Long-Term Effectiveness and Safety of Dexmethylphenidate Extended-Release Capsules in Adult ADHD

ERIC Educational Resources Information Center

Adler, Lenard A.; Spencer, Thomas; McGough, James J.; Jiang, Hai; Muniz, Rafael

2009-01-01

Objective: This study evaluates dexmethylphenidate extended release (d-MPH-ER) in adults with ADHD. Method: Following a 5-week, randomized, controlled, fixed-dose study of d-MPH-ER 20 to 40 mg/d, 170 adults entered a 6-month open-label extension (OLE) to assess long-term safety, with flexible dosing of 20 to 40 mg/d. Exploratory effectiveness…

Dose Equivalents for Second-Generation Antipsychotic Drugs: The Classical Mean Dose Method

PubMed Central

Leucht, Stefan; Samara, Myrto; Heres, Stephan; Patel, Maxine X.; Furukawa, Toshi; Cipriani, Andrea; Geddes, John; Davis, John M.

2015-01-01

Background: The concept of dose equivalence is important for many purposes. The classical approach published by Davis in 1974 subsequently dominated textbooks for several decades. It was based on the assumption that the mean doses found in flexible-dose trials reflect the average optimum dose which can be used for the calculation of dose equivalence. We are the first to apply the method to second-generation antipsychotics. Methods: We searched for randomized, double-blind, flexible-dose trials in acutely ill patients with schizophrenia that examined 13 oral second-generation antipsychotics, haloperidol, and chlorpromazine (last search June 2014). We calculated the mean doses of each drug weighted by sample size and divided them by the weighted mean olanzapine dose to obtain olanzapine equivalents. Results: We included 75 studies with 16 555 participants. The doses equivalent to 1 mg/d olanzapine were: amisulpride 38.3 mg/d, aripiprazole 1.4 mg/d, asenapine 0.9 mg/d, chlorpromazine 38.9 mg/d, clozapine 30.6 mg/d, haloperidol 0.7 mg/d, quetiapine 32.3mg/d, risperidone 0.4mg/d, sertindole 1.1 mg/d, ziprasidone 7.9 mg/d, zotepine 13.2 mg/d. For iloperidone, lurasidone, and paliperidone no data were available. Conclusions: The classical mean dose method is not reliant on the limited availability of fixed-dose data at the lower end of the effective dose range, which is the major limitation of “minimum effective dose methods” and “dose-response curve methods.” In contrast, the mean doses found by the current approach may have in part depended on the dose ranges chosen for the original trials. Ultimate conclusions on dose equivalence of antipsychotics will need to be based on a review of various methods. PMID:25841041

Development of a flexible γ-ray detector using a liquid scintillation light guide (LSLG).

PubMed

Nomura, Kiyoshi; Yunoki, Akira; Hara, Masayuki; Morito, Yuko; Fujishima, Akira

2018-04-10

A flexible γ detector using a liquid scintillation light guide (LSLG) was developed. The analyzed pulse height (PHA) spectrum depended on the diameter, length and scintillator concentration of the LSLG, and the distance of a γ ray irradiation point from the head of photomultiplier tube (PMT). From the analysis of PHA spectrum, it was found that the count ratio of two divided channel regions linearly decreases as the distance from the PMT head increases. It was further found that the radiation dose rate can be estimated by setting the flexible LSLG tube to a circular shape since the count rate is proportional to the dose rate measured by a conventional NaI (Tl) scintillation detector. Therefore, a flexible and long LSLG detector using a single PMT is useful for determination of the dose rate and has a potential to detect local contaminations in a certain narrow space. Copyright © 2018. Published by Elsevier Ltd.

Effect of aripiprazole 2 to 15 mg/d on health-related quality of life in the treatment of irritability associated with autistic disorder in children: a post hoc analysis of two controlled trials.

PubMed

Varni, James W; Handen, Benjamin L; Corey-Lisle, Patricia K; Guo, Zhenchao; Manos, George; Ammerman, Diane K; Marcus, Ronald N; Owen, Randall; McQuade, Robert D; Carson, William H; Mathew, Suja; Mankoski, Raymond

2012-04-01

There are limited published data on the impact of treatment on the health-related quality of life (HRQOL) in individuals with autistic disorder. The aim of this study was to evaluate the impact of aripiprazole on HRQOL in the treatment of irritability in pediatric patients (aged 6-17 years) with autistic disorder. This post hoc analysis assessed data from two 8-week, double-blind, randomized, placebo-controlled studies that compared the efficacy of aripiprazole (fixed-dose study, 5, 10, and 15 mg/d; flexible-dose study, 2-15 mg/d) with placebo in the treatment of irritability associated with autistic disorder. HRQOL was assessed at baseline and week 8 using 3 Pediatric Quality of Life Inventory (PedsQL™) scales. Clinically relevant improvement in HRQOL was determined using an accepted distribution-based criterion-1 standard error of measurement. In total, 316 patients were randomly assigned to receive treatment with aripiprazole (fixed-dose study, 166; flexible-dose study, 47) or placebo (fixed-dose study, 52; flexible-dose study, 51). Aripiprazole was associated with significantly greater improvement than placebo in PedsQL combined-scales total score (difference, 7.8; 95% CI, 3.8-11.8; P < 0.001) and in 3 PedsQL scale scores (differences [95% CI]: Emotional Functioning, 7.8 [3.4-12.2]; Social Functioning, 6.2 [0.7-11.8]; Cognitive Functioning, 9.3 [3.8-14.9]; all, P < 0.05). Patients who received aripiprazole were significantly more likely than those who received placebo to have a clinically meaningful improvement on the combined-scales total score (odds ratio [OR] = 1.9; 95% CI, 1.0-3.3; P < 0.05), Emotional Functioning scale (OR = 2.2; 95% CI, 1.2-4.0; P < 0.05) and Social Functioning scale (OR = 2.2; 95% CI, 1.2-4.1; P < 0.05), and were significantly less likely to experience deterioration (OR: 0.3, 95% CI: 0.1-0.8; P < 0.05) when "Stable" was used as the reference group. The findings from the present post hoc analysis suggest that aripiprazole was associated with improved HRQOL, as assessed using 3 PedsQL scales, in pediatric patients with irritability associated with autistic disorder. Copyright © 2012 Elsevier HS Journals, Inc. All rights reserved.

Effect of ionizing radiation on physicochemical and mechanical properties of commercial multilayer coextruded flexible plastics packaging materials

NASA Astrophysics Data System (ADS)

Goulas, Antonios E.; Riganakos, Kyriakos A.; Kontominas, Michael G.

2003-12-01

The effect of gamma radiation (doses: 5, 10 and 30 kGy) on mechanical properties, gas and water vapour permeability and overall migration values into distilled water, 3% aqueous acetic acid and iso-octane was studied for a series of commercial multilayer flexible packaging materials based on coextruded polypropylene (PP), ethylene vinyl alcohol (EVOH), low-density polyethylene (LDPE), linear low-density polyethylene (LLDPE), polyamide (PA) and Ionomer. The results showed that radiation doses of 5 and 10 kGy induced no statistically significant differences ( p>0.05) in all polymer properties examined. A dose of 30 kGy induced differences ( p<0.05) in the mechanical properties of PA/LDPE, LDPE/EVOH/LDPE and LDPE/PA/Ionomer films. In addition, the same dose induced differences ( p<0.05) in the overall migration from Ionomer/EVOH/LDPE and LDPE/PA/Ionomer films into 3% acetic acid and iso-octane and in the overall migration from PP/EVOH/LDPE-LLDPE into iso-octane. Differences recorded, are discussed in relation to food irradiation applications of respective packaging materials.

Usage and Dose Response of a Mobile Acceptance and Commitment Therapy App: Secondary Analysis of the Intervention Arm of a Randomized Controlled Trial

PubMed Central

Lappalainen, Raimo; Välkkynen, Pasi; Sairanen, Essi; Lappalainen, Päivi; Karhunen, Leila; Peuhkuri, Katri; Korpela, Riitta; Kolehmainen, Marjukka; Ermes, Miikka

2016-01-01

Background Mobile phone apps offer a promising medium to deliver psychological interventions. A mobile app based on Acceptance and Commitment Therapy (ACT) was developed and studied in a randomized controlled trial (RCT). Objective To study usage metrics of a mobile ACT intervention and dose-response relationship between usage and improvement in psychological flexibility. Methods An RCT was conducted to investigate the effectiveness of different lifestyle interventions for overweight people with psychological stress. This paper presents a secondary analysis of the group that received an 8-week mobile ACT intervention. Most of the analyzed 74 participants were female (n=64, 86%). Their median age was 49.6 (interquartile range, IQR 45.4-55.3) years and their mean level of psychological flexibility, measured with the Acceptance and Action Questionnaire II, was 20.4 (95% confidence interval 18.3-22.5). Several usage metrics describing the intensity of use, usage of content, and ways of use were calculated. Linear regression analyses were performed to study the dose-response relationship between usage and the change in psychological flexibility and to identify the usage metrics with strongest association with improvement. Binary logistic regression analyses were further used to assess the role of usage metrics between those who showed improvement in psychological flexibility and those who did not. In addition, associations between usage and baseline participant characteristics were studied. Results The median number of usage sessions was 21 (IQR 11.8-35), the number of usage days was 15 (IQR 9.0-24), and the number of usage weeks was 7.0 (IQR 4.0-8.0). The participants used the mobile app for a median duration of 4.7 (IQR 3.2-7.2) hours and performed a median of 63 (IQR 46-98) exercises. There was a dose-response relationship between usage and the change in psychological flexibility. The strongest associations with psychological flexibility (results adjusted with gender, age, and baseline psychological variables) were found for lower usage of Self as context related exercises (B=0.22, P=.001) and higher intensity of use, described by the number of usage sessions (B=−0.10, P=.01), usage days (B=−0.17, P=.008), and usage weeks (B=−0.73, P=.02), the number of exercises performed (B=−0.02, P=.03), and the total duration of use (B=−0.30, P=.04). Also, higher usage of Acceptance related exercises (B=−0.18, P=.04) was associated with improvement. Active usage was associated with female gender, older age, and not owning a smart mobile phone before the study. Conclusions The results indicated that active usage of a mobile ACT intervention was associated with improved psychological flexibility. Usage metrics describing intensity of use as well as two metrics related to the usage of content were found to be most strongly associated with improvement. Trial Registration ClinicalTrials.gov NCT01738256; https://clinicaltrials.gov/ct2/show/NCT01738256 (Archived by WebCite at http://www.webcitation.org/6iTePjPLL) PMID:27468653

The safety and efficacy of dexmedetomidine-remifentanil in children undergoing flexible bronchoscopy

PubMed Central

Li, Xia; Wang, Xue; Jin, Shuguang; Zhang, Dongsheng; Li, Yanuo

2017-01-01

Abstract Flexible bronchoscopy is more and more used for diagnosis and management of various pulmonary diseases in pediatrics. As poor coordination of children, the procedure is usually performed under general anesthesia with spontaneous or controlled ventilation to increase children and bronchoscopists’ safety and comfort. Previous studies have reported that dexmedetomidine (DEX) could be safely and effectively used for flexible bronchoscopy in both adulate and children. However, there is no trial to evaluate the dose-finding of safety and efficacy of dexmedetomidine-remifentanil (DEX-RF) in children undergoing flexible bronchoscopy. The objective of this study is to evaluate the dose-finding of safety and efficacy of DEX-RF in children undergoing flexible bronchoscopy. One hundred thirty-five children undergoing flexible bronchoscopy with DEX-RF were divided into 3 groups: Group DR1 (n = 47, DEX infusion at 0.5 μg·kg–1 for 10 minutes, then adjusted to 0.5–0.7 μg kg–1 h–1; RF infusion at 0.5 μg kg–1 for 2 minutes, then adjusted to 0.05–0.2 μg kg–1 min–1), Group DR2 (n = 43, DEX infusion at 1 μg kg–1 for 10 minutes, then adjusted to 0.5–0.7 μg kg–1 h–1; RF infusion at 1 μg kg–1 for 2 minutes, then adjusted to 0.05–0.2 μg kg–1 min–1), Group DR3 (n = 45, DEX infusion at 1.5 μg kg–1 for 10 minutes, then adjusted to 0.5–0.7 μg kg–1 h–1; RF infusion at 1 μg kg–1 for 2 minutes, then adjusted to 0.05–0.2 μg kg–1 min–1). Ramsay sedation scale of the 3 groups was maintained 3. Anesthesia onset time, total number of intraoperative children movements, hemodynamics (heart rate, arterial pressure, pulse oxygen saturation (SpO2), respiratory rate), total cumulative dose of dexmedetomidine and remifentanil, the amount of midazolam and lidocaine, time to first dose of rescue midazolam and lidocaine, postoperative recovery time, adverse events, bronchoscopist satisfaction score were recorded. Anesthesia onset time was significantly shorter in DR3 group (14.23 ± 5.45 vs 14.45 ± 5.12 vs 11.13 ± 4.51 minutes, respectively, of DR1, DR2, DR3, P = 0.003). Additionally, the perioperative hemodynamic profile was more stable in group DR3 than that in the other 2 groups. Total number of children movements during flexible bronchoscopy was higher in DR1 group than the other 2 groups (46.81% 22/47 vs 34.88% 15/43 vs 17.78% 8/45, respectively, of DR1, DR2, DR3, P = 0.012). Total doses of rescue midazolam and lidocaine were significantly higher in DR1 and DR2 groups than that of DR3 group (P = 0.000). The time to first dose of rescue midazolam and lidocaine was significantly longer in DR3 group than DR1 and DR2 groups (P = 0.000). Total cumulative dose of dexmedetomidine was more in DR2 and DR3 groups (P = 0.000), while the amount of remifentanil was more in DR1 and DR2 groups (P = 0.000). The time to recovery for discharge from the PACU was significantly shorter in DR1 group compared with the other 2 groups (P = 0.000). Results from bronchoscopist satisfaction score showed significantly higher in DR2 and DR3 groups than that of DR1 group (P = 0.025). There were significant differences among the 3 groups in terms of the overall incidence of hypertension, tachycardia, hypoxemia, and cough (P < 0.05). Though it required longer recovery time, high dose of DEX-RF, which provided better stable hemodynamic profiles and bronchoscopist satisfaction score, less amount of rescue scheme, and children movements, could be safely and efficacy used in children undergoing flexible bronchoscopy. PMID:28296782

NOTE: MMCTP: a radiotherapy research environment for Monte Carlo and patient-specific treatment planning

NASA Astrophysics Data System (ADS)

Alexander, A.; DeBlois, F.; Stroian, G.; Al-Yahya, K.; Heath, E.; Seuntjens, J.

2007-07-01

Radiotherapy research lacks a flexible computational research environment for Monte Carlo (MC) and patient-specific treatment planning. The purpose of this study was to develop a flexible software package on low-cost hardware with the aim of integrating new patient-specific treatment planning with MC dose calculations suitable for large-scale prospective and retrospective treatment planning studies. We designed the software package 'McGill Monte Carlo treatment planning' (MMCTP) for the research development of MC and patient-specific treatment planning. The MMCTP design consists of a graphical user interface (GUI), which runs on a simple workstation connected through standard secure-shell protocol to a cluster for lengthy MC calculations. Treatment planning information (e.g., images, structures, beam geometry properties and dose distributions) is converted into a convenient MMCTP local file storage format designated, the McGill RT format. MMCTP features include (a) DICOM_RT, RTOG and CADPlan CART format imports; (b) 2D and 3D visualization views for images, structure contours, and dose distributions; (c) contouring tools; (d) DVH analysis, and dose matrix comparison tools; (e) external beam editing; (f) MC transport calculation from beam source to patient geometry for photon and electron beams. The MC input files, which are prepared from the beam geometry properties and patient information (e.g., images and structure contours), are uploaded and run on a cluster using shell commands controlled from the MMCTP GUI. The visualization, dose matrix operation and DVH tools offer extensive options for plan analysis and comparison between MC plans and plans imported from commercial treatment planning systems. The MMCTP GUI provides a flexible research platform for the development of patient-specific MC treatment planning for photon and electron external beam radiation therapy. The impact of this tool lies in the fact that it allows for systematic, platform-independent, large-scale MC treatment planning for different treatment sites. Patient recalculations were performed to validate the software and ensure proper functionality.

Azelaic acid 15% gel once daily versus twice daily in papulopustular rosacea.

PubMed

Thiboutot, Diane M; Fleischer, Alan B; Del Rosso, James Q; Graupe, Klaus

2008-06-01

Twice-daily azelaic acid (AzA) is the conventional regimen for papulopustular rosacea, but once-daily AzA may be equally effective, with greater convenience and dosing flexibility. In order to test this hypothesis, an exploratory study was conducted. The evaluable efficacy population of this 12-week double-blind, parallel-group study included 72 patients and the population that was used to report safety results included 92 patients. Baseline characteristics were comparable between the once-daily and twice-daily study groups. Evaluations were performed at baseline and at weeks 4, 8, and 12. No significant difference was found between the once-daily and twice-daily groups at the end of study therapy in mean investigator global assessment (IGA) scores, treatment success, or treatment response. The mean number of inflammatory lesions, the intensity of erythema intensity, and the intensity of telangiectasia at treatment end were likewise not significantly different (P>.205 for all). More than 90% of subjects in each group rated cosmetic acceptability of this AzA gel as satisfactory or better. Based on these findings and those of prior studies, once-daily AzA 15% gel can therefore be utilized as a safe, effective, and economical dosing option for the treatment of mild-to-moderate papulopustular rosacea. Once-daily dosing of AzA 15% gel was well accepted by patients and can offer considerable dosing flexibility and convenience for the patient as well as for the dermatologist.

Cognitive performance of juvenile monkeys after chronic fluoxetine treatment.

PubMed

Golub, Mari S; Hackett, Edward P; Hogrefe, Casey E; Leranth, Csaba; Elsworth, John D; Roth, Robert H

2017-08-01

Potential long term effects on brain development are a concern when drugs are used to treat depression and anxiety in childhood. In this study, male juvenile rhesus monkeys (three-four years of age) were dosed with fluoxetine or vehicle (N=16/group) for two years. Histomorphometric examination of cortical dendritic spines conducted after euthanasia at one year postdosing (N=8/group) suggested a trend toward greater dendritic spine synapse density in prefrontal cortex of the fluoxetine-treated monkeys. During dosing, subjects were trained for automated cognitive testing, and evaluated with a test of sustained attention. After dosing was discontinued, sustained attention, recognition memory and cognitive flexibility were evaluated. Sustained attention was affected by fluoxetine, both during and after dosing, as indexed by omission errors. Response accuracy was not affected by fluoxetine in post-dosing recognition memory and cognitive flexibility tests, but formerly fluoxetine-treated monkeys compared to vehicle controls had more missed trial initiations and choices during testing. Drug treatment also interacted with genetic and environmental variables: MAOA genotype (high- and low transcription rate polymorphisms) and testing location (upper or lower tier of cages). Altered development of top-down cortical regulation of effortful attention may be relevant to this pattern of cognitive test performance after juvenile fluoxetine treatment. Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.

Safety and tolerability of vortioxetine (15 and 20 mg) in patients with major depressive disorder: results of an open-label, flexible-dose, 52-week extension study.

PubMed

Jacobsen, Paula L; Harper, Linda; Chrones, Lambros; Chan, Serena; Mahableshwarkar, Atul R

2015-09-01

Vortioxetine is approved for the treatment of adults with major depressive disorder. This open-label extension (OLE) study evaluated the safety and tolerability of vortioxetine in the long-term treatment of major depressive disorder patients, as well as evaluated its effectiveness using measures of depression, anxiety, and overall functioning. This was a 52-week, flexible-dose, OLE study in patients who completed one of three randomized, double-blind, placebo-controlled, 8-week vortioxetine trials. All patients were switched to 10 mg/day vortioxetine for week 1, then adjusted between 15 and 20 mg for the remainder of the study, but not downtitrated below 15 mg. Safety and tolerability were assessed on the basis of treatment-emergent adverse events (TEAEs), vital signs, laboratory values, physical examination, and the Columbia-Suicide Severity Rating Scale. Efficacy measures included the Montgomery-Åsberg Depression Rating Scale, the Hamilton Anxiety Scale, the Clinical Global Impression Scale-Severity of Illness, and the Sheehan Disability Scale. Of the 1075 patients enrolled, 1073 received at least one dose of vortioxetine and 538 (50.0%) completed the study. A total of 537 patients withdrew early, with 115 (10.7% of the original study population) withdrawing because of TEAEs. Long-term treatment with vortioxetine was well tolerated; the most common TEAEs (≥10%) were nausea and headache. Laboratory values, vital signs, and physical examinations revealed no trends of clinical concern. The mean Montgomery-Åsberg Depression Rating Scale total score was 19.9 at the start of the extension study and 9.0 after 52 weeks of treatment (observed cases). Similar improvements were observed with the Hamilton Anxiety Scale (Δ-4.2), the Clinical Global Impression Scale-Severity of Illness (Δ-1.2), and the Sheehan Disability Scale (Δ-4.7) total scores after 52 weeks of treatment (observed case). In this 52-week, flexible-dose OLE study, 15 and 20 mg vortioxetine were safe and well tolerated. After entry into this study, patients continued to show improvement in depression and anxiety symptoms, as well as overall functioning, throughout the treatment period.

The efficacy of dexmedetomidine-remifentanil versus dexmedetomidine-propofol in children undergoing flexible bronchoscopy

PubMed Central

Zhang, Hongquan; Fang, Baojun; Zhou, Wenjing

2017-01-01

Abstract Flexible bronchoscopy has been more and more used for diagnosis and management diseases of respiratory system in pediatrics. Previous studies have reported that remifentanil (RF) and propofol are safe and effective for flexible bronchoscopy in adults, however, there have no trials evaluate the efficacy of DEX-RF versus dexmedetomidine-propofol in children undergoing flexible bronchoscopy. We divided 123 children undergoing flexible bronchoscopy with DEX-RF or dexmedetomidine-propofol into 2 groups: Group DR (n = 63, DEX infusion at 1.0 μg kg−1 for 10 minutes, then adjusted to 0.5–0.7 μg kg−1 h−1; RF infusion at 1.0 μg kg−1 for 5 minutes, then adjusted to 0.05–0.2 μg kg−1 min−1), Group DP (n = 60, DEX infusion at 1.0 μg kg−1 for 10 minutes, then adjusted to 0.5–0.7 μg kg−1 h−1; propofol infusion at 10 μg kg−1 for 5 minutes, then adjusted to 0.05–0.1 μg kg−1 min−1). Ramsay sedation scale of the 2 groups was maintained at 3. Anesthesia onset time; total number of intraoperative patient movements; hemodynamics; total cumulative dose of DEX; amount of and time to first-dose rescue midazolam and lidocaine; postoperative recovery time; adverse events; and bronchoscopist satisfaction score were recorded. Anesthesia onset time was significantly shorter in DP (8.22 ± 2.48 vs 12.25 ± 6.43 minutes, respectively, for DP, DR, P = 0.015). The perioperative hemodynamic profile was more stable in DR than DP group. More children moved during flexible bronchoscopy in DP group (P = 0.009). Total dose of rescue midazolam and lidocaine was significantly higher in DR than in DP (P < 0.001). Similarly, the time to first dose of rescue midazolam and lidocaine was significantly longer in DP than in DR (P < 0.001). Total cumulative dose of DEX was more in DR than DP group (P < 0.001). The time to recovery for discharge from the postanesthesia care unit (PACU) was significantly shorter in DP than in DR group (P < 0.001). The bronchoscopist-satisfaction scores were higher for DR than DP (P = 0.036). There were significant differences between the 2 groups in terms of the overall incidence of hypertension, tachycardia, and hypoxemia (P < 0.05). Although underwent longer recovery time and more incidence of rescue scheme, DEX-RF resulted in more stable hemodynamic profiles and bronchoscopist-satisfaction scores, lesser patient movements, and can hence be more effectively used in children undergoing flexible bronchoscopy than dexmedetomidine-propofol. PMID:28072737

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

PubMed

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

2016-12-15

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

Cost-effectiveness of rotavirus vaccination in peru.

PubMed

Clark, Andrew D; Walker, Damian G; Mosqueira, N Rocio; Penny, Mary E; Lanata, Claudio F; Fox-Rushby, Julia; Sanderson, Colin F B

2009-11-01

There are plans to introduce the oral rotavirus vaccine Rotarix (GlaxoSmithKline), 1 of 2 recently developed vaccines against rotavirus, in Peru. We modeled the cost-effectiveness of adding a rotavirus vaccine to the Peruvian immunization program under 3 scenarios for the timing of vaccination: (1) strictly according to schedule, at 2 and 4 months of age (on time); (2) distributed around the target ages in the same way as the actual timings in the program (flexible); and (3) flexible but assuming vaccination is not initiated for infants >12 weeks of age (restricted). We assumed an introductory price of US $7.50 per dose, and varied the annual rate of price decrease in sensitivity analyses. The discounted cost per disability-adjusted life-year averted for restricted, flexible, and on-time schedules was $621, $615, and $581, respectively. For each of the 3 scenarios, the percentage reduction in deaths due to rotavirus infection was 53%, 66%, and 69%, respectively. The cost per disability-adjusted life-year averted for alternative "what-if" scenarios ranged from $229 (assuming a 1-dose schedule, administered on time) to $1491 (assuming a 2-dose schedule, with half the baseline vaccine efficacy rates and a restricted timing policy). On the basis of current World Health Organization guidelines, rotavirus vaccination represents a highly cost-effective intervention in Peru. Withholding the vaccine from children who present for their first dose after 12 weeks of age would reduce the number of deaths averted by approximately 20%. A single dose may be more cost-effective than 2 doses, but more evidence on the protection conferred by a single dose is required.

A flexible-dose dispenser for immediate and extended release 3D printed tablets.

PubMed

Pietrzak, Katarzyna; Isreb, Abdullah; Alhnan, Mohamed A

2015-10-01

The advances in personalised medicine increased the demand for a fast, accurate and reliable production method of tablets that can be digitally controlled by healthcare staff. A flexible dose tablet system is presented in this study that proved to be suitable for immediate and extended release tablets with a realistic drug loading and an easy-to-swallow tablet design. The method bridges the affordable and digitally controlled Fused Deposition Modelling (FDM) 3D printing with a standard pharmaceutical manufacturing process, Hot Melt Extrusion (HME). The reported method was compatible with three methacrylic polymers (Eudragit RL, RS and E) as well as a cellulose-based one (hydroxypropyl cellulose, HPC SSL). The use of a HME based pharmaceutical filament preserved the linear relationship between the mass and printed volume and was utilized to digitally control the dose via an input from computer software with dose accuracy in the range of 91-95%. Higher resolution printing quality doubled the printing time, but showed a little effect on in vitro release pattern of theophylline and weight accuracy. Physical characterization studies indicated that the majority of the model drug (theophylline) in the 3D printed tablet exists in a crystal form. Owing to the small size, ease of use and the highly adjustable nature of FDM 3D printers, the method holds promise for future individualised treatment. Copyright © 2015. Published by Elsevier B.V.

Quantifying the dose-response relationship between circulating folate concentrations and colorectal cancer in cohort studies: a meta-analysis based on a flexible meta-regression model.

PubMed

Chuang, Shu-Chun; Rota, Matteo; Gunter, Marc J; Zeleniuch-Jacquotte, Anne; Eussen, Simone J P M; Vollset, Stein Emil; Ueland, Per Magne; Norat, Teresa; Ziegler, Regina G; Vineis, Paolo

2013-10-01

Most epidemiologic studies on folate intake suggest that folate may be protective against colorectal cancer, but the results on circulating (plasma or serum) folate are mostly inconclusive. We conducted a meta-analysis of case-control studies nested within prospective studies on circulating folate and colorectal cancer risk by using flexible meta-regression models to test the linear and nonlinear dose-response relationships. A total of 8 publications (10 cohorts, representing 3,477 cases and 7,039 controls) were included in the meta-analysis. The linear and nonlinear models corresponded to relative risks of 0.96 (95% confidence interval (CI): 0.91, 1.02) and 0.99 (95% CI: 0.96, 1.02), respectively, per 10 nmol/L of circulating folate in contrast to the reference value. The pooled relative risks when comparing the highest with the lowest category were 0.80 (95% CI: 0.61, 0.99) for radioimmunoassay and 1.03 (95% CI: 0.83, 1.22) for microbiological assay. Overall, our analyses suggest a null association between circulating folate and colorectal cancer risk. The stronger association for the radioimmunoassay-based studies could reflect differences in cohorts and study designs rather than assay performance. Further investigations need to integrate more accurate measurements and flexible modeling to explore the effects of folate in the presence of genetic, lifestyle, dietary, and hormone-related factors.

Dose Estimating Application Software Modification: Additional Function of a Size-Specific Effective Dose Calculator and Auto Exposure Control.

PubMed

Kobayashi, Masanao; Asada, Yasuki; Matsubara, Kosuke; Suzuki, Shouichi; Matsunaga, Yuta; Haba, Tomonobu; Kawaguchi, Ai; Daioku, Tomihiko; Toyama, Hiroshi; Kato, Ryoichi

2017-05-01

Adequate dose management during computed tomography is important. In the present study, the dosimetric application software ImPACT was added to a functional calculator of the size-specific dose estimate and was part of the scan settings for the auto exposure control (AEC) technique. This study aimed to assess the practicality and accuracy of the modified ImPACT software for dose estimation. We compared the conversion factors identified by the software with the values reported by the American Association of Physicists in Medicine Task Group 204, and we noted similar results. Moreover, doses were calculated with the AEC technique and a fixed-tube current of 200 mA for the chest-pelvis region. The modified ImPACT software could estimate each organ dose, which was based on the modulated tube current. The ability to perform beneficial modifications indicates the flexibility of the ImPACT software. The ImPACT software can be further modified for estimation of other doses. © The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

No role of beta receptors in cognitive flexibility: Evidence from a task-switching paradigm in a randomized controlled trial.

PubMed

Steenbergen, L; Sellaro, R; de Rover, M; Hommel, B; Colzato, L S

2015-06-04

There is evidence that noradrenergic coeruleo-cortical projections are involved in different forms of cognitive flexibility. So far, no studies in humans have investigated the involvement of beta receptors on task-switching performance, a well-established measure of cognitive flexibility. The present study investigated whether the administration of propranolol (a central and peripheral beta-adrenergic antagonist) affected switching costs (i.e., the increase of reaction time in task-switching trials relative to task-repetition trials). Sixteen healthy adult human subjects performed a global-local task-switching paradigm in a double-blind, within-subjects design study investigating the effects of 80mg of propranolol hydrochloride (a β1 and β2 adrenergic receptor antagonist) vs. an oral dose of microcrystalline cellulose (placebo pill). The acute administration of propranolol did not affect the size of switching costs compared to the intake of the neutral placebo. Our results, corroborated by Bayesian inference, suggest that beta receptors do not modulate cognitive flexibility as measured by task-switching performance. Copyright © 2015 IBRO. Published by Elsevier Ltd. All rights reserved.

Safety and tolerability of vortioxetine (15 and 20 mg) in patients with major depressive disorder: results of an open-label, flexible-dose, 52-week extension study

PubMed Central

Jacobsen, Paula L.; Harper, Linda; Chrones, Lambros; Chan, Serena

2015-01-01

Vortioxetine is approved for the treatment of adults with major depressive disorder. This open-label extension (OLE) study evaluated the safety and tolerability of vortioxetine in the long-term treatment of major depressive disorder patients, as well as evaluated its effectiveness using measures of depression, anxiety, and overall functioning. This was a 52-week, flexible-dose, OLE study in patients who completed one of three randomized, double-blind, placebo-controlled, 8-week vortioxetine trials. All patients were switched to 10 mg/day vortioxetine for week 1, then adjusted between 15 and 20 mg for the remainder of the study, but not downtitrated below 15 mg. Safety and tolerability were assessed on the basis of treatment-emergent adverse events (TEAEs), vital signs, laboratory values, physical examination, and the Columbia-Suicide Severity Rating Scale. Efficacy measures included the Montgomery–Åsberg Depression Rating Scale, the Hamilton Anxiety Scale, the Clinical Global Impression Scale-Severity of Illness, and the Sheehan Disability Scale. Of the 1075 patients enrolled, 1073 received at least one dose of vortioxetine and 538 (50.0%) completed the study. A total of 537 patients withdrew early, with 115 (10.7% of the original study population) withdrawing because of TEAEs. Long-term treatment with vortioxetine was well tolerated; the most common TEAEs (≥10%) were nausea and headache. Laboratory values, vital signs, and physical examinations revealed no trends of clinical concern. The mean Montgomery–Åsberg Depression Rating Scale total score was 19.9 at the start of the extension study and 9.0 after 52 weeks of treatment (observed cases). Similar improvements were observed with the Hamilton Anxiety Scale (Δ−4.2), the Clinical Global Impression Scale-Severity of Illness (Δ−1.2), and the Sheehan Disability Scale (Δ−4.7) total scores after 52 weeks of treatment (observed case). In this 52-week, flexible-dose OLE study, 15 and 20 mg vortioxetine were safe and well tolerated. After entry into this study, patients continued to show improvement in depression and anxiety symptoms, as well as overall functioning, throughout the treatment period. PMID:26020712

Qualitative assessment of user experiences of a novel smart phone application designed to support flexible intensive insulin therapy in type 1 diabetes.

PubMed

Knight, Brigid A; McIntyre, H David; Hickman, Ingrid J; Noud, Marina

2016-09-15

Modern flexible multiple daily injection (MDI) therapy requires people with diabetes to manage complex mathematical calculations to determine insulin doses on a day to day basis. Automated bolus calculators assist with these calculations, add additional functionality to protect against hypoglycaemia and enhance the record keeping process, however uptake and use depends on the devices meeting the needs of the user. We aimed to obtain user feedback on the usability of a mobile phone bolus calculator application in adults with T1DM to inform future development of mobile phone diabetes support applications. Adults with T1DM who had previously received education in flexible MDI therapy were invited to participate. Eligible respondents attended app education and one month later participated in a focus group to provide feedback on the features of the app in relation to usability for patient-based flexible MDI and future app development. Seven adults participated in the app training and follow up interview. App features that support dose adjustment to reduce hypoglycaemia risk and features that enable greater efficiency in dose calculation, record keeping and report generation were highly valued. Adults who are self managing flexible MDI found the Rapidcalc mobile phone app to be a useful self-management tool and additional features to further improve usability, such as connectivity with BG meter and food databases, shortcut options to economise data entry and web based storage of data, were identified. Further work is needed to ascertain specific features and benefit for those with lower health literacy.

A Flexible-Dose Study of Paliperidone ER in Patients With Nonacute Schizophrenia Previously Treated Unsuccessfully With Oral Olanzapine

PubMed Central

KOTLER, MOSHE; DILBAZ, NESRIN; ROSA, FERNANDA; PATERAKIS, PERIKLIS; MILANOVA, VIHRA; SMULEVICH, ANATOLY B.; LAHAYE, MARJOLEIN

2016-01-01

Objective: The goal of this study was to explore the tolerability, safety, and treatment response of switching from oral olanzapine to paliperidone extended release (ER). Methods: Adult patients with nonacute schizophrenia who had been treated unsuccessfully with oral olanzapine were switched to flexible doses of paliperidone ER (3 to 12 mg/d). The primary efficacy outcome was a ≥20% improvement in Positive and Negative Syndrome Scale (PANSS) total scores from baseline to endpoint for patients who switched medications because of lack of efficacy with olanzapine and noninferiority versus previous olanzapine treatment (mean endpoint change in PANSS total scores vs. baseline of ≤5 points) for patients who switched for reasons other than lack of efficacy. Safety and tolerability were assessed by monitoring adverse events, extrapyramidal symptoms, and weight change. Results: Of 396 patients, 65.2% were men, mean age was 40.0±12.0 years, and 75.5% had paranoid schizophrenia. Among the patients whose main reason for switching was lack of efficacy, an improvement in the PANSS total score of ≥20% occurred in 57.4% of patients. Noninferiority was confirmed for each subgroup of patients whose main reason for switching was something other than lack of efficacy. Paliperidone ER was generally well tolerated. Extrapyramidal symptoms as measured by total Extrapyramidal Symptom Rating Scale scores showed statistically significant and clinically relevant improvements at endpoint, the average weight decreased by 0.8±5.2 kg at endpoint, and a clinically relevant weight gain of ≥7% occurred in 8.0% of patients. Conclusion: Paliperidone ER flexibly-dosed over 6 months was well tolerated and associated with a meaningful clinical response in patients with nonacute schizophrenia who had previously been unsuccessfully treated with oral olanzapine. PMID:26813484

A Flexible-Dose Study of Paliperidone ER in Patients With Nonacute Schizophrenia Previously Treated Unsuccessfully With Oral Olanzapine.

PubMed

Kotler, Moshe; Dilbaz, Nesrin; Rosa, Fernanda; Paterakis, Periklis; Milanova, Vihra; Smulevich, Anatoly B; Lahaye, Marjolein; Schreiner, Andreas

2016-01-01

The goal of this study was to explore the tolerability, safety, and treatment response of switching from oral olanzapine to paliperidone extended release (ER). Adult patients with nonacute schizophrenia who had been treated unsuccessfully with oral olanzapine were switched to flexible doses of paliperidone ER (3 to 12 mg/d). The primary efficacy outcome was a ≥ 20% improvement in Positive and Negative Syndrome Scale (PANSS) total scores from baseline to endpoint for patients who switched medications because of lack of efficacy with olanzapine and noninferiority versus previous olanzapine treatment (mean endpoint change in PANSS total scores vs. baseline of ≤ 5 points) for patients who switched for reasons other than lack of efficacy. Safety and tolerability were assessed by monitoring adverse events, extrapyramidal symptoms, and weight change. Of 396 patients, 65.2% were men, mean age was 40.0 ± 12.0 years, and 75.5% had paranoid schizophrenia. Among the patients whose main reason for switching was lack of efficacy, an improvement in the PANSS total score of ≥ 20% occurred in 57.4% of patients. Noninferiority was confirmed for each subgroup of patients whose main reason for switching was something other than lack of efficacy. Paliperidone ER was generally well tolerated. Extrapyramidal symptoms as measured by total Extrapyramidal Symptom Rating Scale scores showed statistically significant and clinically relevant improvements at endpoint, the average weight decreased by 0.8 ± 5.2 kg at endpoint, and a clinically relevant weight gain of ≥ 7% occurred in 8.0% of patients. Paliperidone ER flexibly-dosed over 6 months was well tolerated and associated with a meaningful clinical response in patients with nonacute schizophrenia who had previously been unsuccessfully treated with oral olanzapine.

The safety, tolerability, pharmacokinetics and cognitive effects of GSK239512, a selective histamine H₃ receptor antagonist in patients with mild to moderate Alzheimer's disease: a preliminary investigation.

PubMed

Nathan, Pradeep J; Boardley, Rebecca; Scott, Nicola; Berges, Alienor; Maruff, Paul; Sivananthan, Tharani; Upton, Neil; Lowy, Martin T; Nestor, Peter J; Lai, Robert

2013-03-01

The histamine H3 receptor plays a critical role in the negative neuromodulation of neurotransmitters involved in cognitive function. H3 receptor antagonists/inverse agonists have been shown to exert pro-cognitive effects in pre-clinical models. GSK239512 is a potent and selective H₃ receptor antagonist developed for the treatment of cognitive dysfunction in neurodegenerative disorders. In this study we examined the safety, tolerability, pharmacokinetics and pro-cognitive effects of GSK239512 (oral) in patients with mild to moderate Alzheimer's disease using ascending dose titration regimens. The study was conducted in two parts. Part A was a single-blind, placebo run-in, flexible dose titration over 9 days in two cohorts, each consisting of two patients. Part B was a double-blind, randomised, placebo controlled, parallel group, which investigated 3 flexible dose titration regimens over 4 weeks in 3 cohorts, each consisting of eight patients. Overall, the 5/10/20/40 μg and 10/20/40/80 μg regimens were well-tolerated. The regimen of 20/40/80/150 μg showed the poorest tolerability likely due to the higher starting dose. There were no clinically significant abnormalities in haematology, clinical chemistry, urinalysis parameters and cardiovascular parameters. GSK239512 had positive effects on tasks of attention and memory with effect sizes between 0.56 and 1.37. GSK239512 displayed asatisfactory level of tolerability in patients with Alzheimer's disease with evidence for positive effects on attention and memory. The findings suggest that a titration regimen with a starting dose of 5-10 μg and a maximum dose of 80 μg is likely to be a well-tolerated and potentially efficacious regimen for future clinical trials in patients with Alzheimer's disease. These findings await replication in a larger study.

Software Development for Estimating the Conversion Factor (K-Factor) at Suitable Scan Areas, Relating the Dose Length Product to the Effective Dose.

PubMed

Kobayashi, Masanao; Asada, Yasuki; Matsubara, Kosuke; Suzuki, Syouichi; Koshida, Kichiro; Matsunaga, Yuta; Kawaguchi, Ai; Haba, Tomonobu; Toyama, Hiroshi; Kato, Ryouichi

2017-05-01

We developed a k-factor-creator software (kFC) that provides the k-factor for CT examination in an arbitrary scan area. It provides the k-factor from the effective dose and dose-length product by Imaging Performance Assessment of CT scanners and CT-EXPO. To assess the reliability, we compared the kFC-evaluated k-factors with those of the International Commission on Radiological Protection (ICRP) publication 102. To confirm the utility, the effective dose determined by coronary computed tomographic angiography (CCTA) was evaluated by a phantom study and k-factor studies. In the CCTA, the effective doses were 5.28 mSv in the phantom study, 2.57 mSv (51%) in the k-factor of ICRP, and 5.26 mSv (1%) in the k-factor of the kFC. Effective doses can be determined from the kFC-evaluated k-factors in suitable scan areas. Therefore, we speculate that the flexible k-factor is useful in clinical practice, because CT examinations are performed in various scan regions. © The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

A Bayesian Dose-finding Design for Oncology Clinical Trials of Combinational Biological Agents

PubMed Central

Cai, Chunyan; Yuan, Ying; Ji, Yuan

2013-01-01

Treating patients with novel biological agents is becoming a leading trend in oncology. Unlike cytotoxic agents, for which efficacy and toxicity monotonically increase with dose, biological agents may exhibit non-monotonic patterns in their dose-response relationships. Using a trial with two biological agents as an example, we propose a dose-finding design to identify the biologically optimal dose combination (BODC), which is defined as the dose combination of the two agents with the highest efficacy and tolerable toxicity. A change-point model is used to reflect the fact that the dose-toxicity surface of the combinational agents may plateau at higher dose levels, and a flexible logistic model is proposed to accommodate the possible non-monotonic pattern for the dose-efficacy relationship. During the trial, we continuously update the posterior estimates of toxicity and efficacy and assign patients to the most appropriate dose combination. We propose a novel dose-finding algorithm to encourage sufficient exploration of untried dose combinations in the two-dimensional space. Extensive simulation studies show that the proposed design has desirable operating characteristics in identifying the BODC under various patterns of dose-toxicity and dose-efficacy relationships. PMID:24511160

Effects of ionizing radiation on properties of monolayer and multilayer flexible food packaging materials

NASA Astrophysics Data System (ADS)

Riganakos, K. A.; Koller, W. D.; Ehlermann, D. A. E.; Bauer, B.; Kontominas, M. G.

1999-05-01

Volatile compounds produced in flexible food packaging materials (LDPE, EVAc, PET/PE/EVOH/PE) during electron beam irradiation were isolated by purge and trap technique and identified by combined gas chromatography-mass spectrometry (GC/MS), after thermal desorption and concentration. For comparison purposes non-irradiated films were also studied. Film samples were irradiated at low (5 kGy, corresponding to cold pasteurization), intermediate (20 kGy, corresponding to cold sterilization) and high (100 kGy) doses. It was observed that a number of volatile compounds are produced after irradiation in all cases. Furthermore the amounts of all volatile compounds increase with increasing irradiation dose. Both primary (methyl-derivatives etc.) as well as secondary i.e. oxidation products (ketones, aldehydes, alcohols, carboxylic acids etc.) are produced upon irradiation. These products may affect organoleptic properties and thus shelf-life of prepackaged irradiated foods. No significant changes were observed in the structure of polymer matrices as exhibited by IR spectra after irradiation of the materials at doses tested. Likewise, no significant changes were observed in O 2, H 2O and CO 2 permeability values of plastic packaging materials after irradiation.

A FLEXIBLE APPROACH FOR EVALUATING FIXED RATIO MIXTURES OF FULL AND PARTIAL AGONISTS FOR MIXTURES OF MANY CHEMICALS.

EPA Science Inventory

Detecting interaction in chemical mixtures can be complicated by differences in the shapes of the dose-response curves of the individual components (e.g. mixtures of full and partial agonists with differing response maxima). We present an analysis scheme where flexible single che...

Development and characterization of thermal responsivehydrogel films for biomedical sensor application

NASA Astrophysics Data System (ADS)

López-Barriguete, Jesús Eduardo; Isoshima, Takashi; Bucio, Emilio

2018-04-01

Two flexible stimuli-responsive hydrogel films were elaborated as biomedical sensor application. The hydrogel systems were contained in glass moulds and synthesized using gamma radiation at a dose rate of 10.1 kGy h‑1, and absorbed dose of 50 kGy. The poly(NIPAAm) with a low critical solution temperature (LCST) close to the human body temperature, was employed as the principal component for the responsive materials. The addition of dimethyl acrylamide (DMAAm) for hydrophilic effect, methyl methacrylate (MMA) for mechanical property, and ethoxyethyl methacrylate (EEM) for mechanical property, modified the thermo dynamic transition point, obtaining viable responsive films with LCST of 36 °C and 39 °C. The samples were characterized by DSC to analyse the LCST, FT-IR to characterize the functional groups of the resulting films, AFM to examine the surface morphology, and swelling measurement to support the flexibility. Responsive ‘intelligent’ films with thermo sensitivity, biocompatibility, resistance, and conformableness are important to the development of flexible polymers for the application of biological sensor, smart membranes, or flexible electronics.

In vivo dose verification of IMRT treated head and neck cancer patients.

PubMed

Engström, Per E; Haraldsson, Pia; Landberg, Torsten; Sand Hansen, Hanne; Aage Engelholm, Svend; Nyström, Håkan

2005-01-01

An independent in vivo dose verification procedure for IMRT treatments of head and neck cancers was developed. Results of 177 intracavitary TLD measurements from 10 patients are presented. The study includes data from 10 patients with cancer of the rhinopharynx or the thyroid treated with dynamic IMRT. Dose verification was performed by insertion of a flexible naso-oesophageal tube containing TLD rods and markers for EPID and simulator image detection. Part of the study focussed on investigating the accuracy of the TPS calculations in the presence of inhomogeneities. Phantom measurements and Monte Carlo simulations were performed for a number of geometries involving lateral electronic disequilibrium and steep density shifts. The in vivo TLD measurements correlated well with the predictions of the treatment planning system with a measured/calculated dose ratio of 1.002+/-0.051 (1 SD, N=177). The measurements were easily performed and well tolerated by the patients. We conclude that in vivo intracavitary dosimetry with TLD is suitable and accurate for dose determination in intensity-modulated beams.

Local ROI Reconstruction via Generalized FBP and BPF Algorithms along More Flexible Curves.

PubMed

Yu, Hengyong; Ye, Yangbo; Zhao, Shiying; Wang, Ge

2006-01-01

We study the local region-of-interest (ROI) reconstruction problem, also referred to as the local CT problem. Our scheme includes two steps: (a) the local truncated normal-dose projections are extended to global dataset by combining a few global low-dose projections; (b) the ROI are reconstructed by either the generalized filtered backprojection (FBP) or backprojection-filtration (BPF) algorithms. The simulation results show that both the FBP and BPF algorithms can reconstruct satisfactory results with image quality in the ROI comparable to that of the corresponding global CT reconstruction.

Oral drug delivery in personalized medicine: unmet needs and novel approaches.

PubMed

Wening, Klaus; Breitkreutz, Jörg

2011-02-14

Increasing knowledge into personalized medicine has demonstrated the need for individual dosing. Drug dosage forms are urgently needed enabling an individual therapy, especially for oral drug delivery. This review is focusing on approaches for solid and liquid oral dosage forms for individual dosing. The proposed dosage forms and devices may be distinguished into assembling and partition concepts and have been categorized regarding their applicability, costs, dose flexibility and potential benefits. Opportunities, challenges and further unmet needs are elaborated and critically discussed. Liquid dosage forms can be accurately dosed by novel dropping tubes or oral syringes, but less precisely by dosing spoons and cups. Breaking scored tablets into fragments show major risks such as inaccurate dosing, formation of potent dust and stability issues of the residual segments. Novel approaches are proposed for solid dosage forms enabling a flexible and appropriate therapy such as various dispensers for multiparticulate drug formulations. However, most of the proposals still have to prove their applicability in practice. Promising concepts are the solid dosage pen and drug-loaded oral films which can be cut in individual sections enabling freely selectable doses. Further research and development are required for novel dosage forms and medical devices appropriate for individualized therapy. Copyright © 2010 Elsevier B.V. All rights reserved.

Comparison of a flexible versus a rigid breast compression paddle: pain experience, projected breast area, radiation dose and technical image quality.

PubMed

Broeders, Mireille J M; Ten Voorde, Marloes; Veldkamp, Wouter J H; van Engen, Ruben E; van Landsveld-Verhoeven, Cary; 't Jong-Gunneman, Machteld N L; de Win, Jos; Greve, Kitty Droogh-de; Paap, Ellen; den Heeten, Gerard J

2015-03-01

To compare pain, projected breast area, radiation dose and image quality between flexible (FP) and rigid (RP) breast compression paddles. The study was conducted in a Dutch mammographic screening unit (288 women). To compare both paddles one additional image with RP was made, consisting of either a mediolateral-oblique (MLO) or craniocaudal-view (CC). Pain experience was scored using the Numeric Rating Scale (NRS). Projected breast area was estimated using computer software. Radiation dose was estimated using the model by Dance. Image quality was reviewed by three radiologists and three radiographers. There was no difference in pain experience between both paddles (mean difference NRS: 0.08 ± 0.08, p = 0.32). Mean radiation dose was 4.5 % lower with FP (0.09 ± 0.01 p = 0.00). On MLO-images, the projected breast area was 0.79 % larger with FP. Paired evaluation of image quality indicated that FP removed fibroglandular tissue from the image area and reduced contrast in the clinically relevant retroglandular area at chest wall side. Although FP performed slightly better in the projected breast area, it moved breast tissue from the image area at chest wall side. RP showed better contrast, especially in the retroglandular area. We therefore recommend the use of RP for standard MLO and CC views.

Stability of methadone hydrochloride in 0.9% sodium chloride injection in single-dose plastic containers.

PubMed

Denson, D D; Crews, J C; Grummich, K W; Stirm, E J; Sue, C A

1991-03-01

The stability of methadone hydrochloride in 0.9% sodium chloride injection in flexible polyvinyl chloride containers was studied. Commercially available methadone hydrochloride 20 mg/mL and 25-mL single-dose bags of 0.9% sodium chloride injection were used. Six samples each were prepared at methadone hydrochloride concentrations of 1, 2, and 5 mg/mL. The solutions were stored at room temperature and were not protected from light. Immediately after preparation and after two, three, and four weeks of storage, each of the 18 samples was divided into three aliquots, each of which was analyzed in duplicate for methadone hydrochloride concentration by gas chromatography. There was less than 10% change in methadone hydrochloride concentration in any sample throughout the four-week study period. Methadone hydrochloride at concentrations of 1, 2, and 5 mg/mL prepared in commercially available flexible polyvinyl chloride containers of 0.9% sodium chloride injection and stored at room temperature without deliberate protection from light is stable for at least four weeks.

Efficacy and safety of once-daily, extended-release hydrocodone in individuals previously receiving hydrocodone/acetaminophen combination therapy for chronic pain.

PubMed

Bartoli, Adrian; Michna, Edward; He, Ellie; Wen, Warren

2015-01-01

Hydrocodone/acetaminophen combination analgesics are frequently prescribed for chronic pain management; however, acetaminophen presents potential hepatotoxicity to patients and thus dose limitations. These opioid medications are also widely abused. Once-daily, single-entity hydrocodone (Hysingla™ ER tablets [HYD]) is a novel formulation with abuse-deterrent properties for the management of chronic pain and represents a suitable option for those patients receiving analgesics containing the same opioid analgesic, hydrocodone. This post-hoc analysis evaluated the efficacy and safety of HYD in patients whose primary pre-study analgesic was hydrocodone/acetaminophen analgesics (23-31% of the study populations). Data were analyzed from two Phase III trials, a 12-week randomized, placebo-controlled trial (RCT) and an open-label, 52-week trial. In both trials, a dose-titration period with HYD was followed by respective periods of fixed-dose double-blind (randomized controlled trial [RCT]) or open-label, flexible-dose maintenance treatment. Pain intensity was assessed using a numerical rating scale (0-10, 0 = no pain). For the RCT, primary and sensitivity analyses of pain scores used different approaches to handle missing data. Safety data for both studies were summarized. In the RCT, the mean baseline pain score was 7.3. Pain relief was greater with HYD than placebo during double-blind treatment. In the open-label, flexible-dose trial, the majority of patients were maintained on their titrated dose. Mean baseline pain score was 6.3, about 57% of patients completed the 1-year maintenance period, and mean pain scores were between 3.6 and 4.1 during the maintenance period. Use of supplemental pain medication decreased or was maintained during the maintenance treatment with HYD. Adverse events in both trials were typical of those associated with opioid analgesics. In patients whose primary pretrial analgesic was hydrocodone/acetaminophen combination tablets, single-entity HYD was effective in reducing pain intensity and in maintaining analgesia over time without need for continued dose increase. HYD's safety and tolerability profiles were similar to other opioid analgesics.

The importance of applicator design for intraluminal brachytherapy of rectal cancer.

PubMed

Hansen, Johnny Witterseh; Jakobsen, Anders

2006-09-01

An important aspect of designing an applicator for radiation treatment of rectal cancer is the ability to minimize dose to the mucosa and noninvolved parts of the rectum wall. For this reason we investigated a construction of a flexible multichannel applicator with several channels placed along the periphery of a cylinder and a construction of a rigid cylinder with a central channel and interchangeable shields. Calculations of the dose gradient, dose homogeneity in the tumor, and shielding ability were performed for the two applicators in question. Furthermore, the influence on dose distribution around a flexible multichannel applicator from an unintended off-axis positioning of the source inside a bent channel was investigated by film measurements on a single bent catheter. Calculations showed that a single-channel applicator with interchangeable shields yields a higher degree of shielding and has a better dose homogeneity in the tumor volume than that of a multi-channel applicator. A single-channel applicator with interchangeable shields was manufactured, and the influence of different size of shield angle on dose rate in front of and behind the shields was measured. While dose rate in front of the shield and shielding ability are closely independent of the size of the shield angle when measured 1 cm from the applicator surface, dose rate in more distant volumes will to some extent be influenced by shield angle due to volume scatter conditions.

The importance of applicator design for intraluminal brachytherapy of rectal cancer

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

Hansen, Johnny Witterseh; Jakobsen, Anders; Department of Oncology, Hospital of Vejle, DK-7100 Vejle

2006-09-15

An important aspect of designing an applicator for radiation treatment of rectal cancer is the ability to minimize dose to the mucosa and noninvolved parts of the rectum wall. For this reason we investigated a construction of a flexible multichannel applicator with several channels placed along the periphery of a cylinder and a construction of a rigid cylinder with a central channel and interchangeable shields. Calculations of the dose gradient, dose homogeneity in the tumor, and shielding ability were performed for the two applicators in question. Furthermore, the influence on dose distribution around a flexible multichannel applicator from an unintendedmore » off-axis positioning of the source inside a bent channel was investigated by film measurements on a single bent catheter. Calculations showed that a single-channel applicator with interchangeable shields yields a higher degree of shielding and has a better dose homogeneity in the tumor volume than that of a multichannel applicator. A single-channel applicator with interchangeable shields was manufactured, and the influence of different size of shield angle on dose rate in front of and behind the shields was measured. While dose rate in front of the shield and shielding ability are closely independent of the size of the shield angle when measured 1 cm from the applicator surface, dose rate in more distant volumes will to some extent be influenced by shield angle due to volume scatter conditions.« less

A Randomized, Double-Blind, Placebo-Controlled Study of Modafinil Film-Coated Tablets in Children and Adolescents with Attention-Deficit/Hyperactivity Disorder

ERIC Educational Resources Information Center

Greenhill, Laurence L.; Biederman, Joseph; Boellner, Samuel W.; Rugino, Thomas A.; Sangal, R. Bart; Earl, Craig Q.; Jiang, John G.; Swanson, James M.

2006-01-01

Objective: To evaluate the efficacy and tolerability of modafinil in children and adolescents, ages 7 to 17, with attention-deficit/hyperactivity disorder (ADHD). Method: In this 9-week, double-blind, flexible-dose study, patients were randomized to once-daily modafinil (170-425 mg) or placebo. Assessments included ADHD Rating Scale-IV…

Adjunctive lacosamide for focal epilepsy: an open-label trial evaluating the impact of flexible titration and dosing on safety and seizure outcomes.

PubMed

Baulac, Michel; Coulbaut, Safia; Doty, Pamela; McShea, Cindy; De Backer, Marc; Bartolomei, Fabrice; Vlaicu, Mihaela

2017-06-01

To evaluate the safety and effectiveness of lacosamide in a real-life setting with the use of a flexible dose titration schedule and individualised maintenance doses up to the maximum approved dose of 400 mg/day. Adults with a diagnosis of focal seizures, with or without secondary generalization, were enrolled in this open-label Phase IV trial (NCT01235403). Lacosamide was initiated at 100 mg/day (50 mg bid) and uptitrated over a 12-week period to 200, 300 or 400 mg/day, based on safety and seizure control. Although dose increases were to be in increments of 100 mg/day, intermediate doses were permitted at each escalation step for one week for patients known to be particularly sensitive to starting new AEDs. After receiving a stable, effective dose for three weeks, patients entered the 12-week maintenance period. Primary outcomes were incidence of treatment-emergent adverse events (TEAEs) and withdrawal due to TEAEs. Seizure outcomes, all secondary, were median focal seizure frequency, ≥50% reduction in focal seizure frequency, and seizure freedom. One hundred patients with a mean age of 44 years were enrolled and 74 completed the trial. The incidence of TEAEs was 64.0% (n=100), with the most frequently reported (≥5% of patients) being dizziness, headache, and asthenia. Fourteen patients withdrew due to TEAEs, most frequently due to dizziness (six patients; 6.0%), vomiting (two patients; 2%), and tremor (two patients; 2%). Among patients with baseline and maintenance phase seizure data (n=75), median reduction in focal seizure frequency from baseline was 69.7% and the ≥50% responder rate was 69.3%. Among 74 patients who completed the maintenance phase, 21 (28.4%) were seizure-free. Flexible lacosamide dosing in this open-label trial was associated with a favourable tolerability and safety profile; the nature of the TEAEs was consistent with that observed in previous pivotal trials. Treatment with lacosamide was also associated with effective seizure control.

Local ROI Reconstruction via Generalized FBP and BPF Algorithms along More Flexible Curves

PubMed Central

Ye, Yangbo; Zhao, Shiying; Wang, Ge

2006-01-01

We study the local region-of-interest (ROI) reconstruction problem, also referred to as the local CT problem. Our scheme includes two steps: (a) the local truncated normal-dose projections are extended to global dataset by combining a few global low-dose projections; (b) the ROI are reconstructed by either the generalized filtered backprojection (FBP) or backprojection-filtration (BPF) algorithms. The simulation results show that both the FBP and BPF algorithms can reconstruct satisfactory results with image quality in the ROI comparable to that of the corresponding global CT reconstruction. PMID:23165018

Development of a Bayesian response-adaptive trial design for the Dexamethasone for Excessive Menstruation study.

PubMed

Holm Hansen, Christian; Warner, Pamela; Parker, Richard A; Walker, Brian R; Critchley, Hilary Od; Weir, Christopher J

2017-12-01

It is often unclear what specific adaptive trial design features lead to an efficient design which is also feasible to implement. This article describes the preparatory simulation study for a Bayesian response-adaptive dose-finding trial design. Dexamethasone for Excessive Menstruation aims to assess the efficacy of Dexamethasone in reducing excessive menstrual bleeding and to determine the best dose for further study. To maximise learning about the dose response, patients receive placebo or an active dose with randomisation probabilities adapting based on evidence from patients already recruited. The dose-response relationship is estimated using a flexible Bayesian Normal Dynamic Linear Model. Several competing design options were considered including: number of doses, proportion assigned to placebo, adaptation criterion, and number and timing of adaptations. We performed a fractional factorial study using SAS software to simulate virtual trial data for candidate adaptive designs under a variety of scenarios and to invoke WinBUGS for Bayesian model estimation. We analysed the simulated trial results using Normal linear models to estimate the effects of each design feature on empirical type I error and statistical power. Our readily-implemented approach using widely available statistical software identified a final design which performed robustly across a range of potential trial scenarios.

Low-dose divalproex in agitated patients with Alzheimer's disease.

PubMed

Dolder, Christian; McKinsey, Jonathan

2010-01-01

Adequate treatment of behavioral disturbances in Alzheimer's disease is both important and difficult. This report describes a case series that examined the effectiveness and safety of low-dose divalproex in the treatment of agitated patients with Alzheimer's disease who were admitted to an inpatient geriatric psychiatry unit over a 1-year period. All patients had agitation due to probable Alzheimer's disease or mixed dementia and were prescribed divalproex monotherapy at low and completely flexible doses. Patients and nursing staff were blind to study enrollment. Clinical global impression scale scores, divalproex serum levels, and a variety of medical chart data were collected. Twenty patients met selection criteria and were included in the study. Of those, 13 patients (65%) were considered responders, while 4 patients (20%) required augmentation with other psychotropic medications; divalproex was discontinued in 1 patient. Adverse events occurred in 25% of patients. This case series suggests that low-dose divalproex may offer behavioral improvement and a reduced risk of side effects for some patients with agitation in Alzheimer's disease.

Aripiprazole and Risperidone for Treatment of Methamphetamine-Associated Psychosis in Chinese Patients.

PubMed

Wang, Gang; Zhang, Yao; Zhang, Sheng; Chen, Huijing; Xu, Zaifeng; Schottenfeld, Richard S; Hao, Wei; Chawarski, Marek Cezary

2016-03-01

We evaluated tolerability and efficacy of aripiprazole and risperidone for treatment of methamphetamine (METH) associated psychotic symptoms in China. Patients with acute METH-associated psychotic symptoms (N=42) and with Positive and Negative Syndrome Scale (PANSS) total score between 60 and 120 were randomized to aripiprazole (initial dose 5-10mg per day followed by flexible doses 5-15 mg per day) or risperidone (initial dose 2-4 mg per day followed by flexible doses 4-6 mg per day) from day 3 to 25 of inpatient hospital stay. Outcome measures included PANSS and Clinical Global Impressions-Severity of Illness scale (CGI-S), METH craving Visual Analogue Scale (VAS), Simpson Angus Scale (SAS), Barnes Assessments Akathasia Rating Scale (BARS), and self-reported adverse effects evaluated during treatment. Retention was evaluated using Kaplan-Meier survival analysis and the MIXED models procedure was used to compare the groups on measures of psychotic and extra-pyramidal symptoms. Patients in both aripiprazole and risperidone groups showed statistically significant reductions in psychotic symptomatology from baseline during treatment (p<0.001) with no statistically significant differences between the treatment groups (p=0.73 and p=0.15, respectively). Risperidone-treated patients reported significantly greater METH craving reductions (p<0.001). Overall, 71% of patients completed the entire study, but the aripiprazole group had a significantly lower retention than the risperidone group (p=0.007), primarily due to medication related adverse effects. Aripiprazole-treated patients also had significantly more akathisia (p=0.03) and agitation (p=0.02) than risperidone-treated patients. Patients in both groups who tolerated their medications and completed the entire study achieved comparable reductions of psychotic symptoms. Copyright © 2015 Elsevier Inc. All rights reserved.

Efficacy and tolerability of quetiapine in the treatment of bipolar disorder: preliminary evidence from a 12-month open-label study.

PubMed

Altamura, A C; Salvadori, Daniele; Madaro, Donato; Santini, Annalisa; Mundo, Emanuela

2003-09-01

The literature on the use of quetiapine for the treatment of bipolar disorder (BD) is limited to case reports, and there are no systematic studies on the efficacy of quetiapine in the prophylactic treatment of BD. The aim of the present study was to compare the efficacy of flexible doses of quetiapine and well established mood stabilizers in the maintenance treatment of BD. Twenty-eight DSM-IV BD outpatients were consecutively recruited into the study and were randomized to receive one of two open-label treatments, with quetiapine or classical mood stabilizers at flexible doses for 12 months. Clinical assessment was carried out using BPRS, CGI, YMRS and the 21-item HAM-D at baseline (T0) and every 2 months until the end of the study. ANOVAs with repeated measures were applied to the rating scale scores considering the time and the treatment group as main factors. All patients experienced a significant improvement on the BPRS, CGI and HAM-D scores, with no significant side-effects and a good compliance. This study should be considered preliminary given the small sample size investigated and the open-label design. If these results will be replicated on larger samples and in controlled studies, there could be relevant implications for the use of quetiapine as an alternative maintenance treatment for BD.

In utero and Lactational Exposure to Acetamiprid Induces Abnormalities in Socio-Sexual and Anxiety-Related Behaviors of Male Mice

PubMed Central

Sano, Kazuhiro; Isobe, Tomohiko; Yang, Jiaxin; Win-Shwe, Tin-Tin; Yoshikane, Mitsuha; Nakayama, Shoji F.; Kawashima, Takaharu; Suzuki, Go; Hashimoto, Shunji; Nohara, Keiko; Tohyama, Chiharu; Maekawa, Fumihiko

2016-01-01

Neonicotinoids, a widely used group of pesticides designed to selectively bind to insect nicotinic acetylcholine receptors, were considered relatively safe for mammalian species. However, they have been found to activate vertebrate nicotinic acetylcholine receptors and could be toxic to the mammalian brain. In the present study, we evaluated the developmental neurotoxicity of acetamiprid (ACE), one of the most widely used neonicotinoids, in C57BL/6J mice whose mothers were administered ACE via gavage at doses of either 0 mg/kg (control group), 1.0 mg/kg (low-dose group), or 10.0 mg/kg (high-dose group) from gestational day 6 to lactation day 21. The results of a battery of behavior tests for socio-sexual and anxiety-related behaviors, the numbers of vasopressin-immunoreactive cells in the paraventricular nucleus of the hypothalamus, and testosterone levels were used as endpoints. In addition, behavioral flexibility in mice was assessed in a group-housed environment using the IntelliCage, a fully automated mouse behavioral analysis system. In adult male mice exposed to ACE at both low and high doses, a significant reduction of anxiety level was found in the light-dark transition test. Males in the low-dose group also showed a significant increase in sexual and aggressive behaviors. In contrast, neither the anxiety levels nor the sexual behaviors of females were altered. No reductions in the testosterone level, the number of vasopressin-immunoreactive cells, or behavioral flexibility were detected in either sex. These results suggest the possibility that in utero and lactational ACE exposure interferes with the development of the neural circuits required for executing socio-sexual and anxiety-related behaviors in male mice specifically. PMID:27375407

Is the flexible GnRH antagonist protocol better suited for fresh eSET cycles?

PubMed

Dahdouh, Elias M; Gomes, Francisco L A F; Granger, Louis; Carranza-Mamane, Belina; Faruqi, Faez; Kattygnarath, Tiao-Virirak; St-Michel, Pierre

2014-10-01

This study was performed to evaluate the efficacy of the flexible GnRH antagonist protocol in comparison with the long GnRH agonist protocol in elective single embryo transfer (eSET) practice. It was conducted in a publicly funded in vitro fertilization program. We performed a prospective cohort analysis of data from a private infertility clinic from August 2010 to August 2011. Three hundred fourteen women with normal ovarian reserve and undergoing fresh eSET cycles were included. Sixty-four women underwent follicular stimulation using a flexible GnRH antagonist protocol, and 250 underwent stimulation with a standard long mid-luteal GnRH agonist protocol. Implantation rates (35.9% in the GnRH antagonist group and 29.6% in the GnRH agonist group, P = 0.5) and ongoing pregnancy rates (32.8% in the GnRH antagonist group and 28.8% in the GnRH agonist group, P = 0.5) were equivalent in both groups. The duration of stimulation (9.8 ± 2 days vs. 10.7 ± 1.8 days, P < 0.001) and total FSH dose required (2044 vs. 2775 IU, P < 0.001) were lower in the GnRH antagonist group than in the GnRH agonist group. The number of mature oocytes (6.0 vs. 10.0, P < 0. 001) and number of embryos (5.0 vs. 7.0, P < 0.001) were also lower in GnRH antagonist group. However, the number of embryos cryopreserved was similar in both groups (median 2.0, P = 0.3). In women undergoing in vitro fertilization, the flexible GnRH antagonist protocol yields implantation and ongoing pregnancy rates that are similar to the long GnRH agonist protocol, and requires lower doses of gonadotropins and a shorter duration of treatment. The flexible GnRH antagonist protocol appears to be the protocol of choice for an eSET IVF program.

EXPOSURE RELATED DOSE ESTIMATING MODEL ( ERDEM ) A PHYSIOLOGICALLY-BASED PHARMACOKINETIC AND PHARMACODYNAMIC ( PBPK/PD ) MODEL FOR ASSESSING HUMAN EXPOSURE AND RISK

EPA Science Inventory

The Exposure Related Dose Estimating Model (ERDEM) is a PBPK/PD modeling system that was developed by EPA's National Exposure Research Laboratory (NERL). The ERDEM framework provides the flexibility either to use existing models and to build new PBPK and PBPK/PD models to address...

Patient safety and minimizing risk with insulin administration - role of insulin degludec.

PubMed

Aye, Myint M; Atkin, Stephen L

2014-01-01

Diabetes is a lifelong condition requiring ongoing medical care and patient self-management. Exogenous insulin therapy is essential in type 1 diabetes and becomes a necessity in patients with longstanding type 2 diabetes who fail to achieve optimal control with lifestyle modification, oral agents, and glucagon-like peptide 1-based therapy. One of the risks that hinders insulin use is hypoglycemia. Optimal insulin therapy should therefore minimize the risk of hypoglycemia while improving glycemic control. Insulin degludec (IDeg) is a novel basal insulin that, following subcutaneous injection, assembles into a depot of soluble multihexamer chains. These subsequently release IDeg monomers that are absorbed at a slow and steady rate into the circulation, with the terminal half-life of IDeg being ~25 hours. Thus, it requires only once-daily dosing unlike other basal insulin preparations that often require twice-daily dosing. Despite its long half-life, once-daily IDeg does not cause accumulation of insulin in the circulation after reaching steady state. IDeg once a day will produce a steady-state profile with a lower peak:trough ratio than other basal insulins. In clinical trials, this profile translates into a lower frequency of nocturnal hypoglycemia compared with insulin glargine, as well as an ability to allow some flexibility in dose timing without compromising efficacy and safety. Indeed, a study that tested the extremes of dosing intervals of 8 and 40 hours showed no detriment in either glycemic control or hypoglycemic frequency versus insulin glargine given at the same time each day. While extreme flexibility in dose timing is not recommended, these findings are reassuring. This may be particularly beneficial to elderly patients, patients with learning difficulties, or others who have to rely on health-care professionals for their daily insulin injections. Further studies are required to confirm whether this might benefit adherence to treatment, reduce long-term hypoglycemia or reduce diabetes-related complications.

Dosimetric feasibility of using tungsten-based functional paper for flexible chest wall protectors in intraoperative electron radiotherapy for breast cancer

NASA Astrophysics Data System (ADS)

Kamomae, Takeshi; Monzen, Hajime; Kawamura, Mariko; Okudaira, Kuniyasu; Nakaya, Takayoshi; Mukoyama, Takashi; Miyake, Yoshikazu; Ishihara, Yoshitomo; Itoh, Yoshiyuki; Naganawa, Shinji

2018-01-01

Intraoperative electron radiotherapy (IOERT), which is an accelerated partial breast irradiation method, has been used for early-stage breast cancer treatment. In IOERT, a protective disk is inserted behind the target volume to minimize the dose received by normal tissues. However, to use such a disk, the surgical incision must be larger than the field size because the disk is manufactured from stiff and unyielding materials. In this study, the applicability of newly developed tungsten-based functional paper (TFP) was assessed as an alternative to the existing protective disk. The radiation-shielding performance of the TFP was verified through experimental measurements and Monte Carlo simulations. Percentage depth dose curves and lateral dose profiles with and without TFPs were measured and simulated on a dedicated IOERT accelerator. The number of piled-up TFPs was changed from 1 to 40. In the experimental measurements, the relative doses at the exit plane of the TFPs for 9 MeV were 42.7%, 9.2%, 0.2%, and 0.1% with 10, 20, 30, and 40 TFPs, respectively, whereas those for 12 MeV were 63.6%, 27.1%, 8.6%, and 0.2% with 10, 20, 30, and 40 TFPs, respectively. Slight dose enhancements caused by backscatter radiation from the TFPs were observed at the entrance plane of the TFPs at both beam energies. The results of the Monte Carlo simulation indicated the same tendency as the experimental measurements. Based on the experimental and simulated results, the radiation-shielding performances of 30 TFPs for 9 MeV and 40 TFPs for 12 MeV were confirmed to be acceptable and close to those of the existing protective disk. The findings of this study suggest the feasibility of using TFPs as flexible chest wall protectors in IOERT for breast cancer treatment.

Dosing adjustments in postpartum patients maintained on buprenorphine or methadone.

PubMed

Jones, Hendrée E; Johnson, Rolley E; O'Grady, Kevin E; Jasinski, Donald R; Tuten, Michelle; Milio, Lorraine

2008-06-01

Scant scientific attention has been given to examining the need for agonist medication dose changes in the postpartum period. Study objectives were: 1) to determine the need for medication dose adjustments in participants stabilized on buprenorphine or methadone 3 weeks before and 4 weeks after delivery, and 2) to evaluate the need for methadone dose adjustments during the first 7 days in participants transferred from buprenorphine to methadone at 5 weeks postpartum. Participants were opioid-dependent pregnant women who had completed a randomized, double-blind, double-dummy, flexible dosing comparison of buprenorphine to methadone. Participants received a stable dose of methadone (N = 10) or buprenorphine (N = 8) before and 4 weeks after delivery. Buprenorphine-maintained participants were transferred to methadone at 5 weeks postpartum. There were no significant differences predelivery and/or postdelivery between the buprenorphine and methadone conditions in the mean ratings of dose adequacy, "liking," "hooked," and "craving" of heroin or cocaine. Patient response to the conversion from buprenorphine to methadone seems variable. Buprenorphine-maintained participants required dose changes postpartum only after they transferred to methadone. Regardless of type of medication, postpartum patients should be monitored for signs of overmedication.

How and why do patients with Type 1 diabetes sustain their use of flexible intensive insulin therapy? A qualitative longitudinal investigation of patients' self-management practices following attendance at a Dose Adjustment for Normal Eating (DAFNE) course.

PubMed

Rankin, D; Cooke, D D; Clark, M; Heller, S; Elliott, J; Lawton, J

2011-05-01

Conventional insulin therapy requires patients with Type 1 diabetes to adhere to rigid dietary and insulin injection practices. Recent trends towards flexible intensive insulin therapy enable patients to match insulin to dietary intake and lifestyle; however, little work has examined patients' experiences of incorporating these practices into real-life contexts. This qualitative longitudinal study explored patients' experiences of using flexible intensive insulin therapy to help inform the development of effective long-term support. Semi-structured interviews were conducted with 30 adult patients with Type 1 diabetes following participation in a structured education programme on using flexible intensive insulin therapy, and 6 and 12 months post-course. Longitudinal data analysis used an inductive, thematic approach. Patients consistently reported feeling committed to and wanting to sustain flexible intensive insulin therapy. This regimen was seen as a logical and effective method of self-management, as patients experienced improved blood glucose readings and/or reported feeling better. Implementing and sustaining flexible intensive insulin therapy was enhanced when patients had stable routines, with more challenges reported by those working irregular hours and during weekends/holidays. Some patients re-crafted their lives to make this approach work for them; for instance, by creating dietary routines or adjusting dietary choices. Clinical data have shown that flexible intensive insulin therapy can lead to improvement in glycaemic control. This study, drawing on patients' perspectives, provides further endorsement for flexible intensive insulin therapy by demonstrating patients' liking of, and their motivation to sustain, this approach over time. To help patients implement and sustain flexible intensive insulin therapy, follow-up support should encourage them to identify routines to better integrate this regimen into their lives. © 2011 The Authors. Diabetic Medicine © 2011 Diabetes UK.

Review article: chronobiology: influence of circadian rhythms on the therapy of severe pain.

PubMed

Junker, Uwe; Wirz, Stefan

2010-06-01

Modern pain therapy widely follows the WHO (World Health Organization) guidelines using a three-step 'ladder' for pain relief. This escalating step scheme includes the administration in the order nonopioids, mild opioids and strong opioids, and adjuvants at any step. Analgesics should be given 'by the clock' rather than 'on demand'. However, the chronobiological parameters circadian pain rhythm, circadian efficacy of analgesics, and individual circadian need for analgesics are to be considered. The results of a multitude of studies in chronobiology are not consistent. Therefore, further studies with standardized protocols are needed that allow to assign more consistent rhythms to diseases, pain causes, and analgesic efficacy of opioids. In many cases, each patient perceives pain and its intensity individually during the time of day. By administration of analgesics over a constant or continuous dosage time fluctuations in pain perception and the outcomes of many studies in chronobiology are ignored that prove the influence of biological rhythms on the pharmacokinetic and pharmacodynamic aspects of analgesics. As different types of pain show different rhythms (highest pain intensities arising at different times of the day) analgesics should be dosed flexibly. It is also very important that drug therapy can be adjusted individually to the pain rhythm of the patient as well as to the type and cause of pain. In severe pain, therapy should be particularly careful. A flexible dosage depending on pain intensity and rapid dose adjustment are essentials of a modern pain therapy. Therefore, opioids that are flexible to use are better suited to treat the individual pain of the patient than rigid modified release oral or transdermal systems.

Spline-based procedures for dose-finding studies with active control

PubMed Central

Helms, Hans-Joachim; Benda, Norbert; Zinserling, Jörg; Kneib, Thomas; Friede, Tim

2015-01-01

In a dose-finding study with an active control, several doses of a new drug are compared with an established drug (the so-called active control). One goal of such studies is to characterize the dose–response relationship and to find the smallest target dose concentration d*, which leads to the same efficacy as the active control. For this purpose, the intersection point of the mean dose–response function with the expected efficacy of the active control has to be estimated. The focus of this paper is a cubic spline-based method for deriving an estimator of the target dose without assuming a specific dose–response function. Furthermore, the construction of a spline-based bootstrap CI is described. Estimator and CI are compared with other flexible and parametric methods such as linear spline interpolation as well as maximum likelihood regression in simulation studies motivated by a real clinical trial. Also, design considerations for the cubic spline approach with focus on bias minimization are presented. Although the spline-based point estimator can be biased, designs can be chosen to minimize and reasonably limit the maximum absolute bias. Furthermore, the coverage probability of the cubic spline approach is satisfactory, especially for bias minimal designs. © 2014 The Authors. Statistics in Medicine Published by John Wiley & Sons Ltd. PMID:25319931

Intra-cavitary dosimetry for IMRT head and neck treatment using thermoluminescent dosimeters in a naso-oesophageal tube.

PubMed

Gagliardi, F M; Roxby, K J; Engström, P E; Crosbie, J C

2009-06-21

Complex intensity-modulated radiation therapy (IMRT) treatment plans require rigorous quality assurance tests. The aim of this study was to independently verify the delivered dose inside the patient in the region of the treatment site. A flexible naso-gastric tube containing thermoluminescent dosimeters (TLDs) was inserted into the oesophagus via the sinus cavity before the patient's first treatment. Lead markers were also inserted into the tube in order that the TLD positions could be accurately determined from the lateral and anterior-posterior electronic portal images taken prior to treatment. The measured dose was corrected for both daily linac output variations and the estimated dose received from the portal images. The predicted dose for each TLD was determined from the treatment planning system and compared to the measured TLD doses. The results comprise 431 TLD measurements on 43 patients. The mean measured-to-predicted dose ratio was 0.988 +/- 0.011 (95% confidence interval) for measured doses above 0.2 Gy. There was a variation in this ratio when the measurements were separated into low dose (0.2-1.0 Gy), medium dose (1.0-1.8 Gy) and high dose (>1.8 Gy) measurements. The TLD-loaded, naso-oesophageal tube for in vivo dose verification is straightforward to implement, and well tolerated by patients. It provides independent reassurance of the delivered dose for head and neck IMRT.

Intra-cavitary dosimetry for IMRT head and neck treatment using thermoluminescent dosimeters in a naso-oesophageal tube

NASA Astrophysics Data System (ADS)

Gagliardi, F. M.; Roxby, K. J.; Engström, P. E.; Crosbie, J. C.

2009-06-01

Complex intensity-modulated radiation therapy (IMRT) treatment plans require rigorous quality assurance tests. The aim of this study was to independently verify the delivered dose inside the patient in the region of the treatment site. A flexible naso-gastric tube containing thermoluminescent dosimeters (TLDs) was inserted into the oesophagus via the sinus cavity before the patient's first treatment. Lead markers were also inserted into the tube in order that the TLD positions could be accurately determined from the lateral and anterior-posterior electronic portal images taken prior to treatment. The measured dose was corrected for both daily linac output variations and the estimated dose received from the portal images. The predicted dose for each TLD was determined from the treatment planning system and compared to the measured TLD doses. The results comprise 431 TLD measurements on 43 patients. The mean measured-to-predicted dose ratio was 0.988 ± 0.011 (95% confidence interval) for measured doses above 0.2 Gy. There was a variation in this ratio when the measurements were separated into low dose (0.2-1.0 Gy), medium dose (1.0-1.8 Gy) and high dose (>1.8 Gy) measurements. The TLD-loaded, naso-oesophageal tube for in vivo dose verification is straightforward to implement, and well tolerated by patients. It provides independent reassurance of the delivered dose for head and neck IMRT.

Efficacy and safety of a flexible extended regimen of ethinylestradiol/drospirenone for the treatment of dysmenorrhea: a multicenter, randomized, open-label, active-controlled study.

PubMed

Momoeda, Mikio; Kondo, Masami; Elliesen, Joerg; Yasuda, Masanobu; Yamamoto, Shigetomo; Harada, Tasuku

2017-01-01

Dysmenorrhea is a common condition in women, which is characterized by menstrual pain. Low-dose estrogen/progestin combined oral contraceptives have been shown to reduce the severity of dysmenorrhea symptoms, and a 28-day cyclic regimen of ethinylestradiol/drospirenone (28d regimen) is approved for this indication in Japan. The aim of this study was to assess the safety and efficacy of a flexible extended regimen of ethinylestradiol/drospirenone (flexible regimen) in Japanese women with dysmenorrhea. This multicenter, open-label study was performed in Japanese women with dysmenorrhea who, after a baseline observational phase, were randomized to receive ethinylestradiol 20 μg/drospirenone 3 mg in a flexible regimen (one tablet each day for 24-120 days followed by a 4-day tablet-free interval) or in the standard 28d regimen (one tablet each day for 24 days, followed by 4 days of placebo tablets for six cycles). The primary endpoint was the number of days with dysmenorrhea of at least mild intensity over a 140-day evaluation period. Dysmenorrhea scores, bleeding patterns, and other pain-related parameters were also assessed. A total of 216 women (mean age 29.7 years) were randomized to the flexible regimen (n=108) or 28d regimen (n=108) and 212 were included in the full analysis sets (flexible regimen, n=105; 28d regimen, n=107). Women in the flexible-regimen group reported a mean of 3.4 fewer days with dysmenorrheic pain than women in the 28d-regimen group, with similar decreases in disease severity reported in both treatment groups. According to the investigators, 64.8% and 59.4% of women in the flexible-regimen and 28d-regimen treatment groups had "very much improved" or "much improved" disease, while 54.3% and 50.9% of patients reported being "very much satisfied" or "much satisfied" with their treatment, respectively. In Japanese women with dysmenorrhea, a flexible extended regimen of ethinylestradiol/drospirenone decreased the number of days with dysmenorrheic pain versus the traditional 28d regimen.

Efficacy and safety of a flexible extended regimen of ethinylestradiol/drospirenone for the treatment of dysmenorrhea: a multicenter, randomized, open-label, active-controlled study

PubMed Central

Momoeda, Mikio; Kondo, Masami; Elliesen, Joerg; Yasuda, Masanobu; Yamamoto, Shigetomo; Harada, Tasuku

2017-01-01

Background Dysmenorrhea is a common condition in women, which is characterized by menstrual pain. Low-dose estrogen/progestin combined oral contraceptives have been shown to reduce the severity of dysmenorrhea symptoms, and a 28-day cyclic regimen of ethinylestradiol/drospirenone (28d regimen) is approved for this indication in Japan. Aim The aim of this study was to assess the safety and efficacy of a flexible extended regimen of ethinylestradiol/drospirenone (flexible regimen) in Japanese women with dysmenorrhea. Methods This multicenter, open-label study was performed in Japanese women with dysmenorrhea who, after a baseline observational phase, were randomized to receive ethinylestradiol 20 μg/drospirenone 3 mg in a flexible regimen (one tablet each day for 24–120 days followed by a 4-day tablet-free interval) or in the standard 28d regimen (one tablet each day for 24 days, followed by 4 days of placebo tablets for six cycles). The primary endpoint was the number of days with dysmenorrhea of at least mild intensity over a 140-day evaluation period. Dysmenorrhea scores, bleeding patterns, and other pain-related parameters were also assessed. Results A total of 216 women (mean age 29.7 years) were randomized to the flexible regimen (n=108) or 28d regimen (n=108) and 212 were included in the full analysis sets (flexible regimen, n=105; 28d regimen, n=107). Women in the flexible-regimen group reported a mean of 3.4 fewer days with dysmenorrheic pain than women in the 28d-regimen group, with similar decreases in disease severity reported in both treatment groups. According to the investigators, 64.8% and 59.4% of women in the flexible-regimen and 28d-regimen treatment groups had “very much improved” or “much improved” disease, while 54.3% and 50.9% of patients reported being “very much satisfied” or “much satisfied” with their treatment, respectively. Conclusion In Japanese women with dysmenorrhea, a flexible extended regimen of ethinylestradiol/drospirenone decreased the number of days with dysmenorrheic pain versus the traditional 28d regimen. PMID:28496369

Development of Oral Flexible Tablet (OFT) Formulation for Pediatric and Geriatric Patients: a Novel Age-Appropriate Formulation Platform.

PubMed

Chandrasekaran, Prabagaran; Kandasamy, Ruckmani

2017-08-01

Development of palatable formulations for pediatric and geriatric patients involves various challenges. However, an innovative development with beneficial characteristics of marketed formulations in a single formulation platform was attempted. The goal of this research was to develop solid oral flexible tablets (OFTs) as a platform for pediatrics and geriatrics as oral delivery is the most convenient and widely used mode of drug administration. For this purpose, a flexible tablet formulation using cetirizine hydrochloride as model stability labile class 1 and 3 drug as per the Biopharmaceutical Classification System was developed. Betadex, Eudragit E100, and polacrilex resin were evaluated as taste masking agents. Development work focused on excipient selection, formulation processing, characterization methods, stability, and palatability testing. Formulation with a cetirizine-to-polacrilex ratio of 1:2 to 1:3 showed robust physical strength with friability of 0.1% (w/w), rapid in vitro dispersion within 30 s in 2-6 ml of water, and 0.2% of total organic and elemental impurities. Polacrilex resin formulation shows immediate drug release within 30 min in gastric media, better taste masking, and acceptable stability. Hence, it is concluded that ion exchange resins can be appropriately used to develop taste-masked, rapidly dispersible, and stable tablet formulations with tailored drug release suitable for pediatrics and geriatrics. Flexible formulations can be consumed as swallowable, orally disintegrating, chewable, and as dispersible tablets. Flexibility in dose administration would improve compliance in pediatrics and geriatrics. This drug development approach using ion exchange resins can be a platform for formulating solid oral flexible drug products with low to medium doses.

