Verification of Pharmacogenetics-Based Warfarin Dosing Algorithms in Han-Chinese Patients Undertaking Mechanic Heart Valve Replacement

PubMed Central

Zhao, Li; Chen, Chunxia; Li, Bei; Dong, Li; Guo, Yingqiang; Xiao, Xijun; Zhang, Eryong; Qin, Li

2014-01-01

Objective To study the performance of pharmacogenetics-based warfarin dosing algorithms in the initial and the stable warfarin treatment phases in a cohort of Han-Chinese patients undertaking mechanic heart valve replacement. Methods We searched PubMed, Chinese National Knowledge Infrastructure and Wanfang databases for selecting pharmacogenetics-based warfarin dosing models. Patients with mechanic heart valve replacement were consecutively recruited between March 2012 and July 2012. The predicted warfarin dose of each patient was calculated and compared with the observed initial and stable warfarin doses. The percentage of patients whose predicted dose fell within 20% of their actual therapeutic dose (percentage within 20%), and the mean absolute error (MAE) were utilized to evaluate the predictive accuracy of all the selected algorithms. Results A total of 8 algorithms including Du, Huang, Miao, Wei, Zhang, Lou, Gage, and International Warfarin Pharmacogenetics Consortium (IWPC) model, were tested in 181 patients. The MAE of the Gage, IWPC and 6 Han-Chinese pharmacogenetics-based warfarin dosing algorithms was less than 0.6 mg/day in accuracy and the percentage within 20% exceeded 45% in all of the selected models in both the initial and the stable treatment stages. When patients were stratified according to the warfarin dose range, all of the equations demonstrated better performance in the ideal-dose range (1.88–4.38 mg/day) than the low-dose range (<1.88 mg/day). Among the 8 algorithms compared, the algorithms of Wei, Huang, and Miao showed a lower MAE and higher percentage within 20% in both the initial and the stable warfarin dose prediction and in the low-dose and the ideal-dose ranges. Conclusions All of the selected pharmacogenetics-based warfarin dosing regimens performed similarly in our cohort. However, the algorithms of Wei, Huang, and Miao showed a better potential for warfarin prediction in the initial and the stable treatment phases in Han-Chinese patients undertaking mechanic heart valve replacement. PMID:24728385

Verification of pharmacogenetics-based warfarin dosing algorithms in Han-Chinese patients undertaking mechanic heart valve replacement.

PubMed

Zhao, Li; Chen, Chunxia; Li, Bei; Dong, Li; Guo, Yingqiang; Xiao, Xijun; Zhang, Eryong; Qin, Li

2014-01-01

To study the performance of pharmacogenetics-based warfarin dosing algorithms in the initial and the stable warfarin treatment phases in a cohort of Han-Chinese patients undertaking mechanic heart valve replacement. We searched PubMed, Chinese National Knowledge Infrastructure and Wanfang databases for selecting pharmacogenetics-based warfarin dosing models. Patients with mechanic heart valve replacement were consecutively recruited between March 2012 and July 2012. The predicted warfarin dose of each patient was calculated and compared with the observed initial and stable warfarin doses. The percentage of patients whose predicted dose fell within 20% of their actual therapeutic dose (percentage within 20%), and the mean absolute error (MAE) were utilized to evaluate the predictive accuracy of all the selected algorithms. A total of 8 algorithms including Du, Huang, Miao, Wei, Zhang, Lou, Gage, and International Warfarin Pharmacogenetics Consortium (IWPC) model, were tested in 181 patients. The MAE of the Gage, IWPC and 6 Han-Chinese pharmacogenetics-based warfarin dosing algorithms was less than 0.6 mg/day in accuracy and the percentage within 20% exceeded 45% in all of the selected models in both the initial and the stable treatment stages. When patients were stratified according to the warfarin dose range, all of the equations demonstrated better performance in the ideal-dose range (1.88-4.38 mg/day) than the low-dose range (<1.88 mg/day). Among the 8 algorithms compared, the algorithms of Wei, Huang, and Miao showed a lower MAE and higher percentage within 20% in both the initial and the stable warfarin dose prediction and in the low-dose and the ideal-dose ranges. All of the selected pharmacogenetics-based warfarin dosing regimens performed similarly in our cohort. However, the algorithms of Wei, Huang, and Miao showed a better potential for warfarin prediction in the initial and the stable treatment phases in Han-Chinese patients undertaking mechanic heart valve replacement.

Initial fluid resuscitation following adjusted body weight dosing is associated with improved mortality in obese patients with suspected septic shock.

PubMed

Taylor, Stephanie Parks; Karvetski, Colleen H; Templin, Megan A; Heffner, Alan C; Taylor, Brice T

2018-02-01

The optimal initial fluid resuscitation strategy for obese patients with septic shock is unknown. We evaluated fluid resuscitation strategies across BMI groups. Retrospective analysis of 4157 patients in a multicenter activation pathway for treatment of septic shock between 2014 and 2016. 1293 (31.3%) patients were obese (BMI≥30). Overall, higher BMI was associated with lower mortality, however this survival advantage was eliminated in adjusted analyses. Patients with higher BMI received significantly less fluid per kilogram at 3h than did patients with lower BMI (p≤0.001). In obese patients, fluid given at 3h mimicked a dosing strategy based on actual body weight (ABW) in 780 (72.2%), adjusted body weight (AdjBW) in 95 (8.8%), and ideal body weight (IBW) in 205 (19.0%). After adjusting for condition- and treatment-related variables, dosing based on AdjBW was associated with improved mortality compared to ABW (OR 0.45; 95% CI [0.19, 1.07]) and IBW (OR 0.29; 95% CI [0.11,0.74]). Using AdjBW to calculate initial fluid resuscitation volume for obese patients with suspected shock may improve outcomes compared to other weight-based dosing strategies. The optimal fluid dosing strategy for obese patients should be a focus of future prospective research. Copyright © 2017 Elsevier Inc. All rights reserved.

Comparison of the Performance of the Warfarin Pharmacogenetics Algorithms in Patients with Surgery of Heart Valve Replacement and Heart Valvuloplasty.

PubMed

Xu, Hang; Su, Shi; Tang, Wuji; Wei, Meng; Wang, Tao; Wang, Dongjin; Ge, Weihong

2015-09-01

A large number of warfarin pharmacogenetics algorithms have been published. Our research was aimed to evaluate the performance of the selected pharmacogenetic algorithms in patients with surgery of heart valve replacement and heart valvuloplasty during the phase of initial and stable anticoagulation treatment. 10 pharmacogenetic algorithms were selected by searching PubMed. We compared the performance of the selected algorithms in a cohort of 193 patients during the phase of initial and stable anticoagulation therapy. Predicted dose was compared to therapeutic dose by using a predicted dose percentage that falls within 20% threshold of the actual dose (percentage within 20%) and mean absolute error (MAE). The average warfarin dose for patients was 3.05±1.23mg/day for initial treatment and 3.45±1.18mg/day for stable treatment. The percentages of the predicted dose within 20% of the therapeutic dose were 44.0±8.8% and 44.6±9.7% for the initial and stable phases, respectively. The MAEs of the selected algorithms were 0.85±0.18mg/day and 0.93±0.19mg/day, respectively. All algorithms had better performance in the ideal group than in the low dose and high dose groups. The only exception is the Wadelius et al. algorithm, which had better performance in the high dose group. The algorithms had similar performance except for the Wadelius et al. and Miao et al. algorithms, which had poor accuracy in our study cohort. The Gage et al. algorithm had better performance in both phases of initial and stable treatment. Algorithms had relatively higher accuracy in the >50years group of patients on the stable phase. Copyright © 2015 Elsevier Ltd. All rights reserved.

Impact of sacubitril/valsartan on heart failure admissions: insights from real-world patient prescriptions.

PubMed

Martens, Pieter; Lambeets, Seppe; Lau, Chirikwah; Dupont, Matthias; Mullens, Wilfried

2018-06-17

Sacubitril/valsartan reduced heart failure (HF)-admissions and cardiovascular mortality in the PARADIGM-HF-trial. However, real-world patients are often frailer and less able to tolerate high doses of sacubitril/valsartan. We performed a retrospective analysis of consecutive patients prescribed sacubitril/valsartan in a single tertiary HF-clinic between December 2016 and January 2018. HF-admissions were assessed in a paired fashion, comparing the amount of antecedent HF-episodes with incident HF-episodes after the initiation. Baseline risk for adverse events was assessed by the EMPHASIS-HF-risk-score Results: A total of 201-HF-patients were retrospectively identified (age = 68 ± 11 years, ejection fraction = 29 ± 8%). Real world patients were older, had higher serum creatinine and a higher New-York Heart-Association (NYHA)-class (p < .05 for all) than in the PARADIGM-HF trial. Over a mean duration of 221 ± 114 days after initiation of sacubitril/valsartan a total of 23-individual patients experienced at least one HF-episodes. Over the same time period preceding initiation of sacubitril/valsartan, 51 individual patients experienced a HF-episodes (p < .001). Sacubitril/valsartan significantly reduced the rate of incident vs. antecedent HF-admissions, in patients with low or high baseline NYHA-class (II vs. III and IV; p value = 0.019 respectively p = .004) or patients with an EMPHASIS-HF risk score below or above the mean (p = .002 respectively p = .016). Patients older than 75-years exhibited a trend towards HF-reduction. Higher doses of sacubitril/valsartan were associated with more reduction in incident versus antecedent HF-episodes. Despite being frailer and older, real-world patients exhibit a significant and early reduction in incident HF-hospitalisations following initiation of sacubitril/valsartan. Higher doses might be associated with more reduction in HF-admissions, underscoring the importance of dose uptitration.

Subgroup effects in a randomised trial of different types and doses of exercise during breast cancer chemotherapy.

PubMed

Courneya, K S; McKenzie, D C; Mackey, J R; Gelmon, K; Friedenreich, C M; Yasui, Y; Reid, R D; Vallerand, J R; Adams, S C; Proulx, C; Dolan, L B; Wooding, E; Segal, R J

2014-10-28

The Combined Aerobic and Resistance Exercise Trial tested different types and doses of exercise in breast cancer patients receiving chemotherapy. Here, we explore potential moderators of the exercise training responses. Breast cancer patients initiating chemotherapy (N=301) were randomly assigned to three times a week, supervised exercise of a standard dose of 25-30 min of aerobic exercise, a higher dose of 50-60 min of aerobic exercise, or a higher dose of 50-60 min of combined aerobic and resistance exercise. Outcomes were patient-reported symptoms and health-related fitness. Moderators were baseline demographic, exercise/fitness, and cancer variables. Body mass index moderated the effects of the exercise interventions on bodily pain (P for interaction=0.038), endocrine symptoms (P for interaction=0.029), taxane/neuropathy symptoms (P for interaction=0.013), aerobic fitness (P for interaction=0.041), muscular strength (P for interaction=0.007), and fat mass (P for interaction=0.005). In general, healthy weight patients responded better to the higher-dose exercise interventions than overweight/obese patients. Menopausal status, age, and baseline fitness moderated the effects on patient-reported symptoms. Premenopausal, younger, and fitter patients achieved greater benefits from the higher-dose exercise interventions. Healthy weight, fitter, and premenopausal/younger breast cancer patients receiving chemotherapy are more likely to benefit from higher-dose exercise interventions.

Demographic and socioenvironmental predictors of premorbid marijuana use among patients with first-episode psychosis.

PubMed

Pauselli, Luca; Birnbaum, Michael L; Vázquez Jaime, Beatriz Paulina; Paolini, Enrico; Kelley, Mary E; Broussard, Beth; Compton, Michael T

2018-01-31

We identified, in subjects with first-episode psychosis, demographic and socioenvironmental predictors of three variables pertaining to premorbid marijuana use: age at initiation of marijuana use, trajectories of marijuana use in the five years prior to onset of psychosis, and the cumulative "dose" of marijuana intake in that same premorbid period. We enrolled 247 first-episode psychosis patients and collected data on lifetime marijuana/alcohol/tobacco use, age at onset of psychosis, diverse socioenvironmental variables, premorbid adjustment, past traumatic experiences, perceived neighborhood-level social disorder, and cannabis use experiences. Bivariate tests were used to examine associations between the three premorbid marijuana use variables and hypothesized predictors. Regression models determined which variables remained independently significantly associated. Age at initiation of cigarette smoking was linked to earlier initiation, faster escalation, and higher cumulative dose of premorbid marijuana use. During childhood, poorer academic performance was predictive of an earlier age at initiation of marijuana use, while poorer sociability was related to more rapid escalation to daily use and a higher cumulative dose. As expected, experiencing euphoric effects was positively correlated with trajectories and cumulative dose, but having negative experiences was unrelated. Traumatic childhood/adolescent experiences were correlated with rapid escalation and amount of marijuana used, but not with age at initiation of marijuana use. These data expand the very limited literature on predictors of premorbid marijuana use in first-episode psychosis. Given its association with earlier age at onset of psychosis, and poorer outcomes among first-episode patients, prevention and treatment efforts should be further developed. Copyright © 2018 Elsevier B.V. All rights reserved.

Diabetes Prevention and Treatment Programs for Western PA FY04 and FY05

DTIC Science & Technology

2009-05-01

LDL > 130 mg/dl. First line Rx is HMG CoA reductase inhibitor montotherapy. Initial treatment and dose: Atorvastatin (dose range 10-80 mg) with...necessary. Attempts to decrease higher doses if goals are reached may also be necessary.) High atorvastatin or simvastatin dose (80 mg) may be needed...100mg/dl, add or switch to atorvastatin or simvastatin 10 mg with evening meal. If LDL-C still remains >100 mg/dl after above addition, up-titrate

LDR brachytherapy: can low dose rate hypersensitivity from the "inverse" dose rate effect cause excessive cell killing to peripherial connective tissues and organs?

PubMed

Leonard, B E; Lucas, A C

2009-02-01

Examined here are the possible effects of the "inverse" dose rate effect (IDRE) on low dose rate (LDR) brachytherapy. The hyper-radiosensitivity and induced radioresistance (HRS/IRR) effect benefits cell killing in radiotherapy, and IDRE and HRS/IRR seem to be generated from the same radioprotective mechanisms. We have computed the IDRE excess cell killing experienced in LDR brachytherapy using permanent seed implants. We conclude, firstly, that IDRE is a dose rate-dependent manifestation of HRS/IRR. Secondly, the presence of HRS/IRR or IDRE in a cell species or tissue must be determined by direct dose-response measurements. Thirdly, a reasonable estimate is that 50-80% of human adjoining connective and organ tissues experience IDRE from permanent implanted LDR brachytherapy. If IDRE occurs for tissues at point A for cervical cancer, the excess cell killing will be about a factor of 3.5-4.0 if the initial dose rate is 50-70 cGy h(-1). It is greater for adjacent tissues at lower dose rates and higher for lower initial dose rates at point A. Finally, higher post-treatment complications are observed in LDR brachytherapy, often for unknown reasons. Some of these are probably a result of IDRE excess cell killing. Measurements of IDRE need be performed for connective and adjacent organ tissues, i.e. bladder, rectum, urinary tract and small bowels. The measured dose rate-dependent dose responses should extended to <10 cGy h(-1) and involve multiple patients to detect patient variability. Results may suggest a preference for high dose rate brachytherapy or LDR brachytherapy without permanent retention of the implant seeds (hence the dose rates in peripheral tissues and organs remain above IDRE thresholds).

Gabapentin dose and the 30-day risk of altered mental status in older adults: A retrospective population-based study

PubMed Central

Dixon, Stephanie N.; Kuwornu, Paul John; Dev, Varun K.; Montero-Odasso, Manuel; Burneo, Jorge; Garg, Amit X.

2018-01-01

Gabapentin is an effective treatment for chronic neuropathic pain but may cause dizziness, drowsiness, and confusion in some older adults. The goal of this study was to assess the association between gabapentin dosing and adverse outcomes by obtaining estimates of the 30-day risk of hospitalization with altered mental status and mortality in older adults (mean age 76 years) in Ontario, Canada initiated on high dose (>600 mg/day; n = 34,159) compared to low dose (≤600 mg/day; n = 76,025) oral gabapentin in routine outpatient care. A population-based, retrospective cohort study assessing new gabapentin use between 2002 to 2014 was conducted. The primary outcome was 30-day hospitalization with an urgent head computed tomography (CT) scan in the absence of evidence of stroke (a proxy for altered mental status). The secondary outcome was 30-day all-cause mortality. The baseline characteristics measured in the two dose groups were similar. Initiation of a high versus low dose of gabapentin was associated with a higher risk of hospitalization with head CT scan (1.27% vs. 1.06%, absolute risk difference 0.21%, adjusted relative risk 1.29 [95% CI 1.14 to 1.46], number needed to treat 477) but not a statistically significant higher risk of mortality (1.25% vs. 1.16%, absolute risk difference of 0.09%, adjusted relative risk of 1.01 [95% CI 0.89 to 1.14]). Overall, the risk of being hospitalized with altered mental status after initiating gabapentin remains low, but may be reduced through the judicious use of gabapentin, use of the lowest dose to control pain, and vigilance for early signs of altered mental status. PMID:29538407

Feasibility of online IMPT adaptation using fast, automatic and robust dose restoration

NASA Astrophysics Data System (ADS)

Bernatowicz, Kinga; Geets, Xavier; Barragan, Ana; Janssens, Guillaume; Souris, Kevin; Sterpin, Edmond

2018-04-01

Intensity-modulated proton therapy (IMPT) offers excellent dose conformity and healthy tissue sparing, but it can be substantially compromised in the presence of anatomical changes. A major dosimetric effect is caused by density changes, which alter the planned proton range in the patient. Three different methods, which automatically restore an IMPT plan dose on a daily CT image were implemented and compared: (1) simple dose restoration (DR) using optimization objectives of the initial plan, (2) voxel-wise dose restoration (vDR), and (3) isodose volume dose restoration (iDR). Dose restorations were calculated for three different clinical cases, selected to test different capabilities of the restoration methods: large range adaptation, complex dose distributions and robust re-optimization. All dose restorations were obtained in less than 5 min, without manual adjustments of the optimization settings. The evaluation of initial plans on repeated CTs showed large dose distortions, which were substantially reduced after restoration. In general, all dose restoration methods improved DVH-based scores in propagated target volumes and OARs. Analysis of local dose differences showed that, although all dose restorations performed similarly in high dose regions, iDR restored the initial dose with higher precision and accuracy in the whole patient anatomy. Median dose errors decreased from 13.55 Gy in distorted plan to 9.75 Gy (vDR), 6.2 Gy (DR) and 4.3 Gy (iDR). High quality dose restoration is essential to minimize or eventually by-pass the physician approval of the restored plan, as long as dose stability can be assumed. Motion (as well as setup and range uncertainties) can be taken into account by including robust optimization in the dose restoration. Restoring clinically-approved dose distribution on repeated CTs does not require new ROI segmentation and is compatible with an online adaptive workflow.

Statistical analysis of radiation dose derived from ingestion of foods

NASA Astrophysics Data System (ADS)

Dougherty, Ward L.

2001-09-01

This analysis undertook the task of designing and implementing a methodology to determine an individual's probabilistic radiation dose from ingestion of foods utilizing Crystal Ball. A dietary intake model was determined by comparing previous existing models. Two principal radionuclides were considered-Lead210 (Pb-210) and Radium 226 (Ra-226). Samples from three different local grocery stores-Publix, Winn Dixie, and Albertsons-were counted on a gamma spectroscopy system with a GeLi detector. The same food samples were considered as those in the original FIPR database. A statistical analysis, utilizing the Crystal Ball program, was performed on the data to assess the most accurate distribution to use for these data. This allowed a determination of a radiation dose to an individual based on the above-information collected. Based on the analyses performed, radiation dose for grocery store samples was lower for Radium-226 than FIPR debris analyses, 2.7 vs. 5.91 mrem/yr. Lead-210 had a higher dose in the grocery store sample than the FIPR debris analyses, 21.4 vs. 518 mrem/yr. The output radiation dose was higher for all evaluations when an accurate estimation of distributions for each value was considered. Radium-226 radiation dose for FIPR and grocery rose to 9.56 and 4.38 mrem/yr. Radiation dose from ingestion of Pb-210 rose to 34.7 and 854 mrem/yr for FIPR and grocery data, respectively. Lead-210 was higher than initial doses for many reasons: Different peak examined, lower edge of detection limit, and minimum detectable concentration was considered. FIPR did not utilize grocery samples as a control because they calculated radiation dose that appeared unreasonably high. Consideration of distributions with the initial values allowed reevaluation of radiation does and showed a significant difference to original deterministic values. This work shows the value and importance of considering distributions to ensure that a person's radiation dose is accurately calculated. Probabilistic dose methodology was proved to be a more accurate and realistic method of radiation dose determination. This type of methodology provides a visual presentation of dose distribution that can be a vital aid in risk methodology.

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

Randomized Double-Blinded Dose Escalation Trial of Triptorelin for Ovary Protection in Childhood-Onset Systemic Lupus Erythematosus

PubMed Central

Brunner, Hermine I.; Silva, Clovis A; Reiff, Andreas; Higgins, Gloria C.; Imundo, Lisa; Williams, Calvin B.; Wallace, Carol A; Aikawa, Nadia E.; Nelson, Shannen; Klein-Gitelman, Marisa S.; Rose, Susan R.

2015-01-01

Objectives To determine for females with childhood-onset systemic lupus erythematosus (cSLE) who require cyclophosphamide the dose of triptorelin that suffices to maintain complete ovarian suppression (COS); measure the time needed to achieve ovarian suppression after triptorelin initiation, and explore the safety of triptorelin. Methods In this randomized double-blind placebo-controlled dose-escalation study females (< 21 years) were randomized 4:1 to receive triptorelin or placebo (25 triptorelin, 6 placebo). Starting doses of triptorelin between 25 and 100 microgram/kg/dose were used. Triptorelin dosage was escalated until COS was maintained. The primary outcome was the weight-adjusted dose of triptorelin that for at least 90% of the patients provides COS based on Gonadotropin-releasing-hormone Agonist Stimulation Testing. Secondary outcomes were time to ovarian suppression measured by unstimulated FSH and LH levels after study drug initiation. Results Triptorelin dosed at 120 microgram/kg bodyweight led to sustained COS in 90% of the patients. After the initial dose of triptorelin 22 days were needed for achieve COS. Rates of adverse events (AE) and serious adverse events (SAE) per 100 patient-month of follow-up were not higher in the triptorelin group as compared to the placebo group (triptorelin vs. placebo; AE: 189 vs. 362; SAE: 2.05 vs. 8.48). Conclusions For achieving and maintaining COS high doses of triptorelin are needed but appear to be well tolerated in adolescent females with cSLE. Our data suggest that a lag time of 22 days after triptorelin initiation is required before starting or continuing cyclophosphamide-therapy. Trial Registration Number clinicaltrials.gov identifier: NCT00124514 PMID:25676588

Sunitinib dose escalation overcomes transient resistance in clear cell renal cell carcinoma and is associated with epigenetic modifications.

PubMed

Adelaiye, Remi; Ciamporcero, Eric; Miles, Kiersten Marie; Sotomayor, Paula; Bard, Jonathan; Tsompana, Maria; Conroy, Dylan; Shen, Li; Ramakrishnan, Swathi; Ku, Sheng-Yu; Orillion, Ashley; Prey, Joshua; Fetterly, Gerald; Buck, Michael; Chintala, Sreenivasulu; Bjarnason, Georg A; Pili, Roberto

2015-02-01

Sunitinib is considered a first-line therapeutic option for patients with advanced clear cell renal cell carcinoma (ccRCC). Despite sunitinib's clinical efficacy, patients eventually develop drug resistance and disease progression. Herein, we tested the hypothesis whether initial sunitinib resistance may be transient and could be overcome by dose increase. In selected patients initially treated with 50 mg sunitinib and presenting with minimal toxicities, sunitinib dose was escalated to 62.5 mg and/or 75 mg at the time of tumor progression. Mice bearing two different patient-derived ccRCC xenografts (PDX) were treated 5 days per week with a dose-escalation schema (40-60-80 mg/kg sunitinib). Tumor tissues were collected before dose increments for immunohistochemistry analyses and drug levels. Selected intrapatient sunitinib dose escalation was safe and several patients had added progression-free survival. In parallel, our preclinical results showed that PDXs, although initially responsive to sunitinib at 40 mg/kg, eventually developed resistance. When the dose was incrementally increased, again we observed tumor response to sunitinib. A resistant phenotype was associated with transient increase of tumor vasculature despite intratumor sunitinib accumulation at higher dose. In addition, we observed associated changes in the expression of the methyltransferase EZH2 and histone marks at the time of resistance. Furthermore, specific EZH2 inhibition resulted in increased in vitro antitumor effect of sunitinib. Overall, our results suggest that initial sunitinib-induced resistance may be overcome, in part, by increasing the dose, and highlight the potential role of epigenetic changes associated with sunitinib resistance that can represent new targets for therapeutic intervention. ©2014 American Association for Cancer Research.

Model-based adaptive phase I trial design of post-transplant decitabine maintenance in myelodysplastic syndrome.

PubMed

Han, Seunghoon; Kim, Yoo-Jin; Lee, Jongtae; Jeon, Sangil; Hong, Taegon; Park, Gab-Jin; Yoon, Jae-Ho; Yahng, Seung-Ah; Shin, Seung-Hwan; Lee, Sung-Eun; Eom, Ki-Seong; Kim, Hee-Je; Min, Chang-Ki; Lee, Seok; Yim, Dong-Seok

2015-10-23

This report focuses on the adaptive phase I trial design aimed to find the clinically applicable dose for decitabine maintenance treatment after allogeneic hematopoietic stem cell transplantation in patients with higher-risk myelodysplastic syndrome and secondary acute myeloid leukemia. The first cohort (three patients) was given the same initial daily dose of decitabine (5 mg/m(2)/day, five consecutive days with 4-week intervals). In all cohorts, the doses for Cycles 2 to 4 were individualized using pharmacokinetic-pharmacodynamic modeling and simulations. The goal of dose individualization was to determine the maximum dose for each patient at which the occurrence of grade 4 (CTC-AE) toxicities for both platelet and neutrophil counts could be avoided. The initial doses for the following cohorts were also estimated with the data from the previous cohorts in the same manner. In all but one patient (14 out of 15), neutrophil count was the dose-limiting factor throughout the cycles. In cycles where doses were individualized, the median neutrophil nadir observed was 1100/mm(3) (grade 2) and grade 4 toxicity occurred in 5.1 % of all cycles (while it occurred in 36.8 % where doses were not individualized). The initial doses estimated for cohorts 2 to 5 were 4, 5, 5.5, and 5 mg/m(2)/day, respectively. The median maintenance dose was 7 mg/m(2)/day. We determined the acceptable starting dose and individualized the maintenance dose for each patient, while minimizing the toxicity using the adaptive approach. Currently, 5 mg/m(2)/day is considered to be the most appropriate starting dose for the regimen studied. Clinicaltrials.gov NCT01277484.

Radiolysis of paracetamol in dilute aqueous solution

NASA Astrophysics Data System (ADS)

Szabó, László; Tóth, Tünde; Homlok, Renáta; Takács, Erzsébet; Wojnárovits, László

2012-09-01

Using radiolytic experiments hydroxyl radical (main reactant in advanced oxidation processes) was shown to effectively destroy paracetamol molecules. The basic reaction is attachment to the ring. The hydroxy-cyclohexadienyl radical produced in the further reactions may transform to hydroxylated paracetamol derivatives or to quinone type molecules and acetamide. The initial efficiency of aromatic ring destruction in the absence of dissolved O2 is c.a. 10%. The efficiency is 2-3 times higher in the presence of O2 due to its reaction with intermediate hydroxy-cyclohexadienyl radical and the subsequent ring destruction reactions through peroxi radical. Upon irradiation the toxicity of solutions at low doses increases with the dose and then at higher doses it decreases. This is due to formation of compounds with higher toxicity than paracetamol (e.g. acetamide, hidroquinone). These products, however, are highly sensitive to irradiation and degrade easily.

The outcome of clinical parameters in adults with severe Type I Gaucher disease using very low dose enzyme replacement therapy.

PubMed

Wilson, Callum; Spearing, Ruth; Teague, Lochie; Robertson, Patsy; Blacklock, Hilary

2007-01-01

Enzyme replacement therapy is now well established as the treatment of choice in Type I Gaucher disease. Historically higher dosage regimens have been used in preference to lower doses despite the little clinical evidence in the way of large controlled clinical trials to support this. Moreover, the extraordinary cost of therapy means that not all eligible patients are able to be treated at the higher dose. Twelve type I adult patients with relatively severe disease were commenced on a very low dose of 7.5U of alglucerase/imiglucerase per kg every two weeks (initially given thrice weekly and later weekly). Follow-up 5 year data reveal a good visceral and haematological response with outcomes consistent with recently published treatment guidelines. Satisfactory clinical and radiological skeletal improvement was also demonstrated in most patients. Three patients had an inadequate overall skeletal response to therapy. Biomarkers also steadily improved although perhaps not quite at the same rate as that seen in higher doses. Very low dose enzyme replacement therapy may be appropriate for adult type I Gaucher patients with mild-moderate skeletal disease.

Contrast enema as a guide for senna-based laxatives in managing overflow retentive stool incontinence in pediatrics.

PubMed

Radwan, Ahmed Bassiuony; El-Debeiky, Mohammed Soliman; Abdel-Hay, Sameh

2015-08-01

Overflow retentive stool incontinence (ORSI) is secondary to constipation and fecal loading. In our study, the dose and duration of senna-based laxatives (SBL) treatment to achieve full defecatory control will be examined for possible correlation with new parameters measured from the initial contrast enema. Initially, an observational study was conducted prospectively on a group of patient with ORSI to define the optimum dose of SBL to achieve full defecatory control with measurement of six parameters in the initial contrast enema (level of colonic dilatation, recto-anal angle, ratio of maximal diameter of dilated colon to last lumbar spine, ratio of maximum diameter of dilated colon to normal descending colon, immediate and after 24-h post-evacuation residual contrast). The result was analyzed statistically to reach a correlation between the radiological data and prescribed dose. Over 2 and half years, 72 patients were included in the study; their mean age was 6.3 ± 3.33 years. The mean effective starting dose of SBL was 57 ± 18.13 mg/day and the mean effective ending dose was 75 ± 31.68 mg/day. Time lapsed till full defecatory control ranged from 1 to 16 weeks. Statistical correlation revealed that mean effective ending dose of SBL treatment significantly increased with higher levels of colonic dilatation. A weak positive correlation was found for both the mean effective starting and ending doses with the ratio of maximum colonic diameter to last lumbar spine and descending colonic diameters ratio. Senna-based laxatives are effective treatment for overflow retentive stool incontinence and their doses can be adjusted initially depending on the analysis of the radiological data.

Concordance of adolescent human papillomavirus vaccination parental report with provider report in the National Immunization Survey-Teen (2008-2013).

PubMed

Hirth, Jacqueline; Kuo, Yong-Fang; Laz, Tabassum Haque; Starkey, Jonathan M; Rupp, Richard E; Rahman, Mahbubur; Berenson, Abbey B

2016-08-17

To examine the accuracy of parental report of HPV vaccination through examination of concordance, with healthcare provider vaccination report as the comparison. The 2008-2013 National Immunization Survey (NIS)-Teen was used to examine accuracy of parent reports of HPV vaccination for their female daughters aged 13-17years, as compared with provider report of initiation and number of doses. Multivariable logistic regression models were used to examine associations related to concordance of parent and provider report. Of 51,746 adolescents, 84% concordance for HPV vaccine initiation and 70% concordance for number of doses was observed. Accuracy varied by race/ethnicity, region, time, and income. The parent report of number of doses was more likely to be accurate among parents of 13 and 14year old females than 17year olds. Accuracy of initiation and number of doses were lower among Hispanic and black adolescents compared to white parents. The odds of over-report was higher among minorities compared to whites, but the odds of underreport was also markedly higher in these groups compared to parents of white teens. Accuracy of parental vaccine report decreased across time. These findings are important for healthcare providers who need to ascertain the vaccination status of young adults. Strengthening existing immunization registries to improve data sharing capabilities and record completeness could improve vaccination rates, while avoiding costs associated with over-vaccination. Copyright © 2016 Elsevier Ltd. All rights reserved.

ELDRS Characterization for a Very High Dose Mission

NASA Technical Reports Server (NTRS)

Harris, Richard D.; McClure, Steven S.; Rax, Bernard G.; Kenna, Aaron J.; Thorbourn, Dennis O.; Clark, Karla B.; Yan, Tsun-Yee

2010-01-01

Evaluation of bipolar linear parts which may have Enhanced Low Dose Rate Sensitivity (ELDRS) is problematic for missions that have very high dose radiation requirements. The accepted standards for evaluating parts that display ELDRS require testing at a very low dose rate which could be prohibitively long for very high dose missions. In this work, a methodology for ELDRS characterization of bipolar parts for mission doses up to 1 Mrad(Si) is evaluated. The procedure employs an initial dose rate of 0.01 rad(Si)/s to a total dose of 50 krad(Si) and then changes to 0.04 rad(Si)/s to a total dose of 1 Mrad(Si). This procedure appears to work well. No change in rate of degradation with dose has been observed when the dose rate is changed from 0.01 to 0.04 rad(Si)/s. This is taken as an indication that the degradation due to the higher dose rate is equivalent to that at the lower dose rate at the higher dose levels, at least for the parts studied to date. In several cases, significant parameter degradation or functional failure not observed at HDR was observed at fairly high total doses (50 to 250 krad(Si)) at LDR. This behavior calls into question the use of dose rate trend data and enhancement factors to predict LDR performance.

Physics must join with biology in better assessing risk from low-dose irradiation.

PubMed

Feinendegen, L E; Neumann, R D

2005-01-01

This review summarises the complex response of mammalian cells and tissues to low doses of ionising radiation. This thesis encompasses induction of DNA damage, and adaptive protection against both renewed damage and against propagation of damage from the basic level of biological organisation to the clinical expression of detriment. The induction of DNA damage at low radiation doses apparently is proportional to absorbed dose at the physical/chemical level. However, any propagation of such damage to higher levels of biological organisation inherently follows a sigmoid function. Moreover, low-dose-induced inhibition of damage propagation is not linear, but instead follows a dose-effect function typical for adaptive protection, after an initial rapid rise it disappears at doses higher than approximately 0.1-0.2 Gy to cells. The particular biological response duality at low radiation doses precludes the validity of the linear-no-threshold hypothesis in the attempt to relate absorbed dose to cancer. In fact, theory and observation support not only a lower cancer incidence than expected from the linear-no-threshold hypothesis, but also a reduction of spontaneously occurring cancer, a hormetic response, in the healthy individual.

A review of protocols for 308 nm excimer laser phototherapy in psoriasis.

PubMed

Mudigonda, Tejaswi; Dabade, Tushar S; Feldman, Steven R

2012-01-01

308 nm excimer laser phototherapy is efficacious in the treatment of localized psoriasis. Different approaches regarding dose fluency, number of treatments, and maintenance have been utilized, and there is yet to be a consensus on standard protocol. To characterize treatment parameters for 308 nm excimer laser phototherapy. We performed a PubMed search for studies describing excimer laser treatment protocol with particular attention to dosage determination, dose adjustment, dose fluency, number of treatments, and maintenance. Seven prospective studies were found describing the excimer efficacy for psoriasis. All studies determined the initial treatment dose using either the minimal erythema dose (MED) or induration. Fluency ranged from 0.5 MED (low) to 16 MED (high); one study demonstrated that medium to high fluencies yielded better improvement in fewer number of treatments. Fluency adjustments during the course of treatment were important to minimize phototherapy-associated side effects. The use of higher fluencies was reported to result in higher occurrences of blistering. One study implemented a maintenance tapering of dose-frequency phase to better manage psoriasis flare-ups. The 308 nm excimer laser is an effective therapy for psoriasis regardless of the method used to determine initial dosage, dose fluency, or number of treatments. As its usage as a targeted monotherapy increases, future trials should consider evaluating and modifying these parameters to determine the most optimal management of localized psoriasis. Based on our reviewed studies, there is no consensus for a single excimer laser therapy protocol and as a result, patient preferences should continue to be an important consideration for phototherapy regimen planning.

Patient radiation doses in interventional cardiology in the U.S.: Advisory data sets and possible initial values for U.S. reference levels

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

Miller, Donald L.; Hilohi, C. Michael; Spelic, David C.

2012-10-15

Purpose: To determine patient radiation doses from interventional cardiology procedures in the U.S and to suggest possible initial values for U.S. benchmarks for patient radiation dose from selected interventional cardiology procedures [fluoroscopically guided diagnostic cardiac catheterization and percutaneous coronary intervention (PCI)]. Methods: Patient radiation dose metrics were derived from analysis of data from the 2008 to 2009 Nationwide Evaluation of X-ray Trends (NEXT) survey of cardiac catheterization. This analysis used deidentified data and did not require review by an IRB. Data from 171 facilities in 30 states were analyzed. The distributions (percentiles) of radiation dose metrics were determined for diagnosticmore » cardiac catheterizations, PCI, and combined diagnostic and PCI procedures. Confidence intervals for these dose distributions were determined using bootstrap resampling. Results: Percentile distributions (advisory data sets) and possible preliminary U.S. reference levels (based on the 75th percentile of the dose distributions) are provided for cumulative air kerma at the reference point (K{sub a,r}), cumulative air kerma-area product (P{sub KA}), fluoroscopy time, and number of cine runs. Dose distributions are sufficiently detailed to permit dose audits as described in National Council on Radiation Protection and Measurements Report No. 168. Fluoroscopy times are consistent with those observed in European studies, but P{sub KA} is higher in the U.S. Conclusions: Sufficient data exist to suggest possible initial benchmarks for patient radiation dose for certain interventional cardiology procedures in the U.S. Our data suggest that patient radiation dose in these procedures is not optimized in U.S. practice.« less

Randomized, double-blind, dose-escalation trial of triptorelin for ovary protection in childhood-onset systemic lupus erythematosus.

PubMed

Brunner, Hermine I; Silva, Clovis A; Reiff, Andreas; Higgins, Gloria C; Imundo, Lisa; Williams, Calvin B; Wallace, Carol A; Aikawa, Nadia E; Nelson, Shannen; Klein-Gitelman, Marisa S; Rose, Susan R

2015-05-01

To determine the dose of triptorelin that is sufficient to maintain complete ovarian suppression in female patients with childhood-onset systemic lupus erythematosus (SLE) who require cyclophosphamide therapy, to determine the length of time needed to achieve ovarian suppression after initiation of triptorelin treatment, and to investigate the safety of triptorelin. In this randomized, double-blind, placebo-controlled, dose-escalation study, female patients ages <21 years were randomized 4:1 to receive triptorelin (n = 25) or placebo (n = 6). The starting doses of triptorelin were 25, 50, 75, and 100 μg/kg, and the dose was escalated until complete ovarian suppression was maintained. The primary outcome was the weight-adjusted dose of triptorelin that provided complete ovarian suppression in at least 90% of the patients, as determined by gonadotropin-releasing hormone agonist stimulation testing. The secondary outcome was the period of time required to achieve ovarian suppression, as measured by unstimulated follicle-stimulating hormone and luteinizing hormone levels after the initiation of triptorelin treatment. Treatment with triptorelin at a weight-adjusted dose of 120 μg/kg body weight provided sustained complete ovarian suppression in 90% of the patients. After administration of the initial dose of triptorelin, 22 days were required to achieve complete ovarian suppression. The rates of adverse events (AEs) and serious adverse events (SAEs) per 100 patient-months of followup were not higher in the triptorelin group compared with the placebo group (for AEs, 189 versus 362; for SAEs, 2.1 versus 8.5). High doses of triptorelin are needed to achieve and maintain complete ovarian suppression, but such doses appear to be well tolerated in adolescent female patients with childhood-onset SLE. Our data suggest that a lag time of 22 days after initiation of triptorelin treatment is required before cyclophosphamide therapy is started or continued. © 2015, American College of Rheumatology.

Real-World Treatment Patterns for Golimumab and Concomitant Medications in Japanese Rheumatoid Arthritis Patients.

PubMed

Okazaki, Masateru; Kobayashi, Hisanori; Ishii, Yutaka; Kanbori, Masayoshi; Yajima, Tsutomu

2018-06-01

The aim of this study was to investigate real-world treatment patterns for use of golimumab and concomitant medications in Japanese patients with rheumatoid arthritis. This study was a post hoc retrospective analysis from post-marketing surveillance data on 2350 Japanese patients with moderate/severe rheumatoid arthritis who received golimumab for 24 weeks. The study population was divided based on initiation treatment or dose adjustment patterns with golimumab, methotrexate, or oral glucocorticoids. Logistic regression analysis revealed that the baseline factors associated with administration of golimumab (100 mg) were higher body weight, failure of prior biological therapy (bio-failure), no previous methotrexate use, and respiratory disease, while previous methotrexate use and absence of renal impairment or respiratory disease were associated with concomitant methotrexate therapy, and previous glucocorticoid use was associated with concomitant glucocorticoid therapy. The following associations were identified with regard to dose adjustment during treatment: bio-failure, no previous methotrexate use, previous csDMARDs use, presence of respiratory disease, allergy history, and higher CRP for golimumab dose escalation; shorter disease duration, previous GC, and no previous methotrexate use for methotrexate dose escalation; no prior biological therapy and renal impairment for methotrexate dose reduction; no previous GC use for glucocorticoid dose escalation; and absence of Steinbrocker's stage II/III/IV, absence of Steinbrocker's class II, no bio-failure, and no previous csDMARDs use for glucocorticoid dose reduction. This study revealed that various baseline factors were associated with initiation of treatment and dose adjustment of golimumab, methotrexate, or oral glucocorticoids, reflecting both the treatment strategies of physicians for improving RA symptoms and/or reducing adverse events. Janssen Pharmaceutical K.K. and Mitsubishi Tanabe Pharma Corporation.

Surface dose measurements for highly oblique electron beams.

PubMed

Ostwald, P M; Kron, T

1996-08-01

Clinical applications of electrons may involve oblique incidence of beams, and although dose variations for angles up to 60 degrees from normal incidence are well documented, no results are available for highly oblique beams. Surface dose measurements in highly oblique beams were made using parallel-plate ion chambers and both standard LiF:Mg, Ti and carbon-loaded LiF Thermoluminescent Dosimeters (TLD). Obliquity factors (OBF) or surface dose at an oblique angle divided by the surface dose at perpendicular incidence, were obtained for electron energies between 4 and 20 MeV. Measurements were performed on a flat solid water phantom without a collimator at 100 cm SSD. Comparisons were also made to collimated beams. The OBFs of surface doses plotted against the angle of incidence increased to a maximum dose followed by a rapid dropoff in dose. The increase in OBF was more rapid for higher energies. The maximum OBF occurred at larger angles for higher-energy beams and ranged from 73 degrees for 4 MeV to 84 degrees for 20 MeV. At the dose maximum, OBFs were between 130% and 160% of direct beam doses, yielding surface doses of up to 150% of Dmax for the 20 MeV beam. At 2 mm depth the dose ratio was found to increase initially with angle and then decrease as Dmax moved closer to the surface. A higher maximum dose was measured at 2 mm depth than at the surface. A comparison of ion chamber types showed that a chamber with a small electrode spacing and large guard ring is required for oblique dose measurement. A semiempirical equation was used to model the dose increase at the surface with different energy electron beams.

Three years of GH treatment in Turner's syndrome: complex effect of GH dosage on growth parameters. French Pediatric Clinics and Sanofi-Winthrop.

PubMed

Bertrand, A M; Chaussain, J L; Job, B; Mariani, R; Ponte, C; Rappaport, R; Rochiccioll, P; Chatelain, P

1996-06-01

There have been few studies of GH dose responses in Turner's syndrome. We have therefore compared the growth effect of two doses of subcutaneous GH: 0.45 (D1) or 0.90 (D2) IU/kg/week. Multicentre study with two parallel randomized groups treated with D1 or D2 dose for one year, then with D2 for the second and third years in both groups. Ninety-seven girls with Turner's syndrome aged from 4.8 to 16.5 years. The first mean height velocity (HV) was significantly higher with D2. At one year the girls changed from D1 to D2 showed a further acceleration in HV. During second and third years HV remained above the mean for untreated Turner girls, in both groups. Mean cumulative height gains over the 3 years were 1.06 and 1.17 SDS/CA (Ranke's Turner standard) in groups G1 and G2 respectively. Bone maturation, over 36 months, was 33.7 (G1) and 31.9 (G2) months. These results suggest that, if a higher initial GH dose is associated with a greater net initial height gain, the duration of treatment might affect the long-term results. Intermittent treatment should be considered.

Induction of labor using prostaglandin E2 (PGE2) vaginal gel in triacetin base. An efficacy study comparing two dosage regimens.

PubMed

Seeras, R C; Olatunbosun, O A; Pierson, R A; Turnell, R W

1995-01-01

To compare two dosage regimens for the administration of vaginal prostaglandin gel in triacetin base for induction of labor. Seventy subjects planned for elective induction of labor at term were randomized to treatment with PGE2 vaginal gel every 6 or 12 hours. The 6-hourly group received an initial dose of 1 mg, followed by 2 mg at 6 hour intervals for a maximum of two additional doses if not in active labor. The 12-hourly group had an initial dose of 2 mg followed by two additional doses at 12 hour intervals if not in active labor. Successful induction rate was higher in the 12-hourly as compared to 6-hourly gel regimen (100% vs. 91%, P > 0.05). Twelve hours after the initial dose, delivery occurred in 34% delivery had occurred in 57% and 37% respectively (P < 0.01). We found no difference in the induction-active labor interval (P > 0.05), and the induction-delivery interval (P > 0.05) between the two groups. Active labor followed a single dose of gel in 66% of the 12-hourly group compared to 40% of the 6-hourly group (P < 0.01). Syntocinon augmentation was needed in 6% of subjects in the 12-hourly group as compared to 26% in the 6-hourly group (P < 0.01). The cesarean section rate was similar in both groups. Uterine hyperstimulation occurred less frequently in the 12-hourly group (P < 0.05). The perinatal outcome was similar in both groups. The 12-hourly regimen was more effective than the 6-hourly regimen in initiating labor. The majority of the subjects in the 12 hourly group achieved labor following a single dose of gel. Induction delivery interval, however, was similar in both groups.

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

Yu, Yao; Chen, Josephine; Leary, Celeste I.

Radiation of the low neck can be accomplished using split-field intensity-modulated radiation therapy (sf-IMRT) or extended-field intensity-modulated radiation therapy (ef-IMRT). We evaluated the effect of these treatment choices on target coverage and thyroid and larynx doses. Using data from 14 patients with cancers of the oropharynx, we compared the following 3 strategies for radiating the low neck: (1) extended-field IMRT, (2) traditional split-field IMRT with an initial cord-junction block to 40 Gy, followed by a full-cord block to 50 Gy, and (3) split-field IMRT with a full-cord block to 50 Gy. Patients were planned using each of these 3 techniques.more » To facilitate comparison, extended-field plans were normalized to deliver 50 Gy to 95% of the neck volume. Target coverage was assessed using the dose to 95% of the neck volume (D{sub 95}). Mean thyroid and larynx doses were computed. Extended-field IMRT was used as the reference arm; the mean larynx dose was 25.7 ± 7.4 Gy, and the mean thyroid dose was 28.6 ± 2.4 Gy. Split-field IMRT with 2-step blocking reduced laryngeal dose (mean larynx dose 15.2 ± 5.1 Gy) at the cost of a moderate reduction in target coverage (D{sub 95} 41.4 ± 14 Gy) and much higher thyroid dose (mean thyroid dose 44.7 ± 3.7 Gy). Split-field IMRT with initial full-cord block resulted in greater laryngeal sparing (mean larynx dose 14.2 ± 5.1 Gy) and only a moderately higher thyroid dose (mean thyroid dose 31 ± 8 Gy) but resulted in a significant reduction in target coverage (D{sub 95} 34.4 ± 15 Gy). Extended-field IMRT comprehensively covers the low neck and achieves acceptable thyroid and laryngeal sparing. Split-field IMRT with a full-cord block reduces laryngeal doses to less than 20 Gy and spares the thyroid, at the cost of substantially reduced coverage of the low neck. Traditional 2-step split-field IMRT similarly reduces the laryngeal dose but also reduces low-neck coverage and delivers very high doses to the thyroid.« less

Impact of conventional fractionated RT to pelvic lymph nodes and dose-escalated hypofractionated RT to prostate gland using IMRT treatment delivery in high-risk prostate cancer

NASA Astrophysics Data System (ADS)

Pervez, Nadeem

Prostate cancer is the most common cancer among Canadian men. The standard treatment in high-risk category is radical radiation, with androgen suppression treatment (AST). Significant disease progression is reported despite this approach. Radiation dose escalation has been shown to improve disease-free survival; however, it results in higher toxicities. Hypofractionated radiation schedules (larger dose each fraction in shorter overall treatment time) are expected to deliver higher biological doses. A hypofractionated scheme was used in this study to escalate radiation doses with AST. Treatment was well tolerated acutely. Early results of self-administered quality of life reported by patients shows a decrease in QOL which is comparable to other treatment schedules. Significant positional variation of the prostate was observed during treatment. Therefore, we suggest daily target verification to avoid a target miss. Initial late effects are reasonable and early treatment outcomes are promising. Longer follow-up is required for full outcomes assessments.

A preliminary investigation of high dose ion irradiation response of a lanthana-bearing nanostructured ferritic steel processed via spark plasma sintering

NASA Astrophysics Data System (ADS)

Pasebani, Somayeh; Charit, Indrajit; Guria, Ankan; Wu, Yaqiao; Burns, Jatuporn; Butt, Darryl P.; Cole, James I.; Shao, Lin

2017-11-01

A nanostructured ferritic steel with nominal composition of Fe-14Cr-1Ti-0.3Mo-0.5La2O3 (wt.%) was irradiated with Fe+2 ions at 475 °C for 100, 200, 300 and 400 dpa. Grain coarsening was observed for the samples irradiated for 200-400 dpa resulting in an increase of the average grain size from 152 nm to 620 nm. Growth of submicron grains at higher radiation doses is due to decreased pinning effect imparted by Cr-O rich nanoparticles (NPs) that underwent coarsening via Ostwald ripening. Dislocation density consistently increased with increasing irradiation dose at 300 and 400 dpa. The mean radius of lanthanum-containing nanoclusters (NCs) decreased and their number density increased above 200 dpa, which is likely due to solutes ejection caused by ballistic dissolution and irradiation-enhanced diffusion. Chromium, titanium, oxygen and lanthanum content of nanoclusters irradiated at 200 dpa and higher got reduced by almost half the initial value. The reduction in size of the nanoclusters accompanied with their higher number density and higher dislocation density led to significant radiation hardening with increasing irradiation dose.

Use of the UKHCDO Database for a postmarketing surveillance study of different doses of recombinant factor VIIa in haemophilia.

PubMed

Hay, C R M; Sharpe, T; Dolan, G

2017-05-01

Recombinant factor VIIa (rFVIIa) is recommended in Europe at standard (3 × 90 μg kg -1 ) or high (1 × 270 μg kg -1 ) doses. When granting the license for the high dose, the European Medicines Agency (EMA) requested postmarketing surveillance for thrombosis. This was conducted by the United Kingdom National Haemophilia Database (NHD) on behalf of Novo Nordisk and the EMA. To assess the use and safety of rFVIIa utilizing prospective data collected by the NHD (1 January 2008 to 30 June 2011). Data were obtained from 67 haemophilia A/B patients with inhibitors treated for 1057 bleeds and 31 acquired haemophilia patients treated for 70 bleeds. Initial rFVIIa dose was categorized post hoc as low (<90 μg kg -1 ), intermediate (≥90-<180 μg kg -1 ) or high (≥180-<270 or ≥270 μg kg -1 ). For haemophilia A/B, high and lower initial rFVIIa dose was used for 38.4% and 51.4% of episodes, respectively, while for acquired haemophilia, the values were 11.4% and 77.1% respectively. Median initial doses were higher for haemophilia A/B (146.3 μg kg -1 ) than acquired haemophilia (90.5 μg kg -1 ). A single administration of rFVIIa was the most frequently used regimen for haemophilia A/B, in contrast with standard recommendations and previous reports. For acquired haemophilia, most episodes were treated with multiple doses. No adverse drug reactions or thromboembolic events were reported for any rFVIIa dose. The novel use of a national database for postmarketing surveillance has demonstrated acceptable safety for all recommended doses of rFVIIa. © 2016 John Wiley & Sons Ltd.

Patterns of Care for Biologic-Dosing Outliers and Nonoutliers in Biologic-Naive Patients with Rheumatoid Arthritis.

PubMed

Delate, Thomas; Meyer, Roxanne; Jenkins, Daniel

2017-08-01

Although most biologic medications for patients with rheumatoid arthritis (RA) have recommended fixed dosing, actual biologic dosing may vary among real-world patients, since some patients can receive higher (high-dose outliers) or lower (low-dose outliers) doses than what is recommended in medication package inserts. To describe the patterns of care for biologic-dosing outliers and nonoutliers in biologic-naive patients with RA. This was a retrospective, longitudinal cohort study of patients with RA who were not pregnant and were aged ≥ 18 and < 90 years from an integrated health care delivery system. Patients were newly initiated on adalimumab (ADA), etanercept (ETN), or infliximab (IFX) as index biologic therapy between July 1, 2006, and February 28, 2014. Outlier status was defined as a patient having received at least 1 dose < 90% or > 110% of the approved dose in the package insert at any time during the study period. Baseline patient profiles, treatment exposures, and outcomes were collected during the 180 days before and up to 2 years after biologic initiation and compared across index biologic outlier groups. Patients were followed for at least 1 year, with a subanalysis of those patients who remained as members for 2 years. This study included 434 RA patients with 1 year of follow-up and 372 RA patients with 2 years of follow-up. Overall, the vast majority of patients were female (≈75%) and had similar baseline characteristics. Approximately 10% of patients were outliers in both follow-up cohorts. ETN patients were least likely to become outliers, and ADA patients were most likely to become outliers. Of all outliers during the 1-year follow-up, patients were more likely to be a high-dose outlier (55%) than a low-dose outlier (45%). Median 1- and 2-year adjusted total biologic costs (based on wholesale acquisition costs) were higher for ADA and ETA nonoutliers than for IFX nonoutliers. Biologic persistence was highest for IFX patients. Charlson Comorbidity Index score, ETN and IFX index biologic, and treatment with a nonbiologic disease-modifying antirheumatic drug (DMARD) before biologic initiation were associated with becoming high- or low-dose outliers (c-statistic = 0.79). Approximately 1 in 10 study patients with RA was identified as a biologic-dosing outlier. Dosing outliers did not appear to have better clinical outcomes compared with nonoutliers. Before initiating outlier biologic dosing, health care providers may better serve their RA patients by prescribing alternate DMARD therapy. This study was sponsored by Janssen Scientific Affairs. It is the policy of Janssen Scientific Affairs to publish all sponsored studies unless they are exploratory studies or are determined a priori for internal use only (e.g., to inform business decisions). Meyer is an employee of Janssen Scientific Affairs and a stockholder in Johnson and Johnson, its parent company. Delate and Jenkins have nothing to disclose. Study concept and design were contributed by Delate and Meyer. Delate took the lead in data collection, along with Jenkins. All authors participated in data analysis. The manuscript was written primarily by Delate, along with Meyers and Jenkins, and was revised by Meyer, along with Delate and Jenkins.

Evaluation of an Intervention Providing HPV Vaccine in Schools

PubMed Central

Stubbs, Brenda W.; Panozzo, Catherine A.; Moss, Jennifer L.; Reiter, Paul L.; Whitesell, Dianne H.; Brewer, Noel T.

2014-01-01

Objectives To conduct outcome and process evaluations of school-located HPV vaccination clinics in partnership with a local health department. Methods Temporary clinics provided the HPV vaccine to middle school girls in Guilford County, North Carolina, in 2009–2010. Results HPV vaccine initiation was higher among girls attending host schools than satellite schools (6% vs. 1%, OR = 6.56, CI = 3.99–10.78). Of the girls who initiated HPV vaccine, 80% received all 3 doses. Private insurance or federal programs paid for most vaccine doses. Conclusions Lessons learned for creating more effective school-health department partnerships include focusing on host schools and delivering several vaccines to adolescents, not just HPV vaccine alone. PMID:24034684

Evaluation of the Effectiveness of Two Morphine Protocols to Treat Neonatal Abstinence Syndrome in a Level II Nursery in a Community Hospital.

PubMed

DeAtley, Heather N; Burton, Amanda; Fraley, Michelle DeLuca; Haltom, Joan

2017-07-01

The authors sought to evaluate the impact on length of hospital stay and treatment duration of morphine after implementation of a change in the institutional protocol for managing neonatal abstinence syndrome (NAS) in an effort to improve patient outcomes. A single-center, retrospective chart review was conducted at a Level II nursery in a community hospital in Kentucky. Fifty-nine neonates born between January 1, 2014, and December 31, 2015, who were diagnosed with NAS and received morphine for treatment were included. The protocol 1 group consisted of 33 neonates who received an initial dose of morphine 0.04 mg/kg/dose administered orally every 4 hours (January 1-December 31, 2014), and the protocol 2 group consisted of 26 neonates who received an initial dose of morphine 0.06 mg/kg/dose administered orally every 3 hours (January 1-November 30, 2015), after a change in the protocol for managing NAS was implemented on January 1, 2015. Data were reviewed and compared between the two protocol groups to determine the impact that the dosage change had on length of hospital stay and morphine treatment duration. The average length of stay decreased by 7 days in the protocol 2 group compared with the protocol 1 group (21 vs 28.65 days). The average duration of treatment decreased by 7 days in the protocol 2 group compared with the protocol 1 group (18.3 vs 25.4 days). These differences between groups were not statistically significant, however, because the population size was not large enough to achieve adequate power. These results indicate that protocol 2 displayed the potential to decrease length of stay and duration of treatment compared with protocol 1 at this facility; however, balancing higher starting doses with the risk of oversedation will continue to challenge the health care team. Concern for oversedation when using the higher starting dose in protocol 2 has prompted further research (e.g., protocol 3, initial morphine 0.05 mg/kg/dose every 3 hrs). Continued research is also necessary with larger patient populations to enable generalizability to other institutions. © 2017 Pharmacotherapy Publications, Inc.

Renal Function in De Novo Liver Transplant Recipients Receiving Different Prolonged-Release Tacrolimus Regimens-The DIAMOND Study.

PubMed

TruneČka, P; Klempnauer, J; Bechstein, W O; Pirenne, J; Friman, S; Zhao, A; Isoniemi, H; Rostaing, L; Settmacher, U; Mönch, C; Brown, M; Undre, N; Tisone, G

2015-07-01

DIAMOND: multicenter, 24-week, randomized trial investigating the effect of different once-daily, prolonged-release tacrolimus dosing regimens on renal function after de novo liver transplantation. Arm 1: prolonged-release tacrolimus (initial dose 0.2mg/kg/day); Arm 2: prolonged-release tacrolimus (0.15-0.175mg/kg/day) plus basiliximab; Arm 3: prolonged-release tacrolimus (0.2mg/kg/day delayed until Day 5) plus basiliximab. All patients received MMF plus a bolus of corticosteroid (no maintenance steroids). eGFR (MDRD4) at Week 24. Secondary endpoints: composite efficacy failure, BCAR and AEs. Baseline characteristics were comparable. Tacrolimus trough levels were readily achieved posttransplant; initially lower in Arm 2 versus 1 with delayed initiation in Arm 3. eGFR (MDRD4) was higher in Arms 2 and 3 versus 1 (p = 0.001, p = 0.047). Kaplan-Meier estimates of composite efficacy failure-free survival were 72.0%, 77.6%, 73.9% in Arms 1-3. BCAR incidence was significantly lower in Arm 2 versus 1 and 3 (p = 0.016, p = 0.039). AEs were comparable. Prolonged-release tacrolimus (0.15-0.175mg/kg/day) immediately posttransplant plus basiliximab and MMF (without maintenance corticosteroids) was associated with lower tacrolimus exposure, and significantly reduced renal function impairment and BCAR incidence versus prolonged-release tacrolimus (0.2mg/kg/day) administered immediately posttransplant. Delayed higher-dose prolonged-release tacrolimus initiation significantly reduced renal function impairment compared with immediate posttransplant administration, but BCAR incidence was comparable. © 2015 The Authors. American Journal of Transplantation published by Wiley Periodicals Inc.

pH and Organic Carbon Dose Rates Control Microbially Driven Bioremediation Efficacy in Alkaline Bauxite Residue.

PubMed

Santini, Talitha C; Malcolm, Laura I; Tyson, Gene W; Warren, Lesley A

2016-10-18

Bioremediation of alkaline tailings, based on fermentative microbial metabolisms, is a novel strategy for achieving rapid pH neutralization and thus improving environmental outcomes associated with mining and refining activities. Laboratory-scale bioreactors containing bauxite residue (an alkaline, saline tailings material generated as a byproduct of alumina refining), to which a diverse microbial inoculum was added, were used in this study to identify key factors (pH, salinity, organic carbon supply) controlling the rates and extent of microbially driven pH neutralization (bioremediation) in alkaline tailings. Initial tailings pH and organic carbon dose rates both significantly affected bioremediation extent and efficiency with lower minimum pHs and higher extents of pH neutralization occurring under low initial pH or high organic carbon conditions. Rates of pH neutralization (up to 0.13 mM H + produced per day with pH decreasing from 9.5 to ≤6.5 in three days) were significantly higher in low initial pH treatments. Representatives of the Bacillaceae and Enterobacteriaceae, which contain many known facultative anaerobes and fermenters, were identified as key contributors to 2,3-butanediol and/or mixed acid fermentation as the major mechanism(s) of pH neutralization. Initial pH and salinity significantly influenced microbial community successional trajectories, and microbial community structure was significantly related to markers of fermentation activity. This study provides the first experimental demonstration of bioremediation in bauxite residue, identifying pH and organic carbon dose rates as key controls on bioremediation efficacy, and will enable future development of bioreactor technologies at full field scale.

Oxytocin Augmentation in Spontaneously Laboring, Nulliparous Women: Multilevel Assessment of Maternal BMI and Oxytocin Dose

PubMed Central

Carlson, Nicole S.; Corwin, Elizabeth J.; Lowe, Nancy K.

2017-01-01

Background Synthetic oxytocin, the primary tool for labor augmentation, is less effective among obese women, leading to more unplanned cesarean deliveries for slow labor progress. It is not known if obese women require higher doses of oxytocin due to maternal, fetal, or labor factors related to maternal obesity. Objectives This study had two main objectives: 1) Examine the influence of maternal body mass index (BMI) on hourly doses of oxytocin from augmentation initiation until vaginal delivery in obese women; and 2) Examine the influence of other maternal, fetal, and labor factors on hourly doses of oxytocin in obese women. Study design Longitudinal study of a cohort (N = 136) of healthy, nulliparous, spontaneously laboring obese women (BMI ≥ 30 kg/m2) who received oxytocin augmentation and achieved vaginal delivery. We performed iterative multilevel analyses to examine the influence of maternal BMI and other factors on hourly oxytocin doses. Results Maternal BMI explained 16.56% (95% CI [13.7-20.04], p < 0.001) of the variance in hourly oxytocin doses received in a multilevel model controlling for influence of maternal, fetal, and labor characteristics. Maternal age, gestational age, status of amniotic membranes at hospital admission, and admission cervical dilation examination were not significant; however, neonatal birthweight and cervical dilation at oxytocin initiation were significant predictors of hourly oxytocin dose in these women (p < 0.001). Conclusions Even when parturition preparation has progressed adequately for spontaneous labor initiation, there still may be some obesity-related blunting of myometrial contractility and response to oxytocin used for augmentation. PMID:28347147

Oxytocin Augmentation in Spontaneously Laboring, Nulliparous Women: Multilevel Assessment of Maternal BMI and Oxytocin Dose.

PubMed

Carlson, Nicole S; Corwin, Elizabeth J; Lowe, Nancy K

2017-07-01

Synthetic oxytocin, the primary tool for labor augmentation, is less effective among obese women, leading to more unplanned cesarean deliveries for slow labor progress. It is not known if obese women require higher doses of oxytocin due to maternal, fetal, or labor factors related to maternal obesity. This study had two main objectives: (1) examine the influence of maternal body mass index (BMI) on hourly doses of oxytocin from augmentation initiation until vaginal delivery in obese women; and (2) examine the influence of other maternal, fetal, and labor factors on hourly doses of oxytocin in obese women. Longitudinal study of a cohort ( N = 136) of healthy, nulliparous, spontaneously laboring obese women (BMI ≥ 30 kg/m 2 ) who received oxytocin augmentation and achieved vaginal delivery. We performed iterative multilevel analyses to examine the influence of maternal BMI and other factors on hourly oxytocin doses. Maternal BMI explained 16.56% (95% confidence interval [CI] = [13.7, 20.04], p < .001) of the variance in hourly oxytocin doses received in a multilevel model controlling for influence of maternal, fetal, and labor characteristics. Maternal age, gestational age, status of amniotic membranes at hospital admission, and admission cervical dilation examination were not significant; however, neonatal birthweight and cervical dilation at oxytocin initiation were significant predictors of hourly oxytocin dose in these women ( p < .001). Even when parturition preparation has progressed adequately for spontaneous labor initiation, there still may be some obesity-related blunting of myometrial contractility and response to oxytocin used for augmentation.

Cumulative or delayed nephrotoxicity after cisplatin (DDP) treatment.

PubMed

Pinnarò, P; Ruggeri, E M; Carlini, P; Giovannelli, M; Cognetti, F

1986-04-30

The present retrospective study reports data regarding renal toxicity in 115 patients (63 males, 52 females; median age, 56 years) who received cumulative doses of cisplatin (DDP) greater than or equal to 200 mg/m2. DDP was administered alone or in combination at a dose of 50-70 mg/m2 in 91 patients, and at a dose of 100 mg/m2 in 22 patients. Two patients after progression of ovarian carcinoma treated with conventional doses of DDP received 4 and 2 courses, respectively, of high-dose DDP (40 mg/m2 for 5 days) in hypertonic saline. The median number of DDP courses was 6 (range 2-14), and the median cumulative dose was 350 mg/m2 (range, 200-1200). Serum creatinine and urea nitrogen were determined before initiating the treatment and again 13-16 days after each administration. The incidence of azotemia (creatinina levels that exceeded 1.5 mg/dl) was similar before (7.8%) and after (6.1%) DDP doses of 200 mg/m2. Azotemia appears to be related to the association of DDP with other potentially nephrotoxic antineoplastic drugs (methotrexate) more than to the dose per course of DDP. Of 59 patients followed for 2 months or more after discontinuing the DDP treatment, 3 (5.1%) presented creatinine values higher than 1.5 mg/dl. The data deny that the incidence of nephrotoxicity is higher in patients receiving higher cumulative doses of DDP and confirm that increases in serum creatinine levels may occur some time after discontinuation of the drug.

Optimizing Caffeine Use and Risk of Bronchopulmonary Dysplasia in Preterm Infants: A Systematic Review, Meta-analysis, and Application of Grading of Recommendations Assessment, Development, and Evaluation Methodology.

PubMed

Pakvasa, Mitali Atul; Saroha, Vivek; Patel, Ravi Mangal

2018-06-01

Caffeine reduces the risk of bronchopulmonary dysplasia (BPD). Optimizing caffeine use could increase therapeutic benefit. We performed a systematic-review and random-effects meta-analysis of studies comparing different timing of initiation and dose of caffeine on the risk of BPD. Earlier initiation, compared to later, was associated with a decreased risk of BPD (5 observational studies; n = 63,049, adjusted OR 0.69; 95% CI 0.64-0.75, GRADE: low quality). High-dose caffeine, compared to standard-dose, was associated with a decreased risk of BPD (3 randomized trials, n = 432, OR 0.65; 95% CI 0.43-0.97; GRADE: low quality). Higher quality evidence is needed to guide optimal caffeine use. Copyright © 2018 Elsevier Inc. All rights reserved.

Population pharmacokinetics of busulfan in pediatric and young adult patients undergoing hematopoietic cell transplant: a model-based dosing algorithm for personalized therapy and implementation into routine clinical use.

PubMed

Long-Boyle, Janel R; Savic, Rada; Yan, Shirley; Bartelink, Imke; Musick, Lisa; French, Deborah; Law, Jason; Horn, Biljana; Cowan, Morton J; Dvorak, Christopher C

2015-04-01

Population pharmacokinetic (PK) studies of busulfan in children have shown that individualized model-based algorithms provide improved targeted busulfan therapy when compared with conventional dose guidelines. The adoption of population PK models into routine clinical practice has been hampered by the tendency of pharmacologists to develop complex models too impractical for clinicians to use. The authors aimed to develop a population PK model for busulfan in children that can reliably achieve therapeutic exposure (concentration at steady state) and implement a simple model-based tool for the initial dosing of busulfan in children undergoing hematopoietic cell transplantation. Model development was conducted using retrospective data available in 90 pediatric and young adult patients who had undergone hematopoietic cell transplantation with busulfan conditioning. Busulfan drug levels and potential covariates influencing drug exposure were analyzed using the nonlinear mixed effects modeling software, NONMEM. The final population PK model was implemented into a clinician-friendly Microsoft Excel-based tool and used to recommend initial doses of busulfan in a group of 21 pediatric patients prospectively dosed based on the population PK model. Modeling of busulfan time-concentration data indicates that busulfan clearance displays nonlinearity in children, decreasing up to approximately 20% between the concentrations of 250-2000 ng/mL. Important patient-specific covariates found to significantly impact busulfan clearance were actual body weight and age. The percentage of individuals achieving a therapeutic concentration at steady state was significantly higher in subjects receiving initial doses based on the population PK model (81%) than in historical controls dosed on conventional guidelines (52%) (P = 0.02). When compared with the conventional dosing guidelines, the model-based algorithm demonstrates significant improvement for providing targeted busulfan therapy in children and young adults.

Immediate effects of 33 to 180 rad/min (60)Co exposure on performance and blood pressure in monkeys. Topical report

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

Bruner, A.

1976-09-01

Four groups of monkeys received 1000 rads (60)Co at 33, 50, 75, or 180 rad/min wholebody irradiation while performing a delayed matching-to-sample task. Systematic dose rate effects were observed on performance and blood pressure within the initial 20 min postirradiation. The incidence and severity of performance decrement (PD) increased with higher dose rate. The appearance of postirradiation hypotension was systematically delayed and its rate of fall prolonged as dose rate was lower. The hypotension likewise appeared less deep with lower dose rate exposure. Based on the calculated cumulative dose absorbed at the time of symptom appearance two coactive thresholds weremore » proposed to exist: a total dose threshold of approximately 300 rads (midbody measurement), and a dose rate threshold of about 25 rad/min.« less

Glyceryl triacetate for Canavan disease: a low-dose trial in infants and evaluation of a higher dose for toxicity in the tremor rat model.

PubMed

Madhavarao, C N; Arun, P; Anikster, Y; Mog, S R; Staretz-Chacham, O; Moffett, J R; Grunberg, N E; Gahl, W A; Namboodiri, A M A

2009-10-01

Canavan disease (CD) is a fatal dysmyelinating genetic disorder associated with aspartoacylase deficiency, resulting in decreased brain acetate levels and reduced myelin lipid synthesis in the developing brain. Here we tested tolerability of a potent acetate precursor, glyceryl triacetate (GTA), at low doses in two infants diagnosed with CD, aged 8 and 13 months. Much higher doses of GTA were evaluated for toxicity in the tremor rat model of CD. GTA was given orally to the infants for up to 4.5 and 6 months, starting at 25 mg/kg twice daily, doubling the dose weekly until a maximum of 250 mg/kg reached. Wild-type and tremor rat pups were given GTA orally twice daily, initially at a dose of 4.2 g/kg from postnatal days 7 through 14, and at 5.8 g/kg from day 15 through 23, and thereafter in food (7.5%) and water (5%). At the end of the trial (approximately 90 to 120 days) sera and tissues from rats were analysed for changes in blood chemistry and histopathology. GTA treatment caused no detectable toxicity and the patients showed no deterioration in clinical status. In the high-dose animal studies, no significant differences in the mean blood chemistry values occurred between treated and untreated groups, and no lesions indicating toxicity were detectable in any of the tissues examined. Lack of GTA toxicity in two CD patients in low-dose trials, as well as in high-dose animal studies, suggests that higher, effective dose studies in human CD patients are warranted.

FAILURE OF RADIOACTIVE IODINE IN TREATMENT OF HYPERTHYROIDISM

PubMed Central

Schneider, David F.; Sonderman, Philip E.; Jones, Michaela F.; Ojomo, Kristin A.; Chen, Herbert; Jaume, Juan C.; Elson, Diane F.; Perlman, Scott B.; Sippel, Rebecca S.

2015-01-01

Introduction Persistent or recurrent hyperthyroidism after treatment with radioactive iodine (RAI) is common, and many patients require either additional doses or surgery before they are cured. The purpose of this study was to identify patterns and predictors of failure of RAI in patients with hyperthyroidism. Methods We conducted a retrospective review of patients treated with RAI from 2007–2010. Failure of RAI was defined as receipt of additional dose(s) and/or total thyroidectomy. Using a Cox proportional hazards model, we conducted univariate analysis to identify factors associated with failure of RAI. A final multivariate model was then constructed with significant (p < 0.05) variables from the univariate analysis. Results Of the 325 patients analyzed, 74 patients (22.8%) failed initial RAI treatment. 53 (71.6%) received additional RAI, 13 (17.6%) received additional RAI followed by surgery, and the remaining 8 (10.8%) were cured after thyroidectomy. The percentage of patients who failed decreased in a step-wise fashion as RAI dose increased. Similarly, the incidence of failure increased as the presenting T3 level increased. Sensitivity analysis revealed that RAI doses < 12.5 mCi were associated with failure while initial T3 and free T4 levels of at least 4.5 pg/mL and 2.3 ng/dL, respectively, were associated with failure. In the final multivariate analysis, higher T4 (HR 1.13, 95% CI 1.02–1.26, p=0.02) and methimazole treatment (HR 2.55, 95% CI 1.22–5.33, p=0.01) were associated with failure. Conclusions Laboratory values at presentation can predict which patients with hyperthyroidism are at risk for failing RAI treatment. Higher doses of RAI or surgical referral may prevent the need for repeat RAI in selected patients. PMID:25001092

Failure of radioactive iodine in the treatment of hyperthyroidism.

PubMed

Schneider, David F; Sonderman, Philip E; Jones, Michaela F; Ojomo, Kristin A; Chen, Herbert; Jaume, Juan C; Elson, Diane F; Perlman, Scott B; Sippel, Rebecca S

2014-12-01

Persistent or recurrent hyperthyroidism after treatment with radioactive iodine (RAI) is common and many patients require either additional doses or surgery before they are cured. The purpose of this study was to identify patterns and predictors of failure of RAI in patients with hyperthyroidism. We conducted a retrospective review of patients treated with RAI from 2007 to 2010. Failure of RAI was defined as receipt of additional dose(s) and/or total thyroidectomy. Using a Cox proportional hazards model, we conducted univariate analysis to identify factors associated with failure of RAI. A final multivariate model was then constructed with significant (p < 0.05) variables from the univariate analysis. Of the 325 patients analyzed, 74 patients (22.8 %) failed initial RAI treatment, 53 (71.6 %) received additional RAI, 13 (17.6 %) received additional RAI followed by surgery, and the remaining 8 (10.8 %) were cured after thyroidectomy. The percentage of patients who failed decreased in a stepwise fashion as RAI dose increased. Similarly, the incidence of failure increased as the presenting T3 level increased. Sensitivity analysis revealed that RAI doses <12.5 mCi were associated with failure while initial T3 and free T4 levels of at least 4.5 pg/mL and 2.3 ng/dL, respectively, were associated with failure. In the final multivariate analysis, higher T4 (hazard ratio [HR] 1.13; 95 % confidence interval [CI] 1.02-1.26; p = 0.02) and methimazole treatment (HR 2.55; 95 % CI 1.22-5.33; p = 0.01) were associated with failure. Laboratory values at presentation can predict which patients with hyperthyroidism are at risk for failing RAI treatment. Higher doses of RAI or surgical referral may prevent the need for repeat RAI in selected patients.

Altered mental status in older adults with histamine2-receptor antagonists: a population-based study.

PubMed

Tawadrous, Davy; Dixon, Stephanie; Shariff, Salimah Z; Fleet, Jamie; Gandhi, Sonja; Jain, Arsh K; Weir, Matthew A; Gomes, Tara; Garg, Amit X

2014-10-01

Standard doses of histamine2-receptor antagonists (H2RAs) may induce altered mental status in older adults, especially in those with chronic kidney disease (CKD). Population-based cohort study of older adults who started a new H2RA between 2002 and 2011 was conducted. Ninety percent received the current standard H2RA dose in routine care. There was no significant difference in 27 baseline patient characteristics. The primary outcome was hospitalization with an urgent head computed tomography (CT) scan (proxy for altered mental status), and the secondary outcome was all-cause mortality also within 30days of a new H2RA prescription. Standard vs. low H2RA dose was associated with a higher risk of hospitalization with an urgent head CT scan (0.98% vs. 0.74%, absolute risk difference 0.24% [95% CI 0.11% to 0.36%], relative risk 1.33 [95% CI 1.12 to 1.58]). This risk was not modified by the presence of CKD (interaction P value=0.71). Standard vs. low H2RA dose was associated with a higher risk of mortality (1.07% vs.0.74%; absolute risk difference 0.34% [95% CI 0.20% to 0.46%], relative risk 1.46 [95% CI 1.23 to 1.73]). Compared to a lower dose, initiation of the current standard dose of H2RA in older adults is associated with a small absolute increase in the 30-day risk of altered mental status (using neuroimaging as a proxy), even in the absence of CKD. This risk may be avoided by initiating older adults on low doses of H2RAs for gastroesophogeal reflux disease, and increasing dosing as necessary for symptom control. Copyright © 2014 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved.

Randomized phase 2 trial to evaluate the clinical efficacy of two high-dosage tigecycline regimens versus imipenem-cilastatin for treatment of hospital-acquired pneumonia.

PubMed

Ramirez, Julio; Dartois, Nathalie; Gandjini, Hassan; Yan, Jean Li; Korth-Bradley, Joan; McGovern, Paul C

2013-04-01

In a previous phase 3 study, the cure rates that occurred in patients with hospital-acquired pneumonia treated with tigecycline at the approved dose were lower than those seen with patients treated with imipenem and cilastatin (imipenem/cilastatin). We hypothesized that a higher dose of tigecycline is necessary in patients with hospital-acquired pneumonia. This phase 2 study compared the safety and efficacy of two higher doses of tigecycline with imipenem/cilastatin in subjects with hospital-acquired pneumonia. Subjects with hospital-acquired pneumonia were randomized to receive one of two doses of tigecycline (150 mg followed by 75 mg every 12 h or 200 mg followed by 100 mg every 12 h) or 1 g of imipenem/cilastatin every 8 h. Empirical adjunctive therapy was administered for initial coverage of methicillin-resistant Staphylococcus aureus and Pseudomonas aeruginosa infection, depending on the randomization regimen. Clinical response, defined as cure, failure of treatment, or indeterminate outcome, was assessed 10 to 21 days after the last day of therapy. In the clinically evaluable population, clinical cure with tigecycline 100 mg (17/20, 85.0%) was numerically higher than with tigecycline 75 mg (16/23, 69.6%) and imipenem/cilastatin (18/24, 75.0%). No new safety signals with the high-dose tigecycline were identified. A numerically higher clinical response was observed with the 100-mg dose of tigecycline. This supports our hypothesis that a higher area under the concentration-time curve over 24 h in the steady state divided by the MIC (AUC/MIC ratio) may be necessary to achieve clinical cure in patients with hospital-acquired pneumonia. Further studies are necessary. (The ClinicalTrials.gov identifier for this clinical trial is NCT00707239.).

SU-D-213-07: Initial Characterization of a Gel Patch Dosimeter for in Vivo Dosimetry

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

Matrosic, C; Culberson, W; Rosen, B

Purpose: In vivo dosimetry, despite being the most direct method for monitoring the dose delivered during radiation therapy and being recommended by several national and international organizations (AAPM, ICRU, NACP), is underutilized in the clinic due to issues associated with dose sensitivity, feasibility, and cost. Given the increasing complexity of radiation therapy modern treatments, there is a compelling need for a robust, affordable in vivo dosimetry option. In this work we present the initial characterization of a novel gel patch in vivo dosimeter. Methods: DEFGEL (6%T) was used to make 1-cm thick small cylindrical patch dosimeters. The optical density ofmore » each dosimeter was read before and after irradiation by an in-house laser densitometer. The dosimeters were irradiated using a Varian Clinac EX linac. Three separate batches of gel patches were used to create dose response curves and evaluate repeatability. The development time of the dosimeter was also evaluated. Results: The dose response of the dosimeter was found to be linear from a range of approximately 1-Gy to 20-Gy, which is a larger window of linearity compared to other in vivo dosimeters. At doses below 1-Gy, the cumulative uncertainties were on the order of the measured data. When compared, the three batches demonstrated repeatability from 1-Gy to approximately 13-Gy, with some variation at higher doses. For doses of >8-Gy, the dosimeter reached full optical density after 4-hours, whereas low doses developed within an hour. Conclusion: Initial results indicate that the gel patch dosimeter is a reliable and simple way to measure a large range of doses, including high doses such as those delivered during hypofractionated treatments (e.g. SBRT or MR-guided radiotherapy). The simple fabrication method for the dosimeter and the use of a laser densitometer would allow for the dosimeter to used and read in-house, cheaply and easily.« less

The impact of the oxygen scavenger on the dose-rate dependence and dose sensitivity of MAGIC type polymer gels

NASA Astrophysics Data System (ADS)

Khan, Muzafar; Heilemann, Gerd; Kuess, Peter; Georg, Dietmar; Berg, Andreas

2018-03-01

Recent developments in radiation therapy aimed at more precise dose delivery along with higher dose gradients (dose painting) and more efficient dose delivery with higher dose rates e.g. flattening filter free (FFF) irradiation. Magnetic-resonance-imaging based polymer gel dosimetry offers 3D information for precise dose delivery techniques. Many of the proposed polymer gels have been reported to exhibit a dose response, measured as relaxation rate ΔR2(D), which is dose rate dependent. A lack of or a reduced dose-rate sensitivity is very important for dosimetric accuracy, especially with regard to the increasing clinical use of FFF irradiation protocols with LINACs at high dose rates. Some commonly used polymer gels are based on Methacrylic-Acid-Gel-Initiated-by-Copper (MAGIC). Here, we report on the dose sensitivity (ΔR2/ΔD) of MAGIC-type gels with different oxygen scavenger concentration for their specific dependence on the applied dose rate in order to improve the dosimetric performance, especially for high dose rates. A preclinical x-ray machine (‘Yxlon’, E  =  200 kV) was used for irradiation to cover a range of dose rates from low \\dot{D} min  =  0.6 Gy min-1 to high \\dot{D} max  =  18 Gy min-1. The dose response was evaluated using R2-imaging of the gel on a human high-field (7T) MR-scanner. The results indicate that all of the investigated dose rates had an impact on the dose response in polymer gel dosimeters, being strongest in the high dose region and less effective for low dose levels. The absolute dose rate dependence \\frac{(Δ R2/Δ D)}{Δ \\dot{D}} of the dose response in MAGIC-type gel is significantly reduced using higher concentrations of oxygen scavenger at the expense of reduced dose sensitivity. For quantitative dose evaluations the relative dose rate dependence of a polymer gel, normalized to its sensitivity is important. Based on this normalized sensitivity the dose rate sensitivity was reduced distinctly using an increased oxygen scavenger concentration with reference to standard MAGIC-type gel formulation at high dose rate levels. The proposed gel composition with high oxygen scavenger concentration exhibits a larger linear active dose response and might be used especially in FFF-radiation applications and preclinical dosimetry at high dose rates. We propose in general to use high dose rates for calibration and evaluation as the change in relative dose sensitivity is reduced at higher dose rates in all of the investigated gel types.

Examining the Starting Dose of Glyburide in Gestational Diabetes

PubMed Central

GLOVER, Angelica V.; TITA, Alan; BIGGIO, Joseph R.; HARPER, Lorie M.

2016-01-01

OBJECTIVE The aim of this study was to determine the impact of initial glyburide dosing on pregnancy outcomes. STUDY DESIGN Retrospective cohort of singleton pregnancies complicated by gestational diabetes (GDM) from 2007-2013. Women who received glyburide were compared by initial dose: 2.5mg (n=170) versus 5mg (n=154) total daily dose. The primary maternal outcome was hypoglycemia, defined as a blood glucose <60 mg/dL. The primary neonatal outcome was birth weight. Secondary maternal outcomes included time to blood glucose control, preeclampsia, and cesarean delivery. Secondary neonatal outcomes included macrosomia (>4000g), hypoglycemia (<40 mg/dL), shoulder dystocia, and preterm delivery. RESULTS The 5 mg/day glyburide dose did not increase maternal hypoglycemia (26% in the 2.5 mg/day group versus 27% in the 5 mg/day group, AOR 0.67 (CI 0.30-1.49)). An increase in macrosomia in the 5 mg/day group was not significant after adjusting for maternal obesity (AOR 2.16 (CI 0.96-4.88)). Differences in preterm birth and large for gestational age were not significant after adjusting for prior preterm birth and maternal obesity, respectively. CONCLUSIONS A higher starting dose of glyburide for the management of GDM was not associated with increased maternal hypoglycemia or decreased adverse neonatal outcomes. PMID:26368915

Variation in treatment strategies of Swiss general practitioners for subclinical hypothyroidism in older adults.

PubMed

Baumgartner, Christine; den Elzen, Wendy P J; Blum, Manuel R; Coslovsky, Michael; Streit, Sven; Frey, Peter; Herzig, Lilli; Haller, Dagmar M; Mooijaart, Simon P; Bischoff, Thomas; Rosemann, Thomas; Gussekloo, Jacobijn; Rodondi, Nicolas

2015-01-01

As the best management of subclinical hypothyroidism is controversial, we aimed to assess variations in treatment strategies depending on different Swiss regions, physician and patient characteristics. We performed a case-based survey among general practitioners (GPs) in different Swiss regions, which consisted of eight hypothetical cases presenting a female patient with subclinical hypothyroidism and nonspecific complaints differing by age, vitality status and thyroid-stimulating hormone (TSH) concentration. A total of 262 GPs participated in the survey. There was considerable variation in the levothyroxine starting dose chosen by GPs, ranging from 25 µg to 100 µg. Across the Swiss regions, GPs in the Bern region were significantly more inclined to treat, with a higher probability of initiating treatment (60%, p = 0.01) and higher mean starting doses (45 µg, p <0.01) compared with the French-speaking region (44%, 36 µg); the Zurich region had intermediate values (52%, 39 µg). We found no association between treatment rate and other physician characteristics. GPs were more reluctant to initiate treatment in 85-year-old than in 70-year-old women (odds ratio [OR] 0.77, 95% confidence interval [CI] 0.63-0.94), and more likely to treat women with a TSH of 15 mU/l than those with a TSH of 6mU/l (OR 8.71, 95% CI 6.21-12.20). There are strong variations in treatment strategies for elderly patients with subclinical hypothyroidism across different Swiss regions, including use of higher starting doses than the recommended 25 µg in the Swiss guidelines, which recommend a starting dose of 25 µg. These variations likely reflect the current uncertainty about the benefits of treatment, which arise from the current lack of evidence from adequately powered clinical trials.

The Effects of ELDRS at Ultra-Low Dose Rates

NASA Technical Reports Server (NTRS)

Chen, Dakai; Forney, James; Carts, Martin; Phan, Anthony; Pease, Ronald; Kruckmeyer, Kirby; Cox, Stephen; LaBel, Kenneth; Burns, Samuel; Albarian, Rafi;

Object Kinetic Monte Carlo Simulations of Radiation Damage In Bulk Tungsten

NASA Astrophysics Data System (ADS)

Nandipati, Giridhar; Setyawan, Wahyu; Heinisch, Howard; Roche, Kenneth; Kurtz, Richard; Wirth, Brian

2015-11-01

Results are presented for the evolution of radiation damage in bulk tungsten investigated using the object KMC simulation tool, KSOME, as a function of dose, dose rate and primary knock-on atom (PKA) energies in the range of 10 to 100 keV, at temperatures of 300, 1025 and 2050 K. At 300 K, the number density of vacancies changes minimally with dose rate while the number density of vacancy clusters slightly decreases with dose rate indicating that larger clusters are formed at higher dose rates. Although the average vacancy cluster size increases slightly, the vast majority exists as mono-vacancies. At 1025 K void lattice formation was observed at all dose rates for cascades below 60 keV and at lower dose rates for higher PKA energies. After the appearance of initial features of the void lattice, vacancy cluster density increased minimally while the average vacancy cluster size increases rapidly with dose. At 2050 K, no accumulation of defects was observed over a broad range of dose rates for all PKA energies studied in this work. Further comparisons of results of irradiation simulations at various dose rates and PKA spectra, representative of the High Flux Isotope Reactor and future fusion relevant irradiation facilities will be discussed. The U.S. Department of Energy, Office of Fusion Energy Sciences (FES) and Office of Advanced Scientific Computing Research (ASCR) has supported this study through the SciDAC-3 program.

Platelet response to increased aspirin dose in patients with persistent platelet aggregation while treated with aspirin 81 mg.

PubMed

Gengo, Fran; Westphal, Erica S; Rainka, Michelle M; Janda, Maria; Robson, Matthew J; Hourihane, J Maurice; Bates, Vernice

2016-04-01

This study demonstrates that patients who are taking 81 mg of aspirin and are nonresponsive benefit from a dose of 162 mg or greater vs a different antiplatelet therapy. We identified 100 patients who were nonresponsive to aspirin 81 mg via whole blood aggregometry and observed how many patients became responsive at a dose of 162 mg or greater. Platelet nonresponsiveness was defined as >10 Ω of resistance to collagen 1 µg/mL and/or an ohms ratio of collagen 1 µg/mL to collagen 5 µg/mL >0.5 and/or >6 Ω to arachidonate. Borderline response was defined as an improvement in 1 but not both of the above criteria. Of the initial 100 patients who were nonresponsive to an aspirin dose of 81 mg, 79% became responsive at a dose of 162 mg or >162 mg. Only 6% did not respond to any increase in dose. We believe that patients treated with low-dose aspirin who have significant risk for secondary vascular events should be individually assessed to determine their antiplatelet response. Those found to have persistent platelet aggregation despite treatment with 81 mg of aspirin have a higher likelihood of obtaining an adequate antiplatelet response at a higher aspirin dose. © 2015, The American College of Clinical Pharmacology.

Impact of multiple-dose versus single-dose inhaler devices on COPD patients’ persistence with long-acting β2-agonists: a dispensing database analysis

PubMed Central

van Boven, Job FM; van Raaij, Joost J; van der Galiën, Ruben; Postma, Maarten J; van der Molen, Thys; Dekhuijzen, PN Richard; Vegter, Stefan

2014-01-01

Background: With a growing availability of different devices and types of medication, additional evidence is required to assist clinicians in prescribing the optimal medication in relation to chronic obstructive pulmonary disease (COPD) patients’ persistence with long-acting β2-agonists (LABAs). Aims: To assess the impact of the type of inhaler device (multiple-dose versus single-dose inhalers) on 1-year persistence and switching patterns with LABAs. Methods: A retrospective observational cohort study was performed comparing a cohort of patients initiating multiple-dose inhalers and a cohort initiating single-dose inhalers. The study population consisted of long-acting bronchodilator naive COPD patients, initiating inhalation therapy with mono-LABAs (formoterol, indacaterol or salmeterol). Analyses were performed using pharmacy dispensing data from 1994 to 2012, obtained from the IADB.nl database. Study outcomes were 1-year persistence and switching patterns. Results were adjusted for initial prescriber, initial medication, dosing regimen and relevant comorbidities. Results: In all, 575 patients initiating LABAs were included in the final study cohort. Among them, 475 (83%) initiated a multiple-dose inhaler and 100 (17%) a single-dose inhaler. Further, 269 (47%) initiated formoterol, 9 (2%) indacaterol and 297 (52%) salmeterol. There was no significant difference in persistence between users of multiple-dose or single-dose inhalers (hazard ratio: 0.98, 95% confidence interval: 0.76–1.26, P=0.99). Over 80% re-started or switched medication. Conclusions: There seems no impact of inhaler device (multiple-dose versus single-dose inhalers) on COPD patients’ persistence with LABAs. Over 80% of patients who initially seemed to discontinue LABAs, re-started their initial medication or switched inhalers or medication within 1 year. PMID:25274453

Long-term effects of ionizing radiation after the Chernobyl accident: Possible contribution of historic dose.

PubMed

Omar-Nazir, Laila; Shi, Xiaopei; Moller, Anders; Mousseau, Timothy; Byun, Soohyun; Hancock, Samuel; Seymour, Colin; Mothersill, Carmel

2018-08-01

The impact of the Chernobyl NPP accident on the environment is documented to be greater than expected, with higher mutation rates than expected at the current, chronic low dose rate. In this paper we suggest that the historic acute exposure and resulting non-targeted effects (NTE) such as delayed mutations and genomic instability could account at least in part for currently measured mutation rates and provide an initial test of this concept. Data from Møller and Mousseau on the phenotypic mutation rates of Chernobyl birds 9-11 generations post the Chernobyl accident were used and the reconstructed dose response for mutations was compared with delayed reproductive death dose responses (as a measure of genomic instability) in cell cultures exposed to a similar range of doses. The dose to birds present during the Chernobyl NPP accident was reconstructed through the external pathway due to Cs-137 with an estimate of the uncertainty associated with such reconstruction. The percentage of Chernobyl birds several generations after the accident without mutations followed the general shape of the clonogenic survival percentage of the progeny of irradiated cells, and it plateaued at low doses. This is the expected result if NTE of radiation are involved. We suggest therefore, that NTE induced by the historic dose may play a role in generating mutations in progeny many generations following the initial disaster. Copyright © 2018 Elsevier Inc. All rights reserved.

Improved statistical analysis of moclobemide dose effects on panic disorder treatment.

PubMed

Ross, Donald C; Klein, Donald F; Uhlenhuth, E H

2010-04-01

Clinical trials with several measurement occasions are frequently analyzed using only the last available observation as the dependent variable [last observation carried forward (LOCF)]. This ignores intermediate observations. We reanalyze, with complete data methods, a clinical trial previously reported using LOCF, comparing placebo and five dosage levels of moclobemide in the treatment of outpatients with panic disorder to illustrate the superiority of methods using repeated observations. We initially analyzed unprovoked and situational, major and minor attacks as the four dependent variables, by repeated measures maximum likelihood methods. The model included parameters for linear and curvilinear time trends and regression of measures during treatment on baseline measures. Significance tests using this method take into account the structure of the error covariance matrix. This makes the sphericity assumption irrelevant. Missingness is assumed to be unrelated to eventual outcome and the residuals are assumed to have a multivariate normal distribution. No differential treatment effects for limited attacks were found. Since similar results were obtained for both types of major attack, data for the two types of major attack were combined. Overall downward linear and negatively accelerated downward curvilinear time trends were found. There were highly significant treatment differences in the regression slopes of scores during treatment on baseline observations. For major attacks, all treatment groups improved over time. The flatter regression slopes, obtained with higher doses, indicated that higher doses result in uniformly lower attack rates regardless of initial severity. Lower doses do not lower the attack rate of severely ill patients to those achieved in the less severely ill. The clinical implication is that more severe patients require higher doses to attain best benefit. Further, the significance levels obtained by LOCF analyses were only in the 0.05-0.01 range, while significance levels of <0.00001 were obtained by these repeated measures analyses indicating increased power. The greater sensitivity to treatment effect of this complete data method is illustrated. To increase power, it is often recommended to increase sample size. However, this is often impractical since a major proportion of the cost per subject is due to the initial evaluation. Increasing the number of repeated observations increases power economically and also allows detailed longitudinal trajectory analyses.

Phase I Study of Oral Vinorelbine in Combination with Erlotinib in Advanced Non-Small Cell Lung Cancer (NSCLC) Using Two Different Schedules

PubMed Central

Sutiman, Natalia; Zhang, Zhenxian; Tan, Eng Huat; Ang, Mei Kim; Tan, Shao-Weng Daniel; Toh, Chee Keong; Ng, Quan Sing; Chowbay, Balram; Lim, Wan-Teck

2016-01-01

Purpose This study aimed to evaluate the safety, tolerability and pharmacokinetics of the combination of oral vinorelbine with erlotinib using the conventional (CSV) and metronomic (MSV) dosing schedules in patients with advanced non-small cell lung cancer (NSCLC). Methods This was an open-label, multiple dose-escalation phase I study. An alternating 3+3 phase I design was employed to allow each schedule to enroll three patients sequentially at each dose level. Thirty patients with Stage IIIB/IV NSCLC were treated with escalating doses of oral vinorelbine starting at 40 mg/m2 on day 1 and 8 in the CSV group (N = 16) and at 100 mg/week in the MSV group (N = 14). Erlotinib was administered orally daily. Results The maximum tolerated dose was vinorelbine 80 mg/m2 with erlotinib 100 mg in the CSV group and vinorelbine 120 mg/week with erlotinib 100 mg in the MSV group. Grade 3/4 toxicities included neutropenia (N = 2; 13%) and hyponatremia (N = 1; 6%) in the CSV group, and neutropenia (N = 5; 36%) in the MSV group. Objective response was achieved in 38% and 29% in the CSV and MSV groups respectively. Vinorelbine co-administration did not significantly affect the pharmacokinetics of erlotinib and OSI-420 after initial dose. However, at steady-state, significantly higher Cmax, higher Cmin and lower CL/F of erlotinib were observed with increasing dose levels of vinorelbine in the CSV group. Significantly higher steady-state Cmin, Cavg and AUCss of erlotinib were observed with increasing dose levels of vinorelbine in the MSV group. Conclusions Combination of oral vinorelbine with erlotinib is feasible and tolerable in both the CSV and MSV groups. Trial Registration ClinicalTrials.gov NCT00702182 PMID:27135612

TU-F-CAMPUS-T-05: Dose Escalation to Biological Tumor Volumes of Prostate Cancer Patients Using Gold Nanoparticles

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

Jermoumi, M; Ngwa, W; Department of Radiation Oncology, Dana Farber Cancer Insitute, Brigham and Women’s Hospital, Harvard Medical, Boston, MA

2015-06-15

Purpose: Studies have shown that radiation boosting could help reduce prostate cancer (PCa) recurrence. Biological tumor volumes (BTV) are a high priority for such radiation boosting. The purpose of this study is to investigate the potential of radiation boosting of real patient BTVs using gold nanoparticles (GNP) released from gold-loaded brachytherapy spacers (GBS) during brachytherapy. Methods: The BTVs of 12 patients having prostate adenocarcinoma identified with positron emission tomography (PET) and CT scanner using C-11 labeled tracer [11C]acetate were investigated. The initial GNP concentration and time to achieve a dose enhancement effect (DEF) of 2 was simulated using the freelymore » downloadable software RAID APP. The investigations were carried out for low dose rate (LDR) brachytherapy sources (BTS) described in AAPM Task Group report 43: Cs-131, I-125, and Pd-103. In first case, we used 7 mg/g and 18 mg/g of GNP initial concentrations to estimate the time needed for released GNP to achieve a DEF of 2 for the different BTS, and compare with clinically relevant treatment times. In second case, we calculated the initial concentration of GNPs needed to achieve a DEF of 2 during the time the BTS would typically deliver 50%, 70% and 90% of the total dose. Results: For an initial concentration of 18 mg/g, when using Cs-131, and Pd-103, a DEF of 2 could only be achieved for BTV of 3.3 cm3 and 1 cm3 respectively. Meanwhile a DEF of 2 could be achieved for all 12 BTVs when using I-125. To achieve a DEF of 2 for all patients using Cs-131 and Pd-103, much higher initial concentrations would have to be used than have been typically employed in pre-clinical studies. Conclusion: The I-125 is the most viable BTS that can be employed with GBS to guide dose painting treatment planning for localized PCa.« less

Rapid promotion and progression of fibrovascular polyps by inflammation and/or hyperplasia in hamster check pouch: implications for carcinogenesis assay.

PubMed

McGaughey, C; Jensen, J L

1983-03-01

Tumor initiation by topical application of 7,12-dimethylbenz[a]anthracene (DMBA) in dimethyl sulfoxide (DMSO) followed by topical application of retinyl acetate (RA), ethylphenylpropiolate, or acetic acid in DMSO at inflammatory and hyperplasiogenic dose regimens caused the rapid promotion of fibrovascular polyps with dysplastic epithelium in hamster cheek pouch. Such lesions did not occur in control animals initiated with DMBA followed by application of DMSO only, where inflammation was also minimal. At the dose regimen employed, RA caused obvious cytotoxicity and tissue destruction. With EPP and AA, there was no histological evidence of tissue destruction. At dose regimens resulting in minimal inflammation and no apparent cytotoxicity, RA promoted almost no polyps, but a higher yield of other tumor types. Thus, inflammation and/or hyperplasia apparently exerted a strong polyp-promoting and progressive influence. This and other differences between the tumorigenic responses of hamster-pouch mucosa and mouse skin suggest that the former supplement the latter in carcinogenic risk assessment.

Weekly infusional high-dose 5-fluorouracil and leucovorin and biweekly cisplatin: a convenient treatment option in advanced gastric cancer.

PubMed

Kundel, Yulia; Purim, Ofer; Figer, Arie; Stemmer, Salomon M; Tichler, Thomas; Sulkes, Jaqueline; Sulkes, Aaron; Brenner, Baruch

2008-04-01

To summarize our experience using a regimen of weekly 5-FU and leucovorin (LV) and biweekly cisplatin (CDDP) in advanced gastric cancer (AGC). Patients had previously untreated histologically confirmed AGC. Treatment consisted of intravenous weekly infusional 5-FU and LV and biweekly CDDP, given for 6 weeks followed by a 2-week rest. Initially, a lower dose level was used (5-FU 2000 mg/m(2), LV 500 mg/m(2), CDDP 40 mg/m(2)), which was later increased (5-FU 2600 mg/m(2), LV 500 mg/m(2), CDDP 50 mg/m(2)). Forty-five patients were treated, 18 at the lower dose level and 27 at the higher dose level. The median age was 67 years and 55% were male. Grade > or =3 toxicity was documented in 37% of patients but toxicity related hospitalizations or treatment discontinuation occurred in only 22% and 13%, respectively. There were no toxic deaths. The most common hematological toxicities were anemia and neutropenia and the most common non-hematological toxicities were nausea, vomiting and fatigue. Of the 39 patients evaluable for response, 13 (33%) had partial response (PR) and 11 (28%) had stable disease (SD). Control of disease (PR+SD) was achieved in 61%. The higher dose level was associated with a higher response rate (p=0.07) and an increased toxicity (p=0.01), mostly hematological and gastrointestinal. Median progression-free survival and overall survival were 3.5 and 9.2 months, respectively. This regimen appears safe, with a manageable toxicity profile. Efficacy data resemble those reported for more complex and toxic regimens. The higher dose level had enhanced activity, at the expense of increased toxicity.

