Approaches for characterizing threshold dose-response relationships for DNA-damage pathways involved in carcinogenicity in vivo and micronuclei formation in vitro.

PubMed

Clewell, Rebecca A; Andersen, Melvin E

2016-05-01

Assessing the shape of dose-response curves for DNA-damage in cellular systems and for the consequences of DNA damage in intact animals remains a controversial topic. This overview looks at aspects of the pharmacokinetics (PK) and pharmacodynamics (PD) of cellular DNA-damage/repair and their role in defining the shape of dose-response curves using an in vivo example with formaldehyde and in vitro examples for micronuclei (MN) formation with several test compounds. Formaldehyde is both strongly mutagenic and an endogenous metabolite in cells. With increasing inhaled concentrations, there were transitions in gene changes, from activation of selective stress pathway genes at low concentrations, to activation of pathways for cell-cycle control, p53-DNA damage, and stem cell niche pathways at higher exposures. These gene expression changes were more consistent with dose-dependent transitions in the PD responses to formaldehyde in epithelial cells in the intact rat rather than the low-dose linear extrapolation methods currently used for carcinogens. However, more complete PD explanations of non-linear dose response for creation of fixed damage in cells require detailed examination of cellular responses in vitro using measures of DNA damage and repair that are not easily accessible in the intact animal. In the second section of the article, we illustrate an approach from our laboratory that develops fit-for-purpose, in vitro assays and evaluates the PD of DNA damage and repair through studies using prototypical DNA-damaging agents. Examination of a broad range of responses in these cells showed that transcriptional upregulation of cell cycle control and DNA repair pathways only occurred at doses higher than those causing overt damage fixed damage-measured as MN formation. Lower levels of damage appear to be handled by post-translational repair process using pre-existing proteins. In depth evaluation of the PD properties of one such post-translational process (formation of DNA repair centers; DRCs) has indicated that the formation of DRCs and their ability to complete repair before replication are consistent with threshold behaviours for mutagenesis and, by extension, with chemical carcinogenesis. © The Author 2016. Published by Oxford University Press on behalf of the UK Environmental Mutagen Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Safety of phase I clinical trials with monoclonal antibodies in Germany--the regulatory requirements viewed in the aftermath of the TGN1412 disaster.

PubMed

Liedert, B; Bassus, S; Schneider, C K; Kalinke, U; Löwer, J

2007-01-01

This review summarizes scientific, ethical and regulatory aspects of Phase I clinical trials with monoclonal antibodies. The current standard requirements for pre-clinical testing and for clinical study design are presented. The scientific considerations discussed herein are generally applicable, the view on legal requirements for clinical trials refer to the German jurisdiction only. The adverse effects associated with the TGN1412 Phase I trial indicate that the predictive value of pre-clinical animal models requires reevaluation and that, in certain cases, some issues of clinical trial protocols such as dose fixing may need refinement or redesign. Concrete safety measures, which have been proposed as a consequence of the TGN1412 event include introduction of criteria for high-risk antibodies, sequential inclusion of trial participants and implementation of pre-Phase I studies where dose calculation is based on the pre-clinical No Effect Level instead of the No Observed Adverse Effect Level. The recently established European clinical trials database (EUDRACT Database) is a further safety tool to expedite the sharing of relevant information between scientific authorities.

Organ dose conversion coefficients for tube current modulated CT protocols for an adult population

NASA Astrophysics Data System (ADS)

Fu, Wanyi; Tian, Xiaoyu; Sahbaee, Pooyan; Zhang, Yakun; Segars, William Paul; Samei, Ehsan

2016-03-01

In computed tomography (CT), patient-specific organ dose can be estimated using pre-calculated organ dose conversion coefficients (organ dose normalized by CTDIvol, h factor) database, taking into account patient size and scan coverage. The conversion coefficients have been previously estimated for routine body protocol classes, grouped by scan coverage, across an adult population for fixed tube current modulated CT. The coefficients, however, do not include the widely utilized tube current (mA) modulation scheme, which significantly impacts organ dose. This study aims to extend the h factors and the corresponding dose length product (DLP) to create effective dose conversion coefficients (k factor) database incorporating various tube current modulation strengths. Fifty-eight extended cardiac-torso (XCAT) phantoms were included in this study representing population anatomy variation in clinical practice. Four mA profiles, representing weak to strong mA dependency on body attenuation, were generated for each phantom and protocol class. A validated Monte Carlo program was used to simulate the organ dose. The organ dose and effective dose was further normalized by CTDIvol and DLP to derive the h factors and k factors, respectively. The h factors and k factors were summarized in an exponential regression model as a function of body size. Such a population-based mathematical model can provide a comprehensive organ dose estimation given body size and CTDIvol. The model was integrated into an iPhone app XCATdose version 2, enhancing the 1st version based upon fixed tube current modulation. With the organ dose calculator, physicists, physicians, and patients can conveniently estimate organ dose.

Displacement damage dose and implantation temperature effects on the trapping and release of deuterium implanted into SiC

NASA Astrophysics Data System (ADS)

Muñoz, P.; García-Cortés, I.; Sánchez, F. J.; Moroño, A.; Malo, M.; Hodgson, E. R.

2017-09-01

Radiation damage to flow channel insert (FCI) materials is an important issue for the concept of dual-coolant blanket development in future fusion devices. Silicon Carbide (SiC) is one of the most suitable materials for FCI. Because of the severe radiation environment and exposure to tritium during operation it is of fundamental importance to study hydrogen isotope trapping and release in these materials. Here the trapping, detrapping, and diffusion of deuterium implanted into SiC is studied in correlation with pre- and post-damage induced under different conditions. For this, SiC samples are pre-damaged with 50 keV Ne+ ions at different temperatures (20, 200, 450, 700 °C) to different damage doses (1, 3.6, 7 dpa). Next, deuterium is introduced into the samples at 450 °C by ion implantation at 7 keV. The implanted deuterium retained in the sample is analysed using secondary ion mass spectrometry (SIMS) and thermo-stimulated desorption (TSD) measurements. The results indicate that with increasing neon damage dose, the maximum deuterium desorption occurs at higher temperatures. In contrast, when increasing neon implantation temperature for a fixed dose, the maximum deuterium desorption release temperature decreases. It is interpreted that the neon bombardment produces thermally stable traps for hydrogen isotopes and the stability of this damage increases with neon pre-implantation dose. A decrease of the trapping of implanted deuterium is also observed to occur due to damage recovery by thermal annealing during pre-implantation at the higher temperatures. Finally, direct particle bombardment induced deuterium release is also observed.

SU-E-T-434: Fixed Margin Or Online Adaptation for Intermediate-Risk Prostate Stereotactic Body Radiation Therapy? A Dosimetric Study

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

Sheng, Y; Li, T; Yin, F

2015-06-15

Purpose: To investigate the choice of fixed margin or online adaptation when treating intermediate-risk prostate cancer including seminal vesicles (SV) using stereotactic body radiation therapy (SBRT). Methods: 9 prostate SBRT patients were retrospectively studied. All patients were implanted with fiducial markers in the prostate for daily localization and verification. Each patient had 5 pairs of pre-treatment and post-treatment cone-beam CT (CBCT) per protocol. SVs were contoured on planning CT and all CBCTs by one attending physician. Simultaneous integral boost (SIB) IMRT plans were developed to deliver 25Gy/5fx to the SV while delivering 37Gy/5fx to the prostate. A 3mm isotropic marginmore » was added to the prostate while a 5 mm isotropic margin was used for the SV. The planning CT was registered to daily pre-treatment and post-treatment CBCT based on fiducial markers in the prostate to mimic online prostate localization; and the SV on daily CBCT was transferred to the CT structure set after the prostates were aligned. Daily pre-treatment and post-treatment SV dose coverage and the organ-at-risk (OAR) sparing were evaluated for the SIB regimen. At least 95% of the SV need to receive the prescription dose (5Gy per fraction). Results: For the total of 90 daily SVs analyzed (ten CBCTs for each of nine patients), only 45 daily SVs (50%) were able to meet the coverage that 95% of the SV received 25Gy. The OAR sparing performance was acceptable for most of the dosimetric constraints in low-risk prostate SBRT protocol with only two exceptions in bladder V100 (cc). Conclusion: A fixed 5mm margin for SV is not sufficient to provide consistent daily dose coverage due to SV’s substantial inter- and intra-fractional motion relative to the prostate. This finding calls for innovative strategies in margin design as well as online treatment adaptation. This work is partially supported a master research grant from Varian Medical Systems.« less

Combining benefits of an adrenergic and a muscarinic blocker in a single formulation - a pharmacokinetic evaluation.

PubMed

Nazarudheen, Shabana; Dey, Surajit; Kandhwal, Kirti; Arora, Rachna; Reyar, Simrit; Khuroo, Arshad H; Monif, Tausif; Madan, Sumit; Arora, Vinod

2013-11-01

A pharmacokinetic bioequivalence study was conducted in Asian subjects, to compare a fixed dose combination capsule single oral dose of alpha adrenoceptor blocker-Alfuzosin hydrochloride 10mg extended release and muscarinic antagonists-Solifenacin succinate 5mg against individually administered Xatral XL 10mg tablets (Alfuzosin) of Sanofi Synthelabo Limited, United Kingdom (UK) and Vesicare 5mg tablets (Solifenacin) of Astellas Pharma Limited, UK under fed conditions. Blood samples were collected pre-dose up to 72 h post dose for determination of plasma Alfuzosin and Solifenacin concentrations and calculation of the pharmacokinetic parameters. ANOVA was performed on the log (natural)-transformed pharmacokinetic parameters. A 90% confidence interval for the ratios of the test and reference product averages (least square means) were calculated for alfuzosin and solifenacin. The 90% confidence intervals obtained for alfuzosin for Cmax, AUC0-t and AUC0-∞ were 102.74-122.75%, 95.84-116.96% and 95.82-116.76%, respectively. The 90% confidence intervals obtained for Solifenacin for Cmax, and AUC0-72 were 89.55-97.91% and 90.47-99.38%, respectively. Based on the results, the fixed dose combination was concluded to be bioequivalent to individually administered products. Copyright © 2013 Elsevier Inc. All rights reserved.

Student Performance in Measuring Distance with Wavelengths in Various Settings

NASA Astrophysics Data System (ADS)

White, Gary

2015-04-01

When physics students are asked to measure the distance between two fixed locations using a pre-defined wavelength as a ruler, there is a surprising failure rate, at least partially due to the fact that the ``ruler'' to be used is not fixed in length (see ``Is a Simple Measurement Task a Roadblock to Student Understanding of Wave Phenomena?,'' by and references therein). I will show some data from introductory classes (algebra- and calculus-based) that replicate this result, and also show some interesting features when comparing a setting involving slinkies with a setting involving surface waves on water.

Initiating sacubitril/valsartan (LCZ696) in heart failure: results of TITRATION, a double-blind, randomized comparison of two uptitration regimens.

PubMed

Senni, Michele; McMurray, John J V; Wachter, Rolf; McIntyre, Hugh F; Reyes, Antonio; Majercak, Ivan; Andreka, Peter; Shehova-Yankova, Nina; Anand, Inder; Yilmaz, Mehmet B; Gogia, Harinder; Martinez-Selles, Manuel; Fischer, Steffen; Zilahi, Zsolt; Cosmi, Franco; Gelev, Valeri; Galve, Enrique; Gómez-Doblas, Juanjo J; Nociar, Jan; Radomska, Maria; Sokolova, Beata; Volterrani, Maurizio; Sarkar, Arnab; Reimund, Bernard; Chen, Fabian; Charney, Alan

2016-09-01

To assess the tolerability of initiating/uptitrating sacubitril/valsartan (LCZ696) from 50 to 200 mg twice daily (target dose) over 3 and 6 weeks in heart failure (HF) patients (ejection fraction ≤35%). A 5-day open-label run-in (sacubitril/valsartan 50 mg twice daily) preceded an 11-week, double-blind, randomization period [100 mg twice daily for 2 weeks followed by 200 mg twice daily ('condensed' regimen) vs. 50 mg twice daily for 2 weeks, 100 mg twice daily for 3 weeks, followed by 200 mg twice daily ('conservative' regimen)]. Patients were stratified by pre-study dose of angiotensin-converting enzyme inhibitor/angiotensin-receptor blocker (ACEI/ARB; low-dose stratum included ACEI/ARB-naïve patients). Of 540 patients entering run-in, 498 (92%) were randomized and 429 (86.1% of randomized) completed the study. Pre-defined tolerability criteria were hypotension, renal dysfunction and hyperkalaemia; and adjudicated angioedema, which occurred in ('condensed' vs. 'conservative') 9.7% vs. 8.4% (P = 0.570), 7.3% vs. 7.6% (P = 0.990), 7.7% vs. 4.4% (P = 0.114), and 0.0% vs. 0.8% of patients, respectively. Corresponding proportions for pre-defined systolic blood pressure <95 mmHg, serum potassium >5.5 mmol/L, and serum creatinine >3.0 mg/dL were 8.9% vs. 5.2% (P = 0.102), 7.3% vs. 4.0% (P = 0.097), and 0.4% vs. 0%, respectively. In total, 378 (76%) patients achieved and maintained sacubitril/valsartan 200 mg twice daily without dose interruption/down-titration over 12 weeks (77.8% vs. 84.3% for 'condensed' vs. 'conservative'; P = 0.078). Rates by ACEI/ARB pre-study dose stratification were 82.6% vs. 83.8% (P = 0.783) for high-dose/'condensed' vs. high-dose/'conservative' and 84.9% vs. 73.6% (P = 0.030) for low-dose/'conservative' vs. low-dose/'condensed'. Initiation/uptitration of sacubitril/valsartan from 50 to 200 mg twice daily over 3 or 6 weeks had a tolerability profile in line with other HF treatments. More gradual initiation/uptitration maximized attainment of target dose in the low-dose ACEI/ARB group. © 2016 The Authors. European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.

Pilot validation of an individualised pharmacokinetic algorithm for protamine dosing after systemic heparinisation for cardiopulmonary bypass.

PubMed

Miles, Lachlan F; Marchiori, Paolo; Falter, Florian

2017-09-01

This manuscript represents a pilot study assessing the feasibility of a single-compartment, individualised, pharmacokinetic algorithm for protamine dosing after cardiopulmonary bypass. A pilot cohort study in a specialist NHS cardiothoracic hospital targeting patients undergoing elective cardiac surgery using cardiopulmonary bypass. Patients received protamine doses according to a pharmacokinetic algorithm (n = 30) or using an empirical, fixed-dose model (n = 30). Categorical differences between the groups were evaluated using the Chi-squared test or Fisher's exact test. Continuous data was analysed using a paired Student's t-test for parametric data and the paired samples Wilcoxon test for non-parametric data. Patients who had protamine dosing according to the algorithm demonstrated a lower protamine requirement post-bypass relative to empirical management as measured by absolute dose (243 ± 49mg vs. 305 ± 34.7mg; p<0.001) and the heparin to protamine ratio (0.79 ± 0.12 vs. 1.1 ± 0.15; p<0.001). There was no difference in the pre- to post-bypass activated clotting time (ACT) ratio (1.05 ± 0.12 vs. 1.02 ± 0.15; p=0.9). Patients who received protamine according to the algorithm had no significant difference in transfusion requirement (13.3% vs. 30.0%; p=0.21). This study showed that an individualized pharmacokinetic algorithm for the reversal of heparin after cardiopulmonary bypass is feasible in comparison with a fixed dosing strategy and may reduce the protamine requirement following on-pump cardiac surgery.

A pilot study to evaluate the safety and feasibility of the administration of AZT/3TC fixed dose combination to HIV infected pregnant women and their infants in Rio de Janeiro, Brazil

PubMed Central

Lambert, J; Nogueira, S; Abreu, T; Machado, E; Costa, T; Bondarovsky, M; Andrade, M; Halpern, M; Barbosa, R; Perez, M

2003-01-01

Objectives: To evaluate the safety and feasibility of zidovudine and lamivudine (AZT/3TC) given to HIV infected pregnant women and their infants in Rio de Janeiro, Brazil. Methods: This open label phase II study enrolled 40 HIV infected antiretroviral naive women ⩾20 weeks gestation, CD4 <500 cells x106/l, from two public hospitals. Treatment: fixed dose AZT 300 mg/3TC 150 mg by mouth every 12 hours until labour; AZT 300 mg by mouth every 3 hours until delivery; infants: AZT 4 mg/kg every 12 hours plus 3TC 2 mg/kg every 12 hours for 6 weeks. Blood haematology and chemistry were monitored; adherence evaluated by pills count; efficacy measured by changes in lymphocyte (CD4) and viral load, and by HIV RNA-PCR tests performed at birth, 6 and 12 weeks, to diagnose infant infection. No women breast fed. Results: Patient characteristics: mean age 24.48 (SD 3.5) years; gestational age 24.5 (4.5) weeks; AZT/3TC duration 14.4 (4.4) weeks; vaginal delivery: 11/39; caesarean section: 28/39. Entry and pre-labour CD4: 310/486 cells x106/l (p<0.001); entry and pre-labour viral load: 53 818/2616 copies/ml (p<0.001). Thirty nine women tolerated treatment with >80% adherence; one was lost to follow up. Five newborns were excluded from 3TC receipt. All 39 babies were uninfected. Haematological toxicity in newborns was common: anaemia in 27; neutropenia in five (two severe); platelets counts <100 000 in two. All values recovered on study completion. Conclusions: Fixed dose AZT/3TC is well accepted, gives improvements in CD4 and viral load; no infants were HIV infected. Haematological toxicity in infants needs careful monitoring. PMID:14663118

SU-E-T-539: Fixed Versus Variable Optimization Points in Combined-Mode Modulated Arc Therapy Planning

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

Kainz, K; Prah, D; Ahunbay, E

2014-06-01

Purpose: A novel modulated arc therapy technique, mARC, enables superposition of step-and-shoot IMRT segments upon a subset of the optimization points (OPs) of a continuous-arc delivery. We compare two approaches to mARC planning: one with the number of OPs fixed throughout optimization, and another where the planning system determines the number of OPs in the final plan, subject to an upper limit defined at the outset. Methods: Fixed-OP mARC planning was performed for representative cases using Panther v. 5.01 (Prowess, Inc.), while variable-OP mARC planning used Monaco v. 5.00 (Elekta, Inc.). All Monaco planning used an upper limit of 91more » OPs; those OPs with minimal MU were removed during optimization. Plans were delivered, and delivery times recorded, on a Siemens Artiste accelerator using a flat 6MV beam with 300 MU/min rate. Dose distributions measured using ArcCheck (Sun Nuclear Corporation, Inc.) were compared with the plan calculation; the two were deemed consistent if they agreed to within 3.5% in absolute dose and 3.5 mm in distance-to-agreement among > 95% of the diodes within the direct beam. Results: Example cases included a prostate and a head-and-neck planned with a single arc and fraction doses of 1.8 and 2.0 Gy, respectively. Aside from slightly more uniform target dose for the variable-OP plans, the DVHs for the two techniques were similar. For the fixed-OP technique, the number of OPs was 38 and 39, and the delivery time was 228 and 259 seconds, respectively, for the prostate and head-and-neck cases. For the final variable-OP plans, there were 91 and 85 OPs, and the delivery time was 296 and 440 seconds, correspondingly longer than for fixed-OP. Conclusion: For mARC, both the fixed-OP and variable-OP approaches produced comparable-quality plans whose delivery was successfully verified. To keep delivery time per fraction short, a fixed-OP planning approach is preferred.« less

Association between Pre-Operative Cefazolin Dose and Surgical Site Infection in Obese Patients.

PubMed

Peppard, William J; Eberle, David G; Kugler, Nathan W; Mabrey, Danielle M; Weigelt, John A

A fixed dose of cefazolin results in serum concentrations that decrease as body mass increases. Current national guidelines suggest a pre-operative cefazolin dose of two grams may be insufficient for patients ≥120 kg; thus a three gram dose is recommended. These recommendations, however, are based on pharmacokinetic rather than outcome data. We evaluate the efficacy of pre-operative cefazolin two gram and three gram doses as measured by the rate of surgical site infection (SSI). We conducted a retrospective review of adult patients ≥100 kg who were prescribed cefazolin as surgical prophylaxis between September 1, 2012 and May 31, 2013 at an academic medical center. Patients were excluded if cefazolin was prescribed but not administered, had a known infection at the site of surgery, or inappropriately received cefazolin prophylaxis based on surgical indication. The SSIs were identified by documentation of SSI in the medical record or findings consistent with the standard Centers for Disease Control and Prevention definition. Inpatient and outpatient records up to 90 days post-operative were reviewed for delayed SSI. Four hundred eighty-three surgical cases were identified in which pre-operative cefazolin was prescribed. Forty-seven patients were excluded leaving a total of 436 patients for final analysis: 152 in the cefazolin two gram group and 284 in the three gram group. Baseline demographics were similar between groups with a mean follow-up duration of 77 days for both groups. Unadjusted SSI rates were 7.2% and 7.4% (odds ratio [OR] 0.98, p = 0.95), for the two gram and three gram groups, respectively. When differences in follow-up between groups were considered and logistic regression was adjusted with propensity score, there remained no difference in SSI rates (OR 0.87, 95% confidence interval 0.36-2.06, p = 0.77). In otherwise similar obese surgical patients weighing ≥100 kg, the administration of a pre-operative cefazolin two gram dose is associated with a similar rate of SSI compared with patients who received a three gram dose.

Determinants of virological outcome and adverse events in African children treated with paediatric nevirapine fixed-dose-combination tablets

PubMed Central

BIENCZAK, Andrzej; DENTI, Paolo; Adrian, COOK; WIESNER, Lubbe; MULENGA, Veronica; KITYO, Cissy; KEKITIINWA, Addy; GIBB, Diana M.; BURGER, David; WALKER, A. Sarah; MCILLERON, Helen

2017-01-01

Background Nevirapine is the only non-nucleoside reverse transcriptase inhibitor currently available as a paediatric fixed-dose combination tablet and is widely used in African children. Nonetheless, the number of investigations into pharmacokinetic determinants of virological suppression in African children is limited and the predictive power of the current therapeutic range was never evaluated in this population, thereby limiting treatment optimisation. Methods We analysed data from 322 African children (aged 0.3–13 years) treated with nevirapine, lamivudine, and either abacavir, stavudine, or zidovudine, and followed up to 144 weeks. Nevirapine trough concentration (Cmin) and other factors were tested for associations with viral load (VL)>100 copies/mL and transaminase increases >grade 1 using proportional hazard and logistic models in 219 initially antiretroviral treatment(ART)-naïve children. Results Pre-ART VL, adherence, and nevirapine Cmin were associated with VL non-suppression (hazard-ratio [HR]=2.08 [95% CI: 1.50–2.90, p<0.001] for 10-fold higher pre-ART VL, HR=0.78 [95% CI: 0.68–0.90, p<0.001] for 10% improvement in adherence and HR=0.94 [95% CI: 0.90–0.99, p=0.014] for a 1mg/L increase in nevirapine Cmin). There were additional effects of pre-ART CD4% and clinical site. The risk of virological non-suppression decreased with increasing nevirapine Cmin and there was no clear Cmin threshold predictive of virological non-suppression. Transient transaminase elevations >grade 1 were associated with high Cmin (>12.4 mg/L), HR=5.18 (95%CI 1.95–13.80, p<0.001). Conclusions Treatment initiation at lower pre-ART VL and higher pre-ART CD4%, increased adherence, and maintaining average Cmin higher than current target could improve virological suppression of African children treated with nevirapine without increasing toxicity. PMID:28060017

Impact of tumour motion compensation and delineation methods on FDG PET-based dose painting plan quality for NSCLC radiation therapy.

PubMed

Thomas, Hannah Mary; Kinahan, Paul E; Samuel, James Jebaseelan E; Bowen, Stephen R

2018-02-01

To quantitatively estimate the impact of different methods for both boost volume delineation and respiratory motion compensation of [18F] FDG PET/CT images on the fidelity of planned non-uniform 'dose painting' plans to the prescribed boost dose distribution. Six locally advanced non-small cell lung cancer (NSCLC) patients were retrospectively reviewed. To assess the impact of respiratory motion, time-averaged (3D AVG), respiratory phase-gated (4D GATED) and motion-encompassing (4D MIP) PET images were used. The boost volumes were defined using manual contour (MANUAL), fixed threshold (FIXED) and gradient search algorithm (GRADIENT). The dose painting prescription of 60 Gy base dose to the planning target volume and an integral dose of 14 Gy (total 74 Gy) was discretized into seven treatment planning substructures and linearly redistributed according to the relative SUV at every voxel in the boost volume. Fifty-four dose painting plan combinations were generated and conformity was evaluated using quality index VQ0.95-1.05, which represents the sum of planned dose voxels within 5% deviation from the prescribed dose. Trends in plan quality and magnitude of achievable dose escalation were recorded. Different segmentation techniques produced statistically significant variations in maximum planned dose (P < 0.02), as well as plan quality between segmentation methods for 4D GATED and 4D MIP PET images (P < 0.05). No statistically significant differences in plan quality and maximum dose were observed between motion-compensated PET-based plans (P > 0.75). Low variability in plan quality was observed for FIXED threshold plans, while MANUAL and GRADIENT plans achieved higher dose with lower plan quality indices. The dose painting plans were more sensitive to segmentation of boost volumes than PET motion compensation in this study sample. Careful consideration of boost target delineation and motion compensation strategies should guide the design of NSCLC dose painting trials. © 2017 The Royal Australian and New Zealand College of Radiologists.

SU-E-T-187: Collimation Methods in Spot Scanning Proton Therapy: A Treatment Plan Comparison Between a Fixed Aperture and a Dynamic Collimation System

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

Smith, B; Gelover, E; Wang, D

2015-06-15

Purpose: Low-energy treatments during spot scanning proton therapy (SSPT) suffer from poor conformity due to increased spot size. Collimation devices can reduce the lateral penumbra of a proton therapy dose distribution and improve the overall plan quality. The purpose of this work was to study the advantages of individual energy-layer collimation, which is unique to a recently proposed Dynamic Collimation System (DCS), in comparison to a standard, fixed aperture that allows only a single shape for all energy layers. Methods: Three brain patients previously planned and treated with SSPT were re-planned using an in-house treatment planning system capable of modelingmore » collimated and un-collimated proton beamlets. The un-collimated plans, which served as a baseline for comparison, reproduced the target coverage of the clinically delivered plans. The collimator opening for the aperture based plans included a 0.6 cm expansion of the largest cross section of the target in the Beam’s Eye View, while the DCS based plans were created by optimizing the collimator position for beam spots near the periphery of the target in each energy layer. Results: The reduction of mean dose to normal tissue adjacent to the target, as defined by a 10 mm ring, averaged 9.13% and 3.48% for the DCS and aperture plans, respectively. The conformity index, as defined by the ratio of the volume of the 50% isodose line to the target volume, yielded an average improvement of 16.42% and 8.16% for the DCS and aperture plans, respectively. Conclusion: Collimation reduces the dose to normal tissue adjacent to the target and increases dose conformity to the target region for low-energy SSPT. The ability of the DCS to provide collimation to each energy layer yields better conformity in comparison to fixed aperture plans. This work was partially funded by IBA (Ion Beam Applications S.A.)« less

Reinforcing effects of sigma-receptor agonists in rats trained to self-administer cocaine.

PubMed

Hiranita, Takato; Soto, Paul L; Tanda, Gianluigi; Katz, Jonathan L

2010-02-01

sigma-Receptor (sigmaR) antagonists have been reported to block certain effects of psychostimulant drugs. The present study examined the effects of sigmaR ligands in rats trained to self-administer cocaine (0.032-1.0 mg/kg/inj i.v.) under fixed-ratio 5-response schedules of reinforcement. Maximal rates of responding were maintained by 0.32 mg/kg/inj cocaine, or by the sigmaR agonists, 1,3-di-(2-tolyl)guanidine (DTG; 1.0 mg/kg/inj) or 2-(4-morpholinethyl) 1-phenylcyclohexane-1-carboxylate hydrochloride (PRE-084; 0.32 mg/kg/inj), when substituted for cocaine. Lower response rates were maintained at higher and lower doses of the compounds. No dose of the sigmaR antagonists [N-[2-(3,4-dichlorophenyl)ethyl]-N-methyl-2-(1-pyrrolidinyl)ethylamine (BD 1008), N-[2-(3,4-dichlorophenyl)ethyl]-N-methyl-2-(dimethylamino)ethylamine (BD 1047), N-[2-(3,4-dichlorophenyl)ethyl]-4-methylpiperazine (BD 1063)] maintained responding appreciably above levels obtained when responding had no consequences. Presession treatment with sigmaR agonists dose-dependently shifted the cocaine self-administration dose-effect curve leftward. The dopamine-uptake inhibitor, (-)-2beta-carbomethoxy-3beta-(4-fluorophenyl)tropane (WIN 35,428), dose-dependently shifted the DTG and PRE-084 self-administration dose-effect curves leftward. Treatment with the sigmaR antagonists dose-dependently decreased response rates maintained by DTG or PRE-084, but did not affect cocaine self-administration. Response rates maintained by maximally effective DTG or PRE-084 doses were decreased by sigmaR antagonists at lower doses than those that decreased response rates maintained by food reinforcement. Although sigmaR antagonists block some cocaine-induced effects, the lack of effect on cocaine self-administration suggests that the primary reinforcing effects of cocaine do not involve direct effects at sigmaRs. However, the self-administration of sigmaR agonists in cocaine-trained subjects, facilitation of cocaine self-administration by sigmaR-agonist pretreatment, and the facilitation of sigmaR-agonist self-administration by WIN 35,428, together suggest enhanced abuse-related effects resulting from concomitant dopaminergically mediated actions and sigmaR-mediated actions of the drugs.

Reinforcing Effects of σ-Receptor Agonists in Rats Trained to Self-Administer Cocaine

PubMed Central

Hiranita, Takato; Soto, Paul L.; Tanda, Gianluigi

2010-01-01

σ-Receptor (σR) antagonists have been reported to block certain effects of psychostimulant drugs. The present study examined the effects of σR ligands in rats trained to self-administer cocaine (0.032–1.0 mg/kg/inj i.v.) under fixed-ratio 5-response schedules of reinforcement. Maximal rates of responding were maintained by 0.32 mg/kg/inj cocaine, or by the σR agonists, 1,3-di-(2-tolyl)guanidine (DTG; 1.0 mg/kg/inj) or 2-(4-morpholinethyl) 1-phenylcyclohexane-1-carboxylate hydrochloride (PRE-084; 0.32 mg/kg/inj), when substituted for cocaine. Lower response rates were maintained at higher and lower doses of the compounds. No dose of the σR antagonists [N-[2-(3,4-dichlorophenyl)ethyl]-N-methyl-2-(1-pyrrolidinyl)ethylamine (BD 1008), N-[2-(3,4-dichlorophenyl)ethyl]-N-methyl-2-(dimethylamino)ethylamine (BD 1047), N-[2-(3,4-dichlorophenyl)ethyl]-4-methylpiperazine (BD 1063)] maintained responding appreciably above levels obtained when responding had no consequences. Presession treatment with σR agonists dose-dependently shifted the cocaine self-administration dose-effect curve leftward. The dopamine-uptake inhibitor, (−)-2β-carbomethoxy-3β-(4-fluorophenyl)tropane (WIN 35,428), dose-dependently shifted the DTG and PRE-084 self-administration dose-effect curves leftward. Treatment with the σR antagonists dose-dependently decreased response rates maintained by DTG or PRE-084, but did not affect cocaine self-administration. Response rates maintained by maximally effective DTG or PRE-084 doses were decreased by σR antagonists at lower doses than those that decreased response rates maintained by food reinforcement. Although σR antagonists block some cocaine-induced effects, the lack of effect on cocaine self-administration suggests that the primary reinforcing effects of cocaine do not involve direct effects at σRs. However, the self-administration of σR agonists in cocaine-trained subjects, facilitation of cocaine self-administration by σR-agonist pretreatment, and the facilitation of σR-agonist self-administration by WIN 35,428, together suggest enhanced abuse-related effects resulting from concomitant dopaminergically mediated actions and σR-mediated actions of the drugs. PMID:19892920

The consistency of Fletcher-Suit applicator geometry and of the rectal probe’s position in high dose rate brachytherapy treatment fraction of cervix carcinoma

PubMed Central

2009-01-01

Purpose The dose values computed with the treatment planning system and the in vivo dose measurements with semiconductor detectors in rectum during the high dose rate brachytherapy treatment fraction of the cervix carcinoma are occasionally significantly different. We’ve investigated the consistency of the Fletcher-Suit applicator geometry and the in vivo rectal probe’s position stability during the high dose rate brachytherapy treatment fraction. Material and methods The patient lied in a lithotomic position during a biplane reconstruction images, throughout the treatment planning and dose administration. We obtained post-treatment reconstruction images and prepared a post-treatment plan. The amount of 14 treatment fractions of 10 patients were considered in the study. Two methods were applied: evaluation of the difference of reconstructed pre-treatment and post-treatment applicator points and rectal probe’s detectors being relevant to the co-ordinate system fixed to the applicator, and estimation of applicators and rectal probe’s reallocation with respect to the pelvic bones with registration of pre- and post-treatment reconstruction images. Results We’ve experienced good consistency in the Fletcher-Suit applicator geometry in all treatment fractions. 70% of them presented small variation in the rectal probe’s position, while the rest showed significant shift in the applicator or rectal probe’s position with regard to the pelvic bones. PMID:27807458

Cosmic infinity: a dynamical system approach

NASA Astrophysics Data System (ADS)

Bouhmadi-López, Mariam; Marto, João; Morais, João; Silva, César M.

2017-03-01

Dynamical system techniques are extremely useful to study cosmology. It turns out that in most of the cases, we deal with finite isolated fixed points corresponding to a given cosmological epoch. However, it is equally important to analyse the asymptotic behaviour of the universe. On this paper, we show how this can be carried out for 3-form models. In fact, we show that there are fixed points at infinity mainly by introducing appropriate compactifications and defining a new time variable that washes away any potential divergence of the system. The richness of 3-form models allows us as well to identify normally hyperbolic non-isolated fixed points. We apply this analysis to three physically interesting situations: (i) a pre-inflationary era; (ii) an inflationary era; (iii) the late-time dark matter/dark energy epoch.

Self-assembled nanospheres with multiple endohedral binding sites pre-organize catalysts and substrates for highly efficient reactions

NASA Astrophysics Data System (ADS)

Wang, Qi-Qiang; Gonell, Sergio; Leenders, Stefan H. A. M.; Dürr, Maximilian; Ivanović-Burmazović, Ivana; Reek, Joost N. H.

2016-03-01

Tuning reagent and catalyst concentrations is crucial in the development of efficient catalytic transformations. In enzyme-catalysed reactions the substrate is bound—often by multiple non-covalent interactions—in a well-defined pocket close to the active site of the enzyme; this pre-organization facilitates highly efficient transformations. Here we report an artificial system that co-encapsulates multiple catalysts and substrates within the confined space defined by an M12L24 nanosphere that contains 24 endohedral guanidinium-binding sites. Cooperative binding means that sulfonate guests are bound much more strongly than carboxylates. This difference has been used to fix gold-based catalysts firmly, with the remaining binding sites left to pre-organize substrates. This strategy was applied to a Au(I)-catalysed cyclization of acetylenic acid to enol lactone in which the pre-organization resulted in much higher reaction rates. We also found that the encapsulated sulfonate-containing Au(I) catalysts did not convert neutral (acid) substrates, and so could have potential in the development of substrate-selective catalysis and base-triggered on/off switching of catalysis.

Linear dynamic range enhancement in a CMOS imager

NASA Technical Reports Server (NTRS)

Pain, Bedabrata (Inventor)

2008-01-01

A CMOS imager with increased linear dynamic range but without degradation in noise, responsivity, linearity, fixed-pattern noise, or photometric calibration comprises a linear calibrated dual gain pixel in which the gain is reduced after a pre-defined threshold level by switching in an additional capacitance. The pixel may include a novel on-pixel latch circuit that is used to switch in the additional capacitance.

Dose range finding study for the efficacy of meloxicam administered prior to sodium urate-induced synovitis in cats.

PubMed

Carroll, Gwendolyn L; Narbe, Ruediger; Kerwin, Sharon C; Taylor, Lathrop; Peterson, Kurt; Hartsfield, Sandee M

2011-07-01

To determine the lowest efficacious dose of oral meloxicam for relieving pain in cats with a sodium urate (SU)-induced acute inflammatory synovitis. Randomized, blinded, controlled, and four-way crossover study. Eight surgically neutered cats (four males, four females) paired according to sex. Each pair of cats was treated with 0 (placebo), 0.025, 0.05, or 0.075 mg kg(-1) oral meloxicam once daily for 4 days prior to injection, into alternating stifles, of 1 mL of 20 mg mL(-1) SU crystals, beginning with the right stifle. Each cat received each of the four treatments, separated by at least 21 days. Analgesic efficacy was evaluated based on objective (e.g., pressure mat data total force, contact pressure, and contact area) and subjective (e.g., scores for Analgesia Scale [AS], Lameness Scale [LS], and Visual Analog Scale [VAS]) outcome measures for pain assessment. All outcome measures were recorded before and during 30 hours after SU injection. The pre-defined primary outcome measure was the area under the response-time curve (AUC(0-30) hours) of the total force of the injected limb. Data were analyzed by analysis of variance. A sequential test procedure was applied and the test sequence stopped in case of a nonsignificant result. Meloxicam at doses of 0.05 and 0.075 mg kg(-1) day(-1) PO was significantly different from placebo for the pre-defined primary outcome measure (i.e., AUC(0-30) hours of total force). All tested meloxicam doses were lower than placebo for the subjective outcome measures (i.e., AUC(0-30) hours of AS, LS, and VAS). The lowest efficacious dose of meloxicam for relieving pain in cats with an SU-induced synovitis was 0.05 mg kg(-1) day(-1) PO according to the pre-defined primary outcome measure. However, lower doses may also be effective as seen in the subjective outcome measures. © 2011 The Authors. Veterinary Anaesthesia and Analgesia. © 2011 Association of Veterinary Anaesthetists and the American College of Veterinary Anesthesiologists.

Efficacy and Safety of ‘Fixed Dose’ versus ‘Loose’ Drug Regimens for Treatment of Pulmonary Tuberculosis in Two High TB-Burden African Countries: A Randomized Controlled Trial

PubMed Central

2016-01-01

Background There are limited data on the performance of the use of fixed-dose combination (FDC) TB drugs when used under programmatic settings in high TB-endemic countries. We evaluated the efficacy and safety of FDC versus loose formulation (LF) TB treatment regimens for treatment of pulmonary TB (PTB) in the context of actual medical practice in prevailing conditions within programmatic settings in five sites in two high TB-burden African countries. Methods A two-arm, single-blind, randomized clinical trial comparing FDCs with separate LFs involving 1000 adults newly diagnosed with culture positive PTB was conducted at five sites in two African countries between 2007 and 2011. Participants were randomized to receive daily treatment with anti-TB drugs given as either FDC or separate LFs for 24 weeks (intensive phase– 8 weeks of isoniazid, rifampicin, ethambutol and pyrazinamide; continuation phase– 16 weeks of rifampicin and isoniazid). Primary outcome measures were microbiological cure and safety at the end of six months’ treatment; pre-specified non-inferiority margin for difference in cure rate was 4%. The primary efficacy analysis was based on the modified intent to treat (mITT) cohort comprising all randomized patients with a positive baseline culture result for TB and who received at least one dose of study treatment. Patients missing end of treatment culture results were considered failures. Further analyses were done in which mITT patients without an end of treatment (EOT) culture were excluded in a complete case analysis (mITTcc) and a per protocol cohort analysis defined as mITTcc patients who received at least 95% of their intended doses and had an EOT culture result. Results In the mITT analysis, the cure rate in the FDC group was 86.7% (398/459) and in the LF group 85.2% (396/465) (difference 1.5-% (90% confidence interval (CI) (-2.2%– 5.3%)). Per Protocol analysis showed similar results: FDC 98.9% (359/363) versus LF 96.9% (345/356), (difference 2.0% (90% CI: 0.1%– 3.8%)). The two arms showed no significant differences in terms of safety, early culture conversion and patient adherence to treatment. Interpretation The comparison of the two drug regimens satisfied the pre-specified non-inferiority criterion. Our results support the WHO recommendations for the use of FDC in the context of actual medical practice within health services in high TB-endemic countries. Trial Registration ISRCTN Registry 95204603 PMID:27322164

Osimertinib Western and Asian clinical pharmacokinetics in patients and healthy volunteers: implications for formulation, dose, and dosing frequency in pivotal clinical studies.

PubMed

Planchard, David; Brown, Kathryn H; Kim, Dong-Wan; Kim, Sang-We; Ohe, Yuichiro; Felip, Enriqueta; Leese, Philip; Cantarini, Mireille; Vishwanathan, Karthick; Jänne, Pasi A; Ranson, Malcolm; Dickinson, Paul A

2016-04-01

Osimertinib (AZD9291) 80 mg once daily is approved by the US FDA for the treatment of patients with metastatic EGFR T790M-positive NSCLC whose disease has previously progressed on EGFR-TKI therapy. Osimertinib PK was evaluated to define the dose and dosing interval, whether a fixed-dosing approach can be used globally, and the impact of formulation and food on exposure. AURA (NCT01802632): single- and multiple-dose PK of osimertinib (20-240 mg daily) was determined in patients with advanced NSCLC. Bioavailability study (NCT01951599): single-dose PK of osimertinib (20 mg) was determined in healthy volunteers with administration of capsule, solution, or tablet formulations fasted, and as a tablet in the fed and fasted state. Osimertinib was slowly absorbed and displayed dose-proportional increases in exposure from 20 to 240 mg. Distribution was extensive and clearance low to moderate, resulting in a mean half-life of 48.3 h. Steady state was achieved by 15 days of dosing, consistent with single-dose PK, with a peak-to-trough ratio of 1.6. Two active metabolites circulated at ~10 % of osimertinib exposure. Ethnicity did not appear to affect exposure. Osimertinib PK profiles in healthy volunteers were similar to those in patients and were unaffected by formulation. Food caused a clinically insignificant increase in exposure. Osimertinib PK supports once-daily dosing; the same dose for Asian and non-Asian populations; a fixed-dosing approach; a minimal effect of food on exposure; and a switch to tablet formulation without alteration to dose or schedule. Osimertinib plasma concentrations are sustained throughout the dosing period, which is considered optimal for efficacy.

Evaluation of an Alcohol Withdrawal Protocol and a Preprinted Order Set at a Tertiary Care Hospital

PubMed Central

Ng, Karen; Dahri, Karen; Chow, Ivy; Legal, Michael

2011-01-01

Background: Alcohol withdrawal protocols involving symptom-triggered administration of benzodiazepine have been established to reduce the duration of treatment and the cumulative benzodiazepine dose (relative to usual care). However, the effects of a protocol combining fixed-schedule and symptom-triggered benzodiazepine dosing are less clear. Objective: To assess the efficacy and safety of a combination fixed-scheduled and symptom-triggered benzodiazepine dosing protocol for alcohol withdrawal, relative to usual care, for medical inpatients at a tertiary care hospital. Methods: A chart review of admissions to the internal medicine service for alcohol withdrawal was conducted to compare treatment outcomes before (October 2005 to April 2007) and after (October 2007 to April 2009) implementation of the combination protocol. The primary outcome was duration of benzodiazepine treatment for alcohol withdrawal. The secondary outcomes were cumulative benzodiazepine dose administered, safety implications, and use of adjunctive medications. Results: A total of 159 patients met the inclusion criteria. Assessable data were available for 71 charts from the pre-implementation period and 72 charts from the post-implementation period. The median duration of benzodiazepine treatment was 91 h before implementation and 57 h after implementation (p < 0.001). Use of the protocol was also associated with a significant reduction in severe complications of alcohol withdrawal (50% versus 33%, p = 0.019), median cumulative benzodiazepine dose (in lorazepam equivalents) (20.0 mg versus 15.5 mg, p = 0.026), and use of adjunctive medications (65% versus 38%, p = 0.001). The incidence of serious adverse outcomes of treatment with benzodiazepines was not significantly different between the 2 groups. Conclusions: Implementation of an alcohol withdrawal protocol with a combination of fixed-schedule and symptom-triggered benzodiazepine dosing in a medical ward was associated with a shorter duration of benzodiazepine use and a lower incidence of severe complications of alcohol withdrawal. PMID:22479099

A comparison of masking effects of haloperidol versus molindone in tardive dyskinesia.

PubMed

Glazer, W M; Hafez, H

1990-01-01

An experimental method was utilized to compare the masking effects of two neuroleptic agents--molindone and haloperidol--on 18 neuroleptic-treated schizophrenic patients exhibiting operationally defined withdrawal-exacerbated tardive dyskinesia. After a week on one of these two medications at preestablished doses equivalent to that of the pre-study neuroleptic, molindone-masked total AIMS scores by significantly less (12%) than haloperidol (27%). Similarly, during a second week when the dose of these neuroleptics was equivalent to 200% that of the pre-study dose, molindone masked the total AIMS score significantly less (23%) as compared to haloperidol (53%). Several interpretations of this finding are considered. This study demonstrates the feasibility of a method that may offer a model for understanding pharmacological differences among neuroleptic medications.

Effect of artesunate-mefloquine fixed-dose combination in malaria transmission in amazon basin communities

PubMed Central

2012-01-01

Background Studies in South-East Asia have suggested that early diagnosis and treatment with artesunate (AS) and mefloquine (MQ) combination therapy may reduce the transmission of Plasmodium falciparum malaria and the progression of MQ resistance. Methods The effectiveness of a fixed-dose combination of AS and MQ (ASMQ) in reducing malaria transmission was tested in isolated communities of the Juruá valley in the Amazon region. Priority municipalities within the Brazilian Legal Amazon area were selected according to pre-specified criteria. Routine national malaria control programmatic procedures were followed. Existing health structures were reinforced and health care workers were trained to treat with ASMQ all confirmed falciparum malaria cases that match inclusion criteria. A local pharmacovigilance structure was implemented. Incidence of malaria and hospitalizations were recorded two years before, during, and after the fixed-dose ASMQ intervention. In total, between July 2006 and December 2008, 23,845 patients received ASMQ. Two statistical modelling approaches were applied to monthly time series of P. falciparum malaria incidence rates, P. falciparum/Plasmodium vivax infection ratio, and malaria hospital admissions rates. All the time series ranged from January 2004 to December 2008, whilst the intervention period span from July 2006 to December 2008. Results The ASMQ intervention had a highly significant impact on the mean level of each time series, adjusted for trend and season, of 0.34 (95%CI 0.20 – 0.58) for the P. falciparum malaria incidence rates, 0.67 (95%CI 0.50 – 0.89) for the P. falciparum/P. vivax infection ratio, and 0.53 (95%CI 0.41 – 0.69) for the hospital admission rates. There was also a significant change in the seasonal (or monthly) pattern of the time series before and after intervention, with the elimination of the malaria seasonal peak in the rainy months of the years following the introduction of ASMQ. No serious adverse events relating to the use of fixed-dose ASMQ were reported. Conclusions In the remote region of the Juruá valley, the early detection of malaria by health care workers and treatment with fixed-dose ASMQ was feasible and efficacious, and significantly reduced the incidence and morbidity of P. falciparum malaria. PMID:22905900

Fixed-dose combination therapy for the prevention of cardiovascular disease

PubMed Central

de Cates, Angharad N; Farr, Matthew RB; Wright, Nicola; Jarvis, Morag C; Rees, Karen; Ebrahim, Shah; Huffman, Mark D

2014-01-01

Background Cardiovascular disease (CVD) is the leading cause of death and disability worldwide, yet CVD risk factor control and secondary prevention rates remain low. A fixed-dose combination of blood pressure and cholesterol lowering and antiplatelet treatments into a single pill, or polypill, has been proposed as one strategy to reduce the global burden of CVD by up to 80% given its potential for better adherence and lower costs. Objectives To determine the effectiveness of fixed-dose combination therapy on reducing fatal and non-fatal CVD events and on improving blood pressure and lipid CVD risk factors for both primary and secondary prevention of CVD. We also aimed to determine discontinuation rates, adverse events, health-related quality of life, and costs of fixed-dose combination therapy. Search methods We searched the Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library(2013, Issue 6), MEDLINE Ovid (1946 to week 2 July 2013), EMBASE Ovid (1980 to Week 28 2013), ISI Web of Science (1970 to 19 July 2013), and the Database of Abstracts of Reviews of Effects (DARE), Health Technology Assessment Database (HTA), and Health Economics Evaluations Database (HEED) (2011, Issue 4) in The Cochrane Library. We used no language restrictions. Selection criteria We included randomised controlled trials of a fixed-dose combination therapy including at least one blood pressure lowering and one lipid lowering component versus usual care, placebo, or a single drug active component for any treatment duration in adults ≥ 18 years old with no restrictions on presence or absence of pre-existing cardiovascular disease. Data collection and analysis Three review authors independently selected studies for inclusion and extracted the data. We evaluated risk of bias using the Cochrane risk of bias assessment tool. We sought to include outcome data on all-cause mortality, fatal and non-fatal CVD events, adverse events, changes in systolic and diastolic blood pressure, total and low density lipoprotein (LDL) cholesterol concentrations, discontinuation rates, quality of life, and costs. We calculated risk ratios (RR) for dichotomous data and weighted mean differences (MD) for continuous data with 95% confidence intervals (CI) using fixed-effect models when heterogeneity was low (I2 < 50%) and random-effects models when heterogeneity was high (I2 > 50%). Main results We found nine randomised controlled trials with a total of 7047 participants. Seven of the nine trials evaluated the effects of fixed-dose combination therapy on primary CVD prevention, and the trial length ranged from six weeks to 15 months. We found a moderate to high risk of bias in the domains of selection, performance, detection, attrition, and other types of bias in five of the nine trials. Compared with the comparator groups, the effects of the fixed-dose combination treatment on mortality (1.2% versus 1.0%, RR 1.26, 95% CI 0.67 to 2.38, N = 3465) and cardiovascular events (4.0% versus 2.9%, RR 1.38, 95% CI 0.91 to 2.10, N = 2479) were uncertain (low quality evidence). The low event rates for these outcomes, limited availability of data as only two out of nine trials reported on these outcomes, and a high risk of bias in at least one domain suggest that these results should not be viewed with confidence. Adverse events were common in both the intervention (30%) and comparator (24%) groups, with participants randomised to fixed-dose combination therapy being 20% (95% CI 9% to 30%) more likely to report an adverse event. Notably, no serious adverse events were reported. Compared with placebo, the rate of discontinuation among participants randomised to fixed-dose combination was higher (14% versus 11%, RR 1.26 95% CI 1.02 to 1.55). The weighted mean differences in systolic and diastolic blood pressure between the intervention and control arms were -7.05 mmHg (95% CI -10.18 to -3.87) and -3.65 mmHg (95% CI -5.44 to -1.85), respectively. The weighted mean differences (95% CI) in total and LDL cholesterol between the intervention and control arms were -0.75 mmol/L (95% CI -1.05 to -0.46) and -0.81 mmol/L (95% CI -1.09 to -0.53), respectively. There was a high degree of statistical heterogeneity in comparisons of blood pressure and lipids (I2 ≥ 70% for all) that could not be explained, so these results should be viewed with caution. Fixed-dose combination therapy improved adherence to a multi-drug strategy by 33% (26% to 41%) compared with usual care, but this comparison was reported in only one study. The effects of fixed-dose combination therapy on quality of life are uncertain, though these results were reported in only one trial. No trials reported costs. Authors' conclusions Compared with placebo, single drug active component, or usual care, the effects of fixed-dose combination therapy on all-cause mortality or CVD events are uncertain; only few trials report these outcomes and the included trials were primarily designed to observe changes in CVD risk factor levels rather than clinical events. Reductions in blood pressure and lipid parameters are generally lower than those previously projected, though substantial heterogeneity of results exists. Fixed-dose combination therapy is associated with modest increases in adverse events compared with placebo, single drug active component, or usual care but may be associated with improved adherence to a multidrug regimen. Ongoing trials of fixed-dose combination therapy will likely inform key outcomes. PMID:24737108

From prescriptions to drug use periods - things to notice.

PubMed

Tanskanen, Antti; Taipale, Heidi; Koponen, Marjaana; Tolppanen, Anna-Maija; Hartikainen, Sirpa; Ahonen, Riitta; Tiihonen, Jari

2014-11-14

Electronic prescription registers provide a vast data source for pharmacoepidemiological research. Prescriptions as such are not suitable for all research purposes; e.g., studying concurrent use of different drugs or adverse drug events during current use. For those purposes, data on dispensed prescriptions needs to be transformed to periods of drug use. We used 3,828,292 dispensed prescriptions claimed between 1 January 2002 and 31 December 2009 for 28,093 persons with Alzheimer's disease. Examples of drug use histories are presented to discuss different aspects that should be noticed when using register-based data consisting of drug purchases. There is no simple method for correctly transforming dispensed prescriptions to periods of drug use that is usable for all drugs and drug users. Fixed assumptions of daily dose (in defined daily doses, tablets or other units) and fixed time windows should be used with caution and adjusted for different drug use patterns. We recommend that when transforming prescription drug purchases to drug use periods personal dose, purchasing pattern and other behavioral differences between patients should be taken into account.

Evidence-Based Design of Fixed-Dose Combinations: Principles and Application to Pediatric Anti-Tuberculosis Therapy.

PubMed

Svensson, Elin M; Yngman, Gunnar; Denti, Paolo; McIlleron, Helen; Kjellsson, Maria C; Karlsson, Mats O

2018-05-01

Fixed-dose combination formulations where several drugs are included in one tablet are important for the implementation of many long-term multidrug therapies. The selection of optimal dose ratios and tablet content of a fixed-dose combination and the design of individualized dosing regimens is a complex task, requiring multiple simultaneous considerations. In this work, a methodology for the rational design of a fixed-dose combination was developed and applied to the case of a three-drug pediatric anti-tuberculosis formulation individualized on body weight. The optimization methodology synthesizes information about the intended use population, the pharmacokinetic properties of the drugs, therapeutic targets, and practical constraints. A utility function is included to penalize deviations from the targets; a sequential estimation procedure was developed for stable estimation of break-points for individualized dosing. The suggested optimized pediatric anti-tuberculosis fixed-dose combination was compared with the recently launched World Health Organization-endorsed formulation. The optimized fixed-dose combination included 15, 36, and 16% higher amounts of rifampicin, isoniazid, and pyrazinamide, respectively. The optimized fixed-dose combination is expected to result in overall less deviation from the therapeutic targets based on adult exposure and substantially fewer children with underexposure (below half the target). The development of this design tool can aid the implementation of evidence-based formulations, integrating available knowledge and practical considerations, to optimize drug exposures and thereby treatment outcomes.

Safety and adherence to intermittent pre-exposure prophylaxis (PrEP) for HIV-1 in African men who have sex with men and female sex workers.

PubMed

Mutua, Gaudensia; Sanders, Eduard; Mugo, Peter; Anzala, Omu; Haberer, Jessica E; Bangsberg, David; Barin, Burc; Rooney, James F; Mark, David; Chetty, Paramesh; Fast, Patricia; Priddy, Frances H

2012-01-01

Little is known about safety of and adherence to intermittent HIV PrEP regimens, which may be more feasible than daily dosing in some settings. We present safety and adherence data from the first trial of an intermittent PrEP regimen among Kenyan men who have sex with men (MSM) and female sex workers (FSW). MSM and FSW were randomized to daily oral FTC/TDF or placebo, or intermittent (Monday, Friday and within 2 hours after sex, not to exceed one dose per day) oral FTC/TDF or placebo in a 2:1:2:1 ratio; volunteers were followed monthly for 4 months. Adherence was assessed with the medication event monitoring system (MEMS). Sexual activity data were collected via daily text message (SMS) queries and timeline followback interviews with a one-month recall period. Sixty-seven men and 5 women were randomized into the study. Safety was similar among all groups. Median MEMS adherence rates were 83% [IQR: 63-92] for daily dosing and 55% [IQR:28-78] for fixed intermittent dosing (p = 0.003), while adherence to any post-coital doses was 26% [IQR:14-50]. SMS response rates were low, which may have impaired measurement of post-coital dosing adherence. Acceptability of PrEP was high, regardless of dosing regimen. Adherence to intermittent dosing regimens, fixed doses, and in particular coitally-dependent doses, may be more difficult than adherence to daily dosing. However, intermittent dosing may still be appropriate for PrEP if intracellular drug levels, which correlate with prevention of HIV acquisition, can be attained with less than daily dosing and if barriers to adherence can be addressed. Additional drug level data, qualitative data on adherence barriers, and better methods to measure sexual activity are necessary to determine whether adherence to post-coital PrEP could be comparable to more standard regimens. ClinicalTrials.gov NCT00971230.

Cosmic infinity: a dynamical system approach

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

Bouhmadi-López, Mariam; Marto, João; Morais, João

2017-03-01

Dynamical system techniques are extremely useful to study cosmology. It turns out that in most of the cases, we deal with finite isolated fixed points corresponding to a given cosmological epoch. However, it is equally important to analyse the asymptotic behaviour of the universe. On this paper, we show how this can be carried out for 3-form models. In fact, we show that there are fixed points at infinity mainly by introducing appropriate compactifications and defining a new time variable that washes away any potential divergence of the system. The richness of 3-form models allows us as well to identifymore » normally hyperbolic non-isolated fixed points. We apply this analysis to three physically interesting situations: (i) a pre-inflationary era; (ii) an inflationary era; (iii) the late-time dark matter/dark energy epoch.« less

Assessment of knowledge, attitude, and practices on fixed dose combinations among postgraduate dental students.

PubMed

Vinnakota, Narayana R; Krishna, V; Viswanath, V; Ahmed, Zaheer; Shaik, Kamal S; Boppana, Naveen K

2016-12-01

To assess the knowledge, attitude, and practices of fixed dose combination drugs among postgraduate dental students. A cross-sectional study was carried out among postgraduate dental students of dental colleges in coastal Andhra Pradesh. Three colleges were randomly selected and students of all the three years were included. Data was collected from the specialities of oral medicine and radiology, oral surgery, endodontics, pedodontics, periodontics, and public health dentistry. The total sample was 90 postgraduate students; informed consent was obtained from the participants, and a pretested questionnaire was distributed to them. Data was analyzed using the Statistical Package for the Social Sciences version 20 software. Out of 90 postgraduates, 33 were males and 57 were females. Thirty-five percent were aware of the essential medical list (EML), among them 11% were from oral medicine and radiology and 6.7% were from pedodontics. However, most of them were unaware of the number of fixed dose combination drugs present in the World Health Organization EML. None of them were able to name at least a single banned fixed dose combination drug. Most of them were unaware of the advantages and disadvantages of using fixed dose combination drugs. Amoxicillin with clavulanic acid was the most common drug prescribed by students (73.3%) followed by ofloxacin with ornidazole (54.4%), ibuprofen with paracetamol (53.3%), and sulfamethoxazole with trimethoprim (6%). Most of them were unaware of the rationality in using fixed dose combination drugs. Common sources of information were medical representatives 43 (47.8%), internet 39 (43.3%), and 12 (13.3%) reported using WHO EML. There is an urgent need to improve knowledge on the rationality for using fixed dose combination, EML, and banned fixed dose combination in India to the promote rational use of fixed dose combination.

The discovery and development of aclidinium bromide for the treatment of chronic obstructive pulmonary disease.

PubMed

Malerba, Mario; Radaeli, Alessandro; Santini, Giuseppe; Morjaria, Jaymin; Mores, Nadia; Mondino, Chiara; Macis, Giuseppe; Montuschi, Paolo

2018-06-01

Bronchodilators, including long-acting muscarinic receptor antagonists (LAMAs), are a mainstay of the pharmacological treatment of chronic obstructive pulmonary disease (COPD). LAMAs act as bronchodilators principally by antagonizing airway smooth muscle cells M 3 muscarinic receptors. Aclidinium bromide is a twice-daily LAMA which was developed to improve on the efficacy and/or safety of previous LAMAs. Area covered: Herein, the authors present the pharmacotherapeutic role of aclidinium in COPD and point out unmet need in this research area. The following aspects are covered: a) the discovery and medicinal chemistry of aclidinium bromide; b) an overview of the market; c) its mechanism of action; d) its pharmacokinetic/pharmacodynamic profile derived from pre-clinical studies; e) the clinical studies which led to its licensing; f) the evidence from meta-analyses; g) the aclidinium/formoterol fixed dose combination for COPD and h) priorities in this area of research. Expert opinion: Aclidinium bromide has the pharmacological properties, safety and efficacy profile and inhaler characteristics which makes it a valuable therapeutic option for pharmacological management of patients with COPD. Due to its rapid biotransformation into inactive metabolites, aclidinium is potentially one of the safest LAMAs. Further head-to-head randomized clinical trials are required to define efficacy and safety of aclidinium when compared to once-daily LAMAs. The clinical relevance of airway anti-remodeling effects of aclidinium has to be defined.

Dose conversion ratio in hemodialysis patients switched from darbepoetin alfa to PEG-epoetin beta: AFFIRM study.

PubMed

Choi, Peter; Farouk, Mourad; Manamley, Nick; Addison, Janet

2013-11-01

There is limited information published on switching erythropoiesis-stimulating agent (ESA) treatment for anemia associated with chronic kidney disease (CKD) from darbepoetin alfa (DA) to methoxy polyethylene glycol-epoetin beta (PEG-Epo) outside the protocol of interventional clinical studies. AFFIRM (Aranesp Efficiency Relative to Mircera) was a retrospective, multi-site, observational study designed to estimate the population mean maintenance dose conversion ratio [DCR; dose ratio achieving comparable hemoglobin level (Hb) between two evaluation periods] in European hemodialysis patients whose treatment was switched from DA to PEG-Epo. Eligible patients had received hemodialysis for ≥ 12 months and DA for ≥ 7 months. Data were collected from 7 months before until 7 months after switching treatment. DCR was calculated for patients with Hb and ESA data available in both evaluation periods (EP; Months 1 and 2 were defined as the pre-switch EP, and Months 6 and 7 as the post-switch EP). Red blood cell transfusions pre- and post-switch were quantified. Of 302 patients enrolled, 206 had data available for DCR analysis. The geometric mean DCR was 1.17 (95% CI 1.05, 1.29). Regression analysis indicated a non-linear relationship between pre- and post-switch ESA doses; DCR decreased with increasing pre-switch DA dose. The geometric mean weekly ESA doses were 24.1 μg DA in the pre-switch EP and 28.6 μg PEG-Epo in the post-switch EP. Mean Hb was 11.5 g/dL in the pre-switch EP and 11.4 g/dL in the post-switch EP. There were 16 transfusions and 34 units transfused in the pre-switch period, versus 48 transfusions and 95 units transfused post-switch. Excluding patients receiving a transfusion within 90 days of or during either EP, the DCR was 1.21 (95% CI 1.09, 1.35). In these hemodialysis patients switched from DA to PEG-Epo the DCR was 1.17 and 1.21 after accounting for the effect of transfusions. The number of transfusions and units transfused increased approximately threefold from the pre-switch to the post-switch period.

A novel role for autologous tumour cell vaccination in the immunotherapy of the poorly immunogenic B16-BL6 melanoma.

PubMed

Geiger, J D; Wagner, P D; Shu, S; Chang, A E

1992-06-01

The growth of immunogenic tumours stimulates the generation of tumour-sensitized, but not functional, pre-effector T cells in the draining lymph nodes. These pre-effector cells can mature into effector cells upon in-vitro stimulation with anti-CD3 and IL-2. In the current study, using a defined, poorly immunogenic tumour, B16-BL6 melanoma, the pre-effector cell response was not evident during progressive tumour growth but was elicited by vaccination with irradiated tumour cells admixed with Corynebacterium parvum. After anti-CD3/IL-2 activation, these cells were capable of mediating the regression of established pulmonary metastases. The efficacy of the vaccine depended on the doses of both tumour cells and the adjuvant. While higher numbers of tumour cells were more effective, an optimal dose (12.5 micrograms) of C. parvum was required. The dose of irradiation was not a critical factor. After vaccination, kinetic studies revealed that the pre-effector cell response was evident 4 days later and declined after 14 days. These observations illustrate the potential role of active immunization in the cellular therapy of cancer.

Dose Rationalization of Pembrolizumab and Nivolumab Using Pharmacokinetic Modeling and Simulation and Cost Analysis.

PubMed

Ogungbenro, Kayode; Patel, Alkesh; Duncombe, Robert; Nuttall, Richard; Clark, James; Lorigan, Paul

2018-04-01

Pembrolizumab and nivolumab are highly selective anti-programmed cell death 1 (PD-1) antibodies approved for the treatment of advanced malignancies. Variable exposure and significant wastage have been associated with body size dosing of monoclonal antibodies (mAbs). The following dosing strategies were evaluated using simulations: body weight, dose banding, fixed dose, and pharmacokinetic (PK)-based methods. The relative cost to body weight dosing for band, fixed 150 mg and 200 mg, and PK-derived strategies were -15%, -25%, + 7%, and -16% for pembrolizumab and -8%, -6%, and -10% for band, fixed, and PK-derived strategies for nivolumab, respectively. Relative to mg/kg doses, the median exposures were -1.0%, -4.6%, + 27.1%, and +3.0% for band, fixed 150 mg, fixed 200 mg, and PK-derived strategies, respectively, for pembrolizumab and -3.1%, + 1.9%, and +1.4% for band, fixed 240 mg, and PK-derived strategies, respectively, for nivolumab. Significant wastage can be reduced by alternative dosing strategies without compromising exposure and efficacy. © 2017 American Society for Clinical Pharmacology and Therapeutics.

Cost-effectiveness analysis of individualized mycophenolate mofetil dosing in kidney transplant patients in the APOMYGRE trial.

PubMed

Rousseau, Annick; Laroche, Marie-Laure; Venisse, Nicolas; Loichot-Roselmac, Cecile; Turcant, Alain; Hoizey, Guillaume; Compagnon, Patricia; Hary, Lionel; Debruyne, Danièle; Saivin, Sylvie; Jacqz-Aigrain, Evelyne; Buchler, Mathias; Villeneuve, Claire; Vergnenègre, Alain; Le Meur, Yannick; Marquet, Pierre

2010-05-27

In the prospective, randomized, multicenter APOMYGRE trial conducted in France, concentration-controlled mycophenolate mofetil (MMF) dosing based on mycophenolic acid (MPA) exposure significantly reduced the treatment failure and acute rejection during the first posttransplantation year compared with fixed-dose MMF. This analysis investigated the cost effectiveness of dose individualization. The study included 65 patients per group (intent-to-treat population). Treatment failure (primary efficacy endpoint) was defined as death, graft loss, acute rejection, or MMF discontinuation because of adverse effects. Data on hospitalizations, drugs prescribed, physicians' fees, laboratory expenses, ambulatory visits, and transportation were retrieved. Costs were calculated from the French National Health System perspective. The mean (95% confidence interval) total yearly cost per patient was Euro 47,477 (Euro 43,933; Euro 51,020) in the concentration-controlled group and Euro 46,783 ( Euro 44,152; Euro 49,414) in the fixed-dose group (P=0.7). The observed incremental cost-effectiveness ratio was Euro 3757 per treatment failure (Purchasing Power Parities United States/France: $4129). Hospitalization and drug costs accounted for approximately 50% and 25% of total costs, respectively. The cost for MPA area under the concentration-time curve and dose calculation was Euro 452 per patient, less than 1% of the total cost. In the APOMYGRE trial, therapeutic MPA monitoring using a limited sampling strategy reduced the risk of treatment failure and acute rejection in renal allograft recipients during the first 12 months posttransplantation, at neutral cost.

Pre-emptive therapy against cytomegalovirus (CMV) disease guided by CMV antigenemia assay after allogeneic hematopoietic stem cell transplantation: a single-center experience in Japan.

PubMed

Kanda, Y; Mineishi, S; Saito, T; Seo, S; Saito, A; Suenaga, K; Ohnishi, M; Niiya, H; Nakai, K; Takeuchi, T; Kawahigashi, N; Shoji, N; Ogasawara, T; Tanosaki, R; Kobayashi, Y; Tobinai, K; Kami, M; Mori, S; Suzuki, R; Kunitoh, H; Takaue, Y

2001-02-01

From April 1998 to March 2000, a cytomegalovirus (CMV) antigenemia-guided pre-emptive approach for CMV disease was evaluated in 77 adult patients who received allogeneic hematopoietic stem cell transplantation at the National Cancer Center Hospital. A CMV antigenemia assay was performed at least once a week after engraftment. High-level antigenemia was defined as a positive result with 10 or more positive cells per 50 000 cells and low-level antigenemia was defined as less than 10 positive cells. Among the 74 patients with initial engraftment, 51 developed positive antigenemia. Transplantation from alternative donors and the development of grade II-IV GVHD were independent risk factors for positive antigenemia. Ganciclovir was administered as pre-emptive therapy in 39 patients in a risk-adapted manner. None of the nine low-risk patients with low-level antigenemia as their initial positive result developed high-level antigenemia even though ganciclovir was withheld. Only one patient developed early CMV disease (hepatitis) during the study period. CMV antigenemia resolved in all but two cases, in whom ganciclovir was replaced with foscarnet. In eight patients, however, the neutrophil count decreased to 0.5 x 10(9)/l or less after starting ganciclovir, including three with documented infections and two with subsequent secondary graft failure. The total amount of ganciclovir and possibly the duration of high-dose ganciclovir might affect the incidence of neutropenia. We concluded that antigenemia-guided pre-emptive therapy with a decreased dose of ganciclovir and response-oriented dose adjustment might be appropriate to decrease the toxicity of ganciclovir without increasing the risk of CMV disease.

Regulated partitioning of fixed carbon (14C), sodium (Na+), potassium (K+) and glycine betaine determined salinity stress tolerance of gamma irradiated pigeonpea [Cajanus cajan (L.) Millsp].

PubMed

Kumar, Pankaj; Sharma, Vasundhara; Atmaram, Chobhe Kapil; Singh, Bhupinder

2017-03-01

Soil salinity is a major constraint that limits legume productivity. Pigeonpea is a salt sensitive crop. Seed gamma irradiation at a very low dose (2.5 Gy) is known to enhance seedling establishment, plant growth and yield of cereals and other crops. The present study conducted using two genetically diverse varieties of pigeonpea viz., Pusa-991 and Pusa-992 aimed at establishing the role of pre-sowing seed gamma irradiation at 0, 0.0025, 0.005, 0.01, 0.02, 0.05 and 0.1 kGy on plant growth, seed yield and seed quality under salt stress at 0, 80 and 100 mM NaCl (soil solution EC equivalent 1.92, 5.86 and 8.02 dS/m, respectively) imposed right from the beginning of the experiment. Changes in carbon flow dynamics between shoot and root and concentration of osmolyte, glycine betaine, plant uptake and shoot and root partitioning of Na + and K + and activity of protein degrading enzyme protease were measured under the combined effect of gamma irradiation and salt stress. Positive affect of pre-sowing exposure of seed to low dose of gamma irradiation (<0.01 kGy) under salt stress was evident in pigeonpea. Pigeonpea variety, Pusa-992 showed a better salt tolerance response than Pusa-991 and that the radiated plants performed better than the unirradiated plants even at increasing salinity level. Seed yield and seed protein and iron content were also positively affected by the low dose gamma irradiation under NaCl stress. Multiple factors interacted to determine physiological salt tolerance response of pigeonpea varieties. Gamma irradiation caused a favourable alteration in the source-sink (shoot-root) partitioning of recently fixed carbon ( 14 C) under salt stress in pigeonpea. Gamma irradiation of seeds prior to sowing enhanced glycine betaine content and reduced protease activity at 60-day stage under various salt stress regimes. Lower partitioning of Na + and relatively higher accumulation of K + under irradiation treatment was the other important determinants that differentiated between salt-tolerant and salt-susceptible variety of pigeonpea. The study provides evidence and physiological basis for exploring exploitation of pre-sowing exposure of seeds with low-dose gamma ray for enhancing the salt tolerance response of crop plants.

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

Zhang, P; Kuo, L; Yorke, E

Purpose: To develop a biological modeling strategy which incorporates the response observed on the mid-treatment PET/CT into a dose escalation design for adaptive radiotherapy of non-small-cell lung cancer. Method: FDG-PET/CT was acquired midway through standard fractionated treatment and registered to pre-treatment planning PET/CT to evaluate radiation response of lung cancer. Each mid-treatment PET voxel was assigned the median SUV inside a concentric 1cm-diameter sphere to account for registration and imaging uncertainties. For each voxel, the planned radiation dose, pre- and mid-treatment SUVs were used to parameterize the linear-quadratic model, which was then utilized to predict the SUV distribution after themore » full prescribed dose. Voxels with predicted post-treatment SUV≥2 were identified as the resistant target (response arm). An adaptive simultaneous integrated boost was designed to escalate dose to the resistant target as high as possible, while keeping prescription dose to the original target and lung toxicity intact. In contrast, an adaptive target volume was delineated based only on the intensity of mid-treatment PET/CT (intensity arm), and a similar adaptive boost plan was optimized. The dose escalation capability of the two approaches was compared. Result: Images of three patients were used in this planning study. For one patient, SUV prediction indicated complete response and no necessary dose escalation. For the other two, resistant targets defined in the response arm were multifocal, and on average accounted for 25% of the pre-treatment target, compared to 67% in the intensity arm. The smaller response arm targets led to a 6Gy higher mean target dose in the adaptive escalation design. Conclusion: This pilot study suggests that adaptive dose escalation to a biologically resistant target predicted from a pre- and mid-treatment PET/CT may be more effective than escalation based on the mid-treatment PET/CT alone. More plans and ultimately clinical protocols are needed to validate this approach. MSKCC has a research agreement with Varian Medical System.« less

Comparison of Measured and Estimated CT Organ Doses for Modulated and Fixed Tube Current:: A Human Cadaver Study.

PubMed

Padole, Atul; Deedar Ali Khawaja, Ranish; Otrakji, Alexi; Zhang, Da; Liu, Bob; Xu, X George; Kalra, Mannudeep K

2016-05-01

The aim of this study was to compare the directly measured and the estimated computed tomography (CT) organ doses obtained from commercial radiation dose-tracking (RDT) software for CT performed with modulated tube current or automatic exposure control (AEC) technique and fixed tube current (mAs). With the institutional review board (IRB) approval, the ionization chambers were surgically implanted in a human cadaver (88 years old, male, 68 kg) in six locations such as liver, stomach, colon, left kidney, small intestine, and urinary bladder. The cadaver was scanned with routine abdomen pelvis protocol on a 128-slice, dual-source multidetector computed tomography (MDCT) scanner using both AEC and fixed mAs. The effective and quality reference mAs of 100, 200, and 300 were used for AEC and fixed mAs, respectively. Scanning was repeated three times for each setting, and measured and estimated organ doses (from RDT software) were recorded (N = 3*3*2 = 18). Mean CTDIvol for AEC and fixed mAs were 4, 8, 13 mGy and 7, 14, 21 mGy, respectively. The most estimated organ doses were significantly greater (P < 0.01) than the measured organ doses for both AEC and fixed mAs. At AEC, the mean estimated organ doses (for six organs) were 14.7 mGy compared to mean measured organ doses of 12.3 mGy. Similarly, at fixed mAs, the mean estimated organ doses (for six organs) were 24 mGy compared to measured organ doses of 22.3 mGy. The differences among the measured and estimated organ doses were higher for AEC technique compared to the fixed mAs for most organs (P < 0.01). The most CT organ doses estimated from RDT software are greater compared to directly measured organ doses, particularly when AEC technique is used for CT scanning. Copyright © 2016 The Association of University Radiologists. Published by Elsevier Inc. All rights reserved.

Automated identification of social interaction criteria in Drosophila melanogaster.

PubMed

Schneider, J; Levine, J D

2014-10-01

The study of social behaviour within groups has relied on fixed definitions of an 'interaction'. Criteria used in these definitions often involve a subjectively defined cut-off value for proximity, orientation and time (e.g. courtship, aggression and social interaction networks) and the same numerical values for these criteria are applied to all of the treatment groups within an experiment. One universal definition of an interaction could misidentify interactions within groups that differ in life histories, study treatments and/or genetic mutations. Here, we present an automated method for determining the values of interaction criteria using a pre-defined rule set rather than pre-defined values. We use this approach and show changing social behaviours in different manipulations of Drosophila melanogaster. We also show that chemosensory cues are an important modality of social spacing and interaction. This method will allow a more robust analysis of the properties of interacting groups, while helping us understand how specific groups regulate their social interaction space. © 2014 The Author(s) Published by the Royal Society. All rights reserved.

Bioavailability of rifampicin in a separate formulation and fixed dose combination with isoniazid NIH: a case for a fixed dose combination (FDC) for the treatment of tuberculosis.

PubMed

Nyazema, N Z; Rabvukwa, P; Gumbo, J; Ndudzo, P; Chitemerere, C

1999-06-01

To study and compare the bioavailability of rifampicin (RIF), in two locally manufactured formulations; an FDC and a separate formulation and an imported FDC formulation. Open within subjects, single blind cross over study. Each volunteer subject, acting as their own control, received the two fixed dose combinations and the separate formulation with the same amount of 450 mg RIF. Cmax (peak drug concentration achieved), Tmax (time at which peak drug concentration is achieved), T1/2el (biological half-life of elimination) and area under the curve (AUC) for zero to 10 hours and zero to infinity. These are obtained from plotting plasma concentration against time. There was a significant difference in the Cmax between free and RIF combined with INH (6.1 and 7.6 mg/l respectively) and no significant difference in the other parameters measured, of the local products. Comparison of the local products and imported product showed no significant difference in AUC but significant differences in T1/2el, C max and Tmax (p = 0.003, 0.041 and 0.025 respectively). The Zimbabwe manufactured and the German products had "demonstrable bioavailability" as defined by the International Union Against Tuberculosis and Lung Diseases (IUATLD). The local manufacturer appeared to have the technological capability to produce a registrable combined RIF/INH table to be used in the treatment of tuberculosis and to prevent the irrational use of RIF.

Efficacy and tolerability of a fixed-dose combination of metoprolol extended release/amlodipine in patients with mild-to-moderate hypertension: a randomized, parallel-group, multicentre comparison with losartan plus amlodipine.

PubMed

Pareek, Anil; Chandurkar, Nitin B; Sharma, Ravishankar; Tiwari, Dharmendra; Gupta, Bhagwan S

2010-01-01

Epidemiological studies and clinical trials have shown that prevention of cardiovascular disease, the ultimate goal of hypertension treatment, requires a sufficient reduction in blood pressure. The primary objective of this study was to compare the mean decrease in systolic (SBP) and diastolic (DBP) blood pressure between metoprolol extended release (XL)/amlodipine fixed-dose combination and losartan plus amlodipine combination in patients with mild-to-moderate essential hypertension. The secondary objectives of this study were to compare the proportion of responders in the two treatment groups and to evaluate the tolerability of the study medications. This was a randomized, parallel-group, multicentre comparative study conducted at the outpatient departments of three teaching hospitals in India. Patients with mild-to-moderate hypertension (defined as DBP 90-109 mmHg) aged between 18 and 75 years were enrolled in this study and followed up for 12 weeks. Response to study treatments was evaluated in terms of mean decrease in SBP and DBP and the response rate (reduction to SBP <140 mmHg and DBP <90 mmHg). Out of 152 patients who underwent a 1-week placebo washout, 148 eligible patients were randomized to receive either metoprolol XL 25 mg/amlodipine 2.5 mg fixed-dose combination (76 patients) or losartan 25 mg plus amlodipine 2.5 mg (72 patients). The two treatment groups were similar with respect to demographic and baseline characteristics. Non-responders after 4 weeks of therapy were escalated to metoprolol XL 50 mg/amlodipine 5 mg fixed-dose combination or losartan 50 mg plus amlodipine 5 mg, respectively. The study was completed by 66 patients in each group, of whom 43 patients in each group responded to the starting doses. After 4 weeks' therapy, both treatments were associated with significant decreases in SBP and DBP from baseline (p < 0.001) and were comparable with respect to mean decrease in SBP (p = 0.304), mean decrease in DBP (p = 0.630) and response rate (p = 1.0). Also, both the step-up therapies were comparable with respect to mean decrease in SBP (p = 0.484), mean decrease in DBP (p = 0.650) and response rate (p = 0.134) at week 12. Both treatments were well tolerated in the studied population. Metoprolol XL/amlodipine fixed-dose combination was found to be as effective and well tolerated as losartan plus amlodipine in the treatment of essential hypertension.

Switching to aripiprazole in outpatients with schizophrenia experiencing insufficient efficacy and/or safety/tolerability issues with risperidone: a randomized, multicentre, open-label study.

PubMed

Ryckmans, V; Kahn, J P; Modell, S; Werner, C; McQuade, R D; Kerselaers, W; Lissens, J; Sanchez, R

2009-05-01

This study evaluated the safety/tolerability and effectiveness of aripiprazole titrated-dose versus fixed-dose switching strategies from risperidone in patients with schizophrenia experiencing insufficient efficacy and/or safety/tolerability issues. Patients were randomized to an aripiprazole titrated-dose (starting dose 5 mg/day) or fixed-dose (dose 15 mg/day) switching strategy with risperidone down-tapering. Primary endpoint was rate of discontinuation due to adverse events (AEs) during the 12-week study. Secondary endpoints included positive and negative syndrome scale (PANSS), clinical global impressions - improvement of illness scale (CGI-I), preference of medication (POM), subjective well-being under neuroleptics (SWN-K) and GEOPTE (Grupo Español para la Optimización del Tratamiento de la Esquizofrenia) scales. Rates of discontinuations due to AEs were similar between titrated-dose and fixed-dose strategies (3.5% vs. 5.0%; p=0.448). Improvements in mean PANSS total scores were similar between aripiprazole titrated-dose and fixed-dose strategies (-14.8 vs. -17.2; LOCF), as were mean CGI-I scores (2.9 vs. 2.8; p=0.425; LOCF) and SWN-K scores (+8.6 vs.+10.3; OC,+7.8 vs.+9.8; LOCF). Switching can be effectively and safely achieved through a titrated-dose or fixed-dose switching strategy for aripiprazole, with down-titration of risperidone.

Assessment of the efficacy of a novel tailored vitamin K dosing regimen in lowering the International Normalised Ratio in over-anticoagulated patients: a randomised clinical trial.

PubMed

Kampouraki, Emmanouela; Avery, Peter J; Wynne, Hilary; Biss, Tina; Hanley, John; Talks, Kate; Kamali, Farhad

2017-09-01

Current guidelines advocate using fixed-doses of oral vitamin K to reverse excessive anticoagulation in warfarinised patients who are either asymptomatic or have minor bleeds. Over-anticoagulated patients present with a wide range of International Normalised Ratio (INR) values and response to fixed doses of vitamin K varies. Consequently a significant proportion of patients remain outside their target INR after vitamin K administration, making them prone to either haemorrhage or thromboembolism. We compared the performance of a novel tailored vitamin K dosing regimen to that of a fixed-dose regimen with the primary measure being the proportion of over-anticoagulated patients returning to their target INR within 24 h. One hundred and eighty-one patients with an index INR > 6·0 (asymptomatic or with minor bleeding) were randomly allocated to receive oral administration of either a tailored dose (based upon index INR and body surface area) or a fixed-dose (1 or 2 mg) of vitamin K. A greater proportion of patients treated with the tailored dose returned to within target INR range compared to the fixed-dose regimen (68·9% vs. 52·8%; P = 0·026), whilst a smaller proportion of patients remained above target INR range (12·2% vs. 34·0%; P < 0·001). Individualised vitamin K dosing is more accurate than fixed-dose regimen in lowering INR to within target range in excessively anticoagulated patients. © 2017 John Wiley & Sons Ltd.

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

Shusharina, N; Khan, F; Sharp, G

Purpose: To determine the dose level and timing of the boost in locally advanced lung cancer patients with confirmed tumor recurrence by comparing different boosting strategies by an impact of dose escalation in improvement of the therapeutic ratio. Methods: We selected eighteen patients with advanced NSCLC and confirmed recurrence. For each patient, a base IMRT plan to 60 Gy prescribed to PTV was created. Then we compared three dose escalation strategies: a uniform escalation to the original PTV, an escalation to a PET-defined target planned sequentially and concurrently. The PET-defined targets were delineated by biologically-weighed regions on a pre-treatment 18F-FDGmore » PET. The maximal achievable dose, without violating the OAR constraints, was identified for each boosting method. The EUD for the target, spinal cord, combined lung, and esophagus was compared for each plan. Results: The average prescribed dose was 70.4±13.9 Gy for the uniform boost, 88.5±15.9 Gy for the sequential boost and 89.1±16.5 Gy for concurrent boost. The size of the boost planning volume was 12.8% (range: 1.4 – 27.9%) of the PTV. The most prescription-limiting dose constraints was the V70 of the esophagus. The EUD within the target increased by 10.6 Gy for the uniform boost, by 31.4 Gy for the sequential boost and by 38.2 for the concurrent boost. The EUD for OARs increased by the following amounts: spinal cord, 3.1 Gy for uniform boost, 2.8 Gy for sequential boost, 5.8 Gy for concurrent boost; combined lung, 1.6 Gy for uniform, 1.1 Gy for sequential, 2.8 Gy for concurrent; esophagus, 4.2 Gy for uniform, 1.3 Gy for sequential, 5.6 Gy for concurrent. Conclusion: Dose escalation to a biologically-weighed gross tumor volume defined on a pre-treatment 18F-FDG PET may provide improved therapeutic ratio without breaching predefined OAR constraints. Sequential boost provides better sparing of OARs as compared with concurrent boost.« less

Bayesian approach for assessing non-inferiority in a three-arm trial with pre-specified margin.

PubMed

Ghosh, Samiran; Ghosh, Santu; Tiwari, Ram C

2016-02-28

Non-inferiority trials are becoming increasingly popular for comparative effectiveness research. However, inclusion of the placebo arm, whenever possible, gives rise to a three-arm trial which has lesser burdensome assumptions than a standard two-arm non-inferiority trial. Most of the past developments in a three-arm trial consider defining a pre-specified fraction of unknown effect size of reference drug, that is, without directly specifying a fixed non-inferiority margin. However, in some recent developments, a more direct approach is being considered with pre-specified fixed margin albeit in the frequentist setup. Bayesian paradigm provides a natural path to integrate historical and current trials' information via sequential learning. In this paper, we propose a Bayesian approach for simultaneous testing of non-inferiority and assay sensitivity in a three-arm trial with normal responses. For the experimental arm, in absence of historical information, non-informative priors are assumed under two situations, namely when (i) variance is known and (ii) variance is unknown. A Bayesian decision criteria is derived and compared with the frequentist method using simulation studies. Finally, several published clinical trial examples are reanalyzed to demonstrate the benefit of the proposed procedure. Copyright © 2015 John Wiley & Sons, Ltd.

Multi-centre audit of VMAT planning and pre-treatment verification.

PubMed

Jurado-Bruggeman, Diego; Hernández, Victor; Sáez, Jordi; Navarro, David; Pino, Francisco; Martínez, Tatiana; Alayrach, Maria-Elena; Ailleres, Norbert; Melero, Alejandro; Jornet, Núria

2017-08-01

We performed a multi-centre intercomparison of VMAT dose planning and pre-treatment verification. The aims were to analyse the dose plans in terms of dosimetric quality and deliverability, and to validate whether in-house pre-treatment verification results agreed with those of an external audit. The nine participating centres encompassed different machines, equipment, and methodologies. Two mock cases (prostate and head and neck) were planned using one and two arcs. A plan quality index was defined to compare the plans and different complexity indices were calculated to check their deliverability. We compared gamma index pass rates using the centre's equipment and methodology to those of an external audit (global 3D gamma, absolute dose differences, 10% of maximum dose threshold). Log-file analysis was performed to look for delivery errors. All centres fulfilled the dosimetric goals but plan quality and delivery complexity were heterogeneous and uncorrelated, depending on the manufacturer and the planner's methodology. Pre-treatment verifications results were within tolerance in all cases for gamma 3%-3mm evaluation. Nevertheless, differences between the external audit and in-house measurements arose due to different equipment or methodology, especially for 2%-2mm criteria with differences up to 20%. No correlation was found between complexity indices and verification results amongst centres. All plans fulfilled dosimetric constraints, but plan quality and complexity did not correlate and were strongly dependent on the planner and the vendor. In-house measurements cannot completely replace external audits for credentialing. Copyright © 2017 Elsevier B.V. All rights reserved.

A randomized comparative crossover study to assess the affect on circuit life of varying pre-dilution volume associated with CVVH and CVVHDF.

PubMed

Davies, H T; Leslie, G; Pereira, S M; Webb, S A R

2008-03-01

To determine if circuit life is influenced by a higher pre-dilution volume used in CVVH when compared with a lower pre-dilution volume approach in CVVHDF. A comparative crossover study. Cases were randomized to receive either CVVH or CVVHDF followed by the alternative treatment. All patients >or= 18 yrs of age who required CRRT while in ICU were eligible to participate, but excluded if coagulopathic, thrombocytopenic or unable to receive heparin. Based on an intention-to-treat, 45 patients were randomized to receive either CVVH or CVVHDF followed by the alternative treatment. A 24-bed, tertiary, medical and surgical adult intensive care unit (ICU). Blood flow rate, vascular access device and insertion site, hemofilter, anticoagulation and machine hardware were standardized. An ultrafiltrate dose of 35 ml/ kg/h delivered pre-filter was used for CVVH. A fixed pre-dilution volume of 600 mls/h with a dialysate dose of 1 L was used for CVVHDF. Thirty-one patients received CVVH or CVVHDF out of 45 participants followed by the alternative technique. There was a significant increase in circuit life in favor of CVVHDF (median=16 h 5 min, range=40 h 23 min) compared with CVVH (median=6 h 35 min, range=30 h 45 min). A Mann-Whitney U test was performed to compare circuit life between the two different CRRT modes (Z=-3.478, p<0.001). Measurements of circuit life on the 93 circuits which survived to clotting (50 CVVH and 43 CVVHDF) were log transformed prior to under taking a standard multiple regression analysis. None of the independent variables - activated prothrombin time (aPTT), platelet count, heparin dose, patient hematocrit or urea - had a coefficient partial correlation >0.09 (coefficient of the determination=0.117) or a linear relationship which could be associated with circuit life (p=0.228). Pre-diluted CVVHDF appeared to have a longer circuit life when compared to high volume pre-diluted CVVH. The choice of CRRT mode may be an important independent determinant of circuit life.

Reviewing long-term antidepressants can reduce drug burden: a prospective observational cohort study

PubMed Central

Johnson, Chris F; Macdonald, Hector J; Atkinson, Pauline; Buchanan, Alasdair I; Downes, Noreen; Dougall, Nadine

2012-01-01

Background Antidepressant prescribing continues to rise. Contributing factors are increased long-term prescribing and possibly the use of higher selective serotonin re-uptake inhibitor (SSRI) doses. Aim To review general practice patients prescribed the same antidepressant long-term (≥2 years) and evaluate prescribing and management pre and post-review. Design and setting Prospective observational cohort study using routine data from 78 urban general practices, Scotland. Method All patients prescribed antidepressants (excluding amitriptyline) for ≥2 years were identified from records November 2009 to March 2010. GPs selected patients for face-to-face review of clinical condition and medication, December 2009 to September 2010. Pre- and post-review data were collected; average antidepressant doses and changes in prescribed daily doses were calculated. Onward referral to support services was recorded. Results 8.6% (33 312/388 656) of all registered patients were prescribed an antidepressant, 47.1% (15 689) were defined as long-term users and 2849 (18.2%) were reviewed. 811 (28.5%) patients reviewed had a change in antidepressant therapy: 7.0% stopped, 12.8% reduced dose, 5.3% increased dose, and 3.4% changed antidepressant, resulting in 9.5% (95% CI = 9.1% to 9.8% P<0.001) reduction in prescribed daily dose and 8.1% reduction in prescribing costs. 6.3% were referred onwards, half to NHS Mental Health Services. Pre-review SSRI doses were 10–30% higher than previously reported. Conclusion Almost half of all people prescribed antidepressants were long-term users. Appropriate reductions in prescribing can be achieved by reviewing patients. Higher SSRI doses may be contributing to current antidepressant growth. PMID:23211181

Low dose irradiation facilitates hepatocellular carcinoma genesis involving HULC.

PubMed

Li, Yuan; Ge, Chang; Feng, Guoxing; Xiao, Huiwen; Dong, Jiali; Zhu, Changchun; Jiang, Mian; Cui, Ming; Fan, Saijun

2018-03-24

Irradiation exposure positive correlates with tumor formation, such as breast cancer and lung cancer. However, whether low dose irradiation induces hepatocarcinogenesis and the underlying mechanism remain poorly defined. In the present study, we reported that low dose irradiation facilitated the proliferation of hepatocyte through up-regulating HULC in vitro and in vivo. Low dose irradiation exposure elevated HULC expression level in hepatocyte. Deletion of heightened HULC erased the cells growth accelerated following low dose irradiation exposure. CDKN1, the neighbor gene of HULC, was down-regulated by overexpression of HULC following low dose irradiation exposure via complementary base pairing, resulting in promoting cell cycle process. Thus, our findings provide new insights into the mechanism of low dose irradiation-induced hepatocarcinogenesis through HULC/CDKN1 signaling, and shed light on the potential risk of low dose irradiation for the development of hepatocellular carcinoma in pre-clinical settings. © 2018 Wiley Periodicals, Inc.

[Fixed-dose combination fluticasone propionate/formoterol for the treatment of asthma: a review of its pharmacology, efficacy and tolerability].

PubMed

Quintano Jiménez, J A; Ginel Mendoza, L; Entrenas Costa, L M; Polo García, J

2016-02-01

The fixed-dose combination fluticasone propionate/formoterol (FPF) is a novel combination of a widely known and used inhaled glucocorticoid (IGC) and a long-acting β2-adrenergic agonist (LABA), available for the first time in a single device. This fixed-dose combination of FPF has a demonstrated efficacy and safety profile in clinical trials compared with its individual components and other fixed-dose combinations of IGC/LABA and is indicated for the treatment of persistent asthma in adults and adolescents. FPF is available in a wide range of doses that can adequately cover the therapeutic steps recommended by treatment guidelines, constituting a fixed-dose combination of GCI/LABA that is effective, rapid, well tolerated and with a reasonable acquisition cost. Various assessment agencies of the Spanish Autonomous Communities consider this combination to be an appropriate alternative therapy for asthma in the primary care setting. Copyright © 2016 Elsevier España, S.L.U. y Sociedad Española de Medicina Rural y Generalista (SEMERGEN). All rights reserved.

Effect of fixed-dose combinations of ezetimibe plus rosuvastatin in patients with primary hypercholesterolemia: MRS-ROZE (Multicenter Randomized Study of ROsuvastatin and eZEtimibe).

PubMed

Kim, Kyung-Jin; Kim, Sang-Hyun; Yoon, Young Won; Rha, Seung-Woon; Hong, Soon-Jun; Kwak, Choong-Hwan; Kim, Weon; Nam, Chang-Wook; Rhee, Moo-Yong; Park, Tae-Ho; Hong, Taek-Jong; Park, Sungha; Ahn, Youngkeun; Lee, Namho; Jeon, Hui-Kyung; Jeon, Dong-Woon; Han, Kyoo-Rok; Moon, Keon-Woong; Chae, In-Ho; Kim, Hyo-Soo

2016-10-01

We aimed to compare the effects of fixed-dose combinations of ezetimibe plus rosuvastatin to rosuvastatin alone in patients with primary hypercholesterolemia, including a subgroup analysis of patients with diabetes mellitus (DM) or metabolic syndrome (MetS). This multicenter eight-week randomized double-blind phase III study evaluated the safety and efficacy of fixed-dose combinations of ezetimibe 10 mg plus rosuvastatin, compared with rosuvastatin alone in patients with primary hypercholesterolemia. Four hundred and seven patients with primary hypercholesterolemia who required lipid-lowering treatment according to the ATP III guideline were randomized to one of the following six treatments for 8 weeks: fixed-dose combinations with ezetimibe 10 mg daily plus rosuvastatin (5, 10, or 20 mg daily) or rosuvastatin alone (5, 10, or 20 mg daily). Fixed-dose combination of ezetimibe plus rosuvastatin significantly reduced LDL cholesterol, total cholesterol, and triglyceride levels compared with rosuvastatin alone. Depending on the rosuvastatin dose, these fixed-dose combinations of ezetimibe plus rosuvastatin provided LDL cholesterol, total cholesterol, and triglyceride reductions of 56%-63%, 37%-43%, and 19%-24%, respectively. Moreover, the effect of combination treatment on cholesterol levels was more pronounced in patients with DM or MetS than in non-DM or non-MetS patients, respectively, whereas the effect of rosuvastatin alone did not differ between DM vs non-DM or MetS vs non-MetS patients. Fixed-dose combinations of ezetimibe and rosuvastatin provided significantly superior efficacy to rosuvastatin alone in lowering LDL cholesterol, total cholesterol, and triglyceride levels. Moreover, the reduction rate was greater in patients with DM or MetS. © 2016 The Authors Cardiovascular Therapeutics Published by John Wiley & Sons Ltd.