A computational psychiatry approach identifies how alpha-2A noradrenergic agonist Guanfacine affects feature-based reinforcement learning in the macaque

PubMed Central

Hassani, S. A.; Oemisch, M.; Balcarras, M.; Westendorff, S.; Ardid, S.; van der Meer, M. A.; Tiesinga, P.; Womelsdorf, T.

2017-01-01

Noradrenaline is believed to support cognitive flexibility through the alpha 2A noradrenergic receptor (a2A-NAR) acting in prefrontal cortex. Enhanced flexibility has been inferred from improved working memory with the a2A-NA agonist Guanfacine. But it has been unclear whether Guanfacine improves specific attention and learning mechanisms beyond working memory, and whether the drug effects can be formalized computationally to allow single subject predictions. We tested and confirmed these suggestions in a case study with a healthy nonhuman primate performing a feature-based reversal learning task evaluating performance using Bayesian and Reinforcement learning models. In an initial dose-testing phase we found a Guanfacine dose that increased performance accuracy, decreased distractibility and improved learning. In a second experimental phase using only that dose we examined the faster feature-based reversal learning with Guanfacine with single-subject computational modeling. Parameter estimation suggested that improved learning is not accounted for by varying a single reinforcement learning mechanism, but by changing the set of parameter values to higher learning rates and stronger suppression of non-chosen over chosen feature information. These findings provide an important starting point for developing nonhuman primate models to discern the synaptic mechanisms of attention and learning functions within the context of a computational neuropsychiatry framework. PMID:28091572

Relationship between radiation dose reduction and image quality change in photostimulable phosphor luminescence X-ray imaging systems.

PubMed

Sakurai, T; Kawamata, R; Kozai, Y; Kaku, Y; Nakamura, K; Saito, M; Wakao, H; Kashima, I

2010-05-01

The aim of the study was to clarify the change in image quality upon X-ray dose reduction and to re-analyse the possibility of X-ray dose reduction in photostimulable phosphor luminescence (PSPL) X-ray imaging systems. In addition, the study attempted to verify the usefulness of multiobjective frequency processing (MFP) and flexible noise control (FNC) for X-ray dose reduction. Three PSPL X-ray imaging systems were used in this study. Modulation transfer function (MTF), noise equivalent number of quanta (NEQ) and detective quantum efficiency (DQE) were evaluated to compare the basic physical performance of each system. Subjective visual evaluation of diagnostic ability for normal anatomical structures was performed. The NEQ, DQE and diagnostic ability were evaluated at base X-ray dose, and 1/3, 1/10 and 1/20 of the base X-ray dose. The MTF of the systems did not differ significantly. The NEQ and DQE did not necessarily depend on the pixel size of the system. The images from all three systems had a higher diagnostic utility compared with conventional film images at the base and 1/3 X-ray doses. The subjective image quality was better at the base X-ray dose than at 1/3 of the base dose in all systems. The MFP and FNC-processed images had a higher diagnostic utility than the images without MFP and FNC. The use of PSPL imaging systems may allow a reduction in the X-ray dose to one-third of that required for conventional film. It is suggested that MFP and FNC are useful for radiation dose reduction.

HLW Flexible jumper materials compatibility evaluation

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

Skidmore, T. E.

H-Tank Farm Engineering tasked SRNL/Materials Science & Technology (MS&T) to evaluate the compatibility of Goodyear Viper® chemical transfer hose with HLW solutions. The hose is proposed as a flexible Safety Class jumper for up to six months service. SRNL/MS&T performed various tests to evaluate the effects of radiation, high pH chemistry and elevated temperature on the hose, particularly the inner liner. Test results suggest an upper dose limit of 50 Mrad for the hose. Room temperature burst pressure values at 50 Mrad are estimated at 600- 800 psi, providing a safety factor of 4.0-5.3X over the anticipated operating pressure ofmore » 150 psi and a safety factor of 3.0-4.0X over the working pressure of the hose (200 psi), independent of temperature effects. Radiation effects are minimal at doses less than 10 Mrad. Doses greater than 50 Mrad may be allowed, depending on operating conditions and required safety factors, but cannot be recommended at this time. At 250 Mrad, burst pressure values are reduced to the hose working pressure. At 300 Mrad, burst pressures are below 150 psi. At a bounding continuous dose rate of 57,870 rad/hr, the 50 Mrad dose limit is reached within 1.2 months. Actual dose rates may be lower, particularly during non-transfer periods. Refined dose calculations are therefore recommended to justify longer service. This report details the tests performed and interpretation of the results. Recommendations for shelf-life/storage, component quality verification, and post-service examination are provided.« less

Spatial Prediction of Coxiella burnetii Outbreak Exposure via Notified Case Counts in a Dose-Response Model.

PubMed

Brooke, Russell J; Kretzschmar, Mirjam E E; Hackert, Volker; Hoebe, Christian J P A; Teunis, Peter F M; Waller, Lance A

2017-01-01

We develop a novel approach to study an outbreak of Q fever in 2009 in the Netherlands by combining a human dose-response model with geostatistics prediction to relate probability of infection and associated probability of illness to an effective dose of Coxiella burnetii. The spatial distribution of the 220 notified cases in the at-risk population are translated into a smooth spatial field of dose. Based on these symptomatic cases, the dose-response model predicts a median of 611 asymptomatic infections (95% range: 410, 1,084) for the 220 reported symptomatic cases in the at-risk population; 2.78 (95% range: 1.86, 4.93) asymptomatic infections for each reported case. The low attack rates observed during the outbreak range from (Equation is included in full-text article.)to (Equation is included in full-text article.). The estimated peak levels of exposure extend to the north-east from the point source with an increasing proportion of asymptomatic infections further from the source. Our work combines established methodology from model-based geostatistics and dose-response modeling allowing for a novel approach to study outbreaks. Unobserved infections and the spatially varying effective dose can be predicted using the flexible framework without assuming any underlying spatial structure of the outbreak process. Such predictions are important for targeting interventions during an outbreak, estimating future disease burden, and determining acceptable risk levels.

A flexible Monte Carlo tool for patient or phantom specific calculations: comparison with preliminary validation measurements

NASA Astrophysics Data System (ADS)

Davidson, S.; Cui, J.; Followill, D.; Ibbott, G.; Deasy, J.

2008-02-01

The Dose Planning Method (DPM) is one of several 'fast' Monte Carlo (MC) computer codes designed to produce an accurate dose calculation for advanced clinical applications. We have developed a flexible machine modeling process and validation tests for open-field and IMRT calculations. To complement the DPM code, a practical and versatile source model has been developed, whose parameters are derived from a standard set of planning system commissioning measurements. The primary photon spectrum and the spectrum resulting from the flattening filter are modeled by a Fatigue function, cut-off by a multiplying Fermi function, which effectively regularizes the difficult energy spectrum determination process. Commonly-used functions are applied to represent the off-axis softening, increasing primary fluence with increasing angle ('the horn effect'), and electron contamination. The patient dependent aspect of the MC dose calculation utilizes the multi-leaf collimator (MLC) leaf sequence file exported from the treatment planning system DICOM output, coupled with the source model, to derive the particle transport. This model has been commissioned for Varian 2100C 6 MV and 18 MV photon beams using percent depth dose, dose profiles, and output factors. A 3-D conformal plan and an IMRT plan delivered to an anthropomorphic thorax phantom were used to benchmark the model. The calculated results were compared to Pinnacle v7.6c results and measurements made using radiochromic film and thermoluminescent detectors (TLD).

Cholinesterase inhibitors, donepezil and rivastigmine, attenuate spatial memory and cognitive flexibility impairment induced by acute ethanol in the Barnes maze task in rats.

PubMed

Gawel, Kinga; Labuz, Krzysztof; Gibula-Bruzda, Ewa; Jenda, Malgorzata; Marszalek-Grabska, Marta; Filarowska, Joanna; Silberring, Jerzy; Kotlinska, Jolanta H

2016-10-01

Central cholinergic dysfunction contributes to acute spatial memory deficits produced by ethanol administration. Donepezil and rivastigmine elevate acetylcholine levels in the synaptic cleft through the inhibition of cholinesterases-enzymes involved in acetylcholine degradation. The aim of our study was to reveal whether donepezil (acetylcholinesterase inhibitor) and rivastigmine (also butyrylcholinesterase inhibitor) attenuate spatial memory impairment as induced by acute ethanol administration in the Barnes maze task (primary latency and number of errors in finding the escape box) in rats. Additionally, we compared the influence of these drugs on ethanol-disturbed memory. In the first experiment, the dose of ethanol (1.75 g/kg, i.p.) was selected that impaired spatial memory, but did not induce motor impairment. Next, we studied the influence of donepezil (1 and 3 mg/kg, i.p.), as well as rivastigmine (0.5 and 1 mg/kg, i.p.), given either before the probe trial or the reversal learning on ethanol-induced memory impairment. Our study demonstrated that these drugs, when given before the probe trial, were equally effective in attenuating ethanol-induced impairment in both test situations, whereas rivastigmine, at both doses (0.5 and 1 mg/kg, i.p.), and donepezil only at a higher dose (3 mg/kg, i.p.) given prior the reversal learning, attenuated the ethanol-induced impairment in cognitive flexibility. Thus, rivastigmine appears to exert more beneficial effect than donepezil in reversing ethanol-induced cognitive impairments-probably due to its wider spectrum of activity. In conclusion, the ethanol-induced spatial memory impairment may be attenuated by pharmacological manipulation of central cholinergic neurotransmission.

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

Coburn, Natalie, E-mail: natalie.coburn@swahs.health.nsw.gov.au; Beldham-Collins, Rachael; Radiation Oncology Network, Westmead Cancer Care Centre, University of Sydney, Sydney, New South Wales

Protocols commonly implemented in radiotherapy work areas may be classified as being either rigid (class solution) or flexible. Because formal evaluation of these protocol types has not occurred within the literature, we evaluated the efficiency of a rigid compared with flexible prostate planning protocol by assessing a series of completed 3D conformal prostate plans. Twenty prostate cancer patients with an average age of 70 years (range, 52-77) and sizes comprising 8 small, 10 medium, and 2 large were planned on the Phillips Pinnacle treatment planning system 6 times by radiation therapists with <2 years, 2-5 years, and >5 years ofmore » experience using a rigid and flexible protocol. Plans were critiqued using critical organ doses, confirmation numbers, and conformity index. Plans were then classified as being acceptable or not. Plans produced with the flexible protocol were 53% less likely to require modification (OR 0.47, 95% CI: 0.26, 0.84, p = 0.01). Planners with >5 years of experience were 78% more likely to produce plans requiring modification (OR 1.78, 95% CI: 1.12, 2.83, P = 0.02). Plans according to the flexible protocol took longer (112 min) compared with the time taken using a rigid protocol (68 min) (p < 0.001). The results suggest that further studies are needed; however, we propose that all radiation therapy planners should start with the same limitations, and if an acceptable plan is not reached, then flexibility should be given to improve the plan to meet the desired results.« less

Fabrication of topical metered dose film forming sprays for pain management.

PubMed

Ranade, Sneha; Bajaj, Amrita; Londhe, Vaishali; Babul, Najib; Kao, Danny

2017-03-30

Topical film-forming metered dose spray formulations were designed for management of pain. Ropivacaine, a local anesthetic is explored for its topical efficacy in alleviating pain. Metered dose spray containers, organic solvents, film forming polymers and permeation enhancers were utilized to fabricate the Metered Dose topical spray. Factors like viscosity, spray pattern, spray angle, volume of actuation, droplet size distribution of the metered dose spray formulation and drying time, flexibility and wash-ability of the film formed after spraying were assessed. Permeation of the drug into the porcine skin was observed based on ex-vivo diffusion studies and confocal microscopy. The results indicated a high level of drug concentration in the skin layers. Anti-nociceptive efficacy of the formulations was assessed on Wistar rats by hot plate and tail flick tests, based on the response to pain perception. The results were comparable to the conventional lidocaine gel. Topical film forming sprays have the ability to provide an accurate, long lasting and patient compliant delivery of drugs on the skin as compared to conventional gels. Copyright © 2017 Elsevier B.V. All rights reserved.

An open-label, flexible dose adaptive study evaluating the efficacy of vortioxetine in subjects with panic disorder.

PubMed

Shah, Anish; Northcutt, Joanne

2018-01-01

Despite the current treatments available for panic disorder (PD), as many as one-third of patients have persistent and treatment-resistant panic attacks. Vortioxetine is an approved medicine for major depressive disorder and has been shown to have anxiolytic properties. The purpose of this study was to evaluate its efficacy and safety in an adult population with a diagnosis of PD. The study design was open label with flexible dose strategies (5, 10, or 20 mg) with a treatment period of 10 weeks. 27 male and female subjects aged between 18 and 60 years, who met DSM-IV criteria for PD with or without agoraphobia, or who had a Panic Disorder Severity Scale (PDSS) score > 8 at baseline were enrolled. Statistical significance was established by the Student's T test. A statistically significant decrease in the occurrence of panic attacks was measured with the PDSS with vortioxetine. In addition, a moderate improvement in the quality of life and no significant side effects were observed using the Quality-of-Life Scale and Monitoring of Side Effects Scale, respectively. These results provide some support for the use of vortioxetine in the management of panic disorder. Trial registration ClinicalTrials.gov ID#: NCT02395510. Registered March 23, 2015, https://clinicaltrials.gov/ct2/show/NCT02395510.

Effects of repeated treatment with MDMA on working memory and behavioural flexibility in mice.

PubMed

Viñals, Xavier; Maldonado, Rafael; Robledo, Patricia

2013-03-01

Repeated administration of 3,4-methylenedioxymethamphetamine (MDMA) produces dopaminergic neurotoxicity in mice. However, it is still not clear whether this exposure induces deficits in cognitive processing related to specific subsets of executive functioning. We evaluated the effects of neurotoxic and non-neurotoxic doses of MDMA (0, 3 and 30 mg/kg, twice daily for 4 days) on working memory and attentional set-shifting in mice, and changes in extracellular levels of dopamine (DA) in the striatum. Treatment with MDMA (30 mg/kg) disrupted performance of acquired operant alternation, and this impairment was still apparent 5 days after the last drug administration. Decreased alternation was not related to anhedonia because no differences were observed between groups in the saccharin preference test under similar experimental conditions. Correct responding on delayed alternation was increased 1 day after repeated treatment with MDMA (30 mg/kg), probably because of general behavioural quiescence. Notably, the high dose regimen of MDMA impaired attentional set-shifting related to an increase in total perseveration errors. Finally, basal extracellular levels of DA in the striatum were not modified in mice repeatedly treated with MDMA with respect to controls. However, an acute challenge with MDMA (10 mg/kg) failed to increase DA outflow in mice receiving the highest MDMA dose (30 mg/kg), corroborating a decrease in the functionality of DA transporters. Seven days after this treatment, the effects of MDMA on DA outflow were recovered. These results suggest that repeated neurotoxic doses of MDMA produce lasting impairments in recall of alternation behaviour and reduce cognitive flexibility in mice. © 2012 The Authors, Addiction Biology © 2012 Society for the Study of Addiction.

1% Versus 2% Lignocaine for Airway Anesthesia in Flexible Bronchoscopy Without Lignocaine Nebulization (LIFE): A Randomized Controlled Trial.

PubMed

Madan, Karan; Biswal, Shiba K; Mittal, Saurabh; Hadda, Vijay; Mohan, Anant; Khilnani, Gopi C; Pandey, Ravindra M; Guleria, Randeep

2018-04-01

The ideal concentration of lignocaine for topical anesthesia in bronchoscopy remains investigational. In this randomized, double blind study, we compared 1% versus 2% lignocaine for topical anesthesia. Consecutive patients undergoing bronchoscopy were randomized to receive either 1% or 2% lignocaine solution by spray-as-you-go technique. All received 10% lignocaine spray to the oropharynx along with nasal 2% lignocaine gel. Nebulized lignocaine was not administered. Primary outcomes were operator-rated overall procedural satisfaction, visual analogue scale (VAS)-rated and operator-rated cough, VAS. Secondary objectives were total lignocaine dose administered, patient-rated pain on faces pain scale, cumulative dose of lignocaine and procedural complications. A total of 500 patients (250 in each group) were randomized. Baseline characteristics were comparable. Operator-rated overall procedural satisfaction, VAS (72.05±20.16 and 72.20±21.96 in 1% and 2% group respectively; P=0.93) and operator-rated cough, VAS [1% group: 19.1 (12.6-34.6) and 2% group: 20.6 (12.5-36.9); P>0.05] were similar between the 2 groups. Cumulative dose of lignocaine used in 2% lignocaine group was greater (220.89±12.96 mg in 1% and 319.55±19.32 mg in 2% group; P<0.001). Patients receiving sedation were comparable between the 2 groups. (10% in 1% lignocaine group and 6% in 2% lignocaine group; P=0.13). Minor complications occurred in 2 patients in each group. One percent lignocaine in flexible bronchoscopy is as efficacious as 2% lignocaine when administered using the spray as you go technique without concurrent lignocaine nebulization, at a significantly lower total dose of lignocaine administered.

An Open-Label Study of Risperidone in the Improvement of Quality of Life and Treatment of Symptoms of Violent and Self-Injurious Behaviour in Adults with Intellectual Disability

ERIC Educational Resources Information Center

Read, Stephen G.; Rendall, Maureen

2007-01-01

Background: We examined the benefits of risperidone, including quality of life (QoL), in the treatment of violent and self-injurious behaviour in adults with moderate, severe or profound intellectual disability. Methods: Twenty-four participants received open-label, oral, flexible-dose risperidone of 0.5-6 mg/day for 12 weeks. Efficacy was…

A Flexible Multidose GnRH Antagonist versus a Microdose Flare-Up GnRH Agonist Combined with a Flexible Multidose GnRH Antagonist Protocol in Poor Responders to IVF

PubMed Central

Turgay Çelik, Gayem İnayet; Sütçü, Havva Kömür; Akpak, Yaşam Kemal; Akar, Münire Erman

2015-01-01

Objective. To compare the effectiveness of a flexible multidose gonadotropin-releasing hormone (GnRH) antagonist against the effectiveness of a microdose flare-up GnRH agonist combined with a flexible multidose GnRH antagonist protocol in poor responders to in vitro fertilization (IVF). Study Design. A retrospective study in Akdeniz University, Faculty of Medicine, Department of Obstetrics and Gynecology, IVF Center, for 131 poor responders in the intracytoplasmic sperm injection-embryo transfer (ICSI-ET) program between January 2006 and November 2012. The groups were compared to the patients' characteristics, controlled ovarian stimulation (COH) results, and laboratory results. Results. Combination protocol was applied to 46 patients (group 1), and a single protocol was applied to 85 patients (group 2). In group 1, the duration of the treatment was longer and the dose of FSH was higher. The cycle cancellation rate was significantly higher in group 2 (26.1% versus 38.8%). A significant difference was not observed with respect to the number and quality of oocytes and embryos or to the number of embryos transferred. There were no statistically significant differences in the hCG positivity (9.5% versus 9.4%) or the clinical pregnancy rates (7.1% versus 10.6%). Conclusion. The combination protocol does not provide additional efficacy. PMID:26161425

The influence of electron-beam irradiation on the chemical and the structural properties of medical-grade polyurethane

NASA Astrophysics Data System (ADS)

Shin, Sukyoung; Lee, Soonhyouk

2015-07-01

Thermo plastic polyurethane (TPU) provides excellent bio-compatibility, flexibility and good irradiation resistance; however, extremely high irradiation doses can alter the structure and the function of macromolecules, resulting in oxidation, chain scission and cross-linking. In this study, the effects of e-beam irradiation on the medical-grade thermo plastic polyurethane were studied. Changes in the chain length and their distribution, as well as changes in the molecular structure were studied. The GPC (gel permeation chromatography) results show that the oxidative decomposition is followed by a decrease in the molecular mass and an increase in polydispersity. This indicates a very inhomogeneous degradation, which is a consequence of the specific course and of the intensity of oxidative degradation. This was confirmed by means of mechanical property measurements. Overall, this study demonstrated that medical-grade TPU was affected by radiation exposure, particularly at high irradiation doses.

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

PubMed

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

2017-09-08

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

Embracing model-based designs for dose-finding trials

PubMed Central

Love, Sharon B; Brown, Sarah; Weir, Christopher J; Harbron, Chris; Yap, Christina; Gaschler-Markefski, Birgit; Matcham, James; Caffrey, Louise; McKevitt, Christopher; Clive, Sally; Craddock, Charlie; Spicer, James; Cornelius, Victoria

2017-01-01

Background: Dose-finding trials are essential to drug development as they establish recommended doses for later-phase testing. We aim to motivate wider use of model-based designs for dose finding, such as the continual reassessment method (CRM). Methods: We carried out a literature review of dose-finding designs and conducted a survey to identify perceived barriers to their implementation. Results: We describe the benefits of model-based designs (flexibility, superior operating characteristics, extended scope), their current uptake, and existing resources. The most prominent barriers to implementation of a model-based design were lack of suitable training, chief investigators’ preference for algorithm-based designs (e.g., 3+3), and limited resources for study design before funding. We use a real-world example to illustrate how these barriers can be overcome. Conclusions: There is overwhelming evidence for the benefits of CRM. Many leading pharmaceutical companies routinely implement model-based designs. Our analysis identified barriers for academic statisticians and clinical academics in mirroring the progress industry has made in trial design. Unified support from funders, regulators, and journal editors could result in more accurate doses for later-phase testing, and increase the efficiency and success of clinical drug development. We give recommendations for increasing the uptake of model-based designs for dose-finding trials in academia. PMID:28664918

Evaluation of the timing and coordination of prandial insulin administration in the hospital.

PubMed

Alwan, Dhuha; Chipps, Esther; Yen, Po-Yin; Dungan, Kathleen

2017-09-01

The objective of this study was to examine the relationship between measures of coordinated insulin delivery and capillary blood glucose (CBG) levels among hospitalized patients and to assess nurse perceptions of insulin administration. Hospitalized patients (n=451) receiving rapid acting insulin analog (RAIA) using carbohydrate counting were retrospectively analyzed. Nurses (n=35) were asked to complete an 18-item anonymous survey assessing perception of RAIA dosing. The median time from breakfast CBG to RAIA dose was 93 (IQR 57-138) min. There was no association between timeliness measures and mean CBG at lunch or dinner. Hypoglycemia was rare (N=2). More than half (54%) of nurses were confident all of the time in determining the correct dose of RAIA, though none were confident in administering it on time. The majority of nurses perceived an electronic dosing calculator and a patient reminder to notify the nurse at the end of the meal favorably. The data demonstrate suboptimal coordination of CBG monitoring and insulin doses using a flexible meal insulin dosing strategy, though there was minimal impact on glycemic control. Nurses reported high confidence in the ability to calculate the correct insulin dose but not in the ability to administer it on time. Copyright © 2017 Elsevier B.V. All rights reserved.

SU-F-T-433: Evaluation of a New Dose Mimicking Application for Clinical Flexibility and Reliability

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

Hoffman, D; Nair, C Kumaran; Wright, C

2016-06-15

Purpose: Clinical workflow and machine down time occasionally require patients to be temporarily treated on a system other than the initial treatment machine. A new commercial dose mimicking application provides automated cross-platform treatment planning to expedite this clinical flexibility. The aim of this work is to evaluate the feasibility of automatic plan creation and establish a robust clinical workflow for prostate and pelvis patients. Methods: Five prostate and five pelvis patients treated with helical plans were selected for re-planning with the dose mimicking application, covering both simple and complex scenarios. Two-arc VMAT and 7- and 9-field IMRT plans were generatedmore » for each case, with the objective function of achieving similar dose volume histogram from the initial helical plans. Dosimetric comparisons include target volumes and organs at risk (OARs) (rectum, bladder, small bowel, femoral heads, etc.). Dose mimicked plans were evaluated by a radiation oncologist, and patient-specific QAs were performed to validate delivery. Results: Overall plan generation and transfer required around 30 minutes of dosimetrist’s time once the dose-mimicking protocol is setup for each site. The resulting VMAT and 7- and 9-field IMRT plans achieved equivalent PTV coverage and homogeneity (D99/DRx = 97.3%, 97.2%, 97.2% and HI = 6.0, 5.8, and 5.9, respectively), compared to helical plans (97.6% and 4.6). The OAR dose discrepancies were up to 6% in rectum Dmean, but generally lower in bladder, femoral heads, bowel and penile bulb. In the context of 1–5 fractions, the radiation oncologist evaluated the dosimetric changes as not clinically significant. All delivery QAs achieved >90% pass with a 3%/3mm gamma criteria. Conclusion: The automated dose-mimicking workflow offers a strategy to avoid missing treatment fractions due to machine down time with non-clinically significant changes in dosimetry. Future work will further optimize dose mimicking plans and investigate other cross-platform treatment delivery options.« less

Safety, Tolerability, and Efficacy of Quetiapine in Youth with Schizophrenia or Bipolar I Disorder: A 26-Week, Open-Label, Continuation Study

PubMed Central

Pathak, Sanjeev; Earley, Willie R.; Liu, Sherry; DelBello, Melissa

2013-01-01

Abstract Objective The purpose of this study was to describe the safety, tolerability, and efficacy of quetiapine monotherapy continued for up to 26-weeks in youth with schizophrenia or bipolar I disorder. Methods Medically healthy boys and girls with a baseline Diagnostic and Statistical Manual of Mental Disorders, 4th ed. (DSM-IV-TR) diagnosis of schizophrenia (ages 13–17 years) or a manic episode of bipolar I disorder (ages 10–17 years) who participated in one of two acute, double-blind, placebo-controlled studies of immediate-release quetiapine were potentially eligible to enroll in a 26-week, open-label study. During the open-label study, quetiapine was flexibly dosed at 400–800 mg/day, with options to reduce dosing to 200 mg/day based on tolerability. Safety and tolerability outcomes assessed from open-label baseline to week 26 included adverse events (AEs), metabolic/laboratory parameters, extrapyramidal symptoms, suicidality, and vital signs. Results Of 381 patients enrolled in the open-label study (n=176, schizophrenia; n=205, bipolar disorder diagnosis), 237 patients (62.2%) completed the 26-week study period (71.0%, schizophrenia; 54.6%, bipolar disorder). The most common AEs reported during the study included somnolence, headache, sedation, weight increase, and vomiting. A total of 14.9% of patients experienced a shift to potentially clinically significant low levels of high-density lipoprotein cholesterol and 10.2% of patients experienced a shift to potentially clinically significant high triglyceride levels. Weight gain ≥7% was reported in 35.6% of patients between open-label baseline and final visit. After adjustment for normal growth, 18.3% of study participants experienced clinically significant weight gain (i.e., increase in body mass index ≥0.5 standard deviations from baseline). Conclusions In this 26-week study, quetiapine flexibly dosed at 400–800 mg/day, with options to reduce dosing based on tolerability, was generally safe and well tolerated in youth. Clinicians should monitor lipid profiles and weight gain in youth with schizophrenia or bipolar disorder during treatment with quetiapine. Clinical trial registration information Quetiapine Fumarate (Seroquel) in the Treatment of Adolescent Patients With Schizophrenia and Bipolar I Disorder (ANCHOR 150). Available at: http://clinicaltrials.gov/ct2/show/NCT00227305 PMID:24024534

A neurocognitive comparison of cognitive flexibility and response inhibition in gamblers with varying degrees of clinical severity.

PubMed

Odlaug, B L; Chamberlain, S R; Kim, S W; Schreiber, L R N; Grant, J E

2011-10-01

As a behavioral addiction with clinical and phenomenological similarities to substance addiction, recreational and pathological gambling represent models for studying the neurobiology of addiction, without the confounding deleterious brain effects which may occur from chronic substance abuse. A community sample of individuals aged 18-65 years who gamble was solicited through newspaper advertising. Subjects were grouped a priori into three groups (no-risk, at-risk, and pathological gamblers) based on a diagnostic interview. All subjects underwent a psychiatric clinical interview and neurocognitive tests assessing motor impulsivity and cognitive flexibility. Subjects with a current axis I disorder, history of brain injury/trauma, or implementation or dose changes of psychoactive medication within 6 weeks of study enrollment were excluded. A total of 135 no-risk, 69 at-risk and 46 pathological gambling subjects were assessed. Pathological gamblers were significantly older, and exhibited significant deficiencies in motor impulse control (stop-signal reaction times), response speed (median 'go' trial response latency) and cognitive flexibility [total intra-dimensional/extra-dimensional (IDED) errors] versus controls. The finding of impaired impulse control and cognitive flexibility was robust in an age-matched subgroup analysis of pathological gamblers. The no-risk and at-risk gambling groups did not significantly differ from each other on task performance. Impaired response inhibition and cognitive flexibility exist in people with pathological gambling compared with no-risk and at-risk gamblers. The early identification of such illness in adolescence or young adulthood may aid in the prevention of addiction onset of such disabling disorders.

Virtual reality based adaptive dose assessment method for arbitrary geometries in nuclear facility decommissioning.

PubMed

Liu, Yong-Kuo; Chao, Nan; Xia, Hong; Peng, Min-Jun; Ayodeji, Abiodun

2018-05-17

This paper presents an improved and efficient virtual reality-based adaptive dose assessment method (VRBAM) applicable to the cutting and dismantling tasks in nuclear facility decommissioning. The method combines the modeling strength of virtual reality with the flexibility of adaptive technology. The initial geometry is designed with the three-dimensional computer-aided design tools, and a hybrid model composed of cuboids and a point-cloud is generated automatically according to the virtual model of the object. In order to improve the efficiency of dose calculation while retaining accuracy, the hybrid model is converted to a weighted point-cloud model, and the point kernels are generated by adaptively simplifying the weighted point-cloud model according to the detector position, an approach that is suitable for arbitrary geometries. The dose rates are calculated with the Point-Kernel method. To account for radiation scattering effects, buildup factors are calculated with the Geometric-Progression formula in the fitting function. The geometric modeling capability of VRBAM was verified by simulating basic geometries, which included a convex surface, a concave surface, a flat surface and their combination. The simulation results show that the VRBAM is more flexible and superior to other approaches in modeling complex geometries. In this paper, the computation time and dose rate results obtained from the proposed method were also compared with those obtained using the MCNP code and an earlier virtual reality-based method (VRBM) developed by the same authors. © 2018 IOP Publishing Ltd.

Role of sublingual asenapine in treatment of schizophrenia

PubMed Central

Citrome, Leslie

2011-01-01

Asenapine tablets are a new option for the treatment of schizophrenia. Sublingual administration is essential because bioavailability if ingested is less than 2%. Efficacy is supported by acute and long-term randomized controlled studies conducted by the manufacturer, with asenapine 5 mg twice daily evidencing superiority over placebo in six-week studies of acute schizophrenia, and flexibly-dosed asenapine (modal dose 10 mg twice daily) superior to placebo in a 26-week maintenance of response study. Tolerability advantages over some second-generation antipsychotics, such as olanzapine, include a relatively favorable weight and metabolic profile, as demonstrated in a 52-week randomized, head-to-head, double-blind clinical trial. Although dose-related extrapyramidal symptoms and akathisia can be present, the frequency of these effects is lower than that for haloperidol and risperidone. Somnolence may also occur, and appears to be somewhat dose-dependent when examining rates of this among patients receiving asenapine for schizophrenia and bipolar disorder. Prolactin elevation can occur, but at a rate lower than that observed for haloperidol or risperidone. Unique to asenapine is the possibility of oral hypoesthesia, occurring in about 5% of participants in the clinical trials. Obstacles to the use of asenapine are the recommendations for twice-daily dosing and the need to avoid food or liquids for 10 minutes after administration, although the bioavailability is only minimally reduced if food or liquids are avoided for only two minutes. PMID:21655346

A dual two dimensional electronic portal imaging device transit dosimetry model based on an empirical quadratic formalism

PubMed Central

Metwaly, M; Glegg, M; Baggarley, S P; Elliott, A

2015-01-01

Objective: This study describes a two dimensional electronic portal imaging device (EPID) transit dosimetry model that can predict either: (1) in-phantom exit dose, or (2) EPID transit dose, for treatment verification. Methods: The model was based on a quadratic equation that relates the reduction in intensity to the equivalent path length (EPL) of the attenuator. In this study, two sets of quadratic equation coefficients were derived from calibration dose planes measured with EPID and ionization chamber in water under reference conditions. With two sets of coefficients, EPL can be calculated from either EPID or treatment planning system (TPS) dose planes. Consequently, either the in-phantom exit dose or the EPID transit dose can be predicted from the EPL. The model was tested with two open, five wedge and seven sliding window prostate and head and neck intensity-modulated radiation therapy (IMRT) fields on phantoms. Results were analysed using absolute gamma analysis (3%/3 mm). Results: The open fields gamma pass rates were >96.8% for all comparisons. For wedge and IMRT fields, comparisons between predicted and TPS-computed in-phantom exit dose resulted in mean gamma pass rate of 97.4% (range, 92.3–100%). As for the comparisons between predicted and measured EPID transit dose, the mean gamma pass rate was 97.5% (range, 92.6–100%). Conclusion: An EPID transit dosimetry model that can predict in-phantom exit dose and EPID transit dose was described and proven to be valid. Advances in knowledge: The described model is practical, generic and flexible to encourage widespread implementation of EPID dosimetry for the improvement of patients' safety in radiotherapy. PMID:25969867

Printed dose-recording tag based on organic complementary circuits and ferroelectric nonvolatile memories

PubMed Central

Nga Ng, Tse; Schwartz, David E.; Mei, Ping; Krusor, Brent; Kor, Sivkheng; Veres, Janos; Bröms, Per; Eriksson, Torbjörn; Wang, Yong; Hagel, Olle; Karlsson, Christer

2015-01-01

We have demonstrated a printed electronic tag that monitors time-integrated sensor signals and writes to nonvolatile memories for later readout. The tag is additively fabricated on flexible plastic foil and comprises a thermistor divider, complementary organic circuits, and two nonvolatile memory cells. With a supply voltage below 30 V, the threshold temperatures can be tuned between 0 °C and 80 °C. The time-temperature dose measurement is calibrated for minute-scale integration. The two memory bits are sequentially written in a thermometer code to provide an accumulated dose record. PMID:26307438

WAZA-ARI: computational dosimetry system for X-ray CT examinations II: development of web-based system.

PubMed

Ban, Nobuhiko; Takahashi, Fumiaki; Ono, Koji; Hasegawa, Takayuki; Yoshitake, Takayasu; Katsunuma, Yasushi; Sato, Kaoru; Endo, Akira; Kai, Michiaki

2011-07-01

A web-based dose computation system, WAZA-ARI, is being developed for patients undergoing X-ray CT examinations. The system is implemented in Java on a Linux server running Apache Tomcat. Users choose scanning options and input parameters via a web browser over the Internet. Dose coefficients, which were calculated in a Japanese adult male phantom (JM phantom) are called upon user request and are summed over the scan range specified by the user to estimate a normalised dose. Tissue doses are finally computed based on the radiographic exposure (mA s) and the pitch factor. While dose coefficients are currently available only for limited CT scanner models, the system has achieved a high degree of flexibility and scalability without the use of commercial software.

Dose-time-response association between occupational asbestos exposure and pleural mesothelioma.

PubMed

Lacourt, Aude; Lévêque, Emilie; Guichard, Elie; Gilg Soit Ilg, Anabelle; Sylvestre, Marie-Pierre; Leffondré, Karen

2017-09-01

Early occupational exposure to asbestos has been shown to be associated with an increased risk of pleural mesothelioma (PM), which suggests that the timing of exposure might play a role in the dose-response relationship. However, none studies has evaluated the relative impact of increasing the annual intensity of occupational exposure to asbestos at each time of the whole exposure history. Yet such evaluation would allow the comparison of the risks of PM associated with different longitudinal profiles of occupational exposure to asbestos. Our objective was to estimate the time-dependent relative impact of asbestos exposure intensity over the whole occupational history and to compare the resulting estimated risks of PM associated with different profiles of exposure, using data from a large French case-control study. This study included 1196 male cases recruited in 1987-2006 and 2369 matched controls on birth year. Occupational exposure to asbestos was assessed using a job exposure matrix and represented in logistic regression models using a flexible weighted cumulative index of exposure. Due to much stronger weights of early doses of asbestos exposure, subjects who accumulated 20 fibres/mL over their entire job history with high doses during the first years and low doses thereafter were at higher risk of PM than those who accumulated most of the doses later (OR=2.37 (95% CI 2.01 to 2.87)). This study provides new insights on the dose-time-response relationship between occupational asbestos and PM and illustrates the importance of considering timing of exposure in its association with cancer risk. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

Using machine learning to model dose-response relationships.

PubMed

Linden, Ariel; Yarnold, Paul R; Nallamothu, Brahmajee K

2016-12-01

Establishing the relationship between various doses of an exposure and a response variable is integral to many studies in health care. Linear parametric models, widely used for estimating dose-response relationships, have several limitations. This paper employs the optimal discriminant analysis (ODA) machine-learning algorithm to determine the degree to which exposure dose can be distinguished based on the distribution of the response variable. By framing the dose-response relationship as a classification problem, machine learning can provide the same functionality as conventional models, but can additionally make individual-level predictions, which may be helpful in practical applications like establishing responsiveness to prescribed drug regimens. Using data from a study measuring the responses of blood flow in the forearm to the intra-arterial administration of isoproterenol (separately for 9 black and 13 white men, and pooled), we compare the results estimated from a generalized estimating equations (GEE) model with those estimated using ODA. Generalized estimating equations and ODA both identified many statistically significant dose-response relationships, separately by race and for pooled data. Post hoc comparisons between doses indicated ODA (based on exact P values) was consistently more conservative than GEE (based on estimated P values). Compared with ODA, GEE produced twice as many instances of paradoxical confounding (findings from analysis of pooled data that are inconsistent with findings from analyses stratified by race). Given its unique advantages and greater analytic flexibility, maximum-accuracy machine-learning methods like ODA should be considered as the primary analytic approach in dose-response applications. © 2016 John Wiley & Sons, Ltd.

Discovery of cryptophycin-1 and BCN-183577: examples of strategies and problems in the detection of antitumor activity in mice.

PubMed

Corbett, T H; Valeriote, F A; Demchik, L; Lowichik, N; Polin, L; Panchapor, C; Pugh, S; White, K; Kushner, J; Rake, J; Wentland, M; Golakoti, T; Hetzel, C; Ogino, J; Patterson, G; Moore, R

1997-01-01

Historically, many new anticancer agents were first detected in a prescreen; usually consisting of a molecular/biochemical target or a cellular cytotoxicity assay. The agent then progressed to in vivo evaluation against transplanted human or mouse tumors. If the investigator had a large drug supply and ample resources, multiple tests were possible, with variations in tumor models, tumor and drug routes, dose-decrements, dose-schedules, number of groups, etc. However, in most large programs involving several hundred in vivo tests yearly, resource limitations and drug supply limitations have usually dictated a single trial. Under such restrictive conditions, we have implemented a flexible in vivo testing protocol. With this strategy, the tumor model is dictated by in vitro cellular sensitivity; drug route by water solubility (with water soluble agents injected intravenously); dosage decrement by drug supply, dose-schedule by toxicities encountered, etc. In this flexible design, many treatment parameters can be changed during the course of treatment (e.g., dose and schedule). The discovery of two active agents are presented (Cryptophycin-1, and Thioxanthone BCN 183577). Both were discovered by the intravenous route of administration. Both would have been missed if they were tested intraperitoneally, the usual drug route used in discovery protocols. It is also likely that they would have been missed with an easy to execute fixed protocol design, even if injected i.v.

Low dose radiation risks for women surviving the a-bombs in Japan: generalized additive model.

PubMed

Dropkin, Greg

2016-11-24

Analyses of cancer mortality and incidence in Japanese A-bomb survivors have been used to estimate radiation risks, which are generally higher for women. Relative Risk (RR) is usually modelled as a linear function of dose. Extrapolation from data including high doses predicts small risks at low doses. Generalized Additive Models (GAMs) are flexible methods for modelling non-linear behaviour. GAMs are applied to cancer incidence in female low dose subcohorts, using anonymous public data for the 1958 - 1998 Life Span Study, to test for linearity, explore interactions, adjust for the skewed dose distribution, examine significance below 100 mGy, and estimate risks at 10 mGy. For all solid cancer incidence, RR estimated from 0 - 100 mGy and 0 - 20 mGy subcohorts is significantly raised. The response tapers above 150 mGy. At low doses, RR increases with age-at-exposure and decreases with time-since-exposure, the preferred covariate. Using the empirical cumulative distribution of dose improves model fit, and capacity to detect non-linear responses. RR is elevated over wide ranges of covariate values. Results are stable under simulation, or when removing exceptional data cells, or adjusting neutron RBE. Estimates of Excess RR at 10 mGy using the cumulative dose distribution are 10 - 45 times higher than extrapolations from a linear model fitted to the full cohort. Below 100 mGy, quasipoisson models find significant effects for all solid, squamous, uterus, corpus, and thyroid cancers, and for respiratory cancers when age-at-exposure > 35 yrs. Results for the thyroid are compatible with studies of children treated for tinea capitis, and Chernobyl survivors. Results for the uterus are compatible with studies of UK nuclear workers and the Techa River cohort. Non-linear models find large, significant cancer risks for Japanese women exposed to low dose radiation from the atomic bombings. The risks should be reflected in protection standards.

A mini-review of non-parenteral clonidine preparations for paediatric sedation.

PubMed

Hanning, Sara M; Orlu Gul, Mine; Toni, Irmgard; Neubert, Antje; Tuleu, Catherine

2017-04-01

To provide an overview of non-parenteral clonidine formulations and assess the feasibility of their use for paediatric sedation. A literature search was conducted using electronic databases and a combination of search terms. Forty articles met the inclusion criteria. Publications were grouped into different dosage forms and assessed for their potential application for sedation of children in intensive care. Several routes of clonidine administration have been investigated for numerous indications in children, including perioperative sedation and analgesia. These include oral liquids, tablets, oral transmucosal systems, nasal sprays and rectal suspensions. Conflicting studies on oral transmucosal clonidine formulations suggest that further research is required to fully establish efficacy. Nasal sprays and rectal suspensions have the advantages of rapid onset of action and potential for dose flexibility, but predictable absorption is difficult to obtain. Provided age-appropriate strengths are available, intravenous formulations remain the most predictable in terms of bioavailability and flexible in terms of dose adjustment. However, as with all routes, down-titration is difficult given the long half-life of clonidine. Oral transmucosal systems, nasal sprays and rectal suspensions have potential in a less acute setting, but significant clinical work is required to elucidate a full pharmacokinetic and pharmacodynamic profile. © 2016 Royal Pharmaceutical Society.

A Flexible Workflow for Automated Bioluminescent Kinase Selectivity Profiling.

PubMed

Worzella, Tracy; Butzler, Matt; Hennek, Jacquelyn; Hanson, Seth; Simdon, Laura; Goueli, Said; Cowan, Cris; Zegzouti, Hicham

2017-04-01

Kinase profiling during drug discovery is a necessary process to confirm inhibitor selectivity and assess off-target activities. However, cost and logistical limitations prevent profiling activities from being performed in-house. We describe the development of an automated and flexible kinase profiling workflow that combines ready-to-use kinase enzymes and substrates in convenient eight-tube strips, a bench-top liquid handling device, ADP-Glo Kinase Assay (Promega, Madison, WI) technology to quantify enzyme activity, and a multimode detection instrument. Automated methods were developed for kinase reactions and quantification reactions to be assembled on a Gilson (Middleton, WI) PIPETMAX, following standardized plate layouts for single- and multidose compound profiling. Pipetting protocols were customized at runtime based on user-provided information, including compound number, increment for compound titrations, and number of kinase families to use. After the automated liquid handling procedures, a GloMax Discover (Promega) microplate reader preloaded with SMART protocols was used for luminescence detection and automatic data analysis. The functionality of the automated workflow was evaluated with several compound-kinase combinations in single-dose or dose-response profiling formats. Known target-specific inhibitions were confirmed. Novel small molecule-kinase interactions, including off-target inhibitions, were identified and confirmed in secondary studies. By adopting this streamlined profiling process, researchers can quickly and efficiently profile compounds of interest on site.

Hybrid computational phantoms of the 15-year male and female adolescent: Applications to CT organ dosimetry for patients of variable morphometry

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

Lee, Choonsik; Lodwick, Daniel; Williams, Jonathan L.

Currently, two classes of the computational phantoms have been developed for dosimetry calculation: (1) stylized (or mathematical) and (2) voxel (or tomographic) phantoms describing human anatomy through mathematical surface equations and three-dimensional labeled voxel matrices, respectively. Mathematical surface equations in stylized phantoms provide flexibility in phantom design and alteration, but the resulting anatomical description is, in many cases, not very realistic. Voxel phantoms display far better anatomical realism, but they are limited in terms of their ability to alter organ shape, position, and depth, as well as body posture. A new class of computational phantoms - called hybrid phantoms -more » takes advantage of the best features of stylized and voxel phantoms - flexibility and anatomical realism, respectively. In the current study, hybrid computational phantoms representing reference 15-year male and female body anatomy and anthropometry are presented. For the male phantom, organ contours were extracted from the University of Florida (UF) 14-year series B male voxel phantom, while for the female phantom, original computed tomography (CT) data from two 14-year female patients were used. Polygon mesh models for the major organs and tissues were reconstructed for nonuniform rational B-spline (NURBS) surface modeling. The resulting NURBS/polygon mesh models representing body contour and internal anatomy were matched to anthropometric data and reference organ mass data provided by the Centers for Disease Control and Prevention (CDC) and the International Commission on Radiation Protection (ICRP), respectively. Finally, two hybrid 15-year male and female phantoms were completed where a total of eight anthropometric data categories were matched to standard values within 4% and organ masses matched to ICRP data within 1% with the exception of total skin. To highlight the flexibility of the hybrid phantoms, 10th and 90th weight percentile 15-year male and female phantoms were further developed from the 50th percentile phantoms through adjustments in the body contour to match the total body masses given in CDC pediatric growth curves. The resulting six NURBS phantoms, male and female phantoms representing their 10th, 50th, and 90th weight percentiles, were used to investigate the influence of body fat distributions on internal organ doses following CT imaging. The phantoms were exposed to multislice chest and abdomen helical CT scans, and in-field organ absorbed doses were calculated. The results demonstrated that the use of traditional stylized phantoms yielded organ dose estimates that deviate from those given by the UF reference hybrid phantoms by up to a factor of 2. The study also showed that use of reference, or 50th percentile, phantoms to assess organ doses in underweight 15-year-old children would not lead to significant organ dose errors (typically less than 10%). However, more significant errors were noted (up to {approx}30%) when reference phantoms are used to represent overweight children in CT imaging dosimetry. These errors are expected to only further increase as one considers CT organ doses in overweight and obese individuals of the adult patient population, thus emphasizing the advantages of patient-sculptable phantom technology.« less

Memantine shows promise in reducing gambling severity and cognitive inflexibility in pathological gambling: a pilot study

PubMed Central

Chamberlain, Samuel R.; Odlaug, Brian L.; Potenza, Marc N.; Kim, Suck Won

2012-01-01

Rationale Although pathological gambling (PG) is relatively common, pharmacotherapy research for PG is limited. Memantine, an N-methyl d-aspartate receptor antagonist, appears to reduce glutamate excitability and improve impulsive decision making, suggesting it may help individuals with PG. Objective This study sought to examine the safety and efficacy of Memantine in PG. Methods Twenty-nine subjects (18 females) with DSM-IV PG were enrolled in a 10-week open-label treatment study of memantine (dose ranging from 10 to 30 mg/day). Subjects were enrolled from January 2009 until April 2010. Change from baseline to study endpoint on the Yale Brown Obsessive Compulsive Scale Modified for Pathological Gambling (PG-YBOCS) was the primary outcome measure. Subjects underwent pre- and post-treatment cognitive assessments using the stop-signal task (assessing response impulsivity) and the intra-dimensional/extra-dimensional (ID/ED) set shift task (assessing cognitive flexibility). Results Twenty-eight of the 29 subjects (96.6%) completed the 10-week study. PG-YBOCS scores decreased from a mean of 21.8±4.3 at baseline to 8.9±7.1 at study endpoint (p<0.001). Hours spent gambling per week and money spent gambling both decreased significantly (p<0.001). Subjects also demonstrated a significant improvement in ID/ED total errors (p=0.037) at study endpoint. The mean effective dose of memantine was 23.4±8.1 mg/day. The medication was well-tolerated. Memantine treatment was associated with diminished gambling and improved cognitive flexibility. Conclusions These findings suggest that pharmacological manipulation of the glutamate system may target both gambling and cognitive deficits in PG. Placebo-controlled, double-blind studies are warranted in order to confirm these preliminary findings in a controlled design. PMID:20721537

Memantine shows promise in reducing gambling severity and cognitive inflexibility in pathological gambling: a pilot study.

PubMed

Grant, Jon E; Chamberlain, Samuel R; Odlaug, Brian L; Potenza, Marc N; Kim, Suck Won

2010-12-01

Although pathological gambling (PG) is relatively common, pharmacotherapy research for PG is limited. Memantine, an N-methyl D-aspartate receptor antagonist, appears to reduce glutamate excitability and improve impulsive decision making, suggesting it may help individuals with PG. This study sought to examine the safety and efficacy of Memantine in PG. Twenty-nine subjects (18 females) with DSM-IV PG were enrolled in a 10-week open-label treatment study of memantine (dose ranging from 10 to 30 mg/day). Subjects were enrolled from January 2009 until April 2010. Change from baseline to study endpoint on the Yale Brown Obsessive Compulsive Scale Modified for Pathological Gambling (PG-YBOCS) was the primary outcome measure. Subjects underwent pre- and post-treatment cognitive assessments using the stop-signal task (assessing response impulsivity) and the intra-dimensional/extra-dimensional (ID/ED) set shift task (assessing cognitive flexibility). Twenty-eight of the 29 subjects (96.6%) completed the 10-week study. PG-YBOCS scores decreased from a mean of 21.8 ± 4.3 at baseline to 8.9 ± 7.1 at study endpoint (p < 0.001). Hours spent gambling per week and money spent gambling both decreased significantly (p < 0.001). Subjects also demonstrated a significant improvement in ID/ED total errors (p = 0.037) at study endpoint. The mean effective dose of memantine was 23.4 ± 8.1 mg/day. The medication was well-tolerated. Memantine treatment was associated with diminished gambling and improved cognitive flexibility. These findings suggest that pharmacological manipulation of the glutamate system may target both gambling and cognitive deficits in PG. Placebo-controlled, double-blind studies are warranted in order to confirm these preliminary findings in a controlled design.

The selective serotonin reuptake inhibitor, escitalopram, enhances inhibition of prepotent responding and spatial reversal learning

PubMed Central

Brown, Holden D.; Amodeo, Dionisio A.; Sweeney, John A.; Ragozzino, Michael E.

2011-01-01

Previous findings indicate treatment with a selective serotonin reuptake inhibitor (SSRI) facilitates behavioral flexibility when conditions require inhibition of a learned response pattern. The present experiment investigated whether acute treatment with the SSRI, escitalopram, affects behavioral flexibility when conditions require inhibition of a naturally-biased response pattern (elevated conflict test) and/or reversal of a learned response pattern (spatial reversal learning). An additional experiment was carried out to determine whether escitalopram, at doses that affected behavioral flexibility, also reduced anxiety as tested in the elevated plus-maze. In each experiment, Long-Evans rats received an intraperitoneal injection of either saline or escitalopram (0.03, 0.3 or 1.0 mg/kg) 30 minutes prior to behavioral testing. Escitalopram, at all doses tested, enhanced acquisition in the elevated conflict test, but did not affect performance in the elevated plus-maze. Escitalopram (0.3 and 1.0 mg/kg) did not alter acquisition of the spatial discrimination, but facilitated reversal learning. In the elevated conflict and spatial reversal learning test, escitalopram enhanced the ability to maintain the relevant strategy after being initially selected. The present findings suggest that enhancing serotonin transmission with a SSRI facilitates inhibitory processes when conditions require a shift away from either a naturally-biased response pattern or a learned choice pattern. PMID:22219222

Randomized Prospective Double-Blind Studies to Evaluate the Cognitive Effects of Inositol-Stabilized Arginine Silicate in Healthy Physically Active Adults

PubMed Central

Kalman, Douglas; Harvey, Philip D.; Perez Ojalvo, Sara; Komorowski, James

2016-01-01

Inositol-stabilized arginine silicate (ASI; Nitrosigine®) has been validated to increase levels of arginine, silicon and nitric oxide production. To evaluate potential enhancement of mental focus and clarity, ASI (1500 mg/day) was tested in two double-blind placebo-controlled crossover (DBPC-X) studies using the Trail Making Test (TMT, Parts A and B). In the two studies, healthy males took ASI for 14 and 3 days, respectively. In the first study, after 14 days of dosing, TMT B time decreased significantly from baseline (28% improvement, p = 0.045). In the second study evaluating shorter-term effects, TMT B time decreased significantly compared to placebo (33% improvement, p = 0.024) in a 10-min period. After 3 days of dosing, TMT B time significantly decreased from baseline scores (35% improvement, p < 0.001). These findings show that ASI significantly improved the ability to perform complex cognitive tests requiring mental flexibility, processing speed and executive functioning. PMID:27869715

Reverse Current Blocking Diodes for Flexible Solar Array Protection

DTIC Science & Technology

1975-04-01

the general ’ Tic, ici~cjluir; foreign nations. T1->*.:. ti~c!chnical report has been reviewed and is approved for L .D. Man i c/GS - 3 :P’rojcct nm r...To generate the figures, a set of thermal radiative properties for the diodes and substrate had to be assumed. A second surface mirror made of...simulated nuclear weapon generated gamma pulses. Dose rates of varying levels were delivered by "two radiation effects machines. Lower dose rate

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

Zhu, Yuanyuan; Munro, Catherine J.; Olszta, Matthew J.

In this work, we showcase that through precise control of the electron dose rate, state-of-the-art large solid angle energy dispersive X-ray spectroscopy (EDS) mapping in aberration-corrected scanning transmission electron microscope (STEM) is capable of faithful and unambiguous chemical characterization of the Pt and Pd distribution in a peptide-mediated nanosystem. This low-dose-rate recording scheme adds another dimension of flexibility to the design of elemental mapping experiments, and holds significant potential for extending its application to a wide variety of beam sensitive hybrid nanostructures.

Clean focus, dose and CD metrology for CD uniformity improvement

NASA Astrophysics Data System (ADS)

Lee, Honggoo; Han, Sangjun; Hong, Minhyung; Kim, Seungyoung; Lee, Jieun; Lee, DongYoung; Oh, Eungryong; Choi, Ahlin; Kim, Nakyoon; Robinson, John C.; Mengel, Markus; Pablo, Rovira; Yoo, Sungchul; Getin, Raphael; Choi, Dongsub; Jeon, Sanghuck

2018-03-01

Lithography process control solutions require more exacting capabilities as the semiconductor industry goes forward to the 1x nm node DRAM device manufacturing. In order to continue scaling down the device feature sizes, critical dimension (CD) uniformity requires continuous improvement to meet the required CD error budget. In this study we investigate using optical measurement technology to improve over CD-SEM methods in focus, dose, and CD. One of the key challenges is measuring scanner focus of device patterns. There are focus measurement methods based on specially designed marks on scribe-line, however, one issue of this approach is that it will report focus of scribe line which is potentially different from that of the real device pattern. In addition, scribe-line marks require additional design and troubleshooting steps that add complexity. In this study, we investigated focus measurement directly on the device pattern. Dose control is typically based on using the linear correlation behavior between dose and CD. The noise of CD measurement, based on CD-SEM for example, will not only impact the accuracy, but also will make it difficult to monitor dose signature on product wafers. In this study we will report the direct dose metrology result using an optical metrology system which especially enhances the DUV spectral coverage to improve the signal to noise ratio. CD-SEM is often used to measure CD after the lithography step. This measurement approach has the advantage of easy recipe setup as well as the flexibility to measure critical feature dimensions, however, we observe that CD-SEM metrology has limitations. In this study, we demonstrate within-field CD uniformity improvement through the extraction of clean scanner slit and scan CD behavior by using optical metrology.

Cold Atmospheric Plasma, Created at the Tip of an Elongated Flexible Capillary Using Low Electric Current, Can Slow the Progression of Melanoma

PubMed Central

Binenbaum, Y.; Ben-David, G.; Gil, Z.; Slutsker, Ya. Z.; Ryzhkov, M. A.; Felsteiner, J.; Krasik, Ya. E.; Cohen, J. T.

2017-01-01

Introduction Cold Atmospheric Plasma Jet (CAPJ), with ion temperature close to room temperature, has tremendous potential in biomedical engineering, and can potentially offer a therapeutic option that allows cancer cell elimination without damaging healthy tissue. We developed a hand-held flexible device for the delivery of CAPJ to the treatment site, with a modified high-frequency pulse generator operating at a RMS voltage of <1.2 kV and gas flow in the range 0.3–3 l/min. The aims of our study were to characterize the CAPJ emitted from the device, and to evaluate its efficacy in elimination of cancer cells in-vitro and in-vivo. Methods and Results The power delivered by CAPJ was measured on a floating or grounded copper target. The power did not drastically change over distances of 0–14 mm, and was not dependent on the targets resistance. Temperature of CAPJ-treated target was 23°-36° C, and was dependent on the voltage applied. Spectroscopy indicated that excited OH- radicals were abundant both on dry and wet targets, placed at different distances from the plasma gun. An in-vitro cell proliferation assay demonstrated that CAPJ treatment of 60 seconds resulted in significant reduction in proliferation of all cancer cell lines tested, and that CAPJ activated medium was toxic to cancer cells. In-vivo, we treated cutaneous melanoma tumors in nude mice. Tumor volume was significantly decreased in CAPJ-treated tumors relatively to controls, and high dose per fraction was more effective than low dose per fraction treatment. Importantly, pathologic examination revealed that normal skin was not harmed by CAPJ treatment. Conclusion This preliminary study demonstrates the efficacy of flexible CAPJ delivery system against melanoma progression both in-vitro and in-vivo. It is envisioned that adaptation of CAPJ technology for different kinds of neoplasms use may provide a new modality for the treatment of solid tumors. PMID:28103270

Cold Atmospheric Plasma, Created at the Tip of an Elongated Flexible Capillary Using Low Electric Current, Can Slow the Progression of Melanoma.

PubMed

Binenbaum, Y; Ben-David, G; Gil, Z; Slutsker, Ya Z; Ryzhkov, M A; Felsteiner, J; Krasik, Ya E; Cohen, J T

2017-01-01

Cold Atmospheric Plasma Jet (CAPJ), with ion temperature close to room temperature, has tremendous potential in biomedical engineering, and can potentially offer a therapeutic option that allows cancer cell elimination without damaging healthy tissue. We developed a hand-held flexible device for the delivery of CAPJ to the treatment site, with a modified high-frequency pulse generator operating at a RMS voltage of <1.2 kV and gas flow in the range 0.3-3 l/min. The aims of our study were to characterize the CAPJ emitted from the device, and to evaluate its efficacy in elimination of cancer cells in-vitro and in-vivo. The power delivered by CAPJ was measured on a floating or grounded copper target. The power did not drastically change over distances of 0-14 mm, and was not dependent on the targets resistance. Temperature of CAPJ-treated target was 23°-36° C, and was dependent on the voltage applied. Spectroscopy indicated that excited OH- radicals were abundant both on dry and wet targets, placed at different distances from the plasma gun. An in-vitro cell proliferation assay demonstrated that CAPJ treatment of 60 seconds resulted in significant reduction in proliferation of all cancer cell lines tested, and that CAPJ activated medium was toxic to cancer cells. In-vivo, we treated cutaneous melanoma tumors in nude mice. Tumor volume was significantly decreased in CAPJ-treated tumors relatively to controls, and high dose per fraction was more effective than low dose per fraction treatment. Importantly, pathologic examination revealed that normal skin was not harmed by CAPJ treatment. This preliminary study demonstrates the efficacy of flexible CAPJ delivery system against melanoma progression both in-vitro and in-vivo. It is envisioned that adaptation of CAPJ technology for different kinds of neoplasms use may provide a new modality for the treatment of solid tumors.

Remission and recovery associated with lurasidone in the treatment of major depressive disorder with subthreshold hypomanic symptoms (mixed features): post-hoc analysis of a randomized, placebo-controlled study with longer-term extension.

PubMed

Goldberg, Joseph F; Ng-Mak, Daisy; Siu, Cynthia; Chuang, Chien-Chia; Rajagopalan, Krithika; Loebel, Antony

2017-04-01

This post-hoc analysis assessed rates of symptomatic and functional remission, as well as recovery (combination of symptomatic and functional remission), in patients treated with lurasidone for major depressive disorder (MDD) associated with subthreshold hypomanic symptoms (mixed features). Patients with MDD plus two or three manic symptoms (defined as per the DSM-5 mixed-features specifier) were randomly assigned to flexible-dose lurasidone 20-60 mg/day (n=109) or placebo (n=100) for 6 weeks, followed by a 3-month open-label, flexible-dose extension study for U.S. sites only (n=48). Cross-sectional recovery was defined as the presence of both symptomatic remission (Montgomery-Åsberg Depression Rating Scale score ≤ 12) and functional remission (all Sheehan Disability Scale [SDS] domain scores ≤3) at week 6, and at both months 1 and 3 of the extension study ("sustained recovery"). A significantly higher proportion of lurasidone-treated patients (31.3%) achieved recovery (assessed cross-sectionally) compared to placebo (12.2%, p=0.002) at week 6. The number of manic symptoms at baseline moderated the effect size for attaining cross-sectional recovery for lurasidone treatment (vs. placebo) (p=0.028). Sustained recovery rates were higher in patients initially treated with lurasidone (20.8%) versus placebo (12.5%). In this post-hoc analysis of a placebo-controlled study with open-label extension that involved patients with MDD and mixed features, lurasidone was found to significantly improve the rate of recovery at 6 weeks (vs. placebo) that was sustained at month 3 of the extension study. The presence of two (as opposed to three) manic symptoms moderated recovery at the acute study endpoint.

Dose-finding designs for trials of molecularly targeted agents and immunotherapies

PubMed Central

Chiuzan, Cody; Shtaynberger, Jonathan; Manji, Gulam A.; Duong, Jimmy K.; Schwartz, Gary K.; Ivanova, Anastasia; Lee, Shing M.

2017-01-01

Recently, there has been a surge of early phase trials of molecularly targeted agents (MTAs) and immunotherapies. These new therapies have different toxicity profiles compared to cytotoxic therapies. MTAs can benefit from new trial designs that allow inclusion of low-grade toxicities, late-onset toxicities, addition of an efficacy endpoint, and flexibility in the specification of a target toxicity probability. To study the degree of adoption of these methods, we conducted a Web of Science search of articles published between 2008 and 2014 that describe phase 1 oncology trials. Trials were categorized based on the dose-finding design used and the type of drug studied. Out of 1,712 dose-finding trials that met our criteria, 1,591 (92.9%) utilized a rule-based design, and 92 (5.4%; range 2.3% in 2009 to 9.7% in 2014) utilized a model-based or novel design. Over half of the trials tested an MTA or immunotherapy. Among the MTA and immunotherapy trials, 5.8% used model-based methods, compared to 3.9% and 8.3% of the chemotherapy or radiotherapy trials, respectively. While the percentage of trials using novel dose-finding designs has tripled since 2007, only 7.1% of trials use novel designs. PMID:28166468

A Flexible Multidose GnRH Antagonist versus a Microdose Flare-Up GnRH Agonist Combined with a Flexible Multidose GnRH Antagonist Protocol in Poor Responders to IVF.

PubMed

Çelik, Gayem İnayet Turgay; Sütçü, Havva Kömür; Akpak, Yaşam Kemal; Akar, Münire Erman

2015-01-01

To compare the effectiveness of a flexible multidose gonadotropin-releasing hormone (GnRH) antagonist against the effectiveness of a microdose flare-up GnRH agonist combined with a flexible multidose GnRH antagonist protocol in poor responders to in vitro fertilization (IVF). A retrospective study in Akdeniz University, Faculty of Medicine, Department of Obstetrics and Gynecology, IVF Center, for 131 poor responders in the intracytoplasmic sperm injection-embryo transfer (ICSI-ET) program between January 2006 and November 2012. The groups were compared to the patients' characteristics, controlled ovarian stimulation (COH) results, and laboratory results. Combination protocol was applied to 46 patients (group 1), and a single protocol was applied to 85 patients (group 2). In group 1, the duration of the treatment was longer and the dose of FSH was higher. The cycle cancellation rate was significantly higher in group 2 (26.1% versus 38.8%). A significant difference was not observed with respect to the number and quality of oocytes and embryos or to the number of embryos transferred. There were no statistically significant differences in the hCG positivity (9.5% versus 9.4%) or the clinical pregnancy rates (7.1% versus 10.6%). The combination protocol does not provide additional efficacy.

TU-H-BRC-08: Use and Validation of Flexible 3D Printed Tissue Compensators for Post-Mastectomy Radiation Therapy

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

Craft, D; Kry, S; Salehpour, M

Purpose: Patient-specific tissue equivalent compensators can be used for post-mastectomy radiation therapy (PMRT) to achieve homogenous dose distributions with single-field treatments. However, current fabrication methods are time consuming and expensive. 3D-printing technology could overcome these limitations. The purposes of this study were to [1] evaluate materials for 3D-printed compensators [2] design and print a compensator to achieve a uniform thickness to a clinical target volume (CTV), and [3] demonstrate that a single-field electron compensator plan is a clinically feasible treatment option for PMRT. Methods: Blocks were printed with three materials; print accuracy, density, Hounsfield units (HU), and percent depth dosesmore » (PDD) were evaluated. For a CT scan of an anthropomorphic phantom, we used a ray-tracing method to design a compensator that achieved uniform thickness from compensator surface to CTV. The compensator was printed with flexible tissue equivalent material whose physical and radiological properties were most similar to soft tissue. A single-field electron compensator plan was designed and compared with two standard-of-care techniques. The compensator plan was validated with thermoluminescent dosimeter (TLD) measurements. Results: We identified an appropriate material for 3D-printed compensators that had high print accuracy (99.6%) and was similar to soft tissue; density was 1.04, HU was - 45 ± 43, and PDD curves agreed with clinical curves within 3 mm. We designed and printed a compensator that conformed well to the phantom surface and created a uniform thickness to the CTV. In-house fabrication was simple and inexpensive (<$75). Compared with the two standard plans, the compensator plan resulted in overall more homogeneous dose distributions and performed similarly in terms of lung/heart doses and 90% isodose coverage of the CTV. TLD measurements agreed well with planned doses (within 5 %). Conclusions: We have demonstrated that 3D-printed compensators make single-field electron therapy a clinically feasible treatment option for PMRT.« less

Effectiveness of lurasidone in schizophrenia or schizoaffective patients switched from other antipsychotics: a 6-month, open-label, extension study.

PubMed

Citrome, Leslie; Weiden, Peter J; McEvoy, Joseph P; Correll, Christoph U; Cucchiaro, Josephine; Hsu, Jay; Loebel, Antony

2014-08-01

To evaluate the long-term safety and tolerability of lurasidone in schizophrenia and schizoaffective disorder patients switched to lurasidone. Patients in this multicenter, 6-month open-label, flexible-dose, extension study had completed a core 6-week randomized trial in which clinically stable, but symptomatic, outpatients with schizophrenia or schizoaffective disorder were switched to lurasidone. Patients started the extension study on treatment with the same dose of lurasidone taken at study endpoint of the 6-week core study; following this, lurasidone was flexibly dosed (40-120 mg/day), if clinically indicated, starting on Day 7 of the extension study. The primary safety endpoints were the proportion of patients with treatment emergent adverse events (AEs), serious AEs, or who discontinued due to AEs. Secondary endpoints included metabolic variables and measures of extrapyramidal symptoms and akathisia, as well as the Positive and Negative Syndrome Scale (PANSS), Clinical Global Impressions-Severity (CGI-S), and the Calgary Depression Scale for Schizophrenia (CDSS). The study was conducted from August 2010 to November 2011. Of the 198 patients who completed the 6-week core study, 149 (75.3%) entered the extension study and 148 received study medication. A total of 98 patients (65.8%) completed the 6-month extension study. Lurasidone 40, 80, and 120 mg were the modal daily doses for 19 (12.8%), 65 (43.9%), and 64 (43.2%) of patients, respectively. Overall mean (SD) daily lurasidone dose was 102.0 mg (77.1). The most commonly reported AEs were insomnia (13 patients [8.8%]), nausea (13 patients [8.8%]), akathisia (12 patients [8.1%]), and anxiety (9 patients [6.1%]). A total of 16 patients (10.8%) had at least one AE leading to discontinuation from the study. Consistent with prior studies of lurasidone, there was no signal for clinically relevant adverse changes in body weight, lipids, glucose, insulin, or prolactin. Movement disorder rating scales did not demonstrate meaningful changes. Treatment failure (defined as any occurrence of discontinuation due to insufficient clinical response, exacerbation of underlying disease, or AE) was observed for 19 patients (12.8% of patients entering) and median time to treatment failure was 58 days (95% CI 22-86). The discontinuation rate due to any cause was 50/148 (33.8%), and median time to discontinuation was 62 days (95% CI 30-75). The mean PANSS total score, mean CGI-S score, and mean CDSS score decreased consistently from core study baseline across extension visits, indicating an improvement in overall condition. In this 6-month, open-label extension study, treatment with lurasidone was generally well-tolerated with sustained improvement in efficacy measures observed in outpatients with schizophrenia or schizoaffective disorder who had switched to lurasidone from a broad range of antipsychotic agents.

Dopamine treatment and cognitive functioning in individuals with Parkinson's disease: the "cognitive flexibility" hypothesis seems to work.

PubMed

Costa, Alberto; Peppe, Antonella; Mazzù, Ilenia; Longarzo, Mariachiara; Caltagirone, Carlo; Carlesimo, Giovanni A

2014-01-01

Previous data suggest that (i) dopamine modulates the ability to implement nonroutine schemata and update operations (flexibility processes) and that (ii) dopamine-related improvement may be related to baseline dopamine levels in target pathways (inverted U-shaped hypothesis). To investigate above hypotheses in individuals with Parkinson's disease (PD). Twenty PD patients were administered tasks varying as to flexibility load in two treatment conditions: (i) "off" condition, about 18 hours after dopamine dose and (ii) "on" condition, after dopamine administration. PD patients were separated into two groups: low performers (i.e., performance on Digit Span Backward below the sample mean) and high performers (i.e., performance above the mean). Twenty healthy individuals performed the tasks in two sessions without taking drugs. Passing from the "off" to the "on" state, only low performer PD patients significantly improved their performance on high-flexibility measures (interference condition of the Stroop test; P < 0.05); no significant effect was found on low-flexibility tasks. These findings document that high-flexibility processes are sensitive to dopamine neuromodulation in the early phases of PD. This is in line with the hypothesis that striatal dopamine pathways, affected early by PD, are precociously implicated in the expression of cognitive disorders in these individuals.

Multiple-Objective Optimal Designs for Studying the Dose Response Function and Interesting Dose Levels

PubMed Central

Hyun, Seung Won; Wong, Weng Kee

2016-01-01

We construct an optimal design to simultaneously estimate three common interesting features in a dose-finding trial with possibly different emphasis on each feature. These features are (1) the shape of the dose-response curve, (2) the median effective dose and (3) the minimum effective dose level. A main difficulty of this task is that an optimal design for a single objective may not perform well for other objectives. There are optimal designs for dual objectives in the literature but we were unable to find optimal designs for 3 or more objectives to date with a concrete application. A reason for this is that the approach for finding a dual-objective optimal design does not work well for a 3 or more multiple-objective design problem. We propose a method for finding multiple-objective optimal designs that estimate the three features with user-specified higher efficiencies for the more important objectives. We use the flexible 4-parameter logistic model to illustrate the methodology but our approach is applicable to find multiple-objective optimal designs for other types of objectives and models. We also investigate robustness properties of multiple-objective optimal designs to mis-specification in the nominal parameter values and to a variation in the optimality criterion. We also provide computer code for generating tailor made multiple-objective optimal designs. PMID:26565557

Multiple-Objective Optimal Designs for Studying the Dose Response Function and Interesting Dose Levels.

PubMed

Hyun, Seung Won; Wong, Weng Kee

2015-11-01

We construct an optimal design to simultaneously estimate three common interesting features in a dose-finding trial with possibly different emphasis on each feature. These features are (1) the shape of the dose-response curve, (2) the median effective dose and (3) the minimum effective dose level. A main difficulty of this task is that an optimal design for a single objective may not perform well for other objectives. There are optimal designs for dual objectives in the literature but we were unable to find optimal designs for 3 or more objectives to date with a concrete application. A reason for this is that the approach for finding a dual-objective optimal design does not work well for a 3 or more multiple-objective design problem. We propose a method for finding multiple-objective optimal designs that estimate the three features with user-specified higher efficiencies for the more important objectives. We use the flexible 4-parameter logistic model to illustrate the methodology but our approach is applicable to find multiple-objective optimal designs for other types of objectives and models. We also investigate robustness properties of multiple-objective optimal designs to mis-specification in the nominal parameter values and to a variation in the optimality criterion. We also provide computer code for generating tailor made multiple-objective optimal designs.

A double-blind, randomized, placebo-controlled comparison of botulinum toxin type a injection sites and doses in the prevention of episodic migraine.

PubMed

Saper, Joel R; Mathew, Ninan T; Loder, Elizabeth W; DeGryse, Ronald; VanDenburgh, Amanda M

2007-09-01

Several randomized, controlled studies have reported benefits of botulinum toxin type A (BoNTA; Allergan Inc., Irvine, CA, USA) over placebo in the treatment of migraine. Some studies reported significant benefits at dosages as low as 16 U, while other studies reported safety, tolerability, and efficacy at dosages up to 260 U. However, the optimal treatment paradigm and patient population have yet to be defined. To compare different injection sites and doses of BoNTA in the prevention of episodic migraine. This was a randomized, double-blind, placebo-controlled study of 232 patients with a history of four to eight moderate to severe migraines per month, with or without aura. Patients were randomized to placebo or one of four BoNTA groups that received injections into different muscle regions: frontal (10 U), temporal (6 U), glabellar (9 U), or all three areas (total dose 25 U). For 3 months following a single treatment, patients recorded migraine-related variables in a daily diary. BoNTA and placebo produced comparable decreases from baseline in the frequency of migraines (P > or = 0.411). In general, no statistically significant differences were observed for any efficacy variable. The overall rates of adverse events (any type) or treatment-related adverse events were similar among the groups. In this exploratory study of episodic migraine patients, low-dose injections of BoNTA into the frontal, temporal, and/or glabellar muscle regions were not more effective than placebo. BoNTA was safe and well tolerated. Future studies may examine higher BoNTA doses, flexible injection sites, multiple treatments, and disallow concomitant prophylactic medications.

Efficacy and tolerability of paliperidone ER in patients with unsatisfactorily controlled schizophrenia by other antipsychotics: a flexible-dose approach

PubMed Central

Mauri, Massimo C.; Adami, Marina; Reggiardo, Giorgio; Giulio, Corrivetti

2015-01-01

This study evaluates the effectiveness of paliperidone ER in patients with symptomatic but not highly acute schizophrenia in terms of efficacy, safety, and patients’ perception of their social functioning and well-being. This is a multicenter, open-label prospective study with a flexible-dose approach; 133 patients were enrolled and followed for 13 weeks after switching to paliperidone ER. Outcome efficacy measures were as follows: the Positive and Negative Syndrome Scale (PANSS), the Clinical Global Impression-Severity (CGI-S) scale, and the Personal and Social Performance (PSP) scale; in addition, the Subjective Well-being under Neuroleptics (SWN-20) scale, the Drug Attitude Inventory (DAI-30), and the sleep evaluation scale were used. Symptom Rating Scale (ESRS), adverse events, and subjective side effects were recorded. 118/133(88.7%) patients completed the study. The mean PANSS score decreased (88.98±10.09 to 66.52±16.29; P<0.001); 40.5% of the patients achieved improvement of at least 30%. PSP and CGI-S scores as well as DAI-30 and SWN-20 decreased (P<0.001). ESRS (P<0.001) decreased significantly from the baseline. Throughout the trial, no deaths occurred and only one serious adverse event was reported. Paliperidone ER has proved to be efficacious, safe, and well tolerated also with this approach more closely resembling actual clinical practice. Patient-relevant outcome parameters such as social functioning and quality of life improved, which is crucial for treatment adherence in clinical practice. PMID:26230269

Efficacy and tolerability of paliperidone ER in patients with unsatisfactorily controlled schizophrenia by other antipsychotics: a flexible-dose approach.

PubMed

Mauri, Mauro; Mauri, Massimo C; Adami, Marina; Reggiardo, Giorgio; Giulio, Corrivetti

2015-11-01

This study evaluates the effectiveness of paliperidone ER in patients with symptomatic but not highly acute schizophrenia in terms of efficacy, safety, and patients' perception of their social functioning and well-being. This is a multicenter, open-label prospective study with a flexible-dose approach; 133 patients were enrolled and followed for 13 weeks after switching to paliperidone ER. Outcome efficacy measures were as follows: the Positive and Negative Syndrome Scale (PANSS), the Clinical Global Impression-Severity (CGI-S) scale, and the Personal and Social Performance (PSP) scale; in addition, the Subjective Well-being under Neuroleptics (SWN-20) scale, the Drug Attitude Inventory (DAI-30), and the sleep evaluation scale were used. Symptom Rating Scale (ESRS), adverse events, and subjective side effects were recorded. 118/133(88.7%) patients completed the study. The mean PANSS score decreased (88.98 ± 10.09 to 66.52 ± 16.29; P < 0.001); 40.5% of the patients achieved improvement of at least 30%. PSP and CGI-S scores as well as DAI-30 and SWN-20 decreased (P < 0.001). ESRS (P < 0.001) decreased significantly from the baseline. Throughout the trial, no deaths occurred and only one serious adverse event was reported. Paliperidone ER has proved to be efficacious, safe, and well tolerated also with this approach more closely resembling actual clinical practice. Patient-relevant outcome parameters such as social functioning and quality of life improved, which is crucial for treatment adherence in clinical practice.

Spatial frequency performance limitations of radiation dose optimization and beam positioning

NASA Astrophysics Data System (ADS)

Stewart, James M. P.; Stapleton, Shawn; Chaudary, Naz; Lindsay, Patricia E.; Jaffray, David A.

2018-06-01

The flexibility and sophistication of modern radiotherapy treatment planning and delivery methods have advanced techniques to improve the therapeutic ratio. Contemporary dose optimization and calculation algorithms facilitate radiotherapy plans which closely conform the three-dimensional dose distribution to the target, with beam shaping devices and image guided field targeting ensuring the fidelity and accuracy of treatment delivery. Ultimately, dose distribution conformity is limited by the maximum deliverable dose gradient; shallow dose gradients challenge techniques to deliver a tumoricidal radiation dose while minimizing dose to surrounding tissue. In this work, this ‘dose delivery resolution’ observation is rigorously formalized for a general dose delivery model based on the superposition of dose kernel primitives. It is proven that the spatial resolution of a delivered dose is bounded by the spatial frequency content of the underlying dose kernel, which in turn defines a lower bound in the minimization of a dose optimization objective function. In addition, it is shown that this optimization is penalized by a dose deposition strategy which enforces a constant relative phase (or constant spacing) between individual radiation beams. These results are further refined to provide a direct, analytic method to estimate the dose distribution arising from the minimization of such an optimization function. The efficacy of the overall framework is demonstrated on an image guided small animal microirradiator for a set of two-dimensional hypoxia guided dose prescriptions.

The effect of dosing regimen on the pharmacokinetics of risedronate

PubMed Central

Mitchell, David Y; Heise, Mark A; Pallone, Karen A; Clay, Marian E; Nesbitt, John D; Russell, Darrell A; Melson, Chad W

1999-01-01

Aims To examine the effect of timing of a risedronate dose relative to food intake on the rate and extent of risedronate absorption following single-dose, oral administration to healthy male and female volunteers. Methods A single-dose, randomized, parallel study design was conducted with volunteers assigned to four treatment groups (31 or 32 subjects per group, 127 subjects total). Each subject was orally administered 30 mg risedronate. Group 1 was fasted for 10 h prior to and 4 h after dosing (fasted group); Groups 2 and 3 were fasted for 10 h and were dosed 1 and 0.5 h, respectively, before a high-fat breakfast; and Group 4 was dosed 2 h after a standard dinner. Blood and urine samples were collected for 168 h after dosing. Pharmacokinetic parameters were estimated by simultaneous analysis of risedronate serum concentration and urinary excretion rate-time data. Results Extent of risedronate absorption (AUC and Ae) was comparable (P = 0.4) in subjects dosed 2 h after dinner and 0.5 h before breakfast; however, a significantly greater extent of absorption occurred when risedronate was given 1 or 4 h prior to a meal (1.4- to 2.3-fold greater). Administration 0.5, 1, or 4 h prior to a meal resulted in a significantly greater rate of absorption (Cmax 2.8-, 3.5-, and 4.1-fold greater, respectively) when compared with 2 h after dinner. Conclusions The comparable extent of risedronate absorption when administered either 0.5–1 h before breakfast or 2 h after an evening meal support previous clinical studies where risedronate was found to have similar effectiveness using these dosing regimens. This flexibility in the timing of risedronate administration may provide patients an alternative means to achieve the desired efficacy while maintaining their normal daily routine. PMID:10583024

Introduction of novel 3D-printed superficial applicators for high-dose-rate skin brachytherapy.

PubMed

Jones, Emma-Louise; Tonino Baldion, Anna; Thomas, Christopher; Burrows, Tom; Byrne, Nick; Newton, Victoria; Aldridge, Sarah

Custom-made surface mold applicators often allow more flexibility when carrying out skin brachytherapy, particularly for small treatment areas with high surface obliquity. They can, however, be difficult to manufacture, particularly if there is a lack of experience in superficial high-dose-rate brachytherapy techniques or with limited resources. We present a novel method of manufacturing superficial brachytherapy applicators utilizing three-dimensional (3D)-printing techniques. We describe the treatment planning process and the process of applicator manufacture. The treatment planning process, with the introduction of a pre-plan, allows for an "ideal" catheter arrangement within an applicator to be determined, exploiting varying catheter orientations, heights, and curvatures if required. The pre-plan arrangement is then 3D printed to the exact specifications of the pre-plan applicator design. This results in improved target volume coverage and improved sparing of organs at risk. Using a pre-plan technique for ideal catheter placement followed by automated 3D-printed applicator manufacture has greatly improved the entire process of superficial high-dose-rate brachytherapy treatment. We are able to design and manufacture flexible, well-fitting, superior quality applicators resulting in a more efficient and improved patient pathway and patient experience. Copyright © 2016 American Brachytherapy Society. Published by Elsevier Inc. All rights reserved.

Application of the Scoping of Options and Analyzing Risk Model (SOAR) in the Modeling of Radionuclide Movement and Dose Calculation for a Hypothetical Deep Geological Repository for Nuclear Fuel Wastes

NASA Astrophysics Data System (ADS)

Lei, S.; Osborne, P.

2016-12-01

The Scoping of Options and Analyzing Risk (SOAR) model was developed by the U.S. Nuclear Regulatory Commission staff to assist in their evaluation of potential high-level radioactive waste disposal options. It is a 1-D contaminant transport code that contains a biosphere module to calculate mass fluxes and radiation dose to humans. As part of the Canadian Nuclear Safety Commission (CNSC)'s Coordinated Assessment Program to assist with the review of proposals for deep geological repositories (DGR's) for nuclear fuel wastes, CNSC conducted a research project to find out whether SOAR can be used by CNSC staff as an independent scoping tool to assist review of proponents' submissions related to safety assessment for DGRs. In the research, SOAR was applied to the post-closure safety assessment for a hypothetical DGR in sedimentary rock, as described in the 5th Case Study report by the Nuclear Waste Management Organization (NWMO) of Canada (2011). The report contains, among others, modeling of transport and releases of radionuclides at various locations within the geosphere and the radiation dose to humans over a period of one million years. One aspect covered was 1-D modeling of various scenarios and sensitivity cases with both deterministic and probabilistic approaches using SYVAC3-CC4, which stands for Systems Variability Analysis Code (generation 3, Canadian Concept generation 4), developed by Atomic Energy of Canada Limited (Kitson et al., 2000). Radionuclide fluxes and radiation dose to the humans calculated using SOAR were compared with that from NWMO's modeling. Overall, the results from the two models were similar, although SOAR gave lower mass fluxes and peak dose, mainly due to differences in modeling the waste package configurations. Sensitivity analyses indicate that both models are most sensitive to the diffusion coefficient of the geological media. The research leads to the conclusion that SOAR is a robust, user friendly, and flexible scoping tool that CNSC staff may use for safety assessments; however, some improvements may be needed, such as including dose contributions from other pathways in addition to drinking water and being more flexible for modeling different waste package configurations.

Probabilistic objective functions for margin-less IMRT planning

NASA Astrophysics Data System (ADS)

Bohoslavsky, Román; Witte, Marnix G.; Janssen, Tomas M.; van Herk, Marcel

2013-06-01

We present a method to implement probabilistic treatment planning of intensity-modulated radiation therapy using custom software plugins in a commercial treatment planning system. Our method avoids the definition of safety-margins by directly including the effect of geometrical uncertainties during optimization when objective functions are evaluated. Because the shape of the resulting dose distribution implicitly defines the robustness of the plan, the optimizer has much more flexibility than with a margin-based approach. We expect that this added flexibility helps to automatically strike a better balance between target coverage and dose reduction for surrounding healthy tissue, especially for cases where the planning target volume overlaps organs at risk. Prostate cancer treatment planning was chosen to develop our method, including a novel technique to include rotational uncertainties. Based on population statistics, translations and rotations are simulated independently following a marker-based IGRT correction strategy. The effects of random and systematic errors are incorporated by first blurring and then shifting the dose distribution with respect to the clinical target volume. For simplicity and efficiency, dose-shift invariance and a rigid-body approximation are assumed. Three prostate cases were replanned using our probabilistic objective functions. To compare clinical and probabilistic plans, an evaluation tool was used that explicitly incorporates geometric uncertainties using Monte-Carlo methods. The new plans achieved similar or better dose distributions than the original clinical plans in terms of expected target coverage and rectum wall sparing. Plan optimization times were only about a factor of two higher than in the original clinical system. In conclusion, we have developed a practical planning tool that enables margin-less probability-based treatment planning with acceptable planning times, achieving the first system that is feasible for clinical implementation.

Optimization for high-dose-rate brachytherapy of cervical cancer with adaptive simulated annealing and gradient descent.

PubMed

Yao, Rui; Templeton, Alistair K; Liao, Yixiang; Turian, Julius V; Kiel, Krystyna D; Chu, James C H

2014-01-01

To validate an in-house optimization program that uses adaptive simulated annealing (ASA) and gradient descent (GD) algorithms and investigate features of physical dose and generalized equivalent uniform dose (gEUD)-based objective functions in high-dose-rate (HDR) brachytherapy for cervical cancer. Eight Syed/Neblett template-based cervical cancer HDR interstitial brachytherapy cases were used for this study. Brachytherapy treatment plans were first generated using inverse planning simulated annealing (IPSA). Using the same dwell positions designated in IPSA, plans were then optimized with both physical dose and gEUD-based objective functions, using both ASA and GD algorithms. Comparisons were made between plans both qualitatively and based on dose-volume parameters, evaluating each optimization method and objective function. A hybrid objective function was also designed and implemented in the in-house program. The ASA plans are higher on bladder V75% and D2cc (p=0.034) and lower on rectum V75% and D2cc (p=0.034) than the IPSA plans. The ASA and GD plans are not significantly different. The gEUD-based plans have higher homogeneity index (p=0.034), lower overdose index (p=0.005), and lower rectum gEUD and normal tissue complication probability (p=0.005) than the physical dose-based plans. The hybrid function can produce a plan with dosimetric parameters between the physical dose-based and gEUD-based plans. The optimized plans with the same objective value and dose-volume histogram could have different dose distributions. Our optimization program based on ASA and GD algorithms is flexible on objective functions, optimization parameters, and can generate optimized plans comparable with IPSA. Copyright © 2014 American Brachytherapy Society. Published by Elsevier Inc. All rights reserved.