Metacognition deficits as a risk factor for prospective motivation deficits in schizophrenia spectrum disorders.

PubMed

Luther, Lauren; Firmin, Ruth L; Minor, Kyle S; Vohs, Jenifer L; Buck, Benjamin; Buck, Kelly D; Lysaker, Paul H

2016-11-30

Although motivation deficits are key determinants of functional outcomes, little is known about factors that contribute to prospective motivation in people with schizophrenia. One candidate factor is metacognition, or the ability to form complex representations about oneself, others, and the world. This study aimed to assess whether metacognition deficits were a significant predictor of reduced prospective motivation, after controlling for the effects of baseline motivation, anticipatory pleasure, and antipsychotic medication dose. Fifty-one participants with a schizophrenia spectrum disorder completed measures of metacognition and anticipatory pleasure at baseline; participants also completed a measure of motivation at baseline and six months after the initial assessment. Baseline antipsychotic dose was obtained from medical charts. Hierarchical regression analysis revealed that lower levels of baseline metacognition significantly predicted reduced levels of motivation assessed six months later, after controlling for baseline levels of motivation, anticipatory pleasure, and antipsychotic dose. Higher baseline antipsychotic dose was also a significant predictor of reduced six month motivation. Results suggest that metacognition deficits and higher antipsychotic dose may be risk factors for the development of motivation deficits in schizophrenia. Implications include utilizing interventions to improve metacognition in conjunction with evaluating and possibly lowering antipsychotic dose for people struggling with motivation deficits. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Dosing of selective serotonin reuptake inhibitors in children and adults before and after the FDA black-box warning

PubMed Central

Bushnell, Greta A; Stürmer, Til; Swanson, Sonja A; White, Alice; Azrael, Deborah; Pate, Virginia; Miller, Matthew

2016-01-01

Objective Prior research evaluated various effects of the antidepressant black-box warning on the risk of suicidality in children, but the dosing of antidepressants has not been considered. This study estimated, relative to the FDA warnings, whether the initial antidepressant dose prescribed decreased and the proportion augmenting dose on the second fill increased. Method The study utilized the LifeLink Health Plan Claims Database. The study cohort consisted of commercially insured children (5–17 years), young adults (18–24 years), and adults (25–64 years) initiating an SSRI (citalopram, fluoxetine, paroxetine, or sertraline) from 1/1/2000 to 12/31/2009. Dose-per-day was determined by days supply, strength, and quantity dispensed. Initiation on low dose, defined based on guidelines, and dose augmentations (dose increase >1mg/day) on the second prescription were considered across time periods related to the antidepressant warnings. Results Of 51,948 children who initiated an SSRI, 15% initiated on low dose in the period before the 2004 black-box warning and 31% in the period after the warning (a 16 percentage-point change); there was a smaller percentage-point change in young adults (6%) and adults (3%). The overall increase in dose augmentations in children and young adults was driven by the increase in patients initiating on a low dose. Conclusions As guidelines recommend children initiate antidepressant treatment on low dose, findings that an increased proportion of commercially insured children initiated an SSRI on low dose after the 2004 black-box warning suggest prescribing practices surrounding SSRI dosing improved in children following the warning but dosing practices still fall short of guidelines. PMID:26567938

Extending Prednisolone Treatment Does Not Reduce Relapses in Childhood Nephrotic Syndrome

PubMed Central

Kist-van Holthe, Joana E.; van Rijswijk, Nienske; de Mos, Nienke I.; Hop, Wim C.J.; Wetzels, Jack F.M.; van der Heijden, Albert J.; Nauta, Jeroen

2012-01-01

Prolonged prednisolone treatment for the initial episode of childhood nephrotic syndrome may reduce relapse rate, but whether this results from the increased duration of treatment or a higher cumulative dose remains unclear. We conducted a randomized, double-blind, placebo-controlled trial in 69 hospitals in The Netherlands. We randomly assigned 150 children (9 months to 17 years) presenting with nephrotic syndrome to either 3 months of prednisolone followed by 3 months of placebo (n=74) or 6 months of prednisolone (n=76), and median follow-up was 47 months. Both groups received equal cumulative doses of prednisolone (approximately 3360 mg/m2). Among the 126 children who started trial medication, relapses occurred in 48 (77%) of 62 patients who received 3 months of prednisolone and 51 (80%) of 64 patients who received 6 months of prednisolone. Frequent relapses, according to international criteria, occurred with similar frequency between groups as well (45% versus 50%). In addition, there were no statistically significant differences between groups with respect to the eventual initiation of prednisolone maintenance and/or other immunosuppressive therapy (50% versus 59%), steroid dependence, or adverse effects. In conclusion, in this trial, extending initial prednisolone treatment from 3 to 6 months without increasing cumulative dose did not benefit clinical outcome in children with nephrotic syndrome. Previous findings indicating that prolonged treatment regimens reduce relapses most likely resulted from increased cumulative dose rather than the treatment duration. PMID:23274956

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.

[Community-acquired pneumonia in patients with chronic obstructive pulmonary disease treated with inhaled corticosteroids or other bronchodilators. Study PNEUMOCORT].

PubMed

Morros, Rosa; Vedia, Cristina; Giner-Soriano, Maria; Casellas, Aina; Amado, Ester; Baena, Jose Miguel

2018-04-13

To analyse the risk of pneumonia and/or exacerbations in patients with chronic obstructive pulmonary disease (COPD) who receive treatment with inhaled corticosteroids (CI), in comparison with those who are not treated with inhaled corticosteroids (NCI). To estimate the risk of pneumonia according to CI dose. Population-based cohort study. Primary Healthcare. Institut Català de la Salut. Patients ≥45 years-old diagnosed with COPD between 2007 and 2009 in the Information System for Research in Primary Care (SIDIAP). Two cohorts; patients initiating CI and patients initiating bronchodilators after COPD diagnosis. Demographics, smoking, medical history, pneumonias, exacerbations, vaccinations, and drug therapy. A total of 3,837 patients were included, 58% in the CI and 42% in the NCI group. Higher incidence rates of pneumonia and exacerbations were detected in the CI group compared with the NCI (2.18 vs. 1.37). The risk of pneumonia and severe exacerbations was not significantly different between groups, HR; 1.17 (95% CI; 0.87-1.56) and 1.06 (95% CI; 0.87-1.31), respectively. Patients in the CI group had a higher risk of mild exacerbations, HR; 1.28 (95% CI; 1.10-1.50). Variables associated with a higher risk of pneumonia were age, diabetes, previous pneumonias and bronchitis, very severe COPD, treatment with low doses of β 2 -adrenergic or anticholinergic agents, and previous treatment with oral corticosteroids. There were no differences between cohorts in the risk of pneumonia and severe exacerbations. The risk of mild exacerbations was higher in the CI group. Pneumonias and severe exacerbations were more frequent in patients with severe COPD and in patients receiving high doses of CI. Copyright © 2018 The Authors. Publicado por Elsevier España, S.L.U. All rights reserved.

Optimization of initial propofol bolus dose for EEG Narcotrend Index-guided transition from sevoflurane induction to intravenous anesthesia in children.

PubMed

Dennhardt, Nils; Boethig, Dietmar; Beck, Christiane; Heiderich, Sebastian; Boehne, Martin; Leffler, Andreas; Schultz, Barbara; Sümpelmann, Robert

2017-04-01

Sevoflurane induction followed by intravenous anesthesia is a widely used technique to combine the benefits of an easier and less traumatic venipuncture after sevoflurane inhalation with a recovery with less agitation, nausea, and vomiting after total intravenous anesthesia (TIVA). Combination of two different anesthetics may lead to unwanted burst suppression in the electroencephalogram (EEG) during the transition phase. The objective of this prospective clinical observational study was to identify the optimal initial propofol bolus dose for a smooth transition from sevoflurane induction to TIVA using the EEG Narcotrend Index (NI). Fifty children aged 1-8 years scheduled for elective pediatric surgery were studied. After sevoflurane induction and establishing of an intravenous access, a propofol bolus dose range 0-5 mg·kg -1 was administered at the attending anesthetist's discretion to maintain a NI between 20 and 64, and sevoflurane was stopped. Anesthesia was continued as TIVA with a propofol infusion dose of 15 mg·kg -1 ·h -1 for the first 15 min, followed by stepwise reduction according to McFarlan's pediatric infusion regime, and remifentanil 0.25 μg·kg -1 ·min -1 . Endtidal concentration of sevoflurane, NI, and hemodynamic data were recorded during the whole study period using a standardized case report form. Propofol plasma concentrations were calculated using the paedfusor dataset and a TIVA simulation program. Median endtidal concentration of sevoflurane at the time of administration of the propofol bolus was 5.1 [IQR 4.7-5.9] Vol%. The median propofol bolus dose was 1.2 [IQR 0.9-2.5] mg·kg -1 and median NI thereafter was 33 [IQR 23-40]. Nine children presented with a NI 13-20 and three children with burst suppression in the EEG (NI 0-12); all of them received an initial propofol bolus dose >2 mg·kg -1 . Regression equation demonstrated that NI 20-64 was achieved with a 95% probability when using a propofol bolus dose of 1 mg·kg -1 after sevoflurane induction. Decrease in mean arterial blood pressure correlated significantly with propofol bolus dose (P = 0.038). After 25 min of TIVA, children younger than 2 years had a higher NI (median difference 14.0, 95%CI: 6.0-20.0, P = 0.001), higher deviations from the expected Narcotend Index (median difference 4.1, 95%CI: 3.9-4.2, P < 0.001) and lower calculated propofol plasma concentrations (median difference 0.2 μg·ml -1 , 95% CI: 0.1-0.3 μg·ml -1 , P < 0.001) than older children. After sevoflurane induction, a reduced propofol bolus dose of 1 mg·kg -1 followed by TIVA according to McFarlan's regime resulted in a NI within the recommended range in children aged 1-8 years. During the course of TIVA, children younger than 2 years displayed higher NI values and more pronounced interindividual variation. Processed EEG monitoring is recommended to find adequate individual age-dependent doses. © 2017 John Wiley & Sons Ltd.

Analyzed immunogenicity of fractional doses of Sabin-inactivated poliovirus vaccine (sIPV) with intradermal delivery in rats.

PubMed

Ma, Lei; Cai, Wei; Sun, Mingbo; Cun, Yina; Zhou, Jian; Liu, Jing; Hu, Wenzhu; Zhang, Xinwen; Song, Shaohui; Jiang, Shude; Liao, Guoyang

2016-12-01

The live-attenuated oral polio vaccine (OPV) will be no longer used when wild poliovirus (WPV) eliminating in worldwide, according to GPEI (the Global Polio Eradication Initiative) Reports. It is planning to replace OPV by Sabin-based inactivated poliovirus vaccine (sIPV) in developing countries, with purpose of reducing of the economic burden and maintaining of the appropriate antibody levels in population. It studied serial fractional doses immunized by intradermal injection (ID) in rats, to reduce consume of antigen and financial burden, maintaining sufficient immunogenicity; Methods: Study groups were divided in 4 groups of dose gradient, which were one-tenth (1/10), one-fifth (1/5), one-third (1/3) and one-full dose (1/1), according to the volume of distribution taken from the same batch of vaccine (sIPV). Wistar rats were injected intradermally with the needle and syringe sing the mantoux technique taken once month for 3 times. It was used as positive control that intramuscular inoculation (IM) was injected with one-full dose (1/1) with same batch of sIPV. PBS was used as negative control. Blood samples were collected via tail vein. After 30 d with 3 round of immunization, it analyzed the changes of neutralization antibody titers in the each group by each immunization program end; Results: The results of seroconversion had positive correlation with different doses in ID groups. The higher concentration of D-antigen (D-Ag) could conduct higher seroconversion. Furthermore, different types of viruses had different seroconversion trend. It showed that the geometric mean titers (GMTs) of each fractional-dose ID groups increased by higher concentration of D-Ag, and it got significant lower than the full-dose IM group. At 90 th days of immunization, the GMTs for each poliovirus subtypes of fractional doses were almost higher than 1:8, implied that it could be meaning positive seroprotection titer for polio vaccine types, according to WHO suggestion; Conclusions: The fractional dose with one-fifth (1/5) could be used by intradermal injection to prevent poliovirus infection, if there were more human clinical detail research consistent with this findings in rats.

Simian Immunodeficiency Virus Infection Increases Blood Ethanol Concentration Duration After Both Acute and Chronic Administration.

PubMed

Simon, Liz; Siggins, Robert; Winsauer, Peter; Brashear, Meghan; Ferguson, Tekeda; Mercante, Don; Song, Kejing; Vande Stouwe, Curtis; Nelson, Steve; Bagby, Gregory; Amedee, Angela; Molina, Patricia E

2018-02-01

Alcohol use disorder (AUD) is a frequent comorbidity among people living with HIV/AIDS (PLWHA). Alcohol consumption is a significant predictor of nonadherence to antiretroviral therapy (ART), as well as worsening immunological and virological indicators among PLWHA. Clinical studies indicate that higher viral loads increase sensitivity to alcohol in PLWHA. The factors that influence alcohol kinetics after HIV infection and initiation of ART are not well understood, limiting the information upon which interventions can be designed to ameliorate the impact of alcohol misuse on this vulnerable patient population. To better understand the relationship between viral load and alcohol kinetics, we measured changes in doses of intragastric ethanol administration to achieve target blood ethanol concentration (BEC) in a rhesus macaque model of chronic binge alcohol (CBA) administration and acute changes following a single acute binge dose of alcohol (ABA) pre- and post-simian immunodeficiency virus (SIV) infection, and following ART initiation. Our results from CBA (14 months)-administered SIV-infected male macaques showed that, following ART initiation, macaques required higher doses of alcohol to achieve a target peak BEC compared with non-ART-treated SIV-infected macaques. In animals given ABA, we found prolonged duration of elevated BEC and decreased elimination rate of alcohol that was not corrected following 7 weeks of ART. These findings suggest that binge drinking associated with AUD could negatively interact with HIV infection and enhance disease progression. These findings further support the need for implementation of behavioral or therapeutic interventions to decrease alcohol consumption to improve the quality of life in PLWHA.

Implementation of a pharmacist-managed heart failure medication titration clinic.

PubMed

Martinez, Amanda S; Saef, Jerold; Paszczuk, Anna; Bhatt-Chugani, Hetal

2013-06-15

The development, implementation, and initial results of a pharmacist-managed heart failure (HF) medication titration clinic are described. In a quality-improvement initiative at a Veterans Affairs health care system, clinical pharmacists were incorporated into the hospital system's interprofessional outpatient HF clinic. In addition, a separate pharmacist-managed HF medication titration clinic was established, in which pharmacists were granted an advanced scope of practice and prescribing privileges, enabling them to initiate and adjust medication dosages under specific protocols jointly established by cardiology and pharmacy staff. Pharmacists involved in the titration clinic tracked patients' daily body weight, vital signs, and volume status using telephone-monitoring technology and via patient interviews. A retrospective chart review comparing achievement of target doses of angiotensin-converting enzyme inhibitor (ACEI), angiotensin-receptor blocker (ARB), and β-blocker therapies in a group of patients (n = 28) whose dosage titrations were carried out by nurses or physicians prior to implementation of the pharmacist-managed HF medication titration clinic and a group of patients (n = 27) enrolled in the medication titration clinic during its first six months of operation indicated that target ACEI and ARB doses were achieved in a significantly higher percentage of pharmacist-managed titration clinic enrollees (52.9% versus 31%, p = 0.007). Patients enrolled in the pharmacist-managed HF medication titration clinic also had a significantly higher rate of attainment of optimal β-blocker doses (49% versus 24.7%, p = 0.012). Implementation of a pharmacist-managed HF medication titration clinic increased the percentage of patients achieving optimal ACEI, ARB, and β-blocker dosages.

Population Pharmacokinetics of Busulfan in Pediatric and Young Adult Patients Undergoing Hematopoietic Cell Transplant: A Model-Based Dosing Algorithm for Personalized Therapy and Implementation into Routine Clinical Use

PubMed Central

Long-Boyle, Janel; Savic, Rada; Yan, Shirley; Bartelink, Imke; Musick, Lisa; French, Deborah; Law, Jason; Horn, Biljana; Cowan, Morton J.; Dvorak, Christopher C.

2014-01-01

Background Population pharmacokinetic (PK) studies of busulfan in children have shown that individualized model-based algorithms provide improved targeted busulfan therapy when compared to conventional dosing. The adoption of population PK models into routine clinical practice has been hampered by the tendency of pharmacologists to develop complex models too impractical for clinicians to use. The authors aimed to develop a population PK model for busulfan in children that can reliably achieve therapeutic exposure (concentration-at-steady-state, Css) and implement a simple, model-based tool for the initial dosing of busulfan in children undergoing HCT. Patients and Methods Model development was conducted using retrospective data available in 90 pediatric and young adult patients who had undergone HCT with busulfan conditioning. Busulfan drug levels and potential covariates influencing drug exposure were analyzed using the non-linear mixed effects modeling software, NONMEM. The final population PK model was implemented into a clinician-friendly, Microsoft Excel-based tool and used to recommend initial doses of busulfan in a group of 21 pediatric patients prospectively dosed based on the population PK model. Results Modeling of busulfan time-concentration data indicates busulfan CL displays non-linearity in children, decreasing up to approximately 20% between the concentrations of 250–2000 ng/mL. Important patient-specific covariates found to significantly impact busulfan CL were actual body weight and age. The percentage of individuals achieving a therapeutic Css was significantly higher in subjects receiving initial doses based on the population PK model (81%) versus historical controls dosed on conventional guidelines (52%) (p = 0.02). Conclusion When compared to the conventional dosing guidelines, the model-based algorithm demonstrates significant improvement for providing targeted busulfan therapy in children and young adults. PMID:25162216

Persistence of Antipsychotic Treatment in Elderly Dementia Patients: A Retrospective, Population-Based Cohort Study.

PubMed

Mast, Gavin; Fernandes, Kimberly; Tadrous, Mina; Martins, Diana; Herrmann, Nathan; Gomes, Tara

2016-06-01

Antipsychotics are commonly used to manage behavioral and psychological symptoms of dementia. Concerns over their safety and efficacy in this role have resulted in antipsychotics typically being recommended for short-term usage only when used among dementia patients. However, there is little work examining the duration of antipsychotic treatment in the elderly dementia patient population. To determine the persistence of use of antipsychotics in elderly dementia patients and the role of dose on therapy duration. A retrospective, population-based cohort study using administrative data, including dispensing records from a provincial public drug program, from Ontario, Canada between 2009 and 2012. Elderly dementia patients newly initiated onto antipsychotics were followed until drug discontinuation, death, 2-year follow-up, or end of study. Competing risk analysis was performed to determine time to discontinuation, stratified by categories of initial dose. After 2 years 49.1 % of the cohort ( N  = 22,927 of 46,695) had discontinued treatment. When stratified by dose, the high-dose group (51.1 % discontinued) discontinued more frequently than the medium- (48.7 % discontinued) and low- (47.5 % discontinued) dose groups ( p  < 0.0001). Approximately half of elderly dementia patients treated with antipsychotics discontinue within 2 years, with those on higher doses more likely to discontinue. However, the number of patients remaining on therapy represents a serious public health concern.

Examining the Starting Dose of Glyburide in Gestational Diabetes.

PubMed

Glover, Angelica V; Tita, Alan; Biggio, Joseph R; Harper, Lorie M

2016-01-01

The aim of this study was to determine the impact of initial glyburide dosing on pregnancy outcomes. STUDY DESign: Retrospective cohort of singleton pregnancies complicated by gestational diabetes mellitus (GDM) from 2007 to 2013. Women who received glyburide were compared by initial dose: 2.5 mg (n = 170) versus 5 mg (n = 154) total daily dose. The primary maternal outcome was hypoglycemia, defined as a blood glucose < 60 mg/dL. The primary neonatal outcome was birth weight. Secondary maternal outcomes included time to blood glucose control, preeclampsia, and cesarean delivery. Secondary neonatal outcomes included macrosomia (>4,000 g), hypoglycemia (<40 mg/dL), shoulder dystocia, and preterm delivery. The 5 mg/day glyburide dose did not increase maternal hypoglycemia (26% in the 2.5 mg/day group vs. 27% in the 5 mg/day group; adjusted odds ratio [AOR] 0.67; confidence interval [CI] 0.30-1.49). An increase in macrosomia in the 5 mg/day group was not significant after adjusting for maternal obesity (AOR 2.16; CI 0.96-4.88). Differences in preterm birth and large for gestational age were not significant after adjusting for prior preterm birth and maternal obesity, respectively. A higher starting dose of glyburide for the management of GDM was not associated with increased maternal hypoglycemia or decreased adverse neonatal outcomes. Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

Prevalence of prescription opioid use disorder among chronic opioid therapy patients after health plan opioid dose and risk reduction initiatives.

PubMed

Von Korff, Michael; Walker, Rod L; Saunders, Kathleen; Shortreed, Susan M; Thakral, Manu; Parchman, Michael; Hansen, Ryan N; Ludman, Evette; Sherman, Karen J; Dublin, Sascha

2017-08-01

No studies have assessed the comparative effectiveness of guideline-recommended interventions to reduce risk of prescription opioid use disorder among chronic opioid therapy (COT) patients. We compared the prevalence of prescription opioid use disorder among COT patients from intervention clinics that had implemented opioid dose and risk reduction initiatives for more than 4 years relative to control clinics that had not. After a healthcare system in Washington State implemented interventions to reduce opioid dose and risks, we surveyed 1588 adult primary care COT patients to compare the prevalence of prescription opioid use disorder among COT patients from the intervention and control clinics. Intervention clinics managed COT patients at lower COT doses and with more consistent use of risk reduction practices. Control clinics cared for similar COT patients but prescribed higher opioid doses and used COT risk reduction practices inconsistently. Prescription opioid use disorder was assessed with the Psychiatric Research Interview for Substance and Mental Disorders. The prevalence of prescription opioid use disorder was 21.5% (95% CI=18.9% to 24.4%) among COT patients in the intervention clinics and 23.9% (95% CI=20.5% to 27.6%) among COT patients in the control clinics. The adjusted relative risk of prescription opioid use disorder was 1.08 (95% CI=0.89, 1.32) among the control clinic patients relative to the intervention clinic patients. Long-term implementation of opioid dose and risk reduction initiatives was not associated with lower rates of prescription opioid use disorder among prevalent COT patients. Extreme caution should be exercised by clinicians considering COT for patients with chronic non-cancer pain until benefits of this treatment and attendant risks are clarified. Copyright © 2017 Elsevier B.V. All rights reserved.

Impact of Pharmacy Practice Model Expansion on Pharmacokinetic Services: Optimization of Vancomycin Dosing and Improved Patient Safety.

PubMed

Han, Zhe; Pettit, Natasha N; Landon, Emily M; Brielmaier, Benjamin D

2017-04-01

Background: The impact of pharmacy interventions on optimizing vancomycin therapy has been described, however interventions vary among studies and the most optimal pharmacy practice model (PPM) for pharmacokinetic (PK) services has not been established. Objective: The purpose of this study is to demonstrate the value of 24 hours a day, 7 days a week (24/7) PK services. Methods: New PK services were implemented in 2 phases with institutional PPM expansion. Phase 1 included universal monitoring by pharmacists with recommendations made to prescribers during business hours. Phase 2 expanded clinical pharmacists' coverage to 24/7 and provided an optional 24/7 pharmacist-managed PK consult service. We compared vancomycin therapeutic trough attainment, dosing, and clinical and safety outcomes between phases 1 and 2 in adult inpatients receiving therapeutic intravenous vancomycin. Results. One hundred and fifty patients were included in each phase. Phase 2 had a greater proportion of vancomycin courses with therapeutic initial trough concentrations (27.5% vs 46.1%; p = 0.002), higher initial trough concentrations (10.9 mcg/mL vs 16.4 mcg/mL; p < 0.001), and optimized initial vancomycin dosing (13.5 mg/kg vs 16.2 mg/kg; p < 0.001). Phase 2 also saw significant reduction in the incidence of vancomycin-associated nephrotoxicity (21.1% vs 11.7%; p = 0.038). Dose optimization and improvement in initial target trough attainment were most notable among intensive care unit (ICU) patients. Conclusions. Our study demonstrated that 24/7 PK services implemented with institutional PPM expansion optimized vancomycin target trough attainment and improved patient safety.

Correlates of human papillomavirus vaccine coverage: a state-level analysis.

PubMed

Moss, Jennifer L; Reiter, Paul L; Brewer, Noel T

2015-02-01

We tested the hypothesis that states with higher rates of cancers associated with human papillomavirus (HPV) would have lower HPV vaccine coverage. We gathered state-level data on HPV-related cancer rates and HPV vaccine initiation coverage for girls and boys, separately, and HPV vaccine follow-through (i.e., receipt of 3 doses among those initiating the series) for girls only. In addition, we gathered state-level data on demographic composition and contact with the health care system. We calculated Pearson correlations for these ecological relationships. Human papillomavirus vaccine initiation among girls was lower in states with higher levels of cervical cancer incidence and mortality (r = -0.29 and -0.46, respectively). In addition, vaccine follow-through among girls was lower in states with higher levels of cervical cancer mortality (r = -0.30). Other cancer rates were associated with HPV vaccine initiation and follow-through among girls, but not among boys. Human papillomavirus vaccine initiation among girls was lower in states with higher proportions of non-Hispanic black residents and lower proportions of higher-income residents. Human papillomavirus vaccine follow-through was higher in states with greater levels of adolescents' contact with the health care system. Human papillomavirus vaccine coverage for girls was lower in states with higher HPV-related cancer rates. Public health efforts should concentrate on geographic areas with higher cancer rates. Strengthening adolescent preventive health care use may be particularly important to increase vaccine follow-through. Cost-effectiveness analyses may overestimate the benefits of current vaccination coverage and underestimate the benefits of increasing coverage.

Modeling the effect of boost timing in murine irradiated sporozoite prime-boost vaccines

PubMed Central

Zhang, Min; Herrero, Miguel A.; Acosta, Francisco J.; Tsuji, Moriya

2018-01-01

Vaccination with radiation-attenuated sporozoites has been shown to induce CD8+ T cell-mediated protection against pre-erythrocytic stages of malaria. Empirical evidence suggests that successive inoculations often improve the efficacy of this type of vaccines. An initial dose (prime) triggers a specific cellular response, and subsequent inoculations (boost) amplify this response to create a robust CD8+ T cell memory. In this work we propose a model to analyze the effect of T cell dynamics on the performance of prime-boost vaccines. This model suggests that boost doses and timings should be selected according to the T cell response elicited by priming. Specifically, boosting during late stages of clonal contraction would maximize T cell memory production for vaccines using lower doses of irradiated sporozoites. In contrast, single-dose inoculations would be indicated for higher vaccine doses. Experimental data have been obtained that support theoretical predictions of the model. PMID:29329308

Comparison of two dosing schedules for subcutaneous injections of low-dose anti-CD20 veltuzumab in relapsed immune thrombocytopenia

PubMed Central

Liebman, Howard A.; Saleh, Mansoor N.; Bussel, James B.; Negrea, O. George; Horne, Heather; Wegener, William A.; Goldenberg, David M.

2016-01-01

We compared two dosing schedules for subcutaneous injections of a low-dose humanized anti-CD20 antibody, veltuzumab, in immune thrombocytopenia. Fifty adults with primary immune thrombocytopenia, in whom one or more lines of standard therapy had failed and who had a platelet count <30×109/L but no major bleeding, initially received escalating 80, 160, or 320 mg doses of subcutaneous veltuzumab administered twice, 2 weeks apart; the last group received once-weekly doses of 320 mg for 4 weeks. In all dose groups, injection reactions were transient and mild to moderate; there were no other safety issues. Forty-seven response-evaluable patients had 23 (49%) objective responses (platelet counts ≥30×109/L and ≥2 × baseline) including 15 (32%) complete responses (platelets ≥100×109/L). Responses (including complete responses) and bleeding reduction occurred in all dose groups and were not dose-dependent. In contrast, response duration increased progressively with total dose, reaching a median of 2.7 years with the four once-weekly 320-mg doses. Among nine responders retreated at relapse, three at higher dose levels responded again, including one patient who was retreated four times. In all dose groups, B-cell depletion occurred after the first dose until recovery starting 12 to 16 weeks after treatment. Veltuzumab serum levels increased with dose group according to total dose administered, but terminal half-life and clearance were comparable. Human anti-veltuzumab antibody titers developed without apparent dose dependence in nine patients, of whom six responded including five who had complete responses. Subcutaneous veltuzumab was convenient, well-tolerated, and active, without causing significant safety concerns. Platelet responses and bleeding reduction occurred in all dose groups, and response durability appeared to improve with higher doses. Clinicaltrials.gov identifier: NCT00547066 PMID:27515248

Initial Dosing and Taper Complexity of Methadone and Morphine for Treatment of Neonatal Abstinence Syndrome

PubMed Central

Ibach, Bethany W.; Johnson, Peter N.; Ernst, Kimberly D.; Harrison, Donald; Miller, Jamie L.

2016-01-01

Background: Methadone and morphine are commonly used to treat neonatal abstinence syndrome (NAS). Limited data exist to describe the most appropriate initial doses and taper regimens of these agents. Objectives: Describe the median initial dose and frequency of methadone and morphine for NAS. Compare dose adjustments, time to symptom relief, and taper complexity between groups. Methods: Retrospective study of neonates receiving enteral methadone or morphine for NAS over a 4-year period. Data collection included medication regimen, abstinence scores based on the Modified Finnegan Neonatal Abstinence Scoring Tool, and adverse events. Planned home taper complexity was assessed using the Medication Taper Complexity Score–Revised (MTCS-R). The primary outcome was initial opioid dose. Secondary outcomes included number of dose adjustments, time to symptom relief, and MTCS-R score. Results: Fifty neonates were initially treated for NAS with methadone (n = 36) or morphine (n = 14). The median initial dose was 0.09 mg/kg (range = 0.03-0.2) for methadone and 0.04 mg/kg (range = 0.03-0.4) for morphine. The most common initial dosing interval was q8h for methadone versus q3h for morphine. Number of dose adjustments and time to symptom relief were similar between groups. Median MTCS-R scores were similar between groups. There was no difference in adverse events between groups. Limitations included small sample size, preference toward methadone use, and variability of initial opioid dosing and titration. Conclusions: There was significant variability in initial doses of both agents. Neonates receiving methadone required less frequent dosing than morphine, which may result in easier administration and may allow for safer outpatient administration.

RESULTS OF YEAR-LONG RADIOPHOSPHORUS ADMINISTRATION IN POLYCYTHEMIA VERA (in German)

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

Stecher, G.

1961-10-01

The results of treating 140 cases of polycythemia vera with P/sup 32/ over the last 9 yr are described. Oral doses of 4 to 5 mc P/sup 32/ or intravenous doses of 3 to 8 mc were given. Two-thirds of the patients experienced remission of the disease after the 1st P/sup 32/ dose, the remissions lasting 8 months or longer. The remainder of the patients required a 2nd dose. The average duration of remission was 20 months with over haif exceeding 1 yr. The mean dose to obtain remission was 4.4 mc/yr. The required dose was directly related to themore » degree of splenomegaly, leukocytosis, and duration of the disease. The higher the initial circulating erythrocyte count before P/sup 32/ treatment, the greater the drop after treatment. The average drop in erythrocyte count was 1.8, 2.4, and 2.6 x 10/sup 6/ after P/sup 32/ doses of 3-5, 5-7, and 7 mc, respectively. In cases with initial counts of 7.5 x 10/sup 6//cu mm the respective decrements in the counts were resulted in transitory anemia, leukopenia, or thrombopenia. Five patients died of leukemia but the infiuence of the P/sup 32/ dose, if any, on this complication could not be determined. Twenty other patients died from the complications of polycythemia, such as thrombosis and hemorrhage. The recommended single dose is 4-5 mc P/sup 32/, which should be repeated after 3 to 4 months if there is an inadequate response to the 1st dose. (H.H.D.)« less

Clinical Decision Support Improves Initial Dosing and Monitoring of Tobramycin and Amikacin

PubMed Central

Cox, Zachary L.; Nelsen, Cori L.; Waitman, Lemuel R.; McCoy, Jacob A.; Peterson, Josh F.

2010-01-01

Purpose Clinical decision support (CDS) systems could be valuable tools in reducing aminoglycoside prescribing errors. We evaluated the impact of CDS on initial dosing, interval, and pharmacokinetic outcomes of amikacin and tobramycin therapy. Methods A complex CDS advisor to provide guidance on initial dosing and monitoring, using both traditional and extended interval dosing strategies, was integrated into computerized provider order entry (CPOE) and compared to a control group which featured close pharmacy monitoring of all aminoglycoside orders. A random sample of 118 patients from an academic, tertiary care medical center prescribed amikacin and tobramycin prior to advisor implementation was compared to 98 patients admitted following advisor implementation. Primary outcome was an initial dose within 10% of a dose calculated to be adherent to published dose guidelines. Secondary outcomes were a guideline-adherent interval, trough and peak concentrations in goal range, and incidence of nephrotoxicity. Results Of 216 patients studied, 97 were prescribed amikacin and 119 were prescribed tobramycin. The primary outcome of initial dosing consistent with guideline-based care increased from 40% in the pre-advisor arm to 80% in the post-advisor arm (p<0.001), with a number needed to treat of 3 patients to prevent one incorrect dose. Correct initial interval based on renal function also increased from 63% to 87% (p<0.001). The changes in initial dosing and interval resulted in an increase of trough concentrations in the goal range from 59% pre-advisor to 89% post-advisor implementation (p=0.0004). There was no significant difference in peak concentrations in goal range or incidence of nephrotoxicity (25% vs. 17%, p=0.2). Conclusion An advisor for aminoglycoside dosing and monitoring integrated into CPOE significantly improves initial dosing, selection of interval, and trough concentrations at goal compared to unassisted physician dosing. PMID:21411805

Development and Validation of a Novel Vancomycin Dosing Nomogram for Achieving High-Target Trough Levels at 2 Canadian Teaching Hospitals

PubMed Central

Thalakada, Rosanne; Legal, Michael; Lau, Tim T Y; Luey, Tiffany; Batterink, Josh; Ensom, Mary H H

2012-01-01

Background: Recent guidelines recommend a vancomycin trough (predose) level between 15 and 20 mg/L in the treatment of invasive gram-positive infections, but most initial dosing nomograms are designed to achieve lower targets (5–15 mg/L). Clinicians need guidance about appropriate initial dosing to achieve the higher target. Objective: To develop and validate a high-target vancomycin dosing nomogram to achieve trough levels of 15–20 mg/L. Methods: A retrospective study was conducted at 2 teaching hospitals, St Paul’s Hospital and Vancouver General Hospital in Vancouver, British Columbia. Patients who were treated with vancomycin between January 2008 and June 2010 and who had achieved a trough level of 14.5–20.5 mg/L were identified. Demographic and clinical data were collected. Multiple linear regression was used to develop a vancomycin dosing nomogram for each hospital site. An integrated nomogram was constructed by merging the data from the 2 hospitals. A unique set of patients at each institution was used for validating their respective nomograms and a pooled group of patients for validating the integrated nomogram. Predictive success was evaluated, and a nomogram was deemed significantly different from another nomogram if p < 0.05 via “χ2 testing. Results: Data from 78 patients at one hospital and 91 patients at the other were used in developing the respective institutional nomograms. For each hospital’s data set, both age and initial serum creatinine were significantly associated with the predicted dosing interval (p < 0.001). Validation in a total of 105 test patients showed that the integrated nomogram had a predictive success rate of 56%. Conclusions: A novel vancomycin dosing nomogram was developed and validated at 2 Canadian teaching hospitals. This integrated nomogram is a tool that clinicians can use in selecting appropriate initial vancomycin regimens on the basis of age and serum creatinine, to achieve high-target levels of 15–20 mg/L. The nomogram should not replace clinical judgment for patients with unstable and/or reduced renal function. PMID:22783028

Intravenous heparin dosing strategy in hospitalized patients with atrial dysrhythmias.

PubMed

Roswell, Robert O; Greet, Brian; Shah, Sunny; Bernard, Samuel; Milin, Alexandra; Lobach, Iryna; Guo, Yu; Radford, Martha J; Berger, Jeffrey S

2016-08-01

Patients with non-valvular atrial fibrillation (AF) have an elevated stroke risk that is 2-7 times greater than in those without AF. Intravenous unfractionated heparin (UFH) is commonly used for hospitalized patients with atrial fibrillation and atrial flutter (AFL) to prevent stroke. Dosing strategies exist for intravenous anticoagulation in patients with acute coronary syndromes and venous thromboembolic diseases, but there are no data to guide providers on a dosing strategy for intravenous anticoagulation in patients with AF/AFL. 996 hospitalized patients with AF/AFL on UFH were evaluated. Bolus dosing and initial infusion rates of UFH were recorded along with rates of stroke, thromboemobolic events, and bleeding events as defined by the International Society on Thrombosis and Haemostasis criteria. Among 226 patients included in the analysis, 76 bleeding events occurred. Using linear regression analysis, initial rates of heparin infusion ranging from 9.7 to 11.8 units/kilogram/hour (U/kg/h) resulted in activated partial thromboplastin times that were within therapeutic range. The median initial infusion rate in patients with bleeding was 13.3 U/kg/h, while in those without bleeding it was 11.4 U/kg/h; p = 0.012. An initial infusion rate >11.0 U/kg/h yielded an OR 1.95 (1.06-3.59); p = 0.03 for any bleeding event. Using IV heparin boluses neither increased the probability of attaining a therapeutic aPTT (56.1 vs 56.3 %; p = 0.99) nor did it significantly increase bleeding events in the study (35.7 vs 31.3 %; p = 0.48). The results suggest that higher initial rates of heparin are associated with increased bleeding risk. From this dataset, initial heparin infusion rates of 9.7-11.0 U/kg/h without a bolus can result in therapeutic levels of anticoagulation in hospitalized patients with AF/AFL without increasing the risk of bleeding.

Wildlife disease and conservation in Hawaii: pathogenicity of avian malaria (Plasmodium relictum) in experimentally infected Iiwi (Vestiaria coccinea)

USGS Publications Warehouse

Atkinson, C.T.; Woods, K.L.; Dusek, Robert J.; Sileo, L.S.; Iko, W.M.

1995-01-01

Native Hawaiian forest birds are facing a major extinction crisis with more than 75% of species recorded in historical times either extinct or endangered. Reasons for this catastrophe include habitat destruction, competition with non-native species, and introduction of predators and avian diseases. We tested susceptibility of Iiwi (Vestiaria coccinea), a declining native species, and Nutmeg Mannikins (Lonchura punctulata), a common non-native species, to an isolate of Plasmodium relictum from the island of Hawaii. Food consumption, weight, and parasitaemia were monitored in juvenile Iiwi that were infected by either single (low-dose) or multiple (high-dose) mosquito bites. Mortality in both groups was significantly higher than in uninfected controls, reaching 100% of high-dose birds and 90% of low-dose birds. Significant declines in food consumption and a corresponding loss of body weight occurred in malaria-infected birds. Both sex and body weight had significant effects on survival time, with males more susceptible than females and birds with low initial weights more susceptible than those with higher initial weights. Gross and microscopic lesions in malaria fatalities included massive enlargement of the spleen and liver, hyperplasia of the reticuloendothelial system with extensive deposition of malarial pigment, and overwhelming anaemia in which over 30% of the circulating erythrocytes were parasitized. Nutmeg Mannikins, by contrast, were completely refractory to infection. Our findings support previous studies documenting high susceptibility of native Hawaiian forest birds to avian malaria. This disease continues to threaten remaining high elevation populations of endangered native birds.

32 CFR 218.1 - Policies.

Code of Federal Regulations, 2011 CFR

2011-07-01

... radiation environment to which the veteran was exposed and shall include inhaled, ingested and neutron doses. In determining the veteran's dose, initial neutron, initial gamma, residual gamma, and internal... dose, neutron dose, and internal dose. The minimum standards for reporting dose estimates are set forth...

32 CFR 218.1 - Policies.

Code of Federal Regulations, 2010 CFR

2010-07-01

... radiation environment to which the veteran was exposed and shall include inhaled, ingested and neutron doses. In determining the veteran's dose, initial neutron, initial gamma, residual gamma, and internal... dose, neutron dose, and internal dose. The minimum standards for reporting dose estimates are set forth...

32 CFR 218.1 - Policies.

Code of Federal Regulations, 2012 CFR

2012-07-01

... radiation environment to which the veteran was exposed and shall include inhaled, ingested and neutron doses. In determining the veteran's dose, initial neutron, initial gamma, residual gamma, and internal... dose, neutron dose, and internal dose. The minimum standards for reporting dose estimates are set forth...

32 CFR 218.1 - Policies.

Code of Federal Regulations, 2014 CFR

2014-07-01

... radiation environment to which the veteran was exposed and shall include inhaled, ingested and neutron doses. In determining the veteran's dose, initial neutron, initial gamma, residual gamma, and internal... dose, neutron dose, and internal dose. The minimum standards for reporting dose estimates are set forth...

32 CFR 218.1 - Policies.

Code of Federal Regulations, 2013 CFR

2013-07-01

... radiation environment to which the veteran was exposed and shall include inhaled, ingested and neutron doses. In determining the veteran's dose, initial neutron, initial gamma, residual gamma, and internal... dose, neutron dose, and internal dose. The minimum standards for reporting dose estimates are set forth...

Comparison of Levetiracetam Dosing Regimens in End-Stage Renal Disease Patients Undergoing Intermittent Hemodialysis.

PubMed

Shiue, Harn J; Taylor, Maria; Sands, Kara A

2017-10-01

Levetiracetam (LEV) is primarily renally eliminated. In end-stage renal disease (ESRD) patients on hemodialysis (HD), pharmacokinetic studies recommend daily dosing with 50% supplemental doses after 4-hour HD sessions. However, poor medication adherence after HD could result in fluctuating plasma drug levels. To compare two LEV dosing regimens, daily versus twice-daily (BID), in ESRD patients undergoing HD. Consecutive ESRD patients (April 2013 to May 2014) receiving maintenance inpatient HD and prescribed LEV prior to admission to our academic tertiary hospital were prospectively analyzed. Demographics, initial lab values, adverse reactions, seizures, and LEV regimens were recorded. LEV levels were obtained pre-HD and post-HD along with levels after receiving post-HD doses. Recovery of plasma levels after HD was assessed by comparison of levels predialysis versus postdialysis and post-HD doses. We identified 22 patients who met inclusion criteria; 14 BID and 8 daily dosing. Mean predialysis, postdialysis, and post-HD dose plasma levels were higher in patients receiving LEV BID compared with daily (43.1 ± 6.3, 19.4 ± 5.2, 34.9 ± 4.3 vs 21.1 ± 3.9, 6.9 ± 1.5, 11.9 ± 1.7 µg/mL; P < 0.05). BID post-HD levels were 41.9 ± 4.6% of predialysis levels versus 36.9 ± 7.3% with daily dosing ( P = 0.275). Post-HD dose levels were 81.4±4.3% of predialysis on LEV BID versus 65.7 ± 8.8% on LEV daily ( P = 0.045). No seizures were reported during hospital admission in either group. Compared to LEV daily, BID dosing achieved significantly higher levels and a better recovery to predialysis levels. Although limited by small numbers, a similar relationship between postdialysis levels was not detected.

Paraquat detoxication with multiple emulsions.

PubMed

Frasca, S; Couvreur, P; Seiller, M; Pareau, D; Lacour, B; Stambouli, M; Grossiord, J L

2009-10-01

In this study, we show that detoxifying W/O/W multiple emulsions, prepared with an appropriate extractant/trapping couple, represent a promising technology for quick and safe poisoning treatments, with application to the highly toxic herbicide Paraquat, responsible of poisonings from low-dose exposure leading to several deaths every year. In vitro tests led to the choice of an appropriate extractant/trapping couple system with significant detoxication performance. In vivo tests showed (i) that rats receiving high doses of Paraquat, then a detoxifying emulsion, presented an increase from 50% to 100% of the MST (median survival time) and (ii) that no mortality was observed during 30 days with rats dosed with emulsions initially loaded with Paraquat at a concentration much higher than the lethal dose, proving the stability and the inocuity of the detoxifying multiple emulsion in the gastrointestinal tract.

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

Moignier, Alexandra, E-mail: alexandra.moignier@irsn.fr; Derreumaux, Sylvie; Broggio, David

Purpose: Current retrospective cardiovascular dosimetry studies are based on a representative patient or simple mathematic phantoms. Here, a process of patient modeling was developed to personalize the anatomy of the thorax and to include a heart model with coronary arteries. Methods and Materials: The patient models were hybrid computational phantoms (HCPs) with an inserted detailed heart model. A computed tomography (CT) acquisition (pseudo-CT) was derived from HCP and imported into a treatment planning system where treatment conditions were reproduced. Six current patients were selected: 3 were modeled from their CT images (A patients) and the others were modelled from 2more » orthogonal radiographs (B patients). The method performance and limitation were investigated by quantitative comparison between the initial CT and the pseudo-CT, namely, the morphology and the dose calculation were compared. For the B patients, a comparison with 2 kinds of representative patients was also conducted. Finally, dose assessment was focused on the whole coronary artery tree and the left anterior descending coronary. Results: When 3-dimensional anatomic information was available, the dose calculations performed on the initial CT and the pseudo-CT were in good agreement. For the B patients, comparison of doses derived from HCP and representative patients showed that the HCP doses were either better or equivalent. In the left breast radiation therapy context and for the studied cases, coronary mean doses were at least 5-fold higher than heart mean doses. Conclusions: For retrospective dose studies, it is suggested that HCP offers a better surrogate, in terms of dose accuracy, than representative patients. The use of a detailed heart model eliminates the problem of identifying the coronaries on the patient's CT.« less

Dose-rate effect of ultrashort electron beam radiation on DNA damage and repair in vitro.

PubMed

Babayan, Nelly; Hovhannisyan, Galina; Grigoryan, Bagrat; Grigoryan, Ruzanna; Sarkisyan, Natalia; Tsakanova, Gohar; Haroutiunian, Samvel; Aroutiounian, Rouben

2017-11-01

Laser-generated electron beams are distinguished from conventional accelerated particles by ultrashort beam pulses in the femtoseconds to picoseconds duration range, and their application may elucidate primary radiobiological effects. The aim of the present study was to determine the dose-rate effect of laser-generated ultrashort pulses of 4 MeV electron beam radiation on DNA damage and repair in human cells. The dose rate was increased via changing the pulse repetition frequency, without increasing the electron energy. The human chronic myeloid leukemia K-562 cell line was used to estimate the DNA damage and repair after irradiation, via the comet assay. A distribution analysis of the DNA damage was performed. The same mean level of initial DNA damages was observed at low (3.6 Gy/min) and high (36 Gy/min) dose-rate irradiation. In the case of low-dose-rate irradiation, the detected DNA damages were completely repairable, whereas the high-dose-rate irradiation demonstrated a lower level of reparability. The distribution analysis of initial DNA damages after high-dose-rate irradiation revealed a shift towards higher amounts of damage and a broadening in distribution. Thus, increasing the dose rate via changing the pulse frequency of ultrafast electrons leads to an increase in the complexity of DNA damages, with a consequent decrease in their reparability. Since the application of an ultrashort pulsed electron beam permits us to describe the primary radiobiological effects, it can be assumed that the observed dose-rate effect on DNA damage/repair is mainly caused by primary lesions appearing at the moment of irradiation. © The Author 2017. Published by Oxford University Press on behalf of The Japan Radiation Research Society and Japanese Society for Radiation Oncology.

Dose-response relationship of robot-assisted stroke motor rehabilitation: the impact of initial motor status.

PubMed

Hsieh, Yu-wei; Wu, Ching-yi; Lin, Keh-chung; Yao, Grace; Wu, Kuen-yuh; Chang, Ya-ju

2012-10-01

The increasing availability of robot-assisted therapy (RT), which provides quantifiable, reproducible, interactive, and intensive practice, holds promise for stroke rehabilitation, but data on its dose-response relation are scanty. This study used 2 different intensities of RT to examine the treatment effects of RT and the effect on outcomes of the severity of initial motor deficits. Fifty-four patients with stroke were randomized to a 4-week intervention of higher-intensity RT, lower-intensity RT, or control treatment. The primary outcome, the Fugl-Meyer Assessment, was administered at baseline, midterm, and posttreatment. Secondary outcomes included the Medical Research Council scale, the Motor Activity Log, and the physical domains of the Stroke Impact Scale. The higher-intensity RT group showed significantly greater improvements on the Fugl-Meyer Assessment than the lower-intensity RT and control treatment groups at midterm (P=0.003 and P=0.02) and at posttreatment (P=0.04 and P=0.02). Within-group gains on the secondary outcomes were significant, but the differences among the 3 groups did not reach significance. Recovery rates of the higher-intensity RT group were higher than those of the lower-intensity RT group, particularly on the Fugl-Meyer Assessment. Scatterplots with curve fitting showed that patients with moderate motor deficits gained more improvements than those with severe or mild deficits after the higher-intensity RT. This study demonstrated the higher treatment intensity provided by RT was associated with better motor outcome for patients with stroke, which may shape further stroke rehabilitation. Clinical Trial Registration- URL: http://clinicaltrials.gov. Unique identifier: NCT00917605.

Using Population Dose to Evaluate Community-level Health Initiatives.

PubMed

Harner, Lisa T; Kuo, Elena S; Cheadle, Allen; Rauzon, Suzanne; Schwartz, Pamela M; Parnell, Barbara; Kelly, Cheryl; Solomon, Loel

2018-05-01

Successful community-level health initiatives require implementing an effective portfolio of strategies and understanding their impact on population health. These factors are complicated by the heterogeneity of overlapping multicomponent strategies and availability of population-level data that align with the initiatives. To address these complexities, the population dose methodology was developed for planning and evaluating multicomponent community initiatives. Building on the population dose methodology previously developed, this paper operationalizes dose estimates of one initiative targeting youth physical activity as part of the Kaiser Permanente Community Health Initiative, a multicomponent community-level obesity prevention initiative. The technical details needed to operationalize the population dose method are explained, and the use of population dose as an interim proxy for population-level survey data is introduced. The alignment of the estimated impact from strategy-level data analysis using the dose methodology and the data from the population-level survey suggest that dose is useful for conducting real-time evaluation of multiple heterogeneous strategies, and as a viable proxy for existing population-level surveys when robust strategy-level evaluation data are collected. This article is part of a supplement entitled Building Thriving Communities Through Comprehensive Community Health Initiatives, which is sponsored by Kaiser Permanente, Community Health. Copyright © 2018 American Journal of Preventive Medicine. Published by Elsevier Inc. All rights reserved.

Impact of systolic blood pressure on the safety and tolerability of initiating and up-titrating sacubitril/valsartan in patients with heart failure and reduced ejection fraction: insights from the TITRATION study.

PubMed

Senni, Michele; McMurray, John J V; Wachter, Rolf; McIntyre, Hugh F; Anand, Inder S; Duino, Vincenzo; Sarkar, Arnab; Shi, Victor; Charney, Alan

2018-03-01

The TITRATION trial investigated two strategies to initiate and up-titrate sacubitril/valsartan (LCZ696) to the same target dose, over a condensed (3-week) or conservative (6-week) period, in patients with heart failure with reduced ejection fraction (HFrEF) and systolic blood pressure (SBP) of ≥100 mmHg. This post hoc analysis examined the relationship between baseline SBP at screening and achievement of the target dose of sacubitril/valsartan of 97 mg/103 mg (also termed 'LCZ696 200 mg') twice per day during the study. Patients (n = 498) were categorized in four groups based on SBP at screening: 100-110 mmHg (n = 70); 111-120 mmHg (n = 93); 121-139 mmHg (n = 168) and ≥140 mmHg (n = 167). Overall, 72.7%, 76.1%, 85.6% and 82.9%, respectively, of patients in these SBP categories achieved and maintained the target dose of sacubitril/valsartan without down-titration/dose interruption over 12 weeks ('treatment success'). Compared with patients with SBP of 100-110 mmHg, rates of treatment success among patients in the higher SBP groups [111-120 mmHg (P = 0.96); 121-139 mmHg (P = 0.06) and ≥140 mmHg (P = 0.25)] did not differ significantly. A higher percentage of patients with lower SBP (100-110 mmHg) achieved treatment success with gradual up-titration (6 weeks) (∼80%) than with rapid up-titration (∼69%). Similar findings were observed with regard to 'tolerability success' (maintenance of the target dose for at least the final 2 weeks prior to study completion). Hypotension occurred more frequently in patients with lower SBP. The majority of patients (>80%) with SBP of ≥100 mmHg achieved and maintained the target dose of sacubitril/valsartan if the treatment was titrated gradually. These findings suggest that low SBP should not prevent clinicians from considering the initiation of sacubitril/valsartan. © 2017 The Authors. European Journal of Heart Failure © 2017 European Society of Cardiology.

The effects of co-administration of benzhexol on the peripheral pharmacokinetics of oral levodopa in young volunteers.

PubMed

Roberts, J; Waller, D G; von Renwick, A G; O'Shea, N; Macklin, B S; Bulling, M

1996-04-01

1. The effects of benzhexol on the absorption and pharmacokinetics of an oral dose of levodopa have been studied in 10 young healthy volunteers. Subjects were given a suspension of levodopa (250 mg) 90 min after either benzhexol (5 mg) or placebo in a randomized cross over design with doses separated by at least 1 week; on each occasion carbidopa was given 1 h before and 5 h after the dose of levodopa. Soluble paracetamol and radiolabelled DTPA were given with the levodopa as markers of gastric emptying. 2. Most subjects showed two peaks in the levodopa plasma concentration-time curve on the placebo day, with the second minor peak occurring 1-2 h after the dose. After benzhexol administration all subjects showed two or more peak levodopa concentrations in plasma. Benzhexol administration caused a significant decrease in the maximum concentration (43%; P < 0.05) of the initial peak and an increase (22%; P < 0.1) in the maximum concentration of the second peak. This change in absorption profile caused by benzhexol significantly altered the ratios of the second peak compared with the initial peak for both the maximum concentrations (P < 0.02) and for the AUC values (P < 0.05). Benzhexol administration did not affect the total AUC of levodopa (7.30 +/- 1.09 vs 7.19 +/- 1.26 micrograms ml-1 h; means +/- s.d.). 3. The plasma concentration-time curves for paracetamol showed similar profiles to those for levodopa and the ratios of the peak concentrations and AUC values for the second peak compared with the initial peak were increased significantly by benzhexol administration (P < 0.05). The total AUC of paracetamol was not affected by benzhexol administration (39.4 +/- 8.2 vs 40.0 +/- 8.9 micrograms ml-1 h; mean +/- s.d.) 4. Benzhexol altered the gastric emptying profile, shown by gamma-scintigraphy, with a reduced extent of initial emptying prior to the establishment of the plateau which is characteristic of levodopa administration in the fasting state. In consequence the ratio of the second to the initial phase of emptying was significantly higher (P < 0.01) following benzhexol treatment. 5. Benzhexol reduces the initial phase of gastric emptying after a dose of levodopa so that there is a decrease in the initial peak and a greater proportion of the dose is absorbed subsequently following the second phase of gastric emptying which occurs approximately 1 h later. Theoretically, this altered concentration-time profile could be an advantage for some patients with Parkinson's disease.

Area-based socioeconomic factors and Human Papillomavirus (HPV) vaccination among teen boys in the United States.

PubMed

Henry, Kevin A; Swiecki-Sikora, Allison L; Stroup, Antoinette M; Warner, Echo L; Kepka, Deanna

2017-07-14

This study is the first to examine associations between several area-based socioeconomic factors and human papillomavirus (HPV) vaccine uptake among boys in the United States (U.S.). Data from the 2012-2013 National Immunization Survey-Teen restricted-use data were analyzed to examine associations of HPV vaccination initiation (receipt of ≥1 dose) and series completion (receipt of three doses) among boys aged 13-17 years (N = 19,518) with several individual-level and ZIP Code Tabulation Area (ZCTA) census measures. Multivariable logistic regression was used to estimate the odds of HPV vaccination initiation and series completion separately. In 2012-2013 approximately 27.9% (95% CI 26.6%-29.2%) of boys initiated and 10.38% (95% CI 9.48%-11.29%) completed the HPV vaccine series. Area-based poverty was not statistically significantly associated with HPV vaccination initiation. It was, however, associated with series completion, with boys living in high-poverty areas (≥20% of residents living below poverty) having higher odds of completing the series (AOR 1.22, 95% CI 1.01-1.48) than boys in low-poverty areas (0-4.99%). Interactions between race/ethnicity and ZIP code-level poverty indicated that Hispanic boys living in high-poverty areas had a statistically significantly higher odds of  HPV vaccine initiation (AOR 1.43, 95% CI 1.03-1.97) and series completion (AOR 1.56, 95% CI 1.05-2.32)  than Hispanic boys in  low-poverty areas. Non-Hispanic Black boys in high poverty areas had higher odds of initiation (AOR 2.23, 95% CI 1.33-3.75) and completion (AOR 2.61, 95% CI 1.06-6.44) than non-Hispanic Black boys in low-poverty areas. Rural/urban residence and population density were also significant factors, with boys from urban or densely populated areas having higher odds of initiation and completion compared to boys living in non-urban, less densely populated areas. Higher HPV vaccination coverage in urban areas and among racial/ethnic minorities in areas with high poverty may be attributable to factors such as vaccine acceptance, health-care practices, and their access to HPV vaccines through the Vaccines for Children Program, which provides free vaccines to uninsured and under-insured children. Given the low HPV vaccination rates among boys in the U.S., these results provide important evidence to inform public health interventions to increase HPV vaccination.

PDT: death pathways

NASA Astrophysics Data System (ADS)

Kessel, David

2007-02-01

Cellular targets of photodynamic therapy include mitochondria, lysosomes, the endoplasmic reticulum (ER) and the plasma membrane. PDT can evoke necrosis, autophagy and apoptosis, or combinations of these, depending on the PDT dose, the site(s) of photodamage and the cellular phenotype. It has been established that loss of viability occurs even when the apoptotic program is inhibited. Studies assessing effects of ER or mitochondrial photodamage, involving loss of Bcl-2 function, indicate that low-dose PDT elicited a rapid autophagic response in L1210 cells. This was attributed to the ability of autophagy to recycle photodamaged organelles, and there was partial protection from loss of viability. This effect was not observed in L1210/Atg7, where autophagy was silenced. At higher PDT doses, apoptotic cells were observed within 60 min in both cell lines, but more so in L1210. The ability of L1210 cells to undergo autophagy did not offer protection from cell death at the higher PDT dose. Previous studies had indicated that autophagy can contribute to cell death, since L1210 cells that do not undergo an initial apoptotic response often contain multiple autophagic vacuoles 24 hr later. With L1210/Atg7, apoptosis alone may account for the loss of viability at an LD 90 PDT dose.

Assessment of the effects of CT dose in averaged x-ray CT images of a dose-sensitive polymer gel

NASA Astrophysics Data System (ADS)

Kairn, T.; Kakakhel, M. B.; Johnston, H.; Jirasek, A.; Trapp, J. V.

2015-01-01

The signal-to-noise ratio achievable in x-ray computed tomography (CT) images of polymer gels can be increased by averaging over multiple scans of each sample. However, repeated scanning delivers a small additional dose to the gel which may compromise the accuracy of the dose measurement. In this study, a NIPAM-based polymer gel was irradiated and then CT scanned 25 times, with the resulting data used to derive an averaged image and a "zero-scan" image of the gel. Comparison between these two results and the first scan of the gel showed that the averaged and zero-scan images provided better contrast, higher contrast-to- noise and higher signal-to-noise than the initial scan. The pixel values (Hounsfield units, HU) in the averaged image were not noticeably elevated, compared to the zero-scan result and the gradients used in the linear extrapolation of the zero-scan images were small and symmetrically distributed around zero. These results indicate that the averaged image was not artificially lightened by the small, additional dose delivered during CT scanning. This work demonstrates the broader usefulness of the zero-scan method as a means to verify the dosimetric accuracy of gel images derived from averaged x-ray CT data.

40 CFR Appendix C to Part 132 - Great Lakes Water Quality Initiative Methodologies for Development of Human Health Criteria and...

Code of Federal Regulations, 2013 CFR

2013-07-01

... organisms where higher doses or concentrations resulted in an adverse effect. Quantitative structure... probable or possible human carcinogen, when, because of major qualitative or quantitative limitations, the... quantitative risk assessment, but for which data are inadequate for Tier I criterion development due to a tumor...

40 CFR Appendix C to Part 132 - Great Lakes Water Quality Initiative Methodologies for Development of Human Health Criteria and...

Code of Federal Regulations, 2014 CFR

2014-07-01

... organisms where higher doses or concentrations resulted in an adverse effect. Quantitative structure... probable or possible human carcinogen, when, because of major qualitative or quantitative limitations, the... quantitative risk assessment, but for which data are inadequate for Tier I criterion development due to a tumor...

40 CFR Appendix C to Part 132 - Great Lakes Water Quality Initiative Methodologies for Development of Human Health Criteria and...

Code of Federal Regulations, 2012 CFR

2012-07-01

... organisms where higher doses or concentrations resulted in an adverse effect. Quantitative structure... probable or possible human carcinogen, when, because of major qualitative or quantitative limitations, the... quantitative risk assessment, but for which data are inadequate for Tier I criterion development due to a tumor...

Annealing kinetics of radiation defects in boron-implanted p-Hg1‑xCdxTe

NASA Astrophysics Data System (ADS)

Talipov, Niyaz; Voitsekhovskii, Alexander

2018-06-01

The results of studying the annealing kinetics of the radiation-induced donor-type defects in boron implanted p-type Hg1‑x Cd x Te (MCT) are presented. The annealing kinetics of the radiation donor centers depend significantly on the dose of B+ ions, that is on the initial level of structural defects generated in the MCT lattice by ion bombardment. The activation energy E A of annealing of donor defects generated by implantation of B+ ions increases with increasing dose and temperature of the post-implantation heat treatment under the SiO2 cap. The smaller the dose and the higher the initial hole concentration in p-MCT, the lower the temperature of a complete annealing of donor centers, which lies in the range 220–275 °C. In the initial stages of the post-implantation heat treatment, primary donor defects are annealed, and then, more stable secondary impurity-defect complexes are annealed. It was established for the first time that the activation energy of the donor defects annealing in bulk crystals and heteroepitaxial structures of MCT has two clearly pronounced regions: at low temperatures 90–130 °C, E A = 0.06 eV and at Т = 150–250 °C, E A = 0.71–0.86 eV.

Intermittent preventive treatment of malaria during pregnancy in central Mozambique.

PubMed

Brentlinger, Paula E; Dgedge, Martinho; Correia, Maria Ana Chadreque; Rojas, Ana Judith Blanco; Saúte, Francisco; Gimbel-Sherr, Kenneth H; Stubbs, Benjamin A; Mercer, Mary Anne; Gloyd, Stephen

2007-11-01

New WHO strategies for control of malaria in pregnancy (MiP) recommend intermittent preventive treatment (IPTp), bednet use and improved case management. A pilot MiP programme in Mozambique was designed to determine requirements for scale-up. The Ministry of Health worked with a nongovernmental organization and an academic institution to establish and monitor a pilot programme in two impoverished malaria-endemic districts. Implementing the pilot programme required provision of additional sulfadoxine-pyrimethamine (SP), materials for directly observed SP administration, bednets and a modified antenatal card. National-level formulary restrictions on SP needed to be waived. The original protocol required modification because imprecision in estimation of gestational age led to missed SP doses. Multiple incompatibilities with other health initiatives (including programmes for control of syphilis, anaemia and HIV) were discovered and overcome. Key outputs and impacts were measured; 92.5% of 7911 women received at least 1 dose of SP, with the mean number of SP doses received being 2.2. At the second antenatal visit, 13.5% of women used bednets. In subgroups (1167 for laboratory analyses; 2600 births), SP use was significantly associated with higher haemoglobin levels (10.9 g/dL if 3 doses, 10.3 if none), less malaria parasitaemia (prevalence 7.5% if 3 doses, 39.3% if none), and fewer low-birth-weight infants (7.3% if 3 doses, 12.5% if none). National-level scale-up will require attention to staffing, supplies, bednet availability, drug policy, gestational-age estimation and harmonization of vertical initiatives.

Diuretic downsides--but in low doses they still seem among the best authenticated antihypertensives.

PubMed

Opie, L H

2000-08-01

Diuretics in low doses have the greatest support among current available antihypertensives in that they have been shown to reduce total mortality, coronary mortality, stroke, and congestive heart failure in an important meta-analysis by Psaty. Recently, Messerli has linked longterm diuretic use to renal cell carcinoma in women. In some patients, diuretic use leads to increasing blood cholesterol and blood sugar levels. Impotence is a recognized side effect, with rates rising about twofold with low-dose chlorthalidone and fourfold with a higher dose. Certain population groups such as younger (<60 years) white males often do not respond to low-dose diuretic therapy with an adequate blood pressure fall. In females of a similar age group, Messerli calculates that prolonged diuretic therapy will prevent only one stroke and no coronary events nor any deaths for every renal cell carcinoma that is provoked. Despite these evident problems, the outcome data on hard endpoints in trials with initial low-dose diuretic therapy remain valid and convincing. Thus, it is argued, low- but not high-dose diuretics retain their primacy in the ranking of antihypertensive therapy.

Effect of repeated oral therapeutic doses of methylphenidate on food intake and growth rate in rats.

PubMed

Alam, Nausheen; Najam, Rahila

2015-01-01

Central nervous system stimulants are known to produce anorexia. Previous data suggest that methylphenidate can have variable effects on caloric intake and growth rate. A dose-response study was performed to monitor caloric intake, liquid intake and growth rate in rats following repeated administration of human oral therapeutic doses 2 mg/kg/day, 5mg/kg/day and 8mg/kg/day of methylphenidate. We found that food intake and water intake, increased in all weeks and at all doses used in the study. Growth rate increased more at higher dose (8mg/kg/day) and at low dose (2mg/kg/day) of methylphenidate in 1(st) and 2(nd) week whereas more decreased by the above doses in 3(rd) week, suggesting that food stimulation leads to initial increase in growth rate but long term administration of methylphenidate attenuate growth rate that is not due to modulation of appetite but may be due to anxiety and increased activity produce by stimulants. A possible role of DA, 5HT receptors in modulation of appetite and anxiety is discussed.

Pentadecapeptide BPC 157 attenuates chronic amphetamine-induced behavior disturbances.

PubMed

Sikiric, Predrag; Jelovac, Nikola; Jelovac-Gjeldum, Andjelka; Dodig, Goran; Staresinic, Mario; Anic, Tomislav; Zoricic, Ivan; Rak, Davor; Perovic, Darko; Aralica, Gorana; Buljat, Gojko; Prkacin, Ingrid; Lovric-Bencic, Martina; Separovic, Jadranka; Seiwerth, Sven; Rucman, Rudolf; Petek, Marijan; Turkovic, Branko; Ziger, Tihomil; Boban-Blagaic, Alenka; Bedekovic, Vlado; Tonkic, Ante; Babic, Slaven

2002-05-01

To investigate the effect of pentadecapeptide BPC 157 on chronic exposure to amphetamine in rats, particularly the changes commonly referred in chronic amphetamine studies as tolerance (lesser grade of stereotyped behavior, without increased excitability) and reverse tolerance (ie, prominent stereotyped behavior and heightened startle response upon late amphetamine challenges). After initial application (initial single dose-regimen), amphetamine (10 mg/kg,ip) was given once daily till d 5 (continuous administration-regimen), and thereafter on d 8, 16, and 46 (intermittent administration regimen). Fo r stereotyped behavior and heightened startle response the observation period was 120 min after amphetamine application, and each animal was observed for 10 s in 5 min intervals. Pentadecapeptide BPC 157 (10 microg/kg or 10 ng/k g, ip) or saline (5.0 mL/kg, ip) were given only at the beginning of the experiment, simultaneously with the initial dose of amphetamine. In relation to applied initial-single/continuous/intermittent amphetamine applications regimen, the control amphetamine rats throughout the experiment showed the changes in stereotyped behavior and heightened startle response, increment or decrement, commonly explained in chronic amphetamine studies as tolerance and reverse tolerance. After t he initial application of the amphetamine, the higher BPC 157 dosage apparently attenuated the stereotyped behavior, while the lower dosage of BPC 157 did not reach a statistical significance. Considering the forthcoming amphetamine challenges, in the rats initially treated with pentadecapeptide BPC 157, either 10 microg- or 10 ng-dose, at the time of the first application of amphetamine, the stereotyped behavior remains to be attenuated after all additional amphetamine challenges (on d 2-5, 8, 16, and 46). This attenuation was not limited to stereotyped behavior only. After the initial application of the amphetamine the heighten ed startle response was also apparently mitigated in rats receiving the BPC 157 dosage, either higher or lower. Later, confronted with the forthcoming amphetamine challenges, they showed apparently less abnormal excitability at all tested points. In summary, gastric pentadecapeptide BPC 157 (ie, both microg- and ng-BPC 157 regimens) attenuated chronic amphetamine disturbances. This effect was present throughout the observation period at a statistically significant level. Therefore, it seems that this gastric pentadecapeptide BPC 157 has a modulatory effect on dopamine system, and it could be used in chronic amphetamine disturbances.

Methadone dose at the time of release from prison significantly influences retention in treatment: implications from a pilot study of HIV-infected prisoners transitioning to the community in Malaysia.

PubMed

Wickersham, Jeffrey A; Zahari, Muhammad Muhsin; Azar, Marwan M; Kamarulzaman, Adeeba; Altice, Frederick L

2013-09-01

To evaluate the impact of methadone dose on post-release retention in treatment among HIV-infected prisoners initiating methadone maintenance treatment (MMT) within prison. Thirty HIV-infected prisoners meeting DSM-IV pre-incarceration criteria for opioid dependence were enrolled in a prison-based, pre-release MMT program in Klang Valley, Malaysia; 3 died before release from prison leaving 27 evaluable participants. Beginning 4 months before release, standardized methadone initiation and dose escalation procedures began with 5mg daily for the first week and 5mg/daily increases weekly until 80 mg/day or craving was satisfied. Participants were followed for 12 months post-release at a MMT clinic within 25 kilometers of the prison. Kaplan-Meier survival analysis was used to evaluate the impact of methadone dose on post-release retention in treatment. Methadone dose ≥80 mg/day at the time of release was significantly associated with retention in treatment. After 12 months of release, only 21.4% of participants on <80 mg were retained at 12 months compared to 61.5% of those on ≥80 mg (Log Rank χ(2)=(1,26) 7.6, p<0.01). Higher doses of MMT at time of release are associated with greater retention on MMT after release to the community. Important attention should be given to monitoring and optimizing MMT doses to address cravings and side effects prior to community re-entry from prisons. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

Methadone Dose at the Time of Release from Prison Significantly Influences Retention in Treatment: Implications From a Pilot Study of HIV-Infected Prisoners Transitioning to the Community in Malaysia

PubMed Central

Wickersham, Jeffrey A.; Muhsin Zahari, Muhammad; Azar, Marwan M.; Kamarulzaman, Adeeba; Altice, Frederick L.

2013-01-01

Objective To evaluate the impact of methadone dose on post-release retention in treatment among HIV-infected prisoners initiating methadone maintenance treatment (MMT) within prison. Methods Thirty HIV-infected prisoners meeting DSM-IV pre-incarceration criteria for opioid dependence were enrolled in a prison-based, pre-release MMT program in Klang Valley, Malaysia; 3 died before release from prison leaving 27 evaluable participants. Beginning 4 months before release, standardized methadone initiation and dose escalation procedures began with 5mg daily for the first week and 5mg/daily increases weekly until 80 mg/day or craving was satisfied. Participants were followed for 12 months post-release at a MMT clinic within 25 kilometers of the prison. Kaplan-Meier survival analysis was used to evaluate the impact of methadone dose on post-release retention in treatment. Findings Methadone dose ≥80 mg/day at the time of release was significantly associated with retention in treatment. After 12 months of release, only 21.4% of participants on <80mg were retained at 12 months compared to 61.5% of those on ≥80mg (Log Rank χ2=(1,26) 7.6, p <0.01). Conclusions Higher doses of MMT at time of release are associated with greater retention on MMT after release to the community. Important attention should be given to monitoring and optimizing MMT doses to address cravings and side effects prior to community re-entry from prisons. PMID:23414931

Population Pharmacokinetic Analysis and Model-Based Simulations of Aripiprazole for a 1-Day Initiation Regimen for the Long-Acting Antipsychotic Aripiprazole Lauroxil.

PubMed

Hard, Marjie L; Wehr, Angela Y; Sadler, Brian M; Mills, Richard J; von Moltke, Lisa

2018-06-11

BACKGROUND AND OBJECTIVES: Aripiprazole lauroxil (AL), a long-acting injectable antipsychotic for the treatment of schizophrenia, requires 21 days of oral aripiprazole supplementation upon initiation (21-day initiation regimen). An alternative 1-day initiation regimen utilizing a nano-crystalline milled dispersion of AL (AL NCD ) plus a single 30 mg oral aripiprazole dose achieved aripiprazole concentrations associated with therapeutic doses of aripiprazole in the same time frame as the 21-day initiation regimen when starting AL (441 or 882 mg). A population pharmacokinetic (PopPK) model was developed to describe aripiprazole pharmacokinetics following administration of AL NCD , AL and oral aripiprazole, and evaluate dosing scenarios likely to be encountered in clinical practice. In total, 12,768 plasma aripiprazole concentrations from 343 patients (from 4 clinical studies) were included in the PopPK analysis and used to construct the model. Concomitant administration of the 1-day initiation regimen with all approved AL dosing regimens (441, 662, or 882 mg monthly, 882 mg every 6 weeks, or 1064 mg every 2 months) is predicted to achieve aripiprazole concentrations associated with therapeutic doses of AL using the 21-day initiation regimen within 4 days, maintaining these concentrations until the next AL dose. Administration of the first AL injection 10 days after the 1-day initiation regimen resulted in median aripiprazole concentrations just before the second dose of AL ≥ 77% of that when coadministered on the same day. Coadministration of AL with a single AL NCD injection was predicted to be effective in rapidly re-establishing concentrations associated with therapeutic doses of AL following dose delay. Model-based simulations demonstrate that the 1-day initiation regimen is suitable for starting treatment with all AL doses, allowing a window of ≤ 10 days between initiation and AL administration. AL NCD may also be used to re-establish concentrations associated with therapeutic doses of AL in conjunction with a delayed AL dose.

The role of concomitant methotrexate dosage and maintenance over time in the therapy of rheumatoid arthritis patients treated with adalimumab or etanercept: retrospective analysis of a local registry.

PubMed

Favalli, Ennio Giulio; Becciolini, Andrea; Biggioggero, Martina; Bertoldi, Ilaria; Crotti, Chiara; Raimondo, Maria Gabriella; Marchesoni, Antonio

2018-01-01

To evaluate the pattern of prescription and maintenance over time of concomitant methotrexate (MTX), and its impact on a 2-year clinical response in a cohort of rheumatoid arthritis (RA) patients treated with a first-line tumor necrosis factor alpha inhibitor (TNFi). The study population included all RA patients receiving adalimumab or etanercept a as first-line biologic drug, extracted from a local registry. Enrolled patients were stratified into 3 subgroups according to baseline concomitant MTX: no MTX, low-dose MTX (≤10 mg/wk), and high-dose MTX (≥12.5 mg/wk). The 2-year persistence of the initial MTX regimen was computed by the Kaplan-Meier method, and a Cox proportional hazard model was developed to examine potential predictors of MTX withdrawal/change of dosage. European League Against Rheumatism remission and good-to-moderate response were evaluated according to baseline MTX regimen and MTX maintenance over time. A total of 330 patients (163 treated with adalimumab and 167 with etanercept) were included; 141 were prescribed TNFi without MTX and 112 received low-dose and 77 high-dose concomitant MTX. Male sex, younger age, and shorter mean disease duration were predictors of high-dose MTX use. Among MTX users (76.2% parenteral and 23.8% oral), initial MTX dose persisted over time in 79.9% at 1 year and 70.2% at 2 years. Fifty-one patients (27%) underwent MTX dose de-escalation/discontinuation because of intolerance/adverse events. The 2-year EULAR remission rate was higher in the patients receiving and maintaining high-dose MTX than in those receiving low-dose or no MTX (46.2% vs 29.5% and 23.4%, respectively; p =0.009). The same was true for good-to-moderate response rate (71.2% vs 52.6% and 50.4%, respectively; p =0.031). In a real-life setting, about one-third of RA patients treated with TNFis experienced dose reduction/discontinuation of concomitant MTX because of intolerance/adverse events over a 2-year follow-up period. Initial high-dose MTX and its maintenance over time are associated with better 2-year clinical response.

Abdominal CT with model-based iterative reconstruction (MBIR): initial results of a prospective trial comparing ultralow-dose with standard-dose imaging.

PubMed

Pickhardt, Perry J; Lubner, Meghan G; Kim, David H; Tang, Jie; Ruma, Julie A; del Rio, Alejandro Muñoz; Chen, Guang-Hong

2012-12-01

The purpose of this study was to report preliminary results of an ongoing prospective trial of ultralow-dose abdominal MDCT. Imaging with standard-dose contrast-enhanced (n = 21) and unenhanced (n = 24) clinical abdominal MDCT protocols was immediately followed by ultralow-dose imaging of a matched series of 45 consecutively registered adults (mean age, 57.9 years; mean body mass index, 28.5). The ultralow-dose images were reconstructed with filtered back projection (FBP), adaptive statistical iterative reconstruction (ASIR), and model-based iterative reconstruction (MBIR). Standard-dose series were reconstructed with FBP (reference standard). Image noise was measured at multiple predefined sites. Two blinded abdominal radiologists interpreted randomly presented ultralow-dose images for multilevel subjective image quality (5-point scale) and depiction of organ-based focal lesions. Mean dose reduction relative to the standard series was 74% (median, 78%; range, 57-88%; mean effective dose, 1.90 mSv). Mean multiorgan image noise for low-dose MBIR was 14.7 ± 2.6 HU, significantly lower than standard-dose FBP (28.9 ± 9.9 HU), low-dose FBP (59.2 ± 23.3 HU), and ASIR (45.6 ± 14.1 HU) (p < 0.001). The mean subjective image quality score for low-dose MBIR (3.0 ± 0.5) was significantly higher than for low-dose FBP (1.6 ± 0.7) and ASIR (1.8 ± 0.7) (p < 0.001). Readers identified 213 focal noncalcific lesions with standard-dose FBP. Pooled lesion detection was higher for low-dose MBIR (79.3% [169/213]) compared with low-dose FBP (66.2% [141/213]) and ASIR (62.0% [132/213]) (p < 0.05). MBIR shows great potential for substantially reducing radiation doses at routine abdominal CT. Both FBP and ASIR are limited in this regard owing to reduced image quality and diagnostic capability. Further investigation is needed to determine the optimal dose level for MBIR that maintains adequate diagnostic performance. In general, objective and subjective image quality measurements do not necessarily correlate with diagnostic performance at ultralow-dose CT.

Time-to-Seizure Modeling of Lacosamide Used in Monotherapy in Patients with Newly Diagnosed Epilepsy.

PubMed

Lindauer, Andreas; Laveille, Christian; Stockis, Armel

2017-11-01

To quantify the relationship between exposure to lacosamide monotherapy and seizure probability, and to simulate the effect of changing the dose regimen. Structural time-to-event models for dropouts (not because of a lack of efficacy) and seizures were developed using data from 883 adult patients newly diagnosed with epilepsy and experiencing focal or generalized tonic-clonic seizures, participating in a trial (SP0993; ClinicalTrials.gov identifier: NCT01243177) comparing the efficacy of lacosamide and carbamazepine controlled-release monotherapy. Lacosamide dropout and seizure models were used for simulating the effect of changing the initial target dose on seizure freedom. Repeated time-to-seizure data were described by a Weibull distribution with parameters estimated separately for the first and subsequent seizures. Daily area under the plasma concentration-time curve was related linearly to the log-hazard. Disease severity, expressed as the number of seizures during the 3 months before the trial (baseline), was a strong predictor of seizure probability: patients with 7-50 seizures at baseline had a 2.6-fold (90% confidence interval 2.01-3.31) higher risk of seizures compared with the reference two to six seizures. Simulations suggested that a 400-mg/day, rather than a 200-mg/day initial target dose for patients with seven or more seizures at baseline could potentially result in an additional 8% of seizure-free patients for 6 months at the last evaluated dose level. Patients receiving lacosamide had a slightly lower dropout risk compared with those receiving carbamazepine. Baseline disease severity was the most important predictor of seizure probability. Simulations suggest that an initial target dose >200 mg/day could potentially benefit patients with greater disease severity.

On determining dose rate constants spectroscopically.

PubMed

Rodriguez, M; Rogers, D W O

2013-01-01

To investigate several aspects of the Chen and Nath spectroscopic method of determining the dose rate constants of (125)I and (103)Pd seeds [Z. Chen and R. Nath, Phys. Med. Biol. 55, 6089-6104 (2010)] including the accuracy of using a line or dual-point source approximation as done in their method, and the accuracy of ignoring the effects of the scattered photons in the spectra. Additionally, the authors investigate the accuracy of the literature's many different spectra for bare, i.e., unencapsulated (125)I and (103)Pd sources. Spectra generated by 14 (125)I and 6 (103)Pd seeds were calculated in vacuo at 10 cm from the source in a 2.7 × 2.7 × 0.05 cm(3) voxel using the EGSnrc BrachyDose Monte Carlo code. Calculated spectra used the initial photon spectra recommended by AAPM's TG-43U1 and NCRP (National Council of Radiation Protection and Measurements) Report 58 for the (125)I seeds, or TG-43U1 and NNDC(2000) (National Nuclear Data Center, 2000) for (103)Pd seeds. The emitted spectra were treated as coming from a line or dual-point source in a Monte Carlo simulation to calculate the dose rate constant. The TG-43U1 definition of the dose rate constant was used. These calculations were performed using the full spectrum including scattered photons or using only the main peaks in the spectrum as done experimentally. Statistical uncertainties on the air kerma/history and the dose rate/history were ≤0.2%. The dose rate constants were also calculated using Monte Carlo simulations of the full seed model. The ratio of the intensity of the 31 keV line relative to that of the main peak in (125)I spectra is, on average, 6.8% higher when calculated with the NCRP Report 58 initial spectrum vs that calculated with TG-43U1 initial spectrum. The (103)Pd spectra exhibit an average 6.2% decrease in the 22.9 keV line relative to the main peak when calculated with the TG-43U1 rather than the NNDC(2000) initial spectrum. The measured values from three different investigations are in much better agreement with the calculations using the NCRP Report 58 and NNDC(2000) initial spectra with average discrepancies of 0.9% and 1.7% for the (125)I and (103)Pd seeds, respectively. However, there are no differences in the calculated TG-43U1 brachytherapy parameters using either initial spectrum in both cases. Similarly, there were no differences outside the statistical uncertainties of 0.1% or 0.2%, in the average energy, air kerma/history, dose rate/history, and dose rate constant when calculated using either the full photon spectrum or the main-peaks-only spectrum. Our calculated dose rate constants based on using the calculated on-axis spectrum and a line or dual-point source model are in excellent agreement (0.5% on average) with the values of Chen and Nath, verifying the accuracy of their more approximate method of going from the spectrum to the dose rate constant. However, the dose rate constants based on full seed models differ by between +4.6% and -1.5% from those based on the line or dual-point source approximations. These results suggest that the main value of spectroscopic measurements is to verify full Monte Carlo models of the seeds by comparison to the calculated spectra.

Real-World Data Collection Regarding Titration Algorithms for Insulin Glargine in Patients With Type 2 Diabetes Mellitus

PubMed Central

Pfützner, Andreas; Stratmann, Bernd; Funke, Klaus; Pohlmeier, Harald; Rose, Ludger; Sieber, Jochen; Flacke, Frank; Tschoepe, Diethelm

2016-01-01

The primary objective of this study was to collect data regarding the effectiveness of different dose titration algorithms (TAs) for optimization or initiation of basal insulin supported oral therapy (BOT) in patients with type 2 diabetes. A total of 50 patients were enrolled in this trial (17 women, 33 men, age 63 ± 8 years, HbA1c 7.9 ± 0.8%). The investigator decided on an individual basis to apply any of 4 standard TAs: standard (S: fasting glucose target 90-130 mg/dL, n = 39), standard-fast titration (S-FT: 90-130 mg/dL, larger dose increments at FBG < 180 mg/dl, n = 1), less tight (LT: 110-150 mg/dL, n = 5), and tight (T: 70-100 mg/dL, n = 5). During the next 30 days daily contacts were used to adapt the insulin dose. The majority of all patients (70%) achieved a stable insulin glargine dose within 5 ± 6 days after initiation of the dose titration. HbA1c improved from 7.9 ± 0.8% to 7.5 ± 0.7% (P < .001). In total, 1300 dose decisions were made (1192 according to the TA and 108 by the physicians independently from the TA in 29 patients [58% of study population]). Reasons for TA-overruling dosing decisions were hypoglycemic events (14 mild/4 moderate) in 9 patients. In the majority of these cases (89.8%), the physician recommended continuation of the previous dose or a higher dose. The majority of FBG values were within the respective target range after 4 weeks. In conclusion, the insulin glargine TAs delivered safe dose recommendations with a low risk of hypoglycemia, which successfully led to a stable dose in the vast majority of patients. PMID:27325389

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.

Treatment with α-Lipoic Acid over 16 Weeks in Type 2 Diabetic Patients with Symptomatic Polyneuropathy Who Responded to Initial 4-Week High-Dose Loading.

PubMed

Garcia-Alcala, Hector; Santos Vichido, Celia Isabel; Islas Macedo, Silverio; Genestier-Tamborero, Christelle Nathalie; Minutti-Palacios, Marissa; Hirales Tamez, Omara; García, Carlos; Ziegler, Dan

2015-01-01

Effective treatment of diabetic sensorimotor polyneuropathy remains a challenge. To assess the efficacy and safety of α-lipoic acid (ALA) over 20 weeks, we conducted a multicenter randomized withdrawal open-label study, in which 45 patients with type 2 diabetes and symptomatic polyneuropathy were initially treated with ALA (600 mg tid) for 4 weeks (phase 1). Subsequently, responders were randomized to receive ALA (600 mg qd; n = 16) or to ALA withdrawal (n = 17) for 16 weeks (phase 2). During phase 1, the Total Symptom Score (TSS) decreased from 8.9 ± 1.8 points to 3.46 ± 2.0 points. During phase 2, TSS improved from 3.7 ± 1.9 points to 2.5 ± 2.5 points in the ALA treated group (p < 0.05) and remained unchanged in the ALA withdrawal group. The use of analgesic rescue medication was higher in the ALA withdrawal group than ALA treated group (p < 0.05). In conclusion, in type 2 diabetic patients with symptomatic polyneuropathy who responded to initial 4-week high-dose (600 mg tid) administration of ALA, subsequent treatment with ALA (600 mg qd) over 16 weeks improved neuropathic symptoms, whereas ALA withdrawal was associated with a higher use of rescue analgesic drugs. This trial is registered with ClinicalTrials.gov Identifier: NCT02439879.

Cediranib in patients with malignant mesothelioma: A phase II trial of the University of Chicago Phase II Consortium

PubMed Central

Campbell, Nicholas P.; Kunnavakkam, Rangesh; Leighl, Natasha; Vincent, Mark D.; Gandara, David R.; Koczywas, Marianna; Gitlitz, Barbara J.; Agamah, Edem; Thomas, Sachdev P.; Stadler, Walter M.; Vokes, Everett E.; Kindler, Hedy L.

2013-01-01

Introduction Malignant mesothelioma (MM) is an aggressive disease with limited therapeutic options. In preclinical models, vascular endothelial growth factor (VEGF) stimulates MM proliferation. In MM patients, higher plasma VEGF levels correlate inversely with survival. Cediranib is an orally administered tyrosine kinase inhibitor of VEGF receptors -1, -2, and -3. Methods We conducted a multi-center phase II trial of cediranib in patients with unresectable, histologically-confirmed MM who had received ≤1 prior regimen of chemotherapy. The primary endpoint was objective response rate. Initial cediranib dosing was 45 mg daily during a 28-day cycle. Due to substantial toxicity, the starting dose was subsequently lowered to 30 mg daily. Results Fifty-one patients enrolled at 9 centers; 50 were evaluable for response. Partial responses were observed in 10% of patients; stable disease was seen in 34%. Disease control (PR + SD) was higher at the 45 mg cediranib dose level (67% vs. 34%, p=0.04). Median progression-free survival was 1.8 months (95% CI 0.1, 14.2); median overall survival (OS) was 4.4 months (95% CI 0.9, 41.7). The 1-year survival rate was 15%. Grade 3/4 toxicities were more frequent in the 45 mg dose level group (87% vs. 43%, p=0.002). These included fatigue, hypertension, pulmonary embolism, angioedema, and reversible posterior leukoencephalopathy. Median OS was superior in patients who developed ≥ grade 3 hypertension (8.5 vs. 4.1 months, p=0.024). Conclusion This trial did not meet its pre-specified response endpoint. A higher cediranib dose level was associated with improved disease control, but this dose was poorly tolerated. PMID:22831987

Carbon-ion radiotherapy for marginal lymph node recurrences of cervical cancer after definitive radiotherapy: a case report.

PubMed

Tamaki, Tomoaki; Ohno, Tatsuya; Kiyohara, Hiroki; Noda, Shin-ei; Ohkubo, Yu; Ando, Ken; Wakatsuki, Masaru; Kato, Shingo; Kamada, Tadashi; Nakano, Takashi

2013-04-05

Recurrences of cervical cancer after definitive radiotherapy often occur at common iliac or para-aortic lymph nodes as marginal lymph node recurrences. Patients with these recurrences have a chance of long-term survival by optimal re-treatment with radiotherapy. However, the re-irradiation often overlaps the initial and the secondary radiotherapy fields and can result in increased normal tissue toxicities in the bowels or the stomach. Carbon-ion radiotherapy, a form of particle beam radiotherapy using accelerated carbon ions, offers more conformal and sharp dose distribution than X-ray radiotherapy. Therefore, this approach enables the delivery of high radiation doses to the target while sparing its surrounding normal tissues. Marginal lymph node recurrences in common iliac lymph nodes after radiotherapy were treated successfully by carbon-ion radiotherapy in two patients. These two patients were initially treated with a combination of external beam radiotherapy and intracavitary and interstitial brachytherapy. However, the diseases recurred in the lymph nodes near the border of the initial radiotherapy fields after 22 months and 23 months. Because re-irradiation with X-ray radiotherapy may deliver high doses to a section of the bowels, carbon-ion radiotherapy was selected to treat the lymph node recurrences. A total dose of 48 Gy (RBE) in 12 fractions over 3 weeks was given to the lymph node recurrences, and the tumors disappeared completely with no severe acute toxicities. The two patients showed no evidence of disease for 75 months and 63 months after the initial radiotherapy and for 50 months and 37 months after the carbon-ion radiotherapy, respectively. No severe late adverse effects are observed in these patients. The two presented cases suggest that the highly conformal dose distribution of carbon-ion radiotherapy may be beneficial in the treatment of marginal lymph node recurrences after radiotherapy. In addition, the higher biological effect of carbon-ion radiotherapy and its superior dose distribution may provide more effective tumor control in treatment for re-irradiation of the marginal recurrences in radiation resistant tumors other than cervical cancer.

Using fractional exhaled nitric oxide (FeNO) to diagnose steroid-responsive disease and guide asthma management in routine care.

PubMed

Price, David; Ryan, Dermot; Burden, Annie; Von Ziegenweidt, Julie; Gould, Shuna; Freeman, Daryl; Gruffydd-Jones, Kevin; Copland, Anne; Godley, Clifford; Chisholm, Alison; Thomas, Mike

2013-11-07

Fractional exhaled nitric oxide (FeNO) is a surrogate marker of eosinophilic airway inflammation and good predictor of corticosteroid response. To evaluate how FeNO is being used to guide primary care asthma management in the United Kingdom (UK) with a view to devising practical algorithms for the use of FeNO in the diagnosis of steroid-responsive disease and to guide on-going asthma management. Eligible patients (n = 678) were those in the Optimum Patient Care Research Database (OPCRD) aged 4-80 years who, at an index date, had their first FeNO assessment via NIOX MINO® or Flex®. Eligible practices were those using FeNO measurement in at least ten patients during the study period. Patients were characterized over a one-year baseline period immediately before the index date. Outcomes were evaluated in the year immediately following index date for two patient cohorts: (i) those in whom FeNO measurement was being used to identify steroid-responsive disease and (ii) those in whom FeNO monitoring was being used to guide on-going asthma management. Outcomes for cohort (i) were incidence of new ICS initiation at, or within the one-month following, their first FeNO measurement, and ICS dose during the outcome year. Outcomes for cohort (ii) were adherence, change in adherence (from baseline) and ICS dose. In cohort (i) (n = 304) the higher the FeNO category, the higher the percentage of patients that initiated ICS at, or in the one month immediately following, their first FeNO measurement: 82%, 46% and 26% of patients with high, intermediate and low FeNO, respectively. In cohort (ii) (n = 374) high FeNO levels were associated with poorer baseline adherence (p = 0.005) but greater improvement in adherence in the outcome year (p = 0.017). Across both cohorts, patients with high FeNO levels were associated with significantly higher ICS dosing (p < 0.001). In the UK, FeNO is being used in primary practice to guide ICS initiation and dosing decisions and to identify poor ICS adherence. Simple algorithms to guide clinicians in the practical use of FeNO could improved diagnostic accuracy and better tailored asthma regimens.

Influence of timing and dose of thyroid hormone replacement on mental, psychomotor, and behavioral development in children with congenital hypothyroidism.

PubMed

Bongers-Schokking, Jacoba J; de Muinck Keizer-Schrama, Sabine M P F

2005-12-01

To evaluate the influence of initial and postinitial treatment factors on cognitive, psychomotor, and psychological outcome in schoolchildren with congenital hypothyroidism (CH). We studied 45 patients (19 with severe CH and 26 with mild CH) and 37 control children by correlating initial and postinitial treatment factors (free thyroxine and thyroid-stimulating hormone [TSH] concentrations, and the percentage of overtreatment and undertreatment periods) with the results of neuropsychological tests and behavior (as reported on the Teacher Report Form [TRF]). The global IQ of the children with CH was comparable to that of the controls; visuomotor and verbal scores were lower, and total TRF scores were higher. Ethnic group, previous development, and overtreatment predicted IQ and verbal scores, with higher scores seen for the overtreated patients than for the control children and those patients who had not been overtreated. As initial treatment was less satisfactory, total TRF scores were higher. Our study suggests that initial and postinitial suboptimal treatment of CH leads to abnormalities in IQ and specific fields. Overtreatment may advance cognitive development in 5-1/2- to 7-year-olds. Suboptimal initial treatment may lead to behavioral problems. We recommend that TSH concentrations be maintained within the normal range in patients with CH.

Effect of inhaled corticosteroid use on weight (BMI) in pediatric patients with moderate-severe asthma.

PubMed

Han, Jennifer; Nguyen, John; Kim, Yuna; Geng, Bob; Romanowski, Gale; Alejandro, Lawrence; Proudfoot, James; Xu, Ronghui; Leibel, Sydney

2018-04-19

Assess the relationship between inhaled corticosteroid use (ICS) and weight (BMI) in pediatric patients with moderate-severe asthma. Assess if the number of emergency department (ED) visits correlates with overall BMI trajectory. Assess the trend of prescribing biologic therapy in pediatric patients with moderate-severe asthma and determine its relationship with weight (BMI). A retrospective chart review was performed on 93 pediatric patients with moderate-severe asthma to determine the relationship between ICS use and weight (BMI), biologic therapy and BMI, and number of ED visits and BMI trajectory. A mixed effects model was employed with the correlation between repeated measures accounted for through the random effects. There is a statistically significant increase of 0.369 kg/m 2 in BMI trajectory per year in subjects on high-dose steroids compared to an increase of 0.195 kg/m 2 in the low dose group (p < 0.05). The BMI of subjects initiated on biologic therapy (omalizumab or mepolizumab) had a statistically significant decrease in BMI trajectory of 0.818 kg/m 2 per year (p < 0.05). Subjects with ≥5 ED visits due to asthma exacerbations had a significantly higher BMI trajectory (p < 0.05). The potency of ICS use in pediatric patients with moderate-severe asthma affects BMI trajectory; the higher the dose, the greater the projected BMI increase per year. Initiation of biologic therapy decreased BMI trajectory over time. Lastly, those with frequent ED visits had a higher BMI trend. Future prospective studies are warranted that further evaluate the potential metabolic impacts of ICS and assess the effects of biologic therapy on BMI.

Gut Microbiota and Tacrolimus Dosing in Kidney Transplantation

PubMed Central

Lee, John R.; Muthukumar, Thangamani; Dadhania, Darshana; Taur, Ying; Jenq, Robert R.; Toussaint, Nora C.; Ling, Lilan; Pamer, Eric; Suthanthiran, Manikkam

2015-01-01

Tacrolimus dosing to establish therapeutic levels in recipients of organ transplants is a challenging task because of much interpatient and intrapatient variability in drug absorption, metabolism, and disposition. In view of the reported impact of gut microbial species on drug metabolism, we investigated the relationship between the gut microbiota and tacrolimus dosing requirements in this pilot study of adult kidney transplant recipients. Serial fecal specimens were collected during the first month of transplantation from 19 kidney transplant recipients who either required a 50% increase from initial tacrolimus dosing during the first month of transplantation (Dose Escalation Group, n=5) or did not require such an increase (Dose Stable Group, n=14). We characterized bacterial composition in the fecal specimens by deep sequencing of the PCR amplified 16S rRNA V4-V5 region and we investigated the hypothesis that gut microbial composition is associated with tacrolimus dosing requirements. Initial tacrolimus dosing was similar in the Dose Escalation Group and in the Stable Group (4.2±1.1 mg/day vs. 3.8±0.8 mg/day, respectively, P=0.61, two-way between-group ANOVA using contrasts) but became higher in the Dose Escalation Group than in the Dose Stable Group by the end of the first transplantation month (9.6±2.4 mg/day vs. 3.3±1.5 mg/day, respectively, P<0.001). Our systematic characterization of the gut microbial composition identified that fecal Faecalibacterium prausnitzii abundance in the first week of transplantation was 11.8% in the Dose Escalation Group and 0.8% in the Dose Stable Group (P=0.002, Wilcoxon Rank Sum test, P<0.05 after Benjamini-Hochberg correction for multiple hypotheses). Fecal Faecalibacterium prausnitzii abundance in the first week of transplantation was positively correlated with future tacrolimus dosing at 1 month (R=0.57, P=0.01) and had a coefficient±standard error of 1.0±0.6 (P=0.08) after multivariable linear regression. Our novel observations may help further explain inter-individual differences in tacrolimus dosing to achieve therapeutic levels. PMID:25815766

HPV Vaccination among Adolescent Females from Appalachia: Implications for Cervical Cancer Disparities

PubMed Central

Reiter, Paul L.; Katz, Mira L.; Paskett, Electra D.

2012-01-01

Background Appalachia is a geographic region with high cervical cancer incidence and mortality rates, yet little is known about human papillomavirus (HPV) vaccination in this region. We determined HPV vaccine coverage among adolescent females from Appalachia, made comparisons to non-Appalachian females, and examined how coverage differs across subregions within Appalachia. Methods We analyzed 2008–2010 data from the National Immunization Survey-Teen (NIS-Teen) for adolescent females ages 13–17 (n=1,951 Appalachian females and n=25,468 non-Appalachian females). We examined HPV vaccine initiation (receipt of at least one dose), completion (receipt of at least three doses), and follow-through (completion among initiators). Analyses used weighted logistic regression. Results HPV vaccine initiation (Appalachian=40.8% vs. non-Appalachian=43.6%; OR=0.92, 95% CI: 0.79–1.07) and completion (Appalachian=27.7% vs. non-Appalachian=25.3%; OR=1.12, 95% CI: 0.95–1.32) were similar between Appalachian and non-Appalachian females. HPV vaccine follow-through was higher among Appalachian females than non-Appalachian females (67.8% vs. 58.1%; OR=1.36, 95% CI: 1.07–1.72). Vaccination outcomes tended to be higher in the Northern (completion and follow-through) and South Central (follow-through) subregions of Appalachia compared to non-Appalachian U.S. Conversely, vaccination outcomes tended to be lower in the Central (initiation and completion) and Southern (initiation and completion) subregions. Conclusions In general, HPV vaccination in Appalachia is mostly similar to the rest of the U.S. However, vaccination is lagging in regions of Appalachia where cervical cancer incidence and mortality rates are highest. Impact Current cervical cancer disparities could potentially worsen if HPV vaccine coverage is not improved in regions of Appalachia with low HPV vaccine coverage. PMID:23136141

Does tablet formulation alone improve adherence and persistence: a comparison of ezetimibe fixed dose combination versus ezetimibe separate pill combination?

PubMed

Bartlett, Louise E; Pratt, Nicole; Roughead, Elizabeth E

2017-01-01

The aim of this study was to compare adherence and persistence in patients who add ezetimibe to statin therapy as a separate pill combination (SPC) or fixed dose combination (FDC). This is a retrospective cohort study of prescription data conducted in an Australian health dataset. Two cohorts were identified: those dispensed statins and subsequently ezetimibe as either SPC or FDC. We compared adherence to combination therapy using the medication possession ratio (MPR), multivariate linear and logistic regression. Persistence to initial combination medicines and any lipid-lowering therapies were analysed using Kaplan Meyer survival and Cox proportional hazards models. A total of 3651 people initiated ezetimibe SPC and 5740 ezetimibe FDC. There was no significant difference in adherence with mean MPRs: ezetimibe SPC = 0.99 (95% confidence interval 0.98-1.01) and FDC = 0.97 (95% CI 0.95-0.99). One year persistence rates to initial combination medicines were ezetimibe SPC 49.1% vs. FDC 62.4%; hazard ratio (HR) = 1.81 (95% CI 1.76-1.90). However, persistence to any lipid-lowering therapy was higher in those initiating ezetimibe SPC = 84.9% vs. FDC = 76%; HR = 0.62 (95% CI 0.55-0.72). One year persistence rates to any two lipid-lowering medicines were similar: ezetimibe SPC 65.2% and FDC 65%. In this study FDCs have little impact on either adherence or persistence to combination lipid-lowering therapy in people who have been taking statins. The benefit of higher persistence to FDCs in first episode of treatment with initial medicines is debatable as persistence to dual therapy was similar in both cohorts. © 2016 The British Pharmacological Society.

Does tablet formulation alone improve adherence and persistence: a comparison of ezetimibe fixed dose combination versus ezetimibe separate pill combination?

PubMed Central

Pratt, Nicole; Roughead, Elizabeth E.

