was approved for use in Japan. We evaluated the efficacy of nab-paclitaxel plus GEM with metastatic or recurrent pancreatic cancer.Between December 2014 and March 2016, 11 patients received nab-paclitaxel plus GEM as follows: nab-paclitaxel(125mg/m2 of body-surface area)followed by GEM(1,000mg/m2)on days 1, 8, and 15 every 4 weeks.The treatment was continued until disease progression, unacceptable adverse events, discontinuation as decided by the investigators, or patient refusal. The mean age was 65.6 years(range, 48-75 years), and 8 out of 11 patients were men.Ten patients had an Eastern Cooperative Oncology Group(ECOG)performance status(PS)of 0.Ten patients had metastatic disease.Only 4 patients had no prior therapy.The mean duration of treatment was 10.2 weeks(range, 2-41 weeks).The relative dose intensities of nab-paclitaxel and GEM were 90.6%(66.7-100%)and 87.5%(62.9-100%), respectively.The major Grade 3 or 4 hematological toxicities were leucopenia(54.5%), neutropenia(36.4%), anemia (27.3%), and thrombocytopenia(18.2%).The major grade 2 or 3 non-hematological toxicities were fatigue(45.6%), skin rash(27.3%), peripheral sensory neuropathy(9.1%), anorexia(9.1%), and stomatitis(9.1%).There were no treatmentrelated deaths.Interstitial lung disease was not observed.The 6 month progression-free and overall survival rate were 25.7% and 66.7%, respectively. The disease control rate was 90.9%(complete response, n=0; partial response, n=1; stable disease, n=9; progressive disease, n=1). Nab-paclitaxel plus GEM is well tolerated and associated with efficacy and improved survival outcomes.Nab -paclitaxel plus GEM can be the standard treatment for patients with metastatic pancreatic adenocarcinoma.

Phase I/II dose-finding study of nanoparticle albumin-bound paclitaxel (nab®-Paclitaxel) plus Cisplatin as Treatment for Metastatic Nasopharyngeal Carcinoma.

PubMed

Huang, Yan; Liang, Wenhua; Yang, Yunpeng; Zhao, Liping; Zhao, Hongyun; Wu, Xuan; Zhao, Yuanyuan; Zhang, Yang; Zhang, Li

2016-07-13

This phase I/II study aimed to determine the maximum tolerated dose (MTD) of nanoparticle albumin-bound paclitaxel (nab (®)-paclitaxel) plus cisplatin as treatment for metastatic nasopharyngeal carcinoma (NPC). Patients were enrolled into 1 of 3 dose cohorts, each with 21-day treatment cycles: 1) intravenous (IV) nab-paclitaxel 260 mg/m(2) on day 1; 2) IV nab-paclitaxel 140 mg/m(2) on days 1 and 8; 3) IV nab-paclitaxel 100 mg/m(2) on days 1, 8, and 15. All patients received IV cisplatin 75 mg/m(2) on day 1. Treatment continued for 4-6 cycles, or until progression or unacceptable toxicity. If more than one-third of the patients in a cohort experienced a dose-limiting toxicity (DLT), the dose used in the previous cohort would be designated the MTD. Secreted protein acidic and rich in cysteine (SPARC) expression was detected by immunohistochemistry staining. Sixty-nine patients were enrolled, of whom 64 and 67 were eligible for efficacy and safety analysis, respectively. Two DLTs occurred in cohort 1 (grade 4 febrile neutropenia, grade 3 myalgia), none occurred in cohort 2, and 2 occurred in cohort 3 (both grade 3 fatigue). The MTD was not reached. Partial responses were achieved by 42 patients, 15 had stable disease, and 7 had progressive disease, giving an overall response rate of 66 %. Median progression-free survival was 9 months (95 % CI, 6-12 months). Grade ≥ 3 adverse events were mainly hematologic. There was no significant difference between the 3 cohorts with respect to efficacy or safety. Biomarker analyses indicated that stromal, rather than tumoral, SPARC may predict the response to nab-paclitaxel in NPC. Our findings suggest that nab-paclitaxel plus cisplatin is a highly active regimen with moderate toxicity for the treatment of metastatic NPC, which warrants further investigation in a phase III study. ClinicalTrials.gov ID: NCT01735409 . The trial was registered on November 20th, 2012.

Adjuvant Sunitinib in High-Risk Renal-Cell Carcinoma after Nephrectomy.

PubMed

Ravaud, Alain; Motzer, Robert J; Pandha, Hardev S; George, Daniel J; Pantuck, Allan J; Patel, Anup; Chang, Yen-Hwa; Escudier, Bernard; Donskov, Frede; Magheli, Ahmed; Carteni, Giacomo; Laguerre, Brigitte; Tomczak, Piotr; Breza, Jan; Gerletti, Paola; Lechuga, Mariajose; Lin, Xun; Martini, Jean-Francois; Ramaswamy, Krishnan; Casey, Michelle; Staehler, Michael; Patard, Jean-Jacques

2016-12-08

Sunitinib, a vascular endothelial growth factor pathway inhibitor, is an effective treatment for metastatic renal-cell carcinoma. We sought to determine the efficacy and safety of sunitinib in patients with locoregional renal-cell carcinoma at high risk for tumor recurrence after nephrectomy. In this randomized, double-blind, phase 3 trial, we assigned 615 patients with locoregional, high-risk clear-cell renal-cell carcinoma to receive either sunitinib (50 mg per day) or placebo on a 4-weeks-on, 2-weeks-off schedule for 1 year or until disease recurrence, unacceptable toxicity, or consent withdrawal. The primary end point was disease-free survival, according to blinded independent central review. Secondary end points included investigator-assessed disease-free survival, overall survival, and safety. The median duration of disease-free survival was 6.8 years (95% confidence interval [CI], 5.8 to not reached) in the sunitinib group and 5.6 years (95% CI, 3.8 to 6.6) in the placebo group (hazard ratio, 0.76; 95% CI, 0.59 to 0.98; P=0.03). Overall survival data were not mature at the time of data cutoff. Dose reductions because of adverse events were more frequent in the sunitinib group than in the placebo group (34.3% vs. 2%), as were dose interruptions (46.4% vs. 13.2%) and discontinuations (28.1% vs. 5.6%). Grade 3 or 4 adverse events were more frequent in the sunitinib group (48.4% for grade 3 events and 12.1% for grade 4 events) than in the placebo group (15.8% and 3.6%, respectively). There was a similar incidence of serious adverse events in the two groups (21.9% for sunitinib vs. 17.1% for placebo); no deaths were attributed to toxic effects. Among patients with locoregional clear-cell renal-cell carcinoma at high risk for tumor recurrence after nephrectomy, the median duration of disease-free survival was significantly longer in the sunitinib group than in the placebo group, at a cost of a higher rate of toxic events. (Funded by Pfizer; S-TRAC ClinicalTrials.gov number, NCT00375674 .).

Molten Metal Treatment by Salt Fluxing with Low Environmental Emissions

DOE Office of Scientific and Technical Information (OSTI.GOV)

Yogeshwar Sahai

2007-07-31

Abstract: Chlorine gas is traditionally used for fluxing of aluminum melt for removal of alkali and alkaline earth elements. However this results in undesirable emissions of particulate matter and gases such as HCl and chlorine, which are often at unacceptable levels. Additionally, chlorine gas is highly toxic and its handling, storage, and use pose risks to employees and the local community. Holding of even minimal amounts of chlorine necessitates extensive training for all plant employees. Fugitive emissions from chlorine usage within the plant cause accelerated corrosion of plant equipment. The Secondary Aluminum Maximum Achievable Control Technology (MACT) under the Cleanmore » Air Act, finalized in March 2000 has set very tough new limits on particulate matter (PM) and total hydrogen chloride emissions from aluminum melting and holding furnaces. These limits are 0.4 and 0.1 lbs per ton of aluminum for hydrogen chloride and particulate emissions, respectively. Assuming new technologies for meeting these limits can be found, additional requirements under the Clean Air Act (Prevention of Significant Deterioration and New Source Review) trigger Best Available Control Technology (BACT) for new sources with annual emissions (net emissions not expressed per ton of production) over specified amounts. BACT currently is lime coated bag-houses for control of particulate and HCl emissions. These controls are expensive, difficult to operate and maintain, and result in reduced American competitiveness in the global economy. Solid salt fluxing is emerging as a viable option for the replacement of chlorine gas fluxing, provided emissions can be consistently maintained below the required levels. This project was a cooperative effort between the Ohio State University and Alcoa to investigate and optimize the effects of solid chloride flux addition in molten metal for alkali impurity and non-metallic inclusion removal minimizing dust and toxic emissions and maximizing energy conservation. In this program, the salt metal interactions were studies and the emissions at laboratory scale at OSU were monitored. The goal of the project was to obtain a fundamental understanding, based on first principles, of the pollutant formation that occurs when the salts are used in furnaces. This information will be used to control process parameters so that emissions are consistently below the required levels. The information obtained in these experiments will be used in industrial furnaces at aluminum plants and which will help in optimizing the process.« less

Bugs and burns: effects of fire on ponderosa pine bark beetle (Project INT-F-07-02)

Treesearch

Thomas DeGomez; Thomas Kolb; Sabrina Kleinman; Kelly Williams

2013-01-01

Fire-damaged trees that otherwise would have survived can be killed by bark beetles (McCullough and others 1998, McHugh and others 2003). Wallin and others (2008) found that fire weakens a tree’s defense against bark beetles. An unacceptable level of tree mortality may occur after a controlled burn as a result of weakened tree defenses (Sullivan and others 2003)....

Intercomparison of CO 2 measurements

NASA Astrophysics Data System (ADS)

Poisson, A.; Culkin, F.; Ridout, P.

1990-10-01

Seawater samples, of four different salinities, were analysed for total alkalinity, total CO 2, pH and pCO 2 by up to 12 laboratories. The results showthat although most laboratories are capable of high precision in these determinations, there is an unacceptably high disagreement between their analyses of the same samples. For global programmes involving studies of the CO 2 system in seawater, it is strongly recommended that standard reference materials be made widely available.

Reducing Contingency through Sampling at the Luckey FUSRAP Site - 13186

DOE Office of Scientific and Technical Information (OSTI.GOV)

Frothingham, David; Barker, Michelle; Buechi, Steve

2013-07-01

Typically, the greatest risk in developing accurate cost estimates for the remediation of hazardous, toxic, and radioactive waste sites is the uncertainty in the estimated volume of contaminated media requiring remediation. Efforts to address this risk in the remediation cost estimate can result in large cost contingencies that are often considered unacceptable when budgeting for site cleanups. Such was the case for the Luckey Formerly Utilized Sites Remedial Action Program (FUSRAP) site near Luckey, Ohio, which had significant uncertainty surrounding the estimated volume of site soils contaminated with radium, uranium, thorium, beryllium, and lead. Funding provided by the American Recoverymore » and Reinvestment Act (ARRA) allowed the U.S. Army Corps of Engineers (USACE) to conduct additional environmental sampling and analysis at the Luckey Site between November 2009 and April 2010, with the objective to further delineate the horizontal and vertical extent of contaminated soils in order to reduce the uncertainty in the soil volume estimate. Investigative work included radiological, geophysical, and topographic field surveys, subsurface borings, and soil sampling. Results from the investigative sampling were used in conjunction with Argonne National Laboratory's Bayesian Approaches for Adaptive Spatial Sampling (BAASS) software to update the contaminated soil volume estimate for the site. This updated volume estimate was then used to update the project cost-to-complete estimate using the USACE Cost and Schedule Risk Analysis process, which develops cost contingencies based on project risks. An investment of $1.1 M of ARRA funds for additional investigative work resulted in a reduction of 135,000 in-situ cubic meters (177,000 in-situ cubic yards) in the estimated base volume estimate. This refinement of the estimated soil volume resulted in a $64.3 M reduction in the estimated project cost-to-complete, through a reduction in the uncertainty in the contaminated soil volume estimate and the associated contingency costs. (authors)« less

Characterisation of an accelerator-based neutron source for BNCT versus beam energy

NASA Astrophysics Data System (ADS)

Agosteo, S.; Curzio, G.; d'Errico, F.; Nath, R.; Tinti, R.

2002-01-01

Neutron capture in 10B produces energetic alpha particles that have a high linear energy transfer in tissue. This results in higher cell killing and a higher relative biological effectiveness compared to photons. Using suitably designed boron compounds which preferentially localize in cancerous cells instead of healthy tissues, boron neutron capture therapy (BNCT) has the potential of providing a higher tumor cure rate within minimal toxicity to normal tissues. This clinical approach requires a thermal neutron source, generally a nuclear reactor, with a fluence rate sufficient to deliver tumorcidal doses within a reasonable treatment time (minutes). Thermal neutrons do not penetrate deeply in tissue, therefore BNCT is limited to lesions which are either superficial or otherwise accessible. In this work, we investigate the feasibility of an accelerator-based thermal neutron source for the BNCT of skin melanomas. The source was designed via MCNP Monte Carlo simulations of the thermalization of a fast neutron beam, generated by 7 MeV deuterons impinging on a thick target of beryllium. The neutron field was characterized at several deuteron energies (3.0-6.5 MeV) in an experimental structure installed at the Van De Graaff accelerator of the Laboratori Nazionali di Legnaro, in Italy. Thermal and epithermal neutron fluences were measured with activation techniques and fast neutron spectra were determined with superheated drop detectors (SDD). These neutron spectrometry and dosimetry studies indicated that the fast neutron dose is unacceptably high in the current design. Modifications to the current design to overcome this problem are presented.

Safety results from a phase III study (TURANDOT trial by CECOG) of first-line bevacizumab in combination with capecitabine or paclitaxel for HER-2-negative locally recurrent or metastatic breast cancer.

PubMed

Lang, I; Inbar, M J; Kahán, Z; Greil, R; Beslija, S; Stemmer, S M; Kaufman, B; Zvirbule, Z; Steger, G G; Messinger, D; Brodowicz, T; Zielinski, C

2012-11-01

We report safety data from a randomised, phase III study (CECOG/BC.1.3.005) evaluating first-line bevacizumab plus paclitaxel or capecitabine for locally recurrent or metastatic breast cancer. Patients aged ≥18 years with human epidermal growth factor receptor-2-negative breast adenocarcinoma were randomised to Arm A: bevacizumab 10 mg/kg days 1 and 15; paclitaxel 90 mg/m(2) days 1, 8, and 15, every 4 weeks; or Arm B: bevacizumab 15 mg/kg day 1; capecitabine 1000 mg/m(2) b.i.d., days 1-14, every 3 weeks, until disease progression, unacceptable toxicity or consent withdrawal. A post hoc interim safety analysis included 561 patients (Arm A: 284, Arm B: 277). The regimens demonstrated similar frequencies of all-grade and serious adverse events (SAEs), but different safety profiles. Treatment-related events occurred in 85.2% (Arm A) and 78.0% (Arm B) of patients. Fatigue was most common in Arm A (30.6% versus 23.5% Arm B), and hand-foot syndrome (HFS) most common in Arm B (49.5% versus 2.5% Arm A). Diarrhoea (Arm A: 0.4%, Arm B: 1.4%) and pulmonary embolism (Arm A: 0.7%, Arm B: 1.1%) were the most frequently reported SAEs. These findings are in-line with safety data for bevacizumab plus paclitaxel or capecitabine, reported in previous phase III trials. Copyright © 2012 Elsevier Ltd. All rights reserved.

Personalized biomarkers to monitor disease progression in advanced non-small-cell lung cancer patients treated with icotinib.

PubMed

Song, Gaoguang; Liu, Yujie; Wang, Yanying; Ren, Guanjun; Guo, Shuai; Ren, Junling; Zhang, Li; Li, Zhili

2015-02-02

Disease-specific humoral immune response-related protein complexes in blood are associated with disease progression. Thirty-one patients with stage IIIB and IV non-small-cell lung cancer (NSCLC) were administered with oral dose of icotinib hydrochloride (150 mg twice daily or 125 mg 3 times daily) for a 28-continuous-day cycle until diseases progressed or unacceptable toxicity occurred. The levels of immunoinflammation-related protein complexes (IIRPCs) in a series of plasma samples from 31 NSCLC patients treated with icotinib hydrochloride were determined by an optimized native polyacrylamide gel electrophoresis. Three characteristic patterns of the IIRPCs, named as patterns a, b, and c, respectively, were detected in plasma samples from 31 patients. Prior to the treatment, there were 18 patients in pattern a consisting of 5 IIRPCs, 9 in pattern b consisting of six IIRPCs, and 4 in pattern c without the IIRPCs. The levels of the IIRPCs in 27 patients were quantified. Our results indicate that the time length of humoral immune and inflammation response (TLHIIR) was closely associated with disease progression, and the median TLHIIR was 22.0 weeks, 95% confidence interval: 16.2 to 33.0 weeks, with a lead time of median 11 weeks relative to clinical imaging evidence confirmed by computed tomography or magnetic resonance imaging (the median progression-free survival, 34.0 weeks, 95% confidence interval: 27.9 to 49.0 weeks). The complex relationships between humoral immune response, acquired resistance, and disease progression existed. Personalized IIRPCs could be indicators to monitor the disease progression. Copyright © 2014 Elsevier B.V. All rights reserved.

ANALYSIS OF BORON DILUTION TRANSIENTS IN PWRS.

DOE Office of Scientific and Technical Information (OSTI.GOV)

DIAMOND,D.J.BROMLEY,B.P.ARONSON,A.L.

2004-02-04

A study has been carried out with PARCS/RELAP5 to understand the consequences of hypothetical boron dilution events in pressurized water reactors. The scenarios of concern start with a small-break loss-of-coolant accident. If the event leads to boiling in the core and then the loss of natural circulation, a boron-free condensate can accumulate in the cold leg. The dilution event happens when natural circulation is re-established or a reactor coolant pump (RCP) is restarted in violation of operating procedures. This event is of particular concern in B&W reactors with a lowered-loop design and is a Generic Safety Issue for the U.S.more » Nuclear Regulatory Commission. The results of calculations with the reestablishment of natural circulation show that there is no unacceptable fuel damage. This is determined by calculating the maximum fuel pellet enthalpy, based on the three-dimensional model, and comparing it with the criterion for damage. The calculation is based on a model of a B&W reactor at beginning of the fuel cycle. If an RCP is restarted, unacceptable fuel damage may be possible in plants with sufficiently large volumes of boron-free condensate in the cold leg.« less

Fatty, Fatty, Two-by-Four: Weight-Teasing History and Disturbed Eating in Young Adult Women

PubMed Central

McWilliams, Rita; Byrd-Bredbenner, Carol

2013-01-01

Objective. We investigated the long-term effect of weight teasing during childhood. Methods. Young adult women (n = 1533; aged 18–26 years) from 3 large universities participated in a survey (Fall 2009 to Spring 2010) that assessed disturbed eating behaviors; weight status at ages 6, 12, and 16 years; and weight-teasing history. Results. Nearly half of the participants were weight-teased as a child. Participants who experienced childhood weight teasing were significantly more likely to have disturbed eating behaviors now than non–weight-teased peers. As the variety of weight teasing insults recalled increased, so did disturbed eating behaviors and current body mass index. Those who recalled their weight at ages 6, 12, or 16 years as being heavier than average endured weight teasing significantly more frequently and felt greater distress than their lighter counterparts. Conclusions. Weight teasing may contribute to the development of disturbed eating and eating disorders in young women. Health care professionals, parents, teachers, and other childcare givers must help shift social norms to make weight teasing as unacceptable as other types of bullying. To protect the health of children, efforts to make weight teasing unacceptable are warranted. PMID:23327257

Detraditionalisation and attitudes to sex outside marriage in China.

PubMed

Zheng, Weijun; Zhou, Xudong; Zhou, Chi; Liu, Wei; Li, Lu; Hesketh, Therese

2011-05-01

China has undergone massive socio-economic change over the past 30 years. In parallel, there have been huge changes in social and sexual mores. Until the end of the Mao era strict norms prevailed, with sex outside marriage widely regarded as immoral and unacceptable. Detraditionalisation theory describes the abandonment or reconfiguration of the socio-cultural traditions and has been explored widely in Western settings. This study aimed to explore its relevance for China through exploring attitudes towards premarital sex, extramarital sex, same-sex relations and sex work. We conducted semi-structured interviews with 212 men and women aged 18 to 39 in urban and rural areas of three provinces: Zhejiang, Guizhou and Yunnan. Analysis identified emerging themes. Results show varying degrees of acceptance of the four sexual behaviours, with premarital sex seen as common, homosexuality still regarded as unacceptable by the majority but considerable acceptance of commercial sex work as part of male business transactions and social life. China appears to be on a pathway of detraditionalisation with specific Chinese features. This study suggests that the concept of detraditionalisation applies well to non-Western contexts, but the path it takes is culture-specific and relatively unpredictable. © 2011 Taylor & Francis

Radiographic Evaluation of Root Canal Fillings Accomplished by Undergraduate Dental Students

PubMed Central

Yavari, Hamidreza; Samiei, Mohammad; Shahi, Shahriar; Borna, Zahra; Abdollahi, Amir Ardalan; Ghiasvand, Negar; Shariati, Gholamreza

2015-01-01

Introduction: The purpose of this study was to evaluate the radiographic quality of root canal fillings by fourth-, fifth-, and sixth-year undergraduate students at Tabriz Faculty of Dentistry between 2006 and 2012. Methods and Materials: A total of 1183 root canal fillings in 620 teeth were evaluated by two investigators (and in case of disagreement by a third investigator) regarding the presence or absence of under-fillings, over-fillings and perforations. For each tooth, preoperative, working and postoperative radiographs were checked. The Pearson’s chi-square test was used for statistical evaluation of the data. Inter-examiner agreement was measured by Cohen’s kappa (k) values. The level of significance was set at 0.05. Results: Total frequencies of over-filling, under-filling and perforation were 5.6%, 20.4% and 1.9%, respectively. There were significant differences between frequencies of over- and under-fillings (P<0.05). Unacceptable quality, under- and over-fillings were detected in 27.9% of 1183 evaluated canals. Conclusion: The technical quality of root canal therapies performed by undergraduate dental students using step-back preparation and lateral compaction techniques was unacceptable in almost one-fourth of the cases. PMID:25834598

Effects of irrelevant sounds on phonological coding in reading comprehension and short-term memory.

PubMed

Boyle, R; Coltheart, V

1996-05-01

The effects of irrelevant sounds on reading comprehension and short-term memory were studied in two experiments. In Experiment 1, adults judged the acceptability of written sentences during irrelevant speech, accompanied and unaccompanied singing, instrumental music, and in silence. Sentences varied in syntactic complexity: Simple sentences contained a right-branching relative clause (The applause pleased the woman that gave the speech) and syntactically complex sentences included a centre-embedded relative clause (The hay that the farmer stored fed the hungry animals). Unacceptable sentences either sounded acceptable (The dog chased the cat that eight up all his food) or did not (The man praised the child that sight up his spinach). Decision accuracy was impaired by syntactic complexity but not by irrelevant sounds. Phonological coding was indicated by increased errors on unacceptable sentences that sounded correct. These errors rates were unaffected by irrelevant sounds. Experiment 2 examined effects of irrelevant sounds on ordered recall of phonologically similar and dissimilar word lists. Phonological similarity impaired recall. Irrelevant speech reduced recall but did not interact with phonological similarity. The results of these experiments question assumptions about the relationship between speech input and phonological coding in reading and the short-term store.