Reacidification modeling and dose calculation procedures for calcium-carbonate-treated lakes

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

Scheffe, R.D.

1987-01-01

Two dose calculation models and a reacidification model were developed and applied to two Adirondack acid lakes (Woods Lake and Cranberry Pond) that were treated with calcite during May 30-31, 1985 as part of the EPRI-funded Lake Acidification Mitigation Project. The first dose model extended Sverdrup's (1983) Lake Liming model by incorporating chemical equilibrium routines to eliminate empirical components. The model simulates laboratory column water chemistry profiles (spatially and temporally) and dissolution efficiencies fairly well; however, the model predicted conservative dissolution efficiencies for the study lakes. Time-series water chemistry profiles of the lakes suggest that atmospheric carbon dioxide intrusion ratemore » was far greater than expected and enhanced dissolution efficiency. Accordingly, a second dose model was developed that incorporated ongoing CO/sub 2/ intrusion and added flexibility in the handling of solid and dissolved species transport. This revised model simulated whole-lake water chemistry throughout the three week dissolution period. The Acid Lake Reacidification Model (ALaRM) is a general mass-balance model developed for the temporal prediction of the principal chemical species in both the water column and sediment pore water of small lakes and ponds.« less

Multi-Matrix System (MMX®) mesalamine for the treatment of mild-to-moderate ulcerative colitis.

PubMed

Horst, Sara N; Kane, Sunanda

2012-10-01

Ulcerative colitis (UC) is an inflammatory disease of the colon characterized by periods of active disease and remission. The pathogenesis of this disease is likely a complex interaction of genetic predisposition, environmental factors, and immune system dysregulation, and is not completely understood. A Multi-MatriX (MMX®) system formulation of mesalamine, MMX mesalamine (SPD476; Lialda®; Mesavancol®; Mezavant®), allows for high-dose, once-daily dosing for patients with mild-to-moderate UC. Mesalamine is a topically active agent with anti-inflammatory properties. Available literature regarding MMX mesalamine is extensively reviewed in this article, covering its chemical makeup, mechanism of action, pharmaceutics and pharmacokinetics, clinical efficacy, and safety and tolerability. A dose of 2.4 and 4.8 g was used in large Phase III clinical trials and was efficacious for induction of clinical and endoscopic remission in UC. MMX mesalamine was also efficacious in large multicenter maintenance studies for the maintenance of clinical and endoscopic remission. The introduction of the first once-daily mesalamine has given practitioners and patients more flexibility in dosing administration, which will ultimately lead to higher satisfaction and improved clinical outcomes.

Comparison of normal tissue dose calculation methods for epidemiological studies of radiotherapy patients.

PubMed

Mille, Matthew M; Jung, Jae Won; Lee, Choonik; Kuzmin, Gleb A; Lee, Choonsik

2018-06-01

Radiation dosimetry is an essential input for epidemiological studies of radiotherapy patients aimed at quantifying the dose-response relationship of late-term morbidity and mortality. Individualised organ dose must be estimated for all tissues of interest located in-field, near-field, or out-of-field. Whereas conventional measurement approaches are limited to points in water or anthropomorphic phantoms, computational approaches using patient images or human phantoms offer greater flexibility and can provide more detailed three-dimensional dose information. In the current study, we systematically compared four different dose calculation algorithms so that dosimetrists and epidemiologists can better understand the advantages and limitations of the various approaches at their disposal. The four dose calculations algorithms considered were as follows: the (1) Analytical Anisotropic Algorithm (AAA) and (2) Acuros XB algorithm (Acuros XB), as implemented in the Eclipse treatment planning system (TPS); (3) a Monte Carlo radiation transport code, EGSnrc; and (4) an accelerated Monte Carlo code, the x-ray Voxel Monte Carlo (XVMC). The four algorithms were compared in terms of their accuracy and appropriateness in the context of dose reconstruction for epidemiological investigations. Accuracy in peripheral dose was evaluated first by benchmarking the calculated dose profiles against measurements in a homogeneous water phantom. Additional simulations in a heterogeneous cylinder phantom evaluated the performance of the algorithms in the presence of tissue heterogeneity. In general, we found that the algorithms contained within the commercial TPS (AAA and Acuros XB) were fast and accurate in-field or near-field, but not acceptable out-of-field. Therefore, the TPS is best suited for epidemiological studies involving large cohorts and where the organs of interest are located in-field or partially in-field. The EGSnrc and XVMC codes showed excellent agreement with measurements both in-field and out-of-field. The EGSnrc code was the most accurate dosimetry approach, but was too slow to be used for large-scale epidemiological cohorts. The XVMC code showed similar accuracy to EGSnrc, but was significantly faster, and thus epidemiological applications seem feasible, especially when the organs of interest reside far away from the field edge.

Age-related changes in prefrontal norepinephrine transporter density: The basis for improved cognitive flexibility after low doses of atomoxetine in adolescent rats

PubMed Central

Bradshaw, Sarah E.; Agster, Kara L.; Waterhouse, Barry D.; McGaughy, Jill A.

2016-01-01

Adolescence is a period of major behavioral and brain reorganization. As diagnoses and treatment of disorders like attention deficit hyperactivity disorder (ADHD) often occur during adolescence, it is important to understand how the prefrontal cortices change and how these changes may influence the response to drugs during development. The current study uses an adolescent rat model to study the effect of standard ADHD treatments, atomoxetine and methylphenidate on attentional set shifting and reversal learning. While both of these drugs act as norepinephrine reuptake inhibitors, higher doses of atomoxetine and all doses of methylphenidate also block dopamine transporters (DAT). Low doses of atomoxetine, were effective at remediating cognitive rigidity found in adolescents. In contrast, methylphenidate improved performance in rats unable to form an attentional set due to distractibility but was without effect in normal subjects. We also assessed the effects of GBR 12909, a selective DAT inhibitor, but found no effect of any dose on behavior. A second study in adolescent rats investigated changes in norepinephrine transporter (NET) and dopamine beta hydroxylase (DBH) density in five functionally distinct subregions of the prefrontal cortex: infralimbic, prelimbic, anterior cingulate, medial and lateral orbitofrontal cortices. These regions are implicated in impulsivity and distractibility. We found that NET, but not DBH, changed across adolescence in a regionally selective manner. The prelimbic cortex, which is critical to cognitive rigidity, and the lateral orbitofrontal cortex, critical to reversal learning and some forms of response inhibition, showed higher levels of NET at early than mid- to late adolescence. PMID:26774596

An open-label, multicenter, flexible dose study to evaluate the efficacy and safety of Viagra (sildenafil citrate) in Korean men with erectile dysfunction and arterial hypertension who are taking antihypertensive agents.

PubMed

Park, Hyun Jun; Park, Nam Cheol; Shim, Hong Bang; Park, Jong Kwan; Lee, Sung Won; Park, Kwangsung; Kim, Sae Woong; Moon, Ki Hak; Lee, Dong Hyeon; Yoon, Sang Jin

2008-10-01

Erectile dysfunction (ED) is common among men taking antihypertensive agents to control blood pressure. We evaluated the efficacy and safety of sildenafil citrate in men with ED taking antihypertensive agents. A total of 198 male subjects, aged 20 years and older were enrolled. This study was conducted for 10 weeks as an open-label, multicenter and flexible dose trial with a 2-week screening period and an 8-week treatment phase. Subjects were asked to complete Event Log Worksheets, as well as the International Index of Erectile Function (IIEF) and the Global Efficacy Assessment Questions (GEAQ) questionnaires during the study period. The average age among the 167 subjects who completed the study was 55.8 (31.7 to 77.1). The scores for questions 3 and 4 of IIEF improved from 2.3 and 1.8 at baseline to 3.7 and 3.4 at week 4 and 3.8 and 3.4 at week 8, respectively. There were 86.3% of the patients reported improved erectile function at week 8; 88.3% of the patients reported improved ability to achieve sexual intercourse at week 8. There were no significant differences observed in the responses to questions 3 and 4 of IIEF and GEAQ by the number of antihypertensive agents taken. The adverse events were facial flushing (20.1%), headache (11.7%), palpitation (5.0%), rhinitis (2.8%), URI (2.8%), dizziness (2.2%), dyspnea (2.2%), and nausea (1.7%). Sildenafil citrate is an effective treatment for ED; it is safe and well tolerated by patients with ED taking multiple antihypertensive agents for arterial hypertension.

Mice heterozygous for the oxytocin receptor gene (Oxtr(+/-)) show impaired social behaviour but not increased aggression or cognitive inflexibility: evidence of a selective haploinsufficiency gene effect.

PubMed

Sala, M; Braida, D; Donzelli, A; Martucci, R; Busnelli, M; Bulgheroni, E; Rubino, T; Parolaro, D; Nishimori, K; Chini, B

2013-02-01

We characterised the behavioural phenotype of mice heterozygous (Oxtr(+/-)) for the oxytocin receptor gene (Oxtr) and compared it with that of Oxtr null mice (Oxtr(-/-)), which display autistic-like behaviours, including impaired sociability and preference for social novelty, impaired cognitive flexibility, and increased aggression. Similar to Oxtr(-/-) mice, the Oxtr(+/-) showed impaired sociability and preference for social novelty but, unlike the null genotype, their cognitive flexibility and aggression were normal. By autoradiography, Oxtr(+/-) mice were found to have approximately 50% fewer oxytocin receptors (OXTRs) in all of the examined brain regions. Thus, because a partial reduction in Oxtr gene expression is sufficient to compromise social behaviour, the Oxtr acts as a haploinsufficient gene. Furthermore, the inactivation of the Oxtr gene affects specific behaviours in a dose-dependent manner: social behaviour is sensitive to even a partial reduction in Oxtr gene expression, whereas defects in aggression and cognitive flexibility require the complete inactivation of the Oxtr gene to emerge. We then investigated the rescue of the Oxtr(+/-) social deficits by oxytocin (OT) and Thr(4)Gly(7)OT (TGOT) administered i.c.v. at different doses. TGOT was more potent than OT in rescuing sociability and social novelty in both genotypes. Furthermore, the TGOT doses that reverted impaired sociability and preference for social novelty in Oxtr(+/-) were lower than those required in Oxtr(-/-), thus suggesting that the rescue effect is mediated by OXTR in Oxtr(+/-) and by other receptors (presumably vasopressin V1a receptors) in Oxtr(-/-). In line with this, a low dose of the selective oxytocin antagonist desGlyDTyrOVT blocks the rescue effect of TGOT only in the Oxtr(+/-) genotype, whereas the less selective antagonist SR49059 blocks rescue in both genotypes. In conclusion, the Oxtr(+/-) mouse is a unique animal model for investigating how partial loss of the Oxtr gene impair social interactions, and for designing pharmacological rescue strategies. © 2012 British Society for Neuroendocrinology.

Methylphenidate Transdermal System in Adult ADHD and Impact on Emotional and Oppositional Symptoms

ERIC Educational Resources Information Center

Marchant, Barrie K.; Reimherr, Frederick W.; Robison, Reid J.; Olsen, John L.; Kondo, Douglas G.

2011-01-01

Objective: This trial evaluated the effect of methylphenidate transdermal system (MTS) on the full spectrum of adult symptoms (attention-disorganization, hyperactivity-impulsivity, emotional dysregulation [ED], and oppositional-defiant disorder [ODD]) found in this disorder. Method: This placebo-controlled, double-blind, flexible-dose, crossover…

COMPARISONS OF ACUTE REFERENCE VALUES IN DEVELOPING AN ACUTE INHALATION ASSESSMENT METHOD

EPA Science Inventory

A method is being developed for performing assessments of human health risk from acute (less than 24 hour) inhalation exposures. The methodology will be flexible in its ability to utilize variously robust data sets of dose-response information. A supporting task is a comparati...

Effects of lorazepam on visual perceptual abilities.

PubMed

Pompéia, S; Pradella-Hallinan, M; Manzano, G M; Bueno, O F A

2008-04-01

To evaluate the effects of an acute dose of the benzodiazepine (BZ) lorazepam in young healthy volunteers on five distinguishable visual perception abilities determined by previous factor-analytic studies. This was a double-blind, cross-over design study of acute oral doses of lorazepam (2 mg) and placebo in young healthy volunteers. We focused on a set of paper-and-pencil tests of visual perceptual abilities that load on five correlated but distinguishable factors (Spatial Visualization, Spatial Relations, Perceptual Speed, Closure Speed, and Closure Flexibility). Some other tests (DSST, immediate and delayed recall of prose; measures of subjective mood alterations) were used to control for the classic BZ-induced effects. Lorazepam impaired performance in the DSST and delayed recall of prose, increased subjective sedation and impaired tasks of all abilities except Spatial Visualization and Closure Speed. Only impairment in Perceptual Speed (Identical Pictures task) and delayed recall of prose were not explained by sedation. Acute administration of lorazepam, in a dose that impaired episodic memory, selectively affected different visual perceptual abilities before and after controlling for sedation. Central executive demands and sedation did not account for results, so impairment in the Identical Pictures task may be attributed to lorazepam's visual processing alterations. 2008 John Wiley & Sons, Ltd.

Parotid gland mean dose as a xerostomia predictor in low-dose domains.

PubMed

Gabryś, Hubert Szymon; Buettner, Florian; Sterzing, Florian; Hauswald, Henrik; Bangert, Mark

2017-09-01

Xerostomia is a common side effect of radiotherapy resulting from excessive irradiation of salivary glands. Typically, xerostomia is modeled by the mean dose-response characteristic of parotid glands and prevented by mean dose constraints to either contralateral or both parotid glands. The aim of this study was to investigate whether normal tissue complication probability (NTCP) models based on the mean radiation dose to parotid glands are suitable for the prediction of xerostomia in a highly conformal low-dose regime of modern intensity-modulated radiotherapy (IMRT) techniques. We present a retrospective analysis of 153 head and neck cancer patients treated with radiotherapy. The Lyman Kutcher Burman (LKB) model was used to evaluate predictive power of the parotid gland mean dose with respect to xerostomia at 6 and 12 months after the treatment. The predictive performance of the model was evaluated by receiver operating characteristic (ROC) curves and precision-recall (PR) curves. Average mean doses to ipsilateral and contralateral parotid glands were 25.4 Gy and 18.7 Gy, respectively. QUANTEC constraints were met in 74% of patients. Mild to severe (G1+) xerostomia prevalence at both 6 and 12 months was 67%. Moderate to severe (G2+) xerostomia prevalence at 6 and 12 months was 20% and 15%, respectively. G1 + xerostomia was predicted reasonably well with area under the ROC curve ranging from 0.69 to 0.76. The LKB model failed to provide reliable G2 + xerostomia predictions at both time points. Reduction of the mean dose to parotid glands below QUANTEC guidelines resulted in low G2 + xerostomia rates. In this dose domain, the mean dose models predicted G1 + xerostomia fairly well, however, failed to recognize patients at risk of G2 + xerostomia. There is a need for the development of more flexible models able to capture complexity of dose response in this dose regime.

Simultaneously optimizing dose and schedule of a new cytotoxic agent.

PubMed

Braun, Thomas M; Thall, Peter F; Nguyen, Hoang; de Lima, Marcos

2007-01-01

Traditionally, phase I clinical trial designs are based upon one predefined course of treatment while varying among patients the dose given at each administration. In actual medical practice, patients receive a schedule comprised of several courses of treatment, and some patients may receive one or more dose reductions or delays during treatment. Consequently, the overall risk of toxicity for each patient is a function of both actual schedule of treatment and the differing doses used at each adminstration. Our goal is to provide a practical phase I clinical trial design that more accurately reflects actual medical practice by accounting for both dose per administration and schedule. We propose an outcome-adaptive Bayesian design that simultaneously optimizes both dose and schedule in terms of the overall risk of toxicity, based on time-to-toxicity outcomes. We use computer simulation as a tool to calibrate design parameters. We describe a phase I trial in allogeneic bone marrow transplantation that was designed and is currently being conducted using our new method. Our computer simulations demonstrate that our method outperforms any method that searches for an optimal dose but does not allow schedule to vary, both in terms of the probability of identifying optimal (dose, schedule) combinations, and the numbers of patients assigned to those combinations in the trial. Our design requires greater sample sizes than those seen in traditional phase I studies due to the larger number of treatment combinations examined. Our design also assumes that the effects of multiple administrations are independent of each other and that the hazard of toxicity is the same for all administrations. Our design is the first for phase I clinical trials that is sufficiently flexible and practical to truly reflect clinical practice by varying both dose and the timing and number of administrations given to each patient.

Tolerability of extended-release quetiapine fumarate compared with immediate-release quetiapine fumarate in older patients with Alzheimer's disease with symptoms of psychosis and/or agitation: a randomised, double-blind, parallel-group study.

PubMed

De Deyn, Peter Paul; Eriksson, Hans; Svensson, Hanna

2012-03-01

The objective of this study was to assess the safety and tolerability of extended-release quetiapine fumarate (quetiapine XR) compared with quetiapine immediate-release (quetiapine IR) in older patients with Alzheimer's disease with symptoms of psychosis and/or agitation. This was a 6-week, double-blind, double-dummy, randomised study. Of the 109 patients screened, 100 were randomised to receive quetiapine XR (n = 68) or quetiapine IR (n = 32), at doses of 50 and 25 mg/day, respectively. Treatment was escalated to 100 mg/day by Day 4. At Day 8, a flexible-dose (50-300 mg/day) period began when dose adjustment was made at the investigator's discretion. The primary variable was incidence and type of adverse events (AEs). Secondary variables included efficacy and other safety assessments. Mean daily doses were 143.6 and 142.0 mg in the quetiapine XR and quetiapine IR groups, respectively. Ninety patients completed the study; only one withdrew (in the quetiapine XR group) because of an AE. Laboratory evaluations identified severe neutropaenia (one patient), mild neutropaenia (three patients) and eosinophilia (five patients); however, these were not reported, as AEs and confounding factors, such as patient age, concomitant illness and medication, made it difficult to determine any relationship to quetiapine treatment. Numerical improvements from baseline were seen across both treatment groups in Neuropsychiatric Inventory frequency × severity total, Neuropsychiatric Inventory-Nursing Home version, Cohen-Mansfield Agitation Inventory, Clinical Global Impression-Severity of Illness and Clinical Global Impression-Improvement scores. Quetiapine XR dosed up to 300 mg/day was generally well tolerated, with a similar profile to that of quetiapine IR. Copyright © 2011 John Wiley & Sons, Ltd.

Modified Toxicity Probability Interval Design: A Safer and More Reliable Method Than the 3 + 3 Design for Practical Phase I Trials

PubMed Central

Ji, Yuan; Wang, Sue-Jane

2013-01-01

The 3 + 3 design is the most common choice among clinicians for phase I dose-escalation oncology trials. In recent reviews, more than 95% of phase I trials have been based on the 3 + 3 design. Given that it is intuitive and its implementation does not require a computer program, clinicians can conduct 3 + 3 dose escalations in practice with virtually no logistic cost, and trial protocols based on the 3 + 3 design pass institutional review board and biostatistics reviews quickly. However, the performance of the 3 + 3 design has rarely been compared with model-based designs in simulation studies with matched sample sizes. In the vast majority of statistical literature, the 3 + 3 design has been shown to be inferior in identifying true maximum-tolerated doses (MTDs), although the sample size required by the 3 + 3 design is often orders-of-magnitude smaller than model-based designs. In this article, through comparative simulation studies with matched sample sizes, we demonstrate that the 3 + 3 design has higher risks of exposing patients to toxic doses above the MTD than the modified toxicity probability interval (mTPI) design, a newly developed adaptive method. In addition, compared with the mTPI design, the 3 + 3 design does not yield higher probabilities in identifying the correct MTD, even when the sample size is matched. Given that the mTPI design is equally transparent, costless to implement with free software, and more flexible in practical situations, we highly encourage its adoption in early dose-escalation studies whenever the 3 + 3 design is also considered. We provide free software to allow direct comparisons of the 3 + 3 design with other model-based designs in simulation studies with matched sample sizes. PMID:23569307

Flexible foils formed by a prolonged electron beam irradiation in scanning electron microscope

NASA Astrophysics Data System (ADS)

Čechal, Jan; Šikola, Tomáš

2017-11-01

The ubiquitous presence of hydrocarbon contamination on solid surfaces alters their inherent physical properties and complicates the surface analyses. An irradiation of sample surface with electron beam can lead to the chemical transformation of the hydrocarbon layer to carbon films, which are flexible and capable of acting as a barrier for chemical etching of an underlying material. The growth of these foils is limited by supply of hydrocarbons to the writing beam position rather than the electron dose or electron beam current. The prepared films can find their applications in fabrication of surface nanostructures without a need of an electron sensitive resist material.

Development of a novel method to enhance the therapeutic effect on tumours by simultaneous action of radiation and heating.

PubMed

Kosterev, Vladimir V; Kramer-Ageev, Evgeny A; Mazokhin, Vladimir N; van Rhoon, Gerard C; Crezee, Johannes

2015-06-01

This paper describes the development of a new type of electromagnetic hyperthermia applicator delivering dose control within large application fields and increased effectiveness by providing simultaneous action of radiation and heating (SRH) in malignant tumours, and development of a dosimetric feedback method to support SRH. Single and phased arrays of flexible applicators have been developed to allow simultaneous hyperthermia and external beam therapy. A frequency of 434 MHz is used to heat near-surface and moderately deep-seated tumours and 70 MHz for deep-seated tumours. Phase and amplitude control allows focusing of electromagnetic energy (EM) to deep-seated tumours. The specific absorption rate (SAR) dose distribution can be modified to achieve uniform heating of tumours with complex shapes and heterogeneous tissue properties. A lithium fluoride thermoluminescent dosimeter (TLD) in a flexible film cassette has been developed for real-time dose measurement. Four types of 434 MHz applicators were manufactured with 3, 4, 9 or 12 independent applicators. Two types of 70 MHz applicators were made with 4 or 6 independent applicators. Phantom tests demonstrated the ability to control the SAR pattern by phase and amplitude control. Placement of the dosimeter between bolus and phantom increased the phantom surface temperature up to 3 °C and showed that the ratio of absorbed energy in TLD to dose in water approaches (0.83 ± 3%) for photon energies >60 keV. Simultaneous and controlled radiation and local hyperthermia is technically feasible in a preclinical setting, a clinical feasibility test is the next step.

A preliminary Monte Carlo study for the treatment head of a carbon-ion radiotherapy facility using TOPAS

NASA Astrophysics Data System (ADS)

Liu, Hongdong; Zhang, Lian; Chen, Zhi; Liu, Xinguo; Dai, Zhongying; Li, Qiang; Xu, Xie George

2017-09-01

In medical physics it is desirable to have a Monte Carlo code that is less complex, reliable yet flexible for dose verification, optimization, and component design. TOPAS is a newly developed Monte Carlo simulation tool which combines extensive radiation physics libraries available in Geant4 code, easyto-use geometry and support for visualization. Although TOPAS has been widely tested and verified in simulations of proton therapy, there has been no reported application for carbon ion therapy. To evaluate the feasibility and accuracy of TOPAS simulations for carbon ion therapy, a licensed TOPAS code (version 3_0_p1) was used to carry out a dosimetric study of therapeutic carbon ions. Results of depth dose profile based on different physics models have been obtained and compared with the measurements. It is found that the G4QMD model is at least as accurate as the TOPAS default BIC physics model for carbon ions, but when the energy is increased to relatively high levels such as 400 MeV/u, the G4QMD model shows preferable performance. Also, simulations of special components used in the treatment head at the Institute of Modern Physics facility was conducted to investigate the Spread-Out dose distribution in water. The physical dose in water of SOBP was found to be consistent with the aim of the 6 cm ridge filter.

Markers of serotonergic function in the orbitofrontal cortex and dorsal raphé nucleus predict individual variation in spatial-discrimination serial reversal learning.

PubMed

Barlow, Rebecca L; Alsiö, Johan; Jupp, Bianca; Rabinovich, Rebecca; Shrestha, Saurav; Roberts, Angela C; Robbins, Trevor W; Dalley, Jeffrey W

2015-06-01

Dysfunction of the orbitofrontal cortex (OFC) impairs the ability of individuals to flexibly adapt behavior to changing stimulus-reward (S-R) contingencies. Impaired flexibility also results from interventions that alter serotonin (5-HT) and dopamine (DA) transmission in the OFC and dorsomedial striatum (DMS). However, it is unclear whether similar mechanisms underpin naturally occurring variations in behavioral flexibility. In the present study, we used a spatial-discrimination serial reversal procedure to investigate interindividual variability in behavioral flexibility in rats. We show that flexibility on this task is improved following systemic administration of the 5-HT reuptake inhibitor citalopram and by low doses of the DA reuptake inhibitor GBR12909. Rats in the upper quintile of the distribution of perseverative responses during repeated S-R reversals showed significantly reduced levels of the 5-HT metabolite, 5-hydroxy-indoleacetic acid, in the OFC. Additionally, 5-HT2A receptor binding in the OFC of mid- and high-quintile rats was significantly reduced compared with rats in the low-quintile group. These perturbations were accompanied by an increase in the expression of monoamine oxidase-A (MAO-A) and MAO-B in the lateral OFC and by a decrease in the expression of MAO-A, MAO-B, and tryptophan hydroxylase in the dorsal raphé nucleus of highly perseverative rats. We found no evidence of significant differences in markers of DA and 5-HT function in the DMS or MAO expression in the ventral tegmental area of low- vs high-perseverative rats. These findings indicate that diminished serotonergic tone in the OFC may be an endophenotype that predisposes to behavioral inflexibility and other forms of compulsive behavior.

Markers of Serotonergic Function in the Orbitofrontal Cortex and Dorsal Raphé Nucleus Predict Individual Variation in Spatial-Discrimination Serial Reversal Learning

PubMed Central

Barlow, Rebecca L; Alsiö, Johan; Jupp, Bianca; Rabinovich, Rebecca; Shrestha, Saurav; Roberts, Angela C; Robbins, Trevor W; Dalley, Jeffrey W

2015-01-01

Dysfunction of the orbitofrontal cortex (OFC) impairs the ability of individuals to flexibly adapt behavior to changing stimulus-reward (S-R) contingencies. Impaired flexibility also results from interventions that alter serotonin (5-HT) and dopamine (DA) transmission in the OFC and dorsomedial striatum (DMS). However, it is unclear whether similar mechanisms underpin naturally occurring variations in behavioral flexibility. In the present study, we used a spatial-discrimination serial reversal procedure to investigate interindividual variability in behavioral flexibility in rats. We show that flexibility on this task is improved following systemic administration of the 5-HT reuptake inhibitor citalopram and by low doses of the DA reuptake inhibitor GBR12909. Rats in the upper quintile of the distribution of perseverative responses during repeated S-R reversals showed significantly reduced levels of the 5-HT metabolite, 5-hydroxy-indoleacetic acid, in the OFC. Additionally, 5-HT2A receptor binding in the OFC of mid- and high-quintile rats was significantly reduced compared with rats in the low-quintile group. These perturbations were accompanied by an increase in the expression of monoamine oxidase-A (MAO-A) and MAO-B in the lateral OFC and by a decrease in the expression of MAO-A, MAO-B, and tryptophan hydroxylase in the dorsal raphé nucleus of highly perseverative rats. We found no evidence of significant differences in markers of DA and 5-HT function in the DMS or MAO expression in the ventral tegmental area of low- vs high-perseverative rats. These findings indicate that diminished serotonergic tone in the OFC may be an endophenotype that predisposes to behavioral inflexibility and other forms of compulsive behavior. PMID:25567428

Transitional polytherapy: tricks of the trade for monotherapy to monotherapy AED conversions.

PubMed

Garnett, William R; St Louis, Erik K; Henry, Thomas R; Bramley, Thomas

2009-06-01

The goal of epilepsy therapy is to help patients achieve seizure freedom without adverse effects. While monotherapy is preferable in epilepsy treatment, many patients fail a first drug due to lack of efficacy or failure to tolerate an initial medication, necessitating an alteration in therapy. Sudden changes between monotherapies are rarely feasible and sometimes deleterious given potential hazards of acute seizure exacerbation or intolerable adverse effects. The preferred method for converting between monotherapies is transitional polytherapy, a process involving initiation of a new antiepileptic drug (AED) and adjusting it toward a target dose while maintaining or reducing the dose of the baseline medication. A fixed-dose titration strategy of maintaining the baseline drug dose while titrating the new medication is preferable when breakthrough seizures are occurring and no adverse effects are present. However, a flexible titration strategy involving reduction of the baseline drug dose to ensure adequate tolerability of the new adjunctive medication is preferred when patients are already experiencing adverse effects. This article reviews pharmacokinetic considerations pertinent for ensuring successful transitional polytherapy with the standard and newer antiepileptic drugs. Practical consensus recommendations "from an expect panel (SPECTRA, Study by a Panel of Experts Considerations for Therapy Replacement and Antiepileptics) for a successful monotherapy" AED conversions are then summarized. Transitional polytherapy is most successful when clinicians appropriately manage the titration strategy and consider pharmacokinetic factors germane to the baseline and new adjunctive medication.

Radiation protection for an intra-operative X-ray device

PubMed Central

Eaton, D J; Gonzalez, R; Duck, S; Keshtgar, M

2011-01-01

Objectives Therapeutic partial breast irradiation can be delivered intra-operatively using the Intrabeam 50 kVp compact X-ray device. Spherical applicators are added to the source to give an isotropic radiation dose. The low energy of this unit leads to rapid attenuation with distance, but dose rates are much greater than for diagnostic procedures. Methods To investigate the shielding requirements for this unit, attenuation measurements were carried out with manufacturer-provided tungsten–rubber sheets, lead, plasterboard and bricks. A prospective environmental dose rate survey was also conducted in the designated theatre. Results As a result of isotropic geometry, the scattered dose around shielding can be 1% of primary and thus often dominates measured dose rates compared with transmission. The absorbed dose rate of the unshielded source at 1 m was 11.6 mGy h−1 but this was reduced by 95% with the shielding sheets. Measured values for the common shielding materials were similar to reference data for the attenuation of a 50 kVp diagnostic X-ray beam. Two lead screens were constructed to shield operators remaining in the theatre and an air vent into a service corridor. A lead apron would also provide suitable attenuation, although a screen allows greater flexibility for treatment operators. With these measures, staff doses were reduced to negligible quantities. Survey measurements taken during patient treatments confirmed no additional measures were required, but the theatre should be a controlled area and access restricted. Conclusion Results from this study and reference data can be used for planning other facilities. PMID:21304003

An accelerated gamma irradiation test of low dose rate for a single mode fiber

NASA Astrophysics Data System (ADS)

Chiou, Chung-An; Peng, Tz-Shiuan; Liu, Ren-Young

2017-09-01

Conventional single mode fiber (SMF), due to its electromagnetic interference immunity, light weight, physical flexibility and broad bandwidth for data transmission, has been well employed in space, such as optical communication [1], structural health monitoring of spacecraft [2], and attitude determining applications, e.g. interferometric fiber optic gyroscope (IFOG).

Brain Radiation Information Data Exchange (BRIDE): integration of experimental data from low-dose ionising radiation research for pathway discovery.

PubMed

Karapiperis, Christos; Kempf, Stefan J; Quintens, Roel; Azimzadeh, Omid; Vidal, Victoria Linares; Pazzaglia, Simonetta; Bazyka, Dimitry; Mastroberardino, Pier G; Scouras, Zacharias G; Tapio, Soile; Benotmane, Mohammed Abderrafi; Ouzounis, Christos A

2016-05-11

The underlying molecular processes representing stress responses to low-dose ionising radiation (LDIR) in mammals are just beginning to be understood. In particular, LDIR effects on the brain and their possible association with neurodegenerative disease are currently being explored using omics technologies. We describe a light-weight approach for the storage, analysis and distribution of relevant LDIR omics datasets. The data integration platform, called BRIDE, contains information from the literature as well as experimental information from transcriptomics and proteomics studies. It deploys a hybrid, distributed solution using both local storage and cloud technology. BRIDE can act as a knowledge broker for LDIR researchers, to facilitate molecular research on the systems biology of LDIR response in mammals. Its flexible design can capture a range of experimental information for genomics, epigenomics, transcriptomics, and proteomics. The data collection is available at: .

Development and comparison of computational models for estimation of absorbed organ radiation dose in rainbow trout (Oncorhynchus mykiss) from uptake of iodine-131.

PubMed

Martinez, N E; Johnson, T E; Capello, K; Pinder, J E

2014-12-01

This study develops and compares different, increasingly detailed anatomical phantoms for rainbow trout (Oncorhynchus mykiss) for the purpose of estimating organ absorbed radiation dose and dose rates from (131)I uptake in multiple organs. The models considered are: a simplistic geometry considering a single organ, a more specific geometry employing additional organs with anatomically relevant size and location, and voxel reconstruction of internal anatomy obtained from CT imaging (referred to as CSUTROUT). Dose Conversion Factors (DCFs) for whole body as well as selected organs of O. mykiss were computed using Monte Carlo modeling, and combined with estimated activity concentrations, to approximate dose rates and ultimately determine cumulative radiation dose (μGy) to selected organs after several half-lives of (131)I. The different computational models provided similar results, especially for source organs (less than 30% difference between estimated doses), and whole body DCFs for each model (∼3 × 10(-3) μGy d(-1) per Bq kg(-1)) were comparable to DCFs listed in ICRP 108 for (131)I. The main benefit provided by the computational models developed here is the ability to accurately determine organ dose. A conservative mass-ratio approach may provide reasonable results for sufficiently large organs, but is only applicable to individual source organs. Although CSUTROUT is the more anatomically realistic phantom, it required much more resource dedication to develop and is less flexible than the stylized phantom for similar results. There may be instances where a detailed phantom such as CSUTROUT is appropriate, but generally the stylized phantom appears to be the best choice for an ideal balance between accuracy and resource requirements. Copyright © 2014 Elsevier Ltd. All rights reserved.

Pilot pharmacologic randomized controlled trial for psychogenic nonepileptic seizures(e–Pub ahead of print)(LOE Classification)

PubMed Central

LaFrance, W.C.; Keitner, G.I.; Papandonatos, G.D.; Blum, A.S.; Machan, J.T.; Ryan, C.E.; Miller, I.W.

2010-01-01

Objective: There have been few treatment trials for psychogenic nonepileptic seizures (PNES). Some psychotherapies have been shown to improve PNES and comorbid symptom outcomes. We evaluated a pharmacologic intervention to test the hypothesis that sertraline would reduce PNES. Methods: We conducted a pilot, double-blind, randomized, placebo-controlled trial in an academic medical hospital with epilepsy center outpatients. Subjects aged 18 to 65 years diagnosed with video-EEG–confirmed PNES were treated with flexible-dose sertraline or placebo over 12 weeks. Seizure calendars and symptom scales were charted prospectively. Secondary outcome measures included psychiatric symptom scales and psychosocial variables. Results: Thirty-eight subjects enrolled, and 26 (68%) completed the trial. Thirty-three subjects with nonzero nonepileptic seizure rates at baseline were included in intent-to-treat analysis of the primary outcome. Subjects assigned to the sertraline arm experienced a 45% reduction in seizure rates from baseline to final visit (p = 0.03) vs an 8% increase in placebo (p = 0.78). Secondary outcome scales revealed no significant between-group differences in change scores from baseline to final visit, after adjustment for differences at baseline. Conclusions: PNES were reduced in patients treated with a serotonin selective reuptake inhibitor, whereas those treated with placebo slightly increased. This study provides feasibility data for a larger-scale study. Level of evidence: This study provides Class II evidence that flexible-dose sertraline up to a maximum dose of 200 mg is associated with a nonsignificant reduction in PNES rate compared with a placebo control arm (risk ratio 0.51, 95% confidence interval 0.25–1.05, p = 0.29), adjusting for differences at baseline. GLOSSARY AED = antiepileptic drug; CI = confidence interval; DSM-IV = Diagnostic and Statistical Manual of Mental Disorders, 4th edition; ES = epileptic seizures; ITT = intent to treat; PNES = psychogenic nonepileptic seizures; PTSD = posttraumatic stress disorder; QOL = quality of life; RCT = randomized controlled trial; RIH = Rhode Island Hospital; RR = risk ratio; SSRI = serotonin selective reuptake inhibitor; vEEG = video-EEG. PMID:20739647

Clinical evaluation of paroxetine in post-traumatic stress disorder (PTSD): 52-week, non-comparative open-label study for clinical use experience.

PubMed

Kim, Yoshiharu; Asukai, Nozomu; Konishi, Takako; Kato, Hiroshi; Hirotsune, Hideto; Maeda, Masaharu; Inoue, Hirotaka; Narita, Hiroyasu; Iwasaki, Masaru

2008-12-01

The present study was a 52-week, non-comparative, open-label study of flexible dose paroxetine (20-40 mg) in 52 Japanese post-traumatic stress disorder (PTSD) patients in order to obtain clinical experience regarding efficacy and safety in regular clinical practice. Efficacy was measured using the Clinician-Administered PTSD Scale One Week Symptom Status Version (CAPS-SX). The mean change from baseline in CAPS-SX total score was -19.1, -22.8 and -32.3 at weeks 4, 12 and 52, respectively, and that in the Clinical Global Impression (CGI) Severity of Illness score was -1.1 at week 12 and -1.7 at week 52. A total of 46.9% were CGI responders at week 12, while 67.3% were improved on the CGI at week 52. Of 52 subjects who entered into the drug treatment, 25 completed the study. Only one patient withdrew from the study due to lack of efficacy. In patients who were rated as 'moderately ill' or less at baseline, the proportion of CGI responders at end-point was higher at a dose of 20 mg/day than at higher doses, whereas in patients rated as 'markedly ill' or more, it was higher at 30 and 40 mg/day, suggesting that severely ill patients could benefit from higher doses. Paroxetine appeared generally tolerated in short- and long-term use, and the safety profile in this study was consistent with international trials and other Japanese populations (i.e. patients suffering from depression, panic disorder or obsessive-compulsive disorder). Although the study was not conducted in double-blind fashion, the current findings suggest that paroxetine may contribute to clinically meaningful improvement that is maintained during long-term use and is generally well tolerated.

4'-Ethynyl-2-fluoro-2'-deoxyadenosine, MK-8591: a novel HIV-1 reverse transcriptase translocation inhibitor.

PubMed

Markowitz, Martin; Sarafianos, Stefan G

2018-07-01

4'-Ethynyl-2-fluoro-2'-deoxyadenosine (EFdA) is a nucleoside reverse transcriptase inhibitor (NRTI) with a novel mechanism of action, unique structure, and amongst NRTIs, unparalleled anti-HIV-1 activity. We will summarize its structure and function, antiviral activity, resistance profile, and potential as an antiretroviral for use in the treatment and preexposure prophylaxis of HIV-1 infection. EFdA is active against wild-type (EC50 as low as 50 pmol/l) and most highly NRTI-resistant viruses. The active metabolite, EFdA-triphosphate, has been shown to have a prolonged intracellular half-life in human and rhesus (Rh) blood cells. As a result, single drug doses tested in simian immunodeficiency virus mac251-infected Rh macaques and HIV-1-infected individuals exhibited robust antiviral activity of 7-10 days duration. Preclinical studies of EFdA as preexposure prophylaxis in the Rh macaque/simian/human immunodeficiency virus low-dose intrarectal challenge model have shown complete protection when given in clinically relevant doses. EFdA is a novel antiretroviral with activity against both wild-type and NRTI-resistant viruses. As a result of the prolonged intracellular half-life of its active moiety, it is amenable to flexibility in dosing of at least daily to weekly and perhaps longer.

Safety and efficacy from a 6-week double-blind study and a 52-week open-label extension of aripiprazole in adolescents with schizophrenia in Japan.

PubMed

Matsumoto, Hideo; Ishigooka, Jun; Ono, Hiroaki; Tadori, Yoshihiro

2018-05-18

The purpose of this study was to evaluate the safety and efficacy of aripiprazole in adolescents with schizophrenia in Japan. In a 6-week, randomized, double-blind, dose-comparison study, adolescents (aged 13-17 years) with schizophrenia were randomized to receive aripiprazole 2, 6-12, or 24-30 mg/day. Patients who completed the 6-week study participated in a 52-week, flexible-dose, open-label extension (OLE) study of aripiprazole (initial dose: 2 mg/day, maintenance dose: 6-24 mg/day, maximum dose: 30 mg/day). In the 6-week study, the percentage of patients completing treatment was 77.1% (27/35) for 2 mg/day, 80.0% (24/30) for 6-12 mg/day, and 85.4% (35/41) for 24-30 mg/day. The least squares mean change in the Positive and Negative Syndrome Scale (PANSS) total score from baseline to endpoint (primary efficacy endpoint, last observation carried forward) was -19.6 for 2 mg/day, -16.5 for 6-12 mg/day, and -21.6 for 24-30 mg/day. The most common (≥20% patients in any group) treatment-emergent adverse events (TEAEs) were nausea, akathisia, insomnia, and somnolence. Most TEAEs were mild or moderate in severity. There were no deaths. In the OLE, 60.3% (41/68) of patients completed treatment, and the PANSS total score decreased by -7.9 from OLE baseline to week 52. The most common (≥20% patients) TEAEs were nasopharyngitis and somnolence. Most TEAEs were mild or moderate in severity. There were no deaths. These study results suggested that aripiprazole would be safe and well tolerated in both short- and long-term treatment for adolescents with schizophrenia in Japan. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

Efficacy of Pregabalin in Childhood Refractory Partial Seizure

PubMed Central

Zamani, Gholamreza; Tavasoli, Alireza; Zare-Shahabadi, Ameneh; Rezaei, Nima; Ahmadvand, Alireza

2014-01-01

Objective: About one third of partial seizures are refractory to treatment. Several anticonvulsant drugs have entered the market in recent decades but concerns about intolerance, drug interactions, and the safety of the drug are notable. One of these new anticonvulsants is pregabalin, a safe drug with almost no interaction with other antiepileptic drugs. Methods: In this open label clinical trial study, pregabalin was used for evaluation of its efficacy on reducing seizure frequency in 29 children suffering from refractory partial seizures. Average daily and weekly seizure frequency of the patients was recorded during a 6-week period (baseline period). Then, during a period of 2 weeks (titration period), pregabalin was started with a dose of 25-75 mg/d, using method of flexible dose, and was brought to maximum dose of drug that was intended in this study (450 mg/d) based on clinical response of the patients and seizure frequency. Then the patients were given the drug for 12 weeks and the average frequency of daily and weekly seizures were recorded again (treatment period). Findings : Reduction in seizure frequency in this study was 36% and the responder rate or number of patients who gained more than 50% reduction in seizure frequency was 51.7%. Conclusion: This study showed that pregabalin can be used with safety and an acceptable efficacy in treatment of childhood refractory partial seizures. PMID:25793053

Assessment of dose rate to terrestrial biota in the area around coal fired power plant applying ERICA tool and RESRAD BIOTA code.

PubMed

Ćujić, Mirjana; Dragović, Snežana

2018-08-01

This paper presents the environmental radiation risk assessment based on two software program approaches ERICA Tool (version 1.2) and RESRAD BIOTA (version 1.5) to estimate dose rates to terrestrial biota in the area around the largest coal fired power plant in Serbia. For dose rate assessment software's default reference animals and plants and the best estimated values of activity concentrations of 238 U, 234 U, 234 Th, 232 Th, 230 Th, 226 Ra, 210 Pb, 210 Po, 137 Cs in soil were used. Both approaches revealed the highest contribution to the internal dose rate due to 226 Ra and 210 Po, while 137 Cs contributed the most to the external dose rate. In the investigated area total dose rate to biota derived using ERICA Tool ranged from 0.3 to 14.4 μGy h -1 . The natural radionuclides exhibited significantly higher contribution to the total dose rate than the artificial one. In the investigated area, only dose rate for lichens and bryophytes exceeded ERICA Tool screening value of total dose rate of 10 μGy h -1 suggested as confident that environmental risks are negligible. The assessed total dose rates for reference animals and plants using RESRAD BIOTA were found to be 7 and 3 μGy h -1 , respectively. In RESRAD BIOTA - Level 3, 10 species (Lumbricus terrestris, Rana lessonae, Sciurus vulgaris, Anas platyrhynchos, Lepus europaeus, Vulpes vulpes, Capreolus capreolus, Suss crofa, Quercu srobur, Tilia spp.) representative for the study area were modeled. Among them the highest total dose rate (4.5 μGy h -1 ) was obtained for large mammals. Differences in the predicted dose rates to biota using the two software programs are the consequence of the difference in the values of transfer parameters used to calculate activity concentrations in biota. Doses of ionizing radiation estimated in this study will not exhibit deterministic effects at the population level. Thus, the obtained results indicate no significant radiation impact of coal fired power plant operation on terrestrial biota. This paper confirms the use ERICA Tool and RESRAD BIOTA softwares as flexible and effective means of radiation impact assessment. Copyright © 2017 Elsevier Ltd. All rights reserved.

A double-blind efficacy and safety study of duloxetine flexible dosing in children and adolescents with major depressive disorder.

PubMed

Atkinson, Sarah D; Prakash, Apurva; Zhang, Qi; Pangallo, Beth A; Bangs, Mark E; Emslie, Graham J; March, John S

2014-05-01

The purpose of this study was to evaluate the efficacy and safety of duloxetine flexible dose in children (7-11 years) and adolescents (12-17 years) with major depressive disorder (MDD). Patients (n=337) in this 36 week study (10 week acute and 26 week extension treatment) received duloxetine (60-120 mg once daily [QD], n=117), fluoxetine (20-40 mg QD, n=117), or placebo (n=103). Measures included: Children's Depression Rating Scale-Revised (CDRS-R), treatment-emergent adverse events (TEAEs), and Columbia-Suicide Severity Rating Scale (C-SSRS). Neither active drug (duloxetine or fluoxetine) separated significantly (p<0.05) from placebo on mean change from baseline to end-point (10 weeks) on the CDRS-R total score. There were no significant differences between the duloxetine or fluoxetine groups compared with placebo on serious AEs (SAEs), total TEAEs, or discontinuation for AE during acute treatment. There were no completed suicides or deaths, and no clinically significant electrocardiogram (ECG) abnormalities observed during the study. One fluoxetine and one duloxetine patient experienced alanine aminotransferase (ALT) three or more times the upper limit of normal, which resolved during the study. A total of 8 (7.1%) duloxetine patients, 7 (6.8%) placebo patients, and 9 (8.0%) fluoxetine patients had worsening of suicidal ideation from baseline during acute treatment. Of the patients with suicidal ideation at baseline, 15/19 (79%) duloxetine, 19/19 (100%) placebo, and 16/19 (84%) fluoxetine had improvement in suicidal ideation at end-point during acute treatment. One duloxetine and two fluoxetine patients had treatment-emergent suicidal behavior during the 36 week study. Trial results were inconclusive, as neither the investigational drug (duloxetine) nor the active control (fluoxetine) separated from placebo on the CDRS-R at 10 weeks. No new duloxetine safety signals were identified relative to those seen in adults. Clinical Trial Registry Number: NCT00849901.

RADRUE METHOD FOR RECONSTRUCTION OF EXTERNAL PHOTON DOSES TO CHERNOBYL LIQUIDATORS IN EPIDEMIOLOGICAL STUDIES

PubMed Central

Kryuchkov, Victor; Chumak, Vadim; Maceika, Evaldas; Anspaugh, Lynn R.; Cardis, Elisabeth; Bakhanova, Elena; Golovanov, Ivan; Drozdovitch, Vladimir; Luckyanov, Nickolas; Kesminiene, Ausrele; Voillequé, Paul; Bouville, André

2010-01-01

Between 1986 and 1990, several hundred thousand workers, called “liquidators” or “clean-up workers”, took part in decontamination and recovery activities within the 30-km zone around the Chernobyl nuclear power plant in Ukraine, where a major accident occurred in April 1986. The Chernobyl liquidators were mainly exposed to external ionizing radiation levels that depended primarily on their work locations and the time after the accident when the work was performed. Because individual doses were often monitored inadequately or were not monitored at all for the majority of liquidators, a new method of photon (i.e. gamma and x-rays) dose assessment, called “RADRUE” (Realistic Analytical Dose Reconstruction with Uncertainty Estimation) was developed to obtain unbiased and reasonably accurate estimates for use in three epidemiologic studies of hematological malignancies and thyroid cancer among liquidators. The RADRUE program implements a time-and-motion dose reconstruction method that is flexible and conceptually easy to understand. It includes a large exposure rate database and interpolation and extrapolation techniques to calculate exposure rates at places where liquidators lived and worked within ~70 km of the destroyed reactor. The RADRUE technique relies on data collected from subjects’ interviews conducted by trained interviewers, and on expert dosimetrists to interpret the information and provide supplementary information, when necessary, based upon their own Chernobyl experience. The RADRUE technique was used to estimate doses from external irradiation, as well as uncertainties, to the bone-marrow for 929 subjects and to the thyroid gland for 530 subjects enrolled in epidemiologic studies. Individual bone-marrow dose estimates were found to range from less than one μGy to 3,300 mGy, with an arithmetic mean of 71 mGy. Individual thyroid dose estimates were lower and ranged from 20 μGy to 507 mGy, with an arithmetic mean of 29 mGy. The uncertainties, expressed in terms of geometric standard deviations, ranged from 1.1 to 5.8, with an arithmetic mean of 1.9. PMID:19741357

In utero exposure to di(n)butyl phthalate reduces testicular testosterone and testis size in a dose-dependent manner in Harlan Sprague Dawley fetal rats

EPA Science Inventory

Phthalate esters are widely used to impart flexibility to plastics (e.g. plastic medical devices and children’s toys) as well as other uses in health and beauty products and some pharmaceuticals. Certain phthalate esters cause reproductive malformations and decrease androgen-dep...

A Double-Blind, Randomized, Placebo-Controlled Trial of Escitalopram in the Treatment of Pediatric Depression

ERIC Educational Resources Information Center

Wagner, Karen Dineen; Jonas, Jeffrey; Findling, Robert L.; Ventura, Daniel; Saikali, Khalil

2006-01-01

Objective: Escitalopram is a selective serotonin reuptake inhibitor antidepressant indicated for use in adults. This trial examined the efficacy and safety of escitalopram in pediatric depression. Method: Patients (6-17 years old) with major depressive disorder were randomized to receive 8 weeks of double-blind flexibly dosed treatment with…

Venlafaxine ER for the Treatment of Pediatric Subjects with Depression: Results of Two Placebo-Controlled Trials

ERIC Educational Resources Information Center

Emslie, Graham J.; Findling, Robert L.; Yeung, Paul P.; Kunz, Nadia R.; Li, Yunfeng

2007-01-01

Objective: The safety, efficacy, and tolerability of venlafaxine extended release (ER) in subjects ages 7 to 17 years with major depressive disorder were evaluated in two multicenter, randomized, double-blind, placebo-controlled trials conducted between October 1997 and August 2001. Method: Participants received venlafaxine ER (flexible dose,…

Methylphenidate-induced improvements of various measures of attention in adults with attention deficit hyperactivity disorder.

PubMed

Tucha, O; Mecklinger, L; Laufkötter, R; Klein, H E; Walitza, S; Lange, K W

2006-10-01

The present study examined the effect of the stimulant medication methylphenidate (MPH) on attentional functioning of adults with ADHD. Sixteen adults with a diagnosed ADHD without comorbidity were assessed twice, at baseline off MPH and following MPH treatment. The assessment battery consisted of reaction time tasks of low complexity, including measures of alertness--subdivided into tonic and phasic alertness, vigilance, divided attention, flexibility and such aspects of selective attention as including focused attention, inhibition and integration of sensory information. In addition, 16 healthy participants who were matched to adults with ADHD according to sex, age, education level and intellectual functions were also assessed twice using the same test battery. The results of the present study suggest that adults with ADHD off stimulant medication are seriously impaired in various components of attention including vigilance, divided attention, selective attention and flexibility. These impairments of attention were observed primarily in regard to reaction time and its variability. Treatment of adults with ADHD using individually tailored doses of MPH has a positive effect on measures of alertness, vigilance, selective attention, divided attention and flexibility. However, even on MPH adults with ADHD displayed considerable deficits in vigilance and integration of sensory information. The present findings indicate that adults with ADHD are not differentially impaired in attentional processes but may suffer from a more global deficit of attention. Although MPH treatment has been found to be effective in the treatment of the attention deficit of adults with ADHD, additional treatment appears to be necessary.

Inkjet printing of paracetamol and indomethacin using electromagnetic technology: Rheological compatibility and polymorphic selectivity.

PubMed

Kollamaram, Gayathri; Hopkins, Simon C; Glowacki, Bartek A; Croker, Denise M; Walker, Gavin M

2018-03-30

Drop-on-demand inkjet printing is a potential enabling technology both for continuous manufacturing of pharmaceuticals and for personalized medicine, but its use is often restricted to low-viscosity solutions and nano-suspensions. In the present study, a robust electromagnetic (valvejet) inkjet technology has been successfully applied to deposit prototype dosage forms from solutions with a wide range of viscosities, and from suspensions with particle sizes exceeding 2 μm. A detailed solid-state study of paracetamol, printed from a solution ink on hydroxypropyl methylcellulose (HPMC), revealed that the morphology of the substrate and its chemical interactions can have a considerable influence on polymorphic selectivity. Paracetamol ink crystallized exclusively into form II when printed on a smooth polyethylene terephthalate substrate, and exclusively into form I when in sufficient proximity to the rough surface of the HPMC substrate to be influenced by confinement in pores and chemical interactions. The relative standard deviation in the strength of the dosage forms was <4% in all cases, for doses as low as 0.8 mg, demonstrating the accuracy and reproducibility associated with electromagnetic inkjet technology. Good adhesion of indomethacin on HPMC was achieved using a suspension ink with hydroxypropyl cellulose, but not on an alternative polyethylene terephthalate substrate, emphasising the need to tailor the binder to the substrate. Future work will focus on lower-dose drugs, for which dosing flexibility and fixed dose combinations are of particular interest. Copyright © 2018 Elsevier B.V. All rights reserved.

Colorimetry as Quality Control Tool for Individual Inkjet-Printed Pediatric Formulations.

PubMed

Wickström, Henrika; Nyman, Johan O; Indola, Mathias; Sundelin, Heidi; Kronberg, Leif; Preis, Maren; Rantanen, Jukka; Sandler, Niklas

2017-02-01

Printing technologies were recently introduced to the pharmaceutical field for manufacturing of drug delivery systems. Printing allows on demand manufacturing of flexible pharmaceutical doses in a personalized manner, which is critical for a successful and safe treatment of patient populations with specific needs, such as children and the elderly, and patients facing multimorbidity. Printing of pharmaceuticals as technique generates new demands on the quality control procedures. For example, rapid quality control is needed as the printing can be done on demand and at the point of care. This study evaluated the potential use of a handheld colorimetry device for quality control of printed doses of vitamin Bs on edible rice and sugar substrates. The structural features of the substrates with and without ink were also compared. A multicomponent ink formulation with vitamin B 1 , B 2 , B 3 , and B 6 was developed. Doses (4 cm 2 ) were prepared by applying 1-10 layers of yellow ink onto the white substrates using thermal inkjet technology. The colorimetric method was seen to be viable in detecting doses up to the 5th and 6th printed layers until color saturation of the yellow color parameter (b*) was observed on the substrates. Liquid chromatography mass spectrometry was used as a reference method for the colorimetry measurements plotted against the number of printed layers. It was concluded that colorimetry could be used as a quality control tool for detection of different doses. However, optimization of the color addition needs to be done to avoid color saturation within the planned dose interval.

A statewide effort to reduce high-dose opioid prescribing through coordinated care organizations.

PubMed

Hartung, Daniel M; Alley, Lindsey; Leichtling, Gillian; Korthuis, P Todd; Hildebran, Christi

2018-05-01

Oregon's Medicaid program is delivered through 16 Coordinated Care Organizations (CCOs) participating in a statewide performance improvement program to reduce high-dose opioid prescribing. CCOs were allowed flexibility to develop their own dose targets and any policies, trainings, guidelines, and/or materials to meet these targets. In this study, we characterize CCO strategies to reduce high-dose opioid prescribing across the 16 CCOs. We reviewed relevant CCO documents and conducted semi-structured interviews with CCO administrators to acquire opioid-related policies, practices, timelines and contextual factors. We applied a systematic coding procedure to develop a comprehensive description of each CCO's strategy. We used administrative data from the state to summarize contextual utilization data for each CCO. Most CCOs selected a target daily morphine milligram equivalent (MME) dose of 90 mg. Sixteen issued quantity limits related to dose, eight restricted specific drug formulations (short-acting or long-acting), and 11 allowed for time-limited taper plan periods for patients over threshold. Many CCOs also employed provider trainings, feedback reports, and/or onsite technical assistance. Other innovations included incentive measures, electronic health record alerts, and toolkits with materials on local alternative therapy resources and strategies for patient communication. CCOs leveraging collaborations with regional partners appeared to mount a greater intensity of interventions than independently operating CCOs. CCOs developed a diversity of interventions to confront high-risk opioid prescribing within their organization. As healthcare systems mount interventions to reduce risky opioid prescribing, it is critical to carefully describe these activities and examine their impact on process and health outcomes. Copyright © 2018 Elsevier Ltd. All rights reserved.

[Drugs for attention deficit hyperactivity disorder].

PubMed

Montañés-Rada, F; Gangoso-Fermoso, A B; Martíínez-Granero, M A

Quantitative studies have highlighted differences in several drugs approved for use in Spain in the treatment of attention deficit hyperactivity disorder. No clear differences are observed, however, in the case of qualitative studies. The number of patients needed to be treated in order for one to reach complete remission (NNT) of methylphenidate (MTF) is from 2.2 to 5, and the effect size (ES) is 0.9. Atomoxetine has an NNT of 4 and an ES of 0.7. The advantages of immediate-release MTF (IR-MTF) over the extended-release version (ER-MTF) lie in its low cost, its flexibility and the better results obtained in quantitative studies. In contrast, ER-MTF offers a lower risk of abuse, needs to be taken fewer times with less need for third parties to control administration, and there is a lower risk of stigmatisation. Combination or changes of IR-MTF and ER-MTF and the combination of MTF with atomoxetine are sometimes necessary to adjust the weekday or weekend doses. Starting treatment with IR-MTF and then maintaining or changing to ER-MTF offers certain advantages as regards safety, dose adjustments and dosage. Atomoxetine is the best alternative if there is a background of adverse events with low or moderate doses of stimulants, or lack of response to high doses of stimulants. In cases of notable comorbid anxiety, both MTF and atomoxetine have the same level of indication. If there is a risk of substance abuse, both atomoxetine and ER-MTF are the preferred treatment. For the other indications, MTF is the preferred treatment.

Brachytherapy Application With In Situ Dose Painting Administered by Gold Nanoparticle Eluters

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

Sinha, Neeharika; Cifter, Gizem; Department of Radiation Oncology, Dana-Farber Cancer Institute, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts

Purpose: Recent studies show promise that administering gold nanoparticles (GNP) to tumor cells during brachytherapy could significantly enhance radiation damage to the tumor. A new strategy proposed for sustained administration of the GNP in prostate tumors is to load them into routinely used brachytherapy spacers for customizable in situ release after implantation. This in silico study investigated the intratumor biodistribution and corresponding dose enhancement over time due to GNP released from such GNP-loaded brachytherapy spacers (GBS). Method and Materials: An experimentally determined intratumoral diffusion coefficient (D) for 10-nm nanoparticles was used to estimate D for other sizes by using themore » Stokes-Einstein equation. GNP concentration profiles, obtained using D, were then used to calculate the corresponding dose enhancement factor (DEF) for each tumor voxel, using dose painting-by-numbers approach, for times relevant to the considered brachytherapy sources' lifetimes. The investigation was carried out as a function of GNP size for the clinically applicable low-dose-rate brachytherapy sources iodine-125 (I-125), palladium-103 (Pd-103), and cesium-131 (Cs-131). Results: Results showed that dose enhancement to tumor voxels and subvolumes during brachytherapy can be customized by varying the size of GNP released or eluted from the GBS. For example, using a concentration of 7 mg/g GNP, significant DEF (>20%) could be achieved 5 mm from a GBS after 5, 12, 25, 46, 72, 120, and 195 days, respectively, for GNP sizes of 2, 5, 10, 20, 30, and 50 nm and for 80 nm when treating with I-125. Conclusions: Analyses showed that using Cs-131 provides the highest dose enhancement to tumor voxels. However, given its relatively longer half-life, I-125 presents the most flexibility for customizing the dose enhancement as a function of GNP size. These findings provide a useful reference for further work toward development of potential new brachytherapy application with in situ dose painting administered via gold nanoparticle eluters for prostate cancer.« less

An Exploratory Human Laboratory Experiment Evaluating Vaporized Cannabis in the Treatment of Neuropathic Pain from Spinal Cord Injury and Disease

PubMed Central

Wilsey, Barth; Marcotte, Thomas D.; Deutsch, Reena; Zhao, Holly; Prasad, Hannah; Phan, Amy

2016-01-01

Using eight hour human laboratory experiments, we evaluated the analgesic efficacy of vaporized cannabis in patients with neuropathic pain related to injury or disease of the spinal cord, the majority of whom were experiencing pain despite traditional treatment. After obtaining baseline data, 42 participants underwent a standardized procedure for inhaling 4 puffs of vaporized cannabis containing either placebo, 2.9%, or 6.7% delta-9-tetrahydrocannabinol on three separate occasions. A second dosing occurred 3 hours later; participants chose to inhale 4 to 8 puffs. This flexible dosing was utilized to attempt to reduce the placebo effect. Using an 11-point numerical pain intensity rating scale as the primary outcome, a mixed effects linear regression model demonstrated a significant analgesic response for vaporized cannabis. When subjective and psychoactive side effects (e.g., good drug effect, feeling high, etc.) were added as covariates to the model, the reduction in pain intensity remained significant above and beyond any effect of these measures (all p<0.0004). Psychoactive and subjective effects were dose dependent. Measurement of neuropsychological performance proved challenging because of various disabilities in the population studied. As the two active doses did not significantly differ from each other in terms of analgesic potency, the lower dose appears to offer the best risk-benefit ratio in patients with neuropathic pain associated with injury or disease of the spinal cord. PMID:27286745

Enhanced Oxidation-Resistant Cu@Ni Core-Shell Nanoparticles for Printed Flexible Electrodes.

PubMed

Kim, Tae Gon; Park, Hye Jin; Woo, Kyoohee; Jeong, Sunho; Choi, Youngmin; Lee, Su Yeon

2018-01-10

In this work, the fabrication and application of highly conductive, robust, flexible, and oxidation-resistant Cu-Ni core-shell nanoparticle (NP)-based electrodes have been reported. Cu@Ni core-shell NPs with a tunable Ni shell thickness were synthesized by varying the Cu/Ni molar ratios in the precursor solution. Through continuous spray coating and flash photonic sintering without an inert atmosphere, large-area Cu@Ni NP-based conductors were fabricated on various polymer substrates. These NP-based electrodes demonstrate a low sheet resistance of 1.3 Ω sq -1 under an optical energy dose of 1.5 J cm -2 . In addition, they exhibit highly stable sheet resistances (ΔR/R 0 < 1) even after 30 days of aging at 85 °C and 85% relative humidity. Further, a flexible heater fabricated from the Cu@Ni film is demonstrated, which shows uniform heat distribution and stable temperature compared to those of a pure Cu film.

Flexible Molybdenum Electrodes towards Designing Affinity Based Protein Biosensors.

PubMed

Kamakoti, Vikramshankar; Panneer Selvam, Anjan; Radha Shanmugam, Nandhinee; Muthukumar, Sriram; Prasad, Shalini

2016-07-18

Molybdenum electrode based flexible biosensor on porous polyamide substrates has been fabricated and tested for its functionality as a protein affinity based biosensor. The biosensor performance was evaluated using a key cardiac biomarker; cardiac Troponin-I (cTnI). Molybdenum is a transition metal and demonstrates electrochemical behavior upon interaction with an electrolyte. We have leveraged this property of molybdenum for designing an affinity based biosensor using electrochemical impedance spectroscopy. We have evaluated the feasibility of detection of cTnI in phosphate-buffered saline (PBS) and human serum (HS) by measuring impedance changes over a frequency window from 100 mHz to 1 MHz. Increasing changes to the measured impedance was correlated to the increased dose of cTnI molecules binding to the cTnI antibody functionalized molybdenum surface. We achieved cTnI detection limit of 10 pg/mL in PBS and 1 ng/mL in HS medium. The use of flexible substrates for designing the biosensor demonstrates promise for integration with a large-scale batch manufacturing process.

Dose Reconstruction for the Million Worker Study: Status and Guidelines

DOE PAGES

Bouville, André; Toohey, Richard E.; Boice, John D.; ...

2015-02-01

The primary aim of the epidemiologic study of one million U.S. radiation workers and veterans (the Million-Worker study) is to provide scientifically valid information on the level of radiation risk when exposures are received gradually over time, and not acutely as was the case for Japanese atomic bomb survivors. The primary outcome of the epidemiological study is cancer mortality but other causes of death such as cardiovascular disease and cerebrovascular disease will be evaluated. The success of the study is tied to the validity of the dose reconstruction approaches to provide unbiased estimates of organ-specific radiation absorbed doses and theirmore » accompanying uncertainties. The dosimetry aspects for the Million-Worker study are challenging in that they address diverse exposure scenarios for diverse occupational groups being studied over a period of up to 70 years. The dosimetric issues differ among the varied exposed populations that are considered: atomic veterans, DOE workers exposed to both penetrating radiation and intakes of radionuclides, nuclear power plant workers, medical radiation workers, and industrial radiographers. While a major source of radiation exposure to the study population comes from external gamma-ray or x-ray sources, for certain of the study groups there is a meaningful component of radionuclide intakes that require internal radiation dosimetry measures. Scientific Committee 6-9 has been established by NCRP to produce a report on the comprehensive organ dose assessment (including uncertainty analysis) for the Million-Worker study. The Committee’s report will cover the specifics of practical dose reconstruction for the ongoing epidemiologic studies with uncertainty analysis discussions and will be a specific application of the guidance provided in NCRP Reports 158, 163, 164, and 171. The main role of the Committee is to provide guidelines to the various groups of dosimetrists involved in the various components of the Million-Worker study to make sure that certain dosimetry criteria are respected: calculation of annual absorbed doses in the organs of interest, separation of low-LET and high-LET components, evaluation of uncertainties, and quality assurance and quality control. Lastly, we recognize that the Million-Worker study and its approaches to dosimetry are a work in progress and that there will be flexibility and changes in direction as new information is obtained, both with regard to dosimetry and with regard to the epidemiologic features of the study components.« less

Dose Reconstruction for the Million Worker Study: Status and Guidelines

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

Bouville, André; Toohey, Richard E.; Boice, John D.

The primary aim of the epidemiologic study of one million U.S. radiation workers and veterans (the Million-Worker study) is to provide scientifically valid information on the level of radiation risk when exposures are received gradually over time, and not acutely as was the case for Japanese atomic bomb survivors. The primary outcome of the epidemiological study is cancer mortality but other causes of death such as cardiovascular disease and cerebrovascular disease will be evaluated. The success of the study is tied to the validity of the dose reconstruction approaches to provide unbiased estimates of organ-specific radiation absorbed doses and theirmore » accompanying uncertainties. The dosimetry aspects for the Million-Worker study are challenging in that they address diverse exposure scenarios for diverse occupational groups being studied over a period of up to 70 years. The dosimetric issues differ among the varied exposed populations that are considered: atomic veterans, DOE workers exposed to both penetrating radiation and intakes of radionuclides, nuclear power plant workers, medical radiation workers, and industrial radiographers. While a major source of radiation exposure to the study population comes from external gamma-ray or x-ray sources, for certain of the study groups there is a meaningful component of radionuclide intakes that require internal radiation dosimetry measures. Scientific Committee 6-9 has been established by NCRP to produce a report on the comprehensive organ dose assessment (including uncertainty analysis) for the Million-Worker study. The Committee’s report will cover the specifics of practical dose reconstruction for the ongoing epidemiologic studies with uncertainty analysis discussions and will be a specific application of the guidance provided in NCRP Reports 158, 163, 164, and 171. The main role of the Committee is to provide guidelines to the various groups of dosimetrists involved in the various components of the Million-Worker study to make sure that certain dosimetry criteria are respected: calculation of annual absorbed doses in the organs of interest, separation of low-LET and high-LET components, evaluation of uncertainties, and quality assurance and quality control. Lastly, we recognize that the Million-Worker study and its approaches to dosimetry are a work in progress and that there will be flexibility and changes in direction as new information is obtained, both with regard to dosimetry and with regard to the epidemiologic features of the study components.« less

The Effects of Cannabinoids on Executive Functions: Evidence from Cannabis and Synthetic Cannabinoids-A Systematic Review.

PubMed

Cohen, Koby; Weinstein, Aviv

2018-02-27

Background-Cannabis is the most popular illicit drug in the Western world. Repeated cannabis use has been associated with short and long-term range of adverse effects. Recently, new types of designer-drugs containing synthetic cannabinoids have been widespread. These synthetic cannabinoid drugs are associated with undesired adverse effects similar to those seen with cannabis use, yet, in more severe and long-lasting forms. Method-A literature search was conducted using electronic bibliographic databases up to 31 December 2017. Specific search strategies were employed using multiple keywords (e.g., "synthetic cannabinoids AND cognition," "cannabis AND cognition" and "cannabinoids AND cognition"). Results-The search has yielded 160 eligible studies including 37 preclinical studies (5 attention, 25 short-term memory, 7 cognitive flexibility) and 44 human studies (16 attention, 15 working memory, 13 cognitive flexibility). Both pre-clinical and clinical studies demonstrated an association between synthetic cannabinoids and executive-function impairment either after acute or repeated consumptions. These deficits differ in severity depending on several factors including the type of drug, dose of use, quantity, age of onset and duration of use. Conclusions-Understanding the nature of the impaired executive function following consumption of synthetic cannabinoids is crucial in view of the increasing use of these drugs.

The Effects of Cannabinoids on Executive Functions: Evidence from Cannabis and Synthetic Cannabinoids—A Systematic Review

PubMed Central

Cohen, Koby; Weinstein, Aviv

2018-01-01

Background—Cannabis is the most popular illicit drug in the Western world. Repeated cannabis use has been associated with short and long-term range of adverse effects. Recently, new types of designer-drugs containing synthetic cannabinoids have been widespread. These synthetic cannabinoid drugs are associated with undesired adverse effects similar to those seen with cannabis use, yet, in more severe and long-lasting forms. Method—A literature search was conducted using electronic bibliographic databases up to 31 December 2017. Specific search strategies were employed using multiple keywords (e.g., “synthetic cannabinoids AND cognition,” “cannabis AND cognition” and “cannabinoids AND cognition”). Results—The search has yielded 160 eligible studies including 37 preclinical studies (5 attention, 25 short-term memory, 7 cognitive flexibility) and 44 human studies (16 attention, 15 working memory, 13 cognitive flexibility). Both pre-clinical and clinical studies demonstrated an association between synthetic cannabinoids and executive-function impairment either after acute or repeated consumptions. These deficits differ in severity depending on several factors including the type of drug, dose of use, quantity, age of onset and duration of use. Conclusions—Understanding the nature of the impaired executive function following consumption of synthetic cannabinoids is crucial in view of the increasing use of these drugs. PMID:29495540

Optimal Design for the Precise Estimation of an Interaction Threshold: The Impact of Exposure to a Mixture of 18 Polyhalogenated Aromatic Hydrocarbons

PubMed Central

Yeatts, Sharon D.; Gennings, Chris; Crofton, Kevin M.

2014-01-01

Traditional additivity models provide little flexibility in modeling the dose–response relationships of the single agents in a mixture. While the flexible single chemical required (FSCR) methods allow greater flexibility, its implicit nature is an obstacle in the formation of the parameter covariance matrix, which forms the basis for many statistical optimality design criteria. The goal of this effort is to develop a method for constructing the parameter covariance matrix for the FSCR models, so that (local) alphabetic optimality criteria can be applied. Data from Crofton et al. are provided as motivation; in an experiment designed to determine the effect of 18 polyhalogenated aromatic hydrocarbons on serum total thyroxine (T4), the interaction among the chemicals was statistically significant. Gennings et al. fit the FSCR interaction threshold model to the data. The resulting estimate of the interaction threshold was positive and within the observed dose region, providing evidence of a dose-dependent interaction. However, the corresponding likelihood-ratio-based confidence interval was wide and included zero. In order to more precisely estimate the location of the interaction threshold, supplemental data are required. Using the available data as the first stage, the Ds-optimal second-stage design criterion was applied to minimize the variance of the hypothesized interaction threshold. Practical concerns associated with the resulting design are discussed and addressed using the penalized optimality criterion. Results demonstrate that the penalized Ds-optimal second-stage design can be used to more precisely define the interaction threshold while maintaining the characteristics deemed important in practice. PMID:22640366

Di-(2-ethylhexyl)-phthalate migration from irradiated poly(vinyl chloride) blood bags for graft-vs-host disease prevention.

PubMed

Ferri, Marcella; Marcella, Ferri; Chiellini, Federica; Federica, Chiellini; Pili, Giorgio; Giorgio, Pili; Grimaldi, Luca; Luca, Grimaldi; Florio, Elena Tiziana; Pili, Stefania; Stefania, Pili; Cucci, Francesco; Francesco, Cucci; Latini, Giuseppe; Giuseppe, Latini

2012-07-01

Irradiation with 20-25 kGy is a process commonly used for sterilizing poly(vinyl chloride) (PVC) medical devices. Moreover, whole blood and blood components undergo additional irradiation with 25-50 Gy to inhibit the proliferative capacity of lymphocytes and reduce the risk of transfusion-associated graft-vs-host disease (GVHD). Di-(2-ethylhexyl)-phthalate (DEHP) plasticized PVC is extensively used for the production of flexible medical devices including blood bags, but since DEHP is not covalently bound to PVC, it tends to migrate and leach out of the medical device, with harmful consequences for the patients. In this study, the effects of different doses of gamma irradiation on DEHP migration from PVC blood bags was investigated using differential scanning calorimetry (DSC) analysis. Our findings indicate that irradiation with 25-100 Gy reduces the ability of DEHP to migrate from the blood bags, and in the case of a primary container a correlation between the doses of gamma ray irradiation was also observed. In particular, a decrease in DEHP leachability was obtained by increasing the dose of gamma ray irradiation. Copyright © 2012 Elsevier B.V. All rights reserved.

A comparative pilot study of second-generation antipsychotics in children and adolescents with schizophrenia-spectrum disorders.

PubMed

Jensen, Jonathan B; Kumra, Sanjiv; Leitten, Willa; Oberstar, Joel; Anjum, Afshan; White, Tonya; Wozniak, Jeffrey; Lee, Susanne S; Schulz, S Charles

2008-08-01

There is a limited evidence base to guide treatment of children and adolescents with nonaffective psychoses because few comparative studies of first-line second-generation antipsychotics (SGAs) have been undertaken. To plan the design of a subsequent randomized controlled trial (RCT), the authors conducted this pilot study to demonstrate the feasibility of the treatment and measurement protocols. Thirty children and adolescents (20 males, 10 females), ages 10-18 years, who met unmodified Diagnostic and Statistical Manual of Mental Disorders, 4th edition (DSM-IV) criteria for a schizophrenia-spectrum disorder (schizophrenia, schizoaffective, schizophreniform, psychotic disorder not otherwise specified) were randomized to receive 12 weeks of open-label, flexibly dosed treatment with either risperidone (mean [standard deviation, SD] dose = 3.4 mg [1.5]), olanzapine (mean [SD] dose = 14.0 mg [4.6]) or quetiapine (mean [SD] dose = 611 mg [253.4]). Twenty one (70%) of 30 subjects completed the study. There was no overall statistically significant difference with regard to reduction in Positive and Negative Syndrome Scale (PANSS) total scores in treatment efficacy observed (F((2,24)) = 3.13, p = 0.06). However, the possibility of a large differential treatment effect with regard to change in PANSS total scores favoring risperidone relative to quetiapine (risperidone vs. quetiapine, d = 1.10 [95% confidence interval, CI, 0.09-2.01]) was suggested by the point estimate. These preliminary data, viewed together with the extant literature, suggest that a future larger RCT with only two treatment arms may be warranted to establish whether there is a clinically significant differential treatment effect between risperidone and quetiapine for children and adolescents with nonaffective psychoses. Additional challenges and considerations for mounting a larger RCT are explored.

Drug-printing by flexographic printing technology--a new manufacturing process for orodispersible films.

PubMed

Janssen, Eva Maria; Schliephacke, Ralf; Breitenbach, Armin; Breitkreutz, Jörg

2013-01-30

Orodispersible films (ODFs) are intended to disintegrate within seconds when placed onto the tongue. The common way of manufacturing is the solvent casting method. Flexographic printing on drug-free ODFs is introduced as a highly flexible and cost-effective alternative manufacturing method in this study. Rasagiline mesylate and tadalafil were used as model drugs. Printing of rasagiline solutions and tadalafil suspensions was feasible. Up to four printing cycles were performed. The possibility to employ several printing cycles enables a continuous, highly flexible manufacturing process, for example for individualised medicine. The obtained ODFs were characterised regarding their mechanical properties, their disintegration time, API crystallinity and homogeneity. Rasagiline mesylate did not recrystallise after the printing process. Relevant film properties were not affected by printing. Results were comparable to the results of ODFs manufactured with the common solvent casting technique, but the APIs are less stressed through mixing, solvent evaporation and heat. Further, loss of material due to cutting jumbo and daughter rolls can be reduced. Therefore, a versatile new manufacturing technology particularly for processing high-potent low-dose or heat sensitive drugs is introduced in this study. Copyright © 2012 Elsevier B.V. All rights reserved.

Chemical combination effects predict connectivity in biological systems

PubMed Central

Lehár, Joseph; Zimmermann, Grant R; Krueger, Andrew S; Molnar, Raymond A; Ledell, Jebediah T; Heilbut, Adrian M; Short, Glenn F; Giusti, Leanne C; Nolan, Garry P; Magid, Omar A; Lee, Margaret S; Borisy, Alexis A; Stockwell, Brent R; Keith, Curtis T

2007-01-01

Efforts to construct therapeutically useful models of biological systems require large and diverse sets of data on functional connections between their components. Here we show that cellular responses to combinations of chemicals reveal how their biological targets are connected. Simulations of pathways with pairs of inhibitors at varying doses predict distinct response surface shapes that are reproduced in a yeast experiment, with further support from a larger screen using human tumour cells. The response morphology yields detailed connectivity constraints between nearby targets, and synergy profiles across many combinations show relatedness between targets in the whole network. Constraints from chemical combinations complement genetic studies, because they probe different cellular components and can be applied to disease models that are not amenable to mutagenesis. Chemical probes also offer increased flexibility, as they can be continuously dosed, temporally controlled, and readily combined. After extending this initial study to cover a wider range of combination effects and pathway topologies, chemical combinations may be used to refine network models or to identify novel targets. This response surface methodology may even apply to non-biological systems where responses to targeted perturbations can be measured. PMID:17332758

A double-blind, placebo-controlled, multicenter study with alprazolam and extended-release alprazolam in the treatment of panic disorder.

PubMed

Pecknold, J; Luthe, L; Munjack, D; Alexander, P

1994-10-01

This is a double-blind, placebo-controlled, flexible-dose, multicenter, 6-week study comparing regular alprazolam (compressed tablet, CT), given four times per day, and extended release alprazolam (XR), given once in the morning. The aim of the XR preparation is to offer less frequent dosing and to reduce interdose anxiety. Of the intent-to-treat group of 209 patients, 184 completed 3 weeks of medication and were evaluated according to protocol. There was a completer rate for the 6 weeks of 94% (CT), 97% (XR), and 87% (placebo). On global measures, Hamilton Rating Scale for Anxiety, phobia rating, and work disability measures, both active treatment groups were equally effective and significantly more efficacious than the placebo cell on endpoint MANOVA analysis. On analysis of the panic factor with endpoint data, both active treatment groups were equally effective throughout the 6-week trial and significantly more efficacious than the placebo group. Drowsiness occurred more frequently with CT alprazolam (86% of patients) than with the XR preparation (79%) or placebo (49%).

Improvement of drug dose calculations by classroom teaching or e-learning: a randomised controlled trial in nurses.

PubMed

Simonsen, Bjoerg O; Daehlin, Gro K; Johansson, Inger; Farup, Per G

2014-10-24

Insufficient skills in drug dose calculations increase the risk for medication errors. Even experienced nurses may struggle with such calculations. Learning flexibility and cost considerations make e-learning interesting as an alternative to classroom teaching. This study compared the learning outcome and risk of error after a course in drug dose calculations for nurses with the two methods. In a randomised controlled open study, nurses from hospitals and primary healthcare were randomised to either e-learning or classroom teaching. Before and after a 2-day course, the nurses underwent a multiple choice test in drug dose calculations: 14 tasks with four alternative answers (score 0-14), and a statement regarding the certainty of each answer (score 0-3). High risk of error was being certain that incorrect answer was correct. The results are given as the mean (SD). 16 men and 167 women participated in the study, aged 42.0 (9.5) years with a working experience of 12.3 (9.5) years. The number of correct answers after e-learning was 11.6 (2.0) and after classroom teaching 11.9 (2.0) (p=0.18, NS); improvement were 0.5 (1.6) and 0.9 (2.2), respectively (p=0.07, NS). Classroom learning was significantly superior to e-learning among participants with a pretest score below 9. In support of e-learning was evaluation of specific value for the working situation. There was no difference in risk of error between groups after the course (p=0.77). The study showed no differences in learning outcome or risk of error between e-learning and classroom teaching in drug dose calculations. The overall learning outcome was small. Weak precourse knowledge was associated with better outcome after classroom teaching. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

Improvement of drug dose calculations by classroom teaching or e-learning: a randomised controlled trial in nurses

PubMed Central

Simonsen, Bjoerg O; Daehlin, Gro K; Johansson, Inger; Farup, Per G

2014-01-01

Introduction Insufficient skills in drug dose calculations increase the risk for medication errors. Even experienced nurses may struggle with such calculations. Learning flexibility and cost considerations make e-learning interesting as an alternative to classroom teaching. This study compared the learning outcome and risk of error after a course in drug dose calculations for nurses with the two methods. Methods In a randomised controlled open study, nurses from hospitals and primary healthcare were randomised to either e-learning or classroom teaching. Before and after a 2-day course, the nurses underwent a multiple choice test in drug dose calculations: 14 tasks with four alternative answers (score 0–14), and a statement regarding the certainty of each answer (score 0–3). High risk of error was being certain that incorrect answer was correct. The results are given as the mean (SD). Results 16 men and 167 women participated in the study, aged 42.0 (9.5) years with a working experience of 12.3 (9.5) years. The number of correct answers after e-learning was 11.6 (2.0) and after classroom teaching 11.9 (2.0) (p=0.18, NS); improvement were 0.5 (1.6) and 0.9 (2.2), respectively (p=0.07, NS). Classroom learning was significantly superior to e-learning among participants with a pretest score below 9. In support of e-learning was evaluation of specific value for the working situation. There was no difference in risk of error between groups after the course (p=0.77). Conclusions The study showed no differences in learning outcome or risk of error between e-learning and classroom teaching in drug dose calculations. The overall learning outcome was small. Weak precourse knowledge was associated with better outcome after classroom teaching. PMID:25344483

Continuous Inkjet Printing of Enalapril Maleate onto Orodispersible Film Formulations.

PubMed

Thabet, Yasmin; Lunter, Dominique; Breitkreutz, Joerg

2018-05-10

Piezoelectric inkjet printing onto orodispersible films (ODFs) was proven to be a successful technique applying flexible doses of active pharmaceutical ingredients (APIs) onto edible substrates. The reported API printing and ODF production was conducted in a non-continuous production approach. Within this study, drug-free and hydrochlorothiazide (HCT) containing ODFs should be imprinted in-line with enalapril maleate (EM) ink during continuous ODF production. Macrogol inks based on various solvents and solvent-water mixtures were developed providing dynamic viscosities from 7 to 17 mPa∗s. Water based inks contained 1.25%, methanol based inks up to 10% EM. Both inks could be printed (500-1000 Hz) during continuous ODF production. No EM recrystallization was observed for water-based inks. Mechanical properties were not affected by drug printing using various firing frequencies. ODF imprinted with water-based EM inks contained 0.04 mg EM / 6cm 2 . EM amount can be increased to a paediatric therapeutic dose of 0.5 mg EM utilizing methanol-based inks. These inks were successfully printed onto HCT ODFs resulting in a therapeutically relevant fixed-dose combination. No EM migration into the HCT layer could be observed. In conclusion, it was feasible to print EM doses onto drug-free and HCT ODFs during an in-line continuous manufacturing process. Copyright © 2018 Elsevier B.V. All rights reserved.

A stimuli responsive liposome loaded hydrogel provides flexible on-demand release of therapeutic agents.

PubMed

O'Neill, Hugh S; Herron, Caroline C; Hastings, Conn L; Deckers, Roel; Lopez Noriega, Adolfo; Kelly, Helena M; Hennink, Wim E; McDonnell, Ciarán O; O'Brien, Fergal J; Ruiz-Hernández, Eduardo; Duffy, Garry P

2017-01-15

Lysolipid-based thermosensitive liposomes (LTSL) embedded in a chitosan-based thermoresponsive hydrogel matrix (denoted Lipogel) represents a novel approach for the spatiotemporal release of therapeutic agents. The entrapment of drug-loaded liposomes in an injectable hydrogel permits local liposome retention, thus providing a prolonged release in target tissues. Moreover, release can be controlled through the use of a minimally invasive external hyperthermic stimulus. Temporal control of release is particularly important for complex multi-step physiological processes, such as angiogenesis, in which different signals are required at different times in order to produce a robust vasculature. In the present work, we demonstrate the ability of Lipogel to provide a flexible, easily modifiable release platform. It is possible to tune the release kinetics of different drugs providing a passive release of one therapeutic agent loaded within the gel and activating the release of a second LTSL encapsulated agent via a hyperthermic stimulus. In addition, it was possible to modify the drug dosage within Lipogel by varying the duration of hyperthermia. This can allow for adaption of drug dosing in real time. As an in vitro proof of concept with this system, we investigated Lipogels ability to recruit stem cells and then elevate their production of vascular endothelial growth factor (VEGF) by controlling the release of a pro-angiogenic drug, desferroxamine (DFO) with an external hyperthermic stimulus. Initial cell recruitment was accomplished by the passive release of hepatocyte growth factor (HGF) from the hydrogel, inducing a migratory response in cells, followed by the delayed release of DFO from thermosensitive liposomes, resulting in a significant increase in VEGF expression. This delayed release could be controlled up to 14days. Moreover, by changing the duration of the hyperthermic pulse, a fine control over the amount of DFO released was achieved. The ability to trigger the release of therapeutic agents at a specific timepoint and control dosing level through changes in duration of hyperthermia enables sequential multi-dose profiles. This paper details the development of a heat responsive liposome loaded hydrogel for the controlled release of pro-angiogenic therapeutics. Lysolipid-based thermosensitive liposomes (LTSLs) embedded in a chitosan-based thermoresponsive hydrogel matrix represents a novel approach for the spatiotemporal release of therapeutic agents. This hydrogel platform demonstrates remarkable flexibility in terms of drug scheduling and sequencing, enabling the release of multiple agents and the ability to control drug dosing in a minimally invasive fashion. The possibility to tune the release kinetics of different drugs independently represents an innovative platform to utilise for a variety of treatments. This approach allows a significant degree of flexibility in achieving a desired release profile via a minimally invasive stimulus, enabling treatments to be tuned in response to changing symptoms and complications. Copyright © 2016 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.

