High School-Based Treatment for Adolescents with Attention-Deficit/Hyperactivity Disorder: Results from a Pilot Study Examining Outcomes and Dosage

ERIC Educational Resources Information Center

Evans, Steven W.; Schultz, Brandon K.; DeMars, Christine E.

2014-01-01

The purpose of this study was to examine the efficacy and dose-response relationship of a school-based treatment program for high school students with attention-deficit/hyperactivity disorder (ADHD). Two paraprofessionals provided interventions to 24 students with ADHD randomly assigned to the treatment condition at two public high schools. They…

Approaches for grouping of pesticides into cumulative assessment groups for risk assessment of pesticide residues in food.

PubMed

Colnot, Thomas; Dekant, Wolfgang

2017-02-01

The European Food Safety Authority (EFSA) is developing approaches to cumulative risk assessment of pesticides by assigning individual pesticides to cumulative assessment groups (CAGs). For assignment to CAGs, EFSA recommended to rely on adverse effects on the specific target system. Contractors to EFSA have proposed to allocate individual pesticides into CAGs relying on NOAELs for effects on target organs. This manuscript evaluates the assignments by applying EFSAs criteria to the CAGs "Toxicity to the nervous system" and "Toxicity to the thyroid hormone system (gland or hormones)". Assignment to the CAG "Toxicity to the nervous system" based, for example, on neurochemical effects like choline esterase inhibition is well supported, whereas assignment to the CAG "Toxicity to the thyroid hormone system (gland or hormones)" has been based in the examined case studies on non-reproducible effects seen in single studies or on observations that are not adverse. Therefore, a more detailed effects evaluation is required to assign a pesticide to a CAG for a target organ where many confounders regarding effects are present. Relative potency factors in cumulative risk assessment should be based on benchmark doses from studies in one species with identical study design and human relevance of effects on specific target organs should be analyzed to define minimal margins of exposure. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

Effect of early low-dose hydrocortisone on survival without bronchopulmonary dysplasia in extremely preterm infants (PREMILOC): a double-blind, placebo-controlled, multicentre, randomised trial.

PubMed

Baud, Olivier; Maury, Laure; Lebail, Florence; Ramful, Duksha; El Moussawi, Fatima; Nicaise, Claire; Zupan-Simunek, Véronique; Coursol, Anne; Beuchée, Alain; Bolot, Pascal; Andrini, Pierre; Mohamed, Damir; Alberti, Corinne

2016-04-30

Bronchopulmonary dysplasia, a major complication of extreme prematurity, has few treatment options. Postnatal steroid use is controversial, but low-dose hydrocortisone might prevent the harmful effects of inflammation on the developing lung. In this study, we aimed to assess whether low-dose hydrocortisone improved survival without bronchopulmonary dysplasia in extremely preterm infants. In this double-blind, placebo-controlled, randomised trial done at 21 French tertiary-care neonatal intensive care units (NICUs), we randomly assigned (1:1), via a secure study website, extremely preterm infants inborn (born in a maternity ward at the same site as the NICU) at less than 28 weeks of gestation to receive either intravenous low-dose hydrocortisone or placebo during the first 10 postnatal days. Infants randomly assigned to the hydrocortisone group received 1 mg/kg of hydrocortisone hemisuccinate per day divided into two doses per day for 7 days, followed by one dose of 0·5 mg/kg per day for 3 days. Randomisation was stratified by gestational age and all infants were enrolled by 24 h after birth. Study investigators, parents, and patients were masked to treatment allocation. The primary outcome was survival without bronchopulmonary dysplasia at 36 weeks of postmenstrual age. We used a sequential analytical design, based on intention to treat, to avoid prolonging the trial after either efficacy or futility had been established. This trial is registered with ClinicalTrial.gov, number NCT00623740. 1072 neonates were screened between May 25, 2008, and Jan 31, 2014, of which 523 were randomly assigned (256 hydrocortisone, 267 placebo). 255 infants on hydrocortisone and 266 on placebo were included in analyses after parents withdrew consent for one child in each group. Of the 255 infants assigned to hydrocortisone, 153 (60%) survived without bronchopulmonary dysplasia, compared with 136 (51%) of 266 infants assigned to placebo (odds ratio [OR] adjusted for gestational age group and interim analyses 1·48, 95% CI 1·02-2·16, p=0·04). The number of patients needed to treat to gain one bronchopulmonary dysplasia-free survival was 12 (95% CI 6-200). Sepsis rate was not significantly different in the study population as a whole, but subgroup analyses showed a higher rate only in infants born at 24-25 weeks gestational age who were treated with hydrocortisone (30 [40%] of 83 vs 21 [23%] of 90 infants; sub-hazard ratio 1·87, 95% CI 1·09-3·21, p=0·02). Other potential adverse events, including notably gastrointestinal perforation, did not differ significantly between groups. In extremely preterm infants, the rate of survival without bronchopulmonary dysplasia at 36 weeks of postmenstrual age was significantly increased by prophylactic low-dose hydrocortisone. This strategy, based on a physiological rationale, could lead to substantial improvements in the management of the most premature neonates. Assistance Publique-Hôpitaux de Paris. Copyright © 2016 Elsevier Ltd. All rights reserved.

Randomized study of intensified anthracycline doses for induction and recombinant interleukin-2 for maintenance in patients with acute myeloid leukemia age 50 to 70 years: results of the ALFA-9801 study.