Using translational medicine to understand clinical differences between botulinum toxin formulations.

PubMed

Aoki, K R; Ranoux, D; Wissel, J

2006-12-01

When using botulinum toxin-based products, the physician must decide the optimal location and dose required to alleviate symptoms and improve the patient's quality of life. To deliver effective treatment, the physician needs to understand the importance of accurate target muscle selection and localization and the implications of each product's migration properties when diluted in different volumes. Pre-clinical mouse models of efficacy and safety have been utilized to compare local and distal muscle relaxation effects following defined intramuscular administration. Data from the model allow the products to be ranked based on their propensity for local efficacy versus their distal migration properties. Using standardized dilutions, the non-parallel dose-response curves for the various formulations demonstrate that they have different efficacy profiles. Distal effects were also noted at different treatment doses, which are reflected in the different safety and/or therapeutic margins. Based on these pre-clinical data, the safety and therapeutic margin rankings are ordered, largest to smallest, as BOTOX, Dysport and Myobloc. The results of subsequent clinical trials are variable and dose comparisons are inconclusive, thus supporting the regulatory position that the dose units of the individual preparations are unique and cannot be simply converted between products.

Simulated impact of RTS,S/AS01 vaccination programs in the context of changing malaria transmission.

PubMed

Brooks, Alan; Briët, Olivier J T; Hardy, Diggory; Steketee, Richard; Smith, Thomas A

2012-01-01

The RTS,S/AS01 pre-erythrocytic malaria vaccine is in phase III clinical trials. It is critical to anticipate where and how it should be implemented if trials are successful. Such planning may be complicated by changing levels of malaria transmission. Computer simulations were used to examine RTS,S/AS01 impact, using a vaccine profile based on phase II trial results, and assuming that protection decays only slowly. Settings were simulated in which baseline transmission (in the absence of vaccine) was fixed or varied between 2 and 20 infectious mosquito bites per person per annum (ibpa) over ten years. Four delivery strategies were studied: routine infant immunization (EPI), EPI plus infant catch-up, EPI plus school-based campaigns, and EPI plus mass campaigns. Impacts in changing transmission settings were similar to those in fixed settings. Assuming a persistent effect of vaccination, at 2 ibpa, the vaccine averted approximately 5-7 deaths per 1000 doses of vaccine when delivered via mass campaigns, but the benefit was less at higher transmission levels. EPI, catch-up and school-based strategies averted 2-3 deaths per 1000 doses in settings with 2 ibpa. In settings where transmission was decreasing or increasing, EPI, catch-up and school-based strategies averted approximately 3-4 deaths per 1000 doses. Where transmission is changing, it appears to be sufficient to consider simulations of pre-erythrocytic vaccine impact at a range of initial transmission levels. At 2 ibpa, mass campaigns averted the most deaths and reduced transmission, but this requires further study. If delivered via EPI, RTS,S/AS01 could avert approximately 6-11 deaths per 1000 vaccinees in all examined settings, similar to estimates for pneumococcal conjugate vaccine in African infants. These results support RTS,S/AS01 implementation via EPI, for example alongside vector control interventions, providing that the phase III trials provide support for our assumptions about efficacy.

Safety of dose escalation by simultaneous integrated boosting radiation dose within the primary tumor guided by (18)FDG-PET/CT for esophageal cancer.

PubMed

Yu, Wen; Cai, Xu-Wei; Liu, Qi; Zhu, Zheng-Fei; Feng, Wen; Zhang, Qin; Zhang, Ying-Jian; Yao, Zhi-Feng; Fu, Xiao-Long

2015-02-01

To observe the safety of selective dose boost to the pre-treatment high (18)F-deoxyglucose (FDG) uptake areas of the esophageal GTV. Patients with esophageal squamous cell carcinoma were treated with escalating radiation dose of 4 levels, with a simultaneous integrated boost (SIB) to the pre-treatment 50% SUVmax area of the primary tumor. Patients received 4 monthly cycles of cisplatin and fluorouracil. Dose-limiting toxicity (DLT) was defined as any Grade 3 or higher acute toxicities causing continuous interruption of radiation for over 1 week. From April 2012 to February 2014, dose has been escalated up to LEVEL 4 (70Gy). All of the 25 patients finished the prescribed dose without DLT, and 10 of them developed Grade 3 acute esophagitis. One patient of LEVEL 2 died of esophageal hemorrhage within 1 month after completion of radiotherapy, which was not definitely correlated with treatment yet. Late toxicities remained under observation. With median follow up of 8.9months, one-year overall survival and local control was 69.2% and 77.4%, respectively. Dose escalation in esophageal cancer based on (18)FDG-PET/CT has been safely achieved up to 70Gy using the SIB technique. Acute toxicities were well tolerated, whereas late toxicities and long-term outcomes deserved further observation. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Effectiveness and safety of generic fixed-dose combination of tenofovir/emtricitabine/efavirenz in HIV-1-infected patients in Western India.

PubMed

Pujari, Sanjay; Dravid, Ameet; Gupte, Nikhil; Joshi, Kedar; Bele, Vivek

2008-01-01

To assess effectiveness and safety of a generic fixed-dose combination of tenofovir (TDF)/emtricitabine (FTC)/efavirenz (EFV) among HIV-1-infected patients in Western India. Antiretroviral (ARV)-naive and experienced (thymidine analog nucleoside reverse transcriptase inhibitor [tNRTI] replaced by TDF) patients were started on a regimen of 1 TDF/FTC/EFV pill once a day. They were followed clinically on a periodic basis, and viral loads and CD4 counts were measured at 6 and 12 months. Creatinine clearance was calculated at baseline and at 6 months and/or as clinically indicated. Effectiveness was defined as not having to discontinue the regimen due to failure or toxicity. One hundred forty-one patients who started TDF/FTC/EFV before 1 June 2007 were eligible. Of these, 130 (92.2%) and 44 (31.2%) had 6- and 12-months follow-up, respectively. Thirty-five percent of the patients were ARV-naive. Eleven patients discontinued treatment (4 for virologic failure, 1 for grade 3-4 central nervous system disturbances, 4 for grade 3-4 renal toxicity, and 2 for cost). Ninety-six percent of patients were virologically suppressed at 6 months. Frequency of TDF-associated grade 3-4 renal toxicity was 2.8%; however, 3 of these patients had comorbid conditions associated with renal dysfunction. A fixed-dose combination of generic TDF/FTC/EFV is effective in ARV-naive and experienced patients. Although frequency of severe renal toxicity was higher than has been reported in the literature, it was safe in patients with no comorbid renal conditions.

Effectiveness and Safety of Generic Fixed-Dose Combination of Tenofovir/Emtricitabine/Efavirenz in HIV-1-Infected Patients in Western India.

PubMed

Pujari, Sanjay; Dravid, Ameet; Gupte, Nikhil; Joshix, Kedar; Bele, Vivek

2008-08-20

To assess effectiveness and safety of a generic fixed-dose combination of tenofovir (TDF)/emtricitabine (FTC)/efavirenz (EFV) among HIV-1-infected patients in Western India. Antiretroviral (ARV)-naive and experienced (thymidine analog nucleoside reverse transcriptase inhibitor [tNRTI] replaced by TDF) patients were started on a regimen of 1 TDF/FTC/EFV pill once a day. They were followed clinically on a periodic basis, and viral loads and CD4 counts were measured at 6 and 12 months. Creatinine clearance was calculated at baseline and at 6 months and/or as clinically indicated. Effectiveness was defined as not having to discontinue the regimen due to failure or toxicity. One hundred forty-one patients who started TDF/FTC/EFV before 1 June 2007 were eligible. Of these, 130 (92.2%) and 44 (31.2%) had 6- and 12-months follow-up, respectively. Thirty-five percent of the patients were ARV-naive. Eleven patients discontinued treatment (4 for virologic failure, 1 for grade 3-4 central nervous system disturbances, 4 for grade 3-4 renal toxicity, and 2 for cost). Ninety-six percent of patients were virologically suppressed at 6 months. Frequency of TDF-associated grade 3-4 renal toxicity was 2.8%; however, 3 of these patients had comorbid conditions associated with renal dysfunction. A fixed-dose combination of generic TDF/FTC/EFV is effective in ARV-naive and experienced patients. Although frequency of severe renal toxicity was higher than has been reported in the literature, it was safe in patients with no comorbid renal conditions.

Dose and image quality for a cone-beam C-arm CT system.

PubMed

Fahrig, Rebecca; Dixon, Robert; Payne, Thomas; Morin, Richard L; Ganguly, Arundhuti; Strobel, Norbert

2006-12-01

We assess dose and image quality of a state-of-the-art angiographic C-arm system (Axiom Artis dTA, Siemens Medical Solutions, Forchheim, Germany) for three-dimensional neuro-imaging at various dose levels and tube voltages and an associated measurement method. Unlike conventional CT, the beam length covers the entire phantom, hence, the concept of computed tomography dose index (CTDI) is not the metric of choice, and one can revert to conventional dosimetry methods by directly measuring the dose at various points using a small ion chamber. This method allows us to define and compute a new dose metric that is appropriate for a direct comparison with the familiar CTDIw of conventional CT. A perception study involving the CATPHAN 600 indicates that one can expect to see at least the 9 mm inset with 0.5% nominal contrast at the recommended head-scan dose (60 mGy) when using tube voltages ranging from 70 kVp to 125 kVp. When analyzing the impact of tube voltage on image quality at a fixed dose, we found that lower tube voltages gave improved low contrast detectability for small-diameter objects. The relationships between kVp, image noise, dose, and contrast perception are discussed.

Bronchodilator efficacy of tiotropium in patients with mild to moderate COPD.

PubMed

Johansson, Gunnar; Lindberg, Anne; Romberg, Kerstin; Nordström, Lars; Gerken, Fronke; Roquet, Annika

2008-09-01

Evaluation of tiotropium efficacy in patients with mild chronic obstructive pulmonary disease (COPD) defined by the 2003 Swedish Society of Respiratory Medicine guidelines (post-bronchodilator FEV1/FVC <70%; FEV1 >60% predicted). In this 12-week, randomised, double-blind, placebo-controlled study of tiotropium 18 mcg once daily versus placebo, respiratory function was assessed on Days 1, 15 and 85 (baseline: pre-dose Day 1). Mean+/-SD baseline FEV1 (% predicted) was 73.4+/-12.5 (tiotropium, n=107; placebo, n=117). Tiotropium significantly improved change from baseline in area under the curve from pre-dose to 2 hours post-dose (AUC0-2 h) FEV1 versus placebo, by 166+/-26 mL (mean+/-SE) at study end (p<0.0001). With tiotropium, there were significant increases in the change in AUC0-2 h FVC versus baseline, and trough FEV1 and FVC, versus placebo, on all test days (p<0.01). Adverse event rates were similar. Compared with placebo, tiotropium improved lung function in patients with mild COPD.

Phase I trial of 18F-Fludeoxyglucose based radiation dose painting with concomitant cisplatin in head and neck cancer.

PubMed

Rasmussen, Jacob H; Håkansson, Katrin; Vogelius, Ivan R; Aznar, Marianne C; Fischer, Barbara M; Friborg, Jeppe; Loft, Annika; Kristensen, Claus A; Bentzen, Søren M; Specht, Lena

2016-07-01

The CONTRAST (CONventional vs.Tumor Recurrence Adapted Specification of Target dose) phase I trial tested the safety of FDG PET guided dose redistribution in patients receiving accelerated chemo-radiotherapy for locally advanced head and neck squamous cell carcinoma (HNSCC). CONTRAST was designed with two pre-defined dose-escalation steps to the FDG PET-avid volume (GTVPET). The primary end point was any early grade 4+ toxicity according to Common Terminology Criteria for Adverse Events version 4.0 (CTCAE). The dose to GTVPET was escalated to a uniform prescription of 82Gy EQD2 in the first step. All patients received accelerated radiotherapy (6 fractions a week) delivering 34 fractions of 2.34Gy to the GTVPET as well as concomitant weekly cisplatin. Inclusion criteria were (1) primary SCC of oral cavity, oro- or hypo-pharynx, or laynx, (2) candidates for concomitant chemo-radiotherapy and (3) p16 negative tumors or p16 positive tumors in patients with smoking history of >10 pack years. GTVPET was defined by a specialist in nuclear medicine and a radiologist, while the anatomic GTV was defined in collaboration between an oncologist and a radiologist. Median follow up time from the end of treatment was 18months (range 7-21months). All 15 patients completed treatment without interruptions and no incidents of early grade 4+ toxicity were observed. Four patients had ulceration at the evaluation two months after treatment, two have subsequently healed, but two remain, raising concerns regarding late effects. With all 15 cases having completed four month follow up and no incidence of early grade 4+ toxicity FDG PET based dose escalation to 82Gy passed the protocol-defined criterion for dose escalation. However, two cases of concern regarding late outcome led us to refrain from further dose escalation and proceed with the current dose level in a larger comparative effectiveness trial. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Polypill: Progress and Challenges to Global Use--Update on the Trials and Policy Implementation.

PubMed

Webster, Ruth; Rodgers, Anthony

2015-12-01

Cardiovascular disease (CVD) is the leading cause of mortality globally. Most people with cardiovascular disease do not take long-term cholesterol-lowering, anti-platelet and blood pressure-lowering medications despite proven benefits. Fixed-dose combination pills ('polypills') have been shown to improve adherence to these recommended medications with corresponding improvements in risk factors such as blood pressure and low-density lipoprotein (LDL) cholesterol. Among patients not taking the full complement of recommended CVD preventive therapies, use of a polypill-based strategy (i.e. initiating treatment with single-pill combination medication then titrating further therapy as needed) has large potential benefits in reducing global morbidity and mortality. Despite this, few polypills are available on the market due to market failure in the funding of research and development for affordable non-communicable disease medicines. Additionally, defining a path to market has been problematic in that fixed-dose combinations with multiple different drug classes included are quite novel, and regulatory processes to review these types of applications are not well established. Despite these delays, progress is slowly being made.

Bridging the gap: a review of dose investigations in paediatric investigation plans

PubMed Central

Hampson, Lisa V; Herold, Ralf; Posch, Martin; Saperia, Julia; Whitehead, Anne

2014-01-01

Aims In the EU, development of new medicines for children should follow a prospectively agreed paediatric investigation plan (PIP). Finding the right dose for children is crucial but challenging due to the variability of pharmacokinetics across age groups and the limited sample sizes available. We examined strategies adopted in PIPs to support paediatric dosing recommendations to identify common assumptions underlying dose investigations and the attempts planned to verify them in children. Methods We extracted data from 73 PIP opinions recently adopted by the Paediatric Committee of the European Medicines Agency. These opinions represented 79 medicinal development programmes and comprised a total of 97 dose investigation studies. We identified the design of these dose investigation studies, recorded the analyses planned and determined the criteria used to define target doses. Results Most dose investigation studies are clinical trials (83 of 97) that evaluate a single dosing rule. Sample sizes used to investigate dose are highly variable across programmes, with smaller numbers used in younger children (< 2 years). Many studies (40 of 97) do not pre-specify a target dose criterion. Of those that do, most (33 of 57 studies) guide decisions using pharmacokinetic data alone. Conclusions Common assumptions underlying dose investigation strategies include dose proportionality and similar exposure−response relationships in adults and children. Few development programmes pre-specify steps to verify assumptions in children. There is scope for the use of Bayesian methods as a framework for synthesizing existing information to quantify prior uncertainty about assumptions. This process can inform the design of optimal drug development strategies. PMID:24720849

A Neumann boundary term for gravity

NASA Astrophysics Data System (ADS)

Krishnan, Chethan; Raju, Avinash

2017-05-01

The Gibbons-Hawking-York (GHY) boundary term makes the Dirichlet problem for gravity well-defined, but no such general term seems to be known for Neumann boundary conditions. In this paper, we view Neumann not as fixing the normal derivative of the metric (“velocity”) at the boundary, but as fixing the functional derivative of the action with respect to the boundary metric (“momentum”). This leads directly to a new boundary term for gravity: the trace of the extrinsic curvature with a specific dimension-dependent coefficient. In three dimensions, this boundary term reduces to a “one-half” GHY term noted in the literature previously, and we observe that our action translates precisely to the Chern-Simons action with no extra boundary terms. In four dimensions, the boundary term vanishes, giving a natural Neumann interpretation to the standard Einstein-Hilbert action without boundary terms. We argue that in light of AdS/CFT, ours is a natural approach for defining a “microcanonical” path integral for gravity in the spirit of the (pre-AdS/CFT) work of Brown and York.

Efficacy and Safety of a Single-Pill Fixed-Dose Combination of Azilsartan and Amlodipine.

PubMed

Motozato, Kota; Miura, Shin-Ichiro; Shiga, Yuhei; Kusumoto, Takaaki; Saku, Keijiro

2016-12-01

Guidelines for the management of hypertension recommend the use of drugs with different mechanisms of action in antihypertensive regimens that include single-pill fixed-dose combinations of medications. There is some controversy regarding which single-pill fixed-dose combinations of angiotensin II type 1 receptor blockers (ARBs) and calcium channel blockers (CCBs) are effective at reducing blood pressure (BP). Forty hypertensive patients who were receiving a single-pill fixed-dose combination of valsartan 80 mg/day and amlodipine 5 mg/day or irbesartan 100 mg/day and amlodipine 5 mg/day were enrolled. They were randomly divided into two treatment groups, a group that changed to a single-pill fixed-dose combination of azilsartan 20 mg/day and amlodipine 5 mg/day (changeover group) and a group that continued to receive valsartan 80 mg/day and amlodipine 5 mg/day or irbesartan 100 mg/day and amlodipine 5 mg/day (control group), and treated for 16 weeks. There were no significant differences in systolic blood pressure (SBP), diastolic blood pressure (DBP) or pulse rate (PR) at 16 weeks between the control and changeover groups. In addition, there were no significant changes in biochemical parameters throughout the study period in both groups. The ability of a single-pill fixed-dose combination of azilsartan and amlodipine to reduce BP may be comparable to that of a combination of valsartan and amlodipine or irbesartan and amlodipine.

A proposed performance index for galactic cosmic ray shielding materials

NASA Technical Reports Server (NTRS)

Wilson, John W.; Wood, J. S.; Shinn, Judy L.; Cucinotta, Francis A.; Nealy, John E.

1993-01-01

In past studies, the reductions in absorbed dose and dose equivalent due to choice of material composition have been used to indicate shield effectiveness against exposure to galactic cosmic rays. However, these quantities are highly inaccurate in assessing shield effectiveness for protection against the biological effects of long-term exposure to the galactic heavy ions. A new quantity for shield performance is defined that correlates well with cell killing and cell transformation behind various shield thicknesses and materials. In addition, a relative performance index is identified that is inversely related to biological injury for different materials at a fixed shield mass and is directly related to the ratio of the fourth- and the second-order linear energy transfer (LET) moments.

CPSGrader: Auto-Grading and Feedback Generation for Cyber-Physical Systems Education

DTIC Science & Technology

2014-12-21

to refer to ⋃ C∈C+ Ω(C,Γ(p)) (and⋃ C∈C− Ω(C,Γ(p))). The rationale behind this choice of ρ is two-fold: 1. To increase coverage of fault detection ... fault mentioned in Section 2.3. The purpose of the test is to detect that at some time instant t0, the robot bumps into the obstacle, then turns about...sampling. 5.6 Investigating Unknown Faults Using Clustering CPSGrader works with a fixed pre-defined library of faults and associated test benches

Applications of the generalized information processing system (GIPSY)

USGS Publications Warehouse

Moody, D.W.; Kays, Olaf

1972-01-01

The Generalized Information Processing System (GIPSY) stores and retrieves variable-field, variable-length records consisting of numeric data, textual data, or codes. A particularly noteworthy feature of GIPSY is its ability to search records for words, word stems, prefixes, and suffixes as well as for numeric values. Moreover, retrieved records may be printed on pre-defined formats or formatted as fixed-field, fixed-length records for direct input to other-programs, which facilitates the exchange of data with other systems. At present there are some 22 applications of GIPSY falling in the general areas of bibliography, natural resources information, and management science, This report presents a description of each application including a sample input form, dictionary, and a typical formatted record. It is hoped that these examples will stimulate others to experiment with innovative uses of computer technology.

Impact of antimicrobial stewardship programme on hospitalized patients at the intensive care unit: a prospective audit and feedback study.

PubMed

Khdour, Maher R; Hallak, Hussein O; Aldeyab, Mamoon A; Nasif, Mowaffaq A; Khalili, Aliaa M; Dallashi, Ahamad A; Khofash, Mohammad B; Scott, Michael G

2018-04-01

Inappropriate use of antibiotics is one of the most important factors contributing to the emergence of drug resistant pathogens. The purpose of this study was to measure the clinical impact of antimicrobial stewardship programme (ASP) interventions on hospitalized patients at the Intensive care unit at Palestinian Medical Complex. A prospective audit with intervention and feedback by ASP team within 48-72 h of antibiotic administration began in September 2015. Four months of pre-ASP data were compared with 4 months of post-ASP data. Data collected included clinical and demographic data; use of antimicrobials measured by defined daily doses, duration of therapy, length of stay, readmission and all-cause mortality. Overall, 176 interventions were made the ASP team with an average acceptance rate of 78.4%. The most accepted interventions were dose optimization (87.0%) followed by de-escalation based on culture results with an acceptance rate of 84.4%. ASP interventions significantly reduces antimicrobial use by 24.3% (87.3 defined daily doses/100 beds vs. 66.1 defined daily doses/100 beds P < 0.001). The median (interquartile range) of length of stay was significantly reduced post ASP [11 (3-21) vs. 7 (4-19) days; P < 0.01]. Also, the median (interquartile range) of duration of therapy was significantly reduced post-ASP [8 (5-12) days vs. 5 (3-9); P = 0.01]. There was no significant difference in overall 30-day mortality or readmission between the pre-ASP and post-ASP groups (26.9% vs. 23.9%; P = 0.1) and (26.1% vs. 24.6%; P = 0.54) respectively. Our prospective audit and feedback programme was associated with positive impact on antimicrobial use, duration of therapy and length of stay. © 2017 The British Pharmacological Society.

Comparison of the effects of antipsychotic drugs on the schedule-controlled behavior of squirrel monkeys and pigeons.

PubMed

Barrett, J E

1983-04-01

Lever pressing by squirrel monkeys and key pecking by pigeons were maintained under a multiple 3-min fixed-interval (FI), 30-response fixed-ratio (FR) schedule by the presentation of food. These responses, which differed under the two schedules, but were similar for both species, were used to compare the effects of antipsychotic compounds from different pharmacological classes. Except for differences in potency levels, the effects of intermediate doses of haloperidol and molindone were similar in monkeys and pigeons; these compounds decreased responding under the fixed-interval schedule at doses that did not affect fixed-ratio responding. Similar effects also occurred with chlorpromazine, promazine and thiothixene in pigeons. With monkeys, however, intermediate doses of promazine decreased fixed-ratio responding more than responding maintained under the fixed-interval schedule, while chlorpromazine and thiothixene produced similar effects on responding under both schedules. The effects of novel antipsychotic, clozapine, differed from those of the other agents in both monkeys and pigeons. With both species clozapine increased fixed interval responding at doses that did not affect responding under the fixed-ratio schedule. Doses required to reduce responding at least 50% were approximately 5 to 160 times greater for pigeons than for monkeys for all drugs except clozapine which was equipotent in both species. In monkeys the order of potency was haloperidol greater than molindone = thiothixene greater than chlorpromazine greater than clozapine greater than promazine, whereas in pigeons the order was haloperidol greater than thiothixene greater than clozapine greater than molindone greater than promazine greater than chlorpromazine.

Bridging the gap: a review of dose investigations in paediatric investigation plans.

PubMed

Hampson, Lisa V; Herold, Ralf; Posch, Martin; Saperia, Julia; Whitehead, Anne

2014-10-01

In the EU, development of new medicines for children should follow a prospectively agreed paediatric investigation plan (PIP). Finding the right dose for children is crucial but challenging due to the variability of pharmacokinetics across age groups and the limited sample sizes available. We examined strategies adopted in PIPs to support paediatric dosing recommendations to identify common assumptions underlying dose investigations and the attempts planned to verify them in children. We extracted data from 73 PIP opinions recently adopted by the Paediatric Committee of the European Medicines Agency. These opinions represented 79 medicinal development programmes and comprised a total of 97 dose investigation studies. We identified the design of these dose investigation studies, recorded the analyses planned and determined the criteria used to define target doses. Most dose investigation studies are clinical trials (83 of 97) that evaluate a single dosing rule. Sample sizes used to investigate dose are highly variable across programmes, with smaller numbers used in younger children (< 2 years). Many studies (40 of 97) do not pre-specify a target dose criterion. Of those that do, most (33 of 57 studies) guide decisions using pharmacokinetic data alone. Common assumptions underlying dose investigation strategies include dose proportionality and similar exposure-response relationships in adults and children. Few development programmes pre-specify steps to verify assumptions in children. There is scope for the use of Bayesian methods as a framework for synthesizing existing information to quantify prior uncertainty about assumptions. This process can inform the design of optimal drug development strategies. © 2014 The Authors. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of The British Pharmacological Society.

Pharmacokinetic/pharmacodynamic modelling approaches in paediatric infectious diseases and immunology☆

PubMed Central

Barker, Charlotte I.S.; Germovsek, Eva; Hoare, Rollo L.; Lestner, Jodi M.; Lewis, Joanna; Standing, Joseph F.

2014-01-01

Pharmacokinetic/pharmacodynamic (PKPD) modelling is used to describe and quantify dose–concentration–effect relationships. Within paediatric studies in infectious diseases and immunology these methods are often applied to developing guidance on appropriate dosing. In this paper, an introduction to the field of PKPD modelling is given, followed by a review of the PKPD studies that have been undertaken in paediatric infectious diseases and immunology. The main focus is on identifying the methodological approaches used to define the PKPD relationship in these studies. The major findings were that most studies of infectious diseases have developed a PK model and then used simulations to define a dose recommendation based on a pre-defined PD target, which may have been defined in adults or in vitro. For immunological studies much of the modelling has focused on either PK or PD, and since multiple drugs are usually used, delineating the relative contributions of each is challenging. The use of dynamical modelling of in vitro antibacterial studies, and paediatric HIV mechanistic PD models linked with the PK of all drugs, are emerging methods that should enhance PKPD-based recommendations in the future. PMID:24440429

Bayesian dose selection design for a binary outcome using restricted response adaptive randomization.

PubMed

Meinzer, Caitlyn; Martin, Renee; Suarez, Jose I

2017-09-08

In phase II trials, the most efficacious dose is usually not known. Moreover, given limited resources, it is difficult to robustly identify a dose while also testing for a signal of efficacy that would support a phase III trial. Recent designs have sought to be more efficient by exploring multiple doses through the use of adaptive strategies. However, the added flexibility may potentially increase the risk of making incorrect assumptions and reduce the total amount of information available across the dose range as a function of imbalanced sample size. To balance these challenges, a novel placebo-controlled design is presented in which a restricted Bayesian response adaptive randomization (RAR) is used to allocate a majority of subjects to the optimal dose of active drug, defined as the dose with the lowest probability of poor outcome. However, the allocation between subjects who receive active drug or placebo is held constant to retain the maximum possible power for a hypothesis test of overall efficacy comparing the optimal dose to placebo. The design properties and optimization of the design are presented in the context of a phase II trial for subarachnoid hemorrhage. For a fixed total sample size, a trade-off exists between the ability to select the optimal dose and the probability of rejecting the null hypothesis. This relationship is modified by the allocation ratio between active and control subjects, the choice of RAR algorithm, and the number of subjects allocated to an initial fixed allocation period. While a responsive RAR algorithm improves the ability to select the correct dose, there is an increased risk of assigning more subjects to a worse arm as a function of ephemeral trends in the data. A subarachnoid treatment trial is used to illustrate how this design can be customized for specific objectives and available data. Bayesian adaptive designs are a flexible approach to addressing multiple questions surrounding the optimal dose for treatment efficacy within the context of limited resources. While the design is general enough to apply to many situations, future work is needed to address interim analyses and the incorporation of models for dose response.

Phase I Study of Oxaliplatin in Combination With Capecitabine and Radiotherapy as Postoperative Treatment for Stage II and III Rectal Cancer

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

Jin Jing; Li Yexiong; Wang Jinwan

Purpose: A Phase I study was conducted to determine the maximal tolerated dose and the dose-limiting toxicity (DLT) of oxaliplatin (OXA) combined with capecitabine and radiotherapy as adjuvant treatment in patients with operable rectal cancer. Patients and Methods: A total of 21 patients with Stage II or III rectal adenocarcinoma after curative surgery were treated with radiotherapy to a total dose of 50 Gy in 5 weeks. OXA was administered at a dosage of 40 (n = 6), 50 (n = 3),60 (n = 3), 70 (n = 3), or 80 mg/m{sup 2} (n = 6) once a week formore » 2 weeks (first cycle) followed by a second cycle after a 7-day break. Capecitabine at a fixed dose of 1,300 mg/m{sup 2}/d was administered orally at the same schedule as for OXA. DLT was defined as Grade 3 or 4 hematologic and nonhematologic toxicity. Results: Grade 1-3 leukopenia, diarrhea, and nausea/vomiting were the most common toxic side effects, and most were Grade 1-2. A DLT was first observed in 1 of 3 patients at 40 mg/m{sup 2} (Grade 3 diarrhea) but was not observed in the next 3 patients at the same level or in patients who received a dose level of 50-70 mg/m{sup 2}. At 80 mg/m{sup 2}, DLT occurred in 3 of 6 patients (1 Grade 4 leukopenia and 2 Grade 3 diarrhea). Conclusions: OXA combined with a fixed dose of capecitabine at 625 mg/m{sup 2} twice daily by mouth plus radiotherapy in the adjuvant setting was tolerable and clinically feasible. The maximal tolerated dose of OXA in this setting was 80 mg/m{sup 2}, comparable to the maximal tolerated dose of OXA in the neoadjuvant setting.« less

The value of fixed rasburicase dosing versus weight-based dosing in the treatment and prevention of tumor lysis syndrome.

PubMed

Boutin, Alyssa; Blackman, Alison; O'Sullivan, David M; Forcello, Nicholas

2018-01-01

Background Rasburicase is a recombinant urate oxidase enzyme used for the treatment and prevention of tumor lysis syndrome. Our objective was to assess the efficacy of indication-based, low-dose rasburicase administration compared to the Food and Drug Administration-approved weight-based dosing. Methods This was a retrospective cohort study utilizing data from a tertiary medical center including patients admitted from 2012 to 2016, who received at least one dose of rasburicase. The primary outcome was achieving a uric acid level less than 7.5 mg/dl after a single dose of rasburicase in the preprotocol (Food and Drug Administration-approved weight-based dosing) and postprotocol (indication-based, low-dose) groups. Secondary outcomes included the change in uric acid levels between the pre- and postprotocol groups, adherence to the new institutional protocol, need for repeat rasburicase doses, and a cost analysis. Results Sixty-four patients received at least one dose of rasburicase between 1 January 2012 and 1 December 2016. Twenty-seven (79.4%) doses in the preprotocol group and 28 (82.4%) doses in the postprotocol group successfully achieved a uric acid level less than 7.5 mg/dl after a single dose of rasburicase (p=1.000). The average total monthly cost of rasburicase was reduced by 59.9% after adoption of the new protocol. Conclusions Indication-based, low-dose rasburicase displayed significantly more value when compared to weight-based dosing as shown by achieving cost savings without compromising clinical efficacy.

The effect of pre-dose on thermally and optically stimulated luminescence from α-Al2O3:C,Mg and α-Al2O3:C.

PubMed

Kalita, J M; Chithambo, M L

2018-06-15

We report the effect of pre-dose on the thermoluminescence (TL) and optically stimulated luminescence (OSL) dose response of α-Al 2 O 3 :C,Mg and α-Al 2 O 3 :C. Before any luminescence measurement, the samples were irradiated with different doses, namely 100, 500 and 1000 Gy to populate the deep electron traps. This is the pre-dose. The results from TL and OSL studies are compared with results from samples used without any pre-measurement dose. The TL glow curves and OSL decay curves of α-Al 2 O 3 :C,Mg recorded after pre-doses of 100, 500 and 1000 Gy are identical to those from a sample used without any pre-dose. Further, the TL and OSL dose response of all α-Al 2 O 3 :C,Mg samples are similar regardless of pre-dose. In comparison, the TL glow curves and OSL decay curves of α-Al 2 O 3 :C are influenced by pre-dose. We conclude that the differences in the TL and OSL dose response of various pre-dosed samples of α-Al 2 O 3 :C are due to the concentration of charge in the deep traps. On the other hand, owing to the lower concentration of such deep traps in α-Al 2 O 3 :C,Mg, the TL or OSL dose responses are not affected by pre-dose in this material. Copyright © 2018 Elsevier Ltd. All rights reserved.

Efficacy and Safety of a Single-Pill Fixed-Dose Combination of Azilsartan and Amlodipine

PubMed Central

Motozato, Kota; Miura, Shin-ichiro; Shiga, Yuhei; Kusumoto, Takaaki; Saku, Keijiro

2016-01-01

Background Guidelines for the management of hypertension recommend the use of drugs with different mechanisms of action in antihypertensive regimens that include single-pill fixed-dose combinations of medications. There is some controversy regarding which single-pill fixed-dose combinations of angiotensin II type 1 receptor blockers (ARBs) and calcium channel blockers (CCBs) are effective at reducing blood pressure (BP). Methods Forty hypertensive patients who were receiving a single-pill fixed-dose combination of valsartan 80 mg/day and amlodipine 5 mg/day or irbesartan 100 mg/day and amlodipine 5 mg/day were enrolled. They were randomly divided into two treatment groups, a group that changed to a single-pill fixed-dose combination of azilsartan 20 mg/day and amlodipine 5 mg/day (changeover group) and a group that continued to receive valsartan 80 mg/day and amlodipine 5 mg/day or irbesartan 100 mg/day and amlodipine 5 mg/day (control group), and treated for 16 weeks. Results There were no significant differences in systolic blood pressure (SBP), diastolic blood pressure (DBP) or pulse rate (PR) at 16 weeks between the control and changeover groups. In addition, there were no significant changes in biochemical parameters throughout the study period in both groups. Conclusion The ability of a single-pill fixed-dose combination of azilsartan and amlodipine to reduce BP may be comparable to that of a combination of valsartan and amlodipine or irbesartan and amlodipine. PMID:27829955

Effectiveness and Safety of Generic Fixed-Dose Combination of Tenofovir/Emtricitabine/Efavirenz in HIV-1-Infected Patients in Western India

PubMed Central

2008-01-01

Objective To assess effectiveness and safety of a generic fixed-dose combination of tenofovir (TDF)/emtricitabine (FTC)/efavirenz (EFV) among HIV-1-infected patients in Western India. Methods Antiretroviral (ARV)-naive and experienced (thymidine analog nucleoside reverse transcriptase inhibitor [tNRTI] replaced by TDF) patients were started on a regimen of 1 TDF/FTC/EFV pill once a day. They were followed clinically on a periodic basis, and viral loads and CD4 counts were measured at 6 and 12 months. Creatinine clearance was calculated at baseline and at 6 months and/or as clinically indicated. Effectiveness was defined as not having to discontinue the regimen due to failure or toxicity. Results One hundred forty-one patients who started TDF/FTC/EFV before 1 June 2007 were eligible. Of these, 130 (92.2%) and 44 (31.2%) had 6- and 12-months follow-up, respectively. Thirty-five percent of the patients were ARV-naive. Eleven patients discontinued treatment (4 for virologic failure, 1 for grade 3–4 central nervous system disturbances, 4 for grade 3–4 renal toxicity, and 2 for cost). Ninety-six percent of patients were virologically suppressed at 6 months. Frequency of TDF-associated grade 3–4 renal toxicity was 2.8%; however, 3 of these patients had comorbid conditions associated with renal dysfunction. Conclusion A fixed-dose combination of generic TDF/FTC/EFV is effective in ARV-naive and experienced patients. Although frequency of severe renal toxicity was higher than has been reported in the literature, it was safe in patients with no comorbid renal conditions. PMID:19825144

Effectiveness and Safety of Generic Fixed-Dose Combination of Tenofovir/Emtricitabine/Efavirenz in HIV-1-Infected Patients in Western India

PubMed Central

Pujari, Sanjay; Dravid, Ameet; Gupte, Nikhil; Joshi, Kedar; Bele, Vivek

2008-01-01

Objective To assess effectiveness and safety of a generic fixed-dose combination of tenofovir (TDF)/emtricitabine (FTC)/efavirenz (EFV) among HIV-1-infected patients in Western India. Methods Antiretroviral (ARV)-naive and experienced (thymidine analog nucleoside reverse transcriptase inhibitor [tNRTI] replaced by TDF) patients were started on a regimen of 1 TDF/FTC/EFV pill once a day. They were followed clinically on a periodic basis, and viral loads and CD4 counts were measured at 6 and 12 months. Creatinine clearance was calculated at baseline and at 6 months and/or as clinically indicated. Effectiveness was defined as not having to discontinue the regimen due to failure or toxicity. Results One hundred forty-one patients who started TDF/FTC/EFV before 1 June 2007 were eligible. Of these, 130 (92.2%) and 44 (31.2%) had 6- and 12-months follow-up, respectively. Thirty-five percent of the patients were ARV-naive. Eleven patients discontinued treatment (4 for virologic failure, 1 for grade 3-4 central nervous system disturbances, 4 for grade 3-4 renal toxicity, and 2 for cost). Ninety-six percent of patients were virologically suppressed at 6 months. Frequency of TDF-associated grade 3-4 renal toxicity was 2.8%; however, 3 of these patients had comorbid conditions associated with renal dysfunction. Conclusion A fixed-dose combination of generic TDF/FTC/EFV is effective in ARV-naive and experienced patients. Although frequency of severe renal toxicity was higher than has been reported in the literature, it was safe in patients with no comorbid renal conditions. PMID:18924648

Adherence to Anti-Retroviral Therapy in North Central Nigeria.

PubMed

Avong, Yohanna Kambai; van Wyk, Brian; Njab, Jean; Abimiku, Alash'le G; Ndembi, Nicaise; Okuma, James; Ogbanufe, Obinna; Ekong, Ernest; Dakum, Patrick; Blattner, William A

2015-01-01

Nigeria bears nearly 10% of the global burden of HIV/AIDS. Most of the AIDS patients dwell in the part of Nigeria known as the "North Central" geopolitical region. Sustaining HIV patients in this high risk region is critical for the overall success of the ART program in Nigeria. We assessed the level of adherence to ART and adherence determinants among participants who had been on ART for an average of three and half years. Eligible study participants initiated HAART between 2004 and 2010. HAART regimens contained AZT/3TC +NVP or EFV; AZT/3TC/NVP; 3TC/NVP/d4T; TDF/FTC +EFV or NVP and TDF+3TC+LPV/r. A composite adherence measure defined as not missing a dose and taking the correct dose and adhering to the correct frequency and correct schedule of drug administration was used to assess self-reported adherence over a period of three days. Selfreported adherence was validated with viral load test. Base line adherence was fixed at ≥95% adherence level. Significant test was fixed at p<0.05. We included 502 participants in the analysis. Median age for men was 42 years (IQR: 38 - 44 years) and women, 36 years (IQR: 30-40 years). Mean duration of therapy was 43 (16-70) months. Effective self-reported adherence was 97.3%. Only age and virologic suppression were significantly associated with adherence to ART. Forgetfullness (43%) was the major reason for non-adherence, while improvement in health condition (40%) was the main facilitator of adherence to the medications. Most participants achieved optimal adherence (≥95%) with high virologic suppression. Strategies to sustain optimal adherence, e.g., the use of fixed dose combinations (FDCs) and comprehensive adherence counselling should be maintained.

A retrospective study of artificial insemination of 251 mares using chilled and fixed time frozen-thawed semen.

PubMed

Crowe, C A M; Ravenhill, P J; Hepburn, R J; Shepherd, C H

2008-09-01

Historically, artificial insemination (AI) using frozen semen has been perceived to have poorer success rates and be more labour intensive than using chilled semen. A retrospective study was therefore conducted to compare the conception rate achieved by AI between chilled and frozen semen, using fixed time insemination protocols over 2 breeding seasons. Artificial insemination using chilled semen produces a higher conception rate than that achieved with frozen semen. Mares (n = 251) were inseminated with either chilled (n = 112) or frozen (n = 139) semen in the 2006 and 2007 northern hemisphere breeding season. Per rectum ultrasonography of the mare's reproductive tract determined the timing of insemination, and deslorelin acetate was used to induce ovulation. Chilled semen insemination was performed using a single preovulatory dose delivered into the uterine body. Frozen semen was administered as 2 doses (pre- and post ovulation) using a deep uterine insemination technique. Pregnancy was detected ultrasonographically at 15 days post insemination. Conception rates were compared using a Chi-squared test. Insemination with frozen semen produced a significantly (P = 0.022) higher seasonal conception rate (82.0%) than that achieved with chilled semen (69.6%). Insemination with frozen semen can achieve conception rates equal to those with chilled semen, enabling the mare owner a greater selection of stallions.

The dose-response relationship between pseudoephedrine ingestion and exercise performance.

PubMed

Pritchard-Peschek, Kellie R; Jenkins, David G; Osborne, Mark A; Slater, Gary J; Taaffe, Dennis R

2014-09-01

The purpose of the present study was to examine a possible dose-response between pre-exercise pseudoephedrine intake and cycling time trial performance. Randomised, double-blind, crossover trial. Ten trained male endurance cyclists (26.5 ± 6.2 years, 75.1 ± 5.9 kg, 70.6 ± 6.8 mL kg(-1)min(-1)) undertook three cycling time trials in which a fixed amount of work (7 kJ kg(-1) body mass) was completed in the shortest possible time. Sixty minutes before the start of exercise, subjects orally ingested either 2.3 mg kg(-1) or 2.8 mg kg(-1) body mass of pseudoephedrine or a placebo in a randomised and double-blind manner. Venous blood was sampled at baseline, pre- and post-warm up and post-exercise for the analysis of pH and lactate and glucose concentrations; plasma catecholamine and pseudoephedrine concentrations were measured at all times except post-warm up. Cycling time trial performance (∼ 30 min) was not enhanced by pseudoephedrine ingestion. Plasma pseudoephedrine concentration increased from pre-warm up to post-exercise in both treatment conditions, with the 2.8 mg kg(-1) body mass dose producing the highest concentration at both time points (2.8 mg kg(-1)>2.3 mg kg(-1)>placebo; p<0.001). There was large individual variation in plasma pseudoephedrine concentration between subjects following pseudoephedrine administration. A number of factors clearly influence the uptake and appearance of pseudoephedrine in the blood and these are not yet fully understood. Combined with subsequent differences in plasma pseudoephedrine between individuals, this may partially explain the present findings and also the inconsistencies in performance following pseudoephedrine administration in previous studies. Copyright © 2013 Sports Medicine Australia. Published by Elsevier Ltd. All rights reserved.

Weight-adapted iodinated contrast media administration in abdomino-pelvic CT: Can image quality be maintained?

PubMed

Perrin, E; Jackson, M; Grant, R; Lloyd, C; Chinaka, F; Goh, V

2018-02-01

In many centres, a fixed method of contrast-media administration is used for CT regardless of patient body habitus. The aim of this trial was to assess contrast enhancement of the aorta, portal vein, liver and spleen during abdomino-pelvic CT imaging using a weight-adapted contrast media protocol compared to the current fixed dose method. Thirty-nine oncology patients, who had previously undergone CT abdomino-pelvic imaging at the institution using a fixed contrast media dose, were prospectively imaged using a weight-adapted contrast media dose (1.4 ml/kg). The two sets of images were assessed for contrast enhancement levels (HU) at locations in the liver, aorta, portal vein and spleen during portal-venous enhancement phase. The t-test was used to compare the difference in results using a non-inferiority margin of 10 HU. When the contrast dose was tailored to patient weight, contrast enhancement levels were shown to be non-inferior to the fixed dose method (liver p < 0.001; portal vein p = 0.003; aorta p = 0.001; spleen p = 0.001). As a group, patients received a total contrast dose reduction of 165 ml using the weight-adapted method compared to the fixed dose method, with a mean cost per patient of £6.81 and £7.19 respectively. Using a weight-adapted method of contrast media administration was shown to be non-inferior to a fixed dose method of contrast media administration. Patients weighing 76 kg, or less, received a lower contrast dose which may have associated cost savings. A weight-adapted contrast media protocol should be implemented for portal-venous phase abdomino-pelvic CT for oncology patients with adequate renal function (>70 ml/min/1.73 m 2 ). Crown Copyright © 2017. Published by Elsevier Ltd. All rights reserved.

Fixed-dose combination therapy for the prevention of cardiovascular disease

PubMed Central

de Cates, Angharad N; Farr, Matthew RB; Rees, Karen; Casas, Juan P; Huffman, Mark

2014-01-01

This is the protocol for a review and there is no abstract. The objectives are as follows: To determine the effectiveness of fixed-dose combination therapy on optimising CVD risk factors and reducing CVD fatal and non-fatal events for both primary and secondary prevention of CVD. Details of CVD events and risk factors included are listed in the methods. We will also determine any adverse events associated with taking fixed-dose combination therapy. This will include studies conducted in both developed and developing regions of the world. PMID:25267903

Efficacy and safety of nebivolol and valsartan as fixed-dose combination in hypertension: a randomised, multicentre study.

PubMed

Giles, Thomas D; Weber, Michael A; Basile, Jan; Gradman, Alan H; Bharucha, David B; Chen, Wei; Pattathil, Manoj

2014-05-31

The fixed-dose combination of any two antihypertensive drugs from different drug classes is typically more effective in reducing blood pressure than a dose increase of component monotherapy. We assessed the efficacy and safety of a fixed-dose combination of a vasodilating β blocker (nebivolol) and an angiotensin II receptor blocker (valsartan) in adults with hypertension. We did an 8-week, phase 3, multicentre, randomised, double-blind, placebo-controlled, parallel-group trial at 401 US sites. Participants (age ≥18 years) with hypertension but with blood pressure less than 180/110 mm Hg were randomly assigned (2:2:2:2:2:2:2:1) by a 24-h interactive web response system in blocks of 15 to 4 weeks of double-blind treatment with nebivolol and valsartan fixed-dose combination (5 and 80 mg/day, 5 and 160 mg/day, or 10 and 160 mg/day), nebivolol (5 mg/day or 20 mg/day), valsartan (80 mg/day or 160 mg/day), or placebo. Doses were doubled in weeks 5-8; results are reported according to the final dose. Participants and research staff were masked to treatment allocation. The primary and key secondary endpoints were changes from baseline to week 8 in diastolic and systolic blood pressure, respectively. The primary statistical comparison was between the highest fixed-dose combination dose and the highest monotherapy doses; lower doses were then compared if this comparison was positive (Hochberg method for multiple testing). Efficacy analyses were by intention to treat. Safety assessments included monitoring of adverse events. Continuous efficacy parameters were analysed using an ANCOVA model; binary outcomes were analysed using a logistic regression model. This study is registered with ClinicalTrials.gov, NCT01508026. Between Jan 6, 2012, and March 15, 2013, 4161 patients were randomly assigned (277 to placebo and 554-555 to each active comparator group), 4118 of whom were included in the primary analysis. At week 8, the fixed-dose combination 20 and 320 mg/day group had significantly greater reductions in diastolic blood pressure from baseline than both nebivolol 40 mg/day (least-squares mean difference -1·2 mm Hg, 95% CI -2·3 to -0·1; p=0·030) and valsartan 320 mg/day (-4·4 mm Hg, -5·4 to -3·3; p<0·0001); all other comparisons were also significant, favouring the fixed-dose combinations (all p<0·0001). All systolic blood pressure comparisons were also significant (all p<0·01). At least one treatment-emergent adverse event was experienced by 30-36% of participants in each group. Nebivolol and valsartan fixed-dose combination is an effective and well-tolerated treatment option for patients with hypertension. Forest Research Institute. Copyright © 2014 Elsevier Ltd. All rights reserved.

Effects of Intranasal Oxytocin on Aggressive Responding in Antisocial Personality Disorder.

PubMed

Alcorn, Joseph L; Rathnayaka, Nuvan; Swann, Alan C; Moeller, F Gerard; Lane, Scott D

2015-12-01

The oxytocin receptor is important in several domains of social behavior, and administration of oxytocin modulates social responding in several mammalian species, including humans. Oxytocin has both therapeutic and scientific potential for elucidating the neural and behavioral mechanisms governing social behavior. In the present study, operationally-defined aggressive behavior of six males with Antisocial Personality Disorder (ASPD) was measured following acute intranasal oxytocin dosing (12, 24, and 48 international units) and placebo, using a well-validated laboratory task of human aggression (Point-Subtraction Aggression Paradigm, or PSAP). The PSAP provides participants with concurrently available monetary-earning and operationally-defined aggressive response options, maintained by fixed ratio schedules of consequences. Shifts in response rates and inter-response time (IRT) distributions were observed on the aggressive response option following oxytocin doses, relative to placebo. Few changes were observed in monetary-reinforced responding. However, across participants the direction and magnitude of changes in aggressive responding were not systematically related to dose. No trends were observed between psychometric or physiological data and oxytocin dosing or aggressive behavior. While this report is to our knowledge the first to examine the acute effects of oxytocin in this population at high risk for violence and other forms of antisocial behavior, several limitations in the experimental design and the results cast the study as a preliminary report. Strategies for more extensive future projects are discussed.

Cilazapril stability in the presence of hydrochlorothiazide in model mixtures and fixed dose combination.

PubMed

Paszun, Sylwia K; Stanisz, Beata J; Gradowska, Agnieszka

2013-01-01

The presented study aimed at the evaluation of hydrochlorothiazide influence on cilazapril stability in model mixture and fixed dose tablet formulation. The degradation of cilazapril in the presence of hydrochlorothiazide took place according to autocatalytic reaction kinetic mechanism, described mathematically by Prout-Tompkins equation. Hydrochlorothiazide coexistence with cilazapril in model mixture and fixed dose tablet without blister package accelerated cilazapril degradation in comparison with degradation of cilazapril substance. Values of reaction induction time shortened, while those of observed reaction rate constant increased. Increasing values of relative humidity and temperature have negative impact on cilazapril stability. Determined semi-logarithmic relationships: In k = f(RH) and Arrhenius ln k = f(1/T) are linear and are cilazapril stability predictive. The blister (OPA/Alu/PVC//Alu) package of fixed dose tablets, constitutes absolute moisture protection and prevent cilazapril--hydrochlorothiazide interaction occurrence.

Peripheral Dose Heterogeneity Due to the Thread Effect in Total Marrow Irradiation With Helical Tomotherapy

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

Takahashi, Yutaka; Verneris, Michael R.; Dusenbery, Kathryn E.

Purpose: To report potential dose heterogeneity leading to underdosing at different skeletal sites in total marrow irradiation (TMI) with helical tomotherapy due to the thread effect and provide possible solutions to reduce this effect. Methods and Materials: Nine cases were divided into 2 groups based on patient size, defined as maximum left-to-right arm distance (mLRD): small mLRD (≤47 cm) and large mLRD (>47 cm). TMI treatment planning was conducted by varying the pitch and modulation factor while a jaw size (5 cm) was kept fixed. Ripple amplitude, defined as the peak-to-trough dose relative to the average dose due to themore » thread effect, and the dose–volume histogram (DVH) parameters for 9 cases with various mLRD was analyzed in different skeletal regions at off-axis (eg, bones of the arm or femur), at the central axis (eg, vertebrae), and planning target volume (PTV), defined as the entire skeleton plus 1-cm margin. Results: Average ripple amplitude for a pitch of 0.430, known as one of the magic pitches that reduce thread effect, was 9.2% at 20 cm off-axis. No significant differences in DVH parameters of PTV, vertebrae, or femur were observed between small and large mLRD groups for a pitch of ≤0.287. Conversely, in the bones of the arm, average differences in the volume receiving 95% and 107% dose (V95 and V107, respectively) between large and small mLRD groups were 4.2% (P=.016) and 16% (P=.016), respectively. Strong correlations were found between mLRD and ripple amplitude (rs=.965), mLRD and V95 (rs=−.742), and mLRD and V107 (rs=.870) of bones of the arm. Conclusions: Thread effect significantly influences DVH parameters in the bones of the arm for large mLRD patients. By implementing a favorable pitch value and adjusting arm position, peripheral dose heterogeneity could be reduced.« less

In vivo dose verification method in catheter based high dose rate brachytherapy.

PubMed

Jaselskė, Evelina; Adlienė, Diana; Rudžianskas, Viktoras; Urbonavičius, Benas Gabrielis; Inčiūra, Arturas

2017-12-01

In vivo dosimetry is a powerful tool for dose verification in radiotherapy. Its application in high dose rate (HDR) brachytherapy is usually limited to the estimation of gross errors, due to inability of the dosimetry system/ method to record non-uniform dose distribution in steep dose gradient fields close to the radioactive source. In vivo dose verification in interstitial catheter based HDR brachytherapy is crucial since the treatment is performed inserting radioactive source at the certain positions within the catheters that are pre-implanted into the tumour. We propose in vivo dose verification method for this type of brachytherapy treatment which is based on the comparison between experimentally measured and theoretical dose values calculated at well-defined locations corresponding dosemeter positions in the catheter. Dose measurements were performed using TLD 100-H rods (6 mm long, 1 mm diameter) inserted in a certain sequences into additionally pre-implanted dosimetry catheter. The adjustment of dosemeter positioning in the catheter was performed using reconstructed CT scans of patient with pre-implanted catheters. Doses to three Head&Neck and one Breast cancer patient have been measured during several randomly selected treatment fractions. It was found that the average experimental dose error varied from 4.02% to 12.93% during independent in vivo dosimetry control measurements for selected Head&Neck cancer patients and from 7.17% to 8.63% - for Breast cancer patient. Average experimental dose error was below the AAPM recommended margin of 20% and did not exceed the measurement uncertainty of 17.87% estimated for this type of dosemeters. Tendency of slightly increasing average dose error was observed in every following treatment fraction of the same patient. It was linked to the changes of theoretically estimated dosemeter positions due to the possible patient's organ movement between different treatment fractions, since catheter reconstruction was performed for the first treatment fraction only. These findings indicate potential for further average dose error reduction in catheter based brachytherapy by at least 2-3% in the case that catheter locations will be adjusted before each following treatment fraction, however it requires more detailed investigation. Copyright © 2017 Associazione Italiana di Fisica Medica. Published by Elsevier Ltd. All rights reserved.

A Phase I/II Trial of Intensity Modulated Radiation (IMRT) Dose Escalation With Concurrent Fixed-dose Rate Gemcitabine (FDR-G) in Patients With Unresectable Pancreatic Cancer

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

Ben-Josef, Edgar, E-mail: edgar.ben-josef@uphs.upenn.edu; Schipper, Mathew; Francis, Isaac R.

2012-12-01

Purpose: Local failure in unresectable pancreatic cancer may contribute to death. We hypothesized that intensification of local therapy would improve local control and survival. The objectives were to determine the maximum tolerated radiation dose delivered by intensity modulated radiation with fixed-dose rate gemcitabine (FDR-G), freedom from local progression (FFLP), and overall survival (OS). Methods and Materials: Eligibility included pathologic confirmation of adenocarcinoma, radiographically unresectable, performance status of 0-2, absolute neutrophil count of {>=}1500/mm{sup 3}, platelets {>=}100,000/mm{sup 3}, creatinine <2 mg/dL, bilirubin <3 mg/dL, and alanine aminotransferase/aspartate aminotransferase {<=}2.5 Multiplication-Sign upper limit of normal. FDR-G (1000 mg/m{sup 2}/100 min intravenously) wasmore » given on days -22 and -15, 1, 8, 22, and 29. Intensity modulated radiation started on day 1. Dose levels were escalated from 50-60 Gy in 25 fractions. Dose-limiting toxicity was defined as gastrointestinal toxicity grade (G) {>=}3, neutropenic fever, or deterioration in performance status to {>=}3 between day 1 and 126. Dose level was assigned using TITE-CRM (Time-to-Event Continual Reassessment Method) with the target dose-limiting toxicity (DLT) rate set to 0.25. Results: Fifty patients were accrued. DLTs were observed in 11 patients: G3/4 anorexia, nausea, vomiting, and/or dehydration (7); duodenal bleed (3); duodenal perforation (1). The recommended dose is 55 Gy, producing a probability of DLT of 0.24. The 2-year FFLP is 59% (95% confidence interval [CI]: 32-79). Median and 2-year overall survival are 14.8 months (95% CI: 12.6-22.2) and 30% (95% CI 17-45). Twelve patients underwent resection (10 R0, 2 R1) and survived a median of 32 months. Conclusions: High-dose radiation therapy with concurrent FDR-G can be delivered safely. The encouraging efficacy data suggest that outcome may be improved in unresectable patients through intensification of local therapy.« less

Morphometrics of cellular damage in mice testis receiving X-ray and high-energy particle irradiation

NASA Technical Reports Server (NTRS)

Sapp, Walter J.

1987-01-01

Murine tests were exposed to single, low doses of either X-ray, helium, or argon radiation. Animals were sacrificed seventy-two hours later. Testes were fixed for transmission electron microscopy (TEM) and sectioned at either 60 nm for TEM observation or at 2 micron for counting using routine light microscope methods. Counts of the total population of surviving spermatogonia, including all type A cells, intermediate, and type B cells, were taken from tubule cross sections identified as Stage 6 and Stage 1 according to spermatogonial configuration. The surviving fraction of spermatogonia as compared to control, S/S sub o, was calculated for each dose. For both ions and X-rays, there was a rapid decline in survival at dose levels of .10 to .15 Gy in Stage 6 tubules. This was followed by a more gradual decrease in population. At higher doses, 0.30 Gy for argon and 0.80 Gy for helium and X-rays, the cell survival rates declined rapidly. Pre-leptotene spermatocytes in Stage 1 tubules exhibited a different survival curve indicating the extreme radio-sensitivity of type B spermatogonia. Data verify that the seminiferous tubules are composed of a heterogeneous population of cells with different radio-sensitivities and that these differences are manifested even at very low doses.

Effect of Localizer Radiography Projection on Organ Dose at Chest CT with Automatic Tube Current Modulation.

PubMed

Saltybaeva, Natalia; Krauss, Andreas; Alkadhi, Hatem

2017-03-01

Purpose To calculate the effect of localizer radiography projections to the total radiation dose, including both the dose from localizer radiography and that from subsequent chest computed tomography (CT) with tube current modulation (TCM). Materials and Methods An anthropomorphic phantom was scanned with 192-section CT without and with differently sized breast attachments. Chest CT with TCM was performed after one localizer radiographic examination with anteroposterior (AP) or posteroanterior (PA) projections. Dose distributions were obtained by means of Monte Carlo simulations based on acquired CT data. For Monte Carlo simulations of localizer radiography, the tube position was fixed at 0° and 180°; for chest CT, a spiral trajectory with TCM was used. The effect of tube start angles on dose distribution was investigated with Monte Carlo simulations by using TCM curves with fixed start angles (0°, 90°, and 180°). Total doses for lungs, heart, and breast were calculated as the sum of the dose from localizer radiography and CT. Image noise was defined as the standard deviation of attenuation measured in 14 circular regions of interest. The Wilcoxon signed rank test, paired t test, and Friedman analysis of variance were conducted to evaluate differences in noise, TCM curves, and organ doses, respectively. Results Organ doses from localizer radiography were lower when using a PA instead of an AP projection (P = .005). The use of a PA projection resulted in higher TCM values for chest CT (P < .001) owing to the higher attenuation (P < .001) and thus resulted in higher total organ doses for all investigated phantoms and protocols (P < .001). Noise in CT images was lower with PA localizer radiography than with AP localizer radiography (P = .03). The use of an AP projection allowed for total dose reductions of 16%, 15%, and 12% for lungs, breast, and heart, respectively. Differences in organ doses were not related to tube start angles (P = .17). Conclusion The total organ doses are higher when using PA projection localizer radiography owing to higher TCM values, whereas the organ doses from PA localizer radiography alone are lower. Thus, PA localizer radiography should be used in combination with reduced reference tube current at subsequent chest CT. © RSNA, 2016 Online supplemental material is available for this article.

VMAT vs. 7-Field-IMRT: Assessing the Dosimetric Parameters of Prostate Cancer Treatment with a 292-Patient Sample

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

Kopp, Robert W.; Duff, Michael, E-mail: mduff@cancercarewny.com; Catalfamo, Frank

2011-01-01

We compared normal tissue radiation dose for the treatment of prostate cancer using 2 different radiation therapy delivery methods: volumetric modulated arc therapy (VMAT) vs. fixed-field intensity-modulated radiation therapy (IMRT). Radiotherapy plans for 292 prostate cancer patients treated with VMAT to a total dose of 7740 cGy were analyzed retrospectively. Fixed-angle, 7-field IMRT plans were created using the same computed tomography datasets and contours. Radiation doses to the planning target volume (PTV) and organs at risk (bladder, rectum, penile bulb, and femoral heads) were measured, means were calculated for both treatment methods, and dose-volume comparisons were made with 2-tailed, pairedmore » t-tests. The mean dose to the bladder was lower with VMAT at all measured volumes: 5, 10, 15, 25, 35, and 50% (p < 0.05). The mean doses to 5 and 10% of the rectum, the high-dose regions, were lower with VMAT (p < 0.05). The mean dose to 15% of the rectal volume was not significantly different (p = 0.95). VMAT exposed larger rectal volumes (25, 35, and 50%) to more radiation than fixed-field IMRT (p < 0.05). Average mean dose to the penile bulb (p < 0.05) and mean dose to 10% of the femoral heads (p < 0.05) were lower with VMAT. VMAT therapy for prostate cancer has dosimetric advantages for critical structures, notably for high-dose regions compared with fixed-field IMRT, without compromising PTV coverage. This may translate into reduced acute and chronic toxicity.« less

Decreased fetal hemoglobin over time among youth with sickle cell disease on hydroxyurea is associated with higher urgent hospital use.

PubMed

Green, Nancy S; Manwani, Deepa; Qureshi, Mahvish; Ireland, Karen; Sinha, Arpan; Smaldone, Arlene M

2016-12-01

Hydroxyurea (HU) induces dose-dependent increased fetal hemoglobin (HbF) for sickle cell disease (SCD). Large deviation from historical personal best (PBest) HbF, a clinic-based version of maximum dose, may identify a subset with suboptimal HU adherence over time. Retrospective clinical data from youth ages 10-18 years prescribed HU at two centers were extracted from medical records at three time points: pre-HU initiation, PBest and a recent assessment. Decrease from PBest HbF of 20% or more at recent assessment despite stable dosing was designated as high deviation from PBest. Acute hospital use was compared between 1-year periods, pre-HU and ±6 months for PBest and recent assessment. Groups were compared using descriptive and bivariate nonparametric statistics. Seventy-five youth, mean HU duration 5.9 years, met eligibility criteria. Mean ages of HU initiation, PBest and recent assessment were 8.0, 10.9 and 13.9 years, respectively. Despite stable dosing, average HbF of 19.5% at PBest overall declined by 31.8% at recent assessment. PBest HbF declined by 11.7 and 40.1% in two groups, the latter comprised 70.7% of the sample, had lower pre-HU and recent HbF and higher dosing. They experienced more urgent hospital use during the year framing recent assessment than during PBest; these findings were supported by sensitivity analysis. Decline from PBest HbF is a novel approach to assess HU effectiveness, is common among youth and may represent suboptimal adherence. Larger prospective studies using additional adherence measures are needed to confirm our approach of tracking HbF deviation over time and to define an appropriate cutoff. © 2016 Wiley Periodicals, Inc.

SU-E-T-109: An Investigation of Including Variable Relative Biological Effectiveness in Intensity Modulated Proton Therapy Planning Optimization for Head and Neck Cancer Patients

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

Cao, W; Zaghian, M; Lim, G

2015-06-15

Purpose: The current practice of considering the relative biological effectiveness (RBE) of protons in intensity modulated proton therapy (IMPT) planning is to use a generic RBE value of 1.1. However, RBE is indeed a variable depending on the dose per fraction, the linear energy transfer, tissue parameters, etc. In this study, we investigate the impact of using variable RBE based optimization (vRBE-OPT) on IMPT dose distributions compared by conventional fixed RBE based optimization (fRBE-OPT). Methods: Proton plans of three head and neck cancer patients were included for our study. In order to calculate variable RBE, tissue specific parameters were obtainedmore » from the literature and dose averaged LET values were calculated by Monte Carlo simulations. Biological effects were calculated using the linear quadratic model and they were utilized in the variable RBE based optimization. We used a Polak-Ribiere conjugate gradient algorithm to solve the model. In fixed RBE based optimization, we used conventional physical dose optimization to optimize doses weighted by 1.1. IMPT plans for each patient were optimized by both methods (vRBE-OPT and fRBE-OPT). Both variable and fixed RBE weighted dose distributions were calculated for both methods and compared by dosimetric measures. Results: The variable RBE weighted dose distributions were more homogenous within the targets, compared with the fixed RBE weighted dose distributions for the plans created by vRBE-OPT. We observed that there were noticeable deviations between variable and fixed RBE weighted dose distributions if the plan were optimized by fRBE-OPT. For organs at risk sparing, dose distributions from both methods were comparable. Conclusion: Biological dose based optimization rather than conventional physical dose based optimization in IMPT planning may bring benefit in improved tumor control when evaluating biologically equivalent dose, without sacrificing OAR sparing, for head and neck cancer patients. The research is supported in part by National Institutes of Health Grant No. 2U19CA021239-35.« less

In vitro and in vivo evaluation of combined calcitriol and cisplatin in dogs with spontaneously occurring tumors

PubMed Central

Rassnick, Kenneth M.; Muindi, Josephia R.; Johnson, Candace S.; Balkman, Cheryl E.; Ramnath, Nithya; Yu, Wei-Dong; Engler, Kristie L.; Page, Rodney L.; Trump, Donald L.

2009-01-01

Purpose Calcitriol potentiates cisplatin-mediated activity in a variety of tumor models. We examine here, the effect of calcitriol and cisplatin pre-clinically and clinically in canine spontaneous tumors through in vitro studies on tumor cells and through a phase I study of calcitriol and cisplatin to identify the maximum-tolerated dosage (MTD) of this combination in dogs with cancer and to characterize the pharmacokinetic disposition of calcitriol in dogs. Methods Canine tumor cells were investigated for calcitriol/cisplatin interactions on proliferation using an MTT assay in a median-dose effect analysis; data were used to derive a combination index (CI). Cisplatin was given at a fixed dosage of 60 mg/m2. Calcitriol was given i.v. and the dosage was escalated in cohorts of three dogs until the MTD was defined. Serum calcitriol concentrations were quantified by radioimmunoassay. Results In vitro, CIs<1.0 were obtained for all combinations of calcitriol/cisplatin examined. The MTD was 3.75 μg/kg calcitriol in combination with cisplatin, and hypercalcemia was the dose-limiting toxicosis. The relationship between calcitriol dosage and either Cmax or AUC was linear. Calcitriol dosages >1.5 μg/kg achieved Cmax ≥ 9.8 ng/mL and dosages >1.0 μg/kg achieved AUC ≥ 45 h ng/mL. Conclusions Calcitriol and cisplatin have synergistic antiproliferative effects on multiple canine tumor cells and high-dosages of i.v. calcitriol in combination with cisplatin can be safely administered to dogs. Cmax and AUC at the MTD 3.75 μg/kg calcitriol exceed concentrations associated with antitumor activity in a murine model, indicating this combination might have significant clinical utility in dogs. PMID:18246349

Fixed-dose combinations in the management of hypertension: defining the place of angiotensin receptor antagonists and hydrochlorothiazide.

PubMed

Kjeldsen, Sverre E; Os, Ingrid; Høieggen, Aud; Beckey, Kim; Gleim, Gilbert W; Oparil, Suzanne

2005-01-01

We discuss combination therapy with angiotensin receptor antagonists (angiotensin receptor blockers; ARBs) and thiazide diuretics in light of the independent actions of both types of agents, and the adverse effects of both agents independently and in the context of the physiologic synergy achieved in using these agents together. ARBs counteract many of the adverse events associated with the use of thiazide diuretics and have been shown to reduce the occurrence of new-onset diabetes mellitus. We also review outcome trials in patients with hypertension (such as LIFE [Losartan Intervention For Endpoint reduction in hypertension], VALUE [Valsartan Antihypertensive Long-term Use Evaluation], and SCOPE [Study on COgnition and Prognosis in the Elderly]), in which losartan, valsartan, and candesartan cilexetil were used in combination with hydrochlorothiazide. Fixed combination ARB/hydrochlorothiazide agents make sense as initial therapy for patients in whom BP is >20/10 mm Hg above goal.

[The Dose Effect of Isocenter Selection during IMRT Dose Verification with the 2D Chamber Array].

PubMed

Xie, Chuanbin; Cong, Xiaohu; Xu, Shouping; Dai, Xiangkun; Wang, Yunlai; Han, Lu; Gong, Hanshun; Ju, Zhongjian; Ge, Ruigang; Ma, Lin

2015-03-01

To investigate the dose effect of isocenter difference during IMRT dose verification with the 2D chamber array. The samples collected from 10 patients were respectively designed for IMRT plans, the isocenter of which was independently defined as P(o), P(x) and P(y). P(o) was fixed on the target center and the other points shifted 8cm from the target center in the orientation of x/y. The PTW729 was used for 2D dose verification in the 3 groups which beams of plans were set to 0 degrees. The γ-analysis passing rates for the whole plan and each beam were gotten using the different standards in the 3 groups, The results showed the mean passing rate of γ-analysis was highest in the P(o) group, and the mean passing rate of the whole plan was better than that of each beam. In addition, it became worse with the increase of dose leakage between the leaves in P(y) group. Therefore, the determination of isocenter has a visible effect for IMRT dose verification of the 2D chamber array, The isocenter of the planning design should be close to the geometric center of target.

Phase I study of nintedanib in combination with pemetrexed as second-line treatment of Japanese patients with advanced non-small cell lung cancer.

PubMed

Daga, Haruko; Takeda, Koji; Okada, Hideaki; Miyazaki, Masaki; Ueda, Shinya; Kaneda, Hiroyasu; Okamoto, Isamu; Yoh, Kiyotaka; Goto, Koichi; Konishi, Koichi; Sarashina, Akiko; Tanaka, Tetsuya; Kaiser, Rolf; Nakagawa, Kazuhiko

2015-12-01

This open-label, phase I, dose-escalation part of a phase I/II study evaluated the safety, pharmacokinetics, and preliminary efficacy of nintedanib, a triple angiokinase inhibitor, combined with pemetrexed in Japanese patients with advanced non-small cell lung cancer (NSCLC) after first-line chemotherapy. A fixed dose of pemetrexed (500 mg/m(2) iv) was administered on Day 1 of each 21-day cycle followed by oral nintedanib twice daily (bid) on days 2-21, starting at 100 mg bid and escalating to 200 mg bid in 50-mg intervals, using a standard 3 + 3 design. After ≥4 cycles of combination therapy, patients could continue nintedanib monotherapy until disease progression or undue adverse events (AEs). Primary endpoints were maximum tolerated dose (MTD), defined as the highest dose at which the incidence of dose-limiting toxicities (DLTs) was <33.3 % during the first treatment course, and AEs (CTCAE v3.0). DLTs were primarily defined as grade ≥3 non-hematologic or grade 4 hematologic AEs. Eighteen patients were included in the analysis. DLTs were experienced by 2/9 patients receiving 200 mg bid, 1/6 receiving 150 mg bid, and 0/3 receiving the lowest dose. The MTD of nintedanib plus pemetrexed was 200 mg bid. The most common drug-related AEs were elevated liver enzymes and gastrointestinal AEs. Two patients achieved partial response, and 10 had stable disease. Nintedanib plus pemetrexed had a manageable safety profile and showed promising signs of efficacy in previously treated Japanese patients with advanced NSCLC. As in Caucasian patients, the MTD of nintedanib was 200 mg bid. Clinical trial information NCT00979576.

Global measurement of coagulation in plasma from normal and haemophilia dogs using a novel modified thrombin generation test – Demonstrated in vitro and ex vivo

PubMed Central

Madsen, Daniel Elenius; Nichols, Timothy C.; Merricks, Elizabeth P.; Waters, Emily K.; Wiinberg, Bo

2017-01-01

Introduction Canine models of severe haemophilia resemble their human equivalents both regarding clinical bleeding phenotype and response to treatment. Therefore pre-clinical studies in haemophilia dogs have allowed researchers to make valuable translational predictions regarding the potency and efficacy of new anti-haemophilia drugs (AHDs) in humans. To refine in vivo experiments and reduce number of animals, such translational studies are ideally preceded by in vitro prediction of compound efficacy using a plasma based global coagulation method. One such widely used method is the thrombin generation test (TGT). Unfortunately, commercially available TGTs are incapable of distinguishing between normal and haemophilia canine plasma, and therefore in vitro prediction using TGT has so far not been possible in canine plasma material. Aim Establish a modified TGT capable of: 1) distinguishing between normal and haemophilia canine plasma, 2) monitoring correlation between canine plasma levels of coagulation factor VIII (FVIII) and IX (FIX) and thrombin generation, 3) assessing for agreement between compound activity and thrombin generation in ex vivo samples. Methods A modified TGT assay was established where coagulation was triggered using a commercially available activated partial thromboplastin time reagent. Results With the modified TGT a significant difference was observed in thrombin generation between normal and haemophilia canine plasma. A dose dependent thrombin generation was observed when assessing haemophilia A and B plasma spiked with dilution series of FVIII and FIX, respectively. Correlation between FVIII activity and thrombin generation was observed when analyzing samples from haemophilia A dogs dosed with canine FVIII. Limit of detection was 0.1% (v/v) FVIII or FIX. Conclusion A novel modified TGT suitable for monitoring and prediction of replacement therapy efficacy in plasma from haemophilia A and B dogs was established. PMID:28384182

Linked Orders Improve Safety in Scheduling and Administration of Chemotherapeutic Agents

PubMed Central

Whipple, Nancy; Boulware, Joy; Danca, Kala; Boyarin, Kirill; Ginsberg, Eliot; Poon, Eric; Sweet, Micheal; Schade, Sue; Rogala, Jennifer

2010-01-01

The pharmacologic treatment for cancer must adhere to complex, finely orchestrated treatment plans, including not only chemotherapy medications, but pre/post-hydration, anti-emetics, anti-anxiety, and other medications that are given before, during and after chemotherapy doses. The treatment plans specify the medications and dictate precise dosing, frequency, and timing. This is a challenge to most Computerized Physician Order Entry (CPOE), Pharmacy and Electronic Medication Administration record (eMAR) Systems. Medications are scheduled on specific dates, referred to as chemo days, from the onset of the treatment, and precisely timed on the designated chemo day. For patients enrolled in research protocols, the adherence to the defined schedule takes on additional import, since variation is a violation of the protocol. If the oncologist determines that medications must be administered outside the defined constraints, the patient must be un-enrolled from the protocol and the course of therapy is re-written. Pharmacy and eMAR systems utilized in processing chemotherapy medications must be able to support the intricate relationships between each drug defined in the treatment plans. PMID:21347104

The Caribbean conundrum of Holocene sea level.

NASA Astrophysics Data System (ADS)

Jackson, Luke; Mound, Jon

2014-05-01

In the tropics, pre-historic sea-level curve reconstruction is often problematic because it relies upon sea-level indicators whose vertical relationship to the sea surface is poorly constrained. In the Caribbean, fossil corals, mangrove peats and shell material dominate the pre-historic indicator record. The common approach to reconstruction involves the use of modern analogues to these indicators to establish a fixed vertical habitable range. The aim of these reconstructions is to find spatial variability in the Holocene sea level in an area gradually subsiding (< 1.2 mm yr-1) due the water loading following the deglaciation of the Laurentide ice sheet. We construct two catalogues: one of published Holocene sea-level indicators and the other of published, modern growth rates, abundance and coverage of mangrove and coral species for different depths. We use the first catalogue to calibrate 14C ages to give a probabilistic age range for each indicator. We use the second catalogue to define a depth probability distribution function (pdf) for mangroves and each coral species. The Holocene indicators are grouped into 12 sub-regions around the Caribbean. For each sub-region we apply our sea-level reconstruction, which involves stepping a fixed-length time window through time and calculating the position (and rate) of sea-level (change) using a thousand realisations of the time/depth pdfs to define an envelope of probable solutions. We find that the sub-regional relative sea-level curves display spatio-temporal variability including a south-east to north-west 1500 year lag in the arrival of Holocene sea level to that of the present day. We demonstrate that these variations are primarily due to glacial-isostatic-adjustment induced sea-level change and that sub-regional variations (where sufficient data exists) are due to local uplift variability.

Impact of orbit modeling on DORIS station position and Earth rotation estimates

NASA Astrophysics Data System (ADS)

Štěpánek, Petr; Rodriguez-Solano, Carlos Javier; Hugentobler, Urs; Filler, Vratislav

2014-04-01

The high precision of estimated station coordinates and Earth rotation parameters (ERP) obtained from satellite geodetic techniques is based on the precise determination of the satellite orbit. This paper focuses on the analysis of the impact of different orbit parameterizations on the accuracy of station coordinates and the ERPs derived from DORIS observations. In a series of experiments the DORIS data from the complete year 2011 were processed with different orbit model settings. First, the impact of precise modeling of the non-conservative forces on geodetic parameters was compared with results obtained with an empirical-stochastic modeling approach. Second, the temporal spacing of drag scaling parameters was tested. Third, the impact of estimating once-per-revolution harmonic accelerations in cross-track direction was analyzed. And fourth, two different approaches for solar radiation pressure (SRP) handling were compared, namely adjusting SRP scaling parameter or fixing it on pre-defined values. Our analyses confirm that the empirical-stochastic orbit modeling approach, which does not require satellite attitude information and macro models, results for most of the monitored station parameters in comparable accuracy as the dynamical model that employs precise non-conservative force modeling. However, the dynamical orbit model leads to a reduction of the RMS values for the estimated rotation pole coordinates by 17% for x-pole and 12% for y-pole. The experiments show that adjusting atmospheric drag scaling parameters each 30 min is appropriate for DORIS solutions. Moreover, it was shown that the adjustment of cross-track once-per-revolution empirical parameter increases the RMS of the estimated Earth rotation pole coordinates. With recent data it was however not possible to confirm the previously known high annual variation in the estimated geocenter z-translation series as well as its mitigation by fixing the SRP parameters on pre-defined values.

Optimization of self-aligned double patterning (SADP)-compliant layout designs using pattern matching for sub-20nm metal routing

NASA Astrophysics Data System (ADS)

Wang, Lynn T.-N.; Schroeder, Uwe Paul; Madhavan, Sriram

2017-03-01

A pattern-based methodology for optimizing SADP-compliant layout designs is developed based on identifying cut mask patterns and replacing them with pre-characterized fixing solutions. A pattern-based library of difficult-tomanufacture cut patterns with pre-characterized fixing solutions is built. A pattern-based engine searches for matching patterns in the decomposed layouts. When a match is found, the engine opportunistically replaces the detected pattern with a pre-characterized fixing solution. The methodology was demonstrated on a 7nm routed metal2 block. A small library of 30 cut patterns increased the number of more manufacturable cuts by 38% and metal-via enclosure by 13% with a small parasitic capacitance impact of 0.3%.

Adequacy of Fixed-Dose Heparin Infusions for Venous Thromboembolism Prevention after Microsurgical Procedures.

PubMed

Bertolaccini, Corinne M; Prazak, Ann Marie B; Agarwal, Jayant; Goodwin, Isak A; Rockwell, W Bradford; Pannucci, Christopher J

2018-05-22

 In microvascular surgery, patients often receive unfractionated heparin infusions to minimize risk for microvascular thrombosis. Patients who receive intravenous (IV) heparin are believed to have adequate prophylaxis against venous thromboembolism (VTE). Whether a fixed dose of IV heparin provides detectable levels of anticoagulation, or whether the "one size fits all" approach provides adequate prophylaxis against VTE remains unknown. This study examined the pharmacodynamics of fixed-dose heparin infusions and the effects of real-time, anti-factor Xa (aFXa) level driven heparin dose adjustments.  This prospective clinical trial recruited adult microvascular surgery patients placed on a fixed-dose (500 units/h) unfractionated heparin infusion during their initial microsurgical procedure. Steady-state aFXa levels, a marker of unfractionated heparin efficacy and safety, were monitored. Patients with out-of-range aFXa levels received protocol-driven real-time dose adjustments. Outcomes of interest included aFXa levels in response to heparin 500 units/h, number of dose adjustments required to achieve goal aFXa levels, time to reach goal aFXa level, and 90-day clinically relevant bleeding and VTE.  Twenty patients were recruited prospectively. None of 20 patients had any detectable level of anticoagulation in response to heparin infusions at 500 units/h. The median number of dose adjustments required to reach goal level was five, and median weight-based dose to reach goal level was 11.8 units/kg/h. Real-time dose adjustments significantly increased the proportion of patients with in-range levels (60 vs. 0%, p  = 0.0001). The 90-day VTE rate was 5% and 90-day clinically relevant bleeding rate was 5%.  Fixed-dose heparin infusions at a rate of 500 units/h do not provide a detectable level of anticoagulation after microsurgical procedures and are insufficient for the majority of patients who require VTE prophylaxis. Weight-based heparin infusions at 10 to 12 units/kg/h deserve future study in patients undergoing microsurgical procedures to increase the proportion of patients receiving adequate VTE prophylaxis. Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

Dose-Response Analysis of RNA-Seq Profiles in Archival Formalin-Fixed Paraffin-Embedded (FFPE) Samples.

EPA Science Inventory

Use of archival resources has been limited to date by inconsistent methods for genomic profiling of degraded RNA from formalin-fixed paraffin-embedded (FFPE) samples. RNA-sequencing offers a promising way to address this problem. Here we evaluated transcriptomic dose responses us...

Dose-Response Analysis of RNA-Seq Profiles in Archival Formalin-fixed paraffin-embedded (FFPE) Samples

EPA Science Inventory

Formalin-fixed paraffin-embedded (FFPE) samples provide a vast untapped resource for chemical safety and translational science. To date, genomic profiling of FFPE samples has been limited by poor RNA quality and inconsistent results with limited utility in dose-response assessmen...

Physical stress, mass, and energy for non-relativistic matter

NASA Astrophysics Data System (ADS)

Geracie, Michael; Prabhu, Kartik; Roberts, Matthew M.

2017-06-01

For theories of relativistic matter fields there exist two possible definitions of the stress-energy tensor, one defined by a variation of the action with the coframes at fixed connection, and the other at fixed torsion. These two stress-energy tensors do not necessarily coincide and it is the latter that corresponds to the Cauchy stress measured in the lab. In this note we discuss the corresponding issue for non-relativistic matter theories. We point out that while the physical non-relativistic stress, momentum, and mass currents are defined by a variation of the action at fixed torsion, the energy current does not admit such a description and is naturally defined at fixed connection. Any attempt to define an energy current at fixed torsion results in an ambiguity which cannot be resolved from the background spacetime data or conservation laws. We also provide computations of these quantities for some simple non-relativistic actions.

Ammonia control in children with urea cycle disorders (UCDs); phase 2 comparison of sodium phenylbutyrate and glycerol phenylbutyrate.

PubMed

Lichter-Konecki, Uta; Diaz, G A; Merritt, J L; Feigenbaum, A; Jomphe, C; Marier, J F; Beliveau, M; Mauney, J; Dickinson, K; Martinez, A; Mokhtarani, M; Scharschmidt, B; Rhead, W

2011-08-01

Twenty four hour ammonia profiles and correlates of drug effect were examined in a phase 2 comparison of sodium phenylbutyrate (NaPBA) and glycerol phenylbutyrate (GPB or HPN-100), an investigational drug being developed for urea cycle disorders (UCDs). Protocol HPN-100-005 involved open label fixed-sequence switch-over from the prescribed NaPBA dose to a PBA-equimolar GPB dose with controlled diet. After 7 days on NaPBA or GPB, subjects underwent 24-hour blood sampling for ammonia and drug metabolite levels as well as measurement of 24-hour urinary phenyacetylglutamine (PAGN). Adverse events (AEs), safety labs and triplicate ECGs were monitored. Eleven subjects (9 OTC, 1 ASS, 1 ASL) enrolled and completed the switch-over from NaPBA (mean dose=12.4 g/d or 322 mg/kg/d; range=198-476 mg/kg/d) to GPB (mean dose=10.8 mL or 0.284 mL/kg/d or 313 mg/kg/d; range=192-449 mg/kg/d). Possibly-related AEs were reported in 2 subjects on NaPBA and 4 subjects on GPB. All were mild, except for one moderate AE of vomiting on GPB related to an intercurrent illness. No clinically significant laboratory or ECG changes were observed. Ammonia was lowest after overnight fast, peaked postprandially in the afternoon to early evening and varied widely over 24h with occasional values >100 μmol/L without symptoms. Ammonia values were ~25% lower on GPB vs. NaPBA (p≥0.1 for ITT and p<0.05 for per protocol population). The upper 95% confidence interval for the difference between ammonia on GPB vs. NaPBA in the ITT population (95% CI 0.575, 1.061; p=0.102) was less than the predefined non-inferiority margin of 1.25 and less than 1.0 in the pre-defined per-protocol population (95% CI 0.516, 0.958; p<0.05). No statistically significant differences were observed in plasma phenylacetic acid and PAGN exposure during dosing with GPB vs. NaPBA, and the percentage of orally administered PBA excreted as PAGN (66% for GPB vs. 69% for NaPBA) was very similar. GPB and NaPBA dose correlated best with urinary-PAGN. These findings suggest that GPB is at least equivalent to NaPBA in terms of ammonia control, has potential utility in pediatric UCD patients and that U-PAGN is a clinically useful biomarker for dose selection and monitoring. Copyright © 2011 Elsevier Inc. All rights reserved.

Ammonia control in children with urea cycle disorders (UCDs); Phase 2 comparison of sodium phenylbutyrate and glycerol phenylbutyrate☆

PubMed Central

Lichter-Konecki, Uta; Diaz, G.A.; Merritt, J.L.; Feigenbaum, A.; Jomphe, C.; Marier, J.F.; Beliveau, M.; Mauney, J.; Dickinson, K.; Martinez, A.; Mokhtarani, M.; Scharschmidt, B.; Rhead, W.

2016-01-01

Twenty four hour ammonia profiles and correlates of drug effect were examined in a phase 2 comparison of sodium phenylbutyrate (NaPBA) and glycerol phenylbutyrate (GPB or HPN-100), an investigational drug being developed for urea cycle disorders (UCDs). Study Design Protocol HPN-100-005 involved open label fixed-sequence switch-over from the prescribed NaPBA dose to a PBA-equimolar GPB dose with controlled diet. After 7 days on NaPBA or GPB, subjects underwent 24-hour blood sampling for ammonia and drug metabolite levels as well as measurement of 24-hour urinary phenyacetylglutamine (PAGN). Adverse events (AEs), safety labs and triplicate ECGs were monitored. Results Eleven subjects (9 OTC, 1 ASS, 1 ASL) enrolled and completed the switch-over from NaPBA (mean dose=12.4 g/d or 322 mg/kg/d; range=198–476 mg/kg/d) to GPB (mean dose=10.8 mL or 0.284 mL/kg/d or 313 mg/kg/d; range = 192–449 mg/kg/d). Possibly-related AEs were reported in 2 subjects on NaPBA and 4 subjects on GPB. All were mild, except for one moderate AE of vomiting on GPB related to an intercurrent illness. No clinically significant laboratory or ECG changes were observed. Ammonia was lowest after overnight fast, peaked postprandially in the afternoon to early evening and varied widely over 24 h with occasional values >100 μmol/L without symptoms. Ammonia values were ~25% lower on GPB vs. NaPBA (p ≥ 0.1 for ITT and p<0.05 for per protocol population). The upper 95% confidence interval for the difference between ammonia on GPB vs. NaPBA in the ITT population (95% CI 0.575, 1.061; p = 0.102) was less than the predefined non-inferiority margin of 1.25 and less than 1.0 in the pre-defined per-protocol population (95% CI 0.516, 0.958; p<0.05). No statistically significant differences were observed in plasma phenylacetic acid and PAGN exposure during dosing with GPB vs. NaPBA, and the percentage of orally administered PBA excreted as PAGN (66% for GPB vs. 69% for NaPBA) was very similar. GPB and NaPBA dose correlated best with urinary-PAGN. Conclusions These findings suggest that GPB is at least equivalent to NaPBA in terms of ammonia control, has potential utility in pediatric UCD patients and that U-PAGN is a clinically useful biomarker for dose selection and monitoring. PMID:21612962

TU-G-BRA-01: Assessing Radiation-Induced Reductions in Regional Lung Perfusion Following Stereotactic Radiotherapy for Lung Cancer

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

McGurk, R; Green, R; Lawrence, M

2015-06-15

Purpose: The dose-dependent nature of radiation therapy (RT)-induced lung injury following hypo-fractionated stereotactic RT is unclear. We herein report preliminary results of a prospective study assessing the magnitude of RT-induced reductions in regional lung perfusion following hypo-fractionated stereotactic RT. Methods: Four patients undergoing hypo-fractionated stereotactic lung RT (SBRT: 12 Gy x 4 fractions or 10 Gy x 5 fractions) had a pre-treatment SPECT (single-photon emission computed tomography) perfusion scan providing a 3D map of regional lung perfusion. Scans were repeated 3–6 months post-treatment. Pre- and post SPECT scans were registered to the planning CT scan (and hence the 3D dosemore » data). Changes in regional perfusion (counts per cc on the pre-post scans) were computed in regions of the lung exposed to different doses of radiation (in 5 Gy intervals), thus defining a dose-response function. SPECT scans were internally normalized to the regions receiving <5 Gy. Results: At 3 months post-RT, the changes in perfusion are highly variable. At 6 months, there is a consistent dose-dependent reduction in regional perfusion. The average percent decline in regional perfusion was 10% at 15–20 Gy, 20% at 20–25 Gy, and 30% at 25–30 Gy representing a relatively linear dose response with an approximate 2% reduction per Gray for doses in excess of 10 Gy. There was a subtle increase in perfusion in the lung receiving <10 Gy. Conclusion: Hypo-fractionated stereotactic RT appears to cause a dose-dependent reduction in regional lung perfusion. There appears to be a threshold effect with no apparent perfusion loss at doses <10 Gy, though this might be in part due to the normalization technique used. Additional data is needed from a larger number of patients to better assess this issue. This sort of data can be used to assist optimizing RT treatment plans that minimize the risk of lung injury. Partly supported by the NIH (CA69579) and the Lance Armstrong Foundation.« less

Morphine tolerance as a function of ratio schedule: response requirement or unit price?

PubMed

Hughes, Christine E; Sigmon, Stacey C; Pitts, Raymond C; Dykstra, Linda A

2005-05-01

Key pecking by 3 pigeons was maintained by a multiple fixed-ratio 10, fixed-ratio 30, fixed-ratio 90 schedule of food presentation. Components differed with respect to amount of reinforcement, such that the unit price was 10 responses per 1-s access to food. Acute administration of morphine, l-methadone, and cocaine dose-dependently decreased overall response rates in each of the components. When a rate decreasing dose of morphine was administered daily, tolerance, as measured by an increase in the dose that reduced response rates to 50% of control (i.e., the ED50 value), developed in each of the components; however, the degree of tolerance was smallest in the fixed-ratio 90 component (i.e., the ED50 value increased the least). When the l-methadone dose-effect curve was redetermined during the chronic morphine phase, the degree of cross-tolerance conferred to l-methadone was similar across components, suggesting that behavioral variables may not influence the degree of cross-tolerance between opioids. During the chronic phase, the cocaine dose-effect curve shifted to the right for 2 pigeons and to the left for 1 pigeon, which is consistent with predictions based on the lack of pharmacological similarity between morphine and cocaine. When the morphine, l-methadone, and cocaine dose-effect curves were redetermined after chronic morphine administration ended, the morphine and l-methadone ED50s replicated those obtained prior to chronic morphine administration. The morphine data suggest that the fixed-ratio value (i.e., the absolute output) determines the degree of tolerance and not the unit price.

Correlation of tumor p53 and PCNA with response and survival of glioblastoma in patients treated with an ECOG protocol of pre-irradiation chemotherapy.

PubMed

Grunnet, M L; O'Neill, A; Gilbert, M; Hellman, R

2000-01-01

The ability to predict treatment responsiveness and survival of patients with glioblastoma multiforme, the most malignant and most common primary brain tumor, would be a valuable asset. Tumor and proliferation markers such as p53 and PCNA have been immunohistochemically defined and have been useful in other tumors in determining prognosis. Therefore, the authors studied the correlation of responsiveness to treatment, time to progression and survival with p53 and PCNA labeling indices in a pre-irradiation chemotherapy study of the glioblastoma multiforme. Immunohistopathology for labeling indices for p53 and PCNA using formalin-fixed, paraffin-embedded tissue from the glioblastomas of 23 patients entered into a phase II ECOG trial of pre-irradiation chemotherapy were defined using the streptavidin-peroxidase technique with AEC chromogen. The labeling indices were correlated with response to treatment time to progression and overall survival. Most patients received three cycles of BCNU for three days over three months and cisplatin monthly for three days over three months prior to external beam irradiation. There were no significant differences in treatment response, time to progression or overall survival in glioblastoma, patients with positive p53 labeling index (> 5%) versus a negative p53 labeling index (< or = 5%) or positive PCNA labeling (> 10%) versus a negative labeling index (< or = 10%) or any combination of P53 and PCNA labeling indices. Using this protocol of pre-irradiation chemotherapy, p53 and PCNA labeling indices in the glioblastoma multiforme did not predict treatment benefit.

Low-dose fixed-target serial synchrotron crystallography.

PubMed

Owen, Robin L; Axford, Danny; Sherrell, Darren A; Kuo, Anling; Ernst, Oliver P; Schulz, Eike C; Miller, R J Dwayne; Mueller-Werkmeister, Henrike M

2017-04-01

The development of serial crystallography has been driven by the sample requirements imposed by X-ray free-electron lasers. Serial techniques are now being exploited at synchrotrons. Using a fixed-target approach to high-throughput serial sampling, it is demonstrated that high-quality data can be collected from myoglobin crystals, allowing room-temperature, low-dose structure determination. The combination of fixed-target arrays and a fast, accurate translation system allows high-throughput serial data collection at high hit rates and with low sample consumption.

Improved consistency in dosing anti-tuberculosis drugs in Taipei, Taiwan.

PubMed

Chiang, Chen-Yuan; Yu, Ming-Chih; Shih, Hsiu-Chen; Yen, Muh-Yong; Hsu, Yu-Ling; Yang, Shiang-Lin; Lin, Tao-Ping; Bai, Kuan-Jen

2012-01-01

It was reported that 35.5% of tuberculosis (TB) cases reported in 2003 in Taipei City had no recorded pre-treatment body weight and that among those who had, inconsistent dosing of anti-TB drugs was frequent. Taiwan Centers for Disease Control (CDC) have taken actions to strengthen dosing of anti-TB drugs among general practitioners. Prescribing practices of anti-TB drugs in Taipei City in 2007-2010 were investigated to assess whether interventions on dosing were effective. Lists of all notified culture positive TB cases in 2007-2010 were obtained from National TB Registry at Taiwan CDC. A medical audit of TB case management files was performed to collect pretreatment body weight and regimens prescribed at commencement of treatment. Dosages prescribed were compared with dosages recommended. The proportion of patients with recorded pre-treatment body weight was 64.5% in 2003, which increased to 96.5% in 2007-2010 (p<0.001). The proportion of patients treated with consistent dosing of a 3-drug fixed-dose combination (FDC) increased from 73.9% in 2003 to 87.7% in 2007-2010 (p<0.001), and that for 2-drug FDC from 76.0% to 86.1% (p = 0.024), for rifampicin (RMP) from 62.8% to 85.5% (p<0.001), and for isoniazid from 87.8% to 95.3% (p<0.001). In 2007-2010, among 2917 patients treated with either FDCs or RMP in single-drug preparation, the dosage of RMP was adequate (8-12 mg/kg) in 2571(88.1%) patients, too high in 282(9.7%), too low in 64(2.2%). In multinomial logistic regression models, factors significantly associated with adequate dosage of RMP were body weight and preparations of RMP. Patients weighting <40 kg (relative risk ratio (rrr) 6010.5, 95% CI 781.1-46249.7) and patients weighting 40-49 kg (rrr 1495.3, 95% CI 200.6-11144.6) were more likely to receive higher-than-recommended dose of RMP. Prescribing practice in the treatment of TB in Taipei City has remarkably improved after health authorities implemented a series of interventions.