SU-F-19A-03: Dosimetric Advantages in Critical Structure Dose Sparing by Using a Multichannel Cylinder in High Dose Rate Brachytherapy to Treat Vaginal Cuff Cancer

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

Syh, J; Syh, J; Patel, B

2014-06-15

Purpose: The multichannel cylindrical vaginal applicator is a variation of traditional single channel cylindrical vaginal applicator. The multichannel applicator has additional peripheral channels that provide more flexibility in the planning process. The dosimetric advantage is to reduce dose to adjacent organ at risk (OAR) such as bladder and rectum while maintaining target coverage with the dose optimization from additional channels. Methods: Vaginal HDR brachytherapy plans are all CT based. CT images were acquired in 2 mm thickness to keep integrity of cylinder contouring. The CTV of 5mm Rind with prescribed treatment length was reconstructed from 5mm expansion of inserted cylinder.more » The goal was 95% of CTV covered by 95% of prescribed dose in both single channel planning (SCP)and multichannel planning (MCP) before proceeding any further optimization for dose reduction to critical structures with emphasis on D2cc and V2Gy . Results: This study demonstrated noticeable dose reduction to OAR was apparent in multichannel plans. The D2cc of the rectum and bladder were showing the reduced dose for multichannel versus single channel. The V2Gy of the rectum was 93.72% and 83.79% (p=0.007) for single channel and multichannel respectively (Figure 1 and Table 1). To assure adequate coverage to target while reducing the dose to the OAR without any compromise is the main goal in using multichannel vaginal applicator in HDR brachytherapy. Conclusion: Multichannel plans were optimized using anatomical based inverse optimization algorithm of inverse planning simulation annealing. The optimization solution of the algorithm was to improve the clinical target volume dose coverage while reducing the dose to critical organs such as bladder, rectum and bowels. The comparison between SCP and MCP demonstrated MCP is superior to SCP where the dwell positions were based on geometric array only. It concluded that MCP is preferable and is able to provide certain features superior to SCP.« less

The Effect of Dextromethorphan Premedication on Cough and Patient Tolerance During Flexible Bronchoscopy: A Randomized, Double-blind, Placebo-controlled Trial.

PubMed

Amini, Shahideh; Peiman, Soheil; Khatuni, Mahdi; Ghalamkari, Marziyeh; Rahimi, Besharat

2017-10-01

Patients undergoing bronchoscopy can experience problems such as anxiety and cough, requiring various doses of sedatives and analgesics. The purposes of this study were to investigate the effect of premedication with dextromethorphan on patients' cough and anxiety, and the use of analgesics/sedatives during flexible bronchoscopy (FB). A randomized, double-blind, placebo-controlled, prospective study was performed to assess the effect of dextromethorphan premedication on patients who underwent diagnostic bronchoscopy. Seventy patients included in this study were randomly allocated into 2 groups: group A consisted of 35 patients who received dextromethorphan before FB; and group B consisted of 35 patients who received a placebo. A questionnaire was given to the patients and bronchoscopist about perception of cough, anxiety, and discomfort. The amount of sedative medication and lidocaine use during the procedure and the procedure time were recorded. The group that was premedicated with dextromethorphan had lower complaint scores, significantly less coughing, significantly less stress assessed by the patient and the physician evaluation, shorter total procedure time, and fewer midazolam requirements during FB (P-value <0.05). Considering its safety profile, dextromethorphan premedication is an effective approach to facilitate the performance of FB for the physician, and could improve patient comfort.

SU-E-T-10: A Clinical Implementation and the Dosimetric Evidence in High Dose Rate Vaginal Multichannel Applicator Brachytherapy

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

Syh, J; Syh, J; Patel, B

2015-06-15

Purpose: The multichannel cylindrical applicator has a distinctive modification of the traditional single channel cylindrical applicator. The novel multichannel applicator has additional peripheral channels that provide more flexibility both in treatment planning process and outcomes. To protect by reducing doses to adjacent organ at risk (OAR) while maintaining target coverage with inverse plan optimization are the goals for such novel Brachytherapy device. Through a series of comparison and analysis of reults in more than forty patients who received HDR Brachytherapy using multichannel vaginal applicator, this procedure has been implemented in our institution. Methods: Multichannel planning was CT image based. Themore » CTV of 5mm vaginal cuff rind with prescribed length was well reconstructed as well as bladder and rectum. At least D95 of CTV coverage is 95% of prescribed dose. Multichannel inverse plan optimization algorithm not only shapes target dose cloud but set dose avoids to OAR’s exclusively. The doses of D2cc, D5cc and D5; volume of V2Gy in OAR’s were selected to compare with single channel results when sole central channel is only possibility. Results: Study demonstrates plan superiorly in OAR’s doe reduction in multi-channel plan. The D2cc of the rectum and bladder were showing a little lower for multichannel vs. single channel. The V2Gy of the rectum was 93.72% vs. 83.79% (p=0.007) for single channel vs. multichannel respectively. Absolute reduced mean dose of D5 by multichannel was 17 cGy (s.d.=6.4) and 44 cGy (s.d.=15.2) in bladder and rectum respectively. Conclusion: The optimization solution in multichannel was to maintain D95 CTV coverage while reducing the dose to OAR’s. Dosimetric advantage in sparing critical organs by using a multichannel applicator in HDR Brachytherapy treatment of the vaginal cuff is so promising and has been implemented clinically.« less

Dose of physical activity, physical functioning and disability risk in mobility-limited older adults: Results from the LIFE study randomized trial

PubMed Central

Guralnik, Jack M.; King, Abby C.; Pahor, Marco; McDermott, Mary M.; Tudor-Locke, Catrine; Manini, Todd M.; Glynn, Nancy W.; Marsh, Anthony P.; Axtell, Robert S.; Hsu, Fang-Chi; Rejeski, W. Jack

2017-01-01

Understanding the minimal dose of physical activity required to achieve improvement in physical functioning and reductions in disability risk is necessary to inform public health recommendations. To examine the effect of physical activity dose on changes in physical functioning and the onset of major mobility disability in The Lifestyle Interventions and Independence for Elders (LIFE) Study. We conducted a multicenter single masked randomized controlled trial that enrolled participants in 2010 and 2011 and followed them for an average of 2.6 years. 1,635 sedentary men and women aged 70–89 years who had functional limitations were randomized to a structured moderate intensity walking, resistance, and flexibility physical activity program or a health education program. Physical activity dose was assessed by 7-day accelerometry and self-report at baseline and 24 months. Outcomes included the 400 m walk gait speed, the Short Physical Performance Battery (SPPB), assessed at baseline, 6, 12, and 24 months, and onset of major mobility disability (objectively defined by loss of ability to walk 400 m in 15 min). When the physical activity arm or the entire sample were stratified by change in physical activity from baseline to 24 months, there was a dose-dependent increase in the change in gait speed and SPPB from baseline at 6, 12, and 24 months. In addition, the magnitude of change in physical activity over 24 months was related to the reduction in the onset of major mobility disability (overall P < 0.001) (highest versus the lowest quartile of physical activity change HR 0.23 ((95% CI:0.10–0.52) P = 0.001) in the physical activity arm. We observed a dose-dependent effect of objectively monitored physical activity on physical functioning and onset of major mobility disability. Relatively small increases (> 48 minutes per week) in regular physical activity participation had significant and clinically meaningful effects on these outcomes. Trial registration: ClinicalsTrials.gov NCT00116194 PMID:28820909

Dose of physical activity, physical functioning and disability risk in mobility-limited older adults: Results from the LIFE study randomized trial.

PubMed

Fielding, Roger A; Guralnik, Jack M; King, Abby C; Pahor, Marco; McDermott, Mary M; Tudor-Locke, Catrine; Manini, Todd M; Glynn, Nancy W; Marsh, Anthony P; Axtell, Robert S; Hsu, Fang-Chi; Rejeski, W Jack

2017-01-01

Understanding the minimal dose of physical activity required to achieve improvement in physical functioning and reductions in disability risk is necessary to inform public health recommendations. To examine the effect of physical activity dose on changes in physical functioning and the onset of major mobility disability in The Lifestyle Interventions and Independence for Elders (LIFE) Study. We conducted a multicenter single masked randomized controlled trial that enrolled participants in 2010 and 2011 and followed them for an average of 2.6 years. 1,635 sedentary men and women aged 70-89 years who had functional limitations were randomized to a structured moderate intensity walking, resistance, and flexibility physical activity program or a health education program. Physical activity dose was assessed by 7-day accelerometry and self-report at baseline and 24 months. Outcomes included the 400 m walk gait speed, the Short Physical Performance Battery (SPPB), assessed at baseline, 6, 12, and 24 months, and onset of major mobility disability (objectively defined by loss of ability to walk 400 m in 15 min). When the physical activity arm or the entire sample were stratified by change in physical activity from baseline to 24 months, there was a dose-dependent increase in the change in gait speed and SPPB from baseline at 6, 12, and 24 months. In addition, the magnitude of change in physical activity over 24 months was related to the reduction in the onset of major mobility disability (overall P < 0.001) (highest versus the lowest quartile of physical activity change HR 0.23 ((95% CI:0.10-0.52) P = 0.001) in the physical activity arm. We observed a dose-dependent effect of objectively monitored physical activity on physical functioning and onset of major mobility disability. Relatively small increases (> 48 minutes per week) in regular physical activity participation had significant and clinically meaningful effects on these outcomes. ClinicalsTrials.gov NCT00116194.

FIRE: an open-software suite for real-time 2D/3D image registration for image guided radiotherapy research

NASA Astrophysics Data System (ADS)

Furtado, H.; Gendrin, C.; Spoerk, J.; Steiner, E.; Underwood, T.; Kuenzler, T.; Georg, D.; Birkfellner, W.

2016-03-01

Radiotherapy treatments have changed at a tremendously rapid pace. Dose delivered to the tumor has escalated while organs at risk (OARs) are better spared. The impact of moving tumors during dose delivery has become higher due to very steep dose gradients. Intra-fractional tumor motion has to be managed adequately to reduce errors in dose delivery. For tumors with large motion such as tumors in the lung, tracking is an approach that can reduce position uncertainty. Tumor tracking approaches range from purely image intensity based techniques to motion estimation based on surrogate tracking. Research efforts are often based on custom designed software platforms which take too much time and effort to develop. To address this challenge we have developed an open software platform especially focusing on tumor motion management. FLIRT is a freely available open-source software platform. The core method for tumor tracking is purely intensity based 2D/3D registration. The platform is written in C++ using the Qt framework for the user interface. The performance critical methods are implemented on the graphics processor using the CUDA extension. One registration can be as fast as 90ms (11Hz). This is suitable to track tumors moving due to respiration (~0.3Hz) or heartbeat (~1Hz). Apart from focusing on high performance, the platform is designed to be flexible and easy to use. Current use cases range from tracking feasibility studies, patient positioning and method validation. Such a framework has the potential of enabling the research community to rapidly perform patient studies or try new methods.

Comparison of electromagnetic and hadronic models generated using Geant 4 with antiproton dose measured in CERN.

PubMed

Tavakoli, Mohammad Bagher; Reiazi, Reza; Mohammadi, Mohammad Mehdi; Jabbari, Keyvan

2015-01-01

After proposing the idea of antiproton cancer treatment in 1984 many experiments were launched to investigate different aspects of physical and radiobiological properties of antiproton, which came from its annihilation reactions. One of these experiments has been done at the European Organization for Nuclear Research known as CERN using the antiproton decelerator. The ultimate goal of this experiment was to assess the dosimetric and radiobiological properties of beams of antiprotons in order to estimate the suitability of antiprotons for radiotherapy. One difficulty on this way was the unavailability of antiproton beam in CERN for a long time, so the verification of Monte Carlo codes to simulate antiproton depth dose could be useful. Among available simulation codes, Geant4 provides acceptable flexibility and extensibility, which progressively lead to the development of novel Geant4 applications in research domains, especially modeling the biological effects of ionizing radiation at the sub-cellular scale. In this study, the depth dose corresponding to CERN antiproton beam energy by Geant4 recruiting all the standard physics lists currently available and benchmarked for other use cases were calculated. Overall, none of the standard physics lists was able to draw the antiproton percentage depth dose. Although, with some models our results were promising, the Bragg peak level remained as the point of concern for our study. It is concluded that the Bertini model with high precision neutron tracking (QGSP_BERT_HP) is the best to match the experimental data though it is also the slowest model to simulate events among the physics lists.

Understanding the patient experience of cost-related non-adherence to prescription medications through typology development and application.

PubMed

Goldsmith, Laurie J; Kolhatkar, Ashra; Popowich, Dominic; Holbrook, Anne M; Morgan, Steven G; Law, Michael R

2017-12-01

Many patients report skipping doses, splitting pills, or not filling prescriptions due to out-of-pocket costs-a phenomenon known as cost-related non-adherence (CRNA). This study investigated CRNA from the patient's perspective, and, to our knowledge, is the first study to undertake a qualitative investigation of CRNA specifically. We report the results from 35 semi-structured interviews conducted in 2014-15 with adults in four Canadian cities across two provinces. We used framework analysis to develop a CRNA typology to characterize major factors in patients' CRNA decisions. Our typology identifies four major components: (1) the insurance reason driving the drug cost, (2) the individual's overall financial flexibility, (3) the burden of drug cost on the individual's budget, and (4) the importance of the drug from the individual's perspective. The first two components set the context for CRNA and the final two components are the drivers for the CRNA decision. We also found four major patterns in CRNA experiences: (1) CRNA in individuals with low financial flexibility occurred for all levels of drug importance and all but the lowest level of cost burden; (2) CRNA for high importance drugs only occurred when the drug cost had a high burden on an individual's budget; (3) CRNA in individuals with more financial flexibility primarily occurred in drugs with medium importance but high or very high cost burdens; and (4) CRNA for low importance drugs occurred at almost all levels of drug cost burden. Our study furthers the understanding of how numerous factors such as income, insurance, and individual preferences combine and interact to influence CRNA and suggests that policy interventions must be multi-faceted or encourage significant insurance redesign to reduce CRNA. Copyright © 2017 Elsevier Ltd. All rights reserved.

Combination of behaviorally sub-effective doses of glutamate NMDA and dopamine D1 receptor antagonists impairs executive function.

PubMed

Desai, Sagar J; Allman, Brian L; Rajakumar, Nagalingam

2017-04-14

Impairment of executive function is a core feature of schizophrenia. Preclinical studies indicate that injections of either N-methyl d-aspartate (NMDA) or dopamine D 1 receptor blockers impair executive function. Despite the prevailing notion based on postmortem findings in schizophrenia that cortical areas have marked suppression of glutamate and dopamine, recent in vivo imaging studies suggest that abnormalities of these neurotransmitters in living patients may be quite subtle. Thus, we hypothesized that modest impairments in both glutamate and dopamine function can act synergistically to cause executive dysfunction. In the present study, we investigated the effect of combined administration of "behaviorally sub-effective" doses of NMDA and dopamine D 1 receptor antagonists on executive function. An operant conditioning-based set-shifting task was used to assess behavioral flexibility in rats that were systemically injected with NMDA and dopamine D 1 receptor antagonists individually or in combination prior to task performance. Separate injections of the NMDA receptor antagonist, MK-801, and the dopamine D 1 receptor antagonist, SCH 23390, at low doses did not impair set-shifting; however, the combined administration of these same behaviorally sub-effective doses of the antagonists significantly impaired the performance during set-shifting without affecting learning, retrieval of the memory of the initial rule, latency of responses or the number of omissions. The combined treatment also produced an increased number of perseverative errors. Our results indicate that NMDA and D 1 receptor blockade act synergistically to cause behavioral inflexibility, and as such, subtle abnormalities in glutamatergic and dopaminergic systems may act cooperatively to cause deficits in executive function. Copyright © 2017 Elsevier B.V. All rights reserved.

Aripiprazole for Irritability in Asian Children and Adolescents with Autistic Disorder: A 12-Week, Multinational, Multicenter, Prospective Open-Label Study.

PubMed

Kim, Hyo-Won; Park, Eun-Jin; Kim, Ji-Hoon; Boon-Yasidhi, Vitharon; Tarugsa, Jariya; Reyes, Alexis; Manalo, Stella; Joung, Yoo-Sook

2018-04-24

We investigated the effectiveness and tolerability of aripiprazole in the treatment of irritability in Asian children and adolescents (6-17 years) with autistic disorder in a 12-week, multinational, multicenter, open-label study. Sixty-seven subjects (10.0 ± 3.1 years old, 52 boys) were enrolled and treated with flexibly dosed aripiprazole for 12 weeks (mean dose, 5.1 ± 2.5 mg; range 2-15 mg). Aripiprazole significantly reduced the mean caregiver-rated scores for the Irritability, Lethargy/Social Withdrawal, Stereotypy, Hyperactivity, and Inappropriate Speech subscales of the Aberrant Behavior Checklist from baseline to week 12 (p < 0.001 for all subscales). Clinician-rated Clinical Global Impression Severity of Illness scale score also improved from baseline through week 12 (p < 0.001). The most common adverse event was weight gain and no serious adverse event related to aripiprazole treatment was noted. Our results suggest that aripiprazole is effective and generally tolerable in the treatment of irritability in Asian children and adolescents with autistic disorder. Further studies with larger sample sizes and longer treatment durations are required.

Subcutaneous interferon β-1a in the treatment of clinically isolated syndromes: 3-year and 5-year results of the phase III dosing frequency-blind multicentre REFLEXION study.

PubMed

Comi, Giancarlo; De Stefano, Nicola; Freedman, Mark S; Barkhof, Frederik; Uitdehaag, Bernard M J; de Vos, Marlieke; Marhardt, Kurt; Chen, Liang; Issard, Delphine; Kappos, Ludwig

2017-04-01

Early treatment following a first clinical demyelinating event (FCDE) delays further disease activity in patients with multiple sclerosis (MS). This study determined the effects of early versus delayed treatment (DT) with subcutaneous interferon (sc IFN) β-1a 44 μg in patients with an FCDE up to 60 months postrandomisation. Patients who completed the 24-month double-blind REFLEX (REbif FLEXible dosing in early MS) study entered an extension (REFLEXION, REbif FLEXible dosing in early MS extensION): patients initially randomised to sc IFN β-1a and not reaching clinically definite MS (clinically definite MS, CDMS (second attack or sustained Expanded Disability Status Scale (EDSS) score increase)) continued original treatment (three times weekly (tiw) or once weekly (qw)); placebo patients switched to tiw (DT); patients with CDMS switched to tiw. Clinical, MRI and adverse event data up to month 60 are reported. 402/517 (77.8%) REFLEX patients entered REFLEXION (DT, n=133; tiw, n=127; qw, n=142). At month 60, cumulative probability of CDMS was: DT 44.6%; qw 40.7% (nominal p=0.084 vs DT); tiw 39.2% (nominal p=0.032 vs DT). Cumulative probability of McDonald MS conversion (CDMS or new MRI activity) at month 60 was also reduced for tiw versus DT (nominal p<0.001). At month 60, mean cumulative numbers of new T2, gadolinium-enhancing and T1 hypointense lesions were lower with sc IFN β-1a qw (nominal p<0.05) and tiw versus DT (nominal p<0.001); T2 and T1 hypointense lesion volume change was lower for sc IFN β-1a tiw versus DT (nominal p<0.01). Treatment was well tolerated; fewer patients receiving tiw versus qw were positive for neutralising or binding antibodies. Over 5 years in patients presenting with an FCDE, early sc IFN β-1a tiw administration versus DT prolonged time to CDMS and McDonald MS, and reduced overall MRI activity. NCT00813709; Results. 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/.

Repaglinide--prandial glucose regulator: a new class of oral antidiabetic drugs.

PubMed

Owens, D R

1998-01-01

The highest demand on insulin secretion occurs in connection with meals. In normal people, following a meal, the insulin secretion increases rapidly, reaching peak concentration in the blood within an hour. The mealtime insulin response in patients with Type 2 diabetes is blunted and delayed, whereas basal levels often remain within the normal range (albeit at elevated fasting glucose levels). Restoration of the insulin secretion pattern at mealtimes (prandial phase)--without stimulating insulin secretion in the 'postabsorptive' phase--is the rationale for the development of 'prandial glucose regulators', drugs that are characterized by a very rapid onset and short duration of action in stimulating insulin secretion. Repaglinide, a carbamoylmethyl benzoic acid (CMBA) derivative is the first such compound, which recently has become available for clinical use. Repaglinide is very rapidly absorbed (t(max) less than 1 hour) with a t1/2 of less than one hour. Furthermore, repaglinide is inactivated in the liver and more than 90% excreted via the bile. The implications of tailoring repaglinide treatment to meals were examined in a study where repaglinide was dosed either morning and evening, or with each main meal (i.e. breakfast, lunch, dinner), with the total daily dose of repaglinide being identical. The mealtime dosing caused a significant improvement in both fasting and 24-hour glucose profiles, as well as a significant decrease in HbA1c. In other studies, repaglinide caused a decrease of 5.8 mmol x l(-1) in peak postprandial glucose levels, and a decrease of 3.1 mmol x l(-1) in fasting levels with a reduction in HbA1c of 1.8% compared with placebo. In comparative studies with either sulphonylurea or metformin, repaglinide caused similar or improved control (i.e. HbA1c, mean glucose levels) and the drug was well tolerated (e.g. reported gastrointestinal side-effects were more than halved when patients were switched from metformin to repaglinide). A hallmark of repaglinide treatment is that this medication follows the eating pattern, and not vice versa. Hence the risk of developing severe hypoglycaemia (BG < or = 2.5 mmol x l(-1)) in connection with flexible lifestyles should be reduced. This concept was examined in a study in which patients well controlled on repaglinide skipped their lunch on one occasion. When a meal (i.e. lunch) was skipped--so was the repaglinide dose, whereas in the comparative group on glibenclamide the recommended morning and evening doses were taken. Twenty-four per cent of the patients in the glibenclamide group developed severe hypoglycaemia, whereas no hypoglycaemic events occurred in the group receiving repaglinide. However, in long-term studies the overall prevalence of hypoglycaemia was similar to that found with other insulin secretagogues. In summary, current evidence shows that the concept of prandial glucose regulation offers good long-term glycaemic control combined with a low risk of severe hypoglycaemia with missed meals. The concept should meet the needs of Type 2 diabetic patients, allowing flexibility in their lifestyle.

The effect of prandial glucose regulation with repaglinide on treatment satisfaction, wellbeing and health status in patients with pharmacotherapy naïve Type 2 diabetes: a placebo-controlled, multicentre study.

PubMed

Bech, Per; Moses, Robert; Gomis, Ramón

2003-06-01

This prospective, 16-week, randomised, double-blind, parallel-group study assessed the differential impact of the prandial glucose regulating oral hypoglycaemic drug, repaglinide, and placebo upon perceptions of quality of life (QoL) and treatment satisfaction in pharmacotherapy-naive patients with Type 2 diabetes. In addition, the study assessed whether these outcomes were influenced by the patients' level of glycaemic control. A total of 253 patients were randomised in a 2:1 ratio of repaglinide: placebo, with doses taken flexibly with main meals (2-4 per day), whenever they were eaten. Repaglinide was initiated at 0.5 mg per meal, increased to 1 mg after 4 weeks if fasting plasma glucose exceeded 7.8 mmol/l. QoL and treatment satisfaction outcomes were compared using generic and disease-specific self-assessment measures, previously applied in diabetes: the WHO Wellbeing Questionnaire (WHO-WBQ), WHO Diabetes Treatment Satisfaction Questionnaire (WHO-DTSQ) and EuroQoL EQ-5D. Over the trial period, repaglinide-treated patients reported a significant 9% improvement in (WHO-DTSQ) treatment satisfaction score (p < 0.05). No significant increase was associated with placebo. The correlation between decrease in glycated haemoglobin (HbA1c) and increase in treatment satisfaction (WHO-DTSQ) was -0.22 (p < 0.01). Scores obtained with the other measures did not change significantly during the trial in either group, but the cohort exhibited only a slight reduction in wellbeing (WHO-WBQ) and health status (EQ-5D) at baseline compared with the background population. In conclusion, flexible mealtime dosing with oral medication appears to be well accepted by pharmacotherapy-naïve patients with Type 2 diabetes. The results suggest that repaglinide provides a higher level of treatment satisfaction than placebo, and this may in part relate to improved glycaemic control.

An Exploratory Human Laboratory Experiment Evaluating Vaporized Cannabis in the Treatment of Neuropathic Pain From Spinal Cord Injury and Disease.

PubMed

Wilsey, Barth; Marcotte, Thomas D; Deutsch, Reena; Zhao, Holly; Prasad, Hannah; Phan, Amy

2016-09-01

Using 8-hour human laboratory experiments, we evaluated the analgesic efficacy of vaporized cannabis in patients with neuropathic pain related to injury or disease of the spinal cord, most of whom were experiencing pain despite traditional treatment. After obtaining baseline data, 42 participants underwent a standardized procedure for inhaling 4 puffs of vaporized cannabis containing either placebo, 2.9%, or 6.7% delta 9-THC on 3 separate occasions. A second dosing occurred 3 hours later; participants chose to inhale 4 to 8 puffs. This flexible dosing was used to attempt to reduce the placebo effect. Using an 11-point numerical pain intensity rating scale as the primary outcome, a mixed effects linear regression model showed a significant analgesic response for vaporized cannabis. When subjective and psychoactive side effects (eg, good drug effect, feeling high, etc) were added as covariates to the model, the reduction in pain intensity remained significant above and beyond any effect of these measures (all P < .0004). Psychoactive and subjective effects were dose-dependent. Measurement of neuropsychological performance proved challenging because of various disabilities in the population studied. Because the 2 active doses did not significantly differ from each other in terms of analgesic potency, the lower dose appears to offer the best risk-benefit ratio in patients with neuropathic pain associated with injury or disease of the spinal cord. A crossover, randomized, placebo-controlled human laboratory experiment involving administration of vaporized cannabis was performed in patients with neuropathic pain related to spinal cord injury and disease. This study supports consideration of future research that would include longer duration studies over weeks to months to evaluate the efficacy of medicinal cannabis in patients with central neuropathic pain. Copyright © 2016 American Pain Society. Published by Elsevier Inc. All rights reserved.

Introducing iron isomaltoside 1000 (Monofer®)-development rationale and clinical experience.

PubMed

Kalra, Philip A

2011-06-01

Patients with chronic kidney disease (CKD) often suffer from iron deficiency anaemia necessitating treatment with intravenous (IV) iron. Several studies demonstrate that oral iron is insufficient in these patients and that IV supplementation is a more effective treatment. Until now, use of available parenteral iron preparations has been limited by dosing schedules and the need, in some cases, for a test dose, and despite the availability of a range of different IV iron compounds, there is still a need for improved compounds. The new IV iron, iron isomaltoside 1000 Monofer®, is composed of iron and chemically modified isomalto-oligosaccharides which have a mean molecular weight of 1000 Da and consist predominantly of 3-5 glucose units. In contrast to dextrans, the carbohydrate isomaltoside 1000 is a linear and unbranched structure with theoretically a low immunological potential. Hence, a test dose is not necessary. Iron isomaltoside 1000 contains strongly bound iron within the iron-isomaltoside formulation, which enables a controlled slow release of bioavailable iron to the iron-binding proteins, with potentially a reduced risk of free iron toxicity. This allows flexible dosing including high and rapid dosing securing convenient iron therapy for a wide range of patients. The development of Monofer® has been enthusiastically acknowledged by clinicians, and in 2009, there has been fast approval by European authorities via a decentralized registration procedure. This new IV iron is currently being marketed in several European countries. This article describes the development rationale and summarizes the clinical data assessing the use of iron isomaltoside 1000 administered without a test dose by either repeated bolus injections or fast high single iron infusions [defined as total dose infusion (TDI)] to patients suffering from CKD. Since CKD is associated with a high prevalence of cardiovascular disease, data from a small trial applying high single doses of iron isomatoside 1000 in patients with chronic heart failure (CHF) are also reviewed. Collectively, the available data demonstrate adequate efficacy and a good safety profile of iron isomaltoside 1000 in CKD and CHF patients even when administered without a test dose and as single rapid high-dose infusions.

Time to Analgesia Onset and Pharmacokinetics After Separate and Combined Administration of Liposome Bupivacaine and Bupivacaine HCl: Considerations for Clinicians

PubMed Central

Gadsden, Jeffrey; Long, William J.

2016-01-01

Background: Liposome bupivacaine is a prolonged-release bupivacaine formulation indicated for single-dose administration into the surgical site to produce postsurgical analgesia. Methods: An overview of time to onset of analgesia observed with liposome bupivacaine in human studies is provided, as well as a summary of data from pharmacokinetic studies including those that assessed pharmacokinetics after separate versus coadministration of liposome bupivacaine and bupivacaine HCl. Results: Data from multiple studies show that local administration of liposome bupivacaine is associated with rapid onset and effective analgesia after surgery. However, the efficacy profile observed in controlled settings may not replicate the profile observed in clinical practice; time to onset may be impacted by nonpharmacologic factors, such as amount of drug given, location and relative vascularity, and variances in surgical techniques. Some clinicians coadminister or admix bupivacaine HCl and liposome bupivacaine based on the supposition that adjuvant use will result in more rapid onset of efficacy. To date, no clinical studies have been conducted comparing pain-related outcomes following coadministration versus liposome bupivacaine alone. Preclinical pharmacokinetic studies have assessed the potential impact of combined use, which resulted in predictable, additive systemic exposure without compromising the prolonged-release profile of liposome bupivacaine, and without signs of toxicity. Conclusion: Based on available data and approved package insert, in the setting of wound infiltration, clinicians have the flexibility to administer liposome bupivacaine alone, coadminister separately with bupivacaine HCl, or admix with bupivacaine HCl prior to injection, providing the bupivacaine HCl dose does not exceed 50% of the liposome bupivacaine dose. PMID:27347237

An Approach to Mitigate Particle Formation on the Dilution of a Monoclonal Antibody Drug Product in an IV Administration Fluid.

PubMed

Zheng, Songyan; Adams, Monica; Mantri, Rao V

2016-03-01

To support dose reduction, low dose of a monoclonal antibody (mAb) was required to be administered via IV infusion at a concentration of 0.1 mg/mL. To achieve the target protein concentration, the infusion solution was prepared by diluting the drug product containing 10-mg/mL mAb with normal saline, a 0.9% sodium chloride injection solution. However, particles were observed in the diluted solution. Particle formation must be avoided to administer the low dose using the existing drug product. To mitigate the particle formation, an unconventional compounding approach was used. With this approach, a stabilizing vehicle containing polysorbate-80 was added to saline before drug-product dilution to maintain suitable surfactant level to prevent precipitation of the mAb. In this way, use of the stabilizing vehicle to support low doses ensured suitable quality across a wider range of mAb concentrations, thereby allowing additional flexibility to the clinical trial. Such an approach may be useful for broader application in early-stage clinical trials where there is an uncertainty regarding doses or the need to revise to lower doses based on clinical observations or other drivers. Copyright © 2016. Published by Elsevier Inc.

Design and construction of shoulder recesses into the beam aperture shields for improved patient positioning at the FiR 1 BNCT facility.

PubMed

Auterinen, I; Kotiluoto, P; Hippeläinen, E; Kortesniemi, M; Seppälä, T; Serén, T; Mannila, V; Pöyry, P; Kankaanranta, L; Collan, J; Kouri, M; Joensuu, H; Savolainen, S

2004-11-01

Improvements have been made at the FiR 1 BNCT facility to ease the positioning of the patient with a tumor in the head and neck region into a lateral neutron beam. Shoulder recesses were constructed horizontally on both sides of the beam aperture. When shoulder recesses are not needed, they are filled with neutron attenuating filling blocks. MCNP simulations using an anthropomorphic human model BOMAB phantom showed that the main contribution to the increase in the effective dose to the patient's body due to the shoulder recesses was from the neutron dose of the arm. In a position when one arm is inside the shoulder recess, the maximal effective dose of the patient was estimated to be 0.7Sv/h. Dose measurements using the twin ionization chamber technique showed that the neutron dose increased on the sides as predicted by the MCNP model but there was no noticeable change in the gamma doses. When making the recesses into the lithium containing neutron shield material tritium contamination was confined using an underpressurized glove box and machine tools with local exhaust. The shoulder recesses give space for more flexible patient positioning and can be considered as a significant improvement of the Finnish BNCT facility.

Dose-volume histogram prediction using density estimation.

PubMed

Skarpman Munter, Johanna; Sjölund, Jens

2015-09-07

Knowledge of what dose-volume histograms can be expected for a previously unseen patient could increase consistency and quality in radiotherapy treatment planning. We propose a machine learning method that uses previous treatment plans to predict such dose-volume histograms. The key to the approach is the framing of dose-volume histograms in a probabilistic setting.The training consists of estimating, from the patients in the training set, the joint probability distribution of some predictive features and the dose. The joint distribution immediately provides an estimate of the conditional probability of the dose given the values of the predictive features. The prediction consists of estimating, from the new patient, the distribution of the predictive features and marginalizing the conditional probability from the training over this. Integrating the resulting probability distribution for the dose yields an estimate of the dose-volume histogram.To illustrate how the proposed method relates to previously proposed methods, we use the signed distance to the target boundary as a single predictive feature. As a proof-of-concept, we predicted dose-volume histograms for the brainstems of 22 acoustic schwannoma patients treated with stereotactic radiosurgery, and for the lungs of 9 lung cancer patients treated with stereotactic body radiation therapy. Comparing with two previous attempts at dose-volume histogram prediction we find that, given the same input data, the predictions are similar.In summary, we propose a method for dose-volume histogram prediction that exploits the intrinsic probabilistic properties of dose-volume histograms. We argue that the proposed method makes up for some deficiencies in previously proposed methods, thereby potentially increasing ease of use, flexibility and ability to perform well with small amounts of training data.

Investigation of Radiation and Chemical Resistance of Flexible HLW Transfer Hose

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

E. Skidmore; Billings, K.; Hubbard, M.

A chemical transfer hose constructed of an EPDM (ethylene-propylene diene monomer) outer covering with a modified cross-linked polyethylene (XLPE) lining was evaluated for use in high level radioactive waste transfer applications. Laboratory analysis involved characterization of the hose liner after irradiation to doses of 50 to 300 Mrad and subsequent exposure to 25% NaOH solution at 93 C for 30 days, simulating 6 months intermittent service. The XLPE liner mechanical and structural properties were characterized at varying dose levels. Burst testing of irradiated hose assemblies was also performed. Literature review and test results suggest that radiation effects below doses ofmore » 100 kGy are minimal, with acceptable property changes to 500 kGy. Higher doses may be feasible. At a bounding dose of 2.5 MGy, the burst pressure is reduced to the working pressure (1.38 MPa) at room temperature. Radiation exposure slightly reduces liner tensile strength, with more significant decrease in liner elongation. Subsequent exposure to caustic solutions at elevated temperature slightly increases elongation, suggesting an immersion/hydrolytic effect or possible thermal annealing of radiation damage. This paper summarizes the laboratory results and recommendations for field deployment.« less

A dose assessment method for arbitrary geometries with virtual reality in the nuclear facilities decommissioning

NASA Astrophysics Data System (ADS)

Chao, Nan; Liu, Yong-kuo; Xia, Hong; Ayodeji, Abiodun; Bai, Lu

2018-03-01

During the decommissioning of nuclear facilities, a large number of cutting and demolition activities are performed, which results in a frequent change in the structure and produce many irregular objects. In order to assess dose rates during the cutting and demolition process, a flexible dose assessment method for arbitrary geometries and radiation sources was proposed based on virtual reality technology and Point-Kernel method. The initial geometry is designed with the three-dimensional computer-aided design tools. An approximate model is built automatically in the process of geometric modeling via three procedures namely: space division, rough modeling of the body and fine modeling of the surface, all in combination with collision detection of virtual reality technology. Then point kernels are generated by sampling within the approximate model, and when the material and radiometric attributes are inputted, dose rates can be calculated with the Point-Kernel method. To account for radiation scattering effects, buildup factors are calculated with the Geometric-Progression formula in the fitting function. The effectiveness and accuracy of the proposed method was verified by means of simulations using different geometries and the dose rate results were compared with that derived from CIDEC code, MCNP code and experimental measurements.

Development of a portable graphite calorimeter for radiation dosimetry.

PubMed

Sakama, Makoto; Kanai, Tatsuaki; Fukumura, Akifumi

2008-01-01

We developed and performance-tested a portable graphite calorimeter designed to measure the absolute dosimetry of various beams including heavy-ion beams, based on a flexible and convenient means of measurement. This measurement system is fully remote-controlled by the GPIB system. This system uses a digital PID (Proportional, Integral, Derivative) control method based on the LabVIEW software. It was possible to attain stable conditions in a shorter time by this system. The standard deviation of the measurements using the calorimeter was 0.79% at a dose rate of 0.8 Gy/min in 17 calorimeter runs for a (60)Co photon beam. The overall uncertainties for the absorbed dose to graphite and water of the (60)Co photon beam using the developed calorimeter were 0.89% and 1.35%, respectively. Estimations of the correction factors due to vacuum gaps, impurities in the core, the dose gradient and the radiation profile were included in the uncertainties. The absorbed doses to graphite and water irradiated by the (60)Co photon beam were compared with dosimetry measurements obtained using three ionization chambers. The absorbed doses to graphite and water estimated by the two dosimetry methods agreed within 0.1% and 0.3%, respectively.

Flexible Molybdenum Electrodes towards Designing Affinity Based Protein Biosensors

PubMed Central

Kamakoti, Vikramshankar; Panneer Selvam, Anjan; Radha Shanmugam, Nandhinee; Muthukumar, Sriram; Prasad, Shalini

2016-01-01

Molybdenum electrode based flexible biosensor on porous polyamide substrates has been fabricated and tested for its functionality as a protein affinity based biosensor. The biosensor performance was evaluated using a key cardiac biomarker; cardiac Troponin-I (cTnI). Molybdenum is a transition metal and demonstrates electrochemical behavior upon interaction with an electrolyte. We have leveraged this property of molybdenum for designing an affinity based biosensor using electrochemical impedance spectroscopy. We have evaluated the feasibility of detection of cTnI in phosphate-buffered saline (PBS) and human serum (HS) by measuring impedance changes over a frequency window from 100 mHz to 1 MHz. Increasing changes to the measured impedance was correlated to the increased dose of cTnI molecules binding to the cTnI antibody functionalized molybdenum surface. We achieved cTnI detection limit of 10 pg/mL in PBS and 1 ng/mL in HS medium. The use of flexible substrates for designing the biosensor demonstrates promise for integration with a large-scale batch manufacturing process. PMID:27438863

Maternal Opioid Treatment: Human Experimental Research (MOTHER) – Approach, Issues, and Lessons Learned

PubMed Central

Jones, Hendrée E.; Fischer, Gabriele; Heil, Sarah H.; Kaltenbach, Karol; Martin, Peter R.; Coyle, Mara G.; Selby, Peter; Stine, Susan M.; O’Grady, Kevin E.; Arria, Amelia M.

2015-01-01

Aims The Maternal Opioid Treatment: Human Experimental Research (MOTHER) project, an eight-site randomized, double-blind, double-dummy, flexible-dosing, parallel-group clinical trial is described. This study is the most current – and single most comprehensive – research effort to investigate the safety and efficacy of maternal and prenatal exposure to methadone and buprenorphine. Methods The MOTHER study design is outlined, and its basic features are presented. Conclusions At least seven important lessons have been learned from the MOTHER study: (1) an interdisciplinary focus improves the design and methods of a randomized clinical trial; (2) multiple sites in a clinical trial present continuing challenges to the investigative team due to variations in recruitment goals, patient populations, and hospital practices that in turn differentially impact recruitment rates, treatment compliance, and attrition; (3) study design and protocols must be flexible in order to meet the unforeseen demands of both research and clinical management; (4) staff turnover needs to be addressed with a proactive focus on both hiring and training; (5) the implementation of a protocol for the treatment of a particular disorder may identify important ancillary clinical issues worthy of investigation; (6) timely tracking of data in a multi-site trial is both demanding and unforgiving; and, (7) complex multi-site trials pose unanticipated challenges that complicate the choice of statistical methods, thereby placing added demands on investigators to effectively communicate their results. PMID:23106924

Design and implementation of a programming circuit in radiation-hardened FPGA

NASA Astrophysics Data System (ADS)

Lihua, Wu; Xiaowei, Han; Yan, Zhao; Zhongli, Liu; Fang, Yu; Chen, Stanley L.

2011-08-01

We present a novel programming circuit used in our radiation-hardened field programmable gate array (FPGA) chip. This circuit provides the ability to write user-defined configuration data into an FPGA and then read it back. The proposed circuit adopts the direct-access programming point scheme instead of the typical long token shift register chain. It not only saves area but also provides more flexible configuration operations. By configuring the proposed partial configuration control register, our smallest configuration section can be conveniently configured as a single data and a flexible partial configuration can be easily implemented. The hierarchical simulation scheme, optimization of the critical path and the elaborate layout plan make this circuit work well. Also, the radiation hardened by design programming point is introduced. This circuit has been implemented in a static random access memory (SRAM)-based FPGA fabricated by a 0.5 μm partial-depletion silicon-on-insulator CMOS process. The function test results of the fabricated chip indicate that this programming circuit successfully realizes the desired functions in the configuration and read-back. Moreover, the radiation test results indicate that the programming circuit has total dose tolerance of 1 × 105 rad(Si), dose rate survivability of 1.5 × 1011 rad(Si)/s and neutron fluence immunity of 1 × 1014 n/cm2.

Arsenic in Drinking Water and Mortality for Cancer and Chronic Diseases in Central Italy, 1990-2010

PubMed Central

D’Ippoliti, Daniela; Santelli, Enrica; De Sario, Manuela; Scortichini, Matteo; Davoli, Marina; Michelozzi, Paola

2015-01-01

Background In several volcanic areas of Italy, arsenic levels exceed European regulatory limits (10 μg/L in drinking water). There is still uncertainty about health risks from arsenic at low-medium doses (<100 μg/L). Objectives A large population-based study using an administrative cohort of residents in the Viterbo province (Central Italy), chronically exposed to low-medium arsenic levels via drinking water, was investigated to evaluate the effects of a lifetime exposure to arsenic on mortality from cancers and chronic diseases. Methods The study population consisted of 165,609 residents of 17 municipalities, followed from 1990 until 2010. Average individual arsenic exposure at the first residence (AsI) was estimated through a space-time modeling approach using residential history and arsenic concentrations from water supply. A time-dependent Cumulative Arsenic dose Indicator (CAI) was calculated, accounting for daily water intake and exposure duration. Mortality Hazard Ratios (HR) were estimated by gender for different diseases using Cox proportional models, adjusting for individual and area-level confounders. A flexible non-parametric approach was used to investigate dose-response relationships. Results Mean AsI exposure was 19.3 μg/L, and average exposure duration was 39.5 years. Associations of AsI and CAI indicators with several diseases were found, with greatest risks found for lung cancer in both sexes (HR = 2.61 males; HR = 2.09 females), myocardial infarction, peripheral arterial disease and COPD in males (HR = 2.94; HR = 2.44; HR = 2.54 respectively) and diabetes in females (HR = 2.56). For lung cancer and cardiovascular diseases dose-response relationship is modelled by piecewise linear functions revealing effects even for doses lower than 10 μg/L, and no threshold dose value was identified as safe for health. Conclusions Results provide new evidence for risk assessment of low-medium concentrations of arsenic and contribute to the ongoing debate about the threshold-dose of effect, suggesting that even concentrations below 10 μg/L carry a mortality risk. Policy actions are urgently needed in areas exposed to arsenic like in the Viterbo province, to comply with current EU regulations. PMID:26383851

Randomized, placebo‐controlled trial of incobotulinumtoxina for upper‐limb post‐stroke spasticity

PubMed Central

Munin, Michael C.; Kaňovský, Petr; Hanschmann, Angelika; Hiersemenzel, Reinhard; Marciniak, Christina

2015-01-01

ABSTRACT Introduction: Efficacy and safety of incobotulinumtoxinA in post‐stroke upper‐limb spasticity were studied. Methods: Subjects randomized 2:1 to incobotulinumtoxinA (fixed dose 400 U) or placebo, with fixed doses for the primary target clinical pattern (PTCP; flexed elbow, 200 U; flexed wrist, 150 U; clenched fist, 100 U). Doses for non‐primary patterns were flexible within predefined ranges. Results: At week 4, incobotulinumtoxinA led to larger improvements in PTCP Ashworth scale (AS) scores than placebo [least‐squares mean change ± standard error: –0.9 ± 0.06 (n = 171) vs. –0.5 ± 0.08 (n = 88); P < 0.001], and more subjects were PTCP AS responders (≥1‐point improvement) with incobotulinumtoxinA (69.6%) than with placebo (37.5%; P < 0.001). Investigator's Global Impression of Change confirmed superiority of incobotulinumtoxinA vs. placebo (P = 0.003). IncobotulinumtoxinA was associated with functional improvements, as demonstrated in responder rates for Disability Assessment Scale principal target at week 4 (P = 0.007). Adverse events were mainly mild/moderate, and were reported by 22.4% (incobotulinumtoxinA) and 16.8% (placebo) of subjects. Conclusions: IncobotulinumtoxinA significantly improved upper‐limb spasticity and associated disability, and was well‐tolerated. Muscle Nerve 53: 415–421, 2016 PMID:26201835

Adapting to the global shortage of cholera vaccines: targeted single dose cholera vaccine in response to an outbreak in South Sudan.

PubMed

Parker, Lucy A; Rumunu, John; Jamet, Christine; Kenyi, Yona; Lino, Richard Laku; Wamala, Joseph F; Mpairwe, Allan M; Ciglenecki, Iza; Luquero, Francisco J; Azman, Andrew S; Cabrol, Jean-Clement

2017-04-01

Shortages of vaccines for epidemic diseases, such as cholera, meningitis, and yellow fever, have become common over the past decade, hampering efforts to control outbreaks through mass reactive vaccination campaigns. Additionally, various epidemiological, political, and logistical challenges, which are poorly documented in the literature, often lead to delays in reactive campaigns, ultimately reducing the effect of vaccination. In June 2015, a cholera outbreak occurred in Juba, South Sudan, and because of the global shortage of oral cholera vaccine, authorities were unable to secure sufficient doses to vaccinate the entire at-risk population-approximately 1 million people. In this Personal View, we document the first public health use of a reduced, single-dose regimen of oral cholera vaccine, and show the details of the decision-making process and timeline. We also make recommendations to help improve reactive vaccination campaigns against cholera, and discuss the importance of new and flexible context-specific dose regimens and vaccination strategies. Copyright © 2017 Elsevier Ltd. All rights reserved.

Dosimetric equivalence of nonstandard HDR brachytherapy catheter patterns

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

Cunha, J. A. M.; Hsu, I-C.; Pouliot, J.

2009-01-15

Purpose: To determine whether alternative high dose rate prostate brachytherapy catheter patterns can result in similar or improved dose distributions while providing better access and reducing trauma. Materials and Methods: Standard prostate cancer high dose rate brachytherapy uses a regular grid of parallel needle positions to guide the catheter insertion. This geometry does not easily allow the physician to avoid piercing the critical structures near the penile bulb nor does it provide position flexibility in the case of pubic arch interference. This study used CT datasets with 3 mm slice spacing from ten previously treated patients and digitized new cathetersmore » following three hypothetical catheter patterns: conical, bi-conical, and fireworks. The conical patterns were used to accommodate a robotic delivery using a single entry point. The bi-conical and fireworks patterns were specifically designed to avoid the critical structures near the penile bulb. For each catheter distribution, a plan was optimized with the inverse planning algorithm, IPSA, and compared with the plan used for treatment. Irrelevant of catheter geometry, a plan must fulfill the RTOG-0321 dose criteria for target dose coverage (V{sub 100}{sup Prostate}>90%) and organ-at-risk dose sparing (V{sub 75}{sup Bladder}<1 cc, V{sub 75}{sup Rectum}<1 cc, V{sub 125}{sup Urethra}<<1 cc). Results: The three nonstandard catheter patterns used 16 nonparallel, straight divergent catheters, with entry points in the perineum. Thirty plans from ten patients with prostate sizes ranging from 26 to 89 cc were optimized. All nonstandard patterns fulfilled the RTOG criteria when the clinical plan did. In some cases, the dose distribution was improved by better sparing the organs-at-risk. Conclusion: Alternative catheter patterns can provide the physician with additional ways to treat patients previously considered unsuited for brachytherapy treatment (pubic arch interference) and facilitate robotic guidance of catheter insertion. In addition, alternative catheter patterns may decrease toxicity by avoidance of the critical structures near the penile bulb while still fulfilling the RTOG criteria.« less

A new model for volume recombination in plane-parallel chambers in pulsed fields of high dose-per-pulse

NASA Astrophysics Data System (ADS)

Gotz, M.; Karsch, L.; Pawelke, J.

2017-11-01

In order to describe the volume recombination in a pulsed radiation field of high dose-per-pulse this study presents a numerical solution of a 1D transport model of the liberated charges in a plane-parallel ionization chamber. In addition, measurements were performed on an Advanced Markus ionization chamber in a pulsed electron beam to obtain suitable data to test the calculation. The experiment used radiation pulses of 4 μs duration and variable dose-per-pulse values up to about 1 Gy, as well as pulses of variable duration up to 308 μs at constant dose-per-pulse values between 85 mGy and 400 mGy. Those experimental data were compared to the developed numerical model and existing descriptions of volume recombination. At low collection voltages the observed dose-per-pulse dependence of volume recombination can be approximated by the existing theory using effective parameters. However, at high collection voltages large discrepancies are observed. The developed numerical model shows much better agreement with the observations and is able to replicate the observed behavior over the entire range of dose-per-pulse values and collection voltages. Using the developed numerical model, the differences between observation and existing theory are shown to be the result of a large fraction of the charge being collected as free electrons and the resultant distortion of the electric field inside the chamber. Furthermore, the numerical solution is able to calculate recombination losses for arbitrary pulse durations in good agreement with the experimental data, an aspect not covered by current theory. Overall, the presented numerical solution of the charge transport model should provide a more flexible tool to describe volume recombination for high dose-per-pulse values as well as for arbitrary pulse durations and repetition rates.

Next-Step Strategies for Panic Disorder Refractory to Initial Pharmacotherapy

PubMed Central

Simon, NM; Otto, MW; Worthington, JJ; Hoge, EA; Thompson, EH; LeBeau, RT; Moshier, SJ; Zalta, AK; Pollack, MH

2010-01-01

Background More data is needed to guide next step interventions for panic disorder refractory to initial intervention. Method This 24-week randomized clinical trial (RCT) consisted of three phases. Phase 1 is a 6-week lead-in with open-label sertraline flexibly dosed to 100mg (or escitalopram equivalent) to prospectively define treatment refractoriness (lack of remission). Phase 2 is a six-week double blind RCT of (1) increased dose serotonin selective reuptake inhibitor (SSRI) versus (2) continued SSRI plus placebo. Phase 3 is a 12-week RCT of added cognitive-behavioral therapy (CBT) compared to “medication-optimization” (MO) with SSRI plus clonazepam. Primary endpoints were remission and change in Panic Disorder Severity Scale (PDSS) score in the intent to treat sample in each phase. Results In Phase 1, 20.5% (8/39) achieved remission, and only baseline severity predicted endpoint PDSS (β (SE)= 1.04(0.15), t=6.76, p<0.000). In Phase 2, increasing the SSRI dose did not result in greater improvement or remission rates (placebo 15% [n=2] vs. increased dose 9%[n=1]: FET p=n.s.). In Phase 3, remission was minimal (MO = 11%; CBT =10%), with a lack of group difference in PDSS reduction (t(df)=0.51(17), p>0.60) consistent with a small effect size (d=0.24). Conclusion Although power was limited and larger studies are needed, we failed to find evidence for greater benefit of increased SSRI dose versus continuation of current dose for panic disorder symptomatic after 6 weeks at moderate dose. Further, augmentation with CBT or medication optimization with clonazepam augmentation in non-remitted panic after 12 weeks of an SSRI did not differ, suggesting both are reasonable next-step options. However, low overall remission rates in this comorbid refractory population suggest better predictors of response to specific treatments over time and additional interventions are needed. PMID:19814948

Dynamic gamma knife radiosurgery

NASA Astrophysics Data System (ADS)

Luan, Shuang; Swanson, Nathan; Chen, Zhe; Ma, Lijun

2009-03-01

Gamma knife has been the treatment of choice for various brain tumors and functional disorders. Current gamma knife radiosurgery is planned in a 'ball-packing' approach and delivered in a 'step-and-shoot' manner, i.e. it aims to 'pack' the different sized spherical high-dose volumes (called 'shots') into a tumor volume. We have developed a dynamic scheme for gamma knife radiosurgery based on the concept of 'dose-painting' to take advantage of the new robotic patient positioning system on the latest Gamma Knife C™ and Perfexion™ units. In our scheme, the spherical high dose volume created by the gamma knife unit will be viewed as a 3D spherical 'paintbrush', and treatment planning reduces to finding the best route of this 'paintbrush' to 'paint' a 3D tumor volume. Under our dose-painting concept, gamma knife radiosurgery becomes dynamic, where the patient moves continuously under the robotic positioning system. We have implemented a fully automatic dynamic gamma knife radiosurgery treatment planning system, where the inverse planning problem is solved as a traveling salesman problem combined with constrained least-square optimizations. We have also carried out experimental studies of dynamic gamma knife radiosurgery and showed the following. (1) Dynamic gamma knife radiosurgery is ideally suited for fully automatic inverse planning, where high quality radiosurgery plans can be obtained in minutes of computation. (2) Dynamic radiosurgery plans are more conformal than step-and-shoot plans and can maintain a steep dose gradient (around 13% per mm) between the target tumor volume and the surrounding critical structures. (3) It is possible to prescribe multiple isodose lines with dynamic gamma knife radiosurgery, so that the treatment can cover the periphery of the target volume while escalating the dose for high tumor burden regions. (4) With dynamic gamma knife radiosurgery, one can obtain a family of plans representing a tradeoff between the delivery time and the dose distributions, thus giving the clinician one more dimension of flexibility of choosing a plan based on the clinical situations.

A new model for volume recombination in plane-parallel chambers in pulsed fields of high dose-per-pulse.

PubMed

Gotz, M; Karsch, L; Pawelke, J

2017-11-01

In order to describe the volume recombination in a pulsed radiation field of high dose-per-pulse this study presents a numerical solution of a 1D transport model of the liberated charges in a plane-parallel ionization chamber. In addition, measurements were performed on an Advanced Markus ionization chamber in a pulsed electron beam to obtain suitable data to test the calculation. The experiment used radiation pulses of 4 μs duration and variable dose-per-pulse values up to about 1 Gy, as well as pulses of variable duration up to 308 [Formula: see text] at constant dose-per-pulse values between 85 mGy and 400 mGy. Those experimental data were compared to the developed numerical model and existing descriptions of volume recombination. At low collection voltages the observed dose-per-pulse dependence of volume recombination can be approximated by the existing theory using effective parameters. However, at high collection voltages large discrepancies are observed. The developed numerical model shows much better agreement with the observations and is able to replicate the observed behavior over the entire range of dose-per-pulse values and collection voltages. Using the developed numerical model, the differences between observation and existing theory are shown to be the result of a large fraction of the charge being collected as free electrons and the resultant distortion of the electric field inside the chamber. Furthermore, the numerical solution is able to calculate recombination losses for arbitrary pulse durations in good agreement with the experimental data, an aspect not covered by current theory. Overall, the presented numerical solution of the charge transport model should provide a more flexible tool to describe volume recombination for high dose-per-pulse values as well as for arbitrary pulse durations and repetition rates.

Impaired reward learning and intact motivation after serotonin depletion in rats.

PubMed

Izquierdo, Alicia; Carlos, Kathleen; Ostrander, Serena; Rodriguez, Danilo; McCall-Craddolph, Aaron; Yagnik, Gargey; Zhou, Feimeng

2012-08-01

Aside from the well-known influence of serotonin (5-hydroxytryptamine, 5-HT) on emotional regulation, more recent investigations have revealed the importance of this monoamine in modulating cognition. Parachlorophenylalanine (PCPA) depletes 5-HT by inhibiting tryptophan hydroxylase, the enzyme required for 5-HT synthesis and, if administered at sufficiently high doses, can result in a depletion of at least 90% of the brain's 5-HT levels. The present study assessed the long-lasting effects of widespread 5-HT depletions on two tasks of cognitive flexibility in Long Evans rats: effort discounting and reversal learning. We assessed performance on these tasks after administration of either 250 or 500 mg/kg PCPA or saline (SAL) on two consecutive days. Consistent with a previous report investigating the role of 5-HT on effort discounting, pretreatment with either dose of PCPA resulted in normal effortful choice: All rats continued to climb tall barriers to obtain large rewards and were not work-averse. Additionally, rats receiving the lower dose of PCPA displayed normal reversal learning. However, despite intact motivation to work for food rewards, rats receiving the largest dose of PCPA were unexpectedly impaired relative to SAL rats on the pretraining stages leading up to reversal learning, ultimately failing to approach and respond to the stimuli associated with reward. High performance liquid chromatography (HPLC) with electrochemical detection confirmed 5-HT, and not dopamine, levels in the ventromedial frontal cortex were correlated with this measure of associative reward learning. Copyright © 2012 Elsevier B.V. All rights reserved.

Dose-Related Effects of Alcohol on Cognitive Functioning

PubMed Central

Dry, Matthew J.; Burns, Nicholas R.; Nettelbeck, Ted; Farquharson, Aaron L.; White, Jason M.

2012-01-01

We assessed the suitability of six applied tests of cognitive functioning to provide a single marker for dose-related alcohol intoxication. Numerous studies have demonstrated that alcohol has a deleterious effect on specific areas of cognitive processing but few have compared the effects of alcohol across a wide range of different cognitive processes. Adult participants (N = 56, 32 males, 24 females aged 18–45 years) were randomized to control or alcohol treatments within a mixed design experiment involving multiple-dosages at approximately one hour intervals (attained mean blood alcohol concentrations (BACs) of 0.00, 0.048, 0.082 and 0.10%), employing a battery of six psychometric tests; the Useful Field of View test (UFOV; processing speed together with directed attention); the Self-Ordered Pointing Task (SOPT; working memory); Inspection Time (IT; speed of processing independent from motor responding); the Traveling Salesperson Problem (TSP; strategic optimization); the Sustained Attention to Response Task (SART; vigilance, response inhibition and psychomotor function); and the Trail-Making Test (TMT; cognitive flexibility and psychomotor function). Results demonstrated that impairment is not uniform across different domains of cognitive processing and that both the size of the alcohol effect and the magnitude of effect change across different dose levels are quantitatively different for different cognitive processes. Only IT met the criteria for a marker for wide-spread application: reliable dose-related decline in a basic process as a function of rising BAC level and easy to use non-invasive task properties. PMID:23209840

Effect of dietary protein on post-prandial glucose in patients with type 1 diabetes.

PubMed

Borie-Swinburne, C; Sola-Gazagnes, A; Gonfroy-Leymarie, C; Boillot, J; Boitard, C; Larger, E

2013-12-01

In flexible insulin therapy, determination of the prandial insulin dose only takes into account the carbohydrate content of the evening meal, and not the protein content. Protein can, however, contribute to gluconeogenesis. We compared the glycaemic effect of a standard evening meal with that of a test evening meal enriched in protein. The present study was conducted in 28 C-peptide negative patients with type 1 diabetes. Two evening meals that were similar in content, except that one was enriched by the addition of 300 g of 0%-fat fromage frais, were taken on two consecutive days. Insulin doses were maintained exactly the same before both evening meals. Patients were monitored with a continuous glucose-monitoring device. Patients ate similar quantities at both evening meals, except for protein (21.5 g more at the test evening meal). The preprandial insulin dose was 0.96 (0.4) U per 10 g carbohydrates. After correction for differences of interstitial glucose at the start of the evening meals, both interstitial and capillary glucose levels were similar after both evening meals, except for the late-post-prandial interstitial glucose level. We found no effect of dietary protein on post-prandial-, overnight- or late-night glucose levels in patients with type 1 diabetes. This confirms that dietary proteins need not be included in the calculation of prandial insulin dose. © 2013 The Authors Journal of Human Nutrition and Dietetics © 2013 The British Dietetic Association Ltd.

Efficacy and Safety of Mesalamine Suppositories for Treatment of Ulcerative Proctitis in Children and Adolescents

PubMed Central

Heyman, Melvin B.; Kierkus, Jaroslaw; Spénard, Jean; Shbaklo, Hadia; Giguere, Monique

2011-01-01

Background Treatment of ulcerative proctitis has not been well studied in pediatric populations. We conducted an open-label trial to evaluate the clinical efficacy of a mesalamine suppository (500 mg) to treat pediatric patients with mild to moderate ulcerative proctitis. Methods Pediatric patients (5–17 years of age) with ulcerative proctitis were enrolled for baseline evaluations, including a flexible sigmoidoscopic (or colonoscopic) assessment with biopsies performed at study entry. Eligible patients were started on mesalamine suppositories (500 mg) at bedtime. Two follow-up visits were scheduled after 3 and 6 weeks of treatment. The dose could be increased to 500 mg twice daily at the week 3 follow-up visit if deemed appropriate by the investigator based on the Disease Activity Index (DAI) assessment. The primary outcome measure was a DAI derived from a composite score of stool frequency, urgency of defecation, rectal bleeding, and general well-being. Results Forty-nine patients were included in the intent-to-treat analysis. The mean DAI value decreased from 5.5 at baseline to 1.6 and 1.5 at weeks 3 and 6, respectively (P < 0.0001). Only 4 patients had their dose increased to 500 mg twice daily at week 3. Forty-one patients experienced at least one adverse event, most of which were deemed mild and unrelated to study therapy. The most common treatment-emergent adverse events were gastrointestinal (n = 30, 61.2%). Conclusions This study showed that a daily bedtime dose of a 500 mg mesalamine suppository is safe and efficacious in children with ulcerative proctitis. PMID:20848454

Turning Potential Flexibility Into Flexible Performance: Moderating Effect of Self-Efficacy and Use of Flexible Cognition

PubMed Central

Liu, Ru-De; Wang, Jia; Star, Jon R.; Zhen, Rui; Jiang, Rong-Huan; Fu, Xin-Chen

2018-01-01

This study examined the relationship between two types of mathematical flexibility – potential flexibility, which indicates individuals’ knowledge of multiple strategies and strategy efficiency, and practical flexibility, which refers to individuals’ flexible performances when solving math problems. Both types of flexibility were assessed in the domain of linear equation solving. Furthermore, two types of beliefs – self-efficacy and use of flexible cognition (UFC) – were investigated as potential moderators between potential and practical flexibility. 121 8th grade students from China took part in this study. Results indicate that potential flexibility positively predicted practical flexibility. Additionally, self-efficacy and UFC might moderate the relationship between these two types of flexibility, suggesting that potential flexibility may lead to different degrees of practical flexibility depending on different levels of beliefs. Implications of these findings for research on mathematical flexibility and for educational practice are discussed. PMID:29780344

Estimating the Effects of Astronaut Career Ionizing Radiation Dose Limits on Manned Interplanetary Flight Programs

NASA Technical Reports Server (NTRS)

Koontz, Steven L.; Rojdev, Kristina; Valle, Gerard D.; Zipay, John J.; Atwell, William S.

2013-01-01

Space radiation effects mitigation has been identified as one of the highest priority technology development areas for human space flight in the NASA Strategic Space Technology Investment Plan (Dec. 2012). In this paper we review the special features of space radiation that lead to severe constraints on long-term (more than 180 days) human flight operations outside Earth's magnetosphere. We then quantify the impacts of human space radiation dose limits on spacecraft engineering design and development, flight program architecture, as well as flight program schedule and cost. A new Deep Space Habitat (DSH) concept, the hybrid inflatable habitat, is presented and shown to enable a flexible, affordable approach to long term manned interplanetary flight today.

Personalized Medicine in Pediatrics: The Clinical Potential of Orodispersible Films.

PubMed

Visser, J Carolina; Woerdenbag, Herman J; Hanff, Lidwien M; Frijlink, Henderik W

2017-02-01

Children frequently receive medicines that are designed for adults. The dose of commercially available products is adapted, mostly based on the child's bodyweight, thereby neglecting differences in pharmacokinetic and pharmacodynamics parameters. If commercial products are unsuitable for administration to children or are unavailable, extemporaneous pharmacy preparations are a good alternative. For this particular population, orodispersible films (ODFs) can be a highly attractive dosage form for the oral administration of drugs. ODFs are relatively easy to prepare in a hospital setting, create dose flexibility, and may suit an individual approach, especially for patients having difficulties in swallowing tablets or being fluid restricted. In this article, various aspects related to pharmacy preparations, clinical application, and preparation of ODFs for pediatric patients are highlighted and discussed.

TEN-YEAR FOLLOW UP OF A PHASE II STUDY OF DOSE-INTENSE PACLITAXEL WITH CISPLATIN AND CYCLOPHOSPHAMIDE AS INITIAL THERAPY FOR POOR-PROGNOSIS ADVANCED-STAGE EPITHELIAL OVARIAN CANCER

PubMed Central

Sarosy, Gisele A.; Hussain, Mahrukh M.; Seiden, Michael V.; Fuller, A.F.; Nikrui, N.; Goodman, Annekathryn; Minasian, Lori; Reed, Eddie; Steinberg, Seth M.; Kohn, Elise C.

2009-01-01

SUMMARY Background To assess activity and toxicity in newly diagnosed advanced stage epithelial ovarian cancer (EOC) patients receiving dose-intense paclitaxel, cyclophosphamide, cisplatin, and filgrastim delivered with a flexible dosing schedule. Methods Patients with Stage III/IV EOC received cyclophosphamide 750 mg/m2, followed by 24 hr infusion of paclitaxel 250 mg/m2, and cisplatin 75 mg/m2 on day 2. Filgrastim began on day 3 at 10 μg/kg/d × 9d. Patients received six cycles of all drugs. Those with pathologic complete response or microscopic residual disease at the conclusion of six cycles of therapy received an additional cycles two to four cycles of paclitaxel with cyclophosphamide. Patients with objective response continued cyclophosphamide and paclitaxel. Results 62 patients were enrolled. Thirty-two of these 62 patients had stage IIIC disease, and 26 of 62 had stage IV disease. Using an intent to treat analysis, 55 (89%) experienced clinical complete remission (CCR). With a median potential follow-up of 11.4 years, the median progression free survival is 18.9 months and median survival is 5.4 years. The most serious toxicity was grade 3/4 neutropenic fever (35%). Although all participants developed peripheral neuropathy, improvement in neuropathic symptoms began with decrease or cessation of paclitaxel. Conclusions This regimen yielded a high response rate and encouraging overall survival. These data and those of the Japanese Gynecologic Oncology Group suggest that further study of dose dense or intense paclitaxel regimens in women with newly diagnosed advanced stage EOC is warranted. PMID:20091841

Sublingual Buprenorphine/Naloxone for Chronic Pain in At-Risk Patients: Development and Pilot Test of a Clinical Protocol

PubMed Central

Rosenblum, Andrew; Cruciani, Ricardo A.; Strain, Eric C; Cleland, Charles M.; Joseph, Herman; Magura, Stephen; Marsch, Lisa A; McNicholas, Laura F; Savage, Seddon R; Sundaram, Arun; Portenoy, Russell K.

2013-01-01

Objective Sublingual buprenorphine/naloxone (Bup/Nx) is approved for addiction treatment and may be useful for pain management, particularly in opioid-treated pain patients with nonadherence behaviors. The transition of opioid-treated pain patients to buprenorphine carries the risk of precipitated withdrawal and increased pain. This study convened pain and addiction specialists to develop and pilot a clinical protocol for safe transitioning to Bup/Nx. Design The protocol was revised three times based on outside expert review and pilot study observations. The pilot was conducted with a prospective cohort of 12 patients with moderate to severe chronic pain, who were receiving long-term opioid therapy with any full μ-agonist drug, and had exhibited one or more aberrant drug-related behaviors. Patients were followed up for 3 to 6 months with the expectation that they would experience few adverse events and report lower pain severity. Results The three patients on the highest baseline opioid dose (equivalent to 303–450 mg of oral morphine) and the three on the lowest doses (≤20 mg) had early adverse events (AEs) when switched to Bup/Nx and did not complete the trial. Of the remaining six, one withdrew due to AEs; one responded well, then withdrew; and four completed a three-month trial. A mixed effects model controlling for dropouts found that average and worst pain significantly decreased after the switch to Bup/Nx (both p < .01). Conclusion Based on this experience, the protocol recommends Bup/Nx for pain only when baseline opioid doses are within bounds that reduce AEs at transition and incorporates dose flexibility to further reduce risks. This protocol warrants further testing. PMID:23264315

Role of guaifenesin in the management of chronic bronchitis and upper respiratory tract infections.

PubMed

Albrecht, Helmut H; Dicpinigaitis, Peter V; Guenin, Eric P

2017-01-01

Guaifenesin, a mucoactive drug, acts by loosening mucus in the airways and making coughs more productive. It is used for relief of wet cough and chest congestion due to the common cold, and remains the only legally marketed expectorant in the US (per OTC Monograph). An ingredient in numerous over-the-counter (OTC) cough/cold medications, guaifenesin has a secondary indication for use in stable chronic bronchitis (professional indication). Clinical pharmacology and patient studies support the clinical utility of guaifenesin in respiratory conditions where mucus hypersecretion is prevalent: acute upper respiratory tract infections (URTIs), stable chronic bronchitis, and possibly rhinosinusitis. Guaifenesin has a well-established and favorable safety and tolerability profile in adult and pediatric populations. Its dosing range (200-400 mg 4-hourly, up to 6× daily) allows flexible dose titration to allow an increase of plasma concentrations. Multiple daily doses are needed to maintain 24-h therapeutic effect with immediate-release formulations. Extended-release guaifenesin tablet formulations are available, providing convenience with 12-hourly dosing and portability compared to liquids. Guaifenesin is considered as a safe and effective expectorant for the treatment of mucus-related symptoms in acute URTIs and stable chronic bronchitis. Its clinical efficacy has been demonstrated most widely in chronic respiratory conditions, where excess mucus production and cough are more stable symptoms. Progress is being made to establish clinical models and measures that are more appropriate for studying symptomatic relief with guaifenesin in acute respiratory infections. This will help generate the up-to-date and high-quality data needed to optimize guaifenesin's effectiveness in established uses, and in new respiratory indications associated with mucus hypersecretion.

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

Fontainha, C.C.P.; Baptista Neto, A.T.; Santos, A.P.

Exposure to high radiation dose in medical diagnostic imaging procedures can lead patients to suffer tissue damaging. However, there are several studies that identify significant dose reduction with the use of radiation protective attenuators, minimizing the delivered dose in the region that covers the main beam, while preserving the diagnostic quality of the generated image. Most radiation attenuator materials are produced from shielding metal containing composites, whose efficiency is the goal of investigations around the world. In this context, polymeric materials were chosen for this investigation in order to provide light-weighted and flexible protective composites, a must in personal protectivemore » shielding. Therefore, this work is concerned to the investigation of poly(vinylidene fluoride - try-fluor-ethylene) [P(VDF-TrFE)] copolymers mixed with zirconia nanoparticles. The resulting polymer composites, prepared with 1, 2, 3, 5 and 10 at.% of ZrO{sub 2} nanoparticles, were investigated for application as protective shielding in some interventional radiology procedures. Two variety of composites were produced, one using pure ZrO{sub 2} nanoparticles and the other using sol-gel route with zirconium butoxide as the precursor for zirconium oxide nano-clusters. The P(VDFTrFE)/ ZrO2-MMA polymer composites produced by sol-gel route have provided a much better dispersion of the pure ZrO{sub 2} material into the P(VDF-TrFE) host matrix. UV-Vis and FTIR spectrometry and differential scanning calorimetry (DSC) were used to characterize the composite samples. FTIR data reveal a possible link between the MMA monomers with the P(VDF-TrFE) chain through shared C=O bonds. The radiation shielding characterization was conducted by using a 70 kV x-rays beam which is applicable, for instances, in catheter angiography. The results demonstrate that composites with 10% of ZrO{sub 2}, and only 1.0 mm thick, can attenuate 60% of the x-rays beam. The composite density was evaluated to be 2.20 g/cm{sup 3}. The results indicate that P(VDF-TrFE)/ZrO{sub 2}-MMA polymer composites have potential to be investigated as light-weighted and flexible protective shielding for application in some radiological procedures that uses low kilovoltage x-ray beams. (authors)« less

Optimization of the double dosimetry algorithm for interventional cardiologists

NASA Astrophysics Data System (ADS)

Chumak, Vadim; Morgun, Artem; Bakhanova, Elena; Voloskiy, Vitalii; Borodynchik, Elena

2014-11-01

A double dosimetry method is recommended in interventional cardiology (IC) to assess occupational exposure; yet currently there is no common and universal algorithm for effective dose estimation. In this work, flexible and adaptive algorithm building methodology was developed and some specific algorithm applicable for typical irradiation conditions of IC procedures was obtained. It was shown that the obtained algorithm agrees well with experimental measurements and is less conservative compared to other known algorithms.

Collaborative vaccine development: partnering pays.

PubMed

Ramachandra, Rangappa

2008-01-01

Vaccine development, supported by infusions of public and private venture capital, is re-entering a golden age as one of the fastest growing sectors in the life-sciences industry. Demand is driven by great unmet need in underdeveloped countries, increased resistance to current treatments, bioterrorism, and for prevention indications in travelers, pediatric, and adult diseases. Production systems are becoming less reliant on processes such as egg-based manufacturing, while new processes can help to optimize vaccines. Expeditious development hinges on efficient study conduct, which is greatly enhanced through research partnerships with specialized contract research organizations (CROs) that are licensed and knowledgeable in the intricacies of immunology and with the technologic and scientific foundation to support changing timelines and strategies inherent to vaccine development. The CRO often brings a more objective assessment for probability of success and may offer alternative development pathways. Vaccine developers are afforded more flexibility and are free to focus on innovation and internal core competencies. Functions readily outsourced to a competent partner include animal model development, safety and efficacy studies, immunotoxicity and immunogenicity, dose response studies, and stability and potency testing. These functions capitalize on the CRO partner's regulatory and scientific talent and expertise, and reduce infrastructure expenses for the vaccine developer. Successful partnerships result in development efficiencies, elimination or reduced redundancies, and improved time to market. Keys to success include honest communications, transparency, and flexibility.

Tolerability and efficacy of armodafinil in naïve patients with excessive sleepiness associated with obstructive sleep apnea, shift work disorder, or narcolepsy: a 12-month, open-label, flexible-dose study with an extension period.

PubMed

Schwartz, Jonathan R L; Khan, Arifulla; McCall, W Vaughn; Weintraub, James; Tiller, Jane

2010-10-15

This 12-month, open-label, flexible-dose study with an extension period evaluated the tolerability and efficacy of armodafinil in patients with excessive sleepiness associated with treated obstructive sleep apnea (OSA), shift work disorder (SWD), or narcolepsy. Armodafinil-naïve, adult patients with excessive sleepiness associated with treated OSA (n = 170), SWD (n = 108), or narcolepsy (n = 50) received armodafinil (100-250 mg) once daily (treated OSA or narcolepsy) or before night shifts (SWD). Patients with OSA were regular users of continuous positive airway pressure (CPAP) therapy. Efficacy measures included the Clinical Global Impression of Improvement (CGI-I) and the Epworth Sleepiness Scale (ESS). Across the diagnosis groups, the most commonly occurring adverse event was headache (14%-24%). Forty-three patients (13%) and 13 patients (4%) were withdrawn because of adverse events and insufficient efficacy, respectively. Armodafinil did not adversely affect CPAP therapy. At the final visit, 80% (95% CI: 74.1, 86.7) of patients with treated OSA and 84% (72.7, 94.8) of patients with narcolepsy were rated on the CGI-I as at least minimally improved with regard to overall clinical condition; 98% (95.2, 100.0) of patients with SWD were rated as improved with regard to sleepiness during night shifts, including the commute to and from work. Armodafinil improved ESS total scores in patients with treated OSA (mean [SD] [95% CI] change from baseline, -7.3 [5.6] [-8.39, -6.30]) and patients with narcolepsy (-4.7 [6.0] [-7.41, -1.93]). Armodafinil administered for 12 months or more was generally well tolerated and improved wakefulness in patients with excessive sleepiness associated with treated OSA, SWD, or narcolepsy. Armodafinil improved the overall clinical condition of patients with treated OSA or narcolepsy.

Efficacy and Safety of Vilazodone in Patients With Generalized Anxiety Disorder: A Randomized, Double-Blind, Placebo-Controlled, Flexible-Dose Trial.

PubMed

Durgam, Suresh; Gommoll, Carl; Forero, Giovanna; Nunez, Rene; Tang, Xiongwen; Mathews, Maju; Sheehan, David V

2016-12-01

To evaluate the efficacy, safety, and tolerability of vilazodone as an acute treatment for generalized anxiety disorder (GAD). Vilazodone is a selective serotonin reuptake inhibitor and 5-HT1A receptor partial agonist approved for the treatment of major depressive disorder in adults. This was a randomized, placebo-controlled, parallel-group, multicenter, flexible-dose study conducted from May 2013-March 2014. Adult patients (18-70 years, inclusive) who met DSM-IV-TR criteria for GAD were randomized (1:1) to placebo or vilazodone 20-40 mg/d for 8 weeks of double-blind treatment. Primary and secondary efficacy parameters were change from baseline to week 8 in the Hamilton Anxiety Rating Scale (HARS) total score and in the Sheehan Disability Scale (SDS) total score, respectively, analyzed using a mixed-effects model for repeated measures approach on a modified intent-to-treat population. Safety outcomes were summarized descriptively. Efficacy analyses were based on 400 patients (placebo = 200, vilazodone = 200); 76% completed the study (placebo = 81%, vilazodone = 71%). The least squares mean difference (95% CI) in total score change from baseline to week 8 was statistically significant for vilazodone versus placebo on the HARS (-2.20 [-3.72 to -0.68]; P = .0048) and on the SDS (-1.89 [-3.52 to -0.26]; P = .0236). Treatment-emergent adverse events reported in ≥ 5% of vilazodone patients and at least twice the rate of placebo were nausea, diarrhea, dizziness, fatigue, delayed ejaculation, and erectile dysfunction. Statistically significant differences in favor of vilazodone 20-40 mg/d versus placebo were seen on all measures of anxiety and functional impairment in patients with GAD. Vilazodone was generally well tolerated, and no new safety concerns were noted. ClinicalTrials.gov identifier: NCT01844115. © Copyright 2016 Physicians Postgraduate Press, Inc.

An assessment of prime‐boost vaccination schedules with AS03A‐adjuvanted prepandemic H5N1 vaccines: a randomized study in European adults

PubMed Central

Gillard, Paul; Caplanusi, Adrian; Knuf, Markus; Roman, François; Walravens, Karl; Moris, Philippe; Dramé, Mamadou; Schwarz, Tino F.

2012-01-01

Please cite this paper as: Gillard et al. (2012) An assessment of prime‐boost vaccination schedules with AS03A‐adjuvanted prepandemic H5N1 vaccines: a randomized study in European adults. Influenza and Other Respiratory Viruses DOI: 10.1111/j.1750‐2659.2012.00349.x. Background  Long‐term persistence of immune response and safety of an H5N1 prepandemic influenza vaccine adjuvanted with AS03 (an α‐tocopherol oil‐in‐water emulsion‐based adjuvant system) was evaluated using various prime‐boost schedules that mimicked potential pandemic scenarios (NCT00430521). Methods  Five hundred and twelve healthy adults aged 18–60 years received primary vaccination with one or two doses (0, 21 days schedule) of the A/Vietnam/1194/2004 H5N1 vaccine followed by a booster dose (A/Vietnam/1194/2004 or A/Indonesia/05/2005 strain) six or twelve months later across eight randomized groups. Immunogenicity results by hemagglutination inhibition [HI] assay, microneutralization assay, and the cell‐mediated immune response (CMI) are reported here for the four groups boosted at Month 12. Results  A one‐dose‐adjuvanted primary administration followed 12 months later by a single‐adjuvanted booster dose containing a heterologous vaccine strain met or exceeded all US and European criteria for both strains. Increasing the interval between the first and second dose (from 21 days to 12 months) resulted in stronger cross‐reactive immune responses against the A/Indonesia/05/2005 strain. The HI antibody response against the two strains persisted for 6 months after the booster dose irrespective of the booster vaccine’s strain. The neutralizing antibody responses and the CMI observed in the study population paralleled the HI immune response. Overall, the vaccine had a clinically acceptable safety profile. Conclusion  The H5N1 vaccine in this study allowed for flexibility in the time interval between primary and booster vaccination and the use of a heterologous strain without impacting the strength of the humoral and cellular immune response to both vaccine strains. PMID:22405557

Maintenance treatment for opioid dependence with slow-release oral morphine: a randomized cross-over, non-inferiority study versus methadone

PubMed Central

Beck, Thilo; Haasen, Christian; Verthein, Uwe; Walcher, Stephan; Schuler, Christoph; Backmund, Markus; Ruckes, Christian; Reimer, Jens

2014-01-01

Aims To compare the efficacy of slow-release oral morphine (SROM) and methadone as maintenance medication for opioid dependence in patients previously treated with methadone. Design Prospective, multiple-dose, open label, randomized, non-inferiority, cross-over study over two 11-week periods. Methadone treatment was switched to SROM with flexible dosing and vice versa according to period and sequence of treatment. Setting Fourteen out-patient addiction treatment centres in Switzerland and Germany. Participants Adults with opioid dependence in methadone maintenance programmes (dose ≥50 mg/day) for ≥26 weeks. Measurements The efficacy end-point was the proportion of heroin-positive urine samples per patient and period of treatment. Each week, two urine samples were collected, randomly selected and analysed for 6-monoacetyl-morphine and 6-acetylcodeine. Non-inferiority was concluded if the two-sided 95% confidence interval (CI) in the difference of proportions of positive urine samples was below the predefined boundary of 10%. Findings One hundred and fifty-seven patients fulfilled criteria to form the per protocol population. The proportion of heroin-positive urine samples under SROM treatment (0.20) was non-inferior to the proportion under methadone treatment (0.15) (least-squares mean difference 0.05; 95% CI = 0.02, 0.08; P > 0.01). The 95% CI fell within the 10% non-inferiority margin, confirming the non-inferiority of SROM to methadone. A dose-dependent effect was shown for SROM (i.e. decreasing proportions of heroin-positive urine samples with increasing SROM doses). Retention in treatment showed no significant differences between treatments (period 1/period 2: SROM: 88.7%/82.1%, methadone: 91.1%/88.0%; period 1: P = 0.50, period 2: P = 0.19). Overall, safety outcomes were similar between the two groups. Conclusions Slow-release oral morphine appears to be at least as effective as methadone in treating people with opioid use disorder. PMID:24304412

QR encoded smart oral dosage forms by inkjet printing.

PubMed

Edinger, Magnus; Bar-Shalom, Daniel; Sandler, Niklas; Rantanen, Jukka; Genina, Natalja

2018-01-30

The use of inkjet printing (IJP) technology enables the flexible manufacturing of personalized medicine with the doses tailored for each patient. In this study we demonstrate, for the first time, the applicability of IJP in the production of edible dosage forms in the pattern of a quick response (QR) code. This printed pattern contains the drug itself and encoded information relevant to the patient and/or healthcare professionals. IJP of the active pharmaceutical ingredient (API)-containing ink in the pattern of QR code was performed onto a newly developed porous and flexible, but mechanically stable substrate with a good absorption capacity. The printing did not affect the mechanical properties of the substrate. The actual drug content of the printed dosage forms was in accordance with the encoded drug content. The QR encoded dosage forms had a good print definition without significant edge bleeding. They were readable by a smartphone even after storage in harsh conditions. This approach of efficient data incorporation and data storage combined with the use of smart devices can lead to safer and more patient-friendly drug products in the future. Copyright © 2017 Elsevier B.V. All rights reserved.

Radio Frequency Transistors Using Aligned Semiconducting Carbon Nanotubes with Current-Gain Cutoff Frequency and Maximum Oscillation Frequency Simultaneously Greater than 70 GHz.

PubMed

Cao, Yu; Brady, Gerald J; Gui, Hui; Rutherglen, Chris; Arnold, Michael S; Zhou, Chongwu

2016-07-26

In this paper, we report record radio frequency (RF) performance of carbon nanotube transistors based on combined use of a self-aligned T-shape gate structure, and well-aligned, high-semiconducting-purity, high-density polyfluorene-sorted semiconducting carbon nanotubes, which were deposited using dose-controlled, floating evaporative self-assembly method. These transistors show outstanding direct current (DC) performance with on-current density of 350 μA/μm, transconductance as high as 310 μS/μm, and superior current saturation with normalized output resistance greater than 100 kΩ·μm. These transistors create a record as carbon nanotube RF transistors that demonstrate both the current-gain cutoff frequency (ft) and the maximum oscillation frequency (fmax) greater than 70 GHz. Furthermore, these transistors exhibit good linearity performance with 1 dB gain compression point (P1dB) of 14 dBm and input third-order intercept point (IIP3) of 22 dBm. Our study advances state-of-the-art of carbon nanotube RF electronics, which have the potential to be made flexible and may find broad applications for signal amplification, wireless communication, and wearable/flexible electronics.

A study on ethosomes as mode for transdermal delivery of an antidiabetic drug.

PubMed

Bodade, Siddhodhan S; Shaikh, Karimunnisa Sameer; Kamble, Meghana S; Chaudhari, Praveen D

2013-01-01

A transdermal delivery system is warranted for repaglinide (RPG) which possesses half-life of 1 h and oral bioavailability of 56%. Ethosomes are useful tools for transdermal drug delivery. To prepare and evaluate ethosomes as mode for transdermal delivery of RPG. Ethosomes loaded with RPG were prepared from dipalmitoyl phosphatidylcholine and ethanol by the cold method. They were characterized using Fourier transform infrared spectroscopy and differential scanning calorimetry. They were evaluated for vesicle size, entrapment efficiency and ex-vivo skin permeation. Ethosomal composition was optimized using the 3(2) factorial design. Gel containing optimzsed ethosomes was studied for antidiabetic activity in rats. RPG ethosomes possessing the size of 0.171-1.727 µm and entrapment efficiency of 75-92% were obtained. They demonstrated a significantly higher permeation (64-97% of the administered dose) across excised rat skin when compared to free drug and its hydro alcoholic solution. In-vivo, RPG ethosomal system caused sustained antidiabetic effect. The lipid and ethanol concentration affected the physicochemical attributes and performance of ethosomes. The flexible ethosomes permeated the stratum corneum and improvized the availability of RPG for antidiabetic action. They prolonged the antidiabetic effect of RPG over a significantly longer period of time in comparison with the equivalent oral dose. Ethosomal system can successfully deliver RPG transdermally; sustain its effect and thus reduce its dosing frequency. Ethosomes are useful for enhancing the efficacy of RPG in the treatment of diabetes.

Efficacy and Safety of Lurasidone in Children and Adolescents With Bipolar I Depression: A Double-Blind, Placebo-Controlled Study.