Associations between tobacco control policy awareness, social acceptability of smoking and smoking cessation. Findings from the International Tobacco Control (ITC) Europe Surveys.

PubMed

Rennen, Els; Nagelhout, Gera E; van den Putte, Bas; Janssen, Eva; Mons, Ute; Guignard, Romain; Beck, François; de Vries, Hein; Thrasher, James F; Willemsen, Marc C

2014-02-01

This study examined whether awareness of tobacco control policies was associated with social unacceptability of smoking and whether social unacceptability had an effect on smoking cessation in three European countries. Representative samples (n = 3865) of adult smokers in France, the Netherlands and Germany were used from two survey waves of the longitudinal International Tobacco Control Europe Surveys. Associations were examined of aspects of social unacceptability of smoking (i.e. feeling uncomfortable, important people disapproval and societal disapproval) with tobacco policy awareness (i.e. awareness of warning labels, anti-tobacco information and smoking restrictions at work) and smoking cessation. Only the positive association of awareness of anti-tobacco information with feeling uncomfortable about smoking was significant in each of the three countries. Important people disapproval predicted whether smokers attempted to quit, although this did not reach significance in the French and German samples in multivariate analyses. Our findings suggest that anti-tobacco information campaigns about the dangers of second-hand smoke in France and about smoking cessation in the Netherlands and Germany might have reduced the social acceptability of smoking in these countries. However, campaigns that influence the perceived disapproval of smoking by important people may be needed to ultimately increase attempts to quit smoking.

Associations between tobacco control policy awareness, social acceptability of smoking and smoking cessation. Findings from the International Tobacco Control (ITC) Europe Surveys

PubMed Central

Rennen, Els; Nagelhout, Gera E.; van den Putte, Bas; Janssen, Eva; Mons, Ute; Guignard, Romain; Beck, François; de Vries, Hein; Thrasher, James F.; Willemsen, Marc C.

2014-01-01

This study examined whether awareness of tobacco control policies was associated with social unacceptability of smoking and whether social unacceptability had an effect on smoking cessation in three European countries. Representative samples (n = 3865) of adult smokers in France, the Netherlands and Germany were used from two survey waves of the longitudinal International Tobacco Control Europe Surveys. Associations were examined of aspects of social unacceptability of smoking (i.e. feeling uncomfortable, important people disapproval and societal disapproval) with tobacco policy awareness (i.e. awareness of warning labels, anti-tobacco information and smoking restrictions at work) and smoking cessation. Only the positive association of awareness of anti-tobacco information with feeling uncomfortable about smoking was significant in each of the three countries. Important people disapproval predicted whether smokers attempted to quit, although this did not reach significance in the French and German samples in multivariate analyses. Our findings suggest that anti-tobacco information campaigns about the dangers of second-hand smoke in France and about smoking cessation in the Netherlands and Germany might have reduced the social acceptability of smoking in these countries. However, campaigns that influence the perceived disapproval of smoking by important people may be needed to ultimately increase attempts to quit smoking. PMID:23861478

Direct Computation of Sound Radiation by Jet Flow Using Large-scale Equations

NASA Technical Reports Server (NTRS)

Mankbadi, R. R.; Shih, S. H.; Hixon, D. R.; Povinelli, L. A.

1995-01-01

Jet noise is directly predicted using large-scale equations. The computational domain is extended in order to directly capture the radiated field. As in conventional large-eddy-simulations, the effect of the unresolved scales on the resolved ones is accounted for. Special attention is given to boundary treatment to avoid spurious modes that can render the computed fluctuations totally unacceptable. Results are presented for a supersonic jet at Mach number 2.1.

Lesson learned from nature for the development of novel anti-cancer agents: implication of isoflavone, curcumin, and their synthetic analogs.

PubMed

Sarkar, Fazlul H; Li, Yiwei; Wang, Zhiwei; Padhye, Subhash

2010-06-01

In recent years, naturally occurring dietary compounds have received greater attention in the field of cancer prevention and treatment research. Among them, isoflavone genistein and curcumin are very promising anti-cancer agents because of their non-toxic and potent anti-cancer properties. However, it is important to note that the low water solubility, poor in vivo bioavailability and unacceptable pharmacokinetic profile of these natural compounds limit their efficacy as anti-cancer agents for solid tumors. Therefore, the development of synthetic analogs of isoflavone and curcumin based on the structure-activity assay, and the encapsulation of isoflavone and curcumin with liposome or nanoparticle for enhancing the anti-tumor activity of these natural agents, is an exciting area of research. Emerging in vitro and in vivo studies clearly suggest that these analogs and formulations of natural compounds could be much more potent for the prevention and/or treatment of various cancers. In this review article, we will summarize the current knowledge regarding the anti-cancer effect of natural compounds and their analogs, the regulation of cell signaling by these agents, and the structure-activity relationship for better design of novel anti-cancer agents, which could open newer avenues for the prevention of tumor progression and/or treatment of human malignancies.

Proviral Latency, Persistent Human Immunodeficiency Virus Infection, and the Development of Latency Reversing Agents

PubMed Central

Archin, Nancie M.

2017-01-01

Abstract Quiescent proviral genomes that persist during human immunodeficiency virus type 1 (HIV-1) infection despite effective antiretroviral therapy (ART) can fuel rebound viremia after ART interruption and is a central obstacle to the cure of HIV infection. The induction of quiescent provirus is the goal of a new class of potential therapeutics, latency reversing agents (LRAs). The discovery, development, and testing of HIV LRAs is a key part of current efforts to develop latency reversal and viral clearance strategies to eradicate established HIV infection. The development of LRAs is burdened by many uncertainties that make drug discovery difficult. The biology of HIV latency is complex and incompletely understood. Potential targets for LRAs are host factors, and the potential toxicities of host-directed therapies in individuals that are otherwise clinically stable may be unacceptable. Assays to measure latency reversal and assess the effectiveness of potential therapeutics are complex and incompletely validated. Despite these obstacles, novel LRAs are under development and beginning to enter combination testing with viral clearance strategies. It is hoped that the steady advances in the development of LRAs now being paired with emerging immunotherapeutics to clear persistently infected cells will soon allow measurable clinical advances toward an HIV cure. PMID:28520964

Exposure assessment of carcass disposal options in the event of a notifiable exotic animal disease: application to avian influenza virus.

PubMed

Pollard, Simon J T; Hickman, Gordon A W; Irving, Phil; Hough, Rupert L; Gauntlett, Daniel M; Howson, Simon F; Hart, Alwyn; Gayford, Paul; Gent, Nick

2008-05-01

We present a generalized exposure assessment of 28 disposal options for poultry carcasses in the event of a highly pathogenic avian influenza (HPAI) outbreak. The analysis supports a hereto unverified disposal hierarchy for animal carcasses, placing waste processing (e.g., incineration and rendering) above controlled disposal (e.g., landfill), above uncontrolled disposal (e.g., burial on-farm). We illustrate that early stages of the disposal chain (on-farm) pose greater opportunities for exposure to hazardous agents than later stages, where agents are generally contained, wastes are treated, and residues are managed by regulated processes. In selecting carcass disposal options, practitioners are advised to consider the full range of hazards rather than focusing solely on the HPAI agent, and to give preference to technologies that (i) offer high destruction efficiencies for target pathogens; (ii) do not give rise to significant releases of other pathogenic organisms; and (iii) do not release unacceptable concentrations of toxic chemicals. The approach offers an exposure assessment perspective for carcass disposal, thus providing a risk-informed basis for contingency planning and operational intervention. The authors recognize that relevant legislation, public perception, available capacity, and cost also need to be considered when selecting disposal options in the event of HPAI.

Objective responses in relapsed T-cell lymphomas with single-agent brentuximab vedotin

PubMed Central

Advani, Ranjana H.; Bartlett, Nancy L.; Jacobsen, Eric D.; Sharman, Jeff P.; O’Connor, Owen A.; Siddiqi, Tanya; Kennedy, Dana A.; Oki, Yasuhiro

2014-01-01

This phase 2, open-label, multicenter study evaluated the efficacy and safety of brentuximab vedotin, a CD30-directed antibody-drug conjugate, in relapsed/refractory CD30+ non-Hodgkin lymphomas. The primary end point was objective response rate (ORR). Key secondary end points included safety, correlation of CD30 expression with response, response duration, and progression-free survival (PFS). Brentuximab vedotin 1.8 mg/kg was administered every 3 weeks until progression or unacceptable toxicity. This planned subset analysis included patients with peripheral T-cell lymphomas (PTCLs; n = 35), specifically angioimmunoblastic T-cell lymphoma (AITL; n = 13) and PTCL not otherwise specified (n = 22). Median age was 64 years; 63% were refractory to most recent therapy. Of 34 evaluable patients, ORR was 41% (8 complete remissions [CRs], 6 partial remissions [PRs]), and ORR was 54% in AITL (5 CRs, 2 PRs) with median PFS of 6.7 months thus far. No correlation between CD30 expression per central review and response was observed. Safety data were consistent with the known profile of brentuximab vedotin, and included at least grade 3 events of neutropenia (14%), peripheral sensory neuropathy, and hyperkalemia (9% each). In summary, brentuximab vedotin showed antitumor activity in patients with relapsed PTCL particularly AITL. This trial was registered at www.clinicaltrials.gov as #NCT01421667. PMID:24652992

Mobilizing stem cells from normal donors: is it possible to improve upon G-CSF?

PubMed

Cashen, A F; Lazarus, H M; Devine, S M

2007-05-01

Currently, granulocyte colony stimulating factor (G-CSF) remains the standard mobilizing agent for peripheral blood stem cell (PBSC) donors, allowing the safe collection of adequate PBSCs from the vast majority of donors. However, G-CSF mobilization can be associated with some significant side effects and requires a multi-day dosing regimen. The other cytokine approved for stem cell mobilization, granulocyte-macrophage colony stimulating factor (GM-CSF), alters graft composition and may reduce the development of graft-versus-host disease, but a significant minority of donors fails to provide sufficient CD34+ cells with GM-CSF and some experience unacceptable toxicity. AMD3100 is a promising new mobilizing agent, which may have several advantages over G-CSF for donor mobilization. As it is a direct antagonist of the interaction between the chemokine stromal-derived factor-1 and its receptor CXCR4, AMD3100 mobilizes PBSCs within hours rather than days. It is also well tolerated, with no significant side effects reported in any of the clinical trials to date. Studies of autologous and allogeneic transplantation of AMD3100 mobilized grafts have demonstrated prompt and stable engraftment. Here, we review the current state of stem cell mobilization in normal donors and discuss novel strategies for donor stem cell mobilization.

Lesson Learned from Nature for the Development of Novel Anti-Cancer Agents: Implication of Isoflavone, Curcumin, and their Synthetic Analogs

PubMed Central

Sarkar, Fazlul H.; Li, Yiwei; Wang, Zhiwei; Padhye, Subhash

2011-01-01

In recent years, naturally occurring dietary compounds have received greater attention in the field of cancer prevention and treatment research. Among them, isoflavone genistein and curcumin are very promising anti-cancer agents because of their non-toxic and potent anti-cancer properties. However, it is important to note that the low water solubility, poor in vivo bioavailability and unacceptable pharmacokinetic profile of these natural compounds limit their efficacy as anti-cancer agents for solid tumors. Therefore, the development of synthetic analogs of isoflavone and curcumin based on the structure-activity assay, and the encapsulation of isoflavone and curcumin with liposome or nanoparticle for enhancing the anti-tumor activity of these natural agents, is an exciting area of research. Emerging in vitro and in vivo studies clearly suggest that these analogs and formulations of natural compounds could be much more potent for the prevention and/or treatment of various cancers. In this review article, we will summarize the current knowledge regarding the anti-cancer effect of natural compounds and their analogs, the regulation of cell signaling by these agents, and the structure-activity relationship for better design of novel anti-cancer agents, which could open newer avenues for the prevention of tumor progression and/or treatment of human malignancies. PMID:20345353

Is there any impact of new drugs on the outcome of advanced NSCLC? An overview of the Southern Italy Cooperative Oncology Group trials.

PubMed

Frasci, G; Panza, N; Comella, G; Pacilio, G

1999-01-01

Lung cancer represents the major cause of cancer-related death in Europe and North America, accounting for 28% of all cancer deaths. Seventy to 80% of all lung cancers are non-small cell lung cancers (NSCLCs), and approximately 75 % of these patients present with locally advanced or disseminated disease. Even though chemotherapy is now recommended in the majority of cases of unresectable NSCLC, it still fails to substantially modify the fate of these patients. In recent years, several active cytotoxic drugs (paclitaxel, docetaxel, vinorelbine, gemcitabine, and irinotecan) have been developed, showing an overall response rate (ORR) <20% in NSCLC. Phase II/III trials testing these new agents in combination with cisplatin have been carried out in recent years with inconsistent results. Large randomized trials testing cisplatin-paclitaxel, carboplatin-paclitaxel, and cisplatin-gemcitabine regimens have been reported showing no substantial superiority of these combinations over standard treatments. The ORR remained well below 50%, and the median survival times were quite far from one year. These data could suggest that the addition of a single new agent to a platinum compound could be insufficient to substantially improve the prognosis of advanced NSCLC patients. In view of these disappointing data, the Southern Italy Cooperative Oncology Group has tried to improve the fate of patients with advanced NSCLC by testing new triplet combinations, which combined cisplatin with two rather than one of the newest chemotherapy agents. To avoid an unacceptable increase in toxicity and/or a marked decrease in dose intensity, the standard schedules of administration of the three agents used in these studies were changed, and the schedule changes were evaluated in phase I trials aimed at determining the maximum tolerated dosages of the drugs. Subsequently, phase II and III trials were conducted. The present paper summarizes the results of the clinical trials either completed or under way and aims to evaluate whether this strategy will result in a substantial prognostic improvement.

Three Drug Combinations for Late-Stage Trypanosoma brucei gambiense Sleeping Sickness: A Randomized Clinical Trial in Uganda

PubMed Central

Priotto, Gerardo; Fogg, Carole; Balasegaram, Manica; Erphas, Olema; Louga, Albino; Checchi, Francesco; Ghabri, Salah; Piola, Patrice

2006-01-01

Objectives: Our objective was to compare the efficacy and safety of three drug combinations for the treatment of late-stage human African trypanosomiasis caused by Trypanosoma brucei gambiense. Design: This trial was a randomized, open-label, active control, parallel clinical trial comparing three arms. Setting: The study took place at the Sleeping Sickness Treatment Center run by Médecins Sans Frontières at Omugo, Arua District, Uganda Participants: Stage 2 patients diagnosed in Northern Uganda were screened for inclusion and a total of 54 selected. Interventions: Three drug combinations were given to randomly assigned patients: melarsoprol-nifurtimox (M+N), melarsoprol-eflornithine (M+E), and nifurtimox-eflornithine (N+E). Dosages were uniform: intravenous (IV) melarsoprol 1.8 mg/kg/d, daily for 10 d; IV eflornithine 400 mg/kg/d, every 6 h for 7 d; oral nifurtimox 15 (adults) or 20 (children <15 y) mg/kg/d, every 8 h for 10 d. Patients were followed up for 24 mo. Outcome Measures: Outcomes were cure rates and adverse events attributable to treatment. Results: Randomization was performed on 54 patients before enrollment was suspended due to unacceptable toxicity in one of the three arms. Cure rates obtained with the intention to treat analysis were M+N 44.4%, M+E 78.9%, and N+E 94.1%, and were significantly higher with N+E (p = 0.003) and M+E (p = 0.045) than with M+N. Adverse events were less frequent and less severe with N+E, resulting in fewer treatment interruptions and no fatalities. Four patients died who were taking melarsoprol-nifurtimox and one who was taking melarsoprol-eflornithine. Conclusions: The N+E combination appears to be a promising first-line therapy that may improve treatment of sleeping sickness, although the results from this interrupted study do not permit conclusive interpretations. Larger studies are needed to continue the evaluation of this drug combination in the treatment of T. b. gambiense sleeping sickness. PMID:17160135

Theoretical Modeling of Molecular and Electron Kinetic Processes. Volume I. Theoretical Formulation of Analysis and Description of Computer Program.

DTIC Science & Technology

1979-01-01

syn- thesis proceed s by ignoring unacceptable syntax or other errors , pro- tection against subsequent execution of a faulty reaction scheme can be...resulting TAPE9 . During subroutine syn thesis and reaction processing, a search is made (fo r each secondary electron collision encountered) to...program library, which can be cat- alogued and saved if any future specialized modifications (beyond the scope of the syn thesis capability of LASER

The effect of social marketing communication on safe driving.

PubMed

Yang, Dong-Jenn; Lin, Wan-Chen; Lo, Jyue-Yu

2011-12-01

Processing of cognition, affect, and intention was investigated in viewers of advertisements to prevent speeding while driving. Results indicated that anchoring-point messages had greater effects on viewers' cognition, attitude, and behavioral intention than did messages without anchoring points. Further, the changes in message anchoring points altered participants' perceptions of acceptable and unacceptable judgments: a higher anchoring point in the form of speeding mortality was more persuasive in promoting the idea of reducing driving speed. Implications for creation of effective safe driving communications are discussed.

Guidelines for contingency planning NASA (National Aeronautics and Space Administration) ADP security risk reduction decision studies

NASA Technical Reports Server (NTRS)

Tompkins, F. G.

1984-01-01

Guidance is presented to NASA Computer Security Officials for determining the acceptability or unacceptability of ADP security risks based on the technical, operational and economic feasibility of potential safeguards. The risk management process is reviewed as a specialized application of the systems approach to problem solving and information systems analysis and design. Reporting the results of the risk reduction analysis to management is considered. Report formats for the risk reduction study are provided.

Germ-line gene therapy and the medical imperative.

PubMed

Munson, Ronald; Davis, Lawrence H

1992-06-01

Somatic cell gene therapy has yielded promising results. If germ cell gene therapy can be developed, the promise is even greater: hundreds of genetic diseases might be virtually eliminated. But some claim the procedure is morally unacceptable. We thoroughly and sympathetically examine several possible reasons for this claim but find them inadequate. There is no moral reason, then, not to develop and employ germ-line gene therapy. Taking the offensive, we argue next that medicine has a prima facie moral obligation to do so.

14 CFR 33.25 - Accessory attachments.

Code of Federal Regulations, 2010 CFR

2010-01-01

... mounting attachment must include provisions for sealing to prevent contamination of, or unacceptable... loss of oil and to prevent contamination from sources outside the chamber enclosing the drive...

32 CFR 236.1 - Purpose.

Code of Federal Regulations, 2013 CFR

2013-07-01

... DEFENSE (DOD)-DEFENSE INDUSTRIAL BASE (DIB) VOLUNTARY CYBER SECURITY AND INFORMATION ASSURANCE (CS/IA) ACTIVITIES § 236.1 Purpose. Cyber threats to DIB unclassified information systems represent an unacceptable...

32 CFR 236.1 - Purpose.

Code of Federal Regulations, 2012 CFR

2012-07-01

... DEFENSE (DOD)-DEFENSE INDUSTRIAL BASE (DIB) VOLUNTARY CYBER SECURITY AND INFORMATION ASSURANCE (CS/IA) ACTIVITIES § 236.1 Purpose. Cyber threats to DIB unclassified information systems represent an unacceptable...

MAGNETIC BEHAVIOR OF FUNCTIONALLY MODIFIED SPINEL Ni0.4Ca0.6Fe2O4 NANOFERRITE

NASA Astrophysics Data System (ADS)

Prasad, Arun S.; Dhawan, M. S.; Dolia, S. N.; Samariya, Arvind; Reddy, V. R.; Singhal, R. K.; Predeep, P.

2011-06-01

The editorial board discovered that the data points in several sections of the Mossbauer spectra as given in Figs. 3(a) and 3(b) are exactly identical. This is impossible and nonphysical for the measurement of two different samples (or for that matter not even for the same sample!). The only conclusion we can draw from this figure is that some of the data is fabricated. As a result, the results and conclusions as described in the paper are unacceptable. This article is retracted from its publication in Int. J. Mod. Phys. B.

The impact of symptom dimensions on outcome for exposure and ritual prevention therapy in obsessive-compulsive disorder.

PubMed

Williams, Monnica T; Farris, Samantha G; Turkheimer, Eric N; Franklin, Martin E; Simpson, H Blair; Liebowitz, Michael; Foa, Edna B

2014-08-01

Obsessive-compulsive disorder (OCD) is a severe condition with varied symptom presentations. The behavioral treatment with the most empirical support is exposure and ritual prevention (EX/RP). This study examined the impact of symptom dimensions on EX/RP outcomes in OCD patients. The Yale-Brown Obsessive-Compulsive Scale (Y-BOCS) was used to determine primary symptoms for each participant. An exploratory factor analysis (EFA) of 238 patients identified five dimensions: contamination/cleaning, doubts about harm/checking, hoarding, symmetry/ordering, and unacceptable/taboo thoughts (including religious/moral and somatic obsessions among others). A linear regression was conducted on those who had received EX/RP (n=87) to examine whether scores on the five symptom dimensions predicted post-treatment Y-BOCS scores, accounting for pre-treatment Y-BOCS scores. The average reduction in Y-BOCS score was 43.0%, however the regression indicated that unacceptable/taboo thoughts (β=.27, p=.02) and hoarding dimensions (β=.23, p=.04) were associated with significantly poorer EX/RP treatment outcomes. Specifically, patients endorsing religious/moral obsessions, somatic concerns, and hoarding obsessions showed significantly smaller reductions in Y-BOCS severity scores. EX/RP was effective for all symptom dimensions, however it was less effective for unacceptable/taboo thoughts and hoarding than for other dimensions. Clinical implications and directions for research are discussed. Copyright © 2014 Elsevier Ltd. All rights reserved.

77 FR 20823 - Jyotin Parikh: Debarment Order

Federal Register 2010, 2011, 2012, 2013, 2014

2012-04-06

... failing to properly investigate, log and archive questionable, aberrant, and unacceptable laboratory... market new product lines. In furtherance of the conspiracy, in or around March 2003, Mr. Parikh...

32 CFR 236.1 - Purpose.

Code of Federal Regulations, 2014 CFR

2014-07-01

... DEFENSE (DoD)-DEFENSE INDUSTRIAL BASE (DIB) VOLUNTARY CYBER SECURITY AND INFORMATION ASSURANCE (CS/IA) ACTIVITIES § 236.1 Purpose. Cyber threats to DIB unclassified information systems represent an unacceptable...