Dosimetric accuracy of a treatment planning system for actively scanned proton beams and small target volumes: Monte Carlo and experimental validation

NASA Astrophysics Data System (ADS)

Magro, G.; Molinelli, S.; Mairani, A.; Mirandola, A.; Panizza, D.; Russo, S.; Ferrari, A.; Valvo, F.; Fossati, P.; Ciocca, M.

2015-09-01

This study was performed to evaluate the accuracy of a commercial treatment planning system (TPS), in optimising proton pencil beam dose distributions for small targets of different sizes (5-30 mm side) located at increasing depths in water. The TPS analytical algorithm was benchmarked against experimental data and the FLUKA Monte Carlo (MC) code, previously validated for the selected beam-line. We tested the Siemens syngo® TPS plan optimisation module for water cubes fixing the configurable parameters at clinical standards, with homogeneous target coverage to a 2 Gy (RBE) dose prescription as unique goal. Plans were delivered and the dose at each volume centre was measured in water with a calibrated PTW Advanced Markus® chamber. An EBT3® film was also positioned at the phantom entrance window for the acquisition of 2D dose maps. Discrepancies between TPS calculated and MC simulated values were mainly due to the different lateral spread modeling and resulted in being related to the field-to-spot size ratio. The accuracy of the TPS was proved to be clinically acceptable in all cases but very small and shallow volumes. In this contest, the use of MC to validate TPS results proved to be a reliable procedure for pre-treatment plan verification.

Dosimetric accuracy of a treatment planning system for actively scanned proton beams and small target volumes: Monte Carlo and experimental validation.

PubMed

Magro, G; Molinelli, S; Mairani, A; Mirandola, A; Panizza, D; Russo, S; Ferrari, A; Valvo, F; Fossati, P; Ciocca, M

2015-09-07

This study was performed to evaluate the accuracy of a commercial treatment planning system (TPS), in optimising proton pencil beam dose distributions for small targets of different sizes (5-30 mm side) located at increasing depths in water. The TPS analytical algorithm was benchmarked against experimental data and the FLUKA Monte Carlo (MC) code, previously validated for the selected beam-line. We tested the Siemens syngo(®) TPS plan optimisation module for water cubes fixing the configurable parameters at clinical standards, with homogeneous target coverage to a 2 Gy (RBE) dose prescription as unique goal. Plans were delivered and the dose at each volume centre was measured in water with a calibrated PTW Advanced Markus(®) chamber. An EBT3(®) film was also positioned at the phantom entrance window for the acquisition of 2D dose maps. Discrepancies between TPS calculated and MC simulated values were mainly due to the different lateral spread modeling and resulted in being related to the field-to-spot size ratio. The accuracy of the TPS was proved to be clinically acceptable in all cases but very small and shallow volumes. In this contest, the use of MC to validate TPS results proved to be a reliable procedure for pre-treatment plan verification.

Treatment of subclinical hypothyroidism in pregnancy using fixed thyroxine daily doses of 75 μg.

PubMed

Penin, Manuel; Trigo, Cristina; López, Yolanda; Barragáns, María

2014-01-01

Treatment of hypothyroid pregnant women is usually calculated based on weight (1 μg/kg/day) and TSH levels. This study assessed the usefulness of treating these women with a fixed dose of 75 μg/day. All women with pregnancy diagnosed from January to August 2012 in the Vigo Health Area (Spain) without previous diagnosis of thyroid disease or thyroxine treatment and with TSH levels over 4,5 mUI/ml were enrolled by consecutive sampling. All 116 women in the sample were treated with a fixed daily dose of thyroxine 75 μg-thyroxine levels were measured at two, four, and six months, and thyroxine dose was modified if TSH level was lower than 0.3 or higher than 4.5 mUI/ml. A woman had a TSH level less than 0.3 mUI/ml in a test; reduction of thyroxine dose to 50 μg/day allowed for maintaining TSH level within the desired range until delivery. Six women had TSH levels over 4.5 mUI/ml in one test; in all of them, increase in thyroxine dose to 100 μg/day allowed for maintaining the level within the desired range until delivery. Fixed daily doses of thyroxine 75 μg allowed for achieving goal TSH levels in most of our pregnant women with subclinical hypothyroidism, irrespective of their weight and baseline TSH level. Copyright © 2013 SEEN. Published by Elsevier Espana. All rights reserved.

Efficacy and safety of a four-drug fixed-dose combination regimen versus separate drugs for treatment of pulmonary tuberculosis: a systematic review and meta-analysis.

PubMed

Lima, Glaura C; Silva, Emilia V; Magalhães, Pérola de O; Naves, Janeth S

Tuberculosis, particularly multi-drug-resistant tuberculosis, is a major cause of morbidity and mortality worldwide. To the best of our knowledge, however, no study to date has assessed the combined use of the four available drugs for tuberculosis treatment, which is an issue of great clinical relevance. To determine whether the four-drug fixed-dose combination is safer or more effective than separate drugs for treatment of pulmonary tuberculosis. A systematic review of the literature was performed in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. In pooled results from five randomized controlled trials with 3502 patients across Africa, Asia, and Latin America, four-drug fixed-dose combination therapy was no better than separate drugs therapy in terms of culture conversion after 2 and 6 months of treatment. There were no significant differences between the groups in overall incidence of adverse effects. However, the meta-analytic measure (log odds ratio) revealed that separate drugs treatment had a 1.65 [exp (0.5)=1.65] increased chance of gastrointestinal adverse effects compared to four-drug fixed-dose combination treatment. The reviewed studies showed that four-drug fixed-dose combination therapy provides greater patient comfort by reducing the number of pills and the incidence of gastrointestinal adverse effects, as well as simplifying pharmaceutical management at all levels. Copyright © 2016 Sociedade Brasileira de Microbiologia. Published by Elsevier Editora Ltda. All rights reserved.

Mealtime Insulin Dosing by Carbohydrate Counting in Hospitalized Cardiology Patients: A Retrospective Cohort Study.

PubMed

Thurber, Kristina M; Dierkhising, Ross A; Reiland, Sarah A; Pearson, Kristina K; Smith, Steven A; O'Meara, John G

2016-01-01

Carbohydrate counting may improve glycemic control in hospitalized cardiology patients by providing individualized insulin doses tailored to meal consumption. The purpose of this study was to compare glycemic outcomes with mealtime insulin dosed by carbohydrate counting versus fixed dosing in the inpatient setting. This single-center retrospective cohort study included 225 adult medical cardiology patients who received mealtime, basal, and correction-scale insulin concurrently for at least 72 h and up to 7 days in the interval March 1, 2010-November 7, 2013. Mealtime insulin was dosed by carbohydrate counting or with fixed doses determined prior to meal intake. An inpatient diabetes consult service was responsible for insulin management. Exclusion criteria included receipt of an insulin infusion. The primary end point compared mean daily postprandial glucose values, whereas secondary end points included comparison of preprandial glucose values and mean daily rates of hypoglycemia. Mean postprandial glucose level on Day 7 was 204 and 183 mg/dL in the carbohydrate counting and fixed mealtime dose groups, respectively (unadjusted P=0.04, adjusted P=0.12). There were no statistical differences between groups on Days 2-6. Greater rates of preprandial hypoglycemia were observed in the carbohydrate counting cohort on Day 5 (8.6% vs. 1.5%, P=0.02), Day 6 (1.7% vs. 0%, P=0.01), and Day 7 (7.1% vs. 0%, P=0.008). No differences in postprandial hypoglycemia were seen. Mealtime insulin dosing by carbohydrate counting was associated with similar glycemic outcomes as fixed mealtime insulin dosing, except for a greater incidence of preprandial hypoglycemia. Additional comparative studies that include hospital outcomes are needed.

Pharmacokinetics and pharmacodynamics of sofosbuvir and ledipasvir for the treatment of hepatitis C.

PubMed

Cuenca-Lopez, Francisca; Rivero, Antonio; Rivero-Juárez, Antonio

2017-01-01

The sofosbuvir (SOF) plus ledipasvir (LDV) fixed dose combination is the first direct action antiviral (DAA) single-treatment regimen (STR) to be commercialized. It is approved for the treatment of Hepatitis C virus (HCV) genotypes 1,3,4,5 and 6. Following approval in 2014, new pharmacokinetics and pharmacodynamics data were reported, which led to important clinical applications. Areas covered: This article reviews the pharmacokinetic and pharmacodynamic properties of the SOF/LDV fixed dose combination for the treatment of HCV. The topics covered include data regarding the drug´s absorption, distribution, metabolism and excretion and antiviral activity strategies such as the clinical dose selection and treatment duration. Expert opinion: The SOF/LDV fixed dose combination has good pharmacological properties that lead to a high sustained virological response after 12 or 24 weeks of treatment; there is minimal interference with other drugs or associated renal or hepatic impairment, such that dose adjustment is not necessary.

Volumetric-modulated arc therapy (RapidArc) vs. conventional fixed-field intensity-modulated radiotherapy for {sup 18}F-FDG-PET-guided dose escalation in oropharyngeal cancer: A planning study

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

Teoh, May, E-mail: m.teoh@nhs.net; Beveridge, Sabeena; Wood, Katie

2013-04-01

Fluorine-18-fluorodeoxyglucose-positron emission tomography ({sup 18}F-FDG-PET)–guided focal dose escalation in oropharyngeal cancer may potentially improve local control. We evaluated the feasibility of this approach using volumetric-modulated arc therapy (RapidArc) and compared these plans with fixed-field intensity-modulated radiotherapy (IMRT) focal dose escalation plans. Materials and methods: An initial study of 20 patients compared RapidArc with fixed-field IMRT using standard dose prescriptions. From this cohort, 10 were included in a dose escalation planning study. Dose escalation was applied to {sup 18}F-FDG-PET–positive regions in the primary tumor at dose levels of 5% (DL1), 10% (DL2), and 15% (DL3) above standard radical dose (65 Gymore » in 30 fractions). Fixed-field IMRT and double-arc RapidArc plans were generated for each dataset. Dose-volume histograms were used for plan evaluation and comparison. The Paddick conformity index (CI{sub Paddick}) and monitor units (MU) for each plan were recorded and compared. Both IMRT and RapidArc produced clinically acceptable plans and achieved planning objectives for target volumes. Dose conformity was significantly better in the RapidArc plans, with lower CI{sub Paddick} scores in both primary (PTV1) and elective (PTV2) planning target volumes (largest difference in PTV1 at DL3; 0.81 ± 0.03 [RapidArc] vs. 0.77 ± 0.07 [IMRT], p = 0.04). Maximum dose constraints for spinal cord and brainstem were not exceeded in both RapidArc and IMRT plans, but mean doses were higher with RapidArc (by 2.7 ± 1 Gy for spinal cord and 1.9 ± 1 Gy for brainstem). Contralateral parotid mean dose was lower with RapidArc, which was statistically significant at DL1 (29.0 vs. 29.9 Gy, p = 0.01) and DL2 (29.3 vs. 30.3 Gy, p = 0.03). MU were reduced by 39.8–49.2% with RapidArc (largest difference at DL3, 641 ± 94 vs. 1261 ± 118, p < 0.01). {sup 18}F-FDG-PET–guided focal dose escalation in oropharyngeal cancer is feasible with RapidArc. Compared with conventional fixed-field IMRT, RapidArc can achieve better dose conformity, improve contralateral parotid sparing, and uses fewer MU.« less

The impact of high-dose narrowband ultraviolet A1 on dermal thickness, collagen and matrix-metalloproteinases in animal model of scleroderma.

PubMed

Karpec, Diana; Rudys, Romualdas; Leonaviciene, Laima; Mackiewicz, Zygmunt; Bradunaite, Ruta; Kirdaite, Gailute; Venalis, Algirdas

2017-08-01

The main purpose of the present study was to define the impact of high-dose of 365±5nm ultraviolet A1 (UVA1) on dermal fibrosis in the pre-established, bleomycin-induced mouse model of scleroderma. DBA/2 strain mice with the pre-established, bleomycin-induced scleroderma were irradiated with cumulative UVA1 dose of 1200J/cm 2 and in parallel were challenged with prolonged administration of bleomycin. Non-treated groups served as the control. Light source emitting a narrow band UVA1 light of 365±5nm and 21mW/cm 2 power density was used in the study. Histological analysis was performed for the evaluation of dermal thickness. The expressions of matrix-metalloproteinase-1 (MMP-1), matrix-metalloproteinase-3 (MMP-3), collagen types I and III were evaluated by immunohistochemical analyses. The Mann - Whitney U test was used for statistical analysis. Dermal thickness in mice injected with bleomycin during all the experiment (8weeks) and irradiated with UVA1 for the last 5weeks was significantly lower than that in mice challenged only with bleomycin for 8weeks (253.96±31.83μm and 497.43±57.83μm, respectively; P=0.002). The dermal thickness after phototherapy was lower as compared with the pre-existing fibrotic changes observed after 3weeks of bleomycin injections (253.96±31.83μm and 443.87±41.76μm, respectively; P=0.002). High-dose of UVA1 induced the 5.8- and 5.2-fold increase in MMP-1 and MMP-3 expressions, respectively, and the 1.2- and 1.4-fold decrease in collagen type I and collagen type III expressions in the pre-established, bleomycin-induced scleroderma model as compared to that in the control non-irradiated mice (P=0.002). Our study has demonstrated that a cumulative 365±5nm UVA1 radiation dosage of 1200J/cm 2 not only prevents the progression of dermal fibrosis, but also induces a regression of pre-existing fibrotic changes. Copyright © 2017 Elsevier B.V. All rights reserved.

Employing a gain-of-function factor IX variant R338L to advance the efficacy and safety of hemophilia B human gene therapy: preclinical evaluation supporting an ongoing adeno-associated virus clinical trial.

PubMed

Monahan, Paul E; Sun, Junjiang; Gui, Tong; Hu, Genlin; Hannah, William B; Wichlan, David G; Wu, Zhijian; Grieger, Joshua C; Li, Chengwen; Suwanmanee, Thipparat; Stafford, Darrel W; Booth, Carmen J; Samulski, Jade J; Kafri, Tal; McPhee, Scott W J; Samulski, R Jude

2015-02-01

Vector capsid dose-dependent inflammation of transduced liver has limited the ability of adeno-associated virus (AAV) factor IX (FIX) gene therapy vectors to reliably convert severe to mild hemophilia B in human clinical trials. These trials also identified the need to understand AAV neutralizing antibodies and empty AAV capsids regarding their impact on clinical success. To address these safety concerns, we have used a scalable manufacturing process to produce GMP-grade AAV8 expressing the FIXR338L gain-of-function variant with minimal (<10%) empty capsid and have performed comprehensive dose-response, biodistribution, and safety evaluations in clinically relevant hemophilia models. The scAAV8.FIXR338L vector produced greater than 6-fold increased FIX specific activity compared with wild-type FIX and demonstrated linear dose responses from doses that produced 2-500% FIX activity, associated with dose-dependent hemostasis in a tail transection bleeding challenge. More importantly, using a bleeding model that closely mimics the clinical morbidity of hemophilic arthropathy, mice that received the scAAV8.FIXR338L vector developed minimal histopathological findings of synovitis after hemarthrosis, when compared with mice that received identical doses of wild-type FIX vector. Hemostatically normal mice (n=20) and hemophilic mice (n=88) developed no FIX antibodies after peripheral intravenous vector delivery. No CD8(+) T cell liver infiltrates were observed, despite the marked tropism of scAAV8.FIXR338L for the liver in a comprehensive biodistribution evaluation (n=60 animals). With respect to the role of empty capsids, we demonstrated that in vivo FIXR338L expression was not influenced by the presence of empty AAV particles, either in the presence or absence of various titers of AAV8-neutralizing antibodies. Necropsy of FIX(-/-) mice 8-10 months after vector delivery revealed no microvascular or macrovascular thrombosis in mice expressing FIXR338L (plasma FIX activity, 100-500%). These preclinical studies demonstrate a safety:efficacy profile supporting an ongoing phase 1/2 human clinical trial of the scAAV8.FIXR338L vector (designated BAX335).

Immunogenicity and safety of high-dose trivalent inactivated influenza vaccine compared to standard-dose vaccine in children and young adults with cancer or HIV infection.

PubMed

Hakim, Hana; Allison, Kim J; Van de Velde, Lee-Ann; Tang, Li; Sun, Yilun; Flynn, Patricia M; McCullers, Jonathan A

2016-06-08

Approaches to improve the immune response of immunocompromised patients to influenza vaccination are needed. Children and young adults (3-21 years) with cancer or HIV infection were randomized to receive 2 doses of high-dose (HD) trivalent influenza vaccine (TIV) or of standard-dose (SD) TIV. Hemagglutination inhibition (HAI) antibody titers were measured against H1, H3, and B antigens after each dose and 9 months later. Seroconversion was defined as ≥4-fold rise in HAI titer comparing pre- and post-vaccine sera. Seroprotection was defined as a post-vaccine HAI titer ≥1:40. Reactogenicity events (RE) were solicited using a structured questionnaire 7 and 14 days after each dose of vaccine, and adverse events by medical record review for 21 days after each dose of vaccine. Eighty-five participants were enrolled in the study; 27 with leukemia, 17 with solid tumor (ST), and 41 with HIV. Recipients of HD TIV had significantly greater fold increase in HAI titers to B antigen in leukemia group and to H1 antigen in ST group compared to SD TIV recipients. This increase was not documented in HIV group. There were no differences in seroconversion or seroprotection between HD TIV and SD TIV in all groups. There was no difference in the percentage of solicited RE in recipients of HD TIV (54% after dose 1 and 38% after dose 2) compared to SD TIV (40% after dose 1 and 20% after dose 2, p=0.27 and 0.09 after dose 1 and 2, respectively). HD TIV was more immunogenic than SD TIV in children and young adults with leukemia or ST, but not with HIV. HD TIV was safe and well-tolerated in children and young adults with leukemia, ST, or HIV. Copyright © 2016 Elsevier Ltd. All rights reserved.

Distinguishing dose, focus, and blur for lithography characterization and control

NASA Astrophysics Data System (ADS)

Ausschnitt, Christopher P.; Brunner, Timothy A.

2007-03-01

We derive a physical model to describe the dependence of pattern dimensions on dose, defocus and blur. The coefficients of our model are constants of a given lithographic process. Model inversion applied to dimensional measurements then determines effective dose, defocus and blur for wafers patterned with the same process. In practice, our approach entails the measurement of proximate grating targets of differing dose and focus sensitivity. In our embodiment, the measured attribute of one target is exclusively sensitive to dose, whereas the measured attributes of a second target are distinctly sensitive to defocus and blur. On step-and-scan exposure tools, z-blur is varied in a controlled manner by adjusting the across slit tilt of the image plane. The effects of z-blur and x,y-blur are shown to be equivalent. Furthermore, the exposure slit width is shown to determine the tilt response of the grating attributes. Thus, the response of the measured attributes can be characterized by a conventional focus-exposure matrix (FEM), over which the exposure tool settings are intentionally changed. The model coefficients are determined by a fit to the measured FEM response. The model then fully defines the response for wafers processed under "fixed" dose, focus and blur conditions. Model inversion applied to measurements from the same targets on all such wafers enables the simultaneous determination of effective dose and focus/tilt (DaFT) at each measurement site.

The feasibility assessment of radiation dose of movement 3D NIPAM gel by magnetic resonance imaging

NASA Astrophysics Data System (ADS)

Hsieh, Chih-Ming; Leung, Joseph Hang; Ng, Yu-Bun; Cheng, Chih-Wu; Sun, Jung-Chang; Lin, Ping-Chin; Hsieh, Bor-Tsung

2015-11-01

NIPAM dosimeter is widely accepted and recommended for its 3D distribution and accuracy in dose absorption. Up to the moment, most research works on dose measurement are based on a fixed irradiation target without the consideration of the effect from physiological motion. We present a study to construct a respiratory motion simulating patient anatomical and dosimetry model for the study of dosimetic effect of organ motion. The dose on fixed and motion targets was measured by MRI after a dose adminstration of 1, 2, 5, 8, and 10 Gy from linear accelerator. Comparison of two situations is made. The average sensitivity of fixed NIPAM was 0.1356 s-1/Gy with linearity R2=0.998. The average sensitivity of movement NIPAM was 0.1366 s-1/Gy with linearity R2=0.998 both having only 0.001 of the sensitivity difference. The difference between the two based on dose rate dependency, position and depth was not significant. There was thus no apparent impact on NIPAM dosimeter from physiological motion. The high sensitivity, linearity and stability of NIPAM dosimeter proved to be an ideal apparatus in the dose measurement in these circumstances.

Hardness, function, emotional well-being, satisfaction and the overall sexual experience in men using 100-mg fixed-dose or flexible-dose sildenafil citrate

PubMed Central

Ströberg, P; Kaminetsky, J C; Park, N C; Goldfischer, E R; Creanga, D L; Stecher, V J

2010-01-01

The prescribing information for sildenafil citrate (VIAGRA, Pfizer, New York, NY, USA) recommends flexible dosing (50 mg initially, adjusted to 100 or 25 mg based on effectiveness and tolerability) in most men with erectile dysfunction (ED). In many men, however, 100 mg may be the most appropriate initial dose because it would reduce the need for titration and could prevent discouragement and treatment abandonment should 50 mg be insufficient. Results of two previously published double-blind, placebo-controlled sildenafil trials of similar design except for a fixed-dose vs flexible-dose regimen were analyzed. Relative to the flexible-dose, approximately one-third more men were satisfied with an initial and fixed dose of 100 mg. In addition, tolerability was similar, and improvements from baseline in outcomes on validated, ED-specific, patient-reported questionnaires were either similar (erectile function and the percentage of completely hard and fully rigid erections) or greater (emotional well-being and the overall sexual experience). The similarity in outcomes is not surprising given that almost 90% of the men in the flexible-dose trial titrated to 100 mg after 2 weeks. These data suggest prescription of an initial dose of 100 mg for men with ED, except in those for whom it is inappropriate. PMID:20596083

Co-extrusion as a processing technique to manufacture a dual sustained release fixed-dose combination product.

PubMed

Vynckier, An-Katrien; Voorspoels, Jody; Remon, Jean Paul; Vervaet, Chris

2016-05-01

This study aimed to design a fixed-dose combination dosage form which provides a sustained release profile for both the freely water-soluble metformin HCl and the poorly soluble gliclazide, two antidiabetic compounds used to treat diabetes mellitus. Hot-melt co-extrusion was used as an innovative manufacturing technique for a pharmaceutical fixed-dose combination product. In this way, a matrix formulation that sustained metformin release could be developed, despite the high drug load in the formulation and the freely soluble nature of the drug. It was clear that co-extrusion was perfectly suited to produce a fixed-dose combination product with adequate properties for each of the incorporated APIs. A coat layer, containing at least 30% CAPA(®) 6506 as a hydrophobic polymer, was necessary to adequately sustain the release of the highly dosed freely soluble drug from the 70% metformin HCl-loaded CAPA(®) 6506 core of the co-extrudate. To obtain a complete gliclazide release over 24-h solubilization in Kollidon(®) VA, added as a second polymer to the CAPA(®) 6506 in the coat, was needed. Both active pharmaceutical ingredients (APIs), which have different physicochemical characteristics, were formulated in a single dosage form, using co-extrusion. © 2016 Royal Pharmaceutical Society, Journal of Pharmacy and Pharmacology.

TH-E-BRF-04: Characterizing the Response of Texture-Based CT Image Features for Quantification of Radiation-Induced Normal Lung Damage

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

Krafft, S; Court, L; Briere, T

2014-06-15

Purpose: Radiation induced lung damage (RILD) is an important dose-limiting toxicity for patients treated with radiation therapy. Scoring systems for RILD are subjective and limit our ability to find robust predictors of toxicity. We investigate the dose and time-related response for texture-based lung CT image features that serve as potential quantitative measures of RILD. Methods: Pre- and post-RT diagnostic imaging studies were collected for retrospective analysis of 21 patients treated with photon or proton radiotherapy for NSCLC. Total lung and selected isodose contours (0–5, 5–15, 15–25Gy, etc.) were deformably registered from the treatment planning scan to the pre-RT and availablemore » follow-up CT studies for each patient. A CT image analysis framework was utilized to extract 3698 unique texture-based features (including co-occurrence and run length matrices) for each region of interest defined by the isodose contours and the total lung volume. Linear mixed models were fit to determine the relationship between feature change (relative to pre-RT), planned dose and time post-RT. Results: Seventy-three follow-up CT scans from 21 patients (median: 3 scans/patient) were analyzed to describe CT image feature change. At the p=0.05 level, dose affected feature change in 2706 (73.1%) of the available features. Similarly, time affected feature change in 408 (11.0%) of the available features. Both dose and time were significant predictors of feature change in a total of 231 (6.2%) of the extracted image features. Conclusion: Characterizing the dose and time-related response of a large number of texture-based CT image features is the first step toward identifying objective measures of lung toxicity necessary for assessment and prediction of RILD. There is evidence that numerous features are sensitive to both the radiation dose and time after RT. Beyond characterizing feature response, further investigation is warranted to determine the utility of these features as surrogates of clinically significant lung injury.« less

Low, fixed dose defibrotide in management of hepatic veno-occlusive disease post stem cell transplantation.

PubMed

Bagal, Bhausaheb; Chandrasekharan, Arun; Chougle, Aliya; Khattry, Navin

2018-03-01

Hepatic veno-occlusive disease (VOD) is well recognized potentially serious regimen-related toxicity seen after stem cell transplantation. Severe VOD is associated with poor long-term outcomes with very high mortality. Besides supportive care, only defibrotide has been found to be effective in the management of VOD. The recommended dose of defibrotide is 25mg/kg/d but there has been no classical dose finding study done for this drug. A higher dose of defibrotide is associated with increased risk of bleeding and this drug is prohibitively expensive. We report our experience of using fixed low dose of defibrotide in patients with VOD. We retrospectively evaluated 511 patients who underwent stem cell transplant at our center from November 2007 and December 2015. All patients received ursodeoxycholic acid as VOD prophylaxis. Modified Seattle criterion was used for diagnosis and severity grading of VOD. Patients developing VOD were initially treated with furosemide and adequate analgesia. Defibrotide was started within 12 to 24 hours of diagnosis of VOD. All adult patients received defibrotide at a fixed dose of 200mg twice daily while two children were given dose of 100mg and 50mg twice daily. Nine (1.7%) of our patients developed VOD. Daily dose of defibrotide ranged from 5mg/kg/d to 20mg/kg/d till resolution of VOD. All patients had complete resolution of VOD. None of our patients required ventilator support or dialysis. No episodes of bleeding were observed. No dose response relationship was observed between defibrotide dose and time to resolution of VOD. Low fixed dose defibrotide initiated early seems to be effective and safe in treatment of VOD. This is relevant in a resource limited setting and warrants prospective evaluation. Copyright © 2017 King Faisal Specialist Hospital & Research Centre. Published by Elsevier B.V. All rights reserved.

Prospective ECG-Triggered Coronary CT Angiography: Clinical Value of Noise-Based Tube Current Reduction Method with Iterative Reconstruction

PubMed Central

Shen, Junlin; Du, Xiangying; Guo, Daode; Cao, Lizhen; Gao, Yan; Yang, Qi; Li, Pengyu; Liu, Jiabin; Li, Kuncheng

2013-01-01

Objectives To evaluate the clinical value of noise-based tube current reduction method with iterative reconstruction for obtaining consistent image quality with dose optimization in prospective electrocardiogram (ECG)-triggered coronary CT angiography (CCTA). Materials and Methods We performed a prospective randomized study evaluating 338 patients undergoing CCTA with prospective ECG-triggering. Patients were randomly assigned to fixed tube current with filtered back projection (Group 1, n = 113), noise-based tube current with filtered back projection (Group 2, n = 109) or with iterative reconstruction (Group 3, n = 116). Tube voltage was fixed at 120 kV. Qualitative image quality was rated on a 5-point scale (1 = impaired, to 5 = excellent, with 3–5 defined as diagnostic). Image noise and signal intensity were measured; signal-to-noise ratio was calculated; radiation dose parameters were recorded. Statistical analyses included one-way analysis of variance, chi-square test, Kruskal-Wallis test and multivariable linear regression. Results Image noise was maintained at the target value of 35HU with small interquartile range for Group 2 (35.00–35.03HU) and Group 3 (34.99–35.02HU), while from 28.73 to 37.87HU for Group 1. All images in the three groups were acceptable for diagnosis. A relative 20% and 51% reduction in effective dose for Group 2 (2.9 mSv) and Group 3 (1.8 mSv) were achieved compared with Group 1 (3.7 mSv). After adjustment for scan characteristics, iterative reconstruction was associated with 26% reduction in effective dose. Conclusion Noise-based tube current reduction method with iterative reconstruction maintains image noise precisely at the desired level and achieves consistent image quality. Meanwhile, effective dose can be reduced by more than 50%. PMID:23741444

Innovative public-private partnerships to maximize the delivery of anti-malarial medicines: lessons learned from the ASAQ Winthrop experience

PubMed Central

2011-01-01

Background This case study describes how a public-private partnership initiated to develop a new anti-malarial combination, ASAQ Winthrop, has evolved over time to address issues posed by its effective deployment in the field. Case description In 2002, DNDi created the FACT project to develop two fixed-dose combinations, artesunate-amodiaquine and artesunate-mefloquine, to meet the WHO anti-malarial treatment recommendations and international regulatory agencies approval standards. In 2002, Sanofi-aventis had started a development programme for a fixed-dose combination of artesunate and amodiaquine, to replace its co-blister combination. DNDi and sanofi-aventis joined forces in 2004, with the objective of developing within the shortest possible time frame a non-patented, affordable and easy to use fixed-dose combination of artesunate and amodiaquine adapted to the needs of patients, in particular, those of children. The partners developed Coarsucam®/Artesunate Amodiaquine Winthrop® ("ASAQ Winthrop") which was prequalified by the WHO in 2008. Additional partnerships have since been established by DNDi and sanofi-aventis to ensure: 1) the adoption of this new medicine by malaria-endemic countries, 2) its appropriate usage through a broad range of information tools, and 3) the monitoring of its safety and efficacy in the field through an innovative Risk Management Plan. Discussion and evaluation The partnership between DNDi and sanofi-aventis has enabled the development and pre-qualification of ASAQ Winthrop in a short timeframe. As a result of the multiple collaborations established by the two partners, as of late 2010, ASAQ Winthrop was registered in 30 sub-Saharan African countries and in India, with over 80 million treatments distributed in 21 countries. To date, 10 clinical studies, involving 3432 patients with ASAQ Winthrop were completed to document efficacy and safety issues identified in the Risk Management Plan. Conclusions The speed at which ASAQ Winthrop was adopted in the field shows that this drug fits the needs of patients and health authorities. It also demonstrates the power of partnerships that combine different sets of strengths and skills, and that evolve to include additional actors to meet new global health challenges for poverty-related diseases. PMID:21605364

Innovative public-private partnerships to maximize the delivery of anti-malarial medicines: lessons learned from the ASAQ Winthrop experience.

PubMed

Bompart, François; Kiechel, Jean-René; Sebbag, Robert; Pecoul, Bernard

2011-05-23

This case study describes how a public-private partnership initiated to develop a new anti-malarial combination, ASAQ Winthrop, has evolved over time to address issues posed by its effective deployment in the field. In 2002, DNDi created the FACT project to develop two fixed-dose combinations, artesunate-amodiaquine and artesunate-mefloquine, to meet the WHO anti-malarial treatment recommendations and international regulatory agencies approval standards. In 2002, Sanofi-Aventis had started a development programme for a fixed-dose combination of artesunate and amodiaquine, to replace its co-blister combination. DNDi and Sanofi-Aventis joined forces in 2004, with the objective of developing within the shortest possible time frame a non-patented, affordable and easy to use fixed-dose combination of artesunate and amodiaquine adapted to the needs of patients, in particular, those of children. The partners developed Coarsucam®/Artesunate Amodiaquine Winthrop® ("ASAQ Winthrop") which was prequalified by the WHO in 2008. Additional partnerships have since been established by DNDi and Sanofi-Aventis to ensure: 1) the adoption of this new medicine by malaria-endemic countries, 2) its appropriate usage through a broad range of information tools, and 3) the monitoring of its safety and efficacy in the field through an innovative Risk Management Plan. The partnership between DNDi and Sanofi-Aventis has enabled the development and pre-qualification of ASAQ Winthrop in a short timeframe. As a result of the multiple collaborations established by the two partners, as of late 2010, ASAQ Winthrop was registered in 30 sub-Saharan African countries and in India, with over 80 million treatments distributed in 21 countries. To date, 10 clinical studies, involving 3432 patients with ASAQ Winthrop were completed to document efficacy and safety issues identified in the Risk Management Plan. The speed at which ASAQ Winthrop was adopted in the field shows that this drug fits the needs of patients and health authorities. It also demonstrates the power of partnerships that combine different sets of strengths and skills, and that evolve to include additional actors to meet new global health challenges for poverty-related diseases.

Neuroendocrine and sympathetic responses to an orexin receptor antagonist, SB-649868, and alprazolam following insulin-induced hypoglycemia in humans.

PubMed

Patel, Ameera X; Miller, Sam R; Nathan, Pradeep J; Kanakaraj, Ponmani; Napolitano, Antonella; Lawrence, Philip; Koch, Annelize; Bullmore, Edward T

2014-10-01

The orexin-hypocretin system is important for translating peripheral metabolic signals and central neuronal inputs to a diverse range of behaviors, from feeding, motivation and arousal, to sleep and wakefulness. Orexin signaling is thus an exciting potential therapeutic target for disorders of sleep, feeding, addiction, and stress. Here, we investigated the low dose pharmacology of orexin receptor antagonist, SB-649868, on neuroendocrine, sympathetic nervous system, and behavioral responses to insulin-induced hypoglycemic stress, in 24 healthy male subjects (aged 18-45 years; BMI 19.0-25.9 kg/m(2)), using a randomized, double-blind, placebo-controlled, within-subject crossover design. Alprazolam, a licensed benzodiazepine anxiolytic, was used as a positive comparator, as it has previously been validated using the insulin tolerance test (ITT) model in humans. Of the primary endpoints, ITT induced defined increases in pulse rate, plasma cortisol, and adrenocorticotropic hormone in the placebo condition, but these responses were not significantly impacted by alprazolam or SB-649868 pre-treatment. Of the secondary endpoints, ITT induced a defined increase in plasma concentrations of adrenaline, noradrenaline, growth hormone (GH), and prolactin in the placebo condition. Alprazolam pre-treatment significantly reduced the GH response to ITT (p < 0.003), the peak electromyography (p < 0.0001) and galvanic skin response (GSR, p = 0.04) to acoustic startle, the resting GSR (p = 0.01), and increased appetite following ITT (p < 0.0005). SB-649868 pre-treatment produced no significant results. We concluded that the ITT model may be informative for assessing the effects of drugs directly acting on the neuroendocrine or sympathetic nervous systems, but could not be validated for studying low dose orexin antagonist activity.

Successful transduction of liver in hemophilia by AAV-Factor IX and limitations imposed by the host immune response.

PubMed

Manno, Catherine S; Pierce, Glenn F; Arruda, Valder R; Glader, Bertil; Ragni, Margaret; Rasko, John J; Rasko, John; Ozelo, Margareth C; Hoots, Keith; Blatt, Philip; Konkle, Barbara; Dake, Michael; Kaye, Robin; Razavi, Mahmood; Zajko, Albert; Zehnder, James; Rustagi, Pradip K; Nakai, Hiroyuki; Chew, Amy; Leonard, Debra; Wright, J Fraser; Lessard, Ruth R; Sommer, Jürg M; Tigges, Michael; Sabatino, Denise; Luk, Alvin; Jiang, Haiyan; Mingozzi, Federico; Couto, Linda; Ertl, Hildegund C; High, Katherine A; Kay, Mark A

2006-03-01

We have previously shown that a single portal vein infusion of a recombinant adeno-associated viral vector (rAAV) expressing canine Factor IX (F.IX) resulted in long-term expression of therapeutic levels of F.IX in dogs with severe hemophilia B. We carried out a phase 1/2 dose-escalation clinical study to extend this approach to humans with severe hemophilia B. rAAV-2 vector expressing human F.IX was infused through the hepatic artery into seven subjects. The data show that: (i) vector infusion at doses up to 2 x 10(12) vg/kg was not associated with acute or long-lasting toxicity; (ii) therapeutic levels of F.IX were achieved at the highest dose tested; (iii) duration of expression at therapeutic levels was limited to a period of approximately 8 weeks; (iv) a gradual decline in F.IX was accompanied by a transient asymptomatic elevation of liver transaminases that resolved without treatment. Further studies suggested that destruction of transduced hepatocytes by cell-mediated immunity targeting antigens of the AAV capsid caused both the decline in F.IX and the transient transaminitis. We conclude that rAAV-2 vectors can transduce human hepatocytes in vivo to result in therapeutically relevant levels of F.IX, but that future studies in humans may require immunomodulation to achieve long-term expression.

Autonomous functioning thyroid nodules and 131I in diagnosis and therapy after 50 years of experience: what is still open to debate?

PubMed

Ronga, Giuseppe; Filesi, Mauro; D'Apollo, Rosaria; Toteda, Maria; Di Nicola, Angelo Domenico; Colandrea, Marzia; Travascio, Laura; Vestri, Anna Rita; Montesano, Teresa

2013-05-01

Autonomous functioning thyroid nodules (AFTN), defined as "hot nodules" at thyroid scan, are often cured by radioiodine treatment. The aim of our study was to investigate the long-term outcome in patients treated with an 131I calculated dose, to identify a possible "size-tailored" dose, and to simplify follow-up procedures. Retrospective analysis was carried out on 1402 cases, covering a period of 50 years, of AFTN treated with an 131I calculated dose. Our study focused on nodular size and mean administered dose. Concordance between thyroid scan and serum TSH levels at 3-6 months from treatment was considered. A single 131I dose was effective for the vast majority of patients (93%). The outcome was influenced by nodular size. On the basis of the Italian dose limit for outpatient treatment, our population was divided into subgroups according to administered doses (more or less than 16 mCi) and nodular dimensions: no differences in outcome were observed for each class of nodule size. A dose ≤10 mCi was effective on the smaller nodules (50.1% of our population). The agreement between TSH and scan after treatment was 90.3% at 3 months and 94.5% at 6 months. 131I therapy with a calculated dose is an effective treatment of AFTN. If a fixed dose is chosen, 16 mCi is often resolutive and for nodules <3 cm a dose of 10 mCi can suffice. Nodules >5 cm are eligible for surgery. TSH is the only parameter required to evaluate the outcome.

Comparison of evening and morning dosing of travoprost 0.004%/timolol 0.5% fixed combination in 6 month period.

PubMed

Suić, Smiljka Popović; Laus, Katia Novak; Dosen, Vukosava Maricic; Ekert, Miroslav; Mandić, Zdravko; Bojić, Lovro

2010-09-01

An open label, multi-center, 6 months observational study of new fixed combination (travoprost 0.004%/timolol 0.5%), in order to evaluate both efficacy (intraocular pressure lowering) and tolerability (patient and investigator satisfaction) of two dosing regimens--evening (PM) and morning (AM). After screening for enrollment, to 40 patients (79 eyes with primary open angle glaucoma or ocular hypertension), new fixed combination travoprost 0.004%/timolol 0.5% was prescribed once a day in the evening (PM). Patients were enrolled according to each investigator decision on indication for travoprost 0.004%/timolol 0.5% fixed combination once a day, without washout period after previous medication. Intraocular pressure was measured at 9 AM at all time control points: at baseline, after 1 month, after 3 months and after 6 month. After 1 month, screening for nonresponders (criteria: 20% intraocular pressure lowering) and subjects with major side effects was performed. At second control visit, after 3 months PM dosing, intraocular pressure was measured and patients were instructed to continue once a day the same medication, but in the morning (AM) for consequent 3 months. After 1 month, reduction in mean intraocular pressure value was 21.66%. At the visit after 3 month, the mean intraocular pressure was 15.67 +/- 2.17 mm Hg (reduction 21.14%). 3 month after dosing regimen changed to AM (6 month after beginning of travoprost 0.004%/timolol 0.5% combination therapy), reduction in intraocular pressure value was 19.86%. The differences (mean +/- standard deviation) in intraocular pressure values after 1, 3 and 6 month were all highly statistically significant compared to baseline values. The tolerability was evaluated in five steps (Likert scale) ranging from unsatisfactory to excellent by both patient and investigator--taken at 3 and 6 month control visit. 95% of patients and 100% of investigators were satisfied with the possibility of choosing dosing regimen for travoprost 0.004%/timolol 0.5% fixed combination. Travoprost 0.004%/timolol 0.5% fixed combination proved sufficient intraocular pressure control dosed either PM or AM with no statistically significant difference between two dosing regimens. Possibility to choose between two dosing regimens gives each practitioner additional reassurance that glaucoma therapy will be individualised to needs of each patient.

Three dimensional image correlation of CT, MR, and PET studies in radiotherapy treatment planning of brain tumors.

PubMed

Schad, L R; Boesecke, R; Schlegel, W; Hartmann, G H; Sturm, V; Strauss, L G; Lorenz, W J

1987-01-01

A treatment planning system for stereotactic convergent beam irradiation of deeply localized brain tumors is reported. The treatment technique consists of several moving field irradiations in noncoplanar planes at a linear accelerator facility. Using collimated narrow beams, a high concentration of dose within small volumes with a dose gradient of 10-15%/mm was obtained. The dose calculation was based on geometrical information of multiplanar CT or magnetic resonance (MR) imaging data. The patient's head was fixed in a stereotactic localization system, which is usable at CT, MR, and positron emission tomography (PET) installations. Special computer programs for correction of the geometrical MR distortions allowed a precise correlation of the different imaging modalities. The therapist can use combinations of CT, MR, and PET data for defining target volume. For instance, the superior soft tissue contrast of MR coupled with the metabolic features of PET may be a useful addition in the radiation treatment planning process. Furthermore, other features such as calculated dose distribution to critical structures can also be transferred from one set of imaging data to another and can be displayed as three-dimensional shaded structures.

Signal-to-noise ratio and dose to the lens of the eye for computed tomography examination of the brain using an automatic tube current modulation system.

PubMed

Sookpeng, Supawitoo; Butdee, Chitsanupong

2017-06-01

The study aimed to evaluate the image quality in terms of signal-to-noise ratio (SNR) and dose to the lens of the eye and the other nearby organs from the CT brain scan using an automatic tube current modulation (ATCM) system with or without CT gantry tilt is needed. An anthropomorphic phantom was scanned with different settings including use of different ATCM, fixed tube current time product (mAs) settings and degree angles of gantry tilt. Gafchromic film XR-QA2 was used to measure absorbed dose of the organs. Relative doses and SNR for the various scan settings were compared with the reference setting of the fixed 330 mAs. Average absorbed dose for the lens of the eyes varied from 8.7 to 21.7 mGy. The use of the ATCM system with the gantry tilt resulted in up to 60% decrease in the dose to the lens of the eye. SNR significantly decreased while tilting the gantry using the fixed mAs techniques, compared to that of the reference setting. However, there were no statistical significant differences for SNRs between the reference setting and all ATCM settings. Compared to the reference setting of the fixed effective mAs, using the ATCM system and appropriate tilting, the gantry resulted in a substantial decrease in the dose to the lens of the eye while preserving signal-to-noise ratio. CT brain examination should be carefully controlled to optimize dose for lens of the eye and image quality of the examination.

Efficacy of budesonide/formoterol maintenance and reliever therapy compared with higher-dose budesonide as step-up from low-dose inhaled corticosteroid treatment.

PubMed

Jenkins, Christine R; Eriksson, Göran; Bateman, Eric D; Reddel, Helen K; Sears, Malcolm R; Lindberg, Magnus; O'Byrne, Paul M

2017-04-20

Asthma management may involve a step up in treatment when symptoms are not well controlled. We examined whether budesonide/formoterol maintenance and reliever therapy (MRT) is as effective as higher, fixed-dose budesonide plus as-needed terbutaline in patients requiring step-up from Step 2 treatment (low-dose inhaled corticosteroids), stratified by baseline reliever use. A post-hoc analysis utilized data from three clinical trials of 6-12 months' duration. Patients aged ≥12 years with symptomatic asthma uncontrolled despite Step 2 treatment were included. Severe exacerbation rate, lung function and reliever use were analysed, stratified by baseline reliever use (<1, 1-2 and >2 occasions/day). Overall, 1239 patients were included. Reductions in severe exacerbation rate with budesonide/formoterol MRT versus fixed-dose budesonide were similar across baseline reliever use levels, and were statistically significant in patients using 1-2 (42%, p = 0.01) and >2 (39%, p = 0.02) reliever occasions/day, but not <1 reliever occasion/day (35%, p = 0.11). Both treatments significantly increased mean FEV 1 from baseline; improvements were significantly greater for budesonide/formoterol MRT in all reliever use groups. Reductions in reliever use from baseline were significantly greater with budesonide/formoterol MRT versus fixed-dose budesonide in patients using 1-2 and >2 reliever occasions/day (-0.33 and -0.74 occasions/day, respectively). Treatment benefit with budesonide/formoterol MRT versus higher, fixed-dose budesonide plus short-acting β 2 -agonist was found in Step 2 patients with relatively low reliever use, supporting the proposal that budesonide/formoterol MRT may be useful when asthma is uncontrolled with low-dose inhaled corticosteroid.

Comparison of adherence to generic multi-tablet regimens vs. brand multi-tablet and brand single-tablet regimens likely to incorporate generic antiretroviral drugs by breaking or not fixed-dose combinations in HIV-infected patients.

PubMed

Rwagitinywa, Joseph; Lapeyre-Mestre, Maryse; Bourrel, Robert; Montastruc, Jean-Louis; Sommet, Agnès

2018-03-05

Adherence to antiretroviral (ARV) is crucial to achieve viral load suppression in HIV-infected patients. This study aimed to compare adherence to generic multi-tablet regimens (MTR) vs. brand MTR likely to incorporate ARV drugs without breaking fixed-dose combinations (FDC) and brand single-tablet regimens (STR) likely to incorporate generics by breaking the FDC. Patients aged of 18 years or over exposed to one of the generic or the brand of lamivudine (3TC), zidovudine/lamivudine (AZT/TC), nevirapine (NVP), or efavirenz (EFV), or the brand STR of efavirenz/emtricitabine/tenofovir (EFV/FTC/TDF). Adherence was measured by medication possession ratio (MPR) using both defined daily dose (DDD) and daily number of tablet recommended for adults (DNT). Adherence to generic MTR vs. brand MTR and brand STR was compared using Kruskal-Wallis. The overall median adherence was 0.97 (IQR 0.13) by DNT method and 0.97 (0.14) by DDD method. Adherence in patients exposed to generic MTR (n = 165) vs. brand MTR (n = 481) and brand STR (n = 470) was comparable by DNT and DDD methods. In conclusion, adherence to generic MTR was high and comparable with adherence to brand MTR and to STR. Utilization of DDD instead DNT to measure the MPR led to small but nonsignificant difference that has no clinical impact. © 2018 Société Française de Pharmacologie et de Thérapeutique.

Comparison of the safety and efficacy of a fixed-dose combination regimen and separate formulations for pulmonary tuberculosis treatment.

PubMed

Wu, Jiun-Ting; Chiu, Chien-Tung; Wei, Yu-Feng; Lai, Yung-Fa

2015-06-01

Fixed-dose combination formulations, which simplify the administration of drugs and prevent the development of drug resistance, have been recommended as a standard anti-tuberculosis treatment regimen. However, the composition and dosage recommendations for fixed-dose combination formulations differ from those for separate formulations. Thus, questions about the effectiveness and side effects of combination formulations remain. The aim of this study was to compare the safety and efficacy of these two types of anti-tuberculosis regimens for pulmonary tuberculosis treatment. A prospective, randomized controlled study was conducted using the directly observed treatment short-course strategy. Patients were randomly allocated to one of two short-course regimens. One year after completing the treatment, these patients' outcomes were analyzed. ClinicalTrials.gov: NCT00979290. A total of 161 patients were enrolled, 142 of whom were evaluable for safety assessment. The two regimens had a similar incidence of adverse effects. In the per-protocol population, serum bilirubin concentrations at the peak level, at week 4, and at week 8 were significantly higher for the fixed-dose combination formulation than for the separate formulations. All patients had negative sputum cultures at the end of the treatment, and no relapse occurred after one year of follow-up. In this randomized study, transient higher serum bilirubin levels were noted for the fixed-dose combination regimen compared with the separate formulations during treatment. However, no significant difference in safety or efficacy was found between the groups when the directly observed treatment short-course strategy was used.

Do fixed-dose combination pills or unit-of-use packaging improve adherence? A systematic review.

PubMed Central

Connor, Jennie; Rafter, Natasha; Rodgers, Anthony

2004-01-01

Adequate adherence to medication regimens is central to the successful treatment of communicable and noncommunicable disease. Fixed-dose combination pills and unit-of-use packaging are therapy-related interventions that are designed to simplify medication regimens and so potentially improve adherence. We conducted a systematic review of relevant randomized trials in order to quantify the effects of fixed-dose combination pills and unit-of-use packaging, compared with medications as usually presented, in terms of adherence to treatment and improved outcomes. Only 15 trials met the inclusion criteria; fixed-dose combination pills were investigated in three of these, while unit-of-use packaging was studied in 12 trials. The trials involved treatments for communicable diseases (n = 5), blood pressure lowering medications (n = 3), diabetic patients (n = 1), vitamin supplementation (n = 1) and management of multiple medications by the elderly (n = 5). The results of the trials suggested that there were trends towards improved adherence and/or clinical outcomes in all but three of the trials; this reached statistical significance in four out of seven trials reporting a clinically relevant or intermediate end-point, and in seven out of thirteen trials reporting medication adherence. Measures of outcome were, however, heterogeneous, and interpretation was further limited by methodological issues, particularly small sample size, short duration and loss to follow-up. Overall, the evidence suggests that fixed-dose combination pills and unit-of-use packaging are likely to improve adherence in a range of settings, but the limitations of the available evidence means that uncertainty remains about the size of these benefits. PMID:15654408

Low cost industrial production of coagulation factor IX bioencapsulated in lettuce cells for oral tolerance induction in hemophilia B

PubMed Central

Su, Jin; Zhu, Liqing; Sherman, Alexandra; Wang, Xiaomei; Lin, Shina; Kamesh, Aditya; Norikane, Joey H.; Streatfield, Stephen J.; Herzog, Roland W.; Daniell, Henry

2015-01-01

Antibodies (inhibitors) developed by hemophilia B patients against coagulation factor IX (FIX) are challenging to eliminate because of anaphylaxis or nephrotic syndrome after continued infusion. To address this urgent unmet medical need, FIX fused with a transmucosal carrier (CTB) was produced in a commercial lettuce (Simpson Elite) cultivar using species specific chloroplast vectors regulated by endogenous psbA sequences. CTB-FIX (~1mg/g) in lyophilized cells was stable with proper folding, disulfide bonds and pentamer assembly when stored ~2 years at ambient temperature. Feeding lettuce cells to hemophilia B mice delivered CTB-FIX efficiently to the gut immune system, induced LAP+ regulatory T cells and suppressed inhibitor/IgE formation and anaphylaxis against FIX. Lyophilized cells enabled 10-fold dose escalation studies and successful induction of oral tolerance was observed in all tested doses. Induction of tolerance in such a broad dose range should enable oral delivery to patients of different age groups and diverse genetic background. Using Fraunhofer cGMP hydroponic system, ~870 kg fresh or 43.5 kg dry weight can be harvested per 1000 ft2 per annum yielding 24,000–36,000 doses for 20-kg pediatric patients, enabling first commercial development of an oral drug, addressing prohibitively expensive purification, cold storage/transportation and short shelf life of current protein drugs. PMID:26302233

Symptom-Triggered vs. Fixed-Dosing Management of Alcohol Withdrawal Syndrome.

PubMed

Skinner, Reagan T

2014-01-01

A literature review was conducted with the objective of creating evidence-based recommendations for use of symptom-triggered therapy (STT) or fixed-schedule dosing in treating alcohol withdrawal syndrome in inpatients. Use of STT reduced duration of therapy as well as the number of patients requiring treatment or medication, potentially reducing costs and risk of adverse medication reactions.

Metronidazole stewardship initiative at Christchurch hospitals-achievable with immediate benefits.

PubMed

Gardiner, Sharon J; Metcalf, Sarah Cl; Chin, Paul Kl; Doogue, Matthew P; Dalton, Simon C; Chambers, Stephen T

2018-04-13

To evaluate an antimicrobial stewardship (AMS) initiative to change hospital prescribing practice for metronidazole. In October 2015, the Canterbury District Health Board (CDHB) AMS committee changed advice for metronidazole to promote two times daily dosing for most indications, prioritisation of the oral route and avoidance of double anaerobic cover. Adoption of the initiative was facilitated via change in prescribing guidelines, education and ongoing pharmacy support. Usage and expenditure on metronidazole for adult inpatients were compared for the five years pre- and two years post-change. Other district health boards (DHBs) were surveyed to determine their dosing recommendation for metronidazole IV. Mean annual metronidazole IV use, as defined daily doses per 1,000 occupied bed days, decreased by 43% post-initiative. Use of non-IV (oral or rectal) formulations increased by 104%. Total savings associated with the initiative were approximately $33,400 in drug costs plus $78,200 per annum in IV giving sets and post-dose flushes. Twelve of 20 (60%) DHBs (including CDHB) endorse twice daily IV dosing. In addition to financial savings, reduction in IV doses has potential benefits, including avoidance of IV catheter-associated complications such as bloodstream infections. Approaches to metronidazole dosing vary across DHBs and could benefit from national coordination.

Out of field dose during Gamma Knife treatment: a paediatric case study

NASA Astrophysics Data System (ADS)

Moutrie, V.; Grace, M.; Izard, M. A.; Fuller, J. W.

2017-01-01

An 11-year-old girl with an arteriovenous malformation (AVM) was referred for Gamma Knife treatment. As this would be the first paediatric treatment in Australia, additional investigations were undertaken into out of field dose to assure the best possible long term outcome for the patient. A phantom was constructed from water equivalent materials to simulate the patient. A target volume was defined to emulate the size and location of the AVM visible in diagnostic images. An ionisation chamber and EBT3 Gafchromic film were used to record absorbed dose at strategic points both on the surface and at depth within the phantom. On the day of treatment, EBT3 Gafchromic film was used to conduct in vivo dosimetry. The pre-treatment phantom measurements matched the planning system for the cranial section (the only modelled section) and no measurable dose above background was detected in the extracranial sites. In vivo measurements of the lenses returned doses of up to 2 cGy for imaging and 8 cGy for treatment which was also consistent with the planned dose. Dose to the thyroid, chest and abdomen was not measurable above background.

Immunogenicity of a low-dose diphtheria, tetanus and acellular pertussis combination vaccine with either inactivated or oral polio vaccine compared to standard-dose diphtheria, tetanus, acellular pertussis when used as a pre-school booster in UK children: A 5-year follow-up of a randomised controlled study.

PubMed

John, T; Voysey, M; Yu, L M; McCarthy, N; Baudin, M; Richard, P; Fiquet, A; Kitchin, N; Pollard, A J

2015-08-26

This serological follow up study assessed the kinetics of antibody response in children who previously participated in a single centre, open-label, randomised controlled trial of low-dose compared to standard-dose diphtheria booster preschool vaccinations in the United Kingdom (UK). Children had previously been randomised to receive one of three combination vaccines: either a combined adsorbed tetanus, low-dose diphtheria, 5-component acellular pertussis and inactivated polio vaccine (IPV) (Tdap-IPV, Repevax(®); Sanofi Pasteur MSD); a combined adsorbed tetanus, low-dose diphtheria and 5-component acellular pertussis vaccine (Tdap, Covaxis(®); Sanofi Pasteur MSD) given concomitantly with oral polio vaccine (OPV); or a combined adsorbed standard-dose diphtheria, tetanus, 2-component acellular pertussis and IPV (DTap-IPV, Tetravac(®); Sanofi Pasteur MSD). Blood samples for the follow-up study were taken at 1, 3 and 5 years after participation in the original trial (median, 5.07 years of age at year 1), and antibody persistence to each vaccine antigen measured against defined serological thresholds of protection. All participants had evidence of immunity to diphtheria with antitoxin concentrations greater than 0.01IU/mL five years after booster vaccination and 75%, 67% and 79% of children who received Tdap-IPV, Tdap+OPV and DTap-IPV, respectively, had protective antitoxin levels greater than 0.1IU/mL. Long lasting protective immune responses to tetanus and polio antigens were also observed in all groups, though polio responses were lower in the sera of those who received OPV. Low-dose diphtheria vaccines provided comparable protection to the standard-dose vaccine and are suitable for use for pre-school booster vaccination. Copyright © 2015 The Authors. Published by Elsevier Ltd.. All rights reserved.

Prospective validation of a novel IV busulfan fixed dosing for paediatric patients to improve therapeutic AUC targeting without drug monitoring.

PubMed

Vassal, G; Michel, G; Espérou, H; Gentet, J C; Valteau-Couanet, D; Doz, F; Mechinaud, F; Galambrun, C; Neven, B; Zouabi, H; Nguyen, L; Puozzo, C

2008-01-01

Oral busulfan clearance is age-dependent and children experience a wide variability in plasma exposure. BSA- or age-based dosing is used with therapeutic drug monitoring (TDM) to reduce this variability. A new intravenous (IV) dosing of busulfan (Bu) based on body weight, designed to improve AUC targeting without TDM and dose-adjustment, was prospectively evaluated. Bu was administered as a 2 h IV infusion every 6 h over 4 days (16 administrations). Five dose levels were defined on body weight as follows: 1.0 mg/kg for <9 kg; 1.2 mg/kg for 9 to <16 kg; 1.1 mg/kg for 16-23 kg; 0.95 mg/kg for >23-34 kg; 0.80 mg/kg for >34 kg. Bu treatment was followed by Cyclophosphamide or Melphalan prior to allogeneic or autologous transplantation in 55 children aged 0.3-17.2 years (median 5.6 years). No difference in AUC values was observed between weight strata (mean +/- SD 1248 +/- 205 micromol.min), whereas a significant difference in Bu clearance was demonstrated. This new dosing enabled to achieve a mean exposure comparable to that in adults. At dose 1, 91% of patients achieved the targeted AUC range (900-1500 micromol.min) while no patients were underexposed. At doses 9 and 13, over 75% of patients remained within that target whilst most of the others were slightly above. Successful engraftment was achieved in all patients. In conclusion, from infants to adults this new dosing enabled, without TDM and dose adjustment, to successfully target a therapeutic AUC window.

Prevalence and associated factors of low bone mass in adults with systemic lupus erythematosus.

PubMed

Cramarossa, G; Urowitz, M B; Su, J; Gladman, D; Touma, Z

2017-04-01

Background Systemic lupus erythematosus (SLE) patients are often treated with glucocorticoids, which place them at risk of bone loss. Objectives The objectives of this article are to determine: (1) the prevalence of low bone mineral density (BMD) and factors associated with low BMD and (2) the prevalence of symptomatic fragility fractures in inception patients of the Toronto Lupus Cohort (TLC). Methods Prospectively collected data from the TLC (1996-2015) of inception patients' first BMD were analyzed. For pre-menopausal women/males <50 years, BMD 'below expected range for age' was defined by Z-score ≤ -2.0 SD. For post-menopausal women/males age 50 or older, osteoporosis was defined by T-score ≤ -2.5 SD and low bone mass by T-score between -1.0 and -2.5 SD. Patients' BMDs were defined as abnormal if Z-score ≤ -2.0 or T-score < -1.0 SD, and the remainder as normal. Descriptive analysis and logistic regression were employed. Results Of 1807 patients, 286 are inception patients with BMD results (mean age 37.9 ± 13.7 years); 88.8% are female. The overall prevalence of abnormal BMD is 31.5%. In pre-menopausal women ( n = 173), the prevalence of BMD below expected range is 17.3%. In post-menopausal women ( n = 81), the prevalence of osteoporosis and low BMD are 12.3% and 43.2%, respectively. Age and cumulative dose of glucocorticoids are statistically significantly associated with abnormal BMD in multivariate analysis. Of 769 inception patients from TLC, 11.1% experienced symptomatic fragility fractures (peripheral and vertebral) over the course of their disease. Conclusion The prevalence of low BMD is high in SLE patients, and is associated with older age and higher cumulative glucocorticoid dose.

Differential Response of Immunohistochemically Defined Breast Cancer Subtypes to Anthracycline-Based Adjuvant Chemotherapy with or without Paclitaxel

PubMed Central

Fountzilas, George; Dafni, Urania; Bobos, Mattheos; Batistatou, Anna; Kotoula, Vassiliki; Trihia, Helen; Malamou-Mitsi, Vassiliki; Miliaras, Spyros; Chrisafi, Sofia; Papadopoulos, Savvas; Sotiropoulou, Maria; Filippidis, Theodoros; Gogas, Helen; Koletsa, Triantafyllia; Bafaloukos, Dimitrios; Televantou, Despina; Kalogeras, Konstantine T.; Pectasides, Dimitrios; Skarlos, Dimosthenis V.; Koutras, Angelos; Dimopoulos, Meletios A.

2012-01-01

Background The aim of the present study was to investigate the efficacy of adjuvant dose-dense sequential chemotherapy with epirubicin, paclitaxel, and CMF in subgroups of patients with high-risk operable breast cancer, according to tumor subtypes defined by immunohistochemistry (IHC). Materials and Methods Formalin-fixed paraffin-embedded (FFPE) tumor tissue samples from 1,039 patients participating in two adjuvant dose-dense sequential chemotherapy phase III trials were centrally assessed in tissue micro-arrays by IHC for 6 biological markers, that is, estrogen receptor (ER), progesterone receptor (PgR), HER2, Ki67, cytokeratin 5 (CK5), and EGFR. The majority of the cases were further evaluated for HER2 amplification by FISH. Patients were classified as: luminal A (ER/PgR-positive, HER2-negative, Ki67low); luminal B (ER/PgR-positive, HER2-negative, Ki67high); luminal-HER2 (ER/PgR-positive, HER2-positive); HER2-enriched (ER-negative, PgR-negative, HER2-positive); triple-negative (TNBC) (ER-negative, PgR-negative, HER2-negative); and basal core phenotype (BCP) (TNBC, CK5-positive and/or EGFR-positive). Results After a median follow-up time of 105.4 months the 5-year disease-free survival (DFS) and overall survival (OS) rates were 73.1% and 86.1%, respectively. Among patients with HER2-enriched tumors there was a significant benefit in both DFS and OS (log-rank test; p = 0.021 and p = 0.006, respectively) for those treated with paclitaxel. The subtype classification was found to be of both predictive and prognostic value. Setting luminal A as the referent category, the adjusted for prognostic factors HR for relapse for patients with TNBC was 1.91 (95% CI: 1.31–2.80, Wald's p = 0.001) and for death 2.53 (95% CI: 1.62–3.60, p<0.001). Site of and time to first relapse differed according to subtype. Locoregional relapses and brain metastases were more frequent in patients with TNBC, while liver metastases were more often seen in patients with HER2-enriched tumors. Conclusions Triple-negative phenotype is of adverse prognostic value for DFS and OS in patients treated with adjuvant dose-dense sequential chemotherapy. In the pre-trastuzumab era, the HER2-enriched subtype predicts favorable outcome following paclitaxel-containing treatment. PMID:22679488

Fixed-dose combination of sitagliptin and metformin for the treatment of type 2 diabetes

PubMed Central

Reynolds, Jonathan K

2009-01-01

JanumetTM, a fixed dose combination of sitagliptin/metformin HCL manufactured by Merck Pharmaceuticals, has received US Food and Drug Administration approval for treatment of patients with type 2 diabetes, that are inadequately controlled, either by sitagliptin or metformin alone or together in free-dose combination form. Sitagliptin, an inhibitor of the enzyme DDP-4, assists patients with type 2 diabetes mellitus to achieve glycemic control. It has been shown to be safe and effective at 100 mg daily doses. The effect of giving sitagliptin in combination with metformin is thought to have a complimentary and possibly additive effect on glycemic control. PMID:21437126

Serum thyroxine concentrations following fixed-dose radioactive iodine treatment in hyperthyroid cats: 62 cases (1986-1989)

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

Meric, S.M.; Rubin, S.I.

The medical records of 62 hyperthyroid cats treated with a fixed dose of 4 mCi of radioactive iodine (131I) were reviewed. In 60 cats, serum thyroxine concentrations were determined after treatment, allowing evaluation of treatment success. Eighty-four percent of the cats had normal serum thyroxine concentrations after treatment. Five of the 60 cats (8%) remained hyperthyroxinemic after treatment. Five cats (8%) were hypothyroxinemic when evaluated within 60 days of treatment. Three of these cats had normal serum thyroxine concentrations 6 months after treatment, and none had clinical signs of hypothyroidism. The administration of a fixed dose of 4 mCi ofmore » 131I was determined to be an effective treatment for feline hyperthyroidism.« less

Comparison of flat cleaved and cylindrical diffusing fibers as treatment sources for interstitial photodynamic therapy.

PubMed

Baran, Timothy M; Foster, Thomas H

2014-02-01

For interstitial photodynamic therapy (iPDT) of bulky tumors, careful treatment planning is required in order to ensure that a therapeutic dose is delivered to the tumor, while minimizing damage to surrounding normal tissue. In clinical contexts, iPDT has typically been performed with either flat cleaved or cylindrical diffusing optical fibers as light sources. Here, the authors directly compare these two source geometries in terms of the number of fibers and duration of treatment required to deliver a prescribed light dose to a tumor volume. Treatment planning software for iPDT was developed based on graphics processing unit enhanced Monte Carlo simulations. This software was used to optimize the number of fibers, total energy delivered by each fiber, and the position of individual fibers in order to deliver a target light dose (D90) to 90% of the tumor volume. Treatment plans were developed using both flat cleaved and cylindrical diffusing fibers, based on tissue volumes derived from CT data from a head and neck cancer patient. Plans were created for four cases: fixed energy per fiber, fixed number of fibers, and in cases where both or neither of these factors were fixed. When the number of source fibers was fixed at eight, treatment plans based on flat cleaved fibers required each to deliver 7180-8080 J in order to deposit 90 J/cm(2) in 90% of the tumor volume. For diffusers, each fiber was required to deliver 2270-2350 J (333-1178 J/cm) in order to achieve this same result. For the case of fibers delivering a fixed 900 J, 13 diffusers or 19 flat cleaved fibers at a spacing of 1 cm were required to deliver the desired dose. With energy per fiber fixed at 2400 J and the number of fibers fixed at eight, diffuser fibers delivered the desired dose to 93% of the tumor volume, while flat cleaved fibers delivered this dose to 79%. With both energy and number of fibers allowed to vary, six diffusers delivering 3485-3600 J were required, compared to ten flat cleaved fibers delivering 2780-3600 J. For the same number of fibers, cylindrical diffusers allow for a shorter treatment duration compared to flat cleaved fibers. For the same energy delivered per fiber, diffusers allow for the insertion of fewer fibers in order to deliver the same light dose to a target volume.

Comparison of flat cleaved and cylindrical diffusing fibers as treatment sources for interstitial photodynamic therapy

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

Baran, Timothy M., E-mail: timothy.baran@rochester.edu; Foster, Thomas H.

Purpose: For interstitial photodynamic therapy (iPDT) of bulky tumors, careful treatment planning is required in order to ensure that a therapeutic dose is delivered to the tumor, while minimizing damage to surrounding normal tissue. In clinical contexts, iPDT has typically been performed with either flat cleaved or cylindrical diffusing optical fibers as light sources. Here, the authors directly compare these two source geometries in terms of the number of fibers and duration of treatment required to deliver a prescribed light dose to a tumor volume. Methods: Treatment planning software for iPDT was developed based on graphics processing unit enhanced Montemore » Carlo simulations. This software was used to optimize the number of fibers, total energy delivered by each fiber, and the position of individual fibers in order to deliver a target light dose (D{sub 90}) to 90% of the tumor volume. Treatment plans were developed using both flat cleaved and cylindrical diffusing fibers, based on tissue volumes derived from CT data from a head and neck cancer patient. Plans were created for four cases: fixed energy per fiber, fixed number of fibers, and in cases where both or neither of these factors were fixed. Results: When the number of source fibers was fixed at eight, treatment plans based on flat cleaved fibers required each to deliver 7180–8080 J in order to deposit 90 J/cm{sup 2} in 90% of the tumor volume. For diffusers, each fiber was required to deliver 2270–2350 J (333–1178 J/cm) in order to achieve this same result. For the case of fibers delivering a fixed 900 J, 13 diffusers or 19 flat cleaved fibers at a spacing of 1 cm were required to deliver the desired dose. With energy per fiber fixed at 2400 J and the number of fibers fixed at eight, diffuser fibers delivered the desired dose to 93% of the tumor volume, while flat cleaved fibers delivered this dose to 79%. With both energy and number of fibers allowed to vary, six diffusers delivering 3485–3600 J were required, compared to ten flat cleaved fibers delivering 2780–3600 J. Conclusions: For the same number of fibers, cylindrical diffusers allow for a shorter treatment duration compared to flat cleaved fibers. For the same energy delivered per fiber, diffusers allow for the insertion of fewer fibers in order to deliver the same light dose to a target volume.« less

Spacecraft attitude calibration/verification baseline study

NASA Technical Reports Server (NTRS)

Chen, L. C.

1981-01-01

A baseline study for a generalized spacecraft attitude calibration/verification system is presented. It can be used to define software specifications for three major functions required by a mission: the pre-launch parameter observability and data collection strategy study; the in-flight sensor calibration; and the post-calibration attitude accuracy verification. Analytical considerations are given for both single-axis and three-axis spacecrafts. The three-axis attitudes considered include the inertial-pointing attitudes, the reference-pointing attitudes, and attitudes undergoing specific maneuvers. The attitude sensors and hardware considered include the Earth horizon sensors, the plane-field Sun sensors, the coarse and fine two-axis digital Sun sensors, the three-axis magnetometers, the fixed-head star trackers, and the inertial reference gyros.

A randomized, double-blind, placebo-controlled, dose-ranging study using Genz-644470 and sevelamer carbonate in hyperphosphatemic chronic kidney disease patients on hemodialysis.

PubMed

Moustafa, Moustafa; Lehrner, Lawrence; Al-Saghir, Fahd; Smith, Mark; Goyal, Sunita; Dillon, Maureen; Hunter, John; Holmes-Farley, Randy

2014-01-01

Genz-644470 is a new, nonabsorbed phosphate binding polymer. In an in vitro competitive phosphate binding assay, Genz-644470 bound significantly more phosphate per gram than sevelamer. As a consequence, this clinical study evaluated the ability of Genz-644470 to lower serum phosphorus in patients on hemodialysis and compared serum phosphorus lowering of Genz-644470 with sevelamer carbonate and placebo. Because three different fixed doses of Genz-644470 and sevelamer carbonate were used, phosphate-lowering dose-responses of each agent were also analyzed. A randomized, double-blind, dose-ranging study was conducted. After a 2-week phosphate binder washout, 349 hyperphosphatemic (serum phosphorus >5.5 mg/dL) hemodialysis patients were randomized to one of seven fixed-dose groups: placebo, Genz-644470 2.4 g/day, Genz-644470 4.8 g/day, Genz-644470 7.2 g/day, sevelamer carbonate 2.4 g/day, sevelamer carbonate 4.8 g/day, or sevelamer carbonate 7.2 g/day. Indicated total daily doses were administered in fixed divided doses three times a day with meals for 3 weeks. The change in serum phosphorus during the treatment period and its dose-response patterns were assessed. Dose-dependent reductions in serum phosphorus were observed with both Genz-644470 and sevelamer carbonate. Serum phosphorus-lowering responses to fixed doses of sevelamer carbonate and Genz-644470 were enhanced in a roughly linear fashion with increasing doses over a threefold range after 3 weeks of treatment. Genz-644470 did not show any advantage in phosphorus lowering per gram of binder compared with sevelamer carbonate. Overall toler-ability was similar between active treatment groups. The tolerability of sevelamer carbonate was consistent with prior studies and with the established safety profile of sevelamer. Both Genz-644470 and sevelamer carbonate effectively lowered serum phosphate levels in a dose-dependent fashion in patients with chronic kidney disease on hemodialysis. However, Genz-644470 did not provide any advantage over sevelamer carbonate in phosphate lowering in vivo, as had been demonstrated in vitro.

MSL-RAD Cruise Operations Concept

NASA Technical Reports Server (NTRS)

Brinza, David E.; Zeitlin, Cary; Hassler, Donald; Weigle, Gerald E.; Boettcher, Stephan; Martin, Cesar; Wimmer-Schweingrubber, Robert

2012-01-01

The Mars Science Laboratory (MSL) payload includes the Radiation Assessment Detector (RAD) instrument, intended to fully characterize the radiation environment for the MSL mission. The RAD instrument operations concept is intended to reduce impact to spacecraft resources and effort for the MSL operations team. By design, RAD autonomously performs regular science observations without the need for frequent commanding from the Rover Compute Element (RCE). RAD operates with pre-defined "sleep" and "observe" periods, with an adjustable duty cycle for meeting power and data volume constraints during the mission. At the start of a new science observation, RAD performs a pre-observation activity to assess count rates for selected RAD detector elements. Based on this assessment, RAD can enter "solar event" mode, in which instrument parameters (including observation duration) are selected to more effectively characterize the environment. At the end of each observation period, RAD stores a time-tagged, fixed length science data packet in its non-volatile mass memory storage. The operating cadence is defined by adjustable parameters, also stored in non-volatile memory within the instrument. Periodically, the RCE executes an on-board sequence to transfer RAD science data packets from the instrument mass storage to the MSL downlink buffer. Infrequently, the RAD instrument operating configuration is modified by updating internal parameter tables and configuration entries.

Intraocular pressure decrease with preservative-free fixed and unfixed combination of tafluprost and timolol in pseudoexfoliative glaucoma.

PubMed

Holló, Gábor; Ropo, Auli

2015-01-01

We investigated the intraocular pressure (IOP) lowering efficacy of preservative-free fixed and non-fixed combination of tafluprost 0.0015% and timolol 0.5% in pseudoexfoliative glaucoma (XFG). A per protocol worse eye analysis was made on all XFG patients who participated in a recent 6 month, prospective, randomized, double-masked, parallel group, multicenter phase III study. The mean time-wise IOP decreased by 8.62 to 10.25 mmHg (31.8 to 36.7%) in the fixed dose combination arm (15 patients) and by 5.38 to 11.35 mmHg (21.3 to 41.2%) in the non-fixed combination arm (13 patients), respectively (p < 0.001 for all comparisons). The results show that a preservative-free fixed dose combination of tafluprost and timolol provides a clinically significant IOP reduction in XFG, and may offer an advantage for the XFG patients with dry eye, due to its preservative-free nature.

The evolution of systolic blood pressure as a strong predictor of cardiovascular risk and the effectiveness of fixed-dose ARB/CCB combinations in lowering levels of this preferential target

PubMed Central

Mourad, Jean-Jacques

2008-01-01

Elevated blood pressure is an important cardiovascular risk factor. Although targets for both diastolic blood pressure (DBP) and systolic blood pressure (SBP) are defined by current guidelines, DBP has historically taken precedence in hypertension management. However, there is strong evidence that SBP is superior to DBP as a predictor of cardiovascular events. Moreover, achieving control of SBP is assuming greater importance amongst an aging population. In spite of the growing recognition of the importance of SBP in reducing cardiovascular risk and the emphasis by current guidelines on SBP control, a substantial proportion of patients still fail to achieve SBP targets, and SBP control is achieved much less frequently than DBP control. Thus, new approaches to the management of hypertension are required in order to control SBP and minimize cardiovascular risk. Fixed-dose combination (FDC) therapy is an approach that offers the advantages of multiple drug administration and a reduction in regimen complexity that favors compliance. We have reviewed the latest evidence demonstrating the efficacy in targeting SBP of the most recent FDC products; combinations of the calcium channel blocker (CCB), amlodipine, with angiotensin receptor blockers (ARBs), valsartan or olmesartan. In addition, results from studies with new classes of agent are outlined. PMID:19337545

Point Organ Radiation Dose in Abdominal CT: Effect of Patient Off-Centering in an Experimental Human Cadaver Study.

PubMed

Ali Khawaja, Ranish Deedar; Singh, Sarabjeet; Padole, Atul; Otrakji, Alexi; Lira, Diego; Zhang, Da; Liu, Bob; Primak, Andrew; Xu, George; Kalra, Mannudeep K

2017-08-01

To determine the effect of patient off-centering on point organ radiation dose measurements in a human cadaver scanned with routine abdominal CT protocol. A human cadaver (88 years, body-mass-index 20 kg/m2) was scanned with routine abdominal CT protocol on 128-slice dual source MDCT (Definition Flash, Siemens). A total of 18 scans were performed using two scan protocols (a) 120 kV-200 mAs fixed-mA (CTDIvol 14 mGy) (b) 120 kV-125 ref mAs (7 mGy) with automatic exposure control (AEC, CareDose 4D) at three different positions (a) gantry isocenter, (b) upward off-centering and (c) downward off-centering. Scanning was repeated three times at each position. Six thimble (in liver, stomach, kidney, pancreas, colon and urinary bladder) and four MOSFET dosimeters (on cornea, thyroid, testicle and breast) were placed for calculation of measured point organ doses. Organ dose estimations were retrieved from dose-tracking software (eXposure, Radimetrics). Statistical analysis was performed using analysis of variance. There was a significant difference between the trends of point organ doses with AEC and fixed-mA at all three positions (p < 0.01). Variation in point doses between fixed-mA and AEC protocols were statistically significant across all organs at all Table positions (p < 0.001). There was up to 5-6% decrease in point doses with upward off-centering and in downward off-centering. There were statistical significant differences in point doses from dosimeters and dose-tracking software (mean difference for internal organs, 5-36% for fixed-mA & 7-48% for AEC protocols; p < 0.001; mean difference for surface organs, >92% for both protocols; p < 0.0001). For both protocols, the highest mean difference in point doses was found for stomach and lowest for colon. Measured absorbed point doses in abdominal CT vary with patient-centering in the gantry isocenter. Due to lack of consideration of patient positioning in the dose estimation on automatic software-over estimation of the doses up to 92% was reported. © The Author 2017. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Effect of radiation protraction on BED in the case of large fraction dose

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

Kuperman, V. Y.

2013-08-15

Purpose: To investigate the effect of radiation protraction on biologically effective dose (BED) in the case when dose per fraction is significantly greater than the standard dose of 2 Gy.Methods: By using the modified linear-quadratic model with monoexponential repair, the authors investigate the effect of long treatment times combined with dose escalation.Results: The dependences of the protraction factor and the corresponding BED on fraction time were determined for different doses per fraction typical for stereotactic radiosurgery (SRS) and stereotactic body radiation therapy (SBRT). In the calculations, the authors consider changes in the BED to the normal tissue under the conditionmore » of fixed BED to the target.Conclusion: The obtained results demonstrate that simultaneous increase in fraction time and dose per fraction can be beneficial for SRS and SBRT because of the related decrease in BED to normal structures while BED to the target is fixed.« less

A study of lateral fall-off (penumbra) optimisation for pencil beam scanning (PBS) proton therapy

NASA Astrophysics Data System (ADS)

Winterhalter, C.; Lomax, A.; Oxley, D.; Weber, D. C.; Safai, S.

2018-01-01

The lateral fall-off is crucial for sparing organs at risk in proton therapy. It is therefore of high importance to minimize the penumbra for pencil beam scanning (PBS). Three optimisation approaches are investigated: edge-collimated uniformly weighted spots (collimation), pencil beam optimisation of uncollimated pencil beams (edge-enhancement) and the optimisation of edge collimated pencil beams (collimated edge-enhancement). To deliver energies below 70 MeV, these strategies are evaluated in combination with the following pre-absorber methods: field specific fixed thickness pre-absorption (fixed), range specific, fixed thickness pre-absorption (automatic) and range specific, variable thickness pre-absorption (variable). All techniques are evaluated by Monte Carlo simulated square fields in a water tank. For a typical air gap of 10 cm, without pre-absorber collimation reduces the penumbra only for water equivalent ranges between 4-11 cm by up to 2.2 mm. The sharpest lateral fall-off is achieved through collimated edge-enhancement, which lowers the penumbra down to 2.8 mm. When using a pre-absorber, the sharpest fall-offs are obtained when combining collimated edge-enhancement with a variable pre-absorber. For edge-enhancement and large air gaps, it is crucial to minimize the amount of material in the beam. For small air gaps however, the superior phase space of higher energetic beams can be employed when more material is used. In conclusion, collimated edge-enhancement combined with the variable pre-absorber is the recommended setting to minimize the lateral penumbra for PBS. Without collimator, it would be favourable to use a variable pre-absorber for large air gaps and an automatic pre-absorber for small air gaps.

The effect of dosing strategies on the therapeutic efficacy of artesunate-amodiaquine for uncomplicated malaria: a meta-analysis of individual patient data.

PubMed

Adjuik, Martin A; Allan, Richard; Anvikar, Anupkumar R; Ashley, Elizabeth A; Ba, Mamadou S; Barennes, Hubert; Barnes, Karen I; Bassat, Quique; Baudin, Elisabeth; Björkman, Anders; Bompart, François; Bonnet, Maryline; Borrmann, Steffen; Brasseur, Philippe; Bukirwa, Hasifa; Checchi, Francesco; Cot, Michel; Dahal, Prabin; D'Alessandro, Umberto; Deloron, Philippe; Desai, Meghna; Diap, Graciela; Djimde, Abdoulaye A; Dorsey, Grant; Doumbo, Ogobara K; Espié, Emmanuelle; Etard, Jean-Francois; Fanello, Caterina I; Faucher, Jean-François; Faye, Babacar; Flegg, Jennifer A; Gaye, Oumar; Gething, Peter W; González, Raquel; Grandesso, Francesco; Guerin, Philippe J; Guthmann, Jean-Paul; Hamour, Sally; Hasugian, Armedy Ronny; Hay, Simon I; Humphreys, Georgina S; Jullien, Vincent; Juma, Elizabeth; Kamya, Moses R; Karema, Corine; Kiechel, Jean R; Kremsner, Peter G; Krishna, Sanjeev; Lameyre, Valérie; Ibrahim, Laminou M; Lee, Sue J; Lell, Bertrand; Mårtensson, Andreas; Massougbodji, Achille; Menan, Hervé; Ménard, Didier; Menéndez, Clara; Meremikwu, Martin; Moreira, Clarissa; Nabasumba, Carolyn; Nambozi, Michael; Ndiaye, Jean-Louis; Nikiema, Frederic; Nsanzabana, Christian; Ntoumi, Francine; Ogutu, Bernhards R; Olliaro, Piero; Osorio, Lyda; Ouédraogo, Jean-Bosco; Penali, Louis K; Pene, Mbaye; Pinoges, Loretxu; Piola, Patrice; Price, Ric N; Roper, Cally; Rosenthal, Philip J; Rwagacondo, Claude Emile; Same-Ekobo, Albert; Schramm, Birgit; Seck, Amadou; Sharma, Bhawna; Sibley, Carol Hopkins; Sinou, Véronique; Sirima, Sodiomon B; Smith, Jeffery J; Smithuis, Frank; Somé, Fabrice A; Sow, Doudou; Staedke, Sarah G; Stepniewska, Kasia; Swarthout, Todd D; Sylla, Khadime; Talisuna, Ambrose O; Tarning, Joel; Taylor, Walter R J; Temu, Emmanuel A; Thwing, Julie I; Tjitra, Emiliana; Tine, Roger C K; Tinto, Halidou; Vaillant, Michel T; Valecha, Neena; Van den Broek, Ingrid; White, Nicholas J; Yeka, Adoke; Zongo, Issaka

2015-03-31

Artesunate-amodiaquine (AS-AQ) is one of the most widely used artemisinin-based combination therapies (ACTs) to treat uncomplicated Plasmodium falciparum malaria in Africa. We investigated the impact of different dosing strategies on the efficacy of this combination for the treatment of falciparum malaria. Individual patient data from AS-AQ clinical trials were pooled using the WorldWide Antimalarial Resistance Network (WWARN) standardised methodology. Risk factors for treatment failure were identified using a Cox regression model with shared frailty across study sites. Forty-three studies representing 9,106 treatments from 1999-2012 were included in the analysis; 4,138 (45.4%) treatments were with a fixed dose combination with an AQ target dose of 30 mg/kg (FDC), 1,293 (14.2%) with a non-fixed dose combination with an AQ target dose of 25 mg/kg (loose NFDC-25), 2,418 (26.6%) with a non-fixed dose combination with an AQ target dose of 30 mg/kg (loose NFDC-30), and the remaining 1,257 (13.8%) with a co-blistered non-fixed dose combination with an AQ target dose of 30 mg/kg (co-blistered NFDC). The median dose of AQ administered was 32.1 mg/kg [IQR: 25.9-38.2], the highest dose being administered to patients treated with co-blistered NFDC (median = 35.3 mg/kg [IQR: 30.6-43.7]) and the lowest to those treated with loose NFDC-25 (median = 25.0 mg/kg [IQR: 22.7-25.0]). Patients treated with FDC received a median dose of 32.4 mg/kg [IQR: 27-39.0]. After adjusting for reinfections, the corrected antimalarial efficacy on day 28 after treatment was similar for co-blistered NFDC (97.9% [95% confidence interval (CI): 97.0-98.8%]) and FDC (98.1% [95% CI: 97.6%-98.5%]; P = 0.799), but significantly lower for the loose NFDC-25 (93.4% [95% CI: 91.9%-94.9%]), and loose NFDC-30 (95.0% [95% CI: 94.1%-95.9%]) (P < 0.001 for all comparisons). After controlling for age, AQ dose, baseline parasitemia and region; treatment with loose NFDC-25 was associated with a 3.5-fold greater risk of recrudescence by day 28 (adjusted hazard ratio, AHR = 3.51 [95% CI: 2.02-6.12], P < 0.001) compared to FDC, and treatment with loose NFDC-30 was associated with a higher risk of recrudescence at only three sites. There was substantial variation in the total dose of amodiaquine administered in different AS-AQ combination regimens. Fixed dose AS-AQ combinations ensure optimal dosing and provide higher antimalarial treatment efficacy than the loose individual tablets in all age categories.

TU-EF-204-09: A Preliminary Method of Risk-Informed Optimization of Tube Current Modulation for Dose Reduction in CT

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

Gao, Y; Liu, B; Kalra, M

Purpose: X-rays from CT scans can increase cancer risk to patients. Lifetime Attributable Risk of Cancer Incidence for adult patients has been investigated and shown to decrease as patient age. However, a new risk model shows an increasing risk trend for several radiosensitive organs for middle age patients. This study investigates the feasibility of a general method for optimizing tube current modulation (TCM) functions to minimize risk by reducing radiation dose to radiosensitive organs of patients. Methods: Organ-based TCM has been investigated in literature for eye lens dose and breast dose. Adopting the concept in organ-based TCM, this study seeksmore » to find an optimized tube current for minimal total risk to breasts and lungs by reducing dose to these organs. The contributions of each CT view to organ dose are determined through simulations of CT scan view-by-view using a GPU-based fast Monte Carlo code, ARCHER. A Linear Programming problem is established for tube current optimization, with Monte Carlo results as weighting factors at each view. A pre-determined dose is used as upper dose boundary, and tube current of each view is optimized to minimize the total risk. Results: An optimized tube current is found to minimize the total risk of lungs and breasts: compared to fixed current, the risk is reduced by 13%, with breast dose reduced by 38% and lung dose reduced by 7%. The average tube current is maintained during optimization to maintain image quality. In addition, dose to other organs in chest region is slightly affected, with relative change in dose smaller than 10%. Conclusion: Optimized tube current plans can be generated to minimize cancer risk to lungs and breasts while maintaining image quality. In the future, various risk models and greater number of projections per rotation will be simulated on phantoms of different gender and age. National Institutes of Health R01EB015478.« less

29 CFR 1910.160 - Fixed extinguishing systems, general.

Code of Federal Regulations, 2012 CFR

2012-07-01

... sprinkler systems which are covered by § 1910.159. (2) This section also applies to fixed systems not... flooding systems by means of an approved fire detection device installed and interconnected with a pre... 29 Labor 5 2012-07-01 2012-07-01 false Fixed extinguishing systems, general. 1910.160 Section 1910...

29 CFR 1910.160 - Fixed extinguishing systems, general.

Code of Federal Regulations, 2011 CFR

2011-07-01

... sprinkler systems which are covered by § 1910.159. (2) This section also applies to fixed systems not... flooding systems by means of an approved fire detection device installed and interconnected with a pre... 29 Labor 5 2011-07-01 2011-07-01 false Fixed extinguishing systems, general. 1910.160 Section 1910...

29 CFR 1910.160 - Fixed extinguishing systems, general.

Code of Federal Regulations, 2013 CFR

2013-07-01

... sprinkler systems which are covered by § 1910.159. (2) This section also applies to fixed systems not... flooding systems by means of an approved fire detection device installed and interconnected with a pre... 29 Labor 5 2013-07-01 2013-07-01 false Fixed extinguishing systems, general. 1910.160 Section 1910...

29 CFR 1910.160 - Fixed extinguishing systems, general.

Code of Federal Regulations, 2014 CFR

2014-07-01

... sprinkler systems which are covered by § 1910.159. (2) This section also applies to fixed systems not... flooding systems by means of an approved fire detection device installed and interconnected with a pre... 29 Labor 5 2014-07-01 2014-07-01 false Fixed extinguishing systems, general. 1910.160 Section 1910...

AAV liver expression of FIX-Padua prevents and eradicates FIX inhibitor without increasing thrombogenicity in hemophilia B dogs and mice.

PubMed

Crudele, Julie M; Finn, Jonathan D; Siner, Joshua I; Martin, Nicholas B; Niemeyer, Glenn P; Zhou, Shangzhen; Mingozzi, Federico; Lothrop, Clinton D; Arruda, Valder R

2015-03-05

Emerging successful clinical data on gene therapy using adeno-associated viral (AAV) vector for hemophilia B (HB) showed that the risk of cellular immune response to vector capsid is clearly dose dependent. To decrease the vector dose, we explored AAV-8 (1-3 × 10(12) vg/kg) encoding a hyperfunctional factor IX (FIX-Padua, arginine 338 to leucine) in FIX inhibitor-prone HB dogs. Two naïve HB dogs showed sustained expression of FIX-Padua with an 8- to 12-fold increased specific activity reaching 25% to 40% activity without antibody formation to FIX. A third dog with preexisting FIX inhibitors exhibited a transient anamnestic response (5 Bethesda units) at 2 weeks after vector delivery following by spontaneous eradication of the antibody to FIX by day 70. In this dog, sustained FIX expression reached ∼200% and 30% of activity and antigen levels, respectively. Immune tolerance was confirmed in all dogs after challenges with plasma-derived FIX concentrate. Shortening of the clotting times and lack of bleeding episodes support the phenotypic correction of the severe phenotype, with no clinical or laboratory evidence of risk of thrombosis. Provocative studies in mice showed that FIX-Padua exhibits similar immunogenicity and thrombogenicity compared with FIX wild type. Collectively, these data support the potential translation of gene-based strategies using FIX-Padua for HB. © 2015 by The American Society of Hematology.

Investigation into scatter radiation dose levels received by a restrainer in small animal radiography.

PubMed

Barber, J; McNulty, J P

2012-10-01

To measure the intensity and distribution of scatter radiation received by a restrainer in veterinary radiography including the intensity of scatter radiation passing through lead protective devices at pre-defined positions. Anthropomorphic phantoms and a Labrador dog cadaver were used to simulate a restrainer and patient. Scatter dose measurements were recorded at the position of the restraining hands, thyroid, breast and gonads with and without appropriate lead protection. This was repeated for the eight most common projections as identified in an initial retrospective survey. Manual restraint of an animal for a radiographic procedure will result in a scatter radiation dose to the restrainer. The level of radiation dose varies between body regions and between projections. The use of appropriate lead protection resulted in statistically significant dose reductions to all body regions with maximum scatter dose reductions between 93 and 100%. While the doses recorded were small (μGy) in terms of associated risk, they are nonetheless cumulative which can result in a more significant dose. Therefore manual restraint should be avoided and forms of immobilisation should be used such as mechanical means, sedation or general anaesthesia. However, if completely necessary both principles of distance and adequate lead protection should be employed. © 2012 British Small Animal Veterinary Association.

Pre-load on oral implants after screw tightening fixed full prostheses: an in vivo study.

PubMed

Duyck, J; Van Oosterwyck, H; Vander Sloten, J; De Cooman, M; Puers, R; Naert, I

2001-03-01

The fit of implant supported fixed prostheses is said to be of clinical concern because of the rigid fixation of an oral implant in its surrounding bone. The influence of the torque sequence of the set screws during fixation of implant supported fixed full prostheses on the final pre-load was investigated in vitro. No significant effect of the torque sequence of the set screws on the final pre-load was observed. The main objective of this study was to quantify and qualify the pre-load in vivo on implants supporting a fixed full prosthesis. This was performed when the prostheses were supported by all five or six implants and was repeated when the prostheses were supported by only four and three implants. A total of 13 patients with a fixed full implant supported prosthesis were selected. The existing abutments were changed for strain gauged abutments. After tightening the set screws with a torque of 10 N cm, the pre-load conditions were registered. The average (SEM) axial forces and bending moments in case of five or six, four and three supporting implants were 323 N (43 N), 346 N (59 N), 307 N (60 N) 21 N cm (3 N cm) and 21 N cm (2 N cm), 23 N cm (5 N cm), respectively. In addition, the pre-load was registered after fixation of a machined gold cylinder, as delivered by the manufacturer, on each of the supporting implants, representing the 'optimal fit' situation. The corresponding average (SEM) axial forces and bending moments in case of five or six, four and three supporting implants were 426 N (36 N), 405 N (40 N), 413 N (46 N) and 8 N cm (1 N cm), 8 N cm (1 N cm), 8 N cm (1 N cm), respectively. The induced axial forces after tightening the prostheses were significantly lower then after tightening the gold cylinder in case of five or six supporting implants (P < 0.02). The induced bending moments after tightening the prostheses were statistically significantly higher (P < 0.0001) then after tightening the gold cylinder in all test conditions (five or six, four or three supporting implants). This study underlines the static load present after screw tightening implant supported fixed full prostheses.

Synergistic Interaction of a Gabapentin- Mangiferin Combination in Formalin-Induced Secondary Mechanical Allodynia and Hyperalgesia in Rats Is Mediated by Activation of NO-Cyclic GMP-ATP-Sensitive K+ Channel Pathway.

PubMed

Godínez-Chaparro, Beatriz; Quiñonez-Bastidas, Geovanna Nallely; Rojas-Hernández, Isabel Rocío; Austrich-Olivares, Amaya Montserrat; Mata-Bermudez, Alfonso

2017-12-01

Preclinical Research Gabapentin is an anticonvulsant used to treat neuropathic pain. Mangiferin is an antioxidant that has antinociceptive and antiallodynic effects in inflammatory and neuropathic pain models. The purpose of this study was to determine the interaction between mangiferin and gabapentin in the development and maintenance of formalin-induced secondary allodynia and hyperalgesia in rats. Gabapentin, mangiferin, or their fixed-dose ratio combination were administrated peripherally. Isobolographic analyses was used to define the nature of the interaction of antiallodynic and/or antihyperalgesic effects of the two compounds. Theoretical ED 50 values for the combination were 74.31 µg/paw and 95.20 µg/paw for pre- and post-treatment, respectively. These values were higher than the experimental ED 50 values, 29.45 µg/paw and 37.73 µg/paw respectively, indicating a synergistic interaction in formalin-induced secondary allodynia and hyperalgesia. The antiallodynic and antihyperalgesic effect induced by the gabapentin/mangiferin combination was blocked by administration of L-NAME, the soluble guanylyl cyclase inhibitor, ODQ and glibenclamide. These data suggest that the gabapentin- mangiferin combination produces a synergistic interaction at the peripheral level. Moreover, the antiallodynic and hyperalgesic effect induced by the combination is mediated via the activation of an NO-cyclic GMP-ATP-sensitive K + channel pathway. Drug Dev Res 78 : 390-402, 2017. © 2017 Wiley Periodicals, Inc. © 2017 Wiley Periodicals, Inc.