2016-01-01

Aims The aim of this study was to compare adherence and persistence in patients who add ezetimibe to statin therapy as a separate pill combination (SPC) or fixed dose combination (FDC). Method This is a retrospective cohort study of prescription data conducted in an Australian health dataset. Two cohorts were identified: those dispensed statins and subsequently ezetimibe as either SPC or FDC. We compared adherence to combination therapy using the medication possession ratio (MPR), multivariate linear and logistic regression. Persistence to initial combination medicines and any lipid‐lowering therapies were analysed using Kaplan Meyer survival and Cox proportional hazards models. Results A total of 3651 people initiated ezetimibe SPC and 5740 ezetimibe FDC. There was no significant difference in adherence with mean MPRs: ezetimibe SPC = 0.99 (95% confidence interval 0.98–1.01) and FDC = 0.97 (95% CI 0.95–0.99). One year persistence rates to initial combination medicines were ezetimibe SPC 49.1% vs. FDC 62.4%; hazard ratio (HR) = 1.81 (95% CI 1.76–1.90). However, persistence to any lipid‐lowering therapy was higher in those initiating ezetimibe SPC = 84.9% vs. FDC = 76%; HR = 0.62 (95% CI 0.55–0.72). One year persistence rates to any two lipid‐lowering medicines were similar: ezetimibe SPC 65.2% and FDC 65%. Conclusion In this study FDCs have little impact on either adherence or persistence to combination lipid‐lowering therapy in people who have been taking statins. The benefit of higher persistence to FDCs in first episode of treatment with initial medicines is debatable as persistence to dual therapy was similar in both cohorts. PMID:27517705

Hepatitis A and B vaccination--the rate of uptake and course completion in patients with hepatitis C.

PubMed

Fredericks, Trinity; Kwan, Kellie; Mak, Donna

2010-10-01

Western Australian general practitioners may order Department of Health funded hepatitis A and B vaccines for patients newly notified with hepatitis C to prevent complications associated with co-infections. The aim of this study was to determine vaccination uptake of hepatitis C patients through this program. We reviewed hepatitis C notifications and hepatitis A and B vaccine orders received in 2007 and 2008 to determine the rate of vaccine uptake and course completion. Vaccination orders for initial doses were received for 37% (448/1209) of patients. Vaccination uptake was positively associated with age and non- Aboriginality. Final vaccination doses were ordered for 30% of patients for whom an initial order had been received. Uptake of hepatitis A and B vaccination was higher than that of similar populations. However, vaccination course completion was low. General practitioners need to emphasise to their patients the importance of completing a vaccine course.

Rats classified as low or high cocaine locomotor responders: A unique model involving striatal dopamine transporters that predicts cocaine addiction-like behaviors

PubMed Central

Yamamoto, Dorothy J.; Nelson, Anna M.; Mandt, Bruce H.; Larson, Gaynor A.; Rorabaugh, Jacki M.; Ng, Christopher M.C.; Barcomb, Kelsey M.; Richards, Toni L.; Allen, Richard M.; Zahniser, Nancy R.

2013-01-01

Individual differences are a hallmark of drug addiction. Here, we describe a rat model based on differential initial responsiveness to low dose cocaine. Despite similar brain cocaine levels, individual outbred Sprague-Dawley rats exhibit markedly different magnitudes of acute cocaine-induced locomotor activity and, thereby, can be classified as low or high cocaine responders (LCRs or HCRs). LCRs and HCRs differ in drug-induced, but not novelty-associated, hyperactivity. LCRs have higher basal numbers of striatal dopamine transporters (DATs) than HCRs and exhibit marginal cocaine inhibition of in vivo DAT activity and cocaine-induced increases in extracellular DA. Importantly, lower initial cocaine response predicts greater locomotor sensitization, conditioned place preference and greater motivation to self-administer cocaine following low dose acquisition. Further, outbred Long-Evans rats classified as LCRs, versus HCRs, are more sensitive to cocaine’s discriminative stimulus effects. Overall, results to date with the LCR/HCR model underscore the contribution of striatal DATs to individual differences in initial cocaine responsiveness and the value of assessing the influence of initial drug response on subsequent expression of addiction-like behaviors. PMID:23850581

Effect of a low dose combined oral contraceptive pill on the hormonal profile and cycle outcome following COS with a GnRH antagonist protocol in women over 35 years old.

PubMed

Bakas, Panagiotis; Hassiakos, Dimitrios; Grigoriadis, Charalampos; Vlahos, Nikolaos F; Liapis, Angelos; Creatsas, George

2014-11-01

This prospective study examines if pre-treatment with two different doses of an oral contraceptive pill (OCP) modifies significantly the hormonal profile and/or the IVF/ICSI outcome following COS with a GnRH antagonist protocol. Infertile patients were allocated to receive either OCP containing 0.03 mg of ethinylestradiol and 3 mg of drospirenone, or OCP containing 0.02 mg of ethinylestradiol and 3 mg of drospirenone prior to initiation of controlled ovarian stimulation (COS) with recombinant gonadotropins on a variable multi-dose antagonist protocol (Ganirelix), while the control group underwent COS without OCP pretreatment. Lower dose OCP was associated with recovery of FSH on day 3 instead of day 5, but the synchronization of the follicular cohort, the number of retrieved oocytes and the clinical pregnancy rate were similar to higher dose OCP.

Intravenous Vancomycin Associated With the Development of Nephrotoxicity in Patients With Class III Obesity.

PubMed

Choi, Yookyung Christy; Saw, Stephen; Soliman, Daniel; Bingham, Angela L; Pontiggia, Laura; Hunter, Krystal; Chuang, Linda; Siemianowski, Laura A; Ereshefsky, Benjamin; Hollands, James M

2017-11-01

A consensus statement recommends initial intravenous (IV) vancomycin dosing of 15-20 mg/kg every 8- 24 hours, with an optional 25- to 30-mg/kg loading dose. Although some studies have shown an association between weight and the development of vancomycin-associated nephrotoxicity, results have been inconsistent. To evaluate the correlation between incidence of nephrotoxicity associated with weight-based IV vancomycin dosing strategies in nonobese and obese patients. This retrospective cohort study evaluated hospitalized adult patients admitted who received IV vancomycin. Patients were stratified into nonobese (body mass index [BMI] <25 kg/m 2 ), obesity class I and II (BMI 30-39.9kg/m 2 ), and obesity class III (BMI≥40 kg/m 2 ) groups; patients who were overweight but not obese were excluded. Incidence of nephrotoxicity and serum vancomycin trough concentrations were evaluated. Of a total of 62 documented cases of nephrotoxicity (15.1%), 13 (8.7%), 23 (14.3%), and 26 (26.3%) cases were observed in nonobese, obesity class I and II, and obesity class III groups, respectively ( P=0.002). Longer durations of therapy ( P<0.0001), higher initial maintenance doses in both total milligrams/day ( P=0.0137) and milligrams/kilogram ( P=0.0307), and any trough level >20 mg/L ( P<0.0001) were identified as predictors of development of nephrotoxicity. Concomitant administration of piperacillin/tazobactam, diuretics, and IV contrast were associated with development of nephrotoxicity ( P<0.005, all). Patients with class III obesity were 3-times as likely to develop nephrotoxicity when compared with nonobese patients (odds ratio [OR]=2.99; CI=1.12-7.94) and obesity class I and II patients (OR=3.14; CI=1.27-7.75). Obesity and other factors are associated with a higher risk of vancomycin-associated nephrotoxicity.

Palliative sedation at home for terminally ill children with cancer.

PubMed

Korzeniewska-Eksterowicz, Aleksandra; Przysło, Łukasz; Fendler, Wojciech; Stolarska, Małgorzata; Młynarski, Wojciech

2014-11-01

The presence of symptoms that are difficult to control always requires adjustment of treatment, and palliative sedation (PS) should be considered. We analyzed our experience in conducting PS at home for terminally ill children with cancer during a seven-year period. We performed a retrospective analysis of medical records of children with cancer treated at home between the years 2005 and 2011. We analyzed the data of 42 cancer patients (18% of all patients); in 21 cases, PS was initiated (solid tumors n = 11, brain tumors [5], bone tumors [4], leukemia [1]). Sedation was introduced because of pain (n = 13), dyspnea (9), anxiety (5), or two of those symptoms (6). The main drug used for sedation was midazolam; all patients received morphine. There were no significant differences in the dose of morphine or midazolam depending on the patient's sex; age was correlated with an increase of midazolam dose (R = 0.68; P = 0.005). Duration of sedation (R = 0.61; P = 0.003) and its later initiation (R = 0.43; P = 0.05) were correlated with an increase of the morphine dose. All patients received adjuvant treatment; in patients who required a morphine dose increase, metoclopramide was used more often (P = 0.0002). Patients did not experience any adverse reactions. Later introduction of sedation was associated with a marginally higher number of intervention visits and a significantly higher number of planned visits (R = 0.53; P = 0.013). Sedation may be safely used at home. It requires close monitoring and full cooperation between the family and hospice team. Because of the limited data on home PS in pediatric populations, further studies are needed. Copyright © 2014 American Academy of Hospice and Palliative Medicine. Published by Elsevier Inc. All rights reserved.

Biological Effectiveness of Accelerated Particles for the Induction of Chromosome Damage Measured in Metaphase and Interphase Human Lymphocytes

NASA Technical Reports Server (NTRS)

George, Kerry; Durante, Marco; Willingham, Veronica; Wu, Honglu; Yang, Tracy C.; Cucinotta, Francis A.

2003-01-01

Chromosome aberrations were investigated in human lymphocytes after in vitro exposure to 1H-, 3He-, 12C-, 40Ar-, 28Si-, 56Fe-, or 197Au-ion beams, with LET ranging from approximately 0.4-1393 keV/microm in the dose range of 0.075-3 Gy. Dose-response curves for chromosome exchanges, measured at the first mitosis postirradiation using fluorescence in situ hybridization (FISH) with whole-chromosome probes, were fitted with linear or linear-quadratic functions. The relative biological effectiveness (RBE) was estimated from the initial slope of the dose-response curve for chromosomal damage with respect to low- or high-dose-rate gamma rays. Estimates of RBEmax values for mitotic spreads, which ranged from near 0.7 to 11.1 for total exchanges, increased with LET, reaching a maximum at about 150 keV/microm, and decreased with further increase in LET. RBEs for complex aberrations are undefined due to the lack of an initial slope for gamma rays. Additionally, the effect of mitotic delay on RBE values was investigated by measuring chromosome aberrations in interphase after chemically induced premature chromosome condensation (PCC), and values were up to threefold higher than for metaphase analysis.

Safety and tolerability of adjunctive lacosamide intravenous loading dose in lacosamide-naive patients with partial-onset seizures.

PubMed

Fountain, Nathan B; Krauss, Gregory; Isojarvi, Jouko; Dilley, Deanne; Doty, Pamela; Rudd, G David

2013-01-01

To examine the safety and tolerability of rapidly initiating adjunctive lacosamide via a single intravenous loading dose followed by twice-daily oral lacosamide in lacosamide-naive adults with partial-onset seizures. This open-label, multicenter trial, enrolled patients with epilepsy who were taking 1-2 antiepileptic drugs (AEDs) in one of four sequential cohorts containing 25 subjects each. An intravenous lacosamide loading dose (200, 300, or 400 mg) was administered over 15 min followed 12 h later by initiation of oral dosing consisting of one-half of the loading dose administered twice daily for 6.5 days. The first cohort was administered lacosamide 200 mg/day, followed by a cohort at 300 mg/day, and then a cohort at 400 mg/day. The results from each cohort were evaluated before enrolling the next highest dose level. The fourth cohort enrolled patients at the highest dose with clinically acceptable safety and tolerability results. Safety evaluations included treatment-emergent adverse events (TEAEs), patient withdrawals due to TEAEs, and changes in vital signs, 12-lead electrocardiography (ECG) studies, laboratory parameters, and clinical examinations. Postinfusion lacosamide plasma concentrations were also evaluated. A total of 100 patients were enrolled, 25 in each cohort. The loading dose for the repeat cohort was 300 mg; therefore, 25 patients were enrolled at 200 mg/day, 50 at 300 mg/day, and 25 at 400 mg/day. Most TEAEs occurred within the first 4 h following infusion; dose-related TEAEs (incidence ≥10%) during this timeframe included dizziness, somnolence, and nausea. Seven patients withdrew, all due to TEAEs: three (6%) from the combined 300 mg group and four (16%) from the 400 mg group; four of these patients discontinued within 4 h following infusion. The most common TEAEs leading to discontinuation (overall incidence >1%) were dizziness (6%), nausea (5%), and vomiting (3%). No clinically relevant pattern of changes from baseline ECG, clinical laboratory parameters, or vital signs were observed. Trough plasma concentrations suggested that near steady-state lacosamide concentrations were achieved with a single intravenous loading dose. Intravenous loading doses of 200 and 300 mg lacosamide administered over 15 min followed by oral lacosamide were well tolerated in lacosamide-naive patients. The 400-mg loading dose was less well tolerated due to a higher frequency of dose-related TEAEs. These results support the feasibility of rapid initiation of adjunctive lacosamide treatment. Wiley Periodicals, Inc. © 2012 International League Against Epilepsy.

Photo-catalytic decolourisation of toxic dye with N-doped titania: a case study with Acid Blue 25.

PubMed

Chakrabortty, Dhruba; Gupta, Susmita Sen

2013-05-01

Dyes are one of the hazardous water pollutants. Toxic Acid Blue 25, an anthraquinonic dye, has been decolourised by photo-catalysing it with nitrogen doped titania in aqueous medium. The photo catalyst was prepared from 15% TiCl3 and 25% aqueous NH3 solution as precursor. XRD and TEM revealed the formation of well crystalline anatase phase having particle size in the nano-range. BET surface area of the sample was higher than that of pure anatase TiO2. DRS showed higher absorption of radiation in visible range compared to pure anatase TiO2. XPS revealed the presence of nitrogen in N-Ti-O environment. The experimental parameters, namely, photocatalyst dose, initial dye concentration as well as solution pH influence the decolourisation process. At pH 3.0, the N-TiO2 could decolourise almost 100% Acid Blue 25 within one hour. The influence of N-TiO2 dose, initial concentration of Acid Blue 25 and solution pH on adsorption-desorption equilibrium is also studied. The adsorption process follows Lagergren first order kinetics while the modified Langmuir-Hinselwood model is suitably fitted for photocatalytic decolourisation of Acid Blue 25.

Starting Dose of Sorafenib for the Treatment of Hepatocellular Carcinoma: A Retrospective, Multi-Institutional Study.

PubMed

Reiss, Kim A; Yu, Shun; Mamtani, Ronac; Mehta, Rajni; D'Addeo, Kathryn; Wileyto, E Paul; Taddei, Tamar H; Kaplan, David E

2017-11-01

Purpose Sorafenib is currently the only Food and Drug Administration-approved first-line therapy for patients with advanced hepatocellular carcinoma. There are few data examining how sorafenib starting dose may influence patient outcomes and costs. Patients and Methods We retrospectively evaluated 4,903 patients from 128 Veterans Health Administration hospitals who were prescribed sorafenib for hepatocellular carcinoma between January 2006 and April 2015. After 1:1 propensity score matching to account for potential treatment bias, hazard ratios (HRs) were calculated using Cox regression and were tested against a noninferiority margin of HR = 1.1. A matched multivariate logistic regression was performed to adjust for potential confounders. The primary end point was overall survival (OS) of patients who were prescribed standard starting dosage sorafenib (800 mg/d per os) versus that of patients who were prescribed reduced starting dose sorafenib (< 800 mg/d per os). Results There were 3,094 standard dose sorafenib patients (63%) and 1,809 reduced starting dose sorafenib patients (37%). Reduced starting dose sorafenib patients had more Barcelona Clinic Liver Cancer stage D ( P < .001), higher Model for End-Stage Liver Disease Sodium scores ( P < .001), higher Child-Turcotte-Pugh scores ( P < .001), and higher Cirrhosis Comorbidity Index scores ( P = .01). Consequently, reduced starting dose sorafenib patients had lower OS (median, 200 v 233 days, HR = 1.10). After propensity score matching and adjusting for potential confounders, there was no longer a significant OS difference (adjusted hazard ratio [HR adj ], 0.92; 95% CI, 0.83 to 1.01), and this fell significantly below the noninferiority margin ( P < .001). Reduced starting dose sorafenib patients experienced significantly lower total cumulative sorafenib cost and were less likely to discontinue sorafenib because of gastrointestinal adverse effects (8.7% v 10.8%; P = .047). Conclusion The initiation of sorafenib therapy at reduced dosages was associated with reduced pill burden, reduced treatment costs, and a trend toward a decreased rate of discontinuing sorafenib because of adverse events. Reduced dosing was not associated with inferior OS relative to standard dosing.

Weight changes and their associations with demographic and clinical characteristics in risperidone maintenance treatment for schizophrenia.

PubMed

Xiang, Y-T; Wang, C-Y; Ungvari, G S; Kreyenbuhl, J A; Chiu, H F K; Lai, K Y C; Lee, E H M; Bo, Q-J; Dixon, L B

2011-06-01

This study aimed to characterize weight changes in schizophrenia patients taking risperidone as part of a randomized, controlled, open-label clinical trial. A total of 374 patients with schizophrenia who had been clinically stabilized following an acute episode were randomly assigned to a 'no-dose-reduction' group (initial optimal therapeutic doses continued throughout the study), a '4-week group' (initial optimal therapeutic doses continued for 4 weeks followed by a half dose reduction that was maintained until the end of the study) or a '26-week group' (initial optimal therapeutic doses continued for 26 weeks followed by a half dose reduction until the end of the study). Participants were assessed monthly using standardized assessment instruments during the first 6 months, and then every 2 months until the last recruited patient completed the 1-year follow-up. Weight gain was defined as gaining at least 7% of initial body weight, weight loss as losing at least 7% of initial body weight. A BMI <18.5 kg m⁻² was defined as underweight, 18.5-24.9 kg m⁻² as normal range, and ≥ 25 kg m⁻² as overweight or obese. At the end of follow-up, of the patients who started within the underweight range (n=22), 77.3% gained weight, whereas 4.5% lost weight. The corresponding figures were 39.6% and 4.8% in patients who started at normal weight (n=273), respectively, and 17.7% and 17.7% in patients who started at overweight (n=79), respectively. At the same time, 59.1% of the patients who started at underweight range went into the normal weight and 13.6% into the overweight/obese range, respectively, while 24.5% of those who started at normal weight went into the overweight/obese range, and 1.1% into underweight range, respectively; 20.3% of those who started at overweight range went into normal weight at the end of the follow-up. Multiple logistic regression analyses revealed that being underweight or normal weight at study entry predicted weight gain compared to being overweight, whereas being overweight at entry was associated with a higher likelihood of weight loss compared to being normal weight. No correlation was found between weight change and dose reduction. Weight change is a common, long-term, but heterogeneous side effect in risperidone maintenance treatment for stable schizophrenia patients. Special attention should be paid to fluctuations in weight that may occur throughout the course of treatment with risperidone. © Georg Thieme Verlag KG Stuttgart · New York.

Botulinum Toxin Dosing Trends in Spasmodic Dysphonia Over a 20-year Period.

PubMed

Namin, Arya W; Christopher, Kara M; Eisenbeis, John F

2017-01-01

The study aims to (1) identify the botulinum toxin (BTX) dosing trend in a cohort of patients who received at least 20 injections for the treatment of adductor spasmodic dysphonia (ADSD), (2) describe two distinct BTX dosing trends in treating ADSD (a "classic" dosing trend that initially decreases before stabilizing, and a "fluctuating" dosing trend), and (3) determine if patients with the "classic" dosing trend differed in age or in dosing intervals from those with the "fluctuating" dosing trend. This is a retrospective case series. Of 149 patients who received a total of 2484 BTX injections for the treatment of spasmodic dysphonia in 1993-2013, 49 patients received at least 20 injections. The BTX dose and the interval between doses were recorded. The mean dose of injections 1-20 was determined. The age at initial injection, initial dose, and interval in days between treatments were compared for the "fluctuating" and "classic" groups. The cohort exhibits a significant decrease in dose during the first 10-15 injections. The "fluctuating" group had a significantly shorter interval between injections (mean interval = 97.09 days, SD = 29.41; mean interval = 136.90 days, SD = 43.76, P = 0.002). The mean age at initial dose was not significantly different between the "classic" and "fluctuating" groups. The average BTX dose of patients with ADSD who receive long-term injections significantly decreases during the initial 10-15 injections before stabilizing. Patients who exhibit the "fluctuating" dosing pattern have a significantly shorter interval between injections than those with the "classic" dosing pattern. Copyright © 2017 The Voice Foundation. Published by Elsevier Inc. All rights reserved.

Influence of gamma irradiation on structural, thermal and antibacterial properties of HPMC/ZnO nanocomposites

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

Rao, B. Lakshmeesha; Madhukumar, R.; Latha, S.

This work was carried out to evaluate the effect of gamma irradiation on the structural, thermal and antibacterial properties of HPMC/ZnO nanocomposite films exposed to Cobalt-60 (Average energy: 1.25 MeV). The X-ray diffraction study revealed that the crystallite size (L in Å) decreased as irradiation dose increased. The crystallinity (X{sub c}) of the nanocomposites initially increased and at higher doses it was decreased. The thermal stability of the nanocomposites increased up to 50 kGy and after that decreased as the irradiation dose increased. But, HPMC/ZnO nanocomposite films, showed a promising range of antimicrobial activity against tested micro-organisms making nanocomposites suitablemore » for food packing and other biomedical applications.« less

SU-F-J-56: The Connection Between Cherenkov Light Emission and Radiation Absorbed Dose in Proton Irradiated Phantoms

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

Darafsheh, A; Kassaee, A; Finlay, J

Purpose: Range verification in proton therapy is of great importance. Cherenkov light follows the photon and electron energy deposition in water phantom. The purpose of this study is to investigate the connection between Cherenkov light generation and radiation absorbed dose in a water phantom irradiated with proton beams. Methods: Monte Carlo simulation was performed by employing FLUKA Monte Carlo code to stochastically simulate radiation transport, ionizing radiation dose deposition, and Cherenkov radiation in water phantoms. The simulations were performed for proton beams with energies in the range 50–600 MeV to cover a wide range of proton energies. Results: The mechanismmore » of Cherenkov light production depends on the initial energy of protons. For proton energy with 50–400 MeV energy that is below the threshold (∼483 MeV in water) for Cherenkov light production directly from incident protons, Cherenkov light is produced mainly from the secondary electrons liberated as a result of columbic interactions with the incident protons. For proton beams with energy above 500 MeV, in the initial depth that incident protons have higher energy than the Cherenkov light production threshold, the light has higher intensity. As the slowing down process results in lower energy protons in larger depths in the water phantom, there is a knee point in the Cherenkov light curve vs. depth due to switching the Cherenkov light production mechanism from primary protons to secondary electrons. At the end of the depth dose curve the Cherenkov light intensity does not follow the dose peak because of the lack of high energy protons to produce Cherenkov light either directly or through secondary electrons. Conclusion: In contrast to photon and electron beams, Cherenkov light generation induced by proton beams does not follow the proton energy deposition specially close to the end of the proton range near the Bragg peak.« less

Chinese culture permeation in the treatment of Parkinson disease: a cross-sectional study in four regions of China.

PubMed

Zhang, Zhen-Xin; Chen, Honglei; Chen, Sheng-Di; Shao, Ming; Sun, Sheng-Gang; Qu, Qiu-Min; Zhang, Bao-Rong; Liu, Yi-Ming; Xu, Qun; Wan, Xia; Li, Ling; Wen, Hong-Bo; Chen, Xia; Chen, Hai-Bo; Liu, Zhen-Guo; Wang, Jian; Wang, Gang

2014-01-30

Little is known about the clinical features and treatment of Chinese patients with Parkinson disease (PD). A large cross-sectional survey of clinical features, medication use, and motor complications was conducted in 901 consecutive PD patients, from 42 randomly selected university-affiliated hospitals in four urban economic regions of China, between December 2006 and May 2007. The 901 PD patients had age range 30 to 88, and median disease duration 50 months. Most (737, 81.8%) used L-dopa (median 375 mg/day), and often added low doses of other antiparkinsonian agents. Among L-dopa-treated patients, the prevalence of motor complications was low (dyskinesias: 8.5%; motor fluctuations: 18.6%), even among patients with disease duration ≥11 years (dyskinesias: 18.1%; motor fluctuations: 42.2%). Higher L-dopa use was associated with higher occurrence of dyskinesias (OR 2.44; 95% CI 1.20-5.13) and motor fluctuations (OR 2.48; 95% CI 1.49-4.14). Initiating PD treatment with L-dopa alone (OR 0.46; 95% CI 0.22-0.95) or in combination with other medications (OR 0.41; 95% CI 0.19-0.87) was associated with less dyskinesia than treatment initiated with non-L-dopa medication. Many Chinese PD patients are treated with low-dose L-dopa and added low-dose antiparkinsonian agents, with a low prevalence of motor complications, which might be influenced by Chinese culture.

Leuco-crystal-violet micelle gel dosimeters: Component effects on dose-rate dependence

NASA Astrophysics Data System (ADS)

Xie, J. C.; Katz, E. A. B.; Alexander, K. M.; Schreiner, L. J.; McAuley, K. B.

2017-05-01

Designed experiments were performed to produce empirical models for the dose sensitivity, initial absorbance, and dose-rate dependence respectively for leucocrystal violet (LCV) micelle gel dosimeters containing cetyltrimethylammonium bromide (CTAB) and 2,2,2-trichloroethanol (TCE). Previous gels of this type showed dose-rate dependent behaviour, producing an ˜18% increase in dose sensitivity between dose rates of 100 and 600 cGy min-1. Our models predict that the dose rate dependence can be reduced by increasing the concentration of TCE, CTAB and LCV. Increasing concentrations of LCV and CTAB produces a significant increase in dose sensitivity with a corresponding increase in initial absorbance. An optimization procedure was used to determine a nearly dose-rate independent gel which maintained high sensitivity and low initial absorbance. This gel which contains 33 mM CTAB, 1.25 mM LCV, and 96 mM TCE in 25 mM trichloroacetic acid and 4 wt% gelatin showed an increase in dose sensitivity of only 4% between dose rates of 100 and 600 cGy min-1, and provides an 80% greater dose sensitivity compared to Jordan’s standard gels with similar initial absorbance.

Zolpidem prescribing practices before and after Food and Drug Administration required product labeling changes.

PubMed

Norman, Jessica L; Fixen, Danielle R; Saseen, Joseph J; Saba, Laura M; Linnebur, Sunny A

2017-01-01

Women have higher morning serum zolpidem concentrations than men after taking an evening dose, potentially leading to increased risk of harm. On 19 April 2013, the United States Food and Drug Administration required labeling changes for zolpidem, recommending an initial dose of no greater than 5 mg (immediate release) or 6.25 mg (controlled release) per night in women. The primary objective of this study was to compare prescribing practices before and after the 2013 zolpidem labeling change. A secondary objective was to evaluate serious adverse events potentially related to zolpidem. Electronic medical records of adults receiving care through the University of Colorado Health system were accessed for study inclusion if patients were provided a first-time prescription for zolpidem either prior to or after the Food and Drug Administration labeling change. Patients were randomly chosen from eight strata based on age, gender, and date of zolpidem initiation (before/after the labeling change). Demographic and zolpidem prescribing data were collected. Low-dose zolpidem was considered 5 mg (immediate release) or 6.25 mg (controlled release) daily or less. Documentation of potentially related serious adverse events within the patients' records was also evaluated. A total of 400 patients were included in the study. The overall percentage of patients prescribed low-dose zolpidem increased from 44% to 58% after the labeling change (p = 0.0020). In a pre-specified subgroup analysis, the percentage of patients prescribed low-dose zolpidem increased in all groups, including young men (38%-50%, p = 0.23), elderly men (34%-40%, p = 0.53), and elderly women (60%-74%, p = 0.14), but the change was only significant in young women (42%-70%, p = 0.0045). After Food and Drug Administration-mandated labeling changes for zolpidem in 2013, the percentage of overall patients in our health system, and specifically young women, with initial prescriptions for low-dose zolpidem significantly increased as compared to before the labeling change.

Characterization of efficacy and toxicity after high-dose pelvic reirradiation with palliative intent for genitourinary second malignant neoplasms or local recurrences after full-dose radiation therapy in the pelvis: A high-volume cancer center experience.

PubMed

Kamran, Sophia C; Harshman, Lauren C; Bhagwat, Mandar S; Muralidhar, Vinayak; Nguyen, Paul L; Martin, Neil E; La Follette, Stephanie; Faso, Sarah; Viswanathan, Akila N; Efstathiou, Jason A; Beard, Clair J

2017-01-01

The use of large-field external beam reirradiation (re-RT) after pelvic radiation therapy (RT) for genitourinary (GU) cancers has not been reported. We report the results of such treatment in patients with either symptomatic GU second malignant neoplasms or locally recurrent pelvic tumors after initial RT for whom surgery or further systemic therapy was not an option. The records of 28 consecutive patients with advanced, bulky GU malignancies treated with high-dose, large-field re-RT with palliative intent between 2008 and 2014 were retrospectively reviewed. Descriptive outcome analyses focused on toxicities and symptom control, and responses were evaluated by 2 independent observers. Twenty-seven male patients (96%) were included. Median initial external beam RT dose was 64 Gy (range, 30-75.6 Gy). The median time between initial RT and re-RT was 9.5 years (range, 0.2-32 years). At the time of re-RT, there were 16 local recurrences and 12 second malignant neoplasms together comprising 16 bladder, 10 prostate, 1 ureteral, and 1 penile cancer. Indications for re-RT were pain and bleeding/hemorrhage. The median equivalent sphere diameter planning target volume for re-RT was 8.6 cm (range, 4.7-16.3 cm). Given the severity of the symptoms and the bulk of the disease at the time of re-RT, a higher dose of RT was administered. The median re-RT dose was 50 Gy (range, 27.5-66 Gy). For patients who received <60 Gy, hypofractionation of 250 cGy was used. The median cumulative dose was 113.9 Gy (range, 81.5-132.8 Gy). Re-RT was well tolerated with no Radiation Therapy Oncology Group grade 3-4 toxicities. Twenty-four patients (92%) had complete resolution of symptoms, and relief was durable in 67% of patients. The median overall survival was 5.8 months (range, 0.3-38.9 months). Of those patients who are still alive, 100% remain free of initial symptoms. This small series suggests that aggressive re-RT of inoperable and symptomatic GU malignancies that is undertaken with meticulous treatment planning is well tolerated and provides excellent, durable relief without undue short-term toxicity. Validation in a larger prospective cohort is required.

SU-F-T-43: Prediction of Dose Increments by Brain Metastases Resection Cavity Shrinkage Model with I-125 and Cs-131 LDR Seed Implantations

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

Han, D; Braunstein, S; Sneed, P

Purpose: This work aims to determine dose variability via a brain metastases resection cavity shrinkage model (RC-SM) with I-125 or Cs-131 LDR seed implantations. Methods: The RC-SM was developed to represent sequential volume changes of 95 consecutive brain metastases patients. All patients underwent serial surveillance MR and change in cavity volume was recorded for each patient. For the initial resection cavity, a prolate-ellipsoid cavity model was suggested and applied volume shrinkage rates to correspond to 1.7, 3.6, 5.9, 11.7, and 20.5 months after craniotomy. Extra-ring structure (6mm) was added on a surface of the resection volume and the same shrinkagemore » rates were applied. Total 31 LDR seeds were evenly distributed on the surface of the resection cavity. The Amersham 6711 I-125 seed model (Oncura, Arlington Heights, IL) and the Model Cs-1 Rev2 Cs-131 seed model (IsoRay, Richland, WA) were used for TG-43U1 dose calculation and in-house-programed 3D-volumetric dose calculation system was used for resection cavity rigid model (RC-RM) and the RC-SM dose calculation. Results: The initial resection cavity volume shrunk to 25±6%, 35±6.8%, 42±7.7%, 47±9.5%, and 60±11.6%, with respect to sequential MR images post craniotomy, and the shrinkage rate (SR) was calculated as SR=56.41Xexp(−0.2024Xt)+33.99 and R-square value was 0.98. The normal brain dose as assessed via the dose to the ring structure with the RC-SM showed 29.34% and 27.95% higher than the RC-RM, I-125 and Cs-131, respectively. The dose differences between I-125 and Cs-131 seeds within the same models, I-125 cases were 9.17% and 10.35% higher than Cs-131 cases, the RC-RM and the RC-SM, respectively. Conclusion: A realistic RC-SM should be considered during LDR brain seed implementation and post-implement planning to prevent potential overdose. The RC-SM calculation shows that Cs-131 is more advantageous in sparing normal brain as the resection cavity volume changes with the LDR seeds implementation.« less

Cellular and Humoral Responses to a Second Dose of Herpes Zoster Vaccine Administered 10 Years After the First Dose Among Older Adults.

PubMed

Levin, Myron J; Schmader, Kenneth E; Pang, Lei; Williams-Diaz, Angela; Zerbe, Gary; Canniff, Jennifer; Johnson, Michael J; Caldas, Yupanqui; Cho, Alice; Lang, Nancy; Su, Shu-Chih; Parrino, Janie; Popmihajlov, Zoran; Weinberg, Adriana

2016-01-01

Herpes zoster vaccine (ZV) was administered as a second dose to 200 participants ≥ 70 years old who had received a dose of ZV ≥ 10 years previously (NCT01245751). Varicella zoster virus (VZV) antibody titers (measured by a VZV glycoprotein-based enzyme-linked immunosorbent assay [gpELISA]) and levels of interferon γ (IFN-γ) and interleukin 2 (IL-2; markers of VZV-specific cell-mediated immunity [CMI], measured by means of ELISPOT analysis) in individuals aged ≥ 70 years who received a booster dose of ZV were compared to responses of 100 participants aged 50-59 years, 100 aged 60-69 years, and 200 aged ≥ 70 years who received their first dose of ZV. The study was powered to demonstrate noninferiority of the VZV antibody response at 6 weeks in the booster-dose group, compared with the age-matched first-dose group. Antibody responses were similar at baseline and after vaccination across all age and treatment groups. Both baseline and postvaccination VZV-specific CMI were lower in the older age groups. Peak gpELISA titers and their fold rise from baseline generally correlated with higher baseline and postvaccination VZV-specific CMI. IFN-γ and IL-2 results for subjects ≥ 70 years old were significantly higher at baseline and after vaccination in the booster-dose group, compared with the first-dose group, indicating that a residual effect of ZV on VZV-specific CMI persisted for ≥ 10 years and was enhanced by the booster dose. These findings support further investigation of ZV administration in early versus later age and of booster doses for elderly individuals at an appropriate interval after initial immunization against HZ. NCT01245751. © The Author 2015. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail journals.permissions@oup.com.

SINGLE- VERSUS DOUBLE-DOSE RABIES VACCINATION IN CAPTIVE AFRICAN WILD DOGS (LYCAON PICTUS).

PubMed

Connolly, Maren; Thomas, Patrick; Woodroffe, Rosie; Raphael, Bonnie L

2015-12-01

The immune responses of 35 captive African wild dogs (Lycaon pictus) to an inactivated rabies virus vaccine were evaluated. Seventeen animals received one 1-ml dose of inactivated rabies vaccine administered intramuscularly, while 18 received two 1-ml doses given simultaneously but at different injection sites. Sera were collected from all animals prior to vaccination and intermittently from a subset of animals between 3 and 49 mo postvaccination. Rabies neutralizing serum antibody titers were measured by rapid fluorescent focus inhibition testing. Within 3 mo postvaccination, all 28 animals that were tested within that time period had seroconverted. Overall, titers were significantly higher among animals given two doses of vaccine than among those given a single dose, although this difference was no longer significant by 15 mo postvaccination. Regardless of initial dose, a single administration of inactivated rabies virus vaccine resulted in long-term elevation of titers in the African wild dogs in this study. In the two individuals followed for greater than 36 mo, both (one from each group) maintained detectable titers.

Efficacy and safety of additional 200-mg dose of celecoxib in adult patients with postoperative pain following extraction of impacted third mandibular molar: a multicenter, randomized, double-blind, placebo-controlled, phase II study in Japan.

PubMed

Saito, Ken'ichi; Kaneko, Akihiro; Machii, Katsuyuki; Ohta, Hiroyoshi; Ohkura, Masayuki; Suzuki, Makoto

2012-02-01

Although third mandibular molar extraction is a widely used and validated model of acute pain for evaluating analgesic efficacy, a large proportion of patients experience moderate or severe pain following this procedure and require analgesia. Current treatment options have been associated with safety concerns and alternative therapies are sought. Our aim was to assess the efficacy and safety of an additional 200-mg dose of celecoxib, administered 5 to 12 hours after an initial 400-mg dose of the drug for the treatment of moderate or severe acute pain following extraction of an impacted third mandibular molar. This was a multicenter, randomized, double-blind, placebo-controlled, Phase II study. Patients experiencing moderate or severe pain within 1 to 2 hours following extraction of an impacted third mandibular molar received an initial 400-mg dose of celecoxib. Patients requiring additional analgesia were subsequently randomized to receive either an additional 200-mg dose of celecoxib or placebo 5 to 12 hours after the initial dose. The study was designed and conducted by Pfizer Inc. for approval of celecoxib in Japan for the indication of acute pain. The primary end point was the patient's impression of efficacy (4-category global evaluation scale). Secondary efficacy end points included pain intensity on a 4-category pain intensity scale, pain intensity on a 100-mm visual analog scale (VAS), and the pain intensity difference (100-mm VAS). In an exploratory analysis, use of rescue medication was evaluated. Primary and secondary end points were analyzed using the full analysis set. Assessment of the safety profile included a physical examination, measurement of pulse rate and blood pressure, standard 12-lead ECG, and laboratory tests. A total of 69 patients (celecoxib, 42/64 [65.6%]; placebo, 27/58 [46.6%]) received the additional dose of study medication; all completed the study without the need for rescue medication. A significantly higher proportion of patients in the celecoxib 200 mg group (41/64 [64.1%]) compared with the placebo group (15/58 [25.9%]) rated the study medication as "good" or "excellent" ≥ 2 hours after the additional dose (P < 0.0001). Pain intensity (VAS) 2 hours after the additional dose was significantly higher in the placebo group than in the celecoxib 200 mg group (P = 0.0003). The reduction in pain intensity from baseline to 2 hours after the additional dose of study medication was also significantly greater in the celecoxib 200 mg group than in the placebo group (P < 0.0001). The incidence of treatment-related, all-cause adverse events was slightly lower in patients receiving celecoxib 200 mg (20.3%) compared with placebo (31.0%). Overall, an additional 200-mg dose of celecoxib was well tolerated and efficacious in reducing the pain associated with extraction of an impacted third mandibular molar in the study population. ClinicalTrials.gov identifier: NCT01062113. Copyright © 2012 Elsevier HS Journals, Inc. All rights reserved.

Longitudinal trends in serum ferritin levels and associated factors in a national incident hemodialysis cohort.

PubMed

Kim, Taehee; Rhee, Connie M; Streja, Elani; Obi, Yoshitsugu; Brunelli, Steven M; Kovesdy, Csaba P; Kalantar-Zadeh, Kamyar

2017-02-01

The rise in serum ferritin levels among US maintenance hemodialysis patients has been attributed to higher intravenous iron administration and other changes in practice. We examined ferritin trends over time in hemodialysis patients and whether iron utilization patterns and other factors [erythropoietin-stimulating agent (ESA) prescribing patterns, inflammatory markers] were associated with ferritin trajectory. In a 5-year (January 2007–December 2011) cohort of 81 864 incident US hemodialysis patients, we examined changes in ferritin averaged over 3-month intervals using linear mixed effects models adjusted for intravenous iron dose, malnutrition and inflammatory markers. We then examined ferritin trends across strata of baseline ferritin level, dialysis initiation year, cumulative iron and ESA use in the first dialysis year and baseline hemoglobin level. In models adjusted for iron dose, malnutrition and inflammation, mean ferritin levels increased over time in the overall cohort and across the three lower baseline ferritin strata. Among patients initiating dialysis in 2007, mean ferritin levels increased sharply in the first versus second year of dialysis and again abruptly increased in the fifth year independent of iron dose, malnutrition and inflammatory markers; similar trends were observed among patients who initiated dialysis in 2008 and 2009. In analyses stratified by cumulative iron use, mean ferritin increased among groups receiving iron, but decreased in the no iron group. In analyses stratified by cumulative ESA dose and baseline hemoglobin, mean ferritin increased over time. While ferritin trends correlated with patterns of iron use, increases in ferritin over time persisted independent of intravenous iron and ESA exposure, malnutrition and inflammation.

Automatic spectral imaging protocol selection and iterative reconstruction in abdominal CT with reduced contrast agent dose: initial experience.

PubMed

Lv, Peijie; Liu, Jie; Chai, Yaru; Yan, Xiaopeng; Gao, Jianbo; Dong, Junqiang

2017-01-01

To evaluate the feasibility, image quality, and radiation dose of automatic spectral imaging protocol selection (ASIS) and adaptive statistical iterative reconstruction (ASIR) with reduced contrast agent dose in abdominal multiphase CT. One hundred and sixty patients were randomly divided into two scan protocols (n = 80 each; protocol A, 120 kVp/450 mgI/kg, filtered back projection algorithm (FBP); protocol B, spectral CT imaging with ASIS and 40 to 70 keV monochromatic images generated per 300 mgI/kg, ASIR algorithm. Quantitative parameters (image noise and contrast-to-noise ratios [CNRs]) and qualitative visual parameters (image noise, small structures, organ enhancement, and overall image quality) were compared. Monochromatic images at 50 keV and 60 keV provided similar or lower image noise, but higher contrast and overall image quality as compared with 120-kVp images. Despite the higher image noise, 40-keV images showed similar overall image quality compared to 120-kVp images. Radiation dose did not differ between the two protocols, while contrast agent dose in protocol B was reduced by 33 %. Application of ASIR and ASIS to monochromatic imaging from 40 to 60 keV allowed contrast agent dose reduction with adequate image quality and without increasing radiation dose compared to 120 kVp with FBP. • Automatic spectral imaging protocol selection provides appropriate scan protocols. • Abdominal CT is feasible using spectral imaging and 300 mgI/kg contrast agent. • 50-keV monochromatic images with 50 % ASIR provide optimal image quality.

The effects of co-administration of benzhexol on the peripheral pharmacokinetics of oral levodopa in young volunteers

PubMed Central

ROBERTS, J.; WALLER, D. G.; RENWICK, A. G.; O'SHEA, N.; MACKLIN, B. S.; BULLING, M.

1996-01-01

1 The effects of benzhexol on the absorption and pharmacokinetics of an oral dose of levodopa have been studied in 10 young healthy volunteers. Subjects were given a suspension of levodopa (250 mg) 90 min after either benzhexol (5 mg) or placebo in a randomized cross over design with doses separated by at least 1 week; on each occasion carbidopa was given 1 h before and 5 h after the dose of levodopa. Soluble paracetamol and radiolabelled DTPA were given with the levodopa as markers of gastric emptying. 2 Most subjects showed two peaks in the levodopa plasma concentration–time curve on the placebo day, with the second minor peak occurring 1–2 h after the dose. After benzhexol administration all subjects showed two or more peak levodopa concentrations in plasma. Benzhexol administration caused a significant decrease in the maximum concentration (43%; P<0.05) of the initial peak and an increase (22%; P<0.1) in the maximum concentration of the second peak. This change in absorption profile caused by benzhexol significantly altered the ratios of the second peak compared with the initial peak for both the maximum concentrations (P<0.02) and for the AUC values (P<0.05). Benzhexol administration did not affect the total AUC of levodopa (7.30±1.09 vs 7.19±1.26 μg ml−1 h; means±s.d.). 3 The plasma concentration–time curves for paracetamol showed similar profiles to those for levodopa and the ratios of the peak concentrations and AUC values for the second peak compared with the initial peak were increased significantly by benzhexol administration (P<0.05). The total AUC of paracetamol was not affected by benzhexol administration (39.4±8.2 vs 40.0±8.9 μg ml−1 h; mean±s.d.) 4 Benzhexol altered the gastric emptying profile, shown by γ-scintigraphy, with a reduced extent of initial emptying prior to the establishment of the plateau which is characteristic of levodopa administration in the fasting state. In consequence the ratio of the second to the initial phase of emptying was significantly higher (P<0.01) following benzhexol treatment. 5 Benzhexol reduces the initial phase of gastric emptying after a dose of levodopa so that there is a decrease in the initial peak and a greater proportion of the dose is absorbed subsequently following the second phase of gastric emptying which occurs approximately 1 h later. Theoretically, this altered concentration-time profile could be an advantage for some patients with Parkinson's disease. PMID:8730980

Opioid Patient Controlled Analgesia (PCA) use during the Initial Experience with the IMPROVE PCA Trial: A Phase III Analgesic Trial for Hospitalized Sickle Cell Patients with Painful Episodes

PubMed Central

Dampier, Carlton D.; Smith, Wally R.; Kim, Hae-Young; Wager, Carrie Greene; Bell, Margaret C.; Minniti, Caterina P.; Keefer, Jeffrey; Hsu, Lewis; Krishnamurti, Lakshmanan; Mack, A. Kyle; McClish, Donna; McKinlay, Sonja M.; Miller, Scott T.; Osunkwo, Ifeyinwa; Seaman, Phillip; Telen, Marilyn J.; Weiner, Debra L.

2015-01-01

Opioid analgesics administered by patient-controlled analgesia (PCA) are frequently used for pain relief in children and adults with sickle cell disease (SCD) hospitalized for persistent vaso-occlusive pain, but optimum opioid dosing is not known. To better define PCA dosing recommendations, a multi-center phase III clinical trial was conducted comparing two alternative opioid PCA dosing strategies (HDLI-higher demand dose with low constant infusion or LDHI- lower demand dose and higher constant infusion) in 38 subjects who completed randomization prior to trial closure. Total opioid utilization (morphine equivalents, mg/kg) in 22 adults was 11.6 ± 2.6 and 4.7 ± 0.9 in the HDLI and in the LDHI arms, respectively, and in 12 children it was 3.7 ± 1.0 and 5.8 ± 2.2, respectively. Opioid-related symptoms were mild and similar in both PCA arms (mean daily opioid symptom intensity score: HDLI 0.9 ± 0.1, LDHI 0.9 ± 0.2). The slow enrollment and early study termination limited conclusions regarding superiority of either treatment regimen. This study adds to our understanding of opioid PCA usage in SCD. Future clinical trial protocol designs for opioid PCA may need to consider potential differences between adults and children in PCA usage. PMID:21953763

Opioid patient controlled analgesia use during the initial experience with the IMPROVE PCA trial: a phase III analgesic trial for hospitalized sickle cell patients with painful episodes.

PubMed

Dampier, Carlton D; Smith, Wally R; Kim, Hae-Young; Wager, Carrie Greene; Bell, Margaret C; Minniti, Caterina P; Keefer, Jeffrey; Hsu, Lewis; Krishnamurti, Lakshmanan; Mack, A Kyle; McClish, Donna; McKinlay, Sonja M; Miller, Scott T; Osunkwo, Ifeyinwa; Seaman, Phillip; Telen, Marilyn J; Weiner, Debra L

2011-12-01

Opioid analgesics administered by patient-controlled analgesia (PCA)are frequently used for pain relief in children and adults with sickle cell disease (SCD) hospitalized for persistent vaso-occlusive pain, but optimum opioid dosing is not known. To better define PCA dosing recommendations,a multi-center phase III clinical trial was conducted comparing two alternative opioid PCA dosing strategies (HDLI—higher demand dose with low constant infusion or LDHI—lower demand dose and higher constant infusion) in 38 subjects who completed randomization prior to trial closure. Total opioid utilization (morphine equivalents,mg/kg) in 22 adults was 11.6 ± 2.6 and 4.7 ± 0.9 in the HDLI andin the LDHI arms, respectively, and in 12 children it was 3.7 ± 1.0 and 5.8 ± 2.2, respectively. Opioid-related symptoms were mild and similar in both PCA arms (mean daily opioid symptom intensity score: HDLI0.9 ± 0.1, LDHI 0.9 ± 0.2). The slow enrollment and early study termination limited conclusions regarding superiority of either treatment regimen. This study adds to our understanding of opioid PCA usage in SCD. Future clinical trial protocol designs for opioid PCA may need to consider potential differences between adults and children in PCA usage.

Improving blood pressure control: increase the dose of diuretic or switch to a fixed-dose angiotensin receptor blocker/diuretic? the valsartan hydrochlorothiazide diuretic for initial control and titration to achieve optimal therapeutic effect (Val-DICTATE) trial.

PubMed

White, William B; Calhoun, David A; Samuel, Rita; Taylor, Addison A; Zappe, Dion H; Purkayastha, Das

2008-06-01

To assess the strategy of increasing the dose of a diuretic compared with using an angiotensin receptor blocker in combination with a diuretic, the authors performed a multicenter, randomized, parallel group trial in hypertensive patients (baseline blood pressure [BP], 153/97 mm Hg) whose BP remained uncontrolled on initial low-dose diuretic monotherapy (hydrochlorothiazide [HCTZ] 12.5 mg Hg). Patients with stage 1 and 2 hypertension were randomized to treatment with valsartan/HCTZ (160/12.5 mg) or to doubling of the HCTZ dose (25 mg). The primary end point was the percentage of patients whose clinic BP values were <140/90 mm Hg following 4 weeks of double-blind therapy. A significantly higher proportion (P<.001) of hypertensive patients met BP control levels in the valsartan/HCTZ (160/12.5 mg) group compared with the HCTZ 25 mg group (37% vs 16%). Changes from baseline in BP were significantly greater (P<.001) for both systolic BP and diastolic BP in the combination therapy arm compared with the diuretic monotherapy arm (-12. 4/-7.5 mm Hg in valsartan/HCTZ 160/12.5 mg group vs -5.6/-2.1 mm Hg in HCTZ 25 mg group). Tolerability and adverse events were similar in the 2 treatment groups. This study suggests that in the management of hypertension, utilizing an angiotensin receptor blocker/diuretic combination was more effective in lowering BP and achieving BP goals when compared with increasing the dose of the diuretic.

Warfarin and bosentan interaction in a patient with pulmonary hypertension secondary to bilateral pulmonary emboli.

PubMed

Spangler, Mikayla L; Saxena, Shailendra

2010-01-01

Bosentan is an endothelin-receptor antagonist that reportedly induces both cytochrome P450 (CYP) 3A4 and CYP2C9 enzymes, which are also involved in warfarin metabolism. We present a case report describing a probable drug interaction between warfarin and bosentan in a patient with pulmonary hypertension. A 52-year-old black female (weight, 77 kg) diagnosed with pulmonary hypertension secondary to bilateral pulmonary emboli had a stable international normalized ratio (INR; target range, 2-3) with a weekly warfarin dose of 52.5 mg for 2 months before the initiation of bosentan therapy. Other concurrent medications included telmisartan/ hydrochlorothiazide 40/12.5 mg once daily and a daily multivitamin (which contained no vitamin K). Three weeks after starting bosentan 62.5 mg BID, a therapeutic INR concentration was reached with a weekly warfarin dose 14% higher (an increase of 7.5 mg/wk) than her weekly warfarin dose before initiation of bosentan. After a brief discontinuation (7 days) and retitration of bosentan and warfarin, the final weekly warfarin dose (75 mg/wk) was 43% greater (an increase of 22.5 mg/wk) than the previously stable dose, which enabled the patient to reach her therapeutic INR goal range of 2 to 3. Bosentan has CYP3A4- and CYP2C9-inducing properties and is therefore likely to cause decreased concentrations of warfarin. We describe here a probable drug interaction between bosentan and warfarin that resulted in a 43% increase in warfarin dose to maintain the patient's therapeutic INR.

A prospective randomized study of the efficacy and cost-effectiveness of high and low dose regimens of I-131 treatment in hyperthyroidism.

PubMed

Pusuwan, Pawana; Tuntawiroon, Malulee; Sritongkul, Nopamol; Chaudakshetrin, Pachee; Nopmaneejumruslers, Cherdchai; Komoltri, Chulalak; Thepamongkhol, Kullathorn; Khiewvan, Benjapa; Tuchinda, Pongpija; Sriussadaporn, Sutin

2011-03-01

To compare the efficacy and cost-effectiveness of high and low dose regimens of I-131 treatment in patients with hyperthyroidism. One hundred fifty patients with proven hyperthyroidism were randomly allocated into the high (74 patients) and low (76 patients) dose regimen of I-131 treatment. Four patients of the high dose group and one patient of the low dose group were excluded because of lost follow-up. A gland-specific dosage was calculated on the estimated weight of thyroid gland and 24-hour I-131 uptake. The high and low I-131 dose regimens were 150 microCi/gm and 100 microCi/gm, respectively. The first mean radioiodine activity administered to the high and low dose group was 10.2 and 8 mCi, respectively. Repeated treatment was given to 25 patients of the high dose group and 40 patients of the low dose group. Clinical outcome and calculated costs for outpatient attendances, and laboratory tests together with initial and subsequent treatments were evaluated for one year after I-131 treatment. Elimination of hyperthyroidism that resulted in either euthyroidism or hypothyroidism was classified as therapeutic success. The cost effectiveness was also compared. At 6 months after treatment, 45 (64.3%) patients receiving high dose and 59 (78.7%) patients receiving low dose were hyperthyroidism. Clinical outcome at one year showed persistence of hyperthyroidism in 21 (30%) patients of the high dose regimen and 36 (48%) patients of the low dose regimen. At one year post treatment, it was demonstrated that the high dose regimen could eliminate hyperthyroidism in a significantly shorter time than the low dose regimen, i.e., 259.6 days and 305.5 days, respectively, p = 0.008). For the persistent hyperthyroid patients, the average total cost of treatment in the low dose group was significantly higher than that of the high dose group, i.e., 13,422.78 baht and 10,942.79 baht, respectively; p = 0.050). A high dose regimen of radioactive iodine treatment is more effective than the low dose regimen. The successful outcome of a high dose regimen occurred significantly earlier than that of the low dose regimen. For the persistent hyperthyroid patients, the average total cost in the low dose group was significantly higher than that of the high dose group.

The Randomized CRM: An Approach to Overcoming the Long-Memory Property of the CRM

PubMed Central

Koopmeiners, Joseph S.; Wey, Andrew

2017-01-01

The primary object of a phase I clinical trial is to determine the maximum tolerated dose (MTD). Typically, the MTD is identified using a dose-escalation study, where initial subjects are treated at the lowest dose level and subsequent subjects are treated at progressively higher dose levels until the MTD is identified. The continual reassessment method (CRM) is a popular model-based dose-escalation design, which utilizes a formal model for the relationship between dose and toxicity to guide dose-finding. Recently, it was shown that the CRM has a tendency to get “stuck” on a dose-level, with little escalation or de-escalation in the late stages of the trial, due to the long-memory property of the CRM. We propose the randomized CRM (rCRM), which introduces random escalation and de-escalation into the standard CRM dose-finding algorithm, as well as a hybrid approach that incorporates escalation and de-escalation only when certain criteria are met. Our simulation results show that both the rCRM and the hybrid approach reduce the trial-to-trial variability in the number of cohorts treated at the MTD but that the hybrid approach has a more favorable trade-off with respect to the average number treated at the MTD. PMID:28340333

The Randomized CRM: An Approach to Overcoming the Long-Memory Property of the CRM.

PubMed

Koopmeiners, Joseph S; Wey, Andrew

2017-01-01

The primary object of a Phase I clinical trial is to determine the maximum tolerated dose (MTD). Typically, the MTD is identified using a dose-escalation study, where initial subjects are treated at the lowest dose level and subsequent subjects are treated at progressively higher dose levels until the MTD is identified. The continual reassessment method (CRM) is a popular model-based dose-escalation design, which utilizes a formal model for the relationship between dose and toxicity to guide dose finding. Recently, it was shown that the CRM has a tendency to get "stuck" on a dose level, with little escalation or de-escalation in the late stages of the trial, due to the long-memory property of the CRM. We propose the randomized CRM (rCRM), which introduces random escalation and de-escalation into the standard CRM dose-finding algorithm, as well as a hybrid approach that incorporates escalation and de-escalation only when certain criteria are met. Our simulation results show that both the rCRM and the hybrid approach reduce the trial-to-trial variability in the number of cohorts treated at the MTD but that the hybrid approach has a more favorable tradeoff with respect to the average number treated at the MTD.

Hepatitis A, B, and A/B vaccination series completion among US adults: a claims-based analysis.

PubMed

Ghaswalla, Parinaz K; Patterson, Brandon J; Cheng, Wendy Y; Duchesneau, Emilie; Macheca, Monica; Duh, Mei Sheng

2018-06-20

Hepatitis A and B disease burden persists in the US. We assessed hepatitis A and hepatitis B vaccination series completion rates among 350,240 commercial/Medicare and 12,599 Medicaid enrollees aged ≥19 years. A vaccination series was considered as completed provided that the minimum interval between doses, as defined by the CDC, and the minimum number of doses were reached. We stratified completion rates by vaccine type (i.e. monovalent or bivalent) at initial vaccination for each cohort. In the commercial/Medicare cohort, the series completion rate was 32.0% for hepatitis A and 39.6% for hepatitis B among those who initiated with a monovalent vaccine, and it was 36.2% for hepatitis A and 48.9% for hepatitis B among those who initiated with a bivalent vaccine. In the Medicaid cohort, the series completion rate was 21.0% for hepatitis A and 24.0% for hepatitis B among those who initiated with a monovalent vaccine, and it was 19.0% for hepatitis A and 24.6% for hepatitis B among those who initiated with a bivalent vaccine. In conclusion, hepatitis A and B vaccination series completion rates were low, and appeared to be lower among Medicaid than among commercial/Medicare enrollees. Commercial/Medicare enrollees who initiated with a bivalent vaccine had higher series completion rates than those who initiated with monovalent vaccines - an observation that was not made among Medicaid enrollees.

Impact of Including Higher Actinides in Fast Reactor Transmutation Analyses

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

B. Forget; M. Asgari; R. Ferrer

2007-09-01

Previous fast reactor transmutation studies generally disregarded higher mass minor actinides beyond Cm-246 due to various considerations including deficiencies in nuclear cross-section data. Although omission of these higher mass actinides does not significantly impact the neutronic calculations and fuel cycle performance parameters follow-on neutron dose calculations related to fuel recycling, transportation and handling are significantly impacted. This report shows that including the minor actinides in the equilibrium fast reactor calculations will increase the predicted neutron emission by about 30%. In addition a sensitivity study was initiated by comparing the impact of different cross-section evaluation file for representing these minor actinides.

Qualitative and quantitative approaches in the dose-response assessment of genotoxic carcinogens.

PubMed

Fukushima, Shoji; Gi, Min; Kakehashi, Anna; Wanibuchi, Hideki; Matsumoto, Michiharu

2016-05-01

Qualitative and quantitative approaches are important issues in field of carcinogenic risk assessment of the genotoxic carcinogens. Herein, we provide quantitative data on low-dose hepatocarcinogenicity studies for three genotoxic hepatocarcinogens: 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx), 2-amino-3-methylimidazo[4,5-f]quinoline (IQ) and N-nitrosodiethylamine (DEN). Hepatocarcinogenicity was examined by quantitative analysis of glutathione S-transferase placental form (GST-P) positive foci, which are the preneoplastic lesions in rat hepatocarcinogenesis and the endpoint carcinogenic marker in the rat liver medium-term carcinogenicity bioassay. We also examined DNA damage and gene mutations which occurred through the initiation stage of carcinogenesis. For the establishment of points of departure (PoD) from which the cancer-related risk can be estimated, we analyzed the above events by quantitative no-observed-effect level and benchmark dose approaches. MeIQx at low doses induced formation of DNA-MeIQx adducts; somewhat higher doses caused elevation of 8-hydroxy-2'-deoxyquanosine levels; at still higher doses gene mutations occurred; and the highest dose induced formation of GST-P positive foci. These data indicate that early genotoxic events in the pathway to carcinogenesis showed the expected trend of lower PoDs for earlier events in the carcinogenic process. Similarly, only the highest dose of IQ caused an increase in the number of GST-P positive foci in the liver, while IQ-DNA adduct formation was observed with low doses. Moreover, treatment with DEN at low doses had no effect on development of GST-P positive foci in the liver. These data on PoDs for the markers contribute to understand whether genotoxic carcinogens have a threshold for their carcinogenicity. The most appropriate approach to use in low dose-response assessment must be approved on the basis of scientific judgment. © The Author 2015. 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.

Variation in Prescribing Patterns and Therapeutic Drug Monitoring of Intravenous Busulfan in Pediatric Hematopoietic Cell Transplant Recipients

PubMed Central

McCune, Jeannine S.; Baker, K. Scott; Blough, David K.; Gamis, Alan; Bemer, Meagan J.; Kelton-Rehkopf, Megan C.; Winter, Laura; Barrett, Jeffrey S.

2016-01-01

Personalizing intravenous (IV) busulfan doses in children using therapeutic drug monitoring (TDM) is an integral component of hematopoietic cell transplant. The authors sought to characterize initial dosing and TDM of IV busulfan, along with factors associated with busulfan clearance, in 729 children who underwent busulfan TDM from December 2005 to December 2008. The initial IV busulfan dose in children weighing ≤12 kg ranged 4.8-fold, with only 19% prescribed the package insert dose of 1.1 mg/kg. In those children weighing >12 kg, the initial dose ranged 5.4-fold, and 79% were prescribed the package insert dose. The initial busulfan dose achieved the target exposure in only 24.3% of children. A wide range of busulfan exposures were targeted for children with the same disease (eg, 39 target busulfan exposures for the 264 children diagnosed with acute myeloid leukemia). Considerable heterogeneity exists regarding when TDM is conducted and the number of pharmacokinetic samples obtained. Busulfan clearance varied by age and dosing frequency but not by underlying disease. The authors’ group is currently evaluating how using population pharmacokinetics to optimize initial busulfan dose and TDM (eg, limited sampling schedule in conjunction with maximum a posteriori Bayesian estimation) may affect clinical outcomes in children. PMID:23444282

Production, PET performance and dosimetric considerations of 134Ce/134La, an Auger electron and positron-emitting generator for radionuclide therapy.

PubMed

Lubberink, Mark; Lundqvist, Hans; Tolmachev, Vladimir

2002-02-21

We propose the use of the Auger electron and positron-emitting generator 134Ce/134La (half-lives 3.16 d and 6.45 min) for radionuclide therapy. It combines emission of high-energy beta particles with Auger electrons. The high-energy beta particles have similar energies as those emitted by 90Y. Many cancer patients receiving radionuclide therapy have both bulk tumours, which are best treated with high-energy beta particles, and single spread cells or micrometastasis, which are preferably treated with low-energy electrons such as Auger and conversion electrons. Furthermore, the positron-emitting 134La can be used to study kinetics and dosimetry using PET. Production and PET performance were investigated and theoretical dosimetry calculations were made. PET resolution, recovery and quantitative accuracy were slightly degraded for 134La compared to 18F. 134Ce/134La absorbed doses to single cells were higher than absorbed doses from 90Y and 111In. Absorbed doses to spheres representing bulk tumours were almost as high as for 90Y, and a factor 10 higher than for 111In. Whole-body absorbed doses, based on kinetics of the somatostatin analogue octreotide, were higher for 134Ce/134La than for 90Y because of the 134La annihilation photons. This initial study of the therapeutic possibilities of 134Ce/134La is encouraging and justifies further investigations.

UNUSUAL WARFARIN DOSE TO ACHIEVE THERAPEUTIC INR IN A 4-MONTH OLD CHILD: NON-GENETICS RISK FACTORS ARE STILL A CHALLENGE.

PubMed

Okumura, Lucas Miyake; Negretto, Giovanna Webster; Carvalho, Clarissa Gutiérrez

2017-01-01

To report a case of a 4-month old girl that required 0.7 mg/kg/day (5 mg) of warfarin and discuss relevant risk factors for requiring higher doses. In November 2015, a 5 kg female infant (36-week preterm) was admitted to the hospital due to status epilepticus and fever. Diazepam, phenytoin and ceftriaxone were prescribed. Cerebrospinal fluid contained 7 leukocytes, 150 mg/dL proteins, 1 mg/dL glucose and gram positive cocci were observed. Cranial tomography suggested hypodense signs in the cerebellum, right temporal lobe and left basal nuclei, which was consistent with pneumococcal meningitis-induced infectious vasculitis. She required low molecular weight heparin and warfarin for post-encephalitis thrombosis. About 10 days were required to achieve therapeutic INR, and warfarin was adjusted five times since the initial prescription. The risk factors for higher warfarin doses were age and enteral tube feeding. Phenobarbital and prednisone might also have contributed with one of the highest warfarin dose ever reported. Despite current importance given to genetics testing, clinicians should attempt to identify common contributing factors for prolonged non-therapeutic INR, to minimize the risk of coagulation, and to reduce costs of hospital stay and laboratory exams.

Iterative reconstruction for CT perfusion with a prior-image induced hybrid nonlocal means regularization: Phantom studies

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

Li, Bin; Lyu, Qingwen; Ma, Jianhua

2016-04-15

Purpose: In computed tomography perfusion (CTP) imaging, an initial phase CT acquired with a high-dose protocol can be used to improve the image quality of later phase CT acquired with a low-dose protocol. For dynamic regions, signals in the later low-dose CT may not be completely recovered if the initial CT heavily regularizes the iterative reconstruction process. The authors propose a hybrid nonlocal means (hNLM) regularization model for iterative reconstruction of low-dose CTP to overcome the limitation of the conventional prior-image induced penalty. Methods: The hybrid penalty was constructed by combining the NLM of the initial phase high-dose CT inmore » the stationary region and later phase low-dose CT in the dynamic region. The stationary and dynamic regions were determined by the similarity between the initial high-dose scan and later low-dose scan. The similarity was defined as a Gaussian kernel-based distance between the patch-window of the same pixel in the two scans, and its measurement was then used to weigh the influence of the initial high-dose CT. For regions with high similarity (e.g., stationary region), initial high-dose CT played a dominant role for regularizing the solution. For regions with low similarity (e.g., dynamic region), the regularization relied on a low-dose scan itself. This new hNLM penalty was incorporated into the penalized weighted least-squares (PWLS) for CTP reconstruction. Digital and physical phantom studies were performed to evaluate the PWLS-hNLM algorithm. Results: Both phantom studies showed that the PWLS-hNLM algorithm is superior to the conventional prior-image induced penalty term without considering the signal changes within the dynamic region. In the dynamic region of the Catphan phantom, the reconstruction error measured by root mean square error was reduced by 42.9% in PWLS-hNLM reconstructed image. Conclusions: The PWLS-hNLM algorithm can effectively use the initial high-dose CT to reconstruct low-dose CTP in the stationary region while reducing its influence in the dynamic region.« less

Treatment with α-Lipoic Acid over 16 Weeks in Type 2 Diabetic Patients with Symptomatic Polyneuropathy Who Responded to Initial 4-Week High-Dose Loading

PubMed Central

Garcia-Alcala, Hector; Santos Vichido, Celia Isabel; Islas Macedo, Silverio; Genestier-Tamborero, Christelle Nathalie; Minutti-Palacios, Marissa; Hirales Tamez, Omara; García, Carlos; Ziegler, Dan

2015-01-01

Effective treatment of diabetic sensorimotor polyneuropathy remains a challenge. To assess the efficacy and safety of α-lipoic acid (ALA) over 20 weeks, we conducted a multicenter randomized withdrawal open-label study, in which 45 patients with type 2 diabetes and symptomatic polyneuropathy were initially treated with ALA (600 mg tid) for 4 weeks (phase 1). Subsequently, responders were randomized to receive ALA (600 mg qd; n = 16) or to ALA withdrawal (n = 17) for 16 weeks (phase 2). During phase 1, the Total Symptom Score (TSS) decreased from 8.9 ± 1.8 points to 3.46 ± 2.0 points. During phase 2, TSS improved from 3.7 ± 1.9 points to 2.5 ± 2.5 points in the ALA treated group (p < 0.05) and remained unchanged in the ALA withdrawal group. The use of analgesic rescue medication was higher in the ALA withdrawal group than ALA treated group (p < 0.05). In conclusion, in type 2 diabetic patients with symptomatic polyneuropathy who responded to initial 4-week high-dose (600 mg tid) administration of ALA, subsequent treatment with ALA (600 mg qd) over 16 weeks improved neuropathic symptoms, whereas ALA withdrawal was associated with a higher use of rescue analgesic drugs. This trial is registered with ClinicalTrials.gov Identifier: NCT02439879. PMID:26345602

Assessment of Intervention by a Palliative Care Team Working in a Japanese General Hospital: A Retrospective Study.

PubMed

Amano, Koji; Morita, Tatsuya; Tatara, Ryohei; Katayama, Hirofumi; Aiki, Sayo; Kitada, Namiki; Fumimoto, Hiromi; Sato, Emi

2015-09-01

Our objective was to explore the effectiveness of a palliative care team (PCT) by investigating potential differences in opioid prescription between patients who had had PCT involvement before admission to an inpatient hospice and those who had not. A total of 221 patients met the criteria; they were divided into an intervention group (n = 140) and a control group (n = 81). The daily dose of opioid before admission to the hospice was significantly higher in the intervention group (P < .001). The difference between the maximum opioid dose and the initial dose, the rate of increase in opioids until death, and the length of stay in the hospice were not significantly different between the groups. A PCT contributes to more appropriate use of opioids before admission to a hospice. © The Author(s) 2014.

Thrombelastography-Based Dosing of Enoxaparin for Thromboprophylaxis in Trauma and Surgical Patients: A Randomized Clinical Trial.

PubMed

Connelly, Christopher R; Van, Philbert Y; Hart, Kyle D; Louis, Scott G; Fair, Kelly A; Erickson, Anfin S; Rick, Elizabeth A; Simeon, Erika C; Bulger, Eileen M; Arbabi, Saman; Holcomb, John B; Moore, Laura J; Schreiber, Martin A

2016-10-19

Prophylactic enoxaparin is used to prevent venous thromboembolism (VTE) in surgical and trauma patients. However, VTE remains an important source of morbidity and mortality, potentially exacerbated by antithrombin III or anti-Factor Xa deficiencies and missed enoxaparin doses. Recent data suggest that a difference in reaction time (time to initial fibrin formation) greater than 1 minute between heparinase and standard thrombelastogram (TEG) is associated with a decreased risk of VTE. To evaluate the effectiveness of TEG-adjusted prophylactic enoxaparin dosing among trauma and surgical patients. This randomized clinical trial, conducted from October 2012 to May 2015, compared standard dosing (30 mg twice daily) with TEG-adjusted enoxaparin dosing (35 mg twice daily) for 185 surgical and trauma patients screened for VTE at 3 level I trauma centers in the United States. The incidence of VTE, bleeding complications, anti-Factor Xa deficiency, and antithrombin III deficiency. Of the 185 trial participants, 89 were randomized to the control group (median age, 44.0 years; 55.1% male) and 96 to the intervention group (median age, 48.5 years; 74.0% male). Patients in the intervention group received a higher median enoxaparin dose than control patients (35 mg vs 30 mg twice daily; P < .001). Anti-Factor Xa levels in intervention patients were not higher than levels in control patients until day 6 (0.4 U/mL vs 0.21 U/mL; P < .001). Only 22 patients (11.9%) achieved a difference in reaction time greater than 1 minute, which was similar between the control and intervention groups (10.4% vs 13.5%; P = .68). The time to enoxaparin initiation was similar between the control and intervention groups (median [range] days, 1.0 [0.0-2.0] vs 1.0 [1.0-2.0]; P = .39), and the number of patients who missed at least 1 dose was also similar (43 [48.3%] vs 54 [56.3%]; P = .30). Rates of VTE (6 [6.7%] vs 6 [6.3%]; P > .99) were similar, but the difference in bleeding complications (5 [5.6%] vs 13 [13.5%]; P = .08) was not statistically significant. Antithrombin III and anti-Factor Xa deficiencies and hypercoagulable TEG parameters, including elevated coagulation index (>3), maximum amplitude (>74 mm), and G value (>12.4 dynes/cm2), were prevalent in both groups. Identified risk factors for VTE included older age (61.0 years vs 46.0 years; P = .04), higher body mass index (calculated as weight in kilograms divided by height in meters squared; 30.6 vs 27.1; P = .03), increased Acute Physiology and Chronic Health Evaluation II score (8.5 vs 7.0; P = .03), and increased percentage of missed doses per patient (14.8% vs 2.5%; P = .05). The incidence of VTE was low and similar between groups; however, few patients achieved a difference in reaction time greater than 1 minute. Antithrombin III deficiencies and hypercoagulable TEG parameters were prevalent among patients with VTE. Low VTE incidence may be due to an early time to enoxaparin initiation and an overall healthier and less severely injured study population than previously reported. clinicaltrials.gov Identifier: NCT00990236.

Impact of Hispanic or Asian ethnicity on the treatment outcomes of chronic hepatitis C: results from the WIN-R trial.

PubMed

Hu, Ke-Qin; Freilich, Bradley; Brown, Robert S; Brass, Clifford; Jacobson, Ira M

2011-09-01

African American ethnicity is a well-described negative predictor of treatment outcome for chronic hepatitis C (CHC); however, less is known about the influence of Hispanic and Asian ethnicity. The aim of this subanalysis of the Weight-based Dosing of PegINterferon α-2b and Ribavirin (WIN-R) study was to assess the impact of Asian (n=118), Hispanic (n=289), and white (n=3919) ethnicity on CHC treatment outcomes. WIN-R was an investigator-initiated trial in which patients with CHC received pegylated interferon α-2b (1.5 μg/kg/wk) plus a fixed ribavirin dose (800 mg/d) or a weight-based ribavirin dose (800 to 1400 mg/d) for 24 or 48 weeks. Sustained virologic response was higher in Asian patients than in white patients (56% vs 46%, P=0.041), and higher in Asian and white patients than in Hispanic patients (56% vs 35%, P=0.0001; and 46% vs 35%, P=0.0002, respectively). In genotype 1 patients, sustained virologic response was higher in white and Asian patients than in Hispanic patients (36% and 45% vs 25%, P<0.001 for both comparisons); however, in genotype 2/3 patients, there were no significant differences among ethnic groups. Psychiatric adverse events were less common and anemia was more common in Asians than in white or Hispanic patients. Ribavirin dose reductions were less frequent in Hispanic patients than in white patients, whereas pegylated interferonα-2b dose reductions were more common in white patients than Hispanic patients. These observations highlight the importance of ethnicity as an integral component of the tailored treatment approach to CHC.

Nasal deposition of ciclesonide nasal aerosol and mometasone aqueous nasal spray in allergic rhinitis patients.

PubMed

Emanuel, Ivor A; Blaiss, Michael S; Meltzer, Eli O; Evans, Philip; Connor, Alyson

2014-01-01

Sensory attributes of intranasal corticosteroids, such as rundown to the back of the throat, may influence patient treatment preferences. This study compares the nasal deposition and nasal retention of a radiolabeled solution of ciclesonide nasal aerosol (CIC-hydrofluoroalkane [HFA]) with a radiolabeled suspension of mometasone furoate monohydrate aqueous nasal spray (MFNS) in subjects with either perennial allergic rhinitis (AR) or seasonal AR. In this open-label, single-dose, randomized, crossover scintigraphy study, 14 subjects with symptomatic AR received a single dose of radiolabeled 74-μg CIC-HFA (37 μg/spray, 1 spray/each nostril) via a nasal metered-dose inhaler or a single dose of radiolabeled 200-μg MFNS (50 μg/spray, 2 sprays/each nostril), with a minimum 5-day washout period between treatments. Initial deposition (2 minutes postdose) of radiolabeled CIC-HFA and MFNS in the nasal cavity, nasopharynx, and on nasal wipes, and retention of radioactivity in the nasal cavity and nasal run-out on nasal wipes at 2, 4, 6, 8, and 10 minutes postdose were quantified with scintigraphy. At 2 and 10 minutes postdose, deposition of radiolabeled CIC-HFA was significantly higher in the nasal cavity versus radiolabeled MFNS (99.42% versus 86.50% at 2 minutes, p = 0.0046; and 81.10% versus 54.31% at 10 minutes, p < 0.0001, respectively; p values unadjusted for multiplicity). Deposition of radioactivity on nasal wipes was significantly higher with MFNS versus CIC-HFA at all five time points, and posterior losses of radiolabeled formulation were significantly higher with MFNS at 6, 8, and 10 minutes postdose. In this scintigraphic study, significantly higher nasal deposition and retention of radiolabeled aerosol CIC-HFA were observed versus radiolabeled aqueous MFNS in subjects with AR.

Oral fluid and plasma 3,4-methylenedioxymethamphetamine (MDMA) and metabolite correlation after controlled oral MDMA administration.

PubMed

Desrosiers, Nathalie A; Barnes, Allan J; Hartman, Rebecca L; Scheidweiler, Karl B; Kolbrich-Spargo, Erin A; Gorelick, David A; Goodwin, Robert S; Huestis, Marilyn A

2013-05-01

Oral fluid (OF) offers a noninvasive sample collection for drug testing. However, 3,4-methylenedioxymethamphetamine (MDMA, ecstasy) in OF has not been adequately characterized in comparison to plasma. We administered oral low-dose (1.0 mg/kg) and high-dose (1.6 mg/kg) MDMA to 26 participants and collected simultaneous OF and plasma specimens for up to 143 h after dosing. We compared OF/plasma (OF/P) ratios, time of initial detection (t first), maximal concentrations (C max), time of peak concentrations (t max), time of last detection (t last), clearance, and 3,4-methylenedioxyamphetamine (MDA)-to-MDMA ratios over time. For OF MDMA and MDA, C max was higher, t last was later, and clearance was slower compared to plasma. For OF MDA only, t first was later compared to plasma. Median (range) OF/P ratios were 5.6 (0.1-52.3) for MDMA and 3.7 (0.7-24.3) for MDA. OF and plasma concentrations were weakly but significantly correlated (MDMA: R(2) = 0.438, MDA: R(2) = 0.197, p < 0.0001). Median OF/P ratios were significantly higher following high dose administration: MDMA low = 5.2 (0.1-40.4), high = 6.0 (0.4-52.3, p < 0.05); MDA low = 3.3 (0.7-17.1), high = 4.1 (0.9-24.3, p < 0.001). There was a large inter-subject variation in OF/P ratios. The MDA/MDMA ratios in plasma were higher than those in OF (p < 0.001), and the MDA/MDMA ratios significantly increased over time in OF and plasma. The MDMA and MDA concentrations were higher in OF than in plasma. OF and plasma concentrations were correlated, but large inter-subject variability precludes the estimation of plasma concentrations from OF.

Functional outcomes following the prosthetic training phase of rehabilitation after dysvascular lower extremity amputation

PubMed Central

Christiansen, Cory; Fields, Thomas; Lev, Guy; Stephenson, Ryan O.; Stevens-Lapsley, Jennifer E.

2015-01-01

Objective To describe physical function outcomes and modes of physical therapy intervention for a cohort of patients with dysvascular lower extremity amputation (LEA) during the prosthetic training phase of rehabilitation. Design A retrospective cohort study. Setting Physical rehabilitation clinics at a Veterans Affairs Medical Center and a University Hospital. Patients Forty-two patients (38 men, 4 women, age 60.2±8.4 years) who completed outpatient physical therapy rehabilitation with prosthetic training after dysvascular LEA. Methods All patients underwent a prosthetic training phase of rehabilitation, with standardized outcome measures performed at initiation and discharge. Main Outcome Measures Performance-based physical function measures included: Two-Minute Walk (2MW), Timed-Up and Go (TUG), and 5-meter gait speed. Self-report physical function measures included: the Prosthesis Evaluation Questionnaire – Mobility Section (PEQ-MS) and the Patient-Specific Functional Scale (PSFS). Rehabilitation dose was tracked as total number of clinic visits, rehabilitation duration, and specific intervention modes. Results There were significant improvements in 2MW (mean±SD) [67.5±29.9 m (initial) and 103.3±45.8 m (discharge) (p<0.001)], gait speed [0.58±0.27 m/s (initial) and 0.88±0.39 m/s (discharge) (p<0.001)], TUG [34.8±21.3 s (initial) and 18.6±13.9 s (discharge) (p<0.001)], PEQ-MS [2.2±0.9 (initial) and 2.8±0.8 (discharge) (p<0.001)], and PSFS [3.2±2.0 (initial) and 5.9±2.3 (discharge) (p<0.001)]. Performance-based (TUG) and self-report (PEQ-MS) changes in functional mobility from initial exam to discharge had low or no correlations with rehabilitation dose measures. Number of clinic visits was 12.7±13.1 and rehabilitation duration was 13.7±16.8 weeks. Conclusions Significant improvements in performance-based and self-report measures of physical function occurred during the prosthetic training phase of physical rehabilitation following dysvascular major LEA. Despite improvements in function, gait speed and TUG outcomes remained below clinically important thresholds, indicating patients were limited in community ambulation and at risk for falls. Lack of moderate or higher correlation between rehabilitation dose and outcome measures may indicate need for more specific rehabilitation dose measures. PMID:25978948

Signal one and two blockade are both critical for non-myeloablative murine HSCT across a major histocompatibility complex barrier.

PubMed

Langford-Smith, Kia J; Sandiford, Zara; Langford-Smith, Alex; Wilkinson, Fiona L; Jones, Simon A; Wraith, J Ed; Wynn, Robert F; Bigger, Brian W

2013-01-01

Non-myeloablative allogeneic haematopoietic stem cell transplantation (HSCT) is rarely achievable clinically, except where donor cells have selective advantages. Murine non-myeloablative conditioning regimens have limited clinical success, partly through use of clinically unachievable cell doses or strain combinations permitting allograft acceptance using immunosuppression alone. We found that reducing busulfan conditioning in murine syngeneic HSCT, increases bone marrow (BM):blood SDF-1 ratio and total donor cells homing to BM, but reduces the proportion of donor cells engrafting. Despite this, syngeneic engraftment is achievable with non-myeloablative busulfan (25 mg/kg) and higher cell doses induce increased chimerism. Therefore we investigated regimens promoting initial donor cell engraftment in the major histocompatibility complex barrier mismatched CBA to C57BL/6 allo-transplant model. This requires full myeloablation and immunosuppression with non-depleting anti-CD4/CD8 blocking antibodies to achieve engraftment of low cell doses, and rejects with reduced intensity conditioning (≤75 mg/kg busulfan). We compared increased antibody treatment, G-CSF, niche disruption and high cell dose, using reduced intensity busulfan and CD4/8 blockade in this model. Most treatments increased initial donor engraftment, but only addition of co-stimulatory blockade permitted long-term engraftment with reduced intensity or non-myeloablative conditioning, suggesting that signal 1 and 2 T-cell blockade is more important than early BM niche engraftment for transplant success.

The Effect of Age and Weight on Vancomycin Serum Trough Concentrations in Pediatric Patients

PubMed Central

Madigan, Theresa; Sieve, Ronald M.; Graner, Kevin K.; Banerjee, Ritu

2013-01-01

Background Vancomycin treatment failure has been associated with low serum vancomycin trough concentrations, prompting recommendations to increase the daily doses in adults and children. Despite more aggressive vancomycin dosing, there continues to be significant variability in vancomycin trough concentrations in pediatric patients. Methods To determine if vancomycin trough concentrations in pediatric patients differ by age and weight, we reviewed records of hospitalized patients who received vancomycin between 2008 and 2012. Patients were divided into groups that received vancomycin 40 mg/kg/day (2008 to 2009) or 60 mg/kg/day (2010 to 2012). Vancomycin trough concentrations were compared between groups and within the 60-mg/kg/day group, stratified by patient age and weight. Results After increasing the vancomycin dose from 40 mg/kg/day to 60 mg/kg/day, initial trough concentrations increased significantly in patients younger than 2 and greater than 6 years of age, but not in patients between the ages of 2 and 5 years. In the 60-mg/kg/day group, only 16.7% of patients between 2 and 5 years of age had initial trough concentrations in the therapeutic range (10 mcg/mL to 20 mcg/mL). Initial trough concentrations were therapeutic in a greater proportion of patients ages 6 years to 12 years (38.7%) and 13 years to 18 years (63.0%). Patients between the ages of 13 and 18 had the highest proportion of supratherapeutic initial vancomycin trough concentrations (14.8%). Patients weighing > 50 kg had significantly higher trough concentrations than patients ≤ 50 kg (17.1 mcg/mL vs. 9.3 mcg/mL; p<0.001). Conclusion Although increasing the vancomycin dose from 40 mg/kg/day to 60 mg/kg/day led to a significant increase in vancomycin trough concentrations, a large proportion of patients receiving 60 mg/kg/day of vancomycin had trough concentrations outside of the therapeutic range. Specifically, patients younger than 6 years tend to have low trough concentrations, while adolescents and children > 50 kg are more likely to have elevated trough concentrations. Vancomycin dosing strategies in pediatric patients should consider age and weight as well as renal function and indication. PMID:23864541

Virulence evolution in response to anti-infection resistance: toxic food plants can select for virulent parasites of monarch butterflies.

PubMed

de Roode, J C; de Castillejo, C Lopez Fernandez; Faits, T; Alizon, S

2011-04-01

Host resistance to parasites can come in two main forms: hosts may either reduce the probability of parasite infection (anti-infection resistance) or reduce parasite growth after infection has occurred (anti-growth resistance). Both resistance mechanisms are often imperfect, meaning that they do not fully prevent or clear infections. Theoretical work has suggested that imperfect anti-growth resistance can select for higher parasite virulence by favouring faster-growing and more virulent parasites that overcome this resistance. In contrast, imperfect anti-infection resistance is thought not to select for increased parasite virulence, because it is assumed that it reduces the number of hosts that become infected, but not the fitness of parasites in successfully infected hosts. Here, we develop a theoretical model to show that anti-infection resistance can in fact select for higher virulence when such resistance reduces the effective parasite dose that enters a host. Our model is based on a monarch butterfly-parasite system in which larval food plants confer resistance to the monarch host. We carried out an experiment and showed that this environmental resistance is most likely a form of anti-infection resistance, through which toxic food plants reduce the effective dose of parasites that initiates an infection. We used these results to build a mathematical model to investigate the evolutionary consequences of food plant-induced resistance. Our model shows that when the effective infectious dose is reduced, parasites can compensate by evolving a higher per-parasite growth rate, and consequently a higher intrinsic virulence. Our results are relevant to many insect host-parasite systems, in which larval food plants often confer imperfect anti-infection resistance. Our results also suggest that - for parasites where the infectious dose affects the within-host dynamics - vaccines that reduce the effective infectious dose can select for increased parasite virulence. © 2011 The Authors. Journal of Evolutionary Biology © 2011 European Society For Evolutionary Biology.

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.

Comparative DNA binding of 7,12-dimethylbenz[a]anthracene and some of its metabolites in mouse epidermis in vivo as revealed by the 32P-postlabeling technique.

PubMed

Schoepe, K B; Friesel, H; Schurdak, M E; Randerath, K; Hecker, E

1986-04-01

The binding of some mouse skin metabolites and related derivatives of the tumor initiator 7,12-dimethylbenz[a]anthracene (DMBA) was investigated by 32P-postlabeling analysis after its topical administration. DMBA and trans-3,4-dihydro-3,4-dihydroxy-DMBA (DMBA-3,4-dihydrodiol) both led to the formation of four DNA adducts, which showed a very similar pattern of spots on thin-layer chromatograms. With trans-8,9-dihydro-8,9-dihydroxy-7,12-dimethylbenz[a]anthracene (DMBA-8,9-dihydrodiol) one major adduct was obtained which was chromatographically indistinguishable from one of the DMBA adducts. In contrast, 7-hydroxymethyl-12-methylbenz[a]anthracene (7-OHM-12-MBA) gave rise to two major adducts which were separable from DMBA adducts. 3-hydroxy-7,12-dimethylbenz[a]anthracene (3-OH-DMBA) and 7,12-dimethylbenz[a]anthracene-7,12-epoxide (DMBA-O2) did not lead to detectable amounts of adducts. Quantitative determination of DNA binding showed that an initiating dose (i = 100 nmol) of DMBA yielded approximately 12 adducts/10(7) normal nucleotides. Adduct formation with the same dose of DMBA-3,4-dihydrodiol was 7-8 times higher. At a 4-fold higher dose level, DMBA-8,9-dihydrodiol exhibited a 3- to 6-times weaker binding and 7-OHM-12-MBA a slightly stronger binding than DMBA. Chromatography of the DMBA and DMBA-3,4-dihydrodiol adducts with a solvent containing borate showed a decreased mobility of two out of four adducts in each case. These adducts were also sensitive to oxidation by periodate. The results suggest that two DMBA adducts carried vicinal cis-hydroxyl groups and thus were probably derived from the anti-3,4-dihydrodiol-1,2-oxide(s) of DMBA. The other two adducts were probably derived from the syn-stereoisomer(s). When the DNA-modifying capabilities and initiating activities of the more prominent mouse-skin metabolites are considered in relation to DMBA, DMBA-3,4-dihydrodiol is postulated to be a proximate and DMBA-3,4-dihydrodiol-1,2-oxide(s) to be ultimate initiators.

Phencyclidine retards autoshaping at a dose which does not suppress the required response.

PubMed

Coveney, J R; Sparber, S B

1982-06-01

Four groups of five food-deprived hooded Long-Evans rats were injected subcutaneously with saline (vehicle) or 2, 4 or 8 mg phencyclidine (PCP) hydrochloride/kg fifteen minutes before being placed for the first time into operant chambers modified to detect exploratory behaviors. Rearing was found to be more sensitive to disruption by phencyclidine than was unconditioned level touching (a measure of floor-level exploratory activities). In an autoshaping session immediately following, the group of animals given the low dose of PCP made as many lever-touch responses as the group given saline, but consumed fewer of the food pellets delivered. In addition, none of the animals in the low-dose group showed within-session shortening of the latency to respond which was observed in four of five control animals. The two other groups given higher doses of PCP demonstrated dose-related decrements in responding as well as a reduction in food pellet consumption during the first session of autoshaping. Over the next two daily autoshaping sessions, performance improved in those groups initially suppressed. Performance converged in all group by the third autoshaping session.

Increase in fluoroscopic radiation dose in successive sessions of multistage Onyx embolization of brain arteriovenous malformations compared with the first session.

PubMed

Sheen, Jae Jon; Jiang, Yuan Yuan; Kim, Young Eun; Maeng, Jun Young; Kim, Tae-Il; Lee, Deok Hee

2018-03-23

Onyx embolization is a treatment for brain arteriovenous malformations (AVMs). However, multistage embolization usually involves the presence of radiodense Onyx cast from the previous sessions, which may influence the fluoroscopic radiation dose. We compared the fluoroscopic dose between the initial and final embolization sessions. From January 2014 to September 2016, 18 patients underwent multistage Onyx embolization (more than twice) for brain AVMs. The total fluoroscopic duration (minutes), dose-area product (DAP, Gy×cm 2 ), and cumulative air kerma (CAK, mGy) of both the frontal and lateral planes were obtained. We compared the frontal and lateral fluoroscopic dose rates (dose/time) of the final embolization session with those of the initial session. The relationship between the injected Onyx volume and radiation dose was tested. The initial and final procedures on the frontal plane showed significantly different fluoroscopic dose rates (DAP: initial 0.668 Gy×cm 2 /min, final 0.848 Gy×cm 2 /min, P=0.02; CAK: initial 12.7 mGy/min, final 23.1 mGy/min, P=0.007). Those on the lateral plane also showed a similar pattern (DAP: initial 0.365 Gy×cm 2 /min, final 0.519 Gy×cm 2 /min, P=0.03; CAK: initial 6.2 mGy/min, final 12.9 mGy/min, P=0.01). The correlation between the cumulative Onyx volume (vials) and radiation dose ratio of both planes showed an increasing trend (rho 0.4325-0.7053; P=0.0011-0.0730). Owing to the automatic exposure control function during fluoroscopy, successive Onyx embolization procedures increase the fluoroscopic radiation dose in multistage brain AVM embolization because of the presence of radiodense Onyx mass. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

Grain boundary resistance to amorphization of nanocrystalline silicon carbide

PubMed Central

Chen, Dong; Gao, Fei; Liu, Bo

2015-01-01

Under the C displacement condition, we have used molecular dynamics simulation to examine the effects of grain boundaries (GBs) on the amorphization of nanocrystalline silicon carbide (nc-SiC) by point defect accumulation. The results show that the interstitials are preferentially absorbed and accumulated at GBs that provide the sinks for defect annihilation at low doses, but also driving force to initiate amorphization in the nc-SiC at higher doses. The majority of surviving defects are C interstitials, as either C-Si or C-C dumbbells. The concentration of defect clusters increases with increasing dose, and their distributions are mainly observed along the GBs. Especially these small clusters can subsequently coalesce and form amorphous domains at the GBs during the accumulation of carbon defects. A comparison between displacement amorphized nc-SiC and melt-quenched single crystal SiC shows the similar topological features. At a dose of 0.55 displacements per atom (dpa), the pair correlation function lacks long range order, demonstrating that the nc-SiC is fully amorphilized. PMID:26558694

Grain boundary resistance to amorphization of nanocrystalline silicon carbide.

PubMed

Chen, Dong; Gao, Fei; Liu, Bo

2015-11-12

Under the C displacement condition, we have used molecular dynamics simulation to examine the effects of grain boundaries (GBs) on the amorphization of nanocrystalline silicon carbide (nc-SiC) by point defect accumulation. The results show that the interstitials are preferentially absorbed and accumulated at GBs that provide the sinks for defect annihilation at low doses, but also driving force to initiate amorphization in the nc-SiC at higher doses. The majority of surviving defects are C interstitials, as either C-Si or C-C dumbbells. The concentration of defect clusters increases with increasing dose, and their distributions are mainly observed along the GBs. Especially these small clusters can subsequently coalesce and form amorphous domains at the GBs during the accumulation of carbon defects. A comparison between displacement amorphized nc-SiC and melt-quenched single crystal SiC shows the similar topological features. At a dose of 0.55 displacements per atom (dpa), the pair correlation function lacks long range order, demonstrating that the nc-SiC is fully amorphilized.

Iron-Magnesium Hydroxycarbonate (Fermagate): A Novel Non-Calcium-Containing Phosphate Binder for the Treatment of Hyperphosphatemia in Chronic Hemodialysis Patients

PubMed Central

McIntyre, Christopher W.; Pai, Pearl; Warwick, Graham; Wilkie, Martin; Toft, Alex J.; Hutchison, Alastair J.

2009-01-01

Background and objectives: This phase II study tested the safety and efficacy of fermagate, a calcium-free iron and magnesium hydroxycarbonate binder, for treating hyperphosphatemia in hemodialysis patients. Design, setting, participants, & measurements: A randomized, double-blind, three-arm, parallel-group study compared two doses of fermagate (1 g three times daily or 2 g three times daily with placebo). Sixty-three patients who had been on a stable hemodialysis regimen for ≥3 mo were randomized to the treatment phase. Study medication was administered three times daily just before meals for 21 d. The primary endpoint was reduction in serum phosphate over this period. Results: In the intention-to-treat analysis, mean baseline serum phosphate was 2.16 mmol/L. The fermagate 1- and 2-g three-times-daily treatment arms were associated with statistical reductions in mean serum phosphate to 1.71 and 1.47 mmol/L, respectively. Adverse event (AE) incidence in the 1-g fermagate arm was statistically comparable to the placebo group. The 2-g arm was associated with a statistically higher number of patients reporting AEs than the 1-g arm, particularly gastrointestinal AEs, as well as a higher number of discontinuations, complicating interpretation of this dose's efficacy. Both doses were associated with elevations of prehemodialysis serum magnesium levels. Conclusions: The efficacy and tolerability of fermagate were dose dependent. Fermagate showed promising efficacy in the treatment of hyperphosphatemia in chronic hemodialysis patients as compared with placebo in this initial phase II study. The optimal balance between efficacy and tolerability needs to be determined from future dose-titration studies, or fixed-dose comparisons of more doses. PMID:19158369

Age-dependent effects of initial exposure to nicotine on serotonin neurons.

PubMed

Bang, S J; Commons, K G

2011-04-14

Adolescence is a critical vulnerable period during which exposure to nicotine greatly enhances the possibility to develop drug addiction. Growing evidence suggests that serotonergic (5-HT) neurotransmission may contribute to the initiation and maintenance of addictive behavior. As the dorsal raphe (DR) and median raphe (MnR) nuclei are the primary 5-HT source to the forebrain, the current study tested the hypothesis that there are age-dependent effects of acute nicotine administration on activation of 5-HT neurons within these regions. Both adolescent (Postnatal day 30) and adult (Postnatal day 70) male Sprague-Dawley rats received subcutaneous injection of either saline or nicotine (0.2, 0.4, or 0.8 mg/kg). Subsequently, the number of 5-HT cells that were double-labeled for Fos and tryptophan hydroxylase was counted in seven subregions within the DR and the entire MnR. The results show that acute nicotine injection induces Fos expression in 5-HT neurons in a region-specific manner. In addition, adolescents show broader regional activations at either a lower (0.2 mg/kg) and a higher (0.8 mg/kg) dose of nicotine, displaying a unique U-shape response curve across doses. In contrast, 5-HT cells with activated Fos expression were restricted to fewer regions in adults, and the patterns of expression were more consistent across doses. The results reveal dose-dependent effects of nicotine during adolescence with apparent sensitization at different ends of the dosage spectrum examined compared to adults. These data indicate that initial exposure to nicotine may have unique effects in adolescence on the ascending 5-HT system, with the potential for consequences on the affective-motivational qualities of the drug and the subsequent propensity for repeated use. Copyright © 2011 IBRO. Published by Elsevier Ltd. All rights reserved.

Age-Dependent Effects of Initial Exposure to Nicotine on Serotonin Neurons

PubMed Central

Bang, Sun Jung; Commons, Kathryn G.

2011-01-01

Adolescence is a critical vulnerable period during which exposure to nicotine greatly enhances the possibility to develop drug addiction. Growing evidence suggests that serotonergic (5-HT) neurotransmission may contribute to the initiation and maintenance of addictive behavior. As the dorsal raphe (DR) and median raphe (MnR) nuclei are the primary 5-HT source to the forebrain, the current study tested the hypothesis that there are age-dependent effects of acute nicotine administration on activation of 5-HT neurons within these regions. Both adolescent (Postnatal day 30) and adult (Postnatal day 70) male Sprague-Dawley rats received subcutaneous injection of either saline or nicotine (0.2, 0.4, or 0.8 mg/kg). Subsequently, the number of 5-HT cells that were double-labeled for Fos and tryptophan hydroxylase was counted in 7 subregions within the DR and the entire MnR. The results show that acute nicotine injection induces Fos expression in 5-HT neurons in a region-specific manner. In addition, adolescents show broader regional activations at either a lower (0.2 mg/kg) and a higher (0.8 mg/kg) dose of nicotine, displaying a unique U-shape response curve across doses. In contrast, 5-HT cells with activated Fos expression were restricted to fewer regions in adults, and the patterns of expression were more consistent across doses. The results reveal dose-dependent effects of nicotine during adolescence with apparent sensitization at different ends of the dosage spectrum examined compared to adults. These data indicate that initial exposure to nicotine may have unique effects in adolescence on the ascending 5-HT system, with the potential for consequences on the affective-motivational qualities of the drug and the subsequent propensity for repeated use. PMID:21277949

Comparison of three algorithms for initiation and titration of insulin glargine in insulin-naive patients with type 2 diabetes mellitus.

PubMed

Dailey, George; Aurand, Lisa; Stewart, John; Ameer, Barbara; Zhou, Rong

2014-03-01

Several titration algorithms can be used to adjust insulin dose and attain blood glucose targets. We compared clinical outcomes using three initiation and titration algorithms for insulin glargine in insulin-naive patients with type 2 diabetes mellitus (T2DM); focusing on those receiving both metformin and sulfonylurea (SU) at baseline. This was a pooled analysis of patient-level data from prospective, randomized, controlled 24-week trials. Patients received algorithm 1 (1 IU increase once daily, if fasting plasma glucose [FPG] > target), algorithm 2 (2 IU increase every 3 days, if FPG > target), or algorithm 3 (treat-to-target, generally 2-8 IU increase weekly based on 2-day mean FPG levels). Glycemic control, insulin dose, and hypoglycemic events were compared between algorithms. Overall, 1380 patients were included. In patients receiving metformin and SU at baseline, there were no significant differences in glycemic control between algorithms. Weight-adjusted dose was higher for algorithm 2 vs algorithms 1 and 3 (P = 0.0037 and P < 0.0001, respectively), though results were not significantly different when adjusted for reductions in HbA1c (0.36 IU/kg, 0.43 IU/kg, and 0.31 IU/kg for algorithms 1, 2, and 3, respectively). Yearly hypoglycemic event rates (confirmed blood glucose <56 mg/dL) were higher for algorithm 3 than algorithms 1 (P = 0.0003) and 2 (P < 0.0001). Three algorithms for initiation and titration of insulin glargine in patients with T2DM resulted in similar levels of glycemic control, with lower rates of hypoglycemia for patients treated using simpler algorithms 1 and 2. © 2013 Ruijin Hospital, Shanghai Jiaotong University School of Medicine and Wiley Publishing Asia Pty Ltd.

Azathioprine-Induced Warfarin Resistance

PubMed Central

Vazquez, Sara R; Rondina, Matthew T; Pendleton, Robert C

2011-01-01

OBJECTIVE To describe a case of azathioprine-induced warfarin resistance, present a literature review on warfarin–azathioprine interactions, and provide recommendations on appropriate management of this clinically significant interaction. CASE SUMMARY A 29-year-old female with Cogan’s syndrome experienced thrombosis of the left internal carotid artery. She was treated with an average weekly warfarin dose of 39 mg (5.5 mg daily) prior to beginning azathioprine therapy. Three weeks following initiation of azathioprine 150 mg daily, the international normalized ratio (INR) decreased from 1.9 (prior to the medication change) to 1.0 without any change in the warfarin dose or other relevant factors. Over several weeks, the patient’s warfarin dose was titrated up to 112 mg weekly (16 mg daily) to achieve an INR of 2.5 (a 188%, or 2.9-fold dose increase). Because of elevated liver enzyme levels, the azathioprine dosage was decreased to 100 mg daily. Within 2 weeks following that decrease, warfarin requirements decreased to 105 mg weekly (15 mg daily). DISCUSSION Azathioprine was the probable causative agent of warfarin resistance according to the Naranjo probability scale, and a possible causative agent according to the Drug Interaction Probability Scale. A literature search (PubMed, 1966–December 2007) revealed 8 case reports of this drug interaction and 2 cases involving a similar effect with 6-mercaptopurine, the active metabolite of azathioprine. The exact mechanism of the interaction remains unknown. Previously published case reports point to a rapid onset and offset of the warfarin–azathioprine interaction and a dose-dependent increase of at least 2.5-fold in warfarin dose requirement with the initiation of azathioprine 75–200 mg daily. CONCLUSIONS This case report and several others point toward azathioprine as a clinically significant inducer of warfarin resistance. Providers should anticipate the need for higher warfarin doses, warfarin dose adjustment, and close INR monitoring in patients receiving azathioprine or its active metabolite, 6-mercaptopurine. PMID:18505911

High-dose 8% capsaicin patch in treatment of chemotherapy-induced peripheral neuropathy: single-center experience.