47 CFR 22.971 - Obligation to abate unacceptable interference.

Code of Federal Regulations, 2010 CFR

2010-10-01

... interference, with full cooperation and utmost diligence, in the shortest time practicable. Interfering... severally responsible for abating interference, with full cooperation and utmost diligence, in the shortest...

Previous radiotherapy and the clinical activity and toxicity of pembrolizumab in the treatment of non-small-cell lung cancer: a secondary analysis of the KEYNOTE-001 phase 1 trial.

PubMed

Shaverdian, Narek; Lisberg, Aaron E; Bornazyan, Krikor; Veruttipong, Darlene; Goldman, Jonathan W; Formenti, Silvia C; Garon, Edward B; Lee, Percy

2017-07-01

Preclinical studies have found radiotherapy enhances antitumour immune responses. We aimed to assess disease control and pulmonary toxicity in patients who previously received radiotherapy for non-small-cell lung cancer (NSCLC) before receiving pembrolizumab. We assessed patients with advanced NSCLC treated on the phase 1 KEYNOTE-001 trial at a single institution (University of California, Los Angeles, CA, USA). Patients were aged 18 years or older, had an Eastern Cooperative Oncology Group performance status of 1 or less, had adequate organ function, and no history of pneumonitis. Patients received pembrolizumab at a dose of either 2 mg/kg of bodyweight or 10 mg/kg every 3 weeks, or 10 mg/kg every 2 weeks, until disease progression, unacceptable toxicity, or other protocol-defined reasons for discontinuation. Disease response and pulmonary toxicity were prospectively assessed by Immune-related Response Criteria and Common Terminology Criteria for Adverse Events version 4.0. The primary objective of the KEYNOTE-001 trial was to assess the safety, side-effect profile, and antitumour activity of pembrolizumab. For our secondary analysis, patients were divided into subgroups to compare patients who previously received radiotherapy with patients who had not. Our primary objective was to determine whether previous radiotherapy affected progression-free survival, overall survival, and pulmonary toxicity in the intention-to-treat population. The KEYNOTE-001 trial was registered with ClinicalTrials.gov, number NCT01295827. Between May 22, 2012, and July 11, 2014, 98 patients were enrolled and received their first cycle of pembrolizumab. One patient was lost to follow-up. 42 (43%) of 97 patients had previously received any radiotherapy for the treatment of NSCLC before the first cycle of pembrolizumab. 38 (39%) of 97 patients received extracranial radiotherapy and 24 (25%) of 97 patients received thoracic radiotherapy. Median follow-up for surviving patients was 32·5 months (IQR 29·8-34·1). Progression-free survival with pembrolizumab was significantly longer in patients who previously received any radiotherapy than in patients without previous radiotherapy (hazard ratio [HR] 0·56 [95% CI 0·34-0·91], p=0·019; median progression-free survival 4·4 months [95% CI 2·1-8·6] vs 2·1 months [1·6-2·3]) and for patients who previously received extracranial radiotherapy compared with those without previous extracranial radiotherapy (HR 0·50 [0·30-0·84], p=0·0084; median progression-free survival 6·3 months [95% CI 2·1-10·4] vs 2·0 months [1·8-2·1]). Overall survival with pembrolizumab was significantly longer in patients who previously received any radiotherapy than in patients without previous radiotherapy (HR 0·58 [95% CI 0·36-0·94], p=0·026; median overall survival 10·7 months [95% CI 6·5-18·9] vs 5·3 months [2·7-7·7]) and for patients who previously received extracranial radiotherapy compared with those without previous extracranial radiotherapy (0·59 [95% CI 0·36-0·96], p=0·034; median overall survival 11·6 months [95% CI 6·5-20·5] vs 5·3 months [3·0-8·5]). 15 (63%) of 24 patients who had previously received thoracic radiotherapy had any recorded pulmonary toxicity versus 29 (40%) of 73 patients with no previous thoracic radiotherapy. Three (13%) patients with previous thoracic radiotherapy had treatment-related pulmonary toxicity compared with one (1%) of those without; frequency of grade 3 or worse treatment-related pulmonary toxicities was similar (one patient in each group). Our data suggest that previous treatment with radiotherapy in patients with advanced NSCLC results in longer progression-free survival and overall survival with pembrolizumab treatment than that seen in patients who did not have previous radiotherapy, with an acceptable safety profile. Further clinical trials investigating this combination are needed to determine the optimal treatment strategy for patients with advanced NSCLC. US National Institutes of Health. Copyright © 2017 Elsevier Ltd. All rights reserved.

Fuel processor temperature monitoring and control

DOEpatents

Keskula, Donald H.; Doan, Tien M.; Clingerman, Bruce J.

2002-01-01

In one embodiment, the method of the invention monitors one or more of the following conditions: a relatively low temperature value of the gas stream; a relatively high temperature value of the gas stream; and a rate-of-change of monitored temperature. In a preferred embodiment, the rate of temperature change is monitored to prevent the occurrence of an unacceptably high or low temperature condition. Here, at least two temperatures of the recirculating gas stream are monitored over a period of time. The rate-of-change of temperature versus time is determined. Then the monitored rate-of-change of temperature is compared to a preselected rate-of-change of value. The monitoring of rate-of-change of temperature provides proactive means for preventing occurrence of an unacceptably high temperature in the catalytic reactor.

Plant photonics: application of optical coherence tomography to monitor defects and rots in onion

NASA Astrophysics Data System (ADS)

Meglinski, I. V.; Buranachai, C.; Terry, L. A.

2010-04-01

The incidence of physiological and/or pathological defects in many fresh produce types is still unacceptably high and accounts for a large proportion of waste. With increasing interest in food security their remains strong demand in developing reliable and cost effective technologies for non-destructive screening of internal defects and rots, these being deemed unacceptable by consumers. It is well recognized that the internal defects and structure of turbid scattering media can be effectively visualized by using optical coherence tomography (OCT). In the present study, the high spatial resolution and advantages of OCT have been demonstrated for imaging the skins and outer laminae (concentric tissue layers) of intact whole onion bulbs with a view to non-invasively visualizing potential incidence/severity of internal defects.

When Wife-Beating Is Not Necessarily Abuse: A Feminist and Cross-Cultural Analysis of the Concept of Abuse as Expressed by Tibetan Survivors of Domestic Violence.

PubMed

Rajan, Hamsa

2016-11-20

This article describes the views of Tibetan women who have experienced physical violence from male intimate partners. How they conceptualise abuse, their views on acceptable versus unacceptable hitting, and the acts besides hitting which they felt to be unacceptable or abusive, are explored. Views of survivors' relatives/friends and men who have hit their wives are also included. Western-based domestic violence theory is shown to be incommensurate with abuse in particular socio-cultural settings. As feminist scholars emphasize listening deeply to voices of women in the global South, this article demonstrates how such listening might be undertaken when the views expressed by women diverge from feminism. © The Author(s) 2016.

Workplace bullying--what's it got to do with general practice?

PubMed

Askew, Deborah A; Schluter, Philip J; Dick, Marie-Louise

2013-04-01

Workplace bullying is repeated systematic, interpersonal abusive behaviours that negatively affect the targeted individual and the organisation in which they work. It is generally the result of actual or perceived power imbalances between perpetrator and victim, and includes behaviours that intimidate, offend, degrade or humiliate a worker. It is illegal, and bullied employees can take legal action against their employers for a breach of implied duty of trust and confidence. Despite this, workplace bullying occurs in many Australian workplaces, including Australian general practices. This article explores the issue of workplace bullying with particular reference to bullying within general practice and provides a framework for managing these situations. All general practices need organisation-wide anti-bullying policies that are endorsed by senior management, clearly define workplace bullying, and provide a safe procedure for reporting bullying behaviours. General practitioners should investigate whether workplace issues are a potential contributor to patients who present with depression and/or anxiety and assess the mental health of patients who do disclose that they are victims of workplace bullying, Importantly, the GP should reassure their patient that bullying is unacceptable and illegal, and that everyone has the right to a safe workplace free from violence, harassment and bullying. The time has come for all workplaces to acknowledge that workplace bullying is unacceptable and intolerable.

[Assessment of ecological environment effects of coastal development in Hebei Province, China].

PubMed

Cui, Li-Tuo; Li, Zhi-Wei

2014-07-01

Through the analysis of the development activities and the ecological environment in coastal of Hebei Province, China, an index system for evaluating the ecological environment effect, composed of 28 indices, was set up by the pressure, state and response subsystems. Using the comprehensive index evaluation method, the integrated effects of ecological environment index (EI) was calculated and its grading criterion was founded. The results showed that the ecological environment effect of Hebei Province coastal development varied from being relatively small, normal and then relatively large from 1984 to 2010, and its acceptance degree evolved from being acceptable to being unacceptable. Because the resource and environment pressures caused by coastal development were serious and a delay existed in the state relative to the response, the improvement of various measures in the response subsystem did not show a positive effect on the state, and the environmental quality of ocean showed a degrading trend. Due to the differences in coastal development pattern and strength, the ecological environment effect of development activities showed some spatial differences. The ecological environment effect of Qinhuangdao coastal development was the minimum, followed by Cangzhou and Tangshan. Cangzhou and Tangshan had reached unacceptable levels and needed to further strengthen the restoration and protection of ecological environment.

Influence of acid rain upon water plumbosolvency.

PubMed Central

Moore, M R

1985-01-01

The West of Scotland has had particular problems in the past associated with soft acidic water supplies and uptake of lead from domestic plumbing systems by such water. As a consequence of this, health problems related to overexposure to lead have been identified. The current debate on acidification of ground waters by acid rain is therefore particularly pertinent to this area. Studies have shown that even a modest decrease in pH will result in very substantial increase in plumbosolvency. This was found to be of particular importance in the city of Glasgow and town of Ayr, where prior to water treatment, pH values were 6.3 and 5.4, respectively, and where, consequentially, large numbers of homes did not comply with lead in water standards. Closed-loop lime-dosing systems were introduced in both Glasgow and Ayr to increase the pH with immediate decrease in the lead content of the water and, subsequently, blood lead concentrations of the subjects living in these areas. Such closed-loop systems will compensate for any acidity in water supplies, whether of natural origin or originating from acid rain precipitation. However, when such treatment has not been applied, any increase in water acidity due to acid rain which is, in many cases, already unacceptable. which is, in many cases, already unacceptable. PMID:4076078

Heavy metals contamination and human health risk assessment around Obuasi gold mine in Ghana.

PubMed

Bempah, Crentsil Kofi; Ewusi, Anthony

2016-05-01

Gold mining has increased the prevalence and occurrence of heavy metals contamination at the Earth's surface and is causing major concern due to the potential risk involved. This study investigated the impact of gold mine on heavy metals (As, Cd, Cr, Cu, Pb, Hg, Ni, Fe, Mn, and Zn) pollution and evaluated the potential health risks to local residents via consumption of polluted groundwater, agricultural soils, and vegetable crops grown at three community farms surrounding the mine at Obuasi municipality of Ghana. The results showed levels of As, Cd, Cr, Hg, Fe, and Mn higher than the allowable drinking water standards. The vegetable samples analyzed showed high accumulation of As and Ni above the normal value. Bioaccumulation factors of heavy metals were significantly higher for vegetables grown in the Sanso soils. Estimated average daily intake and hazard quotient for As in drinking water as well as As, Pb, and Hg in vegetable samples exceeded permissible limit. Unacceptable non-cancer health risk levels were found in vegetable samples analyzed for As, Pb, and Hg. An unacceptable cancer risk was found via drinking of groundwater, in consumption of vegetables, and in soil. The hazard index for vegetables was higher than 1, indicating very high health risk to heavy metals contamination through consumption of vegetables grown around the sampling sites. The results recommend the need for regular monitoring of groundwater and food crops to protect consumers' health.

A survey of outcome of adjustable suture as first operation in patients with strabismus

PubMed Central

Razmjoo, Hasan; Attarzadeh, Hosein; Karbasi, Najmeh; Najarzadegan, Mohammad Reza; Salam, Hasan; Jamshidi, Aliraza

2014-01-01

Background: Adjustable suture used for years to improve the outcome of strabismus surgery. We surveyed outcome of our patients with strabismus who underwent adjustable suture. Materials and Methods: This retrospective study was performed at Ophthalmology Centre of Feiz Hospital in Isfahan on 95 participants that candidate for adjustable suture strabismus surgery. Patients were divided into three age groups: Under 10 years, 10-19 years, and 20 years and over. Outcome of adjustable suture surgery consequence of residual postoperative deviation was divided into four groups: Excellent, good, acceptable, and unacceptable. Results: Out of 95 patients studied, 51 (53.7%) were males and 44 (46.3%) were females. The mean of deviation angles were 53.8 ± 17.9 PD (Prism dioptres) in alt XT, 44.5 ± 12 PD in alt ET and 52 ± 13.5 PD in const ET, 47.1 ± 13.1PD in cons XT, respectively. There was no significant difference between the groups (P = 0.051). Results of surgery were in 38 patients (40%) excellent, in 31 patients (32.6%) good, in 19 patients (20%) acceptable, and in 7 patients (7.4%) unacceptable. Seven (7.4%) patients required reoperation. Conclusions: In the present study, the frequency of re-operation was much lower than other similar studies (7.4% vs. 30-50%). This suggests that the adjustable technique that used in our study can be associated with lower reoperation than other adjustable techniques used in the other similar studies. PMID:25250293

How much would each researcher receive if competitive government research funding were distributed equally among researchers?

PubMed Central

Katzav, Joel

2017-01-01

Scientists are increasingly dissatisfied with funding systems that rely on peer assessment and, accordingly, have suggested several proposals for reform. One of these proposals is to distribute available funds equally among all qualified researchers, with no interference from peer review. Despite its numerous benefits, such egalitarian sharing faces the objection, among others, that it would lead to an unacceptable dilution of resources. The aim of the present paper is to assess this particular objection. We estimate (for the Netherlands, the U.S. and the U.K.) how much researchers would receive were they to get an equal share of the government budgets that are currently allocated through competitive peer assessment. For the Netherlands, we furthermore estimate what researchers would receive were we to differentiate between researchers working in low-cost, intermediate-cost and high-cost disciplines. Given these estimates, we then determine what researchers could afford in terms of PhD students, Postdocs, travel and equipment. According to our results, researchers could, on average, maintain current PhD student and Postdoc employment levels, and still have at their disposal a moderate (the U.K.) to considerable (the Netherlands, U.S.) budget for travel and equipment. This suggests that the worry that egalitarian sharing leads to unacceptable dilution of resources is unjustified. Indeed, our results strongly suggest that there is room for far more egalitarian distribution of funds than happens in the highly competitive funding schemes so prevalent today. PMID:28886054

How much would each researcher receive if competitive government research funding were distributed equally among researchers?

PubMed

Vaesen, Krist; Katzav, Joel

2017-01-01

Scientists are increasingly dissatisfied with funding systems that rely on peer assessment and, accordingly, have suggested several proposals for reform. One of these proposals is to distribute available funds equally among all qualified researchers, with no interference from peer review. Despite its numerous benefits, such egalitarian sharing faces the objection, among others, that it would lead to an unacceptable dilution of resources. The aim of the present paper is to assess this particular objection. We estimate (for the Netherlands, the U.S. and the U.K.) how much researchers would receive were they to get an equal share of the government budgets that are currently allocated through competitive peer assessment. For the Netherlands, we furthermore estimate what researchers would receive were we to differentiate between researchers working in low-cost, intermediate-cost and high-cost disciplines. Given these estimates, we then determine what researchers could afford in terms of PhD students, Postdocs, travel and equipment. According to our results, researchers could, on average, maintain current PhD student and Postdoc employment levels, and still have at their disposal a moderate (the U.K.) to considerable (the Netherlands, U.S.) budget for travel and equipment. This suggests that the worry that egalitarian sharing leads to unacceptable dilution of resources is unjustified. Indeed, our results strongly suggest that there is room for far more egalitarian distribution of funds than happens in the highly competitive funding schemes so prevalent today.

40 CFR 240.201-3 - Recommended procedures: Operations.

Code of Federal Regulations, 2010 CFR

2010-07-01

...) SOLID WASTES GUIDELINES FOR THE THERMAL PROCESSING OF SOLID WASTES Requirements and Recommended... precautions to be taken if unacceptable wastes are delivered to the facility or are improperly left there...

40 CFR 240.201-3 - Recommended procedures: Operations.

Code of Federal Regulations, 2011 CFR

2011-07-01

...) SOLID WASTES GUIDELINES FOR THE THERMAL PROCESSING OF SOLID WASTES Requirements and Recommended... precautions to be taken if unacceptable wastes are delivered to the facility or are improperly left there...

Sorafenib in Japanese Patients with Locally Advanced or Metastatic Medullary Thyroid Carcinoma and Anaplastic Thyroid Carcinoma.

PubMed

Ito, Yasuhiro; Onoda, Naoyoshi; Ito, Ken-Ichi; Sugitani, Iwao; Takahashi, Shunji; Yamaguchi, Iku; Kabu, Koki; Tsukada, Katsuya

2017-09-01

Therapeutic options for treating advanced or metastatic medullary thyroid carcinoma (MTC) and anaplastic thyroid carcinoma (ATC) are still limited in Japan, even though vandetanib for MTC and lenvatinib for MTC and ATC have been approved. Sorafenib is an oral multikinase inhibitor approved for the treatment of patients with radioactive iodine-refractory differentiated thyroid cancer (DTC). An uncontrolled, open-label, multicenter, single-arm, Phase 2 clinical study was conducted to evaluate the safety and efficacy of sorafenib in Japanese patients with MTC and ATC. Japanese patients with histologically confirmed ATC and locally advanced or metastatic MTC were enrolled from April to September 2014. The primary endpoint was to evaluate the safety of sorafenib. Treatment efficacy variables including progression-free survival (PFS), overall survival (OS), objective response rate (ORR), disease control rate (DCR), and maximum reduction in tumor size were evaluated as secondary endpoints. Patients received sorafenib 400 mg orally twice daily on a continuous basis and then continued treatment until the occurrence of disease progression, unacceptable toxicity, or withdrawal of consent. A total of 20 patients were screened, and 18 (8 with MTC and 10 with ATC) were enrolled. The most common drug-related adverse events were palmar-plantar erythrodysesthesia (72%), alopecia (56%), hypertension (56%), and diarrhea (44%). In the ATC patients, median PFS was 2.8 months [confidence interval 0.7-5.6], and median OS was 5.0 months [confidence interval 0.7-5.7]; ORR and DCR were 0% and 40%, respectively. In the MTC population, neither median PFS nor OS had been reached at the time of this analysis; ORR was 25% and DCR was 75%. The toxicities reported in this study were consistent with the known safety profile of sorafenib. Sorafenib seems to be effective in the treatment of advanced MTC but not ATC, and could be a new treatment option for locally advanced or metastatic MTC and radioactive iodine-refractory DTC.

Single-agent estramustine phosphate (EMP) is active in advanced breast cancer after failure with anthracyclines and taxanes.

PubMed

Zelek, L; Barthier, S; Riofrio, M; Sevin, D; Fizazi, K; Spielmann, M

2001-09-01

Estramustine phosphate (EMP) is an oral cytotoxic agent that depolymerizes tubuline, a mechanism of action that has been revisited during the last decade. Because of its lack of haematological toxicity and favourable tolerance profile, EMP is a good candidate for palliative chemotherapy. The aim of the study was to assess its tolerance and efficacy in advanced breast cancer after failure with usual regimens. Patients with a life expectancy of at least 12 weeks and bi-dimensionally measurable disease having received at least 1 line of chemotherapy (including taxanes and/or anthracyclines) for advanced breast cancer (ABC) were eligible. EMP was given daily at a dose of 10 mg/kg until disease progression, unacceptable toxicity or patient refusal to continue chemotherapy. Forty patients were included between June 1998 and December 1999. Patients had previously received one to eight chemotherapy regimens (median is two) for ABC. Twenty-two patients (55%) had visceral involvement and eighteen patients (45%) had osseous, chest wall or soft tissue metastases. Adverse events leading to early interruption of EMP were grade 2 allergy (n = 1), grade 2-3 nausea (n = 6), deep-vein thrombosis (n = 1), grade 3 sepsis (n = 1). One patient died at twenty-four weeks from pulmonary embolism, and another at fourteen weeks from unknown cause. Seven objective responses were observed (17.5%; 95% confidence interval (CI): 6%-30%). Median time to failure was 24 weeks (14-52+) in responding patients. All objective responses but one were observed in patients with visceral metastases. In 10 other patients (25%), disease remained stable with a median time to failure of 27 weeks (16-50); 6 of these experienced a decrease of consumption of analgesics or an improvement of performance status. EMP is an active drug in ABC after failure with taxanes and anthracyclines, whose tolerance profile appears favourable.

Risk assessment of occupational exposure to benzene using numerical simulation in a complex geometry of a reforming unit of petroleum refinery.

PubMed

Bayatian, Majid; Ashrafi, Khosro; Azari, Mansour Rezazadeh; Jafari, Mohammad Javad; Mehrabi, Yadollah

2018-04-01

There has been an increasing concern about the continuous and the sudden release of volatile organic pollutants from petroleum refineries and occupational and environmental exposures. Benzene is one of the most prevalent volatile compounds, and it has been addressed by many authors for its potential toxicity in occupational and environmental settings. Due to the complexities of sampling and analysis of benzene in routine and accidental situations, a reliable estimation of the benzene concentration in the outdoor setting of refinery using a computational fluid dynamics (CFD) could be instrumental for risk assessment of occupational exposure. In the present work, a computational fluid dynamic model was applied for exposure risk assessment with consideration of benzene being released continuously from a reforming unit of a refinery. For simulation of benzene dispersion, GAMBIT, FLUENT, and CFD post software are used as preprocessing, processing, and post-processing, respectively. Computational fluid dynamic validation was carried out by comparing the computed data with the experimental measurements. Eventually, chronic daily intake and lifetime cancer risk for routine operations through the two seasons of a year are estimated through the simulation model. Root mean square errors are 0.19 and 0.17 for wind speed and concentration, respectively. Lifetime risk assessments of workers are 0.4-3.8 and 0.0096-0.25 per 1000 workers in stable and unstable atmospheric conditions, respectively. Exposure risk is unacceptable for the head of shift work, chief engineer, and general workers in 141 days (38.77%) in a year. The results of this study show that computational fluid dynamics is a useful tool for modeling of benzene exposure in a complex geometry and can be used to estimate lifetime risks of occupation groups in a refinery setting.

Complications of hematopoietic stem transplantation: Fungal infections.