SU-E-T-400: Evaluation of Shielding and Activation at Two Pencil Beam Scanning Proton Facilities

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

Remmes, N; Mundy, D; Classic, K

2015-06-15

Purpose: To verify acceptably low dose levels around two newly constructed identical pencil beam scanning proton therapy facilities and to evaluate accuracy of pre-construction shielding calculations. Methods: Dose measurements were taken at select points of interest using a WENDI-2 style wide-energy neutron detector. Measurements were compared to pre-construction shielding calculations. Radiation badges with neutron dose measurement capabilities were worn by personnel and also placed at points throughout the facilities. Seven neutron and gamma detectors were permanently installed throughout the facility, continuously logging data. Potential activation hazards have also been investigated. Dose rates near water tanks immediately after prolonged irradiation havemore » been measured. Equipment inside the treatment room and accelerator vault has been surveyed and/or wipe tested. Air filters from air handling units, sticky mats placed outside of the accelerator vault, and water samples from the magnet cooling water loops have also been tested. Results: All radiation badges have been returned with readings below the reporting minimum. Measurements of mats, air filters, cooling water, wipe tests and surveys of equipment that has not been placed in the beam have all come back at background levels. All survey measurements show the analytical shielding calculations to be conservative by at least a factor of 2. No anomalous events have been identified by the building radiation monitoring system. Measurements of dose rates close to scanning water tanks have shown dose rates of approximately 10 mrem/hr with a half-life less than 5 minutes. Measurements around the accelerator show some areas with dose rates slightly higher than 10 mrem/hr. Conclusion: The shielding design is shown to be adequate. Measured dose rates are below those predicted by shielding calculations. Activation hazards are minimal except in certain very well defined areas within the accelerator vault and for objects placed directly in the path of the beam.« less

Low cost industrial production of coagulation factor IX bioencapsulated in lettuce cells for oral tolerance induction in hemophilia B.

PubMed

Su, Jin; Zhu, Liqing; Sherman, Alexandra; Wang, Xiaomei; Lin, Shina; Kamesh, Aditya; Norikane, Joey H; Streatfield, Stephen J; Herzog, Roland W; Daniell, Henry

2015-11-01

Antibodies (inhibitors) developed by hemophilia B patients against coagulation factor IX (FIX) are challenging to eliminate because of anaphylaxis or nephrotic syndrome after continued infusion. To address this urgent unmet medical need, FIX fused with a transmucosal carrier (CTB) was produced in a commercial lettuce (Simpson Elite) cultivar using species specific chloroplast vectors regulated by endogenous psbA sequences. CTB-FIX (∼1 mg/g) in lyophilized cells was stable with proper folding, disulfide bonds and pentamer assembly when stored ∼2 years at ambient temperature. Feeding lettuce cells to hemophilia B mice delivered CTB-FIX efficiently to the gut immune system, induced LAP(+) regulatory T cells and suppressed inhibitor/IgE formation and anaphylaxis against FIX. Lyophilized cells enabled 10-fold dose escalation studies and successful induction of oral tolerance was observed in all tested doses. Induction of tolerance in such a broad dose range should enable oral delivery to patients of different age groups and diverse genetic background. Using Fraunhofer cGMP hydroponic system, ∼870 kg fresh or 43.5 kg dry weight can be harvested per 1000 ft(2) per annum yielding 24,000-36,000 doses for 20-kg pediatric patients, enabling first commercial development of an oral drug, addressing prohibitively expensive purification, cold storage/transportation and short shelf life of current protein drugs. Copyright © 2015 The Authors. Published by Elsevier Ltd.. All rights reserved.

Multimodal analgesia in moderate-to-severe pain: a role for a new fixed combination of dexketoprofen and tramadol.

PubMed

Varrassi, Giustino; Hanna, Magdi; Macheras, Giorgos; Montero, Antonio; Montes Perez, Antonio; Meissner, Winfried; Perrot, Serge; Scarpignato, Carmelo

2017-06-01

Untreated and under-treated pain represent one of the most pervasive health problems, which is worsening as the population ages and accrues risk for pain. Multiple treatment options are available, most of which have one mechanism of action, and cannot be prescribed at unlimited doses due to the ceiling of efficacy and/or safety concerns. Another limitation of single-agent analgesia is that, in general, pain is due to multiple causes. Combining drugs from different classes, with different and complementary mechanism(s) of action, provides a better opportunity for effective analgesia at reduced doses of individual agents. Therefore, there is a potential reduction of adverse events, often dose-related. Analgesic combinations are recommended by several organizations and are used in clinical practice. Provided the two agents are combined in a fixed-dose ratio, the resulting medication may offer advantages over extemporaneous combinations. Dexketoprofen/tramadol (25 mg/75 mg) is a new oral fixed-dose combination offering a comprehensive multimodal approach to moderate-to-severe acute pain that encompasses central analgesic action, peripheral analgesic effect and anti-inflammatory activity, together with a good tolerability profile. The analgesic efficacy of dexketoprofen/tramadol combination is complemented by a favorable pharmacokinetic and pharmacodynamic profile, characterized by rapid onset and long duration of action. This has been well documented in both somatic- and visceral-pain human models. This review discusses the available clinical evidence and the future possible applications of dexketoprofen/tramadol fixed-dose combination that may play an important role in the management of moderate-to-severe acute pain.

Predicting Maintenance Doses of Vancomycin for Hospitalized Patients Undergoing Hemodialysis.

PubMed

El Nekidy, Wasim S; El-Masri, Maher M; Umstead, Greg S; Dehoorne-Smith, Michelle

2016-01-01

Methicillin-resistant Staphylococcus aureus is a leading cause of death in patients undergoing hemodialysis. However, controversy exists about the optimal dose of vancomycin that will yield the recommended pre-hemodialysis serum concentration of 15-20 mg/L. To develop a data-driven model to optimize the accuracy of maintenance dosing of vancomycin for patients undergoing hemodialysis. A prospective observational cohort study was performed with 164 observations obtained from a convenience sample of 63 patients undergoing hemodialysis. All vancomycin doses were given on the floor after completion of a hemodialysis session. Multivariate linear generalized estimating equation analysis was used to examine independent predictors of pre-hemodialysis serum vancomycin concentration. Pre-hemodialysis serum vancomycin concentration was independently associated with maintenance dose ( B = 0.658, p < 0.001), baseline pre-hemodialysis serum concentration of the drug ( B = 0.492, p < 0.001), and interdialytic interval ( B = -2.133, p < 0.001). According to the best of 4 models that were developed, the maintenance dose of vancomycin required to achieve a pre-hemodialysis serum concentration of 15-20 mg/L, if the baseline serum concentration of the drug was also 15-20 mg/L, was 5.9 mg/kg with interdialytic interval of 48 h and 7.1 mg/kg with interdialytic interval of 72 h. However, if the baseline pre-hemodialysis serum concentration was 10-14.99 mg/L, the required dose increased to 9.2 mg/kg with an interdialytic interval of 48 h and 10.0 mg/kg with an interdialytic interval of 72 h. The maintenance dose of vancomycin varied according to baseline pre-hemodialysis serum concentration of the drug and interdialytic interval. The current practice of targeting a pre-hemodialysis concentration of 15-20 mg/L may be difficult to achieve for the majority of patients undergoing hemodialysis.

Documenting the kinetic time course of lambda-cyhalothrin metabolites in orally exposed volunteers for the interpretation of biomonitoring data.

PubMed

Khemiri, Rania; Côté, Jonathan; Fetoui, Hamadi; Bouchard, Michèle

2017-07-05

Lambda-cyhalothrin is a pyrethroid pesticide largely used in agriculture. Exposure assessment can be performed by measuring key urinary metabolites. For a proper use of biomonitoring data, it is however important to gain information on the toxicokinetics of these key biomarkers of exposure. A human volunteer study was performed to document the plasma and urinary time courses of major lambda-cyhalothrin metabolites. Seven volunteers ingested 0.025mgkg -1 body weight of lambda-cyhalothrin. Blood samples were withdrawn prior to dosing and at fixed time periods over the 72 h-period following ingestion and complete urine voids were collected pre-exposure and at pre-established intervals over 84h post-dosing. The cis-3-(2-chloro-3,3,3-trifluoroprop-1-en-1-yl)-2,2-dimethylcyclopropanecarboxylic acid (CFMP) and 3-phenoxybenzoic acid (3-PBA) metabolites were quantified in these samples. Plasma concentrations of CFMP and 3-PBA increased rapidly after ingestion, with average peak values at 3.1 and 4.0h post-dosing, respectively; subsequent elimination phase showed a rapid decay with a mean half-life (t ½ ) of ≈5.3 and 6.4h for CFMP and 3-PBA, respectively. Urinary rate time courses displayed a profile similar to the plasma concentration-time curves with corresponding mean t ½ of ≈4.2 and 5.9h. In the 84-h period post-treatment, on average 21% of lambda-cyhalothrin dose were excreted in urine as CFMP as compared to 30% as 3-PBA. Overall, CFMP and 3-PBA metabolites were confirmed to be major metabolites of lambda-cyhalothrin and exhibited similar kinetics with short half-lives; they thus both appear as useful biomarkers of exposure to lambda-cyhalothrin in humans. Copyright © 2017 Elsevier B.V. All rights reserved.

Statins in hypercholesterolaemia: A dose-specific meta-analysis of lipid changes in randomised, double blind trials

PubMed Central

Edwards, Jayne E; Moore, R Andrew

2003-01-01

Background Statins alter lipid concentrations. This systematic review determined the efficacy of particular statins, in terms of their ability to alter cholesterol. Review methods PubMed, the Cochrane Library, references lists of reports, and reviews were searched (September 2001) for randomised, double blind trials of statins for cholesterol in trials of 12 weeks or longer. Mean change in total cholesterol, LDL-cholesterol, HDL-cholesterol, and triglycerides was calculated using pooled data for particular statins, and for particular doses of a statin. Pre-planned sensitivity analyses were used to determine the effects of initial concentration of total cholesterol, study duration, the effects of major trials, and effects in placebo versus active controlled trials. Information was not collected on adverse events. Results Different statins at a range of doses reduced total cholesterol by 17–35% and LDL-cholesterol by 24–49% from baseline. Lower doses of statins generally produced less cholesterol lowering, though for most statins in trials of 12 weeks or longer there was at best only a weak relationship between dose and cholesterol reduction. Duration of treatment and baseline total cholesterol concentration did not alter the amount of the benefit attained. Conclusions Statins are effective medicines and confer benefit to patients in terms of primary and secondary prevention of coronary heart disease. Reductions in total cholesterol of 25% or more and LDL cholesterol of more than 30% were recorded for fixed doses of simvastatin 40 mg, atorvastatin 10 mg, and rosuvastatin 5 mg and 10 mg. PMID:14969594

Lifetimes and spatio-temporal response of protein crystals in intense X-ray microbeams

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

Warkentin, Matthew A.; Atakisi, Hakan; Hopkins, Jesse B.

Serial synchrotron-based crystallography using intense microfocused X-ray beams, fast-framing detectors and protein microcrystals held at 300 K promises to expand the range of accessible structural targets and to increase overall structure-pipeline throughputs. To explore the nature and consequences of X-ray radiation damage under microbeam illumination, the time-, dose- and temperature-dependent evolution of crystal diffraction have been measured with maximum dose rates of 50 MGy s −1 . At all temperatures and dose rates, the integrated diffraction intensity for a fixed crystal orientation shows non-exponential decays with dose. Non-exponential decays are a consequence of non-uniform illumination and the resulting spatial evolution of diffracted intensitymore » within the illuminated crystal volume. To quantify radiation-damage lifetimes and the damage state of diffracting crystal regions, a revised diffraction-weighted dose (DWD) is defined and it is shown that for Gaussian beams the DWD becomes nearly independent of actual dose at large doses. An apparent delayed onset of radiation damage seen in some intensity–dose curves is in fact a consequence of damage. Intensity fluctuations at high dose rates may arise from the impulsive release of gaseous damage products. Accounting for these effects, data collection at the highest dose rates increases crystal radiation lifetimes near 300 K (but not at 100 K) by a factor of ∼1.5–2 compared with those observed at conventional dose rates. Improved quantification and modeling of the complex spatio-temporal evolution of protein microcrystal diffraction in intense microbeams will enable more efficient data collection, and will be essential in improving the accuracy of structure factors and structural models.« less

Lifetimes and spatio-temporal response of protein crystals in intense X-ray microbeams

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

Warkentin, Matthew A.; Atakisi, Hakan; Hopkins, Jesse B.

Serial synchrotron-based crystallography using intense microfocused X-ray beams, fast-framing detectors and protein microcrystals held at 300 K promises to expand the range of accessible structural targets and to increase overall structure-pipeline throughputs. To explore the nature and consequences of X-ray radiation damage under microbeam illumination, the time-, dose- and temperature-dependent evolution of crystal diffraction have been measured with maximum dose rates of 50 MGy s –1. At all temperatures and dose rates, the integrated diffraction intensity for a fixed crystal orientation shows non-exponential decays with dose. Non-exponential decays are a consequence of non-uniform illumination and the resulting spatial evolution ofmore » diffracted intensity within the illuminated crystal volume. To quantify radiation-damage lifetimes and the damage state of diffracting crystal regions, a revised diffraction-weighted dose (DWD) is defined and it is shown that for Gaussian beams the DWD becomes nearly independent of actual dose at large doses. An apparent delayed onset of radiation damage seen in some intensity–dose curves is in fact a consequence of damage. Intensity fluctuations at high dose rates may arise from the impulsive release of gaseous damage products. Accounting for these effects, data collection at the highest dose rates increases crystal radiation lifetimes near 300 K (but not at 100 K) by a factor of ~1.5–2 compared with those observed at conventional dose rates. As a result, improved quantification and modeling of the complex spatio-temporal evolution of protein microcrystal diffraction in intense microbeams will enable more efficient data collection, and will be essential in improving the accuracy of structure factors and structural models.« less

Lifetimes and spatio-temporal response of protein crystals in intense X-ray microbeams

DOE PAGES

Warkentin, Matthew A.; Atakisi, Hakan; Hopkins, Jesse B.; ...

2017-10-13

Serial synchrotron-based crystallography using intense microfocused X-ray beams, fast-framing detectors and protein microcrystals held at 300 K promises to expand the range of accessible structural targets and to increase overall structure-pipeline throughputs. To explore the nature and consequences of X-ray radiation damage under microbeam illumination, the time-, dose- and temperature-dependent evolution of crystal diffraction have been measured with maximum dose rates of 50 MGy s –1. At all temperatures and dose rates, the integrated diffraction intensity for a fixed crystal orientation shows non-exponential decays with dose. Non-exponential decays are a consequence of non-uniform illumination and the resulting spatial evolution ofmore » diffracted intensity within the illuminated crystal volume. To quantify radiation-damage lifetimes and the damage state of diffracting crystal regions, a revised diffraction-weighted dose (DWD) is defined and it is shown that for Gaussian beams the DWD becomes nearly independent of actual dose at large doses. An apparent delayed onset of radiation damage seen in some intensity–dose curves is in fact a consequence of damage. Intensity fluctuations at high dose rates may arise from the impulsive release of gaseous damage products. Accounting for these effects, data collection at the highest dose rates increases crystal radiation lifetimes near 300 K (but not at 100 K) by a factor of ~1.5–2 compared with those observed at conventional dose rates. As a result, improved quantification and modeling of the complex spatio-temporal evolution of protein microcrystal diffraction in intense microbeams will enable more efficient data collection, and will be essential in improving the accuracy of structure factors and structural models.« less

Lifetimes and spatio-temporal response of protein crystals in intense X-ray microbeams

DOE PAGES

Warkentin, Matthew A.; Atakisi, Hakan; Hopkins, Jesse B.; ...

2017-10-13

Serial synchrotron-based crystallography using intense microfocused X-ray beams, fast-framing detectors and protein microcrystals held at 300 K promises to expand the range of accessible structural targets and to increase overall structure-pipeline throughputs. To explore the nature and consequences of X-ray radiation damage under microbeam illumination, the time-, dose- and temperature-dependent evolution of crystal diffraction have been measured with maximum dose rates of 50 MGy s −1 . At all temperatures and dose rates, the integrated diffraction intensity for a fixed crystal orientation shows non-exponential decays with dose. Non-exponential decays are a consequence of non-uniform illumination and the resulting spatial evolution of diffracted intensitymore » within the illuminated crystal volume. To quantify radiation-damage lifetimes and the damage state of diffracting crystal regions, a revised diffraction-weighted dose (DWD) is defined and it is shown that for Gaussian beams the DWD becomes nearly independent of actual dose at large doses. An apparent delayed onset of radiation damage seen in some intensity–dose curves is in fact a consequence of damage. Intensity fluctuations at high dose rates may arise from the impulsive release of gaseous damage products. Accounting for these effects, data collection at the highest dose rates increases crystal radiation lifetimes near 300 K (but not at 100 K) by a factor of ∼1.5–2 compared with those observed at conventional dose rates. Improved quantification and modeling of the complex spatio-temporal evolution of protein microcrystal diffraction in intense microbeams will enable more efficient data collection, and will be essential in improving the accuracy of structure factors and structural models.« less

13 CFR 123.400 - What is the Pre-Disaster Mitigation Loan Program?

Code of Federal Regulations, 2013 CFR

2013-01-01

... Mitigation Loan Program? 123.400 Section 123.400 Business Credit and Assistance SMALL BUSINESS ADMINISTRATION DISASTER LOAN PROGRAM Pre-Disaster Mitigation Loans § 123.400 What is the Pre-Disaster Mitigation Loan Program? The Pre-Disaster Mitigation Loan Program allows SBA to make low interest, fixed rate loans to...

13 CFR 123.400 - What is the Pre-Disaster Mitigation Loan Program?

Code of Federal Regulations, 2012 CFR

2012-01-01

... Mitigation Loan Program? 123.400 Section 123.400 Business Credit and Assistance SMALL BUSINESS ADMINISTRATION DISASTER LOAN PROGRAM Pre-Disaster Mitigation Loans § 123.400 What is the Pre-Disaster Mitigation Loan Program? The Pre-Disaster Mitigation Loan Program allows SBA to make low interest, fixed rate loans to...

13 CFR 123.400 - What is the Pre-Disaster Mitigation Loan Program?

Code of Federal Regulations, 2014 CFR

2014-01-01

... Mitigation Loan Program? 123.400 Section 123.400 Business Credit and Assistance SMALL BUSINESS ADMINISTRATION DISASTER LOAN PROGRAM Pre-Disaster Mitigation Loans § 123.400 What is the Pre-Disaster Mitigation Loan Program? The Pre-Disaster Mitigation Loan Program allows SBA to make low interest, fixed rate loans to...

13 CFR 123.400 - What is the Pre-Disaster Mitigation Loan Program?

Code of Federal Regulations, 2011 CFR

2011-01-01

... Mitigation Loan Program? 123.400 Section 123.400 Business Credit and Assistance SMALL BUSINESS ADMINISTRATION DISASTER LOAN PROGRAM Pre-Disaster Mitigation Loans § 123.400 What is the Pre-Disaster Mitigation Loan Program? The Pre-Disaster Mitigation Loan Program allows SBA to make low interest, fixed rate loans to...

13 CFR 123.400 - What is the Pre-Disaster Mitigation Loan Program?

Code of Federal Regulations, 2010 CFR

2010-01-01

... Mitigation Loan Program? 123.400 Section 123.400 Business Credit and Assistance SMALL BUSINESS ADMINISTRATION DISASTER LOAN PROGRAM Pre-Disaster Mitigation Loans § 123.400 What is the Pre-Disaster Mitigation Loan Program? The Pre-Disaster Mitigation Loan Program allows SBA to make low interest, fixed rate loans to...

Clinical experience in treating hypertension with fixed-dose combination therapy: angiotensin II receptor blocker losartan plus hydrochlorothiazide.

PubMed

Abe, Masanori; Okada, Kazuyoshi; Matsumoto, Koichi

2009-10-01

The goal of antihypertensive treatment is to reduce cardiovascular and cerebrovascular events associated with high blood pressure. A combination therapy with different antihypertensive agents is more successful than monotherapy in most hypertensive patients, with the added advantage of a better safety profile. Therefore, treatment of hypertensive patients with fixed-dose combination therapy consisting of the angiotensin II receptor blocker losartan along with hydrochlorothiazide (HCTZ) has several potential benefits over monotherapy with each individual component. It provides more effective blood pressure control, a reduction in the likelihood of adverse effects and facilitation of patient compliance due to a simple once-daily regimen. One of the advantages of the combination of losartan with HCTZ is the potential reduction in HCTZ-induced metabolic disorders; in particular, this combination can have attractive benefits for patients of hyperuricemia. Losartan plus HCTZ fixed-dose combination therapy is frequently recommended for the treatment of hypertension and lowers blood pressure in mild-to-moderate and even severe hypertensive patients to a level comparable with other classes of antihypertensive agents in combination with HCTZ. Fixed-dose combination therapy with losartan plus HCTZ is a logical choice as antihypertensive therapy for patients in whom combination therapy is necessary to achieve additional blood pressure reduction.

Is volumetric modulated arc therapy with constant dose rate a valid option in radiation therapy for head and neck cancer patients?

PubMed

Didona, Annamaria; Lancellotta, Valentina; Zucchetti, Claudio; Panizza, Bianca Moira; Frattegiani, Alessandro; Iacco, Martina; Di Pilato, Anna Concetta; Saldi, Simonetta; Aristei, Cynthia

2018-01-01

Intensity-modulated radiotherapy (IMRT) improves dose distribution in head and neck (HN) radiation therapy. Volumetric-modulated arc therapy (VMAT), a new form of IMRT, delivers radiation in single or multiple arcs, varying dose rates (VDR-VMAT) and gantry speeds, has gained considerable attention. Constant dose rate VMAT (CDR-VMAT) associated with a fixed gantry speed does not require a dedicated linear accelerator like VDR-VMAT. The present study explored the feasibility, efficiency and delivery accuracy of CDR-VMAT, by comparing it with IMRT and VDR-VMAT in treatment planning for HN cancer. Step and shoot IMRT (SS-IMRT), CDR-VMAT and VDR-VMAT plans were created for 15 HN cancer patients and were generated by Pinnacle 3 TPS (v 9.8) using 6 MV photon energy. Three PTVs were defined to receive respectively prescribed doses of 66 Gy, 60 Gy and 54 Gy, in 30 fractions. Organs at risk (OARs) included the mandible, spinal cord, brain stem, parotids, salivary glands, esophagus, larynx and thyroid. SS-IMRT plans were based on 7 co-planar beams at fixed gantry angles. CDR-VMAT and VDR-VMAT plans, generated by the SmartArc module, used a 2-arc technique: one clockwise from 182° to 178° and the other one anti-clockwise from 178° to 182°. Comparison parameters included dose distribution to PTVs ( D mean , D 2% , D 50% , D 95% , D 98% and Homogeneity Index), maximum or mean doses to OARs, specific dose-volume data, the monitor units and treatment delivery times. Compared with SS-IMRT, CDR-VMAT significantly reduced the maximum doses to PTV1 and PTV2 and significantly improved all PTV3 parameters, except D 98% and D 95% . It significantly spared parotid and submandibular glands and was associated with a lower D mean to the larynx. Compared with VDR-VMAT, CDR-VMAT was linked to a significantly better D mean , to the PTV3 but results were worse for the parotids, left submandibular gland, esophagus and mandible. Furthermore, the D mean to the larynx was also worse. Compared with SS-IMRT and VDR-VMAT, CDR-VMAT was associated with higher average monitor unit values and significantly shorter average delivery times. CDR-VMAT appeared to be a valid option in Radiation Therapy Centers that lack a dedicated linear accelerator for volumetric arc therapy with variable dose-rates and gantry velocities, and are unwilling or unable to sanction major expenditure at present but want to adopt volumetric techniques.

Improved Consistency in Dosing Anti-Tuberculosis Drugs in Taipei, Taiwan

PubMed Central

Chiang, Chen-Yuan; Yu, Ming-Chih; Shih, Hsiu-Chen; Yen, Muh-Yong; Hsu, Yu-Ling; Yang, Shiang-Lin; Lin, Tao-Ping; Bai, Kuan-Jen

2012-01-01

Background It was reported that 35.5% of tuberculosis (TB) cases reported in 2003 in Taipei City had no recorded pre-treatment body weight and that among those who had, inconsistent dosing of anti-TB drugs was frequent. Taiwan Centers for Disease Control (CDC) have taken actions to strengthen dosing of anti-TB drugs among general practitioners. Prescribing practices of anti-TB drugs in Taipei City in 2007–2010 were investigated to assess whether interventions on dosing were effective. Methodology/Principal Findings Lists of all notified culture positive TB cases in 2007–2010 were obtained from National TB Registry at Taiwan CDC. A medical audit of TB case management files was performed to collect pretreatment body weight and regimens prescribed at commencement of treatment. Dosages prescribed were compared with dosages recommended. The proportion of patients with recorded pre-treatment body weight was 64.5% in 2003, which increased to 96.5% in 2007–2010 (p<0.001). The proportion of patients treated with consistent dosing of a 3-drug fixed-dose combination (FDC) increased from 73.9% in 2003 to 87.7% in 2007–2010 (p<0.001), and that for 2-drug FDC from 76.0% to 86.1% (p = 0.024), for rifampicin (RMP) from 62.8% to 85.5% (p<0.001), and for isoniazid from 87.8% to 95.3% (p<0.001). In 2007–2010, among 2917 patients treated with either FDCs or RMP in single-drug preparation, the dosage of RMP was adequate (8–12 mg/kg) in 2571(88.1%) patients, too high in 282(9.7%), too low in 64(2.2%). In multinomial logistic regression models, factors significantly associated with adequate dosage of RMP were body weight and preparations of RMP. Patients weighting <40kg (relative risk ratio (rrr) 6010.5, 95% CI 781.1–46249.7) and patients weighting 40–49 kg (rrr 1495.3, 95% CI 200.6–11144.6) were more likely to receive higher-than-recommended dose of RMP. Conclusions/Significance Prescribing practice in the treatment of TB in Taipei City has remarkably improved after health authorities implemented a series of interventions. PMID:22952900

A randomized controlled trial of increased dose and frequency of albendazole with standard dose DEC for treatment of Wuchereria bancrofti microfilaremics in Odisha, India.

PubMed

Kar, Shantanu Kumar; Dwibedi, Bhagirathi; Kerketa, Anna Salomi; Maharana, Antaryami; Panda, Sudanshu S; Mohanty, Prafulla Chandra; Horton, John; Ramachandran, Cherubala P

2015-03-01

Although current programmes to eliminate lymphatic filariasis have made significant progress it may be necessary to use different approaches to achieve the global goal, especially where compliance has been poor and 'hot spots' of continued infection exist. In the absence of alternative drugs, the use of higher or more frequent dosing with the existing drugs needs to be explored. We examined the effect of higher and/or more frequent dosing with albendazole with a fixed 300 mg dose of diethylcarbamazine in a Wuchereria bancrofti endemic area in Odisha, India. Following screening, 104 consenting adults were randomly assigned to treatment with the standard regimen annually for 24 months (S1), or annually with increased dose (800 mg albendazole)(H1) or with increased frequency (6 monthly) with either standard (S2) or increased (H2) dose. Pre-treatment microfilaria counts (GM) ranged from 348 to 459 mf/ml. Subjects were followed using microfilaria counts, OG4C3 antigen levels and ultrasound scanning for adult worm nests. Microfilarial counts tended to decrease more rapidly with higher or more frequent dosing at all time points. At 12 months, Mf clearance was marginally greater with the high dose regimens, while by 24 months, there was a trend to higher Mf clearance in the arm with increased frequency and 800 mg of albendazole (76.9%) compared to other arms, (S1:64%, S2:69.2% & H1:73.1%). Although higher and/or more frequent dosing showed a trend towards a greater decline in antigenemia and clearance of "nests", all regimens demonstrated the potential macrofilaricidal effect of the combination. The higher doses of albendazole did not result in a greater number or more severe side effects. The alternative regimens could be useful in the later stages of existing elimination programmes or achieving elimination more rapidly in areas where programmes have yet to start.

Differences in night-time and daytime ambulatory blood pressure when diurnal periods are defined by self-report, fixed-times, and actigraphy: Improving the Detection of Hypertension study.

PubMed

Booth, John N; Muntner, Paul; Abdalla, Marwah; Diaz, Keith M; Viera, Anthony J; Reynolds, Kristi; Schwartz, Joseph E; Shimbo, Daichi

2016-02-01

To determine whether defining diurnal periods by self-report, fixed-time, or actigraphy produce different estimates of night-time and daytime ambulatory blood pressure (ABP). Over a median of 28 days, 330 participants completed two 24-h ABP and actigraphy monitoring periods with sleep diaries. Fixed night-time and daytime periods were defined as 0000-0600 h and 1000-2000 h, respectively. Using the first ABP period, within-individual differences for mean night-time and daytime ABP and kappa statistics for night-time and daytime hypertension (systolic/diastolic ABP≥120/70 mmHg and ≥135/85 mmHg, respectively) were estimated comparing self-report, fixed-time, or actigraphy for defining diurnal periods. Reproducibility of ABP was also estimated. Within-individual mean differences in night-time systolic ABP were small, suggesting little bias, when comparing the three approaches used to define diurnal periods. The distribution of differences, represented by 95% confidence intervals (CI), in night-time systolic and diastolic ABP and daytime systolic and diastolic ABP was narrowest for self-report versus actigraphy. For example, mean differences (95% CI) in night-time systolic ABP for self-report versus fixed-time was -0.53 (-6.61, +5.56) mmHg, self-report versus actigraphy was 0.91 (-3.61, +5.43) mmHg, and fixed-time versus actigraphy was 1.43 (-5.59, +8.46) mmHg. Agreement for night-time and daytime hypertension was highest for self-report versus actigraphy: kappa statistic (95% CI) = 0.91 (0.86,0.96) and 1.00 (0.98,1.00), respectively. The reproducibility of mean ABP and hypertension categories was similar using each approach. Given the high agreement with actigraphy, these data support using self-report to define diurnal periods on ABP monitoring. Further, the use of fixed-time periods may be a reasonable alternative approach.

Ocular pharmacokinetics and tolerability of bimatoprost ophthalmic solutions administered once or twice daily in rabbits, and clinical dosing implications

PubMed Central

Shen, Jie; Goodkin, Margot L; Tong, Warren; Attar, Mayssa

2017-01-01

Purpose Fixed-combination medications can benefit patients requiring multiple agents to lower their intraocular pressure (IOP), but combining agents with complementary mechanisms of action is challenging if their dosing frequency differs. This study compares in vivo pharmacokinetic and ocular tolerability of bimatoprost 0.01% ophthalmic solutions dosed once or twice daily. Reports of twice-daily dosing in glaucoma patients are also reviewed. Methods New Zealand White rabbits were administered bimatoprost 0.01% monotherapy or fixed-combination bimatoprost 0.01%/brimonidine 0.1%, once or twice daily in both eyes for 4 days. Ocular tissues were harvested and analyzed by liquid chromatography-tandem mass spectrometry. The pharmacokinetic parameters calculated included maximum observed concentration, time to maximum concentration, and area under the concentration-time curve. Results Due to extensive metabolism, bimatoprost concentration was below the quantitation limit by 1 hour post-dose in all samples. Bimatoprost acid exposure, however, could be measured up to 6–8 hours post-dose and was similar in the aqueous humor and iris-ciliary body (pharmacological site of action) of animals treated once or twice daily with either bimatoprost 0.01% or fixed-combination bimatoprost 0.01%/brimonidine 0.1%. Increasing dosage frequency in rabbits did not raise the incidence of drug-related conjunctival hyperemia (most common adverse event associated with bimatoprost use in humans), suggesting comparable ocular tolerability of the once- and twice-daily regimens for each formulation. Conclusion Bimatoprost 0.01% administered once or twice daily as monotherapy and in fixed-combination with brimonidine 0.1% in rabbits show similar pharmacokinetic profiles of bimatoprost acid, especially in the iris-ciliary body. Key findings from previous clinical studies suggest that by varying the concentration of benzalkonium chloride (a preservative with corneal penetration-enhancing properties), formulations of bimatoprost 0.01% can be administered once or twice daily. These findings support development of bimatoprost 0.01%-based fixed-dose combination therapies administered twice daily for patients who require multiple adjunctive medications to control their IOP. PMID:29026287

Determining the use of prophylactic antibiotics in breast cancer surgeries: a survey of practice

PubMed Central

2012-01-01

Background Prophylactic antibiotics (PAs) are beneficial to breast cancer patients undergoing surgery because they prevent surgical site infection (SSI), but limited information regarding their use has been published. This study aims to determine the use of PAs prior to breast cancer surgery amongst breast surgeons in Colombia. Methods An online survey was distributed amongst the breast surgeon members of the Colombian Association of Mastology, the only breast surgery society of Colombia. The scope of the questions included demographics, clinical practice characteristics, PA prescription characteristics, and the use of PAs in common breast surgical procedures. Results The survey was distributed amongst eighty-eight breast surgeons of whom forty-seven responded (response rate: 53.4%). Forty surgeons (85.1%) reported using PAs prior to surgery of which >60% used PAs during mastectomy, axillary lymph node dissection, and/or breast reconstruction. Surgeons reported they targeted the use of PAs in cases in which patients had any of the following SSI risk factors: diabetes mellitus, drains in situ, obesity, and neoadjuvant therapy. The distribution of the self-reported PA dosing regimens was as follows: single pre-operative fixed-dose (27.7%), single preoperative dose followed by a second dose if the surgery was prolonged (44.7%), single preoperative dose followed by one or more postoperative doses for >24 hours (10.6%), and single preoperative weight-adjusted dose (2.1%). Conclusion Although this group of breast surgeons is aware of the importance of PAs in breast cancer surgery there is a discrepancy in how they use it, specifically with regards to prescription and timeliness of drug administration. Our findings call for targeted quality-improvement initiatives, such as standardized national guidelines, which can provide sufficient evidence for all stakeholders and therefore facilitate best practice medicine for breast cancer surgery. PMID:22937833

Determining the use of prophylactic antibiotics in breast cancer surgeries: a survey of practice.

PubMed

Acuna, Sergio A; Angarita, Fernando A; Escallon, Jaime; Tawil, Mauricio; Torregrosa, Lilian

2012-08-31

Prophylactic antibiotics (PAs) are beneficial to breast cancer patients undergoing surgery because they prevent surgical site infection (SSI), but limited information regarding their use has been published. This study aims to determine the use of PAs prior to breast cancer surgery amongst breast surgeons in Colombia. An online survey was distributed amongst the breast surgeon members of the Colombian Association of Mastology, the only breast surgery society of Colombia. The scope of the questions included demographics, clinical practice characteristics, PA prescription characteristics, and the use of PAs in common breast surgical procedures. The survey was distributed amongst eighty-eight breast surgeons of whom forty-seven responded (response rate: 53.4%). Forty surgeons (85.1%) reported using PAs prior to surgery of which >60% used PAs during mastectomy, axillary lymph node dissection, and/or breast reconstruction. Surgeons reported they targeted the use of PAs in cases in which patients had any of the following SSI risk factors: diabetes mellitus, drains in situ, obesity, and neoadjuvant therapy. The distribution of the self-reported PA dosing regimens was as follows: single pre-operative fixed-dose (27.7%), single preoperative dose followed by a second dose if the surgery was prolonged (44.7%), single preoperative dose followed by one or more postoperative doses for >24 hours (10.6%), and single preoperative weight-adjusted dose (2.1%). Although this group of breast surgeons is aware of the importance of PAs in breast cancer surgery there is a discrepancy in how they use it, specifically with regards to prescription and timeliness of drug administration. Our findings call for targeted quality-improvement initiatives, such as standardized national guidelines, which can provide sufficient evidence for all stakeholders and therefore facilitate best practice medicine for breast cancer surgery.

Canadian Health Measures Survey pre-test: design, methods, results.

PubMed

Tremblay, Mark; Langlois, Renée; Bryan, Shirley; Esliger, Dale; Patterson, Julienne

2007-01-01

The Canadian Health Measures Survey (CHMS) pre-test was conducted to provide information about the challenges and costs associated with administering a physical health measures survey in Canada. To achieve the specific objectives of the pre-test, protocols were developed and tested, and methods for household interviewing and clinic testing were designed and revised. The cost, logistics and suitability of using fixed sites for the CHMS were assessed. Although data collection, transfer and storage procedures are complex, the pre-test experience confirmed Statistics Canada's ability to conduct a direct health measures survey and the willingness of Canadians to participate in such a health survey. Many operational and logistical procedures worked well and, with minor modifications, are being employed in the main survey. Fixed sites were problematic, and survey costs were higher than expected.

Influence of Prostatic Edema on {sup 131}CS Permanent Prostate Seed Implants: A Dosimetric and Radiobiological Study

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

Kehwar, Than S., E-mail: kehwarts@upmc.ed; Jones, Heather A.; Huq, M. Saiful

2011-06-01

Purpose: To study the influence of prostatic edema on postimplant physical and radiobiological parameters using {sup 131}Cs permanent prostate seed implants. Methods and Materials: Thirty-one patients with early prostate cancer who underwent {sup 131}Cs permanent seed implantation were evaluated. Dose-volume histograms were generated for each set of prostate volumes obtained at preimplantation and postimplantion days 0, 14, and 28 to compute quality indices (QIs) and fractional doses at level x (FD{sub x}). A set of equations for QI, FD{sub x}, and biologically effective doses at dose level D{sub x} (BED{sub x}) were defined to account for edema changes with timemore » after implant. Results: There were statistically significant differences found between QIs of pre- and postimplant plans at day 0, except for the overdose index (ODI). QIs correlated with postimplant time, and FD{sub x} was found to increase with increasing postimplant time. With the effect of edema, BED at different dose levels showed less improvement due to the short half-life of {sup 131}Cs, which delivers about 85% of the prescribed dose before the prostate reaches its original volume due to dissipation of edema. Conclusions: Results of the study show that QIs, FD{sub x}, and BEDs at the level of D{sub x} changed from preneedle plans to postimplant plans and have statistically significant differences (p < 0.05), except for the ODI (p = 0.106), which suggests that at the time of {sup 131}C seed implantation, the effect of edema must be accounted for when defining the seed positions, to avoid the possibility of poor dosimetric and radiobiologic results for {sup 131}Cs seed implants.« less

Sensitivity of disease parameters to flexible budesonide/formoterol treatment in an allergic rat model.

PubMed

Brange, Charlotte; Smailagic, Amir; Jansson, Anne-Helene; Middleton, Brian; Miller-Larsson, Anna; Taylor, John D; Silberstein, David S; Lal, Harbans

2009-02-01

Clinical studies show that flexible dosing (maintenance and symptom-driven dose adjustments) of budesonide and formoterol (BUD/FORM) improves control of asthma exacerbations as compared to fixed maintenance dosing protocols (maintenance therapy) even when the latter utilize higher BUD/FORM doses. This suggests that dose-response relationships for certain pathobiologic mechanisms in asthma shift over time. Here, we have conducted animal studies to address this issue. (1) To test in an animal asthma-like model whether it is possible to achieve the same or greater pharmacological control over bronchoconstriction and airway/lung inflammation, and with less total drug used, by flexible BUD/FORM dosing (upward adjustment of doses) in association with allergen challenges. (2) To determine whether the benefit requires adjustment of both drug components. Rats sensitized on days 0 and 7 were challenged intratracheally with ovalbumin on days 14 and 21. On days 13-21, rats were treated intratracheally with fixed maintenance or flexible BUD/FORM combinations. On day 22, rats were challenged with methacholine and lungs were harvested for analysis. A flexible BUD/FORM dosing regimen (using 3.3 times less total drug than the fixed maintenance high dose regimen), delivered the same or greater reductions of excised lung gas volume (a measure of gas trapped in lung by bronchoconstriction) and lung weight (a measure of inflammatory oedema). When either BUD or FORM alone was increased on days of challenge, the benefit of the flexible dose upward adjustment was lost. Flexible dosing of the BUD/FORM combination improves the pharmacological inhibition of allergen-induced bronchoconstriction and an inflammatory oedema in an allergic asthma-like rat model.

Effects of different radiation doses on the microhardness, superficial morphology, and mineral components of human enamel.

PubMed

de Barros da Cunha, Sandra Ribeiro; Fonseca, Felipe Paiva; Ramos, Pedro Augusto Minorin Mendes; Haddad, Cecília Maria Kalil; Fregnani, Eduardo Rodrigues; Aranha, Ana Cecília Corrêa

2017-08-01

To evaluate the effects of three different radiotherapy doses (20, 40, and 70Gy) on the microhardness, superficial morphology, and mineral content (based on Ca and P values) of three different depths of human enamel (cervical, middle, and occlusal). Thirty-four third molars were cut, separated, and prepared. Microhardness samples (n=30) were embedded in acrylic resin and then polished, and depths were delimited. Microhardness tests were performed on cervical, middle, and occlusal enamel pre- and post-radiotherapy with a load of 50g for 30s. For the scanning electron microscopy (SEM) analysis (n=4) and energy dispersive X-ray spectroscopy (EDS) (n=12), samples were fixed in a 3% glutaraldehyde solution, washed in 0.1M cacodylate solution, and dehydrated in crescent concentrations of ethanol. Microhardness data were tested for significant differences using a two-way analysis of variance (ANOVA) and Tukey's test (p<0.05), while SEM and EDS were evaluated qualitatively. The results showed a decrease in microhardness values only in the cervical enamel, regardless of the radiation dose used; no morphological or mineral change was observed. Radiotherapy can affect the microhardness values of only cervical enamel without compromising the morphological or mineral (Ca and P) content at any depth. Copyright © 2017 Elsevier Ltd. All rights reserved.

Cyclopamine-induced synophthalmia in sheep: defining a critical window and toxicokinetic evaluation.

PubMed

Welch, K D; Panter, K E; Lee, S T; Gardner, D R; Stegelmeier, B L; Cook, D

2009-07-01

Cyclopamine, a steroidal alkaloid, from the plant Veratrum californicum is teratogenic, causing a range of different birth defects. The critical window for cyclopamine-induced synophthalmia formation has been reported to be gestational day (GD) 14. The objectives of this study were to better describe cyclopamine-induced craniofacial deformities, to better define the window of susceptibility to synophthalmia formation, and to characterize cyclopamine toxicokinetics in sheep. Ewes were dosed i.v. with purified cyclopamine for toxicokinetic analysis. Another four groups of ewes were dosed orally twice daily with 0.88 g/kg of V. californicum on GD 13, 14 or 15 or consecutively on GD days 13-15. Pregnancy and pre-partum fetal malformations were determined by ultrasound imaging on GD 60. At parturition lambs were assessed for gross malformations. The elimination half-life of cyclopamine in ewes was determined to be 1.1 +/- 0.1 h. The rapid clearance of cyclopamine indicates that ingestion of V. californicum must occur during a very narrow window for synophthalmia formation to occur. Ewes dosed with V. californicum on GD 13 or 14 had lambs with various craniofacial malformations including cyclopia, maxillary dysplasia and mandibular micrognathia. Ewes dosed on GD 15 delivered normal lambs. Ewes dosed consecutively on GD 13-15 were not pregnant at GD 60 and Veratrum-induced embryonic death was assumed to be the cause. Interestingly, lambs with cyclopia were smaller, under-developed and appeared premature even though their twin appeared fully developed. Initial evaluations suggest this was due to placental dysplasia. 2009 by John Wiley & Sons, Ltd.

Efficacy and safety of a fixed combination of tramadol and paracetamol (acetaminophen) as pain therapy within palliative medicine.

PubMed

Husic, Samir; Izic, Senad; Matic, Srecko; Sukalo, Aziz

2015-02-01

The goal of the research was to determine the efficacy of a fixed combination of tramadol and paracetamol (acetaminophen) in the treatment of pain of patients with the advanced stage of cancer. A prospective study was conducted at the Center for Palliative Care, University Clinical Center Tuzla, Bosnia and Herzegovina, from January 1(st) to December 31(st) 2013. A total of 353 patients who were treated with a fixed combination of tramadol and acetaminophen (37.5 mg and 325 mg) at the initial dosage 3x1 tablet (112.5 mg tramadol and 975 mg acetaminophen) for pain intensity 4, up to 4x2 tablets (300 mg of tramadol and 2600 mg paracetamol) for pain intensity 7 and 8. If the patient during previous day has two or more pain episodes that required a "rescue dose" of tramadol, increased was the dose of fixed combination tramadol and acetaminophen to a maximum of 8 tablets daily (300 mg of tramadol and 2600 mg paracetamol). Statistical analysis was performed by biomedical software MedCalc for Windows version 9.4.2.0. The difference was considered significant for P<0.05. The average duration of treatment with a fixed combination tramadol and acetaminophen was 57 days (13-330 days). Already after 24 hours of treatment the average pain score was significantly lower (p<0.0001) compared to the admission day [5.00 (4:00 to 8:00) during the first days versus 2.00 (1:00 to 7:00) during the second day of treatment]. The average dose of the fixed combination tramadol and acetaminophen tablets was 4.8 ± 1.8 (180 mg of tramadol and 1560 mg paracetamol). Side effects, in the treatment of pain with a fixed combination tramadol and acetaminophen, were found in 29.18% of patients, with a predominance of nausea and vomiting. Fixed combination of tramadol and acetaminophen can be used as an effective combination in the treatment of chronic cancer pain, with frequent dose evaluation and mild side effects.

Investigation of the Behavior of the Co C Eutectic Fixed Point

NASA Astrophysics Data System (ADS)

Girard, F.; Battuello, M.; Florio, M.

2007-12-01

The behavior of the Co C eutectic fixed point was investigated at INRIM. Several cells of different design and volume, and filled with cobalt of different purity were constructed and investigated with both Pt/Pd thermocouples and radiation thermometers. The melting behavior was investigated with respect to the melting rate, the pre-freezing rate, and the annealing time. The melting temperatures, as defined, were not significantly affected by the different testing conditions, even if the shape and duration of the plateaux were influenced. Several tens of melt and freeze cycles were performed with the different cells. The spread in the results for all of the different conditions was very limited in extent, giving rise to a standard deviation of less than 0.04 °C; a repeatability of better than 0.02 °C was found with both Pt/Pd thermocouples and radiation thermometers. The results of our measurements are encouraging and confirm the suitability of Co C as a reference point for the high-temperature range in a possible future temperature scale. Investigations of long-term stability remain ongoing.

The colorimetric analysis of anti-tuberculosis fixed-dose combination tablets and capsules.

PubMed

Ellard, G A

1999-11-01

The perceived need to demonstrate whether or not the actual amounts of rifampicin, isoniazid and pyrazinamide in fixed-dose combination tablets or capsules correspond to their stated drug contents. To adapt specific, robust and simple colorimetric methods that have been previously applied to measuring plasma and urinary rifampicin, isoniazid, pyrazinamide and ethambutol concentrations to estimate tablet and capsule drug contents. The methods were applied to the analysis of 14 commercially manufactured fixed-dose combinations: two capsule and three tablet formulations containing rifampicin and isoniazid; seven tablet formulations containing rifampicin, isoniazid and pyrazinamide; and two tablet formulations containing rifampicin, isoniazid, pyrazinamide and ethambutol. All the combined formulations contained near to their stated drug contents. Replicate analyses confirmed the excellent precision of the drug analyses. Such methods are not only rapid to perform but should be practical in many Third World situations with relatively modest laboratory facilities.

13 CFR 123.406 - What is the interest rate on a pre-disaster mitigation loan?

Code of Federal Regulations, 2010 CFR

2010-01-01

... 13 Business Credit and Assistance 1 2010-01-01 2010-01-01 false What is the interest rate on a pre... ADMINISTRATION DISASTER LOAN PROGRAM Pre-Disaster Mitigation Loans § 123.406 What is the interest rate on a pre-disaster mitigation loan? The interest rate on a pre-disaster mitigation loan will be fixed at 4 percent...

13 CFR 123.406 - What is the interest rate on a pre-disaster mitigation loan?

Code of Federal Regulations, 2011 CFR

2011-01-01

...-disaster mitigation loan? 123.406 Section 123.406 Business Credit and Assistance SMALL BUSINESS ADMINISTRATION DISASTER LOAN PROGRAM Pre-Disaster Mitigation Loans § 123.406 What is the interest rate on a pre-disaster mitigation loan? The interest rate on a pre-disaster mitigation loan will be fixed at 4 percent...

13 CFR 123.406 - What is the interest rate on a pre-disaster mitigation loan?

Code of Federal Regulations, 2014 CFR

2014-01-01

...-disaster mitigation loan? 123.406 Section 123.406 Business Credit and Assistance SMALL BUSINESS ADMINISTRATION DISASTER LOAN PROGRAM Pre-Disaster Mitigation Loans § 123.406 What is the interest rate on a pre-disaster mitigation loan? The interest rate on a pre-disaster mitigation loan will be fixed at 4 percent...

13 CFR 123.406 - What is the interest rate on a pre-disaster mitigation loan?

Code of Federal Regulations, 2012 CFR

2012-01-01

...-disaster mitigation loan? 123.406 Section 123.406 Business Credit and Assistance SMALL BUSINESS ADMINISTRATION DISASTER LOAN PROGRAM Pre-Disaster Mitigation Loans § 123.406 What is the interest rate on a pre-disaster mitigation loan? The interest rate on a pre-disaster mitigation loan will be fixed at 4 percent...

13 CFR 123.406 - What is the interest rate on a pre-disaster mitigation loan?

Code of Federal Regulations, 2013 CFR

2013-01-01

...-disaster mitigation loan? 123.406 Section 123.406 Business Credit and Assistance SMALL BUSINESS ADMINISTRATION DISASTER LOAN PROGRAM Pre-Disaster Mitigation Loans § 123.406 What is the interest rate on a pre-disaster mitigation loan? The interest rate on a pre-disaster mitigation loan will be fixed at 4 percent...

SU-C-202-03: A Tool for Automatic Calculation of Delivered Dose Variation for Off-Line Adaptive Therapy Using Cone Beam CT

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

Zhang, B; Lee, S; Chen, S

Purpose: Monitoring the delivered dose is an important task for the adaptive radiotherapy (ART) and for determining time to re-plan. A software tool which enables automatic delivered dose calculation using cone-beam CT (CBCT) has been developed and tested. Methods: The tool consists of four components: a CBCT Colleting Module (CCM), a Plan Registration Moduel (PRM), a Dose Calculation Module (DCM), and an Evaluation and Action Module (EAM). The CCM is triggered periodically (e.g. every 1:00 AM) to search for newly acquired CBCTs of patients of interest and then export the DICOM files of the images and related registrations defined inmore » ARIA followed by triggering the PRM. The PRM imports the DICOM images and registrations, links the CBCTs to the related treatment plan of the patient in the planning system (RayStation V4.5, RaySearch, Stockholm, Sweden). A pre-determined CT-to-density table is automatically generated for dose calculation. Current version of the DCM uses a rigid registration which regards the treatment isocenter of the CBCT to be the isocenter of the treatment plan. Then it starts the dose calculation automatically. The AEM evaluates the plan using pre-determined plan evaluation parameters: PTV dose-volume metrics and critical organ doses. The tool has been tested for 10 patients. Results: Automatic plans are generated and saved in the order of the treatment dates of the Adaptive Planning module of the RayStation planning system, without any manual intervention. Once the CTV dose deviates more than 3%, both email and page alerts are sent to the physician and the physicist of the patient so that one can look the case closely. Conclusion: The tool is capable to perform automatic dose tracking and to alert clinicians when an action is needed. It is clinically useful for off-line adaptive therapy to catch any gross error. Practical way of determining alarming level for OAR is under development.« less

Evaluation of the use of automatic exposure control and automatic tube potential selection in low-dose cerebrospinal fluid shunt head CT.

PubMed

Wallace, Adam N; Vyhmeister, Ross; Bagade, Swapnil; Chatterjee, Arindam; Hicks, Brandon; Ramirez-Giraldo, Juan Carlos; McKinstry, Robert C

2015-06-01

Cerebrospinal fluid shunts are primarily used for the treatment of hydrocephalus. Shunt complications may necessitate multiple non-contrast head CT scans resulting in potentially high levels of radiation dose starting at an early age. A new head CT protocol using automatic exposure control and automated tube potential selection has been implemented at our institution to reduce radiation exposure. The purpose of this study was to evaluate the reduction in radiation dose achieved by this protocol compared with a protocol with fixed parameters. A retrospective sample of 60 non-contrast head CT scans assessing for cerebrospinal fluid shunt malfunction was identified, 30 of which were performed with each protocol. The radiation doses of the two protocols were compared using the volume CT dose index and dose length product. The diagnostic acceptability and quality of each scan were evaluated by three independent readers. The new protocol lowered the average volume CT dose index from 15.2 to 9.2 mGy representing a 39 % reduction (P < 0.01; 95 % CI 35-44 %) and lowered the dose length product from 259.5 to 151.2 mGy/cm representing a 42 % reduction (P < 0.01; 95 % CI 34-50 %). The new protocol produced diagnostically acceptable scans with comparable image quality to the fixed parameter protocol. A pediatric shunt non-contrast head CT protocol using automatic exposure control and automated tube potential selection reduced patient radiation dose compared with a fixed parameter protocol while producing diagnostic images of comparable quality.

Effects of fixed or self-titrated dosages of Sativex on cannabis withdrawal and cravings

PubMed Central

Trigo, Jose M.; Lagzdins, Dina; Rehm, Jürgen; Selby, Peter; Gamaleddin, Islam; Fischer, Benedikt; Barnes, Allan J.; Huestis, Marilyn A.; Le Foll, Bernard

2016-01-01

Background There is currently no pharmacological treatment approved for cannabis dependence. In this proof of concept study, we assessed the feasibility/effects of fixed and self-titrated dosages of Sativex (1:1, Δ9-tetrahydrocannabinol (THC)/cannabidiol (CBD)) on craving and withdrawal from cannabis among nine community-recruited cannabis-dependent subjects. Methods Participants underwent an 8-week double-blind placebo-controlled trial (an ABACADAE design), with four smoke as usual conditions (SAU) (A) separated by four cannabis abstinence conditions (B–E), with administration of either self-titrated/fixed doses of placebo or Sativex (up to 108 mg THC/100 mg CBD). The order of medication administration during abstinence conditions was randomized and counterbalanced. Withdrawal symptoms and craving were assessed using the Cannabis Withdrawal Scale (CWS), Marijuana Withdrawal Checklist (MWC) and Marijuana Craving Questionnaire (MCQ). Medication use was assessed during the study by means of self-reports, vial weight control, toxicology and metabolite analysis. Cannabis use was assessed by means of self-reports. Results High fixed doses of Sativex were well tolerated and significantly reduced cannabis withdrawal during abstinence, but not craving, as compared to placebo. Self-titrated doses were lower and showed limited efficacy as compared to high fixed doses. Participants reported a significantly lower “high” following Sativex or placebo as compared to SAU conditions. Cannabis/medication use along the study, as per self-reports, suggests compliance with the study conditions. Conclusions The results found in this proof of concept study warrant further systematic exploration of Sativex as a treatment option for cannabis withdrawal and dependence. PMID:26925704

Effects of fixed or self-titrated dosages of Sativex on cannabis withdrawal and cravings.

PubMed

Trigo, Jose M; Lagzdins, Dina; Rehm, Jürgen; Selby, Peter; Gamaleddin, Islam; Fischer, Benedikt; Barnes, Allan J; Huestis, Marilyn A; Le Foll, Bernard

2016-04-01

There is currently no pharmacological treatment approved for cannabis dependence. In this proof of concept study, we assessed the feasibility/effects of fixed and self-titrated dosages of Sativex (1:1, Δ(9)-tetrahydrocannabinol (THC)/cannabidiol (CBD)) on craving and withdrawal from cannabis among nine community-recruited cannabis-dependent subjects. Participants underwent an 8-week double-blind placebo-controlled trial (an ABACADAE design), with four smoke as usual conditions (SAU) (A) separated by four cannabis abstinence conditions (B-E), with administration of either self-titrated/fixed doses of placebo or Sativex (up to 108 mg THC/100 mg CBD). The order of medication administration during abstinence conditions was randomized and counterbalanced. Withdrawal symptoms and craving were assessed using the Cannabis Withdrawal Scale (CWS), Marijuana Withdrawal Checklist (MWC) and Marijuana Craving Questionnaire (MCQ). Medication use was assessed during the study by means of self-reports, vial weight control, toxicology and metabolite analysis. Cannabis use was assessed by means of self-reports. High fixed doses of Sativex were well tolerated and significantly reduced cannabis withdrawal during abstinence, but not craving, as compared to placebo. Self-titrated doses were lower and showed limited efficacy as compared to high fixed doses. Participants reported a significantly lower "high" following Sativex or placebo as compared to SAU conditions. Cannabis/medication use along the study, as per self-reports, suggests compliance with the study conditions. The results found in this proof of concept study warrant further systematic exploration of Sativex as a treatment option for cannabis withdrawal and dependence. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Safety and immunogenicity of the killed bivalent (O1 and O139) whole-cell cholera vaccine in the Philippines.

PubMed

Capeding, Maria Rosario Z; Gonzales, Maria Liza Antoinette M; Dhingra, Mandeep Singh; D'Cor, Naveena Aloysia; Midde, Venkat Jayanth; Patnaik, Badri Narayan; Thollot, Yaël; Desauziers, Eric

2017-10-03

The killed bivalent (O1 and O139) whole cell oral cholera vaccine (OCV) (Shanchol™) was first licensed in India in 2009 and World Health Organization pre-qualified in 2011. We assessed the safety and immunogenicity of this OCV in the Philippines. This was a phase IV, single-arm, descriptive, open-label study. We recruited 336 participants from 2 centers: 112 participants in each age group (1-4, 5-14 and ≥ 15 years). Participants received 2 OCV doses 14 d apart. Safety was monitored throughout the trial. Blood samples were collected at baseline (pre-vaccination) and 14 d after each dose. Serum vibriocidal antibody titers to V. cholerae O1 (El Tor Inaba and El Tor Ogawa) and O139 strains were assessed, with seroconversion defined as ≥ 4-fold increase from baseline in titers. No immediate unsolicited systemic adverse events/reactions were observed. Unsolicited systemic adverse events were mostly grade 1 intensity. One serious adverse event occurred after the first dose, but was unrelated to vaccination. High seroconversion rates (range 69-92%) were achieved against the O1 serotypes with a trend toward higher rates in the 1-4 y (86-92%) and 5-14 y (86-88%) age groups than the ≥ 15 y age group (69-83%). Lower seroconversion rates were achieved against the O139 serotype (35-70%), particularly in those aged ≥ 15 y (35-42%). The 2-dose regimen of the killed bivalent whole cell OCV was well-tolerated in this study conducted in the Philippines, a cholera-endemic country. Robust immune responses were observed even after a single-dose.

Defining the upper age limit of luminescence dating: A case study using long lacustrine records from Chew Bahir, Ethiopia

NASA Astrophysics Data System (ADS)

Chapot, Melissa S.; Roberts, Helen M.; Lamb, Henry F.; Schäbitz, Frank; Asrat, Asfawossen; Trauth, Martin H.

2017-04-01

Optically stimulated luminescence (OSL) dating is a family of numerical chronometric techniques applied to quartz or feldspar mineral grains to assess the time since these grains were last exposed to sunlight (i.e. deposited), based on the amount of energy they absorbed from ambient radiation during burial. The maximum limit of any OSL dating technique is not defined by a fixed upper age limit, but instead by the maximum radiation dose the sample can accurately record before the OSL signal saturates. The challenge is to assess this upper limit of accurate age determination without necessitating comparison to independent age control. Laboratory saturation of OSL signals can be observed using a dose response curve (DRC) plotting OSL signal intensity against absorbed laboratory radiation dose. When a DRC is fitted with a single saturating exponential, one of the equation's parameters can be used to define a pragmatic upper limit beyond which uncertainties become large and asymmetric (Wintle and Murray, 2006). However, many sub-samples demonstrate DRCs that are best defined by double saturating exponential equations, which cannot be used to define this upper limit. To investigate the reliability of luminescence ages approaching saturation, Chapot et al. (2012) developed the Natural DRC concept, which uses expected ages derived from independent age control, combined with sample-specific measurements of ambient radioactivity, to calculate expected doses of absorbed radiation during burial. Natural OSL signal intensity is then plotted against these expected doses and compared to laboratory-generated DRCs. Using this approach, discrepancies between natural and laboratory DRCs have been observed for the same mineral material as natural OSL signal intensities saturate at absorbed radiation doses lower than the pragmatic upper limit defined by laboratory DRCs, leading to increasing age underestimation with depth without a metric for questioning the age reliability. The present study explores a means of defining the upper limit for reliable luminescence ages for sedimentary records without an established chronologic framework, using a long ( 280m; Cohen et al., 2016) lacustrine record from Chew Bahir, Ethiopia, drilled as part of the Hominin Sites and Paleolakes Drilling Project (HSPDP) of the International Continental Scientific Drilling Programme (ICDP) and CRC806 "Our way to Europe". Natural saturation of OSL signals is explored by plotting natural signal intensity against depth, creating a pseudo-Natural DRC that can be compared to laboratory DRCs. Unlike the homogenous deposits of the Chinese Loess Plateau where the Natural DRC concept was developed, the 280m composite core from Chew Bahir shows significant variation in lithology enabling investigation of the effects of sample to sample variability on Natural DRC construction, and facilitating comparison between signals from fine-quartz, fine-polymineral, and coarse-potassium feldspar grains. This work demonstrates how the concepts of Natural DRCs can be used to define the upper dating limit of sample suites without independent age control, providing valuable information for long sedimentary sequences such as the lacustrine deposits from Chew Bahir. Chapot M.S., et al. (2012), Radiation Measurements 47: 1045-1052. Cohen A, et al. (2016), Scientific Drilling 21: 1-16. Wintle, A.G., Murray, A.S. (2006) Radiation Measurements 41: 369-391.

Safety and immunogenicity of conjugate quadrivalent meningococcal vaccination after hematopoietic cell transplantation

PubMed Central

Pandit, Alisha; Antin, Joseph H.; Walsh, Stephen R.; Huynh, Daisy; Ghobrial, Irene M.; Baden, Lindsey R.; Issa, Nicolas C.

2018-01-01

Immunization with the conjugated quadrivalent (serogroups A, C, Y, and W-135) meningococcal vaccine (MCV4) after hematopoietic cell transplantation (HCT) is recommended. However, immune responses to MCV4 have not been prospectively studied after HCT. We conducted a vaccine response study among 67 adults who received 1 MCV4 dose a year after autologous or allogeneic HCT from January to September 2014. Pre- and postvaccination serogroup serum bactericidal antibody (SBA) titers were measured a median of 57 days after vaccination. Serogroup-specific responses were defined as a fourfold increase in SBA titer with postvaccination titers ≥1:8. Prior to vaccination, 44 (65.7%) patients had no protective titers (<1:8) to any meningococcal serogroup, and 3 (4.5%) patients had protective titers to all 4 serogroups. The median serogroup-specific postvaccination SBA titers were 1:2048 for A, 1:64 for C, 1:128 for W-135, and 1:128 for Y (P < .001 for all pre- and postvaccination pairwise comparisons; similar among serogroups, Spearman ρ 0.5-0.6, P < .0001). Among serogroup-specific nonimmune patients prior to vaccination, serogroup-specific response rates were 76.9%, 65.5%, 51.7%, and 65% to serogroups A, C, W-135, and Y, respectively. One dose of MCV4 elicited protective titers in the majority of patients. These data suggest that a second vaccine dose may be beneficial. PMID:29871892

Tell Me about Your Lemonade Stand

NASA Technical Reports Server (NTRS)

Tibbitts, Scott

2004-01-01

At STARSYS, we execute many Firm Fixed Price (FFP) programs for the development of mechanical systems for spacecraft. Contracting this way pre-suppose that we have the ability to establish and hold scope for a system that has yet to be defined. To do FFP, it is critical that we have program managers who are masters at cost control. Fortunately, we have some "masters" in our company. They just seem to have a knack for driving to a financial target. Doesn't matter if the program has contingency or not. Doesn't seem to matter if they use MS Project, Excel spread-sheets, or the back of an envelope. Doesn't even seem to matter whether the program is set up as a financial challenge or a winner.

Network Aggregation in Transportation Planning : Volume II : A Fixed Point Method for Treating Traffic Equilibria

DOT National Transportation Integrated Search

1978-04-01

Volume 2 defines a new algorithm for the network equilibrium model that works in the space of path flows and is based on the theory of fixed point method. The goals of the study were broadly defined as the identification of aggregation practices and ...

Randomized Comparative Study of Intravenous Infusion of Three Different Fixed Doses of Milrinone in Pediatric Patients with Pulmonary Hypertension Undergoing Open Heart Surgery

PubMed Central

Barnwal, Neeraj Kumar; Umbarkar, Sanjeeta Rajendra; Sarkar, Manjula Sudeep; Dias, Raylene J

2017-01-01

Background: Pulmonary hypertension secondary to congenital heart disease is a common problem in pediatric patients presenting for open heart surgery. Milrinone has been shown to reduce pulmonary vascular resistance and pulmonary artery pressure in pediatric patients and neonates postcardiac surgery. We aimed to evaluate the postoperative outcome in such patients with three different fixed maintenance doses of milrinone. Methodology: Patients were randomized into three groups. All patients received fixed bolus dose of milrinone 50 μg/kg on pump during rewarming. Following this, patients in low-dose group received infusion of milrinone at the rate of 0.375 μg/kg/min, medium-dose group received 0.5 μg/kg/min, and high-dose group received 0.75 μg/kg/min over 24 h. Heart rate, mean arterial pressure (MAP), mean airway pressure (MaP), oxygenation index (OI), and central venous pressure (CVP) were compared at baseline and 24 h postoperatively. Dose of inotropic requirement, duration of ventilatory support and Intensive Care Unit (ICU) stay were noted. Results: MAP, MaP, OI, and CVP were comparable in all three groups postoperatively. All patients in the low-dose group required low inotropic support while 70% of patients in the high-dose group needed high inotropic support to manage episodes of hypotension (P = 0.000). Duration of ventilatory support and ICU stay in all three groups was comparable (P = 0.412, P = 0.165). Conclusion: Low-dose infusions while having a clinical impact were more beneficial in avoiding adverse events and decreasing inotropic requirement without affecting duration of ventilatory support and duration of ICU stay. PMID:28701597

Randomized comparative study of intravenous infusion of three different fixed doses of milrinone in pediatric patients with pulmonary hypertension undergoing open heart surgery.

PubMed

Barnwal, Neeraj Kumar; Umbarkar, Sanjeeta Rajendra; Sarkar, Manjula Sudeep; Dias, Raylene J

2017-01-01

Pulmonary hypertension secondary to congenital heart disease is a common problem in pediatric patients presenting for open heart surgery. Milrinone has been shown to reduce pulmonary vascular resistance and pulmonary artery pressure in pediatric patients and neonates postcardiac surgery. We aimed to evaluate the postoperative outcome in such patients with three different fixed maintenance doses of milrinone. Patients were randomized into three groups. All patients received fixed bolus dose of milrinone 50 μg/kg on pump during rewarming. Following this, patients in low-dose group received infusion of milrinone at the rate of 0.375 μg/kg/min, medium-dose group received 0.5 μg/kg/min, and high-dose group received 0.75 μg/kg/min over 24 h. Heart rate, mean arterial pressure (MAP), mean airway pressure (MaP), oxygenation index (OI), and central venous pressure (CVP) were compared at baseline and 24 h postoperatively. Dose of inotropic requirement, duration of ventilatory support and Intensive Care Unit (ICU) stay were noted. MAP, MaP, OI, and CVP were comparable in all three groups postoperatively. All patients in the low-dose group required low inotropic support while 70% of patients in the high-dose group needed high inotropic support to manage episodes of hypotension (P = 0.000). Duration of ventilatory support and ICU stay in all three groups was comparable (P = 0.412, P = 0.165). Low-dose infusions while having a clinical impact were more beneficial in avoiding adverse events and decreasing inotropic requirement without affecting duration of ventilatory support and duration of ICU stay.

Improved muscle-derived expression of human coagulation factor IX from a skeletal actin/CMV hybrid enhancer/promoter.

PubMed

Hagstrom, J N; Couto, L B; Scallan, C; Burton, M; McCleland, M L; Fields, P A; Arruda, V R; Herzog, R W; High, K A

2000-04-15

Hemophilia B is caused by the absence of functional coagulation factor IX (F.IX) and represents an important model for treatment of genetic diseases by gene therapy. Recent studies have shown that intramuscular injection of an adeno-associated viral (AAV) vector into mice and hemophilia B dogs results in vector dose-dependent, long-term expression of biologically active F.IX at therapeutic levels. In this study, we demonstrate that levels of expression of approximately 300 ng/mL (6% of normal human F.IX levels) can be reached by intramuscular injection of mice using a 2- to 4-fold lower vector dose (1 x 10(11) vector genomes/mouse, injected into 4 intramuscular sites) than previously described. This was accomplished through the use of an improved expression cassette that uses the cytomegalovirus (CMV) immediate early enhancer/promoter in combination with a 1.2-kilobase portion of human skeletal actin promoter. These results correlated with enhanced levels of F.IX transcript and secreted F.IX protein in transduced murine C2C12 myotubes. Systemic F.IX expression from constructs containing the CMV enhancer/promoter alone was 120 to 200 ng/mL in mice injected with 1 x 10(11) vector genomes. Muscle-specific promoters performed poorly for F.IX transgene expression in vitro and in vivo. However, the incorporation of a sequence from the alpha-skeletal actin promoter containing at least 1 muscle-specific enhancer and 1 enhancer-like element further improved muscle-derived expression of F.IX from a CMV enhancer/promoter-driven expression cassette over previously published results. These findings will allow the design of a clinical protocol for therapeutic levels of F.IX expression with lower vector doses, thus enhancing efficacy and safety of the protocol. (Blood. 2000;95:2536-2542)

Nodule Classification on Low-Dose Unenhanced CT and Standard-Dose Enhanced CT: Inter-Protocol Agreement and Analysis of Interchangeability.

PubMed

Lee, Kyung Hee; Lee, Kyung Won; Park, Ji Hoon; Han, Kyunghwa; Kim, Jihang; Lee, Sang Min; Park, Chang Min

2018-01-01

To measure inter-protocol agreement and analyze interchangeability on nodule classification between low-dose unenhanced CT and standard-dose enhanced CT. From nodule libraries containing both low-dose unenhanced and standard-dose enhanced CT, 80 solid and 80 subsolid (40 part-solid, 40 non-solid) nodules of 135 patients were selected. Five thoracic radiologists categorized each nodule into solid, part-solid or non-solid. Inter-protocol agreement between low-dose unenhanced and standard-dose enhanced images was measured by pooling κ values for classification into two (solid, subsolid) and three (solid, part-solid, non-solid) categories. Interchangeability between low-dose unenhanced and standard-dose enhanced CT for the classification into two categories was assessed using a pre-defined equivalence limit of 8 percent. Inter-protocol agreement for the classification into two categories {κ, 0.96 (95% confidence interval [CI], 0.94-0.98)} and that into three categories (κ, 0.88 [95% CI, 0.85-0.92]) was considerably high. The probability of agreement between readers with standard-dose enhanced CT was 95.6% (95% CI, 94.5-96.6%), and that between low-dose unenhanced and standard-dose enhanced CT was 95.4% (95% CI, 94.7-96.0%). The difference between the two proportions was 0.25% (95% CI, -0.85-1.5%), wherein the upper bound CI was markedly below 8 percent. Inter-protocol agreement for nodule classification was considerably high. Low-dose unenhanced CT can be used interchangeably with standard-dose enhanced CT for nodule classification.

Energy spectrum control for modulated proton beams.

PubMed

Hsi, Wen C; Moyers, Michael F; Nichiporov, Dmitri; Anferov, Vladimir; Wolanski, Mark; Allgower, Chris E; Farr, Jonathan B; Mascia, Anthony E; Schreuder, Andries N

2009-06-01

In proton therapy delivered with range modulated beams, the energy spectrum of protons entering the delivery nozzle can affect the dose uniformity within the target region and the dose gradient around its periphery. For a cyclotron with a fixed extraction energy, a rangeshifter is used to change the energy but this produces increasing energy spreads for decreasing energies. This study investigated the magnitude of the effects of different energy spreads on dose uniformity and distal edge dose gradient and determined the limits for controlling the incident spectrum. A multilayer Faraday cup (MLFC) was calibrated against depth dose curves measured in water for nonmodulated beams with various incident spectra. Depth dose curves were measured in a water phantom and in a multilayer ionization chamber detector for modulated beams using different incident energy spreads. Some nozzle entrance energy spectra can produce unacceptable dose nonuniformities of up to +/-21% over the modulated region. For modulated beams and small beam ranges, the width of the distal penumbra can vary by a factor of 2.5. When the energy spread was controlled within the defined limits, the dose nonuniformity was less than +/-3%. To facilitate understanding of the results, the data were compared to the measured and Monte Carlo calculated data from a variable extraction energy synchrotron which has a narrow spectrum for all energies. Dose uniformity is only maintained within prescription limits when the energy spread is controlled. At low energies, a large spread can be beneficial for extending the energy range at which a single range modulator device can be used. An MLFC can be used as part of a feedback to provide specified energy spreads for different energies.

Multiscale Resilience of Complex Systems

NASA Astrophysics Data System (ADS)

Tchiguirinskaia, I.; Schertzer, D. J. M.; Giangola-Murzyn, A.; Hoang Cong, T.

2014-12-01

We first argue the need for well defined resilience metrics to better evaluate the resilience of complex systems such as (peri-)urban flood management systems. We review both the successes and limitations of resilience metrics in the framework of dynamical systems and their generalization in the framework of the viability theory. We then point out that the most important step to achieve is to define resilience across scales instead of doing it at a given scale. Our preliminary, critical analysis of the series of attempts to define an operational resilience metrics led us to consider a scale invariant metrics based on the scale independent codimension of extreme singularities. Multifractal downscaling of climate scenarios can be considered as a first illustration. We focussed on a flood scenario evaluation method with the help of two singularities γ_s and γ_Max, corresponding respectively to an effective and a probable maximum singularity, that yield an innovative framework to address the issues of flood resilience systems in a scale independent manner. Indeed, the stationarity of the universal multifractal parameters would result into a rather stable value of probable maximum singularity γ_s. By fixing the limit of acceptability for a maximum flood water depth at a given scale, with a corresponding singularity, we effectively fix the threshold of the probable maximum singularity γ_s as a criterion of the flood resilience we accept. Then various scenarios of flood resilient measures could be simulated with the help of Multi-Hydro under upcoming climat scenarios. The scenarios that result in estimates of either γ_Max or γ_s below the pre-selected γ_s value will assure the effective flood resilience of the whole modeled system across scales. The research for this work was supported, in part, by the EU FP7 SMARTesT and INTERREG IVB RainGain projects.

Effect of Statin Intensity on the Risk of Epilepsy After Ischaemic Stroke: Real-World Evidence from Population-Based Health Claims.

PubMed

Lin, Fang-Ju; Lin, Hung-Wei; Ho, Yunn-Fang

2018-04-01

Statins possess neuroprotective effects. However, real-world evidence supporting their utility in post-stroke epilepsy (PSE) prevention is limited. The association between statin use, including timing of prescribing (pre-stroke vs post-stroke), type (lipophilicity, intensity of therapy) and dose intensity, and risk of developing PSE were investigated by studying Taiwanese health claims (2003-2013). Patients with new-onset ischaemic stroke were identified. The main outcome was a diagnosis of epilepsy after ischaemic stroke. According to pre-stroke statin use, groups of current users, former users, and non-users were compared using ANOVA. An extended Cox regression model was utilized to estimate the hazard ratio (HR) of PSE, with post-stroke statin use and certain comedications as time-dependent variables. Serial sensitivity analyses were performed to ensure study robustness. Of the 20,858 ischaemic stroke patients, 954 (4.6%) developed PSE. Post-stroke statin use (adjusted HR (aHR) 0.55; 95% confidence interval 0.46-0.67, p < 0.001), but not pre-stroke statin use was associated with a significantly reduced risk of developing PSE. A dose-response correlation was also observed between PSE risk reduction and quartiles of the statin cumulative defined daily dose (cDDD) (aHR 0.84, 0.67, 0.53, and 0.50 for the lowest, second, third, and highest quartiles of cDDD, respectively). Risk predictors and protectors against PSE were also characterized. The post-stroke use of statins after ischaemic stroke was associated with PSE risk reduction in a cDDD-dependent manner. Further clinical studies on the potential applications of statins for PSE prophylaxis, particularly among at-risk patients, are warranted.

Empagliflozin as add-on to linagliptin in a fixed-dose combination in Japanese patients with type 2 diabetes: Glycaemic efficacy and safety profile in a 52-week, randomized, placebo-controlled trial.

PubMed

Kawamori, Ryuzo; Haneda, Masakazu; Suzaki, Keiko; Cheng, Gang; Shiki, Kosuke; Miyamoto, Yuki; Solimando, Fernando; Lee, Christopher; Lee, Jisoo; George, Jyothis

2018-05-15

This double-blind, randomized, placebo-controlled trial (ClinicalTrials.gov NCT02453555) evaluated the efficacy and safety of empagliflozin (Empa) 10 or 25 mg as add-on to linagliptin (Lina) 5 mg (fixed-dose combination, Empa/Lina 10/5 or 25/5) in insufficiently controlled Japanese type 2 diabetes patients. The trial (40 sites; May 2015-March 2017) involved screening 433 adults (≥20 years) who were treatment-naive or were using one oral antidiabetic drug for ≥12 weeks, which was discontinued at enrolment. Patients with HbA1c 7.5%-10.0% after ≥16 weeks of using Lina (pre-enrolment or during a 16-week, open-label period) and 2 weeks of using placebo (Plc) for Empa/Lina 10/5, plus Lina, were randomized (2:1) to once-daily Empa/Lina 10/5 (n = 182) or Plc/Lina 10/5 (n = 93) for 24 weeks. Patients with HbA1c ≥ 7.0% at Week 24 received Empa/Lina up-titrated to 25/5 (n = 126) or the corresponding placebo (n = 80), per randomization, from Week 28; 172 Empa/Lina and 84 Plc/Lina patients completed 52 weeks. Change from baseline in HbA1c was greater (P < .0001) with Empa/Lina than with Plc/Lina at Week 24 (primary outcome, -0.93% vs 0.21%; adjusted mean difference, -1.14%) and Week 52 (-1.16% vs 0.06%; adjusted mean difference, -1.22%). More patients with HbA1c < 7.0% and greater decreases in fasting plasma glucose, body weight and systolic blood pressure were seen in the Empa/Lina group than in the Plc/Lina group. Empa/Lina was well tolerated. The adverse events that were more frequent with Empa/Lina were known empagliflozin-associated events (eg, increased urination, increased blood ketones). There were no adjudication-confirmed diabetic ketoacidosis events or lower limb amputations. These results support the notion that empagliflozin-linagliptin in fixed-dose combination is a therapeutic option for Japanese patients with type 2 diabetes. © 2018 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.

Use and effectiveness of a fixed-ratio combination of insulin degludec/liraglutide (IDegLira) in a real-world population with type 2 diabetes: Results from a European, multicentre, retrospective chart review study.

PubMed

Price, Hermione; Blüher, Matthias; Prager, Rudolf; Phan, Tra-Mi; Thorsted, Brian L; Schultes, Bernd

2018-04-01

To describe the real-world use and effectiveness of IDegLira, a fixed-ratio combination of the basal insulin degludec, and the glucagon-like peptide-1 receptor agonist (GLP-1RA) liraglutide. This European, multicentre, retrospective chart review comprised adults (n = 611) with type 2 diabetes, who started IDegLira ≥6 months before data collection. Clinical characteristics were assessed at baseline (defined as the most recent recording during the 6 months before the first IDegLira prescription) and 3, 6, 9 and 12 months (± 45 days for each time point) after commencing IDegLira, where data were available. Baseline regimens included non-injectable medications (19%), basal insulin (19%), GLP-1RA (10%), free combination therapy (insulin/GLP-1RA, 24%) and multiple daily-dose insulin injections (MDI, 28%), all ± oral antidiabetic drugs. After 6 months, significant glycated haemoglobin (HbA1c) reductions were observed in patients overall and in all subgroups (-10 mmol/mol [-0.9%] overall; P < .0001), and a significant reduction in mean body weight (-0.7 kg; P < .05) was observed in patients overall and in patients receiving MDI (-2.4 kg; P < .0001). The mean IDegLira dose was 22, 30 and 32 dose steps at initiation, and at 6 and 12 months follow-up, respectively. In total, only 67 patients reached the maximum 50 dose steps, with most coming from the free combination therapy (n = 31) or MDI (n = 15) baseline regimen groups. Hypoglycaemia rates were reduced by 82% (rate ratio 0.18; P < .0001) in the 6-month period after vs before IDegLira initiation. Overall, a total of 12 patients experienced 15 events in the 6 months after IDegLira initiation. In real-world practice, after 6 months and at a moderate dose, IDegLira resulted in substantial reductions in HbA1c and body weight, with a reduced risk of hypoglycaemia. © 2017 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.

WE-FG-202-07: An MRI-Based Approach to Quantify Radiation-Induced Normal Tissue Injury Applied to Trismus After Head and Neck Cancer Radiotherapy

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

Thor, M; Tyagi, N; Saleh, Z

Purpose: The aim of this study was to investigate if quantitative MRI-derived metrics from four masticatory muscles could explain mouth-opening limitation/trismus following intensity-modulated radiotherapy (IMRT) for head and neck cancer (HNC). Methods: Fifteen intensity-based MRI metrics were derived from the masseter, lateral and medial pterygoid, and temporalis in T1-weighted scans acquired pre- and post gadolinium injection (T1Pre, T1Post) of 16, of in total 20, patients (8 symptomatic; 8 asymptomatic age/sex/tumor location-matched) treated with IMRT to 70 Gy (median) for HNC in 2005–2009. Trismus was defined as “≥decreased range of motion without impaired eating” (CTCAE.v.3: ≥Grade 1). Trismus status was monitoredmore » and MRI scans acquired within 1y post-RT. All MRI-derived metrics were assessed as ΔS=S(T1Pre)-S(T1Post)/S(T1Pre), and were normalized to the corresponding metric of a non-irradiated volume defined in each scan. The T1Pre structures were propagated onto the RT dose distribution, and the max and mean dose (Dmax, Dmean) were extracted. The MRI-derived metrics, Dmax, and Dmean were compared between trismus and non-trismus patients. A two-sided Wilcoxon Signed rank test-based p-value≤0.05 denoted significance. Results: For all four muscles the population mean of Dmax and Dmean was higher for patients with trismus compared to patients without trismus (ΔDmax=2.3–4.9 Gy; ΔDmean=and 2.0–3.8 Gy). The standard deviation (SD), the variance, and the minimum value (min) of ΔS were significantly (p=0.04–0.05) different between patients with and without trismus with trismus patients having significantly lower SD (population median: −0.53 vs. −0.31) and variance (−2.09 vs. −0.73) of the masseter, and significantly lower min of the medial pterygoid (−0.36 vs. −0.19). Conclusion: Quantitative MRI-derived metrics of two masticatory muscles were significantly different between patients with and without trismus following RT for HNC. These metrics could serve as image-based biomarkers to better understand the RT-induced etiology behind trismus, but should be further investigated in the complete cohort.« less

SU-E-T-118: Dose Verification for Accuboost Applicators Using TLD, Ion Chamber and Gafchromic Film Measurements

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

Chisela, W; Yao, R; Dorbu, G

Purpose: To verify dose delivered with HDR Accuboost applicators using TLD, ion chamber and Gafchromic film measurements and to examine applicator leakage. Methods: A microSelectron HDR unit was used to deliver a dose of 50cGy to the mid-plane of a 62mm thick solid water phantom using dwell times from Monte Carlo pre-calculated nomograms for a 60mm, 70mm Round and 60mm Skin-Dose Optimized (SDO) applicators respectively. GafChromic EBT3+ film was embedded in the phantom midplane horizontally to measure dose distribution. Absolute dose was also measured with TLDs and an ADCL calibrated parallel-plate ion chamber placed in the film plane at fieldmore » center for each applicator. The film was calibrated using 6MV x-ray beam. TLDs were calibrated in a Cs-137 source at UW-Madison calibration laboratory. Radiation leakage through the tungsten alloy shell was measured with a film wrapped around outside surface of a 60mm Round applicator. Results: Measured maximum doses at field center are consistently lower than predicated by 5.8% for TLD, 8.8% for ion chamber, and 2.6% for EBT3+ film on average, with measurement uncertainties of 2.2%, 0.3%, and 2.9% for TLD, chamber, film respectively. The total standard uncertainties for ion chamber and Gafchromic film measurement are 4.9% and 4.6% respectively[1]. The area defined by the applicator aperture was covered by 80% of maximum dose for 62mm compression thickness. When 100cGy is delivered to mid-plane with a 60mm Round applicator, surface dose ranges from 60cGy to a maximum of 145cGy, which occurs at source entrance to the applicator. Conclusion: Measured doses by all three techniques are consistently lower than predicted in our measurements. For a compression thickness of 62 mm, the field size defined by the applicator is only covered by 80% of prescribed dose. Radiation leakage of up to 145cGy was found at the source entrance of applicators.« less

Efficacy and Safety of Fixed-Dose Perindopril Arginine/Amlodipine in Hypertensive Patients Not Adequately Controlled with Amlodipine 5 mg or Perindopril tert-Butylamine 4 mg Monotherapy.

PubMed

Hu, Dayi; Sun, Yihong; Liao, Yuhua; Huang, Jing; Zhao, Ruiping; Yang, Kan

2016-01-01

To assess the blood pressure-lowering efficacy and tolerability of perindopril/amlodipine fixed-dose combinations in Chinese patients with mild-to-moderate essential hypertension not adequately controlled with monotherapy alone. In 2 separate double-blind studies, patients received a 4-week run-in monotherapy of amlodipine 5 mg or perindopril 4 mg, respectively. Those whose blood pressure was uncontrolled were then randomized to receive the fixed-dose combination of perindopril 5 mg/amlodipine 5 mg (Per/Amlo group) or remain on the monotherapy for 8 weeks. Patients who were uncontrolled at the week 8 (W8) visit were up-titrated for the Per/Amlo combination, or received additional treatment if on monotherapy, for a further 4 weeks. The main efficacy assessment was at 8 weeks. After 8 weeks, systolic blood pressure (SBP; primary criterion) was statistically significantly lower in the Per/Amlo group (vs. Amlo 5 mg, p = 0.0095; vs. Per 4 mg, p < 0.0001). Uncontrolled patients at W8 who received an up-titration of the Per/Amlo combination showed a further SBP reduction. These changes were mirrored by reassuring reductions in diastolic blood pressure. The fixed-dose combinations were well tolerated. Single-pill combinations of perindopril and amlodipine provide hypertensive patients with a convenient and effective method of reducing blood pressure. © 2016 S. Karger AG, Basel.

Nebivolol and valsartan as a fixed-dose combination for the treatment of hypertension.

PubMed

Sander, Gary E; Giles, Thomas D

2015-04-01

The fixed-dose combination of nebivolol and valsartan drug has been clinically evaluated and demonstrated to represent a unique combination of nebivolol, a selective β1-adrenoceptor antagonist and a β3-adrenoceptor agonist; β3 receptor activation increases endothelial nitric oxide and produces vasodilation. Valsartan is highly selective angiotensin AT1 receptor blocker and exerts its major pharmacological effect by decreasing angiotensin II-induced vasoconstriction and production of aldosterone. The addition of nebivolol counteracts the effects of increased angiotensin II concentrations resulting from potent AT1 blockade. This review describes a recently completed trial establishing the efficacy of the nebivolol/valsartan combination. This review provides a literature search of pertinent pharmacological and clinical data that describes the mechanisms of both drugs individually and the results of a clinical trial comparing fixed-dose combinations of nebivolol with valsartan as compared with each drug as monotherapy. Fixed-dose combination drugs are intended to improve patient compliance and reduce drug costs, as well as to reduce long-term cardiovascular event rates and block counter-regulatory effects due to monotherapy. The vast majority of hypertensive patients will require at least two medications. We believe that the clinical evidence suggests that the combination of nebivolol with valsartan offers a definite clinical benefit, combining β1-adrenoceptor and angiotensin AT1 receptor blockade with β3 receptor activation and resultant increase in nitric oxide and vasodilation.

Comparison of long-term safety of fixed-dose combinations azilsartan medoxomil/chlorthalidone vs olmesartan medoxomil/hydrochlorothiazide.

PubMed

Neutel, Joel M; Cushman, William C; Lloyd, Eric; Barger, Bruce; Handley, Alison

2017-09-01

This 52-week, randomized, open-label study evaluated long-term safety/tolerability of fixed-dose combination azilsartan medoxomil/chlorthalidone (AZL-M/CLD) vs fixed-dose combination olmesartan medoxomil/hydrochlorothiazide (OLM/HCTZ) in patients with essential hypertension (stage 2; clinic systolic blood pressure 160-190 mm Hg). Initial AZL-M/CLD 40/12.5 mg/d (n=418) or OLM/HCTZ 20/12.5 mg/d (n=419) could be uptitrated during weeks 4 to 52 (AZL-M/CLD to 80/25 mg; OLM/HCTZ to 40/25 mg [United States] or 20/25 mg [Europe]) to meet blood pressure targets. Treatment-emergent adverse events/serious adverse events occurred in 78.5%/5.7% of patients taking AZL-M/CLD vs 76.4%/6.2% taking OLM/HCTZ. The most frequent adverse events were dizziness (16.3% vs 12.6%), blood creatinine increase (21.5% vs 8.6%), headache (7.4% vs 11.0%), and nasopharyngitis (12.2% vs 11.5%). Hypokalemia was uncommon (1.0% vs 0.7%). Greater blood pressure reductions with AZL-M/CLD by week 2 were maintained throughout the study, despite less uptitration (32.3% vs 48.9% with OLM/HCTZ). Fixed-dose combination AZL-M/CLD showed an encouraging benefit-risk profile when used per standard clinical practice in a titrate-to-target strategy. ©2017 Wiley Periodicals, Inc.

Phase 1 trial of preoperative, short-course carbon-ion radiotherapy for patients with resectable pancreatic cancer.

PubMed

Shinoto, Makoto; Yamada, Shigeru; Yasuda, Shigeo; Imada, Hiroshi; Shioyama, Yoshiyuki; Honda, Hiroshi; Kamada, Tadashi; Tsujii, Hirohiko; Saisho, Hiromitsu

2013-01-01

The authors evaluated the tolerance and efficacy of carbon-ion radiotherapy (CIRT) as a short-course, preoperative treatment and determined the recommended dose needed to reduce the risk of postoperative local recurrence without excess injury to normal tissue. Patients radiographically defined with potentially resectable pancreatic cancer were eligible. A preoperative, short-course, dose-escalation study was performed with fixed 8 fractions in 2 weeks. The dose of irradiation was increased by 5% increments from 30 grays equivalents (GyE) to 36.8 GyE. Surgery was to be performed 2 to 4 weeks after the completion of CIRT. The study enrolled 26 patients. At the time of restaging after CIRT, disease progression with distant metastasis or refusal ruled out 5 patients from surgery. Twenty-one of 26 patients (81%) patients underwent surgery. The pattern of initial disease progression was distant metastasis in 17 patients (65%) and regional recurrence in 2 patients (8%). No patients experienced local recurrence. The 5-year survival rates for all 26 patients and for those who underwent surgery were 42% and 52%, respectively. Preoperative, short-course CIRT followed by surgery is feasible and tolerable without unacceptable morbidity. Copyright © 2012 American Cancer Society.

Customizing our approach in deep vein thrombosis and pulmonary embolism treatment: overview of our clinical experience.

PubMed

Turpie, A G

1999-08-01

Until recently, the management of established deep vein thrombosis (DVT) and pulmonary embolism remained largely unchanged and unchallenged. Treatment comprised an initial intravenous bolus of unfractionated heparin (UFH), followed by dose-adjusted intravenous UFH for 5-7 days, and oral warfarin for three months. UFH is traditionally administered in hospital, and monitoring and dose adjustment remain essential features of both UFH and warfarin treatment, making therapy both costly and inconvenient. Recent clinical trials have shown that subcutaneous UFH, or low-molecular-weight heparins (LMWHs), administered subcutaneously at a weight-adjusted fixed dose, are at least as effective as standard UFH given intravenously in the treatment of DVT. The feasibility of initial treatment of DVT at home in selected patients, with associated cost-savings and improved convenience have also been demonstrated with LMWHs. Clinical trials are currently investigating the potential value of LMWHs in the treatment of pulmonary embolism and as an alternative to warfarin in secondary prevention of DVT. The role of newer anticoagulants, such as recombinant hirudin, in initial treatment of DVT, and of thrombolysis in the management of pulmonary embolism remain to be defined.

Precision IORT - Image guided intraoperative radiation therapy (igIORT) using online treatment planning including tissue heterogeneity correction.

PubMed

Schneider, Frank; Bludau, Frederic; Clausen, Sven; Fleckenstein, Jens; Obertacke, Udo; Wenz, Frederik

2017-05-01

To the present date, IORT has been eye and hand guided without treatment planning and tissue heterogeneity correction. This limits the precision of the application and the precise documentation of the location and the deposited dose in the tissue. Here we present a set-up where we use image guidance by intraoperative cone beam computed tomography (CBCT) for precise online Monte Carlo treatment planning including tissue heterogeneity correction. An IORT was performed during balloon kyphoplasty using a dedicated Needle Applicator. An intraoperative CBCT was registered with a pre-op CT. Treatment planning was performed in Radiance using a hybrid Monte Carlo algorithm simulating dose in homogeneous (MCwater) and heterogeneous medium (MChet). Dose distributions on CBCT and pre-op CT were compared with each other. Spinal cord and the metastasis doses were evaluated. The MCwater calculations showed a spherical dose distribution as expected. The minimum target dose for the MChet simulations on pre-op CT was increased by 40% while the maximum spinal cord dose was decreased by 35%. Due to the artefacts on the CBCT the comparison between MChet simulations on CBCT and pre-op CT showed differences up to 50% in dose. igIORT and online treatment planning improves the accuracy of IORT. However, the current set-up is limited by CT artefacts. Fusing an intraoperative CBCT with a pre-op CT allows the combination of an accurate dose calculation with the knowledge of the correct source/applicator position. This method can be also used for pre-operative treatment planning followed by image guided surgery. Copyright © 2017 Associazione Italiana di Fisica Medica. Published by Elsevier Ltd. All rights reserved.

Monte Carlo simulations to assess the effects of tube current modulation on breast dose for multidetector CT

NASA Astrophysics Data System (ADS)

Angel, Erin; Yaghmai, Nazanin; Matilda Jude, Cecilia; DeMarco, John J.; Cagnon, Christopher H.; Goldin, Jonathan G.; Primak, Andrew N.; Stevens, Donna M.; Cody, Dianna D.; McCollough, Cynthia H.; McNitt-Gray, Michael F.

2009-02-01

Tube current modulation was designed to reduce radiation dose in CT imaging while maintaining overall image quality. This study aims to develop a method for evaluating the effects of tube current modulation (TCM) on organ dose in CT exams of actual patient anatomy. This method was validated by simulating a TCM and a fixed tube current chest CT exam on 30 voxelized patient models and estimating the radiation dose to each patient's glandular breast tissue. This new method for estimating organ dose was compared with other conventional estimates of dose reduction. Thirty detailed voxelized models of patient anatomy were created based on image data from female patients who had previously undergone clinically indicated CT scans including the chest area. As an indicator of patient size, the perimeter of the patient was measured on the image containing at least one nipple using a semi-automated technique. The breasts were contoured on each image set by a radiologist and glandular tissue was semi-automatically segmented from this region. Previously validated Monte Carlo models of two multidetector CT scanners were used, taking into account details about the source spectra, filtration, collimation and geometry of the scanner. TCM data were obtained from each patient's clinical scan and factored into the model to simulate the effects of TCM. For each patient model, two exams were simulated: a fixed tube current chest CT and a tube current modulated chest CT. X-ray photons were transported through the anatomy of the voxelized patient models, and radiation dose was tallied in the glandular breast tissue. The resulting doses from the tube current modulated simulations were compared to the results obtained from simulations performed using a fixed mA value. The average radiation dose to the glandular breast tissue from a fixed tube current scan across all patient models was 19 mGy. The average reduction in breast dose using the tube current modulated scan was 17%. Results were size dependent with smaller patients getting better dose reduction (up to 64% reduction) and larger patients getting a smaller reduction, and in some cases the dose actually increased when using tube current modulation (up to 41% increase). The results indicate that radiation dose to glandular breast tissue generally decreases with the use of tube current modulated CT acquisition, but that patient size (and in some cases patient positioning) may affect dose reduction.