PubMed

DelBello, Melissa P; Goldman, Robert; Phillips, Debra; Deng, Ling; Cucchiaro, Josephine; Loebel, Antony

2017-12-01

To evaluate the efficacy and safety of lurasidone in children and adolescents with bipolar depression. Patients 10 to 17 years old with a DSM-5 diagnosis of bipolar I depression were randomized to 6 weeks of double-blind treatment with flexible doses of lurasidone 20 to 80 mg/day. The primary endpoint was change from baseline to week 6 in the Children's Depression Rating Scale-Revised (CDRS-R) total score, evaluated by a mixed-model repeated-measures analysis. A total of 347 patients were randomized and received at least 1 dose of lurasidone (n = 175; mean age 14.2 years; mean dose 33.6 mg/day) or placebo (n = 172; mean age 14.3 years). At week 6, treatment with lurasidone was associated with statistically significant improvement compared with placebo in CDRS-R total score (-21.0 versus -15.3; p < .0001; effect size 0.45). Lurasidone also was associated with statistically significant improvement in the Clinical Global Impression-Bipolar Severity depression score (key secondary measure) and in measures of anxiety, quality of life, and global functioning. Study completion rates were 92.0% in the lurasidone group and 89.7% in the placebo group; discontinuation rates due to adverse events were the same for the 2 groups (1.7%). The 2 most common adverse events on lurasidone were nausea and somnolence. Treatment with lurasidone was associated with few effects on weight and metabolic parameters. In this placebo-controlled study, monotherapy with lurasidone, in the dose range of 20 to 80 mg/day, significantly decreased depressive symptoms in children and adolescents with bipolar depression. Lurasidone was well tolerated, with minimal effects on weight and metabolic parameters. Clinical trial registration information-Lurasidone Pediatric Bipolar Study; http://Clinicaltrials.gov; NCT02046369. Copyright © 2017 American Academy of Child and Adolescent Psychiatry. Published by Elsevier Inc. All rights reserved.

Dose response explorer: an integrated open-source tool for exploring and modelling radiotherapy dose volume outcome relationships

NASA Astrophysics Data System (ADS)

El Naqa, I.; Suneja, G.; Lindsay, P. E.; Hope, A. J.; Alaly, J. R.; Vicic, M.; Bradley, J. D.; Apte, A.; Deasy, J. O.

2006-11-01

Radiotherapy treatment outcome models are a complicated function of treatment, clinical and biological factors. Our objective is to provide clinicians and scientists with an accurate, flexible and user-friendly software tool to explore radiotherapy outcomes data and build statistical tumour control or normal tissue complications models. The software tool, called the dose response explorer system (DREES), is based on Matlab, and uses a named-field structure array data type. DREES/Matlab in combination with another open-source tool (CERR) provides an environment for analysing treatment outcomes. DREES provides many radiotherapy outcome modelling features, including (1) fitting of analytical normal tissue complication probability (NTCP) and tumour control probability (TCP) models, (2) combined modelling of multiple dose-volume variables (e.g., mean dose, max dose, etc) and clinical factors (age, gender, stage, etc) using multi-term regression modelling, (3) manual or automated selection of logistic or actuarial model variables using bootstrap statistical resampling, (4) estimation of uncertainty in model parameters, (5) performance assessment of univariate and multivariate analyses using Spearman's rank correlation and chi-square statistics, boxplots, nomograms, Kaplan-Meier survival plots, and receiver operating characteristics curves, and (6) graphical capabilities to visualize NTCP or TCP prediction versus selected variable models using various plots. DREES provides clinical researchers with a tool customized for radiotherapy outcome modelling. DREES is freely distributed. We expect to continue developing DREES based on user feedback.

CT brush and CancerZap!: two video games for computed tomography dose minimization.

PubMed

Alvare, Graham; Gordon, Richard

2015-05-12

X-ray dose from computed tomography (CT) scanners has become a significant public health concern. All CT scanners spray x-ray photons across a patient, including those using compressive sensing algorithms. New technologies make it possible to aim x-ray beams where they are most needed to form a diagnostic or screening image. We have designed a computer game, CT Brush, that takes advantage of this new flexibility. It uses a standard MART algorithm (Multiplicative Algebraic Reconstruction Technique), but with a user defined dynamically selected subset of the rays. The image appears as the player moves the CT brush over an initially blank scene, with dose accumulating with every "mouse down" move. The goal is to find the "tumor" with as few moves (least dose) as possible. We have successfully implemented CT Brush in Java and made it available publicly, requesting crowdsourced feedback on improving the open source code. With this experience, we also outline a "shoot 'em up game" CancerZap! for photon limited CT. We anticipate that human computing games like these, analyzed by methods similar to those used to understand eye tracking, will lead to new object dependent CT algorithms that will require significantly less dose than object independent nonlinear and compressive sensing algorithms that depend on sprayed photons. Preliminary results suggest substantial dose reduction is achievable.

Evaluation of the ergogenic potential of noni juice.

PubMed

Ma, De-lu; West, Brett J; Su, Chen X; Gao, Jian-hua; Liu, Tin-zhong; Liu, Yu-Wen

2007-11-01

Morinda citrifolia (noni) fruit juice is an increasingly popular health food with many reported benefits, such as antioxidant and immunomodulatory properties. Traditionally, noni fruit was used by Polynesians to combat fatigue. Also, clinical studies have revealed that noni juice consumption improves quality of life scores related to physical functioning and energy levels. To further evaluate the ergogenic (antifatigue and endurance promoting) potential of noni juice, aged mice were pretreated orally with increasing doses (10, 20 and 40 mL/kg body weight) of Tahitian Noni Juice (TNJ) and then compared with young and aged controls in the forced swim test and rotarod test. The average times of all TNJ dose groups were significantly longer than the aged controls in both the swim test (36% to 45%) and the rotarod test (59% to 128%), and were similar to those of the young controls. This demonstrates not only an improvement in endurance but also in balance and flexibility. These results confirm the reported use of noni juice to combat fatigue, improve endurance and increase overall physical performance. Copyright (c) 2007 John Wiley & Sons, Ltd.

Comparison of optimal performance at 300 keV of three direct electron detectors for use in low dose electron microscopy

PubMed Central

McMullan, G.; Faruqi, A.R.; Clare, D.; Henderson, R.

2014-01-01

Low dose electron imaging applications such as electron cryo-microscopy are now benefitting from the improved performance and flexibility of recently introduced electron imaging detectors in which electrons are directly incident on backthinned CMOS sensors. There are currently three commercially available detectors of this type: the Direct Electron DE-20, the FEI Falcon II and the Gatan K2 Summit. These have different characteristics and so it is important to compare their imaging properties carefully with a view to optimise how each is used. Results at 300 keV for both the modulation transfer function (MTF) and the detective quantum efficiency (DQE) are presented. Of these, the DQE is the most important in the study of radiation sensitive samples where detector performance is crucial. We find that all three detectors have a better DQE than film. The K2 Summit has the best DQE at low spatial frequencies but with increasing spatial frequency its DQE falls below that of the Falcon II. PMID:25194828

Over-exposure correction in knee cone-beam CT imaging with automatic exposure control using a partial low dose scan

NASA Astrophysics Data System (ADS)

Choi, Jang-Hwan; Muller, Kerstin; Hsieh, Scott; Maier, Andreas; Gold, Garry; Levenston, Marc; Fahrig, Rebecca

2016-03-01

C-arm-based cone-beam CT (CBCT) systems with flat-panel detectors are suitable for diagnostic knee imaging due to their potentially flexible selection of CT trajectories and wide volumetric beam coverage. In knee CT imaging, over-exposure artifacts can occur because of limitations in the dynamic range of the flat panel detectors present on most CBCT systems. We developed a straightforward but effective method for correction and detection of over-exposure for an Automatic Exposure Control (AEC)-enabled standard knee scan incorporating a prior low dose scan. The radiation dose associated with the low dose scan was negligible (0.0042mSv, 2.8% increase) which was enabled by partially sampling the projection images considering the geometry of the knees and lowering the dose further to be able to just see the skin-air interface. We combined the line integrals from the AEC and low dose scans after detecting over-exposed regions by comparing the line profiles of the two scans detector row-wise. The combined line integrals were reconstructed into a volumetric image using filtered back projection. We evaluated our method using in vivo human subject knee data. The proposed method effectively corrected and detected over-exposure, and thus recovered the visibility of exterior tissues (e.g., the shape and density of the patella, and the patellar tendon), incorporating a prior low dose scan with a negligible increase in radiation exposure.

Pathway Based Toxicology and Fit-for-Purpose Assays.

PubMed

Clewell, Rebecca A; McMullen, Patrick D; Adeleye, Yeyejide; Carmichael, Paul L; Andersen, Melvin E

The field of toxicity testing for non-pharmaceutical chemicals is in flux with multiple initiatives in North America and the EU to move away from animal testing to mode-of-action based in vitro assays. In this arena, there are still obstacles to overcome, such as developing appropriate cellular assays, creating pathway-based dose-response models and refining in vitro-in vivo extrapolation (IVIVE) tools. Overall, it is necessary to provide assurances that these new approaches are adequately protective of human and ecological health. Another major challenge for individual scientists and regulatory agencies is developing a cultural willingness to shed old biases developed around animal tests and become more comfortable with mode-of-action based assays in human cells. At present, most initiatives focus on developing in vitro alternatives and assessing how well these alternative methods reproduce past results related to predicting organism level toxicity in intact animals. The path forward requires looking beyond benchmarking against high dose animal studies. We need to develop targeted cellular assays, new cell biology-based extrapolation models for assessing regions of safety for chemical exposures in human populations, and mode-of-action-based approaches which are constructed on an understanding of human biology. Furthermore, it is essential that assay developers have the flexibility to 'validate' against the most appropriate mode-of-action data rather than against apical endpoints in high dose animal studies. This chapter demonstrates the principles of fit-for-purpose assay development using pathway-targeted case studies. The projects include p53-mdm2-mediated DNA-repair, estrogen receptor-mediated cell proliferation and PPARα receptor-mediated liver responses.

Safinamide: A Review in Parkinson's Disease.

PubMed

Blair, Hannah A; Dhillon, Sohita

2017-02-01

Safinamide (Xadago ® ) is an orally active, selective, reversible monoamine oxidase-B inhibitor with both dopaminergic and non-dopaminergic (glutamatergic) properties. In the EU, safinamide is approved for the treatment of mid- to late-stage fluctuating Parkinson's disease (PD) as add-on therapy to a stable dose of levodopa alone or in combination with other PD medications. Safinamide 50-100 mg/day administered as a fixed or flexible dose significantly increased daily 'on' time without dyskinesia (primary endpoint) in patients with mid- to late-stage PD with motor fluctuations in 24-week, placebo-controlled clinical trials. Other outcomes, including motor function, overall clinical status and health-related quality of life, were also generally improved with safinamide. Furthermore, in an 18-month extension of one study, although dyskinesia (primary endpoint) was not significantly improved with safinamide relative to placebo, treatment benefits in other outcomes were generally sustained over 24 months of treatment. Safinamide was generally well tolerated in clinical trials; dyskinesia was the most common adverse event. Although further studies are needed, including comparative and long-term studies, current evidence indicates that safinamide extends the treatment options available for use as add-on therapy to levodopa and other PD medications in patients with mid- to late-stage PD experiencing motor fluctuations.

Optimization of Treatment Geometry to Reduce Normal Brain Dose in Radiosurgery of Multiple Brain Metastases with Single-Isocenter Volumetric Modulated Arc Therapy.

PubMed

Wu, Qixue; Snyder, Karen Chin; Liu, Chang; Huang, Yimei; Zhao, Bo; Chetty, Indrin J; Wen, Ning

2016-09-30

Treatment of patients with multiple brain metastases using a single-isocenter volumetric modulated arc therapy (VMAT) has been shown to decrease treatment time with the tradeoff of larger low dose to the normal brain tissue. We have developed an efficient Projection Summing Optimization Algorithm to optimize the treatment geometry in order to reduce dose to normal brain tissue for radiosurgery of multiple metastases with single-isocenter VMAT. The algorithm: (a) measures coordinates of outer boundary points of each lesion to be treated using the Eclipse Scripting Application Programming Interface, (b) determines the rotations of couch, collimator, and gantry using three matrices about the cardinal axes, (c) projects the outer boundary points of the lesion on to Beam Eye View projection plane, (d) optimizes couch and collimator angles by selecting the least total unblocked area for each specific treatment arc, and (e) generates a treatment plan with the optimized angles. The results showed significant reduction in the mean dose and low dose volume to normal brain, while maintaining the similar treatment plan qualities on the thirteen patients treated previously. The algorithm has the flexibility with regard to the beam arrangements and can be integrated in the treatment planning system for clinical application directly.

Statistical controversies in clinical research: requiem for the 3 + 3 design for phase I trials.

PubMed

Paoletti, X; Ezzalfani, M; Le Tourneau, C

2015-09-01

More than 95% of published phase I trials have used the 3 + 3 design to identify the dose to be recommended for phase II trials. However, the statistical community agrees on the limitations of the 3 + 3 design compared with model-based approaches. Moreover, the mechanisms of action of targeted agents strongly challenge the hypothesis that the maximum tolerated dose constitutes the optimal dose, and more outcomes including clinical and biological activity increasingly need to be taken into account to identify the optimal dose. We review key elements from clinical publications and from the statistical literature to show that the 3 + 3 design lacks the necessary flexibility to address the challenges of targeted agents. The design issues raised by expansion cohorts, new definitions of dose-limiting toxicity and trials of combinations are not easily addressed by the 3 + 3 design or its extensions. Alternative statistical proposals have been developed to make a better use of the complex data generated by phase I trials. Their applications require a close collaboration between all actors of early phase clinical trials. © The Author 2015. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com.

In-situ chemical reduction produced graphene paper for flexible supercapacitors with impressive capacitive performance

NASA Astrophysics Data System (ADS)

Ye, Xingke; Zhu, Yucan; Tang, Zhonghua; Wan, Zhongquan; Jia, Chunyang

2017-08-01

For practical applications of graphene-based materials in flexible supercapacitors, a technological breakthrough is currently required to fabricate high-performance graphene paper by a facile method. Herein, highly conductive (∼6900 S m-1) graphene paper with loose multilayered structure is produced by a high-efficiency in-situ chemical reduction process, which assembles graphite oxide suspensions into film and simultaneously conducts chemical reduction. Graphene papers with different parameters (including different types and doses of reductants, different thicknesses and areas of films) are successfully fabricated through this in-situ chemical reduction method. Meanwhile, the influences of the graphene papers with different parameters upon the supercapacitor performance are systematically investigated. Flexible supercapacitor based on the graphene paper exhibits high areal capacitance (152.4 mF cm-2 at current density of 2.0 mA cm-2 in aqueous electrolyte), and excellent rate performance (88.7% retention at 8.0 mA cm-2). Furthermore, bracelet-shaped all-solid supercapacitor with fascinating cycling stability (96.6% retention after 10 000 cycles) and electrochemical stability (an almost negligible capacity loss under different bending states and 99.6% retention after 4000 bending cycles) is established by employing the graphene paper electrode material and polymer electrolyte.

TH-EF-BRB-11: Volumetric Modulated Arc Therapy for Total Body Irradiation

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

Ouyang, L; Folkerts, M; Hrycushko, B

Purpose: To develop a modern, patient-comfortable total body irradiation (TBI) technique suitable for standard-sized linac vaults. Methods: An indexed rotatable immobilization system (IRIS) was developed to make possible total-body CT imaging and radiation delivery on conventional couches. Treatment consists of multi-isocentric volumetric modulated arc therapy (VMAT) to the upper body and parallel-opposed fields to the lower body. Each isocenter is indexed to the couch and includes a 180° IRIS rotation between the upper and lower body fields. VMAT fields are optimized to satisfy lung dose objectives while achieving a uniform therapeutic dose to the torso. End-to-end tests with a randomore » phantom were used to verify dosimetric characteristics. Treatment plan robustness regarding setup uncertainty was assessed by simulating global and regional isocenter setup shifts on patient data sets. Dosimetric comparisons were made with conventional extended distance, standing TBI (cTBI) plans using a Monte Carlo-based calculation. Treatment efficiency was assessed for eight courses of patient treatment. Results: The IRIS system is level and orthogonal to the scanned CT image plane, with lateral shifts <2mm following rotation. End-to-end tests showed surface doses within ±10% of the prescription dose, field junction doses within ±15% of prescription dose. Plan robustness tests showed <15% changes in dose with global setup errors up to 5mm in each direction. Local 5mm relative setup errors in the chest resulted in < 5% dose changes. Local 5mm shift errors in the pelvic and upper leg junction resulted in <10% dose changes while a 10mm shift error causes dose changes up to 25%. Dosimetric comparison with cTBI showed VMAT-TBI has advantages in preserving chest wall dose with flexibility in leveraging the PTV-body and PTV-lung dose. Conclusion: VMAT-TBI with the IRIS system was shown clinically feasible as a cost-effective approach to TBI for standard-sized linac vaults.« less

Etanercept provides an effective, safe and flexible short- and long-term treatment regimen for moderate-to-severe psoriasis: a systematic review of current evidence.

PubMed

Strohal, Robert; Chimenti, Sergio; Vena, Gino Antonio; Girolomoni, Giampiero

2013-06-01

The treatment of psoriasis requires long-lasting intervention. Conventional treatments for psoriasis comprise topical, phototherapeutic and systemic modalities, such as methotrexate or cyclosporine. Biological therapies are advocated by treatment guidelines for the use in moderate-to-severe psoriasis, when conventional treatments have failed, are contraindicated or are associated with severe adverse events. Etanercept is an anti-TNF recombinant fusion protein that has emerged as a standard biologic treatment option for moderate-to-severe psoriasis. The present review summarizes data from pivotal and post-marketing randomized controlled etanercept trials to treat moderate-to-severe psoriasis for 24 weeks and longer. During the first 12 weeks, etanercept can be administered in different dosing regimens: 50 mg twice weekly (BIW) and 50 mg once weekly. Although both regimens are effective, it has been shown that the 50 mg BIW dosage leads to higher response rates at week 24. In addition, after 24 weeks' treatment etanercept provides the unique possibility of continuous or intermittent long-term treatment programmes. The medium- to long-term efficacy of etanercept was consistent, regardless of whether etanercept therapy was interrupted or continuous. Taking the chronic nature of psoriasis into account, this flexibility in dosing regimen bestows a key advantage in facilitating individualisation of long-term treatment according to patient needs.

SU-G-201-07: Dosimetric Verification of a 3D Printed HDR Skin Brachytherapy Applicator

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

Rasmussen, K; Stanley, D; Eng, T

Purpose: The use of radiation as a treatment modality for skin cancer has increased significantly over the last decade with standardized applicators. Utilizing 3D printing, the ability to make applicators specifically designed for each patient’s anatomy has become economically feasible. With this in mind it was the aim of this study to determine the dosimetric accuracy of a 3-D printed HDR brachytherapy applicator for the skin. Methods: A CT reference image was used to generate a custom applicator based on an anthropomorphic head and neck phantom. To create the applicator a 1cm expansion anteriorly with 0.5cmX0.5cm trenches on the outermore » surface that were spaced 1cm sup-inf to accommodate standard 6F flexible catheters. The applicator was printed using PLA material using a printrbot simple printer. A treatment plan optimized to deliver a clinically representative volume was created in Oncentra and delivered with a nucletron afterloader. Measurements were made using TLDs and EBT3 gafchromic film that were placed between the applicator and the phantom’s forehead. An additional piece of film was also used to qualitatively asses the dose distribution in the transverse plane. Using a standard vaginal cylinder and bolus, a standardized curve correlating TLD and film exposure-to-radiation dose was established by irradiating film to known doses (200,500,700 cGy) at a 3.5 cm radius distance. Results: Evaluated TLDs showed the absolute dose delivered to the skin surface using the 3-D printed bolus was 615cGy±6%, with a mean predicted TPS value in the measured area of 617.5±7%. Additionally, planar dose distributions had good qualitative agreement with calculated TPS isodoses. Conclusion: This work demonstrates patient specific 3-D printed HDR brachytherapy applicators for skin cancer treatments are practical and accurate in TPS calculations but additional measurements are needed to verify additional sites and dose at depth.« less

The Role of Dietary Protein and Fat in Glycaemic Control in Type 1 Diabetes: Implications for Intensive Diabetes Management.

PubMed

Paterson, Megan; Bell, Kirstine J; O'Connell, Susan M; Smart, Carmel E; Shafat, Amir; King, Bruce

2015-09-01

A primary focus of the management of type 1 diabetes has been on matching prandial insulin therapy with carbohydrate amount consumed. However, even with the introduction of more flexible intensive insulin regimes, people with type 1 diabetes still struggle to achieve optimal glycaemic control. More recently, dietary fat and protein have been recognised as having a significant impact on postprandial blood glucose levels. Fat and protein independently increase the postprandial glucose excursions and together their effect is additive. This article reviews how the fat and protein in a meal impact the postprandial glycaemic response and discusses practical approaches to managing this in clinical practice. These insights have significant implications for patient education, mealtime insulin dose calculations and dosing strategies.

Mental health professional experiences of the flexible assertive community treatment model: a grounded theory study.

PubMed

Lexén, Annika; Svensson, Bengt

2016-08-01

Despite the lack of evidence for effectiveness of the Flexible Assertive Community Treatment (Flexible ACT), the model is considered feasible and is well received by mental health professionals. No current studies have adequately examined mental health professional experiences of working with Flexible ACT. The aim of this study was to explore mental health professional experiences of working with the Flexible ACT model compared with standard care. The study was guided by grounded theory and based on the interviews with 19 theoretically chosen mental health professionals in Swedish urban areas primarily working with consumers with psychosis, who had worked with the Flexible ACT model for at least 6 months. The analysis resulted in the core category: "Flexible ACT and the shared caseload create a common action space" and three main categories: (1) "Flexible ACT fills the need for a systematic approach to crisis intervention"; (2) "Flexible ACT has advantages in the psychosocial working environment"; and (3) "Flexible ACT increases the quality of care". Mental health professionals may benefit from working with the Flexible ACT model through decreased job-strain and stress, increased feeling of being in control over their work situation, and experiences of providing higher quality of care.

An open-label extension long-term study of the safety and efficacy of aripiprazole for irritability in children and adolescents with autistic disorder in Japan.

PubMed

Ichikawa, Hironobu; Hiratani, Michio; Yasuhara, Akihiro; Tsujii, Noa; Oshimo, Takashi; Ono, Hiroaki; Tadori, Yoshihiro

2018-02-01

The purpose of this study was to evaluate the long-term safety and efficacy of aripiprazole in treating irritability in pediatric patients (6-17 years) with autistic disorder (AD) in Japan. In this open-label extension study, patients who had completed a previous randomized, double-blind, placebo-controlled 8-week study were enrolled and were flexibly dosed with aripiprazole (1-15 mg/day) until the new indication of irritability in pediatric autism spectrum disorder was approved in Japan. Seventy (81%) out of 86 enrolled patients completed week-48 assessments. The mean duration of treatment was 694.9 days. The mean daily dose of aripiprazole over the treatment period was 7.2 mg and the mean of the final dose was 8.5 mg. The most common treatment-emergent adverse events (TEAE; ≥20%) included nasopharyngitis, somnolence, influenza, and increased weight. The majority of these TEAE were mild or moderate in severity, and there were no deaths, and no clinically relevant findings in laboratory values except prolactin decrease, vital signs, height, or ECG parameters. At week 48 (observed case), the mean change from baseline in the Irritability subscale score for the Aberrant Behavior Checklist Japanese Version was -6.3 in prior placebo patients and -2.6 in prior aripiprazole patients. Aripiprazole was generally safe, well tolerated, and effective in the long-term treatment of irritability associated with AD in Japanese pediatric patients. © 2017 The Authors. Psychiatry and Clinical Neurosciences published by John Wiley & Sons Australia, Ltd on behalf of Japanese Society of Psychiatry and Neurology.

Office-based endoscopic botulinum toxin injection in laryngeal movement disorders.

PubMed

Kaderbay, A; Righini, C A; Castellanos, P F; Atallah, I

2018-06-01

Botulinum toxin injection is widely used for the treatment of laryngeal movement disorders. Electromyography-guided percutaneous injection is the technique most commonly used to perform intralaryngeal botulinum toxin injection. We describe an endoscopic approach for intralaryngeal botulinum toxin injection under local anaesthesia without using electromyography. A flexible video-endoscope with an operating channel is used. After local anaesthesia of the larynx by instillation of lidocaine, a flexible needle is inserted into the operating channel in order to inject the desired dose of botulinum toxin into the vocal and/or vestibular folds. Endoscopic botulinum toxin injection under local anaesthesia is a reliable technique for the treatment of laryngeal movement disorders. It can be performed by any laryngologist without the need for electromyography. It is easy to perform for the operator and comfortable for the patient. Copyright © 2018 Elsevier Masson SAS. All rights reserved.

Systematic review with meta-analysis: the comparative effectiveness of aspirin vs. screening for colorectal cancer prevention.

PubMed

Emilsson, L; Holme, Ø; Bretthauer, M; Cook, N R; Buring, J E; Løberg, M; Adami, H-O; Sesso, H D; Gaziano, M J; Kalager, M

2017-01-01

Both aspirin use and screening with flexible sigmoidoscopy or guaiac faecal occult blood testing (FOBT) may reduce mortality from colorectal cancer, but comparative effectiveness of these interventions is unknown. To compare aspirin to guaiac FOBT screening with regard to incidence and mortality of colorectal cancer in a network meta-analysis. We searched Medline, EMBASE and the COCHRANE central register (CENTRAL) for relevant randomised trials identified until 31 October 2015. Randomised trials in average-risk populations that reported colorectal cancer mortality, colorectal cancer incidence, or both, with a minimum follow-up of 2 years, and more than 100 randomised individuals were included. Three investigators independently extracted data. We calculated relative risks [RR with 95% predictive intervals (PrIs)] for the comparison of the interventions by frequentist network meta-analyses. The effect of aspirin on colorectal cancer mortality was similar to FOBT (RR 1.03; 95% PrI 0.76-1.39) and flexible sigmoidoscopy (RR 1.16; 95% PrI 0.84-1.60). Aspirin was more effective than FOBT (RR 0.36; 95% PrI 0.22-0.59) and flexible sigmoidoscopy (RR 0.37; 95% PrI 0.22-0.62) in preventing death from or cancer in the proximal colon. Aspirin was equally effective as screening in reducing colorectal cancer incidence, while flexible sigmoidoscopy was superior to FOBT (RR 0.84; 95% PrI 0.72-0.97). Low-dose aspirin seems to be equally effective as flexible sigmoidoscopy or guaiac FOBT screening to reduce colorectal cancer incidence and mortality, and more effective for cancers in the proximal colon. A randomised comparative effectiveness trial of aspirin vs. screening is warranted. © 2016 John Wiley & Sons Ltd.

Trace Element Status (Zinc, Copper, Selenium, Iron, Manganese) in Patients with Long-Term Home Parenteral Nutrition.

PubMed

Dastych, Milan; Šenkyřík, Michal; Dastych, Milan; Novák, František; Wohl, Petr; Maňák, Jan; Kohout, Pavel

2016-01-01

The objective of the present study was to determine concentrations of zinc (Zn), copper (Cu), iron (Fe), selenium (Se) in blood plasma and manganese (Mn) in the whole blood in patients with long-term home parenteral nutrition (HPN) in comparison to the control group. We examined 68 patients (16 men and 52 women) aged from 28 to 68 years on a long-term HPN lasting from 4 to 96 months. The short bowel syndrome was an indication for HPN. The daily doses of Zn, Cu, Fe, Se and Mn in the last 3 months were determined. No significant differences in blood plasma were found for Zn, Cu and Fe in patients with HPN and in the control group (p > 0.05). The concentration of Mn in whole blood was significantly increased in HPN patients (p < 0.0001), while Se concentration in these patients was significantly decreased (p < 0.005). The concentration of Mn in the whole blood of 16 patients with cholestasis was significantly increased compared to the patients without cholestasis (p < 0.001). The Cu concentration was increased with no statistical significance. In long-term HPN, the status of trace elements in the patients has to be continually monitored and the daily substitution doses of these elements have to be flexibly adjusted. Dosing schedule needs to be adjusted especially in cases of cholestatic hepatopathy. A discussion about the optimal daily dose of Mn in patients on HPN is appropriate. For clinical practice, the availability of a substitution mixture of trace elements lacking Mn would be advantageous. © 2016 S. Karger AG, Basel.

Microdose flare-up vs. flexible-multidose GnRH antagonist protocols for poor responder patients who underwent ICSI.

PubMed

Esinler, I

2014-01-01

To compare the performance of microdose flare-up (MF) and flexible-multidose gonadotropin-releasing hormone (GnRH) antagonist protocols in poor responder patients who underwent intracytoplasmic sperm injection (ICSI). One hundred and 12 consecutive patients (217 cycles) suspected to have poor ovarian response were enrolled. Group 1 (MF GnRH agonist group) constituted 64 patients (135 cycles) who underwent MF GnRH agonist protocol. Group 2 (flexible-multidose GnRH antagonist group) constituted 48 patients (82 cycles) who underwent flexible-multidose GnRH antagonist protocol. The duration of stimulation (d) (11.5 +/- 2.1 vs. 10.4 +/- 2.7, p < 0.01) and the total dose of gonadotropin used (IU) (5,892.9 +/- 1,725.7 vs. 4,367.5 +/- 1,582.1, p < 0.05) were significantly lower in Group 2 when compared to Group 1. The numbers of retrieved oocyte-cumulus complexes (4.5 +/- 3.6 vs. 5.9 +/- 4.9, p < 0.05), metaphase II oocytes (3.6 +/- 3.1 vs. 4.9 +/- 4.2, p < 0.05), two pronucleated oocytes (2.6 +/- 2.3 vs. 4.0 +/- 3.4, p < 0.05), the number of available embryos at day 3 (2.6 +/- 2.2 vs. 4.2 +/- 3.2, p < 0.05) and the rate of embryos with > or = seven blastomeres and < 10% fragmentation at day 3 (35.9% vs. 65.1%, p < 0.05) were significantly lower in Group 1 when compared to Group 2. The number of embryos transferred (2.2 +/- 1.3 vs. 2.4 +/- 0.9), the clinical pregnancy per embryo transfer (16.3% vs. 25.8%), and the implantation rate (8.6% vs. 12.2%) were comparable between groups. Although the flexible-multidose GnRH antagonist protocol produced better oocyte and embryo parameters, the clinical pregnancy rate and the implantation rates were comparable between the flexible-multidose GnRH antagonist and MF protocols in poor responder patients.

PEGylation of polylysine dendrimers improves absorption and lymphatic targeting following SC administration in rats.

PubMed

Kaminskas, Lisa M; Kota, Jagannath; McLeod, Victoria M; Kelly, Brian D; Karellas, Peter; Porter, Christopher Jh

2009-12-03

Polylysine dendrimers have potential as highly flexible, biodegradable nanoparticular carriers that may also promote lymphatic transport. The current study was undertaken to determine the impact of PEGylation on the absorption and lymphatic transport of polylysine dendrimers modified by surface derivatisation with PEG (200, 570 or 2000Da) or 4-benzene sulphonate following SC or IV dosing. PEGylation led to the PEG(200) derived dendrimer being rapidly and completely absorbed into the blood after SC administration, however only 3% of the administered dose was recovered in pooled thoracic lymph over 30h. Increasing the PEG chain length led to a systematic decrease in absorption into the blood and an enhancement of the proportion recovered in the lymphatics (up to 29% over 30h). For the PEG(570) and PEG(2000) derived dendrimers, indirect access to the lymph via equilibration across the capillary beds also appeared to play a role in lymphatic targeting after both IV and SC dosing. In contrast, the anionic benzene sulphonate-capped dendrimer was not well absorbed from the SC injection site (26% bioavailability) into either the blood or the lymph. The data suggest that PEGylated poly-L-lysine dendrimers are well absorbed from SC injection sites and that the extent of lymphatic transport may be enhanced by increasing the size of the PEGylated dendrimer complex.

[Oligonucleotide derivatives in the nucleic acid hybridization analysis. I. Covalent immobilization of oligonucleotide probes onto the nylon].

PubMed

Dmitrienko, E V; Pyshnaia, I A; Pyshnyĭ, D V

2010-01-01

The features of UV-induced immobilization of oligonucleotides on a nylon membranes and the effectiveness of enzymatic labeling of immobilized probes at heterophase detection of nucleic acids are studied. Short terminal oligothymidilate (up to 10 nt) sequences are suggested to attach to the probe via a flexible ethylene glycol based linker. The presence of such fragment enhances the intensity of immobilization and reduces UV-dependent degradation of the targeted (sequence-specific) part of the probe by reducing the dose needed for the immobilization of DNA. The optimum dose of UV-irradiation is determined to be ~0.4 J/cm(2) at the wavelength 254 nm. This dose provides high level of hybridization signal for immobilized probes with various nucleotide composition of the sequence specific moiety. The amide groups of the polyamide are shown to play the key role in the photoinduced immobilization of nucleic acids, whereas the primary amino groups in the structure of PA is not the center responsible for the covalent binding of DNA by UV-irradiation, as previously believed. Various additives in the soaking solution during the membrane of UV-dependent immobilization of probes are shown to influence its effectiveness. The use of alternative to UV-irradiation system of radical generation are shown to provide the immobilization of oligonucleotides onto the nylon membrane.

Prediction of lethal/effective concentration/dose in the presence of multiple auxiliary covariates and components of variance

USGS Publications Warehouse

Gutreuter, S.; Boogaard, M.A.

2007-01-01

Predictors of the percentile lethal/effective concentration/dose are commonly used measures of efficacy and toxicity. Typically such quantal-response predictors (e.g., the exposure required to kill 50% of some population) are estimated from simple bioassays wherein organisms are exposed to a gradient of several concentrations of a single agent. The toxicity of an agent may be influenced by auxiliary covariates, however, and more complicated experimental designs may introduce multiple variance components. Prediction methods lag examples of those cases. A conventional two-stage approach consists of multiple bivariate predictions of, say, medial lethal concentration followed by regression of those predictions on the auxiliary covariates. We propose a more effective and parsimonious class of generalized nonlinear mixed-effects models for prediction of lethal/effective dose/concentration from auxiliary covariates. We demonstrate examples using data from a study regarding the effects of pH and additions of variable quantities 2???,5???-dichloro-4???- nitrosalicylanilide (niclosamide) on the toxicity of 3-trifluoromethyl-4- nitrophenol to larval sea lamprey (Petromyzon marinus). The new models yielded unbiased predictions and root-mean-squared errors (RMSEs) of prediction for the exposure required to kill 50 and 99.9% of some population that were 29 to 82% smaller, respectively, than those from the conventional two-stage procedure. The model class is flexible and easily implemented using commonly available software. ?? 2007 SETAC.

Extension and validation of an analytical model for in vivo PET verification of proton therapy—a phantom and clinical study

NASA Astrophysics Data System (ADS)

Attanasi, F.; Knopf, A.; Parodi, K.; Paganetti, H.; Bortfeld, T.; Rosso, V.; Del Guerra, A.

2011-08-01

The interest in positron emission tomography (PET) as a tool for treatment verification in proton therapy has become widespread in recent years, and several research groups worldwide are currently investigating the clinical implementation. After the first off-line investigation with a PET/CT scanner at MGH (Boston, USA), attention is now focused on an in-room PET application immediately after treatment in order to also detect shorter-lived isotopes, such as O15 and N13, minimizing isotope washout and avoiding patient repositioning errors. Clinical trials are being conducted by means of commercially available PET systems, and other tests are planned using application-dedicated tomographs. Parallel to the experimental investigation and new hardware development, great interest has been shown in the development of fast procedures to provide feedback regarding the delivered dose from reconstructed PET images. Since the thresholds of inelastic nuclear reactions leading to tissue β+-activation fall within the energy range of 15-20 MeV, the distal activity fall-off is correlated, but not directly matched, to the distal fall-off of the dose distribution. Moreover, the physical interactions leading to β+-activation and energy deposition are of a different nature. All these facts make it essential to further develop accurate and fast methodologies capable of predicting, on the basis of the planned dose distribution, expected PET images to be compared with actual PET measurements, thus providing clinical feedback on the correctness of the dose delivery and of the irradiation field position. The aim of this study has been to validate an analytical model and to implement and evaluate it in a fast and flexible framework able to locally predict such activity distributions directly taking the reference planning CT and planned dose as inputs. The results achieved in this study for phantoms and clinical cases highlighted the potential of the implemented method to predict expected activity distributions with great accuracy. Thus, the analytical model can be used as a powerful substitute method to the sensitive and time-consuming Monte Carlo approach.

Methadone Treatment for HIV Prevention—Feasibility, Retention, and Predictors of Attrition in Dar es Salaam, Tanzania: A Retrospective Cohort Study

PubMed Central

Lambdin, Barrot H.; Masao, Frank; Chang, Olivia; Kaduri, Pamela; Mbwambo, Jessie; Magimba, Ayoub; Sabuni, Norman; Bruce, R. Douglas

2014-01-01

Background. People who inject drugs (PWID) in Dar es Salaam, Tanzania, have an estimated human immunodeficiency virus (HIV) prevalence of 42%–50% compared with 6.9% among the general population. Extensive evidence supports methadone maintenance to lower morbidity, mortality, and transmission of HIV and other infectious diseases among PWID. In 2011, the Tanzanian government launched the first publicly funded methadone clinic on the mainland of sub-Saharan Africa at Muhimbili National Hospital. Methods. We conducted a retrospective cohort study of methadone-naive patients enrolling into methadone maintenance treatment. Kaplan-Meier survival curves were constructed to assess retention probability. Proportional hazards regression models were used to evaluate the association of characteristics with attrition from the methadone program. Results. Overall, 629 PWID enrolled into methadone treatment during the study. At 12 months, the proportion of clients retained in care was 57% (95% confidence interval [CI], 53%–62%). Compared with those receiving a low dose (<40 mg), clients receiving a medium (40–85 mg) (adjusted hazard ratio [aHR], 0.50 [95% CI, .37–.68]) and high (>85 mg) (aHR, 0.41 [95% CI, .29–.59]) dose of methadone had a lower likelihood of attrition, adjusting for other characteristics. Older clients (aHR, 0.53 per 10 years [95% CI, .42–.69]) and female clients (aHR, 0.50 [95% CI, .28–.90]) had a significantly lower likelihood of attrition, whereas clients who reported a history of sexual abuse (aHR, 2.84 [95% CI, 1.24–6.51]) had a significantly higher likelihood of attrition. Conclusions. Patient retention in methadone maintenance is comparable to estimates from programs in North America, Europe, and Asia. Future implementation strategies should focus on higher doses and flexible dosing strategies to optimize program retention and strengthened efforts for clients at higher risk of attrition. PMID:24855149

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

Saleh, H; Ferjani, S; Masssey, V

Purpose: Perform dosimetric comparison between planned and delivered dose in the junction area, measure daily dose variation in the arc junction area for pediatric patients treated for medulloblastoma using Craniospinal axis irradiation(CSI) Material and methods Dose comparison in the junction area, daily dose variation in the arc junction area for a Rando Phantom and 5 pediatric patients treated using CSI technique were analyzed. Plans were created using the Eclipse treatment planning system. Two arcs for cranium and 1 arc for spine region were used. Planar dose matrix was created by projecting phantom and patient plan into the ArcCheck phantom. EBT3more » film was placed in the middle of ArcCheck plug to measure dose distribution in the junction areaDuring patient treatment, strip of EBT3 film was placed daily at each junction area for verification. EBT3 films were scanned using a flatbed scanner, Epson Expression 10000 XL. Film QA pro software was used to analyze film. Scanning and analysis was performed according to vendor recommendations and AAPM TG-55 report. Films were scanned and analyzed daily after each treatment and at the end of treatment course. Planar dose distributions from films were compared with planar dose distribution from treatment planning system. Results: Comparison of planned vs. measured dose distributions for patients have passing rates of 90%–100% with 3% and 3 mm gamma analysis. In some of the treatment fractions, daily setup film showed variation in dose distribution in the junction area. Conclusion: It is critical to measure dose distribution in the arc junction area and use additional quality assurance measures to verify daily setup for CSI patient where one or more junctions are present. EBT3 film prove to be a good tool to achieve this task considering flexibility associated with the film such as symmetry, self-developing and ease of use.« less

Design and stability study of an oral solution of amlodipine besylate for pediatric patients.

PubMed

van der Vossen, A C; van der Velde, I; Smeets, O S N M; Postma, D J; Vermes, A; Koch, B C P; Vulto, A G; Hanff, L M

2016-09-20

Amlodipine is an antihypertensive agent recommended for the management of hypertension in children and adolescents. The commercially available tablets of 5 and 10mg do not provide the necessary flexibility in dosing needed for treating children. Our goal was to develop a pediatric oral solution of amlodipine, using a robust manufacturing process suitable for ex-tempora and larger scale production. The parameters API and preservative content, related substances, appearance and pH were studied under four different storage conditions. Samples were analyzed up to 12months. Microbiological quality was studied in an 18-week in-use test based on a two-times daily dosing schedule. The stability of the formulation was influenced by storage conditions and composition. A formulation containing amlodipine besylate, sucrose syrup and methyl paraben remained physically stable for 12months at 4°C with no loss of amlodipine content. Related substances increased during the study but remained below 0.5%. In-use stability was proven up to 18weeks. Storage under refrigerated conditions was necessary to prevent precipitation and to obtain an acceptable shelf-life. In conclusion, we have developed and validated an amlodipine oral solution, suitable for the pediatric population. This liquid formulation is preferred over manipulated commercial dosage forms or non-standardized extemporaneously compounded formulations. Copyright © 2016 Elsevier B.V. All rights reserved.

Long-term safety and effectiveness of brexpiprazole in Japanese patients with schizophrenia: A 52-week, open-label study.

PubMed

Ishigooka, Jun; Iwashita, Shuichi; Tadori, Yoshihiro

2018-06-01

This study assessed the long-term safety, tolerability, and maintenance of the therapeutic effect of brexpiprazole in Japanese patients with schizophrenia. This 52-week, open-label, flexible-dose (1-4 mg/day) study included patients with schizophrenia who continued treatment from a short-term randomized placebo-controlled fixed-dose (1, 2, or 4 mg/day) trial and de novo patients who switched from other antipsychotics. A total of 282 patients (184 de novo and 98 rolled over from short-term trial) entered the 52-week treatment with brexpiprazole, and 150 (53.2%) patients completed the week-52 assessment. Treatment-emergent adverse events (TEAE) were experienced by 235/281 patients (83.6%), and TEAE reported by ≥10% of all patients were nasopharyngitis (23.1%) and worsening of schizophrenia (22.4%). During the study, most of the TEAE were mild or moderate in severity, and there were no deaths, and no clinically meaningful mean changes in laboratory values, vital signs, or electrocardiogram parameters. Mean scores for the Positive and Negative Syndrome Scale total and Clinical Global Impression-Severity remained stable until week 52. Brexpiprazole was generally safe and well tolerated and maintained therapeutic effects in the long-term treatment of Japanese patients with schizophrenia. © 2018 The Authors. Psychiatry and Clinical Neurosciences © 2018 Japanese Society of Psychiatry and Neurology.

Lumbopelvic flexibility modulates neuromuscular responses during trunk flexion-extension.

PubMed

Sánchez-Zuriaga, Daniel; Artacho-Pérez, Carla; Biviá-Roig, Gemma

2016-06-01

Various stimuli such as the flexibility of lumbopelvic structures influence the neuromuscular responses of the trunk musculature, leading to different load sharing strategies and reflex muscle responses from the afferents of lumbopelvic mechanoreceptors. This link between flexibility and neuromuscular response has been poorly studied. The aim of this study was to investigate the relationship between lumbopelvic flexibility and neuromuscular responses of the erector spinae, hamstring and abdominal muscles during trunk flexion-extension. Lumbopelvic movement patterns were measured in 29 healthy women, who were separated into two groups according to their flexibility during trunk flexion-extension. The electromyographic responses of erector spinae, rectus abdominis and biceps femoris were also recorded. Subjects with greater lumbar flexibility had significantly less pelvic flexibility and vice versa. Subjects with greater pelvic flexibility had a higher rate of relaxation and lower levels of hamstring activation during maximal trunk flexion. The neuromuscular response patterns of the hamstrings seem partially modulated by pelvic flexibility. Not so with the lumbar erector spinae and lumbar flexibility, despite the assertions of some previous studies. The results of this study improve our knowledge of the relationships between trunk joint flexibility and neuromuscular responses, a relationship which may play a role in low back pain. Copyright © 2016 Elsevier Ltd. All rights reserved.

Nonlinear association between betel quid chewing and oral cancer: Implications for prevention.

PubMed

Madathil, Sreenath Arekunnath; Rousseau, Marie-Claude; Wynant, Willy; Schlecht, Nicolas F; Netuveli, Gopalakrishnan; Franco, Eduardo L; Nicolau, Belinda

2016-09-01

Betel quid chewing is a major oral cancer risk factor and the human papillomaviruses (HPV) may play an aetiological role in these cancers. However, little is known about the shape of the dose-response relationship between the betel quid chewing habit and oral cancer risk in populations without HPV. We estimate the shape of this dose-response relationship, and discuss implications for prevention. Cases with oral squamous cell carcinoma (350) and non-cancer controls (371) were recruited from two major teaching hospitals in South India. Information on socio-demographic and behavioral factors was collected using a questionnaire and the life grid technique. The effect of daily amount of use and duration of the habit were estimated jointly as risk associated with cumulative exposure (chew-years). The shape of the dose-response curve was estimated using restricted cubic spline transformation of chew-years in a conditional logistic regression model. Risk estimates for low dose combinations of daily amount and duration of the habit were computed from flexible regression. Most (72%) oral cancer cases were betel quid chewers in contrast to only 18% of controls. A nonlinear dose-response relationship was observed; the risk increased steeply at low doses and plateaued at high exposures to betel quid (>425 chew-years). A threefold increase in risk (OR=3.92, 95%CI: 1.87-8.21) was observed for the lowest dose; equivalent to the use of one quid per day for one year. Our findings may be used to counsel people to refrain from even low betel quid chewing. Copyright © 2016 Elsevier Ltd. All rights reserved.

Number needed to treat to harm for discontinuation due to adverse events in the treatment of bipolar depression, major depressive disorder, and generalized anxiety disorder with atypical antipsychotics.

PubMed

Gao, Keming; Kemp, David E; Fein, Elizabeth; Wang, Zuowei; Fang, Yiru; Ganocy, Stephen J; Calabrese, Joseph R

2011-08-01

To estimate the number needed to treat to harm (NNTH) for discontinuation due to adverse events with atypical antipsychotics relative to placebo during the treatment of bipolar depression, major depressive disorder (MDD), and generalized anxiety disorder (GAD). English-language literature published and cited in MEDLINE from January 1966 to May 2009 was searched with the terms antipsychotic, atypical antipsychotic, generic and brand names of atypical antipsychotics, safety, tolerability, discontinuation due to adverse events, somnolence, sedation, weight gain, akathisia, or extrapyramidal side effect; and bipolar depression, major depressive disorder, or generalized anxiety disorder; and randomized, placebo-controlled clinical trial. This search was augmented with a manual search. Studies with a cumulative sample of ≥ 100 patients were included. The NNTHs for discontinuation due to adverse events, somnolence, sedation, ≥ 7% weight gain, and akathisia relative to placebo were estimated with 95% confidence intervals to reflect the magnitude of variance. Five studies in bipolar depression, 10 studies in MDD, and 4 studies in GAD were identified. Aripiprazole and olanzapine have been studied in bipolar depression and refractory MDD. Only quetiapine extended release (quetiapine-XR) has been studied in 3 psychiatric conditions with different fixed dosing schedules. For aripiprazole, the mean NNTH for discontinuation due to adverse events was 14 in bipolar depression, but was not significantly different from placebo in MDD. For olanzapine, the mean NNTHs were 24 in bipolar depression and 9 in MDD. The risk for discontinuation due to adverse events during quetiapine-XR treatment appeared to be associated with dose. For quetiapine-XR 300 mg/d, the NNTHs for discontinuation due to adverse events were 9 for bipolar depression, 8 for refractory MDD, 9 for MDD, and 5 for GAD. At the same dose of quetiapine-XR, patients with GAD appeared to have a lower tolerability than those with bipolar depression or MDD. Due to flexible dosing, the risk for discontinuation due to adverse events in the treatment of bipolar depression, MDD, or GAD with other atypical antipsychotics could not be compared. © Copyright 2011 Physicians Postgraduate Press, Inc.

Engineering design constraints of the lunar surface environment

NASA Technical Reports Server (NTRS)

Morrison, D. A.

1992-01-01

Living and working on the lunar surface will be difficult. Design of habitats, machines, tools, and operational scenarios in order to allow maximum flexibility in human activity will require paying attention to certain constraints imposed by conditions at the surface and the characteristics of lunar material. Primary design drivers for habitat, crew health and safety, and crew equipment are: ionizing radiation, the meteoroid flux, and the thermal environment. Secondary constraints for engineering derive from: the physical and chemical properties of lunar surface materials, rock distributions and regolith thicknesses, topography, electromagnetic properties, and seismicity. Protection from ionizing radiation is essential for crew health and safety. The total dose acquired by a crew member will be the sum of the dose acquired during EVA time (when shielding will be least) plus the dose acquired during time spent in the habitat (when shielding will be maximum). Minimizing the dose acquired in the habitat extends the time allowable for EVA's before a dose limit is reached. Habitat shielding is enabling, and higher precision in predicting secondary fluxes produced in shielding material would be desirable. Means for minimizing dose during a solar flare event while on extended EVA will be essential. Early warning of the onset of flare activity (at least a half-hour is feasible) will dictate the time available to take mitigating steps. Warning capability affects design of rovers (or rover tools) and site layout. Uncertainty in solar flare timing is a design constraint that points to the need for quickly accessible or constructible safe havens.

Engineering design constraints of the lunar surface environment

NASA Astrophysics Data System (ADS)

Morrison, D. A.

1992-02-01

Living and working on the lunar surface will be difficult. Design of habitats, machines, tools, and operational scenarios in order to allow maximum flexibility in human activity will require paying attention to certain constraints imposed by conditions at the surface and the characteristics of lunar material. Primary design drivers for habitat, crew health and safety, and crew equipment are: ionizing radiation, the meteoroid flux, and the thermal environment. Secondary constraints for engineering derive from: the physical and chemical properties of lunar surface materials, rock distributions and regolith thicknesses, topography, electromagnetic properties, and seismicity. Protection from ionizing radiation is essential for crew health and safety. The total dose acquired by a crew member will be the sum of the dose acquired during EVA time (when shielding will be least) plus the dose acquired during time spent in the habitat (when shielding will be maximum). Minimizing the dose acquired in the habitat extends the time allowable for EVA's before a dose limit is reached. Habitat shielding is enabling, and higher precision in predicting secondary fluxes produced in shielding material would be desirable. Means for minimizing dose during a solar flare event while on extended EVA will be essential. Early warning of the onset of flare activity (at least a half-hour is feasible) will dictate the time available to take mitigating steps. Warning capability affects design of rovers (or rover tools) and site layout. Uncertainty in solar flare timing is a design constraint that points to the need for quickly accessible or constructible safe havens.

Immunogenicity, reactogenicity and safety of the human rotavirus vaccine RIX4414 (Rotarix™) oral suspension (liquid formulation) when co-administered with expanded program on immunization (EPI) vaccines in Vietnam and the Philippines in 2006-2007.

PubMed

Anh, D D; Carlos, C C; Thiem, D V; Hutagalung, Y; Gatchalian, S; Bock, H L; Smolenov, I; Suryakiran, P V; Han, H H

2011-03-03

Evaluation of immunogenicity and safety of a 2-dose liquid formulation of human rotavirus vaccine, RIX4414 following WHO's Expanded Program on Immunization (EPI) schedule (0, 1, and 2 months; Month 0 indicates day of enrollment) in Vietnam and the Philippines. Infants aged 6-10 (mean=8.7 ± 1.07 weeks Vietnam) and 5-10 weeks (mean=6.6 ± 1.03 weeks Philippines) received two doses of RIX4414 vaccine (V) and one dose of placebo (PL) or three placebo doses concomitantly with commercially available diphtheria-tetanus-whole-cell pertussis, hepatitis B and oral poliovirus vaccines. The vaccination schedules were: V-V-PL, V-PL-V and PL-PL-PL (Vietnam); PL-V-V, V-PL-V and PL-PL-PL (Philippines). Anti-rotavirus seroconversion rate was assessed pre-vaccination and post-vaccination (ELISA cut-off=20 U/ml). 375 infants were enrolled in each country. Seroconversion rates at one month post-Dose 2 of RIX4414 were Vietnam 63.3% (95% CI: 54.3-71.6) in V-V-PL group and 81.5% (95% CI: 73.4-88) in V-PL-V group; Philippines 70% (95% CI: 61-78) in PL-V-V group and 59.2% (95% CI: 49.8-68) in V-PL-V group. Frequencies of solicited (8-day post-each dose) and unsolicited symptoms (31-day post-each dose) were similar. Two-doses of rotavirus vaccine administered within the WHO EPI offer flexibility in existing schedule, though both schedules provides good immune responses. Copyright © 2011 Elsevier Ltd. All rights reserved.

DOSE RECONSTRUCTION FOR THE MILLION WORKER STUDY: STATUS AND GUIDELINES

PubMed Central

Bouville, André; Toohey, Richard E.; Boice, John D.; Beck, Harold L.; Dauer, Larry T.; Eckerman, Keith F.; Hagemeyer, Derek; Leggett, Richard W.; Mumma, Michael T.; Napier, Bruce; Pryor, Kathy H.; Rosenstein, Marvin; Schauer, David A.; Sherbini, Sami; Stram, Daniel O.; Thompson, James L.; Till, John E.; Yoder, Craig; Zeitlin, Cary

2016-01-01

The primary aim of the epidemiologic study of one million U.S. radiation workers and veterans [the Million Worker Study (MWS)] is to provide scientifically valid information on the level of radiation risk when exposures are received gradually over time, and not within seconds as was the case for Japanese atomic-bomb survivors. The primary outcome of the epidemiologic study is cancer mortality but other causes of death such as cardiovascular disease and cerebrovascular disease will be evaluated. The success of the study is tied to the validity of the dose reconstruction approaches to provide realistic estimates of organ-specific radiation absorbed doses that are as accurate and precise as possible and to properly evaluate their accompanying uncertainties. The dosimetry aspects for the MWS are challenging in that they address diverse exposure scenarios for diverse occupational groups being studied over a period of up to 70 y. The dosimetric issues differ among the varied exposed populations that are considered: atomic veterans, U.S. Department of Energy workers exposed to both penetrating radiation and intakes of radionuclides, nuclear power plant workers, medical radiation workers, and industrial radiographers. While a major source of radiation exposure to the study population comes from external gamma- or x-ray sources, for some of the study groups there is a meaningful component of radionuclide intakes that require internal radiation dosimetry assessments. Scientific Committee 6–9 has been established by the National Council on Radiation Protection and Measurements (NCRP) to produce a report on the comprehensive organ dose assessment (including uncertainty analysis) for the MWS. The NCRP dosimetry report will cover the specifics of practical dose reconstruction for the ongoing epidemiologic studies with uncertainty analysis discussions and will be a specific application of the guidance provided in NCRP Report Nos. 158, 163, 164, and 171. The main role of the Committee is to provide guidelines to the various groups of dosimetrists involved in the MWS to ensure that certain dosimetry criteria are considered: calculation of annual absorbed doses in the organs of interest, separation of low and high linear-energy transfer components, evaluation of uncertainties, and quality assurance and quality control. It is recognized that the MWS and its approaches to dosimetry are a work in progress and that there will be flexibility and changes in direction as new information is obtained, both with regard to dosimetry and with regard to the epidemiologic features of the study components. This manuscript focuses on the description of the various components of the MWS, on the available dosimetry results, and on the challenges that have been encountered. It is expected that the Committee will complete its report in 2016. PMID:25551504

Design considerations and analysis planning of a phase 2a proof of concept study in rheumatoid arthritis in the presence of possible non-monotonicity.

PubMed

Liu, Feng; Walters, Stephen J; Julious, Steven A

2017-10-02

It is important to quantify the dose response for a drug in phase 2a clinical trials so the optimal doses can then be selected for subsequent late phase trials. In a phase 2a clinical trial of new lead drug being developed for the treatment of rheumatoid arthritis (RA), a U-shaped dose response curve was observed. In the light of this result further research was undertaken to design an efficient phase 2a proof of concept (PoC) trial for a follow-on compound using the lessons learnt from the lead compound. The planned analysis for the Phase 2a trial for GSK123456 was a Bayesian Emax model which assumes the dose-response relationship follows a monotonic sigmoid "S" shaped curve. This model was found to be suboptimal to model the U-shaped dose response observed in the data from this trial and alternatives approaches were needed to be considered for the next compound for which a Normal dynamic linear model (NDLM) is proposed. This paper compares the statistical properties of the Bayesian Emax model and NDLM model and both models are evaluated using simulation in the context of adaptive Phase 2a PoC design under a variety of assumed dose response curves: linear, Emax model, U-shaped model, and flat response. It is shown that the NDLM method is flexible and can handle a wide variety of dose-responses, including monotonic and non-monotonic relationships. In comparison to the NDLM model the Emax model excelled with higher probability of selecting ED90 and smaller average sample size, when the true dose response followed Emax like curve. In addition, the type I error, probability of incorrectly concluding a drug may work when it does not, is inflated with the Bayesian NDLM model in all scenarios which would represent a development risk to pharmaceutical company. The bias, which is the difference between the estimated effect from the Emax and NDLM models and the simulated value, is comparable if the true dose response follows a placebo like curve, an Emax like curve, or log linear shape curve under fixed dose allocation, no adaptive allocation, half adaptive and adaptive scenarios. The bias though is significantly increased for the Emax model if the true dose response follows a U-shaped curve. In most cases the Bayesian Emax model works effectively and efficiently, with low bias and good probability of success in case of monotonic dose response. However, if there is a belief that the dose response could be non-monotonic then the NDLM is the superior model to assess the dose response.

Efficacy and safety of escitalopram versus citalopram in major depressive disorder: a 6-week, multicenter, randomized, double-blind, flexible-dose study.

PubMed

Ou, Jian-Jun; Xun, Guang-Lei; Wu, Ren-Rong; Li, Le-Hua; Fang, Mao-Sheng; Zhang, Hong-Geng; Xie, Shi-Ping; Shi, Jian-Guo; Du, Bo; Yuan, Xue-Qin; Zhao, Jing-Ping

2011-02-01

S-citalopram (escitalopram) is the very active moiety of citalopram. It has been shown in many studies to be an effective and safe antidepressant for treating major depressive disorder (MDD). The aim of our study was to compare the efficacy and safety of escitalopram vs citalopram in Chinese MDD patients. In the double-blind study, 240 MDD patients were randomly assigned to treatment for 6 weeks either with escitalopram (10-20 mg/d) or citalopram (20-40 mg/d). The primary efficacy measurement was the change of 17-item Hamilton Depression Rating Scale (HAMD-17) total score from baseline to the end of study. The secondary efficacy measurements were response and remission rates. The adverse events (AEs) were recorded by the investigator. Two hundred and three (85%) patients completed the trial. The average dose was 13.9 mg/d in the escitalopram group and 27.6 mg/d in the citalopram group. No significant differences were found between the two groups in the change in HAMD-17 total score, response, and remission rate. These results were similar in severe MDD patients. No significant differences were found between the two groups in AEs. No serious AEs were observed in this study. The study suggests that escitalopram 10-20 mg/d are as effective and safe as citalopram 20-40 mg/d in the short-term treatment for Chinese MDD patients.

Hydrodynamics of a flexible plate between pitching rigid plates

NASA Astrophysics Data System (ADS)

Kim, Junyoung; Kim, Daegyoum

2017-11-01

The dynamics of a flexible plate have been studied as a model problem in swimming and flying of animals and fluid-structure interaction of plants and flags. Motivated by fish schooling and an array of sea grasses, we investigate the dynamics of a flexible plate closely placed between two pitching rigid plates. In most studies on passive deformation of the flexible plate, the plate is immersed in a uniform flow or a wavy flow. However, in this study, the flexible plate experiences periodic deformation by the oscillatory flow generated by the prescribed pitching motion of the rigid plates. In our model, the pitching axes of the rigid plates and the clamping position of the flexible plate are aligned on the same line. The flexible plate shows various responses depending on length and pitching frequency of rigid plates, thickness of a flexible plate, and free-stream velocity. To find the effect of each variable on the response of the flexible plate, amplitude of a trailing edge and modal contribution of a flapping motion are compared, and flow structure around the flexible plate is examined.

IMATINIB 800MG DAILY INDUCES DEEPER MOLECULAR RESPONSES THAN IMATINIB 400MG DAILY: RESULTS OF SWOG S0325, AN INTERGROUP RANDOMIZED PHASE II TRIAL IN NEWLY DIAGNOSED CHRONIC PHASE CHRONIC MYELOID LEUKAEMIA

PubMed Central

Deininger, Michael W.; Kopecky, Kenneth J.; Radich, Jerald P.; Kamel-Reid, Suzanne; Stock, Wendy; Paietta, Elisabeth; Emanuel, Peter D.; Tallman, Martin; Wadleigh, Martha; Larson, Richard A.; Lipton, Jeffrey H.; Slovak, Marilyn L.; Appelbaum, Frederick R.; Druker, Brian J.

2014-01-01

The standard dose of imatinib for newly diagnosed patients with chronic phase chronic myeloid leukemia (CP-CML) is 400mg daily (IM400), but the optimal dose is unknown. This randomized phase II study compared the rates of molecular, haematologic and cytogenetic response to IM400 vs. imatinib 400mg twice daily (IM800) in 153 adult patients with CP-CML. Dose adjustments for toxicity were flexible to maximize retention on study. Molecular response (MR) at 12 months was deeper in the IM800 arm (4-log reduction of BCR-ABL1 mRNA: 25% vs. 10% of patients, P=0.038; 3-log reduction: 53% vs. 35%, P=0.049). During the first 12 months BCR-ABL1 levels in the IM800 arm were an average 2.9-fold lower than in the IM400 arm (P=0.010). Complete haematologic response was similar, but complete cytogenetic response was higher with IM800 (85% vs. 67%, P=0.040). Grade 3–4 toxicities were more common for IM800 (58% vs. 31%, P=0.0007), and were most commonly haematologic. Few patients have relapsed, progressed or died, but progression-free (P=0.048) and relapse-free (P=0.031) survival were superior for IM800. In newly diagnosed CP-CML patients, IM800 induced deeper molecular responses than IM400, with a trend for improved progression-free and overall survival, but was associated with more severe toxicity. PMID:24383843

Absolute Bioavailability and Pharmacokinetics of Linezolid in Hospitalized Patients Given Enteral Feedings

PubMed Central

Beringer, Paul; Nguyen, Megan; Hoem, Nils; Louie, Stan; Gill, Mark; Gurevitch, Michael; Wong-Beringer, Annie

2005-01-01

Linezolid is a new antimicrobial agent effective against drug-resistant gram-positive pathogens which are common causes of infections in hospitalized patients. Many such patients rely on the intravenous or enteral route for nutrition and drug administration. Therefore, the bioavailability of linezolid administered enterally in the presence of enteral feedings in hospitalized patients was examined. Eighteen subjects were assessed in a randomized single-dose crossover study; 12 received continuous enteral feedings, while 6 did not (controls). Both groups received linezolid 600 mg intravenously and orally (control) or enterally, with the alternate route of administration separated by a 24-h washout period. Pharmacokinetic parameters derived from noncompartmental and compartmental analysis incorporating linear and nonlinear elimination pathways were compared between groups: F, Ka, Vs, K23, K32, Vmax, Km, and K20 (bioavailability, absorption rate constant, volume of central compartment normalized to body weight, intercompartmental rate constants, maximum velocity, Michaelis-Menten constant, and elimination rate constant, respectively). Pharmacokinetic (PK) data were available from 17 patients. The linezolid oral suspension was rapidly and completely absorbed by either the oral or enteral route of administration. Bioavailability was unaltered in the presence of enteral feedings. PK estimates remain similar regardless of the model applied. At the therapeutic dose used, only slight nonlinearity in elimination was observed. A linezolid oral suspension may be administered via the enteral route to hospitalized patients without compromise in its excellent bioavailability and rapid rate of absorption. Compartmental pharmacokinetic analysis offers a more flexible study application, since bioavailability (F) can be estimated directly with intermixed intravenous/oral doses without a need for a washout period. PMID:16127039

Long-term efficacy and safety of certolizumab pegol in Japanese rheumatoid arthritis patients with an inadequate response to methotrexate: 52-week results from an open-label extension of the J-RAPID study

PubMed Central

Tanaka, Yoshiya; Yamamoto, Kazuhiko; Takeuchi, Tsutomu; Yamanaka, Hisashi; Ishiguro, Naoki; Eguchi, Katsumi; Watanabe, Akira; Origasa, Hideki; Shoji, Toshiharu; Miyasaka, Nobuyuki; Koike, Takao

2014-01-01

Abstract Objectives. To evaluate the long-term efficacy and safety of certolizumab pegol (CZP) plus methotrexate treatment and to assess the efficacy of two CZP maintenance dosing schedules in Japanese rheumatoid arthritis (RA) patients with an inadequate response to methotrexate. Methods. J-RAPID double-blind patients were entered into an open-label extension (OLE) study. Patients withdrawn due to lack of efficacy at 16 weeks and double-blind completers without a week-24 American College of Rheumatology (ACR) 20 response received CZP 200 mg every other week (Q2W) plus methotrexate. Double-blind completers with week-24 ACR20 responses were randomized to CZP 200 mg Q2W plus methotrexate or CZP 400 mg every 4 weeks plus methotrexate. Results. The ACR20/ACR50/ACR70 response rates of double-blind completers (n = 204) were 89.7%/67.2%/36.3% at OLE entry and 95.6%/84.8%/58.3% at 52 weeks, respectively. Other clinical, functional and radiographic outcomes were sustained with long-term CZP plus methotrexate. Long-term treatment with CZP was well-tolerated with no new unexpected adverse events observed. The efficacy and safety of CZP treatment were similar between the two dosing schedules. Conclusions. Continued CZP administration with methotrexate maintained efficacy over 52 weeks and was well-tolerated for Japanese RA patients. No obvious differences in clinical efficacy and safety were observed between the two dosing schedules, giving flexibility in maintenance administration schedules. PMID:24593170

Dosimetric evaluation of a novel high dose rate (HDR) intraluminal / interstitial brachytherapy applicator for gastrointestinal and bladder cancers

PubMed Central

Aghamiri, Seyyed Mahmoud Reza; Najarian, Siamak; Jaberi, Ramin

2010-01-01

High dose rate (HDR) brachytherapy is one of the accepted treatment modalities in gastro‐intestinal tract and bladder carcinomas. Considering the shortcoming of contact brachytherapy routinely used in gastrointestinal tract in treatment of big tumors or invasive method of bladder treatment, an intraluminal applicator with the capability of insertion into the tumor depth seems to be useful. This study presents some dosimetric evaluations to introduce this applicator to the clinical use. The radiation attenuation characteristics of the applicator were evaluated by means of two dosimetric methods including well‐type chamber and radiochromic film. The proposed 110 cm long applicator has a flexible structure made of stainless steel for easy passage through lumens and a needle tip to drill into big tumors. The 2 mm diameter of the applicator is thick enough for source transition, while easy passage through any narrow lumen such as endoscope or cystoscope working channel is ensured. Well‐chamber results showed an acceptably low attenuation of this steel springy applicator. Performing absolute dosimetry resulted in a correlation coefficient of R=0.9916(p‐value≈10−7) between standard interstitial applicator and the one proposed in this article. This study not only introduces a novel applicator with acceptable attenuation but also proves the response independency of the GAFCHROMIC EBT films to energy. By applying the dose response of the applicator in the treatment planning software, it can be used as a new intraluminal / interstitial applicator. PACS number: 87.53.Bn, 87.53.Jw, 29.40.Cs

Buprenorphine tapering schedule and illicit opioid use

PubMed Central

Ling, Walter; Hillhouse, Maureen; Domier, Catherine; Doraimani, Geetha; Hunter, Jeremy; Thomas, Christie; Jenkins, Jessica; Hasson, Albert; Annon, Jeffrey; Saxon, Andrew; Selzer, Jeffrey; Boverman, Joshua; Bilangi, Richard

2011-01-01

Aims To compare the effects of a short or long taper schedule after buprenorphine stabilization on participant outcomes as measured by opioid-free urine tests at the end of each taper period. Design This multi-site study sponsored by Clinical Trials Network (CTN, a branch of the US National Institute on Drug Abuse) was conducted from 2003 to 2005 to compare two taper conditions (7 days and 28 days). Data were collected at weekly clinic visits to the end of the taper periods, and at 1-month and 3-month post-taper follow-up visits. Setting Eleven out-patient treatment programs in 10 US cities. Intervention Non-blinded dosing with Suboxone® during the 1-month stabilization phase included 3 weeks of flexible dosing as determined appropriate by the study physicians. A fixed dose was required for the final week before beginning the taper phase. Measurements The percentage of participants in each taper group providing urine samples free of illicit opioids at the end of the taper and at follow-up. Findings At the end of the taper, 44% of the 7-day taper group (n = 255) provided opioid-free urine specimens compared to 30% of the 28-day taper group (n = 261; P = 0.0007). There were no differences at the 1-month and 3-month follow-ups (7-day = 18% and 12%; 28-day = 18% and 13%, 1 month and 3 months, respectively). Conclusion For individuals terminating buprenorphine pharmacotherapy for opioid dependence, there appears to be no advantage in prolonging the duration of taper. PMID:19149822

Development and initial evaluation of an enhanced measure of boundary flexibility for the work and family domains.

PubMed

Matthews, Russell A; Barnes-Farrell, Janet L

2010-07-01

This manuscript reports the development of a measure of work and family domain boundary flexibility. Building on previous research, we propose an expanded definition of boundary flexibility that includes two components-flexibility-ability and flexibility-willingness-and we develop a measure designed to capture this more comprehensive definition of boundary flexibility. Flexibility-ability is conceptualized as an individual's perception of personal and situational constraints that affect boundary management, and flexibility-willingness is conceptualized as an individual difference variable that captures the motivation to engage in boundary flexing. An additional feature of domain boundaries, permeability, is also examined. Data are presented from two studies. Study 1 (N = 244) describes the development of a multiscale measure that extends current conceptual definitions of boundary flexibility. Study 2 (N = 225) describes the refinement and evaluation of this measure. Confirmatory factor analysis, reliability evidence, interscale correlations, and correlations with important work-family constructs (e.g., domain centrality, work-family conflict) provide initial construct validity evidence for the measure.

Automatic CT simulation optimization for radiation therapy: A general strategy.

PubMed

Li, Hua; Yu, Lifeng; Anastasio, Mark A; Chen, Hsin-Chen; Tan, Jun; Gay, Hiram; Michalski, Jeff M; Low, Daniel A; Mutic, Sasa

2014-03-01

In radiation therapy, x-ray computed tomography (CT) simulation protocol specifications should be driven by the treatment planning requirements in lieu of duplicating diagnostic CT screening protocols. The purpose of this study was to develop a general strategy that allows for automatically, prospectively, and objectively determining the optimal patient-specific CT simulation protocols based on radiation-therapy goals, namely, maintenance of contouring quality and integrity while minimizing patient CT simulation dose. The authors proposed a general prediction strategy that provides automatic optimal CT simulation protocol selection as a function of patient size and treatment planning task. The optimal protocol is the one that delivers the minimum dose required to provide a CT simulation scan that yields accurate contours. Accurate treatment plans depend on accurate contours in order to conform the dose to actual tumor and normal organ positions. An image quality index, defined to characterize how simulation scan quality affects contour delineation, was developed and used to benchmark the contouring accuracy and treatment plan quality within the predication strategy. A clinical workflow was developed to select the optimal CT simulation protocols incorporating patient size, target delineation, and radiation dose efficiency. An experimental study using an anthropomorphic pelvis phantom with added-bolus layers was used to demonstrate how the proposed prediction strategy could be implemented and how the optimal CT simulation protocols could be selected for prostate cancer patients based on patient size and treatment planning task. Clinical IMRT prostate treatment plans for seven CT scans with varied image quality indices were separately optimized and compared to verify the trace of target and organ dosimetry coverage. Based on the phantom study, the optimal image quality index for accurate manual prostate contouring was 4.4. The optimal tube potentials for patient sizes of 38, 43, 48, 53, and 58 cm were 120, 140, 140, 140, and 140 kVp, respectively, and the corresponding minimum CTDIvol for achieving the optimal image quality index 4.4 were 9.8, 32.2, 100.9, 241.4, and 274.1 mGy, respectively. For patients with lateral sizes of 43-58 cm, 120-kVp scan protocols yielded up to 165% greater radiation dose relative to 140-kVp protocols, and 140-kVp protocols always yielded a greater image quality index compared to the same dose-level 120-kVp protocols. The trace of target and organ dosimetry coverage and the γ passing rates of seven IMRT dose distribution pairs indicated the feasibility of the proposed image quality index for the predication strategy. A general strategy to predict the optimal CT simulation protocols in a flexible and quantitative way was developed that takes into account patient size, treatment planning task, and radiation dose. The experimental study indicated that the optimal CT simulation protocol and the corresponding radiation dose varied significantly for different patient sizes, contouring accuracy, and radiation treatment planning tasks.

Chronic Exposure to Methamphetamine Disrupts Reinforcement-Based Decision Making in Rats.

PubMed

Groman, Stephanie M; Rich, Katherine M; Smith, Nathaniel J; Lee, Daeyeol; Taylor, Jane R

2018-03-01

The persistent use of psychostimulant drugs, despite the detrimental outcomes associated with continued drug use, may be because of disruptions in reinforcement-learning processes that enable behavior to remain flexible and goal directed in dynamic environments. To identify the reinforcement-learning processes that are affected by chronic exposure to the psychostimulant methamphetamine (MA), the current study sought to use computational and biochemical analyses to characterize decision-making processes, assessed by probabilistic reversal learning, in rats before and after they were exposed to an escalating dose regimen of MA (or saline control). The ability of rats to use flexible and adaptive decision-making strategies following changes in stimulus-reward contingencies was significantly impaired following exposure to MA. Computational analyses of parameters that track choice and outcome behavior indicated that exposure to MA significantly impaired the ability of rats to use negative outcomes effectively. These MA-induced changes in decision making were similar to those observed in rats following administration of a dopamine D2/3 receptor antagonist. These data use computational models to provide insight into drug-induced maladaptive decision making that may ultimately identify novel targets for the treatment of psychostimulant addiction. We suggest that the disruption in utilization of negative outcomes to adaptively guide dynamic decision making is a new behavioral mechanism by which MA rigidly biases choice behavior.

Effects of a promotor-based intervention to promote physical activity: Familias Sanas y Activas.

PubMed

Ayala, Guadalupe X

2011-12-01

This within-participants, single time-series study tested a train-the-trainer, promotor-based physical activity (PA) intervention to improve fitness and health indicators. Thirty unpaid promotores were trained to promote PA through free exercise classes. Measurements of 337 female community participants at baseline, 6 months, and 12 months assessed changes in health indicators, including systolic and diastolic blood pressure, waist circumference, body mass index (defined as weight in kilograms divided by the square of height in meters), aerobic fitness, and hamstring flexibility, as well as self-reported health indicators (PA, depression) and psychosocial factors (barriers, self-efficacy, and social support-all specific to PA). Mixed effects models showed intervention participation improved systolic blood pressure (P ≤ .001), waist circumference (P ≤ .001), fitness (P ≤ .001), and hamstring flexibility (P ≤ .001). We also noted improvements in use of community resources (P ≤ .05), depressed mood and anhedonia (P ≤ .01), perceived barriers to be physically active (P ≤ .05), and community support for PA (P ≤ .001). Self-efficacy decreased (P ≤ .05), and participation dose (i.e., exposure), as measured by attendance at exercise classes, was not associated with observed changes. Promotores can promote PA in their community and achieve meaningful changes in the residents' health.

Experimental testing of impact force on rigid and flexible barriers - A comparison

NASA Astrophysics Data System (ADS)

Nagl, Georg; Hübl, Johannes; Chiari, Michael

2016-04-01

The Trattenbach endangers the main western railway track of Austria by floods and debris flows. Three check dams for debris retention were built in the proximal fan area several decades ago. With regard to an improvement of the protective function, these structures have to be renewed. The recent concept of the uppermost barrier is a type of an energy dissipation net structure, stopping debris flows with the ability of self-cleaning by subsequent floods or by machinery employment. The access to the basin is achieved through the slit when the net has been removed. This technical structure consists of a rigid open crown dam with a 4m wide slit. This slit is closed with a flexible net. To verify this protective system, 21 small scale experiments were conducted to test and optimize this new type of Slit Net Dam. To determine the forces on the barrier, in a first setup of experiments the impact forces on a rigid wall with 24 load cells were measured. In the second setup the slit barrier with the net was investigated. On four main cables the anchor forces were measured. In a further setup the basal distance between the channel and lowest net was varied. To study the emptying of the basin and the dosing effect on debris flows.

Simulation analysis of resource flexibility on healthcare processes

PubMed Central

Simwita, Yusta W; Helgheim, Berit I

2016-01-01

Purpose This paper uses discrete event simulation to explore the best resource flexibility scenario and examine the effect of implementing resource flexibility on different stages of patient treatment process. Specifically we investigate the effect of resource flexibility on patient waiting time and throughput in an orthopedic care process. We further seek to explore on how implementation of resource flexibility on patient treatment processes affects patient access to healthcare services. We focus on two resources, namely, orthopedic surgeon and operating room. Methods The observational approach was used to collect process data. The developed model was validated by comparing the simulation output with actual patient data collected from the studied orthopedic care process. We developed different scenarios to identify the best resource flexibility scenario and explore the effect of resource flexibility on patient waiting time, throughput, and future changes in demand. The developed scenarios focused on creating flexibility on service capacity of this care process by altering the amount of additional human resource capacity at different stages of patient care process and extending the use of operating room capacity. Results The study found that resource flexibility can improve responsiveness to patient demand in the treatment process. Testing different scenarios showed that the introduction of resource flexibility reduces patient waiting time and improves throughput. The simulation results show that patient access to health services can be improved by implementing resource flexibility at different stages of the patient treatment process. Conclusion This study contributes to the current health care literature by explaining how implementing resource flexibility at different stages of patient care processes can improve ability to respond to increasing patients demands. This study was limited to a single patient process; studies focusing on additional processes are recommended. PMID:27785046

Simulation analysis of resource flexibility on healthcare processes.

PubMed

Simwita, Yusta W; Helgheim, Berit I

2016-01-01

This paper uses discrete event simulation to explore the best resource flexibility scenario and examine the effect of implementing resource flexibility on different stages of patient treatment process. Specifically we investigate the effect of resource flexibility on patient waiting time and throughput in an orthopedic care process. We further seek to explore on how implementation of resource flexibility on patient treatment processes affects patient access to healthcare services. We focus on two resources, namely, orthopedic surgeon and operating room. The observational approach was used to collect process data. The developed model was validated by comparing the simulation output with actual patient data collected from the studied orthopedic care process. We developed different scenarios to identify the best resource flexibility scenario and explore the effect of resource flexibility on patient waiting time, throughput, and future changes in demand. The developed scenarios focused on creating flexibility on service capacity of this care process by altering the amount of additional human resource capacity at different stages of patient care process and extending the use of operating room capacity. The study found that resource flexibility can improve responsiveness to patient demand in the treatment process. Testing different scenarios showed that the introduction of resource flexibility reduces patient waiting time and improves throughput. The simulation results show that patient access to health services can be improved by implementing resource flexibility at different stages of the patient treatment process. This study contributes to the current health care literature by explaining how implementing resource flexibility at different stages of patient care processes can improve ability to respond to increasing patients demands. This study was limited to a single patient process; studies focusing on additional processes are recommended.

The development of a modified human IFN-alpha2b linked to the Fc portion of human IgG1 as a novel potential therapeutic for the treatment of hepatitis C virus infection.

PubMed

Jones, Tim D; Hanlon, Marian; Smith, Beverley J; Heise, Charles T; Nayee, Prakash D; Sanders, Deborah A; Hamilton, Anita; Sweet, Clive; Unitt, Esther; Alexander, Graeme; Lo, Kin-Ming; Gillies, Stephen D; Carr, Frank J; Baker, Matthew P

2004-09-01

Interferon-alpha (IFN-alpha), in conjunction with ribavirin, is the current standard for the treatment of chronic hepatitis C virus (HCV) infection. This treatment requires frequent dosing, with a significant risk of the development of anti-IFN-alpha neutralizing antibodies that correlates with lack of efficacy or relapse. We have developed an IFN-alpha linked to the Fc region of human IgG1 for improved half-life and less frequent dosing. We have also identified, using a human T cell proliferation assay, three regions of IFN-alpha2b that are potentially immunogenic, and a variant containing a total of six mutations within these regions was made. This variant was made as a fusion to Fc either with or without a flexible linker between the fusion partners. Both configurations of the variant were less active than native IFN-alpha alone, although the variant containing the flexible linker had in vitro antiviral activity within the range of other modified IFN-alphas currently in clinical use. Peptides spanning the modified regions were tested in T cell proliferation assays and found to be less immunogenic than native controls when using peripheral blood mononuclear cells (PBMCs) from both healthy individuals and HCV-infected patients who had been treated previously with IFN-alpha2b. Copyright Mary Ann Liebert, Inc.

Measures of Potential Flexibility and Practical Flexibility in Equation Solving.

PubMed

Xu, Le; Liu, Ru-De; Star, Jon R; Wang, Jia; Liu, Ying; Zhen, Rui

2017-01-01

Researchers interested in mathematical proficiency have recently begun to explore the development of strategic flexibility, where flexibility is defined as knowledge of multiple strategies for solving a problem and the ability to implement an innovative strategy for a given problem solving circumstance. However, anecdotal findings from this literature indicate that students do not consistently use an innovative strategy for solving a given problem, even when these same students demonstrate knowledge of innovative strategies. This distinction, sometimes framed in the psychological literature as competence vs. performance-has not been previously studied for flexibility. In order to explore the competence/performance distinction in flexibility, this study developed and validated measures for potential flexibility (e.g., competence, or knowledge of multiple strategies) and practical flexibility (e.g., performance, use of innovative strategies) for solving equations. The measures were administrated to a sample of 158 Chinese middle school students through a Tri-Phase Flexibility Assessment, in which the students were asked to solve each equation, generate additional strategies, and evaluate own multiple strategies. Confirmatory factor analysis supported a two-factor model of potential and practical flexibility. Satisfactory internal consistency was found for the measures. Additional validity evidence included the significant association with flexibility measured with the previous method. Potential flexibility and practical flexibility were found to be distinct but related. The theoretical and practical implications of the concepts and their measures of potential flexibility and practical flexibility are discussed.

Measures of Potential Flexibility and Practical Flexibility in Equation Solving

PubMed Central

Xu, Le; Liu, Ru-De; Star, Jon R.; Wang, Jia; Liu, Ying; Zhen, Rui

2017-01-01

Researchers interested in mathematical proficiency have recently begun to explore the development of strategic flexibility, where flexibility is defined as knowledge of multiple strategies for solving a problem and the ability to implement an innovative strategy for a given problem solving circumstance. However, anecdotal findings from this literature indicate that students do not consistently use an innovative strategy for solving a given problem, even when these same students demonstrate knowledge of innovative strategies. This distinction, sometimes framed in the psychological literature as competence vs. performance—has not been previously studied for flexibility. In order to explore the competence/performance distinction in flexibility, this study developed and validated measures for potential flexibility (e.g., competence, or knowledge of multiple strategies) and practical flexibility (e.g., performance, use of innovative strategies) for solving equations. The measures were administrated to a sample of 158 Chinese middle school students through a Tri-Phase Flexibility Assessment, in which the students were asked to solve each equation, generate additional strategies, and evaluate own multiple strategies. Confirmatory factor analysis supported a two-factor model of potential and practical flexibility. Satisfactory internal consistency was found for the measures. Additional validity evidence included the significant association with flexibility measured with the previous method. Potential flexibility and practical flexibility were found to be distinct but related. The theoretical and practical implications of the concepts and their measures of potential flexibility and practical flexibility are discussed. PMID:28848481

Low-dose intrathecal fluorescein for diagnosis of cerebrospinal fluid rhinorrhea using the scanning fiber endoscope in the human nasal cavities

NASA Astrophysics Data System (ADS)

Hou, Vivian W.; Davis, Calvin G.; Davis, Greg E.; Seibel, Eric J.

2016-03-01

Intrathecal fluorescein (ITF) enhances detection of cerebrospinal fluid rhinorrhea (CSFR). Clinically administered doses fall in the range of 0.1ml to 0.5ml of 5% to 10% fluorescein (1.3×10-3M to 1.3×10-2M). Though uncommon, significant morbidities associated with high doses of fluorescein have been reported. High concentrations are necessary for white light visual assessment; in contrast, fluorescent imaging enhances signal contrast and requires lower ITF concentrations for visualization. The ultrathin and flexible, multimodal scanning fiber endoscope (SFE) can visualize nanomolar concentrations of fluorescein as pseudocolor over reflectance, video-rate imaging. The application of the SFE for CSFR detection was assessed in a cadaver study. Briefly, 10μM (1×10-5M) fluorescein, 100X-1000X less than the standard clinical dose, was injected intra-cranially into the epidural space through an orbital roof puncture. The resulting rhinorrhea was assessed with a conventional, rigid ENT scope and second with the SFE in both video reflectance and multimodal fluorescent imaging modes. Neither system could visualize the 10μM ITF during white light imaging however the nanomolar sensitive SFE visualized the rhinorrhea during fluorescent imaging. Despite the low concentration used, a target-to-background ratio of 5.6 +/- 2.7 was achieved. To demonstrate SFE guidance of CSFR detection and repair, de-identified patient computed tomography (CT) scans were used to generate 3D printed phantoms. Cases were selected for unique anatomical features and overall clinical difficulty as determined by an experienced ENT clinician (GED). The sensitivity and minimally invasive nature of the SFE provide a unique platform for enhancing diagnosis and monitoring interventions in surgical endoscopic approaches into the sinuses.

Edema worsens target coverage in high-dose-rate interstitial brachytherapy of mobile tongue cancer: a report of two cases.

PubMed

Yoshida, Ken; Yamazaki, Hideya; Kotsuma, Tadayuki; Akiyama, Hironori; Takenaka, Tadashi; Masui, Koji; Yoshioka, Yasuo; Uesugi, Yasuo; Shimbo, Taiju; Yoshikawa, Nobuhiko; Yoshioka, Hiroto; Arika, Takumi; Tanaka, Eiichi; Narumi, Yoshifumi

2017-02-01

We report our study on two patients to highlight the risk of underdosage of the clinical target volume (CTV) due to edema during high-dose-rate interstitial brachytherapy (HDR-ISBT) of mobile tongue cancer. To treat the lateral side of the CTV, flexible applicator tubes were implanted on the mouth floor. Two-dimensional planning was performed using X-ray images for Case 1, and three-dimensional (3D) planning was performed using computed tomography (CT) for Case 2. Prescribed doses for both cases were 54 Gy in nine fractions. Case 1 was treated for cancer of the right lateral border of the tongue in 2005. Tongue edema occurred after implantation, and part of the lateral border of the tongue protruded between the applicator tubes. Acute mucosal reaction abated in the protruded area earlier than in the other parts of the CTV. In this case, the tumor recurred in this area 5 months after the treatment. Case 2 was treated for cancer of the left lateral border of the tongue. Because tongue edema occurred in this case also, plastic splints were inserted between the applicator tubes to push the edematous region into the irradiated area. The mucosal surface of the CTV was covered by the 70% isodose, and 100% isodose line for before and after splint insertion. Local control of the tumor was achieved 4 years after treatment. To ensure sufficient target coverage, 3D image-based planning using CT should be performed, followed by re-planning using repeated CT as needed. Also, the development of devices to prevent protrusion of the edematous tissue outside the target area will help to ensure the full dosing of CTV.

The selective glycine uptake inhibitor org 25935 as an adjunctive treatment to atypical antipsychotics in predominant persistent negative symptoms of schizophrenia: results from the GIANT trial.