PubMed

Omrani, Ali S; Almaghrabi, Reem S

2017-12-01

Patients undergoing allogeneic hematopoietic stem cell transplantation (HSCT) are at increased risk of invasive fungal infections, especially during the early neutropenic phase and severe graft-versus-host disease. Mold-active prophylaxis should be limited to the highest risk groups. Empiric antifungal therapy for HSCT with persistent febrile neutropenia is associated with unacceptable response rates, unnecessary antifungal therapy, increased risk of toxicity, and inflated costs. Empiric therapy should not be a substitute for detailed work up to identify the cause of fever in such patients. The improved diagnostic performance of serum biomarkers such as galactomannan and β-D-glucan, as well as polymerase chain reaction assays has allowed the development of diagnostic-driven antifungal therapy strategies for high risk patients. Diagnostic-driven approaches have resulted in reduced unnecessary antifungal exposure, improved diagnosis of invasive fungal disease, and reduced costs without increased risk of mortality. The appropriateness of diagnostic-driven antifungal strategy for individual HSCT centers depends on the availability and turnaround times for diagnostics, multidisciplinary expertise, and the local epidemiology of invasive fungal infections. Echinocandins are the treatment of choice for invasive candidiasis in most HSCT recipients. Fluconazole may be used for the treatment of invasive candidiasis in hemodynamically stable patients with no prior azole exposure. The primary treatment of choice for invasive aspergillosis is voriconazole. Alternatives include isavuconazole and lipid formulations of amphotericin. Currently available evidence does not support routine primary combination antifungal therapy for invasive aspergillosis. However, combination salvage antifungal therapy may be considered in selected patients. Therapeutic drug monitoring is recommended for the majority of HSCT recipients on itraconazole, posaconazole, or voriconazole. Copyright © 2017 King Faisal Specialist Hospital & Research Centre. Published by Elsevier B.V. All rights reserved.

Position statement from the European Board and College of Obstetrics & Gynaecology (EBCOG): The use of medicines during pregnancy - call for action.

PubMed

Van Calsteren, Kristel; Gersak, Ksenija; Sundseth, Hildrun; Klingmann, Ingrid; Dewulf, Lode; Van Assche, André; Mahmood, Tahir

2016-06-01

Less than 10% of medicines approved by the FDA since 1980 have provided enough information as regards risks for birth defects associated with their use (Adam et al. (2011) [1]). Nevertheless, it is estimated that over 90% of pregnant women take over-the-counter (OTC) or prescription medication (Ke et al., 2014 [2]). Considering the fact that the use of medication in the period before conception and during lactation can also influence the development of the child, information on the impact of their usage during reproductive life is important for everyone. The lack of clear information on this topic results in situations where life-saving medication is discontinued, withheld or used in a reduced dosage by pregnant women, while on the other hand medicines with (potential) toxic effects are taken. This is unacceptable and it is a major public concern that must be addressed. Currently, Europe lacks a robust and comprehensive information system about medication use in reproductive life (from preconception, during pregnancy and during lactation). In order to improve maternal health, and subsequently the health of our next generation, reliable and up to date information should be made available. It should be readily accessible for both health care providers and women who are considering getting pregnant or who are already pregnant. In order to tackle this gap in public health, this paper describes current knowledge of the use of medicines before and during pregnancy. It calls upon all stakeholders involved in medical care, research and medicine regulation, such as policy makers, regulators and governmental agencies, to take action to protect patients and improve public health. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Position Statement from the European Board and College of Obstetrics & Gynaecology (EBCOG) : The use of medicines during pregnancy: call for action.

PubMed

Van Calsteren, Kristel; Gersak, Ksenija; Sundseth, Hildrun; Klingmann, Ingrid; Dewulf, Lode; Van Assche, André; Mahmood, Tahir

2016-06-01

Less than 10% of medicines approved by the FDA since 1980 have provided enough information as regard risks for birth defects associated with their use [1]. Nevertheless, it is estimated that over 90% of pregnant women take over-the-counter (OTC) or prescription medication [2]. Considering the fact that the use of medication in the period before conception and during lactation can also influence the development of the child, information on the impact of their usage during reproductive life is important for everyone. The lack of clear information on this topic results in situations where life-saving medication is discontinued, withheld or used in a reduced dosage by pregnant women, while on the other hand medicines with (potential) toxic effects are taken. This is unacceptable and it is a major public concern that must be addressed. Currently, Europe lacks a robust and comprehensive information system about medication use in reproductive life (preconception, pregnancy and lactation). In order to improve maternal health, and subsequently the health of our next generation, reliable and up to date information should be made available. It should be readily accessible for both health care providers and women who are considering getting pregnant or who are already pregnant. In order to tackle this gap in public health, this paper describes current knowledge of the use of medicines before and during pregnancy. It calls upon all stakeholders involved in medical care, research and medicine regulation, such as policy makers, regulators and governmental agencies, to take action to protect patients and improve public health. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Multicenter Phase 2 Trial of the Hsp-90 Inhibitor, IPI-504 (retaspimycin hydrochloride), in Patients with Castration-Resistant Prostate Cancer

PubMed Central

Oh, William K; Galsky, Matthew D.; Stadler, Walter M.; Srinivas, Sandy; Chu, Franklin; Bubley, Glenn; Goddard, J; Dunbar, Joi; Ross, Robert W

2011-01-01

Objectives Evaluation of clinical activity and safety of IPI-504 (retaspimycin hydrochloride) in patients with castration-resistant prostate cancer (CRPC). Methods A single arm trial was conducted in two cohorts: Group A (chemotherapy-naïve), Group B (docetaxel-treated). IPI-504 was administered intravenously at 400 mg/m2 on Days 1, 4, 8, and 11 of a 21-day cycle. Trial expansion was planned if at least one prostate specific antigen (PSA) or radiographic response was noted per cohort. Pharmacokinetic samples were collected following the first dose; safety was assessed throughout. Results Nineteen patients were enrolled (4 in Group A; 15 in Group B), with a median age of 66 years (range 49-78). Group B had received a median of 2 prior chemotherapy regimens. All Group B patients had bone metastases; 66% had measurable soft tissue or visceral metastases. One Group A patient remained on trial for 9 cycles; PSA declined 48% from baseline. No PSA responses were observed in other patients. Adverse events reported in >25% of the study population included nausea (47%), diarrhea (42%), fatigue (32%), anorexia (26%), and arthralgia (26%). Two patients in Group B died on study, involving study drug-related events of hepatic failure and ketoacidosis, respectively. Conclusions In this study, Hsp90 inhibition with IPI-504 administered as a single agent had a minimal effect on PSA or tumor burden and was associated with unacceptable toxicity in several patients; therefore, further evaluation in CRPC patients is not warranted. IPI-504 is being investigated at less intensive doses and schedules in other tumor types. PMID:21762967

Multicenter retrospective study of cetuximab plus platinum-based chemotherapy for recurrent or metastatic oral squamous cell carcinoma.

PubMed

Yanamoto, Souichi; Umeda, Masahiro; Kioi, Mitomu; Kirita, Tadaaki; Yamashita, Tetsuro; Hiratsuka, Hiroyoshi; Yokoo, Satoshi; Tanzawa, Hideki; Uzawa, Narikazu; Shibahara, Takahiko; Ota, Yoshihide; Kurita, Hiroshi; Okura, Masaya; Hamakawa, Hiroyuki; Kusukawa, Jingo; Tohnai, Iwai

2018-03-01

The purpose of this study was to assess the efficacy and safety of cetuximab plus platinum-based chemotherapy for patients specifically diagnosed with recurrent or metastatic oral squamous cell carcinoma (OSCC). We conducted a multicenter retrospective observational study of patients who underwent first-line cetuximab plus platinum-based chemotherapy between December 2012 and June 2015. 65 patients received weekly cetuximab (week 1, 400 mg/m 2 ; subsequent weeks, 250 mg/m 2 ) plus a maximum of six 3-weekly cycles of cisplatin (80 or 100 mg/m 2 , day 1) or carboplatin (at an area under the curve of 5 mg/mL/min as a 1-h intravenous infusion on day 1) and 5-fluorouracil (800 or 1000 mg/m 2 /day, days 1-4). Patients with stable disease who received cetuximab plus platinum-based chemotherapy continued to receive cetuximab until disease progression or unacceptable toxicities, whichever occurred first. The median follow-up was 10.5 (range 1.2-34.2) months. The best overall response and the disease control rates were 46.2 and 67.7%, respectively. The median overall survival and progression-free survival rates were 12.1 and 7.8 months, respectively. The most common grades 3-4 adverse events were skin rash (9.2%) followed by leukopenia (6.2%). None of the adverse events were fatal. The results of our multicenter retrospective study, which was the largest of its kind to date, suggest that first-line cetuximab plus platinum-based chemotherapy is suitable and well-tolerated for the systemic therapy of recurrent or metastatic OSCC.

Protocol Design for the Bench to Bed Trial in Alectinib-Refractory Non-Small-Cell Lung Cancer Patients Harboring the EML4-ALK Fusion Gene (ALRIGHT/OLCSG1405).

PubMed

Isozaki, Hideko; Hotta, Katsuyuki; Ichihara, Eiki; Takigawa, Nagio; Ohashi, Kadoaki; Kubo, Toshio; Ninomiya, Takashi; Ninomiya, Kiichiro; Oda, Naohiro; Yoshioka, Hiroshige; Ichikawa, Hirohisa; Inoue, Masaaki; Takata, Ichiro; Shibayama, Takuo; Kuyama, Shoichi; Sugimoto, Keisuke; Harada, Daijiro; Harita, Shingo; Sendo, Toshiaki; Tanimoto, Mitsune; Kiura, Katsuyuki

2016-11-01

Based on our preclinical study results, which showed that the activation of the hepatocyte growth factor/MET pathway is a potential mechanism of acquired resistance to alectinib, we launched the ALRIGHT (OLCSG1405 [alectinib-refractory non-small-cell lung cancer patients harboring the EML4-ALK fusion gene]), a phase II trial of the anaplastic lymphoma kinase (ALK)/MET inhibitor crizotinib in patients with non-small-cell lung cancer refractory to alectinib and harboring the echinoderm microtubule-associated protein-like 4 (EML4)-ALK fusion gene. Patients with ALK-rearranged tumors who have developed disease progression during alectinib treatment will receive crizotinib monotherapy until disease progression or the occurrence of unacceptable toxicity. The primary endpoint is set as the objective response rate, assuming that a response in 50% of eligible patients will indicate potential usefulness and that 15% would be the lower limit of interest (1-sided α of 0.05, β of 0.20). The estimated accrual number of patients is 9. The secondary endpoints include progression-free survival, overall survival, adverse events, and patient-reported outcomes. We will also take tissue samples before crizotinib monotherapy to conduct an exploratory analysis of ALK and hepatocyte growth factor/MET expression levels and gene alterations (eg, mutations, amplifications, and translocations). We will obtain information regarding whether crizotinib, which targets not only ALK, but also MET, can truly produce efficacy with acceptable safety profiles in ALK + non-small-cell lung cancer even in the alectinib-refractory setting. Copyright © 2016 Elsevier Inc. All rights reserved.

Targeting Bruton tyrosine kinase with ibrutinib in relapsed/refractory marginal zone lymphoma

PubMed Central

de Vos, Sven; Thieblemont, Catherine; Martin, Peter; Flowers, Christopher R.; Morschhauser, Franck; Collins, Graham P.; Ma, Shuo; Coleman, Morton; Peles, Shachar; Smith, Stephen; Barrientos, Jacqueline C.; Smith, Alina; Munneke, Brian; Dimery, Isaiah; Beaupre, Darrin M.; Chen, Robert

2017-01-01

Marginal zone lymphoma (MZL) is a heterogeneous B-cell malignancy for which no standard treatment exists. MZL is frequently linked to chronic infection, which may induce B-cell receptor (BCR) signaling, resulting in aberrant B-cell survival and proliferation. We conducted a multicenter, open-label, phase 2 study to evaluate the efficacy and safety of ibrutinib in previously treated MZL. Patients with histologically confirmed MZL of all subtypes who received ≥1 prior therapy with an anti-CD20 antibody–containing regimen were treated with 560 mg ibrutinib orally once daily until progression or unacceptable toxicity. The primary end point was independent review committee–assessed overall response rate (ORR) by 2007 International Working Group criteria. Among 63 enrolled patients, median age was 66 years (range, 30-92). Median number of prior systemic therapies was 2 (range, 1-9), and 63% received ≥1 prior chemoimmunotherapy. In 60 evaluable patients, ORR was 48% (95% confidence interval [CI], 35-62). With median follow-up of 19.4 months, median duration of response was not reached (95% CI, 16.7 to not estimable), and median progression-free survival was 14.2 months (95% CI, 8.3 to not estimable). Grade ≥3 adverse events (AEs; >5%) included anemia, pneumonia, and fatigue. Serious AEs of any grade occurred in 44%, with grade 3-4 pneumonia being the most common (8%). Rates of discontinuation and dose reductions due to AEs were 17% and 10%, respectively. Single-agent ibrutinib induced durable responses with a favorable benefit–risk profile in patients with previously treated MZL, confirming the role of BCR signaling in this malignancy. As the only approved therapy, ibrutinib provides a treatment option without chemotherapy for MZL. This study is registered at www.clinicaltrials.gov as #NCT01980628. PMID:28167659

Safety of vemurafenib in patients with BRAF V600 mutated metastatic melanoma: the Spanish experience.

PubMed

Arance, A M; Berrocal, A; Lopez-Martin, J A; de la Cruz-Merino, L; Soriano, V; Martín Algarra, S; Alonso, L; Cerezuela, P; La Orden, B; Espinosa, E

2016-11-01

Vemurafenib tolerability was assessed in a large, open-label, multicentre study in patients with BRAF V600 mutated advanced melanoma. We investigated safety, tolerability and efficacy of vemurafenib in Spanish patients participating in that study. Patients with previously treated or treatment-naive, unresectable stage IIIC or stage IV, BRAF V600 mutation-positive melanoma received vemurafenib 960 mg twice daily until disease progression, unacceptable toxicity, withdrawal of consent or death. The primary endpoint was safety; secondary endpoints included overall response rate (ORR), progression-free survival (PFS) and overall survival (OS). 301 Spanish patients were included, 70 % with M1c disease, 22 % with brain metastases and 51 % with prior systemic therapy for metastatic disease. Most frequent adverse events included fatigue (48 %), arthralgia (45 %), rash (41 %), photosensitivity (34 %) and skin neoplasms (21 %). Grade 3/4 adverse events occurred in 156 patients (52 %), including cutaneous squamous cell carcinoma (including keratoacanthoma; 16 %), fatigue (6 %) and arthralgia (5 %). The ORR was 28 % (95 % CI 23-34 %). Responses occurred in patients with brain metastases (18 %), elevated baseline lactate dehydrogenase (19 %) and poor performance status (15 %), and elderly patients (22 %). Median PFS was 5.8 (95 % CI 5.0-6.4) months; median OS was 10.5 (95 % CI 9.5-13.5) months. Our results for Spanish patients in the vemurafenib safety study indicate similar efficacy and a comparable safety profile in Spanish patients with no new safety signals compared with the overall population. Clinical benefit was demonstrated in poor-prognosis patients and in those with favourable baseline characteristics, suggesting that poor-prognosis patients may also benefit from vemurafenib treatment.

Adjuvant Nivolumab versus Ipilimumab in Resected Stage III or IV Melanoma.

PubMed

Weber, Jeffrey; Mandala, Mario; Del Vecchio, Michele; Gogas, Helen J; Arance, Ana M; Cowey, C Lance; Dalle, Stéphane; Schenker, Michael; Chiarion-Sileni, Vanna; Marquez-Rodas, Ivan; Grob, Jean-Jacques; Butler, Marcus O; Middleton, Mark R; Maio, Michele; Atkinson, Victoria; Queirolo, Paola; Gonzalez, Rene; Kudchadkar, Ragini R; Smylie, Michael; Meyer, Nicolas; Mortier, Laurent; Atkins, Michael B; Long, Georgina V; Bhatia, Shailender; Lebbé, Celeste; Rutkowski, Piotr; Yokota, Kenji; Yamazaki, Naoya; Kim, Tae M; de Pril, Veerle; Sabater, Javier; Qureshi, Anila; Larkin, James; Ascierto, Paolo A

2017-11-09

Nivolumab and ipilimumab are immune checkpoint inhibitors that have been approved for the treatment of advanced melanoma. In the United States, ipilimumab has also been approved as adjuvant therapy for melanoma on the basis of recurrence-free and overall survival rates that were higher than those with placebo in a phase 3 trial. We wanted to determine the efficacy of nivolumab versus ipilimumab for adjuvant therapy in patients with resected advanced melanoma. In this randomized, double-blind, phase 3 trial, we randomly assigned 906 patients (≥15 years of age) who were undergoing complete resection of stage IIIB, IIIC, or IV melanoma to receive an intravenous infusion of either nivolumab at a dose of 3 mg per kilogram of body weight every 2 weeks (453 patients) or ipilimumab at a dose of 10 mg per kilogram every 3 weeks for four doses and then every 12 weeks (453 patients). The patients were treated for a period of up to 1 year or until disease recurrence, a report of unacceptable toxic effects, or withdrawal of consent. The primary end point was recurrence-free survival in the intention-to-treat population. At a minimum follow-up of 18 months, the 12-month rate of recurrence-free survival was 70.5% (95% confidence interval [CI], 66.1 to 74.5) in the nivolumab group and 60.8% (95% CI, 56.0 to 65.2) in the ipilimumab group (hazard ratio for disease recurrence or death, 0.65; 97.56% CI, 0.51 to 0.83; P<0.001). Treatment-related grade 3 or 4 adverse events were reported in 14.4% of the patients in the nivolumab group and in 45.9% of those in the ipilimumab group; treatment was discontinued because of any adverse event in 9.7% and 42.6% of the patients, respectively. Two deaths (0.4%) related to toxic effects were reported in the ipilimumab group more than 100 days after treatment. Among patients undergoing resection of stage IIIB, IIIC, or IV melanoma, adjuvant therapy with nivolumab resulted in significantly longer recurrence-free survival and a lower rate of grade 3 or 4 adverse events than adjuvant therapy with ipilimumab. (Funded by Bristol-Myers Squibb and Ono Pharmaceutical; CheckMate 238 ClinicalTrials.gov number, NCT02388906 ; Eudra-CT number, 2014-002351-26 .).

Adjuvant Pembrolizumab versus Placebo in Resected Stage III Melanoma.

PubMed

Eggermont, Alexander M M; Blank, Christian U; Mandala, Mario; Long, Georgina V; Atkinson, Victoria; Dalle, Stéphane; Haydon, Andrew; Lichinitser, Mikhail; Khattak, Adnan; Carlino, Matteo S; Sandhu, Shahneen; Larkin, James; Puig, Susana; Ascierto, Paolo A; Rutkowski, Piotr; Schadendorf, Dirk; Koornstra, Rutger; Hernandez-Aya, Leonel; Maio, Michele; van den Eertwegh, Alfonsus J M; Grob, Jean-Jacques; Gutzmer, Ralf; Jamal, Rahima; Lorigan, Paul; Ibrahim, Nageatte; Marreaud, Sandrine; van Akkooi, Alexander C J; Suciu, Stefan; Robert, Caroline

2018-05-10

The programmed death 1 (PD-1) inhibitor pembrolizumab has been found to prolong progression-free and overall survival among patients with advanced melanoma. We conducted a phase 3 double-blind trial to evaluate pembrolizumab as adjuvant therapy in patients with resected, high-risk stage III melanoma. Patients with completely resected stage III melanoma were randomly assigned (with stratification according to cancer stage and geographic region) to receive 200 mg of pembrolizumab (514 patients) or placebo (505 patients) intravenously every 3 weeks for a total of 18 doses (approximately 1 year) or until disease recurrence or unacceptable toxic effects occurred. Recurrence-free survival in the overall intention-to-treat population and in the subgroup of patients with cancer that was positive for the PD-1 ligand (PD-L1) were the primary end points. Safety was also evaluated. At a median follow-up of 15 months, pembrolizumab was associated with significantly longer recurrence-free survival than placebo in the overall intention-to-treat population (1-year rate of recurrence-free survival, 75.4% [95% confidence interval {CI}, 71.3 to 78.9] vs. 61.0% [95% CI, 56.5 to 65.1]; hazard ratio for recurrence or death, 0.57; 98.4% CI, 0.43 to 0.74; P<0.001) and in the subgroup of 853 patients with PD-L1-positive tumors (1-year rate of recurrence-free survival, 77.1% [95% CI, 72.7 to 80.9] in the pembrolizumab group and 62.6% [95% CI, 57.7 to 67.0] in the placebo group; hazard ratio, 0.54; 95% CI, 0.42 to 0.69; P<0.001). Adverse events of grades 3 to 5 that were related to the trial regimen were reported in 14.7% of the patients in the pembrolizumab group and in 3.4% of patients in the placebo group. There was one treatment-related death due to myositis in the pembrolizumab group. As adjuvant therapy for high-risk stage III melanoma, 200 mg of pembrolizumab administered every 3 weeks for up to 1 year resulted in significantly longer recurrence-free survival than placebo, with no new toxic effects identified. (Funded by Merck; ClinicalTrials.gov number, NCT02362594 ; EudraCT number, 2014-004944-37 .).

Teaching Kids Not to Bully

MedlinePlus

... and ability to form and sustain friendships. Understanding Bullying Behavior Kids bully for many reasons. Some bully ... children they perceive as weak. Helping Kids Stop Bullying Let your child know that bullying is unacceptable ...

Final Rule (signed September 26, 2016)

EPA Pesticide Factsheets

New Listings of Substitutes; Changes of Listing Status; and Reinterpretation of Unacceptability for Closed Cell Foam Products under the SNAP Program; and Revision of Clean Air Act Section 608 Venting Prohibition for Propane.

Skid correction program : user's manual.

DOT National Transportation Integrated Search

2012-06-01

This document outlines methods for use by UDOT personnel to address pavements with unacceptable skid numbers. The program involves coordination between Safety, Pavement Management, Region, and Maintenance managers. A process has been recommended usin...

Superfund: Contaminated Sediments

EPA Pesticide Factsheets

Contaminated sediments are a significant environmental problem and contribute to the over 3,200 fish consumption advisories nationwide. The Superfund program cleans up sediment sites that present an unacceptable risk to human health or the environment.

SDDOT : safety program

DOT National Transportation Integrated Search

2000-05-01

The current safety and loss control program for the South Dakota Department of Transportation is not reaching its full potential and does not adequately prevent accidents and injuries. The Department has experienced an unacceptably high number of acc...

Proposed Rule (April 18, 2016)

EPA Pesticide Factsheets

Proposed Rule - Protection of Stratospheric Ozone: New Listings of Substitutes; Changes of Listing Status; Reinterpretation of Unacceptability for Closed Cell Foam Products under the Significant New Alternatives Policy Program; and Revision of Clean Air Ac

Attitudes toward jaguars and pumas and the acceptability of killing big cats in the Brazilian Atlantic Forest: An application of the Potential for Conflict Index2.