Patient quality of life following induction of oral immunotherapy for food allergy.

PubMed

Epstein Rigbi, Na'ama; Katz, Yitzhak; Goldberg, Michael R; Levy, Michael B; Nachshon, Liat; Elizur, Arnon

2016-05-01

Patient quality of life improves following successful completion of oral immunotherapy (OIT), but the process itself might have undesirable effects. We aimed to evaluate patient quality of life following OIT initial induction. The Hebrew version of the Food Allergy Quality of Life Questionnaire-Parental Form (FAQLQ-PF) was validated and administered to the parents of children following the first week of OIT for food allergy (n = 119). Patient demographics and clinical history as well as the course of initial induction week were reviewed. Pre-OIT severity of food allergy, defined as severity of reactions due to accidental exposure to the allergenic food (anaphylactic reactions, p = 0.017; epinephrine use, p = 0.049; emergency room referrals p = 0.003; and hospital admissions, p = 0.015) and a lower number of tolerated doses during initial induction, reflective of a lower maximal tolerated dose for the different allergens (p = 0.011) were associated with worse total FAQLQ-PF scores. The number of tolerated doses during induction and pre-OIT emergency room referrals remained significantly associated with worse total score of the FAQLQ-PF on multivariate analysis (p = 0.016 and p = 0.005, respectively). The correlation between the number of tolerated doses and quality of life scores was moderate-strong primarily in children aged 6-12 years (Total score, r = -0.41, p = 0.001; Emotional Impact r = -0.42, p = 0.001; Food Anxiety, r = -0.38, p = 0.002; Social and Dietary Limitations, r = -0.33, p = 0.009). Pre-OIT reaction severity affects quality of life in both preschool and school-aged food-allergic children. In contrast, a lower maximal tolerated dose during OIT induction is associated with worse indices of quality of life primarily in children aged 6-12 years. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Safety and efficacy of fixed-dose 10 mg daily isotretinoin treatment for acne vulgaris in Malaysia.

PubMed

Yap, Felix Boon-Bin

2017-09-01

Low-dose isotretinoin is used to reduce side effects albeit higher relapse. This study aimed to determine the efficacy and safety of fixed-dose 10 mg daily isotretinoin for the treatment of acne. This prospective study was performed between 2011 and 2015. All 150 patients were given 10 mg daily isotretinoin until a cumulative dose of 90-110 mg/kg. The mean age was 26.6 years with 64.7% moderate acne, 29.3% severe, and 6% very severe. The mean cumulative dose was 98.8 ± 6.05 mg/kg. All 150 patients had total clearance with a mean time to clearance of 24.0 weeks. Patients with severe/very severe acne had higher cumulative dosage (102.1 vs. 97.0, P < 0.001) and longer duration to clearance (32.9 weeks vs. 19.1 weeks, P < 0.001). Mild relapse was seen in 4%. The mean time to relapse was 32.3 weeks. Lip dryness was the commonest side effects (100%). Mild transient elevation of liver enzymes was detected in 3.3% and a slight increase of serum lipid in 2.7% with no treatment discontinuation. Fixed-dose 10 mg daily treatment with isotretinoin until a cumulative dose of 90-110 mg/kg is safe with low relapse rate. © 2016 Wiley Periodicals, Inc.

Management strategy 3: fixed rate fertilizer applications

USDA-ARS?s Scientific Manuscript database

Previous chapters outlined management strategies for pond fertilization that take into account specific individual pond nutrient needs. Those methods would most likely be more ecologically efficient than a pre-determined fixed-rate nutrient addition strategy. However, the vast majority of available ...

Failure-probability driven dose painting

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

Vogelius, Ivan R.; Håkansson, Katrin; Due, Anne K.

Purpose: To demonstrate a data-driven dose-painting strategy based on the spatial distribution of recurrences in previously treated patients. The result is a quantitative way to define a dose prescription function, optimizing the predicted local control at constant treatment intensity. A dose planning study using the optimized dose prescription in 20 patients is performed.Methods: Patients treated at our center have five tumor subvolumes from the center of the tumor (PET positive volume) and out delineated. The spatial distribution of 48 failures in patients with complete clinical response after (chemo)radiation is used to derive a model for tumor control probability (TCP). Themore » total TCP is fixed to the clinically observed 70% actuarial TCP at five years. Additionally, the authors match the distribution of failures between the five subvolumes to the observed distribution. The steepness of the dose–response is extracted from the literature and the authors assume 30% and 20% risk of subclinical involvement in the elective volumes. The result is a five-compartment dose response model matching the observed distribution of failures. The model is used to optimize the distribution of dose in individual patients, while keeping the treatment intensity constant and the maximum prescribed dose below 85 Gy.Results: The vast majority of failures occur centrally despite the small volumes of the central regions. Thus, optimizing the dose prescription yields higher doses to the central target volumes and lower doses to the elective volumes. The dose planning study shows that the modified prescription is clinically feasible. The optimized TCP is 89% (range: 82%–91%) as compared to the observed TCP of 70%.Conclusions: The observed distribution of locoregional failures was used to derive an objective, data-driven dose prescription function. The optimized dose is predicted to result in a substantial increase in local control without increasing the predicted risk of toxicity.« less

Implementation of IMRT and VMAT using Delta4 phantom and portal dosimetry as dosimetry verification tools

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

Daci, Lulzime, E-mail: lulzime.daci@nodlandssykehuset.no; Malkaj, Partizan, E-mail: malkaj-p@hotmail.com

2016-03-25

In this study we analyzed and compared the dose distribution of different IMRT and VMAT plans with the intent to provide pre-treatment quality assurance using two different tools. Materials/Methods: We have used the electronic portal imaging device EPID after calibration to dose and correction for the background offset signal and also the Delta4 phantom after en evaluation of angular sensitivity. The Delta4 phantom has a two-dimensional array with ionization chambers. We analyzed three plans for each anatomical site calculated by Eclipse treatment planning system. The measurements were analyzed using γ-evaluation method with passing criteria 3% absolute dose and 3 mm distancemore » to agreement (DTA). For all the plans the range of score has been from 97% to 99% for gantry fixed at 0° while for rotational planes there was a slightly decreased pass rates and above 95%. Point measurement with a ionization chamber were done in additional to see the accuracy of portal dosimetry and to evaluate the Delta4 device to various dose rates. Conclusions: Both Delt4 and Portal dosimetry shows good results between the measured and calculated doses. While Delta4 is more accurate in measurements EPID is more time efficient. We have decided to use both methods in the first steps of IMRT and VMAT implementation and later on to decide which of the tools to use depending on the complexity of plans, how much accurate we want to be and the time we have on the machine.« less

[Post marketing surveillance study with an analgesic (transdermal buprenorphine patch) in patients with moderate to severe chronic pain].

PubMed

Tschirner, M; Ritzdorf, I; Brünjes, R

2008-09-18

To obtain information on the efficacy, tolerability and safetyofa transdermal buprenorphine patch (Transtec PRO) in patients with moderate to severe chronic pain. In addition it should be evaluated to what extent the two fixed patch change days per weekare simplifyingthe therapy. In this prospective multi-center post marketing surveillance study patients with chronic cancer and non-cancer pain were treated with transdermal buprenorphine for up to eight weeks. The evaluation included pain intensity, the dosage of the applied analgesics and additional therapies, the renal function (by serum creatinine) and adverse events. 3654 patients were treated for a mean of 50.4 days. Using the NRS-11 the mean pain intensity decreased from 6.3 at the time when patients were switched to the transdermal buprenorphine patch to 2.6 at the last treatment evaluation. The matrix patch was safe and well tolerated also in patients with advanced renal insufficiency. Adverse events were reported in 6.7% of the patients. 89.3% of the physicians quoted to prefer transdermal buprenorphine with the two fixed patch change days per week compared to the pre-treatment. The buprenorphine-containing matrix patch was effective and well tolerated in patients with moderate to severe chronic cancer and noncancer pain. From the physicians view the two fixed patch change days per week facilitate the guidance of therapy. In patients with advanced renal insufficiency a dose adjustment is not necessary.

Intravenous Lidocaine as an Adjuvant for Pain Associated with Sickle Cell Disease.

PubMed

Nguyen, Natalie L; Kome, Anne M; Lowe, Denise K; Coyne, Patrick; Hawks, Kelly G

2015-01-01

The objectives of this study were to evaluate the efficacy and safety of adjuvant intravenous (IV) lidocaine in adults with sickle cell disease (SCD). This was a retrospective review. Adults with SCD receiving at least one IV lidocaine infusion from 2004 to 2014 were included. Patient demographics, lidocaine treatment parameters, pain scores, pain medications, and adverse effects were recorded. Eleven patients were identified, yielding 15 IV lidocaine trials. Clinical improvement in pain scores from pre-lidocaine challenge to 24 hours post-lidocaine challenge, defined by ≥ 20% reduction in pain scores, was achieved in 53.3% (8 of 15) of IV lidocaine challenges. Of the 8 clinically successful trials, the mean reduction in morphine dose equivalents (MDE) from 24 hours pre-lidocaine challenge to 24 hours post-lidocaine challenge was 32.2%. Additionally, clinically successful trials had a mean initial and a maximum dose of 1 mg/kg/h (range: 0.5-2.7 mg/kg/h) and 1.3 mg/kg/h (range: 0.5-1.9 mg/kg/h), respectively. On average, these patients underwent 3 dose titrations (range: 1-8) and received lidocaine infusions for 4.4 days (range: 2-8 days). Two patients experienced disorientation and dizziness. The authors conclude that adjuvant IV lidocaine provided pain relief and a mean reduction in MDE during sickle cell pain crisis. These results provide preliminary insight into the use of IV lidocaine for treating pain in patients with SCD, although prospective studies are needed to determine efficacy, dosing, and tolerability of IV lidocaine in this patient population.

Novel elastic protection against DDF failures in an enhanced software-defined SIEPON

NASA Astrophysics Data System (ADS)

Pakpahan, Andrew Fernando; Hwang, I.-Shyan; Yu, Yu-Ming; Hsu, Wu-Hsiao; Liem, Andrew Tanny; Nikoukar, AliAkbar

2017-07-01

Ever-increasing bandwidth demands on passive optical networks (PONs) are pushing the utilization of every fiber strand to its limit. This is mandating comprehensive protection until the end of the distribution drop fiber (DDF). Hence, it is important to provide refined protection with an advanced fault-protection architecture and recovery mechanism that is able to cope with various DDF failures. We propose a novel elastic protection against DDF failures that incorporates a software-defined networking (SDN) capability and a bus protection line to enhance the resiliency of the existing Service Interoperability in Ethernet Passive Optical Networks (SIEPON) system. We propose the addition of an integrated SDN controller and flow tables to the optical line terminal and optical network units (ONUs) in order to deliver various DDF protection scenarios. The proposed architecture enables flexible assignment of backup ONU(s) in pre/post-fault conditions depending on the PON traffic load. A transient backup ONU and multiple backup ONUs can be deployed in the pre-fault and post-fault scenarios, respectively. Our extensively discussed simulation results show that our proposed architecture provides better overall throughput and drop probability compared to the architecture with a fixed DDF protection mechanism. It does so while still maintaining overall QoS performance in terms of packet delay, mean jitter, packet loss, and throughput under various fault conditions.

Needs-driven versus market-driven pharmaceutical innovation: the consortium for the development of a new medicine against malaria in Brazil.

PubMed

Kameda, Koichi

2014-08-01

The prevailing model for encouraging innovation based on patents and market-oriented raises at least two economic and ethical issues: it imposes barriers on individuals and developing countries governments' access to medicines by defining prices that do not match their income, and the unavailability of new or appropriate products to address the health problems of these populations. In the last decade, this scenario has undergone some changes due to the emergence of new actors, the contribution of aid resources, the introduction to the market of new products against neglected diseases, the development of new governmental healthcare policies and research programs, etc. One example of such initiatives is the Fixed-Dose Artesunate Combination Therapy (FACT) project consortium, which brought together institutions with different natures from both the North and the South, for the development of two antimalarial fixed-dose combinations recommended by the WHO - artesunate-amodiaquine (ASAQ) and artesunate-mefloquine (ASMQ). This paper proposes to describe and analyze the ASMQ consortium, which is the result of a new pharmaceutical development approach, based on a different paradigm - needs-driven instead of market-driven -, collaborative, with strategic participation of institutions from the South, funded by alternative resources (public and philanthropic). Thus, it represents an interesting object of study for bioethical debates on intellectual property and innovation, and its analysis is justified in light of the current debate on ways of stimulating needs-driven pharmaceutical innovation. © 2014 John Wiley & Sons Ltd.

Abacavir/dolutegravir/lamivudine single-tablet regimen: a review of its use in HIV-1 infection.

PubMed

Greig, Sarah L; Deeks, Emma D

2015-04-01

A fixed-dose, single-tablet regimen comprising the integrase strand transfer inhibitor (INSTI) dolutegravir and the nucleos(t)ide reverse transcriptase inhibitors (NRTIs) abacavir and lamivudine (abacavir/dolutegravir/lamivudine; Triumeq®) is now available for the treatment of HIV-1 infection. In a randomized, double-blind, phase III trial in antiretroviral therapy (ART)-naive adults (SINGLE), once-daily dolutegravir plus abacavir/lamivudine had noninferior efficacy to once-daily efavirenz/tenofovir disoproxil fumarate (tenofovir DF)/emtricitabine with regard to establishing and sustaining virological suppression over 144 weeks, and subsequent superiority testing significantly favoured dolutegravir plus abacavir/lamivudine. This outcome was predominantly driven by more favourable rates of discontinuation due to adverse events versus the efavirenz/tenofovir DF/emtricitabine group. These data were generally supported by findings from other phase III trials in ART-naive adults receiving dolutegravir plus either abacavir/lamivudine or tenofovir DF/emtricitabine (SPRING-2 and FLAMINGO). Dolutegravir plus abacavir/lamivudine is generally well tolerated, with a tolerability profile that appears to be more favourable than efavirenz/tenofovir DF/emtricitabine. In the SINGLE trial, there were no major treatment-emergent INSTI or NRTI resistance-associated mutations in dolutegravir plus abacavir/lamivudine recipients with protocol-defined virological failure, indicating a high genetic barrier to resistance. Thus, triple combination therapy with abacavir, dolutegravir and lamivudine is an effective, generally well tolerated option for the management of HIV-1 infection, with the convenient once-daily fixed-dose tablet providing the first single-tablet regimen option without tenofovir DF.

In vivo recovery of factor VIII and factor IX: intra- and interindividual variance in a clinical setting.

PubMed

Björkman, S; Folkesson, A; Berntorp, E

2007-01-01

In vivo recovery (IVR) is traditionally used as a parameter to characterize the pharmacokinetic properties of coagulation factors. It has also been suggested that dosing of factor VIII (FVIII) and factor IX (FIX) can be adjusted according to the need of the individual patient, based on an individually determined IVR value. This approach, however, requires that the individual IVR value is more reliably representative for the patient than the mean value in the population, i.e. that there is less variance within than between the individuals. The aim of this investigation was to compare intra- and interindividual variance in IVR (as U dL1 per U kg1) for FVIII and plasma-derived FIX in a cohort of non-bleeding patients with haemophilia. The data were collected retrospectively from six clinical studies, yielding 297 IVR determinations in 50 patients with haemophilia A and 93 determinations in 13 patients with haemophilia B. For FVIII, the mean variance within patients exceeded the between-patient variance. Thus, an individually determined IVR value is apparently no more informative than an average, or population, value for the dosing of FVIII. There was no apparent relationship between IVR and age of the patient (1.5-67 years). For FIX, the mean variance within patients was lower than the between-patient variance, and there was a significant positive relationship between IVR and age (13-69 years). From these data, it seems probable that using an individual IVR confers little advantage in comparison to using an age-specific population mean value. Dose tailoring of coagulation factor treatment has been applied successfully after determination of the entire single-dose curve of FVIII:C or FIX:C in the patient and calculation of the relevant pharmacokinetic parameters. However, the findings presented here do not support the assumption that dosing of FVIII or FIX can be individualized on the basis of a clinically determined IVR value.

Use of radiation protraction to escalate biologically effective dose to the treatment target

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

Kuperman, V. Y.; Spradlin, G. S.; Department of Mathematics, Embry-Riddle University, Daytona Beach, Florida 32114

2011-12-15

Purpose: The aim of this study is to evaluate how simultaneously increasing fraction time and dose per fraction affect biologically effective dose for the target (BED{sub tar}) while biologically effective dose for the normal tissue (BED{sub nt}) is fixed. Methods: In this investigation, BED{sub tar} and BED{sub nt} were studied by assuming mono-exponential repair of sublethal damage with tissue dependent repair half-time. Results: Our results demonstrate that under certain conditions simultaneously increasing fraction time and dose per fraction result in increased BED{sub tar} while BED{sub nt} is fixed. The dependence of biologically effective dose on fraction time is influenced bymore » the dose rate. In this investigation we analytically determined time-varying dose rate R-tilde which minimizes BED. Changes in BED with fraction time were compared for constant dose rate and for R-tilde. Conclusions: A number of recent experimental and theoretical studies have demonstrated that slow delivery of radiation (known as radiation protraction) leads to reduced therapeutic effect because of increased repair of sublethal damage. In contrast, our analysis shows that under certain conditions simultaneously increasing fraction time and dose per fraction are radiobiologically advantageous.« less

Effect of pre-emptive analgesia by continuous femoral nerve block on early postoperative cognitive function following total knee arthroplasty in elderly patients

PubMed Central

Deng, Li-Qin; Hou, Lei-Na; Song, Feng-Xiang; Zhu, Han-Yue; Zhao, Hai-Ying; Chen, Gang; Li, Jing-Jing

2017-01-01

To the best of our knowledge, the effect of pre-emptively blocking pain transmission on acute postoperative cognitive dysfunction (POCD) has not yet been assessed. Therefore, the present study aimed to investigate the effect of pre-emptive analgesia via a continuous femoral nerve block (CFNB) on postoperative pain and early cognitive function following total knee arthroplasty (TKA) surgery in elderly patients. CFNB was performed prior to TKA surgery in the pre-emptive analgesia group (n=30) and following TKA surgery in the control group (n=30). POCD was defined as a two-point reduction in the postoperative score compared with the preoperative score in the mini-mental state examination. The visual analog scale (VAS) was used to evaluate the intensity of pain at rest and during exercise. The intraoperative dose of remifentanil in the pre-emptive analgesia group was significantly lower than in the control group (P<0.01). In the preemptive analgesia group, VAS scores at three days post-surgery were lower than those in the control group (P<0.01). The incidence of POCD on the third postoperative day was slightly lower in the pre-emptive analgesia group compared with the control group. In conclusion, the results demonstrate that pre-emptive analgesia by CFNB may promote the recovery of early cognitive function following TKA in elderly patients. PMID:28413514

Effect of pre-emptive analgesia by continuous femoral nerve block on early postoperative cognitive function following total knee arthroplasty in elderly patients.

PubMed

Deng, Li-Qin; Hou, Lei-Na; Song, Feng-Xiang; Zhu, Han-Yue; Zhao, Hai-Ying; Chen, Gang; Li, Jing-Jing

2017-04-01

To the best of our knowledge, the effect of pre-emptively blocking pain transmission on acute postoperative cognitive dysfunction (POCD) has not yet been assessed. Therefore, the present study aimed to investigate the effect of pre-emptive analgesia via a continuous femoral nerve block (CFNB) on postoperative pain and early cognitive function following total knee arthroplasty (TKA) surgery in elderly patients. CFNB was performed prior to TKA surgery in the pre-emptive analgesia group (n=30) and following TKA surgery in the control group (n=30). POCD was defined as a two-point reduction in the postoperative score compared with the preoperative score in the mini-mental state examination. The visual analog scale (VAS) was used to evaluate the intensity of pain at rest and during exercise. The intraoperative dose of remifentanil in the pre-emptive analgesia group was significantly lower than in the control group (P<0.01). In the preemptive analgesia group, VAS scores at three days post-surgery were lower than those in the control group (P<0.01). The incidence of POCD on the third postoperative day was slightly lower in the pre-emptive analgesia group compared with the control group. In conclusion, the results demonstrate that pre-emptive analgesia by CFNB may promote the recovery of early cognitive function following TKA in elderly patients.

Application of Monte Carlo Method for Evaluation of Uncertainties of ITS-90 by Standard Platinum Resistance Thermometer

NASA Astrophysics Data System (ADS)

Palenčár, Rudolf; Sopkuliak, Peter; Palenčár, Jakub; Ďuriš, Stanislav; Suroviak, Emil; Halaj, Martin

2017-06-01

Evaluation of uncertainties of the temperature measurement by standard platinum resistance thermometer calibrated at the defining fixed points according to ITS-90 is a problem that can be solved in different ways. The paper presents a procedure based on the propagation of distributions using the Monte Carlo method. The procedure employs generation of pseudo-random numbers for the input variables of resistances at the defining fixed points, supposing the multivariate Gaussian distribution for input quantities. This allows taking into account the correlations among resistances at the defining fixed points. Assumption of Gaussian probability density function is acceptable, with respect to the several sources of uncertainties of resistances. In the case of uncorrelated resistances at the defining fixed points, the method is applicable to any probability density function. Validation of the law of propagation of uncertainty using the Monte Carlo method is presented on the example of specific data for 25 Ω standard platinum resistance thermometer in the temperature range from 0 to 660 °C. Using this example, we demonstrate suitability of the method by validation of its results.

ActiWiz 3 – an overview of the latest developments and their application

NASA Astrophysics Data System (ADS)

Vincke, H.; Theis, C.

2018-06-01

In 2011 the ActiWiz code was developed at CERN in order to optimize the choice of materials for accelerator equipment from a radiological point of view. Since then the code has been extended to allow for calculating complete nuclide inventories and provide evaluations with respect to radiotoxicity, inhalation doses, etc. Until now the software included only pre-defined radiation environments for CERN’s high-energy proton accelerators which were based on FLUKA Monte Carlo calculations. Eventually the decision was taken to invest into a major revamping of the code. Starting with version 3 the software is not limited anymore to pre-defined radiation fields but within a few seconds it can also treat arbitrary environments of which fluence spectra are available. This has become possible due to the use of ~100 CPU years’ worth of FLUKA Monte Carlo simulations as well as the JEFF cross-section library for neutrons < 20 MeV. Eventually the latest code version allowed for the efficient inclusion of 42 additional radiation environments of the LHC experiments as well as considerably more flexibility in view of characterizing also waste from CERN’s Large Electron Positron collider (LEP). New fully integrated analysis functionalities like automatic evaluation of difficult-to-measure nuclides, rapid assessment of the temporal evolution of quantities like radiotoxicity or dose-rates, etc. make the software a powerful tool for characterization complementary to general purpose MC codes like FLUKA. In this paper an overview of the capabilities will be given using recent examples from the domain of waste characterization as well as operational radiation protection.

Development of a national cosmic-ray dose monitoring system with Health Canada's Fixed Point Surveillance network.

PubMed

Liu, Chuanlei; Zhang, Weihua; Ungar, Kurt; Korpach, Ed; White, Brian; Benotto, Mike; Pellerin, Eric

2018-05-07

This work explores the application of Health Canada's Fixed Point Surveillance (FPS) network for cosmic ray monitoring and dose estimation purposes. This network is comprised of RS250 3 inch by 3 inch Sodium Iodide (NaI) spectroscopic dosimeters distributed throughout Canada. The RS250's high channel count rate responds to the electromagnetic and muonic components of cosmic ray shower. These count rates are used to infer cosmic ray doses throughout FPS locations. The derived dose was found to have an accuracy within 6.5% deviation relative to theoretical calculation. The solar cycle effect and meteorologically induced fluctuation can be realistically reflected in the estimated dose. This work may serve as a basis to enable the FPS network to monitor and report both terrestrial and cosmic radiation in quasi-real time. Crown Copyright © 2018. Published by Elsevier Ltd. All rights reserved.

Effects of FVIII immunity on hepatocyte and hematopoietic stem cell–directed gene therapy of murine hemophilia A

PubMed Central

Lytle, Allison M; Brown, Harrison C; Paik, Na Yoon; Knight, Kristopher A; Wright, J Fraser; Spencer, H Trent; Doering, Christopher B

2016-01-01

Immune responses to coagulation factors VIII (FVIII) and IX (FIX) represent primary obstacles to hemophilia treatment. Previously, we showed that hematopoietic stem cell (HSC) retroviral gene therapy induces immune nonresponsiveness to FVIII in both naive and preimmunized murine hemophilia A settings. Liver-directed adeno-associated viral (AAV)-FIX vector gene transfer achieved similar results in preclinical hemophilia B models. However, as clinical immune responses to FVIII and FIX differ, we investigated the ability of liver-directed AAV-FVIII gene therapy to affect FVIII immunity in hemophilia A mice. Both FVIII naive and preimmunized mice were administered recombinant AAV8 encoding a liver-directed bioengineered FVIII expression cassette. Naive animals receiving high or mid-doses subsequently achieved near normal FVIII activity levels. However, challenge with adjuvant-free recombinant FVIII induced loss of FVIII activity and anti-FVIII antibodies in mid-dose, but not high-dose AAV or HSC lentiviral (LV) vector gene therapy cohorts. Furthermore, unlike what was shown previously for FIX gene transfer, AAV-FVIII administration to hemophilia A inhibitor mice conferred no effect on anti-FVIII antibody or inhibitory titers. These data suggest that functional differences exist in the immune modulation achieved to FVIII or FIX in hemophilia mice by gene therapy approaches incorporating liver-directed AAV vectors or HSC-directed LV. PMID:26909355

Interactive Dose Shaping - efficient strategies for CPU-based real-time treatment planning

NASA Astrophysics Data System (ADS)

Ziegenhein, P.; Kamerling, C. P.; Oelfke, U.

2014-03-01

Conventional intensity modulated radiation therapy (IMRT) treatment planning is based on the traditional concept of iterative optimization using an objective function specified by dose volume histogram constraints for pre-segmented VOIs. This indirect approach suffers from unavoidable shortcomings: i) The control of local dose features is limited to segmented VOIs. ii) Any objective function is a mathematical measure of the plan quality, i.e., is not able to define the clinically optimal treatment plan. iii) Adapting an existing plan to changed patient anatomy as detected by IGRT procedures is difficult. To overcome these shortcomings, we introduce the method of Interactive Dose Shaping (IDS) as a new paradigm for IMRT treatment planning. IDS allows for a direct and interactive manipulation of local dose features in real-time. The key element driving the IDS process is a two-step Dose Modification and Recovery (DMR) strategy: A local dose modification is initiated by the user which translates into modified fluence patterns. This also affects existing desired dose features elsewhere which is compensated by a heuristic recovery process. The IDS paradigm was implemented together with a CPU-based ultra-fast dose calculation and a 3D GUI for dose manipulation and visualization. A local dose feature can be implemented via the DMR strategy within 1-2 seconds. By imposing a series of local dose features, equal plan qualities could be achieved compared to conventional planning for prostate and head and neck cases within 1-2 minutes. The idea of Interactive Dose Shaping for treatment planning has been introduced and first applications of this concept have been realized.

A method of estimating conceptus doses resulting from multidetector CT examinations during all stages of gestation

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

Damilakis, John; Tzedakis, Antonis; Perisinakis, Kostas

Purpose: Current methods for the estimation of conceptus dose from multidetector CT (MDCT) examinations performed on the mother provide dose data for typical protocols with a fixed scan length. However, modified low-dose imaging protocols are frequently used during pregnancy. The purpose of the current study was to develop a method for the estimation of conceptus dose from any MDCT examination of the trunk performed during all stages of gestation. Methods: The Monte Carlo N-Particle (MCNP) radiation transport code was employed in this study to model the Siemens Sensation 16 and Sensation 64 MDCT scanners. Four mathematical phantoms were used, simulatingmore » women at 0, 3, 6, and 9 months of gestation. The contribution to the conceptus dose from single simulated scans was obtained at various positions across the phantoms. To investigate the effect of maternal body size and conceptus depth on conceptus dose, phantoms of different sizes were produced by adding layers of adipose tissue around the trunk of the mathematical phantoms. To verify MCNP results, conceptus dose measurements were carried out by means of three physical anthropomorphic phantoms, simulating pregnancy at 0, 3, and 6 months of gestation and thermoluminescence dosimetry (TLD) crystals. Results: The results consist of Monte Carlo-generated normalized conceptus dose coefficients for single scans across the four mathematical phantoms. These coefficients were defined as the conceptus dose contribution from a single scan divided by the CTDI free-in-air measured with identical scanning parameters. Data have been produced to take into account the effect of maternal body size and conceptus position variations on conceptus dose. Conceptus doses measured with TLD crystals showed a difference of up to 19% compared to those estimated by mathematical simulations. Conclusions: Estimation of conceptus doses from MDCT examinations of the trunk performed on pregnant patients during all stages of gestation can be made using the method developed in the current study.« less

Aclidinium bromide plus formoterol for the treatment of chronic obstructive pulmonary disease.

PubMed

Lal, Chitra; Strange, Charlie

2015-02-01

Drugs that target dynamic hyperinflation such as long-acting β-2 agonists and long-acting antimuscarinic antagonists form a cornerstone of chronic obstructive pulmonary disease (COPD) management. The idea of combining these two medications in a single formulation, which may potentially improve patient compliance, is novel and attractive. The pharmacologic profiles of aclidinium bromide and formoterol fumarate are discussed. However, studies to define drug interactions and alterations in the pharmacodynamics and pharmacokinetics of the fixed dose combination (FDC) of aclidinium bromide/formoterol fumarate in large populations remain unpublished. Results of Phase II and two Phase III pivotal trials, ACLIFORM/COPD and AUGMENT COPD, evaluating the FDC are discussed. Initial data for the aclidinium/formoterol inhaler appears to be promising for impacting the lung function. To define if this benefit translates into improved long-term outcomes of decreased exacerbation frequency, improved quality of life and decreased disease-specific mortality are important. The introduction of this combination will likely have a significant impact on the prescribing habits of physicians across the world.

Validation of a rapid conductimetric test for the measurement of wine tartaric stability.

PubMed

Bosso, Antonella; Motta, Silvia; Petrozziello, Maurizio; Guaita, Massimo; Asproudi, Andriani; Panero, Loretta

2016-12-01

This work was aimed at optimizing a rapid and reproducible conductivity test for the evaluation of wine tartaric stability, in order to improve the practices for the prevention of tartaric precipitations during bottle aging. The test consists in measuring the drop of conductivity in wines kept under stirring for a fixed time, at low temperature, after the addition of micronized potassium bitartrate crystals (KHT). An experimental design was planned to study three factors affecting the test: temperature, duration and dose of added potassium bitartrate. A standard protocol was defined to produce a micronized potassium bitartrate starting from available commercial products, since the dimensions of the crystals can affect the final conductivity values. After the choice of the best conditions the method was validated. Two different stability thresholds were defined for white wines and for red/rosé wines by comparing the results of the mini-contact test with those of the cold test. Copyright © 2016 Elsevier Ltd. All rights reserved.

[Absorbed doses to critical organs from full mouth dental radiography].

PubMed

Zhang, G; Yasuhiko, O; Hidegiko, Y

1999-01-01

A few studies were reported in China on radiological risk of dental radiography. The aim of this study is to evaluate the absorbed doses of patients from the full mouth radiographs, and to find out the contribution from each projection to the total absorbed dose of the organs. Absorbed doses to critical organs were measured from 14-film complete dental radiography. The organs included pituitary, optical lens, parotid glands, submandibular glands, sublingual glands, thyroid, breasts, ovary, testes and the skin in center field of each projection were studied. A-radiation analog dosimetry system (RANDO) phantom with thermoluminescent dosimeters (ILD200) was used for the study. All of the exposure parameters were fixed. The total filtration was 2 mm Al equivalent. The column collaboration was 6 cm in diameter and 20 cm in length. The absorbed doses of organs were measured three times in each projection of the full-mouth series (FMS) exposures. The absorbed dose of lenses in FMS (249 microGy) in present study was much less (10%) than the doses (2,630 microGy) reported in 1976. The doses absorbed of other organs in the present study were thyroid gland (125 microGy), pituitary gland (112 microGy), parotid gland (153 microGy), submandibular gland (629 microGy), sublingual gland (1,900 microGy), and breast gland (12 microGy). The doses of the ovary and testis were to small to further analysis. All of the results show that the radiation risk to patients in intraoral radiograph has been reduced significantly. In the pituitary, half of the dose is from both sides of the maxillary molar projection. For the lenses, the largest contribultions of radiation (60%) come from the ipsilateral molar and premolar projection of maxilla. In parotid gland, up to 57% of the dose is from the contralateral molar, pre-molar and canine of maxilla. It could be derived that about 90% of the absorbed doses could be avoided in FMS if the column collimator is 20 cm long and the filter is 2.0 mm thick. If we use the 10-film complete mouth radiograph instead of the 14-film series, more 20% of the doses would be reduced.

Rapamycin Pharmacokinetic and Pharmacodynamic Relationships in Osteosarcoma: A Comparative Oncology Study in Dogs

PubMed Central

Paoloni, Melissa C.; Mazcko, Christina; Fox, Elizabeth; Fan, Timothy; Lana, Susan; Kisseberth, William; Vail, David M.; Nuckolls, Kaylee; Osborne, Tanasa; Yalkowsy, Samuel; Gustafson, Daniel; Yu, Yunkai; Cao, Liang; Khanna, Chand

2010-01-01

Background Signaling through the mTOR pathway contributes to growth, progression and chemoresistance of several cancers. Accordingly, inhibitors have been developed as potentially valuable therapeutics. Their optimal development requires consideration of dose, regimen, biomarkers and a rationale for their use in combination with other agents. Using the infrastructure of the Comparative Oncology Trials Consortium many of these complex questions were asked within a relevant population of dogs with osteosarcoma to inform the development of mTOR inhibitors for future use in pediatric osteosarcoma patients. Methodology/Principal Findings This prospective dose escalation study of a parenteral formulation of rapamycin sought to define a safe, pharmacokinetically relevant, and pharmacodynamically active dose of rapamycin in dogs with appendicular osteosarcoma. Dogs entered into dose cohorts consisting of 3 dogs/cohort. Dogs underwent a pre-treatment tumor biopsy and collection of baseline PBMC. Dogs received a single intramuscular dose of rapamycin and underwent 48-hour whole blood pharmacokinetic sampling. Additionally, daily intramuscular doses of rapamycin were administered for 7 days with blood rapamycin trough levels collected on Day 8, 9 and 15. At Day 8 post-treatment collection of tumor and PBMC were obtained. No maximally tolerated dose of rapamycin was attained through escalation to the maximal planned dose of 0.08 mg/kg (2.5 mg/30kg dog). Pharmacokinetic analysis revealed a dose-dependent exposure. In all cohorts modulation of the mTOR pathway in tumor and PBMC (pS6RP/S6RP) was demonstrated. No change in pAKT/AKT was seen in tumor samples following rapamycin therapy. Conclusions/Significance Rapamycin may be safely administered to dogs and can yield therapeutic exposures. Modulation pS6RP/S6RP in tumor tissue and PBMCs was not dependent on dose. Results from this study confirm that the dog may be included in the translational development of rapamycin and potentially other mTOR inhibitors. Ongoing studies of rapamycin in dogs will define optimal schedules for their use in cancer and evaluate the role of rapamycin use in the setting of minimal residual disease. PMID:20543980

Influence of CT automatic tube current modulation on uncertainty in effective dose.

PubMed

Sookpeng, S; Martin, C J; Gentle, D J

2016-01-01

Computed tomography (CT) scanners are equipped with automatic tube current modulation (ATCM) systems that adjust the current to compensate for variations in patient attenuation. CT dosimetry variables are not defined for ATCM situations and, thus, only the averaged values are displayed and analysed. The patient effective dose (E), which is derived from a weighted sum of organ equivalent doses, will be modified by the ATCM. Values for E for chest-abdomen-pelvis CT scans have been calculated using the ImPACT spreadsheet for patients on five CT scanners. Values for E resulting from the z-axis modulation under ATCM have been compared with results assessed using the same effective mAs values with constant tube currents. Mean values for E under ATCM were within ±10 % of those for fixed tube currents for all scanners. Cumulative dose distributions under ATCM have been simulated for two patient scans using single-slice dose profiles measured in elliptical and cylindrical phantoms on one scanner. Contributions to the effective dose from organs in the upper thorax under ATCM are 30-35 % lower for superficial tissues (e.g. breast) and 15-20 % lower for deeper organs (e.g. lungs). The effect on doses to organs in the abdomen depends on body shape, and they can be 10-22 % higher for larger patients. Results indicate that scan dosimetry parameters, dose-length product and effective mAs averaged over the whole scan can provide an assessment in terms of E that is sufficiently accurate to quantify relative risk for routine patient exposures under ATCM. © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Evaluation of the Lactate-to-N-Acetyl-aspartate Ratio Defined With Magnetic Resonance Spectroscopic Imaging Before Radiation Therapy as a New Predictive Marker of the Site of Relapse in Patients With Glioblastoma Multiforme

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

Deviers, Alexandra; UMR; INP

Purpose: Because lactate accumulation is considered a surrogate for hypoxia and tumor radiation resistance, we studied the spatial distribution of the lactate-to-N-acetyl-aspartate ratio (LNR) before radiation therapy (RT) with 3D proton magnetic resonance spectroscopic imaging (3D-{sup 1}H-MRSI) and assessed its impact on local tumor control in glioblastoma (GBM). Methods and Materials: Fourteen patients with newly diagnosed GBM included in a phase 2 chemoradiation therapy trial constituted our database. Magnetic resonance imaging (MRI) and MRSI data before RT were evaluated and correlated to MRI data at relapse. The optimal threshold for tumor-associated LNR was determined with receiver-operating-characteristic (ROC) curve analysis ofmore » the pre-RT LNR values and MRI characteristics of the tumor. This threshold was used to segment pre-RT normalized LNR maps. Two spatial analyses were performed: (1) a pre-RT volumetric comparison of abnormal LNR areas with regions of MRI-defined lesions and a choline (Cho)-to- N-acetyl-aspartate (NAA) ratio ≥2 (CNR2); and (2) a voxel-by-voxel spatial analysis of 4,186,185 voxels with the intention of evaluating whether pre-RT abnormal LNR areas were predictive of the site of local recurrence. Results: A LNR of ≥0.4 (LNR-0.4) discriminated between tumor-associated and normal LNR values with 88.8% sensitivity and 97.6% specificity. LNR-0.4 voxels were spatially different from those of MRI-defined lesions, representing 44% of contrast enhancement, 64% of central necrosis, and 26% of fluid-attenuated inversion recovery (FLAIR) abnormality volumes before RT. They extended beyond the overlap with CNR2 for most patients (median: 20 cm{sup 3}; range: 6-49 cm{sup 3}). LNR-0.4 voxels were significantly predictive of local recurrence, regarded as contrast enhancement at relapse: 71% of voxels with a LNR-0.4 before RT were contrast enhanced at relapse versus 10% of voxels with a normal LNR (P<.01). Conclusions: Pre-RT LNR-0.4 in GBM indicates tumor areas that are likely to relapse. Further investigations are needed to confirm lactate imaging as a tool to define additional biological target volumes for dose painting.« less

Jet-conversion photons from an anisotropic quark-gluon plasma

NASA Astrophysics Data System (ADS)

Bhattacharya, Lusaka; Roy, Pradip

2010-10-01

We calculate the pT distributions of jet-conversion photons from a quark-gluon plasma with pre-equilibrium momentum-space anisotropy. A phenomenological model has been used for the time evolution of the hard momentum scale phard(τ) and anisotropy parameter ξ(τ). As a result of pre-equilibrium momentum-space anisotropy, we find significant modification of the jet-conversion photon pT distribution. For example, with fixed initial condition pre-equilibrium anisotropy, we predict a significant enhancement of the jet-photon pT distribution in the entire region, whereas for pre-equilibrium anisotropy with fixed final multiplicity (FFM), suppression of the jet-conversion photon pT distribution is observed. The results with FFM (as it is the most realistic situation) have been compared with high pT PHENIX photon data. It is found that the data are reproduced well if the isotropization time lies within 1.5 fm/c.

Preclinical safety and efficacy of a new recombinant FIX drug product for treatment of hemophilia B.

PubMed

Dietrich, Barbara; Schiviz, Alexandra; Hoellriegl, Werner; Horling, Frank; Benamara, Karima; Rottensteiner, Hanspeter; Turecek, Peter L; Schwarz, Hans Peter; Scheiflinger, Friedrich; Muchitsch, Eva-Maria

2013-11-01

Baxter has developed a new recombinant factor IX (rFIX) drug product (BAX326) for treating patients with hemophilia B, or congenital FIX deficiency. An extensive preclinical program evaluated the pharmacokinetics, efficacy, and safety of BAX326 in different species. The efficacy of BAX326 was tested in three mouse models of primary pharmacodynamics: tail-tip bleeding, carotid occlusion, and thrombelastography. The pharmacokinetics was evaluated after a single intravenous bolus injection in mice, rats, and macaques. Toxicity was assessed in rats and macaques, safety pharmacology in rabbits and macaques, and immunogenicity in mice. BAX326 was shown to be efficacious in all three primary pharmacodynamic studies (P ≤ 0.0076). Hemostatic efficacy was dose related and similar for the three lots tested. Pharmacokinetic results showed that rFIX activity and rFIX antigen concentrations declined in a bi-phasic manner, similar to a previously licensed rFIX product. BAX326 was well tolerated in rabbits and macaques at all dose levels; no thrombogenic events and no adverse clinical, respiratory, or cardiovascular effects occurred. BAX326 was also shown to have a similar immunogenicity profile to the comparator rFIX product in mice. These results demonstrate that BAX326 has a favorable preclinical safety and efficacy profile, predictive of a comparable effect to that of the previously licensed rFIX in humans.

Morphine Tolerance as a Function of Ratio Schedule: Response Requirement or Unit Price?

ERIC Educational Resources Information Center

Hughes, Christine; Sigmon, Stacey C.; Pitts, Raymond C.; Dykstra, Linda A.

2005-01-01

Key pecking by 3 pigeons was maintained by a multiple fixed-ratio 10, fixed-ratio 30, fixed-ratio 90 schedule of food presentation. Components differed with respect to amount of reinforcement, such that the unit price was 10 responses per 1-s access to food. Acute administration of morphine, "l"-methadone, and cocaine dose-dependently decreased…

A Randomized Multicenter Phase III Study of Single Administration of Mecapegfilgrastim (HHPG-19K), a Pegfilgrastim Biosimilar, for Prophylaxis of Chemotherapy-Induced Neutropenia in Patients With Advanced Non-Small-Cell Lung Cancer (NSCLC).

PubMed

Zhou, Caicun; Huang, Yunchao; Wang, Donglin; An, Changshan; Zhou, Fuxiang; Li, Yali; Chen, Gongyan; Wu, Changping; He, Jianxing; Wu, Gang; Song, Xia; Gao, Jianfei; Liu, Wei; Li, Baolan; Shi, Jianhua; Huang, Cheng; Yu, Jingrui; Feng, Jueping; Yue, Hongmei; Shi, Meiqi; Xia, Jielai

2016-03-01

Mecapegfilgrastim (code name HHPG-19K) is a biosimilar to pegylated recombinant human granulocyte-colony stimulating factor (PEG-rhG-CSF). The efficacy and safety of mecapegfilgrastim, using a regimen of once-per-cycle injection of 100-μg/kg or a fixed 6-mg dose, were evaluated for the prophylactic therapy for neutropenia in patients with advanced non-small-cell lung cancer (NSCLC) who were treated with myelosuppressive chemotherapy. Patients were randomized (1:1:1) blindly to 3 treatment arms to receive a single injection of mecapegfilgrastim 100 μg/kg, a 6-mg fixed dose of mecapegfilgrastim, or saline (control) in cycle 1. In cycles 2 to 4 following unblinding at the end of cycle 1, patients in the control arm received daily injections of short-acting rhG-CSF at a dose of 5 μg/kg, whereas patients in the 2 mecapegfilgrastim arms continued the same treatment as in cycle 1. All patients received 4 chemotherapy cycles of docetaxel combined with cisplatin or carboplatin every 21 days. The primary endpoint was the incidence of grade ≥ 3 neutropenia in cycle 1. A single dose of 100 μg/kg or a fixed 6-mg dose of mecapegfilgrastim per cycle effectively reduced chemotherapy-induced neutropenia and was comparable to daily rhG-CSF with regard to all efficacy endpoints, including incidence of grade ≥ 3 neutropenia, incidence of febrile neutropenia, duration of grade ≥ 3 neutropenia, and time to neutrophil recovery. No difference in efficacy parameters was observed between the 2-dose regimens of mecapegfilgrastim across all cycles. Mecapegfilgrastim was well-tolerated and was as safe as daily rhG-CSF. Once-per-cycle injection of mecapegfilgrastim is as effective and safe as daily rhG-CSF for prophylaxis of chemotherapy-induced neutropenia in patients with NSCLC. Mecapegfilgrastim (fixed 6-mg dose) is recommended in clinical practice for its convenient dose management. Crown Copyright © 2016. Published by Elsevier Inc. All rights reserved.

32 CFR 37.560 - Must I be able to estimate project expenditures precisely in order to justify use of a fixed...

Code of Federal Regulations, 2010 CFR

2010-07-01

... of Defense OFFICE OF THE SECRETARY OF DEFENSE DoD GRANT AND AGREEMENT REGULATIONS TECHNOLOGY INVESTMENT AGREEMENTS Pre-Award Business Evaluation Fixed-Support Or Expenditure-Based Approach § 37.560 Must...

[Effect of low-dose focused ultrasound pre-irradiation versus microbubbles for enhancing high-intensity focused ultrasound ablation of VX2 hepatic tumor in rabbits].

PubMed

Zhang, Yi; Yang, Chao; Zou, Jian-Zhong; Chen, Fei; Ou, Xia; Zou, Hai-Rong; Wang, Yan

2016-10-20

To compare the effect of low-dose focused ultrasound pre-irradiation and microbubbles for enhancing the ablation effect of high intensity focused ultrasound (HIFU) on VX 2 hepatic tumor in rabbits. Fifty-five rabbits bearing VX 2 hepatic tumor were randomly divided into low-dose pre-irradiation + HIFU ablation group, microbubbles+HIFU ablation group, and HIFU ablation group for corresponding treatments. The pathological changes in the tumors after low-dose irradiation, time for HIFU ablation, tumor volume with coagulative necrosis, energy efficiency factor (EEF), pathological changes in the ablated tumor, and sound channel of HIFU ablation were observed. Tumor cell edema, vacuolar changes in the cytoplasm and tumor interstitial vascular congestion were observed 24 h after low-dose pre-irradiation. The ablation time were significantly shorter, coagulative necrosis volume was larger, and EEF was lower in low-dose irradiation + HIFU ablation group and microbubbles+HIFU ablation group than in simple HIFU ablation group (P<0.05), but the differences between the former two groups were not significant. The effectiveness and stability of the synergistic effect of low-dose pre-irradiation were inferior to microbubbles, but the former ensured a better safety of the sound channel. Low-dose irradiation has comparable synergistic effect in HIFU with microbubbles with such advantages as non-invasiveness, high concentration and good safety, and can be a potentially new method to enhance the efficiency of HIFU.

Repaglinide in type 2 diabetes: a 24-week, fixed-dose efficacy and safety study.

PubMed

Jovanovic, L; Dailey, G; Huang, W C; Strange, P; Goldstein, B J

2000-01-01

In this 24-week multicenter, double-blind, randomized, fixed-dose trial, 361 patients having type 2 diabetes received daily preprandial treatment with placebo (n = 75), repaglinide 1 mg (n = 140), or repaglinide 4 mg (n = 146). By a last-observation carried-forward calculation, repaglinide 1 mg or 4 mg treatment decreased mean fasting plasma glucose (FPG) values (by -47 mg/dL or -49 mg/dL) while the placebo group had increased FPG values (by 19 mg/dL). For the repaglinide treatment groups at the end of the study, changes in HbA1c from baseline values ranged from 1.8 to 1.9 percentage points lower than the placebo group. There were no events of severe hypoglycemia. Nearly all hypoglycemic symptom episodes had blood glucose levels above 45 mg/dL. Repaglinide was well tolerated in a preprandial fixed-dose regimen of 1 mg or 4 mg, assigned without adjustment for clinical parameters.

Effectiveness and tolerability of fixed-dose combination enalapril plus nitrendipine in hypertensive patients: results of the 3-month observational, post-marketing, multicentre, prospective CENIT study.

PubMed

Sierra, Alejandro de la; Roca-Cusachs, Alejandro; Redón, Josep; Marín, Rafael; Luque, Manuel; Figuera, Mariano de la; Garcia-Garcia, Margarida; Falkon, Liliana

2009-01-01

Monotherapy with any class of antihypertensive drug effectively controls blood pressure (BP) in only about 50% of patients. Consequently, the majority of patients with hypertension require combined therapy with two or more medications. This study aimed to evaluate the effectiveness (systolic BP [SBP]/diastolic BP [DBP] control) and tolerability of the fixed-dose combination enalapril/nitrendipine 10 mg/20 mg administered as a single daily dose in hypertensive patients. This was a post-authorization, multicentre, prospective, observational study conducted in primary care with a 3-month follow-up. Patients throughout Spain with uncontrolled hypertension (> or =140/90 mmHg for patients without diabetes mellitus, or > or =130/85 mmHg for patients with diabetes) on monotherapy or with any combination other than enalapril + nitrendipine, or who were unable to tolerate their previous antihypertensive therapy, were recruited. Change from previous to study treatment was according to usual clinical practice. BP was measured once after 5 minutes of rest in the sitting position. Therapeutic response was defined as follows: 'controlled' meant controlled BP (<140/90 mmHg for nondiabetic patients, or <130/85 mmHg for diabetic patients); 'response' meant controlled BP, or a decrease in SBP of > or =20 mmHg and in DBP of > or =10 mmHg. The main laboratory test parameters were documented at baseline and after 3 months. Patients aged >65 years, with diabetes, with isolated systolic hypertension (ISH; SBP > or =140 mmHg for patients without diabetes, SBP > or =130 mmHg for patients with diabetes) and who were obese (body mass index [BMI] > or =30 kg/m2) were analysed separately. Of 6537 patients included, 5010 and 6354 patients were assessed in effectiveness and tolerability analyses, respectively. In the tolerability analysis population, there were 3023 men (47.6%) and 3321 women (52.4%). The mean (+/- SD) age of the tolerability analysis group was 62.8 (+/- 10.7) years. A total of 71.1% of the patients presented at least one clinical cardiovascular risk factor other than hypertension, with the most frequent being dyslipidaemia (42.3%), obesity (29.2%) and diabetes (23.9%). After 3 months of treatment, SBP and DBP showed mean (+/- SD) decreases of 26.5 (+/- 14.4) mmHg and 14.9 (+/- 9.0) mmHg, respectively, and 73.0% of patients responded to treatment while 40.9% achieved BP control (70.8%/36.1% in 2658 patients aged >65 years; 61.7%/46.8% in 1521 patients with diabetes; 55.3%/44.2% in 731 patients with ISH; 72.0%/36.4% in 1762 obese patients). Adverse events were reported in 10.8% of patients (n = 689). During the follow-up period, ten patients died and seven patients had serious adverse events; in no case was a causal relationship attributed to the study product. The rate of SBP/DBP control achieved demonstrates the effectiveness of the fixed-dose enalapril/nitrendipine 10 mg/20 mg combination administered as a single daily dose in patients with essential hypertension not adequately controlled with monotherapy or with any combination other than enalapril + nitrendipine. The proportion and type of adverse events reported were as expected and have already been described for both components of the enalapril/nitrendipine 10 mg/20 mg combination. These results confirm the effectiveness of a strategy based on a fixed-dose enalapril/nitrendipine 10 mg/20 mg combination in reducing BP and achieving BP control goals.

SU-E-J-113: The Influence of Optimizing Pediatric CT Simulator Protocols On the Treatment Dose Calculation in Radiotherapy

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

Zhang, Y; Zhang, J; Hu, Q

2014-06-01

Purpose: To investigate the possibility of applying optimized scanning protocols for pediatric CT simulation by quantifying the dosimetric inaccuracy introduced by using a fixed HU to density conversion. Methods: The images of a CIRS electron density reference phantom (Model 062) were acquired by a Siemens CT simulator (Sensation Open) using the following settings of tube voltage and beam current: 120 kV/190mA (the reference protocol used to calibrate CT for our treatment planning system (TPS)); Fixed 190mA combined with all available kV: 80, 100, and 140; fixed 120 kV and various current from 37 to 444 mA (scanner extremes) with intervalmore » of 30 mA. To avoid the HU uncertainty of point sampling in the various inserts of known electron densities, the mean CT numbers of the central cylindrical volume were calculated using DICOMan software. The doses per 100 MU to the reference point (SAD=100cm, Depth=10cm, Field=10X10cm, 6MV photon beam) in a virtual cubic phantom (30X30X30cm) were calculated using Eclipse TPS (calculation model: AcurosXB-11031) by assigning the CT numbers to HU of typical materials acquired by various protocols. Results: For the inserts of densities less than muscle, CT number fluctuations of all protocols were within the tolerance of 10 HU as accepted by AAPM-TG66. For more condensed materials, fixed kV yielded stable HU with any mA combination where largest disparities were found in 1750mg/cc insert: HU{sub reference}=1801(106.6cGy), HU{sub minimum}=1799 (106.6cGy, error{sub dose}=0.00%), HU{sub maximum}=1815 (106.8cGy, error{sub dose}=0.19%). Yet greater disagreements were observed with increasing density when kV was modified: HU{sub minimum}=1646 (104.5cGy, error{sub dose}=- 1.97%), HU{sub maximum}=2487 (116.4cGy, error{sub dose}=9.19%) in 1750mg/cc insert. Conclusion: Without affecting treatment dose calculation, personalized mA optimization of CT simulator can be conducted by fixing kV for a better cost-effectiveness of imaging dose and quality especially for children. Unless recalibrated, kV should be constant for all anatomical sites if diagnostic CT scanner is used as a simulator. This work was partially supported by Capital Medical Development Scientific Research Fund of China.« less

A pragmatic approach to determine the optimal kVp in cone beam CT: balancing contrast-to-noise ratio and radiation dose

PubMed Central

Silkosessak, O; Jacobs, R; Bogaerts, R; Bosmans, H; Panmekiate, S

2014-01-01

Objectives: To determine the optimal kVp setting for a particular cone beam CT (CBCT) device by maximizing technical image quality at a fixed radiation dose. Methods: The 3D Accuitomo 170 (J. Morita Mfg. Corp., Kyoto, Japan) CBCT was used. The radiation dose as a function of kVp was measured in a cylindrical polymethyl methacrylate (PMMA) phantom using a small-volume ion chamber. Contrast-to-noise ratio (CNR) was measured using a PMMA phantom containing four materials (air, aluminium, polytetrafluoroethylene and low-density polyethylene), which was scanned using 180 combinations of kVp/mA, ranging from 60/1 to 90/8. The CNR was measured for each material using PMMA as background material. The pure effect of kVp and mAs on the CNR values was analysed. Using a polynomial fit for CNR as a function of mA for each kVp value, the optimal kVp was determined at five dose levels. Results: Absorbed doses ranged between 0.034 mGy mAs−1 (14 × 10 cm, 60 kVp) and 0.108 mGy mAs−1 (14 × 10 cm, 90 kVp). The relation between kVp and dose was quasilinear (R2 > 0.99). The effect of mA and kVp on CNR could be modelled using a second-degree polynomial. At a fixed dose, there was a tendency for higher CNR values at increasing kVp values, especially at low dose levels. A dose reduction through mA was more efficient than an equivalent reduction through kVp in terms of image quality deterioration. Conclusions: For the investigated CBCT model, the most optimal contrast at a fixed dose was found at the highest available kVp setting. There is great potential for dose reduction through mA with a minimal loss in image quality. PMID:24708447

Sex-specific performance of pre-imaging diagnostic algorithms for pulmonary embolism.

PubMed

van Mens, T E; van der Pol, L M; van Es, N; Bistervels, I M; Mairuhu, A T A; van der Hulle, T; Klok, F A; Huisman, M V; Middeldorp, S

2018-05-01

Essentials Decision rules for pulmonary embolism are used indiscriminately despite possible sex-differences. Various pre-imaging diagnostic algorithms have been investigated in several prospective studies. When analysed at an individual patient data level the algorithms perform similarly in both sexes. Estrogen use and male sex were associated with a higher prevalence in suspected pulmonary embolism. Background In patients suspected of pulmonary embolism (PE), clinical decision rules are combined with D-dimer testing to rule out PE, avoiding the need for imaging in those at low risk. Despite sex differences in several aspects of the disease, including its diagnosis, these algorithms are used indiscriminately in women and men. Objectives To compare the performance, defined as efficiency and failure rate, of three pre-imaging diagnostic algorithms for PE between women and men: the Wells rule with fixed or with age-adjusted D-dimer cut-off, and a recently validated algorithm (YEARS). A secondary aim was to determine the sex-specific prevalence of PE. Methods Individual patient data were obtained from six studies using the Wells rule (fixed D-dimer, n = 5; age adjusted, n = 1) and from one study using the YEARS algorithm. All studies prospectively enrolled consecutive patients with suspected PE. Main outcomes were efficiency (proportion of patients in which the algorithm ruled out PE without imaging) and failure rate (proportion of patients with PE not detected by the algorithm). Outcomes were estimated using (multilevel) logistic regression models. Results The main outcomes showed no sex differences in any of the separate algorithms. With all three, the prevalence of PE was lower in women (OR, 0.66, 0.68 and 0.74). In women, estrogen use, adjusted for age, was associated with lower efficiency and higher prevalence and D-dimer levels. Conclusions The investigated pre-imaging diagnostic algorithms for patients suspected of PE show no sex differences in performance. Male sex and estrogen use are both associated with a higher probability of having the disease. © 2018 International Society on Thrombosis and Haemostasis.

D-optimal experimental designs to test for departure from additivity in a fixed-ratio mixture ray.

PubMed

Coffey, Todd; Gennings, Chris; Simmons, Jane Ellen; Herr, David W

2005-12-01

Traditional factorial designs for evaluating interactions among chemicals in a mixture may be prohibitive when the number of chemicals is large. Using a mixture of chemicals with a fixed ratio (mixture ray) results in an economical design that allows estimation of additivity or nonadditive interaction for a mixture of interest. This methodology is extended easily to a mixture with a large number of chemicals. Optimal experimental conditions can be chosen that result in increased power to detect departures from additivity. Although these designs are used widely for linear models, optimal designs for nonlinear threshold models are less well known. In the present work, the use of D-optimal designs is demonstrated for nonlinear threshold models applied to a fixed-ratio mixture ray. For a fixed sample size, this design criterion selects the experimental doses and number of subjects per dose level that result in minimum variance of the model parameters and thus increased power to detect departures from additivity. An optimal design is illustrated for a 2:1 ratio (chlorpyrifos:carbaryl) mixture experiment. For this example, and in general, the optimal designs for the nonlinear threshold model depend on prior specification of the slope and dose threshold parameters. Use of a D-optimal criterion produces experimental designs with increased power, whereas standard nonoptimal designs with equally spaced dose groups may result in low power if the active range or threshold is missed.

Pooled solifenacin overactive bladder trial data: Creation, validation and analysis of an integrated database.

PubMed

Chapple, Christopher R; Cardozo, Linda; Snijder, Robert; Siddiqui, Emad; Herschorn, Sender

2016-12-15

Patient-level data are available for 11 randomized, controlled, Phase III/Phase IV solifenacin clinical trials. Meta-analyses were conducted to interrogate the data, to broaden knowledge about solifenacin and overactive bladder (OAB) in general. Before integrating data, datasets from individual studies were mapped to a single format using methodology developed by the Clinical Data Interchange Standards Consortium (CDISC). Initially, the data structure was harmonized, to ensure identical categorization, using the CDISC Study Data Tabulation Model (SDTM). To allow for patient level meta-analysis, data were integrated and mapped to analysis datasets. Mapping included adding derived and categorical variables and followed standards described as the Analysis Data Model (ADaM). Mapping to both SDTM and ADaM was performed twice by two independent programming teams, results compared, and inconsistencies corrected in the final output. ADaM analysis sets included assignments of patients to the Safety Analysis Set and the Full Analysis Set. There were three analysis groupings: Analysis group 1 (placebo-controlled, monotherapy, fixed-dose studies, n = 3011); Analysis group 2 (placebo-controlled, monotherapy, pooled, fixed- and flexible-dose, n = 5379); Analysis group 3 (all solifenacin monotherapy-treated patients, n = 6539). Treatment groups were: solifenacin 5 mg fixed dose, solifenacin 5/10 mg flexible dose, solifenacin 10 mg fixed dose and overall solifenacin. Patient were similar enough for data pooling to be acceptable. Creating ADaM datasets provided significant information about individual studies and the derivation decisions made in each study; validated ADaM datasets now exist for medical history, efficacy and AEs. Results from these meta-analyses were similar over time.

Maintaining radiation exposures as low as reasonably achievable (ALARA) for dental personnel operating portable hand-held x-ray equipment.

PubMed

McGiff, Thomas J; Danforth, Robert A; Herschaft, Edward E

2012-08-01

Clinical experience indicates that newly available portable hand-held x-ray units provide advantages compared to traditional fixed properly installed and operated x-ray units in dental radiography. However, concern that hand-held x-ray units produce higher operator doses than fixed x-ray units has caused regulatory agencies to mandate requirements for use of hand-held units that go beyond those recommended by the manufacturer and can discourage the use of this technology. To assess the need for additional requirements, a hand-held x-ray unit and a pair of manikins were used to measure the dose to a simulated operator under two conditions: exposures made according to the manufacturer's recommendations and exposures made according to manufacturer's recommendation except for the removal of the x-ray unit's protective backscatter shield. Dose to the simulated operator was determined using an array of personal dosimeters and a pair of pressurized ion chambers. The results indicate that the dose to an operator of this equipment will be less than 0.6 mSv y⁻¹ if the device is used according to the manufacturer's recommendations. This suggests that doses to properly trained operators of well-designed, hand-held dental x-ray units will be below 1.0 mSv y⁻¹ (2% of the annual occupational dose limit) even if additional no additional operational requirements are established by regulatory agencies. This level of annual dose is similar to those reported as typical dental personnel using fixed x-ray units and appears to satisfy the ALARA principal for this class of occupational exposures.

Micro-Dose Calibrator for Pre-clinical Radiotracer Assays | NCI Technology Transfer Center | TTC

Cancer.gov

Pre-clinical radiotracer biomedical research involves the use of compounds labeled with radioisotopes, including cell binding studies, immune cell labeling techniques, and radio-ligand bio-distribution studies. Before this Micro-Dose Calibrator, measurement of pre-clinical level dosage for small animal studies was inaccurate and unreliable. This dose calibrator is a prototype ready for manufacturing. It is designed to accurately measure radioactive doses in the range of 50 nCi (1.8 kBq) to 100 µCi (3.7 MBq) with 1% precision. The NCI seeks co-development or licensing to commercialize it. Alternative uses will be considered.

Impact of Mobile Dose-Tracking Technology on Medication Distribution at an Academic Medical Center.

PubMed

Kelm, Matthew; Campbell, Udobi

2016-05-01

Medication dose-tracking technologies have the potential to improve efficiency and reduce costs associated with re-dispensing doses reported as missing. Data describing this technology and its impact on the medication use process are limited. The purpose of this study is to assess the impact of dose-tracking technology on pharmacy workload and drug expense at an academic, acute care medical center. Dose-tracking technology was implemented in June 2014. Pre-implementation data were collected from February to April 2014. Post-implementation data were collected from July to September 2014. The primary endpoint was the percent of re-dispensed oral syringe and compounded sterile product (CSP) doses within the pre- and post-implementation periods per 1,000 discharges. Secondary endpoints included pharmaceutical expense generated from re-dispensing doses, labor costs, and staff satisfaction with the medication distribution process. We observed an average 6% decrease in re-dispensing of oral syringe and CSP doses from pre- to post-implementation (15,440 vs 14,547 doses; p = .047). However, when values were adjusted per 1,000 discharges, this trend did not reach statistical significance (p = .074). Pharmaceutical expense generated from re-dispensing doses was significantly reduced from pre- to post-implementation ($834,830 vs $746,466 [savings of $88,364]; p = .047). We estimated that $2,563 worth of technician labor was avoided in re-dispensing missing doses. We also saw significant improvement in staff perception of technology assisting in reducing missing doses (p = .0003), as well as improvement in effectiveness of resolving or minimizing missing doses (p = .01). The use of mobile dose-tracking technology demonstrated meaningful reductions in both the number of doses re-dispensed and cost of pharmaceuticals dispensed.

32 CFR 37.565 - May I use a hybrid instrument that provides fixed support for only a portion of a project?

Code of Federal Regulations, 2010 CFR

2010-07-01

... Defense OFFICE OF THE SECRETARY OF DEFENSE DoD GRANT AND AGREEMENT REGULATIONS TECHNOLOGY INVESTMENT AGREEMENTS Pre-Award Business Evaluation Fixed-Support Or Expenditure-Based Approach § 37.565 May I use a...

Results of a Markov model analysis to assess the cost-effectiveness of a single tablet of fixed-dose amlodipine and atorvastatin for the primary prevention of cardiovascular disease in Korea.

PubMed

Liew, Danny; Park, Hye-Jin; Ko, Su-Kyoung

2009-10-01

In Korea, the treatment of hypertension and dyslipidemia constitutes an important strategy for the prevention of cardiovascular disease (CVD). This study sought to investigate the cost-effectiveness (from the Korean health care system perspective) of prescribing a proprietary formulation single-tablet fixed-dose combination of amlodipine and atorvastatin (at weighted mean doses of 5 mg and 10.25 mg, respectively) to all eligible patients aged > or = 45 years for the primary prevention of CVD (ie, coronary heart disease and ischemic stroke) in Korea, compared with currently observed patterns of blood-pressure and lipid-lowering medication prescription and use. A Markov model was developed with 4 health states: alive without CVD, alive with CVD, dead from CVD, and dead from non-CVD causes. The model population comprised 244 Koreans aged >/=45 years from the 2005 Korean National Health and Nutrition Examination Survey (KNHNES) without a history of myocardial infarction (MI) or stroke who met current criteria for both blood-pressure and lipid-lowering treatment. From a 2008 baseline, follow-up was simulated for 40 years. Cardiovascular risk was estimated for each subject individually using a multivariate, Asian population-specific equation, and updated with ongoing cycles. Decision analysis compared the effects of prescribing the fixed-dose combination to all subjects versus currently observed patterns of treatment. Data regarding the blood-pressure and lipid-lowering efficacies of combination therapy were drawn from the Respond trial. Costs of the fixed-dose combination tablet and CVD were sourced from pharmaceutical pricing lists and Korean Health Insurance Review and Assessment Services estimates, respectively. Utility values for CVD were obtained from a large Korean utility study. In the model, of the 244 treatment-eligible subjects, 126 (51.6%) and 13 (5.3%) were taking blood-pressure and lipid-lowering therapy, respectively. Use of single-tablet fixed-dose combination amlodipine and atorvastatin by all subjects was associated with estimated incremental cost-effectiveness ratios of 7,773,063 Korean won (KRW) per quality-adjusted life-year gained and 10,378,230 KRW per overall life-year gained (1300 KRW approximately US $1). Sensitivity and uncertainty analyses indicated these results to be robust. In this model, based on data from the 2005 KNHNES, hypertension and dyslipidemia were undertreated among Koreans aged > or = 45 years without a history of MI or stroke. The administration of single-tablet fixed-dose combination amlodipine and atorvastatin to all such individuals was likely to represent a cost-effective means of preventing first-onset CVD (ie, coronary heart disease and ischemic stroke) in this subgroup, compared with current patterns of treatment.

The Efficiency of First-Trimester Uterine Artery Doppler, ADAM12, PAPP-A and Maternal Characteristics in the Prediction of Pre-Eclampsia

PubMed Central

GOETZINGER, Katherine R.; ZHONG, Yan; CAHILL, Alison G.; ODIBO, Linda; MACONES, George A.; ODIBO, Anthony O.

2014-01-01

Objective To estimate the efficiency of first-trimester uterine artery Doppler, A-disintegrin and metalloprotease 12 (ADAM12), pregnancy-associated plasma protein A (PAPP-A) and maternal characteristics in the prediction of pre-eclampsia. Methods This is a prospective cohort study of patients presenting for first-trimester aneuploidy screening between 11-14 weeks’ gestation. Maternal serum ADAM12 and PAPP-A levels were measured by immunoassay, and mean uterine artery Doppler pulsatility indices (PI) were calculated. Outcomes of interest included pre-eclampsia, early pre-eclampsia, defined as requiring delivery at <34 weeks’ gestation, and gestational hypertension. Logistic regression analysis was used to model the prediction of pre-eclampsia using ADAM12 multiples of the median (MoM), PAPP-A MoM, and uterine artery Doppler PI MoM, either individually or in combination. Sensitivity, specificity, and area under the receiver-operating characteristic curves (AUC) were used to compare the screening efficiency of the models using non-parametric U-statistics. Results Of 578 patients with complete outcome data, there were 54 (9.3%) cases of preeclampsia and 13 (2.2%) cases of early pre-eclampsia. Median ADAM12 levels were significantly lower in patients who developed pre-eclampsia compared to those who did not. (0.81 v. 1.01 MoMs; p<0.04) For a fixed false positive rate (FPR) of 10%, ADAM12, PAPP-A, and uterine artery Doppler in combination with maternal characteristics identified 50%, 48%, and 52% of patients who developed pre-eclampsia, respectively. Combining these first-trimester parameters did not improve the predictive efficiency of the models. Conclusion First-trimester ADAM12, PAPP-A, and uterine artery Doppler are not sufficiently predictive of pre-eclampsia. Combinations of these parameters do not further improve their screening efficiency. PMID:23980220

Moving Young Learners Forward: How to Fix No Child Left Behind

ERIC Educational Resources Information Center

Bornfreund, Laura; Williams, Conor P.

2015-01-01

Pre-K and other early learning programs have generated growing interest over the past several years. More and more states are developing pre-K programs, and some states and local communities are thinking about how to better connect and coordinate children's pre-K experiences and learning with what happens in kindergarten and the early grades. At…

75 FR 67777 - Copyright Office; Federal Copyright Protection of Sound Recordings Fixed Before February 15, 1972

Federal Register 2010, 2011, 2012, 2013, 2014

2010-11-03

... institutions, museums, and other cultural institutions? 5. Currently one group of pre-1972 recordings does have... regarding Federal coverage of pre-1972 sound recordings. Specifically, the Office seeks comments on the... interests of rights holders. The Office also seeks comments on how the incorporation of pre-1972 sound...

One-year real-world outcomes in patients receiving fixed-dosing aflibercept for neovascular age-related macular degeneration.

PubMed

Almuhtaseb, H; Kanavati, S; Rufai, S R; Lotery, A J

2017-06-01

PurposeTo investigate 1-year visual and anatomic outcomes of intravitreal aflibercept for neovascular age-related macular degeneration (nAMD) given at a fixed 8-weekly interval.MethodsRetrospective, single-practice data analysis from an electronic medical record system of 255 eyes (223 patients) with treatment-naïve nAMD receiving 8-weekly aflibercept.ResultsMean logarithm of the minimum angle of resolution best-corrected visual acuity (BCVA) improved from 0.66 at baseline to 0.50 at month 11 (P<0.0001). Mean central retinal thickness (CRT) decreased from 311 μm at baseline to 211 μm at month 11 (P<0.0001). Our mean VA gain of eight ETDRS letters was comparable to the VIEW 1 and VIEW 2 Trials' results at the end of year 1. After loading at month 5, mean BCVA was 0.48 (P<0.0001), and mean CRT was 235 μm. At month 5, 143 eyes (56%) were inactive defined by the absence of macular haemorrhage and intraretinal fluid (IRF) and subretinal fluid (SRF) on optical coherence tomography, and 112 eyes (44%) remained active. At month 11, 136 eyes (53%) were inactive, and 119 eyes (47%) remained active. At month 11, 77% of inactive eyes after loading remained inactive, and 77% of the active eyes after loading remained active. At month 11, mean BCVA of the inactive group was 0.51, and mean BCVA of the active group was 0.48 (P=0.54).ConclusionsAflibercept administered by fixed dosing over 1 year improved VA and macular morphology in treatment-naïve eyes. Active lesions at month 11 do not have worse VA outcomes compared with inactive lesions. The macular status after loading is a reliable indicator of disease activity at the end of year 1.

Effect of pre-treatment with dichloroacetic or trichloroacetic acid in drinking water on the pharmacokinetics of a subsequent challenge dose in B6C3F1 mice.

PubMed

Gonzalez-Leon, A; Merdink, J L; Bull, R J; Schultz, I R

1999-12-15

Dichloroacetate (DCA) and trichloroacetate (TCA) are prominent by-products of chlorination of drinking water. Both chemicals have been shown to be hepatic carcinogens in mice. Prior work has demonstrated that DCA inhibits its own metabolism in rats and humans. This study focuses on the effect of prior administration of DCA or TCA in drinking water on the pharmacokinetics of a subsequent challenge dose of DCA or TCA in male B6C3F1 mice. Mice were provided with DCA or TCA in their drinking water at 2 g/l for 14 days and then challenged with a 100 mg/kg i.v. (non-labeled) or gavage (14C-labeled) dose of DCA or TCA. The challenge dose was administered after 16 h fasting and removal of the haloacetate pre-treatment. The haloacetate blood concentration-time profile and the disposition of 14C were characterized and compared with controls. The effect of pre-treatment on the in vitro metabolism of DCA in hepatic S9 was also evaluated. Pre-treatment with DCA caused a significant increase in the blood concentration-time profiles of the challenge dose of DCA. No effect on the blood concentration-time profile of DCA was observed after pre-treatment with TCA. Pre-treatment with TCA had no effect on subsequent doses of DCA. Pre-treatment with DCA did not have a significant effect on the formation of 14CO2 from radiolabeled DCA. In vitro experiments with liver S9 from DCA-pre-treated mice demonstrated that DCA inhibits it own metabolism. These results indicate that DCA metabolism in mice is also susceptible to inhibition by prior treatment with DCA, however the impact on clearance is less marked in mice than in F344 rats. In contrast, the metabolism and pharmacokinetics of TCA is not affected by pre-treatment with either DCA or TCA.

Organ-specific effects of low-dose zinc pre-exposure on high-dose zinc induced mitochondrial dysfunction in large yellow croaker Pseudosciaena crocea.

PubMed

Zheng, Jia-Lang; Yuan, Shuang-Shuang; Shen, Bin; Wu, Chang-Wen

2017-04-01

The study was carried out to evaluate the effects of low-dose zinc (Zn) pre-exposure on survival rate, new Zn accumulation, and mitochondrial bioenergetics in the liver and spleen of large yellow croaker exposed to high-dose Zn. To the end, fish were pre-exposed to 0 and 2 mg L -1 Zn for 48 h and post-exposed to 0 and 12 mg L -1 Zn for 48 h. Twelve milligrams Zn per liter exposure alone reduced survival rate, but the effect did not appear in the 2 mg L -1 Zn pre-exposure groups. Two milligrams per liter Zn pre-exposure also ameliorated 12 mg Zn L -1 induced new Zn accumulation, reactive oxygen species (ROS) levels, and mitochondrial swelling in the liver. However, these effects did not appear in the spleen. In the liver, 2 mg L -1 Zn pre-exposure apparently relieved 12 mg L -1 Zn induced down-regulation of activities of ATP synthase (F-ATPase), succinate dehydrogenase (SDH), and malate dehydrogenase (MDH). The mRNA levels of these genes remained relatively stable in fish exposed to 12 mg L -1 Zn alone, but increased in fish exposed to 12 mg L -1 Zn with 2 mg L -1 Zn pre-treatment. In the spleen, 2 mg Zn L -1 pre-exposure did not mitigate the down-regulation of mRNA levels of genes and activities of relative enzymes induced by 12 mg L -1 Zn. In conclusion, our study demonstrated low-dose zinc pre-exposure ameliorated high-dose zinc induced mitochondrial dysfunction in the liver but not in the spleen of large yellow croaker, indicating an organ-specific effect.

Economic impact of switching to fixed-dose combination therapy for Japanese hypertensive patients: a retrospective cost analysis

PubMed Central

2013-01-01

Background The prescription of fixed-dose combinations (FDC) of antihypertensive drugs has increased rapidly since the relaxation of the prescription-term restriction. In this study, we used the opportunity of this policy change in Japan as an instrument to assess the causal impact of switching to FDC on hypertensive treatment costs. Methods Claims data from 64 community pharmacies located in Tokyo were used to identify hypertensive patients under continuous treatment with angiotensin-receptor blockers (ARBs). Patients switching to FDC between December 2010 and April 2011 were compared to patients who did not receive FDC (control group). Changes in annual antihypertensive drug costs were compared using a difference-in-differences approach to adjust for patient characteristics and use of concomitant medication. Subpopulation analyses were also performed, taking into account pre-index treatment patterns and prescribers’ characteristics. Results There were 542 patients who switched to FDC and 9664 patients in the control group. No significant differences were observed between the 2 groups, except for antihypertensive drug use patterns before the policy change and prescribers’ characteristics. The switch to FDC was associated with an annual saving of 10,420 yen (US$112.0) in antihypertensive drug costs. Approximately 20% of the FDC patients, however, switched from ARB alone, and their drug costs increased by 2376 yen (US$25.5). Conclusions For hypertensive patients who required ARB-based combination therapy, switching to FDC drugs had a significant cost-saving effect. However, the policy change of relaxing the prescription-term restriction could encourage aggressive treatment, i.e., switching to a combination therapy from monotherapy, regardless of medical conditions. Further research is required to evaluate the possible negative aspects of FDC drugs. PMID:23552327

Evaluation of a novel triple-channel radiochromic film analysis procedure using EBT2.

PubMed

van Hoof, Stefan J; Granton, Patrick V; Landry, Guillaume; Podesta, Mark; Verhaegen, Frank

2012-07-07

A novel approach to read out radiochromic film was introduced recently by the manufacturer of GafChromic film. In this study, the performance of this triple-channel film dosimetry method was compared against the conventional single-red-channel film dosimetry procedure, with and without inclusion of a pre-irradiation (pre-IR) film scan, using EBT2 film and kilo- and megavoltage photon beams up to 10 Gy. When considering regions of interest averaged doses, the triple-channel method and both single-channel methods produced equivalent results. Absolute dose discrepancies between the triple-channel method, both single-channel methods and the treatment planning system calculated dose values, were no larger than 5 cGy for dose levels up to 2.2 Gy. Signal to noise in triple-channel dose images was found to be similar to signal to noise in single-channel dose images. The accuracy of resulting dose images from the triple- and single-channel methods with inclusion of pre-IR film scan was found to be similar. Results of a comparison of EBT2 data from a kilovoltage depth dose experiment to corresponding Monte Carlo depth dose data produced dose discrepancies of 9.5 ± 12 cGy and 7.6 ± 6 cGy for the single-channel method with inclusion of a pre-IR film scan and the triple-channel method, respectively. EBT2 showed to be energy sensitive at low kilovoltage energies with response differences of 11.9% and 15.6% in the red channel at 2 Gy between 50-225 kVp and 80-225 kVp photon spectra, respectively. We observed that the triple-channel method resulted in non-uniformity corrections of ±1% and consistency values of 0-3 cGy for the batches and dose levels studied. Results of this study indicate that the triple-channel radiochromic film read-out method performs at least as well as the single-channel method with inclusion of a pre-IR film scan, reduces film non-uniformity and saves time with elimination of a pre-IR film scan.

Pre-transplant donor HLA-specific antibodies: characteristics causing detrimental effects on survival after lung transplantation.

PubMed

Smith, John D; Ibrahim, Mohamed W; Newell, Helen; Danskine, Anna J; Soresi, Simona; Burke, Margaret M; Rose, Marlene L; Carby, Martin

2014-10-01

The impact of Luminex-detected HLA antibodies on outcomes after lung transplantation is unclear. Herein we have undertaken a retrospective study of pre-transplant sera from 425 lung transplants performed between 1991 and 2003. Pre-transplant sera, originally screened by complement-dependent cytotoxicity (CDC) assays, were retrospectively tested for the presence of HLA-specific antibodies using HLA-coated Luminex beads and C4d deposition on Luminex beads. The results were correlated with graft survival at 1 year. Twenty-seven patients were retrospectively identified as having been transplanted against donor-specific HLA antibodies (DSA) and 36 patients against non-donor-specific HLA antibodies (NDSA). DSA-positive patients had 1-year survival of 51.9% compared with 77.8% for NDSA and 71.8% for antibody-negative patients (p = 0.029). One-year survival of patients with complement-fixing DSA was 12.5% compared with 62.5% for non-complement-fixing DSA, 75.8% for non-complement-fixing NDSA and 71.8% for antibody-negative patients (p < 0.0001). DSA-positive patients with mean fluorescence intensity (MFI) >5,000 had 1-year survival of 33.3% compared with 71.4% for MFI 2,000 to 5000 and 62.5% for MFI <2,000 (p = 0.0046). Multivariable analysis revealed DSA to be an independent predictor of poor patient survival within 1 year (p = 0.0010, hazard ratio [HR] = 3.569) as well as complement-fixing DSA (p < 0.0001, HR = 11.083) and DSA with MFI >5,000 (p = 0.0001, HR = 5.512). Pre-formed DSA, particularly complement-fixing DSA, and high MFI are associated with poor survival within the first year after lung transplantation. Risk stratification according to complement fixation or MFI levels may allow for increased transplantation in sensitized patients. Copyright © 2014 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.

Accuracy assessment of pharmacogenetically predictive warfarin dosing algorithms in patients of an academic medical center anticoagulation clinic.

PubMed

Shaw, Paul B; Donovan, Jennifer L; Tran, Maichi T; Lemon, Stephenie C; Burgwinkle, Pamela; Gore, Joel

2010-08-01

The objectives of this retrospective cohort study are to evaluate the accuracy of pharmacogenetic warfarin dosing algorithms in predicting therapeutic dose and to determine if this degree of accuracy warrants the routine use of genotyping to prospectively dose patients newly started on warfarin. Seventy-one patients of an outpatient anticoagulation clinic at an academic medical center who were age 18 years or older on a stable, therapeutic warfarin dose with international normalized ratio (INR) goal between 2.0 and 3.0, and cytochrome P450 isoenzyme 2C9 (CYP2C9) and vitamin K epoxide reductase complex subunit 1 (VKORC1) genotypes available between January 1, 2007 and September 30, 2008 were included. Six pharmacogenetic warfarin dosing algorithms were identified from the medical literature. Additionally, a 5 mg fixed dose approach was evaluated. Three algorithms, Zhu et al. (Clin Chem 53:1199-1205, 2007), Gage et al. (J Clin Ther 84:326-331, 2008), and International Warfarin Pharmacogenetic Consortium (IWPC) (N Engl J Med 360:753-764, 2009) were similar in the primary accuracy endpoints with mean absolute error (MAE) ranging from 1.7 to 1.8 mg/day and coefficient of determination R (2) from 0.61 to 0.66. However, the Zhu et al. algorithm severely over-predicted dose (defined as >or=2x or >or=2 mg/day more than actual dose) in twice as many (14 vs. 7%) patients as Gage et al. 2008 and IWPC 2009. In conclusion, the algorithms published by Gage et al. 2008 and the IWPC 2009 were the two most accurate pharmacogenetically based equations available in the medical literature in predicting therapeutic warfarin dose in our study population. However, the degree of accuracy demonstrated does not support the routine use of genotyping to prospectively dose all patients newly started on warfarin.

Non-steroidal anti-inflammatory drugs and gastroprotection with proton pump inhibitors: a focus on ketoprofen/omeprazole.

PubMed

Gigante, Antonio; Tagarro, Ignacio

2012-04-01

Non-steroidal anti-inflammatory drugs (NSAIDs) are among the most commonly prescribed agents for rheumatic disorders such as osteoarthritis (OA), rheumatoid arthritis (RA) and ankylosing spondylitis (AS). Despite the known association between NSAID use and gastropathy, however, only around one-third of patients at risk of NSAID-induced gastrointestinal toxicity receive adequate gastroprotection, and as many as 44% of these patients are non-adherent. We review the co-prescription of proton pump inhibitors (PPIs) for the prevention of NSAID-induced gastropathy, with a particular focus on the first fixed-dose NSAID/PPI formulation: ketoprofen/omeprazole modified-release capsules. The ketoprofen/omeprazole fixed-dose combination is available in doses of 100 mg/20 mg, 150 mg/20 mg or 200 mg/20 mg as a single capsule for once-daily administration. Ketoprofen monotherapy has been shown to be generally equivalent to other NSAIDs when used in the treatment of OA. In RA, ketoprofen has demonstrated equivalent efficacy to diclofenac, indometacin, piroxicam, aceclofenac, phenylbutazone, naproxen and flurbiprofen. Studies comparing ketoprofen with ibuprofen and sulindac in patients with RA have, in general, favoured ketoprofen. Studies in AS have generally reported similar efficacy between ketoprofen and phenylbutazone and pirprofen. Prophylaxis with omeprazole is effective for the prevention of gastroduodenal ulcers, maintenance of remission and alleviation of dyspeptic symptoms in NSAID recipients. Omeprazole is well tolerated, and adverse events are generally gastrointestinal in nature. The fixed-dose combination of ketoprofen and omeprazole has demonstrated bioequivalence to the respective monotherapies. The incidence of digestive symptoms and the need for dose reduction was reported to be lower with the combination than with its components. Ketoprofen/omeprazole modified-release capsules are the first fixed-dose NSAID/PPI formulation to be approved. This formulation ensures compliance with the gastroprotective prophylaxis, as whenever the NSAID is taken, the PPI is co-administered. Additionally, the once-daily formulation has the potential to improve adherence to anti-inflammatory therapy. © 2012 Adis Data Information BV. All rights reserved.

Azilsartan medoxomil plus chlorthalidone reduces blood pressure more effectively than olmesartan plus hydrochlorothiazide in stage 2 systolic hypertension.

PubMed

Cushman, William C; Bakris, George L; White, William B; Weber, Michael A; Sica, Domenic; Roberts, Andrew; Lloyd, Eric; Kupfer, Stuart

2012-08-01

Azilsartan medoxomil, an effective, long-acting angiotensin II receptor blocker, is a new treatment for hypertension that is also being developed in fixed-dose combinations with chlorthalidone, a potent, long-acting thiazide-like diuretic. We compared once-daily fixed-dose combinations of azilsartan medoxomil/chlorthalidone force titrated to a high dose of either 40/25 mg or 80/25 mg with a fixed-dose combination of the angiotensin II receptor blocker olmesartan medoxomil plus the thiazide diuretic hydrochlorothiazide force titrated to 40/25 mg. The design was a randomized, 3-arm, double-blind, 12-week study of 1071 participants with baseline clinic systolic blood pressure 160 to 190 mm Hg and diastolic blood pressure ≤119 mm Hg. Patients had a mean age of 57 years; 59% were men, 73% were white, and 22% were black. At baseline, mean clinic blood pressure was 165/96 mm Hg and 24-hour mean blood pressure was 150/88 mm Hg. Changes in clinic (primary end point) and ambulatory systolic blood pressures at week 12 were significantly greater in both azilsartan medoxomil/chlorthalidone arms than in the olmesartan/hydrochlorothiazide arm (P<0.001). Changes in clinic systolic blood pressure (mean±SE) were -42.5±0.8, -44.0±0.8, and -37.1±0.8 mm Hg, respectively. Changes in 24-hour ambulatory systolic blood pressure were -33.9±0.8, -36.3±0.8, and -27.5±0.8 mm Hg, respectively. Adverse events leading to permanent drug discontinuation occurred in 7.9%, 14.5%, and 7.1% of the groups given azilsartan medoxomil/chlorthalidone 40/25 mg, azilsartan medoxomil/chlorthalidone 80/25 mg, and olmesartan/hydrochlorothiazide 40/25 mg, respectively. This large, forced-titration study has demonstrated superior antihypertensive efficacy of azilsartan medoxomil/chlorthalidone fixed-dose combinations compared with the maximum approved dose of olmesartan/hydrochlorothiazide.

Effects of changing heart rate on electrophysiological and hemodynamic function in the dog.

PubMed

Hamlin, Robert L; Nakayama, Tomohiro; Nakayama, Hitomi; Carnes, Cynthia A

2003-03-14

Cardiovascular parameters were measured in dogs after RR interval was changed from 0.25 s to 1.2 s with atropine and graded doses of zatebradine, an I(f)-channel blocker. Left ventricular (LV) pre-ejection period (PEP), systemic vascular resistance, tau (an estimate of myocardial stiffness), PQ, QTc, dLVP/dt(max) and dLVP/dt(min), aortic pressure, and right atrial pressure did not change when each parameter was plotted against RR interval (r(2)'s < or = 0.5). LV end-diastolic pressure, stroke volume index, LV ejection time (ET), and QT all increased either linearly or curvilinearly as RR interval prolonged. Cardiac output index and PEP/ET decreased curvilinearly. When heart rate (HR) was fixed by pacing, and graded doses of zatebradine were given, changes in cardiovascular function were minimal. Thus zatebradine affects cardiovascular function principally by changing HR and not by affecting function directly. This study provides data on the effects of changing HR, alone, on cardiovascular parameters measured frequently during pharmacological and toxicological studies. It should prove useful when physiological variables, including HR, change, and there is need to know what change in HR, alone, contributes.

DALI: Defining Antibiotic Levels in Intensive care unit patients: a multi-centre point of prevalence study to determine whether contemporary antibiotic dosing for critically ill patients is therapeutic.

PubMed

Roberts, Jason A; De Waele, Jan J; Dimopoulos, George; Koulenti, Despoina; Martin, Claude; Montravers, Philippe; Rello, Jordi; Rhodes, Andrew; Starr, Therese; Wallis, Steven C; Lipman, Jeffrey

2012-07-06

The clinical effects of varying pharmacokinetic exposures of antibiotics (antibacterials and antifungals) on outcome in infected critically ill patients are poorly described. A large-scale multi-centre study (DALI Study) is currently underway describing the clinical outcomes of patients achieving pre-defined antibiotic exposures. This report describes the protocol. DALI will recruit over 500 patients administered a wide range of either beta-lactam or glycopeptide antibiotics or triazole or echinocandin antifungals in a pharmacokinetic point-prevalence study. It is anticipated that over 60 European intensive care units (ICUs) will participate. The primary aim will be to determine whether contemporary antibiotic dosing for critically ill patients achieves plasma concentrations associated with maximal activity. Secondary aims will compare antibiotic pharmacokinetic exposures with patient outcome and will describe the population pharmacokinetics of the antibiotics included. Various subgroup analyses will be conducted to determine patient groups that may be at risk of very low or very high concentrations of antibiotics. The DALI study should inform clinicians of the potential clinical advantages of achieving certain antibiotic pharmacokinetic exposures in infected critically ill patients.

SU-E-T-56: A Novel Approach to Computing Expected Value and Variance of Point Dose From Non-Gated Radiotherapy Delivery

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

Zhou, S; Zhu, X; Zhang, M

Purpose: Randomness in patient internal organ motion phase at the beginning of non-gated radiotherapy delivery may introduce uncertainty to dose received by the patient. Concerns of this dose deviation from the planned one has motivated many researchers to study this phenomenon although unified theoretical framework for computing it is still missing. This study was conducted to develop such framework for analyzing the effect. Methods: Two reasonable assumptions were made: a) patient internal organ motion is stationary and periodic; b) no special arrangement is made to start a non -gated radiotherapy delivery at any specific phase of patient internal organ motion.more » A statistical ensemble was formed consisting of patient’s non-gated radiotherapy deliveries at all equally possible initial organ motion phases. To characterize the patient received dose, statistical ensemble average method is employed to derive formulae for two variables: expected value and variance of dose received by a patient internal point from a non-gated radiotherapy delivery. Fourier Series was utilized to facilitate our analysis. Results: According to our formulae, the two variables can be computed from non-gated radiotherapy generated dose rate time sequences at the point’s corresponding locations on fixed phase 3D CT images sampled evenly in time over one patient internal organ motion period. The expected value of point dose is simply the average of the doses to the point’s corresponding locations on the fixed phase CT images. The variance can be determined by time integration in terms of Fourier Series coefficients of the dose rate time sequences on the same fixed phase 3D CT images. Conclusion: Given a non-gated radiotherapy delivery plan and patient’s 4D CT study, our novel approach can predict the expected value and variance of patient radiation dose. We expect it to play a significant role in determining both quality and robustness of patient non-gated radiotherapy plan.« less

46 CFR 181.400 - Where required.

Code of Federal Regulations, 2010 CFR

2010-10-01

... 46 Shipping 7 2010-10-01 2010-10-01 false Where required. 181.400 Section 181.400 Shipping COAST... PROTECTION EQUIPMENT Fixed Fire Extinguishing and Detecting Systems § 181.400 Where required. (a) The... cubic meters (6,000 cubic feet); (2) A pre-engineered fixed gas fire extinguishing system must be in...

46 CFR 162.161-1 - Scope.

Code of Federal Regulations, 2014 CFR

2014-10-01

... APPROVAL ENGINEERING EQUIPMENT Fixed Clean Agent Fire Extinguishing Systems § 162.161-1 Scope. (a) This subpart applies to each engineered fixed fire extinguishing system using a halocarbon or an inert gas as an agent. It does not apply to pre-engineered systems. (b) Each system must be designed for...

46 CFR 162.161-1 - Scope.

Code of Federal Regulations, 2013 CFR

2013-10-01

... APPROVAL ENGINEERING EQUIPMENT Fixed Clean Agent Fire Extinguishing Systems § 162.161-1 Scope. (a) This subpart applies to each engineered fixed fire extinguishing system using a halocarbon or an inert gas as an agent. It does not apply to pre-engineered systems. (b) Each system must be designed for...

46 CFR 162.161-1 - Scope.

Code of Federal Regulations, 2012 CFR

2012-10-01

... APPROVAL ENGINEERING EQUIPMENT Fixed Clean Agent Fire Extinguishing Systems § 162.161-1 Scope. (a) This subpart applies to each engineered fixed fire extinguishing system using a halocarbon or an inert gas as an agent. It does not apply to pre-engineered systems. (b) Each system must be designed for...

SAFETY, EFFICACY, PHARMACOKINETICS AND PHARMACODYNAMICS OF THE COMBINATION OF SORAFENIB AND TANESPIMYCIN

PubMed Central

Vaishampayan, Ulka N.; Burger, Angelika M.; Sausville, Edward A.; Heilbrun, Lance K.; Li, Jing; Horiba, Naomi; Egorin, Merrill J.; Ivy, Percy; Pacey, Simon; Lorusso, Patricia M.

2010-01-01

PURPOSE Heat shock protein 90 inhibition affects the Raf-kinase signaling pathway and could enhance anti-tumor effects of sorafenib, a Raf-kinase inhibitor. The combination of sorafenib and tanespimycin (17-AAG/17-allyl-amino-geldanamycin; NSC # 330507/KOS-953) was evaluated in a phase I trial with the primary objective of defining a phase II dose PATIENTS AND METHODS The dose cohorts consisted of fixed continuous oral dosing of sorafenib 400 mg twice daily, starting 14 days prior to tanespimycin which was administered intravenously, at escalating doses, (starting at 300 mg/m,2 with 50 mg/m2 increments), on days 1, 8 and 15, in a 28-day cycle. Toxicity was assessed weekly; response was evaluated every 2 cycles. RESULTS Twenty-seven toxicity-evaluable patients were enrolled and treated at four dose levels. Predominant primary malignancies were: renal cancer (12), melanoma (6) and colorectal cancer (4). Dose-limiting toxicities of grade 4 transaminitis and grade 3 hand-foot syndrome in 1 patient each were observed at 450 mg/m2 of tanespimycin. 114 cycles were administered with a median of four cycles (range 1–17 cycles). Plasma concentrations of sorafenib and metabolites reached steady-state after 7 days. Tanespimycin did not alter sorafenib concentrations. Pharmacodynamics showed a decrease in Hsp90 levels and induction of Hsp70. Clinical efficacy was observed in 9 of 12 renal cancer patients and 4 of 6 melanoma patients CONCLUSIONS Recommended phase II doses of this combination are sorafenib 400 mg twice daily and tanespimycin 400 mg/m2 on days 1, 8 and 15 every 28 days. Clinical and pharmacodynamic activity was observed in kidney cancer and melanoma. PMID:20525756

Sofosbuvir/ledipasvir fixed-dose combination for treatment of chronic hepatitis C virus infection in children.