PubMed

Pautas, Cecile; Merabet, Fatiha; Thomas, Xavier; Raffoux, Emmanuel; Gardin, Claude; Corm, Selim; Bourhis, Jean-Henri; Reman, Oumedaly; Turlure, Pascal; Contentin, Nathalie; de Revel, Thierry; Rousselot, Philippe; Preudhomme, Claude; Bordessoule, Dominique; Fenaux, Pierre; Terré, Christine; Michallet, Mauricette; Dombret, Hervé; Chevret, Sylvie; Castaigne, Sylvie

2010-02-10

PURPOSE In patients with acute myeloid leukemia (AML), induction chemotherapy is based on standard doses of anthracyclines and cytarabine. High doses of cytarabine have been reported as being too toxic for patients older than age 50 years, but few studies have evaluated intensified doses of anthracyclines. PATIENTS AND METHODS In this randomized Acute Leukemia French Association 9801 (ALFA-9801) study, high doses of daunorubicin (DNR; 80 mg/m(2)/d x 3 days) or idarubicin (IDA4; 12 mg/m(2)/d x 4 days) were compared with standard doses of idarubicin (IDA3; 12 mg/m(2)/d x 3 days) for remission induction in patients age 50 to 70 years, with an event-free survival (EFS) end point. After two consolidation courses based on intermediate doses of cytarabine, patients in continuous remission were randomly assigned to receive or not receive maintenance therapy with recombinant interleukin-2 (rIL-2; 5 x 10(6) U/m(2) x 5 days each month) for a total duration of 12 months. A total of 468 patients entered the study (median age, 60 years). Results Overall complete remission rate was 77% with significant differences among the three randomization arms (83%, 78%, and 70% in the IDA3, IDA4, and DNR arms, respectively; P = .04). However, no significant differences were observed in relapse incidence, EFS, or overall survival among the three arms. In the 161 patients randomly assigned for maintenance therapy, no difference in outcome was observed between the rIL-2 and the no further treatment arms. CONCLUSION Neither intensification of anthracycline doses nor maintenance with rIL-2 showed a significant impact on AML course, at least as scheduled in this trial.

Improving target coverage and organ-at-risk sparing in intensity-modulated radiotherapy for cervical oesophageal cancer using a simple optimisation method.

PubMed

Lu, Jia-Yang; Cheung, Michael Lok-Man; Huang, Bao-Tian; Wu, Li-Li; Xie, Wen-Jia; Chen, Zhi-Jian; Li, De-Rui; Xie, Liang-Xi

2015-01-01

To assess the performance of a simple optimisation method for improving target coverage and organ-at-risk (OAR) sparing in intensity-modulated radiotherapy (IMRT) for cervical oesophageal cancer. For 20 selected patients, clinically acceptable original IMRT plans (Original plans) were created, and two optimisation methods were adopted to improve the plans: 1) a base dose function (BDF)-based method, in which the treatment plans were re-optimised based on the original plans, and 2) a dose-controlling structure (DCS)-based method, in which the original plans were re-optimised by assigning additional constraints for hot and cold spots. The Original, BDF-based and DCS-based plans were compared with regard to target dose homogeneity, conformity, OAR sparing, planning time and monitor units (MUs). Dosimetric verifications were performed and delivery times were recorded for the BDF-based and DCS-based plans. The BDF-based plans provided significantly superior dose homogeneity and conformity compared with both the DCS-based and Original plans. The BDF-based method further reduced the doses delivered to the OARs by approximately 1-3%. The re-optimisation time was reduced by approximately 28%, but the MUs and delivery time were slightly increased. All verification tests were passed and no significant differences were found. The BDF-based method for the optimisation of IMRT for cervical oesophageal cancer can achieve significantly better dose distributions with better planning efficiency at the expense of slightly more MUs.

Outcome after reduced chemotherapy for intermediate-risk neuroblastoma.

PubMed

Baker, David L; Schmidt, Mary L; Cohn, Susan L; Maris, John M; London, Wendy B; Buxton, Allen; Stram, Daniel; Castleberry, Robert P; Shimada, Hiroyuki; Sandler, Anthony; Shamberger, Robert C; Look, A Thomas; Reynolds, C Patrick; Seeger, Robert C; Matthay, Katherine K

2010-09-30

The survival rate among patients with intermediate-risk neuroblastoma who receive dose-intensive chemotherapy is excellent, but the survival rate among patients who receive reduced doses of chemotherapy for shorter periods of time is not known. We conducted a prospective, phase 3, nonrandomized trial to determine whether a 3-year estimated overall survival of more than 90% could be maintained with reductions in the duration of therapy and drug doses, using a tumor biology-based therapy assignment. Eligible patients had newly diagnosed, intermediate-risk neuroblastoma without MYCN amplification; these patients included infants (<365 days of age) who had stage 3 or 4 disease, children (≥365 days of age) who had stage 3 tumors with favorable histopathological features, and infants who had stage 4S disease with a diploid DNA index or unfavorable histopathological features. Patients who had disease with favorable histopathological features and hyperdiploidy were assigned to four cycles of chemotherapy, and those with an incomplete response or either unfavorable feature were assigned to eight cycles. Between 1997 and 2005, a total of 479 eligible patients were enrolled in this trial (270 patients with stage 3 disease, 178 with stage 4 disease, and 31 with stage 4S disease). A total of 323 patients had tumors with favorable biologic features, and 141 had tumors with unfavorable biologic features. Ploidy, but not histopathological features, was significantly predictive of the outcome. Severe adverse events without disease progression occurred in 10 patients (2.1%), including secondary leukemia (in 3 patients), death from infection (in 3 patients), and death at surgery (in 4 patients). The 3-year estimate (±SE) of overall survival for the entire group was 96±1%, with an overall survival rate of 98±1% among patients who had tumors with favorable biologic features and 93±2% among patients who had tumors with unfavorable biologic features. A very high rate of survival among patients with intermediate-risk neuroblastoma was achieved with a biologically based treatment assignment involving a substantially reduced duration of chemotherapy and reduced doses of chemotherapeutic agents as compared with the regimens used in earlier trials. These data provide support for further reduction in chemotherapy with more refined risk stratification. (Funded by the National Cancer Institute; ClinicalTrials.gov number, NCT00003093.)