PubMed

Filipczak-Bryniarska, Iwona; Krzyzewski, Roger M; Kucharz, Jakub; Michalowska-Kaczmarczyk, Anna; Kleja, Justyna; Woron, Jarosław; Strzepek, Katarzyna; Kazior, Lucyna; Wordliczek, Jerzy; Grodzicki, Tomasz; Krzemieniecki, Krzysztof

2017-08-17

High-dose capsaicin patch is effective in treatment of neuropathic pain in HIV-associated neuropathy and diabetic neuropathy. There are no studies assessing effectiveness of high-dose capsaicin patch in treatment of chemotherapy-induced peripheral neuropathy. We sought to determine the effectiveness of treatment of pain associated with chemotherapy-induced peripheral neuropathy with high-dose capsaicin patch. Our study group consisted of 18 patients with clinically confirmed oxaliplatin-induced neuropathy. Baseline characteristic including underling disease, received cumulative dose of neurotoxic agent, neuropathic symptoms, prior treatment and initial pain level were recorded. Pain was evaluated with Numeric Rating Scale prior to treatment with high-dose capsaicin and after 1.8 day and after 8 and 12 weeks after introducing treatment. Patients were divided into two groups accordingly to the amount of neurotoxic agent that caused neuropathy (high sensitivity and low sensitivity group). Most frequent symptoms of chemotherapy-induced neuropathy were: pain (88.89%), paresthesis (100%), sock and gloves sensation (100%) and hypoesthesis (100%). Initial pain level was 7.45 ± 1.14. Mean cumulative dose of oxaliplatin after which patients developed symptoms was 648.07 mg/m 2 . Mean pain level after 12 weeks of treatment was 0.20 ± 0.41. When examined according to high and low sensitivity to neurotoxic agent patients with low sensitivity had higher pain reduction, especially after 8 days after introducing treatment (69.55 ± 12.09 vs. 49.40 ± 20.34%; p = 0.02) and after 12 weeks (96.96 ± 5.56 vs. 83.93 ± 18.59%; p = 0.04). High-dose capsaicin patch is an effective treatment for pain associated with chemotherapy-induced neuropathy in patients treated with oxaliplatin. Patients with lower sensitivity to neurotoxic agents have better response to treatment and pain reduction.

Buprenorphine transdermal system utilization.

PubMed

Wallace, Laura; Kadakia, Aditi

2017-01-01

To evaluate utilization patterns in patients initiating buprenorphine transdermal system (BTDS), CIII, and estimate the proportion decreasing their total opioid dose over time. This retrospective cohort study used data from the Truven Health Analytics MarketScan® Commercial Claims and Encounters Database from 1 January 2011 through 31 December 2015. Eligible individuals were adults aged 18-64 years newly dispensed BTDS (index prescription) who had at least six months of insurance coverage prior to (baseline period) and following (study period) the index prescription. Back and neck pain was the most common pain condition in the study population (n = 31,533) and 88% were dispensed opioids in the baseline period. Nearly half (48%) received BTDS in a strength of 10 mcg/hour as their index prescription. Most (80%) patients prescribed BTDS had concomitant prescriptions for other opioids, chiefly immediate-release (IR) opioids (77%). During the baseline period, median opioid dose among patients prescribed opioids was 50 morphine-equivalent doses (MED), with 33% of patients using nonsteroidal anti-inflammatory drugs and 44% adjuvant analgesics. During the study period, BTDS use lasted a median 30 days and mean 100 days. Median dose of BTDS remained largely constant, and median dose of all opioids during continuous use of BTDS was 65.6 units MED. However, 24% of patients reduced total units MED from the baseline period (median mean dose, 74.5 units MED) until the end of the study period (42.8). Most patients initiating treatment with BTDS had a history of treatment with IR opioids. Though the average change in total opioid daily dose after patients were prescribed BTDS was modest, an important subpopulation of approximately one-quarter of patients were able to markedly reduce their total units MED compared with prior opioid therapy. BTDS should be investigated as an option to help patients step down from higher opioid doses.

The effect of well-characterized, very low-dose x-ray radiation on fibroblasts

PubMed Central

Truong, Katelyn; Bradley, Suzanne; Baginski, Bryana; Wilson, Joseph R.; Medlin, Donald; Zheng, Leon; Wilson, R. Kevin; Rusin, Matthew; Takacs, Endre

2018-01-01

The purpose of this study is to determine the effects of low-dose radiation on fibroblast cells irradiated by spectrally and dosimetrically well-characterized soft x-rays. To achieve this, a new cell culture x-ray irradiation system was designed. This system generates characteristic fluorescent x-rays to irradiate the cell culture with x-rays of well-defined energies and doses. 3T3 fibroblast cells were cultured in cups with Mylar® surfaces and were irradiated for one hour with characteristic iron (Fe) K x-ray radiation at a dose rate of approximately 550 μGy/hr. Cell proliferation, total protein analysis, flow cytometry, and cell staining were performed on fibroblast cells to determine the various effects caused by the radiation. Irradiated cells demonstrated increased proliferation and protein production compared to control samples. Flow cytometry revealed that a higher percentage of irradiated cells were in the G0/G1 phase of the cell cycle compared to control counterparts, which is consistent with other low-dose studies. Cell staining results suggest that irradiated cells maintained normal cell functions after radiation exposure, as there were no qualitative differences between the images of the control and irradiated samples. The result of this study suggest that low-dose soft x-ray radiation might cause an initial pause, followed by a significant increase, in proliferation. An initial “pause” in cell proliferation could be a protective mechanism of the cells to minimize DNA damage caused by radiation exposure. The new cell irradiation system developed here allows for unprecedented control over the properties of the x-rays given to the cell cultures. This will allow for further studies on various cell types with known spectral distribution and carefully measured doses of radiation, which may help to elucidate the mechanisms behind varied cell responses to low-dose x-rays reported in the literature. PMID:29300773

Initial Characterization of a Gel Patch Dosimeter for In Vivo Dosimetry

PubMed Central

Matrosic, C; Culberson, W; Rosen, B; Madsen, E; Frank, G; Bednarz, B

2016-01-01

In vivo dosimetry is a greatly underutilized tool for patient safety in clinical external beam radiotherapy treatments, despite being recommended by several national and international organizations (AAPM, ICRU, IAEA, NACP). The reasons for this underutilization mostly relate to the feasibility and cost of in vivo dosimetry methods. Due to the increase in the number of beam angles and dose per fraction in modern treatments, there is a compelling need for a novel dosimeter that is robust and affordable while able to operate properly in these complex conditions. This work presents a gel patch dosimeter as a novel method of in vivo dosimetry. DEFGEL, a 6%T normoxic polyacrylamide gel, was injected into 1-cm thick acrylic molds to create 1-cm thick small cylindrical patch dosimeters. To evaluate the change in optical density due to radiation induced polymerization, dosimeters were scanned before and after irradiation using an in-house developed laser densitometer. The dose-responses of three separate batches of gel were evaluated and compared to check for linearity and repeatability. The response development time was evaluated to ensure that the patch dosimeter could be high throughput. Additionally, the potential of this system to be used as an in vivo dosimeter was tested with a clinically relevant end-to-end in vivo phantom test. All irradiations were performed with a Varian Clinac 21EX at the University of Wisconsin Medical Radiation Research Center (UWMRRC). The dose response of all three batches of gel was found to be linear within the range of 2–20 Gy. At doses below 0.5 Gy the statistical uncertainties were prohibitively large to make quantitative assessments of the results. The three batches demonstrated good repeatability in the range of 2 Gy to up to 10 Gy, with only slight variations in response at higher doses. For low doses the dosimeter fully developed within an hour while at higher doses they fully developed within four hours. During the in vivo phantom test the predicted patch absorbed dose was 4.23 Gy while the readout dose was evaluated to be 4.37 Gy, which corresponds to a 3.2% discrepancy. The dosimeter and densitometer pairing shows promise as an in vivo dosimetry system, especially for hypofractionated or MRI-guided radiotherapy treatments where higher doses are prescribed. PMID:27088207

Initial characterization of a gel patch dosimeter for in vivo dosimetry

NASA Astrophysics Data System (ADS)

Matrosic, C.; Culberson, W.; Rosen, B.; Madsen, E.; Frank, G.; Bednarz, B.

2016-05-01

In vivo dosimetry is a greatly underutilized tool for patient safety in clinical external beam radiotherapy treatments, despite being recommended by several national and international organizations (AAPM, ICRU, IAEA, NACP). The reasons for this underutilization mostly relate to the feasibility and cost of in vivo dosimetry methods. Due to the increase in the number of beam angles and dose per fraction in modern treatments, there is a compelling need for a novel dosimeter that is robust and affordable while able to operate properly in these complex conditions. This work presents a gel patch dosimeter as a novel method of in vivo dosimetry. DEFGEL, a 6% T normoxic polyacrylamide gel, was injected into 1 cm thick acrylic molds to create 1 cm thick small cylindrical patch dosimeters. To evaluate the change in optical density due to radiation induced polymerization, dosimeters were scanned before and after irradiation using an in-house developed laser densitometer. The dose-responses of three separate batches of gel were evaluated and compared to check for linearity and repeatability. The response development time was evaluated to ensure that the patch dosimeter could be high throughput. Additionally, the potential of this system to be used as an in vivo dosimeter was tested with a clinically relevant end-to-end in vivo phantom test. All irradiations were performed with a Varian Clinac 21EX at the University of Wisconsin Medical Radiation Research Center (UWMRRC). The dose-response of all three batches of gel was found to be linear within the range of 2-20 Gy. At doses below 0.5 Gy the statistical uncertainties were prohibitively large to make quantitative assessments of the results. The three batches demonstrated good repeatability in the range of 2 Gy to up to 10 Gy, with only slight variations in response at higher doses. For low doses the dosimeter fully developed within an hour while at higher doses they fully developed within four hours. During the in vivo phantom test the predicted patch absorbed dose was 4.23 Gy while the readout dose was evaluated to be 4.37 Gy, which corresponds to a 3.2% discrepancy. The dosimeter and densitometer pairing shows promise as an in vivo dosimetry system, especially for hypofractionated or MRI-guided radiotherapy treatments where higher doses are prescribed.

Immunological Effect of aGV Rabies Vaccine Administered Using the Essen and Zagreb Regimens: A Double-Blind, Randomized Clinical Trial.

PubMed

Miao, Li; Shi, Liwei; Yang, Yi; Yan, Kunming; Sun, Hongliang; Mo, Zhaojun; Li, Li

2018-04-01

This study evaluated the immunological effect of an aGV rabies virus strain using the Essen and Zagreb immunization programs. A total of 1,944 subjects were enrolled and divided into three groups: the Essen test group, Essen control group, and Zagreb test group. Neutralizing antibody levels and antibody seroconversion rates were determined at 7 and 14 days after the initial inoculations and then 14 days after the final inoculation in all of the subjects. The seroconversion rates for the Essen test group, Essen control group, and Zagreb test group, which were assessed 7 days after the first dosing in a susceptible population, were 35.74%, 26.92%, and 45.49%, respectively, and at 14 days, the seroconversion rates in this population were 100%, 100%, and 99.63%, respectively. At 14 days after the final dosing, the seroconversion rates were 100% in all three of the groups. The neutralizing serum antibody levels of the Essen test group, Essen control group, and Zagreb test group at 7 days after the first dosing in the susceptible population were 0.37, 0.26, and 0.56 IU/mL, respectively, and at 14 days after the initial dosing, these levels were 16.71, 13.85, and 16.80 IU/mL. At 14 days after the final dosing, the neutralizing antibody levels were 22.9, 16.3, and 18.62 IU/mL, respectively. The results of this study suggested that the aGV rabies vaccine using the Essen program resulted in a good serum immune response, and the seroconversion rates and the neutralizing antibody levels generated with the Zagreb regimen were higher than those with the Essen regimen when measured 7 days after the first dose.

Phase I Trial Using Induction Ciplatin, Docetaxel, 5-FU and Erlotinib Followed by Cisplatin, Bevacizumab and Erlotinib With Concurrent Radiotherapy for Advanced Head and Neck Cancer.

PubMed

Ahn, Peter H; Machtay, Mitchell; Anne, Pramila R; Cognetti, David; Keane, William M; Wuthrick, Evan; Dicker, Adam P; Axelrod, Rita S

2018-05-01

Bevacizumab (avastin) and erlotinib (tarceva) had shown early clinical activity against head and neck cancer (HNC). We initiated a phase I trial of induction cisplatin, docetaxel, 5-fluorouracil and erlotinib (TPF-E) followed by cisplatin, bevacizumab and erlotinib (PA-E) with radiotherapy (XRT) for advanced HNC. The goal was to determine maximum tolerated erlotinib dose. Eligible patients had stage IVA or higher HNC with good performance status, hematologic, and renal reserve. Two cycles of induction TPF-E were administered. XRT was administered with concurrent weekly cisplatin and bevacizumab every 2 weeks. Initial erlotinib dose was 50 mg daily from start of induction chemotherapy until radiotherapy completion. Erlotinib dose escalations to 100 and 150 mg were planned. Thirteen patients with previously untreated locoregional disease (11 patients) or oligometastatic (2 patients) HNC were enrolled. Totally, 11 of 13 patients completed XRT as planned. Four of 8 patients in cohort 1 (erlotinib 50 mg), 3 of 4 patients in cohort 2 (100 mg), and 0 of 1 patients in cohort 3 (150 mg) completed the regimen. Two patients had significant gastrointestinal complications (bleeding and perforation), and 1 had dose-limiting diarrhea. Maximum tolerated dose was reached at 50 mg erlotinib. At median 23.4 months follow-up, 5 patients (38%) have no evidence of disease, and 2 (15%) have stable but measurable disease. Erlotinib in combination with induction TPF followed by erlotinib, cisplatin, and bevacizumab with XRT is active but toxic. Gastrointestinal toxicities partly caused high rates of study withdrawal. All doses studied in this protocol caused unexpected toxicities and we do not recommend advancement to phase II.

Caffeine controversies.

PubMed

Gentle, Samuel J; Travers, Colm P; Carlo, Waldemar A

2018-04-01

Caffeine use in preterm infants has endured several paradigms: from standard of care to possible neurotoxin to one of the few medications for which there is evidence of bronchopulmonary dysplasia (BPD) risk reduction. The purpose of the review is to analyze this dynamic trajectory and discuss controversies that still remain after decades of caffeine use. Following concerns for caffeine safety in preterm infants, a large randomized controlled trial demonstrated a reduction in BPD and treatment for patent ductus arteriosus. The lower rate of death or neurodevelopmental impairment noted at 18-21 months was not statistically different at later timepoints; however, infants in the caffeine group had lower rates of motor impairment at 11-year follow-up. The time of caffeine therapy initiation is now substantially earlier, and doses used are sometimes higher that previously used, but there are limited data to support these practices. Caffeine therapy for apnea of prematurity (AOP) remains one of the pillars of neonatal care, although more evidence to support dosing and timing of initiation and discontinuation are needed.

Infections by Pasteuria do not protect its natural host Daphnia magna from subsequent infections.

PubMed

Duneau, David; Ebert, Dieter; Du Pasquier, Louis

2016-04-01

The existence of immunological memory in invertebrates remains a contentious topic. Exposure of Daphnia magna crustaceans to a noninfectious dose of the bacterium Pasteuria ramosa has been reported to reduce the chance of future infection upon exposure to higher doses. Using clonal hosts and parasites, we tested whether initial exposure of the host to the parasite (priming), followed by clearing of the parasite with antibiotic, protects the host from a second exposure (challenge). Our experiments included three treatments: priming and challenge with the same or with a different parasite clone, or no priming. Two independent experiments showed that both the likelihood of infection and the degree of parasite proliferation did not differ between treatments, supporting the conclusion that there is no immunological memory in this system. We discuss the possibility that previous discordant reports could result from immune or stress responses that did not fade following initial priming. Copyright © 2015 Elsevier Ltd. All rights reserved.

Cerebrospinal fluid penetration of high-dose daptomycin in suspected Staphylococcus aureus meningitis.

PubMed

Riser, M Shawn; Bland, Christopher M; Rudisill, Celeste N; Bookstaver, P Brandon

2010-11-01

To report a case of methicillin-sensitive Staphylococcus aureus (MSSA) bacteremia with suspected MSSA meningitis treated with high-dose daptomycin assessed with concurrent serum and cerebrospinal fluid (CSF) concentrations. A 54-year-old male presented to the emergency department with generalized weakness and presumed health-care-associated pneumonia shown on chest radiograph. Treatment was empirically initiated with vancomycin, levofloxacin, and piperacillin/tazobactam. Blood cultures revealed S. aureus susceptible to oxacillin. Empiric antibiotic treatment was narrowed to nafcillin on day 4. On day 8, the patient developed acute renal failure (serum creatinine 1.9 mg/dL, increased from 1.2 mg/dL the previous day and 0.8 mg/dL on admission). The patient's Glasgow Coma Score was 3, with normal findings shown on computed tomography scan of the head 72 hours following an episode of cardiac arrest on day 10. The patient experienced relapsing MSSA bacteremia on day 9, increasing the suspicion for a central nervous system (CNS) infection. Nafcillin was discontinued and daptomycin 9 mg/kg daily was initiated for suspected meningitis and was continued until the patient's death on day 16. Daptomycin serum and CSF trough concentrations were 11.21 μg/mL and 0.52 μg/mL, respectively, prior to the third dose. Lumbar puncture results were inconclusive and no further blood cultures were positive for MSSA. Creatine kinase levels were normal prior to daptomycin therapy and were not reassessed. Daptomycin was initiated in our patient secondary to possible nafcillin-induced acute interstitial nephritis and relapsing bacteremia. At a dose of 9 mg/kg, resultant penetration of 5% was higher than in previous reports, more consistent with inflamed meninges. High-dose daptomycin may be an alternative option for MSSA bacteremia with or without a CNS source in patients who have failed or cannot tolerate standard therapy. Further clinical evaluation in patients with confirmed meningitis is warranted.

Development and validation of a questionnaire to assess carbohydrate and insulin-dosing knowledge in youth with type 1 diabetes.

PubMed

Koontz, Michaela B; Cuttler, Leona; Palmert, Mark R; O'Riordan, Maryann; Borawski, Elaine A; McConnell, Judy; Kern, Elizabeth O

2010-03-01

OBJECTIVE The American Diabetes Association advocates insulin regimens for youth with type 1 diabetes that involve adjusting insulin dose based on carbohydrate intake and blood glucose level. Implementing these regimens requires knowledge about carbohydrate content of foods and subsequent calculations of insulin dose, skills that may be difficult to gauge in practice. Therefore, we sought to develop and validate a questionnaire, the PedCarbQuiz (PCQ), to assess carbohydrate and insulin-dosing knowledge in youth with type 1 diabetes. RESEARCH DESIGN AND METHODS After development by an expert panel, the PCQ was administered to 75 youth with type 1 diabetes or their parents. Reliability was assessed by Cronbach alpha and split-half testing. To assess validity, scores were correlated with A1C, expert assessments, parent educational level, and complexity of insulin regimen. RESULTS PCQ mean score was 87 +/- 9.7% (range 42-98%). Cronbach alpha was 0.88, and correlation of split halves was 0.59 (P < 0.0001). Higher PCQ scores correlated significantly with lower A1C (r = -0.29, P = 0.01) and expert assessments (r = 0.56, P < 0.001). Scores were significantly higher in parents with college degrees than in those without (P = 0.01) and in participants with more complex insulin regimens (P = 0.003). CONCLUSIONS The PCQ is a novel, easily administered instrument to assess knowledge about carbohydrates and insulin dosing calculations. Initial analyses support the reliability and validity of the PCQ.

Dosimetry of intracavitary placements for uterine and cervical carcinoma: results of orthogonal film, TLD, and CT-assisted techniques.

PubMed

Kapp, K S; Stuecklschweiger, G F; Kapp, D S; Hackl, A G

1992-07-01

A total of 720 192Ir high-dose-rate (HDR) applications in 331 patients with gynecological tumors were analyzed to evaluate the dose to normal tissues from brachytherapy. Based on the calculations of bladder base, bladder neck, and rectal doses derived from orthogonal films the planned tumor dose or fractionation was altered in 20.4% of intracavitary placements (ICP) for cervix carcinoma and 9.2% of ICP for treatment of the vaginal vault. In 13.8% of intracervical and 8.1% of intravaginal treatments calculated doses to both the bladder and rectum were greater than or equal to 140% of the initially planned dose fraction. Doses at the bladder base were significantly higher than at the bladder neck (p less than 0.001). In 17.5% of ICP the dose to the bladder base was at least twice as high as to the bladder neck. The ratio of bladder base dose to the bladder neck was 1.5 (+/- 1.19 SD) for intracervical and 1.46 (+/- 1.14 SD) for intravaginal applications. The comparison of calculated doses from orthogonal films with in-vivo readings showed a good correlation of rectal doses with a correlation coefficient factor of 0.9556. CT-assisted dosimetry, however, revealed that the maximum doses to bladder and rectum were generally higher than those obtained from films with ratios of 1-1.7 (average: 1.44) for the bladder neck, 1-5.4 (average: 2.42) for the bladder base, and 1.1-2.7 (average: 1.37) for the rectum. When doses to the specified reference points of bladder neck and rectum from orthogonal film dosimetry were compared with the corresponding points on CT scans, similar values were obtained for both methods with a maximum deviation of +/- 10%. Despite the determination of multiple reference points our study revealed that this information was inadequate to predict doses to the entire rectum and bladder. If conventional methods are used for dosimetry it is recommended that doses to the bladder base should be routinely calculated, since single point measurements at the bladder neck seriously underestimate the dose to the bladder. Also the rectal dose should be determined at several points over the length of the implant due to the wide range of anatomic variations possible.

Reuse of acid coagulant-recovered drinking waterworks sludge residual to remove phosphorus from wastewater

NASA Astrophysics Data System (ADS)

Yang, Lan; Wei, Jie; Zhang, Yumei; Wang, Jianli; Wang, Dongtian

2014-06-01

Acid coagulant-recovered drinking waterworks sludge residual (DWSR) is a waste product from drinking waterworks sludge (DWS) treatment with acid for coagulant recovery. In this study, we evaluated DWSR as a potential phosphorus (P) removing material in wastewater treatment by conducting a series of batch and semi-continuous tests. Batch tests were carried out to study the effects of pH, initial concentration, and sludge dose on P removal. Batch test results showed that the P removal efficiency of DWSR was highly dependent on pH. Calcinated DWSR (C-DWSR) performed better in P removal than DWSR due to its higher pH. At an optimum initial pH value of 5-6 and a sludge dose of 10 g/L, the P removal rates of DWSR and DWS decreased from 99% and 93% to 84% and 14%, respectively, and the specific P uptake of DWSR and DWS increased from 0.19 and 0.19 mg P/g to 33.60 and 5.72 mg P/g, respectively, when the initial concentration was increased from 2 to 400 mg/L. The effective minimum sludge doses of DWSR and DWS were 0.5 g/L and 10 g/L, respectively, when the P removal rates of 90% were obtained at an initial concentration of 10 mg/L. Results from semi-continuous test indicated that P removal rates over 99% were quickly achieved for both synthetic and actual wastewater (lake water and domestic sewage). These rates could be maintained over a certain time under a certain operational conditions including sludge dose, feed flow, and initial concentration. The physicochemical properties analysis results showed that the contents of aluminum (Al) and iron (Fe) in DWSR were reduced by 50% and 70%, respectively, compared with DWS. The insoluble Al and Fe hydroxide in DWS converted into soluble Al and Fe in DWSR. Metal leaching test results revealed that little soluble Al and Fe remained in effluent when DWSR was used for P removal. We deduced that chemical precipitation might be the major action for P removal by DWSR and that adsorption played only a marginal role.

On determining dose rate constants spectroscopically

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

Rodriguez, M.; Rogers, D. W. O.

2013-01-15

Purpose: To investigate several aspects of the Chen and Nath spectroscopic method of determining the dose rate constants of {sup 125}I and {sup 103}Pd seeds [Z. Chen and R. Nath, Phys. Med. Biol. 55, 6089-6104 (2010)] including the accuracy of using a line or dual-point source approximation as done in their method, and the accuracy of ignoring the effects of the scattered photons in the spectra. Additionally, the authors investigate the accuracy of the literature's many different spectra for bare, i.e., unencapsulated {sup 125}I and {sup 103}Pd sources. Methods: Spectra generated by 14 {sup 125}I and 6 {sup 103}Pd seedsmore » were calculated in vacuo at 10 cm from the source in a 2.7 Multiplication-Sign 2.7 Multiplication-Sign 0.05 cm{sup 3} voxel using the EGSnrc BrachyDose Monte Carlo code. Calculated spectra used the initial photon spectra recommended by AAPM's TG-43U1 and NCRP (National Council of Radiation Protection and Measurements) Report 58 for the {sup 125}I seeds, or TG-43U1 and NNDC(2000) (National Nuclear Data Center, 2000) for {sup 103}Pd seeds. The emitted spectra were treated as coming from a line or dual-point source in a Monte Carlo simulation to calculate the dose rate constant. The TG-43U1 definition of the dose rate constant was used. These calculations were performed using the full spectrum including scattered photons or using only the main peaks in the spectrum as done experimentally. Statistical uncertainties on the air kerma/history and the dose rate/history were Less-Than-Or-Slanted-Equal-To 0.2%. The dose rate constants were also calculated using Monte Carlo simulations of the full seed model. Results: The ratio of the intensity of the 31 keV line relative to that of the main peak in {sup 125}I spectra is, on average, 6.8% higher when calculated with the NCRP Report 58 initial spectrum vs that calculated with TG-43U1 initial spectrum. The {sup 103}Pd spectra exhibit an average 6.2% decrease in the 22.9 keV line relative to the main peak when calculated with the TG-43U1 rather than the NNDC(2000) initial spectrum. The measured values from three different investigations are in much better agreement with the calculations using the NCRP Report 58 and NNDC(2000) initial spectra with average discrepancies of 0.9% and 1.7% for the {sup 125}I and {sup 103}Pd seeds, respectively. However, there are no differences in the calculated TG-43U1 brachytherapy parameters using either initial spectrum in both cases. Similarly, there were no differences outside the statistical uncertainties of 0.1% or 0.2%, in the average energy, air kerma/history, dose rate/history, and dose rate constant when calculated using either the full photon spectrum or the main-peaks-only spectrum. Conclusions: Our calculated dose rate constants based on using the calculated on-axis spectrum and a line or dual-point source model are in excellent agreement (0.5% on average) with the values of Chen and Nath, verifying the accuracy of their more approximate method of going from the spectrum to the dose rate constant. However, the dose rate constants based on full seed models differ by between +4.6% and -1.5% from those based on the line or dual-point source approximations. These results suggest that the main value of spectroscopic measurements is to verify full Monte Carlo models of the seeds by comparison to the calculated spectra.« less

Determination of the minimal phototoxic dose and colorimetry in psoralen plus ultraviolet A radiation therapy.

PubMed

Kraemer, Cristine Kloeckner; Menegon, Dóris Baratz; Cestari, Tania Ferreira

2005-10-01

The use of an adequate initial dose of ultraviolet A (UVA) radiation for photochemotherapy is important to prevent burns secondary to overdosage, meanwhile avoiding a reduced clinical improvement and long-term risks secondary to underdosage. The ideal initial dose of UVA can be achieved based on the phototype and the minimal phototoxic dose (MPD). The objective measurement of constitutive skin color (colorimetry) is another method commonly used to quantify the erythematous skin reaction to ultraviolet radiation exposure. The aim of this study was to determine variations in MPD and constitutional skin color (coordinate L(*)) within different phototypes in order to establish the best initial dose of UVA radiation for photochemotherapy patients. Thirty-six patients with dermatological conditions and 13 healthy volunteers were divided into five groups according to phototype. Constitutional skin color of the infra-axillary area was assessed by colorimetry. The infra-axillary area was subsequently divided into twelve 1.5 cm(2) regions to determine the MPD; readings were performed 72 h after oral administration of 8-methoxypsoralen (MOP) followed by exposure of the demarcated regions to increasing doses of UVA. The majority of the participants were women (73.5%) and their mean age was 38.8 years. The MPD ranged from 4 to 12 J/cm(2) in phototypes II and III; from 10 to 18 J/cm(2) in type IV; from 12 to 24 J/cm(2) in type V and from 18 to 32 J/cm(2) in type VI. The analysis of colorimetric values (L(*) coordinate) and MPD values allowed the definition of three distinctive groups of individuals composed by phototypes II and III (group 1), types IV and V (group 2), and phototype VI (group 3). MPD and L(*) coordinate showed variation within the same phototype and superposition between adjacent phototypes. The values of the L(*) coordinate and the MPD lead to the definition of three distinct sensitivity groups: phototypes II and III, IV and V and type VI. Also, the MPD values bear a strong correlation to coordinate L(*) values. Mean MPD values described for each of the three major sensitivity groups were higher than the values commonly used in clinical settings for the different phototypes. Therefore, phototype alone is not a good parameter to define the initial UVA dose. MPD and colorimetry could be used in pre-treatment evaluation of patients who are to be submitted to photochemotherapy, in a non-invasive and more accurate way when compared with the classical phenotype clinical criteria.

Monitoring Compliance to Promote Quality Assurance: Development of a Mental Health Clinical Chart Audit Tool in Belize, 2013.

PubMed

Winer, Rachel A; Bennett, Eleanor; Murillo, Illouise; Schuetz-Mueller, Jan; Katz, Craig L

2015-09-01

Belize trained psychiatric nurse practitioners (PNPs) in the early 1990s to provide mental health services throughout the country. Despite overwhelming success, the program is limited by lack of monitoring, evaluation, and surveillance. To promote quality assurance, we developed a chart audit tool to monitor mental healthcare delivery compliance for initial psychiatric assessment notes completed by PNPs. After reviewing the Belize Health Information System electronic medical record system, we developed a clinical audit tool to capture 20 essential components for initial assessment clinical notes. The audit tool was then piloted for initial assessment notes completed during July through September of 2013. One hundred and thirty-four initial psychiatric interviews were audited. The average chart score among all PNPs was 9.57, ranging from 3 to 15. Twenty-three charts-or 17.2%-had a score of 14 or higher and met a 70% compliance benchmark goal. Among indicators most frequently omitted included labs ordered and named (15.7%) and psychiatric diagnosis (21.6%). Explicit statement of medications initiated with dose and frequency occurred in 47.0% of charts. Our findings provide direction for training and improvement, such as emphasizing the importance of naming labs ordered, medications and doses prescribed, and psychiatric diagnoses in initial assessment clinical notes. We hope this initial assessment helps enhance mental health delivery compliance by prompting creation of BHIS templates, development of audits tools for revisit follow-up visits, and establishment of corrective actions for low-scoring practitioners. These efforts may serve as a model for implementing quality assurance programming in other low resource settings.

High-intensity corneal collagen crosslinking with riboflavin and UVA in rat cornea.

PubMed

Zhu, Yirui; Reinach, Peter S; Zhu, Hanlei; Tan, Qiufan; Zheng, Qinxiang; Qu, Jia; Chen, Wei

2017-01-01

Corneal collagen cross-linking (CXL) halts human corneal ectasias progression by increasing stromal mechanical stiffness. Although some reports describe that this procedure is effective in dealing with some infectious and immunologic corneal thinning diseases, there is a need for more animal models whose corneal thickness more closely resemble those occurring in these patients. To meet this need, we describe here high-intensity protocols that are safe and effective for obtaining CXL in rat corneas. Initially, a range of potentially effective UVA doses were evaluated based on their effectiveness in increasing tissue enzymatic resistance to dissolution. At UVA doses higher than a threshold level of 0.54 J/cm2, resistance to enzymatic digestion increased relative to that in non-irradiated corneas. Based on the theoretical threshold CXL dose, a CXL regimen was established in which the UVA tissue irradiance was 9 mW/cm2, which was delivered at doses of either 2.16, 2.7 or 3.24 J/cm2. Their dose dependent effects were evaluated on ocular surface morphological integrity, keratocyte apoptotic frequency, tissue thickness and endothelial cell layer density. Doses of 2.16 and 2.7 J/cm2 transiently decreased normal corneal transparency and increased thickness. These effects were fully reversed after 14 days. In contrast, 3.24 J/cm2 had more irreversible side effects. Three days after treatment, apoptotic frequency in the CXL-2.16 group was lower than that at higher doses. Endothelial cell losses remained evident only in the CXL-3.24 group at 42 days posttreatment. Stromal fiber thickening was evident in all the CXL-treated groups. We determined both the threshold UVA dose using the high-intensity CXL procedure and identified an effective dose range that provides optimal CXL with minimal transient side effects in the rat cornea. These results may help to provide insight into how to improve the CXL outcome in patients afflicted with a severe corneal thinning disease.

TU-H-CAMPUS-TeP3-03: Dose Enhancement by Gold Nanoparticles Around the Bragg Peak of Proton Beams

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

Kwon, J; Sutherland, K; Hashimoto, T

2016-06-15

Purpose: To make clear the spatial distribution of dose enhancement around gold nanoparticles (GNPs) located near the proton Bragg peak, and to evaluate the potential of GNPs as a radio sensitizer. Methods: The dose enhancement by electrons emitted from GNPs under proton irradiation was estimated by Geant4 Monte Carlo simulation toolkit in two steps. In an initial macroscopic step, 100 and 195 MeV proton beams were incident on a water cube, 30 cm on a side. Energy distributions of protons were calculated at four depths, 50% and 75% proximal to the Bragg peak, 100% peak, and 75% distal to themore » peak (P50, P75, Peak, and D75, respectively). In a subsequent microscopic step, protons with the energy distribution calculated above were incident on a 20 nm diameter GNP in a nanometer-size water box and the spatial distribution of dose around the GNP was determined for each energy distribution. The dose enhancement factor (DEF) was also deduced. Results: The dose enhancement effect was spread to several tens of nanometers in the both depth and radial directions. The enhancement area increased in the order of P50, P75, Peak, and D75 for both cases with 100 and 195 MeV protons. In every position around the Bragg peak, the 100 MeV beam resulted in a higher dose enhancement than the 195 MeV beam. At P75, the average and maximum DEF were 3.9 and 17.0 for 100 MeV, and 3.5 and 16.2 for 195 MeV, respectively. These results indicate that lower energy protons caused higher dose enhancement in this incident proton energy range. Conclusion: The dose enhancement around GNPs spread as the position in the Bragg peak region becomes deeper and depends on proton energy. It is expected that GNPs can be used as a radio sensitizer with consideration of the location and proton beam energy.« less

Naproxen Attenuates Sensitization of Depressive-Like Behavior and Fever during Maternal Separation

PubMed Central

Hennessy, Michael B.; Stafford, Nathan P.; Yusko-Osborne, Brittany; Schiml, Patricia A.; Xanthos, Evan D.; Deak, Terrence

2014-01-01

Early life stress can increase susceptibility for later development of depressive illness though a process thought to involve inflammatory mediators. Isolated guinea pig pups exhibit a passive, depressive-like behavioral response and fever that appear mediated by proinflammatory activity, and which sensitize with repeated separations. Treatment with an anti-inflammatory can attenuate the behavioral response during the initial separation and separation the following day. Here we used the cyclooxygenase inhibitor naproxen to examine the role of prostaglandins in mediating the depressive-like behavior and core body temperature of young guinea pigs during an initial separation, separation the next day, and separation 10 days after the first. The passive, depressive-like behavior as well as fever sensitized with repeated separation. Three days of injection with 14 mg/kg of naproxen prior to the initial separation reduced depressive-like behavior during all three separations. A 28 mg/kg dose of naproxen, however, had minimal effect on behavior. Fever during the early separations was moderated by naproxen, but only at the higher dose. These results suggest a role of prostaglandins in the behavioral and febrile response to maternal separation, and particularly in the sensitization of depressive-like behavior following repeated separation. PMID:25449392

Dose-dependent and cell type-specific cell death and proliferation following in vitro exposure to radial extracorporeal shock waves

PubMed Central

Hochstrasser, Tanja; Frank, Hans-Georg; Schmitz, Christoph

2016-01-01

Radial extracorporeal shock wave (rESW) therapy is widely used in musculoskeletal disorders and wound repair. However, the mechanisms of action are still largely unknown. The current study compared the effects of rESWs on two cell types. Human fetal foreskin fibroblasts (HFFF2) and human placental choriocarcinoma cell line JEG-3 were exposed to 0, 100, 200, 500 or 5000 rESWs generated with a Swiss DolorClast device (2.5 bar, 1 Hz). FACS analysis immediately after rESW exposure showed that initially, rESWs rather induced mechanical cell destruction than regulated or programmed cell death. Cell damage was nearly negated by reducing cavitation. Furthermore, cell viability decreased progressively with higher numbers of rESWs. Exposure to rESWs had no impact on growth potential of JEG-3 cells, but dose-dependently increased growth potential of HFFF2 cells. Cultivation of cells that were initially exposed to sham-rESWs in conditioned media increased the growth potential of HFFF2 cells, nevertheless, an even stronger effect was achieved by direct exposure to rESWs. Additionally, cell cycle distribution analysis demonstrated a shift in proportion from G0/G1 to G2/M phase in HFFF2 cells, but not in JEG-3 cells. These data demonstrate that rESWs leads to initial and subsequent dose-dependent and cell type-specific effects in vitro. PMID:27477873

Dose--response of initial G2-chromatid breaks induced in normal human fibroblasts by heavy ions

NASA Technical Reports Server (NTRS)

Kawata, T.; Durante, M.; Furusawa, Y.; George, K.; Takai, N.; Wu, H.; Cucinotta, F. A.; Dicello, J. F. (Principal Investigator)

2001-01-01

PURPOSE: To investigate initial chromatid breaks in prematurely condensed G2 chromosomes following exposure to heavy ions of different LET. MATERIAL AND METHODS: Exponentially growing human fibroblast cells AG1522 were irradiated with gamma-rays, energetic carbon (13 keV/ microm, 80 keV/microm), silicon (55 keV/microm) and iron (140 keV/microm, 185keV/microm, 440keV/microm) ions. Chromosomes were prematurely condensed using calyculin-A. Initial chromatid-type and isochromatid breaks in G2 cells were scored. RESULTS: The dose response curves for total chromatid breaks were linear regardless of radiation type. The relative biological effectiveness (RBE) showed a LET-dependent increase, peaking around 2.7 at 55-80keV/microm and decreasing at higher LET. The dose response curves for isochromatid-type breaks were linear for high-LET radiations, but linear-quadratic for gamma-rays and 13 keV/microm carbon ions. The RBE for the induction of isochromatid breaks obtained from linear components increased rapidly between 13keV/microm (about 7) and 80keV/microm carbon (about 71), and decreased gradually until 440 keV/microm iron ions (about 66). CONCLUSIONS: High-LET radiations are more effective at inducing isochromatid breaks, while low-LET radiations are more effective at inducing chromatid-type breaks. The densely ionizing track structures of heavy ions and the proximity of sister chromatids in G2 cells result in an increase in isochromatid breaks.

Geographic Factors and Human Papillomavirus (HPV) Vaccination Initiation Among Adolescent Girls in the United States

PubMed Central

Henry, Kevin A.; Stroup, Antoinette M.; Warner, Echo L; Kepka, Deanna

2015-01-01

Background This study is among the first to explore geographic factors that may be associated with HPV vaccine uptake in the United States. Methods Data from the 2011 and 2012 National Immunization Survey-Teen for 20,565 female adolescents aged 13-17 years were analyzed to examine associations of HPV vaccine initiation (receipt of at least one dose) with ZIP code-level geographic factors. Logistic regression including individual and geographic factors was used to estimate the odds of HPV vaccine initiation. Results Approximately 53% of girls initiated the HPV vaccine in both years. Girls in high poverty communities had higher HPV vaccine initiation compared to those in low poverty communities (61.1% vs .52.4%; Adjusted Odds Ratio [AOR] 1.18,95%CI 1.04-1.33). Initiation was higher among girls in communities where the majority of the population was Hispanic (69.0% vs. 49.9%;AOR 1.64, 95%CI 1.43-1.87) or non-Hispanic mixed race (60.4% vs. 49.9%; AOR 1.30, 95%CI 1.17-1.44) compared to majority non-Hispanic white communities. Interactions between individual-level race/ethnicity and community racial–ethnic composition indicated significantly higher odds of initiation among Hispanic girls living in Hispanic communities compared to Hispanic girls living in predominately NHW (AOR 2.23;95%CI 1.87-2.65) or NHB (AOR 1.90; 95%CI 1.20-3.04)communities, respectively Conclusion Initiation rates of HPV vaccination among teen girls were highest in the poorest communities and among Hispanics living in communities where the racial–ethnic composition was predominantly Hispanic or mixed race. Impact Given low HPV vaccination rates in the United States, these results provide important evidence to inform public health interventions to increase HPV vaccination. PMID:26768989

Clozapine Titration for People in Early Psychosis: A Chart Review and Treatment Guideline.

PubMed

Ballon, Jacob S; Ashfaq, Hera; Noordsy, Douglas L

2018-06-01

The use of clozapine, particularly in young people, is often limited by early treatment-emergent adverse effects including drowsiness and lethargy. Concerns about adverse effects, medication adherence, and the need for blood monitoring often impede the use of clozapine in this population, leading to repeated trials of less effective medications. Current clozapine dosing recommendations are based on people further in the course of their illness and thus reflect different responsiveness and sensitivities to antipsychotic medication. As such, there is a need for evidence-based guidelines for titration and dosing of clozapine among people in early psychosis. We performed a chart review of 14 people treated with clozapine within our early psychosis team. Data regarding dose titration, response, time to discontinuation, symptom severity, weight gain, and other adverse effects were gathered at clozapine initiation, 3 months, and last available visit on clozapine. People treated with slow titration within their first year of psychosis onset achieved sustained response at very low maintenance doses (mean dose = 81 mg/d, mean duration of treatment = 200 weeks) compared with slow titration with longer duration of illness (mean dose = 350 mg/d, mean duration of treatment = 68 weeks) or standard dose titration in early psychosis (mean dose = 112 mg/d, mean duration of treatment = 38 weeks). The most common adverse effects in all groups were weight gain and sedation, with the groups requiring higher mean doses reporting a broader range of adverse effects. There was no apparent difference in the clinical global impression for severity or improvement between the slow titration and standard titration groups in people with early psychosis. These observations are synthesized into a proposed treatment guideline for use of clozapine among people in early psychosis. We describe development of a slow titration approach to initiating clozapine among people in early psychosis. This approach resulted in clinical response at remarkably low maintenance doses of clozapine among people within their first year of illness, but not in those with longer duration of symptoms. Slow titration also led to good tolerability and acceptance of clozapine treatment for some patients.

In Vivo Dosimetry for Single-Fraction Targeted Intraoperative Radiotherapy (TARGIT) for Breast Cancer

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

Eaton, David J., E-mail: davideaton@nhs.net; Best, Bronagh; Brew-Graves, Chris

Purpose: In vivo dosimetry provides an independent check of delivered dose and gives confidence in the introduction or consistency of radiotherapy techniques. Single-fraction intraoperative radiotherapy of the breast can be performed with the Intrabeam compact, mobile 50 kV x-ray source (Carl Zeiss Surgical, Oberkochen, Germany). Thermoluminescent dosimeters (TLDs) can be used to estimate skin doses during these treatments. Methods and Materials: Measurements of skin doses were taken using TLDs for 72 patients over 3 years of clinical treatments. Phantom studies were also undertaken to assess the uncertainties resulting from changes in beam quality and backscatter conditions in vivo. Results: Themore » mean measured skin dose was 2.9 {+-} 1.6 Gy, with 11% of readings higher than the prescription dose of 6 Gy, but none of these patients showed increased complications. Uncertainties due to beam hardening and backscatter reduction were small compared with overall accuracy. Conclusions: TLDs are a useful and effective method to measure in vivo skin doses in intraoperative radiotherapy and are recommended for the initial validation or any modification to the delivery of this technique. They are also an effective tool to show consistent and safe delivery on a more frequent basis or to determine doses to other critical structures as required.« less

Postoperative PET/CT and target delineation before adjuvant radiotherapy in patients with oral cavity squamous cell carcinoma.

PubMed

Dutta, Pinaki R; Riaz, Nadeem; McBride, Sean; Morris, Luc G; Patel, Snehal; Ganly, Ian; Wong, Richard J; Palmer, Frank; Schöder, Heiko; Lee, Nancy

2016-04-01

The purpose of this study was for us to present our evaluation of the effectiveness of positron emission tomography (PET)/CT imaging in postoperative patients with oral cavity squamous cell carcinoma (SCC) before initiating adjuvant radiation therapy. Treatment planning PET/CT scans were obtained in 44 patients with oral cavity SCC receiving adjuvant radiation. We identified target areas harboring macroscopic disease requiring higher radiation doses or additional surgery. Fourteen PET/CT scans were abnormal. Thirteen patients underwent surgery and/or biopsy, increased radiation dose, and/or addition of chemotherapy. Eleven patients received higher radiation doses. Patients undergoing imaging >8 weeks were more likely to have abnormal results (p = .01). One-year distant metastases-free survival was significantly worse in patients with positive PET/CT scans (61.5% vs 92.7%; p = .01). The estimated positive predictive value (PPV) was 38% for postoperative PET/CT scanning. We demonstrated that 32% of patients have abnormal PET/CT scans resulting in management changes. Patients may benefit from postoperative PET/CT imaging to optimize adjuvant radiation treatment planning. © 2015 Wiley Periodicals, Inc. Head Neck 38: E1285-E1293, 2016. © 2015 Wiley Periodicals, Inc.

Effects of varied doses of psilocybin on time interval reproduction in human subjects.

PubMed

Wackermann, Jirí; Wittmann, Marc; Hasler, Felix; Vollenweider, Franz X

2008-04-11

Action of a hallucinogenic substance, psilocybin, on internal time representation was investigated in two double-blind, placebo-controlled studies: Experiment 1 with 12 subjects and graded doses, and Experiment 2 with 9 subjects and a very low dose. The task consisted in repeated reproductions of time intervals in the range from 1.5 to 5s. The effects were assessed by parameter kappa of the 'dual klepsydra' model of internal time representation, fitted to individual response data and intra-individually normalized with respect to initial values. The estimates kappa were in the same order of magnitude as in earlier studies. In both experiments, kappa was significantly increased by psilocybin at 90 min from the drug intake, indicating a higher loss rate of the internal duration representation. These findings are tentatively linked to qualitative alterations of subjective time in altered states of consciousness.

Evaluation of the effect of low tube voltage on radiation dose and image quality

NASA Astrophysics Data System (ADS)

Norhasrina Nik Din, Nik; Zainon, Rafidah; Rahman, A. T. Abdul

2017-05-01

Number of Computed Tomography (CT) examinations performed worldwide is increasing. In 2010, the FDA issued an initiative to reduce unnecessary radiation exposure from CT imaging. The aim of this study is to evaluate the effect of low tube voltage on radiation dose and image quality using CTDI phantom. The CTDI phantom was scanned with dual energy CT at 80 kV and 120 kV with the tube current from 150 mAs to 350 mAs. Pitch was 1.0 while slice thickness was 1 mm and 5 mm. Results show if mAs was increased, the SNR values also will be increased. The 5 mm slice thickness shows higher SNR value compared to 1 mm slice thickness. As the voltage and tube current increased, the amount of dose absorbed is also increased because current is proportional to photon flux.

The "doses" of initial, untreated hallucinations and delusions: a proof-of-concept study of enhanced predictors of first-episode symptomatology and functioning relative to duration of untreated psychosis.

PubMed

Compton, Michael T; Gordon, Tynessa L; Weiss, Paul S; Walker, Elaine F

2011-11-01

A prominent limitation of literature on duration of untreated psychosis (DUP) is that researchers have studied only unidimensional duration as an early-course predictor, neglecting potential effects of frequency/severity of initial, untreated psychosis. This study demonstrates utility of the concept of "doses" of initial, untreated hallucinations and delusions-representing more complete measures of "exposure"-as enhanced predictors of symptomatology/functioning relative to DUP alone. 109 first-episode patients with a psychotic disorder based on Structured Clinical Interview for DSM-IV Axis I Disorders criteria were assessed at 3 public-sector psychiatric units serving an urban, socially disadvantaged, predominantly African American community between July 2004 and June 2008. Dependent variables included negative symptoms, general psychopathology, insight, and global functioning at initial hospitalization. When added to a baseline model (age, gender, and premorbid academic and social functioning), DUP predicted current negative symptoms (P = .02, model R(2) = 0.20), though dose of hallucinations and dose of delusions did not. However, regarding general psychopathology symptoms, DUP was not predictive, though dose of delusions was, when controlling for the other 5 variables (P = .02, model R(2) = 0.15). DUP was not a significant predictor of insight, though dose of hallucinations was, such that a greater dose of initial, untreated hallucinations was associated with better insight at initial hospitalization (P < .01, model R(2) = 0.20). DUP was associated with global functioning (P = .05), and dose of delusions added significantly to this prediction (P = .04; model R(2) = 0.13). Doses of initial, untreated hallucinations and delusions add substantively, though differentially, to the prediction of early-course symptomatology and functioning. Findings suggest a need for focused research on frequency/severity of pretreatment psychotic symptoms beyond duration measures. © Copyright 2011 Physicians Postgraduate Press, Inc.

Zolpidem prescribing practices before and after Food and Drug Administration required product labeling changes

PubMed Central

Norman, Jessica L; Fixen, Danielle R; Saseen, Joseph J; Saba, Laura M; Linnebur, Sunny A

2017-01-01

Background: Women have higher morning serum zolpidem concentrations than men after taking an evening dose, potentially leading to increased risk of harm. On 19 April 2013, the United States Food and Drug Administration required labeling changes for zolpidem, recommending an initial dose of no greater than 5 mg (immediate release) or 6.25 mg (controlled release) per night in women. Objectives: The primary objective of this study was to compare prescribing practices before and after the 2013 zolpidem labeling change. A secondary objective was to evaluate serious adverse events potentially related to zolpidem. Methods: Electronic medical records of adults receiving care through the University of Colorado Health system were accessed for study inclusion if patients were provided a first-time prescription for zolpidem either prior to or after the Food and Drug Administration labeling change. Patients were randomly chosen from eight strata based on age, gender, and date of zolpidem initiation (before/after the labeling change). Demographic and zolpidem prescribing data were collected. Low-dose zolpidem was considered 5 mg (immediate release) or 6.25 mg (controlled release) daily or less. Documentation of potentially related serious adverse events within the patients’ records was also evaluated. Results: A total of 400 patients were included in the study. The overall percentage of patients prescribed low-dose zolpidem increased from 44% to 58% after the labeling change (p = 0.0020). In a pre-specified subgroup analysis, the percentage of patients prescribed low-dose zolpidem increased in all groups, including young men (38%–50%, p = 0.23), elderly men (34%–40%, p = 0.53), and elderly women (60%–74%, p = 0.14), but the change was only significant in young women (42%–70%, p = 0.0045). Conclusion: After Food and Drug Administration–mandated labeling changes for zolpidem in 2013, the percentage of overall patients in our health system, and specifically young women, with initial prescriptions for low-dose zolpidem significantly increased as compared to before the labeling change. PMID:28515934

Diagnostic value of CT, PET and combined PET/CT performed with low-dose unenhanced CT and full-dose enhanced CT in the initial staging of lymphoma.

PubMed

Pinilla, I; Gómez-León, N; Del Campo-Del Val, L; Hernandez-Maraver, D; Rodríguez-Vigil, B; Jover-Díaz, R; Coya, J

2011-10-01

The aim of this paper was to compare the accuracy of contrast-enhanced computed tomography (CT), positron emission tomography (PET), unenhanced low-dose PET/CT (LD-PET/CT) and full-dose enhanced PET/CT (FD-PET/CT) for the initial staging of lymphoma. One hundred and one lymphoma patients were examined by [18F]FDG-PET/CT including unenhanced low-dose CT and enhanced full-dose CT. Each modality of PET/CT was evaluated by a nuclear medicine physician and a radiologist unaware of the other modality, while the CT and PET images were interpreted separately by another independent radiologist and nuclear medicine physician respectively. The nodal and extranodal lesions detected by each technique were compared with a reference standard. For nodal assessment, sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), positive likelihood ratio (LR+), and negative LR (LR-) of LD-PET/CT were 97%, 96%, 98%, 95%, 26 and 0.02 respectively, and those of FD-PET/CT were 97%, 97%, 98%, 95%, 36 and 0.02. These results were significantly better than those of PET (sensitivity 82%, specificity 81%, PPV 88%, NPV 72%, LR+ 4.3, LR- 0.21). Likewise, both PET/CT displayed a higher sensitivity, NPV and LR- than CT (91%, 84%, 0.1 respectively). For organ evaluation, both modalities of PET/CT also had significantly better sensitivity and NPV than that of PET (LD-PET/CT: sensitivity 92%, NPV 90%; FD-PET/CT sensitivity 94%, NPV 92%; PET: sensitivity 70%, NPV 69%). The sensitivity, specificity, PPV and NPV for bone marrow involvement were 29%, 84%, 45% and 72% respectively for PET, and 29%, 90%, 56%, and 74% for both, LD-PET/CT, and FD-PET/CT. No significant differences were found between LD-PET/CT and FD-PET/CT, but FD-PET/CT detected important incidental findings in 5.9% of patients. PET/CT is an accurate technique for the initial staging of lymphomas without significant differences between LD-PET/CT and FD-PET/CT. FD-PET/CT detects relevant incidental findings that are missed on LD-PET/CT.

Provider-Verified HPV Vaccine Coverage among a National Sample of Hispanic Adolescent Females

PubMed Central

Reiter, Paul L.; Gupta, Kunal; Brewer, Noel T.; Gilkey, Melissa B.; Katz, Mira L.; Paskett, Electra D.; Smith, Jennifer S.

2014-01-01

Background Hispanic females have the highest cervical cancer incidence rate of any racial or ethnic group in the US, yet relatively little research has examined HPV vaccination among this fast-growing population. We examined HPV vaccination among a national sample of Hispanic adolescent females. Methods We analyzed provider-verified vaccination data from the 2010-2011 National Immunization Survey-Teen for Hispanic females ages 13-17 (n=2,786). We used weighted logistic regression to identify correlates of HPV vaccine initiation (receipt of one or more doses), completion (receipt of three doses), and follow-through (receipt of three doses among those who initiated the series). Results HPV vaccine initiation was 60.9%, completion was 36.0%, and follow-through was 59.1%. Initiation and completion were more common among older daughters and those whose parents had received a provider recommendation to vaccinate (all p<0.05). Completion was less common among daughters who had moved from their birth state (p<0.05). All vaccination outcomes were less common among daughters without health insurance (all p<0.05). Vaccination did not differ by parents’ preferred language (all p>0.05), although intent to vaccinate was higher among Spanish-speaking parents (p<0.01). Spanish-speaking parents were more likely to indicate lack of provider recommendation (20.2% vs. 5.3%) and cost (10.9% vs. 1.8%) as main reasons for not intending to vaccinate (both p<0.05). Conclusions Many Hispanic females have not received HPV vaccine. Several factors, including provider recommendation and health insurance, are key correlates of vaccination. Impact HPV vaccination programs targeting Hispanics are needed and should consider how potential barriers to vaccination may differ by preferred language. PMID:24633142

The Incorporation of Radionuclides After Wounding by a “Dirty Bomb”: The Impact of Time for Decorporation Efficacy and a Model for Cases of Disseminated Fragmentation Wounds

PubMed Central

Rump, Alexis; Stricklin, Daniela; Lamkowski, Andreas; Eder, Stefan; Abend, Michael; Port, Matthias

2017-01-01

Objective: In the case of a terrorist attack by a “dirty bomb” there is a risk of internal contamination with radionuclides through inhalation and wounds. We studied the efficacy of a decorporation treatment depending on the initiation time and duration. Approach: Based on biokinetic models, we simulated the impact of different diethylenetriaminepentaacetic acid treatments on the committed effective dose after the incorporation of plutonium-239. Results: For the same level of radioactivity, the dose was higher after the fast absorption from the wound than after a slow invasion following inhalation. The impact of the treatment initiation time was particularly important in the case of the internal contamination through the wound. Ending the treatment at an early point in time was followed by an augmentation of radioactivity in the blood compartment, reflecting insufficient treatment duration. Treatment efficacy increased only marginally if extended over 90 days. Innovation and Conclusion: For plutonium-239, the committed effective dose and the impact of the treatment initiation time on therapeutic efficacy predominantly depend on the speed of invasion, i.e., the pathway and the physicochemical properties of the compounds involved. Thus, it is prudent to start decorporation therapy as soon as possible, as a loss of efficacy resulting from a delay in treatment initiation cannot be compensated later on. In the case of plutonium-239 incorporation, the treatment must be continued for several months. Multiple fragmentation wounds might be aggregated to a single wound model suited for internal dosimetry calculations by using the “rule of nine.” PMID:28116223

Best Practices for Intrathecal Baclofen Therapy: Dosing and Long-Term Management.

PubMed

Boster, Aaron L; Adair, Roy L; Gooch, Judith L; Nelson, Mary Elizabeth S; Toomer, Andrea; Urquidez, Joe; Saulino, Michael

2016-08-01

Intrathecal baclofen (ITB) therapy aims to reduce spasticity and provide functional control. An expert panel consulted on best practices. Pump fill and drug delivery can be started intraoperatively, with monitoring for at least eight hours. Initiate with the 500 mcg/mL concentration. The starting daily dose should be twice the effective bolus screening dose, or the screening dose if the patient had a prolonged response (greater than eight hours) or negative reactions. Oral antispasmodics can be weaned, one drug at a time beginning with oral baclofen after ITB begins. Assessment should occur within 24 hours of a dose change. For adults, daily dose increases may be 5% to 15% once every 24 hours for cerebral-origin spasticity and 10% to 30% once every 24 hours for spinal-origin spasticity. Daily dose increases can be 5% to 15% once every 24 hours for children. Inpatients should be assessed at least every 24 hours and receive rehabilitation. Step dosing can be used for outpatients who cannot return daily. Dosing options include simple continuous dosing, variable 24-hour flex dosing, or regularly scheduled boluses. Patients/caregivers should understand the care plan, responsibilities, and possible side-effects. Low-reservoir alarm dates and refill schedules should be written down, along with emergency contact information. A higher concentration at refill can extend refill intervals, and a bridge bolus must be programmed. Time changes may affect flex dosing. Pump replacement should be scheduled at least three months in advance. ITB dosing is multistep and individualized. © 2016 International Neuromodulation Society.

Initial experience of ArcCHECK and 3DVH software for RapidArc treatment plan verification

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

Infusino, Erminia; Mameli, Alessandra, E-mail: e.infusino@unicampus.it; Conti, Roberto

2014-10-01

The purpose of this study was to perform delivery quality assurance with ArcCHECK and 3DVH system (Sun Nuclear, FL) and to evaluate the suitability of this system for volumetric-modulated arc therapy (VMAT) (RapidArc [RA]) verification. This software calculates the delivered dose distributions in patients by perturbing the calculated dose using errors detected in fluence or planar dose measurements. The device is tested to correlate the gamma passing rate (%GP) and the composite dose predicted by 3DVH software. A total of 28 patients with prostate cancer who were treated with RA were analyzed. RA treatments were delivered to a diode arraymore » phantom (ArcCHECK), which was used to create a planned dose perturbation (PDP) file. The 3DVH analysis used the dose differences derived from comparing the measured dose with the treatment planning system (TPS)-calculated doses to perturb the initial TPS-calculated dose. The 3DVH then overlays the resultant dose on the patient's structures using the resultant “PDP” beams. Measured dose distributions were compared with the calculated ones using the gamma index (GI) method by applying the global (Van Dyk) normalization and acceptance criteria, i.e., 3%/3 mm. Paired differences tests were used to estimate statistical significance of the differences between the composite dose calculated using 3DVH and %GP. Also, statistical correlation by means of logistic regression analysis has been analyzed. Dose-volume histogram (DVH) analysis for patient plans revealed small differences between treatment plan calculations and 3DVH results for organ at risk (OAR), whereas planning target volume (PTV) of the measured plan was systematically higher than that predicted by the TPS. The t-test results between the planned and the estimated DVH values showed that mean values were incomparable (p < 0.05). The quality assurance (QA) gamma analysis 3%/3 mm showed that in all cases there were only weak-to-moderate correlations (Pearson r: 0.12 to 0.74). Moreover, clinically relevant differences increased with increasing QA passing rate, indicating that some of the largest dose differences occurred in the cases of high QA passing rates, which may be called “false negatives.” The clinical importance of any disagreement between the measured and the calculated dose is often difficult to interpret; however, beam errors (either in delivery or in TPS calculation) can affect the effectiveness of the patient dose. Further research is needed to determinate the role of a PDP-type algorithm to accurately estimate patient dose effect.« less

Anthrax

DTIC Science & Technology

2009-01-01

antimicrobials listed below) Initial therapye (intravenous dosing) Oral dosing Initial therapy (intravenous) IV treatment initially Switch to oral...high index of suspicion for anthrax, initiation of therapy should not be delayed for results of these confirmatory tests. 1. MICROBIOLOGICAL TESTS...Sputum specimens from inhalational anthrax patients should be plated on chocolate agar, SBA, and MAC. Cultures will show isolated B. anthracis

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

Previous Dosage of Allopurinol Is a Strong Determinant of Febuxostat Efficacy.

PubMed

Koide, Hiroyoshi; Hira, Daiki; Tsujimoto, Masayuki; Katsube, Yurie; Minegaki, Tetsuya; Uzu, Takashi; Ikeda, Yoshito; Morita, Shin-Ya; Nishiguchi, Kohshi; Terada, Tomohiro

2017-01-01

Febuxostat has currently played pivotal role in the treatment of hyperuricemia, but there is little comprehensive information for the determinants of individual difference in efficacy of febuxostat. Therefore, the present study, a retrospective investigation, was carried out to analyze the effects of patient characteristics on the efficacy of febuxostat. A total of 225 patients who were continuously prescribed the same dose of febuxostat for 8-12 weeks from the initial therapy were enrolled in the present study. The data, including patient information and laboratory data, were collected from electronic medical records. Serum urate lowering effects of febuxostat were evaluated by calculating the change in serum urate level at baseline and at 8-12 weeks after starting febuxostat. The multiple regression analysis showed the change in serum urate level was significantly lower in male patients and in those with a lower baseline serum urate level, higher previous dose of allopurinol, lower dose of febuxostat and lower body surface area-unadjusted estimated glomerular filtration rate. Concomitantly administered drugs did not show a significantly influence on the efficacy of febuxostat. In conclusion, it should be noted that the serum urate lowering efficacy of febuxostat may decrease in patients with a higher previous dose of allopurinol, renal impairment or male patients. The basic findings of the present study are believed to contribute to the proper use of febuxostat.

In vitro vitamin K3 effect on conjunctival fibroblast migration and proliferation.

PubMed

Pinilla, I; Izaguirre, L B; Gonzalvo, F J; Piazuelo, E; Garcia-Gonzalez, M A; Sanchez-Cano, A I; Sopeña, F

2014-01-01

To evaluate the dose effect of vitamin K3 on wound healing mechanisms. Conjunctival fibroblasts were incubated for 24 hours. An artificial wound was made and the cells were incubated with fresh medium plus doses of vitamin K3 to be tested. Wound repair was monitored at 0, 18, 24, and 48 hours. Proliferation was measured in actively dividing cells by [(3)H]thymidine uptake. Six different groups were tested: group 1/no drugs added, group 2/ethanol 0.1%, group 3/vitamin K3 1 mg/L, group 4/vitamin K3 2 mg/L, group 5/vitamin K3 4 mg/L, and group 6/vitamin K3 6 mg/L. Each experiment was carried out in triplicate and 4 times. There were no differences among groups at the initial time. In vitro wound repair was slower in groups 4, 5, and 6. There were no differences between control and ethanol groups and between control and vitamin K3 1 mg/L groups. Fibroblast mitogenic activity was statistically decreased in all vitamin K groups; statistical differences were found among vitamin K3 1 mg/mL and higher doses too. In groups 5 and 6, cellular toxicity was presented. Vitamin K3 is able to inhibit fibroblast proliferation. Vitamin K3 2 mg/L or higher doses inhibit wound healing repair, exhibiting cellular toxicity at 4 and 6 mg/L.

Nonlinear Simulation of the Tooth Enamel Spectrum for EPR Dosimetry

NASA Astrophysics Data System (ADS)

Kirillov, V. A.; Dubovsky, S. V.

2016-07-01

Software was developed where initial EPR spectra of tooth enamel were deconvoluted based on nonlinear simulation, line shapes and signal amplitudes in the model initial spectrum were calculated, the regression coefficient was evaluated, and individual spectra were summed. Software validation demonstrated that doses calculated using it agreed excellently with the applied radiation doses and the doses reconstructed by the method of additive doses.

Initial apixaban dosing in patients with atrial fibrillation.

PubMed

Buchholz, Alexander; Ueberham, Laura; Gorczynska, Kaja; Dinov, Borislav; Hilbert, Sebastian; Dagres, Nikolaos; Husser, Daniela; Hindricks, Gerhard; Bollmann, Andreas

2018-05-01

Apixaban is a non-vitamin K oral anticoagulant approved for prevention of stroke and systemic embolism in patients with nonvalvular atrial fibrillation (AF). Current labeling recommends dose reduction based on patient age, weight, and renal function. The aim of this study was to analyze adherence to current labeling instructions concerning initial apixaban dosing in clinical practice and identify factors associated with inappropriate dose reduction. Patients with AF initiated on apixaban in 2016 were identified in the Heart Center Leipzig database. Records were screened to identify patient characteristics, prescribed apixaban dose, renal function, and further dosing-relevant secondary diagnoses and co-medication. We identified 569 consecutive patients with AF initiated on apixaban. In 301 (52.9%) patients, apixaban was prescribed in standard dose (5 mg b.i.d.) and in 268 (47.1%) in a reduced dose (2.5 mg b.i.d.). Of 268 patients receiving a reduced dose, 163 (60.8%) did not meet labeling criteria for dose reduction. In univariate and multivariate regression analysis, age (OR: 0.736, 95% CI: 0.664-0.816, P < 0.0001), patient weight (OR: 1.120, 95% CI: 1.076-1.166, P < 0.0001), and serum creatinine level (OR: 0.910, 95% CI: 0.881-0.940, P < 0.0001) were independent predictors for apixaban underdosage. In clinical practice, apixaban dosing is frequently inconsistent with labeling. Factors associated with inappropriate dose reduction are age, patient weight, and serum creatinine level, the same factors used as criteria for dose adjustment. However, in underdosed patients, the 3 factors did not meet the criteria for dose reduction. © 2018 Wiley Periodicals, Inc.

Success rates of single-dose methotrexate and additional dose requirements among women with first and previous ectopic pregnancies.

PubMed

Cirik, Derya Akdag; Kinay, Tugba; Keskin, Ugur; Ozden, Eda; Altay, Metin; Gelisen, Orhan

2016-04-01

To compare the success of the single-dose methotrexate regimen and the requirement for a second or third dose of methotrexate between women with their first ectopic pregnancy (EP) and those with previous EP. In a retrospective cohort study, data were analyzed from women treated for EP by single-dose methotrexate at a Turkish tertiary referral center between January 2010 and December 2013. Data were compared between women with at least one previous EP and those with their first EP. The success rate of the protocol in the first and previous EP groups was similar: 93.0% (320/344) and 87.3% (48/55), respectively. History of previous EP was not a predictor of treatment failure. However, the requirement for additional methotrexate doses was significantly higher in the previous EP group (16/48 [33.4%]) than in the first EP group (55/320 [17.2%]; P=0.03). Multivariate analysis showed that history of tubal surgery (P=0.006) and initial levels of the β-subunit of human chorionic gonadotropin (P=0.001) were significant predictors of treatment failure. Although the single-dose regimen had similar success rates in the previous EP and first EP groups, additional doses of methotrexate were more frequently required in the previous EP group. Copyright © 2015 International Federation of Gynecology and Obstetrics. Published by Elsevier Ireland Ltd. All rights reserved.

Role of alpha2C-adrenoceptor subtype in spatial working memory as revealed by mice with targeted disruption of the alpha2C-adrenoceptor gene.

PubMed

Tanila, H; Mustonen, K; Sallinen, J; Scheinin, M; Riekkinen, P

1999-02-01

The role of the alpha2C-adrenoceptor subtype in mediating the beneficial effect of alpha2-adrenoceptor agonists on spatial working memory was studied in adult mice with targeted inactivation of the alpha2C-receptor gene (KO) and their wild-type controls (WT). A delayed alternation task was run in a T-maze with mixed delays varying from 20 s to 120 s. Dexmedetomidine, a specific but subtype nonselective alpha2-adrenoceptor agonist, dose-dependently decreased the total number of errors. The effect was strongest at the dose of 5 microg/kg (s.c.), and was observed similarly in KO and WT mice. KO mice performed inferior to WT mice due to a higher number of perseverative errors. Dexmedetomidine slowed initiation of the motor response in the start phase at lower doses in WT mice than in KO mice but no such difference was observed in the return phase of the task, suggesting involvement of alpha2C-adrenoceptors in the cognitive aspect of response preparation or in response sequence initiation. According to these findings, enhancement of spatial working memory is best achieved with alpha2-adrenoceptor agonists which have neither agonistic nor antagonistic effects at the alpha2C-adrenoceptor subtype.

New UK nickel-plated steel coins constitute an increased allergy and eczema risk.

PubMed

Julander, Anneli; Midander, Klara; Herting, Gunilla; Thyssen, Jacob P; White, Ian R; Odnevall Wallinder, Inger; Lidén, Carola

2013-06-01

Nickel-plated steel coins have recently been introduced in the United Kingdom. To compare the performance and allergy risk of the new nickel-plated coins (five and ten pence) with those of the cupro-nickel coins being replaced. Coin handling studies with assessment of skin exposure and metal release in artificial sweat were performed. Six volunteers participated. The amount of nickel deposited onto skin during the handling of nickel-plated coins for 1 hr was 7.5 µg/cm(2) , four times higher than that from cupro-nickel coins. The nickel content in the oxidized surface of nickel-plated coins was higher, explaining the higher skin dose. Initial nickel release rates were 10-27 times higher than 1-week rates, emphasizing that brief and repeated contact results in significant nickel exposure. Nickel-plated coins deposit higher levels of nickel onto skin than cupro-nickel coins, and hence pose an increased allergy risk. One-week release in artificial sweat is not suitable for determining the risk of handling items with high nickel release that come into short, repeated contact with the skin. The nickel skin dose is recommended for risk assessment. UK citizens are now, because of this change in coinage, unnecessarily exposed to higher levels of nickel on the skin. This is of public health concern. © 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Considerations for diabetes: treatment with insulin pen devices.

PubMed

Cuddihy, Robert M; Borgman, Sarah K

2013-01-01

Insulin is essential for the treatment of type 1 diabetes, and most patients with type 2 diabetes will eventually require insulin for glycemic control. Several barriers contribute to delays in initiating insulin therapy in type 2 diabetes. Furthermore, insulin-treated patients often miss doses or otherwise fail to self-administer their insulin as prescribed, placing themselves at the risk of developing complications. Insulin pens can help overcome barriers to initiating insulin therapy and can facilitate the self-management of diabetes. Compared with the vial and syringe, insulin pens are more accurate, associated with greater adherence, and preferred by patients because of their convenience and ease of use. Large database analyses suggest that insulin pens may reduce the rate of occurrence of hypoglycemic events in patients with type 2 diabetes. Despite higher costs of insulin pens vs vials and syringes, studies suggest little or no increase in total health care costs and decreases in diabetes-related costs associated with reduced health care utilization with pens. Interestingly, the use of insulin pens within the United States lags far behind the use of pens in Europe and Japan. Insulin pens may be disposable or refillable, and some pens have special features [eg, audible clicks, large-dose selector and dial, memory function, half-unit dosing, high dosing (ie, 80 U)] that offer the opportunity to individualize treatment by meeting patients' needs. This review compares available insulin pens, describes strategies to facilitate their usage, and discusses how insulin pens can improve self-management of diabetes while reducing cost.

Mutation induction by charged particles of defined linear energy transfer.

PubMed

Hei, T K; Chen, D J; Brenner, D J; Hall, E J

1988-07-01

The mutagenic potential of charged particles of defined linear energy transfer (LET) was assessed using the hypoxanthine-guanine phosphoribosyl transferase locus (HGPRT) in primary human fibroblasts. Exponentially growing cultures of early passaged fibroblasts were grown as monolayers on thin mylar sheets and were irradiated with accelerated protons, deuterons or helium-3 ions. The mutation rates were compared with those generated by 137Cs gamma-rays. LET values for charged particles accelerated at the Radiological Research Accelerator Facility, using the track segment mode, ranged from 10 to 150 keV/micron. After irradiation, cells were trypsinized, subcultured and assayed for both cytotoxicity and 6-thioguanine resistance. For gamma-rays, and for the charged particles of lower LET, the dose-response curves for cell survival were characterized by a marked initial shoulder, but approximated to an exponential function of dose for higher LETs. Mutation frequencies, likewise, showed a direct correlation to LET over the dose range examined. Relative biological effectiveness (RBE) for mutagenesis, based on the initial slopes of the dose-response curves, ranged from 1.30 for 10 keV/micron protons to 9.40 for 150 keV/micron helium-3 ions. Results of the present studies indicate that high-LET radiations, apart from being efficient inducers of cell lethality, are even more efficient in mutation induction as compared to low-LET ionizing radiation. These data are consistent with results previously obtained with both rodent and human fibroblast cell lines.

Potentiation of low dose ketamine effects by naltrexone: potential implications for the pharmacotherapy of alcoholism.

PubMed

Krystal, John H; Madonick, Steven; Perry, Edward; Gueorguieva, Ralitza; Brush, Laura; Wray, Yola; Belger, Aysenil; D'Souza, Deepak Cyril

2006-08-01

The interplay of opiate and NMDA glutamate receptors may contribute to psychosis, cognitive function, alcoholism, and substance dependence. Ketamine and ethanol block the NMDA glutamate receptor. The purpose of this randomized double-blind, placebo-controlled human laboratory study was to evaluate whether the interactive effects of drugs acting at opiate and NMDA glutamate receptors might partially explain the efficacy of naltrexone for the treatment of alcoholism, that is, whether naltrexone 25 mg pretreatment would modulate ketamine effects in healthy human subjects. Two groups of healthy subjects were studied. An initial group (n=31) received a perception-altering subanesthetic dose of ketamine (bolus of 0.23 mg/kg over 1 min followed by a 60-min infusion of 0.58 mg/kg or saline bolus and infusion). A second group (n=24) completed the same testing procedures, but received a subperceptual ketamine dose (bolus 0.081 mg/kg over 10 min followed by an infusion of 0.4 mg/kg/h). Ketamine produced positive symptoms, negative symptoms, emotional discomfort, and cognitive effects as measured by the Positive and Negative Syndrome Scale (PANSS) in a dose-related fashion. The lower ketamine dose produced subjective effects similar to two standard ethanol drinks, whereas the higher ketamine dose produced effects similar to five standard drinks. Although naltrexone produced no significant behavioral effects, it significantly magnified the increase in the total PANSS score produced by the lower subperceptual dose of ketamine, but not the higher perception-altering dose of ketamine. These data suggest that the interplay of opiate receptor antagonism and NMDA receptor antagonism may be relevant to the protective effects of naltrexone on alcohol consumption via potentiation of dysphoric effects associated with the NMDA receptor antagonist effects of ethanol. However, these data suggest that at levels of NMDA receptor antagonism associated with heavy drinking, this protective effect of naltrexone on drinking is no longer present.

Intravenous iron administration strategies and anemia management in hemodialysis patients.

PubMed

Michels, Wieneke M; Jaar, Bernard G; Ephraim, Patti L; Liu, Yang; Miskulin, Dana C; Tangri, Navdeep; Crews, Deidra C; Scialla, Julia J; Shafi, Tariq; Sozio, Stephen M; Bandeen-Roche, Karen; Cook, Courtney J; Meyer, Klemens B; Boulware, L Ebony

2017-01-01

The effect of maintenance intravenous (IV) iron administration on subsequent achievement of anemia management goals and mortality among patients recently initiating hemodialysis is unclear. We performed an observational cohort study, in adult incident dialysis patients starting on hemodialysis. We defined IV administration strategies over a 12-week period following a patient's initiation of hemodialysis; all those receiving IV iron at regular intervals were considered maintenance, and all others were considered non-maintenance. We used multivariable models adjusting for demographics, clinical and treatment parameters, iron dose, measures of iron stores and pro-infectious and pro-inflammatory parameters to compare these strategies. The outcomes under study were patients' (i) achievement of hemoglobin (Hb) of 10-12 g/dL, (ii) more than 25% reduction in mean weekly erythropoietin stimulating agent (ESA) dose and (iii) mortality, ascertained over a period of 4 weeks following the iron administration period. Maintenance IV iron was administered to 4511 patients and non-maintenance iron to 8458 patients. Maintenance IV iron administration was not associated with a higher likelihood of achieving an Hb between 10 and 12 g/dL {adjusted odds ratio (OR) 1.01 [95% confidence interval (CI) 0.93-1.09]} compared with non-maintenance, but was associated with a higher odds of achieving a reduced ESA dose of 25% or more [OR 1.33 (95% CI 1.18-1.49)] and lower mortality [hazard ratio (HR) 0.73 (95% CI 0.62-0.86)]. Maintenance IV iron strategies were associated with reduced ESA utilization and improved early survival but not with the achievement of Hb targets. © The Author 2016. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.

Recolonization by heterotrophic bacteria after UV irradiation or ozonation of seawater; a simulation of ballast water treatment.

PubMed

Hess-Erga, Ole-Kristian; Blomvågnes-Bakke, Bente; Vadstein, Olav

2010-10-01

Transport of ballast water with ships represents a risk for introduction of foreign species. If ballast water is treated during uptake, there will be a recolonization of the ballast water by heterotrophic bacteria during transport. We investigated survival and succession of heterotrophic bacteria after disinfection of seawater in the laboratory, representing a model system of ballast water treatment and transport. The seawater was exposed to ultraviolet (UV) irradiation, ozone (2 doses) or no treatment, incubated for 16 days and examined with culture-dependent and -independent methods. The number of colony-forming units (CFU) was reduced below the detection level after disinfection with UV and high ozone dose (700 mV), and 1% of the initial level for the low ozone dose (400 mV). After less than 3 days, the CFU was back or above the starting point for the control, UV and low ozone treatment, whereas it took slightly more than 6 days for the high ozone treatment. Disinfection increased substrate availability and reduced cell densities. Lack of competition and predation induced the recolonization by opportunistic bacteria (r-strategists), with significant increase in bacterial numbers and a low diversity (based on DGGE band pattern). All cultures stabilized after the initial recolonization phase (except Oz700) where competition due to crowding and nutrient limitation favoured bacteria with high substrate affinity (K-strategists), resulting in higher species richness and diversity (based on DGGE band pattern). The bacterial community was significantly altered qualitatively and quantitatively and may have a higher potential as invaders in the recipient depending on disinfection method and the time of release. These results have implications for the treatment strategy used for ballast water. Copyright © 2010 Elsevier Ltd. All rights reserved.

Induction and repair of DNA strand breaks in bovine lens epithelial cells after high LET irradiation

NASA Astrophysics Data System (ADS)

Baumstark-Khan, C.; Heilmann, J.; Rink, H.

The lens epithelium is the initiation site for the development of radiation induced cataracts. Radiation in the cortex and nucleus interacts with proteins, while in the epithelium, experimental results reveal mutagenic and cytotoxic effects. It is suggested that incorrectly repaired DNA damage may be lethal in terms of cellular reproduction and also may initiate the development of mutations or transformations in surviving cells. The occurrence of such genetically modified cells may lead to lens opacification. For a quantitative risk estimation for astronauts and space travelers it is necessary to know the relative biological effectiveness (RBE), because the spacial and temporal distribution of initial physical damage induced by cosmic radiation differ significantly from that of X-rays. RBEs for the induction of DNA strand breaks and the efficiency of repair of these breaks were measured in cultured diploid bovine lens epithelial cells exposed to different LET irradiation to either 300 kV X-rays or to heavy ions at the UNILAC accelerator at GSI. Accelerated ions from Z=8 (O) to Z=92 (U) were used. Strand breaks were measured by hydroxyapatite chromatography of alkaline unwound DNA (overall strand breaks). Results showed that DNA damage occurs as a function of dose, of kinetic energy and of LET. For particles having the same LET the severity of the DNA damage increases with dose. For a given particle dose, as the LET rises, the numbers of DNA strand breaks increase to a maximum and then reach a plateau or decrease. Repair kinetics depend on the fluence (irradiation dose). At any LET value, repair is much slower after heavy ion exposure than after X-irradiation. For ions with an LET of less than 10,000 keV μ -1 more than 90 percent of the strand breaks induced are repaired within 24 hours. At higher particle fluences, especially for low energetic particles with a very high local density of energy deposition within the particle track, a higher proportion of non-rejoined breaks is found, even after prolonged periods of incubation. At the highest LET value (16,300 keV μ -1 no significant repair is observed. These LET-dependencies are consistent with the current mechanistic model for radiation induced cataractogenesis which postulates that genomic damage to the surviving fraction of epithelial cells is responsible for lens opacification.

Subchronic chloroform priming protects mice from a subsequently administered lethal dose of chloroform

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

Philip, Binu K.; Anand, Sathanandam S.; Palkar, Prajakta S.

2006-10-01

Protection offered by pre-exposure priming with a small dose of a toxicant against the toxic and lethal effects of a subsequently administered high dose of the same toxicant is autoprotection. Although autoprotection has been extensively studied with diverse toxicants in acute exposure regimen, not much is known about autoprotection after priming with repeated exposure. The objective of this study was to investigate this concept following repeated exposure to a common water contaminant, chloroform. Swiss Webster (SW) mice, exposed continuously to either vehicle (5% Emulphor, unprimed) or chloroform (150 mg/kg/day po, primed) for 30 days, were challenged with a normally lethalmore » dose of chloroform (750 mg chloroform/kg po) 24 h after the last exposure. As expected, 90% of the unprimed mice died between 48 and 96 h after administration of the lethal dose in contrast to 100% survival of mice primed with chloroform. Time course studies indicated lower hepato- and nephrotoxicity in primed mice as compared to unprimed mice. Hepatic CYP2E1, glutathione levels (GSH), and covalent binding of {sup 14}C-chloroform-derived radiolabel did not differ between livers of unprimed and primed mice after lethal dose exposure, indicating that protection in liver is neither due to decreased bioactivation nor increased detoxification. Kidney GSH and glutathione reductase activity were upregulated, with a concomitant reduction in oxidized glutathione in the primed mice following lethal dose challenge, leading to decreased renal covalent binding of {sup 14}C-chloroform-derived radiolabel, in the absence of any change in CYP2E1 levels. Buthionine sulfoximine (BSO) intervention led to 70% mortality in primed mice challenged with lethal dose. These data suggest that higher detoxification may play a role in the lower initiation of kidney injury observed in primed mice. Exposure of primed mice to a lethal dose of chloroform led to 40% lower chloroform levels (AUC{sub 15-360min}) in the systemic circulation. Exhalation of {sup 14}C-chloroform was unchanged in primed as compared to unprimed mice (AUC{sub 1-6h}). Urinary excretion of {sup 14}C-chloroform was higher in primed mice after administration of the lethal dose. However, neither slightly higher urinary elimination nor unchanged expiration can account for the difference in systemic levels of chloroform. Liver and kidney regeneration was inhibited by the lethal dose in unprimed mice leading to progressive injury, organ failure, and 90% mortality. In contrast, sustained and highly stimulated compensatory hepato- and nephrogenic repair prevented the progression of injury resulting in 100% survival of primed mice challenged with the lethal dose. These findings affirm the critical role of tissue regeneration and favorable detoxification (only in kidney) of the lethal dose of chloroform in subchronic chloroform priming-induced autoprotection.« less

Increasing the dose of television advertising in a national antismoking media campaign: results from a randomised field trial

PubMed Central

McAfee, Tim; Davis, Kevin C; Shafer, Paul; Patel, Deesha; Alexander, Robert; Bunnell, Rebecca

2017-01-01

Background While antismoking media campaigns have demonstrated effectiveness, less is known about the country-level effects of increased media dosing. The 2012 US Tips From Former Smokers (Tips) campaign generated approximately 1.6 million quit attempts overall; however, the specific dose–response from the campaign was only assessed by self-report. Objective Assess the impact of higher ad exposure during the 2013 Tips campaign on quit-related behaviours and intentions, campaign awareness, communication about campaign, and disease knowledge. Methods A 3-month national media buy was supplemented within 67 (of 190) randomly selected local media markets. Higher-dose markets received media buys 3 times that of standard-dose markets. We compared outcomes of interest using data collected via web-based surveys from nationally representative, address-based probability samples of 5733 cigarette smokers and 2843 non-smokers. Results In higher-dose markets, 87.2% of smokers and 83.9% of non-smokers recalled television campaign exposure versus 75.0% of smokers and 73.9% of non-smokers in standard-dose markets. Among smokers overall, the relative quit attempt rate was 11% higher in higher-dose markets (38.8% vs 34.9%; p<0.04). The higher-dose increase was larger in African-Americans (50.9% vs 31.8%; p<0.01). Smokers in higher-dose markets without a mental health condition, with a chronic health condition, or with only some college education made quit attempts at a higher rate than those in standard-dose markets. Non-smokers in higher-dose markets were more likely to talk with family or friends about smoking dangers (43.1% vs 35.7%; p<0.01) and had greater knowledge of smoking-related diseases. Conclusions The US 2013 Tips antismoking media campaign compared standard and higher doses by randomisation of local media markets. Results demonstrate the effectiveness of a higher dose for engaging non-smokers and further increasing quit attempts among smokers, especially African-Americans. PMID:26678518

DNA Damage Levels Determine Cyclobutyl Pyrimidine Dimer Repair Mechanisms in Alfalfa Seedlings.

PubMed Central

Quaite, F. E.; Takayanagi, S.; Ruffini, J.; Sutherland, J. C.; Sutherland, B. M.

1994-01-01

Ultraviolet radiation in sunlight damages DNA in plants, but little is understood about the types, lesion capacity, and coordination of repair pathways. We challenged intact alfalfa seedlings with UV doses that induced different initial levels of cyclobutyl pyrimidine dimers and measured repair by excision and photoreactivation. By using alkaline gel electrophoresis of nonradioactive DNAs treated with a cyclobutyl pyrimidine dimer-specific UV endonuclease, we quantitated ethidium-stained DNA by electronic imaging and calculated lesion frequencies from the number average molecular lengths. At low initial dimer frequencies (less than ~30 dimers per million bases), the seedlings used only photoreactivation to repair dimers; excision repair was not significant. At higher damage levels, both excision and photorepair contributed significantly. This strategy would allow plants with low damage levels to use error-free repair requiring only an external light energy source, whereas seedlings subjected to higher damage frequencies could call on additional repair processes requiring cellular energy. Characterization of repair in plants thus requires an investigation of a range of conditions, including the level of initial damage. PMID:12244228

Development and Validation of a Questionnaire to Assess Carbohydrate and Insulin-Dosing Knowledge in Youth With Type 1 Diabetes

PubMed Central

Koontz, Michaela B.; Cuttler, Leona; Palmert, Mark R.; O'Riordan, MaryAnn; Borawski, Elaine A.; McConnell, Judy; Kern, Elizabeth O.

2010-01-01

OBJECTIVE The American Diabetes Association advocates insulin regimens for youth with type 1 diabetes that involve adjusting insulin dose based on carbohydrate intake and blood glucose level. Implementing these regimens requires knowledge about carbohydrate content of foods and subsequent calculations of insulin dose, skills that may be difficult to gauge in practice. Therefore, we sought to develop and validate a questionnaire, the PedCarbQuiz (PCQ), to assess carbohydrate and insulin-dosing knowledge in youth with type 1 diabetes. RESEARCH DESIGN AND METHODS After development by an expert panel, the PCQ was administered to 75 youth with type 1 diabetes or their parents. Reliability was assessed by Cronbach α and split-half testing. To assess validity, scores were correlated with A1C, expert assessments, parent educational level, and complexity of insulin regimen. RESULTS PCQ mean score was 87 ± 9.7% (range 42–98%). Cronbach α was 0.88, and correlation of split halves was 0.59 (P < 0.0001). Higher PCQ scores correlated significantly with lower A1C (r = −0.29, P = 0.01) and expert assessments (r = 0.56, P < 0.001). Scores were significantly higher in parents with college degrees than in those without (P = 0.01) and in participants with more complex insulin regimens (P = 0.003). CONCLUSIONS The PCQ is a novel, easily administered instrument to assess knowledge about carbohydrates and insulin dosing calculations. Initial analyses support the reliability and validity of the PCQ. PMID:20007940

The Effect of Allopurinol on Renal Function.

PubMed

Krishnamurthy, Aneesa; Lazaro, Deana; Stefanov, Dimitre G; Blumenthal, David; Gerber, Donald; Patel, Sheetal

2017-01-01

Hyperuricemia is associated with development of gout, hypertension, and renal disease. The impact of allopurinol, a urate-lowering therapy, on renal function is unclear, especially in patients with chronic kidney disease who are at higher risk of hypersensitivity reaction. The aim of this study was to determine the effect of allopurinol on kidney function in hyperuricemic male veterans. This is a retrospective cohort study using pharmacy, medical, and laboratory records of veterans enrolled at the Veterans Administration New York Harbor Healthcare System, Brooklyn campus. Fifty patients with hyperuricemia defined as a serum uric acid greater than 7 mg/dL (average of ~9 mg/dL), newly started on allopurinol for any reason, with evidence of treatment compliance, were matched by age, race, sex, and estimated glomerular filtration rate (EGFR) to 50 hyperuricemic control subjects. The retrospective cases were observed from October 2000 until November 2006, at which time there was a change in the laboratory analyzer, making further comparisons inappropriate. On average, patients treated with a mean 221 (SD, 96) mg/d dose of allopurinol achieved 11.9 mL/min higher GFR (95% confidence interval, 4.8-11.9 mg/d dose; P = 0.01) than did the control group. Treatment effect was found to depend on the initial EGFR, as indicated by the significant treatment by initial EGFR interaction (P = 0.004) and increased with a higher initial EGFR. The allopurinol-treated group had a 0.10 mg/dL lower final creatinine level (95% confidence interval, 0.003-0.20 mg/dL; P = 0.04) than did the control subjects, adjusted for initial creatinine and age. The average length of follow-up was 3.4 years. There were 5 mild adverse events in the treated cases. Treatment of hyperuricemic patients with allopurinol over an average of 3.4 years resulted in a significant improvement of kidney function in this male cohort from the Veterans Administration Healthcare System. Clinicians should consider this potential benefit of allopurinol in the treatment of patients with hyperuricemia, those with overall maintained renal function.

Initial clinical results with a new needle screen storage phosphor system in chest radiograms.

PubMed

Körner, M; Wirth, S; Treitl, M; Reiser, M; Pfeifer, K-J

2005-11-01

To evaluate image quality and anatomical detail depiction in dose-reduced digital plain chest radiograms using a new needle screen storage phosphor (NIP) in comparison to full dose conventional powder screen storage phosphor (PIP) images. 24 supine chest radiograms were obtained with PIP at standard dose and compared to follow-up studies of the same patients obtained with NIP with dose reduced to 50 % of the PIP dose (all imaging systems: AGFA-Gevaert, Mortsel, Belgium). In both systems identical versions of post-processing software supplied by the manufacturer were used with matched parameters. Six independent readers blinded to both modality and dose evaluated the images for depiction and differentiation of defined anatomical regions (peripheral lung parenchyma, central lung parenchyma, hilum, heart, diaphragm, upper mediastinum, and bone). All NIP images were compared to the corresponding PIP images using a five-point scale (- 2, clearly inferior to + 2, clearly superior). Overall image quality was rated for each PIP and NIP image separately (1, not usable to 5, excellent). PIP and dose reduced NIP images were rated equivalent. Mean image noise impression was only slightly higher on NIP images. Mean image quality for NIP showed no significant differences (p > 0.05, Mann-Whitney U test). With the use of the new needle structured storage phosphors in chest radiography, dose reduction of up to 50 % is possible without detracting from image quality or detail depiction. Especially in patients with multiple follow-up studies the overall dose can be decreased significantly.

Safety and immunogenicity of a booster dose of a 3-antigen Staphylococcus aureus vaccine (SA3Ag) in healthy adults: A randomized phase 1 study.

PubMed

Marshall, Helen; Nissen, Michael; Richmond, Peter; Shakib, Sepehr; Jiang, Qin; Cooper, David; Rill, Denise; Baber, James; Eiden, Joseph; Gruber, William C; Jansen, Kathrin U; Anderson, Annaliesa S; Zito, Edward T; Girgenti, Douglas

2016-11-01

A 2-stage, phase 1, randomized, placebo-controlled study in healthy adults to assess immunogenicity and safety of a booster dose at three dose levels of a 3-antigen Staphylococcus aureus vaccine (SA3Ag) containing recombinant clumping factor A (ClfA) and capsular polysaccharides 5 and 8 (CP5 and CP8) conjugated to a diphtheria toxoid. Six months after initial single vaccination, in Stage 2, SA3Ag recipients were randomized (1:1) to booster vaccination or placebo, while Stage 1 placebo recipients received placebo again. Pre- and post-vaccination blood samples were analyzed. In Stage 2 (n = 345), pre-booster CP5 and CP8 titers remained high with no increase post-booster. ClfA titers remained high after initial vaccination and increased post-booster, approaching the peak response to the initial dose. Post-booster local reactions were more frequent and of greater severity than reported after the initial vaccination, particularly for the high-dose level recipients. Post hoc analysis showed no dose-response pattern and no obvious association between diphtheria toxoid titers and local reactions after initial or booster vaccination. Immune responses after the initial vaccination persisted for the 12 months studied, with little additional response after the booster dose at 6 months. Post-booster injection site reactions were more frequent and more severe but self-limiting. CLINICALTRIALS. NCT01018641. Copyright © 2016 The British Infection Association. Published by Elsevier Ltd. All rights reserved.

A dose-response relationship between exposure to a large-scale HIV preventive intervention and consistent condom use with different sexual partners of female sex workers in southern India.

PubMed

Deering, Kathleen N; Boily, Marie-Claude; Lowndes, Catherine M; Shoveller, Jean; Tyndall, Mark W; Vickerman, Peter; Bradley, Jan; Gurav, Kaveri; Pickles, Michael; Moses, Stephen; Ramesh, Banadakoppa M; Washington, Reynold; Rajaram, S; Alary, Michel

2011-12-29

The Avahan Initiative, a large-scale HIV preventive intervention targeted to high-risk populations including female sex workers (FSWs), was initiated in 2003 in six high-prevalence states in India, including Karnataka. This study assessed if intervention exposure was associated with condom use with FSWs' sexual partners, including a dose-response relationship. Data were from a cross-sectional study (2006-07) of 775 FSWs in three districts in Karnataka. Survey methods accounted for the complex cluster sampling design. Bivariate and multivariable logistic regression was used to separately model the relationships between each of five intervention exposure variables and five outcomes for consistent condom use (CCU= always versus frequently/sometimes/never) with different sex partners, including with: all clients; occasional clients; most recent repeat client; most recent non-paying partner; and the husband or cohabiting partner. Linear tests for trends were conducted for three continuous intervention exposure variables. FSWs reported highest CCU with all clients (81.7%); CCU was lowest with FSWs' husband or cohabiting partner (9.6%). In multivariable analysis, the odds of CCU with all clients and with occasional clients were 6.3-fold [95% confidence intervals, CIs: 2.8-14.5] and 2.3-fold [95% CIs: 1.4-4.1] higher among FSWs contacted by intervention staff and 4.9-fold [95% CIs: 2.6-9.3] and 2.3-fold [95% CIs: 1.3-4.1] higher among those who ever observed a condom demonstration by staff, respectively, compared to those who had not. A significant dose-response relationship existed between each of these CCU outcomes and increased duration since first contacted by staff (P=0.001; P=0.006) and numbers of condom demonstrations witnessed (P=0.004; P=0.026); a dose-response relationship was also observed between condom use with all clients and number of times contacted by staff (P=0.047). Intervention exposure was not associated with higher odds of CCU with the most recent repeat client, most recent non-paying partner or with the husband or cohabiting partner. Study findings suggest that exposure to a large-scale HIV intervention for FSWs was associated with increased CCU with commercial clients. Moreover, there were dose-response relationships between CCU with clients and increased duration since first contacted by staff, times contacted by staff and number of condom demonstrations. Additional program effort is required to increase condom use with non-commercial partners.

A dose-response relationship between exposure to a large-scale HIV preventive intervention and consistent condom use with different sexual partners of female sex workers in southern India

PubMed Central

2011-01-01

Background The Avahan Initiative, a large-scale HIV preventive intervention targeted to high-risk populations including female sex workers (FSWs), was initiated in 2003 in six high-prevalence states in India, including Karnataka. This study assessed if intervention exposure was associated with condom use with FSWs’ sexual partners, including a dose-response relationship. Methods Data were from a cross-sectional study (2006-07) of 775 FSWs in three districts in Karnataka. Survey methods accounted for the complex cluster sampling design. Bivariate and multivariable logistic regression was used to separately model the relationships between each of five intervention exposure variables and five outcomes for consistent condom use (CCU= always versus frequently/sometimes/never) with different sex partners, including with: all clients; occasional clients; most recent repeat client; most recent non-paying partner; and the husband or cohabiting partner. Linear tests for trends were conducted for three continuous intervention exposure variables. Results FSWs reported highest CCU with all clients (81.7%); CCU was lowest with FSWs’ husband or cohabiting partner (9.6%). In multivariable analysis, the odds of CCU with all clients and with occasional clients were 6.3-fold [95% confidence intervals, CIs: 2.8-14.5] and 2.3-fold [95% CIs: 1.4-4.1] higher among FSWs contacted by intervention staff and 4.9-fold [95% CIs: 2.6-9.3] and 2.3-fold [95% CIs: 1.3-4.1] higher among those who ever observed a condom demonstration by staff, respectively, compared to those who had not. A significant dose-response relationship existed between each of these CCU outcomes and increased duration since first contacted by staff (P=0.001; P=0.006) and numbers of condom demonstrations witnessed (P=0.004; P=0.026); a dose-response relationship was also observed between condom use with all clients and number of times contacted by staff (P=0.047). Intervention exposure was not associated with higher odds of CCU with the most recent repeat client, most recent non-paying partner or with the husband or cohabiting partner. Conclusion Study findings suggest that exposure to a large-scale HIV intervention for FSWs was associated with increased CCU with commercial clients. Moreover, there were dose-response relationships between CCU with clients and increased duration since first contacted by staff, times contacted by staff and number of condom demonstrations. Additional program effort is required to increase condom use with non-commercial partners. PMID:22375863

Breast conserving treatment for breast cancer: dosimetric comparison of sequential versus simultaneous integrated photon boost.

PubMed

Van Parijs, Hilde; Reynders, Truus; Heuninckx, Karina; Verellen, Dirk; Storme, Guy; De Ridder, Mark

2014-01-01

Breast conserving surgery followed by whole breast irradiation is widely accepted as standard of care for early breast cancer. Addition of a boost dose to the initial tumor area further reduces local recurrences. We investigated the dosimetric benefits of a simultaneously integrated boost (SIB) compared to a sequential boost to hypofractionate the boost volume, while maintaining normofractionation on the breast. For 10 patients 4 treatment plans were deployed, 1 with a sequential photon boost, and 3 with different SIB techniques: on a conventional linear accelerator, helical TomoTherapy, and static TomoDirect. Dosimetric comparison was performed. PTV-coverage was good in all techniques. Conformity was better with all SIB techniques compared to sequential boost (P = 0.0001). There was less dose spilling to the ipsilateral breast outside the PTVboost (P = 0.04). The dose to the organs at risk (OAR) was not influenced by SIB compared to sequential boost. Helical TomoTherapy showed a higher mean dose to the contralateral breast, but less than 5 Gy for each patient. SIB showed less dose spilling within the breast and equal dose to OAR compared to sequential boost. Both helical TomoTherapy and the conventional technique delivered acceptable dosimetry. SIB seems a safe alternative and can be implemented in clinical routine.

Breast Conserving Treatment for Breast Cancer: Dosimetric Comparison of Sequential versus Simultaneous Integrated Photon Boost

PubMed Central

Reynders, Truus; Heuninckx, Karina; Verellen, Dirk; Storme, Guy; De Ridder, Mark

2014-01-01

Background. Breast conserving surgery followed by whole breast irradiation is widely accepted as standard of care for early breast cancer. Addition of a boost dose to the initial tumor area further reduces local recurrences. We investigated the dosimetric benefits of a simultaneously integrated boost (SIB) compared to a sequential boost to hypofractionate the boost volume, while maintaining normofractionation on the breast. Methods. For 10 patients 4 treatment plans were deployed, 1 with a sequential photon boost, and 3 with different SIB techniques: on a conventional linear accelerator, helical TomoTherapy, and static TomoDirect. Dosimetric comparison was performed. Results. PTV-coverage was good in all techniques. Conformity was better with all SIB techniques compared to sequential boost (P = 0.0001). There was less dose spilling to the ipsilateral breast outside the PTVboost (P = 0.04). The dose to the organs at risk (OAR) was not influenced by SIB compared to sequential boost. Helical TomoTherapy showed a higher mean dose to the contralateral breast, but less than 5 Gy for each patient. Conclusions. SIB showed less dose spilling within the breast and equal dose to OAR compared to sequential boost. Both helical TomoTherapy and the conventional technique delivered acceptable dosimetry. SIB seems a safe alternative and can be implemented in clinical routine. PMID:25162031

Exposure-safety and efficacy response relationships and population pharmacokinetics of eslicarbazepine acetate.

PubMed

Gidal, B E; Jacobson, M P; Ben-Menachem, E; Carreño, M; Blum, D; Soares-da-Silva, P; Falcão, A; Rocha, F; Moreira, J; Grinnell, T; Ludwig, E; Fiedler-Kelly, J; Passarell, J; Sunkaraneni, S

2018-05-06

Eslicarbazepine acetate (ESL) is a once-daily (QD) oral antiepileptic drug (AED) for focal-onset seizures (FOS). Pharmacokinetic (PK) and pharmacodynamic (PD) models were developed to assess dose selection, identify significant AED drug interactions, and quantitate relationships between exposure and safety and efficacy outcomes from Phase 3 trials of adjunctive ESL. Eslicarbazepine (the primary active metabolite of ESL) population PK was evaluated using data from 1351 subjects enrolled in 14 studies (11 Phase 1 and three Phase 3 studies) after multiple oral doses ranging from 400 to 1200 mg. Population PK and PD models related individual eslicarbazepine exposures to safety outcomes and efficacy responses. Eslicarbazepine PK was described by a one-compartment model with linear absorption and elimination. The probability of a treatment-emergent adverse event (TEAE; dizziness, headache, or somnolence) was higher with an initial dose of ESL 800 mg than with an initial dose of ESL 400 mg QD. Body weight, sex, region, and baseline use of carbamazepine (CBZ) or lamotrigine were also found to influence the probability of TEAEs. Eslicarbazepine exposure influenced serum sodium concentration, standardized seizure frequency, and probability of response; better efficacy outcomes were predicted in patients not from Western Europe (WE; vs WE patients) and those not taking CBZ (vs taking CBZ) at baseline. Pharmacokinetic and PK/PD modeling were implemented during the development of ESL for adjunctive treatment of FOS in adults. This quantitative approach supported decision-making during the development of ESL, and contributed to dosing recommendations and labeling information related to drug interactions. © 2018 The Authors. Acta Neurologica Scandinavica Published by John Wiley & Sons Ltd.