PubMed

Rizza, S A; Nehra, V; Temesgen, Z

2017-08-01

The United States Food and Drug Administration recently approved sofosbuvir and the fixed-dose combination of ledipasvir/sofosbuvir for the treatment of hepatitis C virus (HCV) infection in children ages 12 to 17. These are the first direct-acting antiviral treatments approved for children and adolescents with HCV. Pharmacokinetic data confirm equivalent drug exposure in this population as that found in adults during clinical trials. The efficacy and safety of these drugs has been shown in clinical trials. Copyright 2017 Clarivate Analytics.

WE-AB-202-02: Incorporating Regional Ventilation Function in Predicting Radiation Fibrosis After Concurrent Chemoradiotherapy for Lung Cancer

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

Lan, F; Jeudy, J; Tseng, H

Purpose: To investigate the incorporation of pre-therapy regional ventilation function in predicting radiation fibrosis (RF) in stage III non-small-cell lung cancer (NSCLC) patients treated with concurrent thoracic chemoradiotherapy. Methods: 37 stage III NSCLC patients were retrospectively studied. Patients received one cycle of cisplatin-gemcitabine, followed by two to three cycles of cisplatin-etoposide concurrently with involved-field thoracic radiotherapy between 46 and 66 Gy (2 Gy per fraction). Pre-therapy regional ventilation images of the lung were derived from 4DCT via a density-change-based image registration algorithm with mass correction. RF was evaluated at 6-months post-treatment using radiographic scoring based on airway dilation and volumemore » loss. Three types of ipsilateral lung metrics were studied: (1) conventional dose-volume metrics (V20, V30, V40, and mean-lung-dose (MLD)), (2) dose-function metrics (fV20, fV30, fV40, and functional mean-lung-dose (fMLD) generated by combining regional ventilation and dose), and (3) dose-subvolume metrics (sV20, sV30, sV40, and subvolume mean-lung-dose (sMLD) defined as the dose-volume metrics computed on the sub-volume of the lung with at least 60% of the quantified maximum ventilation status). Receiver operating characteristic (ROC) curve analysis and logistic regression analysis were used to evaluate the predictability of these metrics for RF. Results: In predicting airway dilation, the area under the ROC curve (AUC) values for (V20, MLD), (fV20, fMLD), and (sV20, and sMLD) were (0.76, 0.70), (0.80, 0.74) and (0.82, 0.80), respectively. The logistic regression p-values were (0.09, 0.18), (0.02, 0.05) and (0.004, 0.006), respectively. With regard to volume loss, the corresponding AUC values for these metrics were (0.66, 0.57), (0.67, 0.61) and (0.71, 0.69), and p-values were (0.95, 0.90), (0.43, 0.64) and (0.08, 0.12), respectively. Conclusion: The inclusion of regional ventilation function improved predictability of radiation fibrosis. Dose-subvolume metrics provided a promising method for incorporating functional information into the conventional dose-volume parameters for outcome assessment.« less

Immunogenicity, reactogenicity and safety of 2 doses of an adjuvanted herpes zoster subunit vaccine administered 2, 6 or 12 months apart in older adults: Results of a phase III, randomized, open-label, multicenter study.

PubMed

Lal, Himal; Poder, Airi; Campora, Laura; Geeraerts, Brecht; Oostvogels, Lidia; Vanden Abeele, Carline; Heineman, Thomas C

2018-01-02

In phase III trials, 2 doses of a herpes zoster (HZ) subunit vaccine (HZ/su; 50 µg varicella-zoster virus glycoprotein E [gE] and AS01 B Adjuvant System) administered 2-months apart in older adults (≥50 and ≥70 years) demonstrated >90% efficacy in preventing HZ and had a clinically acceptable safety profile. Here we report immunogenicity, reactogenicity and safety following administration of 2 HZ/su doses at intervals longer than 2 months. In this Phase III, open-label trial conducted in the US and Estonia, 354 adults ≥50 years were randomized 1:1:1 to receive 2 HZ/su doses 2, 6, or 12 months apart. gE-specific humoral immune responses were evaluated at pre-vaccination, 1 and 12 months post-dose 2. Co-primary objectives were to compare immune responses to HZ/su 1 month post-dose 2 when given 6-months or 12-months apart to those administered 2-months apart. For each participant, safety information was collected from dose 1 to 12 months post-dose 2. 346 participants completed the study and 343 were included in the according-to-protocol cohort for immunogenicity. One month post-dose 2, vaccine response rates were 96.5% (97.5% confidence interval [CI]: 90.4; 99.2) and 94.5% (97.5% CI: 87.6; 98.3) for the 0, 6- and 0, 12-month schedules, respectively, both schedules meeting the pre-defined criterion. Non-inferiority of anti-gE geometric mean concentrations was demonstrated for HZ/su administered on 0, 6-month compared to a 0, 2-month schedule; however, HZ/su administered on a 0, 12-month schedule did not meet the non-inferiority criterion. Injection site pain was the most commonly reported solicited adverse event (AE). 26 participants each reported at least 1 serious AE; none were assessed as related to vaccination. Immune responses to HZ/su administered at 0, 6-month were non-inferior to those elicited by a 0, 2-month schedule. HZ/su exhibited a clinically acceptable safety profile for all dosing intervals. Clinicaltrials.gov (NCT01751165). Copyright © 2017. Published by Elsevier Ltd.

Cross state-dependency of learning between arachidonylcyclopropylamide (ACPA) and muscimol in the mouse dorsal hippocampus.

PubMed

Jafari-Sabet, Majid; Karimi, Amir-Mohammad

2017-12-01

The aim of the present study was to examine cross state-dependent learning between ACPA (a selective cannabinoid CB1 receptor agonist) and muscimol (a selective GABAA receptor agonist) in the step-down inhibitory avoidance learning task. The dorsal hippocampal CA1 regions of adult male NMRI mice were bilaterally cannulated, and all drugs were microinjected into the intended sites of injection. Post-training and/or pre-test administration of ACPA (1 and 2ng/mouse) dose-dependently induced amnesia. Pre-test microinjection of the same doses of ACPA reversed the post-training ACPA-induced amnesia. This event has been named ACPA state-dependent learning (SDL). Post-training and/or pre-test microinjection of muscimol (0.05 and 0.1μg/mouse) dose-dependently induced amnesia. Pre-test administration of the same doses of muscimol reversed the post-training muscimol-induced amnesia, suggesting muscimol SDL. The amnesia induced by post-training administration of ACPA was reversed by pre-test administration of muscimol (0.05 and 0.1μg/mouse). Furthermore, the pre-test microinjection of muscimol (0.025 and 0.05μg/mouse) with an ineffective dose of ACPA (0.5ng/mouse) significantly restored memory retrieval and induced ACPA SDL. In another series of experiments, the amnesia induced by post-training administration of muscimol was reversed by pre-test administration of ACPA (1 and 2ng/mouse). Moreover, pre-test microinjection of ACPA (0.5 and 1ng/mouse) with an ineffective dose of muscimol (0.025μg/mouse) significantly restored memory retrieval and induced muscimol SDL. It is important to note that pre-test intra-CA1 injection of a selective GABAA receptor antagonist, bicuculline (0.125 and 0.25μg/mouse), 5min before the administration of muscimol (0.1μg/mouse) or ACPA (2ng/mouse) dose-dependently inhibited muscimol- and ACPA-induced SDL, respectively. Pre-test intra-CA1 administration of bicuculline (0.0625, 0.125 and 0.25μg/mouse) by itself did not affect memory retention. In conclusion, the data strongly revealed a cross SDL among ACPA and muscimol in the dorsal hippocampal CA1 regions. Copyright © 2017 Elsevier Inc. All rights reserved.

Feasibility Study of Solar Dome Encapsulation of Photovoltaic Arrays

NASA Technical Reports Server (NTRS)

1978-01-01

The technical and economic advantages of using air-supported plastic enclosures to protect flat plate photovoltaic arrays are described. Conceptual designs for a fixed, latitude-tilt array and a fully tracking array were defined. Detailed wind loads and strength analyses were performed for the fixed array. Detailed thermal and power output analyses provided array performance for typical seasonal and extreme temperature conditions. Costs of each design as used in a 200 MWe central power station were defined from manufacturing and material cost estimates. The capital cost and cost of energy for the enclosed fixed-tilt array were lower than for the enclosed tracking array. The enclosed fixed-tilt array capital investment was 38% less, and the levelized bus bar energy cost was 26% less than costs for a conventional, glass-encapsulated array design. The predicted energy cost for the enclosed fixed array was 79 mills/kW-h for direct current delivered to the power conditioning units.

Azathioprine and 6-Mercaptopurine Induced Liver Injury: Clinical Features and Outcomes

PubMed Central

Björnsson, Einar S.; Gu, Jiezhun; Kleiner, David E.; Chalasani, Naga; Hayashi, Paul H.; Hoofnagle, Jay H.

2017-01-01

Goals To define the clinical, biochemical and histologic features of liver injury from thiopurines. Background Azathioprine (Aza) and 6-mercaptopurine (6-MP) can cause liver injury but no large series exist. Methods Clinical and laboratory data and 6-months outcomes were analyzed from patients with thiopurine hepatotoxicity from the Drug-Induced Liver Injury Network Prospective Study. Results 22 patients were identified, 12 due to Aza and 10 6-MP, with a median age of 55 years and the majority females (68%). Inflammatory bowel disease was the indication in 55%, and median thiopurine dose 150 (range 25–300) mg daily. The median latency to onset was 75 (range 3 to 2584) days. Injury first arose after a dose escalation in 59% of patients; the median latency after dose increase being 44 (range 3 to 254) days. At onset, the median alanine aminotransferase was 210 U/L, alkaline phosphatase 151 U/L and bilirubin 7.4 mg/dL (peak 13.4 mg/dL). There were no major differences between Aza and 6-MP cases, but anicteric cases typically had non-specific symptoms and a hepatocellular pattern of enzyme elevations, whereas icteric cases experienced a cholestatic hepatitis with modest enzyme elevations in a mixed pattern. One patient with pre-existing cirrhosis required liver transplantation, all others resolved clinically. One patient still had moderate alkaline phosphatase elevations 2 years after onset. Conclusions Nearly three-quarters of patients with thiopurine-induced liver injury present with self-limited, cholestatic hepatitis, typically within 3 months of starting or a dose increase. The prognosis is favorable except in patients with pre-existing cirrhosis. PMID:27648552

Effects of hepatitis B vaccine boosters on anti-HBs-negative children after primary immunization.

PubMed

Lu, Shunshun; Ren, Jingjing; Li, Qian; Jiang, Zhenggang; Chen, Yongdi; Xu, Kaijin; Ruan, Bing; Yang, Shigui; Xie, Tiansheng; Yang, Linna; Li, Jing; Yao, Jun

2017-04-03

This study was aimed at evaluating the changes of hepatitis B surface antibody (anti-HBs) titer after booster vaccinations in 5-15-year-old children with negative antibodies (<10 mIU/mL). 225 subjects (mean age, 9.28 ± 2.95 years) included in the study consisted of 123 males and 102 females, with a complete hepatitis B vaccination during infancy. The participants were divided into 3 groups according to their pre-booster anti-HBs level: Group I, <0.1 mIU/mL; Group II, 0.1 to <1.0 mIU/mL; Group III, 1.0 to <10.0 mIU/mL. All the participants were administered 3 doses of booster hepatitis B vaccination (0-1-6 month, 20 µg), and changes in the levels of antibodies were examined at 4 time-points (one month after the first and the third dose, one year and 5 years after the third dose). The seroprotective rate (defined as anti-HBs ≥10.0 mIU/mL) among 225 subjects at the 4 time-points were 93.8%, 100%, 83.6% and 73.4%, respectively (χ 2 = 90.29, p < 0.05). The seroprotective rate (≥10 mIU/mL) and anti-HBs geometric mean titer (GMT) in Group III were always higher than those in the other 2 groups (all p < 0.05). The immune effect of a 3 -dose booster revaccination is good, and the booster-induced immune response was correlated with the pre-booster titer level, and ≥1.0 mIU/mL ensuring a robust positive response, whereas titers below this value may indicate the need for a course of booster vaccination.

Long-Term Dose-Dependent Agalsidase Effects on Kidney Histology in Fabry Disease.

PubMed

Skrunes, Rannveig; Tøndel, Camilla; Leh, Sabine; Larsen, Kristin Kampevold; Houge, Gunnar; Davidsen, Einar Skulstad; Hollak, Carla; van Kuilenburg, André B P; Vaz, Frédéric M; Svarstad, Einar

2017-09-07

Dose-dependent clearing of podocyte globotriaosylceramide has previously been shown in patients with classic Fabry disease treated with enzyme replacement. Our study evaluates the dose-dependent effects of agalsidase therapy in serial kidney biopsies of patients treated for up to 14 years. Twenty patients with classic Fabry disease (12 men) started enzyme replacement therapy at a median age of 21 (range =7-62) years old. Agalsidase- α or - β was prescribed for a median of 9.4 (range =5-14) years. The lower fixed dose group received agalsidase 0.2 mg/kg every other week throughout the follow-up period. The higher dose group received a range of agalsidase doses (0.2-1.0 mg/kg every other week). Dose changes were made due to disease progression, suboptimal effect, or agalsidase- β shortage. Serial kidney biopsies were performed along with clinical assessment and biomarkers and scored according to recommendations from the International Study Group of Fabry Nephropathy. No statistical differences were found in baseline or final GFR or albuminuria. Kidney biopsies showed significant reduction of podocyte globotriaosylceramide in both the lower fixed dose group (-1.39 [SD=1.04]; P =0.004) and the higher dose group (-3.16 [SD=2.39]; P =0.002). Podocyte globotriaosylceramide (Gb3) reduction correlated with cumulative agalsidase dose ( r =0.69; P =0.001). Arterial/arteriolar intima Gb3 cleared significantly in the higher dose group, all seven patients with baseline intimal Gb3 cleared the intima, one patient gained intimal Gb3 inclusions ( P =0.03), and medial Gb3 did not change statistically in either group. Residual plasma globotriaosylsphingosine levels remained higher in the lower fixed dose group (20.1 nmol/L [SD=11.9]) compared with the higher dose group (10.4 nmol/L [SD=8.4]) and correlated with cumulative agalsidase dose in men ( r =0.71; P =0.01). Reduction of podocyte globotriaosylceramide was found in patients with classic Fabry disease treated with long-term agalsidase on different dosing regimens, correlating with cumulative dose. Limited clearing of arterial/arteriolar globotriaosylceramide raises concerns regarding long-term vascular effects of current therapy. Residual plasma globotriaosylsphingosine correlated with cumulative dose in men. Copyright © 2017 by the American Society of Nephrology.

[Is Herceptin(®) (trastuzumab) by subcutaneous a mini revolution? Pharmaco-economic study].

PubMed

Lieutenant, Vincent; Toulza, Émilie; Pommier, Martine; Lortal-Canguilhem, Barbara

2015-03-01

Herceptin(®) injected by intravenous (IV) is one of the key treatment of breast cancer HER2+. The improvement of galenic form allowed a new way of administration, the sub-cutaneous way (SC), authorized by EMEA in 2013. This new way enables a 5-minute infusion, a fixed dose and a fixed volume of preparation. On 2012, saving-time and financial impacts were calculated by extrapolation of the IV way in a cancer treatment center. The study showed a preparing time-saving of 7.5min/loading dose and of 6.5min/maintenance dose, and a nurse time-saving of 4.5min/loading dose and 4.25min/maintenance dose. Moreover, it can be added a saving of consumable of 13,31€ per injection in case of monotherapy. The SC leads to a new adaptation and reorganization in the preparation of monoclonal antibodies and day hospitals. Copyright © 2015 Société Française du Cancer. Published by Elsevier Masson SAS. All rights reserved.

Safety assessment of combination therapies in the treatment of obesity: focus on naltrexone/bupropion extended release and phentermine-topiramate extended release.

PubMed

Halpern, Bruno; Mancini, Marcio C

2017-01-01

Few studies on combination therapies for the treatment of obesity had been conducted until recently, when two fixed-dose combinations, bupropion-naltrexone ER fixed-dose combination and phentermine-topiramate ER titrated-dose combinations were evaluated in clinical studies that ultimately led to FDA approval. Areas covered: In this review, we discuss safety concerns about both combinations, the rationale and history of combination therapies for obesity (including phentermine plus fenfluramine), and possible future new combinations. Expert opinion: Combination therapies are a promising new area in obesity treatment, similar to what occurs with diabetes and hypertension. Safety assessment is highly important due to the high number of potential users on a chronic basis.

[Granulomatous sporotrichosis: report of two unusual cases].

PubMed

Ramírez-Soto, Max; Lizárraga-Trujillo, José

2013-10-01

Sporotrichosis is a subcutaneous mycosis caused by Sporothrix complex, endemic in Abancay, Peru. Is acquired by traumatic inoculation with plant material. Common clinical presentations are lymphatic cutaneous and fixed cutaneous disease. We report 2 cases of fixed cutaneous sporotrichosis with granulomatous appearance. The first case was a patient of 65 years old with no risk factors and the second case was a 67 year old diabetic patient. Subjects underwent mycological culture with Sabouraud agar, with isolation of Sporothrix schenckii and clinical dignosis of fixed cutaneous sporotrichosis with granulomatous appearance. One patient received oral treatment with saturated solution of potassium iodide (SSKI) with a initial dose of 3 drops tid up to a maximum dose of 40 drops tid. Mycological and clinical cure was achieved after 2 months of treatment. We should consider the unusual clinical presentations of fixed cutaneous sporotrichosis with granulomatous appearance that present morphological and clinical features in diabetic and nondiabetic patients older than 60 years from endemic areas and communicate adequate response to treatment with SSKI in one case.

SU-F-T-492: The Impact of Water Temperature On Absolute Dose Calibration

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

Islam, N; Podgorsak, M; Roswell Park Cancer Institute, Buffalo, NY

Purpose: The Task Group 51 (TG 51) protocol prescribes that dose calibration of photon beams be done by irradiating an ionization chamber in a water tank at pre-defined depths. Methodologies are provided to account for variations in measurement conditions by applying correction factors. However, the protocol does not completely account for the impact of water temperature. It is well established that water temperature will influence the density of air in the ion chamber collecting volume. Water temperature, however, will also influence the size of the collecting volume via thermal expansion of the cavity wall and the density of the watermore » in the tank. In this work the overall effect of water temperature on absolute dosimetry has been investigated. Methods: Dose measurements were made using a Farmer-type ion chamber for 6 and 23 MV photon beams with water temperatures ranging from 10 to 40°C. A reference ion chamber was used to account for fluctuations in beam output between successive measurements. Results: For the same beam output, the dose determined using TG 51 was dependent on the temperature of the water in the tank. A linear regression of the data suggests that the dependence is statistically significant with p-values of the slope equal to 0.003 and 0.01 for 6 and 23 MV beams, respectively. For a 10 degree increase in water phantom temperature, the absolute dose determined with TG 51 increased by 0.27% and 0.31% for 6 and 23 MV beams, respectively. Conclusion: There is a measurable effect of water temperature on absolute dose calibration. To account for this effect, a reference temperature can be defined and a correction factor applied to account for deviations from this reference temperature during beam calibration. Such a factor is expected to be of similar magnitude to most of the existing TG 51 correction factors.« less

Study on the Dose Uncertainties in the Lung during Passive Proton Irradiation with a Proton Beam Range Compensator

NASA Astrophysics Data System (ADS)

Yoo, Seung Hoon; Son, Jae Man; Yoon, Myonggeun; Park, Sung Yong; Shin, Dongho; Min, Byung Jun

2018-06-01

A moving phantom is manufactured for mimicking lung model to study the dose uncertainty from CT number-stopping power conversion and dose calculation in the soft tissue, light lung tissue and bone regions during passive proton irradiation with compensator smearing value. The phantom is scanned with a CT system, and a proton beam irradiation plan is carried out with the use of a treatment planning system (Eclipse). In the case of the moving phantom, a RPM system is used for respiratory gating. The uncertainties in the dose distribution between the measured data and the planned data are investigated by a gamma analysis with 3%-3 mm acceptance criteria. To investigate smearing effect, three smearing values (0.3 cm, 0.7 cm, 1.2 cm) are used to for fixed and moving phantom system. For both fixed and moving phantom, uncertainties in the light lung tissue are severe than those in soft tissue region in which the dose uncertainties are within clinically tolerable ranges. As the smearing value increases, the uncertainty in the proton dose distribution decreases.

Therapeutic effect of Linum usitatissimum (flaxseed/linseed) fixed oil on acute and chronic arthritic models in albino rats.

PubMed

Kaithwas, Gaurav; Majumdar, Dipak K

2010-06-01

The present study was undertaken to assess the activity/anti-inflammatory potential of Linum usitatissimum fixed oil against castor oil-induced diarrhoea, turpentine oil-induced joint oedema, formaldehyde and Complete Freund's Adjuvant (CFA)-induced arthritis in Wistar albino rats. The oil intraperitoneally, significantly inhibited the castor oil-induced diarrhoea and turpentine oil-induced exudative joint oedema in a dose-dependent manner. Significant inhibitory effect of L. usitatissimum fixed oil was observed in formaldehyde-induced proliferative global oedematous arthritis when given intraperitoneally, with significant checking of the serum glutamic oxaloacetic acid transaminase and serum glutamic pyruvic acid transaminase. Further, L. usitatissimum fixed oil showed a significant dose-dependent protective effect against CFA-induced arthritis as well. Secondary lesions produced by CFA due to a delayed hypersensitivity reaction were also reduced in a significant manner. Anti-inflammatory activity of L. usitatissimum fixed oil can be attributed to the presence of alpha linolenic acid (57.38%, an omega-3 fatty acid, 18:3, n-3) having dual inhibitory effect on arachidonate metabolism resulting in suppressed production of proinflammatory n-6 eicosanoids (PGE(2), LTB(4)) and diminished vascular permeability. These observations suggest possible therapeutic potential of L. usitatissimum fixed oil in inflammatory disorders like rheumatoid arthritis.

Interaction of different antidepressants with acute and chronic methadone in mice, and possible clinical implications.

PubMed

Schreiber, Shaul; Barak, Yonatan; Hostovsky, Avner; Baratz-Goldstein, Renana; Volis, Ina; Rubovitch, Vardit; Pick, Chaim G

2014-04-01

We studied the interaction of a single dose of different antidepressant medications with a single (acute) dose or implanted mini-pump (chronic) methadone administration in mice, using the hotplate assay. For the acute experiment, subthreshold doses of six antidepressant drugs were administered separately with a single dose of methadone. The addition of a subthreshold dose of desipramine or clomipramine to methadone produced significant augmentation of the methadone effect with each drug (p < 0.05). Fluvoxamine given at a fixed subthreshold dose induced a synergistic effect only with a low methadone dose. Escitalopram, reboxetine and venlafaxine given separately, each at a fixed subthreshold dose, induced no interaction. Possible clinical implications of these findings are that while escitalopram, reboxetine and venlafaxine do not affect methadone's antinociception in mice and are safe to be given together with methadone when indicated, fluvoxamine, clomipramine and desipramine considerably augment methadone-induced effects and should be avoided in this population due to the risk of inducing opiate overdose. For the chromic experiment, when a subthreshold dose of either escitalopram, desipramine or clomipramine was injected to mice following 2 weeks of methadone administration with the mini-pump, none of the antidepressant drugs strengthened methadone's analgesic effect. Further studies are needed before possible clinical implications can be drawn.

Automatic dispensing of liquid nitrogen in submilliliter doses

NASA Astrophysics Data System (ADS)

Milner, C. J.

1984-10-01

Well-controlled doses of 0.2 to 0.5 ml of liquid nitrogen are delivered, on electrical signal (not more than once per 5 s), as fills of a miniature bucket raised by an automatic hoist. The bucket is lifted, brimming, from the storage flask and then moved sideways until over the receiver. At this point, a steel ball, which has been resting in and sealing a drain hole in the bucket, is lifted from its seat by a magnet fixed alongside the (now descending) bucket. Design features are outlined: some alternative designs, valving liquid through a short drain tube fixed in the storage flask, are briefly reviewed. In tests the device delivered 74 g (approx. 260 doses) during 63 min, the loss by evaporation meanwhile being 11 g from the bucket, implying a transfer efficiency of 87%. An indirect measure indicated the dose sizes as 354±10 μl approximately.

Protocol for a multicentred randomised controlled trial investigating the use of personalised golimumab dosing tailored to inflammatory load in ulcerative colitis: the GOAL-ARC study (GLM dose Optimisation to Adequate Levels to Achieve Response in Colitis) led by the INITIAtive group (NCT 0268772)

PubMed Central

Sheridan, Juliette; Coe, Carol Ann; Doran, Peter; Egan, Laurence; Cullen, Garret; Kevans, David; Leyden, Jan; Galligan, Marie; O’Toole, Aoibhlinn; McCarthy, Jane; Doherty, Glen

2018-01-01

Introduction Ulcerative colitis (UC) is a chronic inflammatory bowel disease (IBD), often leading to an impaired quality of life in affected patients. Current treatment modalities include antitumour necrosis factor (anti-TNF) monoclonal antibodies (mABs) including infliximab, adalimumab and golimumab (GLM). Several recent retrospective and prospective studies have demonstrated that fixed dosing schedules of anti-TNF agents often fails to consistently achieve adequate circulating therapeutic drug levels (DL) with consequent risk of immunogenicity treatment failure and potential risk of hospitalisation and colectomy in patients with UC. The design of GLM dose Optimisation to Adequate Levels to Achieve Response in Colitis aims to address the impact of dose escalation of GLM immediately following induction and during the subsequent maintenance phase in response to suboptimal DL or persisting inflammatory burden as represented by raised faecal calprotectin (FCP). Aim The primary aim of the study is to ascertain if monitoring of FCP and DL of GLM to guide dose optimisation (during maintenance) improves rates of patient continuous clinical response and reduces disease activity in UC. Methods and analysis A randomised, multicentred two-arm trial studying the effect of dose optimisation of GLM based on FCP and DL versus treatment as per SMPC. Eligible patients will be randomised in a 1:1 ratio to 1 of 2 treatment groups and shall be treated over a period of 46 weeks. Ethics and dissemination The study protocol was approved by the Research Ethics committee of St. Vincent’s University Hospital. The results will be published in a peer-reviewed journal and shared with the worldwide medical community. Trial registration numbers EudraCT number: 2015-004724-62; Clinicaltrials.gov Identifier: NCT0268772; Pre-results. PMID:29379609

Optimized enhancement in helical CT: experiences with a real-time bolus tracking system in 628 patients.

PubMed

Kirchner, J; Kickuth, R; Laufer, U; Noack, M; Liermann, D

2000-05-01

Ultrafast detector technology enables bolus-triggered application of contrast media. In a prospective study we investigated the benefit of this new method with the intention of optimizing enhancement during examination of the chest and abdomen. In total, we examined 548 patients under standardized conditions. All examinations were performed on a Somatom Plus 4 Power CT system (Siemens Corp., Forchheim, Germany) using the CARE-Bolus software. This produces repetitive low-dose test images (e.g. for the lung: 140 kV, 43 mA, TI 0.5 s) and measures the Hounsfield attenuation in a pre-selected region of interest. After exceeding a defined threshold, a diagnostic spiral CT examination was begun automatically. The data obtained from 321 abdominal CT and 179 lung CT examinations were correlated with different parameters such as age, weight and height of the patients and parameters of vascular access. In a group of 80 patients, the injection of contrast medium was stopped after reaching a pre-defined threshold of an increase of 100 HU over the baseline. Then, we assessed the maximal enhancement of liver, pulmonal artery trunk and aortic arch. There was no correlation between bolus geometry and age, body surface or weight. In helical CT of the abdomen the threshold was reached after a mean trigger time of 27 s (range 13-67 s) and only 65 ml (range 41-105 ml) of contrast medium were administered. In helical CT of the lung the threshold was reached after 21 s (range 12-48 s) and the mean amount of administered contrast medium was 48 ml (range 38-71 ml). Bolus triggering allows optimized enhancement of the organs and reduces the dose of contrast material required compared with standard administration. Copyright 2000 The Royal College of Radiologists.

SU-E-T-87: The Effect of Bleaching Wavelengths on the Regeneration of the Optically Stimulated Luminescence Signal of NanoDot Dosimeters Pre-Exposed to High-Doses.

PubMed

Omotayo, A; Cygler, J; Sawakuchi, G

2012-06-01

To investigate the effect of bleaching wavelengths on the regeneration of optically stimulated luminescence (OSL) signals in Al 2 O 3 :C nanoDot dosimeters pre-exposed to high doses. Regeneration is the increase in the OSL signal during storage of a bleached nanoDot that was previously pre-exposed to a high dose. This phenomenon affects the accuracy of a calibration protocol proposed by Jursinic 2010 (Med. Phys. 37:102) in which pre-exposure of nanoDots to a high-dose was used to minimize changes in the sensitivity of the detector as a function of accumulated dose. Al 2 O 3 :C OSLDs of the type nanoDot were used throughout this study. Readout was performed using the microStar reader. Bleaching of the OSLDs was performed with four 26 W fluorescent light bulbs in two modes: (i) directly under the lamps; and (ii) with the aid of a long-pass optical filter placed over the nanoDots, partially blocking wavelengths below 495 nm. Eighteen nanoDots were pre-exposed to 1 kGy dose. Then the pre-exposed nanoDots were bleached in two sets of 9 to very low residual OSL signals using bleaching modes (i) and (ii) for 12 h and 45 h, respectively. The nanoDots were then stored in dark and readout after various time intervals to monitor the regeneration of the OSL signal. We fitted the regeneration of the OSL signal using a saturation function and obtained rise-time values of 563 h and 630 h, for bleaching modes (i) and (ii), respectively. At the saturation level, the equivalent doses were about 1.18 Gy and 0.38 Gy for modes (i) and (ii), respectively. The regeneration rates of nanoDot OSLDs pre-exposed to high doses depend on the bleaching light wavelength used to reset the detectors. A bleaching source that has a low component of wavelengths below 495 nm can minimize the regeneration of the OSL signal. Natural Sciences and Engineering Research Council of Canada. © 2012 American Association of Physicists in Medicine.

Tramadol/paracetamol fixed-dose combination in the treatment of moderate to severe pain

PubMed Central

Pergolizzi, Joseph V; van de Laar, Mart; Langford, Richard; Mellinghoff, Hans-Ulrich; Merchante, Ignacio Morón; Nalamachu, Srinivas; O’Brien, Joanne; Perrot, Serge; Raffa, Robert B

2012-01-01

Pain is the most common reason patients seek medical attention and pain relief has been put forward as an ethical obligation of clinicians and a fundamental human right. However, pain management is challenging because the pathophysiology of pain is complex and not completely understood. Widely used analgesics such as nonsteroidal anti-inflammatory drugs (NSAIDs) and paracetamol (acetaminophen) have been associated with adverse events. Adverse event rates are of concern, especially in long-term treatment or at high doses. Paracetamol and NSAIDs are available by prescription, over the counter, and in combination preparations. Patients may be unaware of the risk associated with high dosages or long-term use of paracetamol and NSAIDs. Clinicians should encourage patients to disclose all medications they take in a “do ask, do tell” approach that includes patient education about the risks and benefits of common pain relievers. The ideal pain reliever would have few risks and enhanced analgesic efficacy. Fixed-dose combination analgesics with two or more agents may offer additive or synergistic benefits to treat the multiple mechanisms of pain. Therefore, pain may be effectively treated while toxicity is reduced due to lower doses. One recent fixed-dose combination analgesic product combines tramadol, a centrally acting weak opioid analgesic, with low-dose paracetamol. Evidence-based guidelines recognize the potential value of combination analgesics in specific situations. The current guideline-based paradigm for pain treatment recommends NSAIDs for ongoing use with analgesics such as opioids to manage flares. However, the treatment model should evolve how to use low-dose combination products to manage pain with occasional use of NSAIDs for flares to avoid long-term and high-dose treatment with these analgesics. A next step in pain management guidelines should be targeted therapy when possible, or low-dose combination therapy or both, to achieve maximal efficacy with minimal toxicity. PMID:23055775

Helical tomotherapy with dynamic running-start-stop delivery compared to conventional tomotherapy delivery

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

Rong, Yi, E-mail: yi.rong@osumc.edu; Chen, Yu; Lu, Weiguo

Purpose: Despite superior target dose uniformity, helical tomotherapy{sup ®} (HT) may involve a trade-off between longitudinal dose conformity and beam-on time (BOT), due to the limitation of only three available jaw sizes with the conventional HT (1.0, 2.5, and 5.0 cm). The recently introduced dynamic running-start-stop (RSS) delivery allows smaller jaw opening at the superior and inferior ends of the target when a sharp penumbra is needed. This study compared the dosimetric performance of RSS delivery with the fixed jaw HT delivery. Methods: Twenty patient cases were selected and deidentified prior to treatment planning, including 16 common clinical cases (brain,more » head and neck (HN), lung, and prostate) and four special cases of whole brain with hippocampus avoidance (WBHA) that require a high degree of dose modulation. HT plans were generated for common clinical cases using the fixed 2.5 cm jaw width (HT2.5) and WBHA cases using 1.0 cm (HT1.0). The jaw widths for RSS were preset with a larger size (RSS5.0 vs HT2.5 and RSS2.5 vs HT1.0). Both delivery techniques were planned based on identical contours, prescriptions, and planning objectives. Dose indices for targets and critical organs were compared using dose-volume histograms, BOT, and monitor units. Results: The average BOT was reduced from 4.8 min with HT2.5 to 2.5 min with RSS5.0. Target dose homogeneity with RSS5.0 was shown comparable to HT2.5 for common clinical sites. Superior normal tissue sparing was observed in RSS5.0 for optic nerves and optic chiasm in brain and HN cases. RSS5.0 demonstrated improved dose sparing for cord and esophagus in lung cases, as well as penile bulb in prostate cases. The mean body dose was comparable for both techniques. For the WBHA cases, the target homogeneity was significantly degraded in RSS2.5 without distinct dose sparing for hippocampus, compared to HT1.0. Conclusions: Compared to the fixed jaw HT delivery, RSS combined with a larger jaw width provides faster treatment delivery and improved cranial-caudal target dose conformity. The target coverage achieved by RSS with a large jaw width is comparable to the fixed jaw HT delivery for common cancer sites, but may deteriorate for cases where complex geometry is present in the middle part of the target.« less

A randomized, double-blinded, placebo-controlled study to evaluate the efficacy and safety of venlafaxine extended release and a long-term extension study for patients with major depressive disorder in Japan.

PubMed

Higuchi, Teruhiko; Kamijima, Kunitoshi; Nakagome, Kazuyuki; Itamura, Rio; Asami, Yuko; Kuribayashi, Kazuhiko; Imaeda, Takayuki

2016-01-01

The aim of this study was to assess antidepressant efficacy and safety of venlafaxine extended release in Japanese patients with major depressive disorder (MDD). We carried out a double-blinded, placebo-controlled, randomized study using fixed (75 mg/day) and flexible (75-225 mg/day, most patients attained to 225 mg/day) doses, followed by the long-term, open-labeled, extension study. Outpatients aged at least 20 years diagnosed with MDD were included. The primary efficacy measure was change from baseline in the Hamilton Rating Scale for Depression (HAM-D17) score at week 8; secondary efficacy measures included the Montgomery-Åsberg Depression Rating Scale, the Quick Inventory of Depressive Symptomatology self-report version, HAM-D6, and Clinical Global Impression scales in the double-blinded study. Overall, 538 patients were randomized; significant differences were observed in the primary efficacy variable in the fixed-dose group (-10.76; P=0.031), but not in the flexible-dose (-10.37; P=0.106) group compared with placebo (-9.25). However, the flexible-dose group showed significant efficacy in several secondary measures. Treatment-related adverse events in the treatment period were 51.7 and 67.8% in the fixed-dose and flexible-dose groups, respectively, versus 38.8% with placebo. Throughout the study period, no Japanese-specific adverse events were observed. Thus, venlafaxine extended release was efficacious and safe for MDD treatment in Japan.

A randomized, double-blinded, placebo-controlled study to evaluate the efficacy and safety of venlafaxine extended release and a long-term extension study for patients with major depressive disorder in Japan

PubMed Central

Higuchi, Teruhiko; Kamijima, Kunitoshi; Nakagome, Kazuyuki; Asami, Yuko; Kuribayashi, Kazuhiko; Imaeda, Takayuki

2016-01-01

The aim of this study was to assess antidepressant efficacy and safety of venlafaxine extended release in Japanese patients with major depressive disorder (MDD). We carried out a double-blinded, placebo-controlled, randomized study using fixed (75 mg/day) and flexible (75–225 mg/day, most patients attained to 225 mg/day) doses, followed by the long-term, open-labeled, extension study. Outpatients aged at least 20 years diagnosed with MDD were included. The primary efficacy measure was change from baseline in the Hamilton Rating Scale for Depression (HAM-D17) score at week 8; secondary efficacy measures included the Montgomery–Åsberg Depression Rating Scale, the Quick Inventory of Depressive Symptomatology self-report version, HAM-D6, and Clinical Global Impression scales in the double-blinded study. Overall, 538 patients were randomized; significant differences were observed in the primary efficacy variable in the fixed-dose group (−10.76; P=0.031), but not in the flexible-dose (−10.37; P=0.106) group compared with placebo (−9.25). However, the flexible-dose group showed significant efficacy in several secondary measures. Treatment-related adverse events in the treatment period were 51.7 and 67.8% in the fixed-dose and flexible-dose groups, respectively, versus 38.8% with placebo. Throughout the study period, no Japanese-specific adverse events were observed. Thus, venlafaxine extended release was efficacious and safe for MDD treatment in Japan. PMID:26513202

Estimating time-varying drug adherence using electronic records: extending the proportion of days covered (PDC) method.

PubMed

Bijlsma, Maarten J; Janssen, Fanny; Hak, Eelko

2016-03-01

Accurate measurement of drug adherence is essential for valid risk-benefit assessments of pharmacologic interventions. To date, measures of drug adherence have almost exclusively been applied for a fixed-time interval and without considering changes over time. However, patients with irregular dosing behaviour commonly have a different prognosis than patients with stable dosing behaviour. We propose a method, based on the proportion of days covered (PDC) method, to measure time-varying drug adherence and drug dosage using electronic records. We compare a time-fixed PDC method with the time-varying PDC method through detailed examples and through summary statistics of 100 randomly selected patients on statin therapy. We demonstrate that time-varying PDC method better distinguishes an irregularly dosing patient from a stably dosing patient and demonstrate how the time-fixed method can result in a biassed estimate of drug adherence. Furthermore, the time-varying PDC method may be better used to reduce certain types of confounding and misclassification of exposure. The time-varying PDC method may improve longitudinal and time-to-event studies that associate adherence with a clinical outcome or (intervention) studies that seek to describe changes in adherence over time. Copyright © 2015 John Wiley & Sons, Ltd.

New horizons in orthodontics & dentofacial orthopedics: fixed Twin Blocks & TransForce lingual appliances.

PubMed

Clark, William John

2011-01-01

During the 20th century functional appliances evolved from night time wear to more flexible appliances for increased day time wear to full time wear with Twin Block appliances. The current trend is towards fixed functional appliances and this paper introduces the Fixed Twin Block, bonded to the teeth to eliminate problems of compliance in functional therapy. TransForce lingual appliances are pre-activated and may be used in first phase treatment for sagittal and transverse arch development. Alternatively they may be integrated with fixed appliances at any stage of treatment.

Rapidity distribution of photons from an anisotropic quark-gluon plasma

NASA Astrophysics Data System (ADS)

Bhattacharya, Lusaka; Roy, Pradip

2010-05-01

We calculate rapidity distribution of photons due to Compton and annihilation processes from quark gluon plasma with pre-equilibrium momentum-space anisotropy. We also include contributions from hadronic matter with late-stage transverse expansion. A phenomenological model has been used for the time evolution of hard momentum scale, phard(τ), and anisotropy parameter, ξ(τ). As a result of pre-equilibrium momentum-space anisotropy, we find significant modification of photons rapidity distribution. For example, with the fixed initial condition (FIC) free-streaming (δ=2) interpolating model we observe significant enhancement of photon rapidity distribution at fixed pT, where as for FIC collisionally broadened (δ=2/3) interpolating model the yield increases till y~1. Beyond that suppression is observed. With fixed final multiplicity (FFM) free-streaming interpolating model we predict enhancement of photon yield which is less than the case of FIC. Suppression is always observed for FFM collisionally broadened interpolating model.

Gas flow meter and method for measuring gas flow rate

DOEpatents

Robertson, Eric P.

2006-08-01

A gas flow rate meter includes an upstream line and two chambers having substantially equal, fixed volumes. An adjustable valve may direct the gas flow through the upstream line to either of the two chambers. A pressure monitoring device may be configured to prompt valve adjustments, directing the gas flow to an alternate chamber each time a pre-set pressure in the upstream line is reached. A method of measuring the gas flow rate measures the time required for the pressure in the upstream line to reach the pre-set pressure. The volume of the chamber and upstream line are known and fixed, thus the time required for the increase in pressure may be used to determine the flow rate of the gas. Another method of measuring the gas flow rate uses two pressure measurements of a fixed volume, taken at different times, to determine the flow rate of the gas.

Intravenous paracetamol with a lower dose is also effective for the treatment of patent ductus arteriosus in pre-term infants.

PubMed

Tekgündüz, Kadir Şerafettin; Ceviz, Naci; Caner, İbrahim; Olgun, Haşim; Demirelli, Yaşar; Yolcu, Canan; Şahin, İrfan Oğuz; Kara, Mustafa

2015-08-01

Haemodynamically significant patent ductus arteriosus is a significant cause of morbidity and mortality in pre-term infants. This retrospective study was conducted to investigate the usefulness of lower-dose paracetamol for the treatment of patent ductus arteriosus in pre-term infants. A total of 13 pre-term infants who received intravenous paracetamol because of contrindications or side effects to oral ibuprofen were retrospectively enrolled. In the first patient, the dose regimen was 15 mg/kg/dose, every 6 hours. As the patient developed significant elevation in transaminase levels, the dose was decreased to 10 mg/kg/dose, every 8 hours in the following 12 patients. Echocardiographic examination was conducted daily. In case of closure, it was repeated after 2 days and when needed thereafter in terms of reopening. A total of 13 patients received intravenous paracetamol. Median gestational age was 29 weeks ranging from 24 to 31 weeks and birth weight was 950 g ranging from 470 to 1390 g. The median postnatal age at the first intravenous paracetamol dose was 3 days ranging from 2 to 9 days. In 10 of the 13 patients (76.9%), patent ductus arteriosus was closed at the median 2nd day of intravenous paracetamol ranging from 1 to 4 days. When the patient who developed hepatotoxicity was eliminated, the closure rate was found to be 83.3% (10/12). Intravenous paracetamol may be a useful treatment option for the treatment of patent ductus arteriosus in pre-term infants with contrindication to ibuprofen. In our experience, lower-dose paracetamol is effective in closing the patent ductus arteriosus in 83.3% of the cases.

TU-G-204-09: The Effects of Reduced- Dose Lung Cancer Screening CT On Lung Nodule Detection Using a CAD Algorithm

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

Young, S; Lo, P; Kim, G

2015-06-15

Purpose: While Lung Cancer Screening CT is being performed at low doses, the purpose of this study was to investigate the effects of further reducing dose on the performance of a CAD nodule-detection algorithm. Methods: We selected 50 cases from our local database of National Lung Screening Trial (NLST) patients for which we had both the image series and the raw CT data from the original scans. All scans were acquired with fixed mAs (25 for standard-sized patients, 40 for large patients) on a 64-slice scanner (Sensation 64, Siemens Healthcare). All images were reconstructed with 1-mm slice thickness, B50 kernel.more » 10 of the cases had at least one nodule reported on the NLST reader forms. Based on a previously-published technique, we added noise to the raw data to simulate reduced-dose versions of each case at 50% and 25% of the original NLST dose (i.e. approximately 1.0 and 0.5 mGy CTDIvol). For each case at each dose level, the CAD detection algorithm was run and nodules greater than 4 mm in diameter were reported. These CAD results were compared to “truth”, defined as the approximate nodule centroids from the NLST reports. Subject-level mean sensitivities and false-positive rates were calculated for each dose level. Results: The mean sensitivities of the CAD algorithm were 35% at the original dose, 20% at 50% dose, and 42.5% at 25% dose. The false-positive rates, in decreasing-dose order, were 3.7, 2.9, and 10 per case. In certain cases, particularly in larger patients, there were severe photon-starvation artifacts, especially in the apical region due to the high-attenuating shoulders. Conclusion: The detection task was challenging for the CAD algorithm at all dose levels, including the original NLST dose. However, the false-positive rate at 25% dose approximately tripled, suggesting a loss of CAD robustness somewhere between 0.5 and 1.0 mGy. NCI grant U01 CA181156 (Quantitative Imaging Network); Tobacco Related Disease Research Project grant 22RT-0131.« less

Efficacy and Safety of a Fixed Combination of Tramadol and Paracetamol (Acetaminophen) as Pain Therapy Within Palliative Medicine

PubMed Central

Husic, Samir; Izic, Senad; Matic, Srecko; Sukalo, Aziz

2015-01-01

Goal: The goal of the research was to determine the efficacy of a fixed combination of tramadol and paracetamol (acetaminophen) in the treatment of pain of patients with the advanced stage of cancer. Material and methods: A prospective study was conducted at the Center for Palliative Care, University Clinical Center Tuzla, Bosnia and Herzegovina, from January 1st to December 31st 2013. A total of 353 patients who were treated with a fixed combination of tramadol and acetaminophen (37.5 mg and 325 mg) at the initial dosage 3x1 tablet (112.5 mg tramadol and 975 mg acetaminophen) for pain intensity 4, up to 4x2 tablets (300 mg of tramadol and 2600 mg paracetamol) for pain intensity 7 and 8. If the patient during previous day has two or more pain episodes that required a “rescue dose” of tramadol, increased was the dose of fixed combination tramadol and acetaminophen to a maximum of 8 tablets daily (300 mg of tramadol and 2600 mg paracetamol). Statistical analysis was performed by biomedical software MedCalc for Windows version 9.4.2.0. The difference was considered significant for P<0.05. Results: The average duration of treatment with a fixed combination tramadol and acetaminophen was 57 days (13-330 days). Already after 24 hours of treatment the average pain score was significantly lower (p<0.0001) compared to the admission day [5.00 (4:00 to 8:00) during the first days versus 2.00 (1:00 to 7:00) during the second day of treatment]. The average dose of the fixed combination tramadol and acetaminophen tablets was 4.8 ± 1.8 (180 mg of tramadol and 1560 mg paracetamol). Side effects, in the treatment of pain with a fixed combination tramadol and acetaminophen, were found in 29.18% of patients, with a predominance of nausea and vomiting. Conclusion: Fixed combination of tramadol and acetaminophen can be used as an effective combination in the treatment of chronic cancer pain, with frequent dose evaluation and mild side effects. PMID:25870531

The initial pharmaceutical development of an artesunate/amodiaquine oral formulation for the treatment of malaria: a public-private partnership.

PubMed

Lacaze, Catherine; Kauss, Tina; Kiechel, Jean-René; Caminiti, Antonella; Fawaz, Fawaz; Terrassin, Laurent; Cuart, Sylvie; Grislain, Luc; Navaratnam, Visweswaran; Ghezzoul, Bellabes; Gaudin, Karen; White, Nick J; Olliaro, Piero L; Millet, Pascal

2011-05-23

Artemisinin-based combination therapy is currently recommended worldwide for the treatment of uncomplicated malaria. Fixed-dose combinations are preferred as they favour compliance. This paper reports on the initial phases of the pharmaceutical development of an artesunate-amodiaquine (ASAQ) bilayer co-formulation tablet, undertaken following pre-formulation studies by a network of scientists and industrials from institutions of both industrialized and low income countries. Pharmaceutical development was performed by a research laboratory at the University Bordeaux Segalen, School of Pharmacy, for feasibility and early stability studies of various drug formulations, further transferred to a company specialized in pharmaceutical development, and then provided to another company for clinical batch manufacturing. The work was conducted by a regional public-private not-for-profit network (TropiVal) within a larger Public Private partnership (the FACT project), set up by WHO/TDR, Médecins Sans Frontières and the Drugs for Neglected Disease initiative (DNDi). The main pharmaceutical goal was to combine in a solid oral form two incompatible active principles while preventing artesunate degradation under tropical conditions. Several options were attempted and failed to provide satisfactory stability results: incorporating artesunate in the external phase of the tablets, adding a pH regulator, alcoholic wet granulation, dry granulation, addition of an hydrophobic agent, tablet manufacturing in controlled conditions. However, long-term stability could be achieved, in experimental batches under GMP conditions, by physical separation of artesunate and amodiaquine in a bilayer co-formulation tablet in alu-alu blisters. Conduction of the workplan was monitored by DNDi. Collaborations between research and industrial groups greatly accelerated the process of development of the bi-layered ASAQ tablet. Lack of public funding was the main obstacle hampering the development process, and no intellectual property right was claimed. This approach resulted in a rapid technology transfer to the drug company Sanofi-Aventis, finalizing the process of development, registration and WHO pre-qualification of the fixed-dose co-formulation together with DNDi. The bi-layered tablet is made available under the names of Coarsucam® and Artesunate amodiaquine Winthrop®, Sanofi-Aventis. The issue related to the difficulty of public institutions to valorise their participation in such initiative by lack of priority and funding of applied research is discussed.

The initial pharmaceutical development of an artesunate/amodiaquine oral formulation for the treatment of malaria: a public-private partnership

PubMed Central

2011-01-01

Background Artemisinin-based combination therapy is currently recommended worldwide for the treatment of uncomplicated malaria. Fixed-dose combinations are preferred as they favour compliance. This paper reports on the initial phases of the pharmaceutical development of an artesunate-amodiaquine (ASAQ) bilayer co-formulation tablet, undertaken following pre-formulation studies by a network of scientists and industrials from institutions of both industrialized and low income countries. Methods Pharmaceutical development was performed by a research laboratory at the University Bordeaux Segalen, School of Pharmacy, for feasibility and early stability studies of various drug formulations, further transferred to a company specialized in pharmaceutical development, and then provided to another company for clinical batch manufacturing. The work was conducted by a regional public-private not-for-profit network (TropiVal) within a larger Public Private partnership (the FACT project), set up by WHO/TDR, Médecins Sans Frontières and the Drugs for Neglected Disease initiative (DNDi). Results The main pharmaceutical goal was to combine in a solid oral form two incompatible active principles while preventing artesunate degradation under tropical conditions. Several options were attempted and failed to provide satisfactory stability results: incorporating artesunate in the external phase of the tablets, adding a pH regulator, alcoholic wet granulation, dry granulation, addition of an hydrophobic agent, tablet manufacturing in controlled conditions. However, long-term stability could be achieved, in experimental batches under GMP conditions, by physical separation of artesunate and amodiaquine in a bilayer co-formulation tablet in alu-alu blisters. Conduction of the workplan was monitored by DNDi. Conclusions Collaborations between research and industrial groups greatly accelerated the process of development of the bi-layered ASAQ tablet. Lack of public funding was the main obstacle hampering the development process, and no intellectual property right was claimed. This approach resulted in a rapid technology transfer to the drug company Sanofi-Aventis, finalizing the process of development, registration and WHO pre-qualification of the fixed-dose co-formulation together with DNDi. The bi-layered tablet is made available under the names of Coarsucam® and Artesunate amodiaquine Winthrop®, Sanofi-Aventis. The issue related to the difficulty of public institutions to valorise their participation in such initiative by lack of priority and funding of applied research is discussed. PMID:21605361

SU-F-BRD-05: Dosimetric Comparison of Protocol-Based SBRT Lung Treatment Modalities: Statistically Significant VMAT Advantages Over Fixed- Beam IMRT

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

Best, R; Harrell, A; Geesey, C

2014-06-15

Purpose: The purpose of this study is to inter-compare and find statistically significant differences between flattened field fixed-beam (FB) IMRT with flattening-filter free (FFF) volumetric modulated arc therapy (VMAT) for stereotactic body radiation therapy SBRT. Methods: SBRT plans using FB IMRT and FFF VMAT were generated for fifteen SBRT lung patients using 6 MV beams. For each patient, both IMRT and VMAT plans were created for comparison. Plans were generated utilizing RTOG 0915 (peripheral, 10 patients) and RTOG 0813 (medial, 5 patients) lung protocols. Target dose, critical structure dose, and treatment time were compared and tested for statistical significance. Parametersmore » of interest included prescription isodose surface coverage, target dose heterogeneity, high dose spillage (location and volume), low dose spillage (location and volume), lung dose spillage, and critical structure maximum- and volumetric-dose limits. Results: For all criteria, we found equivalent or higher conformality with VMAT plans as well as reduced critical structure doses. Several differences passed a Student's t-test of significance: VMAT reduced the high dose spillage, evaluated with conformality index (CI), by an average of 9.4%±15.1% (p=0.030) compared to IMRT. VMAT plans reduced the lung volume receiving 20 Gy by 16.2%±15.0% (p=0.016) compared with IMRT. For the RTOG 0915 peripheral lesions, the volumes of lung receiving 12.4 Gy and 11.6 Gy were reduced by 27.0%±13.8% and 27.5%±12.6% (for both, p<0.001) in VMAT plans. Of the 26 protocol pass/fail criteria, VMAT plans were able to achieve an average of 0.2±0.7 (p=0.026) more constraints than the IMRT plans. Conclusions: FFF VMAT has dosimetric advantages over fixed beam IMRT for lung SBRT. Significant advantages included increased dose conformity, and reduced organs-at-risk doses. The overall improvements in terms of protocol pass/fail criteria were more modest and will require more patient data to establish difference trends of more statistical significance.« less

Drug discrimination under two concurrent fixed-interval fixed-interval schedules.

PubMed

McMillan, D E; Li, M

2000-07-01

Pigeons were trained to discriminate 5.0 mg/kg pentobarbital from saline under a two-key concurrent fixed-interval (FI) 100-s FI 200-s schedule of food presentation, and later tinder a concurrent FI 40-s FI 80-s schedule, in which the FI component with the shorter time requirement reinforced responding on one key after drug administration (pentobarbital-biased key) and on the other key after saline administration (saline-biased key). After responding stabilized under the concurrent FI 100-s FI 200-s schedule, pigeons earned an average of 66% (after pentobarbital) to 68% (after saline) of their reinforcers for responding under the FI 100-s component of the concurrent schedule. These birds made an average of 70% of their responses on both the pentobarbital-biased key after the training dose of pentobarbital and the saline-biased key after saline. After responding stabilized under the concurrent FI 40-s FI 80-s schedule, pigeons earned an average of 67% of their reinforcers for responding under the FI 40 component after both saline and the training dose of pentobarbital. These birds made an average of 75% of their responses on the pentobarbital-biased key after the training dose of pentobarbital, but only 55% of their responses on the saline-biased key after saline. In test sessions preceded by doses of pentobarbital, chlordiazepoxide, ethanol, phencyclidine, or methamphetamine, the dose-response curves were similar under these two concurrent schedules. Pentobarbital, chlordiazepoxide, and ethanol produced dose-dependent increases in responding on the pentobarbital-biased key as the doses increased. For some birds, at the highest doses of these drugs, the dose-response curve turned over. Increasing doses of phencyclidine produced increased responding on the pentobarbital-biased key in some, but not all, birds. After methamphetamine, responding was largely confined to the saline-biased key. These data show that pigeons can perform drug discriminations under concurrent schedules in which the reinforcement frequency under the schedule components differs only by a factor of two, and that when other drugs are substituted for the training drugs they produce dose-response curves similar to the curves produced by these drugs under other concurrent interval schedules.

Efficacy and safety of a ceramide containing moisturizer followed by fixed-dose clindamycin phosphate 1.2%/benzoyl peroxide 2.5% gel in the morning in combination with a ceramide containing moisturizer followed by tretinoin 0.05% gel in the evening for the treatment of facial acne vulgaris.

PubMed

Zeichner, Joshua A; Patel, Rita V; Haddican, Madelaine; Wong, Vicky

2012-06-01

Combination therapy addressing multiple pathogenic factors should be used to achieve optimal outcomes in treating acne. The following study demonstrated both safety and efficacy of fixed-dose clindamycin phosphate 1.2%/benzoyl peroxide 2.5% in the morning with micronized tretinoin 0.05% gel in the evening. Both products were applied to the skin following the use of a ceramide containing moisturizing lotion.

COPD prevalence in a random population survey: a matter of definition.

PubMed

Shirtcliffe, P; Weatherall, M; Marsh, S; Travers, J; Hansell, A; McNaughton, A; Aldington, S; Muellerova, H; Beasley, R

2007-08-01

A recent American Thoracic Society and European Respiratory Society joint Task Force report recommends using a lower limit of normal (LLN) of forced expiratory volume in one second/forced vital capacity as opposed to a fixed ratio of <0.7 to diagnose airflow obstruction, in order to reduce false positive diagnoses of chronic obstructive pulmonary disease (COPD) as defined by the Global Initiative for Obstructive Lung Disease (GOLD). To date, there is no reliable spirometry-based prevalence data for COPD in New Zealand and the effect of different definitions of airflow obstruction based on post-bronchodilator spirometry is not known. Detailed written questionnaires, full pulmonary function tests (including pre- and post-bronchodilator flow-volume loops) and atopy testing were completed in 749 subjects recruited from a random population sample. The GOLD-defined, age-adjusted prevalence (95% confidence interval) for adults aged >or=40 yrs was 14.2 (11.0-17.0)% compared with an LLN-defined, age-adjusted, post-bronchodilator prevalence in the same group of 9.0 (6.7-11.3)%. The prevalence of chronic obstructive pulmonary disease varied markedly depending on the definition used. Further research using longitudinal rather than cross-sectional data will help decide the preferred approach in chronic obstructive pulmonary disease prevalence surveys.

Statistical controversies in clinical research: building the bridge to phase II-efficacy estimation in dose-expansion cohorts.

PubMed

Boonstra, P S; Braun, T M; Taylor, J M G; Kidwell, K M; Bellile, E L; Daignault, S; Zhao, L; Griffith, K A; Lawrence, T S; Kalemkerian, G P; Schipper, M J

2017-07-01

Regulatory agencies and others have expressed concern about the uncritical use of dose expansion cohorts (DECs) in phase I oncology trials. Nonetheless, by several metrics-prevalence, size, and number-their popularity is increasing. Although early efficacy estimation in defined populations is a common primary endpoint of DECs, the types of designs best equipped to identify efficacy signals have not been established. We conducted a simulation study of six phase I design templates with multiple DECs: three dose-assignment/adjustment mechanisms multiplied by two analytic approaches for estimating efficacy after the trial is complete. We also investigated the effect of sample size and interim futility analysis on trial performance. Identifying populations in which the treatment is efficacious (true positives) and weeding out inefficacious treatment/populations (true negatives) are competing goals in these trials. Thus, we estimated true and false positive rates for each design. Adaptively updating the MTD during the DEC improved true positive rates by 8-43% compared with fixing the dose during the DEC phase while maintaining false positive rates. Inclusion of an interim futility analysis decreased the number of patients treated under inefficacious DECs without hurting performance. A substantial gain in efficiency is obtainable using a design template that statistically models toxicity and efficacy against dose level during expansion. Design choices for dose expansion should be motivated by and based upon expected performance. Similar to the common practice in single-arm phase II trials, cohort sample sizes should be justified with respect to their primary aim and include interim analyses to allow for early stopping. © 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.

Comparison of computational to human observer detection for evaluation of CT low dose iterative reconstruction

NASA Astrophysics Data System (ADS)

Eck, Brendan; Fahmi, Rachid; Brown, Kevin M.; Raihani, Nilgoun; Wilson, David L.

2014-03-01

Model observers were created and compared to human observers for the detection of low contrast targets in computed tomography (CT) images reconstructed with an advanced, knowledge-based, iterative image reconstruction method for low x-ray dose imaging. A 5-channel Laguerre-Gauss Hotelling Observer (CHO) was used with internal noise added to the decision variable (DV) and/or channel outputs (CO). Models were defined by parameters: (k1) DV-noise with standard deviation (std) proportional to DV std; (k2) DV-noise with constant std; (k3) CO-noise with constant std across channels; and (k4) CO-noise in each channel with std proportional to CO variance. Four-alternative forced choice (4AFC) human observer studies were performed on sub-images extracted from phantom images with and without a "pin" target. Model parameters were estimated using maximum likelihood comparison to human probability correct (PC) data. PC in human and all model observers increased with dose, contrast, and size, and was much higher for advanced iterative reconstruction (IMR) as compared to filtered back projection (FBP). Detection in IMR was better than FPB at 1/3 dose, suggesting significant dose savings. Model(k1,k2,k3,k4) gave the best overall fit to humans across independent variables (dose, size, contrast, and reconstruction) at fixed display window. However Model(k1) performed better when considering model complexity using the Akaike information criterion. Model(k1) fit the extraordinary detectability difference between IMR and FBP, despite the different noise quality. It is anticipated that the model observer will predict results from iterative reconstruction methods having similar noise characteristics, enabling rapid comparison of methods.

COCAINE AND PAVLOVIAN FEAR CONDITIONING: DOSE-EFFECT ANALYSIS

PubMed Central

Wood, Suzanne C.; Fay, Jonathon; Sage, Jennifer R.; Anagnostaras, Stephan G.

2007-01-01

Emerging evidence suggests that cocaine and other drugs of abuse can interfere with many aspects of cognitive functioning. The authors examined the effects of 0.1 – 15 mg/kg of cocaine on Pavlovian contextual and cued fear conditioning in mice. As expected, pre-training cocaine dose-dependently produced hyperactivity and disrupted freezing. Surprisingly, when the mice were tested off-drug later, the group pre-treated with a moderate dose of cocaine (15 mg/kg) displayed significantly less contextual and cued memory, compared to saline control animals. Conversely, mice pre-treated with a very low dose of cocaine (0.1 mg/kg) showed significantly enhanced fear memory for both context and tone, compared to controls. These results were not due to cocaine’s anesthetic effects, as shock reactivity was unaffected by cocaine. The data suggest that despite cocaine’s reputation as a performance-enhancing and anxiogenic drug, this effect is seen only at very low doses, whereas a moderate dose disrupts hippocampus and amygdala-dependent fear conditioning. PMID:17098299

Cocaine and Pavlovian fear conditioning: dose-effect analysis.

PubMed

Wood, Suzanne C; Fay, Jonathan; Sage, Jennifer R; Anagnostaras, Stephan G

2007-01-25

Emerging evidence suggests that cocaine and other drugs of abuse can interfere with many aspects of cognitive functioning. The authors examined the effects of 0.1-15mg/kg of cocaine on Pavlovian contextual and cued fear conditioning in mice. As expected, pre-training cocaine dose-dependently produced hyperactivity and disrupted freezing. Surprisingly, when the mice were tested off-drug later, the group pre-treated with a moderate dose of cocaine (15mg/kg) displayed significantly less contextual and cued memory, compared to saline control animals. Conversely, mice pre-treated with a very low dose of cocaine (0.1mg/kg) showed significantly enhanced fear memory for both context and tone, compared to controls. These results were not due to cocaine's anesthetic effects, as shock reactivity was unaffected by cocaine. The data suggest that despite cocaine's reputation as a performance-enhancing and anxiogenic drug, this effect is seen only at very low doses, whereas a moderate dose disrupts hippocampus and amygdala-dependent fear conditioning.

Use of a medication control officer to reduce bias in a clinical trial: lessons learned from the scleroderma lung study.

PubMed

Hsu, Vivien M; Khanna, Dinesh; Smith, Edwin; Filemon, Tan; Whelton, Sean; Lopata, Mel; Davis, John C; Polito, Albert; Heck, Louis; Molitor, Jerry; Abeles, Micha; Granda, Jose; Korn, Joseph; Clements, Philip

2010-02-01

Scleroderma Lung Study (SLS) was designed to evaluate the efficacy and safety of oral cyclophosphamide (CYC) versus placebo taken for 1 year for scleroderma-associated interstitial lung disease. An independent medication control officer (MCO), usually a physician, at each center was assigned to monitor laboratory and clinical toxicity of study medication and regulate its dosing based on these results. By having an MCO who watched and managed toxicity, the study investigators were free to care for study patients and to assess study outcomes without the potential bias of knowing toxicity data (toxicity from cyclophosphamide is distinctive - cytopenias and hematuria in particular). To assess the usefulness of an MCO, whose chief role was to maintain safety while retaining the blinding in the clinical trial. Patients had safety laboratory testing every 2-4 weeks and results were sent directly to the MCO within 2 days of the test. Other clinical adverse events (AEs) were reported by the patient to a nurse coordinator who reported them to the MCO who then managed the AEs to preserve the blinding of investigators caring for the patients. The MCO was provided pre-determined algorithms for dose adjustments of test medication based on the presence and severity of laboratory abnormalities. Safety monitoring by the MCO was effective in the early detection of drug toxicity with provision of appropriate medical intervention on a timely basis. At the same time, investigator blinding appeared to be maintained. The testing of MCO effectiveness in maintaining blinding and consistency was not defined as an a priori hypothesis and thus complete data relating to the efficacy of the MCO were not collected in a prospective fashion. An MCO and pre-specified monitoring and dosing guidelines, coupled with uniform pre-specified responses to AEs, may be used effectively to preserve investigator blinding and provide consistency in response to AEs in a clinical trial setting, even when AEs of the test medication are distinctive.

Assessment of the anthelmintic efficacy of albendazole in school children in seven countries where soil-transmitted helminths are endemic.

PubMed

Vercruysse, Jozef; Behnke, Jerzy M; Albonico, Marco; Ame, Shaali Makame; Angebault, Cécile; Bethony, Jeffrey M; Engels, Dirk; Guillard, Bertrand; Nguyen, Thi Viet Hoa; Kang, Gagandeep; Kattula, Deepthi; Kotze, Andrew C; McCarthy, James S; Mekonnen, Zeleke; Montresor, Antonio; Periago, Maria Victoria; Sumo, Laurentine; Tchuenté, Louis-Albert Tchuem; Dang, Thi Cam Thach; Zeynudin, Ahmed; Levecke, Bruno

2011-03-29

The three major soil-transmitted helminths (STH) Ascaris lumbricoides, Trichuris trichiura and Necator americanus/Ancylostoma duodenale are among the most widespread parasites worldwide. Despite the global expansion of preventive anthelmintic treatment, standard operating procedures to monitor anthelmintic drug efficacy are lacking. The objective of this study, therefore, was to define the efficacy of a single 400 milligram dose of albendazole (ALB) against these three STH using a standardized protocol. Seven trials were undertaken among school children in Brazil, Cameroon, Cambodia, Ethiopia, India, Tanzania and Vietnam. Efficacy was assessed by the Cure Rate (CR) and the Fecal Egg Count Reduction (FECR) using the McMaster egg counting technique to determine fecal egg counts (FEC). Overall, the highest CRs were observed for A. lumbricoides (98.2%) followed by hookworms (87.8%) and T. trichiura (46.6%). There was considerable variation in the CR for the three parasites across trials (country), by age or the pre-intervention FEC (pre-treatment). The latter is probably the most important as it had a considerable effect on the CR of all three STH. Therapeutic efficacies, as reflected by the FECRs, were very high for A. lumbricoides (99.5%) and hookworms (94.8%) but significantly lower for T. trichiura (50.8%), and were affected to different extents among the 3 species by the pre-intervention FEC counts and trial (country), but not by sex or age. Our findings suggest that a FECR (based on arithmetic means) of >95% for A. lumbricoides and >90% for hookworms should be the expected minimum in all future surveys, and that therapeutic efficacy below this level following a single dose of ALB should be viewed with concern in light of potential drug resistance. A standard threshold for efficacy against T. trichiura has yet to be established, as a single-dose of ALB is unlikely to be satisfactory for this parasite. ClinicalTrials.gov NCT01087099.

A Study to Find Out the Full Immunization Coverage of 12 to 23-month old Children and Areas of Under-Performance using LQAS Technique in a Rural Area of Tripura.

PubMed

Datta, Anjan; Baidya, Subrata; Datta, Srabani; Mog, Chanda; Das, Shampa

2017-02-01

It is very important to analyze the factors which acts as obstacle in achieving 100% immunization among children. Lot Quality Assurance Sampling (LQAS) is one of the effective method to assess such barriers. To assess the full immunization coverage among 12 to 23-month old children of rural field practice area under Department of Community Medicine, Agartala Government Medical College and identify the factors for failure of full immunization. A community based cross-sectional study was conducted from November 2013 to October 2014 on children aged 12 to 23 months old of area under Mohanpur Community health centre. Using LQAS technique 330 samples were selected with multi-stage sampling, each sub-centre being one lot and two calculated to be the decision value. Data was collected using pre-designed pre-tested questionnaire during home visit and verifying immunization card and analysed by computer software SPSS version 21.0. The full immunization coverage among 12 to 23 months old children of Mohanpur area was found as 91.67%. Out of all the 22 sub-centres, 36.36% was found under performing as per pre-fixed criteria and the main reasons for failure of full immunization in those areas are unawareness of need of subsequent doses of vaccines and illness of the children. LQAS is an effective method to identify areas of under-performance even though overall full immunization coverage is high.

Persistence of rabies antibody 5 years after pre-exposure prophylaxis with human diploid cell antirabies vaccine and antibody response to a single booster dose.

PubMed Central

Rodrigues, F. M.; Mandke, V. B.; Roumiantzeff, M.; Rao, C. V.; Mehta, J. M.; Pavri, K. M.; Poonawalla, C.

1987-01-01

In 1978, 22 staff members of the National Institute of Virology, Pune, India, were given two doses of human diploid cell antirabies vaccine (HDCV) for primary pre-exposure prophylactic immunization; the interval between the two doses being approximately 4 weeks. Eighteen of these 22 vaccinees were given a booster dose 1 year later. All 18 vaccinees developed protective levels of antibody; most of them had antibody levels exceeding 10 IU/ml. In 1984, 5 years after the booster dose, 11 (79.0%) of 14 vaccinees tested still possessed neutralizing antibody levels ranging from 0.5 IU/ml to 10 IU/ml. Fourteen days after the administration of a booster dose, the antibody levels ranged from 10 to greater than or equal to 100 IU/ml for all except one vaccine (5.2 IU/ml). These findings demonstrate that the majority of vaccines retained detectable neutralizing antibody after pre-exposure prophylaxis for as long as 5 years and that a single booster dose thereafter evoked a good antibody response. PMID:3609177

Fixed-Tuition Pricing: A Solution that May Be Worse than the Problem

ERIC Educational Resources Information Center

Morphew, Christopher C.

2007-01-01

Fixed-tuition plans, which vary in specifics from institution to institution, rely on a common principle: Students pay the same annual tuition costs over a pre-determined length of time, ostensibly the time required to earn an undergraduate degree. Students, parents, and policymakers are demonstrating growing interest in such plans. At face value,…

Symptomatic treatment of the common cold with a fixed-dose combination of paracetamol, chlorphenamine and phenylephrine: a randomized, placebo-controlled trial.

PubMed

Picon, Paulo Dornelles; Costa, Marisa Boff; da Veiga Picon, Rafael; Fendt, Lucia Costa Cabral; Suksteris, Maurício Leichter; Saccilotto, Indara Carmanim; Dornelles, Alicia Dorneles; Schmidt, Luis Felipe Carissimi

2013-11-22

The common cold and other viral airway infections are highly prevalent in the population, and their treatment often requires the use of medications for symptomatic relief. Paracetamol is as an analgesic and antipyretic; chlorphenamine is an antihistamine; and phenylephrine, a vasoconstrictor and decongestant. This randomized, double-blind, placebo-controlled trial sought to evaluate the efficacy and safety of a fixed-dose combination of paracetamol, chlorphenamine and phenylephrine in the symptomatic treatment of the common cold and flu-like syndrome in adults. This study enrolled 146 individuals aged 18 to 60 years who had moderate to severe flu-like syndrome or common cold. After clinical examination and laboratory tests, individuals were randomly assigned to receive the fixed-dose combination (73) or placebo (73), five capsules per day for 48 to 72 hours. The primary efficacy endpoint was the sum of the scores of 10 symptoms on a four-point Likert-type scale. To evaluate treatment safety, the occurrence of adverse events was also measured. Mean age was 33.5 (±9.5) years in the placebo group and 33.8 (±11.5) in the treatment group. There were 55 women and 18 men in the placebo group, and 46 women and 27 men in the treatment group. Comparison of overall symptom scores in the two groups revealed a significantly greater reduction in the treatment group than in the placebo group (p = 0.015). Analysis at the first 13 dose intervals (± 66 h of treatment) showed a greater reduction of symptom scores in the treatment group than in the placebo group (p < 0.05). The number and distribution of adverse events were similar in both groups. A fixed-dose combination of paracetamol, chlorphenamine and phenylephrine was safe and more effective than placebo in the symptomatic treatment of the common cold or flu-like syndrome in adults. NCT01389518.

Symptomatic treatment of the common cold with a fixed-dose combination of paracetamol, chlorphenamine and phenylephrine: a randomized, placebo-controlled trial

PubMed Central

2013-01-01

Background The common cold and other viral airway infections are highly prevalent in the population, and their treatment often requires the use of medications for symptomatic relief. Paracetamol is as an analgesic and antipyretic; chlorphenamine is an antihistamine; and phenylephrine, a vasoconstrictor and decongestant. This randomized, double-blind, placebo-controlled trial sought to evaluate the efficacy and safety of a fixed-dose combination of paracetamol, chlorphenamine and phenylephrine in the symptomatic treatment of the common cold and flu-like syndrome in adults. Methods This study enrolled 146 individuals aged 18 to 60 years who had moderate to severe flu-like syndrome or common cold. After clinical examination and laboratory tests, individuals were randomly assigned to receive the fixed-dose combination (73) or placebo (73), five capsules per day for 48 to 72 hours. The primary efficacy endpoint was the sum of the scores of 10 symptoms on a four-point Likert-type scale. To evaluate treatment safety, the occurrence of adverse events was also measured. Results Mean age was 33.5 (±9.5) years in the placebo group and 33.8 (±11.5) in the treatment group. There were 55 women and 18 men in the placebo group, and 46 women and 27 men in the treatment group. Comparison of overall symptom scores in the two groups revealed a significantly greater reduction in the treatment group than in the placebo group (p = 0.015). Analysis at the first 13 dose intervals (± 66 h of treatment) showed a greater reduction of symptom scores in the treatment group than in the placebo group (p < 0.05). The number and distribution of adverse events were similar in both groups. Conclusion A fixed-dose combination of paracetamol, chlorphenamine and phenylephrine was safe and more effective than placebo in the symptomatic treatment of the common cold or flu-like syndrome in adults. Trial registration NCT01389518 PMID:24261438

The Safety, Effectiveness and Concentrations of Adjusted Lopinavir/Ritonavir in HIV-Infected Adults on Rifampicin-Based Antitubercular Therapy

PubMed Central

Decloedt, Eric H.; Maartens, Gary; Smith, Peter; Merry, Concepta; Bango, Funeka; McIlleron, Helen

2012-01-01

Objective Rifampicin co-administration dramatically reduces plasma lopinavir concentrations. Studies in healthy volunteers and HIV-infected patients showed that doubling the dose of lopinavir/ritonavir (LPV/r) or adding additional ritonavir offsets this interaction. However, high rates of hepatotoxicity were observed in healthy volunteers. We evaluated the safety, effectiveness and pre-dose concentrations of adjusted doses of LPV/r in HIV infected adults treated with rifampicin-based tuberculosis treatment. Methods Adult patients on a LPV/r-based antiretroviral regimen and rifampicin-based tuberculosis therapy were enrolled. Doubled doses of LPV/r or an additional 300 mg of ritonavir were used to overcome the inducing effect of rifampicin. Steady-state lopinavir pre-dose concentrations were evaluated every second month. Results 18 patients were enrolled with a total of 79 patient months of observation. 11/18 patients were followed up until tuberculosis treatment completion. During tuberculosis treatment, the median (IQR) pre-dose lopinavir concentration was 6.8 (1.1–9.2) mg/L and 36/47 (77%) were above the recommended trough concentration of 1 mg/L. Treatment was generally well tolerated with no grade 3 or 4 toxicity: 8 patients developed grade 1 or 2 transaminase elevation, 1 patient defaulted additional ritonavir due to nausea and 1 patient developed diarrhea requiring dose reduction. Viral loads after tuberculosis treatment were available for 11 patients and 10 were undetectable. Conclusion Once established on treatment, adjusted doses of LPV/r co-administered with rifampicin-based tuberculosis treatment were tolerated and LPV pre-dose concentrations were adequate. PMID:22412856

Early chronic lead exposure reduces exploratory activity in young C57BL/6J mice.

PubMed

Flores-Montoya, Mayra Gisel; Sobin, Christina

2015-07-01

Research has suggested that chronic low-level lead exposure diminishes neurocognitive function in children. Tests that are sensitive to behavioral effects at lowest levels of lead exposure are needed for the development of animal models. In this study we investigated the effects of chronic low-level lead exposure on exploratory activity (unbaited nose poke task), exploratory ambulation (open field task) and motor coordination (Rotarod task) in pre-adolescent mice. C57BL/6J pups were exposed to 0 ppm (controls), 30 ppm (low-dose) or 230 ppm (high-dose) lead acetate via dams' drinking water administered from birth to postnatal day 28, to achieve a range of blood lead levels (BLLs) from not detectable to 14.84 µg dl(-1) ). At postnatal day 28, mice completed behavioral testing and were killed (n = 61). BLLs were determined by inductively coupled plasma mass spectrometry. The effects of lead exposure on behavior were tested using generalized linear mixed model analyses with BLL, sex and the interaction as fixed effects, and litter as the random effect. BLL predicted decreased exploratory activity and no threshold of effect was apparent. As BLL increased, nose pokes decreased. The C57BL/6J mouse is a useful model for examining effects of early chronic low-level lead exposure on behavior. In the C57BL/6J mouse, the unbaited nose poke task is sensitive to the effects of early chronic low-level lead exposure. This is the first animal study to show behavioral effects in pre-adolescent lead-exposed mice with BLL below 5 µg dl(-1). Copyright © 2014 John Wiley & Sons, Ltd.

Early chronic lead exposure reduces exploratory activity in young C57BL/6J mice

PubMed Central

Flores-Montoya, Mayra Gisel; Sobin, Christina

2014-01-01

Research has suggested that chronic low-level lead exposure diminishes neurocognitive function in children. Tests that are sensitive to behavioral effects at lowest levels of lead exposure are needed for the development of animal models. In this study we investigated the effects of chronic low-level lead exposure on exploratory activity (unbaited nose poke task), exploratory ambulation (open field task) and motor coordination (Rotarod task) in pre-adolescent mice. C57BL/6J pups were exposed to 0 ppm (controls), 30 ppm (low-dose) or 230 ppm (high-dose) lead acetate via dams’ drinking water administered from birth to postnatal day 28, to achieve a range of blood lead levels (BLLs) from not detectable to 14.84 μg dl−1). At postnatal day 28, mice completed behavioral testing and were killed (n = 61). BLLs were determined by inductively coupled plasma mass spectrometry. The effects of lead exposure on behavior were tested using generalized linear mixed model analyses with BLL, sex and the interaction as fixed effects, and litter as the random effect. BLL predicted decreased exploratory activity and no threshold of effect was apparent. As BLL increased, nose pokes decreased. The C57BL/6J mouse is a useful model for examining effects of early chronic low-level lead exposure on behavior. In the C57BL/6J mouse, the unbaited nose poke task is sensitive to the effects of early chronic low-level lead exposure. This is the first animal study to show behavioral effects in pre-adolescent lead-exposed mice with BLL below 5 μg dl−1. PMID:25219894

SU-F-T-638: Is There A Need For Immobilization in SRS?

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

Masterova, K; Sethi, A; Anderson, D

2016-06-15

Purpose: Frameless Stereotactic radiosurgery (SRS) is increasingly used in the clinic. Cone-Beam CT (CBCT) to simulation-CT match has replaced the 3-dimensional coordinate based set up using a stereotactic localizing frame. The SRS frame however served as both a localizing and immobilizing device. We seek to measure the quality of frameless (mask based) and frame based immobilization and evaluate its impact on target dose. Methods: Each SRS patient was set up by kV on-board imaging (OBI) and then fine-tuned with CBCT. A second CBCT was done at treatment-end to ascertain intrafraction motion. We compared pre- vs post-treatment CBCT shifts for bothmore » frameless and frame based SRS patients. CBCT to sim-CT fusion was repeated for each patient off-line to assess systematic residual image registration error. Each patient was re-planned with measured shifts to assess effects on target dose. Results: We analyzed 11 patients (12 lesions) treated with frameless SRS and 6 patients (11 lesions) with a fixed frame system. Average intra-fraction iso-center positioning errors for frameless and frame-based treatments were 1.24 ± 0.57 mm and 0.28 ± 0.08 mm (mean ± s.d.) respectively. Residual error in CBCT registration was 0.24 mm. The frameless positioning uncertainties led to target dose errors in Dmin and D95 of 15.5 ± 18.4% and 6.6 ± 9.1% respectively. The corresponding errors in fixed frame SRS were much lower with Dmin and D95 reduced by 4.2 ± 6.5% and D95 2.5 ± 3.8% respectively. Conclusion: Frameless mask provides good immobilization with average patient motion of 1.2 mm during treatment. This exceeds MRI voxel dimensions (∼0.43mm) used for target delineation. Frame-based SRS provides superior patient immobilization with measureable movement no greater than the background noise of the CBCT registration. Small lesions requiring submm precision are better served with a frame based SRS.« less

TH-EF-BRB-10: Dosimetric Validation of a Trajectory Based Cranial SRS Treatment Technique On a Varian TrueBeam Linac

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

Wilson, B; Vancouver Cancer Centre, Vancouver, BC; Gete, E

2016-06-15

Purpose: This work investigates the dosimetric accuracy of a trajectory based delivery technique in which an optimized radiation beam is delivered along a Couch-Gantry trajectory that is formed by simultaneous rotation of the linac gantry and the treatment couch. Methods: Nine trajectory based cranial SRS treatment plans were created using in-house optimization software. The plans were calculated for delivery on the TrueBeam STx linac with 6MV photon beam. Dose optimization was performed along a user-defined trajectory using MLC modulation, dose rate modulation and jaw tracking. The pre-defined trajectory chosen for this study is formed by a couch rotation through itsmore » full range of 180 degrees while the gantry makes four partial arc sweeps which are 170 degrees each. For final dose calculation, the trajectory based plans were exported to the Varian Eclipse Treatment Planning System. The plans were calculated on a homogeneous cube phantom measuring 18.2×18.2×18.2 cm3 with the analytical anisotropic algorithm (AAA) using a 1mm3 calculation voxel. The plans were delivered on the TrueBeam linac via the developer’s mode. Point dose measurements were performed on 9 patients with the IBA CC01 mini-chamber with a sensitive volume of 0.01 cc. Gafchromic film measurements along the sagittal and coronal planes were performed on three of the 9 treatment plans. Point dose values were compared with ion chamber measurements. Gamma analysis comparing film measurement and AAA calculations was performed using FilmQA Pro. Results: The AAA calculations and measurements were in good agreement. The point dose difference between AAA and ion chamber measurements were within 2.2%. Gamma analysis test pass rates (2%, 2mm passing criteria) for the Gafchromic film measurements were >95%. Conclusion: We have successfully tested TrueBeam’s ability to deliver accurate trajectory based treatments involving simultaneous gantry and couch rotation with MLC and dose rate modulation along the trajectory.« less

Absorbed dose estimates from a single measurement one to three days after the administration of 177Lu-DOTATATE/-TOC.

PubMed

Hänscheid, Heribert; Lapa, Constantin; Buck, Andreas K; Lassmann, Michael; Werner, Rudolf A

2017-01-01

To retrospectively analyze the accuracy of absorbed dose estimates from a single measurement of the activity concentrations in tumors and relevant organs one to three days after the administration of 177 Lu-DOTA-TATE/TOC assuming tissue specific effective half-lives. Activity kinetics in 54 kidneys, 30 neuroendocrine tumor lesions, 25 livers, and 27 spleens were deduced from series of planar images in 29 patients. After adaptation of mono- or bi-exponential fit functions to the measured data, it was analyzed for each fit function how precise the time integral can be estimated from fixed tissue-specific half-lives and a single measurement at 24, 48, or 72 h after the administration. For the kidneys, assuming a fixed tissue-specific half-life of 50 h, the deviations of the estimate from the actual integral were median (5 % percentile, 95 % percentile): -3 °% (-15 %>; +16 °%) for measurements after 24 h, +2 %> (-9 %>; +12 %>) for measurements after 48 h, and 0 % (-2 %; +12 %) for measurements after 72 h. The corresponding values for the other tissues, assuming fixed tissue-specific half-lives of 67 h for liver and spleen and 77 h for tumors, were +2 % (-25 %; +20 %) for measurements after 24 h, +2 °% (-16 %>; +17 %>) for measurements after 48 h, and +2 %> (-11 %>; +10 %>) for measurements after 72 h. Especially for the kidneys, which often represent the dose limiting organ, but also for liver, spleen, and neuroendocrine tumors, a meaningful absorbed dose estimate is possible from a single measurement after 2, more preferably 3 days after the administration of 177 Lu-DOTA-TATE/-TOC assuming fixed tissue specific effective half-lives. Schattauer GmbH.

Predicting the 5-Year Risk of Biochemical Relapse After Postprostatectomy Radiation Therapy in ≥PT2, pN0 Patients With a Comprehensive Tumor Control Probability Model

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

Fiorino, Claudio, E-mail: fiorino.claudio@hsr.it; Broggi, Sara; Fossati, Nicola

Purpose: To fit the individual biochemical recurrence-free survival (bRFS) data from patients treated with postprostatectomy radiation therapy (RT) with a comprehensive tumor control probability (TCP) model. Methods and Materials: Considering pre-RT prostate-specific antigen (PSA) as a surrogate of the number of clonogens, bRFS may be expressed as a function of dose-per-fraction–dependent radiosensitivity (α{sub eff}), the number of clonogens for pre-RT PSA = 1 ng/mL (C), and the fraction of patients who relapse because of clonogens outside the treated volume (K), assumed to depend (linearly or exponentially) on pre-RT PSA and Gleason score (GS). Data from 894 node-negative, ≥pT2, pN0 hormone-naive patients treated withmore » adjuvant (n=331) or salvage (n=563) intent were available: 5-year bRFS data were fitted grouping patients according to GS (<7:392, =7:383, >7:119). Results: The median follow-up time, pre-RT PSA, and dose were 72 months, 0.25 ng/mL, and 66.6 Gy (range 59.4-77.4 Gy), respectively. The best-fit values were 0.23 to 0.26 Gy{sup −1} and 10{sup 7} for α{sub eff} and C for the model considering a linear dependence between K and PSA. Calibration plots showed good agreement between expected and observed incidences (slope: 0.90-0.93) and moderately high discriminative power (area under the curve [AUC]: 0.68-0.69). Cross-validation showed satisfactory results (average AUCs in the training/validation groups: 0.66-0.70). The resulting dose-effect curves strongly depend on pre-RT PSA and GS. bRFS rapidly decreases with PSA: the maximum obtainable bRFS (defined as 95% of the maximum) declined by about 2.7% and 4.5% for each increment of 0.1 ng/mL for GS <7 and ≥7, respectively. Conclusions: Individual data were fitted by a TCP model, and the resulting best-fit parameters were radiobiologically consistent. The model suggests that relapses frequently result from clonogens outside the irradiated volume, supporting the choice of lymph-node irradiation, systemic therapy, or both for specific subgroups (GS <7: PSA >0.8-1.0 ng/mL; GS ≥7: PSA >0.3 ng/mL). Early RT should be preferred over delayed RT; the detrimental effect of PSA increase can never be fully compensated by increasing the dose, especially for patients with GS ≥7.« less

Formulation design, challenges, and development considerations for fixed dose combination (FDC) of oral solid dosage forms.

PubMed

Desai, Divyakant; Wang, Jennifer; Wen, Hong; Li, Xuhong; Timmins, Peter

2013-01-01

Fixed dose combination (FDC) products are common in the treatment of hypertension, diabetes, human immunodeficiency virus, and tuberculosis. They make it possible to combine two or more drug molecules with different modes of pharmacological actions in a single dosing unit and optimize the treatment. From a patient perspective, they offer convenience, reduced dosing unit burden, and cost savings. From a clinical perspective, aging population in developed countries will need multiple medications to treat age related diseases and co-morbidities. FDC products simplify dosing regimen and enhance patient compliance. As outlined in the article, the number of FDC products has grown over the years and the trend is likely to continue. This review article gives an overview to pharmaceutical scientists about recent trends in the formulation development of the FDC products and provides decision trees to select most optimum formulation development strategy. While some formulation technologies such as multi-layer tablets, multiparticulate systems, active film coating, and hot-melt granulation are discussed in more detail, a few specialized technologies are also introduced briefly to the readers.

Repeated Post- or Presession Cocaine Administration: Roles of Dose and Fixed-Ratio Schedule

ERIC Educational Resources Information Center

Pinkston, Jonathan W.; Branch, Marc N.

2004-01-01

Effects of repeated administration of cocaine to animals behaving under operant contingencies have depended on when the drug is given. Moderate doses given presession have generally led to a decrease in the drug's effect, an outcome usually referred to as tolerance. When these same doses have been given after sessions, the usual result has been no…

Radiation-Induced Carcinogenesis: Mechanistically Based Differences between Gamma-Rays and Neutrons, and Interactions with DMBA

PubMed Central

Shuryak, Igor; Brenner, David J.; Ullrich, Robert L.

2011-01-01

Different types of ionizing radiation produce different dependences of cancer risk on radiation dose/dose rate. Sparsely ionizing radiation (e.g. γ-rays) generally produces linear or upwardly curving dose responses at low doses, and the risk decreases when the dose rate is reduced (direct dose rate effect). Densely ionizing radiation (e.g. neutrons) often produces downwardly curving dose responses, where the risk initially grows with dose, but eventually stabilizes or decreases. When the dose rate is reduced, the risk increases (inverse dose rate effect). These qualitative differences suggest qualitative differences in carcinogenesis mechanisms. We hypothesize that the dominant mechanism for induction of many solid cancers by sparsely ionizing radiation is initiation of stem cells to a pre-malignant state, but for densely ionizing radiation the dominant mechanism is radiation-bystander-effect mediated promotion of already pre-malignant cell clone growth. Here we present a mathematical model based on these assumptions and test it using data on the incidence of dysplastic growths and tumors in the mammary glands of mice exposed to high or low dose rates of γ-rays and neutrons, either with or without pre-treatment with the chemical carcinogen 7,12-dimethylbenz-alpha-anthracene (DMBA). The model provides a mechanistic and quantitative explanation which is consistent with the data and may provide useful insight into human carcinogenesis. PMID:22194850

SU-E-T-551: PTV Is the Worst-Case of CTV in Photon Therapy

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

Harrington, D; Liu, W; Park, P

2014-06-01

Purpose: To examine the supposition of the static dose cloud and adequacy of the planning target volume (PTV) dose distribution as the worst-case representation of clinical target volume (CTV) dose distribution for photon therapy in head and neck (H and N) plans. Methods: Five diverse H and N plans clinically delivered at our institution were selected. Isocenter for each plan was shifted positively and negatively in the three cardinal directions by a displacement equal to the PTV expansion on the CTV (3 mm) for a total of six shifted plans per original plan. The perturbed plan dose was recalculated inmore » Eclipse (AAA v11.0.30) using the same, fixed fluence map as the original plan. The dose distributions for all plans were exported from the treatment planning system to determine the worst-case CTV dose distributions for each nominal plan. Two worst-case distributions, cold and hot, were defined by selecting the minimum or maximum dose per voxel from all the perturbed plans. The resulting dose volume histograms (DVH) were examined to evaluate the worst-case CTV and nominal PTV dose distributions. Results: Inspection demonstrates that the CTV DVH in the nominal dose distribution is indeed bounded by the CTV DVHs in the worst-case dose distributions. Furthermore, comparison of the D95% for the worst-case (cold) CTV and nominal PTV distributions by Pearson's chi-square test shows excellent agreement for all plans. Conclusion: The assumption that the nominal dose distribution for PTV represents the worst-case dose distribution for CTV appears valid for the five plans under examination. Although the worst-case dose distributions are unphysical since the dose per voxel is chosen independently, the cold worst-case distribution serves as a lower bound for the worst-case possible CTV coverage. Minor discrepancies between the nominal PTV dose distribution and worst-case CTV dose distribution are expected since the dose cloud is not strictly static. This research was supported by the NCI through grant K25CA168984, by The Lawrence W. and Marilyn W. Matteson Fund for Cancer Research, and by the Fraternal Order of Eagles Cancer Research Fund, the Career Development Award Program at Mayo Clinic.« less

Testing for Additivity in Chemical Mixtures Using a Fixed-Ratio Ray Design and Statistical Equivalence Testing Methods

EPA Science Inventory

Fixed-ratio ray designs have been used for detecting and characterizing interactions of large numbers of chemicals in combination. Single chemical dose-response data are used to predict an “additivity curve” along an environmentally relevant ray. A “mixture curve” is estimated fr...

Development and Prospective Federal State-Wide Evaluation of a Device for Height-Based Dose Recommendations in Prehospital Pediatric Emergencies: A Simple Tool to Prevent Most Severe Drug Errors.

PubMed

Kaufmann, Jost; Roth, Bernhard; Engelhardt, Thomas; Lechleuthner, Alex; Laschat, Michael; Hadamitzky, Christoph; Wappler, Frank; Hellmich, Martin

2018-01-01

Drug dosing errors pose a particular threat to children in prehospital emergency care. With the Pediatric emergency ruler (PaedER), we developed a simple height-based dose recommendation system and evaluated its effectiveness in a pre-post interventional trial as the Ethics Committee disapproved randomization due to the expected positive effect of the PaedER on outcome. Pre-interventional data were retrospectively retrieved from the electronic records and medical protocols of the Cologne Emergency Medical Service over a two-year period prior to the introduction of the PaedER. Post-interventional data were collected prospectively over a six-year period in a federal state-wide open trial. The administered doses of either intravenous or intraosseous fentanyl, midazolam, ketamine or epinephrine were recorded. Primary outcome measure was the number and severity of drug dose deviation from recommended dose (DRD) based on the patient's weight. Fifty-nine pre-interventional and 91 post-interventional prehospital drug administrations in children were analyzed. The rate of DRD > 300% overall medications were 22.0% in the pre- and 2.2% in the post-interventional group (p < 0.001). All administrations of epinephrine occurred excessive (DRD > 300%) in pre-interventional and none in post-interventional patients (p < 0.001). The use of the PaedER resulted in a 90% reduction of medication errors (95% CI: 57% to 98%; p < 0.001) and prevented all potentially life-threatening errors associated with epinephrine administration. There is an urgent need to increase the safety of emergency drug dosing in children during emergencies. A simple height-based system can support health care providers and helps to avoid life-threatening medication errors.

Pre-medication and renal pre-conditioning: a role for alprazolam, atropine, morphine and promethazine.