SU-C-BRB-06: Utilizing 3D Scanner and Printer for Dummy Eye-Shield: Artifact-Free CT Images of Tungsten Eye-Shield for Accurate Dose Calculation

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

Park, J; Lee, J; Institute of Radiation Medicine, Seoul National University Medical Research Center, Seoul

Purpose: To evaluate the effect of a tungsten eye-shield on the dose distribution of a patient. Methods: A 3D scanner was used to extract the dimension and shape of a tungsten eye-shield in the STL format. Scanned data was transferred into a 3D printer. A dummy eye shield was then produced using bio-resin (3D systems, VisiJet M3 Proplast). For a patient with mucinous carcinoma, the planning CT was obtained with the dummy eye-shield placed on the patient’s right eye. Field shaping of 6 MeV was performed using a patient-specific cerrobend block on the 15 x 15 cm{sup 2} applicator. Themore » gantry angle was 330° to cover the planning target volume near by the lens. EGS4/BEAMnrc was commissioned from our measurement data from a Varian 21EX. For the CT-based dose calculation using EGS4/DOSXYZnrc, the CT images were converted to a phantom file through the ctcreate program. The phantom file had the same resolution as the planning CT images. By assigning the CT numbers of the dummy eye-shield region to 17000, the real dose distributions below the tungsten eye-shield were calculated in EGS4/DOSXYZnrc. In the TPS, the CT number of the dummy eye-shield region was assigned to the maximum allowable CT number (3000). Results: As compared to the maximum dose, the MC dose on the right lens or below the eye shield area was less than 2%, while the corresponding RTP calculated dose was an unrealistic value of approximately 50%. Conclusion: Utilizing a 3D scanner and a 3D printer, a dummy eye-shield for electron treatment can be easily produced. The artifact-free CT images were successfully incorporated into the CT-based Monte Carlo simulations. The developed method was useful in predicting the realistic dose distributions around the lens blocked with the tungsten shield.« less

Safety of veralipride for the treatment of vasomotor symptoms of menopause.

PubMed

Valencia, Marcelino Hernández; Arias, María de Jesús Vega; González, Cuauhtémoc Celis; Marín, Imelda Hernández; González, Juan Humberto Martín; Campos, Enrique Rafael Morcate; Rodríguez, María Antonia Basavilvazo; Álvarez, Ignacio Morales; Vargas, María Antonia Valdés; Flores, José Braulio Everardo Otero; Haro, Samuel Santoyo; Bonilla, Manuel Cortes; Escudero, Roberto Bernardo; Campero, Rosalba Alonso

2014-05-01

Veralipride is a nonhormonal option for the treatment of vasomotor symptoms of menopause. Incidence of adverse events in a Mexican population and drug compliance according to correct use were evaluated. We carried out a longitudinal, prospective, and analytical study in Mexican women who received veralipride to treat symptoms of menopause from 2011 to 2012. There were 386 treatment cycles; 272 were assigned to dosing schedule 1, which included 20 days of treatment with 10 days of suspension, and 114 were assigned to dosing schedule 2, which included 5 days of treatment and 2 days of suspension. A total of 57 adverse events were registered during the 386-month treatment. For the 20 × 10 dosing schedule, the highest incidence was observed for anxiety (2.2%), drowsiness, and weakness (1.5%); for the 5 × 2 dosing schedule, the highest incidence was observed for drowsiness (5.3%) and headache (2.6%). The Hamilton Depression Rating Scale was used to assess the presence and severity of depression; improvement was noted. The Unified Parkinson's Disease Rating Scale was used to assess neurological movement disorders; no adverse neurological events were detected. Based on the assessments of both women and physicians, the highest frequency was observed for "very satisfied" (45.5% and 52.3%, respectively), followed by "satisfied" (23.9% and 27.3%, respectively). Both dosing schedules show acceptable safety profiles for up to 6 months of use when used according to the contraindications in the current prescribing information for standard use (2012) and recent medical literature.

Shading correction for cone-beam CT in radiotherapy: validation of dose calculation accuracy using clinical images

NASA Astrophysics Data System (ADS)

Marchant, T. E.; Joshi, K. D.; Moore, C. J.

2017-03-01

Cone-beam CT (CBCT) images are routinely acquired to verify patient position in radiotherapy (RT), but are typically not calibrated in Hounsfield Units (HU) and feature non-uniformity due to X-ray scatter and detector persistence effects. This prevents direct use of CBCT for re-calculation of RT delivered dose. We previously developed a prior-image based correction method to restore HU values and improve uniformity of CBCT images. Here we validate the accuracy with which corrected CBCT can be used for dosimetric assessment of RT delivery, using CBCT images and RT plans for 45 patients including pelvis, lung and head sites. Dose distributions were calculated based on each patient's original RT plan and using CBCT image values for tissue heterogeneity correction. Clinically relevant dose metrics were calculated (e.g. median and minimum target dose, maximum organ at risk dose). Accuracy of CBCT based dose metrics was determined using an "override ratio" method where the ratio of the dose metric to that calculated on a bulk-density assigned version of the image is assumed to be constant for each patient, allowing comparison to "gold standard" CT. For pelvis and head images the proportion of dose errors >2% was reduced from 40% to 1.3% after applying shading correction. For lung images the proportion of dose errors >3% was reduced from 66% to 2.2%. Application of shading correction to CBCT images greatly improves their utility for dosimetric assessment of RT delivery, allowing high confidence that CBCT dose calculations are accurate within 2-3%.

Low-dose CT for the diagnosis of appendicitis in adolescents and young adults (LOCAT): a pragmatic, multicentre, randomised controlled non-inferiority trial.