Utilization of cone-beam CT for offline evaluation of target volume coverage during prostate image-guided radiotherapy based on bony anatomy alignment.

PubMed

Paluska, Petr; Hanus, Josef; Sefrova, Jana; Rouskova, Lucie; Grepl, Jakub; Jansa, Jan; Kasaova, Linda; Hodek, Miroslav; Zouhar, Milan; Vosmik, Milan; Petera, Jiri

2012-01-01

To assess target volume coverage during prostate image-guided radiotherapy based on bony anatomy alignment and to assess possibility of safety margin reduction. Implementation of IGRT should influence safety margins. Utilization of cone-beam CT provides current 3D anatomic information directly in irradiation position. Such information enables reconstruction of the actual dose distribution. Seventeen prostate patients were treated with daily bony anatomy image-guidance. Cone-beam CT (CBCT) scans were acquired once a week immediately after bony anatomy alignment. After the prostate, seminal vesicles, rectum and bladder were contoured, the delivered dose distribution was reconstructed. Target dose coverage was evaluated by the proportion of the CTV encompassed by the 95% isodose. Original plans employed a 1 cm safety margin. Alternative plans assuming a smaller 7 mm margin between CTV and PTV were evaluated in the same way. Rectal and bladder volumes were compared with the initial ones. Rectal and bladder volumes irradiated with doses higher than 75 Gy, 70 Gy, 60 Gy, 50 Gy and 40 Gy were analyzed. In 12% of reconstructed plans the prostate coverage was not sufficient. The prostate underdosage was observed in 5 patients. Coverage of seminal vesicles was not satisfactory in 3% of plans. Most of the target underdosage corresponded to excessive rectal or bladder filling. Evaluation of alternative plans assuming a smaller 7 mm margin revealed 22% and 11% of plans where prostate and seminal vesicles coverage, respectively, was compromised. These were distributed over 8 and 7 patients, respectively. Sufficient dose coverage of target volumes was not achieved for all patients. Reducing of safety margin is not acceptable. Initial rectal and bladder volumes cannot be considered representative for subsequent treatment.

Effects of electron beam radiation dose on the compatibilization behaviour in recycled polypropylene/microcrystalline cellulose composites

NASA Astrophysics Data System (ADS)

Samat, N.; Motsidi, S. N. R.; Lazim, N. H. M.

2018-01-01

The purpose of this research was to evaluate the influence of dose level of electron beam on the compatibilization behavior of recycled polypropylene (rPP) in rPP/microcrystalline cellulose (MCC) composites. Initially, the rPP was irradiated with various dose of electron beam (5 kGy up to 250 kGy) which then mixed with unirradiated rPP (u-rPP) at a ratio of 30:70 respectively. The composites were prepared by incorporating a series wt% of MCC fibers into rPP (u-rPP : i-rPP) using extruder and finally moulded with an injection moulding machine. The compatibility behavior of irradiated rPP (i-rPP) were analysed with mechanical tensile and thermal methods. The results of mechanical analysis showed great improvement in tensile modulus but an increase in radiation dosage gradually decreased this property. Nevertheless, the tensile strength exhibited a minor effect. The thermal stability of composites is lowered with increase in the absorbed dose, more significantly at higher content of MCC. Fracture surface observations reveal adhesion between the cellulose and rPP matrix.

TH-C-19A-05: Evaluation of a New Reusable 3D Dosimeter

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

Juang, T; Adamovics, J; Oldham, M

Purpose: PRESAGE is a radiochromic plastic which has demonstrated strong potential for high resolution single-use 3D dosimetry. This study evaluates a new PRESAGE formulation (Presage-RU) in which the radiochromic response is reversible (the dosimeter optically clears after irradiation), enabling the potential for reusability. Methods: Presage-RU dose response and optical-clearing rates were evaluated in both small volume dosimeters (1×1×4.5cm) and a larger cylindrical dosimeter (8cm diameter, 4.5cm length). All dosimeters were allowed to fully optically clear in dark, room temperature conditions between irradiations. Dose response was determined by irradiating small volume samples from 0–8.0Gy and measuring change in optical density. Themore » cylindrical dosimeter was irradiated with a simple 4-field box plan (parallel opposed pairs of 4cm×4cm AP-PA beams and 2cm×4cm lateral beams) to 20Gy. High resolution 3D dosimetry was achieved utilizing optical-CT readout. Readings were tracked up to 14 days to characterize optical clearing. Results: Initial irradiation yielded a response of 0.0119△OD/(Gy*cm) while two subsequent reirradiations yielded a lower but consistent response of 0.0087△OD/(Gy*cm). Strong linearity of dose response was observed for all irradiations. In the large cylindrical dosimeter, the integral dose within the high dose region exhibited an exponential decay in signal over time (halflife= 23.9 hours), with the dosimeter effectively cleared (0.04% of the initial signal) after 10 days. Subsequent irradiation resulted in 19.5% lower initial signal but demonstrated that the exponential clearing rate remained consistent. Results of additional subsequent irradiations will also be presented. Conclusion: This work introduces a new re-usable radiochromic dosimeter (Presage-RU) compatible with high resolution (sub-millimeter) 3D dosimetry. Sensitivity of the initial radiation was observed to be slightly higher than subsequent irradiations, but the clearing time remained constant, indicating the dosimeter can be re-used after 10 days. Presage-RU has potential to dramatically improve cost-effectiveness and thereby lower the barrier for implementing comprehensive, high resolution 3D dosimetry. John Adamovics is the president of Heuris Inc., which commercializes PRESAGE.« less

Evidence for single-dose protection by the bivalent HPV vaccine-Review of the Costa Rica HPV vaccine trial and future research studies.

PubMed

Kreimer, Aimée R; Herrero, Rolando; Sampson, Joshua N; Porras, Carolina; Lowy, Douglas R; Schiller, John T; Schiffman, Mark; Rodriguez, Ana Cecilia; Chanock, Stephen; Jimenez, Silvia; Schussler, John; Gail, Mitchell H; Safaeian, Mahboobeh; Kemp, Troy J; Cortes, Bernal; Pinto, Ligia A; Hildesheim, Allan; Gonzalez, Paula

2018-01-20

The Costa Rica Vaccine Trial (CVT), a phase III randomized clinical trial, provided the initial data that one dose of the HPV vaccine could provide durable protection against HPV infection. Although the study design was to administer all participants three doses of HPV or control vaccine, 20% of women did not receive the three-dose regimens, mostly due to involuntary reasons unrelated to vaccination. In 2011, we reported that a single dose of the bivalent HPV vaccine could be as efficacious as three doses of the vaccine using the endpoint of persistent HPV infection accumulated over the first four years of the trial; findings independently confirmed in the GSK-sponsored PATRICIA trial. Antibody levels after one dose, although lower than levels elicited by three doses, were 9-times higher than levels elicited by natural infection. Importantly, levels remained essentially constant over at least seven years, suggesting that the observed protection provided by a single dose might be durable. Much work has been done to assure these non-randomized findings are valid. Yet, the group of recipients who received one dose of the bivalent HPV vaccine in the CVT and PATRICIA trials was small and not randomly selected nor blinded to the number of doses received. The next phase of research is to conduct a formal randomized, controlled trial to evaluate the protection afforded by a single dose of HPV vaccine. Complementary studies are in progress to bridge our findings to other populations, and to further document the long-term durability of antibody response following a single dose. Published by Elsevier Ltd.

Inflammatory subtypes in cough-variant asthma: association with maintenance doses of inhaled corticosteroids.

PubMed

Matsuoka, Hirofumi; Niimi, Akio; Matsumoto, Hisako; Takemura, Masaya; Ueda, Tetsuya; Yamaguchi, Masafumi; Jinnai, Makiko; Inoue, Hideki; Ito, Isao; Chin, Kazuo; Mishima, Michiaki

2010-12-01

Sputum cell-subtype profiles in cough-variant asthma (CVA) are unknown. Ninety-eight inhaled corticosteroid (ICS)-naive CVA patients were classified according to sputum eosinophil (eos)/neutrophil (neu) counts, as reported in subjects with asthma, as eosinophilic (E) (eos ≥ 1.0%, neu < 61%; n = 28), neutrophilic (N) (eos < 1.0%, neu ≥ 61%; n = 31), mixed granulocytic (M) (eos ≥ 1.0%, neu ≥ 61%; n = 12), and paucigranulocytic (P) (eos < 1.0%, neu < 61%; n = 27) subtypes. Patient characteristics; sputum levels of eosinophil cationic protein (ECP), IL-8, and neutrophil elastase (NE); and daily ICS doses required to maintain control during follow-up (6, 12, 18, and 24 months) were compared, retrospectively. Subtype N patients, predominantly women, were marginally older than the other subtypes, but FEV(1), airway responsiveness, and total and specific IgE results did not differ. ECP levels were higher in M and E than in N and P subtypes, being similar between M and E or N and P subtypes. Levels of IL-8 and NE were higher in M than in other subtypes, being similar among the latter. ICS doses were initially similar in all subtypes (800 μg equivalent of beclomethasone) but were higher in M than in N and P subtypes throughout follow-up, with E being intermediate between M and N or P subtypes. ICS doses decreased (halved or quartered) in E, N, and P patients followed for 24 months (P < .0001 for all) but remained unchanged in M subjects. IL-8 and NE levels correlated positively with ECP levels. In addition to eosinophils, neutrophils, which are possibly activated in the presence of eosinophils, may participate in the pathophysiology of CVA.

Clinical features and prognostic factors in patients with bone metastases from hepatocellular carcinoma receiving external beam radiotherapy.

PubMed

He, Jian; Zeng, Zhao-Chong; Tang, Zhao-You; Fan, Jia; Zhou, Jian; Zeng, Meng-Su; Wang, Jian-Hua; Sun, Jing; Chen, Bing; Yang, Ping; Pan, Bai-Sheng

2009-06-15

The current study was performed to identify clinical features and independent predictors of survival in patients with bone metastases from hepatocellular carcinoma (HCC). Patients (n = 205) with bone metastases from HCC received external beam radiotherapy (EBRT) between 1997 and 2007. Demographic variables, laboratory values, tumor characteristics, and treatment modalities were determined before EBRT. The total radiation dose ranged from 32 to 66 grays (Gy) (median, 50 Gy) and was focused on the involved bone. In 80 of 205 (39.0%) patients with bone metastasis from HCC, tumors were characterized by osteolytic, expansile soft-tissue masses. Overall pain relief from EBRT occurred in 204 patients (99.5%). No consistent dose-response relation was found for palliation of bone metastases with doses between 32 and 66 Gy (P = .068), but the retreatment rate was higher in patients with expansile soft tissue. On univariate analysis, shorter survival was associated with poorer Karnofsky performance status (KPS), higher gamma-glutamyltransferase and alpha-fetoprotein levels, tumor size >5 cm, uncontrolled intrahepatic tumors, multifocal bone lesions, involvement of spinal vertebrae, extraosseous metastases, and a shorter disease-free interval after an initial diagnosis of HCC. On multivariate analysis, pretreatment-unfavorable predictors were associated with lower KPS, higher tumor markers, and uncontrolled intrahepatic tumor when KPS was considered. The median survival was 7.4 months. The results of the current study provide detailed information regarding clinical features, survival outcomes, and prognostic factors for HCC with bone metastases in a relatively large cohort of patients treated with EBRT. These prognostic factors will help in determining which dose and fraction are appropriate. (c) 2009 American Cancer Society.

De novo kidney transplant recipients need higher doses of Advagraf compared with Prograf to get therapeutic levels.

PubMed

Crespo, M; Mir, M; Marin, M; Hurtado, S; Estadella, C; Gurí, X; Rap, O; Moral, R; Puig, J M; Lloveras, J

2009-01-01

Advagraf is a new modified-release once-daily formulation of tacrolimus with a similar efficacy and safety profile to twice-daily tacrolimus (Prograf) according to clinical trials. Few data are published about its use in clinical practice, outside of sponsored clinical trials. We compared efficacy and basic pharmacokinetics of once-daily and twice-daily tacrolimus in de novo renal transplantation. The Advagraf group included 26 de novo renal cases who had received initial immunosuppression with once-daily tacrolimus (0.2 mg/kg from day 1 posttransplantation) combined with mycophenolic acid, steroids, and anti-CD25 monoclonal antibodies (2 doses). We compared them with a Prograf group of 26 transplants performed immediately before, who received equivalent immunosuppression with twice-daily tacrolimus (0.2 mg/kg from day 1). We did not observe significant differences between groups in demographics, efficacy, and basic pharmacokinetics, namely, tacrolimus trough levels at 7, 15, 30, 60, or 90 days. We found that recipients on Advagraf needed significantly higher tacrolimus doses per kg up to 6 months post-transplantation than those on Prograf: 0.16 vs 0.11; 0.14 vs 0.08; and 0.12 vs 0.08 mg/kg at 1, 3, and 6 months. No patient suffered severe liver dysfunction. There were no differences between groups in the administration of drugs interacting with CYP3A4 or prokinetics, which could alter tacrolimus pharmacokinetics. Among de novo renal cases, the new once-daily formulation of tacrolimus offered a similar short-term efficacy profile as the twice-daily tacrolimus. But it was necessary to use up to a 50% higher dose of Advagraf than Prograf to achieve similar trough levels during the first 6 months.

Irradiation of Anastrepha fraterculus (Diptera: Tephritidae) Eggs to Inhibit Fly Emergence in the Mass-Rearing of Diachasmimorpha longicaudata (Hymenoptera: Braconidae)

PubMed Central

Costa, M. L. Z.; Pacheco, M. G.; Lopes, L. A.; Botteon, V. W.; Mastrangelo, T.

2016-01-01

As the incidence of Anastrepha fraterculus (Wiedemann) has increased in Southern Brazil in the past 3 yr, an initiative to release sterile flies and parasitoids has started. In order to make feasible the mass-rearing of the parasitoid Diachasmimorpha longicaudata (Ashmed), this study investigated the suitability of A. fraterculus larvae derived from irradiated eggs as host for D. longicaudata. Two different ages of A. fraterculus eggs (24 and 48 h old) were analyzed for hatchability after the exposure to a range of radiation doses. The hatchability of 48-h-old eggs was not affected by radiation, and no fly emerged at doses higher than 27.5 Gy. The larvae derived from irradiated eggs proved to be suitable hosts for the parasitoid development, with observed parasitism rates higher than 70% and sex ratio values above 0.6. The parasitism capability and longevity of D. longicaudata reared on larvae derived from irradiated eggs were also assessed. During the 10 d of parasitism evaluated, D. longicaudata from the treatments were able to parasitize nonirradiated larvae similarly as the parasitoids from controls and the laboratory colony. The longevity of D. longicaudata from the treatments was not affected either, with survival rates higher than 80% after 20 d of evaluation. The age of 48 h and a dose of 30 Gy could be considered the best age and dose for A. fraterculus eggs to be used in the mass-rearing of D. longicaudata. The results of this study will decrease the costs of mass-rearing D. longicaudata on A. fraterculus. PMID:27638956

Statin Safety in Chinese: A Population-Based Study of Older Adults.

PubMed

Li, Daniel Q; Kim, Richard B; McArthur, Eric; Fleet, Jamie L; Hegele, Robert A; Shah, Baiju R; Weir, Matthew A; Molnar, Amber O; Dixon, Stephanie; Tu, Jack V; Anand, Sonia; Garg, Amit X

2016-01-01

Compared to Caucasians, Chinese achieve a higher blood concentration of statin for a given dose. It remains unknown whether this translates to increased risk of serious statin-associated adverse events amongst Chinese patients. We conducted a population-based retrospective cohort study of older adults (mean age, 74 years) newly prescribed a statin in Ontario, Canada between 2002 and 2013, where 19,033 Chinese (assessed through a validated surname algorithm) were matched (1:3) by propensity score to 57,099 non-Chinese. This study used linked healthcare databases. The follow-up observation period (mean 1.1, maximum 10.8 years) was similar between groups, as were the reasons for censoring the observation period (end of follow-up, death, or statin discontinuation). Forty-seven percent (47%) of Chinese were initiated on a higher than recommended statin dose. Compared to non-Chinese, Chinese ethnicity did not associate with any of the four serious statin-associated adverse events assessed in this study [rhabdomyolysis hazard ratio (HR) 0.61 (95% CI 0.28 to 1.34), incident diabetes HR 1.02 (95% CI 0.80 to 1.30), acute kidney injury HR 0.90 (95% CI 0.72 to 1.13), or all-cause mortality HR 0.88 (95% CI 0.74 to 1.05)]. Similar results were observed in subgroups defined by statin type and dose. We observed no higher risk of serious statin toxicity in Chinese than matched non-Chinese older adults with similar indicators of baseline health. Regulatory agencies should review available data, including findings from our study, to decide if a change in their statin dosing recommendations for people of Chinese ethnicity is warranted.

Increasing the dose of television advertising in a national antismoking media campaign: results from a randomised field trial.

PubMed

McAfee, Tim; Davis, Kevin C; Shafer, Paul; Patel, Deesha; Alexander, Robert; Bunnell, Rebecca

2017-01-01

While antismoking media campaigns have demonstrated effectiveness, less is known about the country-level effects of increased media dosing. The 2012 US Tips From Former Smokers (Tips) campaign generated approximately 1.6 million quit attempts overall; however, the specific dose-response from the campaign was only assessed by self-report. Assess the impact of higher ad exposure during the 2013 Tips campaign on quit-related behaviours and intentions, campaign awareness, communication about campaign, and disease knowledge. A 3-month national media buy was supplemented within 67 (of 190) randomly selected local media markets. Higher-dose markets received media buys 3 times that of standard-dose markets. We compared outcomes of interest using data collected via web-based surveys from nationally representative, address-based probability samples of 5733 cigarette smokers and 2843 non-smokers. In higher-dose markets, 87.2% of smokers and 83.9% of non-smokers recalled television campaign exposure versus 75.0% of smokers and 73.9% of non-smokers in standard-dose markets. Among smokers overall, the relative quit attempt rate was 11% higher in higher-dose markets (38.8% vs 34.9%; p<0.04). The higher-dose increase was larger in African-Americans (50.9% vs 31.8%; p<0.01). Smokers in higher-dose markets without a mental health condition, with a chronic health condition, or with only some college education made quit attempts at a higher rate than those in standard-dose markets. Non-smokers in higher-dose markets were more likely to talk with family or friends about smoking dangers (43.1% vs 35.7%; p<0.01) and had greater knowledge of smoking-related diseases. The US 2013 Tips antismoking media campaign compared standard and higher doses by randomisation of local media markets. Results demonstrate the effectiveness of a higher dose for engaging non-smokers and further increasing quit attempts among smokers, especially African-Americans. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.

The Utility of Low-Dose Aripiprazole for the Treatment of Bipolar II and Bipolar NOS Depression.

PubMed

Kelly, Tammas; Lieberman, Daniel Z

2017-02-01

Despite initial reports of efficacy in bipolar depression, multicenter trials did not show aripiprazole to be better than placebo, possibly because the doses used were too high, leading to lower efficacy and high dropout rates. This study evaluated the effects of low-dose aripiprazole. Extensive clinical experience has suggested that doses beyond 5 mg are rarely efficacious. Data were gathered from patients with bipolar II or bipolar not otherwise specified depression using a retrospective chart review. Efficacy was assessed with the Clinical Global Impression-Improvement score. Patients who had at least 2 trials of aripiprazole were included in a retrospective off-on-off-on experimental design. All patients were on other medications when aripiprazole was started. Patients were treated with doses of 1 to 5 mg. On average, patients were rated improved or very much improved compared with baseline. Sixteen of 211 patients worsened or experienced no change. Forty-four patients (21%) discontinued due to adverse effects. The group of patients who underwent off-on-off-on trials experienced statistically significant improvement when they started and restarted aripiprazole, and statistically significant worsening when they discontinued it. When treating bipolar II or bipolar not otherwise specified depression, low doses of aripiprazole, 5 mg or less, may be more effective and better tolerated than higher ones. Clinicians should start treatment with a very low dose and give patients time to respond.

Predictors of Energy Compensation during Exercise Interventions: A Systematic Review

PubMed Central

Riou, Marie-Ève; Jomphe-Tremblay, Simon; Lamothe, Gilles; Stacey, Dawn; Szczotka, Agnieszka; Doucet, Éric

2015-01-01

Weight loss from exercise-induced energy deficits is usually less than expected. The objective of this systematic review was to investigate predictors of energy compensation, which is defined as body energy changes (fat mass and fat-free mass) over the total amount of exercise energy expenditure. A search was conducted in multiple databases without date limits. Of 4745 studies found, 61 were included in this systematic review with a total of 928 subjects. The overall mean energy compensation was 18% ± 93%. The analyses indicated that 48% of the variance of energy compensation is explained by the interaction between initial fat mass, age and duration of exercise interventions. Sex, frequency, intensity and dose of exercise energy expenditure were not significant predictors of energy compensation. The fitted model suggested that for a shorter study duration, lower energy compensation was observed in younger individuals with higher initial fat mass (FM). In contrast, higher energy compensation was noted for younger individuals with lower initial FM. From 25 weeks onward, energy compensation was no longer different for these predictors. For studies of longer duration (about 80 weeks), the energy compensation approached 84%. Lower energy compensation occurs with short-term exercise, and a much higher level of energy compensation accompanies long-term exercise interventions. PMID:25988763

Sustained availability of trimethoprim in drinking water to achieve higher plasma sulphonamide-trimethoprim antibacterial activity in broilers.

PubMed

Sumano, H; Hernandez, L; Gutierrez, L; Bernad-Bernad, M J

2005-02-01

(1) In order to make trimethoprim (TMP) available to broilers throughout the day, a sustained release formulation (SRF) of the drug in the form of granules was added to the water tank that supplies drinking water. (2) Broilers were initially dosed with sulphachloropiridazine-TMP (SCP-TMP 5:1) and then further medicated throughout the day, achieving in the end a dose of 30 mg/kg each of SCP and TMP (group A). Group B received a preparation with the same dose of SCP and TMP (1:1) as group A, but administered as a single dose without the SRF of TMP. Group C received the customary SCP-TMP 5:1 preparation (30 and 6 mg/kg, respectively). Water tanks were completely consumed in 3 to 4 h. (3) Broilers were bled at different times and concentration of antibacterial activity in serum determined by correlating the composite antibacterial activity of SCP and TMP with actual concentrations of these drugs by means of a microbiological agar diffusion assay. (4) Time vs serum concentrations of activity were higher in group B; the increments in the maximum serum concentration for group B over groups A and C being 39 and 67%, respectively. (5) However, the sustained concentration of activity over time, measured as the area under the cu)rve, was highest in group A. Group B had higher values for area under the curve than group C. (6) An additional dose of TMP to achieve 30 mg/kg of both SCP and TMP improves the serum concentration of this combination over the customary 5:1 proportion. The best values for sustaining antibacterial activity were obtained using a 1:1 ratio as in group A. The use of a SRF as in group A may translate into better clinical results.

Association of both consistency and strength of self-reported clinician recommendation for HPV vaccination and HPV vaccine uptake among 11- to 12-year-old children.

PubMed

Finney Rutten, Lila J; St Sauver, Jennifer L; Beebe, Timothy J; Wilson, Patrick M; Jacobson, Debra J; Fan, Chun; Breitkopf, Carmen Radecki; Vadaparampil, Susan T; MacLaughlin, Kathy L; Jacobson, Robert M

2017-10-27

We tested the hypotheses that consistency and strength of clinician recommendation of the human papillomavirus (HPV) vaccination would be associated with vaccine delivery rates. From October 2015 through January 2016, we conducted a survey of primary care clinicians (n=227) in Southeastern Minnesota to evaluate clinician behaviors regarding HPV vaccination. The survey response rate was 41.0% (51 clinical sites). We used the Rochester Epidemiology Project, a clinical data linkage infrastructure, to ascertain clinical site-level HPV vaccination rates. We examined associations of clinician self-reports of both the consistency and strength of their recommendations for HPV vaccination for patients aged 11-12years (n=14,406) with site-level vaccination rates. The majority of clinicians reported consistently (always or usually) recommending the HPV vaccine to females (79.0%) and to males (62.2%); 71.9% of clinicians reported strongly recommending the vaccine to females while 58.6% reported strongly recommending to males. Consistency and strength of recommending the HPV vaccine was significantly higher among those practicing in pediatrics and board certified in pediatrics compared to family medicine. Higher rates of initiation (1 dose) [Incidence Rate Ratio (IRR)=1.05; 95% CI (1.01-1.09)] and completion (3 doses) [IRR=1.08; 95% CI (1.02-1.13)] were observed among clinical sites where, on average, clinicians more frequently reported always or usually recommending the vaccine for females compared to sites where, on average, clinicians reported recommending the vaccine less frequently. Similarly, higher rates of initiation [IRR=1.03; 95% CI (1.00-1.06)] and completion [IRR=1.04; CI (1.00, 1.08)] were observed among sites where clinicians reported strongly recommending the vaccine to females more frequently compared to sites where, on average, clinicians reported strongly recommending the HPV vaccine less frequently; similar associations were observed for male initiation [IRR=1.05; CI (1.02,1.08)] and completion [IRR=1.05; 95% CI (1.01, 1.09)]. Consistency and strength of HPV vaccination recommendation was associated with higher vaccination rates. Copyright © 2017 Elsevier Ltd. All rights reserved.

Doses of olanzapine, risperidone, and haloperidol used in clinical practice: results of a prospective pharmacoepidemiologic study. EFESO Study Group. Estudio Farmacoepidemiologico en la Esquizofrenia con Olanzapina.

PubMed

Sacristán, J A; Gómez, J C; Montejo, A L; Vieta, E; Gregor, K J

2000-05-01

The objectives of this study were to determine the doses of olanzapine (OLZ), risperidone (RIS), and haloperidol (HAL) used in clinical practice in outpatients with schizophrenia and the rates of occurrence of extrapyramidal symptoms (EPS) and other adverse events, clinical response, and use of concomitant medications. The present study involved a subset of patients from a 6-month, open-label, prospective observational study. Data were collected by 293 psychiatrists at mental health centers and other outpatient treatment facilities in Spain. Medications and doses used, occurrence of EPS and other adverse events, and scores on the Clinical Global Impression (CGI) of Severity Scale and Global Assessment of Function (GAF) were recorded. Clinical response was defined as a decrease of > or = 2 points on the CGI, with a final CGI score < or = 4. A total of 2657 patients were included in the analysis. The initial and overall mean daily doses for the 3 groups were as follows: OLZ, 12.2 and 13.0 mg, respectively; RIS, 5.2 and 5.4 mg; and HAL, 13.9 and 13.6 mg. Initial and overall median daily doses were the same in each group: OLZ, 10 mg; RIS, 6 mg; and HAL, 10 mg. A significantly lower proportion of OLZ-treated patients (36.9%) experienced EPS compared with RIS-treated (49.6%) and HAL-treated (76.0%) patients (P < or = 0.001). A significantly lower proportion of patients in the OLZ group (47.8%) experienced adverse events compared with patients in the RIS (57.2%) and HAL (79.8%) groups (P < or = 0.001). A significantly greater proportion of OLZ-treated patients (37.3%) were responders compared with RIS-treated patients (31.5%) (P < 0.05). In all 3 groups, patients who had an initial CGI score > or = 5 received significantly higher overall mean daily doses than did patients with an initial CGI score < 5 (P < 0.001). A significantly lower proportion of OLZ-treated patients (10.2%) were receiving concomitant anticholinergic medication at the end of the study (month 6) compared with RIS-treated (19.9%) and HAL-treated (44.0%) patients (P < 0.001). The mean daily doses recorded in this analysis based on data from a naturalistic setting are consistent with recommendations based on clinical trials. Compared with both RIS- and HAL-treated patients, OLZ-treated patients were less likely to experience EPS or other adverse events, and less likely to use concomitant anticholinergic medications. OLZ-treated patients were also more likely to respond to treatment than were RIS-treated patients.

A Budget Impact Model of Hemophilia Bypassing Agent Prophylaxis Relative to Recombinant Factor VIIa On-Demand.

PubMed

Mehta, Darshan A; Oladapo, Abiola O; Epstein, Joshua D; Novack, Aaron R; Neufeld, Ellis J; Hay, Joel W

2016-02-01

Hemophilia patients use factor-clotting concentrates (factor VIII for hemophilia A and factor IX for hemophilia B) for improved blood clotting. These products are used to prevent or stop bleeding episodes. However, some hemophilia patients develop inhibitors (i.e., the patient's immune system develops antibodies against these factor concentrates). Hence, these patients do not respond well to the factor concentrates. A majority of hemophilia patients with inhibitors are managed on-demand with the following bypassing agents: recombinant factor VIIa (rFVIIa) and activated prothrombin complex concentrate (aPCC). The recently published U.S. registries Dosing Observational Study in Hemophilia (DOSE) and Hemostasis and Thrombosis Research Society (HTRS) reported higher rFVIIa on-demand use for bleed management than previously described. To estimate aPCC and rFVIIa prophylaxis costs relative to rFVIIa on-demand treatment cost based on rFVIIa doses reported in U.S. registries. A literature-based cost model was developed assuming a base case on-demand annual bleed rate (ABR) of 28.7 per inhibitor patient, which was taken from a randomized phase 3 clinical trial. The doses for rFVIIa on-demand were taken from the median dose per bleed reported by the DOSE and HTRS registries. Model inputs for aPCC and rFVIIa prophylaxis (i.e., dosing and efficacy) were derived from respective randomized clinical trials. Cost analysis was from the U.S. payer perspective, and only direct drug costs were considered. The drug cost was based on the Medicare Part B 2014 average sale price (ASP). Two-way sensitivity and threshold analyses were performed by simultaneously varying on-demand ABR, prophylaxis efficacy, and unit drug cost. In addition to studying relative costs associated with on-demand and prophylaxis treatments, relative cost per bleeding episode avoided were also calculated for aPCC and rFVIIa prophylaxis treatments. The prophylaxis efficacy reported in the trials were used to determine the number of bleeding episodes avoided. Based on the median on-demand dose of 695 mcg per kg per bleed, reported by the DOSE registry, the annual rFVIIa on-demand cost was $34,009 per kg of body weight. The annual rFVIIa on-demand cost was $22,020 per kg of body weight when the median dose of 450 mcg per kg per bleed reported by the HTRS registry was considered. The annual cost rose to $38,461 per kg of body weight when the rFVIIa on-demand dose of 786 mcg per kg per bleed among patients infusing an initial dose ≥ 250 mcg per kg was considered. The aPCC (85 units per kg per every other day) and rFVIIa (90 mcg per kg per every day) annual prophylaxis costs were $26,536 and $60,700, respectively. Also, aPCC and rFVIIa prophyaxis treatments were estimated to prevent a total of 20.8 and 12.9 annual bleeding episodes, respectively. When compared with the on-demand dose of 695 mcg per kg per bleed (DOSE registry), the annual aPCC and rFVIIa prophylaxis costs were 21.9% lower and 78.4% higher, respectively. Additionally, aPCC prophylaxis saved $360 per kg for each bleeding episode avoided. rFVIIa prophylaxis cost $2,066 per kg for each bleeding episode avoided. Compared with the on-demand dose of 450 mcg per kg per bleed (HTRS registry), aPCC and rFVIIa prophylaxis costs were 20.5% and 174.9% higher, respectively. In this case, aPCC and rFVIIa prophylaxis treatment costs were $217 per kg and $2,995 per kg, respectively, for each bleeding episode avoided. aPCC and rFVIIa prophylaxis costs were 31.0% lower and 57.8% higher, respectively, when compared with the rFVIIa on-demand dose of 786 mcg per kg per bleed, among patients infusing an initial dose ≥ 250 mcg per kg (HTRS registry). In this case, aPCC prophylaxis saved $573 per kg for each bleeding episode avoided, while rFVIIa prophylaxis costs $1,724 per kg for each bleeding episode avoided. Results of the 2-way sensitivity analyses were robust in the majority of the scenarios considered. aPCC prophylaxis may be cost saving for managing hemophilia patients with inhibitors who bleed frequently and infuse significant quantities of rFVIIa on-demand.

A comparative study of coagulation, granular- and powdered-activated carbon for the removal of perfluorooctane sulfonate and perfluorooctanoate in drinking water treatment.

PubMed

Pramanik, Biplob Kumar; Pramanik, Sagor Kumar; Suja, Fatihah

2015-01-01

Perfluorooctane sulfonate (PFOS) and perfluorooctanoate (PFOA) are persistent organic pollutants in the environment and their occurrence causes toxicological effects on humans. We examined different conventional coagulant treatments such as alum, ferric chloride and polyaluminium chloride in removing these compounds. These were then compared with a natural coagulant (Moringa oleifera). We also investigated the powdered-activated carbon (PAC) and granular-activated carbon (GAC) for removing these compounds. At an initial dose of 5 mg/L, polyaluminium chloride led to a higher reduction of PFOS/PFOA compared with alum which in turn was higher than ferric. The removal efficiency increased with the increase in coagulant dose and decrease in pH. M. oleifera was very effective in reducing PFOS and PFOA than conventional coagulants, with a reduction efficiencies of 65% and 72%, respectively, at a dose of 30 mg/L. Both PAC and GAC were very effective in reducing these compounds than coagulations. PAC led to a higher reduction in PFOS and PFOA than GAC due to its greater surface area and shorter internal diffusion distances. The addition of PAC (10 min contact time) with coagulation (at 5 mg/L dosage) significantly increased the removal efficiency, and the maximum removal efficiency was for M. oleifera with 98% and 94% for PFOS and PFOA, respectively. The reduction efficiency of PFOS/PFOA was reduced with the increase in dissolved organic concentration due to the adsorption competition between organic molecules and PFOS/PFOA.

Astaxanthin protects against early burn-wound progression in rats by attenuating oxidative stress-induced inflammation and mitochondria-related apoptosis

PubMed Central

Fang, Quan; Guo, Songxue; Zhou, Hanlei; Han, Rui; Wu, Pan; Han, Chunmao

2017-01-01

Burn-wound progression can occur in the initial or peri-burn area after a deep burn injury. The stasis zone has a higher risk of deterioration mediated by multiple factors but is also considered salvageable. Astaxanthin (ATX), which is extracted from some marine organisms, is a natural compound with a strong antioxidant effect that has been reported to attenuate organ injuries caused by traumatic injuries. Hence, we investigated the potential effects of ATX on preventing early burn-wound progression. A classic “comb” burn rat model was established in this study for histological and biological assessments, which revealed that ATX, particularly higher doses, alleviated histological deterioration in the stasis zone. Additionally, we observed dose-dependent improvements in oxidative stress and the release of inflammatory mediators after ATX treatment. Furthermore, ATX dose-dependently attenuated burn-induced apoptosis in the wound areas, and this effect was accompanied by increases in Akt and Bad phosphorylation and a downregulation of cytochrome C and caspase expression. In addition, the administration of Ly 294002 further verified the effect of ATX. In summary, we demonstrated that ATX protected against early burn-wound progression in a rat deep-burn model. This protection might be mediated by the attenuation of oxidative stress-induced inflammation and mitochondria-related apoptosis. PMID:28128352

A STUDY OF THE MECHANISM OF RADIATION-INDUCED GELATION IN MONOMER-POLYMER MIXTURES. Quarterly Summary Report, August 1, 1961-October 31, 1961

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

Odian, G.; Bernstein, B.S.; Kelly, J.J.

1961-11-01

Gel contents can be obtained with polyethylene swollen with inhibitor- free allyl acrylate or inhibitor-free allyl methacrylate at a dose of only 0.05 Mrads Using Co/sup 60/ as the radiation source, allyl methacrylate gives higher gel content than allyl acrylate under similar conditions. icant and continues after Co/sup 60/ irradiation has been completed. Monomer desorption after a dose of 1.2 Mrads is less than after 0.05 Mrads, and does not continue after irradiation is stopped. Gel contents can be obtained without prior equilibrium swelling of polymer--monomer mixtures by irradiating the polymer in the presence of the monomer in a nitrogenmore » atmosphere. By irradiating under these conditions with prior equilibrium swelling, gel fractions appear to be higher than those normally obtained. Gel contents of irradiated equilibrium-swollen polyethylene/ allyl acrylate and polyethylene/allyl methacrylate increase with increasing radiation dose from 0.05 to 1.2 Mrads. Gel contents of 1.2 Mrad irradiated polyethyleneallyl methacrylate systems containing various initial amounts of monomer, increase with increasing monomer content. Polypropylene can be radiation crosslinked to give over 40% gel by prior equilibrium swelling with allyl acrylate or allyl methacrylate. (auth)« less

Aerosol Delivery with Two Nebulizers Through High-Flow Nasal Cannula: A Randomized Cross-Over Single-Photon Emission Computed Tomography-Computed Tomography Study.

PubMed

Dugernier, Jonathan; Hesse, Michel; Jumetz, Thibaud; Bialais, Emilie; Roeseler, Jean; Depoortere, Virginie; Michotte, Jean-Bernard; Wittebole, Xavier; Ehrmann, Stephan; Laterre, Pierre-François; Jamar, François; Reychler, Gregory

2017-10-01

High-flow nasal cannula use is developing in ICUs. The aim of this study was to compare aerosol efficiency by using two nebulizers through a high-flow nasal cannula: the most commonly used jet nebulizer (JN) and a more efficient vibrating-mesh nebulizer (VN). Aerosol delivery of diethylenetriaminepentaacetic acid labeled with technetium-99m (4 mCi/4 mL) to the lungs by using a VN (Aerogen Solo ® ; Aerogen Ltd., Galway, Ireland) and a constant-output JN (Opti-Mist Plus Nebulizer ® ; ConvaTec, Bridgewater, NJ) through a high-flow nasal cannula (Optiflow ® ; Fisher & Paykel, New Zealand) was compared in six healthy subjects. Flow rate was set at 30 L/min through the heated humidified circuit. Pulmonary and extrapulmonary deposition was measured by single-photon emission computed tomography combined with a low-dose computed tomographic scan and by planar scintigraphy. Lung deposition was only 3.6 (2.1-4.4) and 1 (0.7-2)% of the nominal dose with the VN and the JN, respectively (p < 0.05). The JN showed higher retained doses than the VN. However, both nebulizers were associated with substantial deposition in the single limb circuit, the humidification chamber, and the nasal cannula [58.2 (51.6-61.6)% of the nominal dose with the VN versus 19.2 (15.8-22.9)% of the nominal dose with the JN, p < 0.05] and in the upper respiratory tract [17.6 (13.4-27.9)% of the nominal dose with the VN and 8.6 (6.0-11.0)% of the nominal dose with the JN, p < 0.05], especially in the nasal cavity. In the specific conditions of the study, pulmonary drug delivery through the high-flow nasal cannula is about 1%-4% of the initial amount of drugs placed in the nebulizer, despite the higher efficiency of the VN as compared with the JN.

CONIFER - Non-Interventional Study to Evaluate Therapy Monitoring During Deferasirox Treatment of Iron Toxicity in Myelodysplastic Syndrome Patients with Transfusional Iron Overload.

PubMed

Bruch, Harald-Robert; Dencausse, Yves; Heßling, Jörg; Michl, Gerlinde; Schlag, Rudolf; Skorupa, Alexandra; Schneider-Schranz, Cornelia; Wolf, Sebastian; Schulte, Clemens; Tesch, Hans

2016-01-01

The non-interventional study CONIFER was designed to assess the safety and clinical practicability of deferasirox for the treatment of transfusional iron overload in myelodysplastic syndrome (MDS) patients. Patients included in the study were diagnosed with MDS and received at least 1 treatment with deferasirox. The observation period covered the time from the initial visit until the last follow-up. The data of 99 patients with MDS scored mainly as International Prognostic Scoring System (IPSS) low and intermediate 1 were evaluated. The mean age of the participants was 75 years and 58% of the patients were male. Iron overload was assessed by serum ferritin level (mean baseline serum ferritin 2,080 ± 1,244 µg/l). Patients were treated for a mean duration of 16 months (mean daily dose at baseline 11.8 ± 7.0 mg/kg). Stratification of serum ferritin levels by deferasirox dose showed a reduction at the higher but no reduction at the lower dose (< 15 mg/kg vs. ≥ 15 mg/kg and < 20 mg/kg vs. ≥ 20 mg/kg). The majority of patients (81%) were affected by at least 1 adverse event, with decreased renal creatinine clearance being the most frequent. Higher doses (≥ 15 mg/kg) of deferasirox effectively and safely reduced serum ferritin levels in MDS patients with transfusional iron overload. © 2016 S. Karger GmbH, Freiburg.

Bladder pain in an LL-37 interstitial cystitis and painful bladder syndrome model.

PubMed

Jia, Wanjian; Schults, Austin J; Jensen, Mark Martin; Ye, Xiangyang; Alt, Jeremiah A; Prestwich, Glenn D; Oottamasathien, Siam

2017-01-01

Our goal was to evaluate the pain response in an LL-37 induced murine model for interstitial cystitis/painful bladder syndrome (IC/PBS). In particular, we sought to characterize the dose dependence, time-course, and relationship of LL-37 induced bladder inflammation and pain. The IC/PBS model was induced in C57Bl/6 mice by instilling 50 μL of LL-37, an immunomodulatory human cathelicidin (anti-microbial peptide), in the bladder for 1 hr. Pain responses were measured using von Frey filaments (0.04 gm to 4.0 gm) before and after LL-37 instillation. Inflammation was evaluated using tissue myeloperoxidase (MPO) assay, gross inspection, and microscopic histologic examination. The dose response experiment demonstrated a graded pain response, with higher concentrations of LL-37 challenge yielding higher pain responses across all stimuli tested. Statistical significance was seen when comparing 1.0 gm von Frey filament results at 320 μM (68 ± 8% response) vs. 0 μM (38 ± 6% response). Interestingly, pain responses did not attenuate across time but increased significantly after 5 (p=0.0012) and 7 days (p=0.0096). Comparison with MPO data suggested that pain responses could be independent of inflammation. We demonstrated within our LL-37 induced IC/PBS model pain occurs in a dose-dependent fashion, pain responses persist beyond the initial point of insult, and our dose response and time course experiments demonstrated that pain was independent of inflammation.

Metformin as an initial adjunct to low-dose liraglutide enhances the weight-decreasing potential of liraglutide in obese polycystic ovary syndrome: Randomized control study.

PubMed

Jensterle, Mojca; Goricar, Katja; Janez, Andrej

2016-04-01

Liraglutide (LIRA) treatment is associated with the dose-dependent reduction of weight. Higher doses are more effective than lower doses, although higher doses are also more poorly tolerated. Metformin may enhance the weight-lowering potential of LIRA via the stimulatory modulation of incretin in addition to its direct beneficial effects in PCOS. The aim of the present study was to evaluate whether metformin as an adjunct to low-dose LIRA affects body weight with increased efficacy compared with low-dose LIRA alone in obese patients with PCOS. In a 12-week study, 44 obese women with PCOS were randomly offered either combined treatment (COMBO) with 1,000 mg metformin twice a day and 1.2 mg LIRA once a day, or treatment with 1.2 mg LIRA alone. The primary outcome of treatment was an alteration in the levels of obesity. A total of 43 patients [aged 30.3±4.4 years; body mass index (BMI) 37.2±4.5 kg/m 2 ; mean ± standard deviation] completed the study. The subjects treated with COMBO lost on average 6.2±2.4 kg compared with a 3.8±3.5 kg weight loss in the patients treated with LIRA alone (P=0.024). The BMI decreased by 2.2±0.8 kg/m 2 in patients treated with COMBO and by 1.4±1.2 kg/m 2 in patients treated with LIRA alone (P=0.024). A clinically significant ≥5% weight reduction was achieved in 59.1% of patients treated with COMBO and 42.9% of patients treated with LIRA alone. Reductions in glucose levels following oral glucose tolerance testing, as well as in androstenedione levels in the COMBO group were significantly greater compared with those in the LIRA group. The side effects were mild and transient in the two treatment groups. A combination of metformin and low-dose LIRA was more effective than low-dose LIRA alone in reducing body weight in obese patients with PCOS.

Asthma-Related Outcomes in Patients Initiating Extrafine Ciclesonide or Fine-Particle Inhaled Corticosteroids

PubMed Central

Postma, Dirkje S.; Dekhuijzen, Richard; van der Molen, Thys; Martin, Richard J.; van Aalderen, Wim; Roche, Nicolas; Guilbert, Theresa W.; Israel, Elliot; van Eickels, Daniela; Khalid, Javaria Mona; Herings, Ron M.C.; Overbeek, Jetty A.; Miglio, Cristiana; Thomas, Victoria; Hutton, Catherine; Hillyer, Elizabeth V.

2017-01-01

Purpose Extrafine-particle inhaled corticosteroids (ICS) have greater small airway deposition than standard fine-particle ICS. We sought to compare asthma-related outcomes after patients initiated extrafine-particle ciclesonide or fine-particle ICS (fluticasone propionate or non-extrafine beclomethasone). Methods This historical, matched cohort study included patients aged 12-60 years prescribed their first ICS as ciclesonide or fine-particle ICS. The 2 cohorts were matched 1:1 for key demographic and clinical characteristics over the baseline year. Co-primary endpoints were 1-year severe exacerbation rates, risk-domain asthma control, and overall asthma control; secondary endpoints included therapy change. Results Each cohort included 1,244 patients (median age 45 years; 65% women). Patients in the ciclesonide cohort were comparable to those in the fine-particle ICS cohort apart from higher baseline prevalence of hospitalization, gastroesophageal reflux disease, and rhinitis. Median (interquartile range) prescribed doses of ciclesonide and fine-particle ICS were 160 (160-160) µg/day and 500 (250-500) µg/day, respectively (P<0.001). During the outcome year, patients prescribed ciclesonide experienced lower severe exacerbation rates (adjusted rate ratio [95% CI], 0.69 [0.53-0.89]), and higher odds of risk-domain asthma control (adjusted odds ratio [95% CI], 1.62 [1.27-2.06]) and of overall asthma control (2.08 [1.68-2.57]) than those prescribed fine-particle ICS. The odds of therapy change were 0.70 (0.59-0.83) with ciclesonide. Conclusions In this matched cohort analysis, we observed that initiation of ICS with ciclesonide was associated with better 1-year asthma outcomes and fewer changes to therapy, despite data suggesting more difficult-to-control asthma. The median prescribed dose of ciclesonide was one-third that of fine-particle ICS. PMID:28102056

The effects of a brief educational intervention on human papillomavirus knowledge and intention to initiate HPV vaccination in 18-26 year old young adults.

PubMed

Kester, Laura M; Shedd-Steele, Rivienne B; Dotson-Roberts, Crystal A; Smith, Jennifer; Zimet, Gregory D

2014-03-01

Despite the Advisory Committee on Immunization Practices (ACIP) recommendations for young adult females and males to receive the three-dose human papillomavirus (HPV) vaccine, most recent findings show that only 30% of the U.S. females aged 19-26, 2.8% of males aged 19-21, and only 1.7% of males aged 22-26 are initiating vaccination. This study evaluates the effects of a brief (5-10 min) group HPV educational intervention on knowledge and intent to vaccinate among young adults. A sample of 131 18-26 year old females and males was recruited from the 2012 INShape Black and Minority Health Fair in Indiana. We randomized participants into one of two groups: (1) survey completion prior to education (control group) or (2) survey completion following education (intervention group). Written surveys assessed HPV knowledge, vaccination history, and vaccination intent (for unvaccinated participants). Respondents were primarily female (70%), single (85%), and the majority self-identified as non-Hispanic Black (77%). Thirty-seven percent had initiated HPV vaccination (≥1 dose) and 19% had completed the series. The intervention group had higher HPV knowledge scores (M=9.1; SD=1.8) than the control group (M=7.0; SD=2.9; F=22.53). Among unvaccinated individuals (n=79), the intervention group had higher HPV vaccination intent (86%) compared to the control group (67%) (OR=3.09; 95%CI=1.02-9.36). Despite ACIP recommendations, young adults continue to have low awareness of vaccine benefits and low vaccination rates. This study suggests that educational interventions to increase HPV awareness and vaccination may help to boost vaccination rates. Copyright © 2013. Published by Elsevier Inc.

Cell killing and chromatid damage in primary human bronchial epithelial cells irradiated with accelerated 56Fe ions

NASA Technical Reports Server (NTRS)

Suzuki, M.; Piao, C.; Hall, E. J.; Hei, T. K.

2001-01-01

We examined cell killing and chromatid damage in primary human bronchial epithelial cells irradiated with high-energy 56Fe ions. Cells were irradiated with graded doses of 56Fe ions (1 GeV/nucleon) accelerated with the Alternating Gradient Synchrotron at Brookhaven National Laboratory. The survival curves for cells plated 1 h after irradiation (immediate plating) showed little or no shoulder. However, the survival curves for cells plated 24 h after irradiation (delayed plating) had a small initial shoulder. The RBE for 56Fe ions compared to 137Cs gamma rays was 1.99 for immediate plating and 2.73 for delayed plating at the D10. The repair ratio (delayed plating/immediate plating) was 1.67 for 137Cs gamma rays and 1.22 for 56Fe ions. The dose-response curves for initially measured and residual chromatid fragments detected by the Calyculin A-mediated premature chromosome condensation technique showed a linear response. The results indicated that the induction frequency for initially measured fragments was the same for 137Cs gamma rays and 56Fe ions. On the other hand, approximately 85% of the fragments induced by 137Cs gamma rays had rejoined after 24 h of postirradiation incubation; the corresponding amount for 56Fe ions was 37%. Furthermore, the frequency of chromatid exchanges induced by gamma rays measured 24 h after irradiation was higher than that induced by 56Fe ions. No difference in the amount of chromatid damage induced by the two types of radiations was detected when assayed 1 h after irradiation. The results suggest that high-energy 56Fe ions induce a higher frequency of complex, unrepairable damage at both the cellular and chromosomal levels than 137Cs gamma rays in the target cells for radiation-induced lung cancers.

Clomiphene Stair-Step Protocol for Women With Polycystic Ovary Syndrome.

PubMed

Jones, Tiffanny; Ho, Jacqueline R; Gualtieri, Marc; Bruno-Gaston, Janet; Chung, Karine; Paulson, Richard J; Bendikson, Kristin A

2018-01-01

To compare time to ovulation, ovulation rates, and side effect profile of traditional and the stair-step protocol for ovulation induction using clomiphene citrate in women with polycystic ovary syndrome (PCOS). We performed a retrospective study of women seeking care for infertility with a diagnosis of PCOS at a university-based infertility clinic from July 2012 to July 2014. We included patients who were resistant to the initial starting dose of 50 mg clomiphene. The primary outcome was time to ovulation. Secondary outcomes included ovulation rates, clinical pregnancy rates, and mild and moderate-to-severe side effects based on dose. For the traditional protocol, higher doses of clomiphene were used each subsequent month if no ovulation occurred. For the stair-step protocol, higher doses of clomiphene were given 7 days after the last dose if no dominant follicles were seen on ultrasonography. Our study had 80% power to detect a 20% difference in ovulation. One hundred nine patients were included in the analysis with 66 (60.6%) in the traditional and 43 (39.4%) in the stair-step protocol. Age and body mass index were similar between groups. The time to ovulation was decreased in the stair-step protocol group compared with the traditional protocol group (23.1±0.9 days vs 47.5±6.3 days). Ovulation rates were increased in the stair-step group compared with the traditional group at 150 mg (16 [37%] vs 8 [12%], P=.004) and at 200 mg (9 [21%] vs 3 [5%], P=.01). Pregnancy rates were similar between groups once ovulation was achieved (12 [18.1%] vs 7 [16.3%], P=.08). The stair-step protocol had an increased incidence of mild side effects (vasomotor flushes, headaches, gastrointestinal disturbance, mastalgia, changes in mood; 18 [41%] vs 8 [12%]), but there was no difference in the incidence of severe side effects (headaches, visual disturbances). For women with PCOS, the stair-step clomiphene protocol is associated with decreased time to ovulation and increased ovulation rates at higher doses when compared with the traditional protocol.

Dose Trends of Aripiprazole from 2004 to 2014 in Psychiatric Inpatients in Korea.

PubMed

Woo, Young Sup; Shim, In Hee; Lee, Sang-Yeol; Lee, Dae-Bo; Kim, Moon-Doo; Jung, Young-Eun; Lee, Jonghun; Won, Seunghee; Jon, Duk-In; Bahk, Won-Myong

2017-05-31

Although aripiprazole has been widely used to treat various psychiatric disorders, little is known about the adequate dosage for Asian patients in clinical practice. Hence, we evaluated the initial and maximum doses of aripiprazole from 2004 to 2014 to estimate the appropriate dosage for Korean psychiatric inpatients in clinical practice. In this retrospective study, we reviewed the medical records of patients who were hospitalized in five university hospitals in Korea from March 2004 to December 2014. The psychiatric diagnosis according to the text revision of the Diagnostic and Statistical Manual of Mental Disorders, 4th edition during index hospitalization and the initial and maximum doses of aripiprazole were evaluated. There were 74 patients in Wave 1 (2004-2006), 201 patients in Wave 2 (2007-2010), and 353 patients in Wave 3 (2011-2014). The initial doses of aripiprazole in all diagnostic groups were significantly lower in Wave 3 than in Wave 2. The maximum doses of aripiprazole in each diagnostic group were not significantly different among Waves 1, 2, and 3. The relatively low initial doses of aripiprazole documented in our study may reflect a strategy by clinicians to minimize the side effects associated with aripiprazole use, such as akathisia.

Guidelines for the first-line treatment of restless legs syndrome/Willis-Ekbom disease, prevention and treatment of dopaminergic augmentation: a combined task force of the IRLSSG, EURLSSG, and the RLS-foundation.

PubMed

Garcia-Borreguero, Diego; Silber, Michael H; Winkelman, John W; Högl, Birgit; Bainbridge, Jacquelyn; Buchfuhrer, Mark; Hadjigeorgiou, Georgios; Inoue, Yuichi; Manconi, Mauro; Oertel, Wolfgang; Ondo, William; Winkelmann, Juliane; Allen, Richard P

2016-05-01

A Task Force was established by the International Restless Legs Syndrome Study Group (IRLSSG) in conjunction with the European Restless Legs Syndrome Study Group (EURLSSG) and the RLS Foundation (RLS-F) to develop evidence-based and consensus-based recommendations for the prevention and treatment of long-term pharmacologic treatment of dopaminergic-induced augmentation in restless legs syndrome/Willis-Ekbom disease (RLS/WED). The Task Force made the following prevention and treatment recommendations: As a means to prevent augmentation, medications such as α2δ ligands may be considered for initial RLS/WED treatment; these drugs are effective and have little risk of augmentation. Alternatively, if dopaminergic drugs are elected as initial treatment, then the daily dose should be as low as possible and not exceed that recommended for RLS/WED treatment. However, the physician should be aware that even low dose dopaminergics can cause augmentation. Patients with low iron stores should be given appropriate iron supplementation. Daily treatment by either medication should start only when symptoms have a significant impact on quality of life in terms of frequency and severity; intermittent treatment might be considered in intermediate cases. Treatment of existing augmentation should be initiated, where possible, with the elimination/correction of extrinsic exacerbating factors (iron levels, antidepressants, antihistamines, etc.). In cases of mild augmentation, dopamine agonist therapy can be continued by dividing or advancing the dose, or increasing the dose if there are breakthrough night-time symptoms. Alternatively, the patient can be switched to an α2δ ligand or rotigotine. For severe augmentation the patient can be switched either to an α2δ ligand or rotigotine, noting that rotigotine may also produce augmentation at higher doses with long-term use. In more severe cases of augmentation an opioid may be considered, bypassing α2δ ligands and rotigotine. Copyright © 2016 The Authors. Published by Elsevier B.V. All rights reserved.

UDP-glucuronosyltransferase 1A1*6 and *28 polymorphisms as indicators of initial dose level of irinotecan to reduce risk of neutropenia in patients receiving FOLFIRI for colorectal cancer.

PubMed

Miyata, Yoshinori; Touyama, Tetsuo; Kusumi, Takaya; Morita, Yoshitaka; Mizunuma, Nobuyuki; Taniguchi, Fumihiro; Manabe, Mitsuaki

2016-08-01

Irinotecan (CPT-11)-induced neutropenia is associated with UDP-glucuronosyltransferase (UGT) 1A1*6 and *28 polymorphisms. This prospective study investigated whether using these polymorphisms to adjust the initial dose of CPT-11 as part of FOLFIRI treatment in colorectal cancer patients might improve safety. All data were collected by a physician. The relationship between UGT1A1 polymorphisms and first-cycle neutropenia, reasons for treatment discontinuation, and time-to-treatment failure were evaluated. Multivariate analysis was used to assess the risk of neutropenia. A total of 795 patients were divided into wild-type (*1/*1) (50.1 %), heterozygous (*28/*1, *6/*1) (41.1 %), and homozygous (*28/*28, *6/*6, *28/*6) (8.8 %) groups, in which the median starting dose of CPT-11 was 143.0, 143.0, and 115.0 mg/m(2), respectively. First-cycle grade ≥3 neutropenia occurred in 17.3, 25.4, and 28.6 % of these patients, respectively. Multivariate analysis revealed that the incidence of grade ≥3 neutropenia was significantly greater in the heterozygous and homozygous groups than in the wild-type group [odds ratio (OR) 1.67; 95 % confidence interval (CI) 1.16-2.42; p = 0.0060, and OR 2.22; 95 % CI 1.22-4.02; p = 0.0088, respectively]. Age (OR 1.77; 95 % CI 1.24-2.53; p = 0.0017), coelomic fluid (OR 1.84; 95 % CI 1.05-3.25; p = 0.0343), and non-reduction in starting dose (OR 1.53; 95 % CI 1.08-2.18; p = 0.0176) were also identified as significant risk factors. The risk of neutropenia was higher in the heterozygous and homozygous groups at initiation of CPT-11 treatment. This suggests that when a reduction in dose is required in patients harboring two variant alleles, the decrease should be approximately 20 %.

WE-E-18A-04: Precision In-Vivo Dosimetry Using Optically Stimulated Luminescence Dosimeters and a Pulsed-Stimulating Dose Reader

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

Chen, Q; Herrick, A; Hoke, S

Purpose: A new readout technology based on pulsed optically stimulating luminescence is introduced (microSTARii, Landauer, Inc, Glenwood, IL60425). This investigation searches for approaches that maximizes the dosimetry accuracy in clinical applications. Methods: The sensitivity of each optically stimulated luminescence dosimeter (OSLD) was initially characterized by exposing it to a given radiation beam. After readout, the luminescence signal stored in the OSLD was erased by exposing its sensing area to a 21W white LED light for 24 hours. A set of OSLDs with consistent sensitivities was selected to calibrate the dose reader. Higher order nonlinear curves were also derived from themore » calibration readings. OSLDs with cumulative doses below 15 Gy were reused. Before an in-vivo dosimetry, the OSLD luminescence signal was erased with the white LED light. Results: For a set of 68 manufacturer-screened OSLDs, the measured sensitivities vary in a range of 17.3%. A sub-set of the OSLDs with sensitivities within ±1% was selected for the reader calibration. Three OSLDs in a group were exposed to a given radiation. Nine groups were exposed to radiation doses ranging from 0 to 13 Gy. Additional verifications demonstrated that the reader uncertainty is about 3%. With an external calibration function derived by fitting the OSLD readings to a 3rd-order polynomial, the dosimetry uncertainty dropped to 0.5%. The dose-luminescence response curves of individual OSLDs were characterized. All curves converge within 1% after the sensitivity correction. With all uncertainties considered, the systematic uncertainty is about 2%. Additional tests emulating in-vivo dosimetry by exposing the OSLDs under different radiation sources confirmed the claim. Conclusion: The sensitivity of individual OSLD should be characterized initially. A 3rd-order polynomial function is a more accurate representation of the dose-luminescence response curve. The dosimetry uncertainty specified by the manufacturer is 4%. Following the proposed approach, it can be controlled to 2%.« less

Risk of Emergent Bradycardia Associated with Initiation of Immediate- or Slow-Release Metoprolol

PubMed Central

Shin, Jaekyu; Gonzales, Marco; Pletcher, Mark J

2013-01-01

Objectives To estimate and compare the risk of emergent bradycardia associated with initiation of immediate-release (IR) and slow-release (SR) formulations of metoprolol. Design Retrospective analysis of administrative claims data. Data Source State of California Medicaid program (Medi-Cal) claims database. Patients A total of 31,574 adults initiating metoprolol between May 1, 2004, and November 1, 2009, without a pharmacy claim for a beta blocker within the previous 6 months of metoprolol initiation; patients with a primary or secondary diagnosis of symptomatic bradycardia, pacemaker, or implantable cardioverter-defibrillator placement before metoprolol initiation were excluded. Measurements and Main Results The study outcome was the time to first occurrence of emergent bradycardia, measured at an emergency department visit or hospitalization due to diagnosis of symptomatic bradycardia, after metoprolol initiation. We calculated the incidence and compared the risk of emergent bradycardia by using a proportional hazards model that included the metoprolol formulation with adjustment for total daily metoprolol dose and the use of other medications as time-varying covariates, as well as demographics and comorbidities. Among 31,574 patients initiating metoprolol, 18,516 (58.6%) initiated the IR formulation. The incidence of emergent bradycardia was 19.1 per 1000 person-years overall but was nearly twice as common in patients using the IR versus the SR formulation (24.1 per 1000 person-years in the IR group vs. 12.9 per 1000 person-years in the SR group; unadjusted hazard ratio [HR] 1.81; 95% CI 1.28-2.56). Adjustment for other medications also associated with symptomatic bradycardia (cytochrome P450 2D6 inhibitors, class I or III antiarrhythmics, and atrioventricular node–blocking agents), metoprolol dose, and other participant characteristics somewhat attenuated the association (adjusted HR 1.48, 95% CI 1.03-2.13). Conclusion The risk of emergent bradycardia associated with metoprolol initiation was higher with the IR formulation than the SR formulation, although the absolute risk was low. PMID:23813768

Paramedic Initiation of Neuroprotective Agent Infusions: Successful Achievement of Target Blood Levels and Attained Level Effect on Clinical Outcomes in the FAST-MAG Pivotal Trial (Field Administration of Stroke Therapy - Magnesium).

PubMed

Shkirkova, Kristina; Starkman, Sidney; Sanossian, Nerses; Eckstein, Marc; Stratton, Samuel; Pratt, Frank; Conwit, Robin; Hamilton, Scott; Sharma, Latisha; Liebeskind, David; Restrepo, Lucas; Valdes-Sueiras, Miguel; Saver, Jeffrey L

2017-07-01

Paramedic use of fixed-size lumen, gravity-controlled tubing to initiate intravenous infusions in the field may allow rapid start of neuroprotective therapy for acute stroke. In a large, multicenter trial, we evaluated its efficacy in attaining target serum levels of candidate neuroprotective agent magnesium sulfate and the relation of achieved magnesium levels to outcome. The FAST-MAG phase 3 trial (Field Administration of Stroke Therapy - Magnesium) randomized 1700 patients within 2 hours of onset to paramedic-initiated, a 15-minute loading intravenous infusion of magnesium or placebo followed by a 24-hour maintenance dose. The drug delivery strategy included fixed-size lumen, gravity-controlled tubing for field drug administration, and a shrink-wrapped ambulance kit containing both the randomized field loading and hospital maintenance doses for seamless continuation. Among patient randomized to active treatment, magnesium levels in the first 72 hours were assessed 987 times in 572 patients. Mean patient age was 70 years (SD±14 years), and 45% were women. During the 24-hour period of active infusion, mean achieved serum level was 3.91 (±0.8), consistent with trial target. Mg levels were increased by older age, female sex, lower weight, height, body mass index, and estimated glomerular filtration rate, and higher blood urea nitrogen, hemoglobin, and higher hematocrit. Adjusted odds for clinical outcomes did not differ by achieved Mg level, including disability at 90 days, symptomatic hemorrhage, or death. Paramedic infusion initiation using gravity-controlled tubing permits rapid achievement of target serum levels of potential neuroprotective agents. The absence of association of clinical outcomes with achieved magnesium levels provides further evidence that magnesium is not biologically neuroprotective in acute stroke. © 2017 American Heart Association, Inc.

Treatment Patterns and Early Outcomes of ALK-Positive Non-Small Cell Lung Cancer Patients Receiving Ceritinib: A Chart Review Study.

PubMed

Bendaly, Edmond; Dalal, Anand A; Culver, Kenneth; Galebach, Philip; Bocharova, Iryna; Foster, Rebekah; Sasane, Medha; Macalalad, Alexander R; Guérin, Annie

2017-05-01

This study aimed to provide the first real-world description of the characteristics, treatments, dosing patterns, and early outcomes of patients with ALK-positive non-small cell lung cancer (NSCLC) who received ceritinib in US clinical practice. US oncologists provided data from medical charts of adult patients diagnosed with locally advanced or metastatic ALK-positive NSCLC who received ceritinib following crizotinib. Patient characteristics, treatment patterns, ceritinib dosing, early outcomes, and occurrence of gastrointestinal adverse events (AEs) by dose and instructions on food intake were assessed, and Kaplan-Meier analysis was used to describe clinician-defined progression-free survival (PFS) on ceritinib. Medical charts of 58 ALK-positive NSCLC patients treated with ceritinib were reviewed (median age 63 years; 41% male; 21% with prior chemotherapy experience). At ceritinib initiation, 44 patients had multiple distant metastases, most commonly in the liver (60%), bone (53%), and brain (38%). Initial ceritinib dose varied: 71% received 750 mg, 19% 600 mg, and 10% 450 mg. Although median follow-up after ceritinib initiation was short (3.8 months), most patients achieved either a complete or partial response (69%) on ceritinib, regardless of metastatic sites present at initiation or initial dose. Median PFS on ceritinib was 12.9 months. 17% of patients had a gastrointestinal AE reported during follow-up. The majority of events occurred in patients instructed to fast; no patients instructed to take a lower dose of ceritinib with food reported gastrointestinal AEs. These early findings of ceritinib use in clinical practice suggest that ceritinib is effective at treating crizotinib-experienced ALK-positive NSCLC patients, regardless of metastatic sites or initial dose, and dosing ceritinib with food may lead to fewer gastrointestinal AEs. Future studies with larger sample size and longer follow-up are warranted, including an ongoing randomized trial to assess the gastrointestinal tolerability of ceritinib 450 and 600 mg with low-fat meals. Novartis Pharmaceutical Corporation.

High-Dose Methylprednisolone for Veno-Occlusive Disease of the Liver in Pediatric Hematopoietic Stem Cell Transplantation Recipients

PubMed Central

Myers, Kasiani C.; Lawrence, Julia; Marsh, Rebecca A.; Davies, Stella M.; Jodele, Sonata

2017-01-01

Veno-occlusive disease (VOD) of the liver is a well-recognized serious complication of hematopoietic stem cell transplantation (HSCT), with few successful treatment modalities available for severe disease. Some reports have demonstrated success in adults with the use of high-dose steroid therapy, but experience in the pediatric population is lacking. We retrospectively reviewed HSCT patients treated at our institution since 2003 and identified 15 (2.4%) who developed VOD. Of these, nine (60%) were treated with intravenous high-dose methylprednisolone (500 mg/m2 per dose every 12 hours for six doses). Steroid therapy was initiated at or before first ultrasound evidence of reversal of portal venous flow and before meeting criteria for initiation of defibrotide therapy. Four patients were also treated with defibrotide starting 2 to 5 days after initiation of steroids. Eight of nine patients (88%) with VOD were diagnosed with multiorgan failure. Response to high-dose steroid therapy as defined by decrease in bilirubin by 50% in 10 days from therapy initiation was noted in six of nine patients (67%), occurring within 3 to 6 days of steroid therapy. Two patients died from multiorgan failure due to VOD. Seven survivors of VOD recovered at the median 6 days (range, 5 to 38) from VOD diagnosis. Overall, VOD survival as a group was 78%; however, survival among responders was 100%. No serious toxicities related to high-dose steroid therapy were observed. We conclude that high-dose steroid therapy if initiated early may reverse VOD of the liver in pediatric HSCT patients, abrogating the need for defibrotide therapy with its associated toxicities and regulatory difficulties. PMID:23211838

[Infusion of Daratumumab in Combination Therapies - Practical Information for The Outpatient Area].

PubMed

Scheid, Christof; Munder, Markus; Salwender, Hans; Engelhardt, Monika

2018-06-06

Combination therapies such as Dara-Rd and Dara-Vd show significantly higher survival rates after 12 months than the respective therapies without Daratumumab. The initial infusion of Daratumumab is associated with a high incidence of IRR. Dosage and speed of infusion of Daratumumab have to be strictly controlled. Any suspicion of even low IRR requires corrections. Concomitant medication before and after Daratumumab administration is required. For this purpose, various preparations have been tested in everyday clinical practice. Eight hours of infusion may be required. This does not only overwhelm the patient, but also the most ambulant structures. The split-dose concept means to divide the dose into infusions on different days. Again, the dosage is crucial for good compatibility. © Georg Thieme Verlag KG Stuttgart · New York.

Predictors of HbA1c levels in patients initiating metformin.

PubMed

Martono, Doti P; Hak, Eelko; Lambers Heerspink, Hiddo; Wilffert, Bob; Denig, Petra

2016-12-01

The aim was to assess demographic and clinical factors as predictors of short (6 months) and long term (18 months) HbA1c levels in diabetes patients initiating metformin treatment. We conducted a cohort study including type 2 diabetes patients who received their first metformin prescription between 2007 and 2013 in the Groningen Initiative to Analyze Type 2 Diabetes Treatment (GIANTT) database. The primary outcome was HbA1c level at follow-up adjusted for baseline HbA1c; the secondary outcome was failing to achieve the target HbA1c level of 53 mmol/mol. Associations were analyzed by linear and logistic regression. Multiple imputation was used for missing data. Additional analyses stratified by dose and adherence level were conducted. The cohort included 6050 patients initiating metformin. Baseline HbA1c at target consistently predicted better HbA1c outcomes. Longer diabetes duration and lower total cholesterol level at baseline were predictors for higher HbA1c levels at 6 months. At 18 months, cholesterol level was not a predictor. Longer diabetes duration was also associated with not achieving the target HbA1c at follow-up. The association for longer diabetes duration was especially seen in patients starting on low dose treatment. No consistent associations were found for comorbidity and comedication. Diabetes duration was a relevant predictor of HbA1c levels after 6 and 18 months of follow-up in patients initiating metformin treatment. Given the study design, no causal inference can be made. Our study suggests that prompt treatment intensification may be needed in patients who have a longer diabetes duration at treatment initiation.

The effect of different initial densities of nematode (Meloidogyne javanica) on the build-up of Pasteuria penetrans population.

PubMed

Darban, Daim Ali; Pathan, Mumtaz Ali; Bhatti, Abdul Ghaffar; Maitelo, Sultan Ahmed

2005-02-01

Pasteuria penetrans will build-up faster where there is a high initial nematode density and can suppress root-knot nematode populations in the roots of tomato plants. The effect of different initial densities of nematode (Meloidogyne javanica) (150, 750, 1500, 3000) and P. penetrans infected females (F1, F3) densities (F0=control and AC=absolute control without nematode or P. penetrans inoculum) on the build-up of Pasteuria population was investigated over four crop cycles. Two major points of interest were highlighted. First, that within a confined soil volume, densities of P. penetrans can increase >100 times within 2 or 3 crop cycles. Second, from a relatively small amount of spore inoculum, infection of the host is very high. There were more infected females in the higher P. penetrans doses. The root growth data confirms the greater number of females in the controls particularly at the higher inoculum densities in the third and fourth crops. P. penetrans generally caused the fresh root weights to be higher than those in the control. P. penetrans has shown greater reduction of egg masses per plant at most densities. The effects of different initial densities of M. javanica and P. penetrans on the development of the pest and parasite populations were monitored. And no attempt was made to return the P. penetrans spores to the pots after each crop so the build-up in actual numbers of infected females and spores under natural conditions may be underestimated.

The study of changes in structural properties of Cu films under ionizing radiation

NASA Astrophysics Data System (ADS)

Kaliekperov, M.; Kozlovskiy, A.; Shlimas, D.; Kenzhina, I.; Ivanov, I.; Kozin, S.; Aleksandrenko, V.; Kurakhmedov, A.; Sambaev, E.; Seitbaev, A.; Zdorovets, M.; Kadyrzhanov, K.

2018-05-01

In this paper, we present the results of studies of the irradiation effect with low-energy He+2 ions with an energy of 30 keV (15 keV per charge) on the structural properties of Cu films. Using SEM, EDS, and x-ray diffraction analysis, the surface morphology and structural properties of samples before and after irradiation were studied. As a result of irradiation of initial samples with He+2 ions with a dose of 1·1016 ion cm‑2, a change in the Cu surface morphology of films is observed, and the formation of nanoscale inclusions of hexagonal shape is observed. An increase in the irradiation dose to 1·1017 ion cm‑2 and higher leads to the formation of cracks and amorphous oxide inclusions on the sample surface. It is established that an increase in the irradiation dose leads to a decrease in the degree of crystallinity and a change in the basic crystallographic characteristics. The effect of irradiation on the strength characteristics was estimated.

Effect of Piper betle leaf extract on alcoholic toxicity in the rat brain.

PubMed

Saravanan, R; Rajendra Prasad, N; Pugalendi, K V

2003-01-01

The protective effect of Piper betle, a commonly used masticatory, has been examined in the brain of ethanol-administered Wistar rats. Brain of ethanol-treated rats exhibited increased levels of lipids, lipid peroxidation, and disturbances in antioxidant defense. Subsequent to the experimental induction of toxicity (i.e., the initial period of 30 days), aqueous P. betle extract was simultaneously administered in three different doses (100, 200, and 300 mg kg(-1)) for 30 days along with the daily dose of alcohol. P. betle coadministration resulted in significant reduction of lipid levels (free fatty acids, cholesterol, and phospholipids) and lipid peroxidation markers such as thiobarbituric acid reactive substances and hydroperoxides. Further, antioxidants, like reduced glutathione, vitamin C, vitamin E, superoxide dismutase, catalase, and glutathione peroxidase, were increased in P. betle-coadministered rats. The higher dose of extract (300 mg kg(-1)) was more effective, and these results indicate the neuroprotective effect of P. betle in ethanol-treated rats.

Chronic toxic and carcinogenic effects of oral cadmium in the Noble (NBL/Cr) rat: induction of neoplastic and proliferative lesions of the adrenal, kidney, prostate, and testes.

PubMed

Waalkes, M P; Anver, M R; Diwan, B A

1999-10-29

Based on the occurrence of pulmonary cancers in exposed populations, cadmium is classified as a human carcinogen. More controversial target sites for cadmium in humans include the prostate and kidney, where some studies have shown a link between cadmium and cancer. In Wistar rats cadmium induces tumors in the ventral prostate. The relevance of such lesions to humans is debated since the rat ventral lobe, unlike the dorsolateral lobe, has no embryological homolog in the human prostate. Cadmium has not been linked with renal tumors in rodents but is a potent nephrotoxin. In this work we studied the effects of oral cadmium in the Noble (NBL/Cr) rat with particular attention to proliferative lesions of the prostate and kidneys. Cadmium (as CdCl2) was given ad libitum throughout the study in the drinking water at doses of 0, 25, 50, 100, and 200 ppm Cd to groups (initial n = 30) of male rats, which were observed for up to 102 wk. At the lower doses of cadmium (< or =50 ppm) a clear dose-related increase in total proliferative lesions of the prostate (ventral and dorsolateral lesions combined) occurred (0 ppm = 21% incidence, 25 ppm = 46%, 50 ppm = 50%; trend p < .03). These lesions were described as intraepithelial hyperplasia with occasional areas of atypical epithelial cells without stromal invasion. The lesions occurred primarily in the dorsolateral prostate with cadmium exposure and most frequently showed three or more foci within each specimen. At higher doses, prostatic proliferative lesions declined to control levels. The loss of prostatic response at the higher doses was likely due to diminished testicular function secondary to cadmium treatment. This was reflected in lesions indicative of testicular hypofunction at the highest cadmium dose, namely, interstitial cell hyperplasia, and a strong correlation between cadmium dose and total proliferative lesions of the testes (hyperplasias and tumors combined). Renal tumors (mainly mesenchymal and pelvic transitional cell), although few in number, showed a positive correlation with cadmium dose, as did pelvic transitional epithelial hyperplasia. Renal lesions were not associated with any cadmium-induced changes in age-related chronic nephropathy. The incidence of pheochromocytomas of the adrenal was increased by cadmium but only at the 50 ppm dose. Inflammatory lesions of the liver and spleen were common at higher doses and showed strong trends based on dose. These results indicate that oral cadmium can induce proliferative lesions in the prostate and kidney of the Noble rat. The finding of proliferative lesions of dorsolateral prostate in rats has presumed relevance to human prostate cancers.

Immunogenicity and safety of 1 vs 2 doses of quadrivalent meningococcal conjugate vaccine in youth infected with human immunodeficiency virus.

PubMed

Lujan-Zilbermann, Jorge; Warshaw, Meredith G; Williams, Paige L; Spector, Stephen A; Decker, Michael D; Abzug, Mark J; Heckman, Barb; Manzella, Adam; Kabat, Bill; Jean-Philippe, Patrick; Nachman, Sharon; Siberry, George K

2012-10-01

To compare the immunogenicity of 1 vs 2 doses of meningococcal polysaccharide conjugate vaccine (MCV4) in youth infected with human immunodeficiency virus (HIV). P1065 was a phase I/II immunogenicity and safety trial of MCV4 in 324 youth infected with HIV performed at 27 sites of the International Maternal Pediatric Adolescent AIDS Clinical Trials Group network in the US. At entry subjects received 1 dose of MCV4. At 24 weeks, those with screening cluster of differentiation 4 (CD4)% ≥ 15 were randomized to receive a second dose or not, and all with screening CD4% <15 received a second dose. Immunogenicity was evaluated as the proportion of subjects with a ≥ 4-fold rise from entry in serum bactericidal antibody against each meningococcal serogroup (SG) at weeks 28 and 72. Logistic regression models adjusting for HIV disease severity were used to evaluate the effect of 1 vs 2 MCV4 doses among those with screening CD4% ≥ 15. Subjects randomized to receive 2 vs 1 MCV4 dose had significantly higher response rates to all SGs at week 28 and to all except Neisseria meningitidis SG Y at week 72, with adjusted ORs of 2.5-5.6. In 31 subjects with screening CD4% <15 who received 2 MCV4 doses, response rates ranged from 22%-55% at week 28 and 6%-28% at week 72. In youth infected with HIV with a CD4% ≥ 15, a second dose of MCV4 given 6 months after the initial dose significantly improves response rates at 28 and 72 weeks. Subjects with CD4% <15 at entry had lower response rates despite 2 doses of MCV4. Copyright © 2012 Mosby, Inc. All rights reserved.

Predictors of Initial Uptake of Human Papillomavirus Vaccine Uptake Among Rural Appalachian Young Women

PubMed Central

Crosby, Richard A.; Vanderpool, Robin C.; Dignan, Mark; Bates, Wallace

2016-01-01

Women in Appalachian Kentucky experience a high burden of cervical cancer and have low rates of human papillomavirus (HPV) vaccination. The purpose of this study was to identify normative influences predicting initial HPV vaccine uptake among a sample of young women in southeastern Kentucky. Women (N = 495), ages 18 through 26 years, were recruited from clinics and community colleges. After completing a questionnaire, women received a free voucher for HPV vaccination. Whether women redeemed the voucher for Dose 1 served as the primary outcome variable. Hierarchical logistic regression was used to estimate the influence of healthcare providers, friends, mothers, and fathers on vaccine uptake. One-quarter of the total sample (25.9 %) received Dose 1. Uptake was higher in the clinic sample (45.1 %) than in the college sample (6.9 %). On multivariate analysis, women indicating that their healthcare provider suggested the vaccine, that their friends would “definitely” want them to be vaccinated, and that their fathers would “definitely” want them to receive the vaccine all were 1.6 times more likely to receive Dose 1. Interaction effects occurred between recruitment site (clinic vs. community college) and all three of the normative influences retaining multivariate significance, indicating that the associations only applied to the clinic sample. HPV vaccine interventions may benefit from highlighting paternal endorsement, healthcare provider recommendation, and peer support. PMID:23325057

Geographic Factors and Human Papillomavirus (HPV) Vaccination Initiation among Adolescent Girls in the United States.

PubMed

Henry, Kevin A; Stroup, Antoinette M; Warner, Echo L; Kepka, Deanna

2016-02-01

This study is among the first to explore geographic factors that may be associated with human papillomavirus (HPV) vaccine uptake in the United States. Data from the 2011 and 2012 National Immunization Survey-Teen for 20,565 female adolescents aged 13 to 17 years were analyzed to examine associations of HPV vaccine initiation (receipt of at least one dose) with ZIP code-level geographic factors. Logistic regression including individual and geographic factors was used to estimate the odds of HPV vaccine initiation. Approximately 53% of girls initiated the HPV vaccine in both years. Girls in high poverty communities had higher HPV vaccine initiation compared with those in low poverty communities [61.1% vs. 52.4%; adjusted OR (AOR), 1.18; 95% confidence intervals (CI), 1.04-1.33]. Initiation was higher among girls in communities where the majority of the population was Hispanic (69.0% vs. 49.9%; AOR, 1.64; 95% CI, 1.43-1.87) or non-Hispanic mixed race (60.4% vs. 49.9%; AOR, 1.30; 95% CI, 1.17-1.44) compared with majority non-Hispanic white communities. Interactions between individual-level race/ethnicity and community racial-ethnic composition indicated significantly higher odds of initiation among Hispanic girls living in Hispanic communities compared with Hispanic girls living in predominantly non-Hispanic White (NHW) (AOR, 2.23; 95% CI, 1.87-2.65) or non-Hispanic Black (NHB) (AOR, 1.90; 95% CI, 1.20-3.04) communities, respectively. Initiation rates of HPV vaccination among teen girls were highest in the poorest communities and among Hispanics living in communities where the racial-ethnic composition was predominantly Hispanic or mixed race. Given low HPV vaccination rates in the United States, these results provide important evidence to inform public health interventions to increase HPV vaccination. ©2016 American Association for Cancer Research.

Deformable Dose Reconstruction to Optimize the Planning and Delivery of Liver Cancer Radiotherapy

NASA Astrophysics Data System (ADS)

Velec, Michael

The precise delivery of radiation to liver cancer patients results in improved control with higher tumor doses and minimized normal tissues doses. A margin of normal tissue around the tumor requires irradiation however to account for treatment delivery uncertainties. Daily image-guidance allows targeting of the liver, a surrogate for the tumor, to reduce geometric errors. However poor direct tumor visualization, anatomical deformation and breathing motion introduce uncertainties between the planned dose, calculated on a single pre-treatment computed tomography image, and the dose that is delivered. A novel deformable image registration algorithm based on tissue biomechanics was applied to previous liver cancer patients to track targets and surrounding organs during radiotherapy. Modeling these daily anatomic variations permitted dose accumulation, thereby improving calculations of the delivered doses. The accuracy of the algorithm to track dose was validated using imaging from a deformable, 3-dimensional dosimeter able to optically track absorbed dose. Reconstructing the delivered dose revealed that 70% of patients had substantial deviations from the initial planned dose. An alternative image-guidance technique using respiratory-correlated imaging was simulated, which reduced both the residual tumor targeting errors and the magnitude of the delivered dose deviations. A planning and delivery strategy for liver radiotherapy was then developed that minimizes the impact of breathing motion, and applied a margin to account for the impact of liver deformation during treatment. This margin is 38% smaller on average than the margin used clinically, and permitted an average dose-escalation to liver tumors of 9% for the same risk of toxicity. Simulating the delivered dose with deformable dose reconstruction demonstrated the plans with smaller margins were robust as 90% of patients' tumors received the intended dose. This strategy can be readily implemented with widely available technologies and thus can potentially improve local control for liver cancer patients receiving radiotherapy.

The pharmacokinetics of pyridostigmine and 3-hydroxy-N-methylpyridinium in the rat: dose-dependent effects after portal vein administration.

PubMed Central

Barber, H E; Bourne, G R; Calvey, T N; Muir, K T

1975-01-01

1 The elimination kinectis of [14C]-pyridostigmine iodine and [14-C-methyl]-3-hydroxypyridinium bromide (3-OH NMP) have been studied in the rat. 2 For pyridostigmine, at a given dose level, the fraction of the dose eliminated unchanged was reduced and the metabolite fraction was increased after portal vein administration when compared to jugular vein administration. This indicates that pyridostigmine is subject to metabolism during the first passage through the liver. 3 When doses of pyridostigmine 1.25 mumol/kg and higher were injected via the portal vein, the proportion excreted in urine as unchanged drug remained constant; in contrast, the percentage of the dose eliminated as the metabolite was significantly reduced. This indicates that a dose-dependent process is involved in the urinary excretion of 3-OH NMP. 4 This conclusion was supported by studies involving the portal and systemic venous injection of 3-OH NMP at different dose levels. After 4 h, approximately85% of the lowest dose was eliminated unchanged in ug this period. The proportion of the dose eliminated in urine was not related to the route of administration. 5 After the injection of pyridostigmine into the jugular vein, the initial rate of drug excretion fell rapidly for approximately 10 min; in contrast, after injection into the portal vein, the rate of excretion of the drug rose to a maximum at 30 minutes. This suggests that the hepatoportal system behaves as a distinct region during the distribution of this drug. PMID:173444

Tailored interventions for screening mammography among a sample of initially non-adherent women: when is a booster dose important?

PubMed

Skinner, Celette Sugg; Kobrin, Sarah C; Monahan, Patrick O; Daggy, Joanne; Menon, Usha; Todora, Helen Smith; Champion, Victoria L

2007-01-01

To assess added value of a booster dose of a tailored mammography intervention. Participants, non-adherent at baseline, were randomly assigned to usual care or one of three tailored interventions. Intervention group members (n=657) were further randomly assigned to receive/not receive a booster intervention dose. Electronic record mammography data were collected following initial intervention and at 6 and 15 months post-booster. Booster had no effect among women not screened after first intervention dose (n=337). Among women screened after initial dose (n=320), booster predicted re-screening at 6 but not 15 months. A boosterxrace interaction showed a booster effect at 6 months for African Americans (OR=4.66, p=.0005) but not Caucasians (OR=0.74, p=.44). Findings suggest if a first-dose intervention does not facilitate screening, neither will a booster dose. However, among women for whom a first dose is effective, boosters can facilitate timely repeat adherence, especially among African Americans. At 6 months booster recipients were less likely to be off-schedule but, by 15 months, the groups were similar. Boosters may effect when, but not whether, women continue screening.

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.

Reference Levels for Patient Radiation Doses in Interventional Radiology: Proposed Initial Values for U.S. Practice1

PubMed Central

Miller, Donald L.; Kwon, Deukwoo; Bonavia, Grant H.

2009-01-01

Purpose: To propose initial values for patient reference levels for fluoroscopically guided procedures in the United States. Materials and Methods: This secondary analysis of data from the Radiation Doses in Interventional Radiology Procedures (RAD-IR) study was conducted under a protocol approved by the institutional review board and was HIPAA compliant. Dose distributions (percentiles) were calculated for each type of procedure in the RAD-IR study where there were data from at least 30 cases. Confidence intervals for the dose distributions were determined by using bootstrap resampling. Weight banding and size correction methods for normalizing dose to patient body habitus were tested. Results: The different methods for normalizing patient radiation dose according to patient weight gave results that were not significantly different (P > .05). The 75th percentile patient radiation doses normalized with weight banding were not significantly different from those that were uncorrected for body habitus. Proposed initial reference levels for various interventional procedures are provided for reference air kerma, kerma-area product, fluoroscopy time, and number of images. Conclusion: Sufficient data exist to permit an initial proposal of values for reference levels for interventional radiologic procedures in the United States. For ease of use, reference levels without correction for body habitus are recommended. A national registry of radiation-dose data for interventional radiologic procedures is a necessary next step to refine these reference levels. © RSNA, 2009 Supplemental material: http://radiology.rsna.org/lookup/suppl/doi:10.1148/radiol.2533090354/-/DC1 PMID:19789226

Oral Fluid and Plasma 3,4-Methylenedioxymethamphetamine (MDMA) and Metabolite Correlation after Controlled Oral MDMA Administration

PubMed Central

Desrosiers, Nathalie A.; Barnes, Allan J.; Hartman, Rebecca L.; Scheidweiler, Karl B.; Kolbrich-Spargo, Erin A.; Gorelick, David A.; Goodwin, Robert S.; Huestis, Marilyn A.

2013-01-01

Oral fluid (OF) offers a non-invasive sample collection for drug testing. However, 3,4-methylenedioxymethamphetamine (MDMA, ecstasy) in OF has not been adequately characterized in comparison to plasma. We administered oral low (1.0 mg/kg) and high (1.6 mg/kg) dose MDMA to 26 participants and collected simultaneous OF and plasma specimens for up to 143 h after dosing. We compared OF/plasma (OF/P) ratios, time of initial detection (tfirst), maximal concentrations (Cmax), time of peak concentrations (tmax), time of last detection (tlast), clearance, and 3,4-methylenedioxyamphetamine (MDA) to MDMA ratios over time. For OF MDMA and MDA, Cmax was higher, tlast was later, and clearance was slower compared to plasma. For OF MDA only, tfirst was later compared to plasma. Median (range) OF/P ratios were 5.6 (0.1-52.3) for MDMA and 3.7 (0.7-24.3) for MDA. OF and plasma concentrations were weakly but significantly correlated (MDMA R2= 0.438, MDA R2= 0.197, p<0.0001). Median OF/P ratios were significantly higher following high dose: MDMA low 5.2 (0.1-40.4) and high 6.0 (0.4-52.3) (p<0.05); MDA low 3.3 (0.7-17.1) and high 4.1 (0.9-24.3) (p<0.001). There was large inter-subject variation in OF/P ratios. MDA/MDMA ratios in plasma were higher than those in OF (p<0.001), and MDA/MDMA ratios significantly increased over time in OF and plasma. MDMA and MDA concentrations were higher in OF than in plasma. OF and plasma concentrations were correlated, but large inter-subject variability precludes estimation of plasma concentrations from OF. PMID:23471370

78 FR 19489 - Disease, Disability, and Injury Prevention and Control Special Emphasis Panel (SEP): Initial Review

Federal Register 2010, 2011, 2012, 2013, 2014

2013-04-01

... announced below concerns Low Dose CT Lung Cancer Screening: Informed Decision Making and Smoking Cessation... include the initial review, discussion, and evaluation of ``Low Dose CT Lung Cancer Screening: Informed...

The effect of amiodarone on warfarin anticoagulation: a register-based nationwide cohort study involving the Swedish population.

PubMed

Holm, J; Lindh, J D; Andersson, M L; Mannheimer, B

2017-03-01

Essentials Data on the effect of introducing amiodarone in patients already using warfarin regime are scarce. Information on 754 patients was extracted from three nationwide registers in Sweden. With amiodaron, 37% of patients had an international normalized ratio (INR) over 3.0 To avoid bleeding, the initiation of amiodarone should be accompanied by closer INR monitoring. Background Data indicate that the interaction between warfarin and amiodarone results in an increased warfarin effect. There are several large, well-performed studies using genetic and clinical factors such as co-medication to predict an adequate starting dose of warfarin. However, longitudinal data on the effect of introducing amiodarone in patients on an ongoing warfarin regime are more scarce. Objectives An investigation of how initiation of amiodarone affects the anticoagulant effect and dosing of warfarin, using data from three nationwide registries. Patients/Methods In a retrospective cohort study including 754 patients, warfarin doses were compared between two 4-week periods, before and 18-21 weeks after initiating co-treatment with amiodarone. In addition, warfarin doses and international normalized ratio (INR) values were calculated week-by-week after the initiation of amiodarone. Results The initiation of amiodarone increased the mean INR from 2.6 to 3.1. The proportion of patients with a supratherapeutic INR over 3.0 and 4.0 increased from 12% to 37% and 0.9% to 5.5%, respectively. The subsequent mean decrease in warfarin dose was 24.6% (95% confidence interval [CI], 23.5, 25.6). The frequency of INR monitoring within 1 and 2 weeks after initiation of amiodarone was 67% and 90%. Conclusions Although warfarin doses in most patients were within the therapeutic range, more than one in three patients initiating co-treatment with amiodarone were exposed to a supratherapeutic anticoagulative effect within 3 weeks. In order to further avoid severe unnecessary bleeding, the initiation of amiodarone should be accompanied by closer INR monitoring, anticipating an average dose reduction of 25%. © 2017 International Society on Thrombosis and Haemostasis.

Impact of computerized order entry and pre-mixed dialysis solutions for continuous veno-venous hemodiafiltration on selection of therapy for acute renal failure.

PubMed

Saadulla, Lawand; Reeves, W Brian; Irey, Brittany; Ghahramani, Nasrollah

2012-02-01

To investigate the impacts of availability of pre-mixed solutions and computerized order entry on nephrologists' choice of the initial mode of renal replacement therapy in acute renal failure. We studied 898 patients with acute renal failure in 3 consecutive eras: era 1 (custom-mixed solution; n = 309), era 2 (pre-mixed commercial solution; n = 324), and era 3 (post-computerized order entry; n = 265). The proportion of patients treated with renal replacement therapy and the time from consult to initiation of continuous renal replacement therapy was similar in the 3 eras. Following introduction of the pre-mixed solution, the proportion of patients treated with continuous renal replacement therapy increased (20% vs. 33%; p < 0.05), it was initiated at a lower serum creatinine (353 ± 123 μmol/L vs. 300 ± 80 μmol/L; p < 0.05) and in older patients (53 ± 12 vs. 61 ± 14 years; p < 0.05). There was a progressive increase in the use of continuous veno-venous hemodialysis (18% vs. 79% vs. 100%; p < 0.05) and in the total prescribed flow rate (1,382 ± 546 vs. 2,324 ± 737 vs. 2,900 ± 305 mL/hr 3; p < 0.05). There was no significant impact on mortality. The availability of a pre-mixed solution increases the likelihood of initiating continuous renal replacement therapy in acute renal failure, initiating it at a lower creatinine and for older patients, use of continuous veno-venous hemodialysis and higher prescribed continuous renal replacement therapy dose. Computerized order entry implementation is associated with an additional increase in the use of continuous veno-venous hemodialysis, higher total prescribed dialysis dose, and use of CRRT among an increasing number of patients not on mechanical ventilation. The effect of these changes on patient survival is not significant.

The role of aspirin dose on the prevention of preeclampsia and fetal growth restriction: systematic review and meta-analysis.

PubMed

Roberge, Stéphanie; Nicolaides, Kypros; Demers, Suzanne; Hyett, Jon; Chaillet, Nils; Bujold, Emmanuel

2017-02-01

Preeclampsia and fetal growth restriction are major causes of perinatal death and handicap in survivors. Randomized clinical trials have reported that the risk of preeclampsia, severe preeclampsia, and fetal growth restriction can be reduced by the prophylactic use of aspirin in high-risk women, but the appropriate dose of the drug to achieve this objective is not certain. We sought to estimate the impact of aspirin dosage on the prevention of preeclampsia, severe preeclampsia, and fetal growth restriction. We performed a systematic review and meta-analysis of randomized controlled trials comparing the effect of daily aspirin or placebo (or no treatment) during pregnancy. We searched MEDLINE, Embase, Web of Science, and Cochrane Central Register of Controlled Trials up to December 2015, and study bibliographies were reviewed. Authors were contacted to obtain additional data when needed. Relative risks for preeclampsia, severe preeclampsia, and fetal growth restriction were calculated with 95% confidence intervals using random-effect models. Dose-response effect was evaluated using meta-regression and reported as adjusted R 2 . Analyses were stratified according to gestational age at initiation of aspirin (≤16 and >16 weeks) and repeated after exclusion of studies at high risk of biases. In all, 45 randomized controlled trials included a total of 20,909 pregnant women randomized to between 50-150 mg of aspirin daily. When aspirin was initiated at ≤16 weeks, there was a significant reduction and a dose-response effect for the prevention of preeclampsia (relative risk, 0.57; 95% confidence interval, 0.43-0.75; P < .001; R 2 , 44%; P = .036), severe preeclampsia (relative risk, 0.47; 95% confidence interval, 0.26-0.83; P = .009; R 2 , 100%; P = .008), and fetal growth restriction (relative risk, 0.56; 95% confidence interval, 0.44-0.70; P < .001; R 2 , 100%; P = .044) with higher dosages of aspirin being associated with greater reduction of the 3 outcomes. Similar results were observed after the exclusion of studies at high risk of biases. When aspirin was initiated at >16 weeks, there was a smaller reduction of preeclampsia (relative risk, 0.81; 95% confidence interval, 0.66-0.99; P = .04) without relationship with aspirin dosage (R 2 , 0%; P = .941). Aspirin initiated at >16 weeks was not associated with a risk reduction or a dose-response effect for severe preeclampsia (relative risk, 0.85; 95% confidence interval, 0.64-1.14; P = .28; R 2 , 0%; P = .838) and fetal growth restriction (relative risk, 0.95; 95% confidence interval, 0.86-1.05; P = .34; R 2 , not available; P = .563). Prevention of preeclampsia and fetal growth restriction using aspirin in early pregnancy is associated with a dose-response effect. Low-dose aspirin initiated at >16 weeks' gestation has a modest or no impact on the risk of preeclampsia, severe preeclampsia, and fetal growth restriction. Women at high risk for those outcomes should be identified in early pregnancy. Copyright © 2016 Elsevier Inc. All rights reserved.

Standard and reduced doses of dabigatran, rivaroxaban and apixaban for stroke prevention in atrial fibrillation: a nationwide cohort study.

PubMed

Staerk, L; Gerds, T A; Lip, G Y H; Ozenne, B; Bonde, A N; Lamberts, M; Fosbøl, E L; Torp-Pedersen, C; Gislason, G H; Olesen, J B

2018-01-01

Comparative data of non-vitamin K antagonist oral anticoagulants (NOAC) are lacking in patients with atrial fibrillation (AF). We compared effectiveness and safety of standard and reduced dose NOAC in AF patients. Using Danish nationwide registries, we included all oral anticoagulant-naïve AF patients who initiated NOAC treatment (2012-2016). Outcome-specific and mortality-specific multiple Cox regressions were combined to compute average treatment effects as 1-year standardized differences in stroke and bleeding risks (g-formula). Amongst 31 522 AF patients, the distribution of NOAC/dose was as follows: dabigatran standard dose (22.4%), dabigatran-reduced dose (14.0%), rivaroxaban standard dose (21.8%), rivaroxaban reduced dose (6.7%), apixaban standard dose (22.9%), and apixaban reduced dose (12.2%). The 1-year standardized absolute risks of stroke/thromboembolism were 1.73-1.98% and 2.51-2.78% with standard and reduced NOAC dose, respectively, without statistically significant differences between NOACs for given dose level. Comparing standard doses, the 1-year standardized absolute risk (95% CI) for major bleeding was for rivaroxaban 2.78% (2.42-3.17%); corresponding absolute risk differences (95% CI) were for dabigatran -0.93% (-1.45% to -0.38%) and apixaban, -0.54% (-0.99% to -0.05%). The results for major bleeding were similar for reduced NOAC dose. The 1-year standardized absolute risk (95% CI) for intracranial bleeding was for standard dose dabigatran 0.19% (0.22-0.50%); corresponding absolute risk differences (95% CI) were for rivaroxaban 0.23% (0.06-0.41%) and apixaban, 0.18% (0.01-0.34%). Standard and reduced dose NOACs, respectively, showed no significant risk difference for associated stroke/thromboembolism. Rivaroxaban was associated with higher bleeding risk compared with dabigatran and apixaban and dabigatran was associated with lower intracranial bleeding risk compared with rivaroxaban and apixaban. © 2017 The Association for the Publication of the Journal of Internal Medicine.

Low-dose irradiation as a measure to improve microbial quality of ice cream.

PubMed

Kamat, A; Warke, R; Kamat, M; Thomas, P

2000-12-05

The present study was undertaken to investigate the efficacy of low-dose irradiation to improve the microbial safety of ice cream. Initially three different flavors (vanilla, strawberry and chocolate) of ice cream were exposed, at -72 degrees C, to doses of 1, 2, 5, 10 and 30 kGy to gamma-radiation. Irradiation at 1 kGy resulted in reduction of microbial population by one log cycle, thus meeting the requirement limits prescribed by Bureau of Indian Standards. Pathogens such as Listeria monocytogenes 036, Yersinia enterocoliticta 5692 and Escherichia coli O157:H19, respectively, showed the D10 values 0.38, 0.15 and 0.2 kGy in ice cream at -72 degrees C suggesting the efficacy of low doses (1 kGy) in eliminating them. Sensory evaluation studies of ice cream irradiated at 1, 2, 3 and 5 kGy by a 15 member panel demonstrated that doses higher than 2 kGy irradiation induced off-odour and an aftertaste was evident in vanilla ice cream. A radiation dose of 1 kGy was sufficient to eliminate the natural number of pathogens present in the ice cream. No statistically significant differences were observed in the sensory attributes of all the three flavours of ice cream either unirradiated or exposed to 1 kGy (P < 0.05).

Inactivated yellow fever 17D vaccine: development and nonclinical safety, immunogenicity and protective activity.

PubMed

Monath, Thomas P; Lee, Cynthia K; Julander, Justin G; Brown, Alicja; Beasley, David W; Watts, Douglas M; Hayman, Edward; Guertin, Patrick; Makowiecki, Joseph; Crowell, Joseph; Levesque, Philip; Bowick, Gavin C; Morin, Merribeth; Fowler, Elizabeth; Trent, Dennis W

2010-05-14

In the last 10 years new concerns have arisen about safety of the live, attenuated yellow fever (YF) 17D vaccine, in particular viscerotropic adverse events, which have a case-fatality rate of 64%. A non-replicating cell culture-based vaccine would not cause these adverse events, and potentially could be used in persons with precautions or contraindications to use of the live vaccine, including age <9 months and >60 years, egg allergy, immune suppression, and pregnancy. We developed a whole virion vaccine from the 17D strain inactivated with beta-propiolactone, and adsorbed to aluminum hydroxide. The inactivated vaccine was highly immunogenic in mice, hamsters, and cynomolgus macaques. After a single dose in hamsters and macaques, neutralizing antibody titers were similar to those elicited by the live 17D vaccine (YF-VAX, Sanofi Pasteur). After two doses of inactivated vaccine, neutralizing antibody titers in hamsters were significantly higher than after a single dose of YF-VAX [geometric mean titer (GMT) 20,480 vs. 1940, respectively (P<0.001, ANOVA)]. Hamsters given a single dose or two doses of inactivated vaccine or a single dose of YF-VAX were fully protected against hepatitis, viremia, weight loss and death after challenge with YF virus (Jimenez strain). A clinical trial of the inactivated vaccine (XRX-001) has been initiated. Copyright 2010 Elsevier Ltd. All rights reserved.

Efficacy and Safety of a Colistin Loading Dose, High-Dose Maintenance Regimen in Critically Ill Patients With Multidrug-Resistant Gram-Negative Pneumonia.