PubMed

Schoemaker, Joep H; Jansen, Wim T; Schipper, Jacques; Szegedi, Armin

2014-04-01

Using a selective glycine uptake inhibitor as adjunctive to second-generation antipsychotic (SGA) was hypothesized to ameliorate negative and/or cognitive symptoms in subjects with schizophrenia. Subjects with predominant persistent negative symptoms (previously stabilized ≥3 months on an SGA) were enrolled in a randomized, placebo-controlled trial to investigate adjunctive treatment with Org 25935, a selective inhibitor of type 1 glycine transporter, over 12 weeks in a flexible dose design. Org 25935 was tested at 4 to 8 mg twice daily and 12 to 16 mg twice daily versus placebo. Primary efficacy outcome was mean change from baseline in Scale for Assessment of Negative Symptoms composite score. Secondary efficacy end points were Positive and Negative Syndrome Scale total and subscale scores, depressive symptoms (Calgary Depression Scale for Schizophrenia), global functioning (Global Assessment of Functioning scale), and cognitive measures using a computerized battery (Central Nervous System Vital Signs). Responder rates were assessed post hoc. A total of 215 subjects were randomized, of which 187 (87%) completed the trial. Both dose groups of Org 25935 did not differ significantly from placebo on Scale for Assessment of Negative Symptoms, Positive and Negative Syndrome Scale (total or subscale scores), Global Assessment of Functioning, or the majority of tested cognitive domains. Org 25935 was generally well tolerated within the tested dose range, with no meaningful effects on extrapyramidal symptoms and some reports of reversible visual adverse effects. Org 25935 did not differ significantly from placebo in reducing negative symptoms or improving cognitive functioning when administered as adjunctive treatment to SGA. In our study population, Org 25935 appeared to be well tolerated in the tested dose ranges.

Vagal Flexibility: A Physiological Predictor of Social Sensitivity

PubMed Central

Muhtadie, Luma; Akinola, Modupe; Koslov, Katrina; Mendes, Wendy Berry

2015-01-01

This research explores vagal flexibility— dynamic modulation of cardiac vagal control—as an individual-level physiological index of social sensitivity. In 4 studies, we test the hypothesis that individuals with greater cardiac vagal flexibility, operationalized as higher cardiac vagal tone at rest and greater cardiac vagal withdrawal (indexed by a decrease in respiratory sinus arrhythmia) during cognitive or attentional demand, perceive social-emotional information more accurately and show greater sensitivity to their social context. Study 1 sets the foundation for this investigation by establishing that vagal flexibility can be elicited consistently in the laboratory and reliably over time. Study 2 demonstrates that vagal flexibility has different associations with psychological characteristics than does vagal tone, and that these characteristics are primarily social in nature. Study 3 links individual differences in vagal flexibility with accurate detection of social and emotional cues depicted in still facial images. Study 4 demonstrates that individuals with greater vagal flexibility respond to dynamic social feedback in a more context-sensitive manner than do individuals with less vagal flexibility. Specifically, compared with their less flexible counterparts, individuals with greater vagal flexibility, when assigned to receive negative social feedback, report more shame, show more pronounced blood pressure responses, and display less sociable behavior, but when receiving positive social feedback display more sociable behavior. Taken together, these findings suggest that vagal flexibility is a useful individual difference physiological predictor of social sensitivity, which may have implications for clinical, developmental, and health psychologists. PMID:25545841

Dropwise additive manufacturing of pharmaceutical products for amorphous and self emulsifying drug delivery systems.

PubMed

Içten, Elçin; Purohit, Hitesh S; Wallace, Chelsey; Giridhar, Arun; Taylor, Lynne S; Nagy, Zoltan K; Reklaitis, Gintaras V

2017-05-30

The improvements in healthcare systems and the advent of the precision medicine initiative have created the need to develop more innovative manufacturing methods for the delivery and production of individualized dosing and personalized treatments. In accordance with the changes observed in healthcare systems towards more innovative therapies, this paper presents dropwise additive manufacturing of pharmaceutical products (DAMPP) for small scale, distributed manufacturing of individualized dosing as an alternative to conventional manufacturing methods A dropwise additive manufacturing process for amorphous and self-emulsifying drug delivery systems is reported, which utilizes drop-on-demand printing technology for automated and controlled deposition of melt-based formulations onto inert tablets. The advantages of drop on demand technology include reproducible production of droplets with adjustable sizing and high placement accuracy, which enable production of individualized dosing even for low dose and high potency drugs. Flexible use of different formulations, such as lipid-based formulations, allows enhancement of the solubility of poorly water soluble and highly lipophilic drugs with DAMPP. Here, DAMPP is used to produce solid oral dosage forms from melts of an active pharmaceutical ingredient and a surfactant. The dosage forms are analyzed to show the amorphous nature, self-emulsifying drug delivery system characteristics and dissolution behavior of these formulations. Copyright © 2017 Elsevier B.V. All rights reserved.

Flexible organic TFT bio-signal amplifier using reliable chip component assembly process with conductive adhesive.

PubMed

Yoshimoto, Shusuke; Uemura, Takafumi; Akiyama, Mihoko; Ihara, Yoshihiro; Otake, Satoshi; Fujii, Tomoharu; Araki, Teppei; Sekitani, Tsuyoshi

2017-07-01

This paper presents a flexible organic thin-film transistor (OTFT) amplifier for bio-signal monitoring and presents the chip component assembly process. Using a conductive adhesive and a chip mounter, the chip components are mounted on a flexible film substrate, which has OTFT circuits. This study first investigates the assembly technique reliability for chip components on the flexible substrate. This study also specifically examines heart pulse wave monitoring conducted using the proposed flexible amplifier circuit and a flexible piezoelectric film. We connected the amplifier to a bluetooth device for a wearable device demonstration.

Efficacy and Safety of Paliperidone Palmitate 3-Month Formulation for Patients with Schizophrenia: A Randomized, Multicenter, Double-Blind, Noninferiority Study

PubMed Central

Xu, Haiyan; Gopal, Srihari; Nuamah, Isaac; Ravenstijn, Paulien; Janik, Adam; Schotte, Alain; Hough, David; Fleischhacker, Wolfgang W.

2016-01-01

Background: This double-blind, parallel-group, multicenter, phase-3 study was designed to test the noninferiority of paliperidone palmitate 3-month formulation (PP3M) to the currently marketed 1-month formulation (PP1M) in patients (age 18–70 years) with schizophrenia, previously stabilized on PP1M. Methods: After screening (≤3 weeks) and a 17-week, flexible-dosed, open-label phase (PP1M: day 1 [150mg eq. deltoid], day 8 [100mg eq. deltoid.], weeks 5, 9, and 13 [50, 75, 100, or 150mg eq., deltoid/gluteal]), clinically stable patients were randomized (1:1) to PP3M (fixed-dose, 175, 263, 350, or 525mg eq. deltoid/gluteal) or PP1M (fixed-dose, 50, 75, 100, or 150mg eq. deltoid/gluteal) for a 48-week double-blind phase. Results: Overall, 1016/1429 open-label patients entered the double-blind phase (PP3M: n=504; PP1M: n=512) and 842 completed it (including patients with relapse). PP3M was noninferior to PP1M: relapse rates were similar in both groups (PP3M: n=37, 8%; PP1M: n=45, 9%; difference in relapse-free rate: 1.2% [95% CI:-2.7%; 5.1%]) based on Kaplan-Meier estimates (primary efficacy). Secondary endpoint results (changes from double-blind baseline in positive and negative symptom score total and subscale scores, Clinical Global Impression-Severity, and Personal and Social Performance scores) were consistent with primary endpoint results. No clinically relevant differences were observed in pharmacokinetic exposures between PP3M and PP1M. Both groups had similar tolerability profiles; increased weight was the most common treatment-emergent adverse event (double-blind phase; 21% each). No new safety signals were detected. Conclusion: Taken together, PP3M with its 3-month dosing interval is a unique option for relapse prevention in schizophrenia. PMID:26902950

Retrospective review of Contura HDR breast cases to improve our standardized procedure

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

Iftimia, Ileana, E-mail: Ileana.n.iftimia@lahey.org; Cirino, Eileen T.; Ladd, Ron

2013-07-01

To retrospectively review our first 20 Contura high dose rate breast cases to improve and refine our standardized procedure and checklists. We prepared in advance checklists for all steps, developed an in-house Excel spreadsheet for second checking the plan, and generated a procedure for efficient contouring and a set of optimization constraints to meet the dose volume histogram criteria. Templates were created in our treatment planning system for structures, isodose levels, optimization constraints, and plan report. This study reviews our first 20 high dose rate Contura breast treatment plans. We followed our standardized procedure for contouring, planning, and second checking.more » The established dose volume histogram criteria were successfully met for all plans. For the cases studied here, the balloon-skin and balloon-ribs distances ranged between 5 and 43 mm and 1 and 33 mm, respectively; air{sub s}eroma volume/PTV{sub E}val volume≤5.5% (allowed≤10%); asymmetry<1.2 mm (goal≤2 mm); PTV{sub E}val V90%≥97.6%; PTV{sub E}val V95%≥94.9%; skin max dose≤98%Rx; ribs max dose≤137%Rx; V150%≤29.8 cc; V200%≤7.8 cc; the total dwell time range was 225.4 to 401.9 seconds; and the second check agreement was within 3%. Based on this analysis, more appropriate ranges for the total dwell time and balloon diameter tolerance were found. Three major problems were encountered: balloon migration toward the skin for small balloon-to-skin distances, lumen obstruction, and length change for the flexible balloon. Solutions were found for these issues and our standardized procedure and checklists were updated accordingly. Based on our review of these cases, the use of checklists resulted in consistent results, indicating good coverage for the target without sacrificing the critical structures. This review helped us to refine our standardized procedure and update our checklists.« less

SU-F-J-178: A Computer Simulation Model Observer for Task-Based Image Quality Assessment in Radiation Therapy

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

Dolly, S; Mutic, S; Anastasio, M

Purpose: Traditionally, image quality in radiation therapy is assessed subjectively or by utilizing physically-based metrics. Some model observers exist for task-based medical image quality assessment, but almost exclusively for diagnostic imaging tasks. As opposed to disease diagnosis, the task for image observers in radiation therapy is to utilize the available images to design and deliver a radiation dose which maximizes patient disease control while minimizing normal tissue damage. The purpose of this study was to design and implement a new computer simulation model observer to enable task-based image quality assessment in radiation therapy. Methods: A modular computer simulation framework wasmore » developed to resemble the radiotherapy observer by simulating an end-to-end radiation therapy treatment. Given images and the ground-truth organ boundaries from a numerical phantom as inputs, the framework simulates an external beam radiation therapy treatment and quantifies patient treatment outcomes using the previously defined therapeutic operating characteristic (TOC) curve. As a preliminary demonstration, TOC curves were calculated for various CT acquisition and reconstruction parameters, with the goal of assessing and optimizing simulation CT image quality for radiation therapy. Sources of randomness and bias within the system were analyzed. Results: The relationship between CT imaging dose and patient treatment outcome was objectively quantified in terms of a singular value, the area under the TOC (AUTOC) curve. The AUTOC decreases more rapidly for low-dose imaging protocols. AUTOC variation introduced by the dose optimization algorithm was approximately 0.02%, at the 95% confidence interval. Conclusion: A model observer has been developed and implemented to assess image quality based on radiation therapy treatment efficacy. It enables objective determination of appropriate imaging parameter values (e.g. imaging dose). Framework flexibility allows for incorporation of additional modules to include any aspect of the treatment process, and therefore has great potential for both assessment and optimization within radiation therapy.« less

Contribution of N-methyl-D-aspartate receptors to attention and episodic spatial memory during senescence

PubMed Central

Guidi, Michael; Rani, Asha; Karic, Semir; Severance, Barrett; Kumar, Ashok; Foster, Thomas C.

2015-01-01

A decrease in N-methyl-D-aspartate receptor (NMDAR) function is associated with age-related cognitive impairments. However, NMDAR antagonists are prescribed for cognitive decline associated with age-related neurodegenerative disease, raising questions as to the role of NMDAR activity in cognitive function during aging. The current studies examined effects of NMDAR blockade on cognitive task that are sensitive to aging. Young and middle-age rats were trained on the five-choice serial reaction time task (5-CSRTT) and challenged with MK-801 (0.025, 0.05, and 0.1 mg/kg or vehicle). Attention deficits were apparent in middle-age and performance of young and middle-age rats was enhanced for low doses of MK-801 (0.025 and 0.05). The beneficial effects on attention were reversed by the highest dose of MK-801. Older animals exhibited a delay-dependent impairment of episodic spatial memory examined on a delayed-matching to place water maze task. Similarly, a low dose of MK-801 (0.05 mg/kg) impaired performance with increasing delay and aged animals were more susceptible to disruption by NMDAR blockade. Despite MK-801 impairment of episodic spatial memory, MK-801 had minimal effects on spatial reference memory. Our results confirm that NMDARs contribute to rapidly acquired and flexible spatial memory and support the idea that a decline in NMDAR function contributes to the age-related impairments in cognition. PMID:26234588

Contribution of N-methyl-D-aspartate receptors to attention and episodic spatial memory during senescence.

PubMed

Guidi, Michael; Rani, Asha; Karic, Semir; Severance, Barrett; Kumar, Ashok; Foster, Thomas C

2015-11-01

A decrease in N-methyl-D-aspartate receptor (NMDAR) function is associated with age-related cognitive impairments. However, NMDAR antagonists are prescribed for cognitive decline associated with age-related neurodegenerative disease, raising questions as to the role of NMDAR activity in cognitive function during aging. The current studies examined effects of NMDAR blockade on cognitive task that are sensitive to aging. Young and middle-age rats were trained on the five-choice serial reaction time task (5-CSRTT) and challenged with MK-801 (0.025, 0.05, and 0.1mg/kg or vehicle). Attention deficits were apparent in middle-age and performance of young and middle-age rats was enhanced for low doses of MK-801 (0.025 and 0.05). The beneficial effects on attention were reversed by the highest dose of MK-801. Older animals exhibited a delay-dependent impairment of episodic spatial memory examined on a delayed-matching to place water maze task. Similarly, a low dose of MK-801 (0.05mg/kg) impaired performance with increasing delay and aged animals were more susceptible to disruption by NMDAR blockade. Despite MK-801 impairment of episodic spatial memory, MK-801 had minimal effects on spatial reference memory. Our results confirm that NMDARs contribute to rapidly acquired and flexible spatial memory and support the idea that a decline in NMDAR function contributes to the age-related impairments in cognition. Copyright © 2015 Elsevier Inc. All rights reserved.

Self-Mobilization Using a Foam Roller Versus a Roller Massager: Which Is More Effective for Increasing Hamstrings Flexibility?

PubMed

DeBruyne, Danielle M; Dewhurst, Marina M; Fischer, Katelyn M; Wojtanowski, Michael S; Durall, Chris

2017-01-01

Clinical Scenario: Increasing the length of the muscle-tendon unit may prevent musculotendinous injury. Various methods have been proposed to increase muscle-tendon flexibility, including self-mobilization using foam rollers or roller massagers, although the effectiveness of these devices is uncertain. This review was conducted to determine if the use of foam rollers or roller massagers to improve hamstrings flexibility is supported by moderate- to high-quality evidence. Are foam rollers or roller massagers effective for increasing hamstrings flexibility in asymptomatic physically active adults? Summary of Key Findings: The literature was searched for studies on the effects of using foam rollers or roller massagers to increase hamstrings flexibility in asymptomatic physically active adults. Four randomized controlled trials were included; 2 studies provided level 2 or 3 evidence regarding foam rollers and 2 studies provided level 2 or 3 evidence regarding roller massagers. Both roller-massager studies reported increases in hamstrings flexibility after treatment. Data from the foam-roller studies did not demonstrate a statistically significant increase in hamstrings flexibility, but 1 study did demonstrate a strong effect size. Clinical Bottom Line: The reviewed moderate-quality studies support the use of roller massagers but provide limited evidence on the effectiveness of foam rolling to increase hamstrings flexibility in asymptomatic physically active adults. Flexibility gains may be improved by a longer duration of treatment and administration by a trained therapist. Gains appear to decline rapidly postrolling. Neither device has been shown to confer a therapeutic benefit superior to static stretching, and the effectiveness of these devices for preventing injury is unknown. Strength of Recommendation: Grade B evidence supports the use of roller massagers to increase hamstrings flexibility in asymptomatic physically active adults.

Low-dose-rate or high-dose-rate brachytherapy in treatment of prostate cancer – between options

PubMed Central

2013-01-01

Purpose Permanent low-dose-rate (LDR-BT) and temporary high-dose-rate (HDR-BT) brachytherapy are competitive techniques for clinically localized prostate radiotherapy. Although a randomized trial will likely never to be conducted comparing these two forms of brachytherapy, a comparative analysis proves useful in understanding some of their intrinsic differences, several of which could be exploited to improve outcomes. The aim of this paper is to look for possible similarities and differences between both brachytherapy modalities. Indications and contraindications for monotherapy and for brachytherapy as a boost to external beam radiation therapy (EBRT) are presented. It is suggested that each of these techniques has attributes that advocates for one or the other. First, they represent the extreme ends of the spectrum with respect to dose rate and fractionation, and therefore have inherently different radiobiological properties. Low-dose-rate brachytherapy has the great advantage of being practically a one-time procedure, and enjoys a long-term follow-up database supporting its excellent outcomes and low morbidity. Low-dose-rate brachytherapy has been a gold standard for prostate brachytherapy in low risk patients since many years. On the other hand, HDR is a fairly invasive procedure requiring several sessions associated with a brief hospital stay. Although lacking in significant long-term data, it possesses the technical advantage of control over its postimplant dosimetry (by modulating the source dwell time and position), which is absent in LDR brachytherapy. This important difference in dosimetric control allows HDR doses to be escalated safely, a flexibility that does not exist for LDR brachytherapy. Conclusions Radiobiological models support the current clinical evidence for equivalent outcomes in localized prostate cancer with either LDR or HDR brachytherapy, using current dose regimens. At present, all available clinical data regarding these two techniques suggests that they are equally effective, stage for stage, in providing high tumor control rates. PMID:23634153

Effects of dietary calcium fructoborate supplementation on joint comfort and flexibility and serum inflammatory markers in dogs with osteoarthritis.

PubMed

Price, A K; de Godoy, M R C; Harper, T A; Knap, K E; Joslyn, S; Pietrzkowski, Z; Cross, B K; Detweiler, K B; Swanson, K S

2017-07-01

Our objective was to evaluate the short-term effects of calcium fructoborate (CFB) on gait, joint range of motion, serum inflammatory markers, and owner perception of pain in client-owned dogs. We used 59 osteoarthritic dogs with impairment, with dogs being randomly assigned to 4 treatments: placebo (60 mg fructose; = 15), low dose (69 mg CFB; = 14), high dose (127 mg CFB; = 14), or combination (69 mg CFB, 500 mg glucosamine hydrochloride and 200 mg chondroitin sulfate; = 16). Dogs up to 22.9 kg received 1 capsule/d, while dogs weighing 23 to 50 kg received 2 capsules/d. A physical examination, radiographs, goniometry measurements, gait analysis, blood sample collection, and a canine brief pain inventory questionnaire were performed on d 0 and 28. Change from baseline values were statistically analyzed among groups. After 28 d, dogs fed the low and high doses had an improved ( < 0.05) ability to rise from a lying position compared to placebo. Dogs fed the high dose also had a greater ( = 0.05) increase in soluble receptor for advanced glycation end products concentration than dogs fed the placebo. Sub-analysis of only large dogs (> 23 kg) showed that dogs fed the low dose had decreased ( < 0.05) pain severity score and pain at its worst compared to dogs fed the placebo. Large dogs fed the low dose also were shown to improve ( < 0.05) in their ability to rise from a lying position compared to dogs fed the placebo. Overall, CFB supplementation was well-tolerated and may aid in mitigating joint discomfort in dogs.

Demystifying cognitive flexibility: Implications for clinical and developmental neuroscience

PubMed Central

Dajani, Dina R.; Uddin, Lucina Q.

2015-01-01

Cognitive flexibility, the readiness with which one can selectively switch between mental processes to generate appropriate behavioral responses, develops in a protracted manner and is compromised in several prevalent neurodevelopmental disorders. It is unclear whether cognitive flexibility arises from neural substrates distinct from the executive control network, or from the interplay of nodes within this and other networks. Here we review neuroimaging studies of cognitive flexibility, focusing on set shifting and task switching. We propose that more consistent operationalization and study of cognitive flexibility is required in clinical and developmental neuroscience. We suggest that an important avenue for future research is the characterization of the relationship between neural flexibility and cognitive flexibility in typical and atypical development. PMID:26343956

Compounding of vitamin A, D3, E and K3 supplements for cystic fibrosis patients: formulation and stability study.

PubMed

Huyghebaert, N; De Beer, J; Vervaet, C; Remon, J P

2007-10-01

Cystic fibrosis (CF) patients suffer from malabsorption of fat-soluble vitamins (A, D, E and K). These vitamins are available as water-dispersible (A, D(3) and E) or water-soluble grades (K(3)), which is favoured in CF patients as they fail to absorb oil-based products. The objective of this study was to determine stability of these raw materials after opening the original package and to develop a compounded formulation of acceptable quality, stability and taste, allowing flexible dose adaptation and being appropriate for administration to children and elderly people. The raw materials were stored after opening their original package for 8 months at 8 degrees C and room temperature (RT). Stability was assessed using a validated HPLC method after extraction of the vitamin from the cold water-soluble matrix (vitamin A acetate, D(3) and E) or using a spectrophotometrical method (vitamin K(3)). These materials were mixed with an appropriate lactose grade (lactose 80 m for vitamins A and D(3); lactose 90 m for vitamin E, lactose very fine powder for vitamin K(3)) and filled in hard gelatin capsules. Mass and content uniformity were determined and stability of the vitamins in the capsules was assessed after 2 months storage at 8 degrees C and RT. All raw materials showed good stability during storage in the opened original package for 8 months storage at 8 degrees C as well as RT (>95% of the initial content). The compounded formulations complied with the requirements of the European Pharmacopoeia for mass and content uniformity and can be stored for 2 months at 8 degrees C or RT while maintaining the vitamin content between 90% and 110%. As these fat-soluble vitamins are not commercially available on the Belgian market, compounded formulations are a valuable alternative for prophylactic administration of these vitamins to CF patients, i.e. a stable formulation, having an acceptable taste, allowing flexible dose adaptation and being appropriate for administration to children and elderly people.

Selective control of cortical axonal spikes by a slowly inactivating K+ current

PubMed Central

Shu, Yousheng; Yu, Yuguo; Yang, Jing; McCormick, David A.

2007-01-01

Neurons are flexible electrophysiological entities in which the distribution and properties of ionic channels control their behaviors. Through simultaneous somatic and axonal whole-cell recording of layer 5 pyramidal cells, we demonstrate a remarkable differential expression of slowly inactivating K+ currents. Depolarizing the axon, but not the soma, rapidly activated a low-threshold, slowly inactivating, outward current that was potently blocked by low doses of 4-aminopyridine, α-dendrotoxin, and rTityustoxin-Kα. Block of this slowly inactivating current caused a large increase in spike duration in the axon but only a small increase in the soma and could result in distal axons generating repetitive discharge in response to local current injection. Importantly, this current was also responsible for slow changes in the axonal spike duration that are observed after somatic membrane potential change. These data indicate that low-threshold, slowly inactivating K+ currents, containing Kv1.2 α subunits, play a key role in the flexible properties of intracortical axons and may contribute significantly to intracortical processing. PMID:17581873

Ultrathin Two-Dimensional Covalent Organic Framework Nanosheets: Preparation and Application in Highly Sensitive and Selective DNA Detection.

PubMed

Peng, Yongwu; Huang, Ying; Zhu, Yihan; Chen, Bo; Wang, Liying; Lai, Zhuangchai; Zhang, Zhicheng; Zhao, Meiting; Tan, Chaoliang; Yang, Nailiang; Shao, Fangwei; Han, Yu; Zhang, Hua

2017-06-28

The ability to prepare ultrathin two-dimensional (2D) covalent organic framework (COF) nanosheets (NSs) in high yield is of great importance for the further exploration of their unique properties and potential applications. Herein, by elaborately designing and choosing two flexible molecules with C 3v molecular symmetry as building units, a novel imine-linked COF, namely, TPA-COF, with a hexagonal layered structure and sheet-like morphology, is synthesized. Since the flexible building units are integrated into the COF skeletons, the interlayer stacking becomes weak, resulting in the easy exfoliation of TPA-COF into ultrathin 2D NSs. Impressively, for the first time, the detailed structural information, i.e., the pore channels and individual building units in the NSs, is clearly visualized by using the recently developed low-dose imaging technique of transmission electron microscopy (TEM). As a proof-of-concept application, the obtained ultrathin COF NSs are used as a novel fluorescence sensing platform for the highly sensitive and selective detection of DNA.

Electric System Flexibility and Storage | Energy Analysis | NREL

Science.gov Websites

. Featured Studies India Renewable Integration Study Grid Flexibility and Storage Required To Achieve Very demand-in Texas. Key findings from this study include: A highly flexible system with must-run baseload . Publications Renewable Electricity Futures Study. Volume 2: Renewable Electricity Generation and Storage

Proposed changes for part N of suggested state regulations

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

Paris, R.

1997-02-01

This paper discusses proposed changes for Part N regulations regarding naturally occuring radioactive materials. It describes the work of the Commission on NORM of the Conference of Radiation Control Program Directors (CRCPD), toward adjusting the regulations. A set of questions was formulated and a review panel established to address these questions and come back with recommended actions. The panel recommended the distinction that the material being regulated is `Technologically Enhanced Naturally Occurring Radioactive Material` (TENORM). By this they mean `naturally occurring radioactive material not regulated under the Atomic Energy Act (AEA) whose radionuclide concentrations have been increased by or asmore » a result of human practices.` Recommendations also include: using a dose based instead of concentration based standard; refined definition of exemptions from regulations; exclusion of radon from Total Effective Dose Equivalent (TEDE) calculations; provide states flexibility in implementation; inclusion of prospective remedial and operations aspects for TENORM; provision of institutional controls.« less

SynergyFinder: a web application for analyzing drug combination dose-response matrix data.

PubMed

Ianevski, Aleksandr; He, Liye; Aittokallio, Tero; Tang, Jing

2017-08-01

Rational design of drug combinations has become a promising strategy to tackle the drug sensitivity and resistance problem in cancer treatment. To systematically evaluate the pre-clinical significance of pairwise drug combinations, functional screening assays that probe combination effects in a dose-response matrix assay are commonly used. To facilitate the analysis of such drug combination experiments, we implemented a web application that uses key functions of R-package SynergyFinder, and provides not only the flexibility of using multiple synergy scoring models, but also a user-friendly interface for visualizing the drug combination landscapes in an interactive manner. The SynergyFinder web application is freely accessible at https://synergyfinder.fimm.fi ; The R-package and its source-code are freely available at http://bioconductor.org/packages/release/bioc/html/synergyfinder.html . jing.tang@helsinki.fi. © The Author(s) 2017. Published by Oxford University Press.

Treatment of cancer micrometastasis using a multicomponent chain-like nanoparticle.

PubMed

Peiris, Pubudu M; Toy, Randall; Abramowski, Aaron; Vicente, Pete; Tucci, Samantha; Bauer, Lisa; Mayer, Aaron; Tam, Morgan; Doolittle, Elizabeth; Pansky, Jenna; Tran, Emily; Lin, Dishen; Schiemann, William P; Ghaghada, Ketan B; Griswold, Mark A; Karathanasis, Efstathios

2014-01-10

While potent cytotoxic agents are available to oncologists, the clinical utility of these agents is limited due to their non-specific distribution in the body and toxicity to normal tissues leading to use of suboptimal doses for eradication of metastatic disease. Furthermore, treatment of micrometastases is impeded by several biobarriers, including their small size and high dispersion to organs, making them nearly inaccessible to drugs. To circumvent these limitations in treating metastatic disease, we developed a multicomponent, flexible chain-like nanoparticle (termed nanochain) that possesses a unique ability to gain access to and be deposited at micrometastatic sites. Moreover, coupling nanochain particles to radiofrequency (RF)-triggered cargo delivery facilitated widespread delivery of drug into hard-to-reach cancer cells. Collectively, these features synergistically facilitate effective treatment and ultimately eradication of micrometastatic disease using a low dose of a cytotoxic drug. © 2013.

Clinical pharmacokinetics and pharmacodynamics of repaglinide.

PubMed

Hatorp, Vibeke

2002-01-01

Repaglinide is a novel, fast-acting prandial oral hypoglycaemic agent developed for the treatment of patients with type 2 diabetes whose disease cannot be controlled by diet and exercise alone. Although repaglinide binds to the sulphonylurea binding sites on pancreatic beta-cells and has a similar mechanism of action, repaglinide exhibits distinct pharmacological properties compared with these agents. Following administration, repaglinide is absorbed rapidly and has a fast onset of dose-dependent blood-glucose lowering effect. The drug is eliminated rapidly via the biliary route, without accumulation in the plasma after multiple doses. Repaglinide is well tolerated in patients with type 2 diabetes, including elderly patients and patients with hepatic or renal impairment. The pharmacokinetic profile of repaglinide and the improvements in post-prandial hyperglycaemia and overall glycaemic control make repaglinide suitable for administration preprandially, with the opportunity for flexible meal arrangements, including skipped meals, without the risk of hypoglycaemia.

Repaglinide: a new short-acting insulinotropic agent for the treatment of type 2 diabetes.

PubMed

Owens, D R

1999-06-01

Repaglinide, a carbamoylmethyl benzoic acid derivative, is rapidly absorbed, metabolized by the liver and eliminated primarily via the bile. It has a short duration of action and is taken immediately before each main meal. This regimen has been shown to provide superior glycaemic control compared with regular morning and evening dosing. A flexible preprandial only dosing regimen of repaglinide significantly lowers the risk of hypoglycaemia if a meal is missed or postponed. Combination therapy with metformin improves glycaemic control significantly compared with therapy with either drug alone in overweight patients. Repaglinide has an equivalent safety and efficacy profile to the sulphonylureas, although it is superior to glipizide in maintaining long-term glycaemic control The postprandial glucose levels are significantly lower with repaglinide compared with glibenclamide. In naive patients with Type 2 diabetes, repaglinide lowers fasting glucose concentrations and functions also as a prandial glucose regulator.

[Respiratory pathology of isocyanates].

PubMed

Chailleux, E; Dupas, D; Geraut, C; Moigneteau, C; Pariente, R

1983-01-01

Isocyanates are chemical compounds used in making polyurethane (for flexible or rigid foam, paint, varnish, glue and textiles). In strong concentrations isocyanates are powerful irritants producing chemical bronchopulmonary lesions. In weak doses they are responsible for occupational asthma and more rarely allergic alveolitis. Long term exposure to isocyanates may produce a deterioration in pulmonary function in asymptomatic patients. The pathophysiology of isocyanate asthma remains uncertain: immunological data remains contradictory while isocyanates have been shown to have a Betablocking effect. The maximum allowable concentration in the working environment, at present proposed in the U.S.A. is 0.005 ppm.

Initial characterization, dosimetric benchmark and performance validation of Dynamic Wave Arc.

PubMed

Burghelea, Manuela; Verellen, Dirk; Poels, Kenneth; Hung, Cecilia; Nakamura, Mitsuhiro; Dhont, Jennifer; Gevaert, Thierry; Van den Begin, Robbe; Collen, Christine; Matsuo, Yukinori; Kishi, Takahiro; Simon, Viorica; Hiraoka, Masahiro; de Ridder, Mark

2016-04-29

Dynamic Wave Arc (DWA) is a clinical approach designed to maximize the versatility of Vero SBRT system by synchronizing the gantry-ring noncoplanar movement with D-MLC optimization. The purpose of this study was to verify the delivery accuracy of DWA approach and to evaluate the potential dosimetric benefits. DWA is an extended form of VMAT with a continuous varying ring position. The main difference in the optimization modules of VMAT and DWA is during the angular spacing, where the DWA algorithm does not consider the gantry spacing, but only the Euclidian norm of the ring and gantry angle. A preclinical version of RayStation v4.6 (RaySearch Laboratories, Sweden) was used to create patient specific wave arc trajectories for 31 patients with various anatomical tumor regions (prostate, oligometatstatic cases, centrally-located non-small cell lung cancer (NSCLC) and locally advanced pancreatic cancer-LAPC). DWA was benchmarked against the current clinical approaches and coplanar VMAT. Each plan was evaluated with regards to dose distribution, modulation complexity (MCS), monitor units and treatment time efficiency. The delivery accuracy was evaluated using a 2D diode array that takes in consideration the multi-dimensionality of DWA during dose reconstruction. In centrally-located NSCLC cases, DWA improved the low dose spillage with 20 %, while the target coverage was increased with 17 % compared to 3D CRT. The structures that significantly benefited from using DWA were proximal bronchus and esophagus, with the maximal dose being reduced by 17 % and 24 %, respectively. For prostate and LAPC, neither technique seemed clearly superior to the other; however, DWA reduced with more than 65 % of the delivery time over IMRT. A steeper dose gradient outside the target was observed for all treatment sites (p < 0.01) with DWA. Except the oligometastatic cases, where the DWA-MCSs indicate a higher modulation, both DWA and VMAT modalities provide plans of similar complexity. The average ɣ (3 % /3 mm) passing rate for DWA plans was 99.2 ± 1 % (range from 96.8 to 100 %). DWA proven to be a fully functional treatment technique, allowing additional flexibility in dose shaping, while preserving dosimetrically robust delivery and treatment times comparable with coplanar VMAT.

SU-E-T-412: Evaluation of Tungsten-Based Functional Paper for Attenuation Device in Intraoperative Radiotherapy for Breast Cancer

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

Kamomae, T; Monzen, H; Okudaira, K

Purpose: Intraoperative radiotherapy (IORT) with an electron beam is one of the accelerated partial breast irradiation methods that have recently been used in early-stage breast cancer. A protective acrylic resin-copper disk is inserted between the breast tissue and the pectoralis muscle to minimize the dose received by the posterior structures. However, a problem with this protective disk is that the surgical incision must be larger than the field size because the disk is manufactured from stiff and unyielding materials. The purpose of this study was to assess the applicability of a new tungsten-based functional paper (TFP) as an alternative tomore » the existing protective disk in IORT. Methods: The newly introduced TFP (Toppan Printing Co., Ltd., Tokyo, JP) is anticipated to become a useful device that is lead-free, light, flexible, and easily processed. The radiation shielding performance of TFP was verified by experimental measurements and Monte Carlo (MC) simulations using PHITS code. The doses transmitted through the protective disk or TFP were measured on a Mobetron mobile accelerator. The same geometries were then reproduced, and the dose distributions were simulated by the MC method. Results: The percentages of transmitted dose relative to the absence of the existing protective disk were lower than 2% in both the measurements and MC simulations. In the experimental measurements, the percentages of transmitted dose for a 9 MeV electron beam were 48.1, 2.3, and 0.6% with TFP thicknesses of 1.9, 3.7, and 7.4 mm, respectively. The percentages for a 12 MeV were 76.0, 49.3, 20.0, and 5.5% with TFP thicknesses of 1.9, 3.7, 7.4, and 14.8 mm, respectively. The results of the MC simulation showed a slight dose increase at the incident surface of the TFP caused by backscattered radiation. Conclusion: The results indicate that a small-incision procedure may be possible by the use of TFP.« less

Transition of a Text-Based Insulin Titration Program From a Randomized Controlled Trial Into Real-World Settings: Implementation Study

PubMed Central

Orzeck-Byrnes, Natasha A; Aidasani, Sneha R; Moloney, Dana N; Nguyen, Lisa H; Park, Agnes; Hu, Lu; Langford, Aisha T; Wang, Binhuan; Sevick, Mary Ann; Rogers, Erin S

2018-01-01

Background The Mobile Insulin Titration Intervention (MITI) program helps patients with type 2 diabetes find their correct basal insulin dose without in-person care. Requiring only basic cell phone technology (text messages and phone calls), MITI is highly accessible to patients receiving care in safety-net settings. MITI was shown in a randomized controlled trial (RCT) to be efficacious at a New York City (NYC) safety-net clinic where patients often have challenges coming for in-person care. In 2016, MITI was implemented as usual care at Bellevue Hospital (the site of the original RCT) and at Gouverneur Health (a second NYC safety-net clinic) under 2 different staffing models. Objective This implementation study examined MITI’s transition into real-world settings. To understand MITI’s flexibility, generalizability, and acceptability among patients and providers, we evaluated whether MITI continued to produce positive outcomes in expanded underserved populations, outside of an RCT setting. Methods Patients enrolled in MITI received weekday text messages asking for their fasting blood glucose (FBG) values and a weekly titration call. The goal was for patients to reach their optimal insulin dose (OID), defined either as the dose of once-daily basal insulin required to achieve either an FBG of 80-130 mg/dL (4.4-7.2 mmol/L) or as the reaching of the maximum dose of 50 units. After 12 weeks, if OID was not reached, the patients were asked to return to the clinic for in-person care and titration. MITI program outcomes, clinical outcomes, process outcomes, and patient satisfaction were assessed. Results MITI was successful at both sites, each with a different staffing model. Providers referred 170 patients to the program—129 of whom (75.9%, 129/170) were eligible. Of these, 113 (87.6%, 113/129) enrolled. Moreover, 84.1% (95/113) of patients reached their OID, and they did so in an average of 24 days. Clinical outcomes show that mean FBG levels fell from 209 mg/dL (11.6 mmol/L) to 141 mg/dL (7.8 mmol/L), P<.001. HbA1c levels fell from 11.4% (101 mmol/mol) to 10.0% (86 mmol/mol), P<.001. Process outcomes show that 90.1% of MITI’s text message prompts received a response, nurses connected with patients 81.9% of weeks to provide titration instructions, and 85% of attending physicians made at least one referral to the MITI program. Satisfaction surveys showed that most patients felt comfortable sharing information over text and felt the texts reminded them to take their insulin, check their sugar, and make healthy food choices. Conclusions This implementation study showed MITI to have continued success after transitioning from an RCT program into real-world settings. MITI showed itself to be flexible and generalizable as it easily fits into a second site staffed by general medical clinic–registered nurses and remained acceptable to patients and staff who had high levels of engagement with the program. PMID:29555621

The Flexibility Scale: Development and Preliminary Validation of a Cognitive Flexibility Measure in Children with Autism Spectrum Disorders.

PubMed

Strang, John F; Anthony, Laura G; Yerys, Benjamin E; Hardy, Kristina K; Wallace, Gregory L; Armour, Anna C; Dudley, Katerina; Kenworthy, Lauren

2017-08-01

Flexibility is a key component of executive function, and is related to everyday functioning and adult outcomes. However, existing informant reports do not densely sample cognitive aspects of flexibility; the Flexibility Scale (FS) was developed to address this gap. This study investigates the validity of the FS in 221 youth with ASD and 57 typically developing children. Exploratory factor analysis indicates a five-factor scale: Routines/rituals, transitions/change, special interests, social flexibility, and generativity. The FS demonstrated convergent and divergent validity with comparative domains of function in other measures, save for the Generativity factor. The FS discriminated participants with ASD and controls. Thus, this study suggests the FS may be a viable, comprehensive measure of flexibility in everyday settings.

Immediate Effects of Proprioceptive Neuromuscular Facilitation Stretching Programs Compared With Passive Stretching Programs for Hamstring Flexibility: A Critically Appraised Topic.

PubMed

Hill, Kristian J; Robinson, Kendall P; Cuchna, Jennifer W; Hoch, Matthew C

2017-11-01

Clinical Scenario: Increasing hamstring flexibility through clinical stretching interventions may be an effective means to prevent hamstring injuries. However the most effective method to increase hamstring flexibility has yet to be determined. For a healthy individual, are proprioceptive neuromuscular facilitation (PNF) stretching programs more effective in immediately improving hamstring flexibility when compared with static stretching programs? Summary of Key Findings: A thorough literature search returned 195 possible studies; 5 studies met the inclusion criteria and were included. Current evidence supports the use of PNF stretching or static stretching programs for increasing hamstring flexibility. However, neither program demonstrated superior effectiveness when examining immediate increases in hamstring flexibility. Clinical Bottom Line: There were consistent findings from multiple low-quality studies that indicate there is no difference in the immediate improvements in hamstring flexibility when comparing PNF stretching programs to static stretching programs in physically active adults. Strength of Recommendation: Grade B evidence exists that PNF and static stretching programs equally increase hamstring flexibility immediately following the stretching program.

Note: Design and capability verification of fillet triangle flexible support

NASA Astrophysics Data System (ADS)

Wang, Tao; San, Xiao-Gang; Gao, Shi-Jie; Wang, Jing; Ni, Ying-Xue; Sang, Zhi-Xin

2017-12-01

By increasing the section thickness of a triangular flexible hinge, this study focuses on optimal selection of parameters of fillet triangle flexible hinges and flexible support. Based on Castigliano's second theorem, the flexibility expression of the fillet triangle flexible hinge was derived. Then, the case design is performed, and the comparison of three types of flexible hinges with this type of flexible hinge was carried out. The finite element models of fillet triangle flexible hinges and flexible support were built, and then the simulation results of performance parameters were calculated. Finally, the experiment platform was established to validate analysis results. The maximum error is less than 8%, which verifies the accuracy of the simulation process and equations derived; also the fundamental frequency fits the requirements of the system. The fillet triangle flexible hinge is proved to have the advantages of high precision and low flexibility.

Note: Design and capability verification of fillet triangle flexible support.

PubMed

Wang, Tao; San, Xiao-Gang; Gao, Shi-Jie; Wang, Jing; Ni, Ying-Xue; Sang, Zhi-Xin

2017-12-01

By increasing the section thickness of a triangular flexible hinge, this study focuses on optimal selection of parameters of fillet triangle flexible hinges and flexible support. Based on Castigliano's second theorem, the flexibility expression of the fillet triangle flexible hinge was derived. Then, the case design is performed, and the comparison of three types of flexible hinges with this type of flexible hinge was carried out. The finite element models of fillet triangle flexible hinges and flexible support were built, and then the simulation results of performance parameters were calculated. Finally, the experiment platform was established to validate analysis results. The maximum error is less than 8%, which verifies the accuracy of the simulation process and equations derived; also the fundamental frequency fits the requirements of the system. The fillet triangle flexible hinge is proved to have the advantages of high precision and low flexibility.

Imatinib 800 mg daily induces deeper molecular responses than imatinib 400 mg daily: results of SWOG S0325, an intergroup randomized PHASE II trial in newly diagnosed chronic phase chronic myeloid leukaemia.

PubMed

Deininger, Michael W; Kopecky, Kenneth J; Radich, Jerald P; Kamel-Reid, Suzanne; Stock, Wendy; Paietta, Elisabeth; Emanuel, Peter D; Tallman, Martin; Wadleigh, Martha; Larson, Richard A; Lipton, Jeffrey H; Slovak, Marilyn L; Appelbaum, Frederick R; Druker, Brian J

2014-01-01

The standard dose of imatinib for newly diagnosed patients with chronic phase chronic myeloid leukaemia (CP-CML) is 400 mg daily (IM400), but the optimal dose is unknown. This randomized phase II study compared the rates of molecular, haematological and cytogenetic response to IM400 vs. imatinib 400 mg twice daily (IM800) in 153 adult patients with CP-CML. Dose adjustments for toxicity were flexible to maximize retention on study. Molecular response (MR) at 12 months was deeper in the IM800 arm (4-log reduction of BCR-ABL1 mRNA: 25% vs. 10% of patients, P = 0·038; 3-log reduction: 53% vs. 35%, P = 0·049). During the first 12 months BCR-ABL1 levels in the IM800 arm were an average 2·9-fold lower than in the IM400 arm (P = 0·010). Complete haematological response was similar, but complete cytogenetic response was higher with IM800 (85% vs. 67%, P = 0·040). Grade 3-4 toxicities were more common for IM800 (58% vs. 31%, P = 0·0007), and were most commonly haematological. Few patients have relapsed, progressed or died, but both progression-free (P = 0·048) and relapse-free (P = 0·031) survival were superior for IM800. In newly diagnosed CP-CML patients, IM800 induced deeper MRs than IM400, with a trend for improved progression-free and overall survival, but was associated with more severe toxicity. © 2013 John Wiley & Sons Ltd.

Riluzole for relapse prevention following intravenous ketamine in treatment-resistant depression: a pilot randomized, placebo-controlled continuation trial

PubMed Central

Mathew, Sanjay J.; Murrough, James W.; Rot, Marije aan het; Collins, Katherine A.; Reich, David L.; Charney, Dennis S.

2013-01-01

The N-methyl-d-aspartate (NMDA) glutamate receptor antagonist ketamine may have rapid, albeit transient, antidepressant properties. This study in patients with treatment-resistant major depression (TRD) aimed to (1) replicate the acute efficacy of single-dose intravenous (i.v.) ketamine; (2) test the efficacy of the glutamate-modulating agent riluzole in preventing post-ketamine relapse ; and (3) examine whether pretreatment with lamotrigine would attenuate ketamine’s psychotomimetic effects and enhance its antidepressant activity. Twenty-six medication-free patients received open-label i.v. ketamine (0.5 mg/kg over 40 min). Two hours prior to infusion, patients were randomized to lamotrigine (300 mg) or placebo. Seventeen patients (65%) met response criterion (≥50% reduction from baseline on the Montgomery–Asberg Depression Rating Scale) 24 h following ketamine. Lamotrigine failed to attenuate the mild, transient side-effects associated with ketamine and did not enhance its antidepressant effects. Fourteen patients (54%) met response criterion 72 h following ketamine and proceeded to participate in a 32-d, randomized, double-blind, placebo-controlled, flexible-dose continuation trial of riluzole (100–200 mg/d). The main outcome measure was time-to-relapse. An interim analysis found no significant differences in time-to-relapse between riluzole and placebo groups [log-rank χ2 = 0.17, d.f. = 1, p = 0.68], with 80% of patients relapsing on riluzole vs. 50% on placebo. The trial was thus stopped for futility. This pilot study showed that a sub-anaesthetic dose of i.v. ketamine is well-tolerated in TRD, and may have rapid and sustained antidepressant properties. Riluzole did not prevent relapse in the first month following ketamine. Further investigation of relapse prevention strategies post-ketamine is necessary. PMID:19288975

Subcutaneous Trastuzumab for HER2-positive Breast Cancer – Evidence and Practical Experience in 7 German Centers

PubMed Central

Jackisch, C.; Müller, V.; Dall, P.; Neumeister, R.; Park-Simon, T.-W.; Ruf-Dördelmann, A.; Seiler, S.; Tesch, H.; Ataseven, B.

2015-01-01

A subcutaneous formulation of trastuzumab to treat patients with HER2-positive breast cancer is available since August 2013. The subcutaneous formulation is administered as a fixed dose of 600 mg over a period of up to 5 minutes. The HannaH trial compared subcutaneous with intravenous administration and found comparable pharmacokinetics, efficacy and tolerability for both administration forms of trastuzumab in the neoadjuvant setting. The randomized crossover study PrefHer reported a clear preference from the patientʼs point of view for subcutaneous over intravenous administration of trastuzumab. The accompanying time-and-motion study reported a reduction concerning the total time spent for the institution as well as for the patient receiving trastuzumab s. c.. The experience of 7 German centers largely corresponded with the results of these studies. Patients expressed a clear preference for subcutaneous trastuzumab administration, with the time saved by the subcutaneous administration route cited as the greatest benefit. Although the existing reimbursement terms mean that centers will receive a lower remuneration, the centersʼ overall evaluation of the subcutaneous administration route for trastuzumab was overwhelmingly positive. The greatest benefit cited by the centers was the flexibility in scheduling patient appointments. This increased flexibility improved conditions in some centers which were experiencing pressures due to a shortage of staff, particularly at peak times. The general consensus, however, was that the remuneration systems for oncological treatments urgently need to be amended to ensure that the real costs of treatment are covered, even if the administration route has changed. PMID:26166837

The impact of flexible benefits plans on job satisfaction, organizational commitment and turnover intentions.

PubMed

Heshizer, B

1994-01-01

This study assesses the dimensionality of employee attitudes toward flexible benefits plans and the impact of these plans on measures of job satisfaction, commitment and turnover intent. The study points to the need for more work on the measurement of employee attitudes toward flexible benefits and on the nomological framework of flexible benefits as a construct in compensation research.

Standing to Preach, Moving to Teach: What TAs Learned from Teaching in Flexible and Less-Flexible Spaces

ERIC Educational Resources Information Center

Chen, Victoria; Leger, Andy; Riel, Annie

2016-01-01

This paper examines the effect of the architectural layout of two classrooms (one flexible and one less-flexible) on Teaching Assistants' (TAs) movement and interactions with students. Four TAs from a first-year undergraduate introductory course were chosen for the two studies. In study 1, the TAs taught the same lesson twice to two groups of…

Regulatory Forum opinion piece: New testing paradigms for reproductive and developmental toxicity--the NTP modified one generation study and OECD 443.

PubMed

Foster, Paul M D

2014-12-01

The National Toxicology Program (NTP) has developed a new flexible study design, termed the modified one generation (MOG) reproduction study. The MOG study will encompass measurements of developmental and reproductive toxicity parameters as well as enable the setting of appropriate dose levels for a cancer bioassay through evaluation of target organ toxicity that is based on test article exposure that starts during gestation. This study design is compared and contrasted with the new Organization for Economic Co-operation and Development (OECD) 443 test guideline, the extended one generation reproduction study. The MOG study has a number of advantages, with a focus on F 1 animals, the generation of adequately powered, robust data sets that include both pre and postnatal developmental toxicity information, and the measurement of effects on reproductive structure and function in the same animals. This new study design does not employ the use of internal triggers in the design structure for the use of animals already on test and is also consistent with the principles of the 3R's. © 2014 by The Author(s).

Reliability and factorial validity of flexibility tests for team sports.

PubMed

Sporis, Goran; Vucetic, Vlatko; Jovanovic, Mario; Jukic, Igor; Omrcen, Darija

2011-04-01

The main goal of this method paper was to evaluate the reliability and factorial validity of flexibility tests used in soccer, and to do crossvalidation study on 2 other team sports using handball and basketball players. The second aim was to compare the validity of the different tests and evaluate the flexibility of soccer players; the third was to determine the positional differences between attackers, defenders, and midfielders in all flexibility tests. One hundred and fifty (n = 150) elite male junior soccer players, members of the First Croatian Junior League Teams, and 60 (n = 60) handball and 60 (n = 60) basketball players also members of the First Croatian Junior League Teams volunteered to participate in the study, tested for the purpose of crossvalidation. The SAR and V-SAR had the greatest AVR and ICC. The within-subjects variation ranged from between 0.3 and 3.8%. The lowest value of CV was found between the LSPL and LSPR. Low to moderate statistically significant correlation coefficients were found among all the measured flexibility tests. It was observed that the greatest correlations existed between the SAR and V-SAR (r = 0.65) and between the LLSR and LLSL (r = 0.56). Statistically significant correlations were also observed between the BLPL and BLPR (r = 0.62). The principal components factor analysis of 9 flexibility tests resulted in the extraction of 3 significant components. The results of this study have the following implications for the assessment of flexibility in soccer: (a) all flexibility tests used in this study have the acceptable between and within-subjects reliability and they can be used to estimate the flexibility of soccer players; (b) the LSPL and LSPR tests are the most reliable and valid flexibility tests for the estimation of flexibility of professional soccer players.

Paroxetine in the treatment of dysthymic disorder without co-morbidities: A double-blind, placebo-controlled, flexible-dose study.

PubMed

Ravindran, Arun V; Cameron, Colin; Bhatla, Raj; Ravindran, Lakshmi N; da Silva, Tricia L

2013-04-01

Few published studies have evaluated selective serotonin reuptake inhibitors in dysthymia without current co-morbid major depression. In this 12-week study, 40 dysthymic patients were randomly assigned to either placebo (n=19) or 20-40 mg/day of paroxetine (n=21). At endpoint, the paroxetine group showed significantly greater improvement on the Clinical Global Impression Scale, Beck Depression Inventory, and Quality of Life Enjoyment and Satisfaction Questionnaire (p<0.05), and a trend to superiority over placebo on the Hamilton Depression Rating Scale. Response and remission were significantly higher with paroxetine than placebo (p<0.05). There were no significant differences in drop out rates or frequency of adverse effects, except for excessive sweating (greater with paroxetine, p=0.04). Reporting of multiple side effects was also higher with paroxetine than with placebo (p=0.02). Paroxetine is more effective than placebo in improving symptoms and quality of life in dysthymia, and is generally tolerable. Copyright © 2012 Elsevier B.V. All rights reserved.

Hybrid computational phantoms representing the reference adult male and adult female: construction and applications for retrospective dosimetry.

PubMed

Hurtado, Jorge L; Lee, Choonsik; Lodwick, Daniel; Goede, Timothy; Williams, Jonathan L; Bolch, Wesley E

2012-03-01

Currently, two classes of computational phantoms have been developed for dosimetry calculation: (1) stylized (or mathematical) and (2) voxel (or tomographic) phantoms describing human anatomy through mathematical surface equations and 3D voxel matrices, respectively. Mathematical surface equations in stylized phantoms are flexible, but the resulting anatomy is not as realistic. Voxel phantoms display far better anatomical realism, but they are limited in terms of their ability to alter organ shape, position, and depth, as well as body posture. A new class of computational phantoms called hybrid phantoms takes advantage of the best features of stylized and voxel phantoms-flexibility and anatomical realism, respectively. In the current study, hybrid computational phantoms representing the adult male and female reference anatomy and anthropometry are presented. These phantoms serve as the starting framework for creating patient or worker sculpted whole-body phantoms for retrospective dose reconstruction. Contours of major organs and tissues were converted or segmented from computed tomography images of a 36-y-old Korean volunteer and a 25-y-old U.S. female patient, respectively, with supplemental high-resolution CT images of the cranium. Polygon mesh models for the major organs and tissues were reconstructed and imported into Rhinoceros™ for non-uniform rational B-spline (NURBS) surface modeling. The resulting NURBS/polygon mesh models representing body contour and internal anatomy were matched to anthropometric data and reference organ mass data provided by Centers for Disease Control and Prevention and International Commission on Radiation Protection, respectively. Finally, two hybrid adult male and female phantoms were completed where a total of eight anthropometric data categories were matched to standard values within 4% and organ volumes matched to ICRP data within 1% with the exception of total skin. The hybrid phantoms were voxelized from the NURBS phantoms at resolutions of 0.158 × 0.158 × 0.158 cm and 0.126 × 0.126 × 0.126 cm for the male and female, respectively. To highlight the flexibility of the hybrid phantoms, graphical displays are given of (1) underweight and overweight adult male phantoms, (2) a sitting position for the adult female phantom, and (3) extraction and higher-resolution voxelization of the small intestine for localized dosimetry of mucosal and stem cell layers. These phantoms are used to model radioactively contaminated individuals and to then assess time-dependent detector count rate thresholds corresponding to 50, 250, and 500 mSv effective dose, as might be needed during in-field radiological triage by first responders or first receivers.

Impact of Flexibility Options on Grid Economic Carrying Capacity of Solar and Wind: Three Case Studies

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

Denholm, Paul; Novacheck, Joshua; Jorgenson, Jennie

In this study, we attempt to quantify the benefits of various options of grid flexibility by measuring their impact on two measures: economic carrying capacity and system costs. Flexibility can increase ECC and reduce overall system costs. In some cases, options that provide a limited increase in ECC can provide significant operational savings, thus demonstrating the need to evaluate flexibility options using multiple metrics. The value of flexibility options varies regionally due to different generation mixes and types of renewables. The more rapid decline in PV value compared to wind makes PV more dependent on adding flexibility options, including transmissionmore » and energy storage.« less

Effects of a three-month therapeutic exercise programme on flexibility in subjects with low back pain.

PubMed

Kuukkanen, T; Mälkiä, E

2000-01-01

Spinal and muscle flexibility have been studied intensively and used clinically as outcome measurements in the rehabilitation of subjects with low back pain. The results of previous studies are contradictory and there is a lack of longitudinal data on the effects of long term therapeutic exercise on flexibility. A controlled experimental study was conducted to determine the effects of progressive therapeutic exercise on spinal and muscle flexibility. Eighty-six chronic low back pain subjects fulfilled the inclusion criteria and were divided into three study groups: (1) intensive training group, (2) home exercise group and (3) control group. The intervention period lasted three months and measurements were performed at both the beginning of the study and immediately after intervention. Follow-up measurements were carried out six and 12 months after baseline. Spinal flexibility was measured with lumbar flexion, extension, spinal lateral flexion and rotation, and muscle flexibility was measured with measurements of erector spinae, hamstring and iliopsoas muscles. Also self-reported outcomes of the Oswestry Index and Borg Scale--Back Pain Intensity were used. Associations between change (pre- to post-treatment) were determined for the dependent variables. The results showed no correlation between flexibility, the Oswestry Index or back pain intensity. After the first three-month period lumbar flexion, extension and spinal rotation decreased among all subjects. Spinal rotation and erector spinae muscle flexibility improved significantly with intensive training. At the nine-month follow-up, erector spine flexibility was still greater than at baseline. Hamstring flexibility increased among the intensive training and home exercise groups from pre- to post-intervention. However, the degree of hamstring flexibility gained during training was subsequently lost following the period without programmed exercise in both training groups. Self-reported outcome variables showed positive changes among the three study groups after the completion of intervention period, but these changes were only able to be maintained during subsequent follow-ups for the intensive training and home exercise groups. The findings suggest that flexibility does not play an important role in coping with chronic low back pain for subjects whose functional limitations are not severe. Also, it appears that the achieved gains in spinal and muscle flexibility may not be able to be maintained without continued exercise.

SU-E-T-223: Computed Radiography Dose Measurements of External Radiotherapy Beams

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

Aberle, C; Kapsch, R

2015-06-15

Purpose: To obtain quantitative, two-dimensional dose measurements of external radiotherapy beams with a computed radiography (CR) system and to derive volume correction factors for ionization chambers in small fields. Methods: A commercial Kodak ACR2000i CR system with Kodak Flexible Phosphor Screen HR storage foils was used. Suitable measurement conditions and procedures were established. Several corrections were derived, including image fading, length-scale corrections and long-term stability corrections. Dose calibration curves were obtained for cobalt, 4 MV, 8 MV and 25 MV photons, and for 10 MeV, 15 MeV and 18 MeV electrons in a water phantom. Inherent measurement inhomogeneities were studiedmore » as well as directional dependence of the response. Finally, 2D scans with ionization chambers were directly compared to CR measurements, and volume correction factors were derived. Results: Dose calibration curves (0.01 Gy to 7 Gy) were obtained for multiple photon and electron beam qualities. For each beam quality, the calibration curves can be described by a single fit equation over the whole dose range. The energy dependence of the dose response was determined. The length scale on the images was adjusted scan-by-scan, typically by 2 percent horizontally and by 3 percent vertically. The remaining inhomogeneities after the system’s standard calibration procedure were corrected for. After correction, the homogeneity is on the order of a few percent. The storage foils can be rotated by up to 30 degrees without a significant effect on the measured signal. First results on the determination of volume correction factors were obtained. Conclusion: With CR, quantitative, two-dimensional dose measurements with a high spatial resolution (sub-mm) can be obtained over a large dose range. In order to make use of these advantages, several calibrations, corrections and supporting measurements are needed. This work was funded by the European Metrology Research Programme (EMRP) project HLT09 MetrExtRT Metrology for Radiotherapy using Complex Radiation Fields.« less

The Association of Dorsiflexion Flexibility on Landing Mechanics during a Drop Vertical Jump

PubMed Central

Malloy, Philip; Meinerz, Carolyn; Geiser, Christopher; Kipp, Kristof

2016-01-01

Purpose While previous studies have examined the association between ankle dorsiflexion flexibility and deleterious landing postures, it is not currently known how landing kinetics are influenced by ankle dorsiflexion flexibility. The purpose of this study was to examine if ankle dorsiflexion flexibility was associated with landing kinematics and kinetics that have been shown to increase the risk of ACL injury in female athletes. Methods Twenty-three female collegiate soccer players participated in a preseason screening that included the assessment of ankle dorsiflexion flexibility and lower-body kinematics and kinetics during a drop vertical jump task. Results The results demonstrated that females with less ankle dorsiflexion flexibility exhibited greater peak knee abduction moments (r = −.442), greater peak knee abduction angles (r = .355), and less peak knee flexion angles (r = −.385) during landing. The range of dorsiflexion flexibility for the current study was between 9°–23° degrees (mean = 15.0°; SD 3.9°). Conclusion Dorsiflexion flexibility may serve as a useful clinical measure to predict poor landing postures and external forces that have been associated with increased knee injury risk. Rehabilitation specialists can provide interventions aimed at improving dorsiflexion flexibility in order to ameliorate the impact of this modifiable factor on deleterious landing kinematics and kinetics in female athletes. PMID:25112598

Limited access: gender, occupational composition, and flexible work scheduling.

PubMed

Glauber, Rebecca

2011-01-01

The current study draws on national data to explore differences in access to flexible work scheduling by the gender composition of women's and men's occupations. Results show that those who work in integrated occupations are more likely to have access to flexible scheduling. Women and men do not take jobs with lower pay in return for greater access to flexibility. Instead, jobs with higher pay offer greater flexibility. Integrated occupations tend to offer the greatest access to flexible scheduling because of their structural locations. Part-time work is negatively associated with men's access to flexible scheduling but positively associated with women's access. Women have greater flexibility when they work for large establishments, whereas men have greater flexibility when they work for small establishments.

An Overview of the Development of Flexible Sensors.

PubMed

Han, Su-Ting; Peng, Haiyan; Sun, Qijun; Venkatesh, Shishir; Chung, Kam-Sing; Lau, Siu Chuen; Zhou, Ye; Roy, V A L

2017-09-01

Flexible sensors that efficiently detect various stimuli relevant to specific environmental or biological species have been extensively studied due to their great potential for the Internet of Things and wearable electronics applications. The application of flexible and stretchable electronics to device-engineering technologies has enabled the fabrication of slender, lightweight, stretchable, and foldable sensors. Here, recent studies on flexible sensors for biological analytes, ions, light, and pH are outlined. In addition, contemporary studies on device structure, materials, and fabrication methods for flexible sensors are discussed, and a market overview is provided. The conclusion presents challenges and perspectives in this field. © 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Maintaining high vitamin A supplementation coverage in children: lessons from Niger.

PubMed

Aguayo, Victor M; Baker, Shawn K; Crespin, Xavier; Hamani, Harouna; MamadoulTaïbou, Aissa

2005-03-01

In 1997, the reduction of child mortality became a policy priority for the Government of Niger because Niger's child mortality rate was the highest in the world. The Ministry of Public Health, Helen Keller International (HKI), and UNICEF spearheaded a coalition-building process linking vitamin A deficiency (VAD) control to national child survival goals. An evidence-based advocacy strategy was developed around the child survival benefits of adequate and sustained VAD control with one unambiguous message: "VAD control can avert over 25,000 child deaths per year." As a result, in 1997 Niger became one of the first countries in Africa to effectively integrate vitamin A supplementation into National Immunization Days (NIDs) for polio eradication. The challenge was then to provide children with a second annual dose of vitamin A. This led in 1999 to the first ever National Micronutrient Days (NMDs) in Africa. NMDs are mobilization campaigns in which caregivers are actively encouraged to take their children for the delivery of vitamin A supplements. Since 1999, the combination of NIDs and NMDs has ensured that over 80% of children 6 to 59 months of age receive two vitamin A doses annually. The success of NIDs/NMDs has relied on five pillars: leadership and ownership by the Ministry of Public Health; district-level planning and implementation; effective training and flexible delivery mechanisms; effective social information, communication, and mobilization; and responsiveness and flexibility of Ministry of Public Health and development partners. This successful approach has been widely disseminated, notably through the West African Nutrition Focal Points Network.

Implementation study of patient-ready syringes containing 25 mg/mL methotrexate solution for use in treating ectopic pregnancy.

PubMed

Respaud, R; Gaudy, A S; Arlicot, C; Tournamille, J F; Viaud-Massuard, M C; Elfakir, C; Antier, D

2014-01-01

Ectopic pregnancy (EP) is a significant cause of morbidity and mortality during the first trimester of pregnancy. Small unruptured tubal pregnancies can be treated medically with a single dose of methotrexate (MTX). The aim of this study was to evaluate the stability of a 25 mg/mL solution of MTX to devise a secure delivery circuit for the preparation and use of this medication in the management of EP. MTX solutions were packaged in polypropylene syringes, stored over an 84-day period, and protected from light either at +2 to +8°C or at 23°C. We assessed the physical and chemical stability of the solutions at various time points over the storage period. A pharmaceutical delivery circuit was implemented that involved the batch preparation of MTX syringes. We show that 25 mg/mL MTX solutions remain stable over an 84-day period under the storage conditions tested. Standard doses were prepared, ranging from 50 mg to 100 mg. The results of this study suggest that MTX syringes can be prepared in advance by the pharmacy, ready to be dispensed at any time that a diagnosis of EP is made. The high stability of a 25 mg/mL MTX solution in polypropylene syringes makes it possible to implement a flexible and cost-effective delivery circuit for ready-to-use preparations of this drug, providing 24-hour access and preventing treatment delays.

Diet Quality and Physical Activity Outcome Improvements Resulting From a Church-Based Diet and Supervised Physical Activity Intervention for Rural, Southern, African American Adults: Delta Body and Soul III.

PubMed

Thomson, Jessica L; Goodman, Melissa H; Tussing-Humphreys, Lisa

2015-09-01

We assessed the effects of a 6-month, church-based, diet and supervised physical activity intervention, conducted between 2011 and 2012, on improving diet quality and increasing physical activity of Southern, African American adults. Using a quasi-experimental design, eight self-selected, eligible churches were assigned to intervention or control. Assessments included dietary, physical activity, anthropometric, and clinical measures. Mixed model regression analysis and McNemar's test were used to determine if within and between group differences were significant. Cohen's d effect sizes for selected outcomes also were computed and compared with an earlier, lower dose intervention. Retention rates were 84% (102/122) for control and 76% (219/287) for intervention participants. Diet quality components, including fruits, vegetables, discretionary calories, and total quality, improved significantly in the intervention group. Strength/flexibility physical activity also increased in the intervention group, while both aerobic and strength/flexibility physical activity significantly decreased in the control group. Effect sizes for selected health outcomes were larger in the current intervention as compared to an earlier, less intense iteration of the study. Results suggest that more frequent education sessions as well as supervised group physical activity may be key components to increasing the efficacy of behavioral lifestyle interventions in rural, Southern, African American adults. © 2015 Society for Public Health Education.

The Flexibility Scale: Development and Preliminary Validation of a Cognitive Flexibility Measure in Children with Autism Spectrum Disorders

ERIC Educational Resources Information Center

Strang, John F.; Anthony, Laura G.; Yerys, Benjamin E.; Hardy, Kristina K.; Wallace, Gregory L.; Armour, Anna C.; Dudley, Katerina; Kenworthy, Lauren

2017-01-01

Flexibility is a key component of executive function, and is related to everyday functioning and adult outcomes. However, existing informant reports do not densely sample cognitive aspects of flexibility; the Flexibility Scale (FS) was developed to address this gap. This study investigates the validity of the FS in 221 youth with ASD and 57…

Disk flexibility effects on the rotordynamics of the SSME high pressure turbopumps

NASA Technical Reports Server (NTRS)

Flowers, George T.

1990-01-01

Rotordynamical analyses are typically performed using rigid disk models. Studies of rotor models in which the effects of disk flexibility were included indicate that it may be an important effect for many systems. This issue is addressed with respect to the Space Shuttle Main Engine high pressure turbopumps. Finite element analyses were performed for a simplified free-free flexible disk rotor models and the modes and frequencies compared to those of a rigid disk model. Equations were developed to account for disk flexibility in rotordynamical analysis. Simulation studies were conducted to assess the influence of disk flexibility on the HPOTP. Some recommendations are given as to the importance of disk flexibility and for how this project should proceed.

Impact of Flexibility Options on Grid Economic Carrying Capacity of Solar and Wind: Three Case Studies

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

Denholm, Paul; Novacheck, Joshua; Jorgenson, Jennie

In this study, we attempt to quantify the benefits of various options of grid flexibility by measuring their impact on two measures: economic carrying capacity and system costs. Flexibility can increase economic carrying capacity and reduce overall system costs. In some cases, options that provide a limited increase in economic carrying capacity can provide significant operational savings, thus demonstrating the need to evaluate flexibility options using multiple metrics. The value of flexibility options varies regionally due to different generation mixes and types of renewables. The more rapid decline in PV value compared to wind makes PV more dependent on addingmore » flexibility options, including transmission and energy storage.« less

Dropwise additive manufacturing of pharmaceutical products for melt-based dosage forms.

PubMed

Içten, Elçin; Giridhar, Arun; Taylor, Lynne S; Nagy, Zoltan K; Reklaitis, Gintaras V

2015-05-01

The US Food and Drug Administration introduced the quality by design approach and process analytical technology guidance to encourage innovation and efficiency in pharmaceutical development, manufacturing, and quality assurance. As part of this renewed emphasis on the improvement of manufacturing, the pharmaceutical industry has begun to develop more efficient production processes with more intensive use of online measurement and sensing, real-time quality control, and process control tools. Here, we present dropwise additive manufacturing of pharmaceutical products (DAMPP) as an alternative to conventional pharmaceutical manufacturing methods. This mini-manufacturing process for the production of pharmaceuticals utilizes drop on demand printing technology for automated and controlled deposition of melt-based formulations onto edible substrates. The advantages of drop-on-demand technology, including reproducible production of small droplets, adjustable drop sizing, high placement accuracy, and flexible use of different formulations, enable production of individualized dosing even for low-dose and high-potency drugs. In this work, DAMPP is used to produce solid oral dosage forms from hot melts of an active pharmaceutical ingredient and a polymer. The dosage forms are analyzed to show the reproducibility of dosing and the dissolution behavior of different formulations. © 2015 Wiley Periodicals, Inc. and the American Pharmacists Association.

Room-Temperature Activation of InGaZnO Thin-Film Transistors via He+ Irradiation.

PubMed

Stanford, Michael G; Noh, Joo Hyon; Mahady, Kyle; Ievlev, Anton V; Maksymovych, Peter; Ovchinnikova, Olga S; Rack, Philip D

2017-10-11

Amorphous indium gallium zinc oxide (a-IGZO) is a transparent semiconductor which has demonstrated excellent electrical performance as thin-film transistors (TFTs). However, a high-temperature activation process is generally required which is incompatible for next-generation flexible electronic applications. In this work, He + irradiation is demonstrated as an athermal activation process for a-IGZO TFTs. Controlling the He + dose enables the tuning of charge density, and a dose of 1 × 10 14 He + /cm 2 induces a change in charge density of 2.3 × 10 12 cm -2 . Time-dependent transport measurements and time-of-flight secondary ion mass spectroscopy (ToF-SIMS) indicate that the He + -induced trapped charge is introduced because of preferential oxygen-vacancy generation. Scanning microwave impedance microscopy confirms that He + irradiation improves the conductivity of the a-IGZO. For realization of a permanent activation, IGZO was exposed with a He + dose of 5 × 10 14 He + /cm 2 and then aged 24 h to allow decay of the trapped oxide charge originating for electron-hole pair generation. The resultant shift in the charge density is primarily attributed to oxygen vacancies generated by He + sputtering in the near-surface region.

InfuShield: a shielded enclosure for administering therapeutic radioisotope treatments using standard syringe pumps

PubMed Central

Pratt, Brenda E.; Chittenden, Sarah J.; Murray, Iain S.; Causer, Louise; Grey, Matthew J.; Gear, Jonathan I.; Du, Yong; Flux, Glenn D.

2017-01-01

The administration of radionuclide therapies presents significant radiation protection challenges. The aim of this work was to develop a delivery system for intravenous radioisotope therapies to substantially moderate radiation exposures to staff and operators. A novel device (InfuShield) was designed and tested before being used clinically. The device consists of a shielded enclosure which contains the therapeutic activity and, through the hydraulic action of back-to-back syringes, allows the activity to be administered using a syringe pump external to the enclosure. This enables full access to the pump controls while simultaneously reducing dose to the operator. The system is suitable for use with all commercially available syringe pumps and does not require specific consumables, maximising both the flexibility and economy of the system. Dose rate measurements showed that at key stages in an 131I mIBG treatment procedure, InfuShield can reduce dose to operators by several orders of magnitude. Tests using typical syringes and infusion speeds show no significant alteration in administered flow rates (maximum of 1.2%). The InfuShield system provides a simple, safe and low cost method of radioisotope administration. PMID:28187040

Guidelines for Posting Soil Contamination Areas

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

Mcnaughton, Michael; Eisele, William

All soil guidelines were determined using RESRAD, version 6.1. All offsite guidelines are based on 15 mrem/year. This dose rate is sufficiently low to protect human health and is in accordance with DOE guidance and the proposed EPA 40-CFR-196 regulations for members of the public (never promulgated). For those onsite areas where general employees (non-radiological workers) could have routine access, soil concentrations should be based on a dose rate of 30 mrem/year (approximately one-third of the onsite LANL non-radiological worker dose of 100 mrem/year). In this case, soil concentration guidelines may be obtained by doubling the 15 mrem/year guidelines. Severalmore » scenarios were developed to provide maximum flexibility for application of the guidelines. The offsite guidelines were developed using: residential scenarios for both adults and children; a construction worker scenario; a resource user (e.g., a hunter) scenario; a child playing within canyon reaches scenario, a trail using jogger within canyon reaches scenario, and a trail using hiker within canyon reaches scenario. The residential guidelines represent the lowest values from both the adult residential scenario and the child residential scenario.« less

"You are free to set your own hours": governing worker productivity and health through flexibility and resilience.

PubMed

MacEachen, Ellen; Polzer, Jessica; Clarke, Judy

2008-03-01

Flexible work is now endemic in modern economies. A growing literature both praises work flexibility for accommodating employees' needs and criticizes it for fueling contingency and job insecurity. Although studies have identified varied effects of flexible work, questions remain about the workplace dimensions of flexibility and how occupational workplace health is managed in these workplaces. This paper presents findings from a qualitative study of how managers in the computer software industry situate workplace flexibility and approach worker health. In-depth interviews were conducted with managers (and some workers) at 30 firms in Ontario, Canada. Using a critical discourse analysis approach, we examine managers' optimistic descriptions of flexibility which emphasize how flexible work contributes to workers' life balance. We then contrast this with managers' depictions of flexibility work practices as intense and inescapable. We suggest that the discourse of flexibility, and the work practices they foster, make possible and reinforce an increased intensity of work that is driven by the demands of technological pace and change that characterize the global information technology and computer software industries. Finally, we propose that flexible knowledge work has led to a re-framing of occupational health management involving a focus on what we call "strategies of resilience" that aim to buttress workers' capacities to withstand intensive and uncertain working conditions.

Flexible Programmes in Higher Professional Education: Expert Validation of a Flexible Educational Model

ERIC Educational Resources Information Center

Schellekens, Ad; Paas, Fred; Verbraeck, Alexander; van Merrienboer, Jeroen J. G.

2010-01-01

In a preceding case study, a process-focused demand-driven approach for organising flexible educational programmes in higher professional education (HPE) was developed. Operations management and instructional design contributed to designing a flexible educational model by means of discrete-event simulation. Educational experts validated the model…

Flexible Work Options within the Organisational System

ERIC Educational Resources Information Center

Albion, Majella J.; Chee, Munli

2006-01-01

The availability of flexible work options provides an opportunity for individuals to shape their careers in order to optimise their work and life goals. This study takes a systems theory approach to examine how the use of flexible work options influences relationships and interactions in the workplace. The "Flexible Work Options…

Endosymbiotic flexibility associates with environmental sensitivity in scleractinian corals.

PubMed

Putnam, Hollie M; Stat, Michael; Pochon, Xavier; Gates, Ruth D

2012-11-07

Flexibility in biological systems is seen as an important driver of macro-ecosystem function and stability. Spatially constrained endosymbiotic settings, however, are less studied, although environmental thresholds of symbiotic corals are linked to the function of their endosymbiotic dinoflagellate communities. Symbiotic flexibility is a hypothesized mechanism that corals may exploit to adapt to climate change. This study explores the flexibility of the coral-Symbiodinium symbiosis through quantification of Symbiodinium ITS2 sequence assemblages in a range of coral species and genera. Sequence assemblages are expressed as an index of flexibility incorporating phylogenetic divergence and relative abundance of Symbiodinium sequences recovered from the host. This comparative analysis reveals profound differences in the flexibility of corals for Symbiodinium, thereby classifying corals as generalists or specifists. Generalists such as Acropora and Pocillopora exhibit high intra- and inter-species flexibility in their Symbiodinium assemblages and are some of the most environmentally sensitive corals. Conversely, specifists such as massive Porites colonies exhibit low flexibility, harbour taxonomically narrow Symbiodinium assemblages, and are environmentally resistant corals. Collectively, these findings challenge the paradigm that symbiotic flexibility enhances holobiont resilience. This underscores the need for a deeper examination of the extent and duration of the functional benefits associated with endosymbiotic diversity and flexibility under environmental stress.

Flexible Learning in Action: Case Studies in Higher Education. Staff and Educational Development Series.

ERIC Educational Resources Information Center

Hudson, Rachel, Ed.; Maslin-Prothero, Sian, Ed.; Oates, Lyn, Ed.

Following an introduction (Hudson, Maslin-Prothero, Oates), the following 31 case studies describe flexible learning developments in the United Kingdom, Australia, and the United States: "Teaching Business Writing Online" (Fulkerth); "Don't Lecture Me about Flexible Learning!" (Dunning); "Improving Independent Learning…

Pharmacological and Safety Profile of Dexlansoprazole: A New Proton Pump Inhibitor - Implications for Treatment of Gastroesophageal Reflux Disease in the Asia Pacific Region.

PubMed

Goh, Khean Lee; Choi, Myung Gyu; Hsu, Ping I; Chun, Hoon Jai; Mahachai, Varocha; Kachintorn, Udom; Leelakusolvong, Somchai; Kim, Nayoung; Rani, Abdul Aziz; Wong, Benjamin C Y; Wu, Justin; Chiu, Cheng Tang; Shetty, Vikram; Bocobo, Joseph C; Chan, Melchor M; Lin, Jaw-Town

2016-07-30

Although gastroesophageal reflux disease is not as common in Asia as in western countries, the prevalence has increased substantially during the past decade. Gastroesophageal reflux disease is associated with considerable reductions in subjective well-being and work productivity, as well as increased healthcare use. Proton pump inhibitors (PPIs) are currently the most effective treatment for gastroesophageal reflux disease. However, there are limitations associated with these drugs in terms of partial and non-response. Dexlansoprazole is the first PPI with a dual delayed release formulation designed to provide 2 separate releases of medication to extend the duration of effective plasma drug concentration. Dexlansoprazole has been shown to be effective for healing of erosive esophagitis, and to improve subjective well-being by controlling 24-hour symptoms. Dexlansoprazole has also been shown to achieve good plasma concentration regardless of administration with food, providing flexible dosing. Studies in healthy volunteers showed no clinically important effects on exposure to the active metabolite of clopidogrel or clopidogrel-induced platelet inhibition, with no dose adjustment of clopidogrel necessary when coprescribed. This review discusses the role of the new generation PPI, dexlansoprazole, in the treatment of gastroesophageal reflux disease in Asia.

Pharmacological and Safety Profile of Dexlansoprazole: A New Proton Pump Inhibitor – Implications for Treatment of Gastroesophageal Reflux Disease in the Asia Pacific Region

PubMed Central

Goh, Khean Lee; Choi, Myung Gyu; Hsu, Ping I; Chun, Hoon Jai; Mahachai, Varocha; Kachintorn, Udom; Leelakusolvong, Somchai; Kim, Nayoung; Rani, Abdul Aziz; Wong, Benjamin C Y; Wu, Justin; Chiu, Cheng Tang; Shetty, Vikram; Bocobo, Joseph C; Chan, Melchor M; Lin, Jaw-Town

2016-01-01

Although gastroesophageal reflux disease is not as common in Asia as in western countries, the prevalence has increased substantially during the past decade. Gastroesophageal reflux disease is associated with considerable reductions in subjective well-being and work productivity, as well as increased healthcare use. Proton pump inhibitors (PPIs) are currently the most effective treatment for gastroesophageal reflux disease. However, there are limitations associated with these drugs in terms of partial and non-response. Dexlansoprazole is the first PPI with a dual delayed release formulation designed to provide 2 separate releases of medication to extend the duration of effective plasma drug concentration. Dexlansoprazole has been shown to be effective for healing of erosive esophagitis, and to improve subjective well-being by controlling 24-hour symptoms. Dexlansoprazole has also been shown to achieve good plasma concentration regardless of administration with food, providing flexible dosing. Studies in healthy volunteers showed no clinically important effects on exposure to the active metabolite of clopidogrel or clopidogrel-induced platelet inhibition, with no dose adjustment of clopidogrel necessary when coprescribed. This review discusses the role of the new generation PPI, dexlansoprazole, in the treatment of gastroesophageal reflux disease in Asia. PMID:26932927

Opioid Substitution Treatment Planning in a Disaster Context: Perspectives from Emergency Management and Health Professionals in Aotearoa/New Zealand

PubMed Central

Blake, Denise; Lyons, Antonia

2016-01-01

Opioid Substitution Treatment (OST) is a harm reduction strategy enabling opiate consumers to avoid withdrawal symptoms and maintain health and wellbeing. Some research shows that within a disaster context service disruptions and infrastructure damage affect OST services, including problems with accessibility, dosing, and scripts. Currently little is known about planning for OST in the reduction and response phases of a disaster. This study aimed to identify the views of three professional groups working in Aotearoa/New Zealand about OST provision following a disaster. In-depth, semi-structured interviews were conducted with 17 service workers, health professionals, and emergency managers in OST and disaster planning fields. Thematic analysis of transcripts identified three key themes, namely “health and wellbeing”, “developing an emergency management plan”, and “stock, dose verification, and scripts” which led to an overarching concept of “service continuity in OST preparedness planning”. Participants viewed service continuity as essential for reducing physical and psychological distress for OST clients, their families, and wider communities. Alcohol and drug and OST health professionals understood the specific needs of clients, while emergency managers discussed the need for sufficient preparedness planning to minimise harm. It is concluded that OST preparedness planning must be multidisciplinary, flexible, and inclusive. PMID:27834915

Review of extended-release formulations of Tramadol for the management of chronic non-cancer pain: focus on marketed formulations

PubMed Central

Kizilbash, Arshi; Ngô-Minh, Cường

2014-01-01

Patients with chronic non-malignant pain report impairments of physical, social, and psychological well-being. The goal of pain management should include reducing pain and improving quality of life. Patients with chronic pain require medications that are able to provide adequate pain relief, have minimum dosing intervals to maintain efficacy, and avoid breakthrough pain. Tramadol has proven efficacy and a favourable safety profile. The positive efficacy and safety profile has been demonstrated historically in numerous published clinical studies as well as from post-marketing experience. It is a World Health Organization “Step 2” opioid analgesic that has been shown to be effective, well-tolerated, and valuable, where treatment with strong opioids is not required. A number of extended release formulations of Tramadol are available in Canada and the United States. An optimal extended release Tramadol formulation would be expected to provide consistent pain control with once daily dosing, few sleep interruptions, flexible dosing schedules, and no limitation on taking with meals. Appropriate treatment options should be based on the above proposed attributes. A comparative review of available extended release Tramadol formulations shows that these medications are not equivalent in their pharmacokinetic profile and this may have implications for selecting the optimal therapy for patients with pain syndromes where Tramadol is an appropriate analgesic agent. Differences in pharmacokinetics amongst the formulations may also translate into varied clinical responses in patients. Selection of the appropriate formulation by the health care provider should therefore be based on the patient’s chronic pain condition, needs, and lifestyle. PMID:24711710

A multiscale Bayesian data integration approach for mapping air dose rates around the Fukushima Daiichi Nuclear Power Plant.

PubMed

Wainwright, Haruko M; Seki, Akiyuki; Chen, Jinsong; Saito, Kimiaki

2017-02-01

This paper presents a multiscale data integration method to estimate the spatial distribution of air dose rates in the regional scale around the Fukushima Daiichi Nuclear Power Plant. We integrate various types of datasets, such as ground-based walk and car surveys, and airborne surveys, all of which have different scales, resolutions, spatial coverage, and accuracy. This method is based on geostatistics to represent spatial heterogeneous structures, and also on Bayesian hierarchical models to integrate multiscale, multi-type datasets in a consistent manner. The Bayesian method allows us to quantify the uncertainty in the estimates, and to provide the confidence intervals that are critical for robust decision-making. Although this approach is primarily data-driven, it has great flexibility to include mechanistic models for representing radiation transport or other complex correlations. We demonstrate our approach using three types of datasets collected at the same time over Fukushima City in Japan: (1) coarse-resolution airborne surveys covering the entire area, (2) car surveys along major roads, and (3) walk surveys in multiple neighborhoods. Results show that the method can successfully integrate three types of datasets and create an integrated map (including the confidence intervals) of air dose rates over the domain in high resolution. Moreover, this study provides us with various insights into the characteristics of each dataset, as well as radiocaesium distribution. In particular, the urban areas show high heterogeneity in the contaminant distribution due to human activities as well as large discrepancy among different surveys due to such heterogeneity. Copyright © 2016 Elsevier Ltd. All rights reserved.

Evolution of resistance to anti-cancer therapy during general dosing schedules

PubMed Central

Foo, Jasmine; Michor, Franziska

2009-01-01

Anti-cancer drugs targeted to specific oncogenic pathways have shown promising therapeutic results in the past few years; however, drug resistance remains an important obstacle for these therapies. Resistance to these drugs can emerge due to a variety of reasons including genetic or epigenetic changes which alter the binding site of the drug target, cellular metabolism or export mechanisms. Obtaining a better understanding of the evolution of resistant populations during therapy may enable the design of more effective therapeutic regimens which prevent or delay progression of disease due to resistance. In this paper, we use stochastic mathematical models to study the evolutionary dynamics of resistance under time-varying dosing schedules and pharmacokinetic effects. The populations of sensitive and resistant cells are modeled as multi-type non-homogeneous birth-death processes in which the drug concentration affects the birth and death rates of both the sensitive and resistant cell populations in continuous time. This flexible model allows us to consider the effects of generalized treatment strategies as well as detailed pharmacokinetic phenomena such as drug elimination and accumulation over multiple doses. We develop estimates for the probability of developing resistance and moments of the size of the resistant cell population. With these estimates, we optimize treatment schedules over a subspace of tolerated schedules to minimize the risk of disease progression due to resistance as well as locate ideal schedules for controlling the population size of resistant clones in situations where resistance is inevitable. Our methodology can be used to describe dynamics of resistance arising due to a single (epi)genetic alteration in any tumor type. PMID:20004211

Structural studies of human alkaline phosphatase in complex with strontium: Implication for its secondary effect in bones

PubMed Central

Llinas, Paola; Masella, Michel; Stigbrand, Torgny; Ménez, André; Stura, Enrico A.; Le Du, Marie Hélène

2006-01-01

Strontium is used in the treatment of osteoporosis as a ranelate compound, and in the treatment of painful scattered bone metastases as isotope. At very high doses and in certain conditions, it can lead to osteomalacia characterized by impairment of bone mineralization. The osteomalacia symptoms resemble those of hypophosphatasia, a rare inherited disorder associated with mutations in the gene encoding for tissue-nonspecific alkaline phosphatase (TNAP). Human alkaline phosphatases have four metal binding sites—two for zinc, one for magnesium, and one for calcium ion—that can be substituted by strontium. Here we present the crystal structure of strontium-substituted human placental alkaline phosphatase (PLAP), a related isozyme of TNAP, in which such replacement can have important physiological implications. The structure shows that strontium substitutes the calcium ion with concomitant modification of the metal coordination. The use of the flexible and polarizable force-field TCPEp (topological and classical polarization effects for proteins) predicts that calcium or strontium has similar interaction energies at the calcium-binding site of PLAP. Since calcium helps stabilize a large area that includes loops 210–228 and 250–297, its substitution by strontium could affect the stability of this region. Energy calculations suggest that only at high doses of strontium, comparable to those found for calcium, can strontium substitute for calcium. Since osteomalacia is observed after ingestion of high doses of strontium, alkaline phosphatase is likely to be one of the targets of strontium, and thus this enzyme might be involved in this disease. PMID:16815919

Effect of wing flexibility in dragonfly hovering flight

NASA Astrophysics Data System (ADS)

Naidu, Vishal; Young, John; Lai, Joseph

2011-11-01

Dragonflies have two pairs of tandem wings, which can be operated independently. Most studies on tandem wings are based on rigid wings, which is in strong contradiction to the natural, flexible dragonfly wings. The effect of wing flexibility in tandem wings is little known. We carry out a comparative, computational study between rigid and flexible, dragonfly shaped wings for hovering flight. In rigid wings during downstroke, a leading edge vortex (LEV) is formed on the upper surface, which forms a low pressure zone. This conical LEV joins the tip vortex and shortly after the mid downstroke when the wing starts to rotate, these vortices are gradually shed resulting in a drop in lift. The vortex system creates a net downwards momentum in the form of a jet. The flexible wings while in motion deform due to aerodynamic and inertial forces. Since there is a strong interaction between wing deformation and air flow around the deformed wings, flexible wing simulations are carried out using a two way fluid structure interaction. The effect of wing flexibility on the flow structure and the subsequent effect on the aerodynamic forces will be studied and presented.