PubMed

Engel, Monica T; Vaske, Jerry J; Bath, Alistair J; Marchini, Silvio

2017-09-01

We explored the overall acceptability of killing jaguars and pumas in different scenarios of people-big cat interactions, the influence of attitudes toward big cats on acceptability, and the level of consensus on the responses. Data were obtained from 326 self-administered questionnaires in areas adjacent to Intervales State Park and Alto Ribeira State Park. Overall, people held slightly positive attitudes toward jaguars and pumas and viewed the killing of big cats as unacceptable. However, individuals that held negative attitudes were more accepting of killing. As the severity of people-big cat interactions increased, the level of consensus decreased. Knowing whether killing a big cat is acceptable or unacceptable in specific situations allows managers to anticipate conflict and avoid illegal killing of big cats.

Energy balance measurement: when something is not better than nothing.

PubMed

Dhurandhar, N V; Schoeller, D; Brown, A W; Heymsfield, S B; Thomas, D; Sørensen, T I A; Speakman, J R; Jeansonne, M; Allison, D B

2015-07-01

Energy intake (EI) and physical activity energy expenditure (PAEE) are key modifiable determinants of energy balance, traditionally assessed by self-report despite its repeated demonstration of considerable inaccuracies. We argue here that it is time to move from the common view that self-reports of EI and PAEE are imperfect, but nevertheless deserving of use, to a view commensurate with the evidence that self-reports of EI and PAEE are so poor that they are wholly unacceptable for scientific research on EI and PAEE. While new strategies for objectively determining energy balance are in their infancy, it is unacceptable to use decidedly inaccurate instruments, which may misguide health-care policies, future research and clinical judgment. The scientific and medical communities should discontinue reliance on self-reported EI and PAEE. Researchers and sponsors should develop objective measures of energy balance.

DEVELOPMENT OF AN ANTIBIOTIC OPTIONS INDEX FOR ANTIBIOTIC RESISTANCE MONITORING.

PubMed

Manomayitthikan, Taweesuk; Borlace, Glenn N; Kessomboon, Nusaraporn

2016-11-01

Using antibiogram data to indicate the overall antibiotic resistance of a pathogen is complicated by the multiple antibiotic susceptibilities reported in the antibiogram. The objectives of this study were to develop and determine the benefits of an Antibiotic Options Index (AOI); an index that summarizes antibiotic susceptibility data for a pathogen by presenting it as the availability of antibiotic treatment options. The AOI was calculated using antibiogram data for the seven most commonly isolated pathogens from the National Antimicrobial Resistance Surveillance Center of Thailand between 1998 and 2014 and was classified as acceptable (AOI ≥ 0.8) or unacceptable (AOI < 0.8) based on the availability of treatment options. The AOI identified two problematic pathogens: Acinetobacter baumannii and methicillin-resistant Staphylococcus aureus (MRSA). For A. baumannii, the probability of having at least two viable antibiotic treatment options (AOIm2) decreased from an acceptable level (0.93) in 1998 to an unacceptable level (0.53) in 2014 and for MRSA the AOIm2 decreased from an acceptable level (0.82) in 1998 to an unacceptable level (0.47) in 2014. By including the idea that the problem with increasing antibiotic resistance is a problem with treating infections, the AOI effectively compiles susceptibility data to present it as the probability of having effective antibiotic treatment. This index is calculated from widely available antibiogram data, making it more suitable to be used to monitor antibiotic resistance at the hospital, provincial and national levels.

Comparison between auricular and standard rectal thermometers for the measurement of body temperature in dogs

PubMed Central

Sousa, Marlos G.; Carareto, Roberta; Pereira-Junior, Valdo A.; Aquino, Monally C.C.

2011-01-01

Although the rectal mucosa remains the traditional site for measuring body temperature in dogs, an increasing number of clinicians have been using auricular temperature to estimate core body temperature. In this study, 88 mature healthy dogs had body temperatures measured with auricular and rectal thermometers. The mean temperature and confidence intervals were similar for each method, but Bland-Altman plots showed high biases and limits of agreement unacceptable for clinical purposes. The results indicate that auricular and rectal temperatures should not be interpreted interchangeably. PMID:21731094

Comparison between auricular and standard rectal thermometers for the measurement of body temperature in dogs.

PubMed

Sousa, Marlos G; Carareto, Roberta; Pereira-Junior, Valdo A; Aquino, Monally C C

2011-04-01

Although the rectal mucosa remains the traditional site for measuring body temperature in dogs, an increasing number of clinicians have been using auricular temperature to estimate core body temperature. In this study, 88 mature healthy dogs had body temperatures measured with auricular and rectal thermometers. The mean temperature and confidence intervals were similar for each method, but Bland-Altman plots showed high biases and limits of agreement unacceptable for clinical purposes. The results indicate that auricular and rectal temperatures should not be interpreted interchangeably.

Prostate Cancer: Improving the Flow of Research.

PubMed

Lawton, Colleen A F

2018-04-01

Prostate cancer is the most common nonskin cancer diagnosed in U.S. men and kills over 27 000 men annually. Thus, improving the outcomes for patients diagnosed with this disease is imperative. There has been a considerable amount of research done over the past several decades resulting in more cures than ever, but the death rate is still unacceptable. This oration addresses the progress that we have made over the past several decades and outlines the work yet to be done, as well as some processes to make that work happen. © RSNA, 2018.

Joint Polar Satellite System

NASA Technical Reports Server (NTRS)

Trenkle, Timothy; Driggers, Phillip

2011-01-01

The Joint Polar Satellite System (JPSS) is a joint NOAA/NASA mission comprised of a series of polar orbiting weather and climate monitoring satellites which will fly in a sun-synchronous orbit, with a 1330 equatorial crossing time. JPSS resulted from the decision to reconstitute the National Polar-orbiting Operational Environmental Satellite System (NPOESS) into two separate programs, one to be run by the Department of Defense (DOD) and the other by NOAA. This decision was reached in early 2010, after numerous development issues caused a series of unacceptable delays in launching the NPOESS system.

Evaluation of hydrogen as a cryogenic wind tunnel test gas

NASA Technical Reports Server (NTRS)

Haut, R. C.

1977-01-01

The nondimensional ratios used to describe various flow situations in hydrogen were determined and compared with the corresponding ideal diatomic gas ratios. The results were used to examine different inviscid flow configurations. The relatively high value of the characteristic rotational temperature causes the behavior of hydrogen, under cryogenic conditions, to deviate substantially from the behavior of an ideal diatomic gas in the compressible flow regime. Therefore, if an idea diatomic gas is to be modeled, cryogenic hydrogen is unacceptable as a wind tunnel test gas in a compressible flow situation.

Microbiological safety of retail vacuum-packed and modified-atmosphere-packed cooked meats at end of shelf life.

PubMed

Sagoo, S K; Little, C L; Allen, G; Williamson, K; Grant, K A

2007-04-01

A study of retail modified-atmosphere-packed and vacuum-packed cooked ready-to-eat meats was undertaken from September through mid-November 2003 to determine the microbiological quality at the end of shelf life and to establish any risk factors in the production, storage, and display of this product. Examination of 2,981 samples using Microbiological Guidelines criteria revealed that 66% were of satisfactory or acceptable microbiology quality, 33% were of unsatisfactory quality mainly due to high aerobic colony counts and Enterobacteriaceae concentrations, and 1% were of unacceptable quality due to the presence of Listeria monocytogenes at 100 CFU/g or higher (27 samples; range of 10(2) to 106 CFU/g) and Campylobacter jejuni (1 sample), indicating a risk to health. All samples at the end of the shelf life had satisfactory (<20 CFU/g) and/or acceptable (<102 CFU/g) levels of Staphylococcus aureus and Clostridium perfringens, four samples (<1%) had unsatisfactory levels of Escherichia coli (range of 102 to 106 CFU/g) and 5.5% of the samples contained L. monocytogenes at <20 CFU/g (4.8%) or between 20 and 100 CFU/g (0.7%). More samples of chicken (45%; 224 of 495 samples), beef (43%; 160 of 371 samples), and turkey (41%; 219 of 523 samples) were of unsatisfactory or unacceptable quality compared with ham (23%; 317 of 1,351 samples) or pork (32%; 67 of 206 samples). Twelve different L. monocytogenes typing characters (serotype-amplified fragment length polymorphism type-phage type) were evaluated for isolates recovered from samples of unacceptable quality, and the 1/2-IX-NT type was recovered from almost half (48%) of these samples. Salmonella was not detected in any samples examined. Risk factors identified for cooked meats that were microbiologically contaminated more frequently included vacuum packaging, packaging on retail premises, slicing, temperature not monitored in display units, and no hazard analysis system in place. Results from this study also suggest that the shelf life assigned to some modified-atmosphere-packed and vacuum-packed meats may not be appropriate.

A randomized, phase 2 study of cetuximab plus cisplatin with or without paclitaxel for the first-line treatment of patients with recurrent and/or metastatic squamous cell carcinoma of the head and neck.

PubMed

Bossi, P; Miceli, R; Locati, L D; Ferrari, D; Vecchio, S; Moretti, G; Denaro, N; Caponigro, F; Airoldi, M; Moro, C; Vaccher, E; Sponghini, A; Caldara, A; Rinaldi, G; Ferrau, F; Nolè, F; Lo Vullo, S; Tettamanzi, F; Hollander, L; Licitra, L

2017-11-01

B490 (EudraCT# 2011-002564-24) is a randomized, phase 2b, noninferiority study investigating the efficacy and safety of first-line cetuximab plus cisplatin with/without paclitaxel (CetCis versus CetCisPac) in patients with recurrent and/or metastatic squamous cell carcinoma of the head and neck (R/M SCCHN). Eligible patients had confirmed R/M SCCHN (oral cavity/oropharynx/larynx/hypopharynx/paranasal sinus) and no prior therapy for R/M disease. Cetuximab was administered on day 1 (2-h infusion, 400 mg/m2), then weekly (1-h infusions, 250 mg/m2). Cisplatin was given as a 1-h infusion (CetCis arm: 100 mg/m2; CetCisPac arm: 75 mg/m2) on day 1 of each cycle for a maximum of six cycles. Paclitaxel was administered as a 3-h infusion (175 mg/m2) on day 1 of each cycle. After six cycles, maintenance cetuximab was administered until disease progression or unacceptable toxicity. The primary end point was progression-free survival (PFS). We assumed a noninferiority margin of 1.40 as compatible with efficacy. A total of 201 patients were randomized 1 : 1 to each regimen; 191 were assessable. PFS with CetCis (median, 6 months) was noninferior to PFS with CetCisPac (median, 7 months) [HR for CetCis versus CetCisPac 0.99; 95% CI: 0.72-1.36, P = 0.906; margin of noninferiority (90% CI of 1.4) not reached]. Median overall survival was 13 versus 11 months (HR = 0.77; 95% CI: 0.53-1.11, P = 0.117). The overall response rates were 41.8% versus 51.7%, respectively (OR = 0.69; 95% CI: 0.38-1.20, P = 0.181). Grade ≥3 adverse event rates were 76% and 73% for CetCis versus CetCisPac, respectively, while grade 4 toxicities were lower in the two-drug versus three-drug arm (14% versus 33%, P = 0.015). No toxic death or sepsis were reported and cardiac events were negligible (1%). The two-drug CetCis regimen proved to be noninferior in PFS to a three-drug combination with CetCisPac. The median OS of both regimens is comparable with that observed in EXTREME, while the life-threatening toxicity rate appeared reduced. EudraCT# 2011-002564-24. © The Author 2017. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Landscape structure and management alter the outcome of a pesticide ERA: Evaluating impacts of endocrine disruption using the ALMaSS European Brown Hare model.

PubMed

Topping, Chris J; Dalby, Lars; Skov, Flemming

2016-01-15

There is a gradual change towards explicitly considering landscapes in regulatory risk assessment. To realise the objective of developing representative scenarios for risk assessment it is necessary to know how detailed a landscape representation is needed to generate a realistic risk assessment, and indeed how to generate such landscapes. This paper evaluates the contribution of landscape and farming components to a model based risk assessment of a fictitious endocrine disruptor on hares. In addition, we present methods and code examples for generation of landscape structures and farming simulation from data collected primarily for EU agricultural subsidy support and GIS map data. Ten different Danish landscapes were generated and the ERA carried out for each landscape using two different assumed toxicities. The results showed negative impacts in all cases, but the extent and form in terms of impacts on abundance or occupancy differed greatly between landscapes. A meta-model was created, predicting impact from landscape and farming characteristics. Scenarios based on all combinations of farming and landscape for five landscapes representing extreme and middle impacts were created. The meta-models developed from the 10 real landscapes failed to predict impacts for these 25 scenarios. Landscape, farming, and the emergent density of hares all influenced the results of the risk assessment considerably. The study indicates that prediction of a reasonable worst case scenario is difficult from structural, farming or population metrics; rather the emergent properties generated from interactions between landscape, management and ecology are needed. Meta-modelling may also fail to predict impacts, even when restricting inputs to combinations of those used to create the model. Future ERA may therefore need to make use of multiple scenarios representing a wide range of conditions to avoid locally unacceptable risks. This approach could now be feasible Europe wide given the landscape generation methods presented.

Quantitation of methylglyoxal bis(guanylhydrazone) in blood plasma and leukemia cells of patients receiving the drug.

PubMed

Seppänen, P; Alhonen-Hongisto, L; Siimes, M; Jänne, J

1980-11-15

Methylglyoxal bis(guanylhydrazone), a cytostatic compound which apparently interferes with the metabolism and/or functions of the natural polyamines (spermidine and spermine), was effectively taken up by cultured human lymphocytic leukemia cells, rapidly resulting in the formation of a concentration gradient of up to 1,000-fold across the cell membrane in cells grown in the presence of micromolar concentrations of the drug. For an anti-proliferative effect on the leukemia cells, an intracellular concentration of more than 0.5 mM was required. The uptake of methylglyoxal bis(guanylhydrazone) was critically dependent on the growth rate of the leukemia cells. Low intracellular concentrations of the drug were present in cells growing slowly, whereas in rapidly dividing cells the intracellular concentration of the drug approached 5mM. When given as repeated intravenous infusions to two leukemic children, methylglyoxal bis(guanylhydrazone) exhibited sharp and transient peaks of plasma concentration, the drug having an apparent half-life in plasma of only 1-2 h. However, as in cultured cells, the drug was rapidly concentrated in the leukemia cells, reaching concentrations that were distinctly anti-proliferative. In contrast to the rapid disappearance of methylglyoxal bis(guanylhydrazone) from plasma, the circulation leukemia cells retained the drug for a period of several days with only minimal decrease in the initial concentrations. Methylglyoxal bis(guanylhydrazone) was given to the patients for 1 to 2 months as intravenous infusions, the timing of which was determined by regular assays of the drug concentrations in the leukemia cells. In agreement with the results obtained with the cultured cells, and intracellular concentration of about 0.5 to 1mM was apparently required for growth-inhibitory action to occur. Regular determination of the cellular drug concentrations indicated that methylglyoxal bis(quanylhydrazone) could be given as weekly infusions. This treatment schedule represents much lower dosing of the drug than the earlier daily regimens which were commonly associated with unacceptable toxicity.

Compound Words: A Problem in Post-Coordinate Retrieval Systems

ERIC Educational Resources Information Center

Jones, Kevin P.

1971-01-01

Compound words cause some difficulty in post-coordinate indexing systems: if too many are fractured, or the wrong categories are selected for fracturing noise will be produced at unacceptable levels on retrieval. (Author/MM)

DESIGN CONSIDERATION INVOLVING ACTIVE SEDIMENT CAPS

EPA Science Inventory

When contaminated sediments pose unacceptable risks to human health and the environment, management activities such as removal, treatment, or isolation of contaminated sediments may be required. Various capping designs are being considered for isolating contaminated sediment are...

Reception of distorted speech.

DOT National Transportation Integrated Search

1973-12-01

Noise, either in the form of masking or in the form of distortion products, interferes with speech intelligibility. When the signal-to-noise ratio is bad enough, articulation can drop to unacceptably--even dangerously--low levels. However, listeners ...

Evaluation of a modified cleaning procedure in the prevention of carbapenem-resistant Acinetobacter baumannii clonal spread in a burn intensive care unit using a high-sensitivity luminometer.

PubMed

Casini, B; Selvi, C; Cristina, M L; Totaro, M; Costa, A L; Valentini, P; Barnini, S; Baggiani, A; Tagliaferri, E; Privitera, G

2017-01-01

Enhanced environmental cleaning practices are among the most accepted measures for controlling the spread of carbapenem-resistant Acinetobacter baumannii (CR-Ab). To evaluate the impact of heightened cleaning on an ongoing CR-Ab outbreak in a burn intensive care unit (BICU) of an Italian teaching hospital, where chlorhexidine-60% isopropyl alcohol was applied as a complementary disinfectant on high-touch surfaces. Compliance with the microbial limit proposed for the BICU by AFNOR-NF-S90-351 (20 colony-forming units/100cm 2 ) was assessed by plate count, and compared with the results obtained with intracellular adenosine triphosphate (ATP) detection. Genotyping was performed using pulsed-field gel electrophoresis. During the standard cleaning regimen, three out of 23 samples (13%) gave results over the AFNOR limit and five (21.7%) showed unacceptable ATP levels with 100 relative light units/100cm 2 as the benchmark limit (sensibility 86.4%, specificity 92.2%). Following improvement of the cleaning procedure, only two samples out of 50 (4%) did not satisfy the microbiological criteria and seven (14%) exceeded the ATP limit. In a successive phase, eight of 30 samples collected showed unacceptable results (27%). Adding chlorhexidine-60% isopropyl alcohol as complementary disinfectant proved to be effective for reducing environmental microbial contamination, ATP levels and CR-Ab infection/colonization in patients admitted to the BICU. Real-time monitoring by ATP assay was useful for managing the cleaning schedule and reducing hospital infections, although the calculated values must be interpreted as cleanliness indicators rather than risk indicators. Copyright © 2016 The Healthcare Infection Society. Published by Elsevier Ltd. All rights reserved.

Candidiasis drug discovery and development: new approaches targeting virulence for discovering and identifying new drugs

PubMed Central

Pierce, Christopher G.; Lopez-Ribot, Jose L.

2014-01-01

Introduction Targeting pathogenetic mechanisms rather than essential processes represents a very attractive alternative for the development of new antibiotics. This may be particularly important in the case of antimycotics, due to the urgent need for novel antifungal drugs and the paucity of selective fungal targets. The opportunistic pathogenic fungus Candida albicans is the main etiological agent of candidiasis, the most common human fungal infection. These infections carry unacceptably high mortality rates, a clear reflection of the many shortcomings of current antifungal therapy, including the limited armamentarium of antifungal agents, their toxicity, and the emergence of resistance. Moreover the antifungal pipeline is mostly dry. Areas covered This review covers some of the most recent progress towards understanding C. albicans pathogenetic processes and how to harness this information for the development of anti-virulence agents. The two principal areas covered are filamentation and biofilm formation, as C. albicans pathogenicity is intimately linked to its ability to undergo morphogenetic conversions between yeast and filamentous morphologies and to its ability to form biofilms. Expert opinion We argue that filamentation and biofilm formation represent high value targets, yet clinically unexploited, for the development of novel anti-virulence approaches against candidiasis. Although this has proved a difficult task despite increasing understanding at the molecular level of C. albicans virulence, we highlight new opportunities and prospects for antifungal drug development targeting these two important biological processes. PMID:23738751

The European medicines agency review of bosutinib for the treatment of adult patients with chronic myelogenous leukemia: summary of the scientific assessment of the committee for medicinal products for human use.

PubMed

Hanaizi, Zahra; Unkrig, Christoph; Enzmann, Harald; Camarero, Jorge; Sancho-Lopez, Arantxa; Salmonson, Tomas; Gisselbrecht, Christian; Laane, Edward; Pignatti, Francesco

2014-04-01

On March 27, 2013, a conditional marketing authorization valid throughout the European Union was issued for bosutinib (Bosulif) for the treatment of adult patients with chronic-phase, accelerated-phase, and blast-phase Philadelphia chromosome positive (Ph⁺) chronic myelogenous leukemia (CML) previously treated with one tyrosine kinase inhibitor or more and for whom imatinib, nilotinib, and dasatinib are not considered appropriate treatment options. Bosutinib is a kinase inhibitor that targets the BCR-ABL kinase. The recommended dose is 500 mg of bosutinib once daily. The main evidence of efficacy for bosutinib was based on a CML subgroup analysis of study 3160A4-200, a phase I/II study of bosutinib in Ph⁺ leukemia in imatinib-resistant or intolerant CML. The subgroup was defined based on the presence of a BCR-ABL kinase domain mutation that would be expected to confer resistance to dasatinib (F317, E255) or nilotinib (E255, Y253, F359) and expected to have sensitivity to bosutinib or based on the presence of medical conditions or prior toxicities that may predispose the patient to unacceptable risk in the setting of nilotinib or dasatinib therapy. A conditional marketing authorization was granted because of the limited evidence of efficacy and safety currently supporting this last-line indication.

Tamoxifen in the treatment of advanced or recurrent endometrial carcinoma: a Gynecologic Oncology Group study.

PubMed

Thigpen, T; Brady, M F; Homesley, H D; Soper, J T; Bell, J

2001-01-15

In two large Gynecologic Oncology Group studies of patients with advanced or recurrent endometrial carcinoma and no previous systemic therapy, progestins have demonstrated activity against advanced or recurrent endometrial carcinoma with response rates between 15% and 25%. Tamoxifen has been reported as variously active or inactive with or without previous systemic therapy. The purpose of this study was to determine whether tamoxifen exhibits enough activity in patients with advanced or recurrent endometrial carcinoma, who have not received systemic therapy, to warrant a phase III trial. Sixty-eight eligible patients with advanced or recurrent endometrial carcinoma received oral tamoxifen 20 mg bid until toxicity was unacceptable or disease progressed. Three complete (4%) and four partial (6%) responses were observed for an overall response rate of 10% (90% confidence interval [CI], 5.7% to 17.9%). Patients with tumors that were more anaplastic tended to respond less frequently. The median progression-free survival for all 68 eligible patients was 1.9 months (90% CI, 1.7 to 3.2 months). The median survival was 8.8 months (90% CI, 7.0 to 10.1 months). Tamoxifen demonstrated modest activity at best against endometrial carcinoma and does not warrant further investigation as a single agent for this disease. Ongoing trials will assess the sequential use of tamoxifen and progestational agents.

Performance of improved bacterial cellulose application in the production of functional paper.