PubMed

2017-11-01

CT radiation is arguably carcinogenic. Results from single-centre studies, mostly retrospective, have advocated lowering the CT radiation dose for the diagnosis of appendicitis. However, adoption of low-dose CT has been slow. We aimed to assess the effectiveness of low-dose CT compared with standard-dose CT in the diagnosis of appendicitis in adolescents and young adults. We did this pragmatic, multicentre, randomised controlled non-inferiority trial at 20 South Korean teaching hospitals with little experience with low-dose CT. Patients aged 15-44 years with suspected appendicitis were randomly assigned (1:1), via computer-generated random assignments (permuted block sizes of two, four, six, and eight) concealed in sequentially numbered envelopes, to receive low-dose CT (2 mSv) or standard-dose CT (≤8 mSv). Randomisation was stratified by site. Group allocation was concealed from patients, outcome assessors, and adverse event adjudicators; care providers, site pathologists, and data collectors were aware of allocation. The primary endpoint was the negative (unnecessary) appendectomy rate among all appendectomies, with a non-interiority margin of 4·5% for low-dose versus standard-dose CT. Primary analysis was by modified intention to treat, which included all patients who received an appendectomy in the group to which they were assigned. This trial is registered with ClinicalTrials.gov, number NCT01925014. Between Dec 4, 2013, and Aug 18, 2016, we assigned 1535 patients to the low-dose CT group and 1539 patients to the standard-dose CT group. 22 (3·9%) of 559 patients had a negative appendectomy in the low-dose group versus 16 (2·7%) of 601 patients in the standard-dose group (difference 1·3%, 95% CI -0·8 to 3·3; p=0·0022 for the non-inferiority test). We recorded 43 adverse events in 43 (2·8%) of 1535 patients in the low-dose group and 41 adverse events in 40 (2·6%) of 1539 patients in the standard-dose group. One life-threatening adverse event of anaphylaxis caused by an iodinated contrast material occurred in the low-dose group. Radiation dose of appendiceal CT for adolescents and young adults can be reduced to 2 mSv without impairing clinical outcomes. In view of the vast number of appendiceal CT examinations done worldwide, use of low-dose CT could prevent a sizeable number of radiation-associated cancers in the future. Korea Health Industry Development Institute, Seoul National University Bundang Hospital, Dasol Life Science, and Bracco Imaging Korea. Copyright © 2017 Elsevier Ltd. All rights reserved.

Dose heterogeneity correction for low-energy brachytherapy sources using dual-energy CT images

NASA Astrophysics Data System (ADS)

Mashouf, S.; Lechtman, E.; Lai, P.; Keller, B. M.; Karotki, A.; Beachey, D. J.; Pignol, J. P.

2014-09-01

Permanent seed implant brachytherapy is currently used for adjuvant radiotherapy of early stage prostate and breast cancer patients. The current standard for calculation of dose around brachytherapy sources is based on the AAPM TG-43 formalism, which generates the dose in a homogeneous water medium. Recently, AAPM TG-186 emphasized the importance of accounting for tissue heterogeneities. We have previously reported on a methodology where the absorbed dose in tissue can be obtained by multiplying the dose, calculated by the TG-43 formalism, by an inhomogeneity correction factor (ICF). In this work we make use of dual energy CT (DECT) images to extract ICF parameters. The advantage of DECT over conventional CT is that it eliminates the need for tissue segmentation as well as assignment of population based atomic compositions. DECT images of a heterogeneous phantom were acquired and the dose was calculated using both TG-43 and TG-43 × \\text{ICF} formalisms. The results were compared to experimental measurements using Gafchromic films in the mid-plane of the phantom. For a seed implant configuration of 8 seeds spaced 1.5 cm apart in a cubic structure, the gamma passing score for 2%/2 mm criteria improved from 40.8% to 90.5% when ICF was applied to TG-43 dose distributions.

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

Cheung, Michael L M; Chan, Anthony T C; The Chinese University of Hong Kong

Purpose: To develop a formulation for 4D treatment planning for a tumour tracking volumetric modulated arc therapy treatment (VMAT) plan for lung cancer. Methods: A VMAT plan was optimized based on a reference phase of the 4DCT of a lung cancer patient. The PTV was generated from the GTV of the reference phase. The collimator angle was set to 90 degrees such that the MLC travels along superior-inferior direction which is the main component of movement of a lung tumour. Then, each control point of the VMAT plan was assigned to a particular phase of the 4DCT in chronological order.more » The MLC positions of each control point were shifted according to the position of the tumour centroid of its assigned phase to form a tumour tracking VMAT plan. The control points of the same phase were grouped to form a pseudo VMAT plan for that particular phase. Dose calculation was performed for each pseudo VMAT plan on the corresponding phase of the 4DCT. The CTs of all phases were registered to the reference phase CT according to the displacement of the tumour centroid. The individual dose distributions of the pseudo VMAT plans were summed up and displayed on the reference phase of the 4DCT. A control VMAT plan was optimized based on a PTV generated from the ITV of all phases and compared with the tumour tracking VMAT plan. Results: Both plans achieved >95% volume coverage at the prescription dose level (96% for the tumour tracking plan and 97% for the control plan). But the normal lung volume irradiated at the prescription dose level was 39% less for the tumour tracking plan than the control plan. Conclusion: A formulation of 4D treatment planning for tumour tracking VMAT plans for lung cancer was developed.« less

MRI-based treatment planning with pseudo CT generated through atlas registration.

PubMed

Uh, Jinsoo; Merchant, Thomas E; Li, Yimei; Li, Xingyu; Hua, Chiaho

2014-05-01

To evaluate the feasibility and accuracy of magnetic resonance imaging (MRI)-based treatment planning using pseudo CTs generated through atlas registration. A pseudo CT, providing electron density information for dose calculation, was generated by deforming atlas CT images previously acquired on other patients. The authors tested 4 schemes of synthesizing a pseudo CT from single or multiple deformed atlas images: use of a single arbitrarily selected atlas, arithmetic mean process using 6 atlases, and pattern recognition with Gaussian process (PRGP) using 6 or 12 atlases. The required deformation for atlas CT images was derived from a nonlinear registration of conjugated atlas MR images to that of the patient of interest. The contrasts of atlas MR images were adjusted by histogram matching to reduce the effect of different sets of acquisition parameters. For comparison, the authors also tested a simple scheme assigning the Hounsfield unit of water to the entire patient volume. All pseudo CT generating schemes were applied to 14 patients with common pediatric brain tumors. The image similarity of real patient-specific CT and pseudo CTs constructed by different schemes was compared. Differences in computation times were also calculated. The real CT in the treatment planning system was replaced with the pseudo CT, and the dose distribution was recalculated to determine the difference. The atlas approach generally performed better than assigning a bulk CT number to the entire patient volume. Comparing atlas-based schemes, those using multiple atlases outperformed the single atlas scheme. For multiple atlas schemes, the pseudo CTs were similar to the real CTs (correlation coefficient, 0.787-0.819). The calculated dose distribution was in close agreement with the original dose. Nearly the entire patient volume (98.3%-98.7%) satisfied the criteria of chi-evaluation (<2% maximum dose and 2 mm range). The dose to 95% of the volume and the percentage of volume receiving at least 95% of the prescription dose in the planning target volume differed from the original values by less than 2% of the prescription dose (root-mean-square, RMS < 1%). The PRGP scheme did not perform better than the arithmetic mean process with the same number of atlases. Increasing the number of atlases from 6 to 12 often resulted in improvements, but statistical significance was not always found. MRI-based treatment planning with pseudo CTs generated through atlas registration is feasible for pediatric brain tumor patients. The doses calculated from pseudo CTs agreed well with those from real CTs, showing dosimetric accuracy within 2% for the PTV when multiple atlases were used. The arithmetic mean process may be a reasonable choice over PRGP for the synthesis scheme considering performance and computational costs.