PubMed

Pazoki-Toroudi, Hamid Reza; Ajami, Marjan; Habibey, Rouhollah

2010-04-01

Four pre-medication drugs are used to relieve pain, allay anxiety, reduce secretion and enhance hypnosis, were evaluated for their effects on ischemia reperfusion (I/R) injury which is one of the major complications of vascular and transplantation surgery. Right kidney was removed from female rats (210-250 g) 3 weeks before surgical procedure. Different doses of morphine (0.5, 2 and 5 mg/kg), promethazine (1, 2 and 5 mg/kg), atropine (0.1, 0.3 and 0.5 mg/kg) and alprazolam (0.08, 0.32 and 0.64 mg/kg) were administered subcutaneously 30 min before left renal artery occlusion and 6 h reperfusion. Left kidneys were processed for histological evaluations. Creatinine and BUN were measured in serum samples. Morphine, promethazine, atropine and alprazolam at all evaluated doses significantly decreased serum creatinine and BUN levels and histopathological scores. The effects of promethazine (1 mg/kg) and all doses of alprazolam were more potent than other pre-medication drugs and doses. This study suggested a protective effect of these pre-medication drugs on I/R injury. Although obvious studies are required, these findings may lead to effective therapies against I/R injury.

Dose-dependent X-ray measurements using a 64×64 hybrid GaAs pixel detector with photon counting

NASA Astrophysics Data System (ADS)

Schwarz, C.; Campbell, M.; Goeppert, R.; Ludwig, J.; Mikulec, B.; Rogalla, M.; Runge, K.; Soeldner-Rembold, A.; Smith, K. M.; Snoeys, W.; Watt, J.

2001-03-01

New developments in medical imaging head towards semiconductor detectors flip-chip bonded to CMOS readout chips. In this work, detectors fabricated on SI-GaAs bulk material were bonded to Photon Counting Chips. This PCC consists of a matrix of 64×64 identical square pixels (170 μm×170 μm) with a 15-bit counter in each cell. We investigated the imaging properties of these detector systems under exposure of a dental X-ray tube. First, a dose calibration of the X-ray tube was performed. Fixed pattern noise in flood exposure images was determined for a fixed dose and an image correction method, which uses a gain map, was applied. For characterising the imaging properties, the signal-to-noise ratio (SNR) was calculated as function of exposure dose. Finally, the dynamic range of the system was estimated. Developed in the framework of the MEDIPIX collaboration: CERN, Universities of Freiburg, Glasgow, Naples and Pisa.

Expert opinion on a flexible extended regimen of drospirenone/ethinyl estradiol contraceptive.

PubMed

Han, Leo; Jensen, Jeffrey T

2014-10-01

Oral contraceptives are often prescribed in extended or continuous forms in order to manage menstrual bleeding and menstrual-related side effects. However, with extended regimens, unscheduled intracycle bleeding can become problematic. Flexible extended dosing of a contraceptive containing drospirenone (DRSP) and ethinyl estradiol (EE) was designed to improve bleeding profiles during extended cycles through active management of bleeding symptoms. We examine the rationale for flexible extended dosing as well as review the dosing regimen. We will focus on the findings of the two most important clinical trials regarding flexible extended DRSP/EE (3 mg/20 μg), including the bleeding profiles of women in those trials. Pharmacology, mechanisms of action, efficacy as well as safety of DRSP containing pills will also be reviewed. Flexible extended dosing of DRSP/EE (3 mg/20 μg) has similar pharmacokinetics and contraceptive efficacy of both conventional and fixed extended regimens. However, it has the added benefit of fewer days of bleeding/spotting compared to conventional and fixed extended regimens.

Variation in the days supply field for osteoporosis medications in Ontario.

PubMed

Burden, Andrea M; Huang, Anjie; Tadrous, Mina; Cadarette, Suzanne M

2013-01-01

We examined pharmacy claims for osteoporosis medications dispensed in the community (78 %) and long-term care (LTC) to determine if days supply values matched expected dosing intervals. Results identify potential reporting errors that can have implications for drug exposure misclassification, particularly in LTC where only 59 % of reported values matched expected values. The days supply field is commonly used to examine patterns of drug utilization and classify drug exposure, yet its accuracy has received little attention. We sought to describe the days supply reported for osteoporosis drugs and examine if values matched expected therapeutic dosing intervals. We examined days supply values for osteoporosis medications submitted to the Ontario Drug Benefits program for seniors, 1997-2011. Days supply values were evaluated by dosing regimen and setting (community or long-term care [LTC]) and compared to pre-defined expected values. We defined expected days supply by the therapeutic dosing interval: daily in 7- or 30-day intervals, or as 100 days; weekly in 7- or 30-day intervals; monthly and daily nasal spray in 28- or 30-day intervals; and cyclical etidronate as a 90-day supply. We identified 17,615,404 osteoporosis prescriptions, with 78 % dispensed in the community. Most daily oral prescriptions were dispensed by an expected therapeutic dosing interval (97 %). Annual IV zoledronic acid was most commonly dispensed as a 1-day supply (62 %). Distinct differences in agreement were observed for other regimens, with the expected days supply more commonly reported in community versus LTC: cyclical etidronate (86 % vs. 40 %), weekly (91 % vs. 60 %), monthly (94 % vs. 35 %), and nasal spray (84 % vs. 40 %). Results suggest that inaccuracies in the days supply field exist, particularly among prescriptions dispensed in LTC. Inaccurate reporting may have significant implications for osteoporosis drug exposure misclassification.

Adenovirus-Associated Virus Vector–Mediated Gene Transfer in Hemophilia B

PubMed Central

Nathwani, Amit C.; Tuddenham, Edward G.D.; Rangarajan, Savita; Rosales, Cecilia; McIntosh, Jenny; Linch, David C.; Chowdary, Pratima; Riddell, Anne; Pie, Arnulfo Jaquilmac; Harrington, Chris; O’Beirne, James; Smith, Keith; Pasi, John; Glader, Bertil; Rustagi, Pradip; Ng, Catherine Y.C.; Kay, Mark A.; Zhou, Junfang; Spence, Yunyu; Morton, Christopher L.; Allay, James; Coleman, John; Sleep, Susan; Cunningham, John M.; Srivastava, Deokumar; Basner-Tschakarjan, Etiena; Mingozzi, Federico; High, Katherine A.; Gray, John T.; Reiss, Ulrike M.; Nienhuis, Arthur W.; Davidoff, Andrew M.

2012-01-01

BACKGROUND Hemophilia B, an X-linked disorder, is ideally suited for gene therapy. We investigated the use of a new gene therapy in patients with the disorder. METHODS We infused a single dose of a serotype-8–pseudotyped, self-complementary adenovirus-associated virus (AAV) vector expressing a codon-optimized human factor IX (FIX) transgene (scAAV2/8-LP1-hFIXco) in a peripheral vein in six patients with severe hemophilia B (FIX activity, <1% of normal values). Study participants were enrolled sequentially in one of three cohorts (given a high, intermediate, or low dose of vector), with two participants in each group. Vector was administered without immunosuppressive therapy, and participants were followed for 6 to 16 months. RESULTS AAV-mediated expression of FIX at 2 to 11% of normal levels was observed in all participants. Four of the six discontinued FIX prophylaxis and remained free of spontaneous hemorrhage; in the other two, the interval between prophylactic injections was increased. Of the two participants who received the high dose of vector, one had a transient, asymptomatic elevation of serum aminotransferase levels, which was associated with the detection of AAV8-capsid–specific T cells in the peripheral blood; the other had a slight increase in liver-enzyme levels, the cause of which was less clear. Each of these two participants received a short course of glucocorticoid therapy, which rapidly normalized aminotransferase levels and maintained FIX levels in the range of 3 to 11% of normal values. CONCLUSIONS Peripheral-vein infusion of scAAV2/8-LP1-hFIXco resulted in FIX transgene expression at levels sufficient to improve the bleeding phenotype, with few side effects. Although immune-mediated clearance of AAV-transduced hepatocytes remains a concern, this process may be controlled with a short course of glucocorticoids without loss of transgene expression. (Funded by the Medical Research Council and others; ClinicalTrials.gov number, NCT00979238.) PMID:22149959

Influence of beam efficiency through the patient-specific collimator on secondary neutron dose equivalent in double scattering and uniform scanning modes of proton therapy.

PubMed

Hecksel, D; Anferov, V; Fitzek, M; Shahnazi, K

2010-06-01

Conventional proton therapy facilities use double scattering nozzles, which are optimized for delivery of a few fixed field sizes. Similarly, uniform scanning nozzles are commissioned for a limited number of field sizes. However, cases invariably occur where the treatment field is significantly different from these fixed field sizes. The purpose of this work was to determine the impact of the radiation field conformity to the patient-specific collimator on the secondary neutron dose equivalent. Using a WENDI-II neutron detector, the authors experimentally investigated how the neutron dose equivalent at a particular point of interest varied with different collimator sizes, while the beam spreading was kept constant. The measurements were performed for different modes of dose delivery in proton therapy, all of which are available at the Midwest Proton Radiotherapy Institute (MPRI): Double scattering, uniform scanning delivering rectangular fields, and uniform scanning delivering circular fields. The authors also studied how the neutron dose equivalent changes when one changes the amplitudes of the scanned field for a fixed collimator size. The secondary neutron dose equivalent was found to decrease linearly with the collimator area for all methods of dose delivery. The relative values of the neutron dose equivalent for a collimator with a 5 cm diameter opening using 88 MeV protons were 1.0 for the double scattering field, 0.76 for rectangular uniform field, and 0.6 for the circular uniform field. Furthermore, when a single circle wobbling was optimized for delivery of a uniform field 5 cm in diameter, the secondary neutron dose equivalent was reduced by a factor of 6 compared to the double scattering nozzle. Additionally, when the collimator size was kept constant, the neutron dose equivalent at the given point of interest increased linearly with the area of the scanned proton beam. The results of these experiments suggest that the patient-specific collimator is a significant contributor to the secondary neutron dose equivalent to a distant organ at risk. Improving conformity of the radiation field to the patient-specific collimator can significantly reduce secondary neutron dose equivalent to the patient. Therefore, it is important to increase the number of available generic field sizes in double scattering systems as well as in uniform scanning nozzles.

Recommendations for the use of radiotherapy in nodal lymphoma.

PubMed

Hoskin, P J; Díez, P; Williams, M; Lucraft, H; Bayne, M

2013-01-01

These guidelines have been developed to define the use of radiotherapy for lymphoma in the current era of combined modality treatment taking into account increasing concern over the late side-effects associated with previous radiotherapy. The role of reduced volume and reduced doses is addressed, integrating modern imaging with three-dimensional planning and advanced techniques of treatment delivery. Both wide-field and involved-field techniques have now been supplanted by the use of defined volumes based on node involvement shown on computed tomography (CT) and positron emission tomography (PET) imaging and applying the International Commission on Radiation Units and Measurements concepts of gross tumour volume (GTV), clinical target volume (CTV) and planning target volume (PTV). The planning of lymphoma patients for radical radiotherapy should now be based upon contrast enhanced 3 mm contiguous CT with three-dimensional definition of volumes using the convention of GTV, CTV and PTV. The involved-site radiotherapy concept defines the CTV based on the PET-defined pre-chemotherapy sites of involvement with an expansion in the cranio-caudal direction of lymphatic spread by 1.5 cm, constrained to tissue planes such as bone, muscle and air cavities. The margin allows for uncertainties in PET resolution, image registration and changes in patient positioning and shape. There is increasing evidence in both Hodgkin and non-Hodgkin lymphoma that traditional doses are higher than necessary for disease control and related to the incidence of late effects. No more than 30 Gy for Hodgkin and aggressive non-Hodgkin lymphoma and 24 Gy for indolent lymphomas is recommended; lower doses of 20 Gy in combination therapy for early-stage low-risk Hodgkin lymphoma may be sufficient. As yet there are no large datasets validating the use of involved-site radiotherapy; these will emerge from the current generation of clinical trials. Radiotherapy remains the most effective single modality in the treatment of lymphoma. A reduction in both treatment volume and overall treatment dose should now be considered to minimise the risks of late sequelae. However, it is important that this is not at the expense of the excellent disease control currently achieved. Copyright © 2012 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.

Evaluation of the quality and shelf life of gamma irradiated blueberries by quarantine purposes

NASA Astrophysics Data System (ADS)

Lires, Carla M. L.; Docters, Andrea; Horak, Celina I.

2018-02-01

Fresh blueberries (Vaccinium spp.) are considered one of the richest sources of phenolic compounds and are appreciated for their high antioxidant capacity. But they are hosts in Argentina of the quarantine pests Ceratitis capitata and Anastrepha fraterculus, and have to be treated to avoid its spreading. Irradiation is being introduced in the Agricultural World trade, increasing exponentially on the last years. In order to guarantee the success of this process, it is required previous to the rutinary treatment, to define the irradiation dose range to be applied. The minimum dose for these pests has been already approved in the IPPC standard 28. The maximum dose depends on the tolerance of the fruit cultivars, maturity, pre-harvest conditions, harvest time, storage conditions, and interactions among these factors. The postharvest quality of Argentina´s blueberry treated with irradiation doses of 150 (generic quarantine dose used for fruit flies) and 300 Gy (to evaluate tolerance) was evaluated. The studies included blueberries from different harvest seasons 2009-2012). Misty, O'Neal and Emeral varieties were chosen, because they represent the biggest volume of exported blueberry from Argentina. The results indicated that irradiation at 150 Gy and 300 Gy did not significantly affect the postharvest quality and slightly improved shelf life of the different blueberries varieties. Therefore, it is possible to use irradiation as an alternative quarantine treatment for Argentina´s blueberries, establishing a dose range appropriate to be applied on a commercial irradiation facility.

Lesinurad for the treatment of hyperuricaemia in people with gout.

PubMed

Robinson, Philip C; Dalbeth, Nicola

2017-12-01

Gout is a common form of inflammatory arthritis caused by deposition of monosodium urate crystals. The central strategy for effective long-term management of gout is serum urate lowering. Current urate-lowering drugs include both xanthine oxidase inhibitors and uricosuric agents. Lesinurad is a URAT1 inhibitor that selectively inhibits urate rebsorption at the proximal renal tubule. Lesinurad 200mg daily in combination with a xanthine oxidase is approved for urate-lowering therapy in patients with gout. Areas covered: The published literature was searched using Pubmed and additional information was obtained from publically available regulatory documents. Pre-clinical data and clinical trials of lesinurad are described. Serum urate-lowering efficacy and effects on other clinical endpoints are discussed. Adverse event data, focusing on renal safety are also presented. Expert opinion: Lesinurad is an effective urate-lowering drug that has a generally acceptable safety profile when used at 200mg daily dosing in combination with a xanthine oxidase inhibitor. The recent approval of fixed dose combination pills of lesinurad with allopurinol is an important step in improving adherence and reducing risk of renal adverse events. It remains to be seen if this therapy will provide additional benefit for gout management above improved use of widely available generic therapies.

Prescription of fixed dose combination drugs for diarrhoea.

PubMed

Chakrabarti, Amit

2007-01-01

Fixed-dose combinations (FDCs) of an antiprotozoal and an antibacterial, for treatment of diarrhoea, have been available in the Indian pharmaceutical market for about a decade. There is little evidence to substantiate this combination therapy. We evaluated 2,163 physician prescriptions for diarrhoea and found that 59 per cent of prescriptions were for FDCs. This is unethical because prescribing such combinations exposes a patient to higher risks of adverse drug reactions and also increases the chances of drug resistance. Physicians' prescribing practices in India are influenced by socioeconomic factors and the pharmaceutical industry's marketing techniques that include giving incentives to physicians to prescribe certain drugs.

Tramadol/Paracetamol Fixed-Dose Combination for Chronic Pain Management in Family Practice: A Clinical Review

PubMed Central

Morón Merchante, Ignacio; Pergolizzi, Joseph V.; van de Laar, Mart; Mellinghoff, Hans-Ulrich; O'Brien, Joanne; Perrot, Serge; Raffa, Robert B.

2013-01-01

The family practitioner plays an important role in the prevention, diagnosis, and early management of chronic pain. He/she is generally the first to be consulted, the one most familiar with the patients and their medical history, and is likely the first to be alerted in case of inadequate pain control or safety and tolerability issues. The family practitioner should therefore be at the center of the multidisciplinary team involved in a patient's pain management. The most frequent indications associated with chronic pain in family practice are of musculoskeletal origin, and the pain is often multimechanistic. Fixed-dose combination analgesics combine compounds with different mechanisms of action; their broader analgesic spectrum and potentially synergistic analgesic efficacy and improved benefit/risk ratio might thus be useful. A pain specialist meeting held in November 2010 agreed that the fixed-dose combination tramadol/paracetamol might be a useful pharmacological option for chronic pain management in family practice. The combination is effective in a variety of pain conditions with generally good tolerability. Particularly in elderly patients, it might be considered as an alternative to conventional analgesics such as NSAIDs, which should be used rarely with caution in this population. PMID:24959571

Pre-Service Teachers' Mindset Beliefs about Student Ability

ERIC Educational Resources Information Center

Gutshall, C. Anne

2014-01-01

Introduction: We all have beliefs about our ability or intelligence. The extent to which we believe ability is malleable (growth) or stable (fixed) is commonly referred to as our mindset. This research is designed to explore pre-service teachers' mindset beliefs as well as their beliefs when applied to hypothetical student scenarios. Method:…

Development of a pharmacokinetic-guided dose individualization strategy for hydroxyurea treatment in children with sickle cell anaemia.

PubMed

Dong, Min; McGann, Patrick T; Mizuno, Tomoyuki; Ware, Russell E; Vinks, Alexander A

2016-04-01

Hydroxyurea has emerged as the primary disease-modifying therapy for patients with sickle cell anaemia (SCA). The laboratory and clinical benefits of hydroxyurea are optimal at maximum tolerated dose (MTD), but the current empirical dose escalation process often takes up to 12 months. The purpose of this study was to develop a pharmacokinetic-guided dosing strategy to reduce the time required to reach hydroxyurea MTD in children with SCA. Pharmacokinetic (PK) data from the HUSTLE trial (NCT00305175) were used to develop a population PK model using non-linear mixed effects modelling (nonmem 7.2). A D-optimal sampling strategy was developed to estimate individual PK and hydroxyurea exposure (area under the concentration-time curve (AUC)). The initial AUC target was derived from HUSTLE clinical data and defined as the mean AUC at MTD. PK profiles were best described by a one compartment with Michaelis-Menten elimination and a transit absorption model. Body weight and cystatin C were identified as significant predictors of hydroxyurea clearance. The following clinically feasible sampling times are included in a new prospective protocol: pre-dose (baseline), 15-20 min, 50-60 min and 3 h after an initial 20 mg kg(-1) oral dose. The mean target AUC(0,∞) for initial dose titration was 115 mg l(-1)  h. We developed a PK model-based individualized dosing strategy for the prospective Therapeutic Response Evaluation and Adherence Trial (TREAT, ClinicalTrials.gov NCT02286154). This approach has the potential to optimize the dose titration of hydroxyurea therapy for children with SCA, such that the clinical benefits at MTD are achieved more quickly. © 2015 The British Pharmacological Society.

Influence of different treatment techniques on radiation dose to the LAD coronary artery

PubMed Central

Nieder, Carsten; Schill, Sabine; Kneschaurek, Peter; Molls, Michael

2007-01-01

Background The purpose of this proof-of-principle study was to test the ability of an intensity-modulated radiotherapy (IMRT) technique to reduce the radiation dose to the heart plus the left ventricle and a coronary artery. Radiation-induced heart disease might be a serious complication in long-term cancer survivors. Methods Planning CT scans from 6 female patients were available. They were part of a previous study of mediastinal IMRT for target volumes used in lymphoma treatment that included 8 patients and represent all cases where the left anterior descending coronary artery (LAD) could be contoured. We compared 6 MV AP/PA opposed fields to a 3D conformal 4-field technique and an optimised 7-field step-and-shoot IMRT technique and evaluated DVH's for several structures. The planning system was BrainSCAN 5.21 (BrainLAB, Heimstetten, Germany). Results IMRT maintained target volume coverage but resulted in better dose reduction to the heart, left ventricle and LAD than the other techniques. Selective dose reduction could be accomplished, although not to the degree initially attempted. The median LAD dose was approximately 50% lower with IMRT. In 5 out of 6 patients, IMRT was the best technique with regard to heart sparing. Conclusion IMRT techniques are able to reduce the radiation dose to the heart. In addition to dose reduction to whole heart, individualised dose distributions can be created, which spare, e.g., one ventricle plus one of the coronary arteries. Certain patients with well-defined vessel pathology might profit from an approach of general heart sparing with further selective dose reduction, accounting for the individual aspects of pre-existing damage. PMID:17547777

Are Radiation Therapy Oncology Group Para-aortic Contouring Guidelines for Pancreatic Neoplasm Applicable to Other Malignancies—Assessment of Nodal Distribution in Gynecological Malignancies

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

Kabolizadeh, Peyman; Fulay, Suyash; Beriwal, Sushil, E-mail: beriwals@upmc.edu

Purpose: Intensity modulated radiation therapy is used to reduce dose to adjacent critical structures while maintaining adequate target coverage, but it requires precise target localization. We report the 3-dimensional distribution of para-aortic (PA) lymph nodes (LN) in pelvic malignancies. We propose a guideline to accurately define the PA LN by anatomic landmarks and compare our data with published guidelines for pancreatic cancer. Methods and Materials: A retrospective analysis was performed on 46 patients with pelvic malignancies and positive PA LNs. Positive LNs were defined based on size and morphology or fluorodeoxyglucose avidity. All PA LNs were characterized into 3 groupsmore » based on location: left PA (between aorta and left psoas muscle), aortocaval (between aorta and inferior vena cava), and right paracaval (between inferior vena cava and right psoas muscle). Patients with retrocrural LNs were also analyzed. Results: One hundred thirty-three positive PA LNs were evaluated. The majority of the PA LNs were in the left PA (59%) and aortocaval (35) regions, and only 8% were in the right paracaval region. All patients with positive right paracaval LNs also had involved left PA LNs, with only 1 exception. The highest PA LN involvement was at the level of the renal vessels and was seen in 28% of patients. Of these patients with disease extending to renal vessels, 38% had retrocrural LN involvement. Conclusions: The nodal contouring for the PA region should not be defined by a fixed circumferential margin around the vessels. The left PA and aortocaval spaces should be covered adequately because these are common locations of PA LNs. For microscopic disease superiorly, contouring should extend up to renal vessels rather than a fixed bony landmark. For patients who have nodal involvement at renal vessels, one can consider including retrocrural LNs. Radiation Therapy Oncology Group Para-aortic Contouring Guidelines for Pancreatic Neoplasm are not applicable to gynecological malignancies.« less

Optimization of the strength of the efavirenz/lamivudine/abacavir fixed-dose combination for paediatric patients.

PubMed

Bouazza, Naïm; Cressey, Tim R; Foissac, Frantz; Bienczak, Andrzej; Denti, Paolo; McIlleron, Helen; Burger, David; Penazzato, Martina; Lallemant, Marc; Capparelli, Edmund V; Treluyer, Jean-Marc; Urien, Saïk

2017-02-01

Child-friendly, low-cost, solid, oral fixed-dose combinations (FDCs) of efavirenz with lamivudine and abacavir are urgently needed to improve clinical management and drug adherence for children. Data were pooled from several clinical trials and therapeutic drug monitoring datasets from different countries. The number of children/observations was 505/3667 for efavirenz. Population pharmacokinetic analyses were performed using a non-linear mixed-effects approach. For abacavir and lamivudine, data from 187 and 920 subjects were available (population pharmacokinetic models previously published). Efavirenz/lamivudine/abacavir FDC strength options assessed were (I) 150/75/150, (II) 120/60/120 and (III) 200/100/200 mg. Monte Carlo simulations of the different FDC strengths were performed to determine the optimal dose within each of the WHO weight bands based on drug efficacy/safety targets. The probability of being within the target efavirenz concentration range 12 h post-dose (1-4 mg/L) varied between 56% and 60%, regardless of FDC option. Option I provided a best possible balance between efavirenz treatment failure and toxicity risks. For abacavir and lamivudine, simulations showed that for option I >75% of subjects were above the efficacy target. According to simulations, a paediatric efavirenz/lamivudine/abacavir fixed-dose formulation of 150 mg efavirenz, 75 mg lamivudine and 150 mg abacavir provided the most effective and safe concentrations across WHO weight bands, with the flexibility of dosage required across the paediatric population. © The Author 2016. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

Development and testing of an algorithm for efficient resource positioning in pre-hospital emergency care.

PubMed

Saini, Devashish; Mazza, Giovanni; Shah, Najaf; Mirza, Muzna; Gori, Mandar M; Nandigam, Hari Krishna; Orthner, Helmuth F

2006-01-01

Response times for pre-hospital emergency care may be improved with the use of algorithms that analyzes historical patterns in incident location and suggests optimal places for pre-positioning of emergency response units. We will develop such an algorithm based on cluster analysis and test whether it leads to significant improvement in mileage when compared to actual historical data of dispatching based on fixed stations.

Pre-operative combined 5-FU, low dose leucovorin, and sequential radiation therapy for unresectable rectal cancer

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

Minsky, B.D.; Cohen, A.M.; Kemeny, N.

1993-04-02

The authors performed a Phase 1 trial to determine the maximum tolerated dose of combined pre-operative radiation (5040 cGy) and 2 cycles (bolus daily [times] 5) of 5-FU and low dose LV (20 mg/m2), followed by surgery and 10 cycles of post-operative LV/5-FU in patients with unresectable primary or recurrent rectal cancer. Twelve patients were entered. The initial dose of 5-FU was 325 mg/m2. 5-FU was to be escalated while the LV remained constant at 20 mg/m2. Chemotherapy began on day 1 and radiation on day 8. The post-operative chemotherapy was not dose escalated; 5-FU: 425 mg/m2 and LV: 20more » mg/m2. The median follow-up was 14 months (7--16 months). Following pre-operative therapy, the resectability rate with negative margins was 91% and the pathologic complete response rate was 9%. For the combined modality segment (preoperative) the incidence of any grade 3+ toxicity was diarrhea: 17%, dysuria: 8%, mucositis: 8%, and erythema: 8%. The median nadir counts were WBC: 3.1, HGB: 8.8, and PLT: 153000. The maximum tolerated dose of 5-FU for pre-operative combined LV/5-FU/RT was 325 mg/m2 with no escalation possible. Therefore, the recommended dose was less than 325 mg/m2. Since adequate doses of 5-FU to treat systemic disease could not be delivered until at least 3 months (cycle 3) following the start of therapy, the authors do not recommend that this 5-FU, low dose LV, and sequential radiation therapy regimen be used as presently designed. However, given the 91% resectability rate they remain encouraged with this approach. 31 refs., 1 fig., 2 tabs.« less

Predictive models of poly(ethylene-terephthalate) film degradation under multi-factor accelerated weathering exposures

PubMed Central

Ngendahimana, David K.; Fagerholm, Cara L.; Sun, Jiayang; Bruckman, Laura S.

2017-01-01

Accelerated weathering exposures were performed on poly(ethylene-terephthalate) (PET) films. Longitudinal multi-level predictive models as a function of PET grades and exposure types were developed for the change in yellowness index (YI) and haze (%). Exposures with similar change in YI were modeled using a linear fixed-effects modeling approach. Due to the complex nature of haze formation, measurement uncertainty, and the differences in the samples’ responses, the change in haze (%) depended on individual samples’ responses and a linear mixed-effects modeling approach was used. When compared to fixed-effects models, the addition of random effects in the haze formation models significantly increased the variance explained. For both modeling approaches, diagnostic plots confirmed independence and homogeneity with normally distributed residual errors. Predictive R2 values for true prediction error and predictive power of the models demonstrated that the models were not subject to over-fitting. These models enable prediction under pre-defined exposure conditions for a given exposure time (or photo-dosage in case of UV light exposure). PET degradation under cyclic exposures combining UV light and condensing humidity is caused by photolytic and hydrolytic mechanisms causing yellowing and haze formation. Quantitative knowledge of these degradation pathways enable cross-correlation of these lab-based exposures with real-world conditions for service life prediction. PMID:28498875

Lack of asthma and rhinitis control in general practitioner-managed patients prescribed fixed-dose combination therapy in Australia.

PubMed

Bosnic-Anticevich, Sinthia; Kritikos, Vicky; Carter, Victoria; Yan, Kwok Yin; Armour, Carol; Ryan, Dermot; Price, David

2018-06-01

The first aim of the study (i) assess the current asthma status of general-practitioner-managed patients receiving regular fixed-dose combination inhaled corticosteroid and long-acting beta 2 agonist (FDC ICS/LABA) therapy and (ii) explore patients' perceptions of asthma control and attitudes/behaviors regarding preventer inhaler use. A cross-sectional observational study of Australian adults with a current physician diagnosis of asthma receiving ≥2 prescriptions of FDC ICS/LABA therapy in the previous year, who were recruited through general practice to receive a structured in-depth asthma review between May 2012 and January 2014. Descriptive statistics and Chi-Square tests for independence were used for associations across asthma control levels. Only 11.5% of the patients had controlled asthma based on guideline-defined criteria. Contrarily, 66.5% of the patients considered their asthma to be well controlled. Incidence of acute asthma exacerbations in the previous year was 26.5% and 45.6% of the patients were without a diagnosis of rhinitis. Asthma medication use and inhaler technique were sub-optimal; only 41.0% of the preventer users reported everyday use. The side effects of medication were common and more frequently reported among uncontrolled and partially controlled patients. The study revealed the extent to which asthma management needs to be improved in this patient cohort and the numerous unmet needs regarding the current state of asthma care. Not only there is a need for continuous education of patients, but also education of health care practitioners to better understand the way in which patient's perceptions impact on asthma management practices, incorporating these findings into clinical decision making.

Estimating statistical uncertainty of Monte Carlo efficiency-gain in the context of a correlated sampling Monte Carlo code for brachytherapy treatment planning with non-normal dose distribution.

PubMed

Mukhopadhyay, Nitai D; Sampson, Andrew J; Deniz, Daniel; Alm Carlsson, Gudrun; Williamson, Jeffrey; Malusek, Alexandr

2012-01-01

Correlated sampling Monte Carlo methods can shorten computing times in brachytherapy treatment planning. Monte Carlo efficiency is typically estimated via efficiency gain, defined as the reduction in computing time by correlated sampling relative to conventional Monte Carlo methods when equal statistical uncertainties have been achieved. The determination of the efficiency gain uncertainty arising from random effects, however, is not a straightforward task specially when the error distribution is non-normal. The purpose of this study is to evaluate the applicability of the F distribution and standardized uncertainty propagation methods (widely used in metrology to estimate uncertainty of physical measurements) for predicting confidence intervals about efficiency gain estimates derived from single Monte Carlo runs using fixed-collision correlated sampling in a simplified brachytherapy geometry. A bootstrap based algorithm was used to simulate the probability distribution of the efficiency gain estimates and the shortest 95% confidence interval was estimated from this distribution. It was found that the corresponding relative uncertainty was as large as 37% for this particular problem. The uncertainty propagation framework predicted confidence intervals reasonably well; however its main disadvantage was that uncertainties of input quantities had to be calculated in a separate run via a Monte Carlo method. The F distribution noticeably underestimated the confidence interval. These discrepancies were influenced by several photons with large statistical weights which made extremely large contributions to the scored absorbed dose difference. The mechanism of acquiring high statistical weights in the fixed-collision correlated sampling method was explained and a mitigation strategy was proposed. Copyright © 2011 Elsevier Ltd. All rights reserved.

Low-Dose Carcinogenicity Studies

EPA Science Inventory

One of the major deficiencies of cancer risk assessments is the lack of low-dose carcinogenicity data. Most assessments require extrapolation from high to low doses, which is subject to various uncertainties. Only 4 low-dose carcinogenicity studies and 5 low-dose biomarker/pre-n...

Optimizing fluorescently tethered Hsp90 inhibitor dose for maximal specific uptake by breast tumors

NASA Astrophysics Data System (ADS)

Crouch, Brian T.; Duer, Joy; Wang, Roujia; Gallagher, Jennifer; Hall, Allison; Soo, Mary Scott; Hughes, Philip; Haystead, Timothy A. J.; Ramanujam, Nirmala

2018-03-01

Despite improvements in surgical resection, 20-40% of patients undergoing breast conserving surgery require at least one additional re-excision. Leveraging the unique surface expression of heat shock protein 90 (Hsp90), a chaperone protein involved in several key hallmarks of cancer, in breast cancer provides an exciting opportunity to identify residual disease during surgery. We developed a completely non-destructive strategy using HS-27, a fluorescently-tethered Hsp90 inhibitor, to assay surface Hsp90 expression on intact tissue specimens using a fluorescence microendoscope with a field of view of 750 μm and subcellular resolution of 4 μm. HS-27 consists of an FDA approved Hsp90 inhibitor tethered to fluorescein isothiocyanate (EX 488nm, EM 525nm). Here, we optimized ex vivo HS-27 administration in pre-clinical breast cancer models and validated our approach on 21 patients undergoing standard of care ultrasound guided core needle biopsy. HS-27 administration time was fixed at 1- minute to minimize imaging impact on clinical workflow. HS-27 and HS-217 (non-specific control) doses were modulated from 1 μM up to 100 μM to identify the dose maximizing the ratio of specific uptake (HS-27 fluorescence) to non-specific uptake (HS-217 fluorescence). The specificity ratio was maximized at 100 μM and was significantly greater than all other doses (p<0.05). We applied our optimized imaging protocol to clinical samples and demonstrated significantly greater uptake of HS-27 by tumor than non-tumor tissue (p<0.05). The ubiquitous nature of HS-27 binding to all subtypes of breast cancer makes this technology attractive for assessing tumor margins, as one agent can be used for all subtypes.

SU-F-T-132: Variable RBE Models Predict Possible Underestimation of Vaginal Dose for Anal Cancer Patients Treated Using Single-Field Proton Treatments

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

McNamara, A; Underwood, T; Wo, J

2016-06-15

Purpose: Anal cancer patients treated using a posterior proton beam may be at risk of vaginal wall injury due to the increased linear energy transfer (LET) and relative biological effectiveness (RBE) at the beam distal edge. We investigate the vaginal dose received. Methods: Five patients treated for anal cancer with proton pencil beam scanning were considered, all treated to a prescription dose of 54 Gy(RBE) over 28–30 fractions. Dose and LET distributions were calculated using the Monte Carlo simulation toolkit TOPAS. In addition to the standard assumption of a fixed RBE of 1.1, variable RBE was considered via the applicationmore » of published models. Dose volume histograms (DVHs) were extracted for the planning treatment volume (PTV) and vagina, the latter being used to calculate the vaginal normal tissue complication probability (NTCP). Results: Compared to the assumption of a fixed RBE of 1.1, the variable RBE model predicts a dose increase of approximately 3.3 ± 1.7 Gy at the end of beam range. NTCP parameters for the vagina are incomplete in the current literature, however, inferring value ranges from the existing data we use D{sub 50} = 50 Gy and LKB model parameters a=1–2 and m=0.2–0.4. We estimate the NTCP for the vagina to be 37–48% and 42–47% for the fixed and variable RBE cases, respectively. Additionally, a difference in the dose distribution was observed between the analytical calculation and Monte Carlo methods. We find that the target dose is overestimated on average by approximately 1–2%. Conclusion: For patients treated with posterior beams, the vaginal wall may coincide with the distal end of the proton beam and may receive a substantial increase in dose if variable RBE models are applied compared to using the current clinical standard of RBE equal to 1.1. This could potentially lead to underestimating toxicities when treating with protons.« less

Examination of a Method to Determine the Reference Region for Calculating the Specific Binding Ratio in Dopamine Transporter Imaging.

PubMed

Watanabe, Ayumi; Inoue, Yusuke; Asano, Yuji; Kikuchi, Kei; Miyatake, Hiroki; Tokushige, Takanobu

2017-01-01

The specific binding ratio (SBR) was first reported by Tossici-Bolt et al. for quantitative indicators for dopamine transporter (DAT) imaging. It is defined as the ratio of the specific binding concentration of the striatum to the non-specific binding concentration of the whole brain other than the striatum. The non-specific binding concentration is calculated based on the region of interest (ROI), which is set 20 mm inside the outer contour, defined by a threshold technique. Tossici-Bolt et al. used a 50% threshold, but sometimes we couldn't define the ROI of non-specific binding concentration (reference region) and calculate SBR appropriately with a 50% threshold. Therefore, we sought a new method for determining the reference region when calculating SBR. We used data from 20 patients who had undergone DAT imaging in our hospital, to calculate the non-specific binding concentration by the following methods, the threshold to define a reference region was fixed at some specific values (the fixing method) and reference region was visually optimized by an examiner at every examination (the visual optimization method). First, we assessed the reference region of each method visually, and afterward, we quantitatively compared SBR calculated based on each method. In the visual assessment, the scores of the fixing method at 30% and visual optimization method were higher than the scores of the fixing method at other values, with or without scatter correction. In the quantitative assessment, the SBR obtained by visual optimization of the reference region, based on consensus of three radiological technologists, was used as a baseline (the standard method). The values of SBR showed good agreement between the standard method and both the fixing method at 30% and the visual optimization method, with or without scatter correction. Therefore, the fixing method at 30% and the visual optimization method were equally suitable for determining the reference region.

Transforce lingual appliances pre-adjusted invisible appliances simplify treatment.

PubMed

Clark, William John

2011-01-01

Transforce lingual appliances are designed to be used in conjunction with conventional fixed appliances. Lingual arch development is normally followed by bonded fixed appliances to detail the occlusion. Alternatively Transforce appliance treatment is an efficient method of preparing complex malocclusions prior to a finishing stage with invisible appliances. This approach is ideal for adult treatment, using light continuous forces for arch development with appliances that are comfortable to wear. Sagittal and Transverse appliances are designed for arch development in a range of sizes for contracted arches. They can be used to treat all classes of malocclusion and are pre-adjusted fixed/removable devices for non-compliance treatment. Force modules with nickel titanium coil springs enclosed in a tube deliver a gentle, biocompatible continuous force with a long range of action. They are excellent for mixed dentition and ideal for adult arch development. There are multiple sizes for upper and lower arch development and a sizing chart may be placed over a study model for correct selection, eliminating the need for laboratory work.

Seating type and cognitive performance after 3 hours travel by high-speed boat in sea states 2-3.

PubMed

McMorris, Terry; Myers, Stephen; Dobbins, Trevor; Hall, Ben; Dyson, Rosemary

2009-01-01

Transit in high-speed marine craft subjects occupants to a rough ride as the boat impacts the waves. This induces high levels of physical stress, which may inhibit cognitive performance during military operations and life-saving activities. Land-based research suggests that suspension seats reduce vibration and, therefore, stress. We hypothesized that subjects using suspension seats would demonstrate better cognitive performance, lower perceptions of exertion, fatigue, and sleepiness, and lower salivary concentrations of cortisol than those using fixed seats. Subjects, naval personnel, were divided into fixed (N = 6) and suspension seat (N = 6) groups. Subjects undertook forward and backward number recall and random number generation tests pre- and post-transit (3 h in sea states 2-3). Salivary cortisol concentrations were sampled pre- (1100 h) and post-transit (1700 h) and at the same times on a control day. Post-transit perceptions of exertion, fatigue, and sleepiness were measured subjectively. The suspension seat group demonstrated better performance post-transit than the fixed seat group for forward number recall and showed a significant pre- to post-transit improvement in backward number recall. The suspension seat group reported less fatigue and sleepiness. The suspension seat group had significantly higher salivary cortisol concentrations than the fixed seat group post-transit. Regression analyses found a quadratic correlation between delta cortisol concentrations and delta random number generation scores (R2 = 0.68). Results show that the use of suspension seats during transit in high-speed marine craft may be advantageous with regard to cognitive performance.

Fabrication of high quality aspheric microlens array by dose-modulated lithography and surface thermal reflow

NASA Astrophysics Data System (ADS)

Huang, Shengzhou; Li, Mujun; Shen, Lianguan; Qiu, Jinfeng; Zhou, Youquan

2018-03-01

A novel fabrication method for high quality aspheric microlens array (MLA) was developed by combining the dose-modulated DMD-based lithography and surface thermal reflow process. In this method, the complex shape of aspheric microlens is pre-modeled via dose modulation in a digital micromirror device (DMD) based maskless projection lithography. And the dose modulation mainly depends on the distribution of exposure dose of photoresist. Then the pre-shaped aspheric microlens is polished by a following non-contact thermal reflow (NCTR) process. Different from the normal process, the reflow process here is investigated to improve the surface quality while keeping the pre-modeled shape unchanged, and thus will avoid the difficulties in generating the aspheric surface during reflow. Fabrication of a designed aspheric MLA with this method was demonstrated in experiments. Results showed that the obtained aspheric MLA was good in both shape accuracy and surface quality. The presented method may be a promising approach in rapidly fabricating high quality aspheric microlens with complex surface.

Anxiolytic effects of a combination of Melissa officinalis and Valeriana officinalis during laboratory induced stress.

PubMed

Kennedy, David O; Little, Wendy; Haskell, Crystal F; Scholey, Andrew B

2006-02-01

Melissa officinalis (lemon balm) and Valeriana officinalis (valerian) have been used both traditionally and contemporaneously as mild sedatives, anxiolytics and hypnotics. Recent research has suggested that both may attenuate laboratory induced stress. As the two herbs are most often sold in combination with each other the current study assessed the anxiolytic properties of such a combination during laboratory-induced stress. In this double-blind, placebo-controlled, randomized, balanced cross-over experiment, 24 healthy volunteers received three separate single doses (600 mg, 1200 mg, 1800 mg) of a standardized product containing M. officinalis and V. officinalis extracts, plus a placebo, on separate days separated by a 7 day wash out period. Modulation of mood and anxiety were assessed during pre-dose and 1 h, 3 h and 6 h post-dose completions of a 20 min version of the Defined Intensity Stressor Simulation (DISS) battery. Cognitive performance on the four concurrent tasks of the battery was also assessed. The results showed that the 600 mg dose of the combination ameliorated the negative effects of the DISS on ratings of anxiety. However, the highest dose (1800 mg) showed an increase in anxiety that was less marked but which reached significance during one testing session. In addition, all three doses led to decrements in performance on the Stroop task module within the battery, and the two lower doses led to decrements on the overall score generated on the DISS battery. These results suggest that a combination of Melissa officinalis and Valeriana officinalis possesses anxiolytic properties that deserve further investigation. Copyright 2006 John Wiley & Sons, Ltd.

Mercaptopurine metabolite levels are predictors of bone marrow toxicity following high-dose methotrexate therapy of childhood acute lymphoblastic leukaemia.

PubMed

Vang, Sophia Ingeborg; Schmiegelow, Kjeld; Frandsen, Thomas; Rosthøj, Susanne; Nersting, Jacob

2015-05-01

High-dose methotrexate (HD-MTX) courses with concurrent oral low-dose MTX/6-mercaptopurine (6MP) for childhood acute lymphoblastic leukaemia (ALL) are often followed by neutro- and thrombocytopenia necessitating treatment interruptions. Plasma MTX during HD-MTX therapy guides folinic acid rescue to prevent toxicities, but myelosuppression can also be prevented by pre-HD-MTX 6MP dose reductions. Accordingly, we monitored pre-HD-MTX erythrocyte levels of methylated 6MP metabolites (Ery-MeMP) and of thioguanine nucleotides (Ery-6TGN) as well as DNA-incorporated thioguanine nucleotides (DNA-TGN) in circulating leucocytes to identify patients at highest risk of post-HD-MTX myelosuppression. In multiple linear regression analyses of neutrophil and thrombocyte nadir values (adjusted for gender, age, risk group and 6MP dose) after 48 HD-MTX courses in 17 childhood ALL patients on MTX/6MP maintenance therapy, the pre-HD-MTX DNA-TGN levels in neutrophils (P < 0.0001), Ery-MeMP (P < 0.0001) and Ery-6TGN (P = 0.01) levels were significant predictors of post-HD-MTX neutrophil nadirs, whereas Ery-MeMP (P < 0.0001) was the only predictor of post-HD-MTX thrombocyte nadir. In conclusion, pre-HD-MTX 6MP metabolite levels may be applicable for 6MP dose adjustments to prevent HD-MTX-induced myelosuppression.

The ambient dose equivalent at flight altitudes: a fit to a large set of data using a Bayesian approach.

PubMed

Wissmann, F; Reginatto, M; Möller, T

2010-09-01

The problem of finding a simple, generally applicable description of worldwide measured ambient dose equivalent rates at aviation altitudes between 8 and 12 km is difficult to solve due to the large variety of functional forms and parametrisations that are possible. We present an approach that uses Bayesian statistics and Monte Carlo methods to fit mathematical models to a large set of data and to compare the different models. About 2500 data points measured in the periods 1997-1999 and 2003-2006 were used. Since the data cover wide ranges of barometric altitude, vertical cut-off rigidity and phases in the solar cycle 23, we developed functions which depend on these three variables. Whereas the dependence on the vertical cut-off rigidity is described by an exponential, the dependences on barometric altitude and solar activity may be approximated by linear functions in the ranges under consideration. Therefore, a simple Taylor expansion was used to define different models and to investigate the relevance of the different expansion coefficients. With the method presented here, it is possible to obtain probability distributions for each expansion coefficient and thus to extract reliable uncertainties even for the dose rate evaluated. The resulting function agrees well with new measurements made at fixed geographic positions and during long haul flights covering a wide range of latitudes.

Phase I study of combined therapy with vorinostat and gefitinib to treat BIM deletion polymorphism-associated resistance in EGFR-mutant lung cancer (VICTROY-J): a study protocol.

PubMed

Takeuchi, Shinji; Yoshimura, Kenichi; Fujiwara, Tadami; Ando, Masahiko; Shimizu, Shinobu; Nagase, Katsuhiko; Hasegawa, Yoshinori; Takahashi, Toshiaki; Katakami, Nobuyuki; Inoue, Akira; Yano, Seiji

2017-01-01

The BIM deletion polymorphism is reported to be associated with poor outcomes of epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer (NSCLC) treated with EGFR-TKIs, including gefitinib. We have shown that a histone deacetylase inhibitor, vorinostat, can epigenetically restore BIM function and apoptosis sensitivity to EGFR-TKIs in EGFR-mutant NSCLC cells with BIM deletion polymorphisms. The purpose of this study is to determine the feasibility of combined treatment of vorinostat with gefitinib in BIM deletion polymorphism positive EGFR-mutant NSCLC patients. BIM deletion polymorphism positive EGFR-mutant NSCLC patients treated with at least one EGFR-TKI and one regimen of chemotherapy are being recruited to this study. Vorinostat (200-400 mg) will be administered orally once daily on days 1-7, and gefitinib 250 mg orally once daily on days 1-14. With a fixed dose of gefitinib, the dose of vorinostat will be escalated following a conventional 3+3 design. The primary endpoint is to define the maximum tolerated dose (MTD) of vorinostat combined with 250 mg of gefitinib. This is the first phase I study of combined therapy with vorinostat and gefitinib for NSCLC patients double selected for an EGFR mutation and BIM deletion polymorphism. J. Med. Invest. 64: 321-325, August, 2017.

Evaluation of the effect of prostate volume change on tumor control probability in LDR brachytherapy.

PubMed

Knaup, Courtney; Mavroidis, Panayiotis; Stathakis, Sotirios; Smith, Mark; Swanson, Gregory; Papanikolaou, Niko

2011-09-01

This study evaluates low dose-rate brachytherapy (LDR) prostate plans to determine the biological effect of dose degradation due to prostate volume changes. In this study, 39 patients were evaluated. Pre-implant prostate volume was determined using ultrasound. These images were used with the treatment planning system (Nucletron Spot Pro 3.1(®)) to create treatment plans using (103)Pd seeds. Following the implant, patients were imaged using CT for post-implant dosimetry. From the pre and post-implant DVHs, the biologically equivalent dose and the tumor control probability (TCP) were determined using the biologically effective uniform dose. The model used RBE = 1.75 and α/β = 2 Gy. The prostate volume changed between pre and post implant image sets ranged from -8% to 110%. TCP and the mean dose were reduced up to 21% and 56%, respectively. TCP is observed to decrease as the mean dose decreases to the prostate. The post-implant tumor dose was generally observed to decrease, compared to the planned dose. A critical uniform dose of 130 Gy was established. Below this dose, TCP begins to fall-off. It was also determined that patients with a small prostates were more likely to suffer TCP decrease. The biological effect of post operative prostate growth due to operative trauma in LDR was evaluated using the concept. The post-implant dose was lower than the planned dose due to an increase of prostate volume post-implant. A critical uniform dose of 130 Gy was determined, below which TCP begun to decline.

Adjusted-dose warfarin versus low-intensity, fixed-dose warfarin plus aspirin for high-risk patients with atrial fibrillation: Stroke Prevention in Atrial Fibrillation III randomised clinical trial.

PubMed

1996-09-07

Adjusted-dose warfarin is highly efficacious for prevention of ischaemic stroke in patients with atrial fibrillation (AF). However, this treatment carries a risk of bleeding and the need for frequent medical monitoring. We sought an alternative that would be safer and easier to administer to patients with AF who are at high-risk of thromboembolism. 1044 patients with AF and with at least one thromboembolic risk factor (congestive heart failure or left ventricular fractional shortening < or = 25%, previous thromboembolism, systolic blood pressure of more than 160 mm Hg at study enrollment, or being a woman aged over 75 years) were randomly assigned either a combination of low-intensity, fixed-dose warfarin (international normalised ratio [INR] 1.2-1.5 for initial dose adjustment) and aspirin (325 mg/day) or adjusted-dose warfarin (INR 2.0-3.0). Drugs were given open-labelled. The mean INR during follow-up of patients taking combination therapy (n = 521) was 1.3, compared with 2.4 for those taking adjusted-dose warfarin (n = 523). During follow-up, 54% of INRs in patients taking combination therapy were 1.2-1.5 and 34% were less than 1.2. The trial was stopped after a mean, follow-up of 1.1 years when the rate of ischaemic stroke and systemic embolism (primary events) in patients given combination therapy (7.9% per year) was significantly higher than in those given adjusted-dose warfarin (1.9% per year) at an interim analysis (p < 0.0001), an absolute reduction of 6.0% per year (95% Cl 3.4, 8.6) by adjusted-dose warfarin. The annual rates of disabling stroke (5.6% vs 1.7%, p = 0.0007) and of primary event or vascular death (11.8% vs 6.4%, p = 0.002), were also higher with combination therapy. The rates of major bleeding were similar in both treatment groups. Low-intensity, fixed-dose warfarin plus aspirin in this regimen is insufficient for stroke prevention in patients with non-valvular AF at high-risk for thromboembolism; adjusted-dose warfarin (target INR 2.0-3.0) importantly reduces stroke for high-risk patients.

International Conference on Fixed Point Theory and Applications (Colloque International Theorie Du Point Fixe et Applications)

DTIC Science & Technology

1989-06-09

Theorem and the Perron - Frobenius Theorem in matrix theory. We use the Hahn-Banach theorem and do not use any fixed-point related concepts. 179 A...games defined b’, tions 87 Isac G. Fixed point theorems on convex cones , generalized pseudo-contractive mappings and the omplementarity problem 89...and (II), af(x) ° denotes the negative polar cone ot of(x). This condition are respectively called "inward" and "outward". Indeed, when X is convex

TH-AB-207A-12: CT Lung Cancer Screening and the Effects of Further Dose Reduction On CAD Performance

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

Young, S; Lo, P; Hoffman, J

Purpose: CT lung screening is already performed at low doses. In this study, we investigated the effects of further dose reduction on a lung-nodule CAD detection algorithm. Methods: The original raw CT data and images from 348 patients were obtained from our local database of National Lung Screening Trial (NLST) cases. 61 patients (17.5%) had at least one nodule reported on the NLST reader forms. All scans were acquired with fixed mAs (25 for standard-sized patients, 40 for large patients) on a 64-slice scanner (Sensation 64, Siemens Healthcare). All images were reconstructed with 1-mm slice thickness, B50 kernel. Based onmore » a previously-published technique, we added noise to the raw data to simulate reduced-dose versions of each case at 50% and 25% of the original NLST dose (i.e. approximately 1.0 and 0.5 mGy CTDIvol). For each case at each dose level, a CAD detection algorithm was run and nodules greater than 4 mm in diameter were reported. These CAD results were compared to “truth”, defined as the approximate nodule centroids from the NLST forms. Sensitivities and false-positive rates (FPR) were calculated for each dose level, with a sub-analysis by nodule LungRADS category. Results: For larger category 4 nodules, median sensitivities were 100% at all three dose levels, and mean sensitivity decreased with dose. For the more challenging category 2 and 3 nodules, the dose dependence was less obvious. Overall, mean subject-level sensitivity varied from 38.5% at 100% dose to 40.4% at 50% dose, a difference of only 1.9%. However, median FPR quadrupled from 1 per case at 100% dose to 4 per case at 25% dose. Conclusions: Dose reduction affected nodule detectability differently depending on the LungRADS category, and FPR was very sensitive at sub-screening levels. Care should be taken to adapt CAD for the very challenging noise characteristics of screening. Funding support: NIH U01 CA181156; Disclosures (McNitt-Gray): Institutional research agreement, Siemens Healthcare; Past recipient, research grant support, Siemens Healthcare; Consultant, Toshiba America Medical Systems; Consultant, Samsung Electronics.« less

An alpha-numeric code for representing N-linked glycan structures in secreted glycoproteins.

PubMed

Yusufi, Faraaz Noor Khan; Park, Wonjun; Lee, May May; Lee, Dong-Yup

2009-01-01

Advances in high-throughput techniques have led to the creation of increasing amounts of glycome data. The storage and analysis of this data would benefit greatly from a compact notation for describing glycan structures that can be easily stored and interpreted by computers. Towards this end, we propose a fixed-length alpha-numeric code for representing N-linked glycan structures commonly found in secreted glycoproteins from mammalian cell cultures. This code, GlycoDigit, employs a pre-assigned alpha-numeric index to represent the monosaccharides attached in different branches to the core glycan structure. The present branch-centric representation allows us to visualize the structure while the numerical nature of the code makes it machine readable. In addition, a difference operator can be defined to quantitatively differentiate between glycan structures for further analysis. The usefulness and applicability of GlycoDigit were demonstrated by constructing and visualizing an N-linked glycosylation network.

Acquiring Spectra of Solar System Objects with the NIRSpec Instrument on the James Webb Space Telescope

NASA Astrophysics Data System (ADS)

Proffitt, Charles R.; Birkmann, Stephan; Ferruit, Pierre; Guilbert, Aurelie; Holler, Bryan J.; Stansberry, John

2017-10-01

The NIRSpec Instrument on the James Webb Space Telescope will allow near-IR spectroscopy in the wavelength range between 0.6 and 5.3 microns with resolving power of ~100, 1000, or 2700. We review strategies for performing spectral observations of solar system objects using each of NIRSpec's available observing modes, including the integral field unit (IFU), multi-Object Spectroscopy (MOS), and fixed slit (FS) templates, and discuss how the choice of mode affects the limiting target brightness as well as the detailed wavelength and spatial coverage obtained. We also discuss the expected pointing accuracy and target acquisition options for moving targets, including the use and limitations of the Wide Aperture Target Acquisition (WATA) capability and of the pre-defined field points that will be available for use with the MOS template to enable the use of custom micro-shutter patterns including ones emulating very long slits.

Use of fluorine-18-BPA PET images and image registration to enhance radiation treatment planning for boron neutron capture therapy

NASA Astrophysics Data System (ADS)

Khan, Mohammad Khurram

The Monte-Carlo based simulation environment for radiation therapy (SERA) software is used to simulate the dose administered to a patient undergoing boron neutron capture therapy (BNCT). Point sampling of tumor tissue results in an estimate of a uniform boron concentration scaling factor of 3.5. Under conventional treatment protocols, this factor is used to scale the boron component of the dose linearly and homogenously within the tumor and target volumes. The average dose to the tumor cells by such a method could be improved by better methods of quantifying the in-vivo 10B biodistribution. A better method includes radiolabeling para-Boronophenylalanine (p-BPA) with 18F and imaging the pharmaceutical using positron emission tomography (PET). This biodistribution of 18F-BPA can then be used to better predict the average dose delivered to the tumor regions. This work uses registered 18F-BPA PET images to incorporate the in-vivo boron biodistribution within current treatment planning. The registered 18F-BPA PET images are then coupled in a new computer software, PET2MRI.m, to linearly scale the boron component of the dose. A qualititative and quantitative assessment of the dose contours is presented using the two approaches. Tumor volume, tumor axial extent, and target locations are compared between using MRI or PET images to define the tumor volume. In addition, peak-to-normal brain value at tumor axial center is determined for pre and post surgery patients using 18F-BPA PET images. The differences noted between the registered GBM tumor volumes (range: 34.04--136.36%), tumor axial extent (range: 20--150%), and the beam target location (1.27--4.29 cm) are significantly different. The peak-to-normal brain values are also determined at the tumor axial center using the 18F-BPA PET images. The peak-to-normal brain values using the last frame of the pre-surgery study for the GBM patients ranged from 2.05--3.4. For post surgery time weighted PET data, the peak-to-normal brain value in the residual parts of the tumor ranged from 1.5--1.7. Qualitatively, boron dose contours are greatly shifted using PET images when compared with MRI images. Collectively, these differences can lead to significant reorientation of the beam and can significantly impact current BNCT treatment planning.

Quality Control of RNA Preservation and Extraction from Paraffin-Embedded Tissue: Implications for RT-PCR and Microarray Analysis

PubMed Central

Pichler, Martin; Zatloukal, Kurt

2013-01-01

Analysis of RNA isolated from fixed and paraffin-embedded tissues is widely used in biomedical research and molecular pathological diagnostics. We have performed a comprehensive and systematic investigation of the impact of factors in the pre-analytical workflow, such as different fixatives, fixation time, RNA extraction method and storage of tissues in paraffin blocks, on several downstream reactions including complementary DNA (cDNA) synthesis, quantitative reverse transcription polymerase chain reaction (qRT-PCR) and microarray hybridization. We compared the effects of routine formalin fixation with the non-crosslinking, alcohol-based Tissue Tek Xpress Molecular Fixative (TTXMF, Sakura Finetek), and cryopreservation as gold standard for molecular analyses. Formalin fixation introduced major changes into microarray gene expression data and led to marked gene-to-gene variations in delta-ct values of qRT-PCR. We found that qRT-PCR efficiency and gene-to-gene variations were mainly attributed to differences in the efficiency of cDNA synthesis as the most sensitive step. These differences could not be reliably detected by quality assessment of total RNA isolated from formalin-fixed tissues by electrophoresis or spectrophotometry. Although RNA from TTXMF fixed samples was as fragmented as RNA from formalin fixed samples, much higher cDNA yield and lower ct-values were obtained in qRT-PCR underlining the negative impact of crosslinking by formalin. In order to better estimate the impact of pre-analytical procedures such as fixation on the reliability of downstream analysis, we applied a qRT-PCR-based assay using amplicons of different length and an assay measuring the efficiency of cDNA generation. Together these two assays allowed better quality assessment of RNA extracted from fixed and paraffin-embedded tissues and should be used to supplement quality scores derived from automated electrophoresis. A better standardization of the pre-analytical workflow, application of additional quality controls and detailed sample information would markedly improve the comparability and reliability of molecular studies based on formalin-fixed and paraffin-embedded tissue samples. PMID:23936242

TH-A-19A-04: Latent Uncertainties and Performance of a GPU-Implemented Pre-Calculated Track Monte Carlo Method

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

Renaud, M; Seuntjens, J; Roberge, D

Purpose: Assessing the performance and uncertainty of a pre-calculated Monte Carlo (PMC) algorithm for proton and electron transport running on graphics processing units (GPU). While PMC methods have been described in the past, an explicit quantification of the latent uncertainty arising from recycling a limited number of tracks in the pre-generated track bank is missing from the literature. With a proper uncertainty analysis, an optimal pre-generated track bank size can be selected for a desired dose calculation uncertainty. Methods: Particle tracks were pre-generated for electrons and protons using EGSnrc and GEANT4, respectively. The PMC algorithm for track transport was implementedmore » on the CUDA programming framework. GPU-PMC dose distributions were compared to benchmark dose distributions simulated using general-purpose MC codes in the same conditions. A latent uncertainty analysis was performed by comparing GPUPMC dose values to a “ground truth” benchmark while varying the track bank size and primary particle histories. Results: GPU-PMC dose distributions and benchmark doses were within 1% of each other in voxels with dose greater than 50% of Dmax. In proton calculations, a submillimeter distance-to-agreement error was observed at the Bragg Peak. Latent uncertainty followed a Poisson distribution with the number of tracks per energy (TPE) and a track bank of 20,000 TPE produced a latent uncertainty of approximately 1%. Efficiency analysis showed a 937× and 508× gain over a single processor core running DOSXYZnrc for 16 MeV electrons in water and bone, respectively. Conclusion: The GPU-PMC method can calculate dose distributions for electrons and protons to a statistical uncertainty below 1%. The track bank size necessary to achieve an optimal efficiency can be tuned based on the desired uncertainty. Coupled with a model to calculate dose contributions from uncharged particles, GPU-PMC is a candidate for inverse planning of modulated electron radiotherapy and scanned proton beams. This work was supported in part by FRSQ-MSSS (Grant No. 22090), NSERC RG (Grant No. 432290) and CIHR MOP (Grant No. MOP-211360)« less

SU-F-T-345: Quasi-Dead Beams: Clinical Relevance and Implications for Automatic Planning

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

Price, R; Veltchev, I; Lin, T

Purpose: Beam direction selection for fixed-beam IMRT planning is typically a manual process. Severe dose-volume limits on critical structures in the thorax often result in atypical selection of beam directions as compared to other body sites. This work demonstrates the potential consequences as well as clinical relevance. Methods: 21 thoracic cases treated with 5–7 beam directions, 6 cases including non-coplanar arrangements, with fractional doses of 150–411cGy were analyzed. Endpoints included per-beam modulation scaling factor (MSF), variation from equal weighting, and delivery QA passing rate. Results: During analysis of patient-specific delivery QA a sub-standard passing rate was found for a singlemore » 5-field plan (90.48% of pixels evaluated passing 3% dose, 3mm DTA). During investigation it was found that a single beam demonstrated a MSF of 34.7 and contributed only 2.7% to the mean dose of the target. In addition, the variation from equal weighting for this beam was 17.3% absolute resulting in another beam with a MSF of 4.6 contributing 41.9% to the mean dose to the target; a variation of 21.9% from equal weighting. The average MSF for the remaining 20 cases was 4.0 (SD 1.8) with an average absolute deviation of 2.8% from equal weighting (SD 3.1%). Conclusion: Optimization in commercial treatment planning systems typically results in relatively equally weighted beams. Extreme variation from this can result in excessively high MSFs (very small segments) and potential decreases in agreement between planned and delivered dose distributions. In addition, the resultant beam may contribute minimal dose to the target (quasi-dead beam); a byproduct being increased treatment time and associated localization uncertainties. Potential ramifications exist for automatic planning algorithms should they allow for user-defined beam directions. Additionally, these quasi-dead beams may be embedded in the libraries for model-based systems potentially resulting in inefficient and less accurate deliveries.« less

Pharmacokinetics and pharmacodynamics of carboplatin administered in a high-dose combination regimen with thiotepa, cyclophosphamide and peripheral stem cell support.

PubMed Central

van Warmerdam, L. J.; Rodenhuis, S.; van der Wall, E.; Maes, R. A.; Beijnen, J. H.

1996-01-01

The aim of this pharmacokinetic/pharmacodynamic study was to define the relationships of the carboplatin exposure with the toxicity in patients treated with high dose carboplatin (400 mg m-2 day-1), cyclophosphamide (1500 mg m-2 day-1) and thiotepa (120 mg m-2 day-1) for four consecutive days, followed by peripheral stem cell transplantation. Exposure to carboplatin was studied in 200 treatment days by measuring the area under the carboplatin plasma ultrafiltrate (pUF) concentration vs time curve (AUC). The AUC was obtained by using a previously validated limited sampling model. A total of 31 patients was studied who received one, two or three courses of this high-dose chemotherapy regimen. The unbound, plasma ultrafiltrate carboplatin was almost completely cleared from the body before each next treatment day in a course; the day-to-day AUC variation was 3.3%. The mean cumulative AUC over 4 days was 19.6 (range 14.1-27.2) mg ml-1 min-1. In 97 treatment days the carboplatin dose was calculated using the Calvert formula with the creatinine clearance as the measure for the glomerular filtration rate (GFR). For these courses, the inter-patient variability in pharmacokinetics was significantly reduced from 21% to 15% (P = 0.007) in comparison with the schemes where it was given as a fixed dose of 400 mg m-2. There were no relationships found between toxicity and the AUC of carboplatin, which may be due to the influence of overlapping toxicities of cyclophosphamide and thiotepa. However, the ototoxicity was strongly related to the cumulative carboplatin AUC. This toxicity was dose limiting for carboplatin in this schedule. It appeared that the carboplatin pharmacokinetics in these regimens were similar to those reported at conventional dosages. To reduce the inter-patient variation, the carboplatin dose can be calculated using the Calvert-formula with the creatinine clearance as the measure for the GFR. PMID:8611435

REPDOSE: A database on repeated dose toxicity studies of commercial chemicals--A multifunctional tool.

PubMed

Bitsch, A; Jacobi, S; Melber, C; Wahnschaffe, U; Simetska, N; Mangelsdorf, I

2006-12-01

A database for repeated dose toxicity data has been developed. Studies were selected by data quality. Review documents or risk assessments were used to get a pre-screened selection of available valid data. The structure of the chemicals should be rather simple for well defined chemical categories. The database consists of three core data sets for each chemical: (1) structural features and physico-chemical data, (2) data on study design, (3) study results. To allow consistent queries, a high degree of standardization categories and glossaries were developed for relevant parameters. At present, the database consists of 364 chemicals investigated in 1018 studies which resulted in a total of 6002 specific effects. Standard queries have been developed, which allow analyzing the influence of structural features or PC data on LOELs, target organs and effects. Furthermore, it can be used as an expert system. First queries have shown that the database is a very valuable tool.

[Medical expert consensus in AH on the clinical use of triple fixed-dose antihypertensive therapy in Spain].

PubMed

Mazón, P; Galve, E; Gómez, J; Gorostidi, M; Górriz, J L; Mediavilla, J D

The opinion of experts (different specialties) on the triple fixed-dose antihypertensive therapy in clinical practice may differ. Online questionnaire with controversial aspects of the triple therapy answered by panel of experts in hypertension (HT) using two-round modified Delphi method. The questionnaire was completed by 158 experts: Internal Medicine (49), Nephrology (26), Cardiology (83). Consensus was reached (agreement) on 27/45 items (60%); 7 items showed differences statistically significant. Consensus was reached regarding: Predictive factors in the need for combination therapy and its efficacy vs. increasing the dose of a pretreatment, and advantage of triple therapy (prescription/adherence/cost/pressure control) vs. free combination. This consensus provides an overview of the clinical use of triple therapy in moderate-severe and resistant/difficult to control HT. Copyright © 2016 SEH-LELHA. Publicado por Elsevier España, S.L.U. All rights reserved.

p-MOSFET total dose dosimeter

NASA Technical Reports Server (NTRS)

Buehler, Martin G. (Inventor); Blaes, Brent R. (Inventor)

1994-01-01

A p-MOSFET total dose dosimeter where the gate voltage is proportional to the incident radiation dose. It is configured in an n-WELL of a p-BODY substrate. It is operated in the saturation region which is ensured by connecting the gate to the drain. The n-well is connected to zero bias. Current flow from source to drain, rather than from peripheral leakage, is ensured by configuring the device as an edgeless MOSFET where the source completely surrounds the drain. The drain junction is the only junction not connected to zero bias. The MOSFET is connected as part of the feedback loop of an operational amplifier. The operational amplifier holds the drain current fixed at a level which minimizes temperature dependence and also fixes the drain voltage. The sensitivity to radiation is made maximum by operating the MOSFET in the OFF state during radiation soak.

Dose-related difference in progression rates of cytomegalovirus retinopathy during foscarnet maintenance therapy. AIDS Clinical Trials Group Protocol 915 Team.

PubMed

Holland, G N; Levinson, R D; Jacobson, M A

1995-05-01

A previous dose-ranging study of foscarnet maintenance therapy for cytomegalovirus retinopathy showed a positive relationship between dose and survival but could not confirm a relationship between dose and time to first progression. This retrospective analysis of data from that study was undertaken to determine whether there was a relationship between dose and progression rates, which reflects the amount of retina destroyed when progression occurs. Patients were randomly given one of two foscarnet maintenance therapy doses (90 mg/kg of body weight/day [FOS-90 group] or 120 mg/kg of body weight/day [FOS-120 group] after induction therapy. Using baseline and follow-up photographs and pre-established definitions and methodology in a masked analysis, posterior progression rates and foveal proximity rates for individual lesions, selected by prospectively defined criteria, were calculated in each patient. Rates were compared between groups. The following median rates were greater for the FOS-90 group (N = 8) than for the FOS-120 group (N = 10): greatest maximum rate at which lesions enlarged in a posterior direction (43.5 vs 12.5 microns/day; P = .002); posterior progression rate for lesions closest to the fovea (42.8 vs 5.5 microns/day; P = .010); and maximum foveal proximity rate for either eye (32.3 vs 3.4 microns/day; P = .031). Patients receiving higher doses of foscarnet have slower rates of progression and therefore less retinal tissue damage during maintenance therapy. A foscarnet maintenance therapy dose of 120 mg/kg of body weight/day instead of 90 mg/kg of body weight/day may help to preserve vision in patients with cytomegalovirus retinopathy.

Bioequivalence of fixed-dose combination RIN®-150 to each reference drug in loose combination.

PubMed

Wang, H F; Wang, R; O'Gorman, M; Crownover, P; Damle, B

2015-03-01

RIN(®)-150 is a fixed-dose combination (FDC) tablet containing rifampicin (RMP, 150 mg) and isoniazid (INH, 75 mg) developed for the treatment of tuberculosis. This study was conducted at a single center: the Pfizer Clinical Research Unit in Singapore. To demonstrate bioequivalence of each drug component between RIN-150 and individual products in a loose combination. This was a randomized, open-label, single-dose, two-way crossover study. Subjects received single doses of RIN-150 or two individual reference products under fasting conditions in a crossover fashion, with at least 7 days washout between doses. The primary measures for comparison were peak plasma concentration (Cmax) and the area under plasma concentration-time curve (AUC). Of 28 subjects enrolled, 26 completed the study. The adjusted geometric mean ratios of Cmax and AUClast between the FDC and single-drug references and 90% confidence intervals were respectively 91.63% (90%CI 83.13-101.01) and 95.45% (90%CI 92.07-98.94) for RMP, and 107.58% (90%CI 96.07-120.47) and 103.45% (90%CI 99.33-107.75) for INH. Both formulations were generally well tolerated in this study. The RIN-150 FDC tablet formulation is bioequivalent to the two single-drug references for RMP and INH at equivalent doses.

Bioequivalence of fixed-dose combination Myrin®-P Forte and reference drugs in loose combination.

PubMed

Wang, H F; Wang, R; O'Gorman, M; Crownover, P; Naqvi, A; Jafri, I

2013-12-01

Myrin®-P Forte is a fixed-dose combination (FDC) tablet containing rifampicin (RMP, 150 mg), isoniazid (INH, 75 mg), ethambutol (EMB) hydrochloride (275 mg) and pyrazinamide (PZA, 400 mg) developed for the treatment of tuberculosis (TB). This study was conducted at a single centre--the Pfizer Clinical Research Unit in Singapore. To demonstrate the bioequivalence of each drug component of the Myrin-P Forte FDC and the individual product in loose combination. In a randomized, open-label, single-dose, two-way, crossover study, subjects received single doses of Myrin-P Forte or four individual products under fasting conditions in a crossover fashion with at least 7 days washout between doses. The primary measures for comparison were peak plasma concentration (C(max)) and the area under plasma concentration-time curve (AUC). Of 36 subjects enrolled, 35 completed the study. The adjusted geometric mean ratios and 90% confidence intervals for C(max) and AUC values were completely contained within bioequivalence limits (80%, 125%) for all four drugs in both formulations. Both treatments were generally well tolerated in the study. The Myrin-P Forte FDC tablet formulation is bioequivalent to the four single-drug references for RMP, INH, EMB hydrochloride and PZA at equivalent doses.

Processing closely spaced lesions during Nucleotide Excision Repair triggers mutagenesis in E. coli

PubMed Central

Isogawa, Asako; Fujii, Shingo

2017-01-01

It is generally assumed that most point mutations are fixed when damage containing template DNA undergoes replication, either right at the fork or behind the fork during gap filling. Here we provide genetic evidence for a pathway, dependent on Nucleotide Excision Repair, that induces mutations when processing closely spaced lesions. This pathway, referred to as Nucleotide Excision Repair-induced Mutagenesis (NERiM), exhibits several characteristics distinct from mutations that occur within the course of replication: i) following UV irradiation, NER-induced mutations are fixed much more rapidly (t ½ ≈ 30 min) than replication dependent mutations (t ½ ≈ 80–100 min) ii) NERiM specifically requires DNA Pol IV in addition to Pol V iii) NERiM exhibits a two-hit dose-response curve that suggests processing of closely spaced lesions. A mathematical model let us define the geometry (infer the structure) of the toxic intermediate as being formed when NER incises a lesion that resides in close proximity of another lesion in the complementary strand. This critical NER intermediate requires Pol IV / Pol II for repair, it is either lethal if left unrepaired or mutation-prone when repaired. Finally, NERiM is found to operate in stationary phase cells providing an intriguing possibility for ongoing evolution in the absence of replication. PMID:28686598

Serious altitude illness in travelers who visited a pre-travel clinic.

PubMed

Croughs, Mieke; Van Gompel, Alfons; Rameckers, Sarah; Van den Ende, Jef

2014-01-01

Few data are available on the incidence and predictors of serious altitude illness in travelers who visit pre-travel clinics. Travel health consultants advise on measures to be taken in case of serious altitude illness but it is not clear if travelers adhere to these recommendations. Visitors to six travel clinics who planned to travel to an altitude of ≥3,000 m were asked to complete a diary from the first day at 2,000 m until 3 days after reaching the maximum sleeping altitude. Serious altitude illness was defined as having symptoms of serious acute mountain sickness (AMS score ≥ 6) and/or cerebral edema and/or pulmonary edema. The incidence of serious altitude illness in the 401 included participants of whom 90% reached ≥4,000 m, was 35%; 23% had symptoms of serious AMS, 25% symptoms of cerebral edema, and 13% symptoms of pulmonary edema. Independent predictors were young age, the occurrence of dark urine, travel in South America or Africa, and lack of acclimatization between 1,000 and 2,500 m. Acetazolamide was brought along by 77% of the responders of whom 41% took at least one dose. Of those with serious altitude illness, 57% had taken at least one dose of acetazolamide, 20% descended below 2,500 m on the same day or the next, and 11% consulted a physician. Serious altitude illness was a very frequent problem in travelers who visited pre-travel clinics. Young age, dark urine, travel in South America or Africa, and lack of acclimatization nights at moderate altitude were independent predictors. Furthermore, we found that seriously ill travelers seldom followed the advice to descend and to visit a physician. © 2014 International Society of Travel Medicine.

[A dose-response analysis on the association of gestational weight gain rate and the normal term neonate birth weight].

PubMed

Mao, Yuanyuan; Hu, Wenbin; Liu, Qin; Liu, Li; Li, Yuanming; Shen, Yueping

2015-08-01

To examine the dose-response relationship between gestational weight gain rate and the neonate birth weight. A total of 18 868 women with singleton gestations who delivered between January 2006 and December 2013 were included in this study. Maternal and neonate details of these women were drawn from the Perinatal Monitoring System database. Gestational weight gain rate was defined as the total weight gain during the last and first prenatal care visits divided by the interval weeks. Both Multiple logistic regression analysis and restricted cubic spline methods were performed. Confounding factors included maternal age, education, pre-pregnancy body mass index (BMI), state of residence, parity, gestational weeks of prenatal care entry, and sex of the neonate. The adjusted odds ratio for macrosomia was associated with gestational weight gain rate in lower pre-pregnancy BMI (OR = 3.15, 95% CI: 1.40-7.07), normal (OR = 3.64, 95% CI: 2.84-4.66) or overweight (OR = 2.37, 95% CI: 1.71-3.27). The odds ratios of low birth weight appeared a decrease in those women with lower pre-pregnancy BMI (OR = 0.28, 95% CI: 0.13-0.61) while the normal weight (OR = 0.37, 95% CI: 0.22-0.64) group with gestational weight gain, the rate showed an increase. Association of gestational weight gain rate for macrosomia was found a S-curve in those term delivery women (non-linearity test P < 0.000 1). However, L-curve was observed for low birth weight and gestational weight gain rate in term births (non-linearity test P < 0.000 1). A S-curve was seen between gestational weight gain rate and term delivered macrosomia while L-curve was observed among term delivered low birth weight neonates.

A Study to Find Out the Full Immunization Coverage of 12 to 23-month old Children and Areas of Under-Performance using LQAS Technique in a Rural Area of Tripura

PubMed Central

Baidya, Subrata; Datta, Srabani; Mog, Chanda; Das, Shampa

2017-01-01

Introduction It is very important to analyze the factors which acts as obstacle in achieving 100% immunization among children. Lot Quality Assurance Sampling (LQAS) is one of the effective method to assess such barriers. Aim To assess the full immunization coverage among 12 to 23-month old children of rural field practice area under Department of Community Medicine, Agartala Government Medical College and identify the factors for failure of full immunization. Materials and Methods A community based cross-sectional study was conducted from November 2013 to October 2014 on children aged 12 to 23 months old of area under Mohanpur Community health centre. Using LQAS technique 330 samples were selected with multi-stage sampling, each sub-centre being one lot and two calculated to be the decision value. Data was collected using pre-designed pre-tested questionnaire during home visit and verifying immunization card and analysed by computer software SPSS version 21.0. Results The full immunization coverage among 12 to 23 months old children of Mohanpur area was found as 91.67%. Out of all the 22 sub-centres, 36.36% was found under performing as per pre-fixed criteria and the main reasons for failure of full immunization in those areas are unawareness of need of subsequent doses of vaccines and illness of the children. Conclusion LQAS is an effective method to identify areas of under-performance even though overall full immunization coverage is high. PMID:28384892

A novel method for interactive multi-objective dose-guided patient positioning

NASA Astrophysics Data System (ADS)

Haehnle, Jonas; Süss, Philipp; Landry, Guillaume; Teichert, Katrin; Hille, Lucas; Hofmaier, Jan; Nowak, Dimitri; Kamp, Florian; Reiner, Michael; Thieke, Christian; Ganswindt, Ute; Belka, Claus; Parodi, Katia; Küfer, Karl-Heinz; Kurz, Christopher

2017-01-01

In intensity-modulated radiation therapy (IMRT), 3D in-room imaging data is typically utilized for accurate patient alignment on the basis of anatomical landmarks. In the presence of non-rigid anatomical changes, it is often not obvious which patient position is most suitable. Thus, dose-guided patient alignment is an interesting approach to use available in-room imaging data for up-to-date dose calculation, aimed at finding the position that yields the optimal dose distribution. This contribution presents the first implementation of dose-guided patient alignment as multi-criteria optimization problem. User-defined clinical objectives are employed for setting up a multi-objective problem. Using pre-calculated dose distributions at a limited number of patient shifts and dose interpolation, a continuous space of Pareto-efficient patient shifts becomes accessible. Pareto sliders facilitate interactive browsing of the possible shifts with real-time dose display to the user. Dose interpolation accuracy is validated and the potential of multi-objective dose-guided positioning demonstrated for three head and neck (H&N) and three prostate cancer patients. Dose-guided positioning is compared to replanning for all cases. A delineated replanning CT served as surrogate for in-room imaging data. Dose interpolation accuracy was high. Using a 2 % dose difference criterion, a median pass-rate of 95.7% for H&N and 99.6% for prostate cases was determined in a comparison to exact dose calculations. For all patients, dose-guided positioning allowed to find a clinically preferable dose distribution compared to bony anatomy based alignment. For all H&N cases, mean dose to the spared parotid glands was below 26~\\text{Gy} (up to 27.5~\\text{Gy} with bony alignment) and clinical target volume (CTV) {{V}95 % } above 99.1% (compared to 95.1%). For all prostate patients, CTV {{V}95 % } was above 98.9% (compared to 88.5%) and {{V}50~\\text{Gy}} to the rectum below 50 % (compared to 56.1%). Replanning yielded improved results for the H&N cases. For the prostate cases, differences to dose-guided positioning were minor.

TH-AB-201-10: Portal Dosimetry with Elekta IViewDose:Performance of the Simplified Commissioning Approach Versus Full Commissioning

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

Kydonieos, M; Folgueras, A; Florescu, L

2016-06-15

Purpose: Elekta recently developed a solution for in-vivo EPID dosimetry (iViewDose, Elekta AB, Stockholm, Sweden) in conjunction with the Netherlands Cancer Institute (NKI). This uses a simplified commissioning approach via Template Commissioning Models (TCMs), consisting of a subset of linac-independent pre-defined parameters. This work compares the performance of iViewDose using a TCM commissioning approach with that corresponding to full commissioning. Additionally, the dose reconstruction based on the simplified commissioning approach is validated via independent dose measurements. Methods: Measurements were performed at the NKI on a VersaHD™ (Elekta AB, Stockholm, Sweden). Treatment plans were generated with Pinnacle 9.8 (Philips Medical Systems,more » Eindhoven, The Netherlands). A farmer chamber dose measurement and two EPID images were used to create a linac-specific commissioning model based on a TCM. A complete set of commissioning measurements was collected and a full commissioning model was created.The performance of iViewDose based on the two commissioning approaches was compared via a series of set-to-work tests in a slab phantom. In these tests, iViewDose reconstructs and compares EPID to TPS dose for square fields, IMRT and VMAT plans via global gamma analysis and isocentre dose difference. A clinical VMAT plan was delivered to a homogeneous Octavius 4D phantom (PTW, Freiburg, Germany). Dose was measured with the Octavius 1500 array and VeriSoft software was used for 3D dose reconstruction. EPID images were acquired. TCM-based iViewDose and 3D Octavius dose distributions were compared against the TPS. Results: For both the TCM-based and the full commissioning approaches, the pass rate, mean γ and dose difference were >97%, <0.5 and <2.5%, respectively. Equivalent gamma analysis results were obtained for iViewDose (TCM approach) and Octavius for a VMAT plan. Conclusion: iViewDose produces similar results with the simplified and full commissioning approaches. Good agreement is obtained between iViewDose (simplified approach) and the independent measurement tool. This research is funded by Elekta Limited.« less

A pilot stability study on four-drug fixed-dose combination anti-tuberculosis products.

PubMed

Singh, S; Mohan, B

2003-03-01

A pilot stability study was carried out on four fixed-dose combination anti-tuberculosis products at 40 degrees C and 75% RH. The strip-packed products were stable, while the blister-packed products showed both physical and chemical changes. The products in unpacked conditions showed severe (approximately 60%) decomposition of rifampicin and extensive physical changes. The main decomposition product in the solid state was isonicotinyl hydrazone of 3-formylrifamycin and isoniazid. It is suggested that attention should be paid to the detection and quantitation of this product in the marketed formulations. The packing material used in the manufacture of FDC products should also be of the highest quality.

Efficacy and safety of once-daily, extended-release hydrocodone in individuals previously receiving hydrocodone/acetaminophen combination therapy for chronic pain.

PubMed

Bartoli, Adrian; Michna, Edward; He, Ellie; Wen, Warren

2015-01-01

Hydrocodone/acetaminophen combination analgesics are frequently prescribed for chronic pain management; however, acetaminophen presents potential hepatotoxicity to patients and thus dose limitations. These opioid medications are also widely abused. Once-daily, single-entity hydrocodone (Hysingla™ ER tablets [HYD]) is a novel formulation with abuse-deterrent properties for the management of chronic pain and represents a suitable option for those patients receiving analgesics containing the same opioid analgesic, hydrocodone. This post-hoc analysis evaluated the efficacy and safety of HYD in patients whose primary pre-study analgesic was hydrocodone/acetaminophen analgesics (23-31% of the study populations). Data were analyzed from two Phase III trials, a 12-week randomized, placebo-controlled trial (RCT) and an open-label, 52-week trial. In both trials, a dose-titration period with HYD was followed by respective periods of fixed-dose double-blind (randomized controlled trial [RCT]) or open-label, flexible-dose maintenance treatment. Pain intensity was assessed using a numerical rating scale (0-10, 0 = no pain). For the RCT, primary and sensitivity analyses of pain scores used different approaches to handle missing data. Safety data for both studies were summarized. In the RCT, the mean baseline pain score was 7.3. Pain relief was greater with HYD than placebo during double-blind treatment. In the open-label, flexible-dose trial, the majority of patients were maintained on their titrated dose. Mean baseline pain score was 6.3, about 57% of patients completed the 1-year maintenance period, and mean pain scores were between 3.6 and 4.1 during the maintenance period. Use of supplemental pain medication decreased or was maintained during the maintenance treatment with HYD. Adverse events in both trials were typical of those associated with opioid analgesics. In patients whose primary pretrial analgesic was hydrocodone/acetaminophen combination tablets, single-entity HYD was effective in reducing pain intensity and in maintaining analgesia over time without need for continued dose increase. HYD's safety and tolerability profiles were similar to other opioid analgesics.

The value of integrating pre-clinical data to predict nausea and vomiting risk in humans as illustrated by AZD3514, a novel androgen receptor modulator

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

Grant, Claire, E-mail: claire.grant@astrazeneca.com; Ewart, Lorna; Muthas, Daniel

Nausea and vomiting are components of a complex mechanism that signals food avoidance and protection of the body against the absorption of ingested toxins. This response can also be triggered by pharmaceuticals. Predicting clinical nausea and vomiting liability for pharmaceutical agents based on pre-clinical data can be problematic as no single animal model is a universal predictor. Moreover, efforts to improve models are hampered by the lack of translational animal and human data in the public domain. AZD3514 is a novel, orally-administered compound that inhibits androgen receptor signaling and down-regulates androgen receptor expression. Here we have explored the utility ofmore » integrating data from several pre-clinical models to predict nausea and vomiting in the clinic. Single and repeat doses of AZD3514 resulted in emesis, salivation and gastrointestinal disturbances in the dog, and inhibited gastric emptying in rats after a single dose. AZD3514, at clinically relevant exposures, induced dose-responsive “pica” behaviour in rats after single and multiple daily doses, and induced retching and vomiting behaviour in ferrets after a single dose. We compare these data with the clinical manifestation of nausea and vomiting encountered in patients with castration-resistant prostate cancer receiving AZD3514. Our data reveal a striking relationship between the pre-clinical observations described and the experience of nausea and vomiting in the clinic. In conclusion, the emetic nature of AZD3514 was predicted across a range of pre-clinical models, and the approach presented provides a valuable framework for predicition of clinical nausea and vomiting. - Highlights: • Integrated pre-clinical data can be used to predict clinical nausea and vomiting. • Data integrated from standard toxicology studies is sufficient to make a prediction. • The use of the nausea algorithm developed by Parkinson (2012) aids the prediction. • Additional pre-clinical studies can be used to confirm and quantify the risk.« less

Factors impacting the efficacy of venlafaxine extended release 75–225 mg/day in patients with major depressive disorder: exploratory post hoc subgroup analyses of a randomized, double-blind, placebo-controlled study in Japan

PubMed Central

Watanabe, Yoshinori; Asami, Yuko; Hirano, Yoko; Kuribayashi, Kazuhiko; Itamura, Rio; Imaeda, Takayuki

2018-01-01

Purpose To explore the potential factors impacting the efficacy of venlafaxine extended release (ER) and treatment differences between 75 mg/day and 75–225 mg/day dose in patients with major depressive disorder (MDD). Methods We performed exploratory post hoc subgroup analyses of a randomized, double-blind, placebo-controlled study conducted in Japan. A total of 538 outpatients aged 20 years or older with a primary diagnosis of MDD who experienced single or recurrent episodes were randomized into three groups: fixed-dose, flexible-dose, or placebo. Venlafaxine ER was initiated at 37.5 mg/day and titrated to 75 mg/day for both fixed-dose and flexible-dose group, and to 225 mg/day for flexible-dose group (if well tolerated). Efficacy endpoints were changes from baseline at Week 8 using the Hamilton Rating Scale for Depression–17 items (HAM-D17) total score, Hamilton Rating Scale for Depression–6 items score, and Montgomery–Asberg Depression Rating Scale total score. The following factors were considered in the subgroup analyses: sex, age, HAM-D17 total score at baseline, duration of MDD, duration of current depressive episode, history of previous depressive episodes, history of previous medications for MDD, and CYP2D6 phenotype. For each subgroup, an analysis of covariance model was fitted and the adjusted mean of the treatment effect and corresponding 95% CI were computed. Due to the exploratory nature of the investigation, no statistical hypothesis testing was used. Results Venlafaxine ER improved symptoms of MDD compared with placebo in most subgroups. The subgroup with a long duration of MDD (>22 months) consistently showed greater treatment benefits in the flexible-dose group than in the fixed-dose group. Conclusion These results suggest that a greater treatment response to venlafaxine ER (up to 225 mg/day) can be seen in patients with a longer duration of MDD. Further investigations are needed to identify additional factors impacting the efficacy of venlafaxine ER. PMID:29844674

Factors impacting the efficacy of venlafaxine extended release 75-225 mg/day in patients with major depressive disorder: exploratory post hoc subgroup analyses of a randomized, double-blind, placebo-controlled study in Japan.

PubMed

Watanabe, Yoshinori; Asami, Yuko; Hirano, Yoko; Kuribayashi, Kazuhiko; Itamura, Rio; Imaeda, Takayuki

2018-01-01

To explore the potential factors impacting the efficacy of venlafaxine extended release (ER) and treatment differences between 75 mg/day and 75-225 mg/day dose in patients with major depressive disorder (MDD). We performed exploratory post hoc subgroup analyses of a randomized, double-blind, placebo-controlled study conducted in Japan. A total of 538 outpatients aged 20 years or older with a primary diagnosis of MDD who experienced single or recurrent episodes were randomized into three groups: fixed-dose, flexible-dose, or placebo. Venlafaxine ER was initiated at 37.5 mg/day and titrated to 75 mg/day for both fixed-dose and flexible-dose group, and to 225 mg/day for flexible-dose group (if well tolerated). Efficacy endpoints were changes from baseline at Week 8 using the Hamilton Rating Scale for Depression-17 items (HAM-D 17 ) total score, Hamilton Rating Scale for Depression-6 items score, and Montgomery-Asberg Depression Rating Scale total score. The following factors were considered in the subgroup analyses: sex, age, HAM-D 17 total score at baseline, duration of MDD, duration of current depressive episode, history of previous depressive episodes, history of previous medications for MDD, and CYP2D6 phenotype. For each subgroup, an analysis of covariance model was fitted and the adjusted mean of the treatment effect and corresponding 95% CI were computed. Due to the exploratory nature of the investigation, no statistical hypothesis testing was used. Venlafaxine ER improved symptoms of MDD compared with placebo in most subgroups. The subgroup with a long duration of MDD (>22 months) consistently showed greater treatment benefits in the flexible-dose group than in the fixed-dose group. These results suggest that a greater treatment response to venlafaxine ER (up to 225 mg/day) can be seen in patients with a longer duration of MDD. Further investigations are needed to identify additional factors impacting the efficacy of venlafaxine ER.

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

Venencia, C; Vacca, N; Garrigo, E

Purpose: Spine SBRT treatments require high dose to PTV, located close to OAR. Treatment time should be short due to patient condition. The objective of this work is to compare HybridARC (HA) with sliding windows IMRT treatment modality Methods: A 6MV photon beam with 1000MU/min (SRS beam) produced by a NovalisTX (Varian/BrainLAB) equipped with HDMLC was used. The TPS was iPlan v4.5.3 (BrainLAB). Treatment plans comparison was done for 5 patients. Dose prescription was 27Gy in 3 fractions. HA used 1 arc plus 3 (HA), 5 (HA5) and 8 (HA8) IMRT fields. HA plans used OAR high. Between 60–40% ofmore » the prescribed dose was given by the arc. IMRT plans used 15 beams. Treatment times, MU, CI, V50% and V20% was used for plans comparisons. Results: Assuming IMRT plan as reference, the treatment time was reduced by −14.6% with HA8, −8.6% with HA5 and −23% with HA3. Increasing arc dose proportion in HA (arc MU > 2000) requires 2 or more arcs which increments treatment time. HA3 and HA5 exhibits beam hold off for fixed IMRT fields which in some cases need to be split in 2 segments. MU varied +4% with HA8, +3.7% with HA5 and −5% with HA3. CI increased +5% with HA8, +23% with HA5 and +37% with H3. V50% increased +5% with HA8, +43% with HA5 and +62% with HA3. V20% increased +13.2% with HA8, +7.6% with HA5 and +1% with HA3. OARs doses were keep within tolerances in all plans. Conclusion: HybridARC for spine SBRT with 8 fix IMRT gantry angle shows a treatment time reduction, comparable MU and similar dose conformation to dMLC IMRT. HybridARC with 5 or 3 fix IMRT fields produce undesirable beam hold off, worse dose conformation and increments the total volume with 50% of the prescribed dose.« less

[Antihypertensive Efficacy of Fixed Combination Azilsartan Medoxomil / Chlorthalidone in Patients With Uncontrolled Arterial Hypertension].

PubMed

Kobalava, Z D; Villevalde, S V; Kulakov, V V

2017-11-01

To study effects of a fixed azilsartan medoxomil/chlorthalidone combination (Edarbi Clo) on clinical, ambulatory and central blood pressure (BP) in patients with uncontrolled arterial hypertension (AH)). Patients (n=25) with uncontrolled AH were given fixed azilsartan medoxomil/chlorthalidone combination (40 / 12.5 mg / day) for 4 weeks. After 4 weeks, in patients who did not achieve target BP levels the dose was increased up to 40 / 25 mg / day. Duration of the study was 12 weeks. After 12 weeks of treatment 88 % of patients achieved target clinical BP (.

The impact on CT dose of the variability in tube current modulation technology: a theoretical investigation

NASA Astrophysics Data System (ADS)

Li, Xiang; Segars, W. Paul; Samei, Ehsan

2014-08-01

Body CT scans are routinely performed using tube-current-modulation (TCM) technology. There is notable variability across CT manufacturers in terms of how TCM technology is implemented. Some manufacturers aim to provide uniform image noise across body regions and patient sizes, whereas others aim to provide lower noise for smaller patients. The purpose of this study was to conduct a theoretical investigation to understand how manufacturer-dependent TCM scheme affects organ dose, and to develop a generic approach for assessing organ dose across TCM schemes. The adult reference female extended cardiac-torso (XCAT) phantom was used for this study. A ray-tracing method was developed to calculate the attenuation of the phantom for a given projection angle based on phantom anatomy, CT system geometry, x-ray energy spectrum, and bowtie filter filtration. The tube current (mA) for a given projection angle was then calculated as a log-linear function of the attenuation along that projection. The slope of this function, termed modulation control strength, α, was varied from 0 to 1 to emulate the variability in TCM technology. Using a validated Monte Carlo program, organ dose was simulated for five α values (α = 0, 0.25, 0.5, 0.75, and 1) in the absence and presence of a realistic system mA limit. Organ dose was further normalized by volume-weighted CT dose index (CTDIvol) to obtain conversion factors (h factors) that are relatively independent of system specifics and scan parameters. For both chest and abdomen-pelvis scans and for 24 radiosensitive organs, organ dose conversion factors varied with α, following second-order polynomial equations. This result suggested the need for α-specific organ dose conversion factors (i.e., conversion factors specific to the modulation scheme used). On the other hand, across the full range of α values, organ dose in a TCM scan could be derived from the conversion factors established for a fixed-mA scan (hFIXED). This was possible by multiplying hFIXED by a revised definition of CTDIvol that accounts for two factors: (a) the tube currents at the location of an organ and (b) the variation in organ volume along the longitudinal direction. This α-generic approach represents an approximation. The error associated with this approximation was evaluated using the α-specific organ dose (i.e., the organ dose obtained by using α-specific mA profiles as inputs into the Monte Carlo simulation) as the reference standard. When the mA profiles were constrained by a realistic system limit, this α-generic approach had errors of less than ~20% for the full range of α values. This was the case for 24 radiosensitive organs in both chest and abdomen-pelvis CT scans with the exception of thyroid in the chest scan and bladder in the abdomen-pelvis scan. For these two organs, the errors were less than ~40%. The results of this theoretical study suggested that knowing the mA modulation profile and the fixed-mA conversion factors, organ dose may be estimated for a TCM scan independent of the specific modulation scheme applied.

Pharmacodynamic effects of a new fixed-dose clopidogrel-aspirin combination compared with separate administration of clopidogrel and aspirin in patients treated with coronary stents: The ACCEL-COMBO trial.