PubMed

Elefritz, Jessica L; Bauer, Karri A; Jones, Christian; Mangino, Julie E; Porter, Kyle; Murphy, Claire V

2017-09-01

Emergence of multidrug-resistant (MDR) gram-negative (GN) pathogens and lack of novel antibiotics have increased the use of colistin, despite unknown optimal dosing. This study aimed to evaluate the safety and efficacy of a colistin loading dose, high-dose (LDHD) maintenance regimen in patients with MDR-GN pneumonia. A retrospective cohort analysis was performed comparing critically ill patients with MDR-GN pneumonia pre- and postimplementation of a colistin LDHD guideline with a primary outcome of clinical cure. Safety was assessed using incidence of acute kidney injury (AKI) based on RIFLE (risk, injury, failure, loss, end-stage renal disease) criteria. Seventy-two patients met the inclusion criteria (42 preimplementation and 30 postimplementation). Clinical cure was achieved in 23 (55%) patients in the preimplementation group and 20 (67%) patients in the postimplementation group ( P = .31). AKI occurred in 50% of the patients during the preimplementation period and 58% during the postimplementation period ( P = .59) with no difference in initiation rates of renal replacement therapy. The increased clinical cure rate after implementation of the colistin LDHD guideline did not reach statistical significance. The LDHD guideline, however, was not associated with an increased incidence of AKI, despite higher intravenous colistin doses. Opportunity exists to optimize colistin dosage while balancing toxicity, but larger studies are warranted.

Quantifying the effect of electric current on cell adhesion studied by single-cell force spectroscopy.

PubMed

Jaatinen, Leena; Young, Eleanore; Hyttinen, Jari; Vörös, János; Zambelli, Tomaso; Demkó, László

2016-03-20

This study presents the effect of external electric current on the cell adhesive and mechanical properties of the C2C12 mouse myoblast cell line. Changes in cell morphology, viability, cytoskeleton, and focal adhesion structure were studied by standard staining protocols, while single-cell force spectroscopy based on the fluidic force microscopy technology provided a rapid, serial quantification and detailed analysis of cell adhesion and its dynamics. The setup allowed measurements of adhesion forces up to the μN range, and total detachment distances over 40 μm. Force-distance curves have been fitted with a simple elastic model including a cell detachment protocol in order to estimate the Young's modulus of the cells, as well as to reveal changes in the dynamic properties as functions of the applied current dose. While the cell spreading area decreased monotonously with increasing current doses, small current doses resulted only in differences related to cell elasticity. Current doses above 11 As/m(2), however, initiated more drastic changes in cell morphology, viability, cellular structure, as well as in properties related to cell adhesion. The observed differences, eventually leading to cell death toward higher doses, might originate from both the decrease in pH and the generation of reactive oxygen species.

Sun-Induced Changes in Stratum Corneum Function Are Gender and Dose Dependent in a Chinese Population

PubMed Central

Liu, Z.; Fluhr, J.W.; Song, S.P.; Sun, Z.; Wang, H.; Shi, Y.J.; Elias, P.M.; Man, M.-Q.

2010-01-01

Previous studies have demonstrated that UVB radiation changes the epidermal permeability barrier and stratum corneum (SC) hydration. It is well known that sun exposure causes erythema, sunburn and melanoma. However, whether daily sun exposure alters SC integrity and epidermal permeability barrier function is largely unknown, especially in Chinese subjects. In the present study, we assess the SC integrity, SC hydration and epidermal permeability barrier function following various doses of sun exposure. A total of 258 subjects (124 males and 134 females) aged 18–50 years were enrolled. A multifunctional skin physiology monitor (Courage & Khazaka MPA5) was used to measure SC hydration and transepidermal water loss (TEWL) on the forearms. In males, basal TEWL was higher with higher doses of sun exposure than with lower doses and control, whereas in females, basal TEWL was higher with lower doses of sun exposure than with higher doses and control. In the group with higher doses of sun exposure, TEWL in females was significantly lower than that in males. The barrier recovery was faster in females than in males in both control and lower-dose groups. In both males and females, barrier recovery was delayed with higher doses of sun exposure. In males, sun exposure did not alter SC hydration, while in females SC hydration was lower with lower doses of sun exposure as compared with control and higher doses of sun exposure. These results demonstrated that sun-induced changes in SC function and SC hydration vary with gender and the extent of sun exposure. PMID:20571289

SU-F-T-191: 4D Dose Reconstruction of Intensity Modulated Proton Therapy (IMPT) Based On Breathing Probability Density Function (PDF) From 4D Cone Beam Projection Images: A Study for Lung Treatment

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

Zhou, J; Ding, X; Liang, J

2016-06-15

Purpose: With energy repainting in lung IMPT, the dose delivered is approximate to the convolution of dose in each phase with corresponding breathing PDF. This study is to compute breathing PDF weighted 4D dose in lung IMPT treatment and compare to its initial robust plan. Methods: Six lung patients were evaluated in this study. Amsterdam shroud image were generated from pre-treatment 4D cone-beam projections. Diaphragm motion curve was extract from the shroud image and the breathing PDF was generated. Each patient was planned to 60 Gy (12GyX5). In initial plans, ITV density on average CT was overridden with its maximummore » value for planning, using two IMPT beams with robust optimization (5mm uncertainty in patient position and 3.5% range uncertainty). The plan was applied to all 4D CT phases. The dose in each phase was deformed to a reference phase. 4D dose is reconstructed by summing all these doses based on corresponding weighting from the PDF. Plan parameters, including maximum dose (Dmax), ITV V100, homogeneity index (HI=D2/D98), R50 (50%IDL/ITV), and the lung-GTV’s V12.5 and V5 were compared between the reconstructed 4D dose to initial plans. Results: The Dmax is significantly less dose in the reconstructed 4D dose, 68.12±3.5Gy, vs. 70.1±4.3Gy in the initial plans (p=0.015). No significant difference is found for the ITV V100, HI, and R50, 92.2%±15.4% vs. 96.3%±2.5% (p=0.565), 1.033±0.016 vs. 1.038±0.017 (p=0.548), 19.2±12.1 vs. 18.1±11.6 (p=0.265), for the 4D dose and initial plans, respectively. The lung-GTV V12.5 and V5 are significantly high in the 4D dose, 13.9%±4.8% vs. 13.0%±4.6% (p=0.021) and 17.6%±5.4% vs. 16.9%±5.2% (p=0.011), respectively. Conclusion: 4D dose reconstruction based on phase PDF can be used to evaluate the dose received by the patient. A robust optimization based on the phase PDF may even further improve patient care.« less

Rates and Durability of Response to Salvage Radiation Therapy Among Patients With Refractory or Relapsed Aggressive Non-Hodgkin Lymphoma

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

Tseng, Yolanda D., E-mail: ydt2@uw.edu; Chen, Yu-Hui; Catalano, Paul J.

Purpose: To evaluate the response rate (RR) and time to local recurrence (TTLR) among patients who received salvage radiation therapy for relapsed or refractory aggressive non-Hodgkin lymphoma (NHL) and investigate whether RR and TTLR differed according to disease characteristics. Methods and Materials: A retrospective review was performed for all patients who completed a course of salvage radiation therapy between January 2001 and May 2011 at Brigham and Women's Hospital/Dana-Farber Cancer Institute. Separate analyses were conducted for patients treated with palliative and curative intent. Predictors of RR for each subgroup were assessed using a generalized estimating equation model. For patients treatedmore » with curative intent, local control (LC) and progression-free survival were estimated with the Kaplan-Meier method; predictors for TTLR were evaluated using a Cox proportional hazards regression model. Results: Salvage radiation therapy was used to treat 110 patients to 121 sites (76 curative, 45 palliative). Salvage radiation therapy was given as part of consolidation in 18% of patients treated with curative intent. Median dose was 37.8 Gy, with 58% and 36% of curative and palliative patients, respectively, receiving 39.6 Gy or higher. The RR was high (86% curative, 84% palliative). With a median follow-up of 4.8 years among living patients, 5-year LC and progression-free survival for curative patients were 66% and 34%, respectively. Refractory disease (hazard ratio 3.3; P=.024) and lack of response to initial chemotherapy (hazard ratio 4.3; P=.007) but not dose (P=.93) were associated with shorter TTLR. Despite doses of 39.6 Gy or higher, 2-year LC was only 61% for definitive patients with refractory disease or disease that did not respond to initial chemotherapy. Conclusions: Relapsed or refractory aggressive NHL is responsive to salvage radiation therapy, and durable LC can be achieved in some cases. However, refractory disease is associated with a shorter TTLR, suggesting that radiation dose escalation, addition of radiosensitizers, or a combination of both may be indicated in these patients.« less

Inducing rat brain CYP2D with nicotine increases the rate of codeine tolerance; predicting the rate of tolerance from acute analgesic response.

PubMed

McMillan, Douglas M; Tyndale, Rachel F

2017-12-01

Repeated opioid administration produces analgesic tolerance, which may lead to dose escalation. Brain CYP2D metabolizes codeine to morphine, a bioactivation step required for codeine analgesia. Higher brain, but not liver, CYP2D is found in smokers and nicotine induces rat brain, but not liver, CYP2D expression and activity. Nicotine induction of rat brain CYP2D increases acute codeine conversion to morphine, and analgesia, however the role of brain CYP2D on the effects of repeated codeine exposure and tolerance is unknown. Rats were pretreated with nicotine (brain CYP2D inducer; 1mg/kg subcutaneously) or vehicle (saline; 1ml/kg subcutaneously). Codeine (40-60mg/kg oral-gavage) or morphine (20-30mg/kg oral-gavage) was administered daily and analgesia was assessed daily using the tail-flick reflex assay. Nicotine (versus saline) pretreatment increased acute codeine analgesia (1.32-fold change in AUC 0-60 min ; p<0.05) and the rate of loss of peak analgesia (11.42%/day versus 4.20%; p<0.006) across the first four days of codeine administration (time to negligible analgesia). Inducing brain CYP2D with nicotine did not alter acute morphine analgesia (1.03-fold; p>0.8), or the rate of morphine tolerance (8.1%/day versus 7.6%; p>0.9). The rate of both codeine and morphine tolerance (loss in peak analgesia from day 1 to day 4) correlated with initial analgesic response on day 1 (R=0.97, p<001). Increasing brain CYP2D altered initial analgesia and subsequent rate of tolerance. Variation in an individual's initial response to analgesic (e.g. high initial dose, smoking) may affect the rate of tolerance, and thereby the risk for dose escalation and/or opioid dependence. Copyright © 2017 Elsevier Inc. All rights reserved.

A comparison of 20 or 40 mg per day of carbimazole in the initial treatment of hyperthyroidism.

PubMed

Page, S R; Sheard, C E; Herbert, M; Hopton, M; Jeffcoate, W J

1996-11-01

The optimal dosage regimen for carbimazole (CBZ) in the treatment of hyperthyroidism remains uncertain, despite clinical use of the drug for approximately fifty years. We have compared the early clinical and biochemical responses to 20 or 40 mg/day of CBZ given as initial treatment for hyperthyroidism. Prospective open multicentre trial. Sixty-three patients presenting with hyperthyroidism. Serum total and free thyroid hormones, serum TSH and SHBG were measured at baseline and at 4 and 10 weeks after start of therapy. Weight, pulse and a symptom questionnaire were also monitored at 6 and 12 weeks. Patients randomized to a starting dose of 40 mg/day CBZ had lower total (98 +/- 10 vs 158 +/- 11 nmol/l, P < 0.001) and free T4 (19.4 +/- 2.6 vs 35.2 +/- 3.7 pmol/l, P < 0.001) and total (2.6 +/- 0.3 vs 4.3 +/- 0.4 nmol/l, P < 0.001) and free T3 (8.3 +/- 1.0 vs 13.7 +/- 1.2 pmol/l, P < 0.01) at 4 weeks than those receiving 20 mg/day. Clinical responses at 6 and 12 weeks (weight, pulse, symptom score) and SHBG concentrations were similar. Drug-related hypothyroidism was less likely to occur at 4 and 10 weeks in those patient who initially received 20 mg CBZ/day, but this dose was less effective at controlling hyperthyroidism in those with more severe hyperthyroidism with baseline TT4 > 260 nmol/l. In treating hyperthyroidism, 20 mg/day carbimazole is effective, convenient and has a lower risk than 40 mg/day of iatrogenic hypothyroidism in patients with mild or moderate hyperthyroidism. Higher doses are required for those with severe hyperthyroidism.

Impact of prior treatment and depth of response on survival in MM-003, a randomized phase 3 study comparing pomalidomide plus low-dose dexamethasone versus high-dose dexamethasone in relapsed/refractory multiple myeloma

PubMed Central

San Miguel, Jesus F.; Weisel, Katja C.; Song, Kevin W.; Delforge, Michel; Karlin, Lionel; Goldschmidt, Hartmut; Moreau, Philippe; Banos, Anne; Oriol, Albert; Garderet, Laurent; Cavo, Michele; Ivanova, Valentina; Alegre, Adrian; Martinez-Lopez, Joaquin; Chen, Christine; Renner, Christoph; Bahlis, Nizar Jacques; Yu, Xin; Teasdale, Terri; Sternas, Lars; Jacques, Christian; Zaki, Mohamed H.; Dimopoulos, Meletios A.

2015-01-01

Pomalidomide is a distinct oral IMiD® immunomodulatory agent with direct antimyeloma, stromal-support inhibitory, and immunomodulatory effects. The pivotal, multicenter, open-label, randomized phase 3 trial MM-003 compared pomalidomide + low-dose dexamethasone vs high-dose dexamethasone in 455 patients with refractory or relapsed and refractory multiple myeloma after failure of bortezomib and lenalidomide treatment. Initial results demonstrated significantly longer progression-free survival and overall survival with an acceptable tolerability profile for pomalidomide + low-dose dexamethasone vs high-dose dexamethasone. This secondary analysis describes patient outcomes by treatment history and depth of response. Pomalidomide + low-dose dexamethasone significantly prolonged progression-free survival and favored overall survival vs high-dose dexamethasone for all subgroups analyzed, regardless of prior treatments or refractory status. Both univariate and multivariate analyses showed that no variable relating to either the number (≤ or > 3) or type of prior treatment was a significant predictor of progression-free survival or overall survival. No cross-resistance with prior lenalidomide or thalidomide treatment was observed. Patients achieving a minimal response or better to pomalidomide + low-dose dexamethasone treatment experienced a survival benefit, which was even higher in those achieving at least a partial response (17.2 and 19.9 months, respectively, as compared with 7.5 months for patients with less than minimal response). These data suggest that pomalidomide + low-dose dexamethasone should be considered a standard of care in patients with refractory or relapsed and refractory multiple myeloma regardless of prior treatment. ClinicalTrials.gov: NCT01311687; EudraCT: 2010-019820-30. PMID:26160879

Dose-Dependent Effects of Sirolimus on mTOR Signaling and Polycystic Kidney Disease

PubMed Central

Novalic, Zlata; van der Wal, Annemieke M.; Leonhard, Wouter N.; Koehl, Gudrun; Breuning, Martijn H.; Geissler, Edward K.; de Heer, Emile

2012-01-01

Inhibition of the mammalian target of rapamycin (mTOR) shows beneficial effects in animal models of polycystic kidney disease (PKD); however, two clinical trials in patients with autosomal dominant PKD failed to demonstrate a short-term benefit in either the early or progressive stages of disease. The stage of disease during treatment and the dose of mTOR inhibitors may account for these differing results. Here, we studied the effects of a conventional low dose and a higher dose of sirolimus (blood levels of 3 ng/ml and 30–60 ng/ml, respectively) on mTOR activity and renal cystic disease in two Pkd1-mutant mouse models at different stages of the disease. When initiated at early but not late stages of disease, high-dose treatment strongly reduced mTOR signaling in renal tissues, inhibited cystogenesis, accelerated cyst regression, and abrogated fibrosis and the infiltration of immune cells. In contrast, low-dose treatment did not significantly reduce renal cystic disease. Levels of p-S6RpSer240/244, which marks mTOR activity, varied between kidneys; severity of the renal cystic phenotype correlated with the level of mTOR activity. Taken together, these data suggest that long-term treatment with conventional doses of sirolimus is insufficient to inhibit mTOR activity in renal cystic tissue. Mechanisms to increase bioavailability or to target mTOR inhibitors more specifically to kidneys, alone or in combination with other compounds, may improve the potential for these therapies in PKD. PMID:22343118

Ultra low-dose CT attenuation correction in PET SPM

NASA Astrophysics Data System (ADS)

Wang, Shyh-Jen; Yang, Bang-Hung; Tsai, Chia-Jung; Yang, Ching-Ching; Lee, Jason J. S.; Wu, Tung-Hsin

2010-07-01

The use of CT images for attenuation correction (CTAC) allows significantly shorter scanning time and a high quality noise-free attenuation map compared with conventional germanium-68 transmission scan because at least 10 4 times greater of photon flux would be generated from a CT scan under standard operating condition. However, this CTAC technique would potentially introduce more radiation risk to the patients owing to the higher radiation exposure from CT scan. Statistic parameters mapping (SPM) is a prominent technique in nuclear medicine community for the analysis of brain imaging data. The purpose of this study is to assess the feasibility of low-dose CT (LDCT) and ultra low-dose CT (UDCT) in PET SPM applications. The study was divided into two parts. The first part was to evaluate of tracer uptake distribution pattern and quantity analysis by using the striatal phantom to initially assess the feasibility of AC for clinical purpose. The second part was to examine the group SPM analysis using the Hoffman brain phantom. The phantom study is to simulate the human brain and to reduce the experimental uncertainty of real subjects. The initial studies show that the results of PET SPM analysis have no significant differences between LDCT and UDCT comparing to the current used default CTAC. Moreover, the dose of the LDCT is lower than that of the default CT by a factor of 9, and UDCT can even yield a 42 times dose reduction. We have demonstrated the SPM results while using LDCT and UDCT for PET AC is comparable to those using default CT setting, suggesting their feasibility in PET SPM applications. In addition, the necessity of UDCT in PET SPM studies to avoid excess radiation dose is also evident since most of the subjects involved are non-cancer patients or children and some normal subjects are even served as a comparison group in the experiment. It is our belief that additional attempts to decrease the radiation dose would be valuable, especially for children and normal volunteers, to work towards ALARA (as low as reasonably achievable) concept for PET SPM studies.

Real-time dose adjustment using point-of-care platelet reactivity testing in a double-blind study of prasugrel in children with sickle cell anaemia.

PubMed

Jakubowski, Joseph A; Hoppe, Carolyn C; Zhou, Chunmei; Smith, Brendan E; Brown, Patricia B; Heath, Lori E; Inusa, Baba; Rees, David C; Small, David S; Gupta, Neehar; Yao, Suqin; Heeney, Matthew; Kanter, Julie

2017-02-28

Patients with sickle cell anaemia (SCA) have vaso-occlusive crises resulting from occlusive hypoxic-ischaemic injury. Prasugrel inhibits platelet activation and aggregation involved in SCA pathophysiology. Determining Effects of Platelet Inhibition on Vaso-Occlusive Events (DOVE) was a phase 3, double-blind, randomised, placebo-controlled trial assessing prasugrel efficacy. DOVE sought to bring patients' P2Y12 reaction unit (PRU) value within a targeted range via prasugrel dose adjustments using encrypted VerifyNow P2Y12 ® (VN-P2Y12) point-of-care testing and an interactive voice-response system (IVRS). After PRU determination, randomised patients received 0.08 mg/kg/day prasugrel or placebo. Encrypted PRUs and IVRS provided double-blind dose adjustments to achieve a defined PRU target range of 136-231; placebo patients had mock titrations. Of 341 randomised patients, 166 placebo and 160 prasugrel patients reached the fully titrated dose (FTD). Most prasugrel patients (n=104, 65 %) remained on the initial 0.08 mg/kg dose; doses escalations occurred in 23 % of patients (n=36). Mean PRUs for the pharmacodynamic population at baseline were similar in the prasugrel (273 ± 44.9) and placebo groups (273 ± 51.7), with significant reductions in PRU (p<0.001) for prasugrel patients at the FTD and at 9 months. Concomitant use of hydroxyurea did not affect platelet reactivity at any time. The majority of prasugrel patients (n=135, 84.4 %) at the FTD were within the target range of 136-231 PRUs. Mean VN-P2Y12 percentage inhibition at baseline was similar in the prasugrel (2.8  ± 5.4 %) and placebo groups (2.0 ± 4.7 %); prasugrel patients had significant increases in inhibition (p<0.001) at FTD and at 9 months. Patients with higher PRU values at baseline required higher prasugrel doses to bring PRU within the prespecified range. DOVE is the first study to successfully employ double-blind, real-time, encrypted, point-of-care platelet testing and IVRS to dose-adjust antiplatelet therapy to a targeted range of platelet inhibition.

Antenatal magnesium sulfate and spontaneous intestinal perforation in infants less than 25 weeks gestation.

PubMed

Rattray, B N; Kraus, D M; Drinker, L R; Goldberg, R N; Tanaka, D T; Cotten, C M

2014-11-01

Evaluate spontaneous intestinal perforation (SIP)/death among extremely low birthweight (ELBW) infants before, during and after initiation of an antenatal magnesium for neuroprotection protocol (MgPro). We tested associations between SIP/death and magnesium exposure, gestational age (GA) and interactions with GA and magnesium exposure in a cohort of inborn ELBW infants before, during and after MgPro. One hundred and fifty-five ELBW infants were included, 81 before, 23 during and 51 after MgPro. ELBW infants (78.3%) were exposed to Mg during MgPro compared with 50.6% and 60.8% before and after, respectively. Incidence of SIP on protocol was 30.4% vs 12.9% off protocol (P=0.03). GA was strongly associated with SIP (P<0.01). Antenatal Mg dose was also associated with SIP/death regardless of epoch (odds ratio 9.3 (1.04-104.6)), but increased SIP/death was limited to those <25 weeks gestation. Higher Mg dose was associated with higher SIP and death risk among infants with the lowest birthweights. Validation of this observation in larger populations is warranted.

Real-World Dosing Patterns of Atomoxetine in Adults with Attention-Deficit/Hyperactivity Disorder.

PubMed

Kabul, Samaneh; Alatorre, Carlos; Montejano, Leslie B; Farr, Amanda M; Clemow, David B

2015-12-01

The aim was to investigate the dosing patterns of atomoxetine monotherapy in adult patients with attention-deficit/hyperactivity disorder (ADHD) in a retrospective analysis. Adult (≥ 18 years) patients with ADHD newly initiated on atomoxetine with ≥ 1 outpatient pharmacy claim for atomoxetine between January 2006 and December 2011 were selected from the Truven Health MarketScan(®) Commercial database. After a 30-day titration period, dosing patterns of atomoxetine monotherapy were analyzed in the 12 months following initiation. In addition, patient demographic and clinical characteristics were compared to identify characteristics associated with suboptimal versus recommended dosing. Of the 12,412 adult patients with ADHD newly initiated on atomoxetine, 4548 (36.6%) were suboptimally dosed, whereas 3323 (26.7%) were treated at recommended dose. Overall, study patients were treated at a mean (standard deviation [SD]) dose of 68.5 (44.9) mg/day. The suboptimal dosing cohort included significantly more females (54% vs. 44%, P < 0.001) and had fewer patients with pre-index use of other ADHD medications (17% vs. 20%, P < 0.001) compared with the recommended dosing cohort. Adult patients with ADHD receiving atomoxetine therapy in a real-world setting are often dosed suboptimally. Increasing the awareness on optimal dosing strategy among clinicians and patients is warranted to maximize the therapeutic benefits of atomoxetine among adult patients with ADHD. © 2015 Eli Lilly and Company. CNS Neuroscience and Therapeutics published by John Wiley & Sons Ltd.

Acquisition and Retention of Sterile Compounding Accuracy Skills

PubMed Central

Brown, Michael C.; Valdovinos, Katie; Zavala, Pedro J.

2017-01-01

Objective. To determine the accuracy of dose of pharmacy students’ parenteral sterile preparation skills and to measure pharmacy students’ skill retention 1.5 years later. Methods. An exercise was designed to assess each student’s accuracy in compounding a sterile preparation with the correct potency during a second and then third year course. Results. Initially, the mean (standard deviation) of 141 students’ compounded preparation dose was not significantly different than the desired dose. Additionally, 91.5% of products were within 10% of the desired dose. In the follow-up activity the next academic year, the mean dose was not significantly different than the original compounded dose. Similarly 92.9% were within 10% of the desired dose. Conclusion. Students’ overall accuracy of sterile compounding was good initially and well-retained more than a year later, with more than 90% of students being within 10% of the desired dose in both courses. PMID:28970616

Induction and repair of DNA strand breaks in bovine lens epithelial cells after high LET irradiation.

PubMed

Baumstark-Khan, C; Heilmann, J; Rink, H

2003-01-01

The lens epithelium is the initiation site for the development of radiation induced cataracts. Radiation in the cortex and nucleus interacts with proteins, while in the epithelium, experimental results reveal mutagenic and cytotoxic effects. It is suggested that incorrectly repaired DNA damage may be lethal in terms of cellular reproduction and also may initiate the development of mutations or transformations in surviving cells. The occurrence of such genetically modified cells may lead to lens opacification. For a quantitative risk estimation for astronauts and space travelers it is necessary to know the relative biological effectiveness (RBE), because the spacial and temporal distribution of initial physical damage induced by cosmic radiation differ significantly from that of X-rays. RBEs for the induction of DNA strand breaks and the efficiency of repair of these breaks were measured in cultured diploid bovine lens epithelial cells exposed to different LET irradiation to either 300 kV X-rays or to heavy ions at the UNILAC accelerator at GSI. Accelerated ions from Z=8 (O) to Z=92 (U) were used. Strand breaks were measured by hydroxyapatite chromatography of alkaline unwound DNA (overall strand breaks). Results showed that DNA damage occurs as a function of dose, of kinetic energy and of LET. For particles having the same LET the severity of the DNA damage increases with dose. For a given particle dose, as the LET rises, the numbers of DNA strand breaks increase to a maximum and then reach a plateau or decrease. Repair kinetics depend on the fluence (irradiation dose). At any LET value, repair is much slower after heavy ion exposure than after X-irradiation. For ions with an LET of less than 10,000 keV micrometers-1 more than 90 percent of the strand breaks induced are repaired within 24 hours. At higher particle fluences, especially for low energetic particles with a very high local density of energy deposition within the particle track, a higher proportion of non-rejoined breaks is found, even after prolonged periods of incubation. At the highest LET value (16,300 keV micrometers-1) no significant repair is observed. These LET-dependencies are consistent with the current mechanistic model for radiation induced cataractogenesis which postulates that genomic damage to the surviving fraction of epithelial cells is responsible for lens opacification. c2003 COSPAR. Published by Elsevier Science Ltd. All rights reserved.

A Retrospective Analysis of Corticosteroid Utilization Before Initiation of Biologic DMARDs Among Patients with Rheumatoid Arthritis in the United States.

PubMed

Spivey, Christina A; Griffith, Jenny; Kaplan, Cameron; Postlethwaite, Arnold; Ganguli, Arijit; Wang, Junling

2018-06-01

Understanding the effects of corticosteroid utilization prior to initiation of biologic disease-modifying antirheumatic drugs (DMARDs) can inform decision-makers on the appropriate use of these medications. This study examined treatment patterns and associated burden of corticosteroid utilization before initiation of biologic DMARDs among rheumatoid arthritis (RA) patients. A retrospective analysis was conducted of adult RA patients in the US MarketScan Database (2011-2015). The following patterns of corticosteroid utilization were analyzed: whether corticosteroids were used; duration of use (short/long duration defined as < or ≥ 3 months); and dosage (low as < 2.5, medium as 2.5 to < 7.5 and high as ≥ 7.5 mg/day). Effects of corticosteroid use on time to biologic DMARD initiation were examined using Cox proportional hazards models. Likelihood and number of adverse events were examined using logistic and negative binomial regression models. Generalized linear models were used to examine healthcare costs. Independent variables in all models included patient demographics and health characteristics. A total of 25,542 patients were included (40.84% used corticosteroids). Lower hazard of biologic DMARD initiation was associated with corticosteroid use (hazard ratio = 0.89, 95% confidence interval = 0.83-0.96), long duration and lower dose. Corticosteroid users compared to non-users had higher incidence rates of various adverse events including cardiovascular events (P < 0.05). Higher likelihood of adverse events was associated with corticosteroid use and long duration of use, as was increased number of adverse events. Corticosteroid users had a greater annualized mean number of physician visits, hospitalizations, and emergency department (ED) visits than non-users in adjusted analysis. Corticosteroid users compared to non-users had higher mean costs for total healthcare, physician visits, hospitalizations, and ED visits. Among patients with RA, corticosteroid utilization is associated with delayed initiation of biologic DMARDS and higher burden of adverse events and healthcare utilization/costs before the initiation of biologic DMARDs. AbbVie Inc.

Retrospective Analysis of Dose Titration and Serum Testosterone Level Assessments in Patients Treated With Topical Testosterone.

PubMed

Muram, David; Kaltenboeck, Anna; Boytsov, Natalie; Hayes-Larson, Eleanor; Ivanova, Jasmina; Birnbaum, Howard G; Swindle, Ralph

2015-11-01

Patterns of care following topical testosterone agent (TTA) initiation are poorly understood. This study aimed to characterize care following TTA initiation and compare results between patients with and without a serum testosterone (T) assay within 30 days before and including TTA initiation. Adult men (N=4,146) initiating TTAs from January 1, 2011, to March 31, 2012, were identified from a commercially insured database. Patients were included if they initiated at recommended starting dose (RSD) and had ≥12 and ≥6 months of continuous eligibility preinitiation (baseline) and postinitiation (study period), respectively. Patients were stratified by preinitiation T assay. Maintenance dose attainment month was determined using unadjusted generalized estimating equations regression to compare dose relative to RSD month by month. Outcomes included maintenance dose attainment month, time to stopping of index TTA refills or a claim for nonindex testosterone replacement therapy (TRT), and proportion of patients with study period T assay or diagnosis of hypogonadism (HG) or another low testosterone condition, and were compared using chi-square and Wilcoxon rank-sum tests for categorical and continuous variables, respectively. Maintenance dose was attained in Month 4 postinitiation, at 115.2% of RSD. Approximately 46% of patients had a preinitiation T assay; these men were more likely to receive a diagnosis of HG or another low testosterone condition, to have a follow-up T assay, to continue treatment by filling a nonindex TRT, and less likely to stop refilling treatment with their index TTA. Differences in care following TTA initiation suggest that preinitiation T assays (i.e., guideline-based care) may be helpful in ensuring treatment benefits. © The Author(s) 2014.

Is there an ideal way to initiate antiplatelet therapy with aspirin? A crossover study on healthy volunteers evaluating different dosing schemes with whole blood aggregometry

PubMed Central

2011-01-01

Background Guidelines recommend an early initiation of aspirin treatment in patients with acute cerebral ischemia. Comparative studies on the best starting dose for initiating aspirin therapy to achieve a rapid antiplatelet effect do not exist. This study evaluated the platelet inhibitory effect in healthy volunteers by using three different aspirin loading doses to gain a model for initiating antiplatelet treatment in acute strokes patients. Methods Using whole blood aggregometry, this study with a prospective, uncontrolled, open, crossover design examined 12 healthy volunteers treated with three different aspirin loading doses: intravenous 500 mg aspirin, oral 500 mg aspirin, and a course of 200 mg aspirin on two subsequent days followed by a five-day course of 100 mg aspirin. Aspirin low response was defined as change of impedance exceeding 0 Ω after stimulation with arachidonic acid. Results Sufficient antiplatelet effectiveness was gained within 30 seconds when intravenous 500 mg aspirin was used. The mean time until antiplatelet effect was 74 minutes for 500 mg aspirin taken orally and 662 minutes (11.2 hours) for the dose scheme with 200 mg aspirin with a high inter- and intraindividual variability in those two regimes. Platelet aggregation returned to the baseline range during the wash-out phase within 4 days. Conclusion Our study reveals that the antiplatelet effect differs significantly between the three different aspirin starting dosages with a high inter- and intraindividual variability of antiplatelet response in our healthy volunteers. To ensure an early platelet inhibitory effect in acute stroke patients, it could be advantageous to initiate the therapy with an intravenous loading dose of 500 mg aspirin. However, clinical outcome studies must still define the best way to initiate antiplatelet treatment with aspirin. PMID:21466682

Dose-response analysis of testosterone replacement therapy in patients with female to male gender identity disorder.

PubMed

Nakamura, Aya; Watanabe, Masami; Sugimoto, Morito; Sako, Tomoko; Mahmood, Sabina; Kaku, Haruki; Nasu, Yasutomo; Ishii, Kazushi; Nagai, Atsushi; Kumon, Hiromi

2013-01-01

Gender identity disorder (GID) is a conflict between a person's actual physical gender and the one they identify him or herself with. Testosterone is the key agent in the medical treatment of female to male GID patients. We conducted a dose-response analysis of testosterone replacement therapy (TRT) in 138 patients to determine the onset of the therapeutic effects. The TRT consisted of intramuscular injection of testosterone enanthate and patients were divided into three groups; 250 mg every two weeks, 250 mg every three weeks and 125 mg every two weeks. The onset of deepening of voice, increase in facial hair and cessation of menses was evaluated in each group. At one month after the start of TRT, the onset of these physical changes was more prevalent in the group receiving the higher dose of testosterone, and there were dose-dependent effects observed between the three treatment groups. On the other hand, at six months after the start of TRT, most of the patients had achieved treatment responses and there were no dose-dependent effects with regard to the percentage of patients with therapeutic effects. No significant side effects were observed in any of the treatment groups. We demonstrated that the early onset of the treatment effects of TRT is dose-dependent, but within six months of starting TRT, all three doses were highly effective. Current study provides useful information to determine the initial dose of TRT and to suggest possible changes that should be made in the continuous dosage for long term TRT.

Prospective Measurement of Patient Exposure to Radiation During Pediatric Ureteroscopy

PubMed Central

Kokorowski, Paul J.; Chow, Jeanne S.; Strauss, Keith; Pennison, Melanie; Routh, Jonathan C.; Nelson, Caleb P.

2013-01-01

Objective Little data have been reported regarding radiation exposure during pediatric endourologic procedures, including ureteroscopy (URS). We sought to measure radiation exposure during pediatric URS and identify opportunities for exposure reduction. Methods We prospectively observed URS procedures as part of a quality improvement initiative. Pre-operative patient characteristics, operative factors, fluoroscopy settings and radiation exposure were recorded. Our outcomes were entrance skin dose (ESD, in mGy) and midline dose (MLD, in mGy). Specific modifiable factors were identified as targets for potential quality improvement. Results Direct observation was performed on 56 consecutive URS procedures. Mean patient age was 14.8 ± 3.8 years (range 7.4 to 19.2); 9 children were under age 12 years. Mean ESD was 46.4 ± 48 mGy. Mean MLD was 6.2 ± 5.0 mGy. The most important major determinant of radiation dose was total fluoroscopy time (mean 2.68 ± 1.8 min) followed by dose rate setting, child anterior-posterior (AP) diameter, and source to skin distance (all p<0.01). The analysis of factors affecting exposure levels found that the use of ureteral access sheaths (p=0.01) and retrograde pyelography (p=0.04) were significantly associated with fluoroscopy time. We also found that dose rate settings were higher than recommended in up to 43% of cases and ideal C-arm positioning could have reduced exposure 14% (up to 49% in some cases). Conclusions Children receive biologically significant radiation doses during URS procedures. Several modifiable factors contribute to dose and could be targeted in efforts to implement dose reduction strategies. PMID:22341275

Combination of High-Dose Methylprednisolone and Defibrotide for Veno-Occlusive Disease in Pediatric Hematopoietic Stem Cell Transplant Recipients.

PubMed

Gloude, Nicholas J; Jodele, Sonata; Teusink-Cross, Ashley; Grimley, Michael; Davies, Stella M; Lane, Adam; Myers, Kasiani C

2018-01-01

Veno-occlusive disease (VOD) is a serious complication of hematopoietic stem cell transplant (HSCT), with high mortality in severe cases and until recently very limited therapeutic options consisting largely of supportive care. Defibrotide was recently approved in the United States for the treatment of severe VOD in patients with renal or pulmonary dysfunction after HSCT. Our group previously published on the use of high-dose methylprednisolone (500 mg/m 2 per dose every 12 hours for 6 doses) in patients with VOD, showing good success. A small subset of these individuals were also treated with defibrotide, but additional studies using the combination of high-dose methylprednisolone and defibrotide for the treatment of VOD are lacking. We present a single-institution retrospective chart review of 15 HSCT patients with VOD treated with the combination of high-dose methylprednisolone and defibrotide. VOD developed at a median of 17 days post-HSCT, and combination therapy was initiated within 1 day of VOD diagnosis. Twelve of 15 patients (80%) had multiorgan failure. Our single-center experience using both high-dose methylprednisolone and defibrotide showed a day +100 survival rate of 73% and an overall VOD complete resolution rate of 66.7%, higher than the rates reported in the recent literature using defibrotide alone (40% to 50% day +100 overall survival). These data suggest that the combination of high-dose steroids and defibrotide may be superior to defibrotide alone and warrant further investigation. Copyright © 2017 The American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.

Dactinomycin and Vincristine Toxicity in the Treatment of Childhood Cancer: A Retrospective Study from the Children’s Oncology Group

PubMed Central

Langholz, Bryan; Skolnik, Jeffrey M.; Barrett, Jeffrey S.; Renbarger, Jamie; Seibel, Nita L.; Zajicek, Anne; Arndt, Carola A.S.

2011-01-01

Background Dactinomycin (AMD) and vincristine (VCR) have been used for the treatment of childhood cancer over the past 40 years but evidence-based dosing guidance is lacking. Methods Patient AMD and VCR dose and drug-related adverse event (AE) information from four rhabdomyosarcoma (RMS) and two Wilms tumor (WT) studies were assembled. Statistical modeling was used to account for differences in AE data collection across studies, develop rate models for grade 3/4 CTCAE v3 hepatic- (AMD) and neuro- (AMD) toxicity, assess variation in toxicity rates over age and other factors, and predict toxicity risk under current dosing guidelines. Results For the same dose/body size, AMD toxicity rates were higher in patients <1 year than older patients and VCR toxicity rates increased with age. The statistical model provided estimates for AMD and VCR toxicity risk under current dosing schedules and indicated that patients of smaller body size were at lower risk of VCR toxicity than larger patients of the same age. The rate of AMD toxicity was highest early in treatment and was lower in patients who tolerated initial AMD without toxicity. Conclusion The observed decrease in AMD toxicity rate with cumulative dose may indicate sensitivity in a subgroup of patients while the observed increase in VCR toxicity risk with age may indicate changing sensitivity to VCR. Current dosing practices result in a fairly uniform toxicity profile within age group. However, PK/PD studies should be done to provide further provide further information on best dosing guidelines. PMID:21671362

Pharmacokinetics and Pharmacodynamics of Tolvaptan in Autosomal Dominant Polycystic Kidney Disease: Phase 2 Trials for Dose Selection in the Pivotal Phase 3 Trial

PubMed Central

Chapman, Arlene B.; Torres, Vicente E.; Ouyang, John; Czerwiec, Frank S.

2017-01-01

Abstract In the pivotal TEMPO 3:4 trial, the arginine vasopressin V2‐receptor antagonist tolvaptan reduced the rate of kidney growth in patients with autosomal dominant polycystic kidney disease. Tolvaptan was initiated as daily morning/afternoon doses of 45/15 mg, and uptitrated weekly to 60/30 mg and 90/30 mg according to patient‐reported tolerability. The current report describes 3 phase 2 trials in adult autosomal dominant polycystic kidney disease subjects that were the basis for the titrated split‐dose regimen: a single ascending‐dose trial (tolvaptan 15 to 120 mg; n = 11), a multiple split‐dose trial (tolvaptan 15/15 mg, 30/0 mg, 30/15 mg, and 30/30 mg; n = 37), and an 8‐week open‐label safety and efficacy trial in 46 of the 48 subjects who participated in the prior 2 trials (tolvaptan 30/15 mg, 45/15 mg, 60/30 mg, and 90/30 mg). Urine osmolality (Uosm) was chosen as the biomarker of V2 receptor inhibition. Two tolvaptan doses per day were necessary to suppress Uosm to <300 mOsm/kg for 24 hours. The 45/15‐mg regimen was well tolerated and effective in suppressing Uosm in >50% of subjects. Therefore, this regimen was selected as the starting regimen for the TEMPO 3:4 trial. The 90/30‐mg regimen suppressed Uosm in 85% of subjects tested; however, only 28/46 subjects agreed to uptitrate to 90/30 mg due to tolerability. Higher concentrations of tolvaptan were less well tolerated, resulting in adverse events of pollakiuria, thirst, polyuria, nocturia, and a higher number of times out of bed to urinate. Subjects who agreed to uptitrate to 90/30 mg had lower eGFR than those who did not uptitrate. PMID:28218410

Comparison of the hypothetical 57Co brachytherapy source with the 192Ir source

PubMed Central

Toossi, Mohammad Taghi Bahreyni; Rostami, Atefeh; Khosroabadi, Mohsen; Khademi, Sara; Knaup, Courtney

2016-01-01

Aim of the study The 57Co radioisotope has recently been proposed as a hypothetical brachytherapy source due to its high specific activity, appropriate half-life (272 days) and medium energy photons (114.17 keV on average). In this study, Task Group No. 43 dosimetric parameters were calculated and reported for a hypothetical 57Co source. Material and methods A hypothetical 57Co source was simulated in MCNPX, consisting of an active cylinder with 3.5 mm length and 0.6 mm radius encapsulated in a stainless steel capsule. Three photon energies were utilized (136 keV [10.68%], 122 keV [85.60%], 14 keV [9.16%]) for the 57Co source. Air kerma strength, dose rate constant, radial dose function, anisotropy function, and isodose curves for the source were calculated and compared to the corresponding data for a 192Ir source. Results The results are presented as tables and figures. Air kerma strength per 1 mCi activity for the 57Co source was 0.46 cGyh–1 cm 2 mCi–1. The dose rate constant for the 57Co source was determined to be 1.215 cGyh–1U–1. The radial dose function for the 57Co source has an increasing trend due to multiple scattering of low energy photons. The anisotropy function for the 57Co source at various distances from the source is more isotropic than the 192Ir source. Conclusions The 57Co source has advantages over 192Ir due to its lower energy photons, longer half-life, higher dose rate constant and more isotropic anisotropic function. However, the 192Ir source has a higher initial air kerma strength and more uniform radial dose function. These properties make 57Co a suitable source for use in brachytherapy applications. PMID:27688731

Low-dose right unilateral electroconvulsive therapy (ECT): effectiveness of the first treatment.

PubMed

Lapidus, Kyle A B; Shin, Joseph S W; Pasculli, Rosa M; Briggs, Mimi C; Popeo, Dennis M; Kellner, Charles H

2013-06-01

Electroconvulsive therapy (ECT) is a widely used, highly effective antidepressant treatment. Except for the most severely ill patients, right unilateral (RUL) electrode placement is the most frequent initial treatment choice. In current practice, RUL ECT is administered at several multiples of seizure threshold (ST) based on reports that lower stimulus intensity results in lower response/remission rates. Many patients, as part of an initial dose titration to determine ST, will receive a single treatment with low-dose RUL ECT and subsequent treatments with a stimulus at a multiple of ST. To assess response to the first ECT. A retrospective analysis of charts from clinical practice at Mount Sinai Medical Center was performed. A single treatment with low-dose (presumably near ST) RUL ECT had a significant and immediate antidepressant effect in our sample of patients with major depression. We determined that this response is similar to that of patients receiving a single initial treatment with high-dose RUL ECT (at a multiple of ST). These data suggest, contrary to commonly held belief, that RUL ECT may be effective at a low stimulus dose. This argues against restimulating at 6 times ST in the initial session, based on the belief that the near-threshold seizure has no antidepressant efficacy. Our findings suggest a need for further investigation of cases in which low-dose RUL ECT may be an effective antidepressant treatment. Further prospective studies, including larger numbers of patients who receive randomized treatment with low- or high-dose RUL with longer follow-up, are indicated.

ABVD versus BEACOPP for Hodgkin's lymphoma when high-dose salvage is planned.

PubMed

Viviani, Simonetta; Zinzani, Pier Luigi; Rambaldi, Alessandro; Brusamolino, Ercole; Levis, Alessandro; Bonfante, Valeria; Vitolo, Umberto; Pulsoni, Alessandro; Liberati, Anna Marina; Specchia, Giorgina; Valagussa, Pinuccia; Rossi, Andrea; Zaja, Francesco; Pogliani, Enrico M; Pregno, Patrizia; Gotti, Manuel; Gallamini, Andrea; Rota Scalabrini, Delia; Bonadonna, Gianni; Gianni, Alessandro M

2011-07-21

BEACOPP, an intensified regimen consisting of bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone, has been advocated as the new standard of treatment for advanced Hodgkin's lymphoma, in place of the combination of doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD). We randomly assigned 331 patients with previously untreated and unfavorable Hodgkin's lymphoma (stage IIB, III, or IV, or an international prognostic score of ≥3 on a scale of 0 to 7, with higher scores indicating increased risk), to receive either BEACOPP or ABVD, each followed by local radiotherapy when indicated. Patients with residual or progressive disease after the initial therapy were to be treated according to a state-of-the-art high-dose salvage program. The median follow-up period was 61 months. The 7-year rate of freedom from first progression was 85% among patients who had received initial treatment with BEACOPP and 73% among those who had received initial treatment with ABVD (P=0.004), and the 7-year rate of event-free survival was 78% and 71%, respectively (P=0.15). A total of 65 patients (20 in the BEACOPP group, and 45 in the ABVD group) went on to receive the intended high-dose salvage regimen. As of the cutoff date, 3 of the 20 patients in the BEACOPP group and 15 of the 45 in the ABVD group who had had progressive disease or relapse after the initial therapy were alive and free of disease. After completion of the overall planned treatment, including salvage therapy, the 7-year rate of freedom from a second progression was 88% in the BEACOPP group and 82% in the ABVD group (P=0.12), and the 7-year rate of overall survival was 89% and 84%, respectively (P=0.39). Severe adverse events occurred more frequently in the BEACOPP group than in the ABVD group. Treatment with BEACOPP, as compared with ABVD, resulted in better initial tumor control, but the long-term clinical outcome did not differ significantly between the two regimens. (Funded by Fondazione Michelangelo; ClinicalTrials.gov number, NCT01251107.).

Degradation of sulfamethazine by gamma irradiation in the presence of hydrogen peroxide.

PubMed

Liu, Yuankun; Wang, Jianlong

2013-04-15

The gamma irradiation-induced degradation of sulfamethazine (SMT) in aqueous solution in the presence of hydrogen peroxide (H2O2) was investigated. The initial SMT concentration was 20mg/L and it was irradiated in the presence of extra H2O2 with initial concentration of 0, 10 and 30 mg/L. The results showed that gamma irradiation was effective for removing SMT in aqueous solution and its degradation conformed to the pseudo first-order kinetics under the applied conditions. When initial H2O2 concentration was in the range of 0-30 mg/L, higher concentration of H2O2 was more effective for the decomposition and mineralization of SMT. However, the removal of total organic carbon (TOC) was not as effective as that of SMT. Total nitrogen (TN) was not removed even at absorbed dose of 5 kGy, which was highest dose applied in this study. Major decomposition products of SMT, including degradation intermediates, organic acids and some inorganic ions were detected by high performance liquid chromatography (HPLC) and ion chromatography (IC). Sulfate (SO4(2-)), formic acid (HCOOH), acetic acid (CH3COOH), 4-aminophenol, 4-nitrophenol were identified in the irradiated solutions. Possible pathways for SMT decomposition by gamma irradiation in aqueous solution were proposed. Copyright © 2013 Elsevier B.V. All rights reserved.

Safety and tolerability of different titration rates of retigabine (ezogabine) in patients with partial-onset seizures.

PubMed

Biton, Victor; Gil-Nagel, Antonio; Brodie, Martin J; Derossett, Sarah E; Nohria, Virinder

2013-11-01

Retigabine (RTG; international nonproprietary name)/ezogabine (EZG; US adopted name) is an antiepileptic drug (AED) that prolongs neuronal voltage-gated potassium-channel KCNQ2-5 (Kv 7.2-7.5) opening. This double-blind study evaluated different RTG/EZG dose-titration rates. Patients (N=73) with partial-onset seizures receiving concomitant AEDs were randomized to one of three titration groups, all of which were initiated at RTG/EZG 300mg/day divided into three equal doses. Fast-, medium-, and slow-titration groups received dose increments of 150mg/day every 2, 4, and 7 days, respectively, achieving the target dose of 1200mg/day after 13, 25, and 43 days, respectively. Safety assessments were performed throughout. Discontinuation rates due to treatment-emergent adverse events (TEAEs) were numerically higher in the fast- (10/23) and medium- (7/22) titration groups than in the slow-titration group (3/23) but statistical significance was achieved only for the high-titration group compared with the low-titration group (p=0.024). Stratified analysis, with concomitant AEDs divided into enzyme inducers (carbamazepine, phenytoin, oxcarbazepine) or noninducers, showed that the risk of discontinuation due primarily to TEAEs was significantly higher in the fast- (p=0.010) but not in the medium-titration group (p=0.078) when compared with the slow-titration group. Overall, the slow-titration rate appeared to be best tolerated and was used in further efficacy and safety studies with RTG/EZG. Copyright © 2013 Elsevier B.V. All rights reserved.

Investigation into the Manufacture and Properties of Inhalable High-Dose Dry Powders Produced by Comilling API and Lactose with Magnesium Stearate.

PubMed

Lau, Michael; Young, Paul M; Traini, Daniela

2017-08-01

The aim of the study was to understand the impact of different concentrations of the additive material, magnesium stearate (MGST), and the active pharmaceutical ingredient (API), respectively, on the physicochemical properties and aerosol performance of comilled formulations for high-dose delivery. Initially, blends of API/lactose with different concentrations of MGST (1-7.5% w/w) were prepared and comilled by the jet-mill apparatus. The optimal concentration of MGST in comilled formulations was investigated, specifically for agglomerate structure and strength, particle size, uniformity of content, surface coverage, and aerosol performance. Secondly, comilled formulations with different API (1-40% w/w) concentrations were prepared and similarly analyzed. Comilled 5% MGST (w/w) formulation resulted in a significant improvement in in vitro aerosol performance due to the reduction in agglomerate size and strength compared to the formulation comilled without MGST. Higher concentrations of MGST (7.5% w/w) led to reduction in aerosol performance likely due to excessive surface coverage of the micronized particles by MGST, which led to failure in uniformity of content and an increase in agglomerate strength and size. Generally, comilled formulations with higher concentrations of API increased the agglomerate strength and size, which subsequently caused a reduction in aerosol performance. High-dose delivery was achieved at API concentration of >20% (w/w). The study provided a platform for the investigation of aerosol performance and physicochemical properties of other API and additive materials in comilled formulations for the emerging field of high-dose delivery by dry powder inhalation.

Immune memory in children previously vaccinated with an experimental quadrivalent meningococcal polysaccharide diphtheria toxoid conjugate vaccine.

PubMed

Pichichero, Michael; Papa, Thomas; Blatter, Mark; Mitchell, Douglas; Kratz, Richard; Sneed, Jane; Bassily, Ehab; Casey, Janet; Gilmet, Gregory

2006-11-01

In a previous study, a meningococcal diphtheria toxoid conjugate vaccine (MCV-4) triggered robust bactericidal antibody responses against serogroups A, C, Y, and W-135 in 2- to 10-year-old children. A subset of participants, 2 to 3 years of age at the initial vaccination, was evaluated for persistence of antibody, immune memory, and antibody avidity. Participants were healthy children vaccinated 23 to 36 months earlier with MCV-4 (primed) or newly recruited meningococcal vaccine-naive 4-year-olds. Participants in both groups were alternately allocated to provide sera 8 or 28 days after administration of one tenth of the recommended dose of a meningococcal polysaccharide vaccine (PSV-4). Immune responses were assessed in sera obtained at baseline and either 8 or 28 days after reduced-dose PSV-4 administration. Safety was monitored. Before PSV-4 challenge, serum bactericidal antibody geometric mean titers (SBA GMTs) were higher for all 4 serogroups in the MCV-4-primed group than in the vaccine-naive group. SBA GMTs, geometric mean concentrations of immunoglobulin G (IgG) and geometric mean avidity indices for all 4 serogroups were significantly higher among MCV-4-primed versus vaccine-naive participants in the cohorts evaluated at 8 or 28 days after PSV-4 challenge. Adverse events were generally mild, self-limited, and comparable in all groups of children. Persistence of bactericidal antibody was seen for 23 to 36 months after a primary dose of MCV-4 in young children. Booster responses and avidity maturation were evident after a challenge with reduced-dose polysaccharide vaccine.

Palonosetron (Aloxi): a second-generation 5-HT3 receptor antagonist for chemotherapy-induced nausea and vomiting

PubMed Central

2006-01-01

In July 2003, the Food and Drug Administration approved palonosetron hydrochloride injection for the treatment of chemotherapy-induced nausea and vomiting (CINV). The newest agent in the class of 5-HT3 receptor antagonists (5-HT3RAs), palonosetron differs from other agents in its class by its higher receptor-binding affinity and longer half-life. These pharmacological properties have resulted in improved antiemetic activity in clinical trials, particularly in the treatment of delayed CINV following moderate emetogenic chemotherapy. Based on the results of these clinical studies, palonosetron is the only 5-HT3RA approved for delayed CINV. Palonosetron is given as a single 0.25-mg intravenous dose 30 minutes before the initial dose of chemotherapy. Headache and constipation were the most common adverse events reported with palonosetron therapy. PMID:17106506

Rates of escalation to triple COPD therapy among incident users of LAMA and LAMA/LABA.

PubMed

Hahn, Beth; Hull, Michael; Blauer-Peterson, Cori; Buikema, Ami R; Ray, Riju; Stanford, Richard H

2018-06-01

Improved outcomes have been reported for patients with chronic obstructive pulmonary disease (COPD) receiving combination long-acting muscarinic antagonist/long-acting β 2 -agonist (LAMA/LABA) therapy compared with LAMA monotherapy. However, little is known about the relative characteristics of these patients and their rates of escalation to triple therapy (TT, combining a LAMA, LABA, and inhaled corticosteroid). This study aimed to characterize patients initiating treatment with the LAMA tiotropium (TIO) and the fixed-dose LAMA/LABA combination therapy umeclidinium/vilanterol (UMEC/VI), and to compare rates of escalation to TT between patients receiving these therapies. Retrospective study of patients with COPD enrolled in a US health insurance plan during 2013-2015 and newly initiated on TIO or UMEC/VI. Patients were ≥40 years of age at index (date of therapy initiation) with continuous enrollment for 12 months pre-index and ≥30 days post-index. LAMA users were propensity score matched 1:1 to LAMA/LABA users, with TT initiation rates reported by cohort using pharmacy claims. 35,357 patients initiating on TIO and 2407 patients initiating on UMEC/VI were identified. After propensity score matching, the rate of TT initiation was significantly higher in new TIO users (n = 1320) than in new UMEC/VI users (n = 1320) (0.92 vs 0.49 per 100 months of exposure, respectively; p < 0.001). Relative to the UMEC/VI cohort, the TIO cohort had an 87% higher risk of TT initiation (hazard ratio: 1.87; 95% confidence interval: 1.4-2.5; p = 0.001). Patients receiving UMEC/VI progressed to TT more slowly, and were at lower risk of progressing to TT, than patients receiving TIO. Copyright © 2018 The Authors. Published by Elsevier Ltd.. All rights reserved.

Hydrogen peroxide kinetics in water radiolysis

NASA Astrophysics Data System (ADS)

Iwamatsu, Kazuhiro; Sundin, Sara; LaVerne, Jay A.

2018-04-01

The kinetics of the formation and reaction of hydrogen peroxide in the long time γ- radiolysis of water is examined using a combination of experiment with model calculations. Escape yields of hydrogen peroxide on the microsecond time scale are easily measured with added radical scavengers even with substantial amounts of initial added hydrogen peroxide. The γ-radiolysis of aqueous hydrogen peroxide solutions without added radical scavengers reach a steady state limiting concentration of hydrogen peroxide with increasing dose, and that limit is directly proportional to the initial concentration of added hydrogen peroxide. The dose necessary to reach that limiting hydrogen peroxide concentration is also proportional to the initial concentration, but dose rate has a very small effect. The addition of molecular hydrogen to aqueous solutions of hydrogen peroxide leads to a decrease in the high dose limiting hydrogen peroxide concentration that is linear with the initial hydrogen concentration, but the amount of decrease is not stoichiometric. Proton irradiations of solutions with added hydrogen peroxide and hydrogen are more difficult to predict because of the decreased yields of radicals; however, with a substantial increase in dose rate there is a sufficient decrease in radical yields that hydrogen addition has little effect on hydrogen peroxide decay.

Early insights into the characteristics and evolution of clinical parameters in a cohort of patients prescribed sacubitril/valsartan in Germany.

PubMed

Wachter, Rolf; Viriato, Daniel; Klebs, Sven; Grunow, Stefanie S; Schindler, Matthias; Engelhard, Johanna; Proenca, Catia C; Calado, Frederico; Schlienger, Raymond; Dworak, Markus; Balas, Bogdan; Bruce Wirta, Sara

2018-04-01

This study aimed to provide early insights into sacubitril/valsartan (sac/val) prescription patterns and the demographic and clinical characteristics of patients prescribed sac/val in primary care and cardiology settings in Germany. The study used electronic medical records from the German IMS® Disease Analyzer database. Patients with ≥1 prescription for sac/val during 1 January-31 December 2016 (n = 1643) were identified and followed up for ≤12 months from first prescription. Patients with ≥1 heart failure (HF) diagnosis during the study period, ≥1 additional HF diagnosis in the full history of the database, and ≥1 prescription for an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker and a β-blocker during the study period, without a prescription for sac/val (n = 25,264), were included as a reference cohort. Changes in clinical parameters in the 12 months before and after sac/val initiation were investigated and compared with those from the PARADIGM-HF study. The characteristics of patients prescribed sac/val more closely resembled those of patients enrolled in PARADIGM-HF (e.g. younger age, higher proportion of men than women, lower systolic blood pressure) than patients in the reference cohort. Most patients were initiated on the lowest dose of sac/val irrespective of clinical setting. Significant decreases (p < 0.001) in NT-proBNP and glycated haemoglobin levels were observed following sac/val initiation. Patients prescribed sac/val had similar baseline demographics and clinical characteristics to those from PARADIGM-HF, and most patients were initiated on the lowest dose. Changes in clinical parameters before and after initiation mirrored findings from the PARADIGM-HF study.

EFFECT OF FOOD TRAINING AND TRAINING DOSE ON NICOTINE SELF-ADMINISTRATION IN RATS

PubMed Central

Garcia, Kristine L.P.; Lê, Anh Dzung; Tyndale, Rachel F.

2014-01-01

Few studies investigate factors that influence acquisition in nicotine self-administration (NSA), such as food training and training dose. Most have utilized peak doses along nicotine’s dose-response curve (15 and 30 μg/kg) that establish NSA in the majority of animals. To investigate the specific and combined effects of training and dose on NSA acquisition, separate and head-to head experiments using food training (FT) or spontaneous acquisition (SP) at multiple doses on the ascending limb of the dose-response curve were tested. First, rats underwent FT or SP under fixed ratio (FR1 and FR2) and progressive ratio (PR) schedules using 7.5–30 μg/kg nicotine. More rats acquired NSA with FT vs. SP at 3.75 μg/kg (56% vs. 38%) and 7.5 μg/kg (88% vs. 40%, p<0.05) and FT rats responded higher under PR. Based on these findings, rats then underwent identical NSA acquisition and PR (with and without nicotine), extinction and reinstatement induced by cue exposure and nicotine in a head-to-head comparison of FT and SP using 7.5 μg/kg. Acquisition differences were replicated: 100% FT and 60% SP rats met criteria (p<0.05). Without nicotine (cue only), no FT rats and 8% SP rats met criteria. FR and PR responding, extinction, and cue and nicotine-induced reinstatement did not differ between FT and SP. FT versus SP enhances acquisition at lower nicotine doses but does not alter subsequent behaviors. Lower doses can reinforce NSA and be used, in the absence of FT, to study influences on acquisition more closely modelling the initial phases of human smoking. PMID:25101539

Effect of food training and training dose on nicotine self-administration in rats.

PubMed

Garcia, Kristine L P; Lê, Anh Dzung; Tyndale, Rachel F

2014-11-01

Few studies investigate factors that influence acquisition in nicotine self-administration (NSA), such as food training and training dose. Most have utilized peak doses along nicotine's dose-response curve (15 and 30μg/kg) that establish NSA in the majority of animals. To investigate the specific and combined effects of training and dose on NSA acquisition, separate and head-to-head experiments using food training (FT) or spontaneous acquisition (SP) at multiple doses on the ascending limb of the dose-response curve were tested. First, rats underwent FT or SP under fixed ratio (FR1 and FR2) and progressive ratio (PR) schedules using 7.5-30μg/kg nicotine. More rats acquired NSA with FT vs. SP at 3.75μg/kg (56% vs. 38%) and 7.5μg/kg (88% vs. 40%, p<0.05) and FT rats responded higher under PR. Based on these findings, rats then underwent identical NSA acquisition and PR (with and without nicotine), extinction and reinstatement induced by cue exposure and nicotine in a head-to-head comparison of FT and SP using 7.5μg/kg. Acquisition differences were replicated: 100% FT and 60% SP rats met criteria (p<0.05). Without nicotine (cue only), no FT rats and 8% SP rats met criteria. FR and PR responding, extinction, and cue and nicotine-induced reinstatement did not differ between FT and SP. FT versus SP enhances acquisition at lower nicotine doses but does not alter subsequent behaviours. Lower doses can reinforce NSA and be used, in the absence of FT, to study influences on acquisition more closely modelling the initial phases of human smoking. Copyright © 2014 Elsevier B.V. All rights reserved.

Intrathecal morphine for analgesia in children undergoing selective dorsal rhizotomy.

PubMed

Dews, T E; Schubert, A; Fried, A; Ebrahim, Z; Oswalt, K; Paranandi, L

1996-03-01

Selective dorsal root rhizotomy is performed for relief of spasticity in children with cerebral palsy. Postoperative pain relief can be provided by intrathecal morphine administered at the time of the procedure. We sought to define an optimal dose of intrathecal morphine in children undergoing selective rhizotomy, through a randomized, double-blinded prospective trial. After institutional approval and parental written informed consent, 27 patients, ages 3-10 years, were randomized to receive 10, 20, or 30 micrograms.kg-1 (Groups A, B, and C, respectively) of preservative-free morphine administered intrathecally by the surgeon after dural closure. Postoperatively, vital signs, pulse oximetry, and pain intensity scores were recorded hourly for 24 hr. Supplemental intravenous morphine was administered postoperatively according to a predetermined schedule based on pain scores. There was considerable individual variability in the time to initial morphine dosing and cumulative supplemental morphine dose. Time to first supplemental morphine dose was not different between groups. When compared to Groups A and B, cumulative 6-hr supplemental morphine dose was significantly lower in Group C (38.6 +/- 47 micrograms versus 79.1 +/- 74 and 189.6 +/- 126 for Groups A and B, respectively). By 12 hr, cumulative supplemental morphine dose was similar in Groups A and C. Group B consistently had a higher supplemental dose requirement than Groups A and C at 6, 12, and 18 hr. By 24 hr, there was no difference in cumulative dose among groups. Postoperative pain scores and the incidence of respiratory events, nausea, vomiting and pruritus were comparable among groups. These data suggest that intrathecal morphine at 30 micrograms.kg-1 provides the most intense analgesia at 6 hr following selective dorsal root rhizotomy, but was otherwise comparable to the 10 micrograms.kg-1 dose.

Antibody persistence 5 years after vaccination at 2 to 10 years of age with Quadrivalent MenACWY-CRM conjugate vaccine, and responses to a booster vaccination.

PubMed

Block, Stan L; Christensen, Shane; Verma, Bikash; Xie, Fang; Keshavan, Pavitra; Dull, Peter M; Smolenov, Igor

2015-04-27

In a multi-center extension study, children 2-10 years of age, initially vaccinated with one or two doses (2-5 year-olds) or one dose (6-10 year-olds) of quadrivalent meningococcal CRM197-conjugate vaccine (MenACWY-CRM), were assessed five years later for antibody persistence and booster response using serum bactericidal assay with human complement (hSBA). Children 7-10 and 11-15 years of age, who received MenACWY-CRM in the original study, and age-matched vaccine-naïve children, were enrolled in this extension study. After an initial blood draw, children received one dose of MenACWY-CRM as booster or primary dose, with a second blood draw 28 days later. hSBA titers decreased five years after primary vaccination, but were higher than in non-vaccinated controls against serogroups C, W and Y, with substantial proportions having titers ≥8: 7-22% for A, 32-57% for C, 74-83% for W, and 48-54% for Y. Previously-vaccinated children demonstrated booster responses to revaccination against all four serogroups. Responses to primary vaccination in vaccine-naïve controls were lower and similar to primary responses observed in the original study. All vaccinations were generally well tolerated, with no safety concern raised. Approximately half the children vaccinated as 2-10 year-olds maintained protective antibodies against serogroups C, W and Y five years later, but fewer did against serogroup A. Declining titers five years after vaccination and robust booster responses suggest that five years may be an appropriate interval to revaccinate children, subject to epidemiology and delivery considerations. Copyright © 2015 Elsevier Ltd. All rights reserved.

SU-E-T-621: Planning Methodologies for Cancer of the Anal Canal: Comparing IMRT, Rapid Arc, and Pencil Beam Scanning Proton Beam

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

McGlade, J; Kassaee, A

2015-06-15

Purpose: To evaluate planning methods for anal canal cancer and compare the results of 9-field Intensity Modulated Radiotherapy (IMRT), Volumetric Modulated Arc Therapy (Varian, RapidArc), and Proton Pencil Beam Scanning (PBS). Methods: We generated plans with IMRT, RapidArc (RA) and PBS for twenty patients for both initial phase including nodes and cone down phase of treatment using Eclipe (Varian). We evaluated the advantage of each technique for each phase. RA plans used 2 to 4 arcs and various collimator orientations. PBS used two posterior oblique fields. We evaluated the plans comparing dose volume histogram (DVH), locations of hot spots, andmore » PTV dose conformity. Results: Due to complex shape of target, for RA plans, multiple arcs (>2) are required to achieve optimal PTV conformity. When the PTV exceeds 15 cm in the superior-inferior direction, limitations of deliverability start to dominate. The PTV should be divided into a superior and an inferior structure. The optimization is performed with fixed jaws for each structure and collimator set to 90 degrees for the inferior PTV. Proton PBS plans show little advantage in small bowel sparing when treating the nodes. However, PBS plan reduces volumetric dose to the bladder at the cost of higher doses to the perineal skin. IMRT plans provide good target conformity, but they generate hot spots outside of the target volume. Conclusion: When using one planning technique for entire course of treatment, Multiple arc (>2) RA plans are better as compared to IMRT and PBS plans. When combining techniques, RA for the initial phase in combination with PBS for the cone down phase results in the most optimal plans.« less

Multi-dose drug dispensing as a tool to improve medication adherence: A study in patients using vitamin K antagonists.

PubMed

van Rein, Nienke; de Geus, Kristel S; Cannegieter, Suzanne C; Reitsma, Pieter H; van der Meer, Felix J M; Lijfering, Willem M

2018-01-01

Multi-dose drug dispensing (MDD) is a dosing aid that provides patients with disposable bags containing all drugs intended for 1 dosing moment. MDD is believed to increase medication adherence, but studies are based on self-reported data, and results may depend on socially desirable answers. Therefore, our purpose was to determine the effect of MDD on medication adherence in non-adherent patients taking vitamin K antagonists (VKAs), and to compare with instructing patients on medication use. We conducted a before-after study in non-adherent patients where MDD was the exposure and change in adherence after MDD initiation was the outcome (within patient comparison). Time in therapeutic range (TTR) was selected as a measure for adherence, as this reflects stability of VKA treatment. To analyze whether MDD improved adherence as compared with standard care (ie, letters or calls from nurses of the anticoagulation clinic), non-adherent patients without MDD were also followed to estimate their TTR change over time (between patient comparison). Eighty-three non-adherent VKA patients started using MDD. The median TTR was 63% before MDD and 73% 6 months after MDD. The within patient TTR increased on average by 13% (95%CI 6% to 21%) within 1 month after starting MDD and remained stable during the next 5 months. The TTR of MDD-patients increased 10% (95%CI 2% to 19%) higher as compared with non-MDD patients within 1 month but was similar after 4 months (TTR difference 3%, 95%CI -2% to 9%). Adherence improved after initiation of MDD. Compared with instructing patients, MDD was associated with better adherence within 1 month but was associated with similar improvement after 4 months. Copyright © 2017 John Wiley & Sons, Ltd.

Initial formal toxicity evaluation of APC-2, a novel fluorescent tracer agent for real-time measurement of glomerular filtration rate in preparation for a first-in-man clinical trial

NASA Astrophysics Data System (ADS)

Bugaj, Joseph E.; Dorshow, Richard B.

2014-03-01

The fluorescent tracer agent 2,5-bis[N-(1-carboxy-2-hydroxy)]carbamoyl-3,6-diaminopyrazine, designated APC-2, has been developed with properties and attributes necessary for use as a direct measure of glomerular filtration rate (GFR). Comparison to known standard exogenous GFR agents in animal models has demonstrated an excellent correlation. A clinical trial to demonstrate this same correlation in humans is in preparation. A battery of formal toxicity tests necessary for regulatory clearance to proceed with a clinical trial has been recently completed on this new fluorescent tracer agent. These include single dose toxicity studies in rats and dogs to determine overall toxicity and toxicokinetics of the compound. Blood compatibility, mutation assay, chromosomal aberration assay, and several other assays were also completed. Toxicity assessments were based on mortality, clinical signs, body weight, food consumption and anatomical pathology. Blood samples were collected to assess pharmacokinetic parameters including half-life, area under the curve, and clearance. Urine samples were collected to assess distribution. Doses of up to 200-300 times the estimated human dose were administered. No test-article related effects were noted on body weight, food consumption, ophthalmic observations and no abnormal pathology was seen in either macroscopic or microscopic evaluations of any organs or tissues. All animals survived to scheduled sacrifice. Transient discoloration of skin and urine was noted at the higher dose levels in both species as expected from a highly fluorescent compound and was not considered pathological. Thus initial toxicology studies of this new fluorescent tracer agent APC-2 have resulted in no demonstrable pathological test article concerns.

Comparing Usual Care With a Warfarin Initiation Protocol After Mechanical Heart Valve Replacement.

PubMed

Roberts, Gregory; Razooqi, Rasha; Quinn, Stephen

2017-03-01

The immediate postoperative warfarin sensitivity for patients receiving heart valve prostheses is increased. Established warfarin initiation protocols may lack clinical applicability, resulting in dosing based on clinical judgment. To compare current practice for warfarin initiation with a known warfarin initiation protocol, with doses proportionally reduced to account for the increased postoperative sensitivity. We compared the Mechanical Heart Valve Warfarin Initiation Protocol (Protocol group) with current practice (clinical judgment-Empirical group) for patients receiving mechanical heart valves in an observational before-and-after format. End points were the time to achieve a stable therapeutic international normalized ratio (INR), doses held in the first 6 days, and overanticoagulation in the first 6 days. The Protocol group (n = 37) achieved a stable INR more rapidly than the Empirical group (n = 77; median times 5.1 and 8.7 days, respectively; P = 0.002). Multivariable analysis indicated that the Protocol group (hazard ratio [HR] = 2.22; P = 0.005) and men (HR = 1.76; P = 0.043) more rapidly achieved a stable therapeutic INR. Age, serum albumin, amiodarone, presence of severe heart failure, and surgery type had no impact. Protocol patients had fewer doses held (1.1% vs 10.1%, P < 0.001) and no difference in overanticoagulation (2.7% vs 9.1%, P = 0.27). The Mechanical Heart Valve Warfarin Initiation Protocol provided a reliable approach to initiating warfarin in patients receiving mechanical aortic or mitral valves.

Bioleaching of zinc and manganese from spent Zn-Mn batteries and mechanism exploration.

PubMed

Xin, Baoping; Jiang, Wenfeng; Aslam, Hina; Zhang, Kai; Liu, Changhao; Wang, Renqing; Wang, Yutao

2012-02-01

In this work, bioleaching was used to extract valuable Zn and Mn from spent Zn-Mn batteries. The results showed that 96% of Zn extraction was achieved within 24h regardless of energy source types and bioleaching bacteria species. However, initial pH had a remarkable influence on Zn release, extraction dose sharply decreased from 2200 to 500mg/l when the initial pH value increased from 1.5 to 3.0 or higher. In contrast to Zn, all the tested factors evidently affected Mn extraction; the maximum released dose of 3020mg/l was obtained under the optimum conditions. The acidic dissolution by biogenic H(2)SO(4) by the non-contact mechanism was responsible for Zn extraction, while Mn extraction was owed to both contact/biological and non-contact mechanisms. The combined action of acidic dissolution of soluble Mn(2+) by biogenic H(2)SO(4) and reductive dissolution of insoluble Mn(4+) by Fe(2+) resulted in 60% of Mn extraction, while contact of microbial cells with the spent battery material and incubation for more than 7days was required to achieve the maximum extraction of Mn. Copyright © 2011 Elsevier Ltd. All rights reserved.

The cellular immune response of Daphnia magna under host-parasite genetic variation and variation in initial dose

PubMed Central

Auld, Stuart K. J. R; Edel, Kai H.; Little, Tom J.

2013-01-01

In invertebrate-parasite systems, the likelihood of infection following parasite exposure is often dependent on the specific combination of host and parasite genotypes (termed genetic specificity). Genetic specificity can maintain diversity in host and parasite populations and is a major component of the Red Queen hypothesis. However, invertebrate immune systems are thought to only distinguish between broad classes of parasite. Using a natural host-parasite system with a well-established pattern of genetic specificity, the crustacean Daphnia magna and its bacterial parasite Pasteuria ramosa, we found that only hosts from susceptible host-parasite genetic combinations mounted a cellular response following exposure to the parasite. These data are compatible with the hypothesis that genetic specificity is attributable to barrier defenses at the site of infection (the gut), and that the systemic immune response is general, reporting the number of parasite spores entering the hemocoel. Further supporting this, we found that larger cellular responses occurred at higher initial parasite doses. By studying the natural infection route, where parasites must pass barrier defenses before interacting with systemic immune responses, these data shed light on which components of invertebrate defense underlie genetic specificity. PMID:23025616

Biology Based Lung Cancer Model for Chronic Low Radon Exposures

NASA Astrophysics Data System (ADS)

TruÅ£ǎ-Popa, Lucia-Adina; Hofmann, Werner; Fakir, Hatim; Cosma, Constantin

2008-08-01

Low dose effects of alpha particles at the tissue level are characterized by the interaction of single alpha particles, affecting only a small fraction of the cells within that tissue. Alpha particle intersections of bronchial target cells during a given exposure period were simulated by an initiation-promotion model, formulated in terms of cellular hits within the cycle time of the cell (dose-rate) and then integrated over the whole exposure period (dose). For a given average number of cellular hits during the lifetime of bronchial cells, the actual number of single and multiple hits was selected from a Poisson distribution. While oncogenic transformation is interpreted as the primary initiation step, stimulated mitosis by killing adjacent cells is assumed to be the primary radiological promotion event. Analytical initiation and promotion functions were derived from experimental in vitro data on oncogenic transformation and cellular survival. To investigate the shape of the lung cancer risk function at chronic, low level exposures in more detail, additional biological factors describing the tissue response and operating specifically at low doses were incorporated into the initiation-promotion model. These mechanisms modifying the initial response at the cellular level were: adaptive response, genomic instability, induction of apoptosis by surrounding cells, and detrimental as well as protective bystander mechanisms. To quantify the effects of these mechanisms as functions of dose, analytical functions were derived from the experimental evidence presently available. Predictions of lung cancer risk, including these mechanisms, exhibit a distinct sublinear dose-response relationship at low exposures, particularly for very low exposure rates.

SU-F-T-372: Surface and Peripheral Dose in Compensator-Based FFF Beam IMRT

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

Zhang, D; Feygelman, V; Moros, E

2016-06-15

Purpose: Flattening filter free (FFF) beams produce higher dose rates. Combined with compensator IMRT techniques, the dose delivery for each beam can be much shorter compared to the flattened beam MLC-based or compensator-based IMRT. This ‘snap shot’ IMRT delivery is beneficial to patients for tumor motion management. Due to softer energy, surface doses in FFF beam treatment are usually higher than those from flattened beams. Because of less scattering due to no flattening filter, peripheral doses are usually lower in FFF beam treatment. However, in compensator-based IMRT using FFF beams, the compensator is in the beam pathway. Does it introducemore » beam hardening effects and scattering such that the surface dose is lower and peripheral dose is higher compared to FFF beam MLC-based IMRT? Methods: This study applied Monte Carlo techniques to investigate the surface and peripheral doses in compensator-based IMRT using FFF beams and compared it to the MLC-based IMRT using FFF beams and flattened beams. Besides various thicknesses of copper slabs to simulate various thicknesses of compensators, a simple cone-shaped compensator was simulated to mimic a clinical application. The dose distribution in water phantom by the cone-shaped compensator was then simulated by multiple MLC defined FFF and flattened beams with various openings. After normalized to Dmax, the surface and peripheral dose was compared between the FFF beam compensator-based IMRT and FFF/flattened beam MLC-based IMRT. Results: The surface dose at the central 0.5mm depth was close between the compensator and 6FFF MLC dose distributions, and about 8% (of Dmax) higher than the flattened 6MV MLC dose. At 8cm off axis at dmax, the peripheral dose between the 6FFF and flattened 6MV MLC demonstrated similar doses, while the compensator dose was about 1% higher. Conclusion: Compensator does not reduce the surface doses but slightly increases the peripheral doses due to scatter inside compensator.« less

SU-F-T-415: Differences in Lung Sparing in Deep Inspiration Breath-Hold and Free Breathing Breast Plans Calculated in Pinnacle and Monaco

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

Saenz, D; Stathakis, S

Purpose: Deep inspiration breath-hold (DIBH) is used for left-sided breast radiotherapy to spare the heart and lung. The magnitude of sparing has been shown to be significant. Monte Carlo, furthermore, has the potential to calculate most accurately the dose in the heterogeneous lung medium at the interface with the lung wall. The lung dose was investigated in Monaco to determine the level of sparing relative to that calculated in Pinnacle{sup 3}. Methods: Five patients undergoing DIBH radiotherapy on an Elekta Versa HD linear accelerator in conjunction with the Catalyst C-RAD surface imaging system were planned using Phillips Pinnacle{sup 3}. Freemore » breathing plans were also created to clinically assure a benefit. Both plans were re-calculated in Monaco to determine if there were any significant differences. The mean heart dose, mean left lung, and mean total lung dose were compared in addition to the V20 for left and both lungs. Dose was calculated as dose to medium as well as dose to water with a statistical precision of 0.7%. Results: Mean lung dose was significantly different (p < 0.003) between the two calculations for both DIBH (11.6% higher in Monaco) and free breathing (14.2% higher in Monaco). V20 was also higher in Monaco (p < 0.05) for DIBH (5.7% higher) and free breathing (4.9% higher). The mean heart dose was not significantly different between the dose calculations for either DIBH or free breathing. Results were no more than 0.1% different when calculated as dose to water. Conclusion: The use of Monte Carlo can provide insight on the lung dose for both free breathing and DIBH techniques for whole breast irradiation. While the sparing (dose reductions with DIBH as compared to free breathing) is equivalent for either planning system, the lung doses themselves are higher when calculated with Monaco.« less

Impact of biologic agents with and without concomitant methotrexate and at reduced doses in older rheumatoid arthritis patients.

PubMed

Zhang, Jie; Xie, Fenglong; Delzell, Elizabeth; Yun, Huifeng; Lewis, James D; Haynes, Kevin; Chen, Lang; Beukelman, Timothy; Saag, Kenneth G; Curtis, Jeffrey R

2015-05-01

To examine whether concomitant methotrexate (MTX) use is associated with better biologic persistence and whether self-administered anti-tumor necrosis factor (anti-TNF) therapies are used at reduced doses in real-world clinical care settings, not just clinical trials. We conducted a retrospective cohort study among rheumatoid arthritis (RA) patients using Medicare claims data from 2006 to 2012. Subjects were new initiators of etanercept, infliximab, adalimumab, abatacept, and tocilizumab with at least 12 months of continuous medical and pharmacy coverage after treatment initiation. We examined the association between concomitant MTX use and persistence on biologic agents using Cox proportional hazards regression, adjusting for demographics and baseline comorbidities. We further identified a subgroup of patients who initiated and were adherent on etanercept or adalimumab for at least 12 months and examined the proportion of patients who subsequently used these therapies at reduced doses continuously for an additional 12, 18, and 24 months. Of 26,510 eligible RA patients, 10,511 initiated biologic monotherapy. Overall, patients who initiated biologic monotherapy were 1.4 (95% confidence interval [95% CI] 1.3-1.5) times more likely to discontinue at 1 year compared to those who initiated combination therapy, and 1.8 (95% CI 1.7-2.0) times more likely if starting infliximab monotherapy. Approximately 10-20% of patients who initiated and adhered to etanercept and adalimumab for ≥12 months subsequently received reduced-dose therapy for an 12 additional months and beyond. In real-world practice, concomitant MTX was associated with improved persistence on biologic therapy, especially for infliximab users; reduced-dose injectable anti-TNF therapy was used by a substantial proportion of RA patients. © 2015, American College of Rheumatology.

Comparing Pain and Depressive Symptoms of Chronic Opioid Therapy Patients Receiving Dose Reduction and Risk Mitigation Initiatives With Usual Care.

PubMed

Thakral, Manu; Walker, Rod L; Saunders, Kathleen; Shortreed, Susan M; Parchman, Michael; Hansen, Ryan N; Ludman, Evette; Sherman, Karen J; Dublin, Sascha; Von Korff, Michael

2018-01-01

Dose reduction and risk mitigation initiatives have been recommended to reduce opioid-related risks among patients receiving chronic opioid therapy (COT), but questions remain over whether these initiatives worsen pain control and quality of life. In 2014 to 2015, we interviewed 1,588 adult COT patients within a health care system in Washington State and compared those who received dose reduction and risk mitigation initiatives in primary care clinics (intervention) with patients in comparable health care settings without initiatives (control). The primary outcomes were pain assessed using the pain, enjoyment, and general activity (PEG) scale, a 3-item scale to assess global pain intensity and interference, with secondary measures including depression (Patient Health Questionnaire-8 scale). Generalized estimating equations for linear regression models were used to estimate differences in mean scores between intervention and control sites. Estimated differences, adjusted for patient characteristics and weighted for nonresponse, between patients at intervention and control clinics were not clinically significant for the PEG (-.03, 95% confidence interval = -.25 to .19) or Patient Health Questionnaire-8 (-.64, 95% confidence interval = -1.19 to -.08). We found no evidence that COT patients in clinics with dose reduction and risk mitigation initiatives had clinically meaningful differences in pain intensity, interference with activities and enjoyment of life, or depressive symptoms compared with control health care settings. This article evaluates the effect of dose reduction and risk mitigation initiatives, such as those recently recommended by the Centers for Disease Control and Prevention, to reduce risks associated with COT on global pain and interference, depressive symptoms, and perceived pain relief and bothersomeness of side effects. Copyright © 2017 The American Pain Society. Published by Elsevier Inc. All rights reserved.

A 5-month toxicity study of the ethanol extract of the leaves of Heliotropium indicum in Sprague Dawley rats after oral administration.

PubMed

Owolabi, M A; Oribayo, O O; Ukpo, G E; Mbaka, G O; Akindehin, O E

2015-01-01

Heliotropium indicum Linn. (Boraginaceae) is used in Nigerian traditional medicine to treat tuberculosis with treatment lasting for 3 months; however, information on its toxicity is scarce. This study investigated the safety of the leaves of Heliotropium indicum after a 5 month oral administration. The leaves of H. indicum were dried; extracted in 70% ethanol and concentrated to dryness. Swiss mice were administered orally with single doses of the extract (0.5 to 12.0 g/kg b.wt /day); mortality was examined for up to 14 days. In another study, the plant material (0.5 to 2.0 g/kg b.wt /day) were administered daily by oral gavage to Sprague Dawley rats. Body weight was monitored weekly, hematological, biochemical and organ parameters were determined at the end of the 1st, 2nd and 5th months of extract administration. The oral administration of the ethanol extract of H. indicum caused dose-dependent mortality. The LD50 was 9.78 g/kg b.wt for the Swiss mice; no harmful effect was observed on the liver and kidney except the testes which exhibited considerable inflammatory changes at the highest dose of 2.0 g/kg b.wt./day after the 5th month treatment. No significant difference (P>0.05) was shown in the enzyme study, marginal increase occurred in some haematological parameters. The increase in body weight of the treated rats after its initial reduction was consistent and significantly different (P<0.05) from their initial body weight. Prolonged administration of the crude leaf extract of H. indicum is considered to be safe and nontoxic at the doses studied. However, there is a probability of a negative effect on the testes at a higher dose of the extract.

SU-E-T-502: Initial Results of a Comparison of Treatment Plans Produced From Automated Prioritized Planning Method and a Commercial Treatment Planning System

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

Tiwari, P; Chen, Y; Hong, L

2015-06-15

Purpose We developed an automated treatment planning system based on a hierarchical goal programming approach. To demonstrate the feasibility of our method, we report the comparison of prostate treatment plans produced from the automated treatment planning system with those produced by a commercial treatment planning system. Methods In our approach, we prioritized the goals of the optimization, and solved one goal at a time. The purpose of prioritization is to ensure that higher priority dose-volume planning goals are not sacrificed to improve lower priority goals. The algorithm has four steps. The first step optimizes dose to the target structures, whilemore » sparing key sensitive organs from radiation. In the second step, the algorithm finds the best beamlet weight to reduce toxicity risks to normal tissue while holding the objective function achieved in the first step as a constraint, with a small amount of allowed slip. Likewise, the third and fourth steps introduce lower priority normal tissue goals and beam smoothing. We compared with prostate treatment plans from Memorial Sloan Kettering Cancer Center developed using Eclipse, with a prescription dose of 72 Gy. A combination of liear, quadratic, and gEUD objective functions were used with a modified open source solver code (IPOPT). Results Initial plan results on 3 different cases show that the automated planning system is capable of competing or improving on expert-driven eclipse plans. Compared to the Eclipse planning system, the automated system produced up to 26% less mean dose to rectum and 24% less mean dose to bladder while having the same D95 (after matching) to the target. Conclusion We have demonstrated that Pareto optimal treatment plans can be generated automatically without a trial-and-error process. The solver finds an optimal plan for the given patient, as opposed to database-driven approaches that set parameters based on geometry and population modeling.« less

A Comparison of Fospropofol to Midazolam for Moderate Sedation During Outpatient Dental Procedures

PubMed Central

Yen, Philip; Prior, Simon; Riley, Cara; Johnston, William; Smiley, Megann; Thikkurissy, Sarat

2013-01-01

Moderate intravenous (IV) sedation combined with local anesthesia is common for outpatient oral surgery procedures. An ideal sedative agent must be safe and well tolerated by patients and practitioners. This study evaluated fospropofol, a relatively new sedative/hypnotic, in comparison to midazolam, a commonly used benzodiazepine, for IV moderate sedation during oral and maxillofacial surgery. Sixty patients were randomly assigned to either the fospropofol or the midazolam group. Each participant received 1 μg/kg of fentanyl prior to administration of the selected sedative. Those in the fospropofol group received an initial dose of 6.5 mg/kg, with 1.6 mg/kg supplemental doses as needed. Those in the midazolam group received initial doses of 0.05 mg/kg, followed by 0.02 mg/kg supplemental doses. The quality of sedation in each patient was evaluated with regard to (a) onset of sedation, maintenance, and recovery profile; (b) patient and surgeon satisfaction; and (c) hemodynamic stability and adverse effects. The fospropofol group demonstrated shorter physical recovery times than midazolam patients, taking a mean of 11.6 minutes versus 18.4 minutes for physical recovery (P = .007). Cognitive recovery comparison did not find any difference with a mean of 7.5 minutes versus 8.8 minutes between the 2 drug groups (P = .123). The fospropofol group had a higher rate of local anesthetic injection recall (90.5 vs 44.4%, P = .004). Other parameters of recall were comparable. Two adverse effects demonstrated significance, with more patients in the midazolam group experiencing tachycardia (48.2 vs 9.4%, P = .001), and more patients in the fospropofol group experiencing perineal discomfort (40.6 vs 0, P < .001). No significant difference was found in any other measures of sedation safety, maintenance, or satisfaction. Fospropofol, when administered intravenously by a dentist anesthesiologist at the indicated dose in this study, appears to be a safe, well-tolerated alternative to midazolam for intravenous moderate sedation during minor oral surgery procedures. PMID:24423419

False Positive Positron Emission Tomography / Computed Tomography Scans in Treated Head and Neck Cancers

PubMed Central

Cheung, Michael K; Ong, Shawn Y; Goyal, Uma; Wertheim, Betsy C; Hsu, Charles C

2017-01-01

Objective Positron emission tomography/computed tomography (PET/CT) imaging for head and neck cancers (HNC) is commonly utilized for post-treatment assessment. Though PET/CT in this setting has been reported to have high negative predictive values (> 90%), positive predictive values have been reported at approximately 50%, leading to high rates of false positivity (FP) and troubling management decisions for both patient and practitioner. The objective of this study was to identify patient, disease, treatment and imaging factors that might be associated with a higher likelihood of FP on initial post-treatment PET/CT imaging for patients treated for HNC.  Materials and methods A retrospective chart review was performed on 84 patients treated for HNC who received radiation therapy (RT) as part of their overall management from October 2005 to August 2013. Of the patients screened, 19 were found to have mucosally based squamous cell carcinoma (SCC) with positive initial post-treatment PET/CT studies (23%). Fisher’s exact test was used to analyze the association between categorical variables and FP, including patient's gender, disease laterality, primary tumor site and stage, nodal and overall stage, high dose RT fraction size, number of RT fractions completed, total RT dose, biologically effective dose and timing of PET/CT acquisition. Wilcoxon rank-sum test was used to analyze the association between continuous variables and FP, including patient age, total elapsed days of RT, an amount of infused fluorodeoxyglucose 18F-FDG, pre-PET/CT serum glucose levels, and maximum standardized uptake value SUVmax. Statistically significant findings were those that were deemed p <0.05. Results Among patients with positive initial post-treatment PET/CT scans for treated HNC, there was a lower proportion of higher primary disease stage associated with FP versus true positivity (T-stage 3-4: 20 vs 78%, respectively, p=0.023). We also discovered that 50% of patients that underwent confirmation for FP findings suffered serious complications as a direct consequence of invasive exploratory procedures. Conclusions Although PET/CT is known for its exceptional negative predictive value (> 90%) in the post-treatment setting for HNC, high rates of FP remains a clinical challenge. Our study suggests that tumor stage (T-stage) may impact FP rates in positive initial post-treatment PET/CT scans. We recommend careful multidisciplinary discussion regarding positive PET/CT studies in the post-treatment setting for HNC, particularly if invasive intervention is considered. PMID:28497009

Impact of weight-based ribavirin with peginterferon alfa-2b in African Americans with hepatitis C virus genotype 1.

PubMed

Jacobson, Ira M; Brown, Robert S; McCone, Jonathan; Black, Martin; Albert, Clive; Dragutsky, Michael S; Siddiqui, Firdous A; Hargrave, Thomas; Kwo, Paul Y; Lambiase, Louis; Galler, Greg W; Araya, Victor; Freilich, Bradley; Harvey, Joann; Griffel, Louis H; Brass, Clifford A

2007-10-01

WIN-R (Weight-based dosing of pegINterferon alfa-2b and Ribavirin) was a multicenter, randomized, open-label, investigator-initiated trial involving 236 community and academic sites in the United States, comparing response to pegylated interferon (PEG-IFN) alfa-2b plus a flat or weight-based dose of ribavirin (RBV) in treatment-naive patients with chronic hepatitis C and compensated liver disease. Patients were randomized to receive PEG-IFN alfa-2b at 1.5 microg/kg/week plus flat-dose (800 mg/day) or weight-based-dose RBV (800 mg/day for weight <65 kg, 1000 mg/day for 65-85 kg, 1200 mg/day for >85-105 kg, or 1400 mg/day for >105-<125 kg). Sustained virologic response (SVR; undetectable [<125 IU/mL] hepatitis C virus [HCV] RNA at end of follow-up) in patients > or =65 kg was the primary end point. Low SVR rates have been reported among African American individuals, in whom there is a preponderance of HCV genotype 1. This subanalysis of WIN-R was conducted to evaluate the efficacy of weight-based dosing among African American individuals with genotype 1 infection enrolled in the trial. Of 362 African American patients in the primary efficacy analysis, 188 received RBV flat dosing and 174 received weight-based dosing. SVR rates were higher (21% versus 10%; P = 0.0006) and relapse rates were lower (22% versus 30%) in the weight-based-dose group than in the flat-dose group. Safety and rates of drug discontinuation were similar between the 2 groups. Weight-based dosing of RBV is more effective than flat dosing in combination with PEG-IFN alfa-2b in African American individuals with HCV genotype 1. Even with weight-based dosing, response rates in African American individuals are lower than reported in other ethnic groups.

137Cesium-induced chromosome aberrations analyzed by fluorescence in situ hybridization: eight years follow up of the Goiânia radiation accident victims.

PubMed

Natarajan, A T; Santos, S J; Darroudi, F; Hadjidikova, V; Vermeulen, S; Chatterjee, S; Berg, M; Grigorova, M; Sakamoto-Hojo, E T; Granath, F; Ramalho, A T; Curado, M P

1998-05-25

The radiation accident in focus here occurred in a section of Goiânia (Brazil) where more than a hundred individuals were contaminated with 137Cesium on September 1987. In order to estimate the absorbed radiation doses, initial frequencies of dicentrics and rings were determined in 129 victims [A.T. Ramalho, PhD Thesis, Subsidios a tecnica de dosimetria citogenetica gerados a partir da analise de resultados obtidos com o acidente radiologico de Goiânia, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil, 1992]. We have followed some of these victims cytogenetically over the years seeking for parameters that could be used as basis for retrospective radiation dosimetry. Our data on translocation frequencies obtained by fluorescence in situ hybridization (FISH) could be directly compared to the baseline frequencies of dicentrics available for those same victims. Our results provided valuable information on how precise these estimates are. The frequencies of translocations observed years after the radiation exposure were two to three times lower than the initial dicentrics frequencies, the differences being larger at higher doses (>1 Gy). The accuracy of such dose estimates might be increased by scoring sufficient amount of cells. However, factors such as the persistence of translocation carrying lymphocytes, translocation levels not proportional to chromosome size, and inter-individual variation reduce the precision of these estimates. Copyright 1998 Elsevier Science B.V. All rights reserved.

Biological impact of low dose-rate simulated solar particle event radiation in vivo.

PubMed

Chang, P Y; Doppalapudi, R; Bakke, J; Wang, A; Menda, S; Davis, Z

2010-08-01

C57Bl6-lacZ animals were exposed to a range of low dose-rate simulated solar particle event (sSPE) radiation at the NASA-sponsored Research Laboratory (NSRL) at Brookhaven National Laboratory (BNL). Peripheral blood was harvested from animals from 1 to 12 days after total body irradiation (TBI) to quantify the level of circulating reticulocytes (RET) and micronucleated reticulocytes (MN-RET) as an early indicator of radiation-induced genotoxicity. Bone marrow lymphocytes and hippocampal tissues from each animal were collected at 12 days and up to two months, to evaluate dose-dependent late effects after sSPE exposure. Early hematopoietic changes show that the % RET was reduced up to 3 days in response to radiation exposure but recovered at 12 days postirradiation. The % MN-RET in peripheral blood was temporally regulated and dependant on the total accumulated dose. Total chromosome aberrations in lymphocytes increased linearly with dose within a week after radiation and remained significantly higher than the control values at 4 weeks after exposure. The level of aberrations in the irradiated animals returned to control levels by 8 weeks postirradiation. Measurements of chromosome 2 and 8 specific aberrations indicate that, consistent with conventional giemsa-staining methods, the level of aberrations is also not significantly higher than in control animals at 8 weeks postirradiation. The hippocampus was surveyed for differential transcriptional regulation of genes known to be associated with neurogenesis. Our results showed differential expression of neurotrophin and their associated receptor genes within 1 week after sSPE exposure. Progressive changes in the profile of expressed genes known to be involved in neurogenic signaling pathways were dependent on the sSPE dose. Our results to date suggest that radiation-induced changes in the hematopoietic system, i.e., chromosome aberrations in lymphocytes, are transient and do not persist past 4 weeks after radiation. On the other hand, alteration in the profile of genes known to be involved in neurotrophic functions in the hippocampal tissue appears to persist for up to 8 weeks after radiation exposure. Such temporal changes confirm that, although cytogenetic changes after a single dose of low-dose and low-dose-rate protons appear to be transient, the impact of this exposure is sufficient to lead to persistent dynamic changes in neuronal tissues long after the initial radiation exposure.

Treatment of experimental pneumonia due to penicillin-resistant Streptococcus pneumoniae in immunocompetent rats.

PubMed Central

Gavaldà, J; Capdevila, J A; Almirante, B; Otero, J; Ruiz, I; Laguarda, M; Allende, H; Crespo, E; Pigrau, C; Pahissa, A

1997-01-01

A model of pneumonia due to Streptococcus pneumoniae resistant to penicillin was developed in immunocompetent Wistar rats and was used to evaluate the efficacies of different doses of penicillin, cefotaxime, cefpirome, and vancomycin. Adult Wistar rats were challenged by intratracheal inoculation with 3 x 10(9) CFU of one strain of S. pneumoniae resistant to penicillin (MICs of penicillin, cefotaxime, cefpirome, and vancomycin, 2, 1, 0.5, and 0.5 microg/ml, respectively) suspended in brain heart broth supplemented with 0.7% agar. The rats experienced a fatal pneumonia, dying within 5 days and with peak mortality (70 to 80%) occurring 48 to 72 h after infection, and the bacterial counts in the lungs persisted from 8.87 +/- 0.3 log10 CFU/g of lung at 24 h of the infection to 9.1 +/- 0.3 log10 CFU/g at 72 h. Four hours after infection the animals were randomized into the following treatment groups: (i) control without treatment, (ii) penicillin G at 100,000 IU/kg of body weight every 2 h, (iii) penicillin G at 250,000 IU/kg every 2 h, (iv) cefotaxime at 100 mg/kg every 2 h, (v) cefpirome at 200 mg/kg every 2 h, and (vi) vancomycin at 50 mg/kg every 8 h. Two different protocols were used for the therapeutic efficacy studies: four doses of beta-lactams and one dose of vancomycin or eight doses of beta-lactams and two doses of vancomycin. Results of the therapy for experimental pneumonia caused by penicillin-resistant S. pneumoniae showed that initially, all the antimicrobial agents tested had similar efficacies, but when we prolonged the treatment, higher doses of penicillin, cefotaxime, and cefpirome were more effective than penicillin at lower doses in decreasing the residual bacterial titers in the lungs. Also, when we extended the treatment, vancomycin was more efficacious than penicillin at lower doses but was less efficacious than higher doses of penicillin or cefpirome. The model that we have developed is simple and amenable for inducing pneumonia in immunocompetent rats and could be used to explore the pathophysiology and to evaluate optimal therapy of this infection in the immunocompetent host. PMID:9087492

Pharmacokinetics of heparin and related polysaccharides

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

Boneu, B.; Dol, F.; Caranobe, C.

1989-01-01

The pharmacodynamic profile of standard heparin (SH), a low molecular weight derivative (CY 216) and of dermatan sulfate (DS), a new potential antithrombotic drug, was investigated in the rabbit over a large range of doses. After bolus i.v. injection of low doses, the biological activity of SH disappeared exponentially; however, its half-life was prolonged when the dose injected increased, and over 158 micrograms/kg (100 anti-factor Xa U/kg) the biological activity disappeared as a concave-convex curve. CY 216 disappeared more slowly than SH at low doses but faster than SH at higher doses. More than 90% of the DS biological activitymore » present 1 minute after the i.v. injection disappeared exponentially without dose-dependent effects. Increasing doses of the three drugs were then delivered for 5 h under continuous infusions. Below 500 micrograms/kg/h the DS and CY 216 plateau concentrations were higher than that of SH while above this dose the SH concentration was higher than that of DS and CY 216. These observations may be explained by the results of pharmacokinetics experiments where /sup 125/I-labeled compounds were delivered by bolus i.v. injection in association with increasing doses of their unlabeled counterparts. For SH there was a 10-fold difference between the half-life of the lower dose (32 micrograms/kg or 5 anti-factor Xa U/kg) and that of the higher dose (3200 micrograms/kg); it was demonstrated that the half-life of SH continuously shortened as its plasma concentration decreased. In contrast the CY 216 and DS half-lives were very close, independent of the dose delivered, and therefore longer than that of SH at low doses and shorter than that of SH at higher doses.« less

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

Iwai, P; Lins, L Nadler

Purpose: There is a lack of studies with significant cohort data about patients using pacemaker (PM), implanted cardioverter defibrillator (ICD) or cardiac resynchronization therapy (CRT) device undergoing radiotherapy. There is no literature comparing the cumulative doses delivered to those cardiac implanted electronic devices (CIED) calculated by different algorithms neither studies comparing doses with heterogeneity correction or not. The aim of this study was to evaluate the influence of the algorithms Pencil Beam Convolution (PBC), Analytical Anisotropic Algorithm (AAA) and Acuros XB (AXB) as well as heterogeneity correction on risk categorization of patients. Methods: A retrospective analysis of 19 3DCRT ormore » IMRT plans of 17 patients was conducted, calculating the dose delivered to CIED using three different calculation algorithms. Doses were evaluated with and without heterogeneity correction for comparison. Risk categorization of the patients was based on their CIED dependency and cumulative dose in the devices. Results: Total estimated doses at CIED calculated by AAA or AXB were higher than those calculated by PBC in 56% of the cases. In average, the doses at CIED calculated by AAA and AXB were higher than those calculated by PBC (29% and 4% higher, respectively). The maximum difference of doses calculated by each algorithm was about 1 Gy, either using heterogeneity correction or not. Values of maximum dose calculated with heterogeneity correction showed that dose at CIED was at least equal or higher in 84% of the cases with PBC, 77% with AAA and 67% with AXB than dose obtained with no heterogeneity correction. Conclusion: The dose calculation algorithm and heterogeneity correction did not change the risk categorization. Since higher estimated doses delivered to CIED do not compromise treatment precautions to be taken, it’s recommend that the most sophisticated algorithm available should be used to predict dose at the CIED using heterogeneity correction.« less

Standing sedation in African elephants (Loxodonta africana) using detomidine-butorphanol combinations.