MRI-based treatment planning with pseudo CT generated through atlas registration

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

Uh, Jinsoo, E-mail: jinsoo.uh@stjude.org; Merchant, Thomas E.; Hua, Chiaho

2014-05-15

Purpose: To evaluate the feasibility and accuracy of magnetic resonance imaging (MRI)-based treatment planning using pseudo CTs generated through atlas registration. Methods: A pseudo CT, providing electron density information for dose calculation, was generated by deforming atlas CT images previously acquired on other patients. The authors tested 4 schemes of synthesizing a pseudo CT from single or multiple deformed atlas images: use of a single arbitrarily selected atlas, arithmetic mean process using 6 atlases, and pattern recognition with Gaussian process (PRGP) using 6 or 12 atlases. The required deformation for atlas CT images was derived from a nonlinear registration ofmore » conjugated atlas MR images to that of the patient of interest. The contrasts of atlas MR images were adjusted by histogram matching to reduce the effect of different sets of acquisition parameters. For comparison, the authors also tested a simple scheme assigning the Hounsfield unit of water to the entire patient volume. All pseudo CT generating schemes were applied to 14 patients with common pediatric brain tumors. The image similarity of real patient-specific CT and pseudo CTs constructed by different schemes was compared. Differences in computation times were also calculated. The real CT in the treatment planning system was replaced with the pseudo CT, and the dose distribution was recalculated to determine the difference. Results: The atlas approach generally performed better than assigning a bulk CT number to the entire patient volume. Comparing atlas-based schemes, those using multiple atlases outperformed the single atlas scheme. For multiple atlas schemes, the pseudo CTs were similar to the real CTs (correlation coefficient, 0.787–0.819). The calculated dose distribution was in close agreement with the original dose. Nearly the entire patient volume (98.3%–98.7%) satisfied the criteria of chi-evaluation (<2% maximum dose and 2 mm range). The dose to 95% of the volume and the percentage of volume receiving at least 95% of the prescription dose in the planning target volume differed from the original values by less than 2% of the prescription dose (root-mean-square, RMS < 1%). The PRGP scheme did not perform better than the arithmetic mean process with the same number of atlases. Increasing the number of atlases from 6 to 12 often resulted in improvements, but statistical significance was not always found. Conclusions: MRI-based treatment planning with pseudo CTs generated through atlas registration is feasible for pediatric brain tumor patients. The doses calculated from pseudo CTs agreed well with those from real CTs, showing dosimetric accuracy within 2% for the PTV when multiple atlases were used. The arithmetic mean process may be a reasonable choice over PRGP for the synthesis scheme considering performance and computational costs.« less

MRI-based treatment planning with pseudo CT generated through atlas registration

PubMed Central

Uh, Jinsoo; Merchant, Thomas E.; Li, Yimei; Li, Xingyu; Hua, Chiaho

2014-01-01

Purpose: To evaluate the feasibility and accuracy of magnetic resonance imaging (MRI)-based treatment planning using pseudo CTs generated through atlas registration. Methods: A pseudo CT, providing electron density information for dose calculation, was generated by deforming atlas CT images previously acquired on other patients. The authors tested 4 schemes of synthesizing a pseudo CT from single or multiple deformed atlas images: use of a single arbitrarily selected atlas, arithmetic mean process using 6 atlases, and pattern recognition with Gaussian process (PRGP) using 6 or 12 atlases. The required deformation for atlas CT images was derived from a nonlinear registration of conjugated atlas MR images to that of the patient of interest. The contrasts of atlas MR images were adjusted by histogram matching to reduce the effect of different sets of acquisition parameters. For comparison, the authors also tested a simple scheme assigning the Hounsfield unit of water to the entire patient volume. All pseudo CT generating schemes were applied to 14 patients with common pediatric brain tumors. The image similarity of real patient-specific CT and pseudo CTs constructed by different schemes was compared. Differences in computation times were also calculated. The real CT in the treatment planning system was replaced with the pseudo CT, and the dose distribution was recalculated to determine the difference. Results: The atlas approach generally performed better than assigning a bulk CT number to the entire patient volume. Comparing atlas-based schemes, those using multiple atlases outperformed the single atlas scheme. For multiple atlas schemes, the pseudo CTs were similar to the real CTs (correlation coefficient, 0.787–0.819). The calculated dose distribution was in close agreement with the original dose. Nearly the entire patient volume (98.3%–98.7%) satisfied the criteria of chi-evaluation (<2% maximum dose and 2 mm range). The dose to 95% of the volume and the percentage of volume receiving at least 95% of the prescription dose in the planning target volume differed from the original values by less than 2% of the prescription dose (root-mean-square, RMS < 1%). The PRGP scheme did not perform better than the arithmetic mean process with the same number of atlases. Increasing the number of atlases from 6 to 12 often resulted in improvements, but statistical significance was not always found. Conclusions: MRI-based treatment planning with pseudo CTs generated through atlas registration is feasible for pediatric brain tumor patients. The doses calculated from pseudo CTs agreed well with those from real CTs, showing dosimetric accuracy within 2% for the PTV when multiple atlases were used. The arithmetic mean process may be a reasonable choice over PRGP for the synthesis scheme considering performance and computational costs. PMID:24784377

Independent dose verification system with Monte Carlo simulations using TOPAS for passive scattering proton therapy at the National Cancer Center in Korea