PubMed

Basta, A H; El-Saied, H

2009-12-01

The purpose of this work was to study the feasibility of producing economic flame retardant bacterial cellulose (BC) and evaluating its behaviour in paper production. This type of BC was prepared by Gluconacetobacter subsp. xylinus and substituting the glucose in the cultivation medium by glucose phosphate as a carbon source; as well as using corn steep liquor as a nitrogen source. The investigated processing technique did not dispose any toxic chemicals that pollute the surroundings or cause unacceptable effluents, making the process environmentally safe. The fire retardant behaviour of the investigated BC has been studied by non-isothermal thermogravimetric analysis (TGA & DTGA). The activation energy of each degradation stage and the order of degradation were estimated using the Coats-Redfern equation and the least square method. Strength, optical properties, and thermogravimetric analysis of BC-phosphate added paper sheets were also tested. The study confirmed that the use of glucose phosphate along with glucose was significant in the high yield production of phosphate containing bacterial cellulose (PCBC1); more so than the use of glucose phosphate alone (PCBC2). Incorporating 5% of the PCBC with wood pulp during paper sheet formation was found to significantly improve kaolin retention, strength, and fire resistance properties as compared to paper sheets produced from incorporating bacterial cellulose (BC). This modified BC is a valuable product for the preparation of specialized paper, in addition to its function as a fillers aid.

Necessity of toxicity assessment in Turkish industrial discharges (examples from metal and textile industry effluents).

PubMed

Sponza, Delia Teresa

2002-01-01

Toxicity of some organic and inorganic chemicals to microorganisms is an important consideration in assessing their environmental impact against their economic benefits. Microorganisms play an important role in several environmental processes, both natural and engineered. Some organic and inorganics at toxic levels have been detected in industrial discharges resulting in plant upsets and discharge permit violations. In addition to this, even though in some cases the effluent wastewater does not exceed the discharge limits, the results of toxicity tests show potential toxicity. Toxicity knowledge of effluents can benefit treatment plant operators in optimising plant operation, setting pre-treatment standards, and protecting receiving water quality and in establishing sewer discharge permits to safeguard the plant. In the Turkish regulations only toxicity dilution factor (TDF) with fish is part of the toxicity monitoring program of permissible wastewater discharge. In various countries, laboratory studies involving the use of different organisms and protocol for toxicity assessment was conducted involving a number of discharges. In this study, it was aimed to investigate the acute toxicity of textile and metal industry wastewaters by traditional and enrichment toxicity tests and emphasize the importance of toxicity tests in wastewater discharge regulations. The enrichment toxicity tests are novel applications and give an idea whether there is potential toxicity or growth limiting and stimulation conditions. Different organisms were used such as bacteria (Floc and Coliform bacteria) algae (Chlorella sp.). fish (Lepistes sp.) and protozoan (Vorticella sp.) to represent four tropic levels. The textile industry results showed acute toxicity for at least one organism in 8 out of 23 effluent samples. Acute toxicity for at least two organisms in 7 out of 23 effluent sampling was observed for the metal industry. The toxicity test results were assessed with chemical analyses such as COD, BOD, color and heavy metals. It was observed that the toxicity of the effluents could not be explained by using physicochemical analyses in 5 cases for metal and 4 cases for the textile industries. The results clearly showed that the use of bioassay tests produce additional information about the toxicity potential of industrial discharges and effluents.

Overview of SNAP

EPA Pesticide Factsheets

Section 612(c) of the Clean Air Act (CAA) requires the Agency to publish a list of acceptable and unacceptable substitutes for ozone-depleting substances (ODS). The SNAP program does not require that substitutes be risk- free to be found acceptable.

DESIGN CONSIDERATION INVOLVING ACTIVE SEDIMENT CAPS (PRESENTATION)

EPA Science Inventory

When contaminated sediments pose unacceptable risks to human health and the environment, management activities such as removal, treatment, or isolation of contaminated sediments may be required. Various capping designs are being considered for isolating contaminated sediment are...

19 CFR 134.45 - Approved markings of country name.

Code of Federal Regulations, 2011 CFR

2011-04-01

... “Brasil” for “Brazil” and “Italie” for “Italy,” are acceptable. (c) Adjectival form. The adjectival form... “Brazil nuts” are unacceptable. (d) Colonies, possessions, or protectorates. The name of a colony...

19 CFR 134.45 - Approved markings of country name.

Code of Federal Regulations, 2014 CFR

2014-04-01

... “Brasil” for “Brazil” and “Italie” for “Italy,” are acceptable. (c) Adjectival form. The adjectival form... “Brazil nuts” are unacceptable. (d) Colonies, possessions, or protectorates. The name of a colony...

19 CFR 134.45 - Approved markings of country name.

Code of Federal Regulations, 2013 CFR

2013-04-01

... “Brasil” for “Brazil” and “Italie” for “Italy,” are acceptable. (c) Adjectival form. The adjectival form... “Brazil nuts” are unacceptable. (d) Colonies, possessions, or protectorates. The name of a colony...

19 CFR 134.45 - Approved markings of country name.

Code of Federal Regulations, 2012 CFR

2012-04-01

... “Brasil” for “Brazil” and “Italie” for “Italy,” are acceptable. (c) Adjectival form. The adjectival form... “Brazil nuts” are unacceptable. (d) Colonies, possessions, or protectorates. The name of a colony...

43 CFR 3101.1-4 - Modification or waiver of lease terms and stipulations.

Code of Federal Regulations, 2013 CFR

2013-10-01

... determines that the factors leading to its inclusion in the lease have changed sufficiently to make the... unacceptable impacts. If the authorized officer has determined, prior to lease issuance, that a stipulation...

43 CFR 3101.1-4 - Modification or waiver of lease terms and stipulations.

Code of Federal Regulations, 2012 CFR

2012-10-01

... determines that the factors leading to its inclusion in the lease have changed sufficiently to make the... unacceptable impacts. If the authorized officer has determined, prior to lease issuance, that a stipulation...

10 CFR 862.5 - Procedures for removal of downed aircraft.

Code of Federal Regulations, 2014 CFR

2014-01-01

... this section, may be assumed to be indicative of hostile intent by security forces at such sites. (b)(1... excessive resource loss of property damage or an unacceptable disruption of federal activities; (iii) The...

10 CFR 862.5 - Procedures for removal of downed aircraft.

Code of Federal Regulations, 2011 CFR

2011-01-01

... this section, may be assumed to be indicative of hostile intent by security forces at such sites. (b)(1... excessive resource loss of property damage or an unacceptable disruption of federal activities; (iii) The...

10 CFR 862.5 - Procedures for removal of downed aircraft.

Code of Federal Regulations, 2010 CFR

2010-01-01

... this section, may be assumed to be indicative of hostile intent by security forces at such sites. (b)(1... excessive resource loss of property damage or an unacceptable disruption of federal activities; (iii) The...

10 CFR 862.5 - Procedures for removal of downed aircraft.

Code of Federal Regulations, 2012 CFR

2012-01-01

... this section, may be assumed to be indicative of hostile intent by security forces at such sites. (b)(1... excessive resource loss of property damage or an unacceptable disruption of federal activities; (iii) The...

10 CFR 862.5 - Procedures for removal of downed aircraft.

Code of Federal Regulations, 2013 CFR

2013-01-01

... this section, may be assumed to be indicative of hostile intent by security forces at such sites. (b)(1... excessive resource loss of property damage or an unacceptable disruption of federal activities; (iii) The...

The use of micro-surfacing for pavement preservation : final report.

DOT National Transportation Integrated Search

2009-04-01

The Maine Department of Transportation (MaineDOT) is responsible for maintaining approximately 8300 : miles of public highways. Maintenance of these highways consists of rehabilitation or reconstruction : when the road has deteriorated to an unaccept...

Performance evaluation of subgrade stabilization with recycled materials.

DOT National Transportation Integrated Search

2016-02-29

Due to rising costs of good quality acceptable materials for remove/replace options and traditional : subgrade stabilization materials, MDOT is in need to identify potential recycled materials to treat : unacceptable subgrade soils. Use of recycled m...

Cluster-sample surveys and lot quality assurance sampling to evaluate yellow fever immunisation coverage following a national campaign, Bolivia, 2007.

PubMed

Pezzoli, Lorenzo; Pineda, Silvia; Halkyer, Percy; Crespo, Gladys; Andrews, Nick; Ronveaux, Olivier

2009-03-01

To estimate the yellow fever (YF) vaccine coverage for the endemic and non-endemic areas of Bolivia and to determine whether selected districts had acceptable levels of coverage (>70%). We conducted two surveys of 600 individuals (25 x 12 clusters) to estimate coverage in the endemic and non-endemic areas. We assessed 11 districts using lot quality assurance sampling (LQAS). The lot (district) sample was 35 individuals with six as decision value (alpha error 6% if true coverage 70%; beta error 6% if true coverage 90%). To increase feasibility, we divided the lots into five clusters of seven individuals; to investigate the effect of clustering, we calculated alpha and beta by conducting simulations where each cluster's true coverage was sampled from a normal distribution with a mean of 70% or 90% and standard deviations of 5% or 10%. Estimated coverage was 84.3% (95% CI: 78.9-89.7) in endemic areas, 86.8% (82.5-91.0) in non-endemic and 86.0% (82.8-89.1) nationally. LQAS showed that four lots had unacceptable coverage levels. In six lots, results were inconsistent with the estimated administrative coverage. The simulations suggested that the effect of clustering the lots is unlikely to have significantly increased the risk of making incorrect accept/reject decisions. Estimated YF coverage was high. Discrepancies between administrative coverage and LQAS results may be due to incorrect population data. Even allowing for clustering in LQAS, the statistical errors would remain low. Catch-up campaigns are recommended in districts with unacceptable coverage.

Classroom Misbehavior in the Eyes of Students: A Qualitative Study

PubMed Central

Sun, Rachel C. F.; Shek, Daniel T. L.

2012-01-01

Using individual interviews, this study investigated perceptions of classroom misbehaviors among secondary school students in Hong Kong (N = 18). Nineteen categories of classroom misbehaviors were identified, with talking out of turn, disrespecting teacher, and doing something in private being most frequently mentioned. Findings revealed that students tended to perceive misbehaviors as those actions inappropriate in the classroom settings and even disrupting teachers' teaching and other students' learning. Among various misbehaviors, talking out of turn and disrespecting teacher were seen as the most disruptive and unacceptable. These misbehaviors were unacceptable because they disturbed teaching and learning, and violated the values of respect, conformity, and obedience in the teacher-student relationship within the classroom. The frequency and intensity of misbehaviors would escalate if students found it fun, no punishment for such misbehaviors, or teachers were not authoritative enough in controlling the situations. Implications for further research and classroom management are discussed. PMID:22919316

For the greater goods? Ownership rights and utilitarian moral judgment.

PubMed

Millar, J Charles; Turri, John; Friedman, Ori

2014-10-01

People often judge it unacceptable to directly harm a person, even when this is necessary to produce an overall positive outcome, such as saving five other lives. We demonstrate that similar judgments arise when people consider damage to owned objects. In two experiments, participants considered dilemmas where saving five inanimate objects required destroying one. Participants judged this unacceptable when it required violating another's ownership rights, but not otherwise. They also judged that sacrificing another's object was less acceptable as a means than as a side-effect; judgments did not depend on whether property damage involved personal force. These findings inform theories of moral decision-making. They show that utilitarian judgment can be decreased without physical harm to persons, and without personal force. The findings also show that the distinction between means and side-effects influences the acceptability of damaging objects, and that ownership impacts utilitarian moral judgment. Copyright © 2014 Elsevier B.V. All rights reserved.

An audit of the quality of operation notes in an otolaryngology unit.

PubMed

Bateman, N D; Carney, A S; Gibbin, K P

1999-04-01

Hand-written operation notes are often produced as evidence in medico-legal cases. Incomplete and illegible notes, along with the use of confusing abbreviations, are a common source of weakness in a surgeon's defence. An audit of 100 sets of operation notes was carried out in a single otolaryngology department. Notes were scrutinised for the accuracy of data, ward, department and name of surgeon, as well as for the inclusion of unacceptable abbreviations. Using an aide-memoire attached to the front of the operation sheet, the audit was repeated with identical criteria. The aide-memoire improved the standard of operation note with respect to all measured criteria. Clear identification of operating surgeon improved from 74% to 93%, and the avoidance of unacceptable abbreviations rose from 53% to 84%. We conclude that a simple aide-memoire attached to operation note sheets can significantly improve the quality of note-keeping and potentially avoid medico-legal problems.

Effects of sevoflurane anaesthesia on recovery in children: a comparison with halothane.

PubMed

Lapin, S L; Auden, S M; Goldsmith, L J; Reynolds, A M

1999-01-01

We prospectively studied one hundred ASA physical status I-II children, ages six months to six years, undergoing myringotomy surgery. Children were randomly assigned to one of four anaesthetic groups receiving either halothane or sevoflurane for anaesthesia and oral midazolam premedication or no premedication. We found that children anaesthetized with sevoflurane had significantly faster recovery times and discharge home times than those who received halothane. Patients given oral midazolam premedication had significantly longer recovery times, but no delay in discharge home compared with those not premedicated. However, children anaesthetized with sevoflurane and no premedication had an unacceptably high incidence (67%) of postoperative agitation. The use of oral midazolam preoperatively did decrease the amount of postoperative agitation seen with sevoflurane. We conclude that although sevoflurane does shorten recovery times, the degree of associated postoperative agitation makes it unacceptable as a sole anaesthetic for myringotomy surgery.

Pulse compression using a tapered microstructure optical fiber.

PubMed

Hu, Jonathan; Marks, Brian S; Menyuk, Curtis R; Kim, Jinchae; Carruthers, Thomas F; Wright, Barbara M; Taunay, Thierry F; Friebele, E J

2006-05-01

We calculate the pulse compression in a tapered microstructure optical fiber with four layers of holes. We show that the primary limitation on pulse compression is the loss due to mode leakage. As a fiber's diameter decreases due to the tapering, so does the air-hole diameter, and at a sufficiently small diameter the guided mode loss becomes unacceptably high. For the four-layer geometry we considered, a compression factor of 10 can be achieved by a pulse with an initial FWHM duration of 3 ps in a tapered fiber that is 28 m long. We find that there is little difference in the pulse compression between a linear taper profile and a Gaussian taper profile. More layers of air-holes allows the pitch to decrease considerably before losses become unacceptable, but only a moderate increase in the degree of pulse compression is obtained.

Ecotoxicological studies of environmental samples from Buenos Aires area using a standardized amphibian embryo toxicity test (AMPHITOX).

PubMed

Herkovits, Jorge; Perez-Coll, Cristina; Herkovits, Francisco D

2002-01-01

The toxicity of 34 environmental samples from potentially polluted and reference stations were evaluated by means of the AMPHITOX test from acute to chronic exposure according to the toxicity found in each sample. The samples were obtained from surface and ground water, leaches, industrial effluents and soils. The data, expressed in acute, short-term chronic and chronic Toxicity Units (TUa, TUstc and TUc) resulted in a maximal value of 1000 TUc, found in a leach, while the lower toxicity value was 1.4 TUa corresponding to two surface water samples. In five samples (four providing from reference places) no toxicity was detected. The results point out the possibility of evaluating the toxicity of a wide diversity of samples by means of AMPHITOX as a customized toxicity test. The fact that almost all samples with suspected toxicity in rivers and streams from the Metropolitan area of Buenos Aires city resulted toxic, indicates the need of enhanced stewardship of chemical substances for environmental and human health protection purposes.

A Framework to Evaluate Wildlife Feeding in Research, Wildlife Management, Tourism and Recreation

PubMed Central

Dubois, Sara; Fraser, David

2013-01-01

Simple Summary Human feeding of wildlife is a world-wide phenomenon with very diverse effects on conservation, animal welfare and public safety. From a review of the motivations, types and consequences of wildlife feeding, an evaluative framework is presented to assist policy-makers, educators and managers to make ethical- and biologically-based decisions about the appropriateness of feeding wildlife in the context of research, wildlife management, tourism and recreation. Abstract Feeding of wildlife occurs in the context of research, wildlife management, tourism and in opportunistic ways. A review of examples shows that although feeding is often motivated by good intentions, it can lead to problems of public safety and conservation and be detrimental to the welfare of the animals. Examples from British Columbia illustrate the problems (nuisance animal activity, public safety risk) and consequences (culling, translocation) that often arise from uncontrolled feeding. Three features of wildlife feeding can be distinguished: the feasibility of control, the effects on conservation and the effects on animal welfare. An evaluative framework incorporating these three features was applied to examples of feeding from the literature. The cases of feeding for research and management purposes were generally found to be acceptable, while cases of feeding for tourism or opportunistic feeding were generally unacceptable. The framework should allow managers and policy-makers to distinguish acceptable from unacceptable forms of wildlife feeding as a basis for policy, public education and enforcement. Many harmful forms of wildlife feeding seem unlikely to change until they come to be seen as socially unacceptable. PMID:26479747

Community attitudes toward breastfeeding in public places among Western Australia Adults, 1995-2009.

PubMed

Meng, Xingqiong; Daly, Alison; Pollard, Christina Mary; Binns, Colin William

2013-05-01

Community attitudes toward breastfeeding in public influence how comfortable women feel about continuing breastfeeding. Knowledge of the social context helps target breastfeeding-promoting interventions. To examine trends in Western Australian adult attitudes toward breastfeeding in public places. As part of 5 cross-sectional surveys from the Western Australian Nutrition Monitor Survey Series conducted between 1995 and 2009, 5496 adults aged 18 to 64 years were asked whether it was acceptable for mothers to breastfeed their babies in public places, including shopping centers, workplaces, and restaurants, and on public transport. Descriptive statistics and multinomial regressions were used to describe factors associated with attitudes toward publicly breastfeeding. There was no change in the acceptance of breastfeeding in shopping centers, restaurants, and workplaces and on public transport over time, but in 2009, significantly fewer people said that it was unacceptable to breastfeed in public compared with 1995. Women, people older than 44 years, those born outside Australia, and the less educated were those most likely to say that breastfeeding in public was unacceptable. In the years that the question was asked, more than 97% of respondents said that breastfeeding was acceptable if a separate room was provided. Making breastfeeding acceptable and pleasant for mothers in public spaces is a key policy recommendation. Women, people older than 44 years, and those born outside Australia were most likely to respond that breastfeeding in public was unacceptable unless a room was provided. Given that, on average, 70% of the population said that breastfeeding in public was acceptable, investigation into why some women do not think so is warranted.

A Comparison of Spectacles Purchased Online and in UK Optometry Practice.

PubMed

Alderson, Alison J; Green, Alison; Whitaker, David; Scally, Andrew J; Elliott, David B

2016-10-01

To compare spectacles bought online with spectacles from optometry practices. Thirty-three participants consisting of single vision spectacle wearers with either a low (N = 12, mean age 34 ± 14 years) or high prescription (N = 11, mean age 28 ± 9 years) and 10 presbyopic participants (mean age 59 ± 4 years) wearing progressive addition lenses (PALs) purchased 154 pairs of spectacles online and 154 from UK optometry practices. The spectacles were compared via participant-reported preference, acceptability, and safety; the assessment of lens, frame, and fit quality; and the accuracy of the lens prescriptions to international standard ISO 21987:2009. Participants preferred the practice spectacles (median ranking 4th, IQR 1-6) more than online (6th, IQR 4-8; Mann-Whitney U = 7345, p < 0.001) and practice PALs (median ranking 2nd, IQR 1-4) were particularly preferred (online 6.5th, IQR 4-9, Mann-Whitney U = 455, p < 0.001). Of those deemed unacceptable and unsafe, significantly more were bought online (unacceptable: online 43/154 vs. practice 15/154, Fisher's exact p = 0.0001; unsafe: online 14/154 vs. practice 5/154, Fisher's exact p = 0.03). Participants preferred spectacles from optometry practice rather than those bought online, despite lens quality and prescription accuracy being similar. A greater number of online spectacles were deemed unsafe or unacceptable because of poor spectacle frame fit, poor cosmetic appearance, and inaccurate optical centration. This seems particularly pertinent to PAL lenses, which are known to increase falls risk. Recommendations are made to improve both forms of spectacle provision.

Optical analysis of high power free electron laser resonators

NASA Astrophysics Data System (ADS)

Knapp, C. E.; Viswanathan, V. K.; Appert, Q. D.; Bender, S. C.; McVey, B. D.

1987-06-01

The first part of this paper briefly describes the optics code used at Los Alamos National Laboratory to do optical analyses of various components of a free electron laser. The body of the paper then discusses the recent results in modeling low frequency gratings and ripple on the surfaces of liquid-cooled mirrors. The ripple is caused by structural/thermal effects in the mirror surface due to heating by optical absorption in high power resonators. Of interest is how much ripple can be permitted before diffractive losses or optical mode distortions become unacceptable. Preliminary work is presented involving classical diffraction problems to support the ripple study. The limitations of the techniques are discussed and the results are compared to experimental results where available.

24 CFR 51.102 - Responsibilities.

Code of Federal Regulations, 2011 CFR

2011-04-01

... areas and advise local officials, developers, and planning groups of the unacceptability of sites... the suitability of the acoustical environment of proposed projects; (2) Notify applicants of any... acceptability standards in commenting on the prospective impacts of transportation facilities and other noise...

24 CFR 51.102 - Responsibilities.

Code of Federal Regulations, 2010 CFR

2010-04-01

... areas and advise local officials, developers, and planning groups of the unacceptability of sites... the suitability of the acoustical environment of proposed projects; (2) Notify applicants of any... acceptability standards in commenting on the prospective impacts of transportation facilities and other noise...

Time out

MedlinePlus

... but no more than 5 minutes. Once your child shows bad behavior, explain clearly what the unacceptable behavior is, and ... a grudge -- let the issue go. Since your child has done the time out, there is no need to continue to discuss the bad behavior.

Railroad right-of-way incident analysis research.

DOT National Transportation Integrated Search

2011-04-01

Locations of railroad right-of-way incidents in this research were identified as hotspots. These can be defined as highway-rail grade crossings or locations along the railroad right-of-way where collision or trespassing risk is unacceptably high and ...

Analysis of en route operational errors : probability of resolution and time-on-position.

DOT National Transportation Integrated Search

2012-02-01

The Federation Administrations Air Traffic Control Organization Safety Management System (SMS) is : designed to prevent the introduction of unacceptable safety risk into the National Airspace System. One of the : most important safety metrics used...

JPRS Report, West Europe.

DTIC Science & Technology

1987-08-12

Isleifur Gunnarsson, Thorsteinn Palsson, Fridrik Sophusson, Fridjon Thordarson , Ellert Schräm and Thorvaldur Gardar Kristjansson. They received from three...Fridjon Thordarson and Eggert Haukdal, agreed with that view that the share of the regions was unacceptable. Matthias Bjarnason only said that he

Low-energy impact resistance of graphite-epoxy plates and ALS honeycomb sandwich panels

NASA Technical Reports Server (NTRS)

Hui, David

1989-01-01

Low energy impact may be potentially dangerous for many highly optimized stiff structures. Impact by foreign objects such as birds, ice, and runways stones or dropping of tools occur frequently and the resulting damage and stress concentrations may be unacceptable from a designer's standpoint. The barely visible, yet potentially dangerous dents due to impact of foreign objects on the Advanced Launch System (ALS) structure are studied. Of particular interest is the computation of the maximum peak impact force for a given impactor mass and initial velocity. The theoretical impact forces will be compared with the experimental dropweight results for the ALS face sheets alone as well as the ALS honeycomb sandwich panels.