Comparing Safety and Efficacy of "Third-Generation" Antiepileptic Drugs: Long-Term Extension and Post-marketing Treatment.

PubMed

Kwok, Charlotte S; Johnson, Emily L; Krauss, Gregory L

2017-11-01

Four "third-generation" antiepileptic drugs (AEDs) were approved for adjunctive treatment of refractory focal onset seizures during the past 10 years. Long-term efficacy and safety of the drugs were demonstrated in large extension studies and in reports of subgroups of patients not studied in pivotal trials. Reviewing extension study and post-marketing outcome series for the four newer AEDs-lacosamide, perampanel, eslicarbazepine acetate and brivaracetam-can guide clinicians in treating and monitoring patients. AED extension studies evaluate treatment retention, drug tolerability, and drug safety during individualized treatment with flexible dosing and thus provide information not available in rigid pivotal trials. Patient retention in the studies ranged from 75 to 80% at 1 year and from 36 to 68% at 2-year treatment intervals. Safety findings were generally similar to those of pivotal trials, with no major safety risks identified and with several specific adverse drug effects, such as hyponatremia, reported. The third-generation AEDs, some through new mechanisms and others with improved tolerability compared to related AEDs, provide new options in efficacy and tolerability.

The role of body image psychological flexibility on the treatment of eating disorders in a residential facility.

PubMed

Bluett, E J; Lee, E B; Simone, M; Lockhart, G; Twohig, M P; Lensegrav-Benson, Tera; Quakenbush-Roberts, Benita

2016-12-01

The purpose of this study was to test whether pre-treatment levels of psychological flexibility would longitudinally predict quality of life and eating disorder risk in patients at a residential treatment facility for eating disorders. Data on body image psychological flexibility, quality of life, and eating disorder risk were collected from 63 adolescent and 50 adult, female, residential patients (N=113) diagnosed with an eating disorder. These same measures were again collected at post-treatment. Sequential multiple regression analyses were performed to test whether pre-treatment levels of psychological flexibility longitudinally predicted quality of life and eating disorder risk after controlling for age and baseline effects. Pre-treatment psychological flexibility significantly predicted post-treatment quality of life with approximately 19% of the variation being attributable to age and pre-treatment psychological flexibility. Pre-treatment psychological flexibility also significantly predicted post-treatment eating disorder risk with nearly 30% of the variation attributed to age and pre-treatment psychological flexibility. This study suggests that levels of psychological flexibility upon entering treatment for an eating disorder longitudinally predict eating disorder outcome and quality of life. Copyright © 2016 Elsevier Ltd. All rights reserved.

Perceived versus used workplace flexibility in Singapore: predicting work-family fit.

PubMed

Jones, Blake L; Scoville, D Phillip; Hill, E Jeffrey; Childs, Geniel; Leishman, Joan M; Nally, Kathryn S

2008-10-01

This study examined the relationship of 2 types of workplace flexibility to work-family fit and work, personal, and marriage-family outcomes using data (N = 1,601) representative of employed persons in Singapore. We hypothesized that perceived and used workplace flexibility would be positively related to the study variables. Results derived from structural equation modeling revealed that perceived flexibility predicted work-family fit; however, used flexibility did not. Work-family fit related positively to each work, personal, and marriage-family outcome; however, workplace flexibility only predicted work and personal outcomes. Findings suggest work-family fit may be an important facilitating factor in the interface between work and family life, relating directly to marital satisfaction and satisfaction in other family relationships. Implications of these findings are discussed. Copyright 2008 APA, all rights reserved.

Workplace flexibility: from research to action.

PubMed

Galinsky, Ellen; Sakai, Kelly; Wigton, Tyler

2011-01-01

Ellen Galinsky, Kelly Sakai, and Tyler Wigton explore the "time famine" among American workers-the continuing sense among employees of not having enough time to manage the multiple responsibilities of work and personal and family life. Noting that large shares of U.S. employees report feeling the need for greater workplace flexibility to enable them to take better care of family responsibilities, the authors examine a large-scale community-engagement initiative to increase workplace flexibility voluntarily. Using the 2008 National Study of the Changing Workforce as a primary source of data, the authors begin with an overview of the prevalence of flexibility in today's American workplace. They track which categories of employees have access to various flexibility options, as well as the extent to which employees with access to various types of flexibility use those options. Findings from the study indicate that the majority of employees want flexibility but that access to it varies, with more advantaged employees--those who are well educated, have high salaries, and work full time, for example--being doubly advantaged in having greater access to flexibility. A number of employers, say the authors, tend to be skeptical of the value of workplace flexibility and to fear that employees will abuse it if it is offered. But the study data reveal that most employees use flexibility quite conservatively. When the authors use their nationally representative data set to investigate correlations between access to workplace flexibility and a range of workplace outcomes especially valued by employers--employee engagement, job satisfaction, retention, and health--they find that employers as well as employees can benefit from flexibility. Finally, the authors discuss When Work Works, a large, national community-based initiative under way since 2003 to increase voluntary adoption of workplace flexibility. The authors detail the conceptual basis of the project's design, noting its emphasis on flexibility as one component of effective workplaces that can benefit employers, employees, and communities alike. Galinsky, Sakai, and Wigton conclude by drawing lessons learned from the project and briefly discussing the implications of using research to bring about workplace change.

Development of a Radiation Dose Reporting Software for X-ray Computed Tomography (CT)

NASA Astrophysics Data System (ADS)

Ding, Aiping

X-ray computed tomography (CT) has experienced tremendous technological advances in recent years and has established itself as one of the most popular diagnostic imaging tools. While CT imaging clearly plays an invaluable role in modern medicine, its rapid adoption has resulted in a dramatic increase in the average medical radiation exposure to the worldwide and United States populations. Existing software tools for CT dose estimation and reporting are mostly based on patient phantoms that contain overly simplified anatomies insufficient in meeting the current and future needs. This dissertation describes the development of an easy-to-use software platform, “VirtualDose”, as a service to estimate and report the organ dose and effective dose values for patients undergoing the CT examinations. “VirtualDose” incorporates advanced models for the adult male and female, pregnant women, and children. To cover a large portion of the ignored obese patients that frequents the radiology clinics, a new set of obese male and female phantoms are also developed and applied to study the effects of the fat tissues on the CT radiation dose. Multi-detector CT scanners (MDCT) and clinical protocols, as well as the most recent effective dose algorithms from the International Commission on Radiological Protection (ICRP) Publication 103 are adopted in “VirtualDose” to keep pace with the MDCT development and regulatory requirements. A new MDCT scanner model with both body and head bowtie filter is developed to cover both the head and body scanning modes. This model was validated through the clinical measurements. A comprehensive slice-by-slice database is established by deriving the data from a larger number of single axial scans simulated on the patient phantoms using different CT bowtie filters, beam thicknesses, and different tube voltages in the Monte Carlo N-Particle Extended (MCNPX) code. When compared to the existing CT dose software packages, organ dose data in this software provides a better CT dose assessment by using anatomically realistic patient phantoms. All the related organ doses are incorporated into a standardized database compiled using Microsoft Structured Query Language (SQL) server 2008. Organ doses from contiguous axial or helical scans defined by a specific protocol can be rapidly obtained from the database. A next-generation software architecture and Active Server Pages (ASP) .NET framework are adopted to create a browser-hosted application to improve the user interactivity and reporting functionality including scanning parameter selection and organ dose reporting. “VirtualDose” has been developed as a web-based CT dose reporting platform to facilitate several important features including: (1) easy access via Internet; (2) no need for installation on the local computer; (3) a user-friendly, dynamic, browser-hosted graphical user interface; (4) use of advanced patient models for the adult male and female, pregnant women, children, and obese patient models; (5) adoption of modern CT scanners and protocols, as well as the most recent ICRP 103 effective dose algorithms; and (6) flexibility to manage and easily upgrade without impacting user’s usage.

An automated DICOM database capable of arbitrary data mining (including radiation dose indicators) for quality monitoring.

PubMed

Wang, Shanshan; Pavlicek, William; Roberts, Catherine C; Langer, Steve G; Zhang, Muhong; Hu, Mengqi; Morin, Richard L; Schueler, Beth A; Wellnitz, Clinton V; Wu, Teresa

2011-04-01

The U.S. National Press has brought to full public discussion concerns regarding the use of medical radiation, specifically x-ray computed tomography (CT), in diagnosis. A need exists for developing methods whereby assurance is given that all diagnostic medical radiation use is properly prescribed, and all patients' radiation exposure is monitored. The "DICOM Index Tracker©" (DIT) transparently captures desired digital imaging and communications in medicine (DICOM) tags from CT, nuclear imaging equipment, and other DICOM devices across an enterprise. Its initial use is recording, monitoring, and providing automatic alerts to medical professionals of excursions beyond internally determined trigger action levels of radiation. A flexible knowledge base, aware of equipment in use, enables automatic alerts to system administrators of newly identified equipment models or software versions so that DIT can be adapted to the new equipment or software. A dosimetry module accepts mammography breast organ dose, skin air kerma values from XA modalities, exposure indices from computed radiography, etc. upon receipt. The American Association of Physicists in Medicine recommended a methodology for effective dose calculations which are performed with CT units having DICOM structured dose reports. Web interface reporting is provided for accessing the database in real-time. DIT is DICOM-compliant and, thus, is standardized for international comparisons. Automatic alerts currently in use include: email, cell phone text message, and internal pager text messaging. This system extends the utility of DICOM for standardizing the capturing and computing of radiation dose as well as other quality measures.

Optimization of the strength of the efavirenz/lamivudine/abacavir fixed-dose combination for paediatric patients.

PubMed

Bouazza, Naïm; Cressey, Tim R; Foissac, Frantz; Bienczak, Andrzej; Denti, Paolo; McIlleron, Helen; Burger, David; Penazzato, Martina; Lallemant, Marc; Capparelli, Edmund V; Treluyer, Jean-Marc; Urien, Saïk

2017-02-01

Child-friendly, low-cost, solid, oral fixed-dose combinations (FDCs) of efavirenz with lamivudine and abacavir are urgently needed to improve clinical management and drug adherence for children. Data were pooled from several clinical trials and therapeutic drug monitoring datasets from different countries. The number of children/observations was 505/3667 for efavirenz. Population pharmacokinetic analyses were performed using a non-linear mixed-effects approach. For abacavir and lamivudine, data from 187 and 920 subjects were available (population pharmacokinetic models previously published). Efavirenz/lamivudine/abacavir FDC strength options assessed were (I) 150/75/150, (II) 120/60/120 and (III) 200/100/200 mg. Monte Carlo simulations of the different FDC strengths were performed to determine the optimal dose within each of the WHO weight bands based on drug efficacy/safety targets. The probability of being within the target efavirenz concentration range 12 h post-dose (1-4 mg/L) varied between 56% and 60%, regardless of FDC option. Option I provided a best possible balance between efavirenz treatment failure and toxicity risks. For abacavir and lamivudine, simulations showed that for option I >75% of subjects were above the efficacy target. According to simulations, a paediatric efavirenz/lamivudine/abacavir fixed-dose formulation of 150 mg efavirenz, 75 mg lamivudine and 150 mg abacavir provided the most effective and safe concentrations across WHO weight bands, with the flexibility of dosage required across the paediatric population. © The Author 2016. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

Management Flexibility and State Regulation in Higher Education.

ERIC Educational Resources Information Center

Mingle, James R., Ed.

Findings of a Southern Regional Education Board study of management flexibility and state regulation in higher education are discussed in five chapters. James R. Mingle in "Management Flexibility and State Regulation: An Overview" outlines the scope of the study, which focused on administrators' and board members' views on management…

Development of the Coping Flexibility Scale: Evidence for the Coping Flexibility Hypothesis

ERIC Educational Resources Information Center

Kato, Tsukasa

2012-01-01

"Coping flexibility" was defined as the ability to discontinue an ineffective coping strategy (i.e., evaluation coping) and produce and implement an alternative coping strategy (i.e., adaptive coping). The Coping Flexibility Scale (CFS) was developed on the basis of this definition. Five studies involving approximately 4,400 Japanese…

Cognitive flexibility and changes in hopelessness across time: A moderation hypothesis.

PubMed

Yu, Junhong; Lee, Tatia M C

2017-01-01

Prior literature has suggested that cognitive flexibility is implicated in the feeling of hopelessness. However, studies on the nature of their relationship have been scarce. This study posits a moderation hypothesis on the relationship between cognitive flexibility and hopelessness. A total of 78 elderly participants (M age  = 70, SD = 6.1) were administered a self-report measure of hopelessness across two time points approximately 10 months apart and a measure of cognitive flexibility. We hypothesized that baseline hopelessness scores would moderate the relationship between cognitive flexibility and hopelessness scores 10 months later. Specifically, among the high baseline hopelessness group, we predicted that cognitively flexible participants would report lower hopelessness scores 10 months later. However, for the low baseline hopelessness group, cognitive flexibility would be unrelated to hopelessness scores 10 months later. The results of a bootstrapped moderation analysis controlling for age, sex, education, and general cognitive status supported our moderation hypothesis and predictions. These findings reveal the complex nature of the relationship between cognitive flexibility and hopelessness. The implications of these findings in the wider clinical context were discussed.

Cognitive flexibility predicts early reading skills

PubMed Central

Colé, Pascale; Duncan, Lynne G.; Blaye, Agnès

2014-01-01

An important aspect of learning to read is efficiency in accessing different kinds of linguistic information (orthographic, phonological, and semantic) about written words. The present study investigates whether, in addition to the integrity of such linguistic skills, early progress in reading may require a degree of cognitive flexibility in order to manage the coordination of this information effectively. Our study will look for evidence of a link between flexibility and both word reading and passage reading comprehension, and examine whether any such link involves domain-general or reading-specific flexibility. As the only previous support for a predictive relationship between flexibility and early reading comes from studies of reading comprehension in the opaque English orthography, another possibility is that this relationship may be largely orthography-dependent, only coming into play when mappings between representations are complex and polyvalent. To investigate these questions, 60 second-graders learning to read the more transparent French orthography were presented with two multiple classification tasks involving reading-specific cognitive flexibility (based on words) and non-specific flexibility (based on pictures). Reading skills were assessed by word reading, pseudo-word decoding, and passage reading comprehension measures. Flexibility was found to contribute significant unique variance to passage reading comprehension even in the less opaque French orthography. More interestingly, the data also show that flexibility is critical in accounting for one of the core components of reading comprehension, namely, the reading of words in isolation. Finally, the results constrain the debate over whether flexibility has to be reading-specific to be critically involved in reading. PMID:24966842

Effects of two types of medical contrast media on routine chemistry results by three automated chemistry analyzers.

PubMed

Park, Yu Jin; Rim, John Hoon; Yim, Jisook; Lee, Sang-Guk; Kim, Jeong-Ho

2017-08-01

The use of iodinated contrast media has grown in popularity in the past two decades, but relatively little attention has been paid to the possible interferential effects of contrast media on laboratory test results. Herein, we investigate medical contrast media interference with routine chemistry results obtained by three automated chemistry analyzers. Ten levels of pooled serum were used in the study. Two types of medical contrast media [Iopamiro (iopamidol) and Omnipaque (iohexol)] were evaluated. To evaluate the dose-dependent effects of the contrast media, iopamidol and iohexol were spiked separately into aliquots of serum for final concentrations of 1.8%, 3.6%, 5.5%, 7.3%, and 9.1%. The 28 analytes included in the routine chemistry panel were measured by using Hitachi 7600, AU5800, and Cobas c702 analyzers. We calculated the delta percentage difference (DPD) between the samples and the control, and examined dose-dependent trends. When the mean DPD values were compared with the reference cut-off criteria, the only uniformly interferential effect observed for all analyzers was in total protein with iopamidol. Two additional analytes that showed trends toward interferential effects only in few analyzers and exceeded the limits of the allowable error were the serum iron and the total CO 2 . The other combinations of analyzer and contrast showed no consistent dose-dependent propensity for change in any analyte level. Our study suggests that many of the analytes included in routine chemistry results, except total protein and serum iron, are not significantly affected by iopamidol and iohexol. These results suggest that it would be beneficial to apply a flexible medical evaluation process for patients requiring both laboratory tests and imaging studies, minimizing the need for strict regulations for sequential tests. Copyright © 2017 The Canadian Society of Clinical Chemists. Published by Elsevier Inc. All rights reserved.

Association Between Flexible Duty Hour Policies and General Surgery Resident Examination Performance: A Flexibility in Duty Hour Requirements for Surgical Trainees (FIRST) Trial Analysis.

PubMed

Blay, Eddie; Hewitt, D Brock; Chung, Jeanette W; Biester, Thomas; Fiore, James F; Dahlke, Allison R; Quinn, Christopher M; Lewis, Frank R; Bilimoria, Karl Y

2017-02-01

Concerns persist about the effect of current duty hour reforms on resident educational outcomes. We investigated whether a flexible, less-restrictive duty hour policy (Flexible Policy) was associated with differential general surgery examination performance compared with current ACGME duty hour policy (Standard Policy). We obtained examination scores on the American Board of Surgery In-Training Examination, Qualifying Examination (written boards), and Certifying Examination (oral boards) for residents in 117 general surgery residency programs that participated in the Flexibility in Duty Hour Requirements for Surgical Trainees (FIRST) Trial. Using bivariate analyses and regression models, we compared resident examination performance across study arms (Flexible Policy vs Standard Policy) for 2015 and 2016, and 1 year of the Qualifying Examination and Certifying Examination. Adjusted analyses accounted for program-level factors, including the stratification variable for randomization. In 2016, FIRST trial participants were 4,363 general surgery residents. Mean American Board of Surgery In-Training Examination scores for residents were not significantly different between study groups (Flexible Policy vs Standard Policy) overall (Flexible Policy: mean [SD] 502.6 [100.9] vs Standard Policy: 502.7 [98.6]; p = 0.98) or for any individual postgraduate year level. There was no difference in pass rates between study arms for either the Qualifying Examination (Flexible Policy: 90.4% vs Standard Policy: 90.5%; p = 0.99) or Certifying Examination (Flexible Policy: 86.3% vs Standard Policy: 88.6%; p = 0.24). Results from adjusted analyses were consistent with these findings. Flexible, less-restrictive duty hour policies were not associated with differences in general surgery resident performance on examinations during the FIRST Trial. However, more years under flexible duty hour policies might be needed to observe an effect. Copyright © 2016 American College of Surgeons. Published by Elsevier Inc. All rights reserved.

Neighborhood-targeted and case-triggered use of a single dose of oral cholera vaccine in an urban setting: Feasibility and vaccine coverage.

PubMed

Parker, Lucy A; Rumunu, John; Jamet, Christine; Kenyi, Yona; Lino, Richard Laku; Wamala, Joseph F; Mpairwe, Allan M; Muller, Vincent; Llosa, Augusto E; Uzzeni, Florent; Luquero, Francisco J; Ciglenecki, Iza; Azman, Andrew S

2017-06-01

In June 2015, a cholera outbreak was declared in Juba, South Sudan. In addition to standard outbreak control measures, oral cholera vaccine (OCV) was proposed. As sufficient doses to cover the at-risk population were unavailable, a campaign using half the standard dosing regimen (one-dose) targeted high-risk neighborhoods and groups including neighbors of suspected cases. Here we report the operational details of this first public health use of a single-dose regimen of OCV and illustrate the feasibility of conducting highly targeted vaccination campaigns in an urban area. Neighborhoods of the city were prioritized for vaccination based on cumulative attack rates, active transmission and local knowledge of known cholera risk factors. OCV was offered to all persons older than 12 months at 20 fixed sites and to select groups, including neighbors of cholera cases after the main campaign ('case-triggered' interventions), through mobile teams. Vaccination coverage was estimated by multi-stage surveys using spatial sampling techniques. 162,377 individuals received a single-dose of OCV in the targeted neighborhoods. In these neighborhoods vaccine coverage was 68.8% (95% Confidence Interval (CI), 64.0-73.7) and was highest among children ages 5-14 years (90.0%, 95% CI 85.7-94.3), with adult men being less likely to be vaccinated than adult women (Relative Risk 0.81, 95% CI: 0.68-0.96). In the case-triggered interventions, each lasting 1-2 days, coverage varied (range: 30-87%) with an average of 51.0% (95% CI 41.7-60.3). Vaccine supply constraints and the complex realities where cholera outbreaks occur may warrant the use of flexible alternative vaccination strategies, including highly-targeted vaccination campaigns and single-dose regimens. We showed that such campaigns are feasible. Additional work is needed to understand how and when to use different strategies to best protect populations against epidemic cholera.

SU-F-T-667: Development and Validation of Dose Calculation for An Open-Source KV Treatment Planning System for Small Animal Radiotherapy

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

Prajapati, S; Mo, X; Bednarz, B

Purpose: An open-source, convolution/superposition based kV-treatment planning system(TPS) was developed for small animal radiotherapy from previously existed in-house MV-TPS. It is flexible and applicable to both step and shoot and helical tomotherapy treatment delivery. For initial commissioning process, the dose calculation from kV-TPS was compared with measurements and Monte Carlo(MC) simulations. Methods: High resolution, low energy kernels were simulated using EGSnrc user code EDKnrc, which was used as an input in kV-TPS together with MC-simulated x-ray beam spectrum. The Blue Water™ homogeneous phantom (with film inserts) and heterogeneous phantom (with film and TLD inserts) were fabricated. Phantom was placed atmore » 100cm SSD, and was irradiated with 250 kVp beam for 10mins with 1.1cm × 1.1cm open field (at 100cm) created by newly designed binary micro-MLC assembly positioned at 90cm SSD. Gafchromic™ EBT3 film was calibrated in-phantom following AAPM TG-61 guidelines, and were used for measurement at 5 different depths in phantom. Calibrated TLD-100s were obtained from ADCL. EGS and MNCP5 simulation were used to model experimental irradiation set up calculation of dose in phantom. Results: Using the homogeneous phantom, dose difference between film and kV-TPS was calculated: mean(x)=0.9%; maximum difference(MD)=3.1%; standard deviation(σ)=1.1%. Dose difference between MCNP5 and kV-TPS was: x=1.5%; MD=4.6%; σ=1.9%. Dose difference between EGS and kV-TPS was: x=0.8%; MD=1.9%; σ=0.8%. Using the heterogeneous phantom, dose difference between film and kV-TPS was: x=2.6%; MD=3%; σ=1.1%; and dose difference between TLD and kV-TPS was: x=2.9%; MD=6.4%; σ=2.5%. Conclusion: The inhouse, open-source kV-TPS dose calculation system was comparable within 5% of measurements and MC simulations in both homogeneous and heterogeneous phantoms. The dose calculation system of the kV-TPS is validated as a part of initial commissioning process for small animal radiotherapy. The kV-TPS has the potential for accurate dose calculation for any kV treatment or imaging modalities.« less

Reversal-specific learning impairments after a binge regimen of methamphetamine in rats: possible involvement of striatal dopamine.

PubMed

Izquierdo, Alicia; Belcher, Annabelle M; Scott, Lori; Cazares, Victor A; Chen, Jack; O'Dell, Steven J; Malvaez, Melissa; Wu, Tiffany; Marshall, John F

2010-01-01

A growing body of evidence indicates that protracted use of methamphetamine (mAMPH) causes long-term impairments in cognitive function in humans. Aside from the widely reported problems with attention, mAMPH users exhibit learning and memory deficits, particularly on tasks requiring response control. Although binge mAMPH administration to animals results in cognitive deficits, few studies have attempted to test behavioral flexibility in animals after mAMPH exposure. The aim of this study was to evaluate whether mAMPH would produce impairments in two tasks assessing flexible responding in rats: a touchscreen-based discrimination-reversal learning task and an attentional set shift task (ASST) based on a hallmark test of executive function in humans, the Wisconsin Card Sort. We treated male Long-Evans rats with a regimen of four injections of 2 mg/kg mAMPH (or vehicle) within a single day, a dosing regimen shown earlier to produce object recognition impairments. We then tested them on (1) reversal learning after pretreatment discrimination learning or (2) the ASST. Early reversal learning accuracy was impaired in mAMPH-treated rats. MAMPH pretreatment also selectively impaired reversal performance during ASST testing, leaving set-shifting performance intact. Postmortem analysis of [(125)I]RTI-55 binding revealed small (10-20%) but significant reductions in striatal dopamine transporters produced by this mAMPH regimen. Together, these results lend new information to the growing field documenting impaired cognition after mAMPH exposure, and constitute a rat model of the widely reported decision-making deficits resulting from mAMPH abuse seen in humans.

Oxcarbazepine for the treatment of trichotillomania.

PubMed

Leombruni, Paolo; Gastaldi, Filippo

2010-01-01

There is no pharmacological treatment of trichotillomania that has consistently demonstrated efficacy, although good results have been obtained with antidepressants and other drugs such as atypical antipsychotics, bupropion, lithium, and topiramate. The anticonvulsant oxcarbazepine has also been used as mood stabilizer and has been tested for treating binge eating, but there is no report on oxcarbazepine in trichotillomania. We report the case of an obese 43-year-old woman with a diagnosis of trichotillomania in comorbidity with binge eating disorder who was treated with a flexible dose of the anticonvulsant oxcarbazepine. We administered oxcarbazepine at a dosage of 1200 mg/d, and this subject improved both in hair pulling and in eating behaviors with no relapse after 9 months. Further studies with a wide sample of patients are needed to prove the efficacy of oxcarbazepine and the long-term maintenance of these benefits. Relationships of trichotillomania with bipolar spectrum should also be investigated.

A Flexible Pilot-Scale Setup for Real-Time Studies in Process Systems Engineering

ERIC Educational Resources Information Center

Panjapornpon, Chanin; Fletcher, Nathan; Soroush, Masoud

2006-01-01

This manuscript describes a flexible, pilot-scale setup that can be used for training students and carrying out research in process systems engineering. The setup allows one to study a variety of process systems engineering concepts such as design feasibility, design flexibility, control configuration selection, parameter estimation, process and…

Contagious flexibility? A study on whether schedule flexibility facilitates work-life enrichment.

PubMed

Pedersen, Vivi Bach; Jeppesen, Hans Jeppe

2012-08-01

Schedule flexibility defines an important generating resource for work-life enrichment; however, our knowledge about how such spillovers take place is limited. This multiple case study examines how workers from different working time contexts with varying levels of schedule flexibility experience work-life interplay. Given the adopted explorative design, it is important to interpret the findings in a tentative light. Nonetheless, the study offers important insight into work-life enrichment that may guide future research in this field. The findings indicate that schedule flexibility may act as a boundary-spanning resource owing to the agency potential it offers workers. Thus, it seemed that flexible schedule opportunities enabled workers to engage more fully in personal life activities, which in turn had a positive influence on their work involvement through positive affect. Such positive role engagements appeared, however, to be greatly determined by workers' boundary management and by time conditions of work and family. In conclusion, the major findings and limitation of the study are discussed against existing research and theory. © 2012 The Authors. Scandinavian Journal of Psychology © 2012 The Scandinavian Psychological Associations.

Coping with occupational stress: the role of optimism and coping flexibility.

PubMed

Reed, Daniel J

2016-01-01

The current study aimed at measuring whether coping flexibility is a reliable and valid construct in a UK sample and subsequently investigating the association between coping flexibility, optimism, and psychological health - measured by perceived stress and life satisfaction. A UK university undergraduate student sample (N=95) completed an online questionnaire. The study is among the first to examine the validity and reliability of the English version of a scale measuring coping flexibility in a Western population and is also the first to investigate the association between optimism and coping flexibility. The results revealed that the scale had good reliability overall; however, factor analysis revealed no support for the existing two-factor structure of the scale. Coping flexibility and optimism were found to be strongly correlated, and hierarchical regression analyses revealed that the interaction between them predicted a large proportion of the variance in both perceived stress and life satisfaction. In addition, structural equation modeling revealed that optimism completely mediated the relationship between coping flexibility and both perceived stress and life satisfaction. The findings add to the occupational stress literature to further our understanding of how optimism is important in psychological health. Furthermore, given that optimism is a personality trait, and consequently relatively stable, the study also provides preliminary support for the potential of targeting coping flexibility to improve psychological health in Western populations. These findings must be replicated, and further analyses of the English version of the Coping Flexibility Scale are needed.

Impact of anxiety on prefrontal cortex encoding of cognitive flexibility

PubMed Central

Park, Junchol; Moghaddam, Bita

2016-01-01

Anxiety often is studied as a stand-alone construct in laboratory models. But in the context of coping with real-life anxiety, its negative impacts extend beyond aversive feelings and involve disruptions in ongoing goal-directed behaviors and cognitive functioning. Critical examples of cognitive constructs affected by anxiety are cognitive flexibility and decision making. In particular, anxiety impedes the ability to shift flexibly between strategies in response to changes in task demands, as well as the ability to maintain a strategy in the presence of distractors. The brain region most critically involved in behavioral flexibility is the prefrontal cortex (PFC), but little is known about how anxiety impacts PFC encoding of internal and external events that are critical for flexible behavior. Here we review animal and human neurophysiological and neuroimaging studies implicating PFC neural processing in anxiety-induced deficits in cognitive flexibility. We then suggest experimental and analytical approaches for future studies to gain a better mechanistic understanding of impaired cognitive inflexibility in anxiety and related disorders. PMID:27316551

[An Exploration of Working Conditions and Flexible System for Hospital Nurses].

PubMed

Huang, Chung-I; Yu, Chien; Yu, Chin-Cheh

2016-04-01

The lack of sufficient numbers of professional nurses in the healthcare system in Taiwan is an issue that affects the sustainability of this system and that relates closely to working conditions. The present study explores the expectations that nurses hold with regard to working conditions and the operation of a flexible system in hospitals. A literature review and focus-group interviews were used to develop the questionnaire Working Conditions and Flexible System. A total of 1,150 copies of this questionnaire were distributed to practicing nurses using stratified random sampling, with 1,146 valid copies returned for a valid recovery rate of 99.65%. The results show that the expectations of participants concerning working conditions and a flexible system focus on the 6 factors of task, numerical, divisional, temporal, wages, and leading flexibility. The total mean was 4.35 (SD=0.42). The means for the 6 types of flexibility were all greater than 4.0. Participants deemed flexibility to be of high importance. The demographic variables hospital, work location, age, education level, work position, work unit, and total work years all affected the 6 types of flexibility significantly. The present study supports that the retention of nurses is significantly associated with working conditions and the operation of a flexible system. Administrators and mangers must create positive working conditions and a flexible system in order to enhance the retention and career development of nurses.

Flexible Pedagogies: Employer Engagement and Work-Based Learning. Flexible Pedagogies: Preparing for the Future Series

ERIC Educational Resources Information Center

Kettle, Jane

2013-01-01

This publication focuses on national and international policy initiatives to develop a better understanding of work-based learners and the types of flexibility that may well enhance their study especially pedagogically. As part of our five-strand research project "Flexible Pedagogies: preparing for the future" it: (1) highlights the…

Knowledge and Control in the Flexible Workplace. EAE610 The Changing Workplace: Part B.

ERIC Educational Resources Information Center

Watkins, Peter

This publication is part of the study materials for the distance education course, The Changing Workplace: Part B, in the Open Campus Program at Deakin University. The first part of the document examines current thinking regarding knowledge and control in workplaces emphasizing flexible production systems, flexible technology, and a flexible work…

Flexible Pedagogies: Part-Time Learners and Learning in Higher Education. Flexible Pedagogies: Preparing for the Future Series

ERIC Educational Resources Information Center

McLinden, Michael

2013-01-01

This publication focuses on national and international policy initiatives to develop a better understanding of part-time learners and the types of flexibility that may enhance their study especially pedagogically. As part of our five-strand research project "Flexible Pedagogies: preparing for the future" it: (1) highlights the challenges…

Effects of carbohydrate counting method on metabolic control in children with type 1 diabetes mellitus.

PubMed

Gökşen, Damla; Atik Altınok, Yasemin; Ozen, Samim; Demir, Günay; Darcan, Sükran

2014-01-01

Medical nutritional therapy is important for glycemic control in children and adolescents with type 1 diabetes mellitus (T1DM). Carbohydrate (carb) counting, which is a more flexible nutritional method, has become popular in recent years. This study aimed to investigate the effects of carb counting on metabolic control, body measurements and serum lipid levels in children and adolescents with T1DM. T1DM patients aged 7-18 years and receiving flexible insulin therapy were divided into carb counting (n=52) and control (n=32) groups and were followed for 2 years in this randomized, controlled study. Demographic characteristics, body measurements, insulin requirements, hemoglobin A1c (HbA1c) and serum lipid levels at baseline and at follow-up were evaluated. There were no statistically significant differences between the groups in mean HbA1c values in the year preceding the study or in age, gender, duration of diabetes, puberty stage, total daily insulin dose, body mass index (BMI) standard deviation score (SDS) and serum lipid values. While there were no differences in BMI SDS, daily insulin requirement, total cholesterol, low-density lipoprotein and triglyceride values between the two groups (p>0.05) during the follow-up, annual mean HbA1c levels of the 2nd year were significantly lower in the carb counting group (p=0.010). The mean values of high-density lipoprotein were also significantly higher in the first and 2nd years in the carb counting group (p=0.02 and p=0.043, respectively). Carb counting may provide good metabolic control in children and adolescents with T1DM without causing any increase in weight or in insulin requirements.

Factors impeding flexible inpatient unit design.

PubMed

Pati, Debajyoti; Evans, Jennie; Harvey, Thomas E; Bazuin, Doug

2012-01-01

To identify and examine factors extraneous to the design decision-making process that could impede the optimization of flexibility on inpatient units. A 2006 empirical study to identify domains of design decisions that affect flexibility on inpatient units found some indication in the context of the acuity-adaptable operational model that factors extraneous to the design process could have negatively influenced the successful implementation of the model. This raised questions regarding extraneous factors that might influence the successful optimization of flexibility. An exploratory, qualitative method was adopted to examine the question. Stakeholders from five recently built acute care inpatient units participated in the study, which involved three types of data collection: (1) verbal protocol data from a gaming session; (2) in-depth semi-structured interviews; and (3) shadowing frontline personnel. Data collection was conducted between June 2009 and November 2010. The study revealed at least nine factors extraneous to the design process that have the potential to hinder the optimization of flexibility in four domains: (1) systemic; (2) cultural; (3) human; and (4) financial. Flexibility is critical to hospital operations in the new healthcare climate, where cost reduction constitutes a vital target. From this perspective, flexibility and efficiency strategies can be influenced by (1) return on investment, (2) communication, (3) culture change, and (4) problem definition. Extraneous factors identified in this study could also affect flexibility in other care settings; therefore, these findings may be viewed from the overall context of hospital design.

An industrial perspective on the design and development of medicines for older patients.

PubMed

Page, Sharon; Coupe, Alastair; Barrett, Andrew

2016-10-30

An increasing elderly population is leading to a change in the global demographics. This presents a new challenge to society and the pharmaceutical industry. This demographic shift is providing an opportunity for the pharmaceutical industry to meet the specific needs of the changing patient population. One issue that has been identified is defining what is meant by "an older patient", since this definition cannot be simply limited to chronological age. The fundamental purpose of the design and development process is to create a product that can be used by the patient group in a safe and efficacious manner. In the pharmaceutical industry ICH Q8 is used to guide the design and development of medicines. The process leads to the definition of the Quality Target Product Profile (QTPP) for a specific drug product and patient population. One can imagine a product with various presentations described in the QTPP which suit paediatrics, adults and older patients. It is recognised that designing medicines for smaller population groups will result in multiple presentations that could lead to smaller manufacturing batch sizes. In the short to medium term; dose flexibility, easy-to-swallow formulations, and easier access packaging are all factors under consideration. Dose flexibility could be achieved with various dosage forms such as oral liquids, mini-tablets, or multi-particulates. Whilst patient dosage preferences are beginning to be understood, further investigation is needed to balance the needs of the patient, care giver, prescriber, and payer. There also remain a number of challenges with the engineering solutions and delivery device for mini-tablets and multi-particulates (aside from filled capsules) to accurately and robustly deliver the dose, and issues with handling the device and the packaging for an older patient. It is also recognised that there are numerous challenges, not least of which is the definition of the older patient and a generic QTPP for an older patients' drug product. It is likely that there will be no simple solution or 'one-size-fits-all' approach in drug product development to resolve the complex issues presented by the ageing population. Copyright © 2016 Elsevier B.V. All rights reserved.

Testing of the coping flexibility hypothesis based on the dual-process theory: Relationships between coping flexibility and depressive Symptoms.

PubMed

Kato, Tsukasa

2015-12-15

According to the dual-process theory of coping flexibility (Kato, 2012), coping flexibility is the ability to discontinue an ineffective coping strategy (i.e., evaluation coping process) and implement an alternative strategy (i.e., adaptive coping process). The coping flexibility hypothesis (CFH) proposes that the ability to engage in flexible coping is related to better psychological functioning and physical health, including less depression. I the present study, participants were 393 American Whites, 429 Australian Whites, and 496 Chinese, selected from the data pool of the 2013 Coping and Health Survey (see Kato, 2014b). They completed both the Coping Flexibility Scale (Kato, 2012), which is based on the dual-process theory of coping flexibility, and the Center for Epidemiologic Studies Depression Scale (CES-D). For all nationalities and genders, evaluation coping and adaptive coping were significantly correlated with lower levels of depressive symptoms. Structural equation modeling revealed that evaluation coping was associated with lower depressive symptoms for all nationalities and genders, whereas no significant relationships between adaptive coping and depressive symptoms were found for any nationalities. Our results partially supported that the CFH fits with the dual-process theory of coping flexibility. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Are the Most Plastic Species the Most Abundant Ones? An Assessment Using a Fish Assemblage

PubMed Central

Vidal, Nicolás; Zaldúa, Natalia; D'Anatro, Alejandro; Naya, Daniel E.

2014-01-01

Few studies have evaluated phenotypic plasticity at the community level, considering, for example, plastic responses in an entire species assemblage. In addition, none of these studies have addressed the relationship between phenotypic plasticity and community structure. Within this context, here we assessed the magnitude of seasonal changes in digestive traits (seasonal flexibility), and of changes during short-term fasting (flexibility during fasting), occurring in an entire fish assemblage, comprising ten species, four trophic levels, and a 37-fold range in body mass. In addition, we analyzed the relationship between estimates of digestive flexibility and three basic assemblage structure attributes, i.e., species trophic position, body size, and relative abundance. We found that: (1) Seasonal digestive flexibility was not related with species trophic position or with body size; (2) Digestive flexibility during fasting tended to be inversely correlated with body size, as expected from scaling relationships; (3) Digestive flexibility, both seasonal and during fasting, was positively correlated with species relative abundance. In conclusion, the present study identified two trends in digestive flexibility in relation to assemblage structure, which represents an encouraging departure point in the search of general patterns in phenotypic plasticity at the local community scale. PMID:24651865

Flexible and rigid cystoscopy in women.

PubMed

Gee, Jason R; Waterman, Bradley J; Jarrard, David F; Hedican, Sean P; Bruskewitz, Reginald C; Nakada, Stephen Y

2009-01-01

Previous studies have evaluated the tolerability of rigid versus flexible cystoscopy in men. Similar studies, however, have not been performed in women. We sought to determine whether office-based flexible cystoscopy was better tolerated than rigid cystoscopy in women. Following full IRB approval, women were prospectively randomized in a single-blind manner. Patients were randomized to flexible or rigid cystoscopy and draped in the lithotomy position to maintain blinding of the study. Questionnaires evaluated discomfort before, during, and after cystoscopy. Thirty-six women were randomized to flexible (18) or rigid (18) cystoscopy. Indications were surveillance (16), hematuria (15), recurrent UTIs (2), voiding dysfunction (1), and other (2). All questionnaires were returned by 31/36 women. Using a 10-point visual analog scale (VAS), median discomfort during the procedure for flexible and rigid cystoscopy were 1.4 and 1.8, respectively, in patients perceiving pain. Median recalled pain 1 week later was similar at 0.8 and 1.15, respectively. None of these differences were statistically significant. Flexible and rigid cystoscopy are well tolerated in women. Discomfort during and after the procedure is minimal in both groups. Urologists should perform either procedure in women based on their preference and skill level.

Lacosamide for uncontrolled primary generalized tonic-clonic seizures: An open-label pilot study with 59-week extension.

PubMed

Wechsler, Robert T; Yates, Stephen L; Messenheimer, John; Leroy, Robert; Beller, Cynthia; Doty, Pamela

2017-02-01

Assess the safety of adjunctive lacosamide for the treatment of uncontrolled primary generalized tonic-clonic seizures in patients (16-65 years) with primary generalized (genetic) epilepsy (PGE). An open-label pilot safety study (SP0961; NCT01118949), comprising 12 weeks' historical baseline, 4 weeks' prospective baseline, 3 weeks' titration (target: 400mg/day adjunctive lacosamide) and 6 weeks' maintenance. Patients who continued to the extension study (SP0962; NCT01118962) then received ≤59 weeks of flexible treatment (100-800mg/day lacosamide with flexible dosing of concomitant antiepileptic drugs). The primary outcomes for SP0961 were the mean change (±standard deviation) in absence seizure or myoclonic seizure days per 28days from prospective baseline to maintenance; for SP0962, the incidence of treatment-emergent adverse events (TEAEs) and withdrawals because of TEAEs. Of the 49 patients who enrolled, 40 (82%) completed the pilot study and 9 discontinued (5 because of adverse events). Of the 39 patients who continued to the extension study, 10 discontinued (2 owing to TEAEs) and 29 (74%) completed the study. During the pilot study, patients reported a reduction in mean (±standard deviation) absence and myoclonic seizure days per 28days (-0.37±4.80, -2.19±5.80). Reductions were also observed during the extension study (-2.38±5.54, -2.78±6.43). Five patients in SP0961 and 2 patients in SP0962 experienced TEAEs of new or increased frequency of absence seizures or myoclonic seizures. The most common TEAEs during SP0961 were dizziness (39%) and nausea (27%), and during SP0962 were dizziness (26%) and upper respiratory tract infection (26%). The safety profile of adjunctive lacosamide was similar to that previously published. Adjunctive lacosamide did not systematically worsen absence or myoclonic seizures, and appears to be well tolerated in patients with PGE. Copyright © 2016. Published by Elsevier B.V.

A bio-inspired study on tidal energy extraction with flexible flapping wings.

PubMed

Liu, Wendi; Xiao, Qing; Cheng, Fai

2013-09-01

Previous research on the flexible structure of flapping wings has shown an improved propulsion performance in comparison to rigid wings. However, not much is known about this function in terms of power efficiency modification for flapping wing energy devices. In order to study the role of the flexible wing deformation in the hydrodynamics of flapping wing energy devices, we computationally model the two-dimensional flexible single and twin flapping wings in operation under the energy extraction conditions with a large Reynolds number of 106. The flexible motion for the present study is predetermined based on a priori structural result which is different from a passive flexibility solution. Four different models are investigated with additional potential local distortions near the leading and trailing edges. Our simulation results show that the flexible structure of a wing is beneficial to enhance power efficiency by increasing the peaks of lift force over a flapping cycle, and tuning the phase shift between force and velocity to a favourable trend. Moreover, the impact of wing flexibility on efficiency is more profound at a low nominal effective angle of attack (AoA). At a typical flapping frequency f * = 0.15 and nominal effective AoA of 10°, a flexible integrated wing generates 7.68% higher efficiency than a rigid wing. An even higher increase, around six times that of a rigid wing, is achievable if the nominal effective AoA is reduced to zero degrees at feathering condition. This is very attractive for a semi-actuated flapping energy system, where energy input is needed to activate the pitching motion. The results from our dual-wing study found that a parallel twin-wing device can produce more power compared to a single wing due to the strong flow interaction between the two wings.

MO-FG-CAMPUS-TeP3-03: Calculation of Proton Pencil Beam Properties with Full Beamline Model in TOPAS

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

Wulff, J; Abel, E

2016-06-15

Purpose: Introducing Monte Carlo based dose calculation algorithms into proton therapy planning systems (TPS) leads to improved accuracy. However accurate modelling of the proton pencil beam impinging the patient is necessary. Current approaches rely on measurement-driven reconstruction of phase-space and spectrum properties, typically constrained to analytical model functions. In this study a detailed Monte Carlo model of the complete cyclotron-based delivery system was created with the aim of providing more representative beam properties at treatment position. Methods: A model of the Varian Probeam proton system from the cyclotron exit to isocenter was constructed in the TOPAS Monte Carlo framework. Themore » beam evolution through apertures and magnetic elements was validated using Transport/Turtle calculations and additionally against measurements from the Probeam™ system at Scripps Proton Therapy Center (SPTC) in San Diego, CA. A voxelized water phantom at isocenter allowed for comparison of the dose-depth curve from the Probeam model with that of a corresponding Gaussian beam over the entire energy range (70–240 MeV). Measurements of relative beam fluence cross-profiles and depth-dose curves at and around isocenter were also compared to the MC results. Results: The simulated TOPAS beam envelope was found to agree with both the Transport/Turtle and measurements to within 5% for most of the beamline. The MC predicted energy spectrum at isocenter was found to deviate increasingly from Gaussian at energies below 160 MeV. The corresponding effects on the depth dose curve agreed well with measurements. Conclusion: Given the flexibility of TOPAS and available details of the delivery system, an accurate characterization of a proton pencil beam at isocenter is possible. Incorporation of the MC derived properties of the proton pencil beam can eliminate analytical approximations and ultimately increase treatment plan accuracy and quality. Both authors are employees of Varian Medical Systems.« less

Thermoluminescence properties of Yb-Tb-doped SiO2 optical fiber subject to 6 and 10 MV photon irradiation

NASA Astrophysics Data System (ADS)

Sahini, M. H.; Wagiran, H.; Hossain, I.; Saeed, M. A.; Ali, H.

2014-08-01

This paper reports thermoluminescence characteristics of thermoluminescence dosimetry 100 chips and Yb-Tb-doped optical fibers irradiated with 6 and 10 MV photons. Thermoluminescence response of both dosimeters increases over a wide photon dose range from 0.5 to 4 Gy. Yb-Tb-doped optical fibers demonstrate useful thermoluminescence properties and represent a good candidate for thermoluminescence dosimetry application with ionizing radiation. The results of this fiber have been compared with those of commercially available standard thermoluminescence dosimetry-100 media. Commercially available Yb-Tb-doped optical fibers and said standard media are found to yield a linear relationship between dose- and thermoluminescence signal, although Yb-Tb-doped optical fibers provide only 10 % of the sensitivity of thermoluminescence dosimetry-100. With better thermoluminescence characteristics such as small size (125 μm diameter), high flexibility, easy of handling and low cost, as compared to other thermoluminescence materials, indicate that commercial Yb-Tb-doped optical fiber is a promising thermoluminescence material for variety of applications.

Dead space variability of face masks for valved holding chambers.

PubMed

Amirav, Israel; Newhouse, Michael T

2008-03-01

Valved holding chambers with masks are commonly used to deliver inhaled medications to young children with asthma. Optimal mask properties such as their dead space volume have received little attention. The smaller the mask the more likely it is that a greater proportion of the dose in the VHC will be inhaled with each breath, thus speeding VHC emptying and improving overall aerosol delivery efficiency and dose. Masks may have different DSV and thus different performance. To compare both physical dead space and functional dead space of different face masks under various applied pressures. The DSV of three commonly used face masks of VHCs was measured by water displacement both under various pressures (to simulate real-life application, dynamic DSV) and under no pressure (static DSV). There was a great variability of both static and dynamic dead space among various face mask for VHCs, which is probably related to their flexibility. Different masks have different DSV characteristics. This variability should be taken into account when comparing the clinical efficacy of various VHCs.

Potential energy hypersurface and molecular flexibility

NASA Astrophysics Data System (ADS)

Koča, Jaroslav

1993-02-01

The molecular flexibility phenomenon is discussed from the conformational potential energy(hyper) surface (PES) point of view. Flexibility is considered as a product of three terms: thermodynamic, kinetic and geometrical. Several expressions characterizing absolute and relative molecular flexibility are introduced, depending on a subspace studied of the entire conformational space, energy level E of PES as well as absolute temperature. Results obtained by programs DAISY, CICADA and PANIC in conjunction with molecular mechanics program MMX for flexibility analysis of isopentane, 2,2-dimethylpentane and isohexane molecules are introduced.

Global mapping of DNA conformational flexibility on Saccharomyces cerevisiae.

PubMed

Menconi, Giulia; Bedini, Andrea; Barale, Roberto; Sbrana, Isabella

2015-04-01

In this study we provide the first comprehensive map of DNA conformational flexibility in Saccharomyces cerevisiae complete genome. Flexibility plays a key role in DNA supercoiling and DNA/protein binding, regulating DNA transcription, replication or repair. Specific interest in flexibility analysis concerns its relationship with human genome instability. Enrichment in flexible sequences has been detected in unstable regions of human genome defined fragile sites, where genes map and carry frequent deletions and rearrangements in cancer. Flexible sequences have been suggested to be the determinants of fragile gene proneness to breakage; however, their actual role and properties remain elusive. Our in silico analysis carried out genome-wide via the StabFlex algorithm, shows the conserved presence of highly flexible regions in budding yeast genome as well as in genomes of other Saccharomyces sensu stricto species. Flexibile peaks in S. cerevisiae identify 175 ORFs mapping on their 3'UTR, a region affecting mRNA translation, localization and stability. (TA)n repeats of different extension shape the central structure of peaks and co-localize with polyadenylation efficiency element (EE) signals. ORFs with flexible peaks share common features. Transcripts are characterized by decreased half-life: this is considered peculiar of genes involved in regulatory systems with high turnover; consistently, their function affects biological processes such as cell cycle regulation or stress response. Our findings support the functional importance of flexibility peaks, suggesting that the flexible sequence may be derived by an expansion of canonical TAYRTA polyadenylation efficiency element. The flexible (TA)n repeat amplification could be the outcome of an evolutionary neofunctionalization leading to a differential 3'-end processing and expression regulation in genes with peculiar function. Our study provides a new support to the functional role of flexibility in genomes and a strategy for its characterization inside human fragile sites.

Global Mapping of DNA Conformational Flexibility on Saccharomyces cerevisiae

PubMed Central

Menconi, Giulia; Bedini, Andrea; Barale, Roberto; Sbrana, Isabella

2015-01-01

In this study we provide the first comprehensive map of DNA conformational flexibility in Saccharomyces cerevisiae complete genome. Flexibility plays a key role in DNA supercoiling and DNA/protein binding, regulating DNA transcription, replication or repair. Specific interest in flexibility analysis concerns its relationship with human genome instability. Enrichment in flexible sequences has been detected in unstable regions of human genome defined fragile sites, where genes map and carry frequent deletions and rearrangements in cancer. Flexible sequences have been suggested to be the determinants of fragile gene proneness to breakage; however, their actual role and properties remain elusive. Our in silico analysis carried out genome-wide via the StabFlex algorithm, shows the conserved presence of highly flexible regions in budding yeast genome as well as in genomes of other Saccharomyces sensu stricto species. Flexibile peaks in S. cerevisiae identify 175 ORFs mapping on their 3’UTR, a region affecting mRNA translation, localization and stability. (TA)n repeats of different extension shape the central structure of peaks and co-localize with polyadenylation efficiency element (EE) signals. ORFs with flexible peaks share common features. Transcripts are characterized by decreased half-life: this is considered peculiar of genes involved in regulatory systems with high turnover; consistently, their function affects biological processes such as cell cycle regulation or stress response. Our findings support the functional importance of flexibility peaks, suggesting that the flexible sequence may be derived by an expansion of canonical TAYRTA polyadenylation efficiency element. The flexible (TA)n repeat amplification could be the outcome of an evolutionary neofunctionalization leading to a differential 3’-end processing and expression regulation in genes with peculiar function. Our study provides a new support to the functional role of flexibility in genomes and a strategy for its characterization inside human fragile sites. PMID:25860149

Worker Learning and Worktime Flexibility. A Policy Discussion Paper.

ERIC Educational Resources Information Center

Meier, Gretl S.

A study explored the feasibility of research on the impact of flexible work patterns on the educational and training opportunities available to women in low-status jobs. Intended to provide a basis for a more informed discussion of policy questions pertaining to flexible worktime, the study involved a review of related literature, a series of…

Flexibility and running economy in female collegiate track athletes.

PubMed

Beaudoin, C M; Whatley Blum, J

2005-09-01

Limited information exists regarding the association between flexibility and running economy in female athletes. This study examined relationships between lower limb and trunk flexibility and running economy in 17 female collegiate track athletes (20.12+/-1.80 y). Correlational design, subjects completed 4 testing sessions over a 2-week period. The 1st session assessed maximal oxygen uptake (VO2max=55.39+/-6.96 ml.kg-1.min-1). The 2nd session assessed trunk and lower limb flexibility. Two sets of 6 trunk and lower limb flexibility measures were performed after a 10-min treadmill warm-up at 2.68 m.s-1. The 3rd session consisted of 3 10-min accommodation runs at a speed of 2.68 m.s-1 which was approximately 60% VO2max. Each accommodation bout was separated by a 10-min rest. The 4th session assessed running economy. Subjects completed a 5-min warm-up at 2.68 m.s-1 followed by 10-min economy run at 2.68 m.s-1. Pearson product moment correlations revealed no significant correlations between running economy and flexibility measures. Results are in contrast to studies demonstrating an inverse relationship between trunk and/or lower limb flexibility and running economy in males. Furthermore, results are in contrast to studies reporting positive relationships between flexibility and running economy.

Does cognitive behavioral therapy alter mental defeat and cognitive flexibility in patients with panic disorder?

PubMed

Nagata, Shinobu; Seki, Yoichi; Shibuya, Takayuki; Yokoo, Mizue; Murata, Tomokazu; Hiramatsu, Yoichi; Yamada, Fuminori; Ibuki, Hanae; Minamitani, Noriko; Yoshinaga, Naoki; Kusunoki, Muga; Inada, Yasushi; Kawasoe, Nobuko; Adachi, Soichiro; Oshiro, Keiko; Matsuzawa, Daisuke; Hirano, Yoshiyuki; Yoshimura, Kensuke; Nakazato, Michiko; Iyo, Masaomi; Nakagawa, Akiko; Shimizu, Eiji

2018-01-12

Mental defeat and cognitive flexibility have been studied as explanatory factors for depression and posttraumatic stress disorder. This study examined mental defeat and cognitive flexibility scores in patients with panic disorder (PD) before and after cognitive behavioral therapy (CBT), and compared them to those of a gender- and age-matched healthy control group. Patients with PD (n = 15) received 16 weekly individual CBT sessions, and the control group (n = 35) received no treatment. Patients completed the Mental Defeat Scale and the Cognitive Flexibility Scale before the intervention, following eight CBT sessions, and following 16 CBT sessions, while the control group did so only prior to receiving CBT (baseline). The patients' pre-CBT Mental Defeat and Cognitive Flexibility Scale scores were significantly higher on the Mental Defeat Scale and lower on the Cognitive Flexibility Scale than those of the control group participants were. In addition, the average Mental Defeat Scale scores of the patients decreased significantly, from 22.2 to 12.4, while their average Cognitive Flexibility Scale scores increased significantly, from 42.8 to 49.5. These results suggest that CBT can reduce mental defeat and increase cognitive flexibility in patients with PD Trial registration The study was registered retrospectively in the national UMIN Clinical Trials Registry on June 10, 2016 (registration ID: UMIN000022693).

No Relationship Between Hamstring Flexibility and Hamstring Injuries in Male Amateur Soccer Players: A Prospective Study.

PubMed

van Doormaal, Mitchell C M; van der Horst, Nick; Backx, Frank J G; Smits, Dirk-Wouter; Huisstede, Bionka M A

2017-01-01

In soccer, although hamstring flexibility is thought to play a major role in preventing hamstring injuries, the relationship between hamstring flexibility and hamstring injuries remains unclear. To investigate the relationship between hamstring flexibility and hamstring injuries in male amateur soccer players. Case-control study; Level of evidence, 3. This study included 450 male first-class amateur soccer players (mean age, 24.5 years). Hamstring flexibility was measured by performing the sit-and-reach test (SRT). The relationship between hamstring flexibility and the occurrence of hamstring injuries in the following year, while adjusting for the possible confounding effects of age and previous hamstring injuries, was determined with a multivariate logistic regression analysis. Of the 450 soccer players, 21.8% reported a hamstring injury in the previous year. The mean (±SD) baseline score for the SRT was 21.2 ± 9.2 cm. During the 1-year follow-up period, 23 participants (5.1%) suffered a hamstring injury. In the multivariate analysis, while adjusting for age and previous injuries, no significant relationship was found between hamstring flexibility and hamstring injuries ( P = .493). In this group of soccer players, hamstring flexibility (measured with the SRT) was not related to hamstring injuries. Age and previous hamstring injuries as possible confounders did not appear to influence this relationship. Other etiological factors need to be examined to further elucidate the mechanism of hamstring injuries.

Advancing Patient-Centered Care in Tuberculosis Management: A Mixed-Methods Appraisal of Video Directly Observed Therapy

PubMed Central

Holzman, Samuel B; Zenilman, Avi; Shah, Maunank

2018-01-01

Abstract Background Directly observed therapy (DOT) remains an integral component of treatment support and adherence monitoring in tuberculosis care. In-person DOT is resource intensive and often burdensome for patients. Video DOT (vDOT) has been proposed as an alternative to increase treatment flexibility and better meet patient-specific needs. Methods We conducted a pragmatic, prospective pilot implementation of vDOT at 3 TB clinics in Maryland. A mixed-methods approach was implemented to assess (1) effectiveness, (2) acceptability, and (3) cost. Medication adherence on vDOT was compared with that of in-person DOT. Interviews and surveys were conducted with patients and providers before and after implementation, with framework analysis utilized to extract salient themes. Last, a cost analysis assessed the economic impacts of vDOT implementation across heterogeneous clinic structures. Results Medication adherence on vDOT was comparable to that of in-person DOT (94% vs 98%, P = .17), with a higher percentage of total treatment doses (inclusive of weekend/holiday self-administration) ultimately observed during the vDOT period (72% vs 66%, P = .03). Video DOT was well received by staff and patients alike, who cited increased treatment flexibility, convenience, and patient privacy. Our cost analysis estimated a savings with vDOT of $1391 per patient for a standard 6-month treatment course. Conclusions Video DOT is an acceptable and important option for measurement of TB treatment adherence and may allow a higher proportion of prescribed treatment doses to be observed, compared with in-person DOT. Video DOT may be cost-saving and should be considered as a component of individualized, patient-centered case management plans. PMID:29732378

Advancing Patient-Centered Care in Tuberculosis Management: A Mixed-Methods Appraisal of Video Directly Observed Therapy.

PubMed

Holzman, Samuel B; Zenilman, Avi; Shah, Maunank

2018-04-01

Directly observed therapy (DOT) remains an integral component of treatment support and adherence monitoring in tuberculosis care. In-person DOT is resource intensive and often burdensome for patients. Video DOT (vDOT) has been proposed as an alternative to increase treatment flexibility and better meet patient-specific needs. We conducted a pragmatic, prospective pilot implementation of vDOT at 3 TB clinics in Maryland. A mixed-methods approach was implemented to assess (1) effectiveness, (2) acceptability, and (3) cost. Medication adherence on vDOT was compared with that of in-person DOT. Interviews and surveys were conducted with patients and providers before and after implementation, with framework analysis utilized to extract salient themes. Last, a cost analysis assessed the economic impacts of vDOT implementation across heterogeneous clinic structures. Medication adherence on vDOT was comparable to that of in-person DOT (94% vs 98%, P = .17), with a higher percentage of total treatment doses (inclusive of weekend/holiday self-administration) ultimately observed during the vDOT period (72% vs 66%, P = .03). Video DOT was well received by staff and patients alike, who cited increased treatment flexibility, convenience, and patient privacy. Our cost analysis estimated a savings with vDOT of $1391 per patient for a standard 6-month treatment course. Video DOT is an acceptable and important option for measurement of TB treatment adherence and may allow a higher proportion of prescribed treatment doses to be observed, compared with in-person DOT. Video DOT may be cost-saving and should be considered as a component of individualized, patient-centered case management plans.

The Relationship of the Sit and Reach Test to Criterion Measures of Hamstring and Back Flexibility in Young Females.

ERIC Educational Resources Information Center

Jackson, Allen W.; Baker, Alice A.

1986-01-01

This study tested 100 female adolescents to determine the relationships of the sit and reach test, a component of the Health Related Fitness Test, with back and hamstring flexibility. Findings indicate the sit and reach test is moderately related to hamstring flexibility but not to back and low back flexibility. (Author/MT)

The paradox of cognitive flexibility in autism

PubMed Central

Geurts, Hilde M.; Corbett, Blythe; Solomon, Marjorie

2017-01-01

We present an overview of current literature addressing cognitive flexibility in autism spectrum disorders. Based on recent studies at multiple sites, using diverse methods and participants of different autism subtypes, ages and cognitive levels, no consistent evidence for cognitive flexibility deficits was found. Researchers and clinicians assume that inflexible everyday behaviors in autism are directly related to cognitive flexibility deficits as assessed by clinical and experimental measures. However, there is a large gap between the day-to-day behavioral flexibility and that measured with these cognitive flexibility tasks. To advance the field, experimental measures must evolve to reflect mechanistic models of flexibility deficits. Moreover, ecologically valid measures are required to be able to resolve the paradox between cognitive and behavioral inflexibility. PMID:19138551

The IL-6/sIL-6R treatment of a malignant melanoma cell line enhances susceptibility to TNF-{alpha}-induced apoptosis

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

Wagley, Yadav; Yoo, Yung-Choon; Seo, Han Geuk

2007-03-23

Melanoma is an intractable tumor that has shown very impressive and promising response to local administration of high dose recombinant TNF-{alpha} in combination with IFN-{gamma} in clinical studies. In this study, we investigated the effect of IL-6/sIL-6R on TNF-{alpha}-resistant B16/F10.9 melanoma cells. A low dose of TNF-{alpha} or IL-6/sIL-6R had minimal affect on the cell growth. However, the highly active fusion protein of sIL-6R and IL-6 (IL6RIL6), covalently linked by a flexible peptide, sensitized TNF-{alpha}-resistant F10.9 melanoma cells to TNF-{alpha}-induced apoptosis. Stimulation of the cells with IL6RIL6 plus TNF-{alpha} resulted in both the activation of caspase-3 and the reduction ofmore » bcl-2 expression. Flow cytometry analysis showed that IL6RIL6-upregulated TNF-R55 and TNF-R75 expression, suggesting an increase in TNF-{alpha} responsiveness by IL6RIL6 resulting from the induction of TNF receptors. Moreover, exposure of F10.9 cells to neutralizing antibody to TNF-R55 significantly inhibited IL6RIL6/TNF-{alpha}-induced cytotoxicity. These results suggest that the IL6/sIL6R/gp130 system, which sensitizes TNF-{alpha}-resistant melanoma cells to TNF-{alpha}-induced apoptosis, may provide a new target for immunotherapy.« less

Development of a manualized protocol of massage therapy for clinical trials in osteoarthritis.

PubMed

Ali, Ather; Kahn, Janet; Rosenberger, Lisa; Perlman, Adam I

2012-10-04

Clinical trial design of manual therapies may be especially challenging as techniques are often individualized and practitioner-dependent. This paper describes our methods in creating a standardized Swedish massage protocol tailored to subjects with osteoarthritis of the knee while respectful of the individualized nature of massage therapy, as well as implementation of this protocol in two randomized clinical trials. The manualization process involved a collaborative process between methodologic and clinical experts, with the explicit goals of creating a reproducible semi-structured protocol for massage therapy, while allowing some latitude for therapists' clinical judgment and maintaining consistency with a prior pilot study. The manualized protocol addressed identical specified body regions with distinct 30- and 60-min protocols, using standard Swedish strokes. Each protocol specifies the time allocated to each body region. The manualized 30- and 60-min protocols were implemented in a dual-site 24-week randomized dose-finding trial in patients with osteoarthritis of the knee, and is currently being implemented in a three-site 52-week efficacy trial of manualized Swedish massage therapy. In the dose-finding study, therapists adhered to the protocols and significant treatment effects were demonstrated. The massage protocol was manualized, using standard techniques, and made flexible for individual practitioner and subject needs. The protocol has been applied in two randomized clinical trials. This manualized Swedish massage protocol has real-world utility and can be readily utilized both in the research and clinical settings. Clinicaltrials.gov NCT00970008 (18 August 2009).

Selective robust optimization: A new intensity-modulated proton therapy optimization strategy

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

Li, Yupeng; Niemela, Perttu; Siljamaki, Sami

2015-08-15

Purpose: To develop a new robust optimization strategy for intensity-modulated proton therapy as an important step in translating robust proton treatment planning from research to clinical applications. Methods: In selective robust optimization, a worst-case-based robust optimization algorithm is extended, and terms of the objective function are selectively computed from either the worst-case dose or the nominal dose. Two lung cancer cases and one head and neck cancer case were used to demonstrate the practical significance of the proposed robust planning strategy. The lung cancer cases had minimal tumor motion less than 5 mm, and, for the demonstration of the methodology,more » are assumed to be static. Results: Selective robust optimization achieved robust clinical target volume (CTV) coverage and at the same time increased nominal planning target volume coverage to 95.8%, compared to the 84.6% coverage achieved with CTV-based robust optimization in one of the lung cases. In the other lung case, the maximum dose in selective robust optimization was lowered from a dose of 131.3% in the CTV-based robust optimization to 113.6%. Selective robust optimization provided robust CTV coverage in the head and neck case, and at the same time improved controls over isodose distribution so that clinical requirements may be readily met. Conclusions: Selective robust optimization may provide the flexibility and capability necessary for meeting various clinical requirements in addition to achieving the required plan robustness in practical proton treatment planning settings.« less

The linearized multistage model and the future of quantitative risk assessment.

PubMed

Crump, K S

1996-10-01

The linearized multistage (LMS) model has for over 15 years been the default dose-response model used by the U.S. Environmental Protection Agency (USEPA) and other federal and state regulatory agencies in the United States for calculating quantitative estimates of low-dose carcinogenic risks from animal data. The LMS model is in essence a flexible statistical model that can describe both linear and non-linear dose-response patterns, and that produces an upper confidence bound on the linear low-dose slope of the dose-response curve. Unlike its namesake, the Armitage-Doll multistage model, the parameters of the LMS do not correspond to actual physiological phenomena. Thus the LMS is 'biological' only to the extent that the true biological dose response is linear at low dose and that low-dose slope is reflected in the experimental data. If the true dose response is non-linear the LMS upper bound may overestimate the true risk by many orders of magnitude. However, competing low-dose extrapolation models, including those derived from 'biologically-based models' that are capable of incorporating additional biological information, have not shown evidence to date of being able to produce quantitative estimates of low-dose risks that are any more accurate than those obtained from the LMS model. Further, even if these attempts were successful, the extent to which more accurate estimates of low-dose risks in a test animal species would translate into improved estimates of human risk is questionable. Thus, it does not appear possible at present to develop a quantitative approach that would be generally applicable and that would offer significant improvements upon the crude bounding estimates of the type provided by the LMS model. Draft USEPA guidelines for cancer risk assessment incorporate an approach similar to the LMS for carcinogens having a linear mode of action. However, under these guidelines quantitative estimates of low-dose risks would not be developed for carcinogens having a non-linear mode of action; instead dose-response modelling would be used in the experimental range to calculate an LED10* (a statistical lower bound on the dose corresponding to a 10% increase in risk), and safety factors would be applied to the LED10* to determine acceptable exposure levels for humans. This approach is very similar to the one presently used by USEPA for non-carcinogens. Rather than using one approach for carcinogens believed to have a linear mode of action and a different approach for all other health effects, it is suggested herein that it would be more appropriate to use an approach conceptually similar to the 'LED10*-safety factor' approach for all health effects, and not to routinely develop quantitative risk estimates from animal data.

The effects of vortioxetine on cognitive dysfunction in patients with inadequate response to current antidepressants in major depressive disorder: A short-term, randomized, double-blind, exploratory study versus escitalopram.

PubMed

Vieta, Eduard; Sluth, Lasse B; Olsen, Christina K

2018-02-01

Major Depressive Disorder (MDD) is a heterogeneous disease characterized by emotional, physical and cognitive symptoms. This study explored the effects of vortioxetine versus escitalopram on outcomes of cognition, functioning and mood symptoms in depressed patients with inadequate response to current antidepressant treatment. In this parallel-group, active-comparator study, adult patients (18-65 years, N = 101) with MDD, with inadequate response to current antidepressant monotherapy, were randomized 1:1 to 8 weeks' double-blind treatment with flexible doses (10-20mg/day) of either vortioxetine or escitalopram. Primary and key secondary efficacy measures were the Digit Symbol Substitution Test (DSST), analyzed using a mixed model for repeated measurements, and the University of San Diego Performance-based Skills Assessment - Brief (UPSA-B), analyzed using analysis of covariance (last observation carried forward method). At week 8, DSST and UPSA-B performance had improved in both treatment groups, with no statistically significant treatment differences. Numerical improvements across measures of cognition, functioning and mood symptoms generally favored vortioxetine. Most adverse events were mild or moderate, with nausea being the most common adverse event. This was an exploratory study with small sample sizes implying limited statistical power. Although this explorative study did not meet primary endpoints, the results confirm vortioxetine in doses of 10-20mg/day as an efficacious and well-tolerated antidepressant switch treatment. The overall direction of numerical effect sizes across cognition endpoints support previous findings that vortioxetine specifically benefits cognitive function in MDD. Copyright © 2017 H Lundbeck A/S. Published by Elsevier B.V. All rights reserved.

Implementation Study of Patient-Ready Syringes Containing 25 mg/mL Methotrexate Solution for Use in Treating Ectopic Pregnancy

PubMed Central

Respaud, R.; Gaudy, A. S.; Arlicot, C.; Tournamille, J. F.; Viaud-Massuard, M. C.; Elfakir, C.; Antier, D.

2014-01-01

Background. Ectopic pregnancy (EP) is a significant cause of morbidity and mortality during the first trimester of pregnancy. Small unruptured tubal pregnancies can be treated medically with a single dose of methotrexate (MTX). Objective. The aim of this study was to evaluate the stability of a 25 mg/mL solution of MTX to devise a secure delivery circuit for the preparation and use of this medication in the management of EP. Method. MTX solutions were packaged in polypropylene syringes, stored over an 84-day period, and protected from light either at +2 to +8°C or at 23°C. We assessed the physical and chemical stability of the solutions at various time points over the storage period. A pharmaceutical delivery circuit was implemented that involved the batch preparation of MTX syringes. Results. We show that 25 mg/mL MTX solutions remain stable over an 84-day period under the storage conditions tested. Standard doses were prepared, ranging from 50 mg to 100 mg. The results of this study suggest that MTX syringes can be prepared in advance by the pharmacy, ready to be dispensed at any time that a diagnosis of EP is made. Conclusion. The high stability of a 25 mg/mL MTX solution in polypropylene syringes makes it possible to implement a flexible and cost-effective delivery circuit for ready-to-use preparations of this drug, providing 24-hour access and preventing treatment delays. PMID:24900977

SU-F-J-105: Towards a Novel Treatment Planning Pipeline Delivering Pareto- Optimal Plans While Enabling Inter- and Intrafraction Plan Adaptation

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

Kontaxis, C; Bol, G; Lagendijk, J

2016-06-15

Purpose: To develop a new IMRT treatment planning methodology suitable for the new generation of MR-linear accelerator machines. The pipeline is able to deliver Pareto-optimal plans and can be utilized for conventional treatments as well as for inter- and intrafraction plan adaptation based on real-time MR-data. Methods: A Pareto-optimal plan is generated using the automated multicriterial optimization approach Erasmus-iCycle. The resulting dose distribution is used as input to the second part of the pipeline, an iterative process which generates deliverable segments that target the latest anatomical state and gradually converges to the prescribed dose. This process continues until a certainmore » percentage of the dose has been delivered. Under a conventional treatment, a Segment Weight Optimization (SWO) is then performed to ensure convergence to the prescribed dose. In the case of inter- and intrafraction adaptation, post-processing steps like SWO cannot be employed due to the changing anatomy. This is instead addressed by transferring the missing/excess dose to the input of the subsequent fraction. In this work, the resulting plans were delivered on a Delta4 phantom as a final Quality Assurance test. Results: A conventional static SWO IMRT plan was generated for two prostate cases. The sequencer faithfully reproduced the input dose for all volumes of interest. For the two cases the mean relative dose difference of the PTV between the ideal input and sequenced dose was 0.1% and −0.02% respectively. Both plans were delivered on a Delta4 phantom and passed the clinical Quality Assurance procedures by achieving 100% pass rate at a 3%/3mm gamma analysis. Conclusion: We have developed a new sequencing methodology capable of online plan adaptation. In this work, we extended the pipeline to support Pareto-optimal input and clinically validated that it can accurately achieve these ideal distributions, while its flexible design enables inter- and intrafraction plan adaptation. This research is financially supported by Elekta AB, Stockholm, Sweden.« less

Tunnel flexibility effect on the ground surface acceleration response

NASA Astrophysics Data System (ADS)

Baziar, Mohammad Hassan; Moghadam, Masoud Rabeti; Choo, Yun Wook; Kim, Dong-Soo

2016-09-01

Flexibility of underground structures relative to the surrounding medium, referred to as the flexibility ratio, is an important factor that influences their dynamic interaction. This study investigates the flexibility effect of a box-shaped subway tunnel, resting directly on bedrock, on the ground surface acceleration response using a numerical model verified against dynamic centrifuge test results. A comparison of the ground surface acceleration response for tunnel models with different flexibility ratios revealed that the tunnels with different flexibility ratios influence the acceleration response at the ground surface in different ways. Tunnels with lower flexibility ratios have higher acceleration responses at short periods, whereas tunnels with higher flexibility ratios have higher acceleration responses at longer periods. The effect of the flexibility ratio on ground surface acceleration is more prominent in the high range of frequencies. Furthermore, as the flexibility ratio of the tunnel system increases, the acceleration response moves away from the free field response and shifts towards the longer periods. Therefore, the flexibility ratio of the underground tunnels influences the peak ground acceleration (PGA) at the ground surface, and may need to be considered in the seismic zonation of urban areas.

The Role of Learning Tasks on Attitude Change Using Cognitive Flexibility Hypertext Systems

ERIC Educational Resources Information Center

Godshalk, Veronica M.; Harvey, Douglas M.; Moller, Leslie

2004-01-01

In this study, the authors examined the impact of task assignment on the effectiveness of a Web-based experiential exercise based on cognitive flexibility theory to enlighten learner attitudes toward the ill-structured topic of sexual harassment. In the research study, we sought to shed light on the use of a cognitive flexibility approach when…

Thermal Insulation Performance of Flexible Piping for Use in HTS Power Cables

NASA Technical Reports Server (NTRS)

Fesmire, James E.; Augustynowicz, S. D.; Demko, J. A.; Thompson, Karen (Technical Monitor)

2001-01-01

High-temperature superconducting (HTS) cables that typically operate at temperatures below 80 K are being developed for power transmission. The practical application of HTS power cables will require the use of flexible piping to contain the cable and the liquid nitrogen coolant. A study of thermal performance of multilayer insulation (MLI) was conducted in geometries representing both rigid and flexible piping. This experimental study performed at the Cryogenics Test Laboratory of NASA Kennedy Space Center provides a framework for the development of cost-effective, efficient thermal insulation systems that will support these long-distance flexible lines containing HTS power cables. The overall thermal performance of the insulation system for a rigid configuration and for a flexible configuration, simulating a flexible HTS power cable, was determined by the steady-state liquid nitrogen boiloff method under the full range of vacuum levels. Two different cylindrically rolled material systems were tested: a standard MLI and a layered composite insulation (LCI). Comparisons of ideal MLI, MLI on rigid piping, and MLI between flexible piping are presented.

The effect of chordwise flexibility on flapping foil propulsion in quiescent fluid

NASA Astrophysics Data System (ADS)

Shinde, Sachin; Arakeri, Jaywant

2010-11-01

Motivated to understand the role of wing flexibility of flying creatures during hovering, we experimentally study the effect of chordwise flexibility on the flow generated in quiescent fluid by a sinusoidally pitching rigid symmetrical foil with a flexible flap attached at the trailing edge. This foil produces a narrow, coherent jet containing reverse Karman vortex street, and a corresponding thrust. The thrust and flow is similar to that produced by a hovering bird or insect, however the mechanism seems to be different from known hovering mechanisms. Novelty of the present hovering mechanism is that the thrust generation is due to the coordinated pushing action of rigid foil and flexible flap. We identify the flow and vortex generation mechanism. This foil produces jet flows over a range of flapping frequencies and amplitudes. In contrast, the foil without flap i.e. with rigid trailing edge produces a weak, divergent jet that meanders randomly. Appending a flexible flap to the foil suppresses jet-meandering and strengthens the jet. Flexibility of flap is crucial in determining the flow structure. This study is useful in designing MAVs and thrusters.

Flexible solid-state supercapacitors based on three-dimensional graphene hydrogel films.

PubMed

Xu, Yuxi; Lin, Zhaoyang; Huang, Xiaoqing; Liu, Yuan; Huang, Yu; Duan, Xiangfeng

2013-05-28

Flexible solid-state supercapacitors are of considerable interest as mobile power supply for future flexible electronics. Graphene or carbon nanotubes based thin films have been used to fabricate flexible solid-state supercapacitors with high gravimetric specific capacitances (80-200 F/g), but usually with a rather low overall or areal specific capacitance (3-50 mF/cm(2)) due to the ultrasmall electrode thickness (typically a few micrometers) and ultralow mass loading, which is not desirable for practical applications. Here we report the exploration of a three-dimensional (3D) graphene hydrogel for the fabrication of high-performance solid-state flexible supercapacitors. With a highly interconnected 3D network structure, graphene hydrogel exhibits exceptional electrical conductivity and mechanical robustness to make it an excellent material for flexible energy storage devices. Our studies demonstrate that flexible supercapacitors with a 120 μm thick graphene hydrogel thin film can exhibit excellent capacitive characteristics, including a high gravimetric specific capacitance of 186 F/g (up to 196 F/g for a 42 μm thick electrode), an unprecedented areal specific capacitance of 372 mF/cm(2) (up to 402 mF/cm(2) for a 185 μm thick electrode), low leakage current (10.6 μA), excellent cycling stability, and extraordinary mechanical flexibility. This study demonstrates the exciting potential of 3D graphene macrostructures for high-performance flexible energy storage devices.

Agreement Between Face-to-Face and Free Software Video Analysis for Assessing Hamstring Flexibility in Adolescents.

PubMed

Moral-Muñoz, José A; Esteban-Moreno, Bernabé; Arroyo-Morales, Manuel; Cobo, Manuel J; Herrera-Viedma, Enrique

2015-09-01

The objective of this study was to determine the level of agreement between face-to-face hamstring flexibility measurements and free software video analysis in adolescents. Reduced hamstring flexibility is common in adolescents (75% of boys and 35% of girls aged 10). The length of the hamstring muscle has an important role in both the effectiveness and the efficiency of basic human movements, and reduced hamstring flexibility is related to various musculoskeletal conditions. There are various approaches to measuring hamstring flexibility with high reliability; the most commonly used approaches in the scientific literature are the sit-and-reach test, hip joint angle (HJA), and active knee extension. The assessment of hamstring flexibility using video analysis could help with adolescent flexibility follow-up. Fifty-four adolescents from a local school participated in a descriptive study of repeated measures using a crossover design. Active knee extension and HJA were measured with an inclinometer and were simultaneously recorded with a video camera. Each video was downloaded to a computer and subsequently analyzed using Kinovea 0.8.15, a free software application for movement analysis. All outcome measures showed reliability estimates with α > 0.90. The lowest reliability was obtained for HJA (α = 0.91). The preliminary findings support the use of a free software tool for assessing hamstring flexibility, offering health professionals a useful tool for adolescent flexibility follow-up.

Mechanical behaviour study on SBR/EVA composite for FDM feedstock fabrication

NASA Astrophysics Data System (ADS)

Raveverma, P.; Ibrahim, M.; Sa'ude, N.; Yarwindran, M.; Nasharuddin, M.

2017-04-01

This paper presents the research development of a new SBR/EVA composite flexible feedstock material by the injection moulding machine. The material consists of poly (ethylene-co-vinyl acetate) in styrene butadiene rubber cross-linked by Dicumyl Peroxide. In this study, the mechanical behaviour of injection moulded SBR/EVA composite with different blend ratio investigated experimentally. The formulations of blend ratio with several combinations of a new SBR/EVA flexible feedstock was done by volume percentage (vol. %). Based on the result obtained from the mechanical testing done which is tensile and hardness the composite of SBR/EVA has the high potency to be fabricated as the flexible filament feedstock. The ratio of 80:20 which as an average hardness and tensile strength proved to be the suitable choice to be fabricated as the flexible filament feedstock. The study has reached its goals on the fabricating and testing a new PMC which is flexible.

Hyaluronan-decorated liposomes as drug delivery systems for cutaneous administration.

PubMed

Franzé, Silvia; Marengo, Alessandro; Stella, Barbara; Minghetti, Paola; Arpicco, Silvia; Cilurzo, Francesco

2018-01-15

The work aimed to evaluate the feasibility to design hyaluronic acid (HA) decorated flexible liposomes to enhance the skin penetration of nifedipine. Egg phosphatidylcholine (e-PC) based transfersomes (Tween 80) and transethosomes (ethanol) were prepared. HA was reacted with 1,2-dipalmitoyl-sn-glycero-3-phosphoethanolamine (HA-DPPE) and two molar ratios (0.5 and 3%) of conjugate with respect to e-PC were tested. The presence of HA significantly increased the packing order of the bilayer (as verified by differential scanning calorimetry), reducing both the encapsulation efficiency and the flexibility of the decorated liposomes in a dose-dependent manner. In fact, at the highest HA content the constant of deformability (K, N/mm) increased and the carriers remained on the skin surface after topical application. The stiffening effect of HA was counterbalanced by the addition of ethanol as fluidizing agent that allowed to maintain the highest HA concentration, meanwhile reducing the K value of the vesicles. HA-transethosomes allowed a suitable nifedipine permeation (J ∼ 30 ng/cm 2 /h) and significantly improved the drug penetration, favouring the formation of a drug depot in the epidermis. These data suggest the potentialities of HA-transethosomes as drug delivery systems intended for the treatment of cutaneous pathologies and underline the importance of studying the effect of surface functionalization on carrier deformability to rationalize the design of such systems. Copyright © 2017 Elsevier B.V. All rights reserved.

A Double-Blind, Double-Dummy, Flexible-Design Randomized Multicenter Trial: Early Safety of Single- Versus Divided-Dose Rabbit Anti-Thymocyte Globulin Induction in Renal Transplantation.

PubMed

Stevens, R B; Wrenshall, L E; Miles, C D; Farney, A C; Jie, T; Sandoz, J P; Rigley, T H; Osama Gaber, A

2016-06-01

A previous nonblinded, randomized, single-center renal transplantation trial of single-dose rabbit anti-thymocyte globulin induction (SD-rATG) showed improved efficacy compared with conventional divided-dose (DD-rATG) administration. The present multicenter, double-blind/double-dummy STAT trial (Single dose vs. Traditional Administration of Thymoglobulin) evaluated SD-rATG versus DD-rATG induction for noninferiority in early (7-day) safety and tolerability. Ninety-five patients (randomized 1:1) received 6 mg/kg SD-rATG or 1.5 mg/kg/dose DD-rATG, with tacrolimus-mycophenolate maintenance immunosuppression. The primary end point was a composite of fever, hypoxia, hypotension, cardiac complications, and delayed graft function. Secondary end points included 12-month patient survival, graft survival, and rejection. Target enrollment was 165 patients with an interim analysis scheduled after 80 patients. Interim analysis showed primary end point noninferiority of SD-rATG induction (p = 0.6), and a conditional probability of <1.73% of continued enrollment producing a significant difference (futility analysis), leading to early trial termination. Final analysis (95 patients) showed no differences in occurrence of primary end point events (p = 0.58) or patients with no, one, or more than one event (p = 0.81), or rejection, graft, or patient survival (p = 0.78, 0.47, and 0.35, respectively). In this rigorously blinded trial in adult renal transplantation, we have shown SD-rATG induction to be noninferior to DD-rATG induction in early tolerability and equivalent in 12-month safety. (Clinical Trials.gov #NCT00906204.). © Copyright 2016 The Authors. American Journal of Transplantation published by Wiley Periodicals, Inc. on behalf of the American Society of Transplantation and the American Society of Transplant Surgeons.

A biosphere modeling methodology for dose assessments of the potential Yucca Mountain deep geological high level radioactive waste repository.

PubMed

Watkins, B M; Smith, G M; Little, R H; Kessler, J

1999-04-01

Recent developments in performance standards for proposed high level radioactive waste disposal at Yucca Mountain suggest that health risk or dose rate limits will likely be part of future standards. Approaches to the development of biosphere modeling and dose assessments for Yucca Mountain have been relatively lacking in previous performance assessments due to the absence of such a requirement. This paper describes a practical methodology used to develop a biosphere model appropriate for calculating doses from use of well water by hypothetical individuals due to discharges of contaminated groundwater into a deep well. The biosphere model methodology, developed in parallel with the BIOMOVS II international study, allows a transparent recording of the decisions at each step, from the specification of the biosphere assessment context through to model development and analysis of results. A list of features, events, and processes relevant to Yucca Mountain was recorded and an interaction matrix developed to help identify relationships between them. Special consideration was given to critical/potential exposure group issues and approaches. The conceptual model of the biosphere system was then developed, based on the interaction matrix, to show how radionuclides migrate and accumulate in the biosphere media and result in potential exposure pathways. A mathematical dose assessment model was specified using the flexible AMBER software application, which allows users to construct their own compartment models. The starting point for the biosphere calculations was a unit flux of each radionuclide from the groundwater in the geosphere into the drinking water in the well. For each of the 26 radionuclides considered, the most significant exposure pathways for hypothetical individuals were identified. For 14 of the radionuclides, the primary exposure pathways were identified as consumption of various crops and animal products following assumed agricultural use of the contaminated water derived from the deep well. Inhalation of dust (11 radionuclides) and external irradiation (1 radionuclide) were also identified as significant exposure modes. Contribution to the total flux to dose conversion factor from the drinking water pathway for each radionuclide was also assessed and for most radionuclides was found to be less than 10% of the total flux to dose conversion factor summed across all pathways. Some of the uncertainties related to the results were considered. The biosphere modeling results have been applied within an EPRI Total Systems Performance Assessment of Yucca Mountain. Conclusions and recommendations for future performance assessments are provided.