NASA Astrophysics Data System (ADS)

Shin, Wook-Geun; Testa, Mauro; Kim, Hak Soo; Jeong, Jong Hwi; Byeong Lee, Se; Kim, Yeon-Joo; Min, Chul Hee

2017-10-01

For the independent validation of treatment plans, we developed a fully automated Monte Carlo (MC)-based patient dose calculation system with the tool for particle simulation (TOPAS) and proton therapy machine installed at the National Cancer Center in Korea to enable routine and automatic dose recalculation for each patient. The proton beam nozzle was modeled with TOPAS to simulate the therapeutic beam, and MC commissioning was performed by comparing percent depth dose with the measurement. The beam set-up based on the prescribed beam range and modulation width was automated by modifying the vendor-specific method. The CT phantom was modeled based on the DICOM CT files with TOPAS-built-in function, and an in-house-developed C++ code directly imports the CT files for positioning the CT phantom, RT-plan file for simulating the treatment plan, and RT-structure file for applying the Hounsfield unit (HU) assignment, respectively. The developed system was validated by comparing the dose distributions with those calculated by the treatment planning system (TPS) for a lung phantom and two patient cases of abdomen and internal mammary node. The results of the beam commissioning were in good agreement of up to 0.8 mm2 g-1 for B8 option in both of the beam range and the modulation width of the spread-out Bragg peaks. The beam set-up technique can predict the range and modulation width with an accuracy of 0.06% and 0.51%, respectively, with respect to the prescribed range and modulation in arbitrary points of B5 option (128.3, 132.0, and 141.2 mm2 g-1 of range). The dose distributions showed higher than 99% passing rate for the 3D gamma index (3 mm distance to agreement and 3% dose difference) between the MC simulations and the clinical TPS in the target volume. However, in the normal tissues, less favorable agreements were obtained for the radiation treatment planning with the lung phantom and internal mammary node cases. The discrepancies might come from the limitations of the clinical TPS, which is the inaccurate dose calculation algorithm for the scattering effect, in the range compensator and inhomogeneous material. Moreover, the steep slope of the compensator, conversion of the HU values to the human phantom, and the dose calculation algorithm for the HU assignment also could be reasons of the discrepancies. The current study could be used for the independent dose validation of treatment plans including high inhomogeneities, the steep compensator, and riskiness such as lung, head & neck cases. According to the treatment policy, the dose discrepancies predicted with MC could be used for the acceptance decision of the original treatment plan.

Safety and immunogenicity of a novel recombinant adenovirus type-5 vector-based Ebola vaccine in healthy adults in China: preliminary report of a randomised, double-blind, placebo-controlled, phase 1 trial.

PubMed

Zhu, Feng-Cai; Hou, Li-Hua; Li, Jing-Xin; Wu, Shi-Po; Liu, Pei; Zhang, Gui-Rong; Hu, Yue-Mei; Meng, Fan-Yue; Xu, Jun-Jie; Tang, Rong; Zhang, Jin-Long; Wang, Wen-Juan; Duan, Lei; Chu, Kai; Liang, Qi; Hu, Jia-Lei; Luo, Li; Zhu, Tao; Wang, Jun-Zhi; Chen, Wei

2015-06-06

Up to now, all tested Ebola virus vaccines have been based on the virus strain from the Zaire outbreak in 1976. We aimed to assess the safety and immunogenicity of a novel recombinant adenovirus type-5 vector-based Ebola vaccine expressing the glycoprotein of the 2014 epidemic strain. We did this randomised, double-blind, placebo-controlled, phase 1 clinical trial at one site in Taizhou County, Jiangsu Province, China. Healthy adults (aged 18-60 years) were sequentially enrolled and randomly assigned (2:1), by computer-generated block randomisation (block size of six), to receive placebo, low-dose adenovirus type-5 vector-based Ebola vaccine, or high-dose vaccine. Randomisation was pre-stratified by dose group. All participants, investigators, and laboratory staff were masked to treatment allocation. The primary safety endpoint was occurrence of solicited adverse reactions within 7 days of vaccination. The primary immunogenicity endpoints were glycoprotein-specific antibody titres and T-cell responses at day 28 after the vaccination. Analysis was by intention to treat. The study is registered with ClinicalTrials.gov, number NCT02326194. Between Dec 28, 2014, and Jan 9, 2015, 120 participants were enrolled and randomly assigned to receive placebo (n=40), low-dose vaccine (n=40), or high-dose vaccine. Participants were followed up for 28 days. Overall, 82 (68%) participants reported at least one solicited adverse reaction within 7 days of vaccination (n=19 in the placebo group vs n=27 in the low-dose group vs n=36 in the high-dose group; p=0·0002). The most common reaction was mild pain at the injection site, which was reported in eight (20%) participants in the placebo group, 14 (35%) participants in the low-dose group, and 29 (73%) participants in the high-dose vaccine group (p<0·0001). We recorded no statistical differences in other adverse reactions and laboratory tests across groups. Glycoprotein-specific antibody titres were significantly increased in participants in the low-dose and high-dose vaccine groups at both day 14 (geometric mean titre 421·4 [95% CI 249·7-711·3] and 820·5 [598·9-1124·0], respectively; p<0·0001) and day 28 (682·7 [424·3-1098·5] and 1305·7 [970·1-1757·2], respectively; p<0·0001). T-cell responses peaked at day 14 at a median of 465·0 spot-forming cells (IQR 180·0-1202·5) in participants in the low-dose group and 765·0 cells (400·0-1460·0) in those in the high-dose group. 21 (18%) participants had mild fever (n=9 in the placebo group, n=6 in the low-dose group, and n=6 in the high-dose group). No serious adverse events were recorded. Our findings show that the high-dose vaccine is safe and robustly immunogenic. One shot of the high-dose vaccine could mount glycoprotein-specific humoral and T-cell response against Ebola virus in 14 days. China National Science and Technology, Beijing Institute of Biotechnology, and Tianjin CanSino Biotechnology. Copyright © 2015 Elsevier Ltd. All rights reserved.