PubMed

Neiffer, Donald L; Miller, Michele A; Weber, Martha; Stetter, Mark; Fontenot, Deidre K; Robbins, P K; Pye, Geoffrey W

2005-06-01

Standing sedation was provided for 14 clinical procedures in three African elephants (Loxodonta africana) managed by combined protected and modified-protected contact and trained through operant conditioning. An initial hand-injection of detomidine hydrochloride and butorphanol tartrate at a ratio of 1:1 on a microg:microg basis was administered intramuscularly, with a dosage range of 50-70 mg (12.9-19.7 microg/kg) for each drug. The initial injection resulted in adequate sedation for initiation and completion of eight procedures, whereas supplemental doses were required for the remaining procedures. The dosage range for the supplemental injections of each drug was 4.0-7.3 microg/kg. Initial effect was noted within 3.0-25 min (mean = 11.6 min, SD +/- 5.9 min), with maximal effect occurring at 25-30 min for those procedures not requiring supplementation. In all but one procedure, this effect was maintained until the end of the procedure, which ranged from 47 to 98 min (mean = 74.7 min, SD +/- 18.8 min). No cardiac or respiratory depression was appreciated. Recovery after administration of reversal agents was rapid and complete, ranging from 2 to 20 min (mean = 9.0 min, SD +/- 7.0 min). On the basis of the authors' experience, recommended dosage ranges for reversal agents would be intravenous yohimbine (73.4-98.5 microg/kg), intravenous naltrexone (48.9-98.5 microg/kg), and intramuscular naltrexone (73.4-98.5 microg/kg). Approximately one-third to one-half of the total naltrexone dose should be administered intravenously. Mild adverse side effects limited to the gastrointestinal tract were observed in association with five procedures including abdominal distention with or without transient anorexia. Administration of reversal agents, encouraging exercise and water consumption, and administration of flunixin meglumine were helpful in the resolution of signs. In addition to gastrointestinal signs, slight ataxia was observed before initiation of surgical stimulation during one procedure in which 19.7 microg/kg of each drug was administered. On the basis of the procedures that did not require supplementation to initiate treatment and taking into consideration the potential for ataxia at higher doses, a starting dosage range of 14.7-16.2 microg/kg of both detomidine and butorphanol in a ratio of 1:1 on a microg:microg basis administered i.m. simultaneously is recommended.

Intermediate-dose cidofovir without probenecid in the treatment of BK virus allograft nephropathy.

PubMed

Araya, Carlos E; Lew, Judy F; Fennell, Robert S; Neiberger, Richard E; Dharnidharka, Vikas R

2006-02-01

BK virus allograft nephropathy (BKVAN) is a rising complication in kidney transplant recipients. Reducing immunosuppression has been the initial form of therapy in most cases, but is not always associated with improvement in graft function. Anti-viral therapy with low-dose cidofovir (0.25-0.42 mg/kg/dose) has been used successfully in some patients, but dose-related nephrotoxicity has limited its use. We present our experience with 3 kidney transplant recipients diagnosed with BKVAN who received intermediate-dose cidofovir (0.75-1.0 mg/kg/dose) without probenecid, and without concomitant nephrotoxicity. Three female patients, ages 8, 19 and 20 yr, presented with elevated serum creatinine (SCr) values, BK virus stain positive on renal biopsy and high plasma BK viral loads. As a result of viral loads being >2 million copies/ml in two patients and a lack of response to reduction in immunosuppression in the third, we initiated therapy with low-dose cidofovir. Because of persistent positive BK stain and positive plasma viral load, we then administered intermediate-dose cidofovir, without probenecid, for several subsequent doses (seven to 15 infusions till date). All patients tolerated the intermediate-dose cidofovir with no significant rise in SCr during the course of the infusions. The most recent SCr values in all three patients were improved from those at the initial diagnosis of BKVAN. All three patients showed a marked drop in BK viral loads when on intermediate-dose cidofovir, with complete clearing of viremia in two patients. In our experience, intermediate-dose cidofovir without probenecid, used judiciously, is not associated with additional nephrotoxicity and may provide an additional alternative for treatment.

Correlation between Colon Transit Time Test Value and Initial Maintenance Dose of Laxative in Children with Chronic Functional Constipation.

PubMed

Kim, Mock Ryeon; Park, Hye Won; Son, Jae Sung; Lee, Ran; Bae, Sun Hwan

2016-09-01

To evaluate the correlation between colon transit time (CTT) test value and initial maintenance dose of polyethylene glycol (PEG) 4000 or lactulose. Of 415 children with chronic functional constipation, 190 were enrolled based on exclusion criteria using the CTT test, defecation diary, and clinical chart. The CTT test was performed with prior disimpaction. The laxative dose for maintenance was determined on the basis of the defecation diary and clinical chart. The Shapiro-Wilk test and Pearson's and Spearman's correlations were used for statistical analysis. The overall group median value and interquartile range of the CTT test was 43.8 (31.8) hours. The average PEG 4000 dose for maintenance in the overall group was 0.68±0.18 g/kg/d; according to age, the dose was 0.73±0.16 g/kg/d (<8 years), 0.53±0.12 g/kg/d (8 to <12 years), and 0.36±0.05 g/kg/d (12 to 15 years). The dose of lactulose was 1.99±0.43 mL/kg/d (<8 years) or 1.26±0.25 mL/kg/d (8 to <12 years). There was no significant correlation between CTT test value and initial dose of laxative, irrespective of the subgroup (encopresis, abnormal CTT test subtype) for either laxative. Even in the largest group (overall, n=109, younger than 8 years and on PEG 4000), the correlation was weak (Pearson's correlation coefficient [R]=0.268, p =0.005). Within the abnormal transit group, subgroup (n=73, younger than 8 years and on PEG 4000) correlation was weak (R=0.267, p =0.022). CTT test value cannot predict the initial maintenance dose of PEG 4000 or lactulose with linear correlation.

Poor guideline adherence in the initiation of antidepressant treatment in children and adolescents in the Netherlands: choice of antidepressant and dose.

PubMed

de Vries, Ymkje Anna; de Jonge, Peter; Kalverdijk, Luuk; Bos, Jens H J; Schuiling-Veninga, Catharina C M; Hak, Eelko

2016-11-01

The Dutch guideline for the treatment of depression in young people recommends initiating antidepressant treatment with fluoxetine, as the evidence for its efficacy is strongest and the risk of suicidality may be lower than with other antidepressants. Furthermore, low starting doses are recommended. We aimed to determine whether antidepressant prescriptions are in accord with guidelines. A cohort of young people aged between 6 and 17 at the time of antidepressant initiation was selected from IABD, a Dutch pharmacy prescription database. The percentage of prescriptions for each antidepressant was determined. Starting and maintenance doses were determined and compared with recommendations for citalopram, fluoxetine, fluvoxamine, and sertraline. During the study period, 2942 patients initiated antidepressant treatment. The proportion of these young people who were prescribed fluoxetine increased from 10.1 % in 1994-2003 to 19.7 % in 2010-2014. However, the most commonly prescribed antidepressants were paroxetine in 1994-2003 and citalopram in 2004-2014. The median starting and maintenance doses were ≤0.5 DDD/day for tricyclic antidepressants and 0.5-1 DDD/day for SSRIs and other antidepressants. Starting doses were guideline-concordant 58 % of the time for children, 31 % for preteens, and 16 % for teens. Sixty percent of teens were prescribed an adult starting dose. In conclusion, guideline adherence was poor. Physicians preferred citalopram over fluoxetine, in contrast to the recommendations. Furthermore, although children were prescribed a low starting dose relatively frequently, teens were often prescribed an adult starting dose. These results suggest that dedicated effort may be necessary to improve guideline adherence.

Timing of two versus three doses of quadrivalent HPV vaccine and associated effectiveness against condyloma in Sweden: a nationwide cohort study

PubMed Central

F, Lamb; E, Herweijer; A, Ploner; I, Uhnoo; K, Sundström; P, Sparén; L, Arnheim-Dahlström

2017-01-01

Objective To assess incidence of condyloma after two doses of quadrivalent human papillomavirus (qHPV) vaccine, by time since first vaccine dose, in girls and women initiating vaccination before age 20 years. Design Register-based nationwide open cohort study. Setting Sweden. Participants Girls and women initiating qHPV vaccination before age 20 years between 2006 and 2012. The study cohort included 264 498 girls, of whom 72 042 had received two doses of qHPV vaccine and 185 456 had received all three doses. Main outcome measure Incidence rate ratios (IRRs) of condyloma estimated by time between first and second doses of qHPV in months (m) and age at vaccination, adjusted for attained age. Results For girls first vaccinated with two doses before the age of 17 years, the IRR of condyloma for 0–3 months between the first and second doses was 1.96 (95% CI 1.43 to 2.68) as compared with the standard three-dose schedule. The IRRs were 1.27 (95% CI 0.63 to 2.58) and 4.36 (95% CI 2.05 to 9.28) after receipt of two doses with 4–7 months and 8+ months between doses, respectively. For women first vaccinated after the age of 17 years, vaccination with two doses of qHPV vaccine and 0–3 months between doses was associated with an IRR of 2.12 (95% CI 1.62 to 2.77). For an interval of 4–7 months between doses, the IRR did not statistically significantly differ to the standard three-dose schedule (IRR=0.81, 95% CI 0.36 to 1.84). For women with 8+ months between dose 1 and dose 2 the IRR was 3.16 (95% CI 1.40 to 7.14). Conclusion A two-dose schedule for qHPV vaccine with 4–7 months between the first and second doses may be as effective against condyloma in girls and women initiating vaccination under 20 years as a three-dose schedule. Results from this nationwide study support immunogenicity data from clinical trials. PMID:28600369

Treating Brain Tumor with Microbeam Radiation Generated by a Compact Carbon-Nanotube-Based Irradiator: Initial Radiation Efficacy Study.

PubMed

Yuan, Hong; Zhang, Lei; Frank, Jonathan E; Inscoe, Christina R; Burk, Laurel M; Hadsell, Mike; Lee, Yueh Z; Lu, Jianping; Chang, Sha; Zhou, Otto

2015-09-01

Microbeam radiation treatment (MRT) using synchrotron radiation has shown great promise in the treatment of brain tumors, with a demonstrated ability to eradicate the tumor while sparing normal tissue in small animal models. With the goal of expediting the advancement of MRT research beyond the limited number of synchrotron facilities in the world, we recently developed a compact laboratory-scale microbeam irradiator using carbon nanotube (CNT) field emission-based X-ray source array technology. The focus of this study is to evaluate the effects of the microbeam radiation generated by this compact irradiator in terms of tumor control and normal tissue damage in a mouse brain tumor model. Mice with U87MG human glioblastoma were treated with sham irradiation, low-dose MRT, high-dose MRT or 10 Gy broad-beam radiation treatment (BRT). The microbeams were 280 μm wide and spaced at 900 μm center-to-center with peak dose at either 48 Gy (low-dose MRT) or 72 Gy (high-dose MRT). Survival studies showed that the mice treated with both MRT protocols had a significantly extended life span compared to the untreated control group (31.4 and 48.5% of life extension for low- and high-dose MRT, respectively) and had similar survival to the BRT group. Immunostaining on MRT mice demonstrated much higher DNA damage and apoptosis level in tumor tissue compared to the normal brain tissue. Apoptosis in normal tissue was significantly lower in the low-dose MRT group compared to that in the BRT group at 48 h postirradiation. Interestingly, there was a significantly higher level of cell proliferation in the MRT-treated normal tissue compared to that in the BRT-treated mice, indicating rapid normal tissue repairing process after MRT. Microbeam radiation exposure on normal brain tissue causes little apoptosis and no macrophage infiltration at 30 days after exposure. This study is the first biological assessment on MRT effects using the compact CNT-based irradiator. It provides an alternative technology that can enable widespread MRT research on mechanistic studies using a preclinical model, as well as further translational research towards clinical applications.

Effect of piracetam, a nootropic agent, on rat brain monoamines and prostaglandins.

PubMed

Bhattacharya, S K; Upadhyay, S N; Jaiswal, A K; Bhattacharya, S

1989-03-01

Piracetam is the prototype of a new class of psychotropic drugs, the nootropic agents, which are claimed to selectively improve the higher telencephalic integrative activities. The effect of piracetam on rat brain monoamines and prostaglandins (PGs) was assessed so as to garner information on its mode of action. Two doses of the drug were used, a lower dose (20 mg/kg ip) and a higher dose (100 mg/kg, ip), the latter being known to exert a facilitatory effect on learning and memory. Piracetam produced a dose-related effect on rat brain serotonin (5HT) and noradrenaline (NA), with the lower dose inducing a decrease in 5HT levels and an increase in NA concentrations. The higher dose of piracetam produced the opposite effect. Dopamine (DA) levels were not significantly affected. The lower dose of the drug attenuated 5HT turnover and augmented that of NA, whereas the higher dose of piracetam produced the reverse effects, in clorgyline treated rats. The lower dose of piracetam produced a slight and statistically insignificant increase in rat brain PGE2 and PGF2 alpha. However, the higher dose of the drug produced marked increase in the levels of both the PGs. The observed biochemical effects may provide a basis for the nootropic effect of piracetam. However, they may also be due to the GA-BA-mimetic action of the drug, particularly those observed with the lower dose of piracetam.

Comparison of normal tissue pharmacokinetics with {sup 111}In/{sup 9}Y monoclonal antibody m170 for breast and prostate cancer

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

Lehmann, Joerg; Department of Radiodiagnosis and Therapy, Division of Hematology/Oncology, University of California Davis School of Medicine, Sacramento, CA; DeNardo, Gerald L.

Purpose: Radioactivity deposition in normal tissues limits the dose deliverable by radiopharmaceuticals (RP) in radioimmunotherapy (RIT). This study investigated the absorbed radiation dose in normal tissues for prostate cancer patients in comparison to breast cancer patients for 2 RPs using the monoclonal antibody (MAb) m170. Methods and Materials: {sup 111}In-DOTA-glycylglycylglycyl-L-p-isothiocyanatophenylalanine amide (GGGF)-m170 and {sup 111}In-1,4,7,10-tetraazacyclododecane-N,N',N'',N'''-tetraacetic acid (DOTA) 2-iminothiolane (2IT)-m170, representing the same MAb and chelate with and without a cleavable linkage, were studied in 13 breast cancer and 26 prostate cancer patients. Dosimetry for {sup 9}Y was calculated using {sup 111}In MAb pharmacokinetics from the initial imaging study for eachmore » patient, using reference man- and patient-specific masses. Results: The reference man-specific radiation doses (cGy/MBq) were not significantly different for the breast and the prostate cancer patients for both RPs in all but one tissue-RP combination (liver, DOTA-2IT). The patient-specific doses had differences between the groups most of which can be related to weight differences. Conclusions: Similar normal tissue doses were calculated for two groups of patients having different cancers and genders. This similarity combined with continued careful analysis of the imaging data might allow the use of higher starting doses in early phase RIT studies.« less

SparseCT: interrupted-beam acquisition and sparse reconstruction for radiation dose reduction

NASA Astrophysics Data System (ADS)

Koesters, Thomas; Knoll, Florian; Sodickson, Aaron; Sodickson, Daniel K.; Otazo, Ricardo

2017-03-01

State-of-the-art low-dose CT methods reduce the x-ray tube current and use iterative reconstruction methods to denoise the resulting images. However, due to compromises between denoising and image quality, only moderate dose reductions up to 30-40% are accepted in clinical practice. An alternative approach is to reduce the number of x-ray projections and use compressed sensing to reconstruct the full-tube-current undersampled data. This idea was recognized in the early days of compressed sensing and proposals for CT dose reduction appeared soon afterwards. However, no practical means of undersampling has yet been demonstrated in the challenging environment of a rapidly rotating CT gantry. In this work, we propose a moving multislit collimator as a practical incoherent undersampling scheme for compressed sensing CT and evaluate its application for radiation dose reduction. The proposed collimator is composed of narrow slits and moves linearly along the slice dimension (z), to interrupt the incident beam in different slices for each x-ray tube angle (θ). The reduced projection dataset is then reconstructed using a sparse approach, where 3D image gradients are employed to enforce sparsity. The effects of the collimator slits on the beam profile were measured and represented as a continuous slice profile. SparseCT was tested using retrospective undersampling and compared against commercial current-reduction techniques on phantoms and in vivo studies. Initial results suggest that SparseCT may enable higher performance than current-reduction, particularly for high dose reduction factors.

SU-E-T-500: Initial Implementation of GPU-Based Particle Swarm Optimization for 4D IMRT Planning in Lung SBRT

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

Modiri, A; Hagan, A; Gu, X

Purpose 4D-IMRT planning, combined with dynamic MLC tracking delivery, utilizes the temporal dimension as an additional degree of freedom to achieve improved OAR-sparing. The computational complexity for such optimization increases exponentially with increase in dimensionality. In order to accomplish this task in a clinically-feasible time frame, we present an initial implementation of GPU-based 4D-IMRT planning based on particle swarm optimization (PSO). Methods The target and normal structures were manually contoured on ten phases of a 4DCT scan of a NSCLC patient with a 54cm3 right-lower-lobe tumor (1.5cm motion). Corresponding ten 3D-IMRT plans were created in the Eclipse treatment planning systemmore » (Ver-13.6). A vendor-provided scripting interface was used to export 3D-dose matrices corresponding to each control point (10 phases × 9 beams × 166 control points = 14,940), which served as input to PSO. The optimization task was to iteratively adjust the weights of each control point and scale the corresponding dose matrices. In order to handle the large amount of data in GPU memory, dose matrices were sparsified and placed in contiguous memory blocks with the 14,940 weight-variables. PSO was implemented on CPU (dual-Xeon, 3.1GHz) and GPU (dual-K20 Tesla, 2496 cores, 3.52Tflops, each) platforms. NiftyReg, an open-source deformable image registration package, was used to calculate the summed dose. Results The 4D-PSO plan yielded PTV coverage comparable to the clinical ITV-based plan and significantly higher OAR-sparing, as follows: lung Dmean=33%; lung V20=27%; spinal cord Dmax=26%; esophagus Dmax=42%; heart Dmax=0%; heart Dmean=47%. The GPU-PSO processing time for 14940 variables and 7 PSO-particles was 41% that of CPU-PSO (199 vs. 488 minutes). Conclusion Truly 4D-IMRT planning can yield significant OAR dose-sparing while preserving PTV coverage. The corresponding optimization problem is large-scale, non-convex and computationally rigorous. Our initial results indicate that GPU-based PSO with further software optimization can make such planning clinically feasible. This work was supported through funding from the National Institutes of Health and Varian Medical Systems.« less

Effects of nighttime single-dose administration of vasodilating vs sympatholytic antihypertensive agents on sleep blood pressure in hypertensive patients with sleep apnea syndrome.

PubMed

Kario, Kazuomi; Kuwabara, Mitsuo; Hoshide, Satoshi; Nagai, Michiaki; Shimpo, Masahisa

2014-06-01

Obstructive sleep apneas syndrome (OSAS) is associated with nocturnal hypertension with higher sleep blood pressure (BP) and its variability, both of which increase cardiovascular risk. In this crossover design study, the effect of nighttime single-dose administration of vasodilating (nifedipine 40 mg) vs sympatholytic (carvedilol 20 mg) antihypertensive agents on sleep BP in 11 hypertensive OSAS patients was evaluated. The authors recently developed a trigger sleep BP monitor with an oxygen-triggered function that initiates BP measurement when oxygen desaturation falls. The BP-lowering effects of nifedipine on the mean (P<.05) and minimum sleep systolic BPs (SBPs) (P<.01) were stronger than those of carvedilol. Sleep SBP surge (difference between the hypoxia-peak SBP measured by oxygen-triggered function and SBPs within 30 minutes before and after the peak SBP) was only significantly reduced by carvedilol (P<.05). The nighttime dosing of both vasodilating and sympatholytic antihypertensive drugs is effective to reduce sleep BP but with different BP-lowering profiles. ©2014 Wiley Periodicals, Inc.

Novel Application of Helical Tomotherapy in Whole Skull Palliative Radiotherapy

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

Rodrigues, George; Yartsev, Slav; Coad, Terry

2008-01-01

Helical tomotherapy (HT) is a radiation planning/delivery platform that combines inversely planned IMRT with on-board megavoltage imaging. A unique HT radiotherapy whole skull brain sparing technique is described in a patient with metastatic prostate cancer. An inverse HT plan and an accompanying back-up conventional lateral 6-MV parallel opposed pair (POP) plan with corresponding isodose distributions and dose-volume histograms (DVH) were created and assessed prior to initiation of therapy. Plans conforming to the planning treatment volume (PTV) with significant sparing of brain, optic nerve, and eye were created. Dose heterogeneity to the PTV target was slightly higher in the HT planmore » compared to the back-up POP plan. Conformal sparing of brain, optic nerve, and eye was achieved by the HT plan. Similar lens and brain stem/spinal cord doses were seen with both plans. Prospective clinical evaluation with relevant end points (quality of life, symptom relief) are required to confirm the potential benefits of highly conformal therapies applied to palliative situations such as this case.« less

Low dose scatter correction for digital chest tomosynthesis

NASA Astrophysics Data System (ADS)

Inscoe, Christina R.; Wu, Gongting; Shan, Jing; Lee, Yueh Z.; Zhou, Otto; Lu, Jianping

2015-03-01

Digital chest tomosynthesis (DCT) provides superior image quality and depth information for thoracic imaging at relatively low dose, though the presence of strong photon scatter degrades the image quality. In most chest radiography, anti-scatter grids are used. However, the grid also blocks a large fraction of the primary beam photons requiring a significantly higher imaging dose for patients. Previously, we have proposed an efficient low dose scatter correction technique using a primary beam sampling apparatus. We implemented the technique in stationary digital breast tomosynthesis, and found the method to be efficient in correcting patient-specific scatter with only 3% increase in dose. In this paper we reported the feasibility study of applying the same technique to chest tomosynthesis. This investigation was performed utilizing phantom and cadaver subjects. The method involves an initial tomosynthesis scan of the object. A lead plate with an array of holes, or primary sampling apparatus (PSA), was placed above the object. A second tomosynthesis scan was performed to measure the primary (scatter-free) transmission. This PSA data was used with the full-field projections to compute the scatter, which was then interpolated to full-field scatter maps unique to each projection angle. Full-field projection images were scatter corrected prior to reconstruction. Projections and reconstruction slices were evaluated and the correction method was found to be effective at improving image quality and practical for clinical implementation.

A 3-lever discrimination procedure reveals differences in the subjective effects of low and high doses of MDMA.

PubMed

Harper, David N; Langen, Anna-Lena; Schenk, Susan

2014-01-01

Drug discrimination studies have suggested that the subjective effects of low doses of (±)3,4-methylenedioxymethamphetamine (MDMA) are readily differentiated from those of d-amphetamine (AMPH) and that the discriminative stimulus properties are mediated by serotonergic and dopaminergic mechanisms, respectively. Previous studies, however, have primarily examined responses to doses that do not produce substantial increases in extracellular dopamine. The present study determined whether doses of MDMA that produce increases in synaptic dopamine would also produce subjective effects that were more like AMPH and were sensitive to pharmacological manipulation of D1-like receptors. A three-lever drug discrimination paradigm was used. Rats were trained to respond on different levers following saline, AMPH (0.5mg/kg, IP) or MDMA (1.5mg/kg, IP) injections. Generalization curves were generated for a range of different doses of both drugs and the effect of the D1-like antagonist, SCH23390 on the discriminative stimulus effects of different doses of MDMA was determined. Rats accurately discriminated MDMA, AMPH and saline. Low doses of MDMA produced almost exclusive responding on the MDMA lever but at doses of 3.0mg/kg MDMA or higher, responding shifted to the AMPH lever. The AMPH response produced by higher doses of MDMA was attenuated by pretreatment with SCH23390. The data suggest that low doses and higher doses of MDMA produce distinct discriminative stimuli. The shift to AMPH-like responding following administration of higher doses of MDMA, and the decrease in this response following administration of SCH23390 suggests a dopaminergic component to the subjective experience of MDMA at higher doses. Copyright © 2013 Elsevier Inc. All rights reserved.

Motion induced interplay effects for VMAT radiotherapy.

PubMed

Edvardsson, Anneli; Nordström, Fredrik; Ceberg, Crister; Ceberg, Sofie

2018-04-19

The purpose of this study was to develop a method to simulate breathing motion induced interplay effects for volumetric modulated arc therapy (VMAT), to verify the proposed method with measurements, and to use the method to investigate how interplay effects vary with different patient- and machine specific parameters. VMAT treatment plans were created on a virtual phantom in a treatment planning system (TPS). Interplay effects were simulated by dividing each plan into smaller sub-arcs using an in-house developed software and shifting the isocenter for each sub-arc to simulate a sin 6 breathing motion in the superior-inferior direction. The simulations were performed for both flattening-filter (FF) and flattening-filter free (FFF) plans and for different breathing amplitudes, period times, initial breathing phases, dose levels, plan complexities, CTV sizes, and collimator angles. The resulting sub-arcs were calculated in the TPS, generating a dose distribution including the effects of motion. The interplay effects were separated from dose blurring and the relative dose differences to 2% and 98% of the CTV volume (ΔD 98% and ΔD 2% ) were calculated. To verify the simulation method, measurements were carried out, both static and during motion, using a quasi-3D phantom and a motion platform. The results of the verification measurements during motion were comparable to the results of the static measurements. Considerable interplay effects were observed for individual fractions, with the minimum ΔD 98% and maximum ΔD 2% being  -16.7% and 16.2%, respectively. The extent of interplay effects was larger for FFF compared to FF and generally increased for higher breathing amplitudes, larger period times, lower dose levels, and more complex treatment plans. Also, the interplay effects varied considerably with the initial breathing phase, and larger variations were observed for smaller CTV sizes. In conclusion, a method to simulate motion induced interplay effects was developed and verified with measurements, which allowed for a large number of treatment scenarios to be investigated. The simulations showed large interplay effects for individual fractions and that the extent of interplay effects varied with the breathing pattern, FFF/FF, dose level, CTV size, collimator angle, and the complexity of the treatment plan.

Motion induced interplay effects for VMAT radiotherapy

NASA Astrophysics Data System (ADS)

Edvardsson, Anneli; Nordström, Fredrik; Ceberg, Crister; Ceberg, Sofie

2018-04-01

The purpose of this study was to develop a method to simulate breathing motion induced interplay effects for volumetric modulated arc therapy (VMAT), to verify the proposed method with measurements, and to use the method to investigate how interplay effects vary with different patient- and machine specific parameters. VMAT treatment plans were created on a virtual phantom in a treatment planning system (TPS). Interplay effects were simulated by dividing each plan into smaller sub-arcs using an in-house developed software and shifting the isocenter for each sub-arc to simulate a sin6 breathing motion in the superior–inferior direction. The simulations were performed for both flattening-filter (FF) and flattening-filter free (FFF) plans and for different breathing amplitudes, period times, initial breathing phases, dose levels, plan complexities, CTV sizes, and collimator angles. The resulting sub-arcs were calculated in the TPS, generating a dose distribution including the effects of motion. The interplay effects were separated from dose blurring and the relative dose differences to 2% and 98% of the CTV volume (ΔD98% and ΔD2%) were calculated. To verify the simulation method, measurements were carried out, both static and during motion, using a quasi-3D phantom and a motion platform. The results of the verification measurements during motion were comparable to the results of the static measurements. Considerable interplay effects were observed for individual fractions, with the minimum ΔD98% and maximum ΔD2% being  ‑16.7% and 16.2%, respectively. The extent of interplay effects was larger for FFF compared to FF and generally increased for higher breathing amplitudes, larger period times, lower dose levels, and more complex treatment plans. Also, the interplay effects varied considerably with the initial breathing phase, and larger variations were observed for smaller CTV sizes. In conclusion, a method to simulate motion induced interplay effects was developed and verified with measurements, which allowed for a large number of treatment scenarios to be investigated. The simulations showed large interplay effects for individual fractions and that the extent of interplay effects varied with the breathing pattern, FFF/FF, dose level, CTV size, collimator angle, and the complexity of the treatment plan.

Human Papillomavirus Vaccine Coverage and Prevalence of Missed Opportunities for Vaccination in an Integrated Healthcare System.

PubMed

Irving, Stephanie A; Groom, Holly C; Stokley, Shannon; McNeil, Michael M; Gee, Julianne; Smith, Ning; Naleway, Allison L

2018-03-01

Human papillomavirus (HPV) vaccination has been recommended in the United States for female and male adolescents since 2006 and 2011, respectively. Coverage rates are lower than those for other adolescent vaccines. The objective of this study was to evaluate an assessment and feedback intervention designed to increase HPV vaccination coverage and quantify missed opportunities for HPV vaccine initiation at preventive care visits. We examined changes in HPV vaccination coverage and missed opportunities within the adolescent (11-17 years) population at 9 Oregon-based Kaiser Permanente Northwest outpatient clinics after an assessment and feedback intervention. Quarterly coverage rates were calculated for the adolescent populations at the clinics, according to age group (11-12 and 13-17 years), sex, and department (Pediatrics and Family Medicine). Comparison coverage assessments were calculated at 3 nonintervention (control) clinics. Missed opportunities for HPV vaccine initiation, defined as preventive care visits in which a patient eligible for HPV dose 1 remained unvaccinated, were examined according to sex and age group. An average of 29,021 adolescents were included in coverage assessments. Before the intervention, 1-dose and 3-dose quarterly coverage rates were increasing at intervention as well as at control clinics in both age groups. Postimplementation quarterly trends in 1-dose or 3-dose coverage did not differ significantly between intervention and control clinics for either age group. One-dose coverage rates among adolescents with Pediatrics providers were significantly higher than those with Family Medicine providers (56% vs 41% for 11- to 12-year-old and 82% vs 69% for 13- to 17-year-old girls; 55% vs 40% for 11- to 12-year-old and 78% vs 62% for 13- to 17-year-old boys). No significant differences in HPV vaccine coverage were identified at intervention clinics. However, coverage rates were increasing before the start of the intervention and might have been influenced by ongoing health system best practices. HPV vaccine coverage rates varied significantly according to department, which could allow for targeted improvement opportunities. Copyright © 2017 Academic Pediatric Association. All rights reserved.

Association Between the Lower Extremity Deep Venous Thrombosis, the Warfarin Maintenance Dose, and CYP2C9*3, CYP2D6*10, and CYP3A5*3 Genetic Polymorphisms: A Case-Control Study.

PubMed

Ju, Shang; Gao, Yu; Cao, Xin; Zhang, Xiao-Fu; Yan, Cheng-Cheng; Liu, Feng-Tong

2017-09-01

This study explored the association between the CYP2C9*3/CYP2D6*10/CYP3A5*3 genetic polymorphisms with lower extremity deep venous thrombosis (LEDVT) and the warfarin maintenance dose. Five hundred thirty-six patients who were pathologically diagnosed with LEDVT after surgery were included in the LEDVT group. At the same time, 540 patients without LEDVT who underwent surgery were recruited as the control group. Patients were given warfarin at an initial dose of 2.5-3.0 mg. Blood samples were collected to detect the initial and stable international normalized ratio (INR) values. The warfarin maintenance dose was obtained if the INR remained within a range of 2.0-3.0 for 3 consecutive days. The genotype distribution and haplotype analysis of the CYP2C9*3/CYP2D6*10/CYP3A5*3 alleles were analyzed using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) testing and SHEsis software, respectively. Logistic regression analysis was used to analyze the risk and protective factors for LEDVT. The A/G genotypes, G/G genotypes, and G allele of CYP3A5*3 in the LEDVT group were observed with increased frequency compared with the control group. The LEDVT group displayed a higher ACG haplotype frequency, and lower ACA and ATA haplotype frequencies than the control group. Age, diabetes, low-density lipoprotein, CYP3A5*3 and the ACG haplotype were independent risk factors for LEDVT. High-density lipoprotein and the ACA haplotype were independent protective factors for LEDVT. The genotype distributions of the CYP2C9*3, CYP2D6*10, and CYP3A5*3 genetic polymorphisms were associated with the warfarin maintenance dose. The CYP3A5*3 genetic polymorphism may be an important risk factor for LEDVT. Moreover, CYP2C9*3, CYP2D6*10, and CYP3A5*3 are associated with the warfarin maintenance dose.

Experimental Study of In-vivo Dosimetry Using Glass Rod Dosimeters to Minimize the Initialization

NASA Astrophysics Data System (ADS)

Jeon, Hosang; Nam, Jiho; Lee, Jayoung; Lee, Juhye; Park, Dahl; Kim, Wontaek; Ki, Yongkan; Kim, Donghyun

2018-03-01

In-vivo dosimetry, in which small detector elements are attached to a patient's body, is an important technique for directly evaluating radiation treatment doses. The glass rod dosimeter (GRD) possesses several advantages over alternatives, which makes it one of the most useful detectors for in-vivo dosimetry. However, because the GRD initialization process requires a prolonged exposure at very high temperatures, as well as subsequent gradual quenching, each measurement takes approximately a day to complete. Therefore, we investigated the reliability of a GRD used repeatedly without initialization processes to improve efficiency. Ten doses of 0.5 Gy were delivered and read using three GRD elements. Then, the same procedure was performed for doses of 1.0 Gy. A readout error of less than 2% was maintained for up to three irradiation doses. However, the fluctuations in the readout data increased significantly as the number of irradiation doses increased. In addition, we discovered that the combined uncertainty of the readouts was influenced more heavily by the cumulative amount of irradiation than it was by the number of doses. Our results should provide guidance for accurate and efficient GRD use.

USING THE HERMITE POLYNOMIALS IN RADIOLOGICAL MONITORING NETWORKS.

PubMed

Benito, G; Sáez, J C; Blázquez, J B; Quiñones, J

2018-03-15

The most interesting events in Radiological Monitoring Network correspond to higher values of H*(10). The higher doses cause skewness in the probability density function (PDF) of the records, which there are not Gaussian anymore. Within this work the probability of having a dose >2 standard deviations is proposed as surveillance of higher doses. Such probability is estimated by using the Hermite polynomials for reconstructing the PDF. The result is that the probability is ~6 ± 1%, much >2.5% corresponding to Gaussian PDFs, which may be of interest in the design of alarm level for higher doses.

Optimal dose and volume for postoperative radiotherapy in brain oligometastases from lung cancer: a retrospective study.

PubMed

Chung, Seung Yeun; Chang, Jong Hee; Kim, Hye Ryun; Cho, Byoung Chul; Lee, Chang Geol; Suh, Chang-Ok

2017-06-01

To evaluate intracranial control after surgical resection according to the adjuvant treatment received in order to assess the optimal radiotherapy (RT) dose and volume. Between 2003 and 2015, a total of 53 patients with brain oligometastases from non-small cell lung cancer (NSCLC) underwent metastasectomy. The patients were divided into three groups according to the adjuvant treatment received: whole brain radiotherapy (WBRT) ± boost (WBRT ± boost group, n = 26), local RT/Gamma Knife surgery (local RT group, n = 14), and the observation group (n = 13). The most commonly used dose schedule was WBRT (25 Gy in 10 fractions, equivalent dose in 2 Gy fractions [EQD2] 26.04 Gy) with tumor bed boost (15 Gy in 5 fractions, EQD2 16.25 Gy). The WBRT ± boost group showed the lowest 1-year intracranial recurrence rate of 30.4%, followed by the local RT and observation groups, at 66.7%, and 76.9%, respectively (p = 0.006). In the WBRT ± boost group, there was no significant increase in the 1-year new site recurrence rate of patients receiving a lower dose of WBRT (EQD2) <27 Gy compared to that in patients receiving a higher WBRT dose (p = 0.553). The 1-year initial tumor site recurrence rate was lower in patients receiving tumor bed dose (EQD2) of ≥42.3 Gy compared to those receiving <42.3 Gy, although the difference was not significant (p = 0.347). Adding WBRT after resection of brain oligometastases from NSCLC seems to enhance intracranial control. Furthermore, combining lower-dose WBRT with a tumor bed boost may be an attractive option.

Optimal dose and volume for postoperative radiotherapy in brain oligometastases from lung cancer: a retrospective study

PubMed Central

Chung, Seung Yeun; Chang, Jong Hee; Kim, Hye Ryun; Cho, Byoung Chul; Lee, Chang Geol; Suh, Chang-Ok

2017-01-01

Purpose To evaluate intracranial control after surgical resection according to the adjuvant treatment received in order to assess the optimal radiotherapy (RT) dose and volume. Materials and Methods Between 2003 and 2015, a total of 53 patients with brain oligometastases from non-small cell lung cancer (NSCLC) underwent metastasectomy. The patients were divided into three groups according to the adjuvant treatment received: whole brain radiotherapy (WBRT) ± boost (WBRT ± boost group, n = 26), local RT/Gamma Knife surgery (local RT group, n = 14), and the observation group (n = 13). The most commonly used dose schedule was WBRT (25 Gy in 10 fractions, equivalent dose in 2 Gy fractions [EQD2] 26.04 Gy) with tumor bed boost (15 Gy in 5 fractions, EQD2 16.25 Gy). Results The WBRT ± boost group showed the lowest 1-year intracranial recurrence rate of 30.4%, followed by the local RT and observation groups, at 66.7%, and 76.9%, respectively (p = 0.006). In the WBRT ± boost group, there was no significant increase in the 1-year new site recurrence rate of patients receiving a lower dose of WBRT (EQD2) <27 Gy compared to that in patients receiving a higher WBRT dose (p = 0.553). The 1-year initial tumor site recurrence rate was lower in patients receiving tumor bed dose (EQD2) of ≥42.3 Gy compared to those receiving <42.3 Gy, although the difference was not significant (p = 0.347). conclusions Adding WBRT after resection of brain oligometastases from NSCLC seems to enhance intracranial control. Furthermore, combining lower-dose WBRT with a tumor bed boost may be an attractive option. PMID:28712276

Serotonin transporter occupancy by escitalopram and citalopram in the non-human primate brain: a [(11)C]MADAM PET study.

PubMed

Finnema, Sjoerd J; Halldin, Christer; Bang-Andersen, Benny; Bundgaard, Christoffer; Farde, Lars

2015-11-01

A number of serotonin receptor positron emission tomography (PET) radioligands have been shown to be sensitive to changes in extracellular serotonin concentration, in a generalization of the well-known dopamine competition model. High doses of selective serotonin reuptake inhibitors (SSRIs) decrease serotonin receptor availability in monkey brain, consistent with increased serotonin concentrations. However, two recent studies on healthy human subjects, using a single, lower and clinically relevant SSRI dose, showed increased cortical serotonin receptor radioligand binding, suggesting potential decreases in serotonin concentration in projection regions when initiating treatment. The cross-species differential SSRI effect may be partly explained by serotonin transporter (SERT) occupancy in monkey brain being higher than is clinically relevant. We here determine SERT occupancy after single doses of escitalopram or citalopram by conducting PET measurements with [(11)C]MADAM in monkeys. Relationships between dose, plasma concentration and SERT occupancy were estimated by one-site binding analyses. Binding affinity was expressed as dose (ID50) or plasma concentration (K i) where 50 % SERT occupancy was achieved. Estimated ID50 and K i values were 0.020 mg/kg and 9.6 nmol/L for escitalopram and 0.059 mg/kg and 9.7 nmol/L for citalopram, respectively. Obtained K i values are comparable to values reported in humans. Escitalopram or citalopram doses nearly saturated SERT in previous monkey studies which examined serotonin sensitivity of receptor radioligands. PET-measured cross-species differential effects of SSRI on cortical serotonin concentration may thus be related to SSRI dose. Future monkey studies using SSRI doses inducing clinically relevant SERT occupancy may further illuminate the delayed onset of SSRI therapeutic effects.

SEMICONDUCTOR TECHNOLOGY: Influence of nitrogen dose on the charge density of nitrogen-implanted buried oxide in SOI wafers

NASA Astrophysics Data System (ADS)

Zhongshan, Zheng; Zhongli, Liu; Ning, Li; Guohua, Li; Enxia, Zhang

2010-02-01

To harden silicon-on-insulator (SOI) wafers fabricated using separation by implanted oxygen (SIMOX) to total-dose irradiation, the technique of nitrogen implantation into the buried oxide (BOX) layer of SIMOX wafers can be used. However, in this work, it has been found that all the nitrogen-implanted BOX layers reveal greater initial positive charge densities, which increased with increasing nitrogen implantation dose. Also, the results indicate that excessively large nitrogen implantation dose reduced the radiation tolerance of BOX for its high initial positive charge density. The bigger initial positive charge densities can be ascribed to the accumulation of implanted nitrogen near the Si-BOX interface after annealing. On the other hand, in our work, it has also been observed that, unlike nitrogen-implanted BOX, all the fluorine-implanted BOX layers show a negative charge density. To obtain the initial charge densities of the BOX layers, the tested samples were fabricated with a metal-BOX-silicon (MBS) structure based on SIMOX wafers for high-frequency capacitance-voltage (C-V) analysis.

Life-saving rectal artesunate for complicated malaria in children.

PubMed

Pengsaa, Krisana; Sirivichayakul, Chukiat; Na-Bangchang, Kesara; Thaiarporn, Itthipon; Chaivisuth, Anong; Wongsuwan, Amnaj; Attanath, Phanorsri; Pojjaroen-Anant, Chanathep; Wisetsing, Pataraporn; Chanthavanich, Pornthep; Sabchareon, Arunee

2005-05-01

We report the effectiveness of two regimens of rectal artesunate formulation in treating 13 Thai children with cerebral/complicated falciparum malaria. The drug was given at an initial dose of 40 mg/kg bodyweight, in 3 or 4 divided doses in the first 24 hours, followed by 10 mg/kg bodyweight once daily for three consecutive days. Mefloquine, at a dose of 15 mg/kg bodyweight was given orally at 72 hours after the initial dose of artesunate, followed by 10 mg/kg bodyweight 6 hours later. Three cases with cerebral malaria gained consciousness within 20 hours of artesunate administration. The median time required for reduction of parasitemia by 90% of the initial value (P90) in 13 children was 11.2 hours. No recrudescence was observed in any of the patients during the 28-day follow-up period. Plasma concentrations of artesunate and dihydroartemisinin (active plasma metabolite of artesunate) measured in two patients who received the high initial dose regimen (20 mg/ kg bodyweight) suggested rapid absorption and adequate plasma concentrations of both compounds following the administration of artesunate via the rectal route. Further studies for the optimized regimen of rectal artesunate in the treatment of cerebral/complicated childhood falciparum malaria in areas of multidrug resistance are warranted.

SU-F-BRD-07: Fast Monte Carlo-Based Biological Optimization of Proton Therapy Treatment Plans for Thyroid Tumors

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

Wan Chan Tseung, H; Ma, J; Ma, D

2015-06-15

Purpose: To demonstrate the feasibility of fast Monte Carlo (MC) based biological planning for the treatment of thyroid tumors in spot-scanning proton therapy. Methods: Recently, we developed a fast and accurate GPU-based MC simulation of proton transport that was benchmarked against Geant4.9.6 and used as the dose calculation engine in a clinically-applicable GPU-accelerated IMPT optimizer. Besides dose, it can simultaneously score the dose-averaged LET (LETd), which makes fast biological dose (BD) estimates possible. To convert from LETd to BD, we used a linear relation based on cellular irradiation data. Given a thyroid patient with a 93cc tumor volume, we createdmore » a 2-field IMPT plan in Eclipse (Varian Medical Systems). This plan was re-calculated with our MC to obtain the BD distribution. A second 5-field plan was made with our in-house optimizer, using pre-generated MC dose and LETd maps. Constraints were placed to maintain the target dose to within 25% of the prescription, while maximizing the BD. The plan optimization and calculation of dose and LETd maps were performed on a GPU cluster. The conventional IMPT and biologically-optimized plans were compared. Results: The mean target physical and biological doses from our biologically-optimized plan were, respectively, 5% and 14% higher than those from the MC re-calculation of the IMPT plan. Dose sparing to critical structures in our plan was also improved. The biological optimization, including the initial dose and LETd map calculations, can be completed in a clinically viable time (∼30 minutes) on a cluster of 25 GPUs. Conclusion: Taking advantage of GPU acceleration, we created a MC-based, biologically optimized treatment plan for a thyroid patient. Compared to a standard IMPT plan, a 5% increase in the target’s physical dose resulted in ∼3 times as much increase in the BD. Biological planning was thus effective in escalating the target BD.« less

Delayed-release oral mesalamine 4.8 g/day (800 mg tablets) compared with 2.4 g/day (400 mg tablets) for the treatment of mildly to moderately active ulcerative colitis: The ASCEND I trial

PubMed Central

Hanauer, Stephen B; Sandborn, William J; Dallaire, Christian; Archambault, André; Yacyshyn, Bruce; Yeh, Chyon; Smith-Hall, Nancy

2007-01-01

BACKGROUND: Delayed-release oral mesalamine 2.4 g/day to 4.8 g/day has been shown to be effective in treating mildly to moderately active ulcerative colitis (UC), but it is unknown whether an initial dose of 4.8 g/day is more effective than 2.4 g/day in patients with mildly to moderately active UC and in the subgroup with moderate disease. PATIENTS AND METHODS: A six-week, multicentre, randomized, double-blind, controlled trial assessing the safety and clinical efficacy of a new dose (ASCEND I) of medication randomly assigned 301 adults with mildly to moderately active UC to delayed-release oral mesalamine 2.4 g/day (400 mg tablet [n=154]) or 4.8 g/day (800 mg tablet [n=147]). The primary efficacy end point was overall improvement (ie, treatment success), defined as complete remission or response to therapy from baseline to week 6. Primary safety end points were adverse events and laboratory evaluations. Data were also analyzed separately for the prespecified subgroup of patients with moderate UC at baseline. RESULTS: Treatment success was not statistically different between the treatment groups at week 6; 51% of the group (77 of 150) who received delayed-release oral mesalamine 2.4 g/day and 56% of the group (76 of 136) who received 4.8 g/day reached the efficacy end point (P=0.441). Among the moderate disease subgroup, however, the higher initial dose was more effective; 57% of patients (53 of 93) given delayed-release oral mesalamine 2.4 g/day and 72% of patients (55 of 76) given 4.8 g/day achieved treatment success (P=0.0384). Both regimens were well tolerated. CONCLUSIONS: Delayed-release oral mesalamine is an effective and well-tolerated initial therapy in patients with mildly to moderately active UC, and a 4.8 g/day dose may enhance treatment success rates in patients with moderate disease compared with mesalamine 2.4 g/day. PMID:18080055

The Influence of Tumor Necrosis Factor-α –308 G/A and IL-6 –174 G/C on Pain and Analgesia Response in Lung Cancer Patients Receiving Supportive Care

PubMed Central

Reyes-Gibby, Cielito C.; Osta, Badi El; Spitz, Margaret R.; Parsons, Henrique; Kurzrock, Razelle; Wu, Xifeng; Shete, Sanjay; Bruera, Eduardo

2012-01-01

Introduction We previously showed that select cytokine gene polymorphisms are a significant predictor for pain reported at initial presentation in 446 white patients newly diagnosed with non–small cell lung cancer. This follow-up study explores the extent to which polymorphisms in tumor necrosis factor-α (TNF- α-308 G/A), interleukin (IL)-6 −174G/C, and IL-8 −251T/A could explain variability in pain and analgesic response among those patients (n = 140) subsequently referred for pain treatment. Methods Pain severity (0, no pain; 10, worst pain) was assessed at initial consultation and at follow-up visit. The total dose of opioids at the time of first-follow up visit (30 days postconsult) was converted to an equivalent dose of parenteral morphine. Results Forty-one percent (57 of 140) of the patients reported severe pain (score >7/10) at initial consultation (mean, 5.5), which significantly decreased to 25% (mean, 4) at first follow-up visit (McNemar = P < 0.001). Polymorphisms in TNF and IL-6 were significantly associated with pain severity (for TNF GG, 4.12; GA, 5.38; AA, 5.50; P = 0.04) and with morphine equivalent daily dose (IL-6 GG, 69.61; GC, 73.17; CC, 181.67; P = 0.004), respectively. Adjusting for demographic and clinical variables, variant alleles in TNFα −308 G/A remained significantly associated with pain severity (b = 0.226; P = 0.036) and carriers of the IL-6 −174C/C genotypes required 4.7 times higher dose of opioids for pain relief (odds ratio, 4.7; 95% confidence interval, 1.2;15.0) relative to GG and GC genotypes. Conclusions We provide preliminary evidence of the influence of cytokine genes on pain and response to analgesia in lung cancer patients. Additional studies are needed to validate our findings. The long-term application is to tailored pain therapies. PMID:18990769

Effect of low-dose irradiation on growth of and toxin production by Staphylococcus aureus and Bacillus cereus in roast beef and gravy.

PubMed

Grant, I R; Nixon, C R; Patterson, M F

1993-03-01

The effect of irradiation (2 kGy) on growth of and toxin production by Staphylococcus aureus and Bacillus cereus in roast beef and gravy during storage at abuse temperatures (15 and 22 degrees C) was assessed by inoculation studies. Irradiation resulted in a 3-4 log10 reduction in numbers of both pathogens. Whenever B. cereus and S. aureus numbers reached 10(6) and 10(7) cfu/g, respectively, during storage their toxins were detectable. As the time taken to attain these levels was longer in irradiated than in unirradiated samples, toxin production by both pathogens was delayed by irradiation. When samples initially containing low levels (10(2)/g) of S. aureus were irradiated no toxin was produced during subsequent storage at 15 or 22 degrees C. Diarrhoeal toxin produced by B. cereus was detected after 2 days at 22 degrees C, but not at 15 degrees C, in samples containing 10(2) cells/g prior to irradiation. When higher numbers (10(6)/g) of either pathogen were present prior to irradiation, toxins were produced by both pathogens at 22 degrees C, but not at 15 degrees C. Microbial competition had an effect on the growth of B. cereus and S. aureus after irradiation when a low initial inoculum was applied. However, when a higher inoculum was used the pathogens outnumbered their competitors and competition effects were less important. It was concluded that low-dose irradiation would improve the microbiological safety of roast beef and gravy.

SU-F-J-86: Method to Include Tissue Dose Response Effect in Deformable Image Registration

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

Zhu, J; Liang, J; Chen, S

Purpose: Organ changes shape and size during radiation treatment due to both mechanical stress and radiation dose response. However, the dose response induced deformation has not been considered in conventional deformable image registration (DIR). A novel DIR approach is proposed to include both tissue elasticity and radiation dose induced organ deformation. Methods: Assuming that organ sub-volume shrinkage was proportional to the radiation dose induced cell killing/absorption, the dose induced organ volume change was simulated applying virtual temperature on each sub-volume. Hence, both stress and heterogeneity temperature induced organ deformation. Thermal stress finite element method with organ surface boundary condition wasmore » used to solve deformation. Initial boundary correspondence on organ surface was created from conventional DIR. Boundary condition was updated by an iterative optimization scheme to minimize elastic deformation energy. The registration was validated on a numerical phantom. Treatment dose was constructed applying both the conventional DIR and the proposed method using daily CBCT image obtained from HN treatment. Results: Phantom study showed 2.7% maximal discrepancy with respect to the actual displacement. Compared with conventional DIR, subvolume displacement difference in a right parotid had the mean±SD (Min, Max) to be 1.1±0.9(−0.4∼4.8), −0.1±0.9(−2.9∼2.4) and −0.1±0.9(−3.4∼1.9)mm in RL/PA/SI directions respectively. Mean parotid dose and V30 constructed including the dose response induced shrinkage were 6.3% and 12.0% higher than those from the conventional DIR. Conclusion: Heterogeneous dose distribution in normal organ causes non-uniform sub-volume shrinkage. Sub-volume in high dose region has a larger shrinkage than the one in low dose region, therefore causing more sub-volumes to move into the high dose area during the treatment course. This leads to an unfavorable dose-volume relationship for the normal organ. Without including this effect in DIR, treatment dose in normal organ could be underestimated affecting treatment evaluation and planning modification. Acknowledgement: Partially Supported by Elekta Research Grant.« less

Late effect of atomic bomb radiation on myeloid disorders: leukemia and myelodysplastic syndromes.

PubMed

Tsushima, Hideki; Iwanaga, Masako; Miyazaki, Yasushi

2012-03-01

Leukemia was the first malignancy linked to radiation exposure in atomic bomb survivors. Clear evidence of the dose-dependent excess risk of three major types of leukemia (acute lymphocytic leukemia, acute myeloid leukemia [AML], and chronic myeloid leukemia) was found, especially in people exposed at young ages. Such leukemia risks were at their highest in the late 1950s, and declined gradually thereafter over the past 50 years. Findings from recent risk analyses, however, suggest the persistence of AML risk even after 1990, and evidence of increased risk of myelodysplastic syndromes (MDS) due to atomic bomb radiation has recently been shown. High-risk MDS and forms involving complex chromosomal aberrations were found to be much more frequent in people exposed to higher radiation doses. These lines of epidemiological evidence suggest that the risk of radiation-induced hematological malignancies has persisted for six decades since the initial exposure.

Early outcomes following low dose naltrexone enhancement of opioid detoxification.

PubMed

Mannelli, Paolo; Patkar, Ashwin A; Peindl, Kathleen; Gottheil, Edward; Wu, Li-Tzy; Gorelick, David A

2009-01-01

Although withdrawal severity and treatment completion are the initial focus of opioid detoxification, post-detoxification outcome better defines effective interventions. Very low dose naltrexone (VLNTX) in addition to methadone taper was recently associated with attenuated withdrawal intensity during detoxification. We describe the results of a seven-day follow-up evaluation of 96 subjects who completed inpatient detoxification consisting of the addition of VLNTX (0.125 or 0.250 mg per day) or placebo to methadone taper in a double blind, randomized investigation. Individuals receiving VLNTX during detoxification reported reduced withdrawal and drug use during the first 24 hours after discharge. VLNTX addition was also associated with higher rates of negative drug tests for opioids and cannabis and increased engagement in outpatient treatment after one week. Further studies are needed to test the utility of this approach in easing the transition from detoxification to various follow-up treatment modalities designed to address opioid dependence.

Booster and higher antigen doses of inactivated influenza vaccine in HIV-infected patients.

PubMed

Johnston, Jessica A; Tincher, Lindsey B; Lowe, Denise K

2013-12-01

To review the literature regarding booster or higher doses of influenza antigen for increasing immunogenicity of inactivated influenza vaccine (IIV) in HIV-infected patients. MEDLINE (1966 to September 2013) was searched using the terms immunize, influenza, vaccine, and HIV or AIDS in combination with two-dose, booster-dose, increased antigen, or high-dose. One trial of booster dosing with standard doses (SDs) of IIV, trivalent (IIV3); 2 trials of booster dosing with intermediate doses (ID) of H1N1 IIV or IIV3; and 1 trial of high-dose (HD) IIV3 were identified. Trials administering 2-dose, booster-dose, or increased antigen of influenza vaccine to patients with HIV were reviewed. Because adjuvanted IIV is not available and IIV, quadrivalent was recently approved in the United States, studies evaluating these vaccines were excluded. HIV-infected individuals are at high risk for influenza-related complications; however, vaccination with SD IIV may not confer optimal protection. It has been postulated that booster or higher doses of influenza antigen may lead to increased immunogenicity. When ID and SD or ID with boosters were evaluated in HIV-infected patients, significant increases in surrogate markers for influenza protection were not achieved. However, HD IIV3 did result in significant increases in seroprotective antibody levels, though 'clinical' influenza was not evaluated. Currently, evidence is insufficient to reach conclusions about the efficacy of booster dosing, ID, or HD influenza vaccine in HIV-infected patients. Trials evaluating booster or higher-antigen doses of IIV for 'clinical' influenza are necessary before routinely recommending for HIV-infected patients.

Testicular toxicity in cannabis extract treated mice: association with oxidative stress and role of antioxidant enzyme systems.

PubMed

Mandal, Tapas K; Das, Nildari S

2010-02-01

Intraperitoneal injection of cannabis extract at low doses (total doses ranging from 40 mg to 60 mg per mouse) induced adverse effect on testes and oxidative stress. At low doses, there was a significant increase in lipid peroxidation and decrease in testicular lipid content, but the effects were significantly less at higher doses and at the withdrawal of cannabis treatment (recovery dose). There was a marked decrease in antioxidant enzyme profiles (superoxide dismutase, catalase and glutathione peroxidase) and glutathione content at low doses, but these effects were higher at higher dose and at withdrawal of the treatment (recovery effect). Histology revealed significant shrinkage of tubular diameter and detrimental changes in seminiferous epithelium of testis with resulting lowered serum testosterone and pituitary gonadotropins (follicular stimulating [FSH] and luteinizing hormones [LH]) levels at low doses. But at higher doses and particularly at withdrawal of the treatment, regression of various germ cell layers of testes through the revival of testosterone hormone and pituitary gonadotropins (FSH and LH) were observed, indicating that recovery effects on testes became operative possibly through the corrective measure of endogenous testicular antioxidant enzymes profiles and pituitary gonadotropins hormones feedback mechanisms.

The influence of angiotensin-converting enzyme inhibitors on the aorta elastin metabolism in diet-induced hypercholesterolaemia in rabbits.

PubMed

Wojakowski, W; Gminski, J; Siemianowicz, K; Goss, M; Machalski, M

2001-03-01

Aortic elastin turnover is significantly accelerated in atherosclerosis, partly because of activation of the renin-angiotensin-aldosterone system caused by hypercholesterolaemia. We postulated that angiotensin-converting enzyme inhibitors (ACE-I) prevent the aortic elastin loss in experimental hypercholesterolaemia. Two doses of ACE-I (captopril, enalapril and quinapril) were used: a dose equivalent to that applied to human subjects and a dose 10 times higher. We found that the increase in serum and aortic elastolytic activity in cholesterol-fed rabbits was prevented by high-dose captopril. The elastin content in aorta homogenates from cholesterol-fed rabbits was significantly decreased. The higher dose of captopril, but no other ACE-I, prevented this decrease in aortic elastin content. In cholesterol-fed rabbits the elastin-bound calcium content was significantly elevated. The higher doses of captopril and enalapril lowered the elastin-bound calcium content. In serum and aortic homogenates of cholesterol-fed rabbits, ACE activity was elevated by 15% and 77%, respectively. Both doses of captopril, enalapril and quinapril prevented this cholesterol-induced increase in serum and aortic ACE activity. We conclude that: 1) administration of captopril at doses 10 times higher than those used in humans prevents hypercholesterolaemia increased aortic elastin loss. 2) higher doses of captopril and enalapril prevent the hypercholesterolaemia-induced increase in aortic elastin-bound calcium.

Influence of titration schedule and maintenance dose on the tolerability of adjunctive eslicarbazepine acetate: An integrated analysis of three randomized placebo-controlled trials.

PubMed

Krauss, Gregory; Biton, Victor; Harvey, Jay H; Elger, Christian; Trinka, Eugen; Soares da Silva, Patrício; Gama, Helena; Cheng, Hailong; Grinnell, Todd; Blum, David

2018-01-01

To examine the influence of titration schedule and maintenance dose on the incidence and type of treatment-emergent adverse events (TEAEs) associated with adjunctive eslicarbazepine acetate (ESL). Data from three randomized, double-blind, placebo-controlled trials were analyzed. Patients with refractory partial-onset seizures were randomized to maintenance doses of ESL 400, 800, or 1200mg QD (dosing was initiated at 400 or 800mg QD) or placebo. The incidence of TEAEs was analyzed during the double-blind period (2-week titration phase; 12-week maintenance phase), according to the randomized maintenance dose and the titration schedule. 1447 patients were included in the analysis. During the first week of treatment, 62% of patients taking ESL 800mg QD had ≥1 TEAE, vs 35% of those taking 400mg QD and 32% of the placebo group; dizziness, somnolence, nausea, and headache were numerically more frequent in patients taking ESL 800mg than those taking ESL 400mg QD. During the double-blind period, the incidences of common TEAEs were lower in patients who initiated ESL at 400mg vs 800mg QD. For the 800 and 1200mg QD maintenance doses, rates of TEAEs leading to discontinuation were lower in patients who began treatment with 400mg than in those who began taking ESL 800mg QD. Initiation of ESL at 800mg QD is feasible. However, initiating treatment with ESL 400mg QD for 1 or 2 weeks is recommended, being associated with a lower incidence of TEAEs, and related discontinuations. For some patients, treatment may be initiated at 800mg QD, if the need for more immediate seizure reduction outweighs concerns about increased risk of adverse reactions during initiation. Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.

Decomposition of 2,4,6-trinitrotoluene (TNT) by gamma irradiation.

PubMed

Lee, Byungjin; Lee, Myunjoo

2005-12-01

The purpose of this study was to evaluate the potential of gamma irradiation to decompose 2,4,6-trinitrotoluene (TNT) in an aqueous solution; the concentration range of the TNT solution was 0.11-0.44 mmol/L. The decomposition rate of TNT by gamma irradiation was pseudo-first-order kinetic over the applied initial concentrations. The dose constant was strongly dependent on the initial concentration of TNT. Increasing the concentration of dissolved oxygen in the solution was more effective on the decomposition of TNT as well as its mineralization. The required irradiation dose to remove 90% of initial TNT (0.44 mmol/L) was 58, 41, 32, 28, and 25 kGy at the dissolved oxygen concentration of 0.025, 0.149, 0.3, 0.538, and 0.822 mmol/L, respectively. However, TOC still remained as 30% of the initial TOC (3.19 mmol/L) when 200 kGy irradiation dose was applied to the TNT solution (0.44 mmol/L) containing dissolved oxygen of 0.822 mmol/L. The removal of the TNT was more efficient at a pH below 3 and at a pH above 11 than at neutral pH (pH 5-9). The required irradiation dose to remove over 99% of the initial TNT (0.44 mmol/L) was 39, 76, and 10 kGy at pH 2, 7, and 13, respectively. The dose constant was increased 1.6-fold and over 15.6-fold at pH 2 and 13, respectively, compared to that at pH 7. When an irradiation dose of 200 kGy was applied, the removal efficiencies of the TOC (initial concentration 3.19 mmol/L) were 91, 46, and 53% at pH 2, 7, and 13, respectively. Ammonia and nitrate were detected as the main nitrogen byproducts of TNT, and glyoxalic acid and oxalic acid were detected as organic byproducts.

Phase stability and microstructures of high entropy alloys ion irradiated to high doses

NASA Astrophysics Data System (ADS)

Xia, Songqin; Gao, Michael C.; Yang, Tengfei; Liaw, Peter K.; Zhang, Yong

2016-11-01

The microstructures of AlxCoCrFeNi (x = 0.1, 0.75 and 1.5 in molar ratio) high entropy alloys (HEAs) irradiated at room temperature with 3 MeV Au ions at the highest fluence of 105, 91, and 81 displacement per atom, respectively, were studied. Transmission electron microscopy (TEM) and high-resolution TEM (HRTEM) analyses show that the initial microstructures and phase composition of all three alloys are retained after ion irradiation and no phase decomposition is observed. Furthermore, it is demonstrated that the disordered face-centered cubic (FCC) and disordered body-centered cubic (BCC) phases show much less defect cluster formation and structural damage than the NiAl-type ordered B2 phase. This effect is explained by higher entropy of mixing, higher defect formation/migration energies, substantially lower thermal conductivity, and higher atomic level stress in the disordered phases.

Frequency, predictors, and economic impact of upward dose adjustment of infliximab in managed care patients with rheumatoid arthritis.

PubMed

Ollendorf, Daniel A; Massarotti, Elena; Birbara, Charles; Burgess, Somali Misra

2005-06-01

To examine dosing patterns and costs among rheumatoid arthritis (RA) patients newly treated with infliximab in a large national health care claims database. Using data from a proprietary database of pharmacy and medical claims for 75 U.S. health plans, RA patients newly treated with infliximab between June 2000 and June 2002 were selected and assigned an .index date. based on the first infusion. A pretreatment period of 6 months was created; patients were also followed for a minimum of 6 months after the initial infusion. Follow-up was allowed to vary beyond this minimum 6 months in order to preserve all available patient data. A maintenance number of infliximab vials was determined as of the second infusion; patients with 1 subsequent increase in vials used or 2 intervals between infusions of <49 days were considered to have had an upward dose adjustment. Differences (i.e., between those with upward dose adjustment and those with no upward dose) in patient characteristics were examined using descriptive statistics. In addition, time to upward dose adjustment and factors influencing its likelihood were analyzed using Kaplan-Meier and Cox proportional hazards techniques. Finally, differences in RA-related and unrelated costs (medication, outpatient, inpatient, and total, expressed in 2003 dollars) were examined using Wilcoxon rank-sum tests and were also stratified by a number of patient characteristics found to differ between the 2 groups. A total of 1,236 patients met all study entry criteria and were included in these analyses. One or more upward dose adjustments were experienced by 61.7% (N=762) of patients during an average of 15 months of follow-up (median =13 months, range=6 to 31 months). The majority (63.3%) of upward dose adjustments were due to increases in the number of billed vials. Median time to upward dose adjustment was 254 days and declined steadily based on year of initiation (from 330 days in 2000 to 224 days in 2002). Factors significantly influencing upward dose adjustment included pretreatment use of leflunomide, comorbid Crohn.s disease, and pretreatment liver function testing. During followup, patients in the upward dose adjustment group used a mean (SD) of 30.28 (20.90) vials of infliximab, compared with 15.90 (14.28) among those not adjusting dose (P<0.001). Annualized (i.e., standardized to a 365-day rate) RA-related costs were higher by more than 50% among patients with upward dose adjustment (SD $22,283 [$20,517] versus $14,425 [$10,828] for those without upward dose adjustment; P<0.001); differences were driven almost entirely by the costs of infliximab itself ($16,336 [$9,490] versus $9,573 [$6,790], P<0.001). In a cohort of managed care members with RA, upward dose adjustment with infliximab was frequent and appeared to occur earlier in the drug therapy in 2002 compared with 2000. Upward dose adjustment was associated with significant increases in drug treatment costs; therefore, payers and providers should consider the impact of current dosing trends when monitoring the use of biologics for autoimmune diseases.

Preventive sparing of spinal cord and brain stem in the initial irradiation of locally advanced head and neck cancers.

PubMed

Farace, Paolo; Piras, Sara; Porru, Sergio; Massazza, Federica; Fadda, Giuseppina; Solla, Ignazio; Piras, Denise; Deidda, Maria Assunta; Amichetti, Maurizio; Possanzini, Marco

2014-01-06

Since reirradiation in recurrent head and neck patients is limited by previous treatment, a marked reduction of maximum doses to spinal cord and brain stem was investigated in the initial irradiation of stage III/IV head and neck cancers. Eighteen patients were planned by simultaneous integrated boost, prescribing 69.3 Gy to PTV1 and 56.1 Gy to PTV2. Nine 6 MV coplanar photon beams at equispaced gantry angles were chosen for each patient. Step-and-shoot IMRT was calculated by direct machine parameter optimization, with the maximum number of segments limited to 80. In the standard plan, optimization considered organs at risk (OAR), dose conformity, maximum dose < 45 Gy to spinal cord and < 50 Gy to brain stem. In the sparing plans, a marked reduction to spinal cord and brain stem were investigated, with/without changes in dose conformity. In the sparing plans, the maximum doses to spinal cord and brain stem were reduced from the initial values (43.5 ± 2.2 Gy and 36.7 ± 14.0 Gy), without significant changes on the other OARs. A marked difference (-15.9 ± 1.9 Gy and -10.1 ± 5.7 Gy) was obtained at the expense of a small difference (-1.3% ± 0.9%) from initial PTV195% coverage (96.6% ± 0.9%). Similar difference (-15.7 ± 2.2 Gy and -10.2 ± 6.1 Gy) was obtained compromising dose conformity, but unaffecting PTV195% and with negligible decrease in PTV295% (-0.3% ± 0.3% from the initial 98.3% ± 0.8%). A marked spinal cord and brain stem preventive sparing was feasible at the expense of a decrease in dose conformity or slightly compromising target coverage. A sparing should be recommended in highly recurrent tumors, to make potential reirradiation safer.

Cranial CT with adaptive statistical iterative reconstruction: improved image quality with concomitant radiation dose reduction.

PubMed

Rapalino, O; Kamalian, Shervin; Kamalian, Shahmir; Payabvash, S; Souza, L C S; Zhang, D; Mukta, J; Sahani, D V; Lev, M H; Pomerantz, S R

2012-04-01

To safeguard patient health, there is great interest in CT radiation-dose reduction. The purpose of this study was to evaluate the impact of an iterative-reconstruction algorithm, ASIR, on image-quality measures in reduced-dose head CT scans for adult patients. Using a 64-section scanner, we analyzed 100 reduced-dose adult head CT scans at 6 predefined levels of ASIR blended with FBP reconstruction. These scans were compared with 50 CT scans previously obtained at a higher routine dose without ASIR reconstruction. SNR and CNR were computed from Hounsfield unit measurements of normal GM and WM of brain parenchyma. A blinded qualitative analysis was performed in 10 lower-dose CT datasets compared with higher-dose ones without ASIR. Phantom data analysis was also performed. Lower-dose scans without ASIR had significantly lower mean GM and WM SNR (P = .003) and similar GM-WM CNR values compared with higher routine-dose scans. However, at ASIR levels of 20%-40%, there was no statistically significant difference in SNR, and at ASIR levels of ≥60%, the SNR values of the reduced-dose scans were significantly higher (P < .01). CNR values were also significantly higher at ASIR levels of ≥40% (P < .01). Blinded qualitative review demonstrated significant improvements in perceived image noise, artifacts, and GM-WM differentiation at ASIR levels ≥60% (P < .01). These results demonstrate that the use of ASIR in adult head CT scans reduces image noise and increases low-contrast resolution, while allowing lower radiation doses without affecting spatial resolution.

Neuroprotective effects of AT1 receptor antagonists after experimental ischemic stroke: what is important?

PubMed

Culman, Juraj; Jacob, Toni; Schuster, Sven O; Brolund-Spaether, Kjell; Brolund, Leonie; Cascorbi, Ingolf; Zhao, Yi; Gohlke, Peter

2017-09-01

The present study conducted in rats defines the requirements for neuroprotective effects of systemically administered AT1 receptor blockers (ARBs) in acute ischaemic stroke. The inhibition of central effects to angiotensin II (ANG II) after intravenous (i.v.) treatment with candesartan (0.3 and 3 mg/kg) or irbesartan and losartan (3 and 30 mg/kg) was employed to study the penetration of these ARBs across the blood-brain barrier. Verapamil and probenecid were used to assess the role of the transporters, P-glycoprotein and the multidrug resistance-related protein 2, in the entry of losartan and irbesartan into the brain. Neuroprotective effects of i.v. treatment with the ARBs were investigated after transient middle cerebral artery occlusion (MCAO) for 90 min. The treatment with the ARBs was initiated 3 h after the onset of MCAO and continued for two consecutive days. Blood pressure was continuously recorded before and during MCAO until 5.5 h after the onset of reperfusion. The higher dose of candesartan completely abolished, and the lower dose of candesartan and higher doses of irbesartan and losartan partially inhibited the drinking response to intracerebroventricular ANG II. Only 0.3 mg/kg candesartan improved the recovery from ischaemic stroke, and 3 mg/kg candesartan did not exert neuroprotective effects due to marked blood pressure reduction during reperfusion. Both doses of irbesartan and losartan had not any effect on the stroke outcome. An effective, long-lasting blockade of brain AT1 receptors after systemic treatment with ARBs without extensive blood pressure reductions is the prerequisite for neuroprotective effects in ischaemic stroke.

A rapid infusion protocol is safe for total dose iron polymaltose: time for change.

PubMed

Garg, M; Morrison, G; Friedman, A; Lau, A; Lau, D; Gibson, P R

2011-07-01

Intravenous correction of iron deficiency by total dose iron polymaltose is inexpensive and safe, but current protocols entail prolonged administration over more than 4 h. This results in reduced patient acceptance, and hospital resource strain. We aimed to assess prospectively the safety of a rapid intravenous protocol and compare this with historical controls. Consecutive patients in whom intravenous iron replacement was indicated were invited to have up to 1.5 g iron polymaltose by a 58-min infusion protocol after an initial 15-min test dose without pre-medication. Infusion-related adverse events (AE) and delayed AE over the ensuing 5 days were also prospectively documented and graded as mild, moderate or severe. One hundred patients, 63 female, mean age 54 (range 18-85) years were studied. Thirty-four infusion-related AE to iron polymaltose occurred in a total of 24 patients--25 mild, 8 moderate and 1 severe; higher than previously reported for a slow protocol iron infusion. Thirty-one delayed AE occurred in 26 patients--26 mild, 3 moderate and 2 severe; similar to previously reported. All but five patients reported they would prefer iron replacement through the rapid protocol again. The presence of inflammatory bowel disease (IBD) predicted infusion-related reactions (54% vs 14% without IBD, P < 0.001) and the serum C-reactive protein was higher in those with reactions (P = 0.043). Iron polymaltose can be successfully administered using a rapid total dose infusion protocol and was well accepted by patients. It offers significant cost, resource utilization and time benefits for the patient and hospital system. © 2011 The Authors. Internal Medicine Journal © 2011 Royal Australasian College of Physicians.

Star-Shaped Intense Uptake of ¹³¹I on Whole Body Scans Can Reflect Good Therapeutic Effects of Low-Dose Radioactive Iodine Treatment of 1.1 GBq.

PubMed

Kong, Sung Hye; Lim, Jung Ah; Song, Young Shin; Moon, Shinje; Kim, Ye An; Kim, Min Joo; Cho, Sun Wook; Moon, Jae Hoon; Yi, Ka Hee; Park, Do Joon; Cho, Bo Youn; Park, Young Joo

2018-05-04

After initial radioactive iodine (RAI) treatment in differentiated thyroid cancer patients, we sometimes observe a star-shaped region of intense uptake of ¹³¹I on whole body scans (WBSs), called a 'star artifact.' We evaluated the clinical implications of star artifacts on the success rate of remnant ablation and long-term prognosis. Total 636 patients who received ¹³¹I dose of 1.1 GBq for the initial RAI therapy and who did not show distant metastasis at the time of diagnosis were retrospectively evaluated. A negative second WBS was used for evaluating the ablation efficacy of the RAI therapy. Among them, 235 patients (36.9%) showed a star artifact on their first WBS. In patients with first stimulated thyroglobulin (sTg) levels ≤2 ng/mL, patients with star artifacts had a higher rate of negative second WBS compared with those without star artifacts (77.8% vs. 63.9%, P=0.044), and showed significantly higher recurrence-free survival (P=0.043) during the median 8.0 years (range, 1.0 to 10.0) of follow-up. The 5- and 10-year recurrence rates (5YRR, 10YRR) were also significantly lower in patients with star artifacts compared with those without (0% vs. 4.9%, respectively, P=0.006 for 5YRR; 0% vs. 6.4%, respectively, P=0.005 for 10YRR). However, ablation success rate or recurrence-free survival was not different among patients whose first sTg levels >2 ng/mL regardless of star artifacts. Therefore, star artifacts at initial RAI therapy imply a good ablation efficacy or a favorable long-term prognosis in patients with sTg levels ≤2 ng/mL. Copyright © 2018 Korean Endocrine Society.

Radiation exposure in the young level 1 trauma patient: a retrospective review.

PubMed

Gottschalk, Michael B; Bellaire, Laura L; Moore, Thomas

2015-01-01

Computed tomography (CT) has become an increasingly popular and powerful tool for clinicians managing trauma patients with life-threatening injuries, but the ramifications of increasing radiation burden on individual patients are not insignificant. This study examines a continuous series of 337 patients less than 40 years old admitted to a level 1 trauma center during a 4-month period. Primary outcome measures included number of scans; effective dose of radiation from radiographs and CT scans, respectively; and total effective dose from both sources over patients' hospital stays. Several variables, including hospital length of stay, initial Glasgow Coma Scale score, and Injury Severity Score, correlated with greater radiation exposure. Blunt trauma victims were more prone to higher doses than those with penetrating or combined penetrating and blunt trauma. Location and mechanism of injury were also found to correlate with radiation exposure. Trauma patients as a group are exposed to high levels of radiation from X-rays and CT scans, and CT scans contribute a very high proportion (91.3% ± 11.7%) of that radiation. Certain subgroups of patients are at a particularly high risk of exposure, and greater attention to cumulative radiation dose should be paid to patients with the above mentioned risk factors.

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

Magallanes, L., E-mail: lorena.magallanes@med.uni-heidelberg.de; Rinaldi, I., E-mail: ilaria.rinaldi@med.uni-heidelberg.de; Brons, S., E-mail: stephan.brons@med.uni-heidelberg.de

External beam radiotherapy techniques have the common aim to maximize the radiation dose to the target while sparing the surrounding healthy tissues. The inverted and finite depth-dose profile of ion beams (Bragg peak) allows for precise dose delivery and conformai dose distribution. Furthermore, increased radiobiological effectiveness of ions enhances the capability to battle radioresistant tumors. Ion beam therapy requires a precise determination of the ion range, which is particularly sensitive to range uncertainties. Therefore, novel imaging techniques are currently investigated as a tool to improve the quality of ion beam treatments. Approaches already clinically available or under development are basedmore » on the detection of secondary particles emitted as a result of nuclear reactions (e.g., positron-annihilation or prompt gammas, charged particles) or transmitted high energy primary ion beams. Transmission imaging techniques make use of the beams exiting the patient, which have higher initial energy and lower fluence than the therapeutic ones. At the Heidelberg Ion Beam Therapy Center, actively scanned energetic proton and carbon ion beams provide an ideal environment for the investigation of ion-based radiography and tomography. This contribution presents the rationale of ion beam therapy, focusing on the role of ion-based transmission imaging methods towards the reduction of range uncertainties and potential improvement of treatment planning.« less

Impact of Biologics With and Without Concomitant MTX and at Reduced Doses in Older Rheumatoid Arthritis Patients

PubMed Central

Zhang, Jie; Xie, Fenglong; Delzell, Elizabeth; Yun, Huifeng; Lewis, James D; Haynes, Kevin; Chen, Lang; Beukelman, Timothy; Saag, Kenneth G; Curtis, Jeffrey R

2014-01-01

Background This study examines whether concomitant methotrexate (MTX) use is associated with better biologic persistence and whether self-administered anti-TNF therapies are used at reduced doses in real-world clinical care settings, not just clinical trials. Methods We conducted a retrospective cohort study among RA patients using Medicare claims data from 2006 to 2012. Subjects were new initiators of etanercept, infliximab, adalimumab, abatacept and tocilizumab with at least 12 months of continuous medical and pharmacy coverage after treatment initiation. We examined the association between concomitant MTX use and persistence on biologics using Cox proportional hazard regression adjusting for demographics and baseline co-morbidities. We further identified a subgroup of patients who initiated and were adherent on etanercept or adalimumab for at least 12 months and examined the proportion of patients who subsequently used these therapies at reduced doses continuously for an additional 12, 18, and 24 months. Results Of 26,510 eligible RA patients, 10,511 initiated biologic monotherapy. Overall, patients initiated biologic monotherapy were 1.4 (95% CI, 1.3–1.5) times more likely to discontinue at 1-year and 1.8 (95% CI, 1.7–2.0) times more likely if starting infliximab monotherapy. Approximately 10–20% of patients who initiated and adhered to etanercept and adalimumab for ≥ 12 months subsequently used reduced-dose therapy for an 12 additional months and beyond. Conclusion In real-world practice, concomitant MTX was associated with improved persistence on biologic therapy, especially for infliximab users; reduced-dose injectable anti-TNF therapy was used by a substantial proportion of RA patients. PMID:25370912

SU-F-J-87: Impact Of The Dosimetric Consequences From Minimal Displacements Throughout The Treatment Time In APBI With SAVI Applicators

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

Chandrasekara, S; Pella, S; Hyvarinen, M

2016-06-15

Purpose: To assess the variation in dose received by the organs at risk (OARs) due to inter-fractional motion by SAVI to determine the importance of providing proper immobilization Methods: An analysis of 15 patients treated with SAVI applicators were considered for this study. Treatment planning teams did not see significant changes in their CT scans through scout images and initial treatment plan was used for the entire treatment. These scans, taken before each treatment were imported in to the treatment planning system and were fused together with respective to the applicator, using landmark registration. Dosimetric evaluations were performed. Dose receivedmore » by skin, ribs and PTV(Planning target volume) respect to the initial treatment plan were measured. Results: Contours of the OARs were not similar with the initial image. Deduction in volumes of PTV and cavity, small deviations in displacements from the applicator to the OARs, difference in doses received by the OARs between treatments were noticed. The maximum, minimum, average doses varied between 10% to 20% 5% to 8% and 15% to 20% in ribs and skin. The 0.1cc doses to OARs showed an average change of 10% of the prescribed dose. PTV was receiving a different dose than the estimated dose Conclusion: The variation in volumes and isodoses related to the OARs, PTV receiving a lesser dose than the prescribed dose indicate that the estimated doses are different from the received dose. This study reveals the urgent need of improving the immobilization methods. Taking a CT scan before each treatment and replanning is helpful to minimize the risk of delivering undesired high doses to the OARs. Patient positioning, motion, respiration, observer differences and time lap between the planning and treating can arise more complications. VacLock, Positioning cushions, Image guided brachytherapy and adjustable registration should be used for further improvements.« less

Canakinumab reduces the risk of acute gouty arthritis flares during initiation of allopurinol treatment: results of a double-blind, randomised study

PubMed Central

Schlesinger, Naomi; Mysler, Eduardo; Lin, Hsiao-Yi; De Meulemeester, Marc; Rovensky, Jozef; Arulmani, Udayasankar; Balfour, Alison; Krammer, Gerhard; Sallstig, Peter; So, Alexander

2011-01-01

Objective This study assessed the efficacy and safety of canakinumab, a fully human anti-interleukin 1β monoclonal antibody, for prophylaxis against acute gouty arthritis flares in patients initiating urate-lowering treatment. Methods In this double-blind, double-dummy, dose-ranging study, 432 patients with gouty arthritis initiating allopurinol treatment were randomised 1:1:1:1:1:1:2 to receive: a single dose of canakinumab, 25, 50, 100, 200, or 300 mg subcutaneously; 4×4-weekly doses of canakinumab (50+50+25+25 mg subcutaneously); or daily colchicine 0.5 mg orally for 16 weeks. Patients recorded details of flares in diaries. The study aimed to determine the canakinumab dose having equivalent efficacy to colchicine 0.5 mg at 16 weeks. Results A dose-response for canakinumab was not apparent with any of the four predefined dose-response models. The estimated canakinumab dose with equivalent efficacy to colchicine was below the range of doses tested. At 16 weeks, there was a 62% to 72% reduction in the mean number of flares per patient for canakinumab doses ≥50 mg versus colchicine based on a negative binomial model (rate ratio: 0.28–0.38, p≤0.0083), and the percentage of patients experiencing ≥1 flare was significantly lower for all canakinumab doses (15% to 27%) versus colchicine (44%, p<0.05). There was a 64% to 72% reduction in the risk of experiencing ≥1 flare for canakinumab doses ≥50 mg versus colchicine at 16 weeks (hazard ratio (HR): 0.28–0.36, p≤0.05). The incidence of adverse events was similar across treatment groups. Conclusions Single canakinumab doses ≥50 mg or four 4-weekly doses provided superior prophylaxis against flares compared with daily colchicine 0.5 mg. PMID:21540198

Comparison of dosimetric and radiobiological parameters on plans for prostate stereotactic body radiotherapy using an endorectal balloon for different dose-calculation algorithms and delivery-beam modes

NASA Astrophysics Data System (ADS)

Kang, Sang-Won; Suh, Tae-Suk; Chung, Jin-Beom; Eom, Keun-Yong; Song, Changhoon; Kim, In-Ah; Kim, Jae-Sung; Lee, Jeong-Woo; Cho, Woong

2017-02-01

The purpose of this study was to evaluate the impact of dosimetric and radiobiological parameters on treatment plans by using different dose-calculation algorithms and delivery-beam modes for prostate stereotactic body radiation therapy using an endorectal balloon. For 20 patients with prostate cancer, stereotactic body radiation therapy (SBRT) plans were generated by using a 10-MV photon beam with flattening filter (FF) and flattening-filter-free (FFF) modes. The total treatment dose prescribed was 42.7 Gy in 7 fractions to cover at least 95% of the planning target volume (PTV) with 95% of the prescribed dose. The dose computation was initially performed using an anisotropic analytical algorithm (AAA) in the Eclipse treatment planning system (Varian Medical Systems, Palo Alto, CA) and was then re-calculated using Acuros XB (AXB V. 11.0.34) with the same monitor units and multileaf collimator files. The dosimetric and the radiobiological parameters for the PTV and organs at risk (OARs) were analyzed from the dose-volume histogram. An obvious difference in dosimetric parameters between the AAA and the AXB plans was observed in the PTV and rectum. Doses to the PTV, excluding the maximum dose, were always higher in the AAA plans than in the AXB plans. However, doses to the other OARs were similar in both algorithm plans. In addition, no difference was observed in the dosimetric parameters for different delivery-beam modes when using the same algorithm to generate plans. As a result of the dosimetric parameters, the radiobiological parameters for the two algorithm plans presented an apparent difference in the PTV and the rectum. The average tumor control probability of the AAA plans was higher than that of the AXB plans. The average normal tissue complication probability (NTCP) to rectum was lower in the AXB plans than in the AAA plans. The AAA and the AXB plans yielded very similar NTCPs for the other OARs. In plans using the same algorithms, the NTCPs for delivery-beam modes showed no differences. This study demonstrated that the dosimetric and the radiobiological parameters for the PTV and the rectum affected the dose-calculation algorithms for prostate SBRT using an endorectal balloon. However, the dosimetric and the radiobiological parameters in the AAA and the AXB plans for other OARs were similar. Furthermore, difference between the dosimetric and the radiobiological parameters for different delivery-beam modes were not found when the same algorithm was used to generate the treatment plan.

Effect of feeding isolates of anaerobic fungus Neocallimastix sp. CF 17 on growth rate and fibre digestion in buffalo calves.

PubMed

Paul, Shyam S; Deb, Sitangshu M; Punia, Balbir S; Das, Kalyan S; Singh, Ghansham; Ashar, Manisha N; Kumar, Rajiv

2011-06-01

In this investigation, the effects of feeding encapsulated cells (rhizomycelia and zoospores) of a fibrolytic isolate from an anaerobic fungus (Neocallimastix sp. CF 17) on nutrient digestion, ruminal fermentation, microbial populations, enzyme profile and growth performance were evaluated in buffaloes. In three in vitro studies, the true digestibility of wheat straw was increased after addition of CF 17 to buffalo rumen fluid (p < 0.05). In Exp. 1, three groups of six buffaloes each (initial BW [body weight] 148 +/- 12.0 kg) were allotted to three dosing regimes: Group 1 received 200 ml of liquid culture of Neocallimastix sp. CF 17 (about 10(6) TFU [thallus-forming units]/ml); Group 2 received an encapsulated culture of the same fungi prepared from 200 ml liquid culture; Group 3: received 200 ml of autoclaved culture (Control). The supplementations were given weekly for four weeks (on days 1,7, 14 and 21). During the dosing period, the average daily gain of Group 2 was higher than in the Control group (444 g/d compared with 264 g/d; p < 0.05). Furthermore, the digestibility of organic matter increased in Group 1 and 2 compared with the Control (64.8, 64.0 and 60.4% respectively; p < 0.05), resulting in an increase in the total digestible nutrient (TDN) percent of ration (p < 0.05). But these effects disappeared post-dosing. There were also an increase in concentration of volatile fatty acids, trichloroacetic acid precipitable N and number of fibrolytic microbes in the rumen during the dosing period (p < 0.05), but these effects declined post-dosing. Results of Exp 2., where the encapsulated culture was applied at intervals of 4 d or 8 d for 120 d, showed that a shorter dosing frequency did not improve growth performance or feed intake. However, independent of the dosing frequency the growth rate of both groups fed the encapsulated culture were about 20% higher than in the Control group (p < 0.05). The present study showed that encapsulated fungi have a high potential to be used as feed additive at the farmers' level and that weekly dosing can increase growth performance of wheat straw based diets.

Intrathecal 2-hydroxypropyl-β-cyclodextrin decreases neurological disease progression in Niemann-Pick disease, type C1: a non-randomised, open-label, phase 1-2 trial.

PubMed

Ory, Daniel S; Ottinger, Elizabeth A; Farhat, Nicole Yanjanin; King, Kelly A; Jiang, Xuntian; Weissfeld, Lisa; Berry-Kravis, Elizabeth; Davidson, Cristin D; Bianconi, Simona; Keener, Lee Ann; Rao, Ravichandran; Soldatos, Ariane; Sidhu, Rohini; Walters, Kimberly A; Xu, Xin; Thurm, Audrey; Solomon, Beth; Pavan, William J; Machielse, Bernardus N; Kao, Mark; Silber, Steven A; McKew, John C; Brewer, Carmen C; Vite, Charles H; Walkley, Steven U; Austin, Christopher P; Porter, Forbes D

2017-10-14

Niemann-Pick disease, type C1 (NPC1) is a lysosomal storage disorder characterised by progressive neurodegeneration. In preclinical testing, 2-hydroxypropyl-β-cyclodextrins (HPβCD) significantly delayed cerebellar Purkinje cell loss, slowed progression of neurological manifestations, and increased lifespan in mouse and cat models of NPC1. The aim of this study was to assess the safety and efficacy of lumbar intrathecal HPβCD. In this open-label, dose-escalation phase 1-2a study, we gave monthly intrathecal HPβCD to participants with NPC1 with neurological manifestation at the National Institutes of Health (NIH), Bethesda, MD, USA. To explore the potential effect of 2-week dosing, three additional participants were enrolled in a parallel study at Rush University Medical Center (RUMC), Chicago, IL, USA. Participants from the NIH were non-randomly, sequentially assigned in cohorts of three to receive monthly initial intrathecal HPβCD at doses of 50, 200, 300, or 400 mg per month. A fifth cohort of two participants received initial doses of 900 mg. Participants from RUMC initially received 200 or 400 mg every 2 weeks. The dose was escalated based on tolerance or safety data from higher dose cohorts. Serum and CSF 24(S)-hydroxycholesterol (24[S]-HC), which serves as a biomarker of target engagement, and CSF protein biomarkers were evaluated. NPC Neurological Severity Scores (NNSS) were used to compare disease progression in HPβCD-treated participants relative to a historical comparison cohort of 21 NPC1 participants of similar age range. Between Sept 21, 2013, and Jan 19, 2015, 32 participants with NPC1 were assessed for eligibility at the National Institutes of Health. 18 patients were excluded due to inclusion criteria not met (six patients), declined to participate (three patients), pursued independent expanded access and obtained the drug outside of the study (three patients), enrolled in the RUMC cohort (one patient), or too late for the trial enrolment (five patients). 14 patients were enrolled and sequentially assigned to receive intrathecal HPβCD at a starting dose of 50 mg per month (three patients), 200 mg per month (three patients), 300 mg per month (three patients), 400 mg per month (three patients), or 900 mg per month (two patients). During the first year, two patients had treatment interrupted for one dose, based on grade 1 ototoxicity. All 14 patients were assessed at 12 months. Between 12 and 18 months, one participant had treatment interrupted at 17 months due to hepatocellular carcinoma, one patient had dose interruption for 2 doses based on caregiver hardship and one patient had treatment interrupted for 1 dose for mastoiditis. 11 patients were assessed at 18 months. Between Dec 11, 2013, and June 25, 2014, three participants were assessed for eligibility and enrolled at RUMC, and were assigned to receive intrathecal HPβCD at a starting dose of 200 mg every 2 weeks (two patients), or 400 mg every two weeks (one patient). There were no dropouts in this group and all 3 patients were assessed at 18 months. Biomarker studies were consistent with improved neuronal cholesterol homoeostasis and decreased neuronal pathology. Post-drug plasma 24(S)-HC area under the curve (AUC 8-72 ) values, an indicator of neuronal cholesterol homoeostasis, were significantly higher than post-saline plasma 24(S)-HC AUC 8-72 after doses of 900 mg (p=0·0063) and 1200 mg (p=0·0037). CSF 24(S)-HC concentrations in three participants given either 600 or 900 mg of HPβCD were increased about two fold (p=0·0032) after drug administration. No drug-related serious adverse events were observed. Mid-frequency to high-frequency hearing loss, an expected adverse event, was documented in all participants. When managed with hearing aids, this did not have an appreciable effect on daily communication. The NNSS for the 14 participants treated monthly increased at a rate of 1·22, SEM 0·34 points per year compared with 2·92, SEM 0·27 points per year (p=0·0002) for the 21 patient comparison group. Decreased progression was observed for NNSS domains of ambulation (p=0·0622), cognition (p=0·0040) and speech (p=0·0423). Patients with NPC1 treated with intrathecal HPβCD had slowed disease progression with an acceptable safety profile. These data support the initiation of a multinational, randomised, controlled trial of intrathecal HPβCD. National Institutes of Health, Dana's Angels Research Trust, Ara Parseghian Medical Research Foundation, Hope for Haley, Samantha's Search for the Cure Foundation, National Niemann-Pick Disease Foundation, Support of Accelerated Research for NPC Disease, Vtesse, Janssen Research and Development, a Johnson & Johnson company, and Johnson & Johnson. Copyright © 2017 Elsevier Ltd. All rights reserved.

Diabetes mellitus remission in a cat with pituitary-dependent hyperadrenocorticism after trilostane treatment.

PubMed

Muschner, Adriana Cunha; Varela, Fernanda Venzon; Hazuchova, Katarina; Niessen, Stijn Jm; Pöppl, Álan Gomes

2018-01-01

An 8-year-old male neutered Persian cat was presented with polyuria, polydipsia, polyphagia and muscle weakness associated with a 7 month history of diabetes mellitus (DM). The cat had initially been treated with neutral protamine Hagedorn (NPH) insulin 2 U q12h, followed by porcine lente insulin 2 U q12h and, most recently, 3 U glargine insulin q12h, without improvement of clinical signs. The cat also suffered from concurrent symmetrical bilateral alopecia of thorax and forelimbs, abdominal distension and lethargy. Hyperadrenocorticism (HAC), specifically pituitary-dependent HAC, was suspected and confirmed through abdominal ultrasonography demonstrating bilateral adrenal enlargement, and a low-dose dexamethasone suppression test using 0.1 mg/kg dexamethasone intravenously. Trilostane treatment (initially 10 mg/cat PO q24h then increased to 10 mg/cat PO q12h) was started and insulin sensitivity gradually improved, ultimately leading to diabetic remission after an increased in trilostane dose to 13mg/cat PO q12h, 14 months after the DM diagnosis and 7 months after the initiation of trilostane therapy. DM in cats with HAC is a difficult combination of diseases to treat. To our knowledge this is the first reported case of diabetic remission in a feline patient with HAC as a result of treatment with trilostane. Further work should focus on whether fine-tuning of trilostane-treatment protocols in cats with concurrent DM and HAC could lead to a higher proportion of diabetic remissions in this patient group.

A theoretical framework to predict the most likely ion path in particle imaging.

PubMed

Collins-Fekete, Charles-Antoine; Volz, Lennart; Portillo, Stephen K N; Beaulieu, Luc; Seco, Joao

2017-03-07

In this work, a generic rigorous Bayesian formalism is introduced to predict the most likely path of any ion crossing a medium between two detection points. The path is predicted based on a combination of the particle scattering in the material and measurements of its initial and final position, direction and energy. The path estimate's precision is compared to the Monte Carlo simulated path. Every ion from hydrogen to carbon is simulated in two scenarios, (1) where the range is fixed and (2) where the initial velocity is fixed. In the scenario where the range is kept constant, the maximal root-mean-square error between the estimated path and the Monte Carlo path drops significantly between the proton path estimate (0.50 mm) and the helium path estimate (0.18 mm), but less so up to the carbon path estimate (0.09 mm). However, this scenario is identified as the configuration that maximizes the dose while minimizing the path resolution. In the scenario where the initial velocity is fixed, the maximal root-mean-square error between the estimated path and the Monte Carlo path drops significantly between the proton path estimate (0.29 mm) and the helium path estimate (0.09 mm) but increases for heavier ions up to carbon (0.12 mm). As a result, helium is found to be the particle with the most accurate path estimate for the lowest dose, potentially leading to tomographic images of higher spatial resolution.

Thymoglobulin induction in liver transplant recipients with a tacrolimus, mycophenolate mofetil, and steroid immunosuppressive regimen: a five-year randomized prospective study.

PubMed

Boillot, Olivier; Seket, Belhassen; Dumortier, Jérôme; Pittau, Gabriella; Boucaud, Catherine; Bouffard, Yves; Scoazec, Jean-Yves

2009-11-01

This randomized, comparative study assessed the long-term efficacy and tolerability of thymoglobulin (TMG) induction in 93 liver transplant patients with an initial regimen of tacrolimus (Tac), mycophenolate mofetil (MMF), and steroids. Forty-four patients were randomly allocated to the TMG+ group, and 49 patients were randomly allocated to the TMG- group. In both groups, Tac was given orally at the initial daily dose of 0.075 mg/kg twice daily, and MMF was given at the initial daily dose of 2 g/day. Steroid withdrawal was planned at 3 months after liver transplantation. The results were evaluated with respect to acute rejection incidence, patient and graft survival, graft function, and medical complications until 5 years or death for all patients. No significant differences were found between groups for the incidence of acute rejection at 5 years (11.4% versus 14.3%), 5-year patient survival (77.3% versus 87.8%), graft function, or postoperative renal function. One patient in the TMG- group underwent retransplantation. There was no difference between groups with respect to the incidence of medical complications, excepted for a higher rate of leukopenia in the TMG+ group, during the 5-year follow-up. In conclusion, the results of this prospective randomized study suggest that the addition of TMG to a triple immunosuppressive regimen (Tac, MMF, and steroids) did not modify the incidence of acute rejection episodes or long-term survival and was responsible for increased leukopenia rates.

Distribution, pharmacokinetics and primary metabolism model of tramadol in zebrafish.

PubMed

Zhuo, Huiqin; Jin, Hongwei; Peng, Huifang; Huang, Heqing

2016-12-01

The current study aimed to develop a rapid, robust and adequately sensitive method for simultaneous determination of the concentration of tramadol and its active metabolites in zebrafish. The pharmacokinetic and elimination pattern of tramadol and its major phase I metabolites following oral or intramuscular administration in zebrafish tissues was achieved using electrospray ionization‑quadrupole‑time of flight/mass spectrometry (ESI‑Q‑TOF/MS) and gas chromatography/mass spectrometry (GC‑MS). Following administration, the metabolisms were detected in the brain, eyes, muscle and gill tissues within 1 h. Two tramadol metabolites, O‑ and N‑desmethyltramadol, were detected in brain tissue, with N‑desmethyltramadol detected at a higher level. Following GC‑MS detection the curve indicated an initial rapid phase, corresponding to the detection of the tramadol within 1 min, and reached peak value in the brain at 5 min. Faster drug clearance was detected in low‑dose groups, and concentration had dropped around the to initial level (1.11 µg) at 20 min, but was detectable for up to 3 h. However, it took 80 min to fall back to the initial value (1.73 µg) in the high‑dose groups, and tramadol was detectable for up to 4 h. This study developed and validated a simple and high throughput analytical procedure to determine the distribution and pharmacokinetic profiles of tramadol, and its primary metabolites in tissues of zebrafish.

Influence of CYP2C9 polymorphism and phenytoin co-administration on acenocoumarol dose in patients with cerebral venous thrombosis.

PubMed

De, Tanima; Christopher, Rita; Nagaraja, Dindagur

2014-05-01

The study aimed at evaluating the contribution of genetic variations in the drug metabolizing enzyme, CYP2C9, and the influence of co-medication with the antiepileptic drug, phenytoin, to variability in acenocoumarol response, in patients with cerebral venous thrombosis (CVT). 476 acenocoumarol-treated CVT patients (153 males and 323 females) were genotyped for CYP2C9*2 and CYP2C9*3 polymorphisms by PCR-RFLP method. Mean acenocoumarol dose required for achieving and maintaining a stable international normalized ratio (INR) was calculated for different genotypes. The effect of co-administration with phenytoin was determined. Genotype distributions of CYP2C9 were as follows: 83%CYP2C9*1/*1, 8.6%CYP2C9*1/*3, 5.9%CYP2C9*1/*2, 1.9%CYP2C9*3/*3, 0.4%CYP2C9*2/*3 and 0.2%CYP2C9*2/*2. During the initiation phase of anticoagulation the CYP2C9*2 allele was independently associated with low acenocoumarol dose requirement (Adjusted OR 5.38; 95%CI 1.65-17.49; p=0.005). Similarly, the adjusted odds ratio for requiring a low dose during the induction phase in patients bearing the CYP2C9*3 allele was 12.79 (95%CI 4.74-34.57; p<0.0001). During the maintenance phase, CYP2C9*2 and CYP2C9*3 alleles were associated with 19-fold (Adjusted OR 19.67; 95%CI 2.46-157.19; p=0.005) and 11.9-fold odds (Adjusted OR 11.98; 95%CI 2.61-55.08; p=0.001) of requiring a low dose. Clinical covariates such as age, alcohol consumption, postpartum state and oral contraceptive intake also influenced acenocoumarol dosage. Co-medication with phenytoin was associated with lower dose requirement across genotypes during the initiation phase. However, during the maintenance phase, phenytoin-treated patients of all genotypes required higher doses of acenocoumarol. This study emphasizes the fact that polymorphisms in CYP2C9 gene and co-medication with phenytoin alter the anticoagulant effect of acenocoumarol. Copyright © 2014 Elsevier Ltd. All rights reserved.

A comparison between simplified and intensive dose-titration algorithms using AIR inhaled insulin for insulin-naive patients with type 2 diabetes in a randomized noninferiority trial.

PubMed

Mathieu, C; Cuddihy, R; Arakaki, R F; Belin, R M; Planquois, J-M; Lyons, J N; Heilmann, C R

2009-09-01

Insulin initiation and optimization is a challenge for patients with type 2 diabetes. Our objective was to determine whether safety and efficacy of AIR inhaled insulin (Eli Lilly and Co., Indianapolis, IN) (AIR is a registered trademark of Alkermes, Inc., Cambridge, MA) using a simplified regimen was noninferior to an intensive regimen. This was an open-label, randomized study in insulin-naive adults not optimally controlled by oral antihyperglycemic medications. Simplified titration included a 6 U per meal AIR insulin starting dose. Individual doses were adjusted at mealtime in 2-U increments from the previous day's four-point self-monitored blood glucose (SMBG) (total < or =6 U). Starting Air insulin doses for intensive titration were based on fasting blood glucose, gender, height, and weight. Patients conducted four-point SMBG daily for the study duration. Insulin doses were titrated based on the previous 3 days' mean SMBG (total < or =8 U). End point hemoglobin A1C (A1C) was 7.07 +/- 0.09% and 6.87 +/- 0.09% for simplified (n = 178) and intensive (n = 180) algorithms, respectively. Noninferiority between algorithms was not established. The fasting blood glucose (least squares mean +/- standard error) values for the simplified (137.27 +/- 3.42 mg/dL) and intensive (133.13 +/- 3.42 mg/dL) algorithms were comparable. Safety profiles were comparable. The hypoglycemic rate at 4, 8, 12, and 24 weeks was higher in patients receiving intensive titration (all P < .0001). The nocturnal hypoglycemic rate for patients receiving intensive titration was higher than for those receiving simplified titration at 8 (P < 0.015) and 12 weeks (P < 0.001). Noninferiority between the algorithms, as measured by A1C, was not demonstrated. This finding re-emphasizes the difficulty of identifying optimal, simplified insulin regimens for patients.