Workplace Flexibility and Daily Stress Processes in Hotel Employees and their Children

PubMed Central

Almeida, David M.; Davis, Kelly D.

2013-01-01

Our research aims to understand the consequences of inadequate workplace flexibility through the lens of daily stress processes. Using a sample of hourly hotel employees with children aged 10 to 18 who participated in a daily diary study, we compared workers with low and high flexibility on stressor exposure, reactivity, and transmission. Our findings showed a consistent pattern of hourly workers with low flexibility having greater exposure to work stressors in general and to work place arguments in particular. Workers with low flexibility were also more emotional and physically reactive to work stressors. There was some evidence of stressor transmission to children when parents had low flexibility. Increasing workplace flexibility could serve as a protective factor in exposure and reactivity to stressors that are experienced in daily life. PMID:23833321

The role of psychological flexibility in a self-help acceptance and commitment therapy intervention for psychological distress in a randomized controlled trial.

PubMed

Fledderus, Martine; Bohlmeijer, Ernst T; Fox, Jean-Paul; Schreurs, Karlein M G; Spinhoven, Philip

2013-03-01

This study examined the role of psychological flexibility, as a risk factor and as a process of change, in a self-help Acceptance and Commitment Therapy (ACT) intervention for adults with mild to moderate depression and anxiety. Participants were randomized to the self-help programme with e-mail support (n=250), or to a waiting list control group (n=126). All participants completed measures before and after the intervention to assess depression, anxiety and psychological flexibility. Participants in the experimental condition also completed these measures during the intervention (after three and six weeks) and at a three-month follow-up. With multilevel modelling, it was shown that the effects of the intervention on psychological distress were stronger for participants with higher levels of psychological flexibility. Furthermore, our study showed that improved psychological flexibility mediated the effects of the ACT intervention. With a cross-lagged panel design, it was shown that especially improvements in psychological flexibility in the last three sessions of the intervention were important for further reductions in anxiety. To conclude, our study showed the importance of targeting psychological flexibility during an ACT intervention for a reduction in depressive and anxiety symptoms. Copyright © 2012 Elsevier Ltd. All rights reserved.

Nonlinear transient analysis of multi-mass flexible rotors - theory and applications

NASA Technical Reports Server (NTRS)

Kirk, R. G.; Gunter, E. J.

1973-01-01

The equations of motion necessary to compute the transient response of multi-mass flexible rotors are formulated to include unbalance, rotor acceleration, and flexible damped nonlinear bearing stations. A method of calculating the unbalance response of flexible rotors from a modified Myklestad-Prohl technique is discussed in connection with the method of solution for the transient response. Several special cases of simplified rotor-bearing systems are presented and analyzed for steady-state response, stability, and transient behavior. These simplified rotor models produce extensive design information necessary to insure stable performance to elastic mounted rotor-bearing systems under varying levels and forms of excitation. The nonlinear journal bearing force expressions derived from the short bearing approximation are utilized in the study of the stability and transient response of the floating bush squeeze damper support system. Both rigid and flexible rotor models are studied, and results indicate that the stability of flexible rotors supported by journal bearings can be greatly improved by the use of squeeze damper supports. Results from linearized stability studies of flexible rotors indicate that a tuned support system can greatly improve the performance of the units from the standpoint of unbalanced response and impact loading. Extensive stability and design charts may be readily produced for given rotor specifications by the computer codes presented in this analysis.

Health and psychosocial effects of flexible working hours.

PubMed

Janssen, Daniela; Nachreiner, Friedhelm

2004-12-01

To examine whether any impairments in health and social lives can be found under different kinds of flexible working hours, and whether such effects are related to specific characteristics of these working hours. Two studies -- a company based survey (N=660) and an internet survey (N=528) -- have been conducted. The first one was a questionnaire study (paper and pencil) on employees working under some 'typical' kinds of different flexible working time arrangements in different companies and different occupational fields (health care, manufacturing, retail, administration, call centres). The second study was an internet-based survey, using an adaptation of the questionnaire from the first study. The results of both studies consistently show that high variability of working hours is associated with increased impairments in health and well-being and this is especially true if this variability is company controlled. These effects are less pronounced if variability is self-controlled; however, autonomy does not compensate the effects of variability. Recommendations for an appropriate design of flexible working hours should be developed in order to minimize any impairing effects on health and psychosocial well-being; these recommendations should include -- besides allowing for discretion in controlling one's (flexible) working hours -- that variability in flexible working hours should be kept low (or at least moderate), even if this variability is self-controlled.

A dual tracer ratio method for comparative emission measurements in an experimental dairy housing

NASA Astrophysics Data System (ADS)

Mohn, Joachim; Zeyer, Kerstin; Keck, Margret; Keller, Markus; Zähner, Michael; Poteko, Jernej; Emmenegger, Lukas; Schrade, Sabine

2018-04-01

Agriculture, and in particular dairy farming, is an important source of ammonia (NH3) and non-carbon dioxide greenhouse gas (GHG) emissions. This calls for the development and quantification of effective mitigation strategies. Our study presents the implementation of a dual tracer ratio method in a novel experimental dairy housing with two identical, but spatially separated housing areas. Modular design and flexible floor elements allow the assessment of structural, process engineering and organisational abatement measures at practical scale. Thereby, the emission reduction potential of specific abatement measures can be quantified in relation to a reference system. Emissions in the naturally ventilated housing are determined by continuous dosing of two artificial tracers (sulphur hexafluoride SF6, trifluoromethylsulphur pentafluoride SF5CF3) and their real-time detection in the ppt range with an optimized GC-ECD method. The two tracers are dosed into different experimental sections, which enables the independent assessment of both housing areas. Mass flow emissions of NH3 and GHGs are quantified by areal dosing of tracer gases and multipoint sampling as well as real-time analysis of both tracer and target gases. Validation experiments demonstrate that the technique is suitable for both areal and point emission sources and achieves an uncertainty of less than 10% for the mass emissions of NH3, methane (CH4) and carbon dioxide (CO2), which is superior to other currently available methods. Comparative emission measurements in this experimental dairy housing will provide reliable, currently unavailable information on emissions for Swiss dairy farming and demonstrate the reduction potential of mitigation measures for NH3, GHGs and potentially other pollutants.

Safety of atomoxetine in combination with intravenous cocaine in cocaine-experienced participants.

PubMed

Cantilena, Louis; Kahn, Roberta; Duncan, Connie C; Li, Shou-Hua; Anderson, Ann; Elkashef, Ahmed

2012-12-01

Atomoxetine has been considered as an agonist replacement therapy for cocaine. We investigated the safety of the interaction of atomoxetine with cocaine and also whether cognitive function was affected by atomoxetine during short-term administration. In a double-blind placebo-controlled inpatient study of 20 cocaine-dependent volunteers, participants received atomoxetine 80 mg daily followed by 100 mg daily for 5 days each. On the fourth and fifth day at each dose, cocaine (20 and 40 mg) was infused intravenously in sequential daily sessions. Preinfusion mean systolic pressures showed a small but statistically significant difference between placebo and both doses of atomoxetine. Preinfusion mean diastolic pressures were significant between placebo and atomoxetine 80 mg only. The diastolic pressure response to 40 mg cocaine was statistically significant only between the 80- and 100-mg atomoxetine doses. All electrocardiogram parameters were unchanged. Visual Analog Scale (VAS) scores for "bad effect" in the atomoxetine group were significantly higher at baseline, then declined, and for "likely to use" declined with atomoxetine treatment. On the Addiction Research Center Inventory, the atomoxetine group scored significantly lower on amphetamine, euphoria, and energy subscales (P < 0.0001). Other VAS descriptors, Brief Substance Craving Scale, Profile of Moods State, and Brief Psychiatric Rating Scale showed no differences. Atomoxetine did not affect cocaine pharmacokinetics. In tests of working memory, sustained attention, cognitive flexibility, and decision-making, atomoxetine improved performance on the visual n-back task. There were no differences in any pharmacokinetic parameters for cocaine with atomoxetine. Atomoxetine was tolerated safely by all participants. Certain cognitive improvements and a dampening effect on VAS scores after cocaine were observed, but should be weighed against small but significant differences in hemodynamic responses after atomoxetine.

Safety of Atomoxetine in Combination with Intravenous Cocaine in Cocaine- Experienced Participants

PubMed Central

Cantilena, Louis; Kahn, Roberta; Duncan, Connie C.; Li, Shou-Hua; Anderson, Ann; Elkashef, Ahmed

2012-01-01

Objectives Atomoxetine has been considered as an agonist replacement therapy for cocaine. We investigated the safety of the interaction of atomoxetine with cocaine, and also whether cognitive function was affected by atomoxetine during short-term administration. Methods In a double-blind placebo-controlled inpatient study of 20 cocaine-dependent volunteers, participants received atomoxetine 80 mg daily followed by 100 mg daily for 5 days each. On the fourth and fifth day at each dose, cocaine (20 mg and 40 mg) was infused intravenously in sequential daily sessions. Results Pre-infusion mean systolic pressures showed a small but statistically significant difference between placebo and both doses of atomoxetine. Pre-infusion mean diastolic pressures were significant between placebo and atomoxetine 80 mg only. The diastolic pressure response to 40 mg cocaine was statistically significant only between the 80 mg and 100 mg atomoxetine doses. All ECG parameters were unchanged. VAS scores for “bad effect” in the atomoxetine group were significantly higher at baseline, then declined, and for “likely to use” declined with atomoxetine treatment. On the ARCI the atomoxetine group scored significantly lower on amphetamine, euphoria and energy subscales (p<0.0001). Other VAS descriptors, BSCS, POMS, and BPRS showed no differences. Atomoxetine did not affect cocaine pharmacokinetics. In tests of working memory, sustained attention, cognitive flexibility, and decision-making, atomoxetine improved performance on the visual n-back task. There were no differences in any pharmacokinetic parameters for cocaine with atomoxetine. Conclusions Atomoxetine was tolerated safely by all participants. Certain cognitive improvements and a dampening effect on VAS scores after cocaine were observed, but should be weighed against small but significant differences in hemodynamic responses after atomoxetine. PMID:22987022

The selective M1 muscarinic cholinergic agonist CDD-0102A enhances working memory and cognitive flexibility.

PubMed

Ragozzino, Michael E; Artis, Sonja; Singh, Amritha; Twose, Trevor M; Beck, Joseph E; Messer, William S

2012-03-01

Various neurodegenerative diseases and psychiatric disorders are marked by alterations in brain cholinergic function and cognitive deficits. Efforts to alleviate such deficits have been limited by a lack of selective M(1) muscarinic agonists. 5-(3-Ethyl-1,2,4-oxadiazol-5-yl)-1,4,5,6-tetrahydropyrimidine hydrochloride (CDD-0102A) is a partial agonist at M(1) muscarinic receptors with limited activity at other muscarinic receptor subtypes. The present studies investigated the effects of CDD-0102A on working memory and strategy shifting in rats. CDD-0102A administered intraperitoneally 30 min before testing at 0.1, 0.3, and 1 mg/kg significantly enhanced delayed spontaneous alternation performance in a four-arm cross maze, suggesting improvement in working memory. In separate experiments, CDD-0102A had potent enhancing effects on learning and switching between a place and visual cue discrimination. Treatment with CDD-0102A did not affect acquisition of either a place or visual cue discrimination. In contrast, CDD-0102A at 0.03 and 0.1 mg/kg significantly enhanced a shift between a place and visual cue discrimination. Analysis of the errors in the shift to the place or shift to the visual cue strategy revealed that in both cases CDD-0102A significantly increased the ability to initially inhibit a previously relevant strategy and maintain a new, relevant strategy once selected. In anesthetized rats, the minimum dose required to induce salivation was approximately 0.3 mg/kg i.p. Salivation increased with dose, and the estimated ED(50) was 2.0 mg/kg. The data suggest that CDD-0102A has unique memory and cognitive enhancing properties that might be useful in the treatment of neurological disorders at doses that do not produce adverse effects such as salivation.

Adaptation and evaluation of the bottle assay for monitoring insecticide resistance in disease vector mosquitoes in the Peruvian Amazon

PubMed Central

Zamora Perea, Elvira; Balta León, Rosario; Palomino Salcedo, Miriam; Brogdon, William G; Devine, Gregor J

2009-01-01

Background The purpose of this study was to establish whether the "bottle assay", a tool for monitoring insecticide resistance in mosquitoes, can complement and augment the capabilities of the established WHO assay, particularly in resource-poor, logistically challenging environments. Methods Laboratory reared Aedes aegypti and field collected Anopheles darlingi and Anopheles albimanus were used to assess the suitability of locally sourced solvents and formulated insecticides for use with the bottle assay. Using these adapted protocols, the ability of the bottle assay and the WHO assay to discriminate between deltamethrin-resistant Anopheles albimanus populations was compared. The diagnostic dose of deltamethrin that would identify resistance in currently susceptible populations of An. darlingi and Ae. aegypti was defined. The robustness of the bottle assay during a surveillance exercise in the Amazon was assessed. Results The bottle assay (using technical or formulated material) and the WHO assay were equally able to differentiate deltamethrin-resistant and susceptible An. albimanus populations. A diagnostic dose of 10 μg a.i./bottle was identified as the most sensitive discriminating dose for characterizing resistance in An. darlingi and Ae. aegypti. Treated bottles, prepared using locally sourced solvents and insecticide formulations, can be stored for > 14 days and used three times. Bottles can be stored and transported under local conditions and field-assays can be completed in a single evening. Conclusion The flexible and portable nature of the bottle assay and the ready availability of its components make it a potentially robust and useful tool for monitoring insecticide resistance and efficacy in remote areas that require minimal cost tools. PMID:19728871

Trunk-rotation flexibility in collegiate softball players with or without a history of shoulder or elbow injury.

PubMed

Aragon, Veronica J; Oyama, Sakiko; Oliaro, Scott M; Padua, Darin A; Myers, Joseph B

2012-01-01

Throwing is a whole-body motion that requires the transfer of momentum from the lower extremity to the upper extremity via the trunk. No research to date examines the association between a history of shoulder or elbow injury and trunk flexibility in overhead athletes. To determine if injury history and trunk-rotation flexibility are associated and to compare trunk-rotation flexibility measured using 3 clinical tests: half-kneeling rotation test with the bar in the back, half-kneeling rotation test with the bar in the front, and seated rotation test in softball position players with or without a history of shoulder or elbow injury. Cross-sectional design. University softball facilities. Sixty-five female National Collegiate Athletic Association Division I softball position players. Trunk-rotation flexibility was measured with 3 clinical tests. Recent injury history was obtained using a questionnaire and verified by the certified athletic trainer. Binomial regression models were used to determine if injury history was associated with flexibility categories (high, normal, or limited tertiles) for each of the 6 (3 tests × 2 directions) trunk-rotation flexibility measures. Trunk-rotation flexibility measures from 3 clinical tests were compared between participants with and without a history of shoulder or elbow injury using analysis-of-variance models. When measured using the half-kneeling rotation test with the bar in the back and the seated rotation test, injury history and forward trunk-rotation flexibility were associated. However, no mean group differences were seen in trunk-rotation flexibility between participants with and without a history of shoulder or elbow injury. Limited forward trunk-rotation flexibility may be a risk factor for shoulder or elbow injuries. However, further study is needed to confirm the study finding.

A comparative study of velocity increment generation between the rigid body and flexible models of MMET

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

Ismail, Norilmi Amilia, E-mail: aenorilmi@usm.my

The motorized momentum exchange tether (MMET) is capable of generating useful velocity increments through spin–orbit coupling. This study presents a comparative study of the velocity increments between the rigid body and flexible models of MMET. The equations of motions of both models in the time domain are transformed into a function of true anomaly. The equations of motion are integrated, and the responses in terms of the velocity increment of the rigid body and flexible models are compared and analysed. Results show that the initial conditions, eccentricity, and flexibility of the tether have significant effects on the velocity increments ofmore » the tether.« less

Implications of the INF (intermediate nuclear force) treaty on NATO strategy. Student report

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

Amend, J.H.

1988-03-01

The INF Treaty has refocused NATO attention on the longstanding concern of the applicability of the current NATO strategy. This study examines the implications of the INF Treaty on the current NATO strategy of Flexible Response. The tenets of Flexible Response include sustainability and escalation control. This study concludes that even prior to the INF Treaty, Flexible Response was not a valid strategy due to lack of sustainability and escalation control. In the absence of a valid Flexible Response Doctrine, NATO strategy reverts to massive Retaliation. Recommendations to alleviate this situation are suggested.

Shaft flexibility effects on the forced response of a bladed-disk assembly

NASA Technical Reports Server (NTRS)

Khader, N.; Loewy, R. G.

1990-01-01

A model analysis approach is used to study the forced response of an actual flexible bladed-disk-shaft system. Both in-plane and out-of-plane flexible deformations of the bladed-disk assembly are considered, in addition to its rigid-body translations and rotations, resulting from the bending of the supporting flexible shaft in two orthogonal planes. The effects of Coriolis forces and structural coupling between flexible and rigid disk motions on the system's response are investigated. Aerodynamic loads acting on the rotating and vibrating bladed-disk assembly are accounted for through a simple quasi-steady representation, to evaluate their influence, combined with shaft flexibility and Coriolis effects.

Dynamic Flexibility and Proprioceptive Neuromuscular Facilitation.

ERIC Educational Resources Information Center

Hardy, Lew; Jones, David

1986-01-01

Two experiments are described which investigated whether results obtained in studies of static flexibility tranfer to dynamic flexibility. In both experiments, subjects were assigned to a group receiving proprioceptive neuromuscular facilitation training, ballistic stretching technique training or a control group. Results are presented and…

Flexible Parsing.

DTIC Science & Technology

1986-06-30

Machine Studies .. 14. Minton, S. N., Hayes, P. J., and Fain, J. E. Controlling Search in Flexible Parsing. Proc. Ninth Int. Jt. Conf. on Artificial...interaction through the COUSIN command interface", International Journal of Man- Machine Studies , Vol. 19, No. 3, September 1983, pp. 285-305. 8...in a gracefully interacting user interface," "Dynamic strategy selection in flexible parsing," and "Parsing spoken language: a semantic case frame

Modular C3 Interface Analysis (Flexible Intraconnect). Volume 1, Part 1

DTIC Science & Technology

1980-04-01

was prepared in parallel with a separate Flexible^ Intraconnect design definition study conducted by Hughes Aircraft Company under F19628-77-O-0261...reported herein consists of Task I, Task II, and Task III of Phase I of an on-going study being conducted by the Air Force to develop a Flexible...Intraconnect for tactical C^ tivity. equipment connec- As evidenced by the quantity of analyses performed and docu- mented during the period of this study

Do flexible inter-injection intervals improve the effects of botulinum toxin A treatment in reducing impairment and disability in patients with spasticity?

PubMed

Trompetto, Carlo; Marinelli, Lucio; Mori, Laura; Puce, Luca; Pelosin, Elisa; Serrati, Carlo; Fattapposta, Francesco; Rinalduzzi, Steno; Abbruzzese, Giovanni; Currà, Antonio

2017-05-01

In patients treated with botulinum toxin-A (BoNT-A), toxin-directed antibody formation was related to the dosage and frequency of injections, leading to the empirical adoption of minimum time intervals between injections of 3months or longer. However, recent data suggest that low immunogenicity of current BoNT-A preparations could allow more frequent injections. Our hypothesis is that a short time interval between injections may be safe and effective in reducing upper limb spasticity and related disability. IncobotulinumtoxinA was injected under ultrasound guidance in spastic muscles of 11 subjects, who were evaluated just before BoNT-A injection (T0), and 1month (T1), 2months (T2) and 4months (T3) after injecting. At T1, in the case of persistent disability related to spasticity interfering with normal activities, patients received an additional toxin dose. Seven subjects received the additional dose at T1 because of persistent disability; 4 of them had a decrease of disability 1month later (T2). Rethinking the injection scheme for BoNT-A treatment may have a major impact in the management of spasticity and related disability. Future studies with larger sample sizes are warranted to confirm that injection schedules with short time intervals should no longer be discouraged in clinical practice. Copyright © 2017 Elsevier Ltd. All rights reserved.

Intraperitoneal administration of chitosan/DsiRNA nanoparticles targeting TNFα prevents radiation-induced fibrosis.

PubMed

Nawroth, Isabel; Alsner, Jan; Behlke, Mark A; Besenbacher, Flemming; Overgaard, Jens; Howard, Kenneth A; Kjems, Jørgen

2010-10-01

One of the most common and dose-limiting long-term adverse effects of radiation therapy is radiation-induced fibrosis (RIF), which is characterized by restricted tissue flexibility, reduced compliance or strictures, pain and in severe cases, ulceration and necrosis. Several strategies have been proposed to ameliorate RIF but presently no effective one is available. Recent studies have reported that tumor necrosis factor-α (TNFα) plays a role in fibrogenesis. Male CDF1 mice were radiated with a single dose of 45 Gy. Chitosan/DsiRNA nanoparticles targeting TNFα were intraperitoneal injected and late radiation-induced fibrosis (RIF) was assessed using a modification of the leg contracture model. Additionally, the effect of these nanoparticles on tumor growth and tumor control probability in the absence of radiation was examined in a C3H mammary carcinoma model. We show in this work, that targeting TNFα in macrophages by intraperitoneal administration of chitosan/DsiRNA nanoparticles completely prevented radiation-induced fibrosis in CDF1 mice without revealing any cytotoxic side-effects after a long-term administration. Furthermore, such TNFα targeting was selective without any significant influence on tumor growth or irradiation-related tumor control probability. This nanoparticle-based RNAi approach represents a novel approach to prevent RIF with potential application to improve clinical radiation therapeutic strategies. Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.

Continuous cell lines from the Muscovy duck as potential replacement for primary cells in the production of avian vaccines.

PubMed

Jordan, Ingo; John, Katrin; Höwing, Kristin; Lohr, Verena; Penzes, Zoltán; Gubucz-Sombor, Erzsébet; Fu, Yan; Gao, Peng; Harder, Timm; Zádori, Zoltán; Sandig, Volker

2016-01-01

Veterinary vaccines contribute to food security, interrupt zoonotic transmissions, and help to maintain overall health in livestock. Although vaccines are usually cost-effective, their adoption depends on a multitude of factors. Because poultry vaccines are usually given to birds with a short life span, very low production cost per dose is one important challenge. Other hurdles are to ensure a consistent and reliable supply of very large number of doses, and to have flexible production processes to accommodate a range of different pathogens and dosage requirements. Most poultry vaccines are currently being produced on primary avian cells derived from chicken or waterfowl embryos. This production system is associated with high costs, logistic complexities, rigid intervals between harvest and production, and supply limitations. We investigated whether the continuous cell lines Cairina retina and CR.pIX may provide a substrate independent of primary cell cultures or embryonated eggs. Viruses examined for replication in these cell lines are strains associated with, or contained in vaccines against egg drop syndrome, Marek's disease, Newcastle disease, avian influenza, infectious bursal disease and Derzsy's disease. Each of the tested viruses required the development of unique conditions for replication that are described here and can be used to generate material for in vivo efficacy studies and to accelerate transfer of the processes to larger production volumes.

Invertible flexible matrices

NASA Astrophysics Data System (ADS)

Justino, Júlia

2017-06-01

Matrices with coefficients having uncertainties of type o (.) or O (.), called flexible matrices, are studied from the point of view of nonstandard analysis. The uncertainties of the afore-mentioned kind will be given in the form of the so-called neutrices, for instance the set of all infinitesimals. Since flexible matrices have uncertainties in their coefficients, it is not possible to define the identity matrix in an unique way and so the notion of spectral identity matrix arises. Not all nonsingular flexible matrices can be turned into a spectral identity matrix using Gauss-Jordan elimination method, implying that that not all nonsingular flexible matrices have the inverse matrix. Under certain conditions upon the size of the uncertainties appearing in a nonsingular flexible matrix, a general theorem concerning the boundaries of its minors is presented which guarantees the existence of the inverse matrix of a nonsingular flexible matrix.

A flexible skin patch for continuous physiological monitoring of mental disorders

NASA Astrophysics Data System (ADS)

Jang, Won Ick; Lee, Bong Kuk; Ryu, Jin Hwa; Baek, In-Bok; Yu, Han Young; Kim, Seunghwan

2017-10-01

In this study, we have newly developed a flexible adhesive skin patch of electrocardiogram (ECG) device for continuous physiological monitoring of mental disorders. In addition, this flexible patch did not cause any damage to the skin even after 24 hours attachment. We have also suggested the possibility of novel interconnection for copper film on polyimide and polydimethylsiloxane (PDMS) layers of the flexible patch. Self-align and soldering of IC chips such as resistor between metal pads on flexible skin patch have also successfully fabricated for 5 min at 180 °C in vacuum oven. Low temperature interconnection technology based on a Sn42/Bi58 solder was also developed for flexible ECG devices. As a result, we can monitor the mental health status through a comprehensive analysis of biological signals from flexible ECG devices.

Van der Waals epitaxy of functional MoO{sub 2} film on mica for flexible electronics

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

Ma, Chun-Hao; Department of Materials Science and Engineering, National Chiao Tung University, Hsinchu 30010, Taiwan; Lin, Jheng-Cyuan

Flexible electronics have a great potential to impact consumer electronics and with that our daily life. Currently, no direct growth of epitaxial functional oxides on commercially available flexible substrates is possible. In this study, in order to address this challenge, muscovite, a common layered oxide, is used as a flexible substrate that is chemically similar to typical functional oxides. We fabricated epitaxial MoO{sub 2} films on muscovite via pulsed laser deposition technique. A combination of X-ray diffraction and transmission electron microscopy confirms van der Waals epitaxy of the heterostructures. The electrical transport properties of MoO{sub 2} films are similar tomore » those of the bulk. Flexible or free-standing MoO{sub 2} thin film can be obtained and serve as a template to integrate additional functional oxide layers. Our study demonstrates a remarkable concept to create flexible electronics based on functional oxides.« less

Conceptual approach study of a 200 watt per kilogram solar array

NASA Technical Reports Server (NTRS)

Stanhouse, R. W.; Fox, D.; Wilson, W.

1976-01-01

Solar array candidate configurations (flexible rollup, flexible flat-pact, semi-rigid panel, semi-rigid flat-pack) were analyzed with particular attention to the specific power (W/kg) requirement. Two of these configurations (flexible rollup and flexible flat-pack) are capable of delivering specific powers equal to or exceeding the baseline requirement of 200 W/kg. Only the flexible rollup is capable of in-flight retraction and subsequent redeployment. The wrap-around contact photovoltaic cell configuration has been chosen over the conventional cell. The demand for ultra high specific power forces the selection of ultra-thin cells and cover material. Based on density and mass range considerations, it was concluded that 13 micrometers of FEP Teflon is sufficient to protect the cell from a total proton fluency of 2(10 to the 12th power) particles/sq cm over a three-year interplanetary mission. The V-stiffened, lattice boom deployed, flexible substrate rollup array holds the greatest promise of meeting the baseline requirements set for this study.

Improving general flexibility with a mind-body approach: a randomized, controlled trial using neuro emotional Technique®.

PubMed

Jensen, Anne M; Ramasamy, Adaikalavan; Hall, Michael W

2012-08-01

General flexibility is a key component of health, well-being, and general physical conditioning. Reduced flexibility has both physical and mental/emotional etiologies and can lead to musculoskeletal injuries and athletic underperformance. Few studies have tested the effectiveness of a mind-body therapy on general flexibility. The aim of this study was to investigate if Neuro Emotional Technique® (NET), a mind-body technique shown to be effective in reducing stress, can also improve general flexibility. The sit-and-reach test (SR) score was used as a measure of general flexibility. Forty-five healthy participants were recruited from the general population and assessed for their initial SR score before being randomly allocated to receive (a) two 20-minute sessions of NET (experimental group); (b) two 20-minute sessions of stretching instruction (active control group); or (c) no intervention or instruction (passive control group). After intervention, the participants were reassessed in a similar manner by the same blind assessor. The participants also answered questions about demographics, usual water and caffeine consumption, and activity level, and they completed an anxiety/mood psychometric preintervention and postintervention. The mean (SD) change in the SR score was +3.1 cm (2.5) in the NET group, +1.2 cm (2.3) in the active control group and +1.0 cm (2.6) in the passive control group. Although all the 3 groups showed some improvement, the improvement in the NET group was statistically significant when compared with that of either the passive controls (p = 0.015) or the active controls (p = 0.021). This study suggests that NET could provide an effective treatment in improving general flexibility. A larger study is required to confirm these findings and also to assess longer term effectiveness of this therapy on general flexibility.

Do flexible work policies improve parents' health? A natural experiment based on the UK Millennium Cohort Study.

PubMed

Avendano, Mauricio; Panico, Lidia

2018-03-01

There is limited evidence of the impact of policies to promote work-family balance on family health. Exploiting the introduction of the UK Flexible Working Act (2003), we examined whether a policy that grants parents the right to request flexible work influences their health and well-being. Using the UK Millennium Cohort Study, we focus on 6424 mothers employed in 2001-2002, when the cohort child was 9 months old, until their child's seventh birthday. We used a difference-in-differences (DiD) approach to compare changes in outcomes before and after the policy among mothers most likely to benefit and mothers unlikely to benefit from the policy. Flexible working increased in a small group of mothers (n=548) whose employer did not offer work flexibility before the reform (treatment group). By contrast, among mothers whose employer already offered flexible work before the reform (control group, n=5810), there was little change or a slight decline in flexible working. DiD estimates suggest that the policy was associated with an increase in flexible working (37.5 percentage points, 95% CI 32.9 to 41.6), but it had no impact on self-rated health (-1.6 percentage points, 95% CI -4.4 to 1.1), long-term illness (-1.87 percentage points, 95% CI -4.3 to 0.5) or life satisfaction scores (β=0.04, 95% CI -0.08 to 0.16). The Flexible Working Act increased flexible working only among a small group of mothers who had not yet the right to request work flexibility, but it had no impact on their health and well-being. Policies promoting work flexibility may require stronger incentives for both parents and employers. © 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.

Light-driven 3D droplet manipulation on flexible optoelectrowetting devices fabricated by a simple spin-coating method.

PubMed

Jiang, Dongyue; Park, Sung-Yong

2016-05-21

Technical advances in electrowetting-on-dielectric (EWOD) over the past few years have extended our attraction to three-dimensional (3D) devices capable of providing more flexibility and functionality with larger volumetric capacity than conventional 2D planar ones. However, typical 3D EWOD devices require complex and expensive fabrication processes for patterning and wiring of pixelated electrodes that also restrict the minimum droplet size to be manipulated. Here, we present a flexible single-sided continuous optoelectrowetting (SCOEW) device which is not only fabricated by a spin-coating method without the need for patterning and wiring processes, but also enables light-driven 3D droplet manipulations. To provide photoconductive properties, previous optoelectrowetting (OEW) devices have used amorphous silicon (a-Si) typically fabricated through high-temperature processes over 300 °C such as CVD or PECVD. However, most of the commercially-available flexible substrates such as polyethylene terephthalate (PET) and polyethylene naphthalate (PEN) experience serious thermal deformation under such high-temperature processes. Because of this compatibility issue of conventional OEW devices with flexible substrates, light-driven 3D droplet manipulations have not yet been demonstrated on flexible substrates. Our study overcomes this compatibility issue by using a polymer-based photoconductive material, titanium oxide phthalocyanine (TiOPc) and thus SCOEW devices can be simply fabricated on flexible substrates through a low-cost, spin-coating method. In this paper, analytical studies were conducted to understand the effects of light patterns on static contact angles and EWOD forces. For experimental validations of our study, flexible SCOEW devices were successfully fabricated through the TiOPc-based spin-coating method and light-driven droplet manipulations (e.g. transportation, merging, and splitting) have been demonstrated on various 3D terrains such as inclined, vertical, upside-down, and curved surfaces. Our flexible SCOEW technology offers the benefits of device simplicity, flexibility, and functionality over conventional EWOD and OEW devices by enabling optical droplet manipulations on a 3D featureless surface.

Flexible working and the contribution of nurses in mid-life to the workforce: a qualitative study.

PubMed

Harris, Ruth; Bennett, Janette; Davey, Barbara; Ross, Fiona

2010-04-01

With the changing demographic profile of the nursing workforce, retaining the skill and experience of nurses in mid-life is very important. Work-life balance is a concept that is gaining increasing prominence in today's society. However, little is known about older nurses' experience of family friendly policies and flexible working. This study explored the organisational, professional and personal factors that influence perceptions of commitment and participation in the workforce for nurses working in mid-life (aged 45 and over). A qualitative study using a range of methods including biographical methods, semi-structured face-to-face interviews, focus groups and telephone interviews. Data were analysed using constant comparative method. A large inner city acute teaching hospital and an inner city mental health and social care trust providing both community and inpatient health and social care. 34 nurses and 3 health care assistants participated in individual interviews, 10 nurses participated in two focus groups and 17 managers participated in individual telephone interviews. Four themes emerged: the nature of nursing poses a challenge to the implementation of flexible working, differences in perceptions of the availability of flexible working, ward managers have a crucial role in the implementation of flexible working policies and the implementation of flexible working may be creating an inflexible workforce. The findings suggest that there are limits to the implementation of flexible working for nurses. In some areas there is evidence that the implementation of flexible working may be producing an inflexible workforce as older nurses are required to compensate for the flexible working patterns of their colleagues. Ward managers have a key role in the implementation of family friendly policies and require support to fulfil this role. There is a need for creative solutions to address implementation of flexible working for all nurses to ensure that workforce policy addresses the need to retain nurses in the workforce in a fair and equitable way. Copyright 2009 Elsevier Ltd. All rights reserved.

Effect of Flexible Duty Hour Policies on Length of Stay for Complex Intra-Abdominal Operations: A Flexibility in Duty Hour Requirements for Surgical Trainees (FIRST) Trial Analysis.

PubMed

Stulberg, Jonah J; Pavey, Emily S; Cohen, Mark E; Ko, Clifford Y; Hoyt, David B; Bilimoria, Karl Y

2017-02-01

Changes to resident duty hour policies in the Flexibility in Duty Hour Requirements for Surgical Trainees (FIRST) trial could impact hospitalized patients' length of stay (LOS) by altering care coordination. Length of stay can also serve as a reflection of all complications, particularly those not captured in the FIRST trial (eg pneumothorax from central line). Programs were randomized to either maintaining current ACGME duty hour policies (Standard arm) or more flexible policies waiving rules on maximum shift lengths and time off between shifts (Flexible arm). Our objective was to determine whether flexibility in resident duty hours affected LOS in patients undergoing high-risk surgical operations. Patients were identified who underwent hepatectomy, pancreatectomy, laparoscopic colectomy, open colectomy, or ventral hernia repair (2014-2015 academic year) at 154 hospitals participating in the FIRST trial. Two procedure-stratified evaluations of LOS were undertaken: multivariable negative binomial regression analysis on LOS and a multivariable logistic regression analysis on the likelihood of a prolonged LOS (>75 th percentile). Before any adjustments, there was no statistically significant difference in overall mean LOS between study arms (Flexible Policy: mean [SD] LOS 6.03 [5.78] days vs Standard Policy: mean LOS 6.21 [5.82] days; p = 0.74). In adjusted analyses, there was no statistically significant difference in LOS between study arms overall (incidence rate ratio for Flexible vs Standard: 0.982; 95% CI, 0.939-1.026; p = 0.41) or for any individual procedures. In addition, there was no statistically significant difference in the proportion of patients with prolonged LOS between study arms overall (Flexible vs Standard: odds ratio = 1.028; 95% CI, 0.871-1.212) or for any individual procedures. Duty hour flexibility had no statistically significant effect on LOS in patients undergoing complex intra-abdominal operations. Copyright © 2016 American College of Surgeons. Published by Elsevier Inc. All rights reserved.

Inflexible parents, inflexible kids: a 6-year longitudinal study of parenting style and the development of psychological flexibility in adolescents.

PubMed

Williams, Kathryn E; Ciarrochi, Joseph; Heaven, Patrick C L

2012-08-01

Parenting behaviors have been linked to children's self regulation, but it is less clear how they relate to adolescent psychological flexibility. Psychological flexibility is a broad construct that describes an individual's ability to respond appropriately to environmental demands and internal experiences in the service of their goals. We examined the longitudinal relationships between perceived parenting style and psychological flexibility among students at five Australian schools (N= 749) over 6 years, beginning in Grade 7 (50.3% female, mean age 12.39 years). Parenting style was measured in Grades 7 and 12, and psychological flexibility from Grade 9 through 12. Psychological flexibility decreased, on average, with age. Multi-level modelling indicated that authoritarian parenting (low warmth, high control) in Grade 7 predicted later (low) psychological flexibility. Moreover, increases in authoritarian parenting and decreases in authoritative parenting (high warmth and control) were associated with adolescent psychological flexibility across the high school years. Change in parenting predicted future psychological flexibility but did not predict change over time. Structural Equation Modelling revealed that adolescent psychological flexibility in Grade 9 predicted later decreases in authoritarian and increases in authoritative parenting. We discuss the implications of these findings for understanding how parenting changes and the consequences of such change for the development of psychological flexibility.

An open treatment trial of duloxetine in elderly patients with dysthymic disorder.

PubMed

Kerner, Nancy; D'Antonio, Kristina; Pelton, Gregory H; Salcedo, Elianny; Ferrar, Jennifer; Roose, Steven P; Devanand, Dp

2014-05-08

We evaluated the efficacy and side effects of the selective serotonin and norepinephrine reuptake inhibitor antidepressant duloxetine in older adults with dysthymic disorder. Patients ≥ 60 years old with dysthymic disorder received flexible dose duloxetine 20-120 mg daily in an open-label 12-week trial. The main outcomes were change from baseline to 12 weeks in 24-item Hamilton Depression Rating Scale scores and Treatment Emergent Symptoms Scale scores. Response required ≥ 50% decline in Hamilton Depression Rating Scale scores with a Clinical Global Impression of much improved or better, and remission required final Hamilton Depression Rating Scale ≤ 6. Intent-to-treat analyses were conducted with the last observation carried forward. In 30 patients, the mean age was 70.7 (standard deviation (SD) = 7.6) years and 56.7% were female. In intent-to-treat analyses, there were 16 responders (53.3%) and 10 remitters (33.3%). Of these, 19 patients completed the trial. The mean maximum dose was 76.3 mg (SD = 38.5) in the total sample and 101 mg (SD = 17.9) in completers. In the total sample, the mean final dose was 51 mg (SD = 27.2) and correlated significantly with decline in Hamilton Depression Rating Scale ( p < .03); decline in Hamilton Depression Rating Scale correlated significantly with decline in Treatment Emergent Symptoms Scale ( p < .001). Daily doses above 60 mg were associated with greater improvement and well tolerated. This result was partly confounded by early dropouts having received low doses. Demographic and medical comorbidities, including cardiac disease and hypertension, were not related to response. Somatic side effects were common prior to duloxetine treatment and improved rather than worsened with duloxetine. There were no serious adverse events. Duloxetine at relatively high doses showed moderate efficacy in elderly patients with dysthymic disorder and was well tolerated in successful completers. Reduced somatic symptoms were associated with improvement in depressive symptoms. A systematic placebo-controlled trial of duloxetine in older patients with dysthymic disorder may be warranted.

Work schedule flexibility is associated with emotional exhaustion among registered nurses in Swiss hospitals: A cross-sectional study.

PubMed

Dhaini, Suzanne R; Denhaerynck, Kris; Bachnick, Stefanie; Schwendimann, René; Schubert, Maria; De Geest, Sabina; Simon, Michael

2018-06-01

Emotional exhaustion among healthcare workers is a widely investigated, well-recognized problem, the incidence of which has recently been linked to work environment factors, particularly work/family conflict. However, another environmental feature that may be equally influential, but that is more amenable to nurse manager action, remains less recognized: shift schedule flexibility. This study's main purposes were to assess variations in work schedule flexibility between Swiss acute care hospital units, and to investigate associations between psychosocial work environment (e.g. work schedule flexibility) and self-reported emotional exhaustion among registered nurses. This is a secondary analysis of data collected for the multi-center observational cross-sectional Match RN study, which included a national sample of 23 hospitals and 1833 registered nurses across Switzerland. Overall, self-reported work schedule flexibility among registered nurses was limited: 32% of participants reported little or no influence in planning their own shifts. Work schedule flexibility (β -0.11; CI -0.16; -0.06) and perceived nurse manager ability (β -0.30; CI -0.49; -0.10) were negatively related to self-reported emotional exhaustion. Work-family conflict (β 0.39; CI 0.33; 0.45) was positively correlated to emotional exhaustion. The study results indicate that managerial efforts to improve working environments, including special efforts to improve work schedule flexibility, might play an important role in promoting nurses' emotional health. Copyright © 2018 Elsevier Ltd. All rights reserved.

Sympathetic arousal, but not disturbed executive functioning, mediates the impairment of cognitive flexibility under stress.

PubMed

Marko, Martin; Riečanský, Igor

2018-05-01

Cognitive flexibility emerges from an interplay of multiple cognitive systems, of which lexical-semantic and executive are thought to be the most important. Yet this has not been addressed by previous studies demonstrating that such forms of flexible thought deteriorate under stress. Motivated by these shortcomings, the present study evaluated several candidate mechanisms implied to mediate the impairing effects of stress on flexible thinking. Fifty-seven healthy adults were randomly assigned to psychosocial stress or control condition while assessed for performance on cognitive flexibility, working memory capacity, semantic fluency, and self-reported cognitive interference. Stress response was indicated by changes in skin conductance, hearth rate, and state anxiety. Our analyses showed that acute stress impaired cognitive flexibility via a concomitant increase in sympathetic arousal, while this mediator was positively associated with semantic fluency. Stress also decreased working memory capacity, which was partially mediated by elevated cognitive interference, but neither of these two measures were associated with cognitive flexibility or sympathetic arousal. Following these findings, we conclude that acute stress impairs cognitive flexibility via sympathetic arousal that modulates lexical-semantic and associative processes. In particular, the results indicate that stress-level of sympathetic activation may restrict the accessibility and integration of remote associates and bias the response competition towards prepotent and dominant ideas. Importantly, our results indicate that stress-induced impairments of cognitive flexibility and executive functions are mediated by distinct neurocognitive mechanisms. Copyright © 2018 Elsevier B.V. All rights reserved.

Stress analysis in a pedicle screw fixation system with flexible rods in the lumbar spine.

PubMed

Kim, Kyungsoo; Park, Won Man; Kim, Yoon Hyuk; Lee, SuKyoung

2010-01-01

Breakage of screws has been one of the most common complications in spinal fixation systems. However, no studies have examined the breakage risk of pedicle screw fixation systems that use flexible rods, even though flexible rods are currently being used for dynamic stabilization. In this study, the risk of breakage of screws for the rods with various flexibilities in pedicle screw fixation systems is investigated by calculating the von Mises stress as a breakage risk factor using finite element analysis. Three-dimensional finite element models of the lumbar spine with posterior one-level spinal fixations at L4-L5 using four types of rod (a straight rod, a 4 mm spring rod, a 3 mm spring rod, and a 2 mm spring rod) were developed. The von Mises stresses in both the pedicle screws and the rods were analysed under flexion, extension, lateral bending, and torsion moments of 10 Nm with a follower load of 400 N. The maximum von Mises stress, which was concentrated on the neck region of the pedicle screw, decreased as the flexibility of the rod increased. However, the ratio of the maximum stress in the rod to the yield stress increased substantially when a highly flexible rod was used. Thus, the level of rod flexibility should be considered carefully when using flexible rods for dynamic stabilization because the intersegmental motion facilitated by the flexible rod results in rod breakage.

Goal driven kinematic simulation of flexible arm robot for space station missions

NASA Technical Reports Server (NTRS)

Janssen, P.; Choudry, A.

1987-01-01

Flexible arms offer a great degree of flexibility in maneuvering in the space environment. The problem of transporting an astronaut for extra-vehicular activity using a space station based flexible arm robot was studied. Inverse kinematic solutions of the multilink structure were developed. The technique is goal driven and can support decision making for configuration selection as required for stability and obstacle avoidance. Details of this technique and results are given.

Soft Encapsulation of Flexible Electrical Stimulation Implant: Challenges and Innovations

PubMed Central

Debelle, Adrien; Hermans, Laura; Bosquet, Maxime; Dehaeck, Sam; Lonys, Laurent; Scheid, Benoit; Nonclercq, Antoine; Vanhoestenberghe, Anne

2016-01-01

In this document we discuss the main challenges encountered when producing flexible electrical stimulation implants, and present our approach to solving them for prototype production. We include a study of the optimization of the flexible PCB design, the selection of additive manufacturing materials for the mold, and the chemical compatibility of the different materials. Our approach was tested on a flexible gastro-stimulator as part of the ENDOGES research program. PMID:28078073

Balancing Flexible Constraints and Measurement Precision in Computerized Adaptive Testing

ERIC Educational Resources Information Center

Moyer, Eric L.; Galindo, Jennifer L.; Dodd, Barbara G.

2012-01-01

Managing test specifications--both multiple nonstatistical constraints and flexibly defined constraints--has become an important part of designing item selection procedures for computerized adaptive tests (CATs) in achievement testing. This study compared the effectiveness of three procedures: constrained CAT, flexible modified constrained CAT,…

Cognitive Flexibility in Children with and without Speech Disorder

ERIC Educational Resources Information Center

Crosbie, Sharon; Holm, Alison; Dodd, Barbara

2009-01-01

Most children's speech difficulties are "functional" (i.e. no known sensory, motor or intellectual deficits). Speech disorder may, however, be associated with cognitive deficits considered core abilities in executive function: rule abstraction and cognitive flexibility. The study compares the rule abstraction and cognitive flexibility of…

Long-term safety and efficacy of single-tablet combinations of solifenacin and tamsulosin oral controlled absorption system in men with storage and voiding lower urinary tract symptoms: results from the NEPTUNE Study and NEPTUNE II open-label extension.

PubMed

Drake, Marcus J; Chapple, Christopher; Sokol, Roman; Oelke, Matthias; Traudtner, Klaudia; Klaver, Monique; Drogendijk, Ted; Van Kerrebroeck, Philip

2015-02-01

Short-term trials have demonstrated the efficacy and safety of combination therapy using antimuscarinics and α-blockers in men with lower urinary tract symptoms (LUTS). The Study of Solifenacin Succinate and Tamsulosin Hydrochloride OCAS (oral controlled absorption system) in Males with Lower Urinary Tract Symptoms (NEPTUNE) II is the first long-term study using solifenacin (Soli) and the oral controlled absorption system formulation of tamsulosin (TOCAS). To evaluate long-term (up to 52 wk) safety and efficacy of flexible dosing of two fixed-dose combinations (FDC) of Soli plus TOCAS in men with moderate to severe storage symptoms and voiding symptoms. Patients with both storage and voiding LUTS, maximum urinary flow rate of 4.0-12.0 ml/s, prostate size <75 ml, and postvoid residuals ≤ 150 ml, who completed the 12-wk, double-blind NEPTUNE study could continue in the 40-wk, open-label NEPTUNE II study. FDC of Soli 6 mg plus TOCAS 0.4 mg, or Soli 9 mg plus TOCAS 0.4mg; patients could switch between doses in NEPTUNE II. Safety and efficacy data from NEPTUNE and NEPTUNE II were combined to cover a 52-wk period. Primary efficacy end points were total International Prostate Symptom Score (IPSS) and total urgency and frequency score (TUFS); secondary end points included IPSS storage and voiding subscores, micturition diary variables, and quality of life parameters. In all, 1066 men completed NEPTUNE and received one dose or more of study medication in NEPTUNE II. Treatment-emergent adverse events were reported in 499 (46.8%) patients who participated in NEPTUNE II; most were mild or moderate. Urinary retention occurred in 13 of 1208 (1.1%) patients receiving one or more FDCs in NEPTUNE and/or NEPTUNE II; 8 (0.7%) required catheterisation (acute urinary retention [AUR]). Reductions in total IPSS and TUFS during NEPTUNE were maintained for up to 52 wk of FDC treatment, with mean reductions of 9.0 (standard deviation [SD]: 5.7) and 10.1 (SD: 9.2), respectively, from baseline to end of treatment. Clinically relevant improvements were also observed for secondary efficacy end points. Long-term treatment with FDC Soli plus TOCAS was well tolerated and efficacious in men with storage and voiding LUTS, with a low incidence of AUR. Treatment with solifenacin plus tamsulosin in a fixed-dose combination tablet was well tolerated by men with lower urinary tract symptoms. Improvements in symptoms were achieved after 4 wk of treatment, with further improvements at week 16 maintained for up to 52 wk throughout the study. Copyright © 2014 European Association of Urology. Published by Elsevier B.V. All rights reserved.

Issues and Challenges Facing Flexible Lithium-Ion Batteries for Practical Application.

PubMed

Cha, Hyungyeon; Kim, Junhyeok; Lee, Yoonji; Cho, Jaephil; Park, Minjoon

2017-12-27

With the advent of flexible electronics, lithium-ion batteries have become a key component of high performance energy storage systems. Thus, considerable effort is made to keep up with the development of flexible lithium-ion batteries. To date, many researchers have studied newly designed batteries with flexibility, however, there are several significant challenges that need to be overcome, such as degradation of electrodes under external load, poor battery performance, and complicated cell preparation procedures. In addition, an in-depth understanding of the current challenges for flexible batteries is rarely addressed in a systematical and practical way. Herein, recent progress and current issues of flexible lithium-ion batteries in terms of battery materials and cell designs are reviewed. A critical overview of important issues and challenges for the practical application of flexible lithium-ion batteries is also provided. Finally, the strategies are discussed to overcome current limitations of the practical use of flexible lithium-based batteries, providing a direction for future research. © 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

The effectiveness of whole-body-vibration training in improving hamstring flexibility in physically active adults.

PubMed

Houston, Megan N; Hodson, Victoria E; Adams, Kelda K E; Hoch, Johanna M

2015-02-01

Hamstring tightness is common among physically active individuals. In addition to limiting range of motion and increasing the risk of muscle strain, hamstring tightness contributes to a variety of orthopedic conditions. Therefore, clinicians continue to identify effective methods to increase flexibility. Although hamstring tightness is typically treated with common stretching techniques such as static stretching and proprioceptive neuromuscular facilitation, it has been suggested that whole-body-vibration (WBV) training may improve hamstring flexibility. Can WBV training, used in isolation or in combination with common stretching protocols or exercise, improve hamstring flexibility in physically active young adults? Summary of Key Findings: Of the included studies, 4 demonstrated statistically significant improvements in hamstring flexibility in the intervention group, and 1 study found minor improvements over time in the intervention group after treatment. Clinical Bottom Line: There is moderate evidence to support the use of WBV training to improve hamstring flexibility in physically active young adults. There is grade B evidence that WBV training improves hamstring flexibility in physically active adults. The Centre of Evidence Based Medicine recommends a grade of B for level 2 evidence with consistent findings.

Flexible magnetic thin films and devices

NASA Astrophysics Data System (ADS)

Sheng, Ping; Wang, Baomin; Li, Runwei

2018-01-01

Flexible electronic devices are highly attractive for a variety of applications such as flexible circuit boards, solar cells, paper-like displays, and sensitive skin, due to their stretchable, biocompatible, light-weight, portable, and low cost properties. Due to magnetic devices being important parts of electronic devices, it is essential to study the magnetic properties of magnetic thin films and devices fabricated on flexible substrates. In this review, we mainly introduce the recent progress in flexible magnetic thin films and devices, including the study on the stress-dependent magnetic properties of magnetic thin films and devices, and controlling the properties of flexible magnetic films by stress-related multi-fields, and the design and fabrication of flexible magnetic devices. Project supported by the National Key R&D Program of China (No. 2016YFA0201102), the National Natural Science Foundation of China (Nos. 51571208, 51301191, 51525103, 11274321, 11474295, 51401230), the Youth Innovation Promotion Association of the Chinese Academy of Sciences (No. 2016270), the Key Research Program of the Chinese Academy of Sciences (No. KJZD-EW-M05), the Ningbo Major Project for Science and Technology (No. 2014B11011), the Ningbo Science and Technology Innovation Team (No. 2015B11001), and the Ningbo Natural Science Foundation (No. 2015A610110).

Flexible ferroelectric element based on van der Waals heteroepitaxy.

PubMed

Jiang, Jie; Bitla, Yugandhar; Huang, Chun-Wei; Do, Thi Hien; Liu, Heng-Jui; Hsieh, Ying-Hui; Ma, Chun-Hao; Jang, Chi-Yuan; Lai, Yu-Hong; Chiu, Po-Wen; Wu, Wen-Wei; Chen, Yi-Chun; Zhou, Yi-Chun; Chu, Ying-Hao

2017-06-01

We present a promising technology for nonvolatile flexible electronic devices: A direct fabrication of epitaxial lead zirconium titanate (PZT) on flexible mica substrate via van der Waals epitaxy. These single-crystalline flexible ferroelectric PZT films not only retain their performance, reliability, and thermal stability comparable to those on rigid counterparts in tests of nonvolatile memory elements but also exhibit remarkable mechanical properties with robust operation in bent states (bending radii down to 2.5 mm) and cycling tests (1000 times). This study marks the technological advancement toward realizing much-awaited flexible yet single-crystalline nonvolatile electronic devices for the design and development of flexible, lightweight, and next-generation smart devices with potential applications in electronics, robotics, automotive, health care, industrial, and military systems.

Flexible ferroelectric element based on van der Waals heteroepitaxy

PubMed Central

Jiang, Jie; Bitla, Yugandhar; Huang, Chun-Wei; Do, Thi Hien; Liu, Heng-Jui; Hsieh, Ying-Hui; Ma, Chun-Hao; Jang, Chi-Yuan; Lai, Yu-Hong; Chiu, Po-Wen; Wu, Wen-Wei; Chen, Yi-Chun; Zhou, Yi-Chun; Chu, Ying-Hao

2017-01-01

We present a promising technology for nonvolatile flexible electronic devices: A direct fabrication of epitaxial lead zirconium titanate (PZT) on flexible mica substrate via van der Waals epitaxy. These single-crystalline flexible ferroelectric PZT films not only retain their performance, reliability, and thermal stability comparable to those on rigid counterparts in tests of nonvolatile memory elements but also exhibit remarkable mechanical properties with robust operation in bent states (bending radii down to 2.5 mm) and cycling tests (1000 times). This study marks the technological advancement toward realizing much-awaited flexible yet single-crystalline nonvolatile electronic devices for the design and development of flexible, lightweight, and next-generation smart devices with potential applications in electronics, robotics, automotive, health care, industrial, and military systems. PMID:28630922

Di-Isobutyl Phthalate (DIBP) Hazard Identification [Abstract ...

EPA Pesticide Factsheets

The hazard potential for DIBP is being evaluated as part of EPA’s Integrated Risk Information System (IRIS) Toxicological Review. DIBP is a plasticizer that confers flexibility and durability in industrial and consumer products. A literature search identified a relatively small epidemiology and animal toxicology database for DIBP. The epidemiological database includes studies that assessed the relationship between urinary concentrations of the DIBP metabolite mono-isobutyl phthalate (MIBP)and developmental, neurodevelopmental, immunological or breast cancer outcomes. There is limited support for associations between MIBP and inflammatory biomarker levels and decreased masculine play behavior. The animal toxicological database includes studies that assessed “phthalate syndrome” male reproductive developmental endpoints after in utero DIBP exposure. Data from the largest developmental study, Saillenfait et al. (2008), shows changes in anogenital distance, male reproductive organ weights, and litter incidence of phthalate syndrome endpoints in the lower dose range after early gestational exposure. Other studies observed increased fetal mortality, male postnatal and adult growth decrements, decreased fetal testicular testosterone and changes in expression of genes in androgen production pathways. The developmental reproductive effects observed in animal studies are consistent with the reduced testicular testosterone mode of action that is well-characterize

Self-discrepancies in work-related upper extremity pain: relation to emotions and flexible-goal adjustment.

PubMed

Goossens, Mariëlle E; Kindermans, Hanne P; Morley, Stephen J; Roelofs, Jeffrey; Verbunt, Jeanine; Vlaeyen, Johan W

2010-08-01

Recurrent pain not only has an impact on disability, but on the long term it may become a threat to one's sense of self. This paper presents a cross-sectional study of patients with work-related upper extremity pain and focuses on: (1) the role of self-discrepancies in this group, (2) the associations between self-discrepancies, pain, emotions and (3) the interaction between self-discrepancies and flexible-goal adjustment. Eighty-nine participants completed standardized self-report measures of pain intensity, pain duration, anxiety, depression and flexible-goal adjustment. A Selves Questionnaire was used to generate self-discrepancies. A series of hierarchical regression analyses showed relationships between actual-ought other, actual-ought self, actual-feared self-discrepancies and depression as well as a significant association between actual-ought other self-discrepancy and anxiety. Furthermore, significant interactions were found between actual-ought other self-discrepancies and flexibility, indicating that less flexible participants with large self-discrepancies score higher on depression. This study showed that self-discrepancies are related to negative emotions and that flexible-goal adjustment served as a moderator in this relationship. The view of self in pain and flexible-goal adjustment should be considered as important variables in the process of chronic pain. Copyright (c) 2009 European Federation of International Association for the Study of Pain Chapters. Published by Elsevier Ltd. All rights reserved.

Role of Protein Flexibility in Ion Permeation: A Case Study in Gramicidin A

PubMed Central

Baştuğ, Turgut; Gray-Weale, Angus; Patra, Swarna M.; Kuyucak, Serdar

2006-01-01

Proteins have a flexible structure, and their atoms exhibit considerable fluctuations under normal operating conditions. However, apart from some enzyme reactions involving ligand binding, our understanding of the role of flexibility in protein function remains mostly incomplete. Here we investigate this question in the realm of membrane proteins that form ion channels. Specifically, we consider ion permeation in the gramicidin A channel, and study how the energetics of ion conduction changes as the channel structure is progressively changed from completely flexible to a fixed one. For each channel structure, the potential of mean force for a permeating potassium ion is determined from molecular dynamics (MD) simulations. Using the same molecular dynamics data for completely flexible gramicidin A, we also calculate the average densities and fluctuations of the peptide atoms and investigate the correlations between these fluctuations and the motion of a permeating ion. Our results show conclusively that peptide flexibility plays an important role in ion permeation in the gramicidin A channel, thus providing another reason—besides the well-known problem with the description of single file pore water—why this channel cannot be modeled using continuum electrostatics with a fixed structure. The new method developed here for studying the role of protein flexibility on its function clarifies the contributions of the fluctuations to energy and entropy, and places limits on the level of detail required in a coarse-grained model. PMID:16415054

Zinc phthalocyanine nanowires based flexible sensor for room temperature Cl2 detection

NASA Astrophysics Data System (ADS)

Devi, Pooja; Saini, Rajan; Singh, Rajinder; Mahajan, A.; Bedi, R. K.; Aswal, D. K.; Debnath, A. K.

2018-04-01

We have fabricated highly sensitive and Cl2 selective flexible sensor by depositing solution processed zinc phthalocyanine nanowires onto the flexible PET substrate and studied its Cl2 sensing characteristics in Cl2 concentration range 5-1500 ppb. The flexible sensor has a minimum detection limit as low as 5 ppb of Cl2 and response as high as 550% within 10 seconds. Interestingly, the sensor exhibited enhanced and faster response kinetics under bending conditions. The gas sensing mechanism of sensor has been discussed on the basis of XPS and Raman spectroscopic studies which revealed that zinc ions were the preferred sites for Cl2 interactions.

Optimization of flexible substrate by gradient elastic modulus design for performance improvement of flexible electronic devices

NASA Astrophysics Data System (ADS)

Xia, Minggang; Liang, Chunping; Hu, Ruixue; Cheng, Zhaofang; Liu, Shiru; Zhang, Shengli

2018-05-01

It is imperative and highly desirable to buffer the stress in flexible electronic devices. In this study, we designed and fabricated lamellate poly(dimethylsiloxane) (PDMS) samples with gradient elastic moduli, motivated by the protection of the pomelo pulp by its skin, followed by the measurements of their elastic moduli. We demonstrated that the electrical and fatigue performances of a Ag-nanowire thin film device on the PDMS substrate with a gradient elastic modulus are significantly better than those of a device on a substrate with a monolayer PDMS. This study provides a robust scheme to effectively protect flexible electronic devices.

Expressive flexibility in combat veterans with posttraumatic stress disorder and depression.

PubMed

Rodin, Rebecca; Bonanno, George A; Rahman, Nadia; Kouri, Nicole A; Bryant, Richard A; Marmar, Charles R; Brown, Adam D

2017-01-01

A growing body of evidence suggests that the ability to flexibly express and suppress emotions ("expressive flexibility") supports successful adaptation to trauma and loss. However, studies have yet to examine whether individuals that meet criteria for posttraumatic stress disorder (PTSD) or depression exhibit alterations in expressive flexibility. The present study aims to test whether lower levels of expressive flexibility are associated with PTSD and depression in combat-exposed veterans. Fifty-nine combat veterans with and without PTSD completed self-report measures assessing symptoms of depression, PTSD, and combat exposure. Participants also completed an expressive flexibility task in which they were asked to either enhance or suppress their expressions of emotion while viewing affective images on a computer screen. Expressive flexibility was assessed by both expressive enhancement ability and expressive suppression ability. Repeated measures ANOVA's showed that both PTSD and depression were associated with lower levels of emotional enhancement ability. In addition, a series of linear regressions demonstrated that lower levels of emotional enhancement ability were associated with greater symptom severity of PTSD and depression. The ability to suppress emotional responses did not differ among individuals with and without PTSD or depression. of the study include a cross-sectional design, precluding causality; the lack of a non-trauma exposed group and predominantly male participants limit the generalizability to other populations. Alterations in expressive flexibility is a previously unrecognized affective mechanism associated with PTSD and depression. Clinical strategies aimed at enhancing emotional expression may aid in the treatment of these disorders. Copyright © 2016 Elsevier B.V. All rights reserved.

Variability of the Cyclin-Dependent Kinase 2 Flexibility Without Significant Change in the Initial Conformation of the Protein or Its Environment; a Computational Study.

PubMed

Taghizadeh, Mohammad; Goliaei, Bahram; Madadkar-Sobhani, Armin

2016-06-01

Protein flexibility, which has been referred as a dynamic behavior has various roles in proteins' functions. Furthermore, for some developed tools in bioinformatics, such as protein-protein docking software, considering the protein flexibility, causes a higher degree of accuracy. Through undertaking the present work, we have accomplished the quantification plus analysis of the variations in the human Cyclin Dependent Kinase 2 (hCDK2) protein flexibility without affecting a significant change in its initial environment or the protein per se. The main goal of the present research was to calculate variations in the flexibility for each residue of the hCDK2, analysis of their flexibility variations through clustering, and to investigate the functional aspects of the residues with high flexibility variations. Using Gromacs package (version 4.5.4), three independent molecular dynamics (MD) simulations of the hCDK2 protein (PDB ID: 1HCL) was accomplished with no significant changes in their initial environments, structures, or conformations, followed by Root Mean Square Fluctuations (RMSF) calculation of these MD trajectories. The amount of variations in these three curves of RMSF was calculated using two formulas. More than 50% of the variation in the flexibility (the distance between the maximum and the minimum amount of the RMSF) was found at the region of Val-154. As well, there are other major flexibility fluctuations in other residues. These residues were mostly positioned in the vicinity of the functional residues. The subsequent works were done, as followed by clustering all hCDK2 residues into four groups considering the amount of their variability with respect to flexibility and their position in the RMSF curves. This work has introduced a new class of flexibility aspect of the proteins' residues. It could also help designing and engineering proteins, with introducing a new dynamic aspect of hCDK2, and accordingly, for the other similar globular proteins. In addition, it could provide a better computational calculation of the protein flexibility, which is, especially important in the comparative studies of the proteins' flexibility.

Variability of the Cyclin-Dependent Kinase 2 Flexibility Without Significant Change in the Initial Conformation of the Protein or Its Environment; a Computational Study

PubMed Central

Taghizadeh, Mohammad; Goliaei, Bahram; Madadkar-Sobhani, Armin

2016-01-01

Background Protein flexibility, which has been referred as a dynamic behavior has various roles in proteins’ functions. Furthermore, for some developed tools in bioinformatics, such as protein-protein docking software, considering the protein flexibility, causes a higher degree of accuracy. Through undertaking the present work, we have accomplished the quantification plus analysis of the variations in the human Cyclin Dependent Kinase 2 (hCDK2) protein flexibility without affecting a significant change in its initial environment or the protein per se. Objectives The main goal of the present research was to calculate variations in the flexibility for each residue of the hCDK2, analysis of their flexibility variations through clustering, and to investigate the functional aspects of the residues with high flexibility variations. Materials and Methods Using Gromacs package (version 4.5.4), three independent molecular dynamics (MD) simulations of the hCDK2 protein (PDB ID: 1HCL) was accomplished with no significant changes in their initial environments, structures, or conformations, followed by Root Mean Square Fluctuations (RMSF) calculation of these MD trajectories. The amount of variations in these three curves of RMSF was calculated using two formulas. Results More than 50% of the variation in the flexibility (the distance between the maximum and the minimum amount of the RMSF) was found at the region of Val-154. As well, there are other major flexibility fluctuations in other residues. These residues were mostly positioned in the vicinity of the functional residues. The subsequent works were done, as followed by clustering all hCDK2 residues into four groups considering the amount of their variability with respect to flexibility and their position in the RMSF curves. Conclusions This work has introduced a new class of flexibility aspect of the proteins’ residues. It could also help designing and engineering proteins, with introducing a new dynamic aspect of hCDK2, and accordingly, for the other similar globular proteins. In addition, it could provide a better computational calculation of the protein flexibility, which is, especially important in the comparative studies of the proteins’ flexibility. PMID:28959320

The effects of wing flexibility on the flight performance and stability of flapping wing micro air vehicles

NASA Astrophysics Data System (ADS)

Bluman, James Edward

Insect wings are flexible. However, the influence of wing flexibility on the flight dynamics of insects and flapping wing micro air vehicles is unknown. Most studies in the literature consider rigid wings and conclude that the hover equilibrium is unstable. This dissertation shows that a flapping wing flyer with flexible wings exhibits stable natural modes of the open loop system in hover, never reported before. The free-flight insect flight dynamics is modeled for both flexible and rigid wings. Wing mass and inertia are included in the nonlinear equations of motion. The flapping wing aerodynamics are modeled using a quasi-steady model, a well-validated two dimensional Navier Stokes model, and a coupled, two dimensional Navier Stokes - Euler Bernoulli beam model that accurately models the fluid-structure interaction of flexible wings. Hover equilibrium is systematically and efficiently determined with a coupled quasi-steady and Navier-Stokes equation trimmer. The power and stability are reported at hover while parametrically varying the pitch axis location for rigid wings and the structural stiffness for flexible wings. The results indicate that the rigid wings possess an unstable oscillatory mode mainly due to their pitch sensitivity to horizontal velocity perturbations. The flexible wings stabilize this mode primarily by adjusting their wing shape in the presence of perturbations. The wing's response to perturbations generates significantly more horizontal velocity damping and pitch rate damping than in rigid wings. Furthermore, the flexible wings experience substantially less wing wake interaction, which, for rigid wings, is destabilizing. The power required to hover a fruit fly with actively rotating rigid wings varies between 16.9 and 34.2 W/kg. The optimal power occurs when the pitch axis is located at 30% chord, similar to some biological observations. Flexible wings require 23.1 to 38.5 W/kg. However, flexible wings exhibit more stable system dynamics and allow for simpler and lighter designs since they do not require pitch actuation mechanisms. This study is the first to evaluate the impact of wing flexibility on the hovering stability of flapping flyers, which can explain the ranges of flexibility seen in insects and can inform designs of synthetic flapping wing robots.

Coupled nonlinear aeroelasticity and flight dynamics of fully flexible aircraft

NASA Astrophysics Data System (ADS)

Su, Weihua

This dissertation introduces an approach to effectively model and analyze the coupled nonlinear aeroelasticity and flight dynamics of highly flexible aircraft. A reduced-order, nonlinear, strain-based finite element framework is used, which is capable of assessing the fundamental impact of structural nonlinear effects in preliminary vehicle design and control synthesis. The cross-sectional stiffness and inertia properties of the wings are calculated along the wing span, and then incorporated into the one-dimensional nonlinear beam formulation. Finite-state unsteady subsonic aerodynamics is used to compute airloads along lifting surfaces. Flight dynamic equations are then introduced to complete the aeroelastic/flight dynamic system equations of motion. Instead of merely considering the flexibility of the wings, the current work allows all members of the vehicle to be flexible. Due to their characteristics of being slender structures, the wings, tail, and fuselage of highly flexible aircraft can be modeled as beams undergoing three dimensional displacements and rotations. New kinematic relationships are developed to handle the split beam systems, such that fully flexible vehicles can be effectively modeled within the existing framework. Different aircraft configurations are modeled and studied, including Single-Wing, Joined-Wing, Blended-Wing-Body, and Flying-Wing configurations. The Lagrange Multiplier Method is applied to model the nodal displacement constraints at the joint locations. Based on the proposed models, roll response and stability studies are conducted on fully flexible and rigidized models. The impacts of the flexibility of different vehicle members on flutter with rigid body motion constraints, flutter in free flight condition, and roll maneuver performance are presented. Also, the static stability of the compressive member of the Joined-Wing configuration is studied. A spatially-distributed discrete gust model is incorporated into the time simulation of the framework. Gust responses of the Flying-Wing configuration subject to stall effects are investigated. A bilinear torsional stiffness model is introduced to study the skin wrinkling due to large bending curvature of the Flying-Wing. The numerical studies illustrate the improvements of the existing reduced-order formulation with new capabilities of both structural modeling and coupled aeroelastic and flight dynamic analysis of fully flexible aircraft.

A Cross-Cultural Comparison of Children's Imitative Flexibility

ERIC Educational Resources Information Center

Clegg, Jennifer M.; Legare, Cristine H.

2016-01-01

Recent research with Western populations has demonstrated that children use imitation flexibly to engage in both instrumental and conventional learning. Evidence for children's imitative flexibility in non-Western populations is limited, however, and has only assessed imitation of instrumental tasks. This study (N = 142, 6- to 8-year-olds)…

Students Flourish and Tutors Wither: A Study of Participant Experiences in a First-Year Online Unit

ERIC Educational Resources Information Center

Dodo-Balu, Andrea

2017-01-01

Contemporary higher education has been affected by policy pressures built around "flexibility". The policies of widening student participation and expanding flexible online delivery combine to provide the opportunity for a university education to students hitherto largely excluded. Flexible employment policies have increasingly placed…

The Moderating Effects of IT Training Programs: A Study of IT Flexibility Investments

ERIC Educational Resources Information Center

Plickebaum, Terry L.

2012-01-01

Information technology (IT) flexibility continues to grow in importance as organizations become increasingly dependent on IT in increasingly dynamic business environments. The contribution of IT infrastructure towards IT flexibility is fairly well understood and managed within organizations today. The contribution of IT personnel capabilities…

Performance Evaluation of the Gravity Probe B Design

NASA Technical Reports Server (NTRS)

Francis, Ronnie; Wells, Eugene M.

1996-01-01

This report documents the simulation of the Lockheed Martin designed Gravity Probe B (GPB) spacecraft developed tool by bd Systems Inc using the TREETOPS simulation. This study quantifies the effects of flexibility and liquid helium slosh on GPB spacecraft control performance. The TREETOPS simulation tool permits the simulation of flexible structures given that a flexible body model of the structure is available. For purposes of this study, a flexible model of the GPB spacecraft was obtained from Lockheed Martin. To model the liquid helium slosh effects, computational fluid dynamics (CFD) results' were obtained, and used to develop a dynamic model of the slosh effects. The flexible body and slosh effects were incorporated separately into the TREETOPS simulation, which places the vehicle in a 650 km circular polar orbit and subjects the spacecraft to realistic environmental disturbances and sensor error quantities. In all of the analysis conducted in this study the spacecraft is pointed at an inertially fixed guide star (GS) and is rotating at a constant rate about this line of sight.

Martial arts training attenuates arterial stiffness in middle aged adults.

PubMed

Douris, Peter C; Ingenito, Teresa; Piccirillo, Barbara; Herbst, Meredith; Petrizzo, John; Cherian, Vincen; McCutchan, Christopher; Burke, Caitlin; Stamatinos, George; Jung, Min-Kyung

2013-09-01

Arterial stiffness increases with age and is related to an increased risk of coronary artery disease. Poor trunk flexibility has been shown to be associated with arterial stiffness in middle-aged subjects. The purpose of our research study was to measure arterial stiffness and flexibility in healthy middle-aged martial artists compared to age and gender matched healthy sedentary controls. Ten martial artists (54.0 ± 2.0 years), who practice Soo Bahk Do (SBD), a Korean martial art, and ten sedentary subjects (54.7 ± 1.8 years) for a total of twenty subjects took part in this cross-sectional study. Arterial stiffness was assessed in all subjects using pulse wave velocity (PWV), a recognized index of arterial stiffness. Flexibility of the trunk and hamstring were also measured. The independent variables were the martial artists and matched sedentary controls. The dependent variables were PWV and flexibility. There were significant differences, between the SBD practitioners and sedentary controls, in PWV (P = 0.004), in trunk flexibility (P= 0.002), and in hamstring length (P= 0.003). The middle-aged martial artists were more flexible in their trunk and hamstrings and had less arterial stiffness compared to the healthy sedentary controls. The flexibility component of martial art training or flexibility exercises in general may be considered as a possible intervention to reduce the effects of aging on arterial stiffness.

Martial Arts Training Attenuates Arterial Stiffness in Middle Aged Adults

PubMed Central

Douris, Peter C.; Ingenito, Teresa; Piccirillo, Barbara; Herbst, Meredith; Petrizzo, John; Cherian, Vincen; McCutchan, Christopher; Burke, Caitlin; Stamatinos, George; Jung, Min-Kyung

2013-01-01

Purpose Arterial stiffness increases with age and is related to an increased risk of coronary artery disease. Poor trunk flexibility has been shown to be associated with arterial stiffness in middle-aged subjects. The purpose of our research study was to measure arterial stiffness and flexibility in healthy middle-aged martial artists compared to age and gender matched healthy sedentary controls. Methods Ten martial artists (54.0 ± 2.0 years), who practice Soo Bahk Do (SBD), a Korean martial art, and ten sedentary subjects (54.7 ± 1.8 years) for a total of twenty subjects took part in this cross-sectional study. Arterial stiffness was assessed in all subjects using pulse wave velocity (PWV), a recognized index of arterial stiffness. Flexibility of the trunk and hamstring were also measured. The independent variables were the martial artists and matched sedentary controls. The dependent variables were PWV and flexibility. Results There were significant differences, between the SBD practitioners and sedentary controls, in PWV (P = 0.004), in trunk flexibility (P= 0.002), and in hamstring length (P= 0.003). Conclusion The middle-aged martial artists were more flexible in their trunk and hamstrings and had less arterial stiffness compared to the healthy sedentary controls. The flexibility component of martial art training or flexibility exercises in general may be considered as a possible intervention to reduce the effects of aging on arterial stiffness. PMID:24427479

The Influence of Intrinsic Framework Flexibility on Adsorption in Nanoporous Materials

DOE PAGES

Witman, Matthew; Ling, Sanliang; Jawahery, Sudi; ...

2017-03-30

For applications of metal–organic frameworks (MOFs) such as gas storage and separation, flexibility is often seen as a parameter that can tune material performance. In this work we aim to determine the optimal flexibility for the shape selective separation of similarly sized molecules (e.g., Xe/Kr mixtures). To obtain systematic insight into how the flexibility impacts this type of separation, we develop a simple analytical model that predicts a material’s Henry regime adsorption and selectivity as a function of flexibility. We elucidate the complex dependence of selectivity on a framework’s intrinsic flexibility whereby performance is either improved or reduced with increasingmore » flexibility, depending on the material’s pore size characteristics. However, the selectivity of a material with the pore size and chemistry that already maximizes selectivity in the rigid approximation is continuously diminished with increasing flexibility, demonstrating that the globally optimal separation exists within an entirely rigid pore. Molecular simulations show that our simple model predicts performance trends that are observed when screening the adsorption behavior of flexible MOFs. These flexible simulations provide better agreement with experimental adsorption data in a high-performance material that is not captured when modeling this framework as rigid, an approximation typically made in high-throughput screening studies. We conclude that, for shape selective adsorption applications, the globally optimal material will have the optimal pore size/chemistry and minimal intrinsic flexibility even though other nonoptimal materials’ selectivity can actually be improved by flexibility. In conclusion, equally important, we find that flexible simulations can be critical for correctly modeling adsorption in these types of systems.« less

Inter-Vertebral Flexibility of the Ostrich Neck: Implications for Estimating Sauropod Neck Flexibility

PubMed Central

Cobley, Matthew J.; Rayfield, Emily J.; Barrett, Paul M.

2013-01-01

The flexibility and posture of the neck in sauropod dinosaurs has long been contentious. Improved constraints on sauropod neck function will have major implications for what we know of their foraging strategies, ecology and overall biology. Several hypotheses have been proposed, based primarily on osteological data, suggesting different degrees of neck flexibility. This study attempts to assess the effects of reconstructed soft tissues on sauropod neck flexibility through systematic removal of muscle groups and measures of flexibility of the neck in a living analogue, the ostrich (Struthio camelus). The possible effect of cartilage on flexibility is also examined, as this was previously overlooked in osteological estimates of sauropod neck function. These comparisons show that soft tissues are likely to have limited the flexibility of the neck beyond the limits suggested by osteology alone. In addition, the inferred presence of cartilage, and varying the inter-vertebral spacing within the synovial capsule, also affect neck flexibility. One hypothesis proposed that flexibility is constrained by requiring a minimum overlap between successive zygapophyses equivalent to 50% of zygapophyseal articular surface length (ONP50). This assumption is tested by comparing the maximum flexibility of the articulated cervical column in ONP50 and the flexibility of the complete neck with all tissues intact. It is found that this model does not adequately convey the pattern of flexibility in the ostrich neck, suggesting that the ONP50 model may not be useful in determining neck function if considered in isolation from myological and other soft tissue data. PMID:23967284

Identification of critical factors affecting flexibility in hospital construction projects.

PubMed

Olsson, Nils E O; Hansen, Geir K

2010-01-01

This paper analyzes the dynamics relating to flexibility in a hospital project context. Three research questions are addressed: (1) When is flexibility used in the life cycle of a project? (2) What are the stakeholders' perspectives on project flexibility? And (3) What is the nature of the interaction between flexibility in the process of a project and flexibility in terms of the characteristics of a building? Flexibility is discussed from both a project management point of view and from a hospital architecture perspective. Flexibility in project life cycle and from a stakeholder perspective is examined, and the interaction between flexibility in scope lock-in and building flexibility is investigated. The results are based on case studies of four Norwegian hospital projects. Information relating to the projects has been obtained from evaluation reports, other relevant documents, and interviews. Observations were codified and analyzed based on selected parameters that represent different aspects of flexibility. One of the cases illustrates how late changes can have a significant negative impact on the project itself, contributing to delays and cost overruns. Another case illustrates that late scope lock-in on a limited part of the project, in this case related to medical equipment, can be done in a controlled manner. Project owners and users appear to have given flexibility high priority. Project management teams are less likely to embrace changes and late scope lock-in. Architects and consultants are important for translating program requirements into physical design. A highly flexible building did not stop some stakeholders from pushing for significant changes and extensions during construction.

The Influence of Intrinsic Framework Flexibility on Adsorption in Nanoporous Materials

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

Witman, Matthew; Ling, Sanliang; Jawahery, Sudi

For applications of metal–organic frameworks (MOFs) such as gas storage and separation, flexibility is often seen as a parameter that can tune material performance. In this work we aim to determine the optimal flexibility for the shape selective separation of similarly sized molecules (e.g., Xe/Kr mixtures). To obtain systematic insight into how the flexibility impacts this type of separation, we develop a simple analytical model that predicts a material’s Henry regime adsorption and selectivity as a function of flexibility. We elucidate the complex dependence of selectivity on a framework’s intrinsic flexibility whereby performance is either improved or reduced with increasingmore » flexibility, depending on the material’s pore size characteristics. However, the selectivity of a material with the pore size and chemistry that already maximizes selectivity in the rigid approximation is continuously diminished with increasing flexibility, demonstrating that the globally optimal separation exists within an entirely rigid pore. Molecular simulations show that our simple model predicts performance trends that are observed when screening the adsorption behavior of flexible MOFs. These flexible simulations provide better agreement with experimental adsorption data in a high-performance material that is not captured when modeling this framework as rigid, an approximation typically made in high-throughput screening studies. We conclude that, for shape selective adsorption applications, the globally optimal material will have the optimal pore size/chemistry and minimal intrinsic flexibility even though other nonoptimal materials’ selectivity can actually be improved by flexibility. In conclusion, equally important, we find that flexible simulations can be critical for correctly modeling adsorption in these types of systems.« less

Functional Data Analysis in NTCP Modeling: A New Method to Explore the Radiation Dose-Volume Effects

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

Benadjaoud, Mohamed Amine, E-mail: mohamedamine.benadjaoud@gustaveroussy.fr; Université Paris sud, Le Kremlin-Bicêtre; Institut Gustave Roussy, Villejuif

2014-11-01

Purpose/Objective(s): To describe a novel method to explore radiation dose-volume effects. Functional data analysis is used to investigate the information contained in differential dose-volume histograms. The method is applied to the normal tissue complication probability modeling of rectal bleeding (RB) for patients irradiated in the prostatic bed by 3-dimensional conformal radiation therapy. Methods and Materials: Kernel density estimation was used to estimate the individual probability density functions from each of the 141 rectum differential dose-volume histograms. Functional principal component analysis was performed on the estimated probability density functions to explore the variation modes in the dose distribution. The functional principalmore » components were then tested for association with RB using logistic regression adapted to functional covariates (FLR). For comparison, 3 other normal tissue complication probability models were considered: the Lyman-Kutcher-Burman model, logistic model based on standard dosimetric parameters (LM), and logistic model based on multivariate principal component analysis (PCA). Results: The incidence rate of grade ≥2 RB was 14%. V{sub 65Gy} was the most predictive factor for the LM (P=.058). The best fit for the Lyman-Kutcher-Burman model was obtained with n=0.12, m = 0.17, and TD50 = 72.6 Gy. In PCA and FLR, the components that describe the interdependence between the relative volumes exposed at intermediate and high doses were the most correlated to the complication. The FLR parameter function leads to a better understanding of the volume effect by including the treatment specificity in the delivered mechanistic information. For RB grade ≥2, patients with advanced age are significantly at risk (odds ratio, 1.123; 95% confidence interval, 1.03-1.22), and the fits of the LM, PCA, and functional principal component analysis models are significantly improved by including this clinical factor. Conclusion: Functional data analysis provides an attractive method for flexibly estimating the dose-volume effect for normal tissues in external radiation therapy.« less

Dissociable Changes of Frontal and Parietal Cortices in Inherent Functional Flexibility across the Human Life Span.

PubMed

Yin, Dazhi; Liu, Wenjing; Zeljic, Kristina; Wang, Zhiwei; Lv, Qian; Fan, Mingxia; Cheng, Wenhong; Wang, Zheng

2016-09-28

Extensive evidence suggests that frontoparietal regions can dynamically update their pattern of functional connectivity, supporting cognitive control and adaptive implementation of task demands. However, it is largely unknown whether this flexibly functional reconfiguration is intrinsic and occurs even in the absence of overt tasks. Based on recent advances in dynamics of resting-state functional resonance imaging (fMRI), we propose a probabilistic framework in which dynamic reconfiguration of intrinsic functional connectivity between each brain region and others can be represented as a probability distribution. A complexity measurement (i.e., entropy) was used to quantify functional flexibility, which characterizes heterogeneous connectivity between a particular region and others over time. Following this framework, we identified both functionally flexible and specialized regions over the human life span (112 healthy subjects from 13 to 76 years old). Across brainwide regions, we found regions showing high flexibility mainly in the higher-order association cortex, such as the lateral prefrontal cortex (LPFC), lateral parietal cortex, and lateral temporal lobules. In contrast, visual, auditory, and sensory areas exhibited low flexibility. Furthermore, we observed that flexibility of the right LPFC improved during maturation and reduced due to normal aging, with the opposite occurring for the left lateral parietal cortex. Our findings reveal dissociable changes of frontal and parietal cortices over the life span in terms of inherent functional flexibility. This study not only provides a new framework to quantify the spatiotemporal behavior of spontaneous brain activity, but also sheds light on the organizational principle behind changes in brain function across the human life span. Recent neuroscientific research has demonstrated that the human capability of adaptive task control is primarily the result of the flexible operation of frontal brain networks. However, it remains unclear whether this flexibly functional reconfiguration is intrinsic and occurs in the absence of an overt task. In this study, we propose a probabilistic framework to quantify the functional flexibility of each brain region using resting-state fMRI. We identify regions showing high flexibility mainly in the higher-order association cortex. In contrast, primary and unimodal visual and sensory areas show low flexibility. On the other hand, our findings reveal dissociable changes of frontal and parietal cortices in terms of inherent functional flexibility over the life span. Copyright © 2016 the authors 0270-6474/16/3610060-15$15.00/0.

Gantries and dose delivery systems

NASA Astrophysics Data System (ADS)

Meer, David; Psoroulas, Serena

2015-06-01

Particle therapy is a field in remarkable development, with the goal of increasing the number of indications which could benefit from such treatments and the access to the therapy. The therapeutic usage of a particle beam defines the technical requirements of all the elements of the therapy chain: we summarize the main characteristics of accelerators, the beam line, the treatment room, the integrated therapy and imaging systems used in particle therapy. Aiming at a higher flexibility in the choice of treatments, an increasing number of centers around the world have chosen to equip their treatment rooms with gantries, rotating beam line structures that allow a complete flexibility in the choice of the treatment angle. We review the current designs. A particle therapy gantry though is a quite expensive structure, and future development will increasingly consider reducing the cost and the footprint. Increasing the number of indications also means development in the delivery techniques and solving some of the issues which traditionally affected particle therapy, for example the precision of the delivery in presence of motion and the large penumbras for low depths. We show the current strategies in these fields, focusing on pencil beam scanning (PBS), and give some hints about future developments.

What Is the Optimal Target Convective Volume in On-Line Hemodiafiltration Therapy?

PubMed

Canaud, Bernard; Koehler, Katrin; Bowry, Sudhir; Stuard, Stefano

2017-01-01

Conventional diffusion-based dialysis modalities including high-flux hemodialysis are limited in their capacity to effectively remove large uremic toxins and to improve outcomes for end-stage chronic kidney disease (ESKD) patients. By increasing convective solute transport, hemodiafiltration (HDF) enhances solute removal capacity over a broad range of middle- and large-size uremic toxins implicated in the pathophysiology of chronic kidney disease. Furthermore, by offering flexible convection volume, on-line HDF permits customizing the treatment dose to the patient's needs. In addition, convective-based modalities have been shown to improve hemodynamic stability and to reduce patients' inflammation profile - both of which are implicated in CKD morbidity and mortality. Growing clinical evidence indicates that HDF-based modalities provide ESKD patients with a number of clinical and biological benefits, including improved outcomes. Interestingly, it has recently emerged that the clinical benefits associated with HDF are positively associated with the total ultrafiltered volume per session (and per week), namely convective dose. In this chapter, we revisit the concept of convective dose and discuss the threshold value above which an improvement in ESKD patient outcome can be expected. This particular point will be addressed by stratifying the level of efficacy of convective volumes, schematically defined as minimal, optimal, personalized, and maximal. In addition, factors and best clinical practices implicated in the achievement of an optimal convective dose are reviewed. To conclude, we show how HDF differs from standard hemodialysis and why HDF offers a paradigm shift in renal replacement therapy. © 2017 S. Karger AG, Basel.