Comparative oral dose toxicokinetics of sodium selenite and selenomethionine

USDA-ARS?s Scientific Manuscript database

The toxicokinetics of selenium (Se) absorption, distribution, and elimination were determined in serum and whole blood of lambs that were orally dosed with various doses of Se as sodium selenite (inorganic Se) or selenomethionine (organic Se). Thirty-two lambs were randomly assigned to eight treatm...

Efficacy and safety of weight-based insulin glargine dose titration regimen compared with glucose level- and current dose-based regimens in hospitalized patients with type 2 diabetes: a randomized, controlled study.

PubMed

Li, Xiaowei; Du, Tao; Li, Wangen; Zhang, Tong; Liu, Haiyan; Xiong, Yifeng

2014-09-01

Insulin glargine is widely used as basal insulin. However, published dose titration regimens for insulin glargine are complex. This study aimed to compare the efficacy and safety profile of a user-friendly, weight-based insulin glargine dose titration regimen with 2 published regimens. A total of 160 hospitalized patients with hyperglycemia in 3 medical centers were screened. Our inclusion criteria included age 18 to 80 years and being conscious. Exclusion criteria included pregnancy or breast-feeding and hepatic or renal dysfunction. A total of 149 patients were randomly assigned to receive weight-based, glucose level-based, or dose-based insulin glargine dose titration regimen between January 2011 and February 2013. The initial dose of insulin glargine was 0.2 U/kg. In the weight-based regimen (n = 49), the dose was titrated by increments of 0.1 U/kg daily. In the glucose level-based regimen (n = 51), the dose was titrated by 2, 4, 6, or 8 U daily when fasting blood glucose (FBG) was, respectively, between 7.0 and 7.9, 8.0 and 8.9, 9.0 and 9.9, or ≥10 mmol/L. In the current dose-based regimen (n = 49), titration was by daily increments of 20% of the current dose. The target FBG in all groups was ≤7.0 mmol/L. The incidence of hypoglycemia was recorded. One-way ANOVA and χ(2) test were used to compare data between the 3 groups. All but 1 patient who required additional oral antidiabetic medication completed the study. The mean (SD) time to achieve target FBG was 3.2 (1.2) days with the weight-based regimen and 3.7 (1.5) days with the glucose level-based regimen (P = 0.266). These times were both shorter than that achieved with the current dose-based regimen (4.8 [2.8] days; P = 0.0001 and P = 0.005, respectively). The daily doses of insulin glargine at the study end point were 0.43 (0.13) U/kg with the weight-based regimen, 0.50 (0.20) U/kg with the glucose level-based regimen, and 0.47 (0.23) U/kg with the current dose-based regimen (P = 0.184). The incidence of hypoglycemia was 4.1%, 2.0%, and 6.3%, respectively (P = 0.557). The currently proposed weight-based insulin glargine dose titration regimen is effective, tolerable, and user-friendly at achieving FBG target levels in hospitalized patients with hyperglycemia. Copyright © 2014 Elsevier HS Journals, Inc. All rights reserved.

Process evaluation of a food marketing and environmental change intervention in Tiendas that serve Latino immigrants in North Carolina.

PubMed

Baquero, Barbara; Linnan, Laura; Laraia, Barbara A; Ayala, Guadalupe X

2014-11-01

This article describes a comprehensive process evaluation of an efficacious store-based intervention that increased store customers' fruit and vegetable consumption. The process evaluation plan was designed at study inception and implemented at baseline, during the intervention, and at immediate postintervention. Four Latino food stores were randomly assigned either to an intervention or to a control condition. Data were collected from store managers, employees, and 139 Latino customers. Researchers used manager, employee, and customer interviews; weekly observations of the store environment; and implementation logs to assess reach, dose delivered, dose received, and fidelity. Results indicated that it is possible to reach customers in a store-based intervention. Indicators of dose delivered demonstrated that the intervention was implemented as planned, and in the case of employee training, it exceeded the plan. Dose received data indicated that customers moderately engaged with the intervention activities. Together these suggest that the intervention was delivered with good fidelity. Comprehensive process evaluation efforts can facilitate the identification and elimination of barriers to implementation. This approach can serve as a model for future store-based interventions. The study demonstrated that it is feasible to implement Latino food store-based interventions to increase access to and consumption of fruits and vegetables. © 2014 Society for Public Health Education.

Skin Carotenoid Response to a High-Carotenoid Juice in Children: A Randomized Clinical Trial.

PubMed

Aguilar, Sheryl S; Wengreen, Heidi J; Dew, Jeffrey

2015-11-01

Previous studies have shown an increase in serum carotenoid status among children when fed carotenoids. This study looked at the effect and dose-response of a known amount of carotenoid consumption on change in skin carotenoid status among children. Participants were children aged 5 to 17 years from Cache County, UT (n=58). Children were randomly assigned to one of three groups: high (n=18) or low (n=18) dose of a carotenoid-rich juice (2.75 mg carotenoids/30 mL juice), or placebo juice (n=22). Children were asked to drink an assigned dose of the juice (30 to 120 mL/day) based on the weight of the child and group assignment, every day for 8 weeks. Skin carotenoids were measured every 2 weeks by resonance Raman spectroscopy. Participants were asked to maintain their usual diet throughout the study. Usual diet was assessed using three averaged 24-hour recalls; diet constancy was measured using food frequency questionnaires administered at baseline, Week 4, and Week 8. Repeated measures analysis of variance was used to assess the group differences in skin carotenoid status over time. The high-dose and low-dose groups had mean±standard deviation increases in skin carotenoid status of 11,515±1,134 and 10,009±1,439 Raman intensity counts, respectively (both P values <0.001, for change in means compared with baseline) at Week 8, although they showed significant change from baseline by Week 2. The placebo group's change of 985 Raman intensity counts was not statistically significant. The difference in change between the 2 experimental groups was not significant at Week 2, 4, 6, or 8. Consumption of 30 to 120 mL (2.75 to 11 mg carotenoids) of a carotenoid-rich juice significantly increased skin carotenoid status over an 8-week period among children aged 5 to 17 years. The amount of carotenoids found in this amount of juice is equal to the amount found in approximately 23 to 92 g cooked carrots per day. Copyright © 2015 Academy of Nutrition and Dietetics. Published by Elsevier Inc. All rights reserved.