Testing of selected pharmacological agents for capturing waterfowl [Annual Progress Report

USGS Publications Warehouse

Cline, D.R.

1970-01-01

The response of game-farm mallards (Frost strain) to seven pharmacological immobilizing agents was evaluated in Phase I of a planned four-phase study. A limited amount of testing was also done with wild mallards. Single dosages were administered to determine the mean effective dose (ED50) and mean lethal dose (LD50), The therapeutic index, or safety factor (LD50/ED50), and palatability were also established. Optimum dosage rates of compounds administered orally on baits were not considered in this phase of the study. Compounds were-administered by intubation and calculated in terms of mg/kg. All except one compound produced narcosis within 5 minutes at the effective dose rate.Immobilization periods for the seven compounds ranged from 7-24 minutes, and recovery periods from 1.0-6.5 hours. Such wide variations in actions of the compounds can be attributed to a compound's rate of absorption, the ease with which it passes the blood-brain barrier, its solubility in tissues, and its rate of metabolism in the liver and kidneys. Length of both the immobilization and recovery periods were extended when dosages were increased. There was no delayed mortality among survivors with any of the seven compounds at either the ED50 or LD50. Females were generally more sensitive to the anesthetizing agents than males. The ED50 for wild mallards was substantially higher than that for the experimental game-farm birds for the two compounds on which this was tested.Tribromoethanol (Avertin of Winthrop Laboratories) satisfied all test criteria an Phase I and will be subjected to more intensive investigation in ensuing tests. Thiopental sodium (Pentothal of Amdal Company) and pentobarbital sodium (Nembutal of Abbott Laboratories) were judged to be marginal. Although their therapeutic indexes were good (5.00), recovery periods were prolonged and toxic convulsions occurred at medium to high dose rates as the LD50 was approached.Alpha-chloralose (Fisher Scientific) proved least promising of the seven compounds, mainly because of its unacceptable therapeutic index (2.25) and because it possesses prolonged induction and recovery periods. Two new experimental drugs, methoxymol and metomidate (Pitman-Moore), appeared effective and safe when administered by intubation but produced a taste aversion when added to bait. Rejection because of taste was also a problem with secobarbital (Seconal of Elanco Products), and its therapeutic index of 2.75 was unacceptable. Monitoring of heart and respiratory rates, and body temperature by telemetry showed promise as a technique for determining physiological response to drug action.

Noninvasive sensors in critical care medicine: near-infrared spectroscopy for the detection of altered microvascular blood flow in severe sepsis and septic shock

NASA Astrophysics Data System (ADS)

Walz, J. Matthias; Soller, Babs; Soyemi, Olusola; Yang, Ye; Landry, Michelle; Heard, Stephen O.

2006-10-01

It is estimated that 750,000 cases of severe sepsis occur in the United States annually, at least 225,000 of which are fatal, resulting in significant utilization of healthcare resources and expenses. Significant progress in the understanding of pathophysiology and treatment of this condition has been made lately. Among the newer treatment strategies for critically ill patients are the administration of early goal directed therapy, and Recombinant Human Activated Protein C (Drotrecogrin alfa (activated) [DTAA]) for severe sepsis. However, mortality remains unacceptably high.

Thermal Modeling and Testing of the Edison Demonstration of Smallsat Networks Project

NASA Technical Reports Server (NTRS)

Coker, Robert

2014-01-01

NASA's Edison program is intending to launch the Edison Demonstration of Smallsat Networks (EDSN) project, a swarm of 8 1.5U cubesats in the fall of 2014 to demonstrate intra-swarm communications and multi-point in situ space physics data acquisition. Due to late changes in the duty cycles of various components, potential overheating issues appeared. In addition, it was determined that capacity loss due to the coldness of the batteries was unacceptable, so mitigation was required. This paper will discuss the thermal modeling, testing, and results of the EDSN mission.

STEWARDSHIP: A Conceptual Imperative For Managerial Effectiveness In The Nigerian Health System

PubMed Central

2007-01-01

Unacceptable health status indicators such as high infant and maternal mortality rates and low life expectancy have continued unabated inspite of government efforts to change it. This paper espouses the concept of stewardship as a selfless, ethical, cost effective and outcome oriented approach to governance. It is believed that through stewardship approach governments would improve the health status of their populations considerably. The paper implores not only government and health care managers but the Nigerian society also to imbibe the concept of stewardship to make the development of a result-oriented health system easy. PMID:25161436

STEWARDSHIP: A Conceptual Imperative For Managerial Effectiveness In The Nigerian Health System.

PubMed

2007-12-01

Unacceptable health status indicators such as high infant and maternal mortality rates and low life expectancy have continued unabated inspite of government efforts to change it. This paper espouses the concept of stewardship as a selfless, ethical, cost effective and outcome oriented approach to governance. It is believed that through stewardship approach governments would improve the health status of their populations considerably. The paper implores not only government and health care managers but the Nigerian society also to imbibe the concept of stewardship to make the development of a result-oriented health system easy.

Latest trends in parts SEP susceptibility from heavy ions

NASA Technical Reports Server (NTRS)

Nichols, Donald K.; Smith, L. S.; Soli, George A.; Koga, R.; Kolasinski, W. A.

1989-01-01

JPL and Aerospace have collected a third set of heavy-ion single-event phenomena (SEP) test data since their last joint IEEE publications in December 1985 and December 1987. Trends in SEP susceptibility (e.g., soft errors and latchup) for state-of-the-art parts are presented. Results of the study indicate that hard technologies and unacceptably soft technologies can be flagged. In some instances, specific tested parts can be taken as candidates for key microprocessors or memories. As always with radiation test data, specific test data for qualified flight parts is recommended for critical applications.

Design of New-Generation Open-Graded Friction Courses (Revised)

DOT National Transportation Integrated Search

1999-12-01

Open-graded friction course (OGFC) has been used by several state departments of transportation (DOT) since 1950. While many DOTs report good performance, many other states stopped using OGFC due to unacceptable performance and/or lack of adequate du...

Improving Public Health through Innovations in Exposure Science

EPA Science Inventory

In the traditional risk assessment paradigm, exposure science is relegated to a supporting role, providing an exposure estimate for comparison with hazard-based guidance values to determine whether there may be an unacceptable risk to public health. More recently, exposure scien...

Framing bioremediation decision making as negotiation: Rationale & guidelineFraming bioremediation decision making as negotiation: Rationale & guidelines

DOE Office of Scientific and Technical Information (OSTI.GOV)

Bjornstad, David J.; Wolfe, Amy K.

Framing remediation decision making as negotiation: (1) social choice, not technology choice; (2) prompts decision makers to identify interested and affected parties, anticipate objections, effectively address and ameliorate objections, and avoid unacceptable decisions.

HiveScience: A Citizen Science Project for Beekeepers##

EPA Science Inventory

Over the past decade, beekeepers have been experiencing unacceptably high colony losses while the demand for insect-pollinated crops has tripled during the same time period. Underscoring the need to develop reliable methods for predicting colony health, the United States Departme...

77 FR 38211 - Rescission of Quarterly Financial Reporting Requirements

Federal Register 2010, 2011, 2012, 2013, 2014

2012-06-27

... No. FMCSA-2012-0020] RIN-2126-AB48 Rescission of Quarterly Financial Reporting Requirements AGENCY..., the Federal Motor Carrier Safety Administration (FMCSA) eliminates the quarterly financial reporting... would be ineffective or unacceptable without a change. III. Background Annual Financial Reporting...

New Bedford Harbor Long Term Monitoring Program

EPA Science Inventory

New Bedford Harbor (NBH), located in southeastern Massachusetts, was designated as a Superfund site in 1983 due to unacceptably high levels of sediment contamination by polychlorinated biphenyls (PCBs). Based on human health and environmental concerns, the decision was made to d...

Performing the lockout/tagout risk assessment.

PubMed

Wallace, W Jon

2007-03-01

Lockout/tagout provides the greatest level routine, repetitive, and integral to the production process, a risk assessment should be performed. If the task performed poses an unacceptable risk, acceptable risk reduction methods should be implemented to reduce the risk to acceptable levels.

Clean Water Act Section 404(c) Factsheet

EPA Pesticide Factsheets

404(c) authorizes EPA to restrict, prohibit, deny, or withdraw the use of an area as a disposal site for dredged or fill material if the discharge will have unacceptable adverse effects on municipal water supplies, shellfish beds, fishery areas, etc.

Gender differences in a refractive surgery population of civilian aviators : final report.

DOT National Transportation Integrated Search

2000-07-01

INTRODUCTION. Refractive surgical procedures performed in the United States have increased in recent years and : continued growth is projected. Postoperative side effects can affect the quality of vision and may be unacceptable in a : cockpit environ...

Gender differences in a refractive surgery population of civilian aviators : final report.

DOT National Transportation Integrated Search

2000-07-01

INTRODUCTION. Refractive surgical procedures performed in the United States have increased in recent years and continued growth is projected. Postoperative side effects can affect the quality of vision and may be unacceptable in a cockpit environment...

40 CFR 141.21 - Coliform sampling.

Code of Federal Regulations, 2014 CFR

2014-07-01

... water) with the intent that if the method they choose has an unacceptable false-positive or negative...), supplemented with 100 µg/mL of MUG. If the 18th edition is used, incubate the agar plate at 35 °C for 4 hours...

40 CFR 141.21 - Coliform sampling.

Code of Federal Regulations, 2012 CFR

2012-07-01

... water) with the intent that if the method they choose has an unacceptable false-positive or negative...), supplemented with 100 µg/mL of MUG. If the 18th edition is used, incubate the agar plate at 35 °C for 4 hours...

40 CFR 141.21 - Coliform sampling.

Code of Federal Regulations, 2013 CFR

2013-07-01

... water) with the intent that if the method they choose has an unacceptable false-positive or negative...), supplemented with 100 µg/mL of MUG. If the 18th edition is used, incubate the agar plate at 35 °C for 4 hours...

Addressing Uncertainty in Fecal Indicator Bacteria Dark Inactivation Rates

EPA Science Inventory

Fecal contamination is a leading cause of surface water quality degradation. Roughly 20% of all total maximum daily load assessments approved by the United States Environmental Protection Agency since 1995, for example, address water bodies with unacceptably high fecal indicator...

THERMODYNAMIC REACTION CONSTANTS FOR MODELING AQUEOUS ENVIRONMENTAL MERCURY SPECIATION

EPA Science Inventory

Unacceptably high fish tissue mercury residues are responsible for the majority of fish consumption advisories issued in 48 states of the United States of America. Mercury also has emerged as a transboundary contaminant of global concern. Although monomethylmercury is generally...

Review of toxicity studies performed on an underground coal gasification condensate water

DOE Office of Scientific and Technical Information (OSTI.GOV)

Barker, F.P.

1987-09-01

Three studies related to the toxicity of underground coal gasification (UCG) waters have bee conducted: (1) toxicity study of UCG water and its fractions as determined by the Microtox test, (2) toxicity study of biotreated UCG water as determined by the Microtox test, and (3) toxicity study of UCG water to macroinvertebrates. The results of these studies are summarized herein. The gas condensate water from the UCG process is extremely toxic as determined by assays with photoluminescent bacteria (Microtox), benthic (bottom-dwelling) macroinvertebrates (mayflies), and Daphnia magna (water flea). Microtox bioassays reveal that the toxic components of the water reside inmore » both the organophilic and hydrophilic fractions, although the organophilic fraction is notably more toxic. A sequential treatment process reduced the toxicity of the UCG water, as measured by the Microtox test. Solvent extraction (to remove phenols) followed by ammonia stripping yielded a less toxic water. Additional treatment by activated sludge further reduced toxicity. Finally, the addition of powdered activated carbon to the activated sludge yielded the least toxic water. A bioassay technique was developed for lotic (running water) macroinvertebrates (Drunella doddsi and Iron longimanus). The toxicity results were compared with results from the traditional test animal, Daphnia magna. Short-term exposures to the UCG waters were more toxic to Daphnia magna than to Drunella doddsi or Iron longimanus, although the toxicity values begin to merge with longer test exposure. The greater toxicity seems to be related to a thinner exoskeleton. 26 refs., 2 figs., 6 tabs.« less

WHAT’S CAUSING TOXICITY IN SEDIMENTS? RESULTS OF 20 YEARS OF TOXICITY IDENTIFICATION AND EVALUATIONS

EPA Science Inventory

Sediment toxicity identification and evaluation (TIE) methods have been used for 20 yr to identify the causes of toxicity in sediments around the world. In the present study, the authors summarize and categorize results of 36 peer-reviewed TIE studies (67 sediments) into nonioni...

What’s Causing Toxicity in Sediments? Results of Twenty Years of Toxicity Identification and Evaluations (TIEs)

EPA Science Inventory

Sediment Toxicity Identification and Evaluation (TIEs) methods have been used for twenty years to identify the causes of toxicity in sediments around the world. We summarized and categorized results of more than 80 peer-reviewed TIE studies into non-ionic organic, cationic, ammo...

Randomized Adjuvant Chemotherapy of EGFR-Mutated Non-Small Cell Lung Cancer Patients with or without Icotinib Consolidation Therapy

PubMed Central

Cai, Kaican; Wu, Hua; Xiong, Gang; Wang, Haofei; Zhang, Ziliang

2015-01-01

Background Epidermal growth factor receptor (EGFR) mutations occur in up to 50% of Asian patients with non-small cell lung cancer (NSCLC). Treatment of advanced NSCLC patients with EGFR-tyrosine kinase inhibitor (EGFR-TKI) confers a significant survival benefit. This study assessed the efficacy and safety of chemotherapy with or without icotinib in patients undergoing resection of stage IB to ⅢA EGFR-mutated NSCLC. Methods Patients with surgically resected stage IB (with high risk factors) to ⅢA EGFR-mutated NSCLC were randomly assigned (1:1) to one of two treatment plans. One group received four cycles of platinum-based doublet chemotherapy every three weeks, and the other group received platinum-based chemotherapy supplemented with consolidation therapy of orally administered icotinib (125 mg thrice daily) two weeks after chemotherapy. The icotinib treatment continued for four to eight months, or until the occurrence of disease relapse, metastasis or unacceptable icotinib or chemotherapy toxicity. The primary endpoint was disease-free survival (DFS). Results 41 patients were enrolled between Feb 9, 2011 and Dec 17, 2012. 21 patients were assigned to the combined chemotherapy plus icotinib treatment group, while 20 patients received chemotherapy only. DFS at 12 months was 100% for icotinib-treated patients and 88.9% for chemotherapy-only patients (p = 0. 122). At 18 months DFS for icotinib-treated vs. chemotherapy-only patients was 95.2% vs. 83.3% (p = 0. 225), respectively, and at 24 months DFS was 90.5% vs. 66.7% (p = 0. 066). The adverse chemotherapy effects predominantly presented as gastrointestinal reactions and marrow suppression, and there was no significant difference between the two treatment groups. Patients in the chemotherapy plus icotinib treatment group showed favorable tolerance to oral icotinib. Conclusions The results suggest that chemotherapy plus orally icotinib displayed better DFS compared with chemotherapy only, yet the difference in DFS was not significant. We would think the preliminary result here was promising, and further trials with larger sample sizes might confirm the efficiency of adjuvant TKI in selected patients. Trial Registration ClinicalTrials.gov NCT02430974 PMID:26474174

Design, Construction, and Performance of New-generation Open-graded Friction Courses

DOT National Transportation Integrated Search

2000-04-01

Open-graded friction course (OGFC) has been used by several state departments of transportation (DOT) since 1950. While many DOTs report good performance, many other states stopped using OGFC due to unacceptable performance and/or lack of adequate du...

STREAM RESTORATION STRATEGIES FOR REDUCING RIVER NITROGEN LOADS

EPA Science Inventory

Despite decades of work implementing agricultural and urban best management practices to reduce the movement of excess nitrogen (N) from the land to aquatic ecosystems, the amount of N moving down streams and rivers remains unacceptably high in many watersheds. During this same ...

Psychology's Contributions to Classroom Management

ERIC Educational Resources Information Center

Little, Steven G.; Akin-Little, Angeleque

2008-01-01

Classroom management (CRM) has been associated with discipline, control, or other terms that connote reducing unacceptable student behavior. However, CRM involves not merely responding effectively when problems occur, but also preventing problems from occurring by creating environments that encourage learning and appropriate behavior. Teachers'…

Templates Aid Removal Of Defects From Castings

NASA Technical Reports Server (NTRS)

Hendrickson, Robert G.

1992-01-01

Templates used to correlate defects in castings with local wall thicknesses. Placed on part to be inspected after coated with penetrant dye. Positions of colored spots (indicative of defects) noted. Ultrasonic inspector measures thickness of wall at unacceptable defects only - overall inspection not necessary.

How to Curb the Dropout Rate.

ERIC Educational Resources Information Center

Vallejo, M. Edmund

1987-01-01

Although the Pueblo (Colorado) School District's student dropout rate compares favorably with national and state data, the community found the disproportionate number of Hispanic dropouts unacceptable. This article describes the district's efforts to reorganize staff, strengthen existing programs, and institute teen mother, inhouse suspension,…

DEVELOPMENT, DESIGN AND CONSUMER TESTING OF MARKETABLE RESIDENTIAL LED LIGHT LUMINAIRES

EPA Science Inventory

Developing marketable LED luminaires poses challenges, even though LEDs are energy-efficient and an ecological alternative to conventionally lighting. Challenges include: perceptions that the color rendition of LEDs is unacceptable to the public; numbers of LEDs must be grou...

24 CFR 1000.428 - For what reasons may HUD disapprove an application or approve an application for an amount less...

Code of Federal Regulations, 2011 CFR

2011-04-01

... following reasons: (a) HUD determines that the guarantee constitutes an unacceptable risk. Factors that will be considered in assessing financial risk shall include, but not be limited to, the following: (1...

24 CFR 1000.428 - For what reasons may HUD disapprove an application or approve an application for an amount less...

Code of Federal Regulations, 2010 CFR

2010-04-01

... following reasons: (a) HUD determines that the guarantee constitutes an unacceptable risk. Factors that will be considered in assessing financial risk shall include, but not be limited to, the following: (1...

14 CFR 33.78 - Rain and hail ingestion.

Code of Federal Regulations, 2010 CFR

2010-01-01

....78 Aeronautics and Space FEDERAL AVIATION ADMINISTRATION, DEPARTMENT OF TRANSPORTATION AIRCRAFT AIRWORTHINESS STANDARDS: AIRCRAFT ENGINES Design and Construction; Turbine Aircraft Engines § 33.78 Rain and... aircraft operating in rough air, with the engine at maximum continuous power, may not cause unacceptable...

5 CFR 432.103 - Definitions.

Code of Federal Regulations, 2010 CFR

2010-01-01

... performance above “unacceptable” in the critical element(s) at issue. (b) Critical element means a work... to the work. (h) Unacceptable performance means performance of an employee that fails to meet... Administrative Personnel OFFICE OF PERSONNEL MANAGEMENT CIVIL SERVICE REGULATIONS PERFORMANCE BASED REDUCTION IN...

7 CFR 1753.1 - General.

Code of Federal Regulations, 2010 CFR

2010-01-01

... unacceptable loan security risks to RUS. (4) The P&S or contract have been modified. (e) The requirements and... Telecommunications Loan Documents contain provisions regarding procurement of materials and equipment and... and procedures whenever using loan funds to purchase materials and equipment or perform construction...

7 CFR 1737.41 - Procedure for obtaining approval.

Code of Federal Regulations, 2010 CFR

2010-01-01

... RUS financing. (3) The proposed interim financing presents unacceptable loan security risks to RUS, or..., DEPARTMENT OF AGRICULTURE PRE-LOAN POLICIES AND PROCEDURES COMMON TO INSURED AND GUARANTEED TELECOMMUNICATIONS LOANS Interim Financing of Construction of Telephone Facilities § 1737.41 Procedure for obtaining...

48 CFR 25.504 - Evaluation Examples.

Code of Federal Regulations, 2011 CFR

2011-10-01

... PROGRAMS FOREIGN ACQUISITION Evaluating Foreign Offers-Supply Contracts 25.504 Evaluation Examples. The... examples assume that the contracting officer has eliminated all offers that are unacceptable for reasons... 48 Federal Acquisition Regulations System 1 2011-10-01 2011-10-01 false Evaluation Examples. 25...

47 CFR 25.273 - Duties regarding space communications transmissions.

Code of Federal Regulations, 2011 CFR

2011-10-01

... angles for proper illumination of a given transponder. (c) Space station licensees are responsible for.... Based on this information, space station licensees shall exchange among themselves general technical... any potential cases of unacceptable interference between their satellite systems. (d) Space stations...

47 CFR 25.273 - Duties regarding space communications transmissions.

Code of Federal Regulations, 2014 CFR

2014-10-01

... angles for proper illumination of a given transponder. (c) Space station licensees are responsible for.... Based on this information, space station licensees shall exchange among themselves general technical... any potential cases of unacceptable interference between their satellite systems. (d) Space stations...

47 CFR 25.273 - Duties regarding space communications transmissions.

Code of Federal Regulations, 2012 CFR

2012-10-01

... angles for proper illumination of a given transponder. (c) Space station licensees are responsible for.... Based on this information, space station licensees shall exchange among themselves general technical... any potential cases of unacceptable interference between their satellite systems. (d) Space stations...

47 CFR 25.273 - Duties regarding space communications transmissions.

Code of Federal Regulations, 2013 CFR

2013-10-01

... angles for proper illumination of a given transponder. (c) Space station licensees are responsible for.... Based on this information, space station licensees shall exchange among themselves general technical... any potential cases of unacceptable interference between their satellite systems. (d) Space stations...

Direct toxicity assessment - Methods, evaluation, interpretation.