In vivo evaluation of the genetic toxicity of Rubus niveus Thunb. (Rosaceae) extract and initial screening of its potential chemoprevention against doxorubicin-induced DNA damage.

PubMed

Tolentino, Flora; Araújo, Priscila Alves de; Marques, Eduardo de Souza; Petreanu, Marcel; Andrade, Sérgio Faloni de; Niero, Rivaldo; Perazzo, Fábio F; Rosa, Paulo César Pires; Maistro, Edson Luis

2015-04-22

Rubus niveus Thunb. plant belongs to Rosaceae family and have been used traditionally to treat wounds, burns, inflammation, dysentery, diarrhea and for curing excessive bleeding during menstrual cycle. The present study was undertaken to investigate the in vivo genotoxicity of Rubus niveus aerial parts extract and its possible chemoprotection on doxorubicin (DXR)-induced DNA damage. In parallel, the main phytochemicals constituents in the extract were determined. The animals were exposed to the extract for 24 and 48 h, and the doses selected were 500, 1000 and 2000 mg/kg b.w. administered by gavage alone or prior to DXR (30 mg/kg b.w.) administered by intraperitoneal injection. The endpoints analyzed were DNA damage in bone marrow and peripheral blood cells assessed by the alkaline alkaline (pH>13) comet assay and bone marrow micronucleus test. The results of chemical analysis of the extract showed the presence of tormentic acid, stigmasterol, quercitinglucoronide (miquelianin) and niga-ichigoside F1 as main compounds. Both cytogenetic endpoints analyzed showed that there were no statistically significant differences (p>0.05) between the negative control and the treated groups with the two higher doses of Rubus niveus extract alone, demonstrating absence of genotoxic and mutagenic effects. Aneugenic/clastogenic effect was observed only at 2000 mg/kg dose. On the other hand, in the both assays and all tested doses were observed a significant reduction of DNA damage and chromosomal aberrations in all groups co-treated with DXR and extract compared to those which received only DXR. These results indicate that Rubus niveus aerial parts extract did not revealed any genotoxic effect, but presented some aneugenic/clastogenic effect at higher dose; and suggest that it could be a potential adjuvant against development of second malignant neoplasms caused by the cancer chemotherapic DXR. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Fetal progenitor cell transplantation treats methylmalonic aciduria in a mouse model

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

Buck, Nicole E., E-mail: nicole.buck@mcri.edu.au; Pennell, Samuel D.; Wood, Leonie R.

Highlights: Black-Right-Pointing-Pointer Fetal cells were transplanted into a methylmalonic acid mouse model. Black-Right-Pointing-Pointer Cell engraftment was detected in liver, spleen and bone marrow. Black-Right-Pointing-Pointer Biochemical disease correction was measured in blood samples. Black-Right-Pointing-Pointer A double dose of 5 million cells (1 week apart) proved more effective. Black-Right-Pointing-Pointer Higher levels of engraftment may be required for greater disease correction. -- Abstract: Methylmalonic aciduria is a rare disorder caused by an inborn error of organic acid metabolism. Current treatment options are limited and generally focus on disease management. We aimed to investigate the use of fetal progenitor cells to treat this disordermore » using a mouse model with an intermediate form of methylmalonic aciduria. Fetal liver cells were isolated from healthy fetuses at embryonic day 15-17 and intravenously transplanted into sub-lethally irradiated mice. Liver donor cell engraftment was determined by PCR. Disease correction was monitored by urine and blood methylmalonic acid concentration and weight change. Initial studies indicated that pre-transplantation sub-lethal irradiation followed by transplantation with 5 million cells were suitable. We found that a double dose of 5 million cells (1 week apart) provided a more effective treatment. Donor cell liver engraftment of up to 5% was measured. Disease correction, as defined by a decrease in blood methylmalonic acid concentration, was effected in methylmalonic acid mice transplanted with a double dose of cells and who showed donor cell liver engraftment. Mean plasma methylmalonic acid concentration decreased from 810 {+-} 156 (sham transplanted) to 338 {+-} 157 {mu}mol/L (double dose of 5 million cells) while mean blood C3 carnitine concentration decreased from 20.5 {+-} 4 (sham transplanted) to 5.3 {+-} 1.9 {mu}mol/L (double dose of 5 million cells). In conclusion, higher levels of engraftment may be required for greater disease correction; however these studies show promising results for cell transplantation biochemical correction of a metabolic disorder.« less

A phase I/II trial of hydroxychloroquine in conjunction with radiation therapy and concurrent and adjuvant temozolomide in patients with newly diagnosed glioblastoma multiforme

PubMed Central

Rosenfeld, Myrna R; Ye, Xiaobu; Supko, Jeffrey G; Desideri, Serena; Grossman, Stuart A; Brem, Steven; Mikkelson, Tom; Wang, Daniel; Chang, Yunyoung C; Hu, Janice; McAfee, Quentin; Fisher, Joy; Troxel, Andrea B; Piao, Shengfu; Heitjan, Daniel F; Tan, Kay-See; Pontiggia, Laura; O’Dwyer, Peter J; Davis, Lisa E; Amaravadi, Ravi K

2014-01-01

Preclinical studies indicate autophagy inhibition with hydroxychloroquine (HCQ) can augment the efficacy of DNA-damaging therapy. The primary objective of this trial was to determine the maximum tolerated dose (MTD) and efficacy of HCQ in combination with radiation therapy (RT) and temozolomide (TMZ) for newly diagnosed glioblastoma (GB). A 3 + 3 phase I trial design followed by a noncomparative phase II study was conducted in GB patients after initial resection. Patients received HCQ (200 to 800 mg oral daily) with RT and concurrent and adjuvant TMZ. Quantitative electron microscopy and immunoblotting were used to assess changes in autophagic vacuoles (AVs) in peripheral blood mononuclear cells (PBMC). Population pharmacokinetic (PK) modeling enabled PK-pharmacodynamic correlations. Sixteen phase I subjects were evaluable for dose-limiting toxicities. At 800 mg HCQ/d, 3/3 subjects experienced Grade 3 and 4 neutropenia and thrombocytopenia, 1 with sepsis. HCQ 600 mg/d was found to be the MTD in this combination. The phase II cohort (n = 76) had a median survival of 15.6 mos with survival rates at 12, 18, and 24 mo of 70%, 36%, and 25%. PK analysis indicated dose-proportional exposure for HCQ. Significant therapy-associated increases in AV and LC3-II were observed in PBMC and correlated with higher HCQ exposure. These data establish that autophagy inhibition is achievable with HCQ, but dose-limiting toxicity prevented escalation to higher doses of HCQ. At HCQ 600 mg/d, autophagy inhibition was not consistently achieved in patients treated with this regimen, and no significant improvement in overall survival was observed. Therefore, a definitive test of the role of autophagy inhibition in the adjuvant setting for glioma patients awaits the development of lower-toxicity compounds that can achieve more consistent inhibition of autophagy than HCQ. PMID:24991840

A phase I/II trial of hydroxychloroquine in conjunction with radiation therapy and concurrent and adjuvant temozolomide in patients with newly diagnosed glioblastoma multiforme.

PubMed

Rosenfeld, Myrna R; Ye, Xiaobu; Supko, Jeffrey G; Desideri, Serena; Grossman, Stuart A; Brem, Steven; Mikkelson, Tom; Wang, Daniel; Chang, Yunyoung C; Hu, Janice; McAfee, Quentin; Fisher, Joy; Troxel, Andrea B; Piao, Shengfu; Heitjan, Daniel F; Tan, Kay-See; Pontiggia, Laura; O'Dwyer, Peter J; Davis, Lisa E; Amaravadi, Ravi K

2014-08-01

Preclinical studies indicate autophagy inhibition with hydroxychloroquine (HCQ) can augment the efficacy of DNA-damaging therapy. The primary objective of this trial was to determine the maximum tolerated dose (MTD) and efficacy of HCQ in combination with radiation therapy (RT) and temozolomide (TMZ) for newly diagnosed glioblastoma (GB). A 3 + 3 phase I trial design followed by a noncomparative phase II study was conducted in GB patients after initial resection. Patients received HCQ (200 to 800 mg oral daily) with RT and concurrent and adjuvant TMZ. Quantitative electron microscopy and immunoblotting were used to assess changes in autophagic vacuoles (AVs) in peripheral blood mononuclear cells (PBMC). Population pharmacokinetic (PK) modeling enabled PK-pharmacodynamic correlations. Sixteen phase I subjects were evaluable for dose-limiting toxicities. At 800 mg HCQ/d, 3/3 subjects experienced Grade 3 and 4 neutropenia and thrombocytopenia, 1 with sepsis. HCQ 600 mg/d was found to be the MTD in this combination. The phase II cohort (n = 76) had a median survival of 15.6 mos with survival rates at 12, 18, and 24 mo of 70%, 36%, and 25%. PK analysis indicated dose-proportional exposure for HCQ. Significant therapy-associated increases in AV and LC3-II were observed in PBMC and correlated with higher HCQ exposure. These data establish that autophagy inhibition is achievable with HCQ, but dose-limiting toxicity prevented escalation to higher doses of HCQ. At HCQ 600 mg/d, autophagy inhibition was not consistently achieved in patients treated with this regimen, and no significant improvement in overall survival was observed. Therefore, a definitive test of the role of autophagy inhibition in the adjuvant setting for glioma patients awaits the development of lower-toxicity compounds that can achieve more consistent inhibition of autophagy than HCQ.

Retrospective evaluation of xylitol ingestion in dogs: 192 cases (2007-2012).

PubMed

DuHadway, Meghan R; Sharp, Claire R; Meyers, Katherine E; Koenigshof, Amy M

2015-01-01

To summarize the signalment, clinical signs, prevalence of decreased blood glucose concentration (BG), prevalence of increased liver values, treatment, and outcome in dogs known to have ingested xylitol. Retrospective study from December 2007 to February 2012 SETTING: Three university teaching hospitals. One hundred ninety-two client-owned dogs with known or suspected xylitol ingestion. None. The median ingested xylitol dose was 0.32 g/kg (range 0.03-3.64 g/kg). Clinical signs were present in 39 (20%) dogs on presentation to the veterinary teaching hospitals. The most common clinical sign was vomiting (n = 25), followed by lethargy (12). The median duration of clinical signs prior to presentation was 93 minutes (range 0-5,040 minutes). Dogs that developed clinical signs ingested a significantly higher dose of xylitol than those that were asymptomatic. Thirty dogs became hypoglycemic (BG ≤ 3.3 mmol/L [60 mg/dL]) at some time point during their hospitalization. When evaluating all dogs, there was a significant difference between the initial and lowest BGs. Thirty dogs had increased alanine aminotransferase activity or total serum bilirubin concentration. Dogs with increases in alanine aminotransferase activity or total serum bilirubin concentration had a significantly lower nadir BG. All dogs survived to discharge and 158 were known to be alive at 28 days. The rest were lost to follow up. The prognosis for dogs evaluated by a veterinarian that ingest lower doses of xylitol and do not develop liver failure is excellent. Dogs ingesting xylitol should be hospitalized and monitored for variations in BG, because BG drops in most dogs following presentation. Additional studies are needed in dogs ingesting higher doses of xylitol before correlations between dose and the development of clinical signs or liver failure can be established. Treatment and prognosis for these dogs warrants further investigation. © Veterinary Emergency and Critical Care Society 2015.

Whole-body CT-based imaging algorithm for multiple trauma patients: radiation dose and time to diagnosis

PubMed Central

Gordic, S; Hodel, S; Simmen, H-P; Brueesch, M; Frauenfelder, T; Wanner, G; Sprengel, K

2015-01-01

Objective: To determine the number of imaging examinations, radiation dose and the time to complete trauma-related imaging in multiple trauma patients before and after introduction of whole-body CT (WBCT) into early trauma care. Methods: 120 consecutive patients before and 120 patients after introduction of WBCT into the trauma algorithm of the University Hospital Zurich were compared regarding the number and type of CT, radiography, focused assessment with sonography for trauma (FAST), additional CT examinations (defined as CT of the same body regions after radiography and/or FAST) and the time to complete trauma-related imaging. Results: In the WBCT cohort, significantly more patients underwent CT of the head, neck, chest and abdomen (p < 0.001) than in the non-WBCT cohort, whereas the number of radiographic examinations of the cervical spine, chest and pelvis and of FAST examinations were significantly lower (p < 0.001). There were no significant differences between cohorts regarding the number of radiographic examinations of the upper (p = 0.56) and lower extremities (p = 0.30). We found significantly higher effective doses in the WBCT (29.5 mSv) than in the non-WBCT cohort (15.9 mSv; p < 0.001), but fewer additional CT examinations for completing the work-up were needed in the WBCT cohort (p < 0.001). The time to complete trauma-related imaging was significantly shorter in the WBCT (12 min) than in the non-WBCT cohort (75 min; p < 0.001). Conclusion: Including WBCT in the initial work-up of trauma patients results in higher radiation doses, but fewer additional CT examinations are needed, and the time for completing trauma-related imaging is shorter. Advances in knowledge: WBCT in trauma patients is associated with a high radiation dose of 29.5 mSv. PMID:25594105

Targeting higher ferritin concentrations with intravenous iron dextran lowers erythropoietin requirement in hemodialysis patients.

PubMed

DeVita, M V; Frumkin, D; Mittal, S; Kamran, A; Fishbane, S; Michelis, M F

2003-11-01

Although clinical use of recombinant human erythropoietin (rHuEPO) since 1989 has improved anemia in most end-stage renal disease patients, there are still many hemodialysis patients unable to maintain an adequate hematocrit (HCT) without large doses of rHuEPO. This suggests that anemia is not solely a consequence of rHuEPO deficiency, but may be due to other factors including functional iron deficiency. Since the optimal prescription for iron replacement is not yet known, we evaluated the effect of intravenous iron dextran (IVFe) infusion on serum ferritin (SFer) concentration and rHuEPO dose. Our objective was to raise and maintain serum ferritin concentrations to 2 different levels above the National Kidney Foundation Dialysis Outcome Quality Initiative standard of 100 ng/ml to determine whether, and by what degree rHuEPO dose could be lowered. HD patients on i.v. rHuEPO with a SFer concentration > or = 70 ng/ml and an HCT of < or = 33% were enrolled. Subjects were divided as follows: Group 1: target SFer of 200 ng/ml, Group 2: target SFer of 400 ng/ml. Each subject below the target level received IVFe in up to 10 divided doses during consecutive dialysis sessions as needed to reach the target. HCT was maintained between 32.5% and 36% by adjusting rHuEPO dosage. Mean SFer concentration at the study conclusion in Group 1: 261 ng/ml; Group 2: 387 ng/ml. The mean decrease in rHuEPO dose for Group 1 was 31 U/kg body weight/week (250 - 219 U/kg bw/wk) while in Group 2 it was 154 U/kg body weight/week (312 - 158 U/kg bw/wk) (p < 0.001). There was no difference in HCT between groups. Our results suggest that higher target serum ferritin concentrations can be well tolerated and lower rHuEPO requirements.

Early Adoption of HPV Vaccine among Hispanic Adolescent Males in the United States

PubMed Central

Reiter, Paul L.; Brewer, Noel T.; Gilkey, Melissa B.; Katz, Mira L.; Paskett, Electra D.; Smith, Jennifer S.

2015-01-01

Background Human papillomavirus (HPV) infection is common among Hispanic males, but little is known about HPV vaccination in this population. We examined the early adoption of HPV vaccine among a national sample of Hispanic adolescent males. Methods We analyzed provider-verified HPV vaccination data from the 2010–2012 National Immunization Survey-Teen (NIS-Teen) for Hispanic males ages 13–17 (n=4,238). Weighted logistic regression identified correlates of HPV vaccine initiation (receipt of one or more doses). Results HPV vaccine initiation was 17.1% overall, increasing from 2.8% in 2010 to 31.7% in 2012 (p<0.0001). Initiation was higher among sons whose parents had received a provider recommendation to vaccinate compared to those whose parents had not (53.3% vs. 9.0%; OR=8.77, 95% CI: 6.05–12.70). Initiation was also higher among sons who had visited a healthcare provider in the previous year (OR=2.42, 95% CI: 1.39–4.23). Among parents with unvaccinated sons, Spanish-speaking parents reported much higher intent to vaccinate compared to English-speaking parents (means: 3.52 vs. 2.54, p<0.0001). Spanish-speaking parents were more likely to indicate lack of knowledge (32.9% vs. 19.9%) and not having received a provider recommendation (32.2% vs. 17.7%) as a main reason for not intending to vaccinate (both p<0.05). Conclusions HPV vaccination among Hispanic adolescent males has increased substantially in recent years. Ensuring healthcare visits and provider recommendation will be key for continuing this trend. Preferred language may also be important for increasing HPV vaccination and addressing potential barriers to vaccination. PMID:24948439

Oral matrix tablet formulations for concomitant controlled release of anti-tubercular drugs: design and in vitro evaluations.

PubMed

Hiremath, Praveen S; Saha, Ranendra N

2008-10-01

The aim of the present investigation was to develop controlled release (C.R.) matrix tablet formulations of rifampicin and isoniazid combination, to study the design parameters and to evaluate in vitro release characteristics. In the present study, a series of formulations were developed with different release rates and duration using hydrophilic polymers hydroxypropyl methylcellulose (HPMC) and hydroxypropyl cellulose (HPC). The duration of rifampicin and isoniazid release could be tailored by varying the polymer type, polymer ratio and processing techniques. Further, Eudragit L100-55 was incorporated in the matrix tablets to compensate for the pH-dependent release of rifampicin. Rifampicin was found to follow linear release profile with time from HPMC formulations. In case of formulations with HPC, there was an initial higher release in simulated gastric fluid (SGF) followed by zero order release profiles in simulated intestinal fluid (SIFsp) for rifampicin. The release of isoniazid was found to be predominantly by diffusion mechanism in case of HPMC formulations, and with HPC formulations release was due to combination of diffusion and erosion. The initial release was sufficiently higher for rifampicin from HPC thus ruling out the need to incorporate a separate loading dose. The initial release was sufficiently higher for isoniazid in all formulations. Thus, with the use of suitable polymer or polymer combinations and with the proper optimization of the processing techniques it was possible to design the C.R. formulations of rifampicin and isoniazid combination that could provide the sufficient initial release and release extension up to 24h for both the drugs despite of the wide variations in their physicochemical properties.

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

Son, Christina H.; Law, Ethel; Oh, Jung Hun

Purpose: Although vaginal stenosis (VS) is a recognized toxicity in women who receive pelvic radiation therapy (RT), the relationship between RT dose and the volume and extent of toxicity has not been analyzed. We modeled this relationship to identify predictors of VS. Methods and Materials: We evaluated 54 women, aged 29 to 78 years, who underwent pelvic RT for rectal or anal cancer during 2008 to 2011 and were enrolled in a prospective study evaluating vaginal dilator use. Maximum dilator size was measured before RT (baseline) and 1 month and 12 months after RT. Dilator use was initiated at 1 month. The difference (D)more » in dilator size before and after RT was recorded. Those with D ≤−1 were classified as having VS (n=35); those with D ≥0 were classified as having no VS (n=19 at 1 month). Dose-volume parameters were extracted, and the generalized equivalent uniform dose (gEUD) was used to build a predictive model. Results: The mean vaginal doses were 50.0 Gy and 36.8 Gy for anal and rectal cancer patients, respectively. One month after RT, a gEUD model using a wide range of a values suggests that sparing of vaginal volume to a low dose may be important. When gEUD (a = −1) was <35 Gy and the mean vaginal dose was <43 Gy, severe VS was reduced (P=.02). A 1-year analysis suggests increasingly negative D values with increasing mean dose. However, patients with compliance <40% were more likely to have toxicity. Conclusions: Vaginal stenosis is influenced by multiple RT dose-volume characteristics. Mean dose and gEUD constraints together may reduce the risk of severe VS. Patients receiving higher mean vaginal doses should have greater compliance with dilator therapy to minimize risk of toxicity. Further validation with independent datasets is needed.« less

TU-AB-303-12: Towards Inter and Intra Fraction Plan Adaptation for the MR-Linac

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

Kontaxis, C; Bol, G; Lagendijk, J

Purpose: To develop a new sequencer for IMRT that during treatment can account for anatomy changes provided by online and real-time MRI. This sequencer employs a novel inter and intra fraction scheme that converges to the prescribed dose without a final segment weight optimization (SWO) and enables immediate optimization and delivery of radiation adapted to the deformed anatomy. Methods: The sequencer is initially supplied with a voxel-based dose prescription and during the optimization iteratively generates segments that provide this prescribed dose. Every iteration selects the best segment for the current anatomy state, calculates the dose it will deliver, warps itmore » back to the reference prescription grid and subtracts it from the remaining prescribed dose. This process continues until a certain percentage of dose or a number of segments has been delivered. The anatomy changes that occur during treatment require that convergence is achieved without a final SWO. This is resolved by adding the difference between the prescribed and delivered dose up to this fraction to the prescription of the subsequent fraction. This process is repeated for all fractions of the treatment. Results: Two breast cases were selected to stress test the pipeline by producing artificial inter and intra fraction anatomy deformations using a combination of incrementally applied rigid transformations. The dose convergence of the adaptive scheme over the entire treatment, relative to the prescribed dose, was on average 8.6% higher than the static plans delivered to the respective deformed anatomies and only 1.6% less than the static segment weighted plans on the static anatomy. Conclusion: This new adaptive sequencing strategy enables dose convergence without the need of SWO while adapting the plan to intermediate anatomies, which is a prerequisite for online plan adaptation. We are now testing our pipeline on prostate cases using clinical anatomy deformation data from our department. This work is financially supported by Elekta AB, Stockholm, Sweden.« less

Multi-component assessment of chronic obstructive pulmonary disease: an evaluation of the ADO and DOSE indices and the global obstructive lung disease categories in international primary care data sets

PubMed Central

Jones, Rupert C; Price, David; Chavannes, Niels H; Lee, Amanda J; Hyland, Michael E; Ställberg, Björn; Lisspers, Karin; Sundh, Josefin; van der Molen, Thys; Tsiligianni, Ioanna

2016-01-01

Suitable tools for assessing the severity of chronic obstructive pulmonary disease (COPD) include multi-component indices and the global initiative for chronic obstructive lung disease (GOLD) categories. The aim of this study was to evaluate the dyspnoea, obstruction, smoking, exacerbation (DOSE) and the age, dyspnoea, obstruction (ADO) indices and GOLD categories as measures of current health status and future outcomes in COPD patients. This was an observational cohort study comprising 5,114 primary care COPD patients across three databases from UK, Sweden and Holland. The associations of DOSE and ADO indices with (i) health status using the Clinical COPD Questionnaire (CCQ) and St George’s Respiratory Questionnaire (SGRQ) and COPD Assessment test (CAT) and with (ii) current and future exacerbations, admissions and mortality were assessed in GOLD categories and DOSE and ADO indices. DOSE and ADO indices were significant predictors of future exacerbations: incident rate ratio was 1.52 (95% confidence intervals 1.46–1.57) for DOSE, 1.16 (1.12–1.20) for ADO index and 1.50 (1.33–1.68) and 1.23 (1.10–1.39), respectively, for hospitalisations. Negative binomial regression showed that the DOSE index was a better predictor of future admissions than were its component items. The hazard ratios for mortality were generally higher for ADO index groups than for DOSE index groups. The GOLD categories produced widely differing assessments for future exacerbation risk or for hospitalisation depending on the methods used to calculate them. None of the assessment systems were excellent at predicting future risk in COPD; the DOSE index appears better than the ADO index for predicting many outcomes, but not mortality. The GOLD categories predict future risk inconsistently. The DOSE index and the GOLD categories using exacerbation frequency may be used to identify those at high risk for exacerbations and admissions. PMID:27053297

Multi-component assessment of chronic obstructive pulmonary disease: an evaluation of the ADO and DOSE indices and the global obstructive lung disease categories in international primary care data sets.

PubMed

Jones, Rupert C; Price, David; Chavannes, Niels H; Lee, Amanda J; Hyland, Michael E; Ställberg, Björn; Lisspers, Karin; Sundh, Josefin; van der Molen, Thys; Tsiligianni, Ioanna

2016-04-07

Suitable tools for assessing the severity of chronic obstructive pulmonary disease (COPD) include multi-component indices and the global initiative for chronic obstructive lung disease (GOLD) categories. The aim of this study was to evaluate the dyspnoea, obstruction, smoking, exacerbation (DOSE) and the age, dyspnoea, obstruction (ADO) indices and GOLD categories as measures of current health status and future outcomes in COPD patients. This was an observational cohort study comprising 5,114 primary care COPD patients across three databases from UK, Sweden and Holland. The associations of DOSE and ADO indices with (i) health status using the Clinical COPD Questionnaire (CCQ) and St George's Respiratory Questionnaire (SGRQ) and COPD Assessment test (CAT) and with (ii) current and future exacerbations, admissions and mortality were assessed in GOLD categories and DOSE and ADO indices. DOSE and ADO indices were significant predictors of future exacerbations: incident rate ratio was 1.52 (95% confidence intervals 1.46-1.57) for DOSE, 1.16 (1.12-1.20) for ADO index and 1.50 (1.33-1.68) and 1.23 (1.10-1.39), respectively, for hospitalisations. Negative binomial regression showed that the DOSE index was a better predictor of future admissions than were its component items. The hazard ratios for mortality were generally higher for ADO index groups than for DOSE index groups. The GOLD categories produced widely differing assessments for future exacerbation risk or for hospitalisation depending on the methods used to calculate them. None of the assessment systems were excellent at predicting future risk in COPD; the DOSE index appears better than the ADO index for predicting many outcomes, but not mortality. The GOLD categories predict future risk inconsistently. The DOSE index and the GOLD categories using exacerbation frequency may be used to identify those at high risk for exacerbations and admissions.

Evaluation of an artificial intelligence guided inverse planning system: clinical case study.

PubMed

Yan, Hui; Yin, Fang-Fang; Willett, Christopher

2007-04-01

An artificial intelligence (AI) guided method for parameter adjustment of inverse planning was implemented on a commercial inverse treatment planning system. For evaluation purpose, four typical clinical cases were tested and the results from both plans achieved by automated and manual methods were compared. The procedure of parameter adjustment mainly consists of three major loops. Each loop is in charge of modifying parameters of one category, which is carried out by a specially customized fuzzy inference system. A physician prescribed multiple constraints for a selected volume were adopted to account for the tradeoff between prescription dose to the PTV and dose-volume constraints for critical organs. The searching process for an optimal parameter combination began with the first constraint, and proceeds to the next until a plan with acceptable dose was achieved. The initial setup of the plan parameters was the same for each case and was adjusted independently by both manual and automated methods. After the parameters of one category were updated, the intensity maps of all fields were re-optimized and the plan dose was subsequently re-calculated. When final plan arrived, the dose statistics were calculated from both plans and compared. For planned target volume (PTV), the dose for 95% volume is up to 10% higher in plans using the automated method than those using the manual method. For critical organs, an average decrease of the plan dose was achieved. However, the automated method cannot improve the plan dose for some critical organs due to limitations of the inference rules currently employed. For normal tissue, there was no significant difference between plan doses achieved by either automated or manual method. With the application of AI-guided method, the basic parameter adjustment task can be accomplished automatically and a comparable plan dose was achieved in comparison with that achieved by the manual method. Future improvements to incorporate case-specific inference rules are essential to fully automate the inverse planning process.

Microfluidic Thrombosis under Multiple Shear Rates and Antiplatelet Therapy Doses

PubMed Central

Ku, David N.; Forest, Craig R.

2014-01-01

The mainstay of treatment for thrombosis, the formation of occlusive platelet aggregates that often lead to heart attack and stroke, is antiplatelet therapy. Antiplatelet therapy dosing and resistance are poorly understood, leading to potential incorrect and ineffective dosing. Shear rate is also suspected to play a major role in thrombosis, but instrumentation to measure its influence has been limited by flow conditions, agonist use, and non-systematic and/or non-quantitative studies. In this work we measured occlusion times and thrombus detachment for a range of initial shear rates (500, 1500, 4000, and 10000 s−1) and therapy concentrations (0–2.4 µM for eptifibatide, 0–2 mM for acetyl-salicylic acid (ASA), 3.5–40 Units/L for heparin) using a microfluidic device. We also measured complete blood counts (CBC) and platelet activity using whole blood impedance aggregometry. Effects of shear rate and dose were analyzed using general linear models, logistic regressions, and Cox proportional hazards models. Shear rates have significant effects on thrombosis/dose-response curves for all tested therapies. ASA has little effect on high shear occlusion times, even at very high doses (up to 20 times the recommended dose). Under ASA therapy, thrombi formed at high shear rates were 4 times more prone to detachment compared to those formed under control conditions. Eptifibatide reduced occlusion when controlling for shear rate and its efficacy increased with dose concentration. In contrast, the hazard of occlusion from ASA was several orders of magnitude higher than that of eptifibatide. Our results show similar dose efficacy to our low shear measurements using whole blood aggregometry. This quantitative and statistically validated study of the effects of a wide range of shear rate and antiplatelet therapy doses on occlusive thrombosis contributes to more accurate understanding of thrombosis and to models for optimizing patient treatment. PMID:24404131

Randomized controlled trial of letrozole, berberine, or a combination for infertility in the polycystic ovary syndrome.

PubMed

Wu, Xiao-Ke; Wang, Yong-Yan; Liu, Jian-Ping; Liang, Rui-Ning; Xue, Hui-Ying; Ma, Hong-Xia; Shao, Xiao-Guang; Ng, Ernest H Y

2016-09-01

To study whether a combination of berberine and letrozole results in higher live births than letrozole alone in infertile women with polycystic ovary syndrome (PCOS). A multicenter randomized double-blinded placebo-controlled trial. Reproductive and developmental network sites. Eligible women had PCOS as defined by the Rotterdam criteria. We enrolled 644 participants randomized 1:1:1 among letrozole, berberine, and combination groups. Berberine or berberine placebo were administrated orally at a daily dose of 1.5 g for up to 6 months. Patients received an initial dose of 2.5 mg letrozole or placebo on days 3-7 of the first three treatment cycles. This dose was increased to 5 mg on the last three cycles if not pregnant. Cumulative live births. The cumulative live births were similar between the letrozole and combination groups after treatment (36% and 34%), and were superior to those in the berberine group (22%). Likely, conception, pregnancy, and ovulation rates were similar between the letrozole and combination groups, and these were significantly higher than in the berberine group. There was one twin birth in the letrozole group, three twin births in the combination group, and none in the berberine group. Berberine did not add fecundity in PCOS when used in combination with the new ovulation agent letrozole. ChiCTR-TRC-09000376 (http://apps.who.int/trialsearch/). Copyright © 2016. Published by Elsevier Inc.

Feasibility of using optical coherence tomography to detect acute radiation-induced esophageal damage in small animal models

NASA Astrophysics Data System (ADS)

Jelvehgaran, Pouya; de Bruin, Daniel Martijn; Salguero, F. Javier; Borst, Gerben Roelof; Song, Ji-Ying; van Leeuwen, Ton G.; de Boer, Johannes F.; Alderliesten, Tanja; van Herk, Marcel

2018-04-01

Lung cancer survival is poor, and radiation therapy patients often suffer serious treatment side effects. The esophagus is particularly sensitive leading to acute radiation-induced esophageal damage (ARIED). We investigated the feasibility of optical coherence tomography (OCT) for minimally invasive imaging of the esophagus with high resolution (10 μm) to detect ARIED in mice. Thirty mice underwent cone-beam computed tomography imaging for initial setup assessment and dose planning followed by a single-dose delivery of 4.0, 10.0, 16.0, and 20.0 Gy on 5.0-mm spots, spaced 10.0 mm apart in the esophagus. They were repeatedly imaged using OCT up to three months postirradiation. We compared OCT findings with histopathology obtained three months postirradiation qualitatively and quantitatively using the contrast-to-background-noise ratio (CNR). Histopathology mostly showed inflammatory infiltration and edema at higher doses; OCT findings were in agreement with most of the histopathological reports. We were able to identify the ARIED on OCT as a change in tissue scattering and layer thickness. Our statistical analysis showed significant difference between the CNR values of healthy tissue, edema, and inflammatory infiltration. Overall, the average CNR for inflammatory infiltration and edema damages was 1.6-fold higher and 1.6-fold lower than for the healthy esophageal wall, respectively. Our results showed the potential role of OCT to detect and monitor the ARIED in mice, which may translate to humans.

The effects of two different doses of hydrocortisone on cognition in patients with secondary adrenal insufficiency--results from a randomized controlled trial.

PubMed

Werumeus Buning, Jorien; Brummelman, Pauline; Koerts, Janneke; Dullaart, Robin P F; van den Berg, Gerrit; van der Klauw, Melanie M; Tucha, Oliver; Wolffenbuttel, Bruce H R; van Beek, André P

2015-05-01

A wide variety in hydrocortisone (HC) substitution dose-regimens are considered physiological for patients with secondary adrenal insufficiency (SAI). However, it is likely that cognition is negatively influenced by higher cortisol exposure to the brain. To examine the effects of a high physiological HC dose in comparison to a low physiological HC dose on cognition. This study was a randomized double blind cross-over study at the University Medical Center Groningen. This study is registered with ClinicalTrials.gov, number NCT01546922. Forty-seven patients (29 males, 18 females; mean [SD] age, 51 [14] years, range 19-73) with SAI participated. Patients randomly received first a low dose of HC (0.2-0.3 mg/kg body weight/day) during 10 weeks followed by a high dose (0.4-0.6 mg/kg body weight/day) for another 10 weeks, or vice versa. HC substitution was given in three divided doses with the highest dose in the morning. Cognitive performance (memory, attention, executive functioning and social cognition) of patients was measured at baseline and after each treatment period using a battery of 12 standardized cognitive tests. The higher dose of HC resulted in significantly higher systemic cortisol exposure for example measured at 1h after first dose ingestion (mean [SD], low dose: 653 [281] nmol/L; high dose: 930 [148] nmol/L; P<0.001). No differences in cognitive performance were found between the two dose regimens. No negative influence on memory, attention, executive functioning and social cognition was observed after 10 weeks of treatment with a higher physiological dose of HC in patients with SAI when compared to a lower dose. Copyright © 2015 Elsevier Ltd. All rights reserved.

Pediatric defibrillation after cardiac arrest: initial response and outcome

PubMed Central

Rodríguez-Núñez, Antonio; López-Herce, Jesús; García, Cristina; Domínguez, Pedro; Carrillo, Angel; Bellón, Jose María

2006-01-01

Introduction Shockable rhythms are rare in pediatric cardiac arrest and the results of defibrillation are uncertain. The objective of this study was to analyze the results of cardiopulmonary resuscitation that included defibrillation in children. Methods Forty-four out of 241 children (18.2%) who were resuscitated from inhospital or out-of-hospital cardiac arrest had been treated with manual defibrillation. Data were recorded according to the Utstein style. Outcome variables were a sustained return of spontaneous circulation (ROSC) and one-year survival. Characteristics of patients and of resuscitation were evaluated. Results Cardiac disease was the major cause of arrest in this group. Ventricular fibrillation (VF) or pulseless ventricular tachycardia (PVT) was the first documented electrocardiogram rhythm in 19 patients (43.2%). A shockable rhythm developed during resuscitation in 25 patients (56.8%). The first shock (dose, 2 J/kg) terminated VF or PVT in eight patients (18.1%). Seventeen children (38.6%) needed more than three shocks to solve VF or PVT. ROSC was achieved in 28 cases (63.6%) and it was sustained in 19 patients (43.2%). Only three patients (6.8%), however, survived at 1-year follow-up. Children with VF or PVT as the first documented rhythm had better ROSC, better initial survival and better final survival than children with subsequent VF or PVT. Children who survived were older than the finally dead patients. No significant differences in response rate were observed when first and second shocks were compared. The survival rate was higher in patients treated with a second shock dose of 2 J/kg than in those who received higher doses. Outcome was not related to the cause or the location of arrest. The survival rate was inversely related to the duration of cardiopulmonary resuscitation. Conclusion Defibrillation is necessary in 18% of children who suffer cardiac arrest. Termination of VF or PVT after the first defibrillation dose is achieved in a low percentage of cases. Despite a sustained ROSC being obtained in more than one-third of cases, the final survival remains low. The outcome is very poor when a shockable rhythm develops during resuscitation efforts. New studies are needed to ascertain whether the new international guidelines will contribute to improve the outcome of pediatric cardiac arrest. PMID:16882339

Induction and repair of DNA strand breaks in bovine lens epithelial cells after high LET irradiation

NASA Astrophysics Data System (ADS)

Baumstark-Khan, C.; Heilmann, J.; Rink, H.

The lens epithelium is the initiation site for the development of radiation induced cataracts. While in the cortex and nucleus radiation interacts with proteins, experimental results from cultured lenses and lens epithelial cells demonstrate mutagenic and cytotoxic effects in the epithelium. It is suggested that incorrectly repaired DNA damage may be lethal in terms of cellular reproduction and also may initiate the development of mutations or transformations in surviving cells. The occurrence of such genetically modified cells may lead to lens opacification. For a quantitative risk estimation for astronauts and space travelers it is necessary to know the radiation's relative biological effectiveness (RBE), because cosmic rays differ significantly from X-rays. RBEs for the induction of DNA strand breaks and the efficiency of repair of these breaks were measured in cultured diploid bovine lens epithelial cells exposed to different LET irradiations. Irradiations were performed either with 300 kV X-rays or at the UNILAC accelerator at GSI. Accelerated ions from Z=8 (O) to Z=92 (U) were used. For strand break measurements hydroxyapatite chromatography of alka-line unwound DNA (overall strand breaks) and non-denaturing filter elution technique (double strand breaks) were applied. Experiments showed that DNA damage occurs as a function of dose, of kinetic energy and of LET. For particles having the same LET the severity of the DNA damage increases with dose. For a given particle dose, as the LET rises, the numbers of DNA strand breaks increase to a maximum and then reach a plateau or decrease. Repair kinetics depend on the fluence (irradiation dose). At any LET value, repair is much slower after heavy ion exposure than after X-irradiation. For ions with an LET of less than 10,000 keV/μm more than 90 percent of the strand breaks induced are repaired within 24 hours. At higher particle fluences, especially for low energetic particles with a very high local density of energy deposition within the particle track, a higher proportion of non-rejoined breaks is found, even after prolonged periods of incubation. At the highest LET value (16,300 keV/μm) no significant repair is observed. These observations are consistent with the current theory of the mechanism of radiation induced cataractogenesis which posts that genomic damage to the epithelial cells surviving the exposure is responsible for lens opacification.

Definitive Reirradiation for Locoregionally Recurrent Non-Small Cell Lung Cancer With Proton Beam Therapy or Intensity Modulated Radiation Therapy: Predictors of High-Grade Toxicity and Survival Outcomes

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

McAvoy, Sarah; Ciura, Katherine; Wei, Caimiao

2014-11-15

Purpose: Intrathoracic recurrence of non-small cell lung cancer (NSCLC) after initial treatment remains a dominant cause of death. We report our experience using proton beam therapy and intensity modulated radiation therapy for reirradiation in such cases, focusing on patterns of failure, criteria for patient selection, and predictors of toxicity. Methods and Materials: A total of 102 patients underwent reirradiation for intrathoracic recurrent NSCLC at a single institution. All doses were recalculated to an equivalent dose in 2-Gy fractions (EQD2). All patients had received radiation therapy for NSCLC (median initial dose of 70 EQD2 Gy), with median interval to reirradiation ofmore » 17 months and median reirradiation dose of 60.48 EQD2 Gy. Median follow-up time was 6.5 months (range, 0-72 months). Results: Ninety-nine patients (97%) completed reirradiation. Median local failure-free survival, distant metastasis-free survival (DMFS), and overall survival times were 11.43 months (range, 8.6-22.66 months), 11.43 months (range, 6.83-23.84 months), and 14.71 (range, 10.34-20.56 months), respectively. Toxicity was acceptable, with rates of grade ≥3 esophageal toxicity of 7% and grade ≥3 pulmonary toxicity of 10%. Of the patients who developed local failure after reirradiation, 88% had failure in either the original or the reirradiation field. Poor local control was associated with T4 disease, squamous histology, and Eastern Cooperative Oncology Group performance status score >1. Concurrent chemotherapy improved DMFS, but T4 disease was associated with poor DMFS. Higher T status, Eastern Cooperative Oncology Group performance status ≥1, squamous histology, and larger reirradiation target volumes led to worse overall survival; receipt of concurrent chemotherapy and higher EQD2 were associated with improved OS. Conclusions: Intensity modulated radiation therapy and proton beam therapy are options for treating recurrent non-small cell lung cancer. However, rates of locoregional recurrence and distant metastasis are high, and patients should be selected carefully to maximize the benefit of additional aggressive local therapy while minimizing the risk of adverse side effects.« less

Comparison of dose volume parameters evaluated using three forward planning – optimization techniques in cervical cancer brachytherapy involving two applicators

PubMed Central

Basu-Roy, Somapriya; Kar, Sanjay Kumar; Das, Sounik; Lahiri, Annesha

2017-01-01

Purpose This study is intended to compare dose-volume parameters evaluated using different forward planning- optimization techniques, involving two applicator systems in intracavitary brachytherapy for cervical cancer. It looks for the best applicator-optimization combination to fulfill recommended dose-volume objectives in different high-dose-rate (HDR) fractionation schedules. Material and methods We used tandem-ring and Fletcher-style tandem-ovoid applicator in same patients in two fractions of brachytherapy. Six plans were generated for each patient utilizing 3 forward optimization techniques for each applicator used: equal dwell weight/times (‘no optimization’), ‘manual dwell weight/times’, and ‘graphical’. Plans were normalized to left point A and dose of 8 Gy was prescribed. Dose volume and dose point parameters were compared. Results Without graphical optimization, maximum width and thickness of volume enclosed by 100% isodose line, dose to 90%, and 100% of clinical target volume (CTV); minimum, maximum, median, and average dose to both rectum and bladder are significantly higher with Fletcher applicator. Even if it is done, dose to both points B, minimum dose to CTV, and treatment time; dose to 2 cc (D2cc) rectum and rectal point etc.; D2cc, minimum, maximum, median, and average dose to sigmoid colon; D2cc of bladder remain significantly higher with this applicator. Dose to bladder point is similar (p > 0.05) between two applicators, after all optimization techniques. Conclusions Fletcher applicator generates higher dose to both CTV and organs at risk (2 cc volumes) after all optimization techniques. Dose restriction to rectum is possible using graphical optimization only during selected HDR fractionation schedules. Bladder always receives dose higher than recommended, and 2 cc sigmoid colon always gets permissible dose. Contrarily, graphical optimization with ring applicators fulfills all dose volume objectives in all HDR fractionations practiced. PMID:29204164

The influence of angiotensin converting enzyme inhibitors on lipid peroxidation in sera and aorta of rabbits in diet-induced hypercholesterolemia.

PubMed

Wojakowski, W; Gminski, J; Siemianowicz, K; Goss, M; Machalski, M

2000-11-01

In hypercholesterolemia increased lipid and lipoprotein peroxidation occurs. The renin-angiotensin system plays an important role in atherogenesis. Angiotensin II induces smooth muscle cells proliferation and stimulates oxidation of LDL particles and foam cell accumulation. Inhibition of ang II production leads to decrease in lipid peroxide production. The aim of this study was to assess the lipid peroxidation expressed as concentration of thiobarbituric acid reactive species (TBARS) in sera and aorta homogenates after administration of two doses of angiotensin-converting enzyme (ACE) inhibitors (captopril, enalapril and quinapril) in diet-induced hypercholesterolemia in rabbits. Sixty-four New Zealand rabbits were used. Animals were fed with standard fodder, special diet (1% cholesterol content) or special diet + tested ACEI. Two doses of ACE inhibitors were used: i), equivalent to applied to humans, ii), dose 10 times higher. The animals were divided into 8 groups: control, standard fodder; B, special diet; C1, C2, special diet + captopril in doses 2.5 and 25 mg/kg/24 h, respectively; E1, E2, special diet + enalapril in doses 0.75 and 7.5 mg/kg/24 h, respectively; Q1 and Q2, special diet + quinapril in doses 0.75 and 7.5 mg/kg per day, respectively. In cholesterol-fed rabbits and in groups receiving lower doses of tested ACE inhibitors, the serum TBARS concentration at 6 months was significantly higher in comparison to the control. The higher doses of enalapril, quinapril and captopril, prevented the cholesterol-induced rise in TBARS concentration. Lower dose of captopril attenuated the rise in TBARS concentration, it was significantly lower in comparison to group B, but higher than in the control group. In animals from groups B, E1, C1, Q1 TBARS concentration in aortae was significantly higher as compared to control group. Both doses of captopril and higher doses of enalapril and quinapril inhibited the rise of lipid peroxides concentration induced by cholesterol-rich diet.

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.

Safety and immunogenicity of modified vaccinia Ankara in hematopoietic stem cell transplant recipients: a randomized, controlled trial.

PubMed

Walsh, Stephen R; Wilck, Marissa B; Dominguez, David J; Zablowsky, Elise; Bajimaya, Shringkhala; Gagne, Lisa S; Verrill, Kelly A; Kleinjan, Jane A; Patel, Alka; Zhang, Ying; Hill, Heather; Acharyya, Aruna; Fisher, David C; Antin, Joseph H; Seaman, Michael S; Dolin, Raphael; Baden, Lindsey R

2013-06-15

Modified vaccinia Ankara (MVA-BN, IMVAMUNE) is emerging as a primary immunogen and as a delivery system to treat or prevent a wide range of diseases. Defining the safety and immunogenicity of MVA-BN in key populations is therefore important. We performed a dose-escalation study of MVA-BN administered subcutaneously in 2 doses, one on day 0 and another on day 28. Twenty-four hematopoietic stem cell transplant recipients were enrolled sequentially into the study, and vaccine or placebo was administered under a randomized, double-blind allocation. Ten subjects received vaccine containing 10(7) median tissue culture infective doses (TCID50) of MVA-BN, 10 subjects received vaccine containing 10(8) TCID50 of MVA-BN, and 4 subjects received placebo. MVA-BN was generally well tolerated at both doses. No vaccine-related serious adverse events were identified. Transient local reactogenicity was more frequently seen at the higher dose. Neutralizing antibodies (NAb) to Vaccinia virus (VACV) were elicited by both doses of MVA-BN and were greater for the higher dose. Median peak anti-VACV NAb titers were 1:49 in the lower-dose group and 1:118 in the higher-dose group. T-cell immune responses to VACV were detected by an interferon γ enzyme-linked immunosorbent spot assay and were higher in the higher-dose group. MVA-BN is safe, well tolerated, and immunogenic in HSCT recipients. These data support the use of 10(8) TCID50 of MVA-BN in this population. NCT00565929.

Mechanism for Clastogenic Activity of Naphthalene

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

Buchholz, Bruce A.

2016-06-24

Naphthalene incubations form DNA adducts in vitro in a dose dependent manner in both mouse and rat tissues. Rodent tissue incubations with naphthalene indicate that naphthalene forms as many DNA adducts as Benzo(a)pyrene, a known DNA binding carcinogen. The mouse airway has the greatest number of DNA adducts, corresponding to the higher metabolic activation of naphthalene in this location. Both rat tissues, the rat olfactory (tumor target) and the airways (non-tumor target), have similar levels of NA-DNA adducts, indicating that short term measures of initial adduct formation do not directly correlate with sites of tumor formation in the NTP bioassays.

The dosimetric effects of tissue heterogeneities in intensity-modulated radiation therapy (IMRT) of the head and neck

NASA Astrophysics Data System (ADS)

Al-Hallaq, H. A.; Reft, C. S.; Roeske, J. C.

2006-03-01

The dosimetric effects of bone and air heterogeneities in head and neck IMRT treatments were quantified. An anthropomorphic RANDO phantom was CT-scanned with 16 thermoluminescent dosimeter (TLD) chips placed in and around the target volume. A standard IMRT plan generated with CORVUS was used to irradiate the phantom five times. On average, measured dose was 5.1% higher than calculated dose. Measurements were higher by 7.1% near the heterogeneities and by 2.6% in tissue. The dose difference between measurement and calculation was outside the 95% measurement confidence interval for six TLDs. Using CORVUS' heterogeneity correction algorithm, the average difference between measured and calculated doses decreased by 1.8% near the heterogeneities and by 0.7% in tissue. Furthermore, dose differences lying outside the 95% confidence interval were eliminated for five of the six TLDs. TLD doses recalculated by Pinnacle3's convolution/superposition algorithm were consistently higher than CORVUS doses, a trend that matched our measured results. These results indicate that the dosimetric effects of air cavities are larger than those of bone heterogeneities, thereby leading to a higher delivered dose compared to CORVUS calculations. More sophisticated algorithms such as convolution/superposition or Monte Carlo should be used for accurate tailoring of IMRT dose in head and neck tumours.

Treatment Sequencing for Childhood ADHD: A Multiple-Randomization Study of Adaptive Medication and Behavioral Interventions.

PubMed

Pelham, William E; Fabiano, Gregory A; Waxmonsky, James G; Greiner, Andrew R; Gnagy, Elizabeth M; Pelham, William E; Coxe, Stefany; Verley, Jessica; Bhatia, Ira; Hart, Katie; Karch, Kathryn; Konijnendijk, Evelien; Tresco, Katy; Nahum-Shani, Inbal; Murphy, Susan A

2016-01-01

Behavioral and pharmacological treatments for children with attention deficit/hyperactivity disorder (ADHD) were evaluated to address whether endpoint outcomes are better depending on which treatment is initiated first and, in case of insufficient response to initial treatment, whether increasing dose of initial treatment or adding the other treatment modality is superior. Children with ADHD (ages 5-12, N = 146, 76% male) were treated for 1 school year. Children were randomized to initiate treatment with low doses of either (a) behavioral parent training (8 group sessions) and brief teacher consultation to establish a Daily Report Card or (b) extended-release methylphenidate (equivalent to .15 mg/kg/dose bid). After 8 weeks or at later monthly intervals as necessary, insufficient responders were rerandomized to secondary interventions that either increased the dose/intensity of the initial treatment or added the other treatment modality, with adaptive adjustments monthly as needed to these secondary treatments. The group beginning with behavioral treatment displayed significantly lower rates of observed classroom rule violations (the primary outcome) at study endpoint and tended to have fewer out-of-class disciplinary events. Further, adding medication secondary to initial behavior modification resulted in better outcomes on the primary outcomes and parent/teacher ratings of oppositional behavior than adding behavior modification to initial medication. Normalization rates on teacher and parent ratings were generally high. Parents who began treatment with behavioral parent training had substantially better attendance than those assigned to receive training following medication. Beginning treatment with behavioral intervention produced better outcomes overall than beginning treatment with medication.

Joint European League Against Rheumatism and European Renal Association–European Dialysis and Transplant Association (EULAR/ERA-EDTA) recommendations for the management of adult and paediatric lupus nephritis

PubMed Central

Bertsias, George K; Tektonidou, Maria; Amoura, Zahir; Aringer, Martin; Bajema, Ingeborg; Berden, Jo H M; Boletis, John; Cervera, Ricard; Dörner, Thomas; Doria, Andrea; Ferrario, Franco; Floege, Jürgen; Houssiau, Frederic A; Ioannidis, John P A; Isenberg, David A; Kallenberg, Cees G M; Lightstone, Liz; Marks, Stephen D; Martini, Alberto; Moroni, Gabriela; Neumann, Irmgard; Praga, Manuel; Schneider, Matthias; Starra, Argyre; Tesar, Vladimir; Vasconcelos, Carlos; van Vollenhoven, Ronald F; Zakharova, Helena; Haubitz, Marion; Gordon, Caroline; Jayne, David; Boumpas, Dimitrios T

2012-01-01

Objectives To develop recommendations for the management of adult and paediatric lupus nephritis (LN). Methods The available evidence was systematically reviewed using the PubMed database. A modified Delphi method was used to compile questions, elicit expert opinions and reach consensus. Results Immunosuppressive treatment should be guided by renal biopsy, and aiming for complete renal response (proteinuria <0.5 g/24 h with normal or near-normal renal function). Hydroxychloroquine is recommended for all patients with LN. Because of a more favourable efficacy/toxicity ratio, as initial treatment for patients with class III–IVA or A/C (±V) LN according to the International Society of Nephrology/Renal Pathology Society 2003 classification, mycophenolic acid (MPA) or low-dose intravenous cyclophosphamide (CY) in combination with glucocorticoids is recommended. In patients with adverse clinical or histological features, CY can be prescribed at higher doses, while azathioprine is an alternative for milder cases. For pure class V LN with nephrotic-range proteinuria, MPA in combination with oral glucocorticoids is recommended as initial treatment. In patients improving after initial treatment, subsequent immunosuppression with MPA or azathioprine is recommended for at least 3 years; in such cases, initial treatment with MPA should be followed by MPA. For MPA or CY failures, switching to the other agent, or to rituximab, is the suggested course of action. In anticipation of pregnancy, patients should be switched to appropriate medications without reducing the intensity of treatment. There is no evidence to suggest that management of LN should differ in children versus adults. Conclusions Recommendations for the management of LN were developed using an evidence-based approach followed by expert consensus. PMID:22851469

Relapse risk after autologous stem cell transplantation in patients with lymphoma based on CD34+ cell dose.

PubMed

Sorigue, Marc; Sancho, Juan-Manuel; Morgades, Mireia; Moreno, Miriam; Grífols, Juan-Ramon; Alonso, Eva; Juncà, Jordi; Ferrà, Christelle; Batlle, Montserrat; Vives, Susana; Motlló, Cristina; García-Caro, Montserrat; Navarro, Jose-Tomás; Millà, Fuensanta; Feliu, Evarist; Ribera, Josep-María

2017-04-01

It is unclear whether higher CD34 + cell doses infused for ASCT have any influence on survival or relapse in patients with lymphoma. We analyzed the correlation of infused CD34 + cell dose with relapse, survival, and hematopoietic recovery in 146 consecutive patients undergoing ASCT for lymphoma. Higher doses (>5 × 10 6 /kg) were significantly correlated with earlier hematopoietic recovery, fewer infectious episodes, lower transfusion needs. No differences were observed in lymphoma outcomes (4-year relapse incidence of 38% [95%CI: 29%-48%] in the lower dose group versus 51% [95%CI: 30%-69%] in the higher dose group, 10-year OS probabilities of 58% [95%CI: 48%-68%] versus 75% [95%CI: 59%-91%], 10-year DFS probabilities of 47% [95%CI: 37%-57%] versus 42% [95%CI: 23%-61%], p = NS for all outcomes). In this series, a higher infused CD34 + cell dose did not correlate with survival or relapse but correlated with earlier hematopoietic recovery and lower resource consumption.

WE-D-BRE-06: Quantification of Dose-Response for High Grade Esophagtis Patients Using a Novel Voxel-To-Voxel Method

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

Niedzielski, J; Martel, M; Tucker, S

2014-06-15

Purpose: Radiation induces an inflammatory response in the esophagus, discernible on CT studies. This work objectively quantifies the voxel esophageal radiation-response for patients with acute esophagitis. This knowledge is an important first-step towards predicting the effect of complex dose distributions on patient esophagitis symptoms. Methods: A previously validated voxel-based methodology of quantifying radiation esophagitis severity was used to identify the voxel dose-response for 18 NSCLC patients with severe esophagitis (CTCAE grading criteria, grade2 or higher). The response is quantified as percent voxel volume change for a given dose. During treatment (6–8 weeks), patients had weekly 4DCT studies and esophagitis scoring.more » Planning CT esophageal contours were deformed to each weekly CT using a demons DIR algorithm. An algorithm using the Jacobian Map from the DIR of the planning CT to all weekly CTs was used to quantify voxel-volume change, along with corresponding delivered voxel dose, to the planning voxel. Dose for each voxel for each time-point was calculated on each previous weekly CT image, and accumulated using DIR. Thus, for each voxel, the volume-change and delivered dose was calculated for each time-point. The data was binned according to when the volume-change first increased by a threshold volume (10%–100%, in 10% increments), and the average delivered dose calculated for each bin. Results: The average dose resulting in a voxel volume increase of 10–100% was 21.6 to 45.9Gy, respectively. The mean population dose to give a 50% volume increase was 36.3±4.4Gy, (range:29.8 to 43.5Gy). The average week of 50% response was 4.1 (range:4.9 to 2.8 weeks). All 18 patients showed similar dose to first response curves, showing a common trend in the initial inflammatoryresponse. Conclusion: We extracted the dose-response curve of the esophagus on a voxel-to-voxel level. This may be useful for estimating the esophagus response (and patient symptoms) to complicated dose distributions.« less

SU-F-T-377: Monte Carlo Re-Evaluation of Volumetric-Modulated Arc Plans of Advanced Stage Nasopharygeal Cancers Optimized with Convolution-Superposition Algorithm

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

Lee, K; Leung, R; Law, G

Background: Commercial treatment planning system Pinnacle3 (Philips, Fitchburg, WI, USA) employs a convolution-superposition algorithm for volumetric-modulated arc radiotherapy (VMAT) optimization and dose calculation. Study of Monte Carlo (MC) dose recalculation of VMAT plans for advanced-stage nasopharyngeal cancers (NPC) is currently limited. Methods: Twenty-nine VMAT prescribed 70Gy, 60Gy, and 54Gy to the planning target volumes (PTVs) were included. These clinical plans achieved with a CS dose engine on Pinnacle3 v9.0 were recalculated by the Monaco TPS v5.0 (Elekta, Maryland Heights, MO, USA) with a XVMC-based MC dose engine. The MC virtual source model was built using the same measurement beam datasetmore » as for the Pinnacle beam model. All MC recalculation were based on absorbed dose to medium in medium (Dm,m). Differences in dose constraint parameters per our institution protocol (Supplementary Table 1) were analyzed. Results: Only differences in maximum dose to left brachial plexus, left temporal lobe and PTV54Gy were found to be statistically insignificant (p> 0.05). Dosimetric differences of other tumor targets and normal organs are found in supplementary Table 1. Generally, doses outside the PTV in the normal organs are lower with MC than with CS. This is also true in the PTV54-70Gy doses but higher dose in the nasal cavity near the bone interfaces is consistently predicted by MC, possibly due to the increased backscattering of short-range scattered photons and the secondary electrons that is not properly modeled by the CS. The straight shoulders of the PTV dose volume histograms (DVH) initially resulted from the CS optimization are merely preserved after MC recalculation. Conclusion: Significant dosimetric differences in VMAT NPC plans were observed between CS and MC calculations. Adjustments of the planning dose constraints to incorporate the physics differences from conventional CS algorithm should be made when VMAT optimization is carried out directly with MC dose engine.« less

Evaluation of the absorbed dose to the breast using radiochromic film in a dedicated CT mammotomography system employing a quasi-monochromatic x-ray beam.

PubMed

Crotty, Dominic J; Brady, Samuel L; Jackson, D'Vone C; Toncheva, Greta I; Anderson, Colin E; Yoshizumi, Terry T; Tornai, Martin P

2011-06-01

A dual modality SPECT-CT prototype system dedicated to uncompressed breast imaging (mammotomography) has been developed. The computed tomography subsystem incorporates an ultrathick K-edge filtration technique producing a quasi-monochromatic x-ray cone beam that optimizes the dose efficiency of the system for lesion imaging in an uncompressed breast. Here, the absorbed dose in various geometric phantoms and in an uncompressed and pendant cadaveric breast using a normal tomographic cone beam imaging protocol is characterized using both thermoluminescent dosimeter (TLD) measurements and ionization chamber-calibrated radiochromic film. Initially, two geometric phantoms and an anthropomorphic breast phantom are filled in turn with oil and water to simulate the dose to objects that mimic various breast shapes having effective density bounds of 100% fatty and glandular breast compositions, respectively. Ultimately, an excised human cadaver breast is tomographically scanned using the normal tomographic imaging protocol, and the dose to the breast tissue is evaluated and compared to the earlier phantom-based measurements. Measured trends in dose distribution across all breast geometric and anthropomorphic phantom volumes indicate lower doses in the medial breast and more proximal to the chest wall, with consequently higher doses near the lateral peripheries and nipple regions. Measured doses to the oil-filled phantoms are consistently lower across all volume shapes due to the reduced mass energy-absorption coefficient of oil relative to water. The mean measured dose to the breast cadaver, composed of adipose and glandular tissues, was measured to be 4.2 mGy compared to a mean whole-breast dose of 3.8 and 4.5 mGy for the oil- and water-filled anthropomorphic breast phantoms, respectively. Assuming rotational symmetry due to the tomographic acquisition exposures, these results characterize the 3D dose distributions in an uncompressed human breast tissue volume for this dedicated breast imaging device and illustrate advantages of using the novel ultrathick K-edge filtered beam to minimize the dose to the breast during fully-3D imaging.

Evaluation of the absorbed dose to the breast using radiochromic film in a dedicated CT mammotomography system employing a quasi-monochromatic x-ray beam

PubMed Central

Crotty, Dominic J.; Brady, Samuel L.; Jackson, D’Vone C.; Toncheva, Greta I.; Anderson, Colin E.; Yoshizumi, Terry T.; Tornai, Martin P.

2011-01-01

Purpose: A dual modality SPECT-CT prototype system dedicated to uncompressed breast imaging (mammotomography) has been developed. The computed tomography subsystem incorporates an ultrathick K-edge filtration technique producing a quasi-monochromatic x-ray cone beam that optimizes the dose efficiency of the system for lesion imaging in an uncompressed breast. Here, the absorbed dose in various geometric phantoms and in an uncompressed and pendant cadaveric breast using a normal tomographic cone beam imaging protocol is characterized using both thermoluminescent dosimeter (TLD) measurements and ionization chamber-calibrated radiochromic film. Methods: Initially, two geometric phantoms and an anthropomorphic breast phantom are filled in turn with oil and water to simulate the dose to objects that mimic various breast shapes having effective density bounds of 100% fatty and glandular breast compositions, respectively. Ultimately, an excised human cadaver breast is tomographically scanned using the normal tomographic imaging protocol, and the dose to the breast tissue is evaluated and compared to the earlier phantom-based measurements. Results: Measured trends in dose distribution across all breast geometric and anthropomorphic phantom volumes indicate lower doses in the medial breast and more proximal to the chest wall, with consequently higher doses near the lateral peripheries and nipple regions. Measured doses to the oil-filled phantoms are consistently lower across all volume shapes due to the reduced mass energy-absorption coefficient of oil relative to water. The mean measured dose to the breast cadaver, composed of adipose and glandular tissues, was measured to be 4.2 mGy compared to a mean whole-breast dose of 3.8 and 4.5 mGy for the oil- and water-filled anthropomorphic breast phantoms, respectively. Conclusions: Assuming rotational symmetry due to the tomographic acquisition exposures, these results characterize the 3D dose distributions in an uncompressed human breast tissue volume for this dedicated breast imaging device and illustrate advantages of using the novel ultrathick K-edge filtered beam to minimize the dose to the breast during fully-3D imaging. PMID:21815398

Effects of a higher dose of near-infrared light on clinical signs and neuroprotection in a monkey model of Parkinson's disease.

PubMed

Moro, Cécile; El Massri, Nabil; Darlot, Fannie; Torres, Napoleon; Chabrol, Claude; Agay, Diane; Auboiroux, Vincent; Johnstone, Daniel M; Stone, Jonathan; Mitrofanis, John; Benabid, Alim-Louis

2016-10-01

We have reported previously that intracranial application of near-infrared light (NIr) - when delivered at the lower doses of 25J and 35J - reduces clinical signs and offers neuroprotection in a subacute MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) monkey model of Parkinson's disease. In this study, we explored whether a higher NIr dose (125J) generated beneficial effects in the same MPTP monkey model (n=15). We implanted an NIr (670nm) optical fibre device within a midline region of the midbrain in macaque monkeys, close to the substantia nigra of both sides. MPTP injections (1.8-2.1mg/kg) were made over a five day period, during which time the NIr device was turned on and left on continuously throughout the ensuing three week survival period. Monkeys were evaluated clinically and their brains processed for immunohistochemistry and stereology. Our results showed that the higher NIr dose did not have any toxic impact on cells at the midbrain implant site. Further, this NIr dose resulted in a higher number of nigral tyrosine hydroxylase immunoreactive cells when compared to the MPTP group. However, the higher NIr dose monkeys showed little evidence for an increase in mean clinical score, number of nigral Nissl-stained cells and density of striatal tyrosine hydroxylase terminations. In summary, the higher NIr dose of 125J was not as beneficial to MPTP-treated monkeys as compared to the lower doses of 25J and 35J, boding well for strategies of NIr dose delivery and device energy consumption in a future clinical trial. Copyright © 2016 Elsevier B.V. All rights reserved.

Effect of operational and water quality parameters on conventional ozonation and the advanced oxidation process O3/H2O2: Kinetics of micropollutant abatement, transformation product and bromate formation in a surface water.

PubMed

Bourgin, Marc; Borowska, Ewa; Helbing, Jakob; Hollender, Juliane; Kaiser, Hans-Peter; Kienle, Cornelia; McArdell, Christa S; Simon, Eszter; von Gunten, Urs

2017-10-01

The efficiency of ozone-based processes under various conditions was studied for the treatment of a surface water (Lake Zürich water, Switzerland) spiked with 19 micropollutants (pharmaceuticals, pesticides, industrial chemical, X-ray contrast medium, sweetener) each at 1 μg L -1 . Two pilot-scale ozonation reactors (4-5 m 3  h -1 ), a 4-chamber reactor and a tubular reactor, were investigated by either conventional ozonation and/or the advanced oxidation process (AOP) O 3 /H 2 O 2 . The effects of selected operational parameters, such as ozone dose (0.5-3 mg L -1 ) and H 2 O 2 dose (O 3 :H 2 O 2  = 1:3-3:1 (mass ratio)), and selected water quality parameters, such as pH (6.5-8.5) and initial bromide concentration (15-200 μg L -1 ), on micropollutant abatement and bromate formation were investigated. Under the studied conditions, compounds with high second-order rate constants k O3 >10 4  M -1  s -1 for their reaction with ozone were well abated (>90%) even for the lowest ozone dose of 0.5 mg L -1 . Conversely, the abatement efficiency of sucralose, which only reacts with hydroxyl radicals (OH), varied between 19 and 90%. Generally, the abatement efficiency increased with higher ozone doses and higher pH and lower bromide concentrations. H 2 O 2 addition accelerated the ozone conversion to OH, which enables a faster abatement of ozone-resistant micropollutants. Interestingly, the abatement of micropollutants decreased with higher bromide concentrations during conventional ozonation due to competitive ozone-consuming reactions, except for lamotrigine, due to the suspected reaction of HOBr/OBr - with the primary amine moieties. In addition to the abatement of micropollutants, the evolution of the two main transformation products (TPs) of hydrochlorothiazide (HCTZ) and tramadol (TRA), chlorothiazide (CTZ) and tramadol N-oxide (TRA-NOX), respectively, was assessed by chemical analysis and kinetic modeling. Both selected TPs were quickly formed initially to reach a maximum concentration followed by a decrease of their concentrations for longer contact times. For the studied conditions, the TP's concentrations at the outlet of the reactors ranged from 0 to 61% of the initial parent compound concentration, CTZ being a more persistent TP against further oxidation than TRA-NOX. Finally, it was demonstrated in both reactors that the formation of bromate (BrO 3 - ), a potentially carcinogenic oxidation by-product, could be controlled by H 2 O 2 addition with a general improvement on micropollutant abatement. Post-treatment by granular activated carbon (GAC) filtration enabled the reduction of micropollutants and TPs concentrations but no changes in bromate were observed. The combined algae assay showed that water quality was significantly improved after oxidation and GAC post-treatment, driven by the abatement of the spiked pesticides (diuron and atrazine). Copyright © 2017 Elsevier Ltd. All rights reserved.

Does S-Metolachlor Affect the Performance of Pseudomonas sp. Strain ADP as Bioaugmentation Bacterium for Atrazine-Contaminated Soils?

PubMed Central

Viegas, Cristina A.; Costa, Catarina; André, Sandra; Viana, Paula; Ribeiro, Rui; Moreira-Santos, Matilde

2012-01-01

Atrazine (ATZ) and S-metolachlor (S-MET) are two herbicides widely used, often as mixtures. The present work examined whether the presence of S-MET affects the ATZ-biodegradation activity of the bioaugmentation bacterium Pseudomonas sp. strain ADP in a crop soil. S-MET concentrations were selected for their relevance in worst-case scenarios of soil contamination by a commercial formulation containing both herbicides. At concentrations representative of application of high doses of the formulation (up to 50 µg g−1 of soil, corresponding to a dose approximately 50× higher than the recommended field dose (RD)), the presence of pure S-MET significantly affected neither bacteria survival (∼107 initial viable cells g−1 of soil) nor its ATZ-mineralization activity. Consistently, biodegradation experiments, in larger soil microcosms spiked with 20× or 50×RD of the double formulation and inoculated with the bacterium, revealed ATZ to be rapidly (in up to 5 days) and extensively (>96%) removed from the soil. During the 5 days, concentration of S-MET decreased moderately to about 60% of the initial, both in inoculated and non-inoculated microcosms. Concomitantly, an accumulation of the two metabolites S-MET ethanesulfonic acid and S-MET oxanilic acid was found. Despite the dissipation of almost all the ATZ from the treated soils, the respective eluates were still highly toxic to an aquatic microalgae species, being as toxic as those from the untreated soil. We suggest that this high toxicity may be due to the S-MET and/or its metabolites remaining in the soil. PMID:22615921

Dose Regimens, Variability, and Complications Associated with Using Repeat-Bolus Dosing to Extend a Surgical Plane of Anesthesia in Laboratory Mice

PubMed Central

Jaber, Samer M; Hankenson, F Claire; Heng, Kathleen; McKinstry-Wu, Andrew; Kelz, Max B; Marx, James O

2014-01-01

Extending a surgical plane of anesthesia in mice by using injectable anesthetics typically is accomplished by repeat-bolus dosing. We compared the safety and efficacy of redosing protocols administered either during an anesthetic surgical plane (maintaining a continuous surgical plane, CSP), or immediately after leaving this plane (interrupted surgical plane, ISP) in C57BL/6J mice. Anesthesia was induced with ketamine, xylazine, and acepromazine (80, 8, and 1 mg/kg IP, respectively), and redosing protocols included 25% (0.25K), 50% (0.5K), or 100% (1.0K) of the initial ketamine dose or 25% (0.25KX) or 50% (0.5KX) of the initial ketamine–xylazine dose. In the ISP group, the surgical plane was extended by 13.8 ± 2.1 min (mean ± SEM) after redosing for the 0.25K redose with 50% returning to a surgical plane, 42.7 ± 4.5 min for the 0.5K redose with 88% returning to a surgical plane, and 44.3 ± 15.4 min for the 1.0K redose, 52.8 ± 7.2 min for the 0.25KX redose, and 45.9 ± 2.9 min for the 0.5KX redose, with 100% of mice returning to a surgical plane of anesthesia in these 3 groups. Mortality rates for ISP groups were 0%, 12%, 33%, 12%, and 18%, respectively. Mice in CSP groups had 50% mortality, independent of the repeat-dosing protocol. We recommend redosing mice with either 50% of the initial ketamine dose or 25% of the initial ketamine–xylazine dose immediately upon return of the pedal withdrawal reflex to extend the surgical plane of anesthesia in mice, optimize the extension of the surgical plane, and minimize mortality. PMID:25650976

Correlation between Colon Transit Time Test Value and Initial Maintenance Dose of Laxative in Children with Chronic Functional Constipation

PubMed Central

Kim, Mock Ryeon; Park, Hye Won; Son, Jae Sung; Lee, Ran

2016-01-01

Purpose To evaluate the correlation between colon transit time (CTT) test value and initial maintenance dose of polyethylene glycol (PEG) 4000 or lactulose. Methods Of 415 children with chronic functional constipation, 190 were enrolled based on exclusion criteria using the CTT test, defecation diary, and clinical chart. The CTT test was performed with prior disimpaction. The laxative dose for maintenance was determined on the basis of the defecation diary and clinical chart. The Shapiro-Wilk test and Pearson's and Spearman's correlations were used for statistical analysis. Results The overall group median value and interquartile range of the CTT test was 43.8 (31.8) hours. The average PEG 4000 dose for maintenance in the overall group was 0.68±0.18 g/kg/d; according to age, the dose was 0.73±0.16 g/kg/d (<8 years), 0.53±0.12 g/kg/d (8 to <12 years), and 0.36±0.05 g/kg/d (12 to 15 years). The dose of lactulose was 1.99±0.43 mL/kg/d (<8 years) or 1.26±0.25 mL/kg/d (8 to <12 years). There was no significant correlation between CTT test value and initial dose of laxative, irrespective of the subgroup (encopresis, abnormal CTT test subtype) for either laxative. Even in the largest group (overall, n=109, younger than 8 years and on PEG 4000), the correlation was weak (Pearson's correlation coefficient [R]=0.268, p=0.005). Within the abnormal transit group, subgroup (n=73, younger than 8 years and on PEG 4000) correlation was weak (R=0.267, p=0.022). Conclusion CTT test value cannot predict the initial maintenance dose of PEG 4000 or lactulose with linear correlation. PMID:27738600

Tolerance of the Brachial Plexus to High-Dose Reirradiation

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

Chen, Allen M., E-mail: achen5@kumc.edu; Yoshizaki, Taeko; Velez, Maria A.

Purpose: To study the tolerance of the brachial plexus to high doses of radiation exceeding historically accepted limits by analyzing human subjects treated with reirradiation for recurrent tumors of the head and neck. Methods and Materials: Data from 43 patients who were confirmed to have received overlapping dose to the brachial plexus after review of radiation treatment plans from the initial and reirradiation courses were used to model the tolerance of this normal tissue structure. A standardized instrument for symptoms of neuropathy believed to be related to brachial plexus injury was utilized to screen for toxicity. Cumulative dose was calculatedmore » by fusing the initial dose distributions onto the reirradiation plan, thereby creating a composite plan via deformable image registration. The median elapsed time from the initial course of radiation therapy to reirradiation was 24 months (range, 3-144 months). Results: The dominant complaints among patients with symptoms were ipsilateral pain (54%), numbness/tingling (31%), and motor weakness and/or difficulty with manual dexterity (15%). The cumulative maximum dose (Dmax) received by the brachial plexus ranged from 60.5 Gy to 150.1 Gy (median, 95.0 Gy). The cumulative mean (Dmean) dose ranged from 20.2 Gy to 111.5 Gy (median, 63.8 Gy). The 1-year freedom from brachial plexus–related neuropathy was 67% and 86% for subjects with a cumulative Dmax greater than and less than 95.0 Gy, respectively (P=.05). The 1-year complication-free rate was 66% and 87%, for those reirradiated within and after 2 years from the initial course, respectively (P=.06). Conclusion: The development of brachial plexus–related symptoms was less than expected owing to repair kinetics and to the relatively short survival of the subject population. Time-dose factors were demonstrated to be predictive of complications.« less

Thrombotic safety of prothrombin complex concentrate (Beriplex P/N) for dabigatran reversal in a rabbit model.

PubMed

Herzog, Eva; Kaspereit, Franz J; Krege, Wilfried; Doerr, Baerbel; van Ryn, Joanne; Dickneite, Gerhard; Pragst, Ingo

2014-09-01

In vivo animal data have shown prothrombin complex concentrate (PCC) to be effective in preventing bleeding induced by excessive plasma levels of the direct thrombin inhibitor dabigatran. This animal model study was designed to determine the risk of thrombosis associated with administration of a PCC (Beriplex P/N) to reverse dabigatran-induced bleeding. Anesthetized rabbits were treated with initial 0, 75, 200 or 450 μg kg(-1) dabigatran boluses followed by continuous infusions to maintain elevated plasma dabigatran levels. At 15 min after the start of dabigatran administration, PCC doses of 0, 50 or 300 IU kg(-1) were administered. Thereafter, coagulation in an arteriovenous (AV) shunt was evaluated and histopathologic examination for thrombotic changes performed. Venous thrombosis was also assessed in a modified Wessler model. At the suprapharmacologic dose of 300 IU kg(-1), PCC increased thrombus weight during AV shunting, but this effect could be prevented by dabigatran at all tested doses. AV shunt occlusion after PCC administration was delayed by 75 μg kg(-1) dabigatran and abolished by progressively higher dabigatran doses. High-dose treatment with 300 IU kg(-1) PCC resulted in histologically evident low-grade pulmonary thrombi; however, that effect could be blocked by dabigatran in a dose-dependent manner (p=0.034). In rabbits treated with high-dose PCC, dabigatran inhibited thrombus formation during venous stasis. PCC effectively reversed dabigatran-induced bleeding. In this animal study, thrombosis after PCC administration could be prevented in the presence of dabigatran. PCC reversed dabigatran-induced excessive bleeding while retaining protective anticoagulatory activity of dabigatran. Copyright © 2014. Published by Elsevier Ltd.

Visual grading analysis of digital neonatal chest phantom X-ray images: Impact of detector type, dose and image processing on image quality.

PubMed

Smet, M H; Breysem, L; Mussen, E; Bosmans, H; Marshall, N W; Cockmartin, L

2018-07-01

To evaluate the impact of digital detector, dose level and post-processing on neonatal chest phantom X-ray image quality (IQ). A neonatal phantom was imaged using four different detectors: a CR powder phosphor (PIP), a CR needle phosphor (NIP) and two wireless CsI DR detectors (DXD and DRX). Five different dose levels were studied for each detector and two post-processing algorithms evaluated for each vendor. Three paediatric radiologists scored the images using European quality criteria plus additional questions on vascular lines, noise and disease simulation. Visual grading characteristics and ordinal regression statistics were used to evaluate the effect of detector type, post-processing and dose on VGA score (VGAS). No significant differences were found between the NIP, DXD and CRX detectors (p>0.05) whereas the PIP detector had significantly lower VGAS (p< 0.0001). Processing did not influence VGAS (p=0.819). Increasing dose resulted in significantly higher VGAS (p<0.0001). Visual grading analysis (VGA) identified a detector air kerma/image (DAK/image) of ~2.4 μGy as an ideal working point for NIP, DXD and DRX detectors. VGAS tracked IQ differences between detectors and dose levels but not image post-processing changes. VGA showed a DAK/image value above which perceived IQ did not improve, potentially useful for commissioning. • A VGA study detects IQ differences between detectors and dose levels. • The NIP detector matched the VGAS of the CsI DR detectors. • VGA data are useful in setting initial detector air kerma level. • Differences in NNPS were consistent with changes in VGAS.

Predicting prolonged dose titration in patients starting warfarin.

PubMed

Finkelman, Brian S; French, Benjamin; Bershaw, Luanne; Brensinger, Colleen M; Streiff, Michael B; Epstein, Andrew E; Kimmel, Stephen E

2016-11-01

Patients initiating warfarin therapy generally experience a dose-titration period of weeks to months, during which time they are at higher risk of both thromboembolic and bleeding events. Accurate prediction of prolonged dose titration could help clinicians determine which patients might be better treated by alternative anticoagulants that, while more costly, do not require dose titration. A prediction model was derived in a prospective cohort of patients starting warfarin (n = 390), using Cox regression, and validated in an external cohort (n = 663) from a later time period. Prolonged dose titration was defined as a dose-titration period >12 weeks. Predictor variables were selected using a modified best subsets algorithm, using leave-one-out cross-validation to reduce overfitting. The final model had five variables: warfarin indication, insurance status, number of doctor's visits in the previous year, smoking status, and heart failure. The area under the ROC curve (AUC) in the derivation cohort was 0.66 (95%CI 0.60, 0.74) using leave-one-out cross-validation, but only 0.59 (95%CI 0.54, 0.64) in the external validation cohort, and varied across clinics. Including genetic factors in the model did not improve the area under the ROC curve (0.59; 95%CI 0.54, 0.65). Relative utility curves indicated that the model was unlikely to provide a clinically meaningful benefit compared with no prediction. Our results suggest that prolonged dose titration cannot be accurately predicted in warfarin patients using traditional clinical, social, and genetic predictors, and that accurate prediction will need to accommodate heterogeneities across clinical sites and over time. Copyright © 2016 John Wiley & Sons, Ltd. Copyright © 2016 John Wiley & Sons, Ltd.

Shipboard testing of the efficacy of SeaKleen as a ballast water treatment to eliminate non-indigenous species aboard a working tanker in Pacific waters.

PubMed

Wright, D A; Dawson, R; Caceres, V; Orano-Dawson, C E; Kananen, G E; Cutler, S J; Cutler, H G

2009-08-01

Trials were conducted aboard the tanker Seabulk Mariner to test a natural product, SeaKleen, as a biocide controlling non-indigenous populations of plankton and bacteria in ballast water. SeaKleen was dosed into matched ballast tanks at two different concentrations, 0.8 mg L(-1) active ingredient (a.i.) and 1.6 mg L(-1) a.i. during ballasting off the Oregon coast during a three-day passage to Prince William Sound, Alaska. Live organism counts from treated ballast water were compared with those from untreated (control tank) water collected from the same source location. Shipboard chemical analyses were made to verify dose and quantify chemical degradation and residuals following dilution. Results indicated that both SeaKleen doses resulted in complete zooplankton and phytoplankton mortality and that the higher dose (1.6 mg L(-1) a.i.) caused a two-log removal of culturable bacteria over a 92 h grow-out period. Spectrophotometry confirmed initial dosing to within 5% of nominal values. Shipboard bioassays were conducted using larval fish (Cyprinodon variegatus), brine shrimp (Artemia salina) and the bioluminescent dinoflagellate Pyrocystis lunula. Exposure of the test organisms to water drawn from treated ballast tanks 48 h after SeaKleen was added to the tanks resulted in 100% mortalities in Cyprinodon and Pyrocystis at both doses. Corresponding mortalities for Artemia larvae were 100% and 60% for high and low SeaKleen doses, respectively. Toxicity testing of treated water, subjected to varying dilutions, indicated that residual toxicity to even the most sensitive organisms would be eliminated once the discharge had dispersed beyond 100 feet from the vessel.

Amoxicillin/clavulanate for infections in infants and children: past, present and future.

PubMed

Klein, Jerome O

2003-08-01

Chemical synthesis of the penicillin nucleus in the 1950s made introduction of a broad array of new and important antimicrobials, including ampicillin and amoxicillin, possible. Ampicillin was introduced in 1962 in oral and parenteral forms as the first of the semisynthetic penicillins to provide increased activity against Gram-negative bacteria. Amoxicillin replaced oral ampicillin beginning in 1974 because amoxicillin resulted in higher and more prolonged serum concentrations than did equivalent doses of ampicillin. Amoxicillin/clavulanate (Augmentin) was introduced in the United States in 1984 to enhance the activity of amoxicillin by addition of the beta-lactamase inhibitor, clavulanic acid. During the past 20 years, amoxicillin/clavulanate has proven effective for a variety of pediatric infectious diseases, particularly acute otitis media (AOM). In 2001, a new pediatric formulation, high dose amoxicillin/clavulanate (Augmentin ES-600) was approved for use in the United States. The high dose preparation addressed the needs of pediatricians by providing greater amounts of amoxicillin while maintaining the same daily dose of clavulanic acid as the regular strength formulation. Doubling the dose of amoxicillin for management of recurrent and persistent AOM was recommended in 1999 by the Centers for Disease Control and Prevention because of concern about the increased incidence of nonsusceptible strains of Streptococcus pneumoniae. The original formulation combined amoxicillin/clavulanate in a 4:1 ratio and was followed by a 7:1 ratio formulation. The high dose formulation (600 mg of amoxicillin per 5 ml) provides a 14:1 ratio of amoxicillin to clavulanate. Although management of AOM will likely undergo changes in the coming years, amoxicillin is expected to remain first line therapy for AOM. For children who fail initial therapy with amoxicillin, high dose amoxicillin/clavulanate, an oral cephalosporin or parenteral ceftriaxone is recommended.

A randomised clinical trial on the efficacy of oxytetracycline dose through water medication of nursery pigs on diarrhoea, faecal shedding of Lawsonia intracellularis and average daily weight gain.

PubMed

Larsen, Inge; Hjulsager, Charlotte Kristiane; Holm, Anders; Olsen, John Elmerdahl; Nielsen, Søren Saxmose; Nielsen, Jens Peter

2016-01-01

Oral treatment with antimicrobials is widely used in pig production for the control of gastrointestinal infections. Lawsonia intracellularis (LI) causes enteritis in pigs older than six weeks of age and is commonly treated with antimicrobials. The objective of this study was to evaluate the efficacy of three oral dosage regimens (5, 10 and 20mg/kg body weight) of oxytetracycline (OTC) in drinking water over a five-day period on diarrhoea, faecal shedding of LI and average daily weight gain (ADG). A randomised clinical trial was carried out in four Danish pig herds. In total, 539 animals from 37 batches of nursery pigs were included in the study. The dosage regimens were randomly allocated to each batch and initiated at presence of assumed LI-related diarrhoea. In general, all OTC doses used for the treatment of LI infection resulted in reduced diarrhoea and LI shedding after treatment. Treatment with a low dose of 5mg/kg OTC per kg body weight, however, tended to cause more watery faeces and resulted in higher odds of pigs shedding LI above detection level when compared to medium and high doses (with odds ratios of 5.5 and 8.4, respectively). No association was found between the dose of OTC and the ADG. In conclusion, a dose of 5mg OTC per kg body weight was adequate for reducing the high-level LI shedding associated with enteropathy, but a dose of 10mg OTC per kg body weight was necessary to obtain a maximum reduction in LI shedding. Copyright © 2015 Elsevier B.V. All rights reserved.

Poster — Thur Eve — 23: Dose and Position Quality Assurance using the RADPOS System for 4D Radiotherapy with CyberKnife

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

Marants, R; Vandervoort, E; Cygler, J E

2014-08-15

Introduction: RADPOS 4D dosimetry system consists of a microMOSFET dosimeter combined with an electromagnetic positioning sensor, which allows for performing real-time dose and position measurements simultaneously. In this report the use of RADPOS as an independent quality assurance (QA) tool during CyberKnife 4D radiotherapy treatment is described. In addition to RADPOS, GAFCHROMIC® films were used for simultaneous dose measurement. Methods: RADPOS and films were calibrated in a Solid Water® phantom at 1.5 cm depth, SAD= 80 cm, using 60 mm cone. CT based treatment plan was created for a Solid Water® breast phantom containing metal fiducials and RADPOS probe. Dosemore » calculations were performed using iPlan pencil beam algorithm. Before the treatment delivery, GAFCHROMIC® film was inserted inside the breast phantom, next to the RADPOS probe. Then the phantom was positioned on the chest platform of the QUASAR, to which Synchrony LED optical markers were also attached. Position logging began for RADPOS and the Synchrony tracking system, the QUASAR motion was initiated and the treatment was delivered. Results: RADPOS position measurements very closely matched the LED marker positions recorded by the Synchrony camera tracking system. The RADPOS measured dose was 2.5% higher than the average film measured dose, which is within the experimental uncertainties. Treatment plan calculated dose was 4.1 and 1.6% lower than measured by RADPOS and film, respectively. This is most likely due to the inferior nature of the dose calculation algorithm. Conclusions: Our study demonstrates that RADPOS system is a useful tool for independent QA of CyberKnife treatments.« less

Comparison of two neonatal indomethacin protocols: efficacy and outcome for patent ductus arteriosus closure.

PubMed

Rosito, G; Sum, K; Chorne, N

2010-10-01

Indomethacin, a non-selective inhibitor of prostaglandin synthesis, is the gold standard treatment for patent ductus arteriosus (PDA). Indomethacin has been shown to permanently close the ductus and when given prophylactically, it reduces the incidence of PDA (1, 2). This study compares PDA closure and surgical ligation rates between patients using two different indomethacin administration protocols. This is a retrospective comparison analysis of 72 neonates, who received one of two indomethacin administration protocols. Our previous protocol suggested an initial dose of 0·2 mg/kg followed by two 0·1 mg/kg, with doses infused over 4 h and a 24-h dosing interval. A new potentially more useful protocol using the same mg/kg dose regimen but with doses infused over 30 min and a 12-h dosing interval, was evaluated. Each neonate was allowed three courses of treatment before surgical ligation was performed for persistent PDA. There were no statistically significant differences between the two protocol groups when comparing percentages of neonates with gestational age≤28 weeks, birth weight≤1000 g, male gender or receiving indomethacin for the indication of PDA prophylaxis vs. treatment. There was a trend towards a higher PDA closure rate and subsequently a lower PDA ligation rate in the new protocol when compared with the previous protocol. In this small population of premature neonates, there was a trend, but no significant difference, towards increasing PDA closure and lower surgical ligation rates in neonates given indomethacin with more frequent dosing and shorter infusion time. A well-powered randomized controlled trial is now needed. Copyright © 2010 The Authors. JCPT © 2010 Blackwell Publishing Ltd.

Triiodothyronine-predominant Graves' disease in childhood: detection and therapeutic implications.

PubMed

Harvengt, Julie; Boizeau, Priscilla; Chevenne, Didier; Zenaty, Delphine; Paulsen, Anne; Simon, Dominique; Guilmin Crepon, Sophie; Alberti, Corinne; Carel, Jean-Claude; Léger, Juliane

2015-06-01

To assess in a pediatric population, the clinical characteristics and management of triiodothyronine-predominant Graves' disease (T3-P-GD), a rare condition well known in adults, but not previously described in children. We conducted a university hospital-based observational study. All patients with GD followed for more than 1 year between 2003 and 2013 (n=60) were included. T3-P-GD (group I) was defined as high free T3 (fT3) concentration (>8.0 pmol/l) associated with a normal free thyroxine (fT4) concentration and undetectable TSH more than 1 month after the initiation of antithyroid drug (ATD) treatment. Group II contained patients with classical GD without T3-P-GD. Eight (13%) of the patients were found to have T3-P-GD, a median of 6.3 (3.0-10.5) months after initial diagnosis (n=4) or 2.8 (2.0-11.9) months after the first relapse after treatment discontinuation (n=4). At GD diagnosis, group I patients were more likely to be younger (6.8 (4.3-11.0) vs 10.7 (7.2-13.7) years) and had more severe disease than group II patients, with higher serum TSH receptor autoantibodies (TRAb) levels: 40 (31-69) vs 17 (8-25) IU/l, P<0.04, and with slightly higher serum fT4 (92 (64-99) vs 63 (44-83) pmol/l) and fT3 (31 (30-46) vs 25 (17-31) pmol/l) concentrations. During the 3 years following T3-P-GD diagnosis, a double dose of ATD was required and median serum fT4:fT3 ratio remained lower in group I than in group II. Severe hyperthyroidism, with particularly high TRAb concentrations at diagnosis, may facilitate the identification of patients requiring regular serum fT3 determinations and potentially needing higher doses of ATD dosage during follow-up. © 2015 European Society of Endocrinology.

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

Calcium/vitamin D supplementation and coronary artery calcification in the Women's Health Initiative.

PubMed

Manson, JoAnn E; Allison, Matthew A; Carr, J Jeffrey; Langer, Robert D; Cochrane, Barbara B; Hendrix, Susan L; Hsia, Judith; Hunt, Julie R; Lewis, Cora E; Margolis, Karen L; Robinson, Jennifer G; Rodabough, Rebecca J; Thomas, Asha M

2010-07-01

Coronary artery calcified plaque is a marker for atheromatous plaque burden and predicts future risk of cardiovascular events. The relationship between calcium plus vitamin D (calcium/D) supplementation and coronary artery calcium (CAC) has not been previously assessed in a randomized trial setting. We compared CAC scores after trial completion between women randomized to calcium/vitamin D supplementation and women randomized to placebo. In an ancillary substudy of women randomized to calcium carbonate (1,000 mg of elemental calcium daily) plus vitamin D3 (400 IU daily) or placebo, nested within the Women's Health Initiative trial of estrogen among women who underwent hysterectomy, we measured CAC with cardiac CT in 754 women aged 50 to 59 years at randomization. Imaging for CAC was performed at 28 of 40 centers after a mean of 7 years of treatment, and scans were read centrally. CAC scores were measured by a central reading center with masking to randomization assignments. Posttrial CAC measurements were similar in women randomized to calcium/D supplementation and those receiving placebo. The mean CAC score was 91.6 for women receiving calcium/D and 100.5 for women receiving placebo (rank test P value = 0.74). After adjustment for coronary risk factors, multivariate odds ratios for increasing CAC score cutpoints (CAC >0, > or =10, and > or =100) for calcium/D versus placebo were 0.92 (95% CI, 0.64-1.34), 1.29 (0.88-1.87), and 0.90 (0.56-1.44), respectively. Corresponding odds ratios among women with a 50% or higher adherence to study pills and for higher levels of CAC (>300) were similar. Treatment with moderate doses of calcium plus vitamin D3 did not seem to alter coronary artery calcified plaque burden among postmenopausal women. Whether higher or lower doses would affect this outcome remains uncertain.

The Influence of Shielding on the Biological Effectiveness of Accelerated Particles for the Induction of Chromosome Damage

NASA Technical Reports Server (NTRS)

Goeorge, Kerry; Cucinotta, Francis A.

2007-01-01

Chromosome damage was assessed in human peripheral blood lymphocytes after in vitro exposure to the either Si-28 (490 or 600 MeV/n), Ti-48 (1000 MeV/n), or Fe-56 (600, 1000, or 5000 MeV/n). LET values for these ions ranged from 51 to 184 keV/micron and doses ranged from 10 to 200 cGy. The effect of either aluminum or polyethylene shielding on the induction of chromosome aberrations was investigated for each ion. Chromosome exchanges were measured using fluorescence in situ hybridization (FISH) with whole chromosome probes in cells collected at G2 and mitosis in first division post irradiation after chromosomes were prematurely condensed using calyculin-A. The yield of chromosomal aberrations increased linearly with dose and the relative biological effectiveness (RBE) for the primary beams, estimated from the initial slope of the dose response curve for total chromosomal exchanges with respect to gamma-rays, ranged from 9 to 35. The RBE values increased with LET, reaching a maximum for the 600 MeV/n Fe ions with LET of 184 keV/micron. When the LET of the primary beam was below approximately 100 keV/micron, the addition of shielding material increased the effectiveness per unit dose. Whereas shielding decreased the effectiveness per unit dose when the LET of primary beams was higher than 100 keV/micron. The yield of aberrations correlated with the dose-average LET of the beam after traversal through the shielding.

Modulation of inflammation by low and high doses of ionizing radiation: Implications for benign and malign diseases.

PubMed

Frey, Benjamin; Hehlgans, Stephanie; Rödel, Franz; Gaipl, Udo S

2015-11-28

Inflammation is a homeostatic mechanism aiming to maintain tissue integrity. The underlying immunological mechanisms and the interrelationship between ionizing radiation and inflammation are complex and multifactorial on cellular and chemical levels. On the one hand, radiation with single doses exceeding 1 Gy might initiate inflammatory reactions and thereby impact on tumor development. On the other hand, radiation is capable of attenuating an established inflammatory process, which is clinically used for the treatment of inflammatory and degenerative diseases with low-dose radiotherapy (single dose <1 Gy). At higher doses, ionizing radiation, especially in combination with additional immune stimulation, fosters the induction of immunogenic forms of tumor cell death and shifts the tumor microenvironment as well as the infiltration of immune cells from an anti- to a pro-inflammatory state. Distinct tumor infiltrating immune cells predict the response to radiochemotherapy in a multitude of tumor entities. While a high tumor infiltration of these adaptive immune cells mostly predicts a favorable disease outcome, a high infiltration of tumor-associated macrophages predicts an unfavorable response. Pro-inflammatory events should dominate over anti-inflammatory ones in this scenario. This review focuses on how ionizing radiation modulates inflammatory events in benign inflammatory and in malign diseases. A special focus is set on the role of tumor infiltrating lymphocytes and macrophages as biomarkers to predict treatment response and anti-tumor immunity and on mechanisms implicated in the anti-inflammatory effects of low-dose radiation therapy. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Using the Concept of "Population Dose" in Planning and Evaluating Community-Level Obesity Prevention Initiatives

ERIC Educational Resources Information Center

Cheadle, Allen; Schwartz, Pamela M.; Rauzon, Suzanne; Bourcier, Emily; Senter, Sandra; Spring, Rebecca; Beery, William L.

2013-01-01

When planning and evaluating community-level initiatives focused on policy and environment change, it is useful to have estimates of the impact on behavioral outcomes of particular strategies (e.g., building a new walking trail to promote physical activity). We have created a measure of estimated strategy-level impact--"population dose"--based on…

High-Dose Micafungin for Preterm Neonates and Infants with Invasive and Central Nervous System Candidiasis.

PubMed

Auriti, Cinzia; Falcone, Marco; Ronchetti, Maria Paola; Goffredo, Bianca Maria; Cairoli, Sara; Crisafulli, Rosamaria; Piersigilli, Fiammetta; Corsetti, Tiziana; Dotta, Andrea; Pai, Manjunath P

2016-12-01

High doses of micafungin are advocated in neonates with systemic candidiasis, but limited pharmacokinetic (PK) and safety data are available to support their use. Eighteen preterm neonates and infants with systemic candidiasis, three of whom had meningitis, were treated for at least 14 days with 8 to 15 mg/kg of body weight/day of intravenous micafungin. Plasma micafungin concentrations (four measurements for each patient) were determined after the third dose, and the cerebrospinal fluid (CSF) micafungin concentrations in three patients were also obtained. Population PK analyses were used to identify the optimal model, and the model was further validated using external data (n = 5). The safety of micafungin was assessed by measurement of the levels of liver and kidney function biomarkers. The mean age and weight at the initiation of treatment were 2.33 months (standard deviation [SD], 1.98 months) and 3.24 kg (SD, 1.61 kg), respectively. The optimal PK model was one that scaled plasma clearance to weight and the transaminase concentration ratio. The CSF of three patients was sampled, and the observed concentrations were between 0.80 and 1.80 mg/liter. The model-predicted mean micafungin area under the concentration-time curve over 24 h was 336 mg · h/liter (SD, 165 mg · h/liter) with the 10-mg/kg/day dosage. Eighteen of the 23 subjects (78.2%) had clinical resolution of their infection, but 5 had neurologic impairments. Among the transaminases, alkaline phosphatase measurements were significantly higher posttreatment, with a geometric mean ratio of 1.17 (90% confidence interval, 1.01, 1.37). Furthermore, marked elevations in the gamma-glutamyltransferase (GGT) level were observed in three patients treated with 10- to 15-mg/kg/day doses, and improvement of the GGT level was noted after a dose reduction. Higher weight-based doses of micafungin were generally well tolerated in neonates and infants and achieved pharmacokinetic profiles predictive of an effect. Copyright © 2016, American Society for Microbiology. All Rights Reserved.

A randomized primary care trial of steroid titration against mannitol in persistent asthma: STAMINA trial.

PubMed

Lipworth, Brian J; Short, Philip M; Williamson, Peter A; Clearie, Karine L; Fardon, Thomas C; Jackson, Cathy M

2012-03-01

We compared titrating inhaled corticosteroid (ICS) against mannitol airway hyperresponsiveness (AHR) or a reference strategy (control) based on symptoms, reliever use, and lung function in primary care. One hundred sixty-four patients with persistent asthma were randomized in parallel group fashion following an initial ICS tapering. Subsequent ICS doses (as ciclesonide) were titrated against either the provocative dose of mannitol causing a 10% fall in FEV(1) (PD(10)) (AHR strategy) or a control group (reference strategy) over a 1-year period. One hundred nineteen participants (n = 61 AHR, n = 58 control) completed the study. Time to first mild exacerbation was not significantly different: hazard ratio, 1.29; 95% CI, 0.716-2.31; P = .40. Although there were 27% fewer total number of mild exacerbations over 12 months in AHR vs control groups (n = 84 vs n = 115, P = .03), there was no difference in severe exacerbations (n = 12 vs n = 13). No other significant differences were seen between groups with the exception of mannitol PD(10) and ICS dose. There was a 1.52 (95% CI, 0.61-2.42; P = .001) doubling dose difference in mannitol PD(10) between AHR vs control groups. The final mean daily ciclesonide dose was higher (P < .0001) in AHR vs control groups (514 μg vs 208 μg), with no associated significant suppression of overnight urinary cortisol/creatinine. Significant improvements were seen within the AHR group but not the control group for the provocative concentration of methacholine causing a 20% fall in FEV(1) (P < .05), salivary eosinophilic cationic protein (P < .05), exhaled nitric oxide (P < .05), symptoms (P < .005), and reliever use (P < .001). Mannitol challenge was well tolerated in a primary care setting. Using mannitol resulted in exposure to a higher dose of ciclesonide, which was associated with equivocal effects on exacerbations without associated adrenal suppression. Large-scale trials using mannitol in patients with more severe disease may now be warranted to further define its role. ClinicalTrials.gov; No.: NCT01216579; URL: www.clinicaltrials.gov.

Effects of carvedilol on structural and functional outcomes and plasma biomarkers in the mouse transverse aortic constriction heart failure model.

PubMed

Hampton, Caryn; Rosa, Raymond; Szeto, Daphne; Forrest, Gail; Campbell, Barry; Kennan, Richard; Wang, Shubing; Huang, Chin-Hu; Gichuru, Loise; Ping, Xiaoli; Shen, Xiaolan; Small, Kersten; Madwed, Jeffrey; Lynch, Joseph J

2017-01-01

Despite the widespread use of the mouse transverse aortic constriction heart failure model, there are no reports on the characterization of the standard-of-care agent carvedilol in this model. Left ventricular pressure overload was produced in mice by transverse aortic constriction between the innominate and left common carotid arteries. Carvedilol was administered at multiple dose levels (3, 10 and 30 mg/kg/day per os ; yielding end-study mean plasma concentrations of 0.002, 0.015 and 0.044 µM, respectively) in a therapeutic design protocol with treatment initiated after the manifestation of left ventricular remodeling at 3 weeks post transverse aortic constriction and continued for 10 weeks. Carvedilol treatment in transverse aortic constriction mice significantly decreased heart rate and left ventricular dP/dt (max) at all dose levels consistent with β-adrenoceptor blockade. The middle dose of carvedilol significantly decreased left ventricular weight, whereas the higher dose decreased total heart, left and right ventricular weight and wet lung weight compared to untreated transverse aortic constriction mice. The higher dose of carvedilol significantly increased cardiac performance as measured by ejection fraction and fractional shortening and decreased left ventricular end systolic volume consistent with the beneficial effect on cardiac function. End-study plasma sST-2 and Gal-3 levels did not differ among sham, transverse aortic constriction control and transverse aortic constriction carvedilol groups. Plasma b rain natriuretic peptide concentrations were elevated significantly in transverse aortic constriction control animals (~150%) compared to shams in association with changes in ejection fraction and heart weight and tended to decrease (~30%, p = 0.10-0.12) with the mid- and high-dose carvedilol treatment. A comparison of carvedilol hemodynamic and structural effects in the mouse transverse aortic constriction model versus clinical use indicates a strong agreement in effect profiles preclinical versus clinical, providing important translational validation for this widely used animal model. The present plasma brain natriuretic peptide biomarker findings support the measurement of plasma natriuretic peptides in the mouse transverse aortic constriction model to extend the translational utility of the model.