PubMed

Koh, Jin-Sin; Park, Yongwhi; Tantry, Udaya S; Ahn, Jong-Hwa; Kang, Min Gyu; Kim, Kyehwan; Jang, Jeong Yoon; Park, Hyun Woong; Park, Jeong Rang; Hwang, Seok-Jae; Kwak, Choong Hwan; Hwang, Jin-Yong; Gurbel, Paul A; Jeong, Young-Hoon

2017-03-01

Dual antiplatelet therapy (DAPT) with clopidogrel and aspirin is a widely prescribed regimen to prevent ischemic events in patients undergoing percutaneous coronary intervention (PCI). A fixed-dose combination (FDC) capsule (HCP0911) has been developed to provide dosing convenience and improve adherence. We compared the antiplatelet effects of single daily dose HCP0911 with separate treatment with daily 75 mg clopidogrel plus 100 mg aspirin. This was a randomized, open-label, two-period, crossover, non-inferiority study conducted in stented patients who had been treated for at least 6 months with clopidogrel and aspirin. Thirty patients were randomly assigned to receive either daily 75 mg clopidogrel plus 100 mg aspirin treatment or HCP0911 for 2 weeks and then were crossed over to the other treatment for 2 weeks. Pharmacodynamic effects were measured with VerifyNow, light transmittance aggregometry (LTA), and thromboelastography (TEG ® ). The primary endpoint was P2Y12 Reaction Units (PRU) measured by VerifyNow. PRUs during treatment with HCP0911 were not inferior to those during separate treatment (202 ± 52 vs. 207 ± 60 PRU; mean difference, -5 PRU; 90% confidence interval of difference, -23 to 13 PRU; P for non-inferiority = 0.015 for predetermined limit). "BASE" and Aspirin Reaction Units by VerifyNow did not differ between the two treatments. During each treatment, there were no differences in maximal and final platelet aggregations by LTA (all P values ≥0.822) and TEG ® measurements. In conclusion, in stented patients, the antiplatelet effect of a fixed-dose clopidogrel-aspirin combination, HCP0911, was not inferior to separate administration of clopidogrel and aspirin.

Time dependent pre-treatment EPID dosimetry for standard and FFF VMAT.

PubMed

Podesta, Mark; Nijsten, Sebastiaan M J J G; Persoon, Lucas C G G; Scheib, Stefan G; Baltes, Christof; Verhaegen, Frank

2014-08-21

Methods to calibrate Megavoltage electronic portal imaging devices (EPIDs) for dosimetry have been previously documented for dynamic treatments such as intensity modulated radiotherapy (IMRT) using flattened beams and typically using integrated fields. While these methods verify the accumulated field shape and dose, the dose rate and differential fields remain unverified. The aim of this work is to provide an accurate calibration model for time dependent pre-treatment dose verification using amorphous silicon (a-Si) EPIDs in volumetric modulated arc therapy (VMAT) for both flattened and flattening filter free (FFF) beams. A general calibration model was created using a Varian TrueBeam accelerator, equipped with an aS1000 EPID, for each photon spectrum 6 MV, 10 MV, 6 MV-FFF, 10 MV-FFF. As planned VMAT treatments use control points (CPs) for optimization, measured images are separated into corresponding time intervals for direct comparison with predictions. The accuracy of the calibration model was determined for a range of treatment conditions. Measured and predicted CP dose images were compared using a time dependent gamma evaluation using criteria (3%, 3 mm, 0.5 sec). Time dependent pre-treatment dose verification is possible without an additional measurement device or phantom, using the on-board EPID. Sufficient data is present in trajectory log files and EPID frame headers to reliably synchronize and resample portal images. For the VMAT plans tested, significantly more deviation is observed when analysed in a time dependent manner for FFF and non-FFF plans than when analysed using only the integrated field. We show EPID-based pre-treatment dose verification can be performed on a CP basis for VMAT plans. This model can measure pre-treatment doses for both flattened and unflattened beams in a time dependent manner which highlights deviations that are missed in integrated field verifications.

Safety and pharmacokinetic profile of fixed-dose ivermectin with an innovative 18mg tablet in healthy adult volunteers.

PubMed

Muñoz, Jose; Ballester, Maria Rosa; Antonijoan, Rosa Maria; Gich, Ignasi; Rodríguez, Montse; Colli, Enrico; Gold, Silvia; Krolewiecki, Alejandro J

2018-01-01

Ivermectin is a pivotal drug for the control of onchocerciasis and lymphatic filariasis, which is increasingly identified as a useful drug for the control of other Neglected Tropical Diseases. Its role in the treatment of soil transmitted helminthiasis through improved efficacy against Trichuris trichiura in combination with other anthelmintics might accelerate the progress towards breaking transmission. Ivermectin is a derivative of Avermectin B1, and consists of an 80:20 mixture of the equipotent homologous 22,23 dehydro B1a and B1b. Pharmacokinetic characteristics and safety profile of ivermectin allow to explore innovative uses to further expand its utilization through mass drug administration campaigns to improve coverage rates. We conducted a phase I clinical trial with 54 healthy adult volunteers who sequentially received 2 experimental treatments using a new 18 mg ivermectin tablet in a fixed-dose strategy of 18 and 36 mg single dose regimens, compared to the standard, weight based 150–200 μg/kg, regimen. Volunteers were recruited in 3 groups based on body weight. Plasma concentrations of ivermectin were measured through HPLC up to 168 hours post treatment. Safety data showed no significant differences between groups and no serious adverse events: headache was the most frequent adverse event in all treatment groups, none of them severe. Pharmacokinetic parameters showed a half-life between 81 and 91 h in the different treatment groups. When comparing the systemic bioavailability (AUC0t and Cmax) of the reference product (WA-ref) with the other two study groups using fixed doses, we observed an overall increase in AUC0t and Cmax for the two experimental treatments of 18 mg and 36 mg. Body mass index (BMI) and weight were associated with t1/2 and V/F, probably reflecting the high liposolubility of IVM with longer retention times proportional to the presence of more adipose tissue. Systemic exposure to ivermectin (AUC0t or Cmax) was not associated with BMI or weight in our study. These findings contribute to further understand the pharmacokinetic characteristics of ivermectin, highlighting its safety across different dosing regimens. They also correlate with known pharmacokinetic parameters showing stable levels of AUC and Cmax across a wide range of body weights, which justifies the strategy of fix dosing from a pharmacokinetic perspective. ClinicalTrials.gov NCT03173742.

Safety and pharmacokinetic profile of fixed-dose ivermectin with an innovative 18mg tablet in healthy adult volunteers

PubMed Central

Antonijoan, Rosa Maria; Gich, Ignasi; Rodríguez, Montse; Colli, Enrico; Gold, Silvia

2018-01-01

Ivermectin is a pivotal drug for the control of onchocerciasis and lymphatic filariasis, which is increasingly identified as a useful drug for the control of other Neglected Tropical Diseases. Its role in the treatment of soil transmitted helminthiasis through improved efficacy against Trichuris trichiura in combination with other anthelmintics might accelerate the progress towards breaking transmission. Ivermectin is a derivative of Avermectin B1, and consists of an 80:20 mixture of the equipotent homologous 22,23 dehydro B1a and B1b. Pharmacokinetic characteristics and safety profile of ivermectin allow to explore innovative uses to further expand its utilization through mass drug administration campaigns to improve coverage rates. We conducted a phase I clinical trial with 54 healthy adult volunteers who sequentially received 2 experimental treatments using a new 18 mg ivermectin tablet in a fixed-dose strategy of 18 and 36 mg single dose regimens, compared to the standard, weight based 150–200 μg/kg, regimen. Volunteers were recruited in 3 groups based on body weight. Plasma concentrations of ivermectin were measured through HPLC up to 168 hours post treatment. Safety data showed no significant differences between groups and no serious adverse events: headache was the most frequent adverse event in all treatment groups, none of them severe. Pharmacokinetic parameters showed a half-life between 81 and 91 h in the different treatment groups. When comparing the systemic bioavailability (AUC0t and Cmax) of the reference product (WA-ref) with the other two study groups using fixed doses, we observed an overall increase in AUC0t and Cmax for the two experimental treatments of 18 mg and 36 mg. Body mass index (BMI) and weight were associated with t1/2 and V/F, probably reflecting the high liposolubility of IVM with longer retention times proportional to the presence of more adipose tissue. Systemic exposure to ivermectin (AUC0t or Cmax) was not associated with BMI or weight in our study. These findings contribute to further understand the pharmacokinetic characteristics of ivermectin, highlighting its safety across different dosing regimens. They also correlate with known pharmacokinetic parameters showing stable levels of AUC and Cmax across a wide range of body weights, which justifies the strategy of fix dosing from a pharmacokinetic perspective. Trial registration ClinicalTrials.gov NCT03173742. PMID:29346388

Left-sided breast cancer irradiation using rotational and fixed-field radiotherapy

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

Qi, X. Sharon, E-mail: xqi@mednet.ucla.edu; Liu, Tian X.; Liu, Arthur K.

2014-10-01

The 3-dimensional conformal radiotherapy (3DCRT) technique is the standard for breast cancer radiotherapy. During treatment planning, not only the coverage of the planning target volume (PTV) but also the minimization of the dose to critical structures, such as the lung, heart, and contralateral breast tissue, need to be considered. Because of the complexity and variations of patient anatomy, more advanced radiotherapy techniques are sometimes desired to better meet the planning goals. In this study, we evaluated external-beam radiation treatment techniques for left breast cancer using various delivery platforms: fixed-field including TomoDirect (TD), static intensity-modulated radiotherapy (sIMRT), and rotational radiotherapy includingmore » Elekta volumetric-modulated arc therapy (VMAT) and tomotherapy helical (TH). A total of 10 patients with left-sided breast cancer who did or did not have positive lymph nodes and were previously treated with 3DCRT/sIMRT to the entire breast were selected, their treatment was planned with Monaco VMAT, TD, and TH. Dosimetric parameters including PTV coverage, organ-at-risk (OAR) sparing, dose-volume histograms, and target minimum/maximum/mean doses were evaluated. It is found that for plans providing comparable PTV coverage, the Elekta VMAT plans were generally more inhomogeneous than the TH and TD plans. For the cases with regional node involvement, the average mean doses administered to the heart were 9.2 (± 5.2) and 8.8 (± 3.0) Gy in the VMAT and TH plans compared with 11.9 (± 6.4) and 11.8 (± 9.2) Gy for the 3DCRT and TD plans, respectively, with slightly higher doses given to the contralateral lung or breast or both. On average, the total monitor units for VMAT plans are 11.6% of those TH plans. Our studies have shown that VMAT and TH plans offer certain dosimetric advantages over fixed-field IMRT plans for advanced breast cancer requiring regional nodal treatment. However, for early-stage breast cancer fixed-field radiotherapy is potentially more beneficial in terms of OAR sparing.« less

Left-sided breast cancer irradiation using rotational and fixed-field radiotherapy.

PubMed

Qi, X Sharon; Liu, Tian X; Liu, Arthur K; Newman, Francis; Rabinovitch, Rachel; Kavanagh, Brian; Hu, Y Angie

2014-01-01

The 3-dimensional conformal radiotherapy (3DCRT) technique is the standard for breast cancer radiotherapy. During treatment planning, not only the coverage of the planning target volume (PTV) but also the minimization of the dose to critical structures, such as the lung, heart, and contralateral breast tissue, need to be considered. Because of the complexity and variations of patient anatomy, more advanced radiotherapy techniques are sometimes desired to better meet the planning goals. In this study, we evaluated external-beam radiation treatment techniques for left breast cancer using various delivery platforms: fixed-field including TomoDirect (TD), static intensity-modulated radiotherapy (sIMRT), and rotational radiotherapy including Elekta volumetric-modulated arc therapy (VMAT) and tomotherapy helical (TH). A total of 10 patients with left-sided breast cancer who did or did not have positive lymph nodes and were previously treated with 3DCRT/sIMRT to the entire breast were selected, their treatment was planned with Monaco VMAT, TD, and TH. Dosimetric parameters including PTV coverage, organ-at-risk (OAR) sparing, dose-volume histograms, and target minimum/maximum/mean doses were evaluated. It is found that for plans providing comparable PTV coverage, the Elekta VMAT plans were generally more inhomogeneous than the TH and TD plans. For the cases with regional node involvement, the average mean doses administered to the heart were 9.2 (± 5.2) and 8.8 (± 3.0)Gy in the VMAT and TH plans compared with 11.9 (± 6.4) and 11.8 (± 9.2)Gy for the 3DCRT and TD plans, respectively, with slightly higher doses given to the contralateral lung or breast or both. On average, the total monitor units for VMAT plans are 11.6% of those TH plans. Our studies have shown that VMAT and TH plans offer certain dosimetric advantages over fixed-field IMRT plans for advanced breast cancer requiring regional nodal treatment. However, for early-stage breast cancer fixed-field radiotherapy is potentially more beneficial in terms of OAR sparing. Copyright © 2014 American Association of Medical Dosimetrists. Published by Elsevier Inc. All rights reserved.

Ballistic impact to access the high-rate behaviour of individual silk fibres

NASA Astrophysics Data System (ADS)

Drodge, Daniel R.; Mortimer, Beth; Holland, Chris; Siviour, Clive R.

2012-10-01

A revision of a classic transverse fibre impact technique is presented, as applied to the problem of obtaining the high strain-rate constitutive behaviour of commercial Bombyx mori silk. Medium tenacity nylon was also studied. Two approaches are presented: firstly a fixed pre-stress, varied impact velocity method that derives stress-strain behaviour by inverse fit; and secondly a fixed impact velocity, varied pre-stress approach, assuming basic elastic jump conditions to obtain a locus of post-impact states. The post-impact stress-strain states obtained using the two approaches converge for silk but diverge for nylon. This we attribute to silk's fine structure being able to homogenise energy dissipation at static and dynamic deformation rates. However, the coarser microstructure of nylon results in a different loading path dependence, thus divergence in the two approaches. It was also noted that silk exhibited a comparatively stable level of impact energy absorption under varying pre-stress, when compared to nylon.

Use of generic and essential medicines for prevention and treatment of cardiovascular diseases in Portugal.

PubMed

Gama, Helena; Torre, Carla; Guerreiro, José Pedro; Azevedo, Ana; Costa, Suzete; Lunet, Nuno

2017-06-29

The successful control of cardiovascular diseases at the lowest possible cost requires the use of the most effective and affordable medicines. We aimed to describe the trends in the ambulatory use of medicines for prevention and treatment of cardiovascular diseases [Anatomic Therapeutic Chemical classification system (ATC): C and B01A] in Portugal, between 2004 and 2012, and to estimate the potential for expenditure reduction through changes in patterns of use. We analysed sell-out data, expressed as defined daily doses (DDD) and pharmacy retail price (€), from a nationwide database. We estimated potential reduction in expenditures through the increase, up to 90% of the volume of DDD, in the use of generic and essential medicines; the latter were defined according to guidelines from Portugal and another European country. Overall consumption increased by approximately 50% from 2004 to 2012, reaching nearly 2400 million DDD, whereas expenditure decreased to 753 million € (-31.3% since 2006). Use of generics and essential medicines increased, representing 43.6 and 39.9% of DDD consumption in 2012, respectively. The 40 most used groups of medicines in 2012 accounted for just over 80% of overall consumption; among these, increase in use of generics and essential medicines would have contributed to a saving of 275 million €. Changes in patterns of consumption of medicines towards a more frequent use of generics, a preferential use of essential medicines and a more rational use of fixed-dose combinations may contribute to a more efficient use of health resources.

Cyclophosphamide priming reduces intestinal damage in man following high dose melphalan chemotherapy.

PubMed Central

Selby, P. J.; Lopes, N.; Mundy, J.; Crofts, M.; Millar, J. L.; McElwain, T. J.

1987-01-01

A small pre-treatment 'priming' dose of cyclophosphamide will reduce gut damage due to high dose i.v. melphalan in mice and sheep but efforts to demonstrate this effect in man have been hampered by difficulty in the measurement of gut damage. We have evaluated the 51CR EDTA absorption test, a new method for measuring intestinal permeability, as a means of assessing damage due to high dose melphalan. The test was reliable, with a narrow normal range, easy to use and well tolerated. It detected an increase in intestinal permeability after high dose melphalan with a maximum occurring between 9 and 15 days after treatment and subsequently returning to normal. It was shown in 19 patients that a pre-treatment dose of cyclophosphamide was capable of significantly reducing the abnormalities in intestinal permeability which resulted from high dose melphalan. PMID:3111515

Chloral hydrate enteral infusion for sedation in ventilated children: the CHOSEN pilot study.

PubMed

Joffe, Ari R; Hogan, Jessica; Sheppard, Cathy; Tawfik, Gerda; Duff, Jonathan P; Garcia Guerra, Gonzalo

2017-11-26

We aimed to test a novel method of delivery of chloral hydrate (CH) sedation in ventilated critically ill young children. Children < 12 years old, within 72 hours of admission, who were ventilated, receiving enteral tube-feeds, with intermittent CH ordered were enrolled after signed consent. Patients received a CH loading-dose of 10 mg/kg enterally, then a syringe-pump enteral infusion at 5 mg/kg/hour, increasing to a maximum of 9 mg/kg/hour. Cases were compared to historical controls matched for age group and Pediatric Risk of Mortality score (PRISM) category, using Fisher's exact test and the t test. The primary outcome was feasibility, defined as the use of an enteral CH continuous infusion without discontinuation attributable to a pre-specified potential harm. There were 21 patients enrolled, at age 11.4 (12.1) months, with bronchiolitis in 10 (48%), a mean Pediatric Logistic Organ Dysfunction (PELOD) score of 6.2 (5.2), and having received enteral CH continuous infusion for 4.5 (2.2) days. Infusion of CH was feasible in 20/21 (95%; 95% CI 76-99%) patients, with one (5%) adverse event of duodenal ulcer perforation on day 3 in a patient with croup receiving regular ibuprofen and dexamethasone. The CH infusion dose (mg/kg/h) on day 2 (n = 20) was 8.9 (IQR 5.9, 9), and on day 4 (n = 11) was 8.8 (IQR 7, 9). Days to titration of adequate sedation (defined as ≤ 3 PRN doses/shift) was 1 (IQR 0.5, 2.5), and hours to awakening for extubation was 5 (IQR 2, 9). Cases (versus controls) had less positive fluid balance at 48 h (-2 (45) vs. 26 (46) ml/kg, p = 0.051), and a decrease in number of PRN sedation doses from 12 h pre to 12 hours post starting CH (4.7 (3.3) to 2.6 (2.8), p = 0.009 versus 2.9 (3.9) to 3.4 (5), p = 0.74). There were no statistically significant differences between cases and controls in inotrope scores, signs or treatment of withdrawal, or PICU days. Delivering CH by continuous enteral infusion is feasible, effective, and may be associated with less positive fluid balance. Whether there is a risk of duodenal perforation requires further study.

Impact of treatment planning with deformable image registration on dose distribution for carbon-ion beam lung treatment using a fixed irradiation port and rotating couch.

PubMed

Kumagai, M; Mori, S; Yamamoto, N

2015-06-01

When using a fixed irradiation port, treatment couch rotation is necessary to increase beam angle selection. We evaluated dose variations associated with positional morphological changes to organs. We retrospectively chose the data sets of ten patients with lung cancer who underwent respiratory-gated CT at three different couch rotation angles (0°, 20° and -20°). The respective CT data sets are referred to as CT0, CT20 and CT-20. Three treatment plans were generated as follows: in Plan 1, all compensating bolus designs and dose distributions were calculated using CT0. To evaluate the rotation effect without considering morphology changes, in Plan 2, the compensating boli designed using CT0 were applied to the CT±20 images. Plan 3 involved compensating boli designed using the CT±20 images. The accumulated dose distributions were calculated using deformable image registration (DIR). A sufficient prescribed dose was calculated for the planning target volume (PTV) in Plan 1 [minimum dose received by a volume ≥95% (D95) > 95.8%]. By contrast, Plan 2 showed degraded dose conformation to the PTV (D95 > 90%) owing to mismatch of the bolus design to the morphological positional changes in the respective CT. The dose assessment results of Plan 3 were very close to those of Plan 1. Dose distribution is significantly affected by whether or not positional organ morphology changes are factored into dose planning. In treatment planning using multiple CT scans with different couch positions, it is mandatory to calculate the accumulated dose using DIR.

Saxagliptin/Dapagliflozin: A Review in Type 2 Diabetes Mellitus.

PubMed

Garnock-Jones, Karly P

2017-03-01

Saxagliptin/dapagliflozin fixed-dose combination tablets (Qtern ® ) are indicated in the EU for the improvement of glycaemic control in adults with type 2 diabetes mellitus (T2DM), either when treatment with metformin and/or a sulfonylurea plus a monocomponent of saxagliptin/dapagliflozin provides inadequate glycaemic control, or when the patient is already being treated with the free combination of saxagliptin + dapagliflozin. This narrative review summarizes pharmacological, efficacy and tolerability data relevant to the use of saxagliptin/dapagliflozin in this indication. The agents have complementary mechanisms of action, and saxagliptin/dapagliflozin fixed-dose combination tablets are bioequivalent to free combination of saxagliptin + dapagliflozin. In three phase III trials, saxagliptin + dapagliflozin + metformin was more effective at providing glycaemic control than saxagliptin + metformin or dapagliflozin + metformin in previously treated patients with T2DM and inadequate glycaemic control on metformin monotherapy or metformin plus one of the monocomponents. The combination is associated with decreased bodyweight and a low risk of hypoglycaemia. As the first dipeptidyl peptidase-4 (DPP-4) inhibitor/sodium-glucose co-transporter (SGLT2) inhibitor fixed-dose combination available in the EU for glycaemic control in patients with T2DM, saxagliptin/dapagliflozin is a useful new option in this setting.

Asthma control in patients on fixed dose combination evaluated with mannitol challenge test.

PubMed

Romberg, Kerstin A M; Berggren, Anna-Carin; Bjermer, Leif

2014-02-01

Asthma is often difficult to control and it is likely that not all patients are optimally treated. This study aimed to explore asthma control in adults receiving fixed dose combination (FDC) therapy. Control of asthma was assessed using the mannitol challenge test as a monitoring tool to see if this would give additional information compared to the asthma control test (ACT). The study was an open-label, prospective study on 98 adults prescribed with FDC therapies for at least three months. 74 patients considered that their asthma was well controlled. However, 60 patients had a positive mannitol challenge test (PD15 < 635 mg), and when those with a positive response to the short-acting β2-agonist (≥15%) after the mannitol challenge test were included, this increased to 64 patients (65%). Exploratory analysis determined that the spirometry parameters; FEV1/FVC and FEV1% of predicted, were statistically significant predictors of a positive mannitol challenge test. Co-morbid conditions such as concomitant upper airway involvement or eczema did not predict mannitol reactivity. Although most patients rated their asthma as well controlled, many provided a positive mannitol challenge test, suggesting the presence of underlying inflammation, despite treatment with fixed dose combination therapy. Copyright © 2013 The Authors. Published by Elsevier Ltd.. All rights reserved.

High-dose-rate stereotactic body radiation therapy for postradiation therapy locally recurrent prostatic carcinoma: Preliminary prostate-specific antigen response, disease-free survival, and toxicity assessment.

PubMed

Fuller, Donald B; Wurzer, James; Shirazi, Reza; Bridge, Stephen S; Law, Jonathan; Mardirossian, George

2015-01-01

Patients with locally recurrent adenocarcinoma of the prostate following radiation therapy (RT) present a challenging problem. We prospectively evaluated the use of "high-dose-rate-like" prostate stereotactic body RT (SBRT) salvage for this circumstance, evaluating prostate-specific antigen response, disease-free survival, and toxicity. Between February 2009 and March 2014, 29 patients with biopsy-proven recurrent locally prostate cancer >2 years post-RT were treated. Median prior RT dose was 73.8 Gy and median interval to SBRT salvage was 88 months. Median recurrence Gleason score was 7 (79% was ≥7). Pre-existing RT toxicity >grade 1 was a reason for exclusion. Magnetic resonance imaging-defined prostate volume including any suspected extraprostatic extension, comprising the planning target volume. A total of 34 Gy/5 fractions was given, delivering a heterogeneous, high-dose-rate-like dose-escalation pattern. Toxicities were assessed using Common Terminology Criteria for Adverse Events, version 3.0, criteria. Twenty-nine treated patients had a median 24-month follow-up (range, 3-60 months). A median pre-SBRT salvage baseline prostate-specific antigen level of 3.1 ng/mL decreased to 0.65 ng/mL and 0.16 ng/mL at 1 and 2 years, respectively. Actuarial 2-year biochemical disease-free survival measured 82%, with no local failures. Toxicity >grade 1 was limited to the genitourinary domain, with 18% grade 2 or higher and 7% grade 3 or higher. No gastrointestinal toxicity >grade 1 occurred. Two-year disease-free survival is encouraging, and the prostate-specific antigen response kinetic appears comparable with that seen in de novo patients treated with SBRT, albeit still a preliminary finding. Grade ≥2 genitourinary toxicity was occasionally seen with no obvious predictive factor. Noting that our only brachytherapy case was 1 of the 2 cases with ≥grade 3 genitourinary toxicity, caution is recommended treating these patients. SBRT salvage of post-RT local recurrence appears clinically feasible, with longer term evaluation required to assess ultimate efficacy and late toxicity rates. Copyright © 2015 American Society for Radiation Oncology. Published by Elsevier Inc. All rights reserved.

Antituberculosis Drug-Induced Fixed Drug Eruption: A Case Report.

PubMed

Vaghela, Jitendra H; Nimbark, Vivek; Barvaliya, Manish; Mehta, Hita; Chavada, Bhavesh

2018-05-21

Fixed drug eruption (FDE) was caused by fixed-dose combination (FDC) of antituberculosis drugs in the form of tablet Forecox ® (rifampicin [rifampin] 225 mg + isoniazid 150 mg + pyrazinamide 750 mg + ethambutol 400 mg) in a 40-year-old male patient with a history of drug allergy. The patient developed FDE after taking the third dose of tablet Forecox ® for pulmonary tuberculosis. Tablet Forecox ® was withdrawn and the patient recovered from the reaction after 15 days of treatment for FDE. As per World Health Organization-Uppsala Monitoring Centre (WHO-UMC) and Naranjo causality assessment criteria, the association between the reaction and tablet Forecox ® was possible and probable, respectively. The reaction was moderately (Level 4b) severe according to the Modified Hartwig and Siegel scale. As there is an increased risk of allergic reaction in patients with a history of drug allergy, FDCs should not be used in order to avoid complexity in identifying the culprit drug.

Benchmarking the performance of fixed-image receptor digital radiography systems. Part 2: system performance metric.

PubMed

Lee, Kam L; Bernardo, Michael; Ireland, Timothy A

2016-06-01

This is part two of a two-part study in benchmarking system performance of fixed digital radiographic systems. The study compares the system performance of seven fixed digital radiography systems based on quantitative metrics like modulation transfer function (sMTF), normalised noise power spectrum (sNNPS), detective quantum efficiency (sDQE) and entrance surface air kerma (ESAK). It was found that the most efficient image receptors (greatest sDQE) were not necessarily operating at the lowest ESAK. In part one of this study, sMTF is shown to depend on system configuration while sNNPS is shown to be relatively consistent across systems. Systems are ranked on their signal-to-noise ratio efficiency (sDQE) and their ESAK. Systems using the same equipment configuration do not necessarily have the same system performance. This implies radiographic practice at the site will have an impact on the overall system performance. In general, systems are more dose efficient at low dose settings.

Fixed-dose combinations of drugs versus single-drug formulations for treating pulmonary tuberculosis

PubMed Central

Gallardo, Carmen R; Rigau Comas, David; Valderrama Rodríguez, Angélica; Roqué i Figuls, Marta; Parker, Lucy Anne; Caylà, Joan; Bonfill Cosp, Xavier

2016-01-01

Background People who are newly diagnosed with pulmonary tuberculosis (TB) typically receive a standard first-line treatment regimen that consists of two months of isoniazid, rifampicin, pyrazinamide, and ethambutol followed by four months of isoniazid and rifampicin. Fixed-dose combinations (FDCs) of these drugs are widely recommended. Objectives To compare the efficacy, safety, and acceptability of anti-tuberculosis regimens given as fixed-dose combinations compared to single-drug formulations for treating people with newly diagnosed pulmonary tuberculosis. Search methods We searched the Cochrane Infectious Disease Group Specialized Register; the Cochrane Central Register of Controlled Trials (CENTRAL, published in the Cochrane Library, Issue 11 2015); MEDLINE (1966 to 20 November 2015); EMBASE (1980 to 20 November 2015); LILACS (1982 to 20 November 2015); the metaRegister of Controlled Trials; and the World Health Organization International Clinical Trials Registry Platform (WHO ICTRP), without language restrictions, up to 20 November 2015. Selection criteria Randomized controlled trials that compared the use of FDCs with single-drug formulations in adults (aged 15 years or more) newly diagnosed with pulmonary TB. Data collection and analysis Two review authors independently assessed studies for inclusion, and assessed the risk of bias and extracted data from the included trials. We used risk ratios (RRs) for dichotomous data and mean differences (MDs) for continuous data with 95% confidence intervals (CIs). We attempted to assess the effect of treatment for time-to-event measures with hazard ratios and their 95% CIs. We used the Cochrane 'Risk of bias' assessment tool to determine the risk of bias in included trials. We used the fixed-effect model when there was little heterogeneity and the random-effects model with moderate heterogeneity. We used an I² statistic value of 75% or greater to denote significant heterogeneity, in which case we did not perform a meta-analysis. We assessed the quality of evidence using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. Main results We included 13 randomized controlled trials (RCTs) in the review, which enrolled 5824 participants. Trials were published between 1987 and 2015 and included participants in treatment with newly diagnosed pulmonary TB in countries with high TB prevalence. Only two trials reported the HIV status of included participants. Overall there is little or no difference detected between FDCs and single-drug formulations for most outcomes reported. We did not detect a difference in treatment failure between FDCs compared with single-drug formulations (RR 1.28, 95% CI 0.82 to 2.00; 3606 participants, seven trials, moderate quality evidence). Relapse may be more frequent in people treated with FDCs compared to single-drug formulations, although the confidence interval (CI) includes no difference (RR 1.28, 95% CI 1.00 to 1.64; 3621 participants, 10 trials, low quality evidence). We did not detect any difference in death between fixed-dose and single-drug formulation groups (RR 0.96, 95% CI 0.67 to 1.39; 4800 participants, 11 trials, moderate quality evidence). When we compared FDCs with single-drug formulations we found little or no difference for sputum smear or culture conversion at the end of treatment (RR 0.99, 95% CI 0.96 to 1.02; 2319 participants, seven trials, high quality evidence), for serious adverse events (RR 1.45, 95% CI 0.90 to 2.33; 3388 participants, six trials, moderate quality evidence), and for adverse events that led to discontinuation of therapy (RR 0.96, 95% CI 0.56 to 1.66; 5530 participants, 13 trials, low quality evidence). We conducted a sensitivity analysis excluding studies at high risk of bias and this did not alter the review findings. Authors' conclusions Fixed-dose combinations and single-drug formulations probably have similar effects for treating people with newly diagnosed pulmonary TB. PLAIN LANGUAGE SUMMARY Fixed-dose combinations for treating pulmonary tuberculosis What are fixed-dose combinations and how might they improve care of people with tuberculosis Tuberculosis (TB) is an important health problem, especially in developing countries. The treatment for pulmonary TB in new patients includes four oral medicines taken for six months, sometimes as fixed-dose combinations (FDCs) that are combined in one tablet, or taken separately as single-drug formulations. The World Health Organization recommends prescribers use fixed-dose combinations to reduce the number of tablets that people take. On the supply side, this might reduce prescribing errors and improve drug supply efficiency; on the patient's side, FDCS simplify treatment and improve adherence. We conducted a review to assess the efficacy, safety, and acceptability of FDCs compared with single-drug formulations for treating people with newly diagnosed pulmonary TB. What the research says We searched for relevant trials up to 20 November 2015, and included 13 randomized controlled trials that enrolled 5824 people. Trials were published between 1987 and 2015 and included participants in treatment with newly diagnosed pulmonary TB in countries with high TB prevalence. Only two trials reported the HIV status of included participants. There is probably little or no difference in FDCs compared to single-drug formulations for treatment failure (moderate quality evidence); relapse may be more frequent (low quality evidence); and the number of deaths were similar (moderate quality evidence). There is little or no difference in sputum smear or culture conversion (high quality evidence), and no difference was shown for serious adverse events (moderate quality evidence) or adverse events that led to discontinuation of therapy (low quality evidence). Authors' conclusions We concluded that fixed-dose combinations have similar efficacy to single-drug formulations for treating people with newly diagnosed pulmonary TB. PMID:27186634

A comparative study of restricted randomization procedures for multiarm trials with equal or unequal treatment allocation ratios.

PubMed

Ryeznik, Yevgen; Sverdlov, Oleksandr

2018-06-04

Randomization designs for multiarm clinical trials are increasingly used in practice, especially in phase II dose-ranging studies. Many new methods have been proposed in the literature; however, there is lack of systematic, head-to-head comparison of the competing designs. In this paper, we systematically investigate statistical properties of various restricted randomization procedures for multiarm trials with fixed and possibly unequal allocation ratios. The design operating characteristics include measures of allocation balance, randomness of treatment assignments, variations in the allocation ratio, and statistical characteristics such as type I error rate and power. The results from the current paper should help clinical investigators select an appropriate randomization procedure for their clinical trial. We also provide a web-based R shiny application that can be used to reproduce all results in this paper and run simulations under additional user-defined experimental scenarios. Copyright © 2018 John Wiley & Sons, Ltd.

Rational pharmacotherapy (RPT) in goutology: Define the serum uric acid target & treat-to-target patient cohort and review on urate lowering therapy (ULT) applying synthetic drugs.

PubMed

Jansen, Tim L

2015-07-01

A gout revolution is at hand as can be seen from the number of publications and our recent increase in a better understanding of gout regarding imaging, regarding pathogenetic involvement of crystals, cells and cytokines, as well as regarding new pharmacotherapeutic options. We should now focus on rational pharmacotherapy to significantly improve gout care. With modern combinations of xanthine oxidase inhibition PLUS uricosuric all serum urate concentrations can be targeted. The pharmacotherapeutic literature of synthetic urate lowering treatment is reviewed and a plea is given for rational pharmacotherapy combining different modes of action aiming at the rheumatologically predefined optimal serum urate concentrations instead of a more reluctant approach to just lower a serum urate to any lower level with a fixed dose allopurinol. Copyright © 2014. Published by Elsevier SAS.

Hypofractionated Image-Guided IMRT in Advanced Pancreatic Cancer With Simultaneous Integrated Boost to Infiltrated Vessels Concomitant With Capecitabine: A Phase I Study

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

Passoni, Paolo, E-mail: passoni.paolo@hsr.it; Reni, Michele; Cattaneo, Giovanni M.

2013-12-01

Purpose: To determine the maximum tolerated radiation dose (MTD) of an integrated boost to the tumor subvolume infiltrating vessels, delivered simultaneously with radical dose to the whole tumor and concomitant capecitabine in patients with pretreated advanced pancreatic adenocarcinoma. Methods and Materials: Patients with stage III or IV pancreatic adenocarcinoma without progressive disease after induction chemotherapy were eligible. Patients underwent simulated contrast-enhanced four-dimensional computed tomography and fluorodeoxyglucose-labeled positron emission tomography. Gross tumor volume 1 (GTV1), the tumor, and GTV2, the tumor subvolume 1 cm around the infiltrated vessels, were contoured. GTVs were fused to generate Internal Target Volume (ITV)1 and ITV2.more » Biological tumor volume (BTV) was fused with ITV1 to create the BTV+Internal Target Volume (ITV) 1. A margin of 5/5/7 mm (7 mm in cranium-caudal) was added to BTV+ITV1 and to ITV2 to create Planning Target Volume (PTV) 1 and PTV2, respectively. Radiation therapy was delivered with tomotherapy. PTV1 received a fixed dose of 44.25 Gy in 15 fractions, and PTV2 received a dose escalation from 48 to 58 Gy as simultaneous integrated boost (SIB) in consecutive groups of at least 3 patients. Concomitant chemotherapy was capecitabine, 1250 mg/m{sup 2} daily. Dose-limiting toxicity (DLT) was defined as any treatment-related G3 nonhematological or G4 hematological toxicity occurring during the treatment or within 90 days from its completion. Results: From June 2005 to February 2010, 25 patients were enrolled. The dose escalation on the SIB was stopped at 58 Gy without reaching the MTD. One patient in the 2{sup nd} dose level (50 Gy) had a DLT: G3 acute gastric ulcer. Three patients had G3 late adverse effects associated with gastric and/or duodenal mucosal damage. All patients received the planned dose of radiation. Conclusions: A dose of 44.25 Gy in 15 fractions to the whole tumor with an SIB of 58 Gy to small tumor subvolumes concomitant with capecitabine is feasible in chemotherapy-pretreated patients with advanced pancreatic cancer.« less

Radioiodine therapy of hyperfunctioning thyroid nodules: usefulness of an implemented dose calculation algorithm allowing reduction of radioiodine amount.

PubMed

Schiavo, M; Bagnara, M C; Pomposelli, E; Altrinetti, V; Calamia, I; Camerieri, L; Giusti, M; Pesce, G; Reitano, C; Bagnasco, M; Caputo, M

2013-09-01

Radioiodine is a common option for treatment of hyperfunctioning thyroid nodules. Due to the expected selective radioiodine uptake by adenoma, relatively high "fixed" activities are often used. Alternatively, the activity is individually calculated upon the prescription of a fixed value of target absorbed dose. We evaluated the use of an algorithm for personalized radioiodine activity calculation, which allows as a rule the administration of lower radioiodine activities. Seventy-five patients with single hyperfunctioning thyroid nodule eligible for 131I treatment were studied. The activities of 131I to be administered were estimated by the method described by Traino et al. and developed for Graves'disease, assuming selective and homogeneous 131I uptake by adenoma. The method takes into account 131I uptake and its effective half-life, target (adenoma) volume and its expected volume reduction during treatment. A comparison with the activities calculated by other dosimetric protocols, and the "fixed" activity method was performed. 131I uptake was measured by external counting, thyroid nodule volume by ultrasonography, thyroid hormones and TSH by ELISA. Remission of hyperthyroidism was observed in all but one patient; volume reduction of adenoma was closely similar to that assumed by our model. Effective half-life was highly variable in different patients, and critically affected dose calculation. The administered activities were clearly lower with respect to "fixed" activities and other protocols' prescription. The proposed algorithm proved to be effective also for single hyperfunctioning thyroid nodule treatment and allowed a significant reduction of administered 131I activities, without loss of clinical efficacy.

Challenges in early clinical development of adjuvanted vaccines.

PubMed

Della Cioppa, Giovanni; Jonsdottir, Ingileif; Lewis, David

2015-06-08

A three-step approach to the early development of adjuvanted vaccine candidates is proposed, the goal of which is to allow ample space for exploratory and hypothesis-generating human experiments and to select dose(s) and dosing schedule(s) to bring into full development. Although the proposed approach is more extensive than the traditional early development program, the authors suggest that by addressing key questions upfront the overall time, size and cost of development will be reduced and the probability of public health advancement enhanced. The immunogenicity end-points chosen for early development should be critically selected: an established immunological parameter with a well characterized assay should be selected as primary end-point for dose and schedule finding; exploratory information-rich end-points should be limited in number and based on pre-defined hypothesis generating plans, including system biology and pathway analyses. Building a pharmacodynamic profile is an important aspect of early development: to this end, multiple early (within 24h) and late (up to one year) sampling is necessary, which can be accomplished by sampling subgroups of subjects at different time points. In most cases the final target population, even if vulnerable, should be considered for inclusion in early development. In order to obtain the multiple formulations necessary for the dose and schedule finding, "bed-side mixing" of various components of the vaccine is often necessary: this is a complex and underestimated area that deserves serious research and logistical support. Copyright © 2015 Elsevier Ltd. All rights reserved.

Sex, PrEP, and Stigma: Experiences with HIV Pre-exposure Prophylaxis Among New York City MSM Participating in the HPTN 067/ADAPT Study.

PubMed

Franks, Julie; Hirsch-Moverman, Yael; Loquere, Avelino S; Amico, K Rivet; Grant, Robert M; Dye, Bonnie J; Rivera, Yan; Gamboa, Robert; Mannheimer, Sharon B

2018-04-01

The HPTN 067/Alternative Dosing to Augment Pre-Exposure Prophylaxis Pill Taking (ADAPT) study evaluated daily and non-daily dosing schedules for oral pre-exposure prophylaxis (PrEP) to prevent HIV. A qualitative sub-study including focus groups and in-depth interviews was conducted among men who have sex with men participating in New York City to understand their experience with PrEP and study dosing schedules. The 37 sub-study participants were 68% black, 11% white, and 8% Asian; 27% were of Hispanic/Latino ethnicity. Mean age was 34 years. Themes resulting from qualitative analysis include: PrEP is a significant advance for HIV prevention; non-daily dosing of PrEP is congruent with HIV risk; and pervasive stigma connected to HIV and risk behavior is a barrier to PrEP adherence, especially for non-daily dosing schedules. The findings underscore how PrEP intersects with other HIV prevention practices and highlight the need to understand and address multidimensional stigma related to PrEP use.

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

Marsh, I; Otto, M; Weichert, J

Purpose: The focus of this work is to perform Monte Carlo-based dosimetry for several pediatric cancer xenografts in mice treated with a novel radiopharmaceutical {sup 131}I-CLR1404. Methods: Four mice for each tumor cell line were injected with 8–13 µCi/g of the {sup 124}124I-CLR1404. PET/CT images of each individual mouse were acquired at 5–6 time points over the span of 96–170 hours post-injection. Following acquisition, the images were co-registered, resampled, rescaled, corrected for partial volume effects (PVE), and masked. For this work the pre-treatment PET images of {sup 124}I-CLR1404 were used to predict therapeutic doses from {sup 131}I-CLR1404 at each timemore » point by assuming the same injection activity and accounting for the difference in physical decay rates. Tumors and normal tissues were manually contoured using anatomical and functional images. The CT and the PET images were used in the Geant4 (v9.6) Monte Carlo simulation to define the geometry and source distribution, respectively. The total cumulated absorbed dose was calculated by numerically integrating the dose-rate at each time point over all time on a voxel-by-voxel basis. Results: Spatial distributions of the absorbed dose rates and dose volume histograms as well as mean, minimum, maximum, and total dose values for each ROI were generated for each time point. Conclusion: This work demonstrates how mouse-specific MC-based dosimetry could potentially provide more accurate characterization of efficacy of novel radiopharmaceuticals in radionuclide therapy. This work is partially funded by NIH grant CA198392.« less

P.F.C Sigma® cruciate retaining fixed-bearing versus mobile-bearing knee arthroplasty: a prospective comparative study with minimum 10-year follow-up.

PubMed

Riaz, O; Aqil, A; Sisodia, G; Chakrabarty, G

2017-12-01

To prospectively compare long-term clinical and radiological outcomes following a cruciate retaining fixed-bearing (FB) and a mobile-bearing (MB) primary total knee replacement (TKR). We prospectively reviewed 113 TKRs in 99 patients (14 bilateral) with a PFC sigma cruciate retaining rotating platform system, at an average follow-up of 11.1 years (range 10-12). Results were contrasted with those from 89 TKRs in 72 patients (17 bilateral) with a PFC sigma cruciate fixed-bearing prosthesis, at an average follow-up of 12.1 years (range 10-14.1). Outcomes collected included pre- and post-operative range of motion, Oxford Knee Scores, complications encountered, as well as radiographical assessments of polyethylene wear. In the MB group, mean Oxford Knee Scores improved from 16 pre-operatively to 42 at final follow-up. The mean range of motion was 115° (75-130). In the FB group, mean Oxford Knee Scores improved from 16.2 pre-operatively to 42.5 at final follow-up. The mean range of motion was 111.2 (80-135) degrees at final follow-up. We failed to elicit an objectively demonstrable clinical difference between the MB- and FB-implanted knees. Similarly, radiological benefits of the MB implants with regard to polyethylene wear were not evident at a minimum 10-year follow-up.

The story of artesunate–mefloquine (ASMQ), innovative partnerships in drug development: case study

PubMed Central

2013-01-01

Background The Drugs for Neglected Diseases initiative (DNDi) is a not-for profit organization committed to providing affordable medicines and access to treatments in resource-poor settings. Traditionally drug development has happened “in house” within pharmaceutical companies, with research and development costs ultimately recuperated through drug sales. The development of drugs for the treatment of neglected tropical diseases requires a completely different model that goes beyond the scope of market-driven research and development. Artesunate and mefloquine are well-established drugs for the treatment of uncomplicated malaria, with a strong safety record based on many years of field-based studies and use. The administration of such artemisinin-based combination therapy in a fixed-dose combination is expected to improve patient compliance and to reduce the risk of emerging drug resistance. Case description DNDi developed an innovative approach to drug development, reliant on strong collaborations with a wide range of partners from the commercial world, academia, government institutions and NGOs, each of which had a specific role to play in the development of a fixed dose combination of artesunate and mefloquine. Discussion and evaluation DNDi undertook the development of a fixed-dose combination of artesunate with mefloquine. Partnerships were formed across five continents, addressing formulation, control and production through to clinical trials and product registration, resulting in a safe and efficacious fixed dose combination treatment which is now available to treat patients in resource-poor settings. The south-south technology transfer of production from Farmanguinhos/Fiocruz in Brazil to Cipla Ltd in India was the first of its kind. Of additional benefit was the increased capacity within the knowledge base and infrastructure in developing countries. Conclusions This collaborative approach to drug development involving international partnerships and independent funding mechanisms is a powerful new way to develop drugs for tropical diseases. PMID:23433060

Defined contribution: a part of our future.

PubMed Central

Baugh, Reginald F.

2003-01-01

Rising employer health care costs and consumer backlash against managed care are trends fostering the development of defined contribution plans. Defined contribution plans limit employer responsibility to a fixed financial contribution rather than a benefit program and dramatically increase consumer responsibility for health care decision making. Possible outcomes of widespread adoption of defined contribution plans are presented. PMID:12934869

Lung texture in serial thoracic CT scans: correlation with radiologist-defined severity of acute changes following radiation therapy

NASA Astrophysics Data System (ADS)

Cunliffe, Alexandra R.; Armato, Samuel G., III; Straus, Christopher; Malik, Renuka; Al-Hallaq, Hania A.

2014-09-01

This study examines the correlation between the radiologist-defined severity of normal tissue damage following radiation therapy (RT) for lung cancer treatment and a set of mathematical descriptors of computed tomography (CT) scan texture (‘texture features’). A pre-therapy CT scan and a post-therapy CT scan were retrospectively collected under IRB approval for each of the 25 patients who underwent definitive RT (median dose: 66 Gy). Sixty regions of interest (ROIs) were automatically identified in the non-cancerous lung tissue of each post-therapy scan. A radiologist compared post-therapy scan ROIs with pre-therapy scans and categorized each as containing no abnormality, mild abnormality, moderate abnormality, or severe abnormality. Twenty texture features that characterize gray-level intensity, region morphology, and gray-level distribution were calculated in post-therapy scan ROIs and compared with anatomically matched ROIs in the pre-therapy scan. Linear regression and receiver operating characteristic (ROC) analysis were used to compare the percent feature value change (ΔFV) between ROIs at each category of visible radiation damage. Most ROIs contained no (65%) or mild abnormality (30%). ROIs with moderate (3%) or severe (2%) abnormalities were observed in 9 patients. For 19 of 20 features, ΔFV was significantly different among severity levels. For 12 features, significant differences were observed at every level. Compared with regions with no abnormalities, ΔFV for these 12 features increased, on average, by 1.5%, 12%, and 30%, respectively, for mild, moderate, and severe abnormalitites. Area under the ROC curve was largest when comparing ΔFV in the highest severity level with the remaining three categories (mean AUC across features: 0.84). In conclusion, 19 features that characterized the severity of radiologic changes from pre-therapy scans were identified. These features may be used in future studies to quantify acute normal lung tissue damage following RT. Presented, in part at the IASLC 15th World Conference on Lung Conference, Sydney, AUS (2013).

Applicator-guided volumetric-modulated arc therapy for low-risk endometrial cancer

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

Cilla, Savino, E-mail: savinocilla@gmail.com; Macchia, Gabriella; Sabatino, Domenico

2013-04-01

The aim of this study was to report the feasibility of volumetric-modulated arc therapy (VMAT) in the postoperative irradiation of the vaginal vault. Moreover, the VMAT technique was compared with 3D conformal radiotherapy (3D-CRT) and fixed-field intensity-modulated radiotherapy (IMRT), in terms of target coverage and organs at risk sparing. The number of monitor units and the delivery time were analyzed to score the treatment efficiency. All plans were verified in a dedicated solid water phantom using a 2D array of ionization chambers. Twelve patients with endometrial carcinoma who underwent radical hystero-adenexectomy and fixed-field IMRT treatments were retrospectively included in thismore » analysis; for each patient, plans were compared in terms of dose-volume histograms, homogeneity index, and conformity indexes. All techniques met the prescription goal for planning target volume coverage, with VMAT showing the highest level of conformity at all dose levels. VMAT resulted in significant reduction of rectal and bladder volumes irradiated at all dose levels compared with 3D-CRT. No significant differences were found with respect to IMRT. Moreover, a significant improvement of the dose conformity was reached by VMAT technique not only at the 95% dose level (0.74 vs. 0.67 and 0.62) but also at 50% and 75% levels of dose prescription. In addition, VMAT plans showed a significant reduction of monitor units by nearly 28% with respect to IMRT, and reduced treatment time from 11 to <3 minutes for a single 6-Gy fraction. In conclusion, VMAT plans can be planned and carried out with high quality and efficiency for the irradiation of vaginal vault alone, providing similar or better sparing of organs at risk to fixed-field IMRT and resulting in the most efficient treatment option. VMAT is currently our standard approach for radiotherapy of low-risk endometrial cancer.« less

Office and ambulatory blood pressure control with a fixed-dose combination of candesartan and hydrochlorothiazide in previously uncontrolled hypertensive patients: results of CHILI CU Soon

PubMed Central

Mengden, Thomas; Hübner, Reinhold; Bramlage, Peter

2011-01-01

Background Fixed-dose combinations of candesartan 32 mg and hydrochlorothiazide (HCTZ) have been shown to be effective in clinical trials. Upon market entry we conducted a noninterventional study to document the safety and effectiveness of this fixed-dose combination in an unselected population in primary care and to compare blood pressure (BP) values obtained during office measurement (OBPM) with ambulatory blood pressure measurement (ABPM). Methods CHILI CU Soon was a prospective, noninterventional, noncontrolled, open-label, multicenter study with a follow-up of at least 10 weeks. High-risk patients aged ≥18 years with previously uncontrolled hypertension were started on candesartan 32 mg in a fixed-dose combination with either 12.5 mg or 25 mg HCTZ. OBPM and ABPM reduction and adverse events were documented. Results A total of 4131 patients (52.8% male) with a mean age of 63.0 ± 11.0 years were included. BP was 162.1 ± 14.8/94.7 ± 9.2 mmHg during office visits at baseline. After 10 weeks of candesartan 32 mg/12.5 mg or 25 mg HCTZ, mean BP had lowered to 131.7 ± 10.5/80.0 ± 6.6 mmHg (P < 0.0001 for both comparisons). BP reduction was comparable irrespective of prior or concomitant medication. In patients for whom physicians regarded an ABPM to be necessary (because of suspected noncontrol over 24 hours), ABP at baseline was 158.2/93.7 mmHg during the day and 141.8/85.2 mmHg during the night. At the last visit, BP had significantly reduced to 133.6/80.0 mmHg and 121.0/72.3 mmHg, respectively, resulting in 20.8% being normotensive over 24 hours (<130/80 mmHg). The correlation between OBPM and ABPM was good (r = 0.589 for systolic BP and r = 0.389 for diastolic BP during the day). Of those who were normotensive upon OBPM, 35.1% had high ABPM during the day, 49.3% were nondippers, and 3.4% were inverted dippers. Forty-nine adverse events (1.19%) were reported, of which seven (0.17%) were regarded as serious. Conclusion Candesartan 32 mg in a fixed-dose combination with either 12.5 mg or 25 mg HCTZ is safe and effective for further BP lowering irrespective of prior antihypertensive drug class not being able to control BP. PMID:22241950

Cost-utility analysis of the fixed-dose combination of dolutegravir/abacavir/lamivudine as initial treatment of HIV+ patients in Spain.

PubMed

Moreno Guillen, Santiago; Losa García, Juan Emilio; Berenguer Berenguer, Juan; Martínez Sesmero, José Manuel; Cenoz Gomis, Santiago; Graefenhain, Ruth; Lopez Sanchez-Cambronero, David; Parrondo Garcia, Francisco Javier

2017-09-01

Fixed-dose combinations of antiretroviral drugs have meant an important step forward in simplifying treatment and improving compliance and has led to an increased effectiveness of therapy, a viral load decrease and improving the quality of life of patients. The single-table formulation of dolutegravir with abacavir and lamivudine (DTG/ABC/3TC) is a highly efficacious and well-tolerated once-daily regimen for HIV-infected patients. The objective of the study was to assess the incremental cost-utility ratio of the fixed-dose combination of (DTG/ABC/3TC) versus the combinations emtricitabine/tenofovir/efavirenz (FTC/TDF/EFV), and darunavir/r (DRV/r) or raltegravir (RAL) with emtricitabine/tenofovir (FTC/TDF) or abacavir/lamivudine (ABC/3TC) as initial antiretroviral therapy in patients infected with HIV-1 from the perspective of the Spanish National Health System. The ARAMIS model, which uses a microsimulation approach to simulate the individual changes in each patient from the start of treatment to death through a Markov chain of descriptive health states of the disease, was adapted to Spain. The alternatives used for comparison were the fixed-dose combination of emtricitabine/tenofovir/efavirenz (FTC/TDF/EFV), and the fixed- dose combinations of emtricitabine/tenofovir (FTC/TDF) or abacavir/lamivudine (ABC/3TC) with darunavir/r (DRV/r) or raltegravir (RAL). The probability of achieving virological suppression by the treatments included in the model was obtained from clinical trials SINGLE, SPRING-2 and FLAMINGO and the costs were expressed in € (2015). The model use the perspective of the Spanish National Health System, with a lifetime horizon and a discount rate of 3% was applied to cost and effectiveness. Treatment initiation with DTG/ABC/3TC was dominant when it was compared with treatment initiation with all the comparators: vs. FTC/TDF/EFV (-67 210.71€/QALY), vs. DRV/r + FTC/TDF or ABC/3TC (-1 787 341.44€/QALY), and vs. RAL + FTC/TDF or ABC/3TC (-1 005 117.13€/QALY). All the sensitivity analyses performed showed the consistency of these findings. With the premises considered, treatment initiation with DTG/ABC/3TC STR appears to be the most cost-effective option in ARTnaïve HIV infected patients from the Spanish Health System perspective. Copyright AULA MEDICA EDICIONES 2014. Published by AULA MEDICA. All rights reserved.

FIXED DOSE COMBINATIONS WITH SELECTIVE BETA-BLOCKERS: QUANTITATIVE DETERMINATION IN BIOLOGICAL FLUIDS.

PubMed

Mahu, Ştefania Corina; Hăncianu, Monica; Agoroaei, Luminiţa; Grigoriu, Ioana Cezara; Strugaru, Anca Monica; Butnaru, Elena

2015-01-01

Hypertension is one of the most common causes of death, a complex and incompletely controlled disease for millions of patients. Metoprolol, bisoprolol, nebivolol and atenolol are selective beta-blockers frequently used in the management of arterial hypertension, alone or in fixed combination with other substances. This study presents the most used analytical methods for simultaneous determination in biological fluids of fixed combinations containing selective beta-blockers. Articles in Pub-Med, Science Direct and Wiley Journals databases published between years 2004-2014 were reviewed. Methods such as liquid chromatography--mass spectrometry--mass spectrometry (LC-MS/MS), high performance liquid chromatography (HPLC) or high performance liquid chromatography--mass spectrometry (HPLC-MS) were used for determination of fixed combination with beta-blockers in human plasma, rat plasma and human breast milk. LC-MS/MS method was used for simultaneous determination of fixed combinations of metoprolol with simvastatin, hydrochlorothiazide or ramipril, combinations of nebivolol and valsartan, or atenolol and amlodipine. Biological samples were processed by protein precipitation techniques or by liquid-liquid extraction. For the determination of fixed dose combinations of felodipine and metoprolol in rat plasma liquid chromatography--electrospray ionization--mass spectrometry (LC-ESI-MS/MS) was applied, using phenacetin as internal standard. HPLC-MS method was applied for the determination of bisoprolol and hydrochlorothiazide in human plasma. For the determination of atenolol and chlorthalidone from human breast milk and human plasma the HPLC method was used. The analytical methods were validated according to the specialized guidelines, and were applied to biological samples, thing that confirms the permanent concern of researchers in this field.

Artemether-lumefantrine dosing for malaria treatment in young children and pregnant women: A pharmacokinetic-pharmacodynamic meta-analysis.

PubMed

Kloprogge, Frank; Workman, Lesley; Borrmann, Steffen; Tékété, Mamadou; Lefèvre, Gilbert; Hamed, Kamal; Piola, Patrice; Ursing, Johan; Kofoed, Poul Erik; Mårtensson, Andreas; Ngasala, Billy; Björkman, Anders; Ashton, Michael; Friberg Hietala, Sofia; Aweeka, Francesca; Parikh, Sunil; Mwai, Leah; Davis, Timothy M E; Karunajeewa, Harin; Salman, Sam; Checchi, Francesco; Fogg, Carole; Newton, Paul N; Mayxay, Mayfong; Deloron, Philippe; Faucher, Jean François; Nosten, François; Ashley, Elizabeth A; McGready, Rose; van Vugt, Michele; Proux, Stephane; Price, Ric N; Karbwang, Juntra; Ezzet, Farkad; Bakshi, Rajesh; Stepniewska, Kasia; White, Nicholas J; Guerin, Philippe J; Barnes, Karen I; Tarning, Joel

2018-06-01

The fixed dose combination of artemether-lumefantrine (AL) is the most widely used treatment for uncomplicated Plasmodium falciparum malaria. Relatively lower cure rates and lumefantrine levels have been reported in young children and in pregnant women during their second and third trimester. The aim of this study was to investigate the pharmacokinetic and pharmacodynamic properties of lumefantrine and the pharmacokinetic properties of its metabolite, desbutyl-lumefantrine, in order to inform optimal dosing regimens in all patient populations. A search in PubMed, Embase, ClinicalTrials.gov, Google Scholar, conference proceedings, and the WorldWide Antimalarial Resistance Network (WWARN) pharmacology database identified 31 relevant clinical studies published between 1 January 1990 and 31 December 2012, with 4,546 patients in whom lumefantrine concentrations were measured. Under the auspices of WWARN, relevant individual concentration-time data, clinical covariates, and outcome data from 4,122 patients were made available and pooled for the meta-analysis. The developed lumefantrine population pharmacokinetic model was used for dose optimisation through in silico simulations. Venous plasma lumefantrine concentrations 7 days after starting standard AL treatment were 24.2% and 13.4% lower in children weighing <15 kg and 15-25 kg, respectively, and 20.2% lower in pregnant women compared with non-pregnant adults. Lumefantrine exposure decreased with increasing pre-treatment parasitaemia, and the dose limitation on absorption of lumefantrine was substantial. Simulations using the lumefantrine pharmacokinetic model suggest that, in young children and pregnant women beyond the first trimester, lengthening the dose regimen (twice daily for 5 days) and, to a lesser extent, intensifying the frequency of dosing (3 times daily for 3 days) would be more efficacious than using higher individual doses in the current standard treatment regimen (twice daily for 3 days). The model was developed using venous plasma data from patients receiving intact tablets with fat, and evaluations of alternative dosing regimens were consequently only representative for venous plasma after administration of intact tablets with fat. The absence of artemether-dihydroartemisinin data limited the prediction of parasite killing rates and recrudescent infections. Thus, the suggested optimised dosing schedule was based on the pharmacokinetic endpoint of lumefantrine plasma exposure at day 7. Our findings suggest that revised AL dosing regimens for young children and pregnant women would improve drug exposure but would require longer or more complex schedules. These dosing regimens should be evaluated in prospective clinical studies to determine whether they would improve cure rates, demonstrate adequate safety, and thereby prolong the useful therapeutic life of this valuable antimalarial treatment.

Development and Validation of a Heart Atlas to Study Cardiac Exposure to Radiation Following Treatment for Breast Cancer

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

Feng, Mary, E-mail: maryfeng@umich.ed; Moran, Jean M.; Koelling, Todd

2011-01-01

Purpose: Cardiac toxicity is an important sequela of breast radiotherapy. However, the relationship between dose to cardiac structures and subsequent toxicity has not been well defined, partially due to variations in substructure delineation, which can lead to inconsistent dose reporting and the failure to detect potential correlations. Here we have developed a heart atlas and evaluated its effect on contour accuracy and concordance. Methods and Materials: A detailed cardiac computed tomography scan atlas was developed jointly by cardiology, cardiac radiology, and radiation oncology. Seven radiation oncologists were recruited to delineate the whole heart, left main and left anterior descending interventricularmore » branches, and right coronary arteries on four cases before and after studying the atlas. Contour accuracy was assessed by percent overlap with gold standard atlas volumes. The concordance index was also calculated. Standard radiation fields were applied. Doses to observer-contoured cardiac structures were calculated and compared with gold standard contour doses. Pre- and post-atlas values were analyzed using a paired t test. Results: The cardiac atlas significantly improved contour accuracy and concordance. Percent overlap and concordance index of observer-contoured cardiac and gold standard volumes were 2.3-fold improved for all structures (p < 0.002). After application of the atlas, reported mean doses to the whole heart, left main artery, left anterior descending interventricular branch, and right coronary artery were within 0.1, 0.9, 2.6, and 0.6 Gy, respectively, of gold standard doses. Conclusions: This validated University of Michigan cardiac atlas may serve as a useful tool in future studies assessing cardiac toxicity and in clinical trials which include dose volume constraints to the heart.« less

The Effect of High Dose Cilostazol and Rosuvastatin on Periprocedural Myocardial Injury in Patients with Elective Percutaneous Coronary Intervention

PubMed Central

H., Ari; N., Emlek; S., Ari; S., Coşar; K., Doğanay; C., Aydin; E., Tenekecioğlu; A., Tütüncü; O.C., Yontar; M., Gürdoğan; T., Bozat; M., Melek

2015-01-01

Background The aim of our study was to assess the effect of pretreatment with cilostazol and rosuvastatin combination before elective percutaneous coronary intervention (PCI) on peri-procedural myocardial injury (PPMIJ). Methods We randomly assigned 172 patients with stable angina pectoris scheduled for elective PCI to pre- treatment with Cilostazol 200mg and Rosuvastatin 40 mg (group 1), or to pretreatment with Rosuvastatin 40 mg group (group 2). The primary end-point was the occurrence of PPMIJ defined as any cardiac troponin I (Tn I) level elevated above the upper normal limit (UNL). The occurrence of peri-procedural myocardial infarction (PPMIN) was defined as a post-procedural increase in cTnI level ≥ 5 times above the UNL. Results There was no significant difference in baseline characteristics between group 1 (n = 86) and group 2 (n = 86). The rate of PPMIJ (21% vs. 24%, p = 0.58) and PPMIN (2.3% vs. 7%, p = 0.27) were similar between the two study groups. Subgroup analysis performed on those patients without statin therapy before PCI (53 patients in group 1 and 50 patients in group 2) showed that the incidence of PPMIJ was significantly lower in the group 1 patients without chronic statin treatment [17% (9/53) versus 34% (17/50); p = 0.04], but the rate of PPMIN was similar between the two groups for those patients without chronic statin treatment [1.9% (1/53) versus 10% (5/50); p = 0.07]. Conclusions We found that adjunct cilostazol and rosuvastatin pre-treatment did not significantly reduce PPMIJ after elective PCI in patients with stable angina pectoris. However, adjunct cilostazol pre-treatment could reduce PPMIJ in patients without chronic statin therapy before elective PCI. PMID:27122885

The Effect of High Dose Cilostazol and Rosuvastatin on Periprocedural Myocardial Injury in Patients with Elective Percutaneous Coronary Intervention.

PubMed

H, Ari; N, Emlek; S, Ari; S, Coşar; K, Doğanay; C, Aydin; E, Tenekecioğlu; A, Tütüncü; O C, Yontar; M, Gürdoğan; T, Bozat; M, Melek

2015-07-01

The aim of our study was to assess the effect of pretreatment with cilostazol and rosuvastatin combination before elective percutaneous coronary intervention (PCI) on peri-procedural myocardial injury (PPMIJ). We randomly assigned 172 patients with stable angina pectoris scheduled for elective PCI to pre- treatment with Cilostazol 200mg and Rosuvastatin 40 mg (group 1), or to pretreatment with Rosuvastatin 40 mg group (group 2). The primary end-point was the occurrence of PPMIJ defined as any cardiac troponin I (Tn I) level elevated above the upper normal limit (UNL). The occurrence of peri-procedural myocardial infarction (PPMIN) was defined as a post-procedural increase in cTnI level ≥ 5 times above the UNL. There was no significant difference in baseline characteristics between group 1 (n = 86) and group 2 (n = 86). The rate of PPMIJ (21% vs. 24%, p = 0.58) and PPMIN (2.3% vs. 7%, p = 0.27) were similar between the two study groups. Subgroup analysis performed on those patients without statin therapy before PCI (53 patients in group 1 and 50 patients in group 2) showed that the incidence of PPMIJ was significantly lower in the group 1 patients without chronic statin treatment [17% (9/53) versus 34% (17/50); p = 0.04], but the rate of PPMIN was similar between the two groups for those patients without chronic statin treatment [1.9% (1/53) versus 10% (5/50); p = 0.07]. We found that adjunct cilostazol and rosuvastatin pre-treatment did not significantly reduce PPMIJ after elective PCI in patients with stable angina pectoris. However, adjunct cilostazol pre-treatment could reduce PPMIJ in patients without chronic statin therapy before elective PCI. Cilostazol; Myocardial injury; Percutaneous coronary intervention; Statin.

40 CFR 63.1042 - Standards-Separator fixed roof.

Code of Federal Regulations, 2010 CFR

2010-07-01

... 40 Protection of Environment 10 2010-07-01 2010-07-01 false Standards-Separator fixed roof. 63.1042 Section 63.1042 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED) AIR PROGRAMS..., ignitable, explosive, reactive, or hazardous materials. (3) Opening of a safety device, as defined in § 63...

Occupational exposures to solvents and metals are associated with fixed airflow obstruction.

PubMed

Alif, Sheikh M; Dharmage, Shyamali C; Benke, Geza; Dennekamp, Martine; Burgess, John A; Perret, Jennifer L; Lodge, Caroline J; Morrison, Stephen; Johns, David P; Giles, Graham G; Gurrin, Lyle C; Thomas, Paul S; Hopper, John L; Wood-Baker, Richard; Thompson, Bruce R; Feather, Iain H; Vermeulen, Roel; Kromhout, Hans; Walters, E Haydn; Abramson, Michael J; Matheson, Melanie C

2017-11-01

Objectives This study investigated the associations between occupational exposures to solvents and metals and fixed airflow obstruction (AO) using post-bronchodilator spirometry. Methods We included 1335 participants from the 2002-2008 follow-up of the Tasmanian Longitudinal Health Study. Ever-exposure and cumulative exposure-unit (EU) years were calculated using the ALOHA plus job exposure matrix (JEM). Fixed AO was defined as post-bronchodilator forced expiratory volume in one second (FEV1)/forced vital capacity (FVC) <0.7 and FEV 1 /FVC

The effect of statistical noise on IMRT plan quality and convergence for MC-based and MC-correction-based optimized treatment plans.

PubMed

Siebers, Jeffrey V

2008-04-04

Monte Carlo (MC) is rarely used for IMRT plan optimization outside of research centres due to the extensive computational resources or long computation times required to complete the process. Time can be reduced by degrading the statistical precision of the MC dose calculation used within the optimization loop. However, this eventually introduces optimization convergence errors (OCEs). This study determines the statistical noise levels tolerated during MC-IMRT optimization under the condition that the optimized plan has OCEs <100 cGy (1.5% of the prescription dose) for MC-optimized IMRT treatment plans.Seven-field prostate IMRT treatment plans for 10 prostate patients are used in this study. Pre-optimization is performed for deliverable beams with a pencil-beam (PB) dose algorithm. Further deliverable-based optimization proceeds using: (1) MC-based optimization, where dose is recomputed with MC after each intensity update or (2) a once-corrected (OC) MC-hybrid optimization, where a MC dose computation defines beam-by-beam dose correction matrices that are used during a PB-based optimization. Optimizations are performed with nominal per beam MC statistical precisions of 2, 5, 8, 10, 15, and 20%. Following optimizer convergence, beams are re-computed with MC using 2% per beam nominal statistical precision and the 2 PTV and 10 OAR dose indices used in the optimization objective function are tallied. For both the MC-optimization and OC-optimization methods, statistical equivalence tests found that OCEs are less than 1.5% of the prescription dose for plans optimized with nominal statistical uncertainties of up to 10% per beam. The achieved statistical uncertainty in the patient for the 10% per beam simulations from the combination of the 7 beams is ~3% with respect to maximum dose for voxels with D>0.5D(max). The MC dose computation time for the OC-optimization is only 6.2 minutes on a single 3 Ghz processor with results clinically equivalent to high precision MC computations.

Optimal mapping of terrestrial gamma dose rates using geological parent material and aerogeophysical survey data.

PubMed

Rawlins, B G; Scheib, C; Tyler, A N; Beamish, D

2012-12-01

Regulatory authorities need ways to estimate natural terrestrial gamma radiation dose rates (nGy h⁻¹) across the landscape accurately, to assess its potential deleterious health effects. The primary method for estimating outdoor dose rate is to use an in situ detector supported 1 m above the ground, but such measurements are costly and cannot capture the landscape-scale variation in dose rates which are associated with changes in soil and parent material mineralogy. We investigate the potential for improving estimates of terrestrial gamma dose rates across Northern Ireland (13,542 km²) using measurements from 168 sites and two sources of ancillary data: (i) a map based on a simplified classification of soil parent material, and (ii) dose estimates from a national-scale, airborne radiometric survey. We used the linear mixed modelling framework in which the two ancillary variables were included in separate models as fixed effects, plus a correlation structure which captures the spatially correlated variance component. We used a cross-validation procedure to determine the magnitude of the prediction errors for the different models. We removed a random subset of 10 terrestrial measurements and formed the model from the remainder (n = 158), and then used the model to predict values at the other 10 sites. We repeated this procedure 50 times. The measurements of terrestrial dose vary between 1 and 103 (nGy h⁻¹). The median absolute model prediction errors (nGy h⁻¹) for the three models declined in the following order: no ancillary data (10.8) > simple geological classification (8.3) > airborne radiometric dose (5.4) as a single fixed effect. Estimates of airborne radiometric gamma dose rate can significantly improve the spatial prediction of terrestrial dose rate.

Efficacy of dosing and re-dosing of two oral fixed combinations of indomethacin, prochlorperazine and caffeine compared with oral sumatriptan in the acute treatment of multiple migraine attacks: a double-blind, double-dummy, randomised, parallel group, multicentre study

PubMed Central

Sandrini, G; Cerbo, R; Del Bene, E; Ferrari, A; Genco, S; Grazioli, I; Martelletti, P; Nappi, G; Pinessi, L; Sarchielli, P; Tamburro, P; Uslenghi, C; Zanchin, G

2007-01-01

Aims and methods: In this double-blind, double-dummy, randomised, parallel group, multicentre study, the efficacy of dosing and re-dosing of a fixed combination of indomethacin, prochlorperazine and caffeine (Indoprocaf) was compared with encapsulated sumatriptan in the acute treatment of two migraine attacks. Additionally, in the group taking Indoprocaf, two different oral formulations were tested: effervescent tablets and encapsulated coated tablets. Results: Of 297 patients randomised (150 assigned to Indoprocaf and 147 to sumatriptan), 281 were included in the intention-to-treat efficacy analysis. The initial dosing of Indoprocaf and sumatriptan was similarly effective with pain-free rates higher than 30% (95% CI of odds-ratio: 0.57–1.28) and headache relief rates of about 60% (95% CI of odds-ratio: 0.82–1.84) with both the drugs. The efficacy of re-dosing of Indoprocaf as rescue medication was more effective than that of sumatriptan with pain-free values of 47% vs. 27% in the total attacks with a statistically significant difference in the first migraine attack in favour of Indoprocaf. The efficacy of re-dosing to treat a recurrence/relapse was very high without differences between the drugs (pain-free: 60% with Indoprocaf and 50% with sumatriptan in the total attacks). Indoprocaf and sumatriptan were well-tolerated. Conclusion: The study demonstrated that the efficacy of the initial dosing of Indoprocaf was not higher than that of sumatriptan, but that the strategy to use the lowest effective dose as soon as the headache occurred, followed by a second dose if the headache has not relieved or to treat a relapse, was very effective, especially with Indoprocaf. PMID:17627707

Medical expenditure and unmet need of the pre-elderly and the elderly according to job status in Korea: Are the elderly indeed most vulnerable?

PubMed Central

Lee, Hwa-Young; Kondo, Naoki

2018-01-01

Increase in the elderly population and early retirement imposes immense economic burden on societies. Previous studies on the association between medical expenditure and working status in the elderly population have not adequately addressed reverse causality problem. In addition, the pre-elderly group has hardly been discussed in this regard. This study assessed possible causal association between employment status and medical expenditure as well as employment status and medical unmet needs in a representative sample of the Korean elderly (aged≧65) and the pre-elderly (aged ≧50 and < 65) adults from the Korea Health Panel Data (KHP). Dynamic panel Generalized Method of Moments (GMM) estimation was employed for the analysis of medical expenditure to address reverse causality, and fixed effect panel logistic regression was used for the analysis of unmet need. The results showed no significant association between job status and medical expenditure in the elderly, but a negative and significant influence on the level of medical expenditure in the pre-elderly. Unemployment was a significant determinant of lowering unmet need from lack of time while it was not associated with unmet need from financial burden in the fixed-effect panel model for both the elderly and pre-elderly groups. The pre-elderly adults were more likely to reduce necessary health service utilization due to unemployment compared to the elderly group because there is no proper financial safety net for the pre-elderly, which may cause non-adherence to treatment and therefore lead to negative health effects. The policy dialogue on safety net currently centers only on the elderly, but should be extended to the pre-elderly population. PMID:29570736

A 3D correction method for predicting the readings of a PinPoint chamber on the CyberKnife® M6™ machine

NASA Astrophysics Data System (ADS)

Zhang, Yongqian; Brandner, Edward; Ozhasoglu, Cihat; Lalonde, Ron; Heron, Dwight E.; Saiful Huq, M.

2018-02-01

The use of small fields in radiation therapy techniques has increased substantially in particular in stereotactic radiosurgery (SRS) and stereotactic body radiation therapy (SBRT). However, as field size reduces further still, the response of the detector changes more rapidly with field size, and the effects of measurement uncertainties become increasingly significant due to the lack of lateral charged particle equilibrium, spectral changes as a function of field size, detector choice, and subsequent perturbations of the charged particle fluence. This work presents a novel 3D dose volume-to-point correction method to predict the readings of a 0.015 cc PinPoint chamber (PTW 31014) for both small static-fields and composite-field dosimetry formed by fixed cones on the CyberKnife® M6™ machine. A 3D correction matrix is introduced to link the 3D dose distribution to the response of the PinPoint chamber in water. The parameters of the correction matrix are determined by modeling its 3D dose response in circular fields created using the 12 fixed cones (5 mm-60 mm) on a CyberKnife® M6™ machine. A penalized least-square optimization problem is defined by fitting the calculated detector reading to the experimental measurement data to generate the optimal correction matrix; the simulated annealing algorithm is used to solve the inverse optimization problem. All the experimental measurements are acquired for every 2 mm chamber shift in the horizontal planes for each field size. The 3D dose distributions for the measurements are calculated using the Monte Carlo calculation with the MultiPlan® treatment planning system (Accuray Inc., Sunnyvale, CA, USA). The performance evaluation of the 3D conversion matrix is carried out by comparing the predictions of the output factors (OFs), off-axis ratios (OARs) and percentage depth dose (PDD) data to the experimental measurement data. The discrepancy of the measurement and the prediction data for composite fields is also performed for clinical SRS plans. The optimization algorithm used for generating the optimal correction factors is stable, and the resulting correction factors were smooth in the spatial domain. The measurement and prediction of OFs agree closely with percentage differences of less than 1.9% for all the 12 cones. The discrepancies between the prediction and the measurement PDD readings at 50 mm and 80 mm depth are 1.7% and 1.9%, respectively. The percentage differences of OARs between measurement and prediction data are less than 2% in the low dose gradient region, and 2%/1 mm discrepancies are observed within the high dose gradient regions. The differences between the measurement and prediction data for all the CyberKnife based SRS plans are less than 1%. These results demonstrate the existence and efficiency of the novel 3D correction method for small field dosimetry. The 3D correction matrix links the 3D dose distribution and the reading of the PinPoint chamber. The comparison between the predicted reading and the measurement data for static small fields (OFs, OARs and PDDs) yield discrepancies within 2% for low dose gradient regions and 2%/1 mm for high dose gradient regions; the discrepancies between the predicted and the measurement data are less than 1% for all the SRS plans. The 3D correction method provides an access to evaluate the clinical measurement data and can be applied to non-standard composite fields intensity modulated radiation therapy point dose verification.

Pre-procedural antibiotics for endoscopic urological procedures: Initial experience in individuals with spinal cord injury and asymptomatic bacteriuria.

PubMed

Chong, Julio T; Klausner, Adam P; Petrossian, Albert; Byrne, Michael D; Moore, Jewel R; Goetz, Lance L; Gater, David R; Grob, B Mayer

2015-03-01

The objective of this study was to compare the safety, efficacy, quality-of-life impact, and costs of a single dose or a longer course of pre-procedural antibiotics prior to elective endoscopic urological procedures in individuals with spinal cord injury and disorders (SCI/D) and asymptomatic bacteriuria. A prospective observational study. Hunter Holmes McGuire Veterans Affairs Medical Center, Richmond, Virginia, USA. Sixty persons with SCI/D and asymptomatic bacteriuria scheduled to undergo elective endoscopic urological procedures. A single pre-procedural dose of antibiotics vs. a 3-5-day course of pre-procedural antibiotics. Objective and subjective measures of health, costs, and quality of life. There were no significant differences in vital signs, leukocytosis, adverse events, and overall satisfaction in individuals who received short-course vs. long-course antibiotics. There was a significant decrease in antibiotic cost (33.1 ± 47.6 vs. 3.6 ± 6.1 US$, P = 0.01) for individuals in the short-course group. In addition, there was greater pre-procedural anxiety (18 vs. 0%, P < 0.05) for individuals who received long-course antibiotics. SCI/D individuals with asymptomatic bacteriuria may be able to safely undergo most endoscopic urological procedures with a single dose of pre-procedural antibiotics. However, further research is required and even appropriate pre-procedural antibiotics may not prevent severe infections.

Fraction-variant beam orientation optimization for non-coplanar IMRT

NASA Astrophysics Data System (ADS)

O'Connor, Daniel; Yu, Victoria; Nguyen, Dan; Ruan, Dan; Sheng, Ke

2018-02-01

Conventional beam orientation optimization (BOO) algorithms for IMRT assume that the same set of beam angles is used for all treatment fractions. In this paper we present a BOO formulation based on group sparsity that simultaneously optimizes non-coplanar beam angles for all fractions, yielding a fraction-variant (FV) treatment plan. Beam angles are selected by solving a multi-fraction fluence map optimization problem involving 500-700 candidate beams per fraction, with an additional group sparsity term that encourages most candidate beams to be inactive. The optimization problem is solved using the fast iterative shrinkage-thresholding algorithm. Our FV BOO algorithm is used to create five-fraction treatment plans for digital phantom, prostate, and lung cases as well as a 30-fraction plan for a head and neck case. A homogeneous PTV dose coverage is maintained in all fractions. The treatment plans are compared with fraction-invariant plans that use a fixed set of beam angles for all fractions. The FV plans reduced OAR mean dose and D 2 values on average by 3.3% and 3.8% of the prescription dose, respectively. Notably, mean OAR dose was reduced by 14.3% of prescription dose (rectum), 11.6% (penile bulb), 10.7% (seminal vesicle), 5.5% (right femur), 3.5% (bladder), 4.0% (normal left lung), 15.5% (cochleas), and 5.2% (chiasm). D 2 was reduced by 14.9% of prescription dose (right femur), 8.2% (penile bulb), 12.7% (proximal bronchus), 4.1% (normal left lung), 15.2% (cochleas), 10.1% (orbits), 9.1% (chiasm), 8.7% (brainstem), and 7.1% (parotids). Meanwhile, PTV homogeneity defined as D 95/D 5 improved from .92 to .95 (digital phantom), from .95 to .98 (prostate case), and from .94 to .97 (lung case), and remained constant for the head and neck case. Moreover, the FV plans are dosimetrically similar to conventional plans that use twice as many beams per fraction. Thus, FV BOO offers the potential to reduce delivery time for non-coplanar IMRT.

NASA Solar Array Demonstrates Commercial Potential

NASA Technical Reports Server (NTRS)

Creech, Gray

2006-01-01

A state-of-the-art solar-panel array demonstration site at NASA's Dryden Flight Research Center provides a unique opportunity for studying the latest in high-efficiency solar photovoltaic cells. This five-kilowatt solar-array site (see Figure 1) is a technology-transfer and commercialization success for NASA. Among the solar cells at this site are cells of a type that was developed in Dryden Flight Research Center s Environmental Research Aircraft and Sensor Technology (ERAST) program for use in NASA s Helios solar-powered airplane. This cell type, now denoted as A-300, has since been transferred to SunPower Corporation of Sunnyvale, California, enabling mass production of the cells for the commercial market. High efficiency separates these advanced cells from typical previously commercially available solar cells: Whereas typical previously commercially available cells are 12 to 15 percent efficient at converting sunlight to electricity, these advanced cells exhibit efficiencies approaching 23 percent. The increase in efficiency is due largely to the routing of electrical connections behind the cells (see Figure 2). This approach to increasing efficiency originated as a solution to the problem of maximizing the degree of utilization of the limited space available atop the wing of the Helios airplane. In retrospect, the solar cells in use at this site could be used on Helios, but the best cells otherwise commercially available could not be so used, because of their lower efficiencies. Historically, solar cells have been fabricated by use of methods that are common in the semiconductor industry. One of these methods includes the use of photolithography to define the rear electrical-contact features - diffusions, contact openings, and fingers. SunPower uses these methods to produce the advanced cells. To reduce fabrication costs, SunPower continues to explore new methods to define the rear electrical-contact features. The equipment at the demonstration site includes two fixed-angle solar arrays and one single-axis Sun-tracking array. One of the fixed arrays contains typical less-efficient commercial solar cells and is being used as a baseline for comparison of the other fixed array, which contains the advanced cells. The Sun-tracking array tilts to follow the Sun, using an advanced, real-time tracking device rather than customary pre-programmed mechanisms. Part of the purpose served by the demonstration is to enable determination of any potential advantage of a tracking array over a fixed array. The arrays are monitored remotely on a computer that displays pertinent information regarding the functioning of the arrays.

Including robustness in multi-criteria optimization for intensity-modulated proton therapy

NASA Astrophysics Data System (ADS)

Chen, Wei; Unkelbach, Jan; Trofimov, Alexei; Madden, Thomas; Kooy, Hanne; Bortfeld, Thomas; Craft, David

2012-02-01

We present a method to include robustness in a multi-criteria optimization (MCO) framework for intensity-modulated proton therapy (IMPT). The approach allows one to simultaneously explore the trade-off between different objectives as well as the trade-off between robustness and nominal plan quality. In MCO, a database of plans each emphasizing different treatment planning objectives, is pre-computed to approximate the Pareto surface. An IMPT treatment plan that strikes the best balance between the different objectives can be selected by navigating on the Pareto surface. In our approach, robustness is integrated into MCO by adding robustified objectives and constraints to the MCO problem. Uncertainties (or errors) of the robust problem are modeled by pre-calculated dose-influence matrices for a nominal scenario and a number of pre-defined error scenarios (shifted patient positions, proton beam undershoot and overshoot). Objectives and constraints can be defined for the nominal scenario, thus characterizing nominal plan quality. A robustified objective represents the worst objective function value that can be realized for any of the error scenarios and thus provides a measure of plan robustness. The optimization method is based on a linear projection solver and is capable of handling large problem sizes resulting from a fine dose grid resolution, many scenarios, and a large number of proton pencil beams. A base-of-skull case is used to demonstrate the robust optimization method. It is demonstrated that the robust optimization method reduces the sensitivity of the treatment plan to setup and range errors to a degree that is not achieved by a safety margin approach. A chordoma case is analyzed in more detail to demonstrate the involved trade-offs between target underdose and brainstem sparing as well as robustness and nominal plan quality. The latter illustrates the advantage of MCO in the context of robust planning. For all cases examined, the robust optimization for each Pareto optimal plan takes less than 5 min on a standard computer, making a computationally friendly interface possible to the planner. In conclusion, the uncertainty pertinent to the IMPT procedure can be reduced during treatment planning by optimizing plans that emphasize different treatment objectives, including robustness, and then interactively seeking for a most-preferred one from the solution Pareto surface.

Clonidine Extended-Release Tablets for Pediatric Patients with Attention-Deficit/Hyperactivity Disorder

ERIC Educational Resources Information Center

Jain, Rakesh; Segal, Scott; Kollins, Scott H.; Khayrallah, Moise

2011-01-01

Objective: This study examined the efficacy and safety of clonidine hydrochloride extended-release tablets (CLON-XR) in children and adolescents with attention-deficit/hyperactivity disorder (ADHD). Method: This 8-week, placebo-controlled, fixed-dose trial, including 3 weeks of dose escalation, of patients 6 to 17 years old with ADHD evaluated the…

A randomized, double-blind, active control, multicenter, dose-finding study of lipegfilgrastim (XM22) in breast cancer patients receiving myelosuppressive therapy.

PubMed

Buchner, Anton; Elsässer, Reiner; Bias, Peter

2014-11-01

This dose-ranging study was conducted to identify the optimal fixed dose of lipegfilgrastim compared with pegfilgrastim 6.0 mg for the provision of neutrophil support during myelosuppressive chemotherapy in patients with breast cancer. A phase 2 study was conducted in which 208 chemotherapy-naive patients were randomized to receive lipegfilgrastim 3.0, 4.5, or 6.0 mg or pegfilgrastim 6.0 mg. Study drugs were administered as a single subcutaneous injection on day 2 of each chemotherapy cycle (doxorubicin/docetaxel on day 1 for four 3-week cycles). The primary outcome measure was duration of severe neutropenia (DSN) in cycle 1. Patients treated with lipegfilgrastim experienced shorter DSN in cycle 1 with higher doses. The mean DSN was 0.76 days in the lipegfilgrastim 6.0-mg group and 0.87 days in the pegfilgrastim 6.0-mg group, with no significant differences between treatment groups. Treatment with lipegfilgrastim 6.0 mg was consistently associated with a higher absolute neutrophil count (ANC) at nadir, shorter ANC recovery time, and a similar safety and tolerability profile compared with pegfilgrastim. This phase 2 study demonstrated that lipegfilgrastim 6.0 mg is the optimal dose for patients with breast cancer and provides neutrophil support that is at least equivalent to the standard 6.0-mg fixed dose of pegfilgrastim.

Management of rivaroxaban in relation to bodyweight and body mass index

PubMed Central

Uprichard, James

2016-01-01

Being overweight or obese is associated with a higher individual risk of venous thromboembolism and poorer postprocedural outcomes after hip or knee replacement surgery. In addition, there is evidence that obesity represents a significant driving factor for the current and projected prevalence of atrial fibrillation. Rivaroxaban and other direct oral anticoagulants offer fixed-dose regimens for these indications. They do not require therapeutic drug monitoring or dose adjustment according to the weight of the patient. However, primary care physicians seem to be hesitant to accept the concept of a fixed-dose regimen for patients at extremes of weight, perhaps because of familiarity with weight-based dosing of other drugs including low molecular weight heparins. The main concerns related to unadjusted dosing are increased exposure in underweight patients leading to a risk of excessive bleeding and conversely to underanticoagulation of overweight patients. Rivaroxaban has shown similar efficacy and a similar or better safety profile compared with standard treatment for several venous and arterial indications, including venous thromboembolism, nonvalvular atrial fibrillation, and acute coronary syndrome. Prespecified subgroup analyses of patients stratified by weight or body mass index demonstrated outcomes that were consistent with the overall analysis and within each weight and body mass index group. The results suggest that standard-dose rivaroxaban can be safely prescribed in adult patients of all weights. PMID:27090286

Asymmetric C7 pedicle subtraction osteotomy for correction of rigid cervical coronal imbalance secondary to post-traumatic heterotopic ossification: a case report, description of a novel surgical technique, and literature review.

PubMed

Theologis, Alexander A; Bellevue, Kate D; Qamirani, Erion; Ames, Christopher P; Deviren, Vedat

2017-05-01

Deformities of the cervical spine are uncommon in the coronal plane. In this report, a unique case of a 31-year-old male with a fixed, 30° left coronal deformity due to heterotopic ossification 3 years status post poly-trauma was treated with an asymmetric C7 pedicle subtraction osteotomy (PSO). Case report. Pre-operatively, the patient had a fixed 45-degree left tilt of his neck and radiographs demonstrated a rigid 30° scoliosis, 7 cm coronal imbalance, and 4 cm negative sagittal balance, diffuse bridging bone between the spinous processes and the facet joints of C5 to T1 bilaterally. An asymmetric C7 PSO with C2-T3 posterior spinal fusion was completed without complication. There was residual 9° coronal deformity, 2.9 cm left coronal imbalance, and 2.3 cm sagittal imbalance. He had a marked improvement in his function, as assessed by the SF-36 physical component score (pre-op 31.1; post-op 44.7) and mental component score (pre-op 46.0; post-op 66.8). Post-operatively, neck disability index scores also improved (pre-op 38; post-op 16). Although the patient passed away from a drug overdose 14 months post-operatively, he did not report neck pain, he had not sought evaluation from another physician for his neck, and he had not undergone a subsequent neck operation before his passing. In this one patient, an asymmetric C7 PSO was performed safely. While it was effective in addressing a fixed cervical coronal imbalance, its efficacy and safety profile should be confirmed in larger cohorts.

The impact of pre-oxidation with potassium permanganate on cyanobacterial organic matter removal by coagulation.

PubMed

Naceradska, Jana; Pivokonsky, Martin; Pivokonska, Lenka; Baresova, Magdalena; Henderson, Rita K; Zamyadi, Arash; Janda, Vaclav

2017-05-01

The study investigates the effect of permanganate pre-oxidation on the coagulation of peptides/proteins of Microcystis aeruginosa which comprise a major proportion of the organic matter during cyanobacterial bloom decay. Four different permanganate dosages (0.1, 0.2, 0.4 and 0.6 mg KMnO 4 mg -1 DOC) were applied prior to coagulation by ferric sulphate. Moreover, changes in sample characteristics, such as UV 254 , DOC content and molecular weight distribution, after pre-oxidation were monitored. The results showed that permanganate pre-oxidation led to a reduction in coagulant dose, increased organic matter removals by coagulation (by 5-12% depending on permanganate dose), microcystin removal (with reductions of 91-96%) and a shift of the optimum pH range from 4.3 to 6 without to 5.5-7.3 with pre-oxidation. Degradation of organic matter into inorganic carbon and adsorption of organic matter onto hydrous MnO 2 are suggested as the main processes responsible for coagulation improvement. Moreover, permanganate prevented the formation of Fe-peptide/protein complexes that inhibit coagulation at pH about 6.2 without pre-oxidation. The study showed that carefully optimized dosing of permanganate improves cyanobacterial peptide/protein removal, with the benefit of microcystin elimination. Copyright © 2017 Elsevier Ltd. All rights reserved.

Formulation of a novel fixed dose combination of salmeterol xinafoate and mometasone furoate for inhaled drug delivery.

PubMed

Liu, Sha; Watts, Alan B; Du, Ju; Bui, Amanda; Hengsawas, Soraya; Peters, Jay I; Williams, Robert O

2015-10-01

Co-administration of an inhaled corticosteroid and long acting beta agonist for chronic obstructive pulmonary disease has reduced mortality compared to either drug alone. This combination reduces exacerbations, hospitalization, emergency department visits and health care costs. A novel fixed-dose combination of the long acting beta-2 agonist salmeterol xinafoate (SX) and the corticosteroid mometasone furoate (MF) were prepared in a composite particle formulation as brittle matrix powder (BMP) and investigated for suitability as an inhaled combination product. In this study, BMP fixed dose combinations of SX and MF with or without stabilizing excipients (lactose, mannitol, glycine and trehalose) were prepared and characterized with respect to their thermal properties, morphology, aerodynamic performance and physical stability. BMP combination formulations of SX and MF exhibited improved aerodynamic properties when delivered by dry powder inhalation as compared to the micronized blends of the same substances. Aerodynamic evaluation was carried out by next generation pharmaceutical impactor (NGI) with a marketed DPI device. Results demonstrated that co-deposition occurred when SX and MF were formulated together as composite particles in a BMP, while physical blends resulted in inconsistent deposition and dose uniformity. As a result of the bottom-up particle engineering approach, combination BMP formulations allow for dual API composite formulations to be dispersed as aerosolized particles. Aerosolized BMP combination formulations resulted in delivered dose uniformity and co-deposition of each API. Further, an excipient-free formulation, BMP SXMF, delivered approximately 50% of the loaded dose in the respirable range and demonstrated stability at ambient conditions for 6months. Single dose 24-h pharmacokinetic studies in rats demonstrated that lung tissue deposition and blood circulation (AUC0-24h) of two APIs were higher for the BMP combination group exhibiting a significantly higher lung concentration of drugs than for the crystalline physical blend. While high system drug levels are generally undesirable in lung targeted therapies, high blood levels in this rodent study could be indicative of increased pulmonary tissue exposure using BMP formulations. Copyright © 2015 Elsevier B.V. All rights reserved.

[Effectiveness and safety of losartan and its combination with hydrochlorothiazide in patients with hypertension: in result study].

PubMed

Glezer, M G; Saĭgitov, R T

2012-01-01

There are limited data on the results of Russia's use of losartan in clinical practice for the treatment of patients with arterial hypertension (AH). The purpose of the study was to assess the efficacy and safety of losartan and its fixed combination with hydrochlorothiazide (HCTZ) in patients with hypertension. Primary care physicians (n=644) for 8 weeks evaluated outcomes of treatment of hypertensive patients who were assigned to losartan monotherapy (12.5, 25, 50 or 100 mg) or a fixed combination with hydrochlorothiazide (losartan 50 mg/hydrochlorothiazide 12.5 mg , losartan 100 mg/hydrochlorothiazide 25 mg). The effectiveness of treatment was assessed by size reduction of systolic/diastolic blood pressure (SBP/DBP), and the frequency of achieving target blood pressure (<140/90 or <130/80 mm Hg in patients with diabetes). Losartan at a dose 12.5 mg was assigned to 382 (3.8%), at a dose of 25 mg - to 1061 (10.7%), at a dose of 50 mg - to 3545 (35.6%), at a dose of 100 mg - to 3247 (32.6%), at a dose of 50 mg / hydrochlorothiazide 12.5 mg - to 893 (9.0%), at a dose of 100 mg / hydrochlorothiazide 25 mg - to 820 (8.2%) of 9948 patients included in the study. According to multivariate analysis, dose selection of losartan was determined by an attending physician, mainly (85% according to the estimate of the explained variance), based on the baseline SBP. As a result of treatment (41 to 53% of patients received losartan only or in combination with HCTZ) SBP decrease in the groups ranged from 20 to 38 mm Hg, DBP - from 10 to 17 mm Hg, the target blood pressure is achieved in 29-66% of patients. At least one adverse event occurred in 141 (1.4%) patients, with lower frequency in patients receiving losartan 50 mg (adjusted odds ratio 0.34, 95% confidence interval 0.19 to 0.63; the reference group - patients receiving losartan 100 mg/hydrochlorothiazide 25 mg). Thus losartan as monotherapy or in fixed combination with HCTZ for hypertensive patients is characterized by high antihypertensive efficacy and safety.