PubMed

Gruiz, Katalin; Fekete-Kertész, Ildikó; Kunglné-Nagy, Zsuzsanna; Hajdu, Csilla; Feigl, Viktória; Vaszita, Emese; Molnár, Mónika

2016-09-01

Direct toxicity assessment (DTA) results provide the scale of the actual adverse effect of contaminated environmental samples. DTA results are used in environmental risk management of contaminated water, soil and waste, without explicitly translating the results into chemical concentration. The end points are the same as in environmental toxicology in general, i.e. inhibition rate, decrease in the growth rate or in yield and the 'no effect' or the 'lowest effect' measurement points of the sample dilution-response curve. The measurement unit cannot be a concentration, since the contaminants and their content in the sample is unknown. Thus toxicity is expressed as the sample proportion causing a certain scale of inhibition or no inhibition. Another option for characterizing the scale of toxicity of an environmental sample is equivalencing. Toxicity equivalencing represents an interpretation tool which enables toxicity of unknown mixtures of chemicals be converted into the concentration of an equivalently toxic reference substance. Toxicity equivalencing, (i.e. expressing the toxicity of unknown contaminants as the concentration of the reference) makes DTA results better understandable for non-ecotoxicologists and other professionals educated and thinking based on the chemical model. This paper describes and discusses the role, the principles, the methodology and the interpretation of direct toxicity assessment (DTA) with the aim to contribute to the understanding of the necessity to integrate DTA results into environmental management of contaminated soil and water. The paper also introduces the benefits of the toxicity equivalency method. The use of DTA is illustrated through two case studies. The first case study focuses on DTA of treated wastewater with the aim to characterize the treatment efficacy of a biological wastewater treatment plant by frequent bioassaying. The second case study applied DTA to investigate the cover layers of two bauxite residue (red mud) reservoirs. Based on the DTA results the necessary toxicity attenuation rate of the cover layers was estimated. Copyright © 2016 Elsevier B.V. All rights reserved.

The case against libertarian arguments for compulsory vaccination.

PubMed

Bernstein, Justin

2017-11-01

In a recent paper in this journal, Jason Brennan correctly notes that libertarians struggle to justify a policy of compulsory vaccination. The most straightforward argument that justifies compulsory vaccination is that such a policy promotes welfare. But libertarians cannot make this argument because they claim that the state is justified only in protecting negative rights, not in promoting welfare. I consider two representative libertarian attempts to justify compulsory vaccination, and I argue that such arguments are unsuccessful. They either fail to show that the state is justified in implementing the policy or overgeneralise. I suggest that Brennan's solution is especially well motivated insofar as it addresses the shortcomings of these arguments. Brennan argues that we violate the rights of others by participating in an activity that imposes an unacceptable collective risk of harm. Going unvaccinated is an activity that imposes an unacceptable collective risk of harm, and thus amounts to a rights violation. So, the state can implement a policy of compulsory vaccination I object, however, that Brennan's delineation of acceptable and unacceptable risk implicitly rests on classical liberal rather than libertarian principles; he justifies compulsory vaccination on the grounds that it promotes welfare. I also object that Brennan's argument would entail significant departures from libertarian institutional arrangements. This leaves libertarians with a choice: they can develop new arguments to demonstrate that their position is compatible with compulsory vaccination, or they can accept that their view entails the impermissibility of compulsory vaccination, and argue that this is not an unpalatable implication of their view. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.

Predicting children's behaviour during dental treatment under oral sedation.

PubMed

Lourenço-Matharu, L; Papineni McIntosh, A; Lo, J W

2016-06-01

The primary aim of this study was to assess whether parents' own anxiety and their perception of their child's dental fear and child's general fear can predict preoperatively their child's behaviour during dental treatment under oral sedation. The secondary aim was to assess whether the child's age, gender and ASA classification grade are associated with a child's behaviour under oral sedation. Cross-sectional prospective study. The Corah's Dental Anxiety Scale (DAS), Children's Fear Survey Schedule Dental-Subscale (CFSS-DS) and Children's Fear Survey Schedule Short-Form (CFSS-SF) questionnaires were completed by parents of children undergoing dental treatment with oral midazolam. Behaviour was rated by a single clinician using the overall behaviour section of the Houpt-Scale and scores dichotomised into acceptable or unacceptable behaviour. Data were analysed using χ (2), t test and logistic regression analysis. In total 404 children (215 girls, 53 %) were included, with the mean age of 4.57 years, SD = 1.9. Behaviour was scored as acceptable in 336 (83 %) and unacceptable in 68 (17 %) children. The level of a child's dental fear, as perceived by their parent, was significantly associated with the behaviour outcome (p = 0.001). Logistic regression analysis revealed that if the parentally perceived child's dental fear (CFSS-DS) rating was high, the odds of the child exhibiting unacceptable behaviour under oral sedation was two times greater than if their parents scored them a low dental fear rating (OR 2.27, 95 % CI 1.33-3.88, p = 0.003). CFSS-DS may be used preoperatively to help predict behaviour outcome when children are treated under oral sedation and facilitate treatment planning.

Toxicity evaluation of the process effluent streams of a petrochemical industry.

PubMed

Reis, J L R; Dezotti, M; Sant'Anna, G L

2007-02-01

The physico-chemical characteristics and the acute toxicity of several wastewater streams, generated in the industrial production of synthetic rubber, were determined. The acute toxicity was evaluated in bioassays using different organisms: Danio rerio (fish), Lactuca sativa (lettuce) and Brachionus calyciflorus (rotifer). The removal of toxicity attained in the industrial wastewater treatment plant was also determined upstream and downstream of the activated sludge process. The results obtained indicate that the critical streams in terms of acute toxicity are the effluents from the liquid polymer unit and the spent caustic butadiene washing stage. The biological treatment was able to partially remove the toxicity of the industrial wastewater. However, a residual toxicity level persisted in the biotreated wastewater. The results obtained with Lactuca sativa showed a high degree of reproducibility, using root length or germination index as evaluation parameters. The effect of volatile pollutants on the toxicity results obtained with lettuce seeds was assessed, using ethanol as a model compound. Modifications on the assay procedure were proposed. A strong correlation between the toxic responses of Lactuca sativa and Danio rerio was observed for most industrial effluent streams.

GHS additivity formula: can it predict the acute systemic toxicity of agrochemical formulations that contain acutely toxic ingredients?

PubMed

Van Cott, Andrew; Hastings, Charles E; Landsiedel, Robert; Kolle, Susanne; Stinchcombe, Stefan

2018-02-01

In vivo acute systemic testing is a regulatory requirement for agrochemical formulations. GHS specifies an alternative computational approach (GHS additivity formula) for calculating the acute toxicity of mixtures. We collected acute systemic toxicity data from formulations that contained one of several acutely-toxic active ingredients. The resulting acute data set includes 210 formulations tested for oral toxicity, 128 formulations tested for inhalation toxicity and 31 formulations tested for dermal toxicity. The GHS additivity formula was applied to each of these formulations and compared with the experimental in vivo result. In the acute oral assay, the GHS additivity formula misclassified 110 formulations using the GHS classification criteria (48% accuracy) and 119 formulations using the USEPA classification criteria (43% accuracy). With acute inhalation, the GHS additivity formula misclassified 50 formulations using the GHS classification criteria (61% accuracy) and 34 formulations using the USEPA classification criteria (73% accuracy). For acute dermal toxicity, the GHS additivity formula misclassified 16 formulations using the GHS classification criteria (48% accuracy) and 20 formulations using the USEPA classification criteria (36% accuracy). This data indicates the acute systemic toxicity of many formulations is not the sum of the ingredients' toxicity (additivity); but rather, ingredients in a formulation can interact to result in lower or higher toxicity than predicted by the GHS additivity formula. Copyright © 2018 Elsevier Inc. All rights reserved.

Whole-body vibration and ergonomic study of US railroad locomotives

NASA Astrophysics Data System (ADS)

Johanning, Eckardt; Landsbergis, Paul; Fischer, Siegfried; Christ, Eberhard; Göres, Benno; Luhrman, Raymond

2006-12-01

US locomotive operators have exposure to multi-axis whole-body vibration (WBV) and shocks while seated. This study assessed operator-related and ergonomic seating design factors that may have confounding or mitigating influence on WBV exposure and its effects. Vibration exposure was measured according to international guidelines (ISO 2631-1; 1997); ergonomic work place factors and vibration effects were studied with a cross-sectional survey instrument distributed to a randomly selected group of railroad engineers ( n=2546) and a control group; and during vehicle inspections. The survey response rate was 47% for the RR engineers ( n=1195) and 41% for the controls ( n=323). Results of the mean basic vibration measurements were for the x, y, z-direction and vector sum 0.14, 0.22, 0.28 and 0.49 m/s 2 respectively; almost all crest factors (CF), MTVV and VDV values were above the critical ratios given in ISO 2631-1. The prevalence of serious neck and lower back disorders among locomotive engineers was found to be nearly double that of the sedentary control group without such exposure. Railroad engineers rated their seats mostly unacceptable regarding different adjustment and comfort aspects (3.02-3.51; scale 1=excellent to 4=unacceptable), while the control group rated their chairs more favorably (1.96-3.44). Existing cab and seat design in locomotives can result in prolonged forced awkward spinal posture of the operator combined with WBV exposure. In a logistic regression analysis, time at work being bothered by vibration (h/day) was significantly associated with an increased risk of low back pain, shoulder and neck pain, and sciatic pain among railroad engineers. Customized vibration attenuation seats and improved cab design of the locomotive controls should be further investigated.

Unacceptably High Error Rates in Vitek 2 Testing of Cefepime Susceptibility in Extended-Spectrum-β-Lactamase-Producing Escherichia coli

PubMed Central

Rhodes, Nathaniel J.; Richardson, Chad L.; Heraty, Ryan; Liu, Jiajun; Malczynski, Michael; Qi, Chao

2014-01-01

While a lack of concordance is known between gold standard MIC determinations and Vitek 2, the magnitude of the discrepancy and its impact on treatment decisions for extended-spectrum-β-lactamase (ESBL)-producing Escherichia coli are not. Clinical isolates of ESBL-producing E. coli were collected from blood, tissue, and body fluid samples from January 2003 to July 2009. Resistance genotypes were identified by PCR. Primary analyses evaluated the discordance between Vitek 2 and gold standard methods using cefepime susceptibility breakpoint cutoff values of 8, 4, and 2 μg/ml. The discrepancies in MICs between the methods were classified per convention as very major, major, and minor errors. Sensitivity, specificity, and positive and negative predictive values for susceptibility classifications were calculated. A total of 304 isolates were identified; 59% (179) of the isolates carried blaCTX-M, 47% (143) carried blaTEM, and 4% (12) carried blaSHV. At a breakpoint MIC of 8 μg/ml, Vitek 2 produced a categorical agreement of 66.8% and exhibited very major, major, and minor error rates of 23% (20/87 isolates), 5.1% (8/157 isolates), and 24% (73/304), respectively. The sensitivity, specificity, and positive and negative predictive values for a susceptibility breakpoint of 8 μg/ml were 94.9%, 61.2%, 72.3%, and 91.8%, respectively. The sensitivity, specificity, and positive and negative predictive values for a susceptibility breakpoint of 2 μg/ml were 83.8%, 65.3%, 41%, and 93.3%, respectively. Vitek 2 results in unacceptably high error rates for cefepime compared to those of agar dilution for ESBL-producing E. coli. Clinicians should be wary of making treatment decisions on the basis of Vitek 2 susceptibility results for ESBL-producing E. coli. PMID:24752253

Validation of the CME Geomagnetic Forecast Alerts Under the COMESEP Alert System

NASA Astrophysics Data System (ADS)

Dumbović, Mateja; Srivastava, Nandita; Rao, Yamini K.; Vršnak, Bojan; Devos, Andy; Rodriguez, Luciano

2017-08-01

Under the European Union 7th Framework Programme (EU FP7) project Coronal Mass Ejections and Solar Energetic Particles (COMESEP, http://comesep.aeronomy.be), an automated space weather alert system has been developed to forecast solar energetic particles (SEP) and coronal mass ejection (CME) risk levels at Earth. The COMESEP alert system uses the automated detection tool called Computer Aided CME Tracking (CACTus) to detect potentially threatening CMEs, a drag-based model (DBM) to predict their arrival, and a CME geoeffectiveness tool (CGFT) to predict their geomagnetic impact. Whenever CACTus detects a halo or partial halo CME and issues an alert, the DBM calculates its arrival time at Earth and the CGFT calculates its geomagnetic risk level. The geomagnetic risk level is calculated based on an estimation of the CME arrival probability and its likely geoeffectiveness, as well as an estimate of the geomagnetic storm duration. We present the evaluation of the CME risk level forecast with the COMESEP alert system based on a study of geoeffective CMEs observed during 2014. The validation of the forecast tool is made by comparing the forecasts with observations. In addition, we test the success rate of the automatic forecasts (without human intervention) against the forecasts with human intervention using advanced versions of the DBM and CGFT (independent tools available at the Hvar Observatory website, http://oh.geof.unizg.hr). The results indicate that the success rate of the forecast in its current form is unacceptably low for a realistic operation system. Human intervention improves the forecast, but the false-alarm rate remains unacceptably high. We discuss these results and their implications for possible improvement of the COMESEP alert system.

National turnaround time survey: professional consensus standards for optimal performance and thresholds considered to compromise efficient and effective clinical management.

PubMed

McKillop, Derek J; Auld, Peter

2017-01-01

Background Turnaround time can be defined as the time from receipt of a sample by the laboratory to the validation of the result. The Royal College of Pathologists recommends that a number of performance indicators for turnaround time should be agreed with stakeholders. The difficulty is in arriving at a goal which has some evidence base to support it other than what may simply be currently achievable technically. This survey sought to establish a professional consensus on the goals and meaning of targets for laboratory turnaround time. Methods A questionnaire was circulated by the National Audit Committee to 173 lead consultants for biochemistry in the UK. The survey asked each participant to state their current target turnaround time for core investigations in a broad group of clinical settings. Each participant was also asked to provide a professional opinion on what turnaround time would pose an unacceptable risk to patient safety for each departmental category. A super majority (2/3) was selected as the threshold for consensus. Results The overall response rate was 58% ( n = 100) with a range of 49-72% across the individual Association for Clinical Biochemistry and Laboratory Medicine regions. The consensus optimal turnaround time for the emergency department was <1 h with >2 h considered unacceptable. The times for general practice and outpatient department were <24 h and >48 h and for Wards <4 h and >12 h, respectively. Conclusions We consider that the figures provide a useful benchmark of current opinion, but clearly more empirical standards will have to develop alongside other aspects of healthcare delivery.

Acceleration of yoghurt fermentation time by yeast extract and partial characterisation of the active components.

PubMed

Smith, Esti-Andrine; Myburgh, Jacobus; Osthoff, Gernot; de Wit, Maryna

2014-11-01

Water soluble autolysate of yeast, usually utilised for microbial growth support, was used as additive in yoghurt fermentation. The yeast extract (YE) resulted in a decrease of fermentation time by 21% to reach a pH of 4·6. However, the YE resulted in unacceptable flavour and taste. By size exclusion chromatography, a fraction of the YE was obtained that could account for the observed 21% decrease in fermentation time. The fraction contained molecules of low molecular weight, consisting of minerals, free amino acids and peptides. The acceleration of the yoghurt fermentation was ascribed to the short peptides in the fraction. It is proposed that the application of this extract in industrial yoghurt manufacture would result in savings for both the industry and the consumer.

Intravenous rocuronium 0.3 mg/kg improves the conditions for tracheal intubation in cats: a randomized, placebo-controlled trial.

PubMed

Sakai, Daniel M; Zornow, Kailee Anne; Campoy, Luis; Cable, Christina; Appel, Leslie D; Putnam, Holly J; Martin-Flores, Manuel

2018-01-01

Objectives We evaluated the use of rocuronium 0.3 mg/kg intravenously (IV) to facilitate tracheal intubation in cats anesthetized for elective ovariohysterectomy. Methods Thirty female cats were randomly allocated to receive rocuronium 0.3 mg/kg IV or an equal volume of normal saline, following induction of anesthesia with ketamine and midazolam. Thirty seconds after induction, a single investigator, unaware of treatment allocation, attempted tracheal intubation. The number of attempts and the time to complete intubation were measured. Intubating conditions were assessed as acceptable or unacceptable based on a composite score consisting of five different components. Duration of apnea after induction was measured and cases of hemoglobin desaturation (SpO 2 <90%) were identified. Results Intubation was completed faster (rocuronium 12 s [range 8-75 s]; saline 60 s [range 9-120 s]) and with fewer attempts (rocuronium 1 [range 1-2]; saline 2 [range 1-3], both P = 0.006) in cats receiving rocuronium. Unacceptable intubating conditions on the first attempt occurred in 3/15 cats with rocuronium and in 10/15 with saline ( P = 0.01). Apnea lasted 4 ± 1.6 mins with rocuronium and 2.3 ± 0.5 mins with saline ( P = 0.0007). No cases of desaturation were observed. Conclusions and relevance Rocuronium 0.3 mg/kg IV improves intubating conditions compared with saline and reduces the time and number of attempts to intubate with only a short period of apnea in cats.

Non-advertising alcohol promotions in licensed premises: does the Code of Practice ensure responsible promotion of alcohol?

PubMed

Jones, Sandra C; Lynch, Melissa

2007-09-01

Binge drinking is a major public health issue in Australia, particularly among young people. There has been a considerable focus on alcohol advertising, among both researchers and policy makers, resulting in efforts to bring about some level of regulation of unacceptable advertising practices. However - despite the existence of a Code of Practice for Responsible Promotion of Liquor Products which provides 'a framework of practices which are considered acceptable and reasonable' for licensed premises - there are few, if any, data on the nature and extent of promotions which could arguably fall under either 'acceptable' or 'unacceptable' practices. Over an 8-week period we monitored promotions offered by licensed venues (pubs, bars and clubs) in the Wollongong central area. Seventeen venues were identified, and each venue was visited daily for 1 week. Trained research assistants took notes on all promotions/events in visited venues, including both manufacturer- and management-initiated. We identified a range of different types of promotions, including low cost and free drinks. Some of the promotions identified could be seen to have a positive public health impact, such as free food and free transport. However, the majority of promotions were of a nature likely to increase the likelihood of excessive drinking. It is evident from this review that there are numerous examples of promotions which breach both the spirit and the letter of the Code. It is equally evident that the system for monitoring compliance with the Code is fundamentally inadequate.

A survey of outcome of adjustable suture as first operation in patients with strabismus.

PubMed

Razmjoo, Hasan; Attarzadeh, Hosein; Karbasi, Najmeh; Najarzadegan, Mohammad Reza; Salam, Hasan; Jamshidi, Aliraza

2014-01-01

Adjustable suture used for years to improve the outcome of strabismus surgery. We surveyed outcome of our patients with strabismus who underwent adjustable suture. This retrospective study was performed at Ophthalmology Centre of Feiz Hospital in Isfahan on 95 participants that candidate for adjustable suture strabismus surgery. Patients were divided into three age groups: Under 10 years, 10-19 years, and 20 years and over. Outcome of adjustable suture surgery consequence of residual postoperative deviation was divided into four groups: Excellent, good, acceptable, and unacceptable. Out of 95 patients studied, 51 (53.7%) were males and 44 (46.3%) were females. The mean of deviation angles were 53.8 ± 17.9 PD (Prism dioptres) in alt XT, 44.5 ± 12 PD in alt ET and 52 ± 13.5 PD in const ET, 47.1 ± 13.1PD in cons XT, respectively. There was no significant difference between the groups (P = 0.051). Results of surgery were in 38 patients (40%) excellent, in 31 patients (32.6%) good, in 19 patients (20%) acceptable, and in 7 patients (7.4%) unacceptable. Seven (7.4%) patients required reoperation. In the present study, the frequency of re-operation was much lower than other similar studies (7.4% vs. 30-50%). This suggests that the adjustable technique that used in our study can be associated with lower reoperation than other adjustable techniques used in the other similar studies.

An Ethical Review of Euthanasia and Physician-assisted Suicide

PubMed Central

BANOVIĆ, Božidar; TURANJANIN, Veljko; MILORADOVIĆ, Anđela

2017-01-01

Background: In the majority of countries, active direct euthanasia is a forbidden way of the deprivation of the patients’ life, while its passive form is commonly accepted. This distinction between active and passive euthanasia has no justification, viewed through the prism of morality and ethics. Therefore, we focused on attention on the moral and ethical implications of the aforementioned medical procedures. Methods: Data were obtained from the Clinical Hospital Center in Kragujevac, collected during the first half of the 2015. The research included 88 physicians: 57 male physicians (representing 77% of the sample) and 31 female physicians (23% of the sample). Due to the nature, subject and hypothesis of the research, the authors used descriptive method and the method of the theoretical content analysis. Results: A slight majority of the physicians (56, 8%) believe that active euthanasia is ethically unacceptable, while 43, 2% is for another solution (35, 2% took a viewpoint that it is completely ethically acceptable, while the remaining 8% considered it ethically acceptable in certain cases). From the other side, 56, 8% of respondents answered negatively on the ethical acceptability of the physician-assisted suicide, while 33% of them opted for a completely ethic viewpoint of this procedure. Out of the remaining 10, 2% opted for the ethical acceptability in certain cases. Conclusion: Physicians in Serbia are divided on this issue, but a group that considers active euthanasia and physician-assisted suicide as ethically unacceptable is a bit more numerous. PMID:28451551

Modification of potato steroidal glycoalkaloids with silencing RNA constructs

USDA-ARS?s Scientific Manuscript database

Steroidal glycoalkaloids (SGAs), while found in many solanaceous plants, can accumulate to unacceptably high levels in potatoes. The two primary SGAs that occur in potatoes are the tri-glycosylated alkaloids, a-solanine and a-chaconine. The first glycosylation steps in their biosynthetic pathways ...

The Aggregate Exposure Pathway (AEP): A conceptual framework for advancing exposure science research and applications

EPA Science Inventory

Historically, risk assessment has relied upon toxicological data to obtain hazard-based reference levels, which are subsequently compared to exposure estimates to determine whether an unacceptable risk to public health may exist. Recent advances in analytical methods, biomarker ...

PRN 75-5: Unacceptable Use of the Word Chlorine in the Name and Labeling of Pesticides

EPA Pesticide Factsheets

Use of the word CHLORINE on labels other than in products containing liquified chlorine under pressure has been determined to be in violation of Section 2(q)(l)(A) of the Federal Insecticide, Fungicide, and Rodenticide Act.

Playground Games and Playtime: The Children's View.

ERIC Educational Resources Information Center

Blatchford, Peter; And Others

1990-01-01

Interviews with 174 11-year olds in London schools determined that playtime was very popular, but concerns were expressed about bad weather, not knowing what to do, and disruptive behavior. Unacceptable playground behavior was taken too much for granted. Football seemed to dominate other activities. (SK)

Trade and food safety aspects for animal influenza viruses

USDA-ARS?s Scientific Manuscript database

The World Organization for Animal Health provides sanitary standards for international trade and emphasizes science-based risk assessment for safe trade of animals and animal products. The goal is to prevent unacceptable risks to animal and human health while avoiding unjustified or politically mot...

75 FR 69063 - Extension of the Period for Preparation of the Clean Water Act Section 404(c) Final Determination...

Federal Register 2010, 2011, 2012, 2013, 2014

2010-11-10

... also notified the Department of the Army, the State of West Virginia, Arch Coal, Inc. (the permittee... process described in 40 CFR 231.6, that would prevent the likely unacceptable adverse effects described in...