Improved tissue assignment using dual-energy computed tomography in low-dose rate prostate brachytherapy for Monte Carlo dose calculation

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

Côté, Nicolas; Bedwani, Stéphane; Carrier, Jean-François, E-mail: jean-francois.carrier.chum@ssss.gouv.qc.ca

Purpose: An improvement in tissue assignment for low-dose rate brachytherapy (LDRB) patients using more accurate Monte Carlo (MC) dose calculation was accomplished with a metallic artifact reduction (MAR) method specific to dual-energy computed tomography (DECT). Methods: The proposed MAR algorithm followed a four-step procedure. The first step involved applying a weighted blend of both DECT scans (I {sub H/L}) to generate a new image (I {sub Mix}). This action minimized Hounsfield unit (HU) variations surrounding the brachytherapy seeds. In the second step, the mean HU of the prostate in I {sub Mix} was calculated and shifted toward the mean HUmore » of the two original DECT images (I {sub H/L}). The third step involved smoothing the newly shifted I {sub Mix} and the two original I {sub H/L}, followed by a subtraction of both, generating an image that represented the metallic artifact (I {sub A,(H/L)}) of reduced noise levels. The final step consisted of subtracting the original I {sub H/L} from the newly generated I {sub A,(H/L)} and obtaining a final image corrected for metallic artifacts. Following the completion of the algorithm, a DECT stoichiometric method was used to extract the relative electronic density (ρ{sub e}) and effective atomic number (Z {sub eff}) at each voxel of the corrected scans. Tissue assignment could then be determined with these two newly acquired physical parameters. Each voxel was assigned the tissue bearing the closest resemblance in terms of ρ{sub e} and Z {sub eff}, comparing with values from the ICRU 42 database. A MC study was then performed to compare the dosimetric impacts of alternative MAR algorithms. Results: An improvement in tissue assignment was observed with the DECT MAR algorithm, compared to the single-energy computed tomography (SECT) approach. In a phantom study, tissue misassignment was found to reach 0.05% of voxels using the DECT approach, compared with 0.40% using the SECT method. Comparison of the DECT and SECT D {sub 90} dose parameter (volume receiving 90% of the dose) indicated that D {sub 90} could be underestimated by up to 2.3% using the SECT method. Conclusions: The DECT MAR approach is a simple alternative to reduce metallic artifacts found in LDRB patient scans. Images can be processed quickly and do not require the determination of x-ray spectra. Substantial information on density and atomic number can also be obtained. Furthermore, calcifications within the prostate are detected by the tissue assignment algorithm. This enables more accurate, patient-specific MC dose calculations.« less

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

PubMed

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

2007-01-01

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

Application of Adaptive Design Methodology in Development of a Long-Acting Glucagon-Like Peptide-1 Analog (Dulaglutide): Statistical Design and Simulations

PubMed Central

Skrivanek, Zachary; Berry, Scott; Berry, Don; Chien, Jenny; Geiger, Mary Jane; Anderson, James H.; Gaydos, Brenda

2012-01-01

Background Dulaglutide (dula, LY2189265), a long-acting glucagon-like peptide-1 analog, is being developed to treat type 2 diabetes mellitus. Methods To foster the development of dula, we designed a two-stage adaptive, dose-finding, inferentially seamless phase 2/3 study. The Bayesian theoretical framework is used to adaptively randomize patients in stage 1 to 7 dula doses and, at the decision point, to either stop for futility or to select up to 2 dula doses for stage 2. After dose selection, patients continue to be randomized to the selected dula doses or comparator arms. Data from patients assigned the selected doses will be pooled across both stages and analyzed with an analysis of covariance model, using baseline hemoglobin A1c and country as covariates. The operating characteristics of the trial were assessed by extensive simulation studies. Results Simulations demonstrated that the adaptive design would identify the correct doses 88% of the time, compared to as low as 6% for a fixed-dose design (the latter value based on frequentist decision rules analogous to the Bayesian decision rules for adaptive design). Conclusions This article discusses the decision rules used to select the dula dose(s); the mathematical details of the adaptive algorithm—including a description of the clinical utility index used to mathematically quantify the desirability of a dose based on safety and efficacy measurements; and a description of the simulation process and results that quantify the operating characteristics of the design. PMID:23294775

Peginterferon alfa-2b and weight-based or flat-dose ribavirin in chronic hepatitis C patients: a randomized trial.

PubMed

Jacobson, Ira M; Brown, Robert S; Freilich, Bradley; Afdhal, Nezam; Kwo, Paul Y; Santoro, John; Becker, Scott; Wakil, Adil E; Pound, David; Godofsky, Eliot; Strauss, Robert; Bernstein, David; Flamm, Steven; Pauly, Mary Pat; Mukhopadhyay, Pabak; Griffel, Louis H; Brass, Clifford A

2007-10-01

This prospective, multicenter, community-based and academic-based, open-label, investigator-initiated, U.S. study evaluated efficacy and safety of pegylated interferon (PEG-IFN) alfa-2b plus a flat or weight-based dose of ribavirin (RBV) in adults with chronic hepatitis C. Patients (n = 5027) were randomly assigned to receive PEG-IFN alfa-2b 1.5 microg/kg/week plus flat-dose (800 mg/day) or weight-based (800-1400 mg/day) RBV for 48 weeks (patients with genotype 1, 4, 5, or 6) and for 24 or 48 weeks (genotype 2/3 patients). Primary end point was sustained virologic response (undetectable [<125 IU/mL] serum hepatitis C virus RNA at 24-week follow-up). Sustained virologic response, but not end-of-treatment, rates were significantly higher with weight-based than with flat-dose RBV (44.2% versus 40.5%; P = 0.008). Sustained virologic response rates by intention-to-treat analysis were 34.0% and 28.9%, respectively, in genotype 1 patients (P = 0.005) and 31.2% and 26.7%, respectively, in genotype 1 patients with high baseline viral load (P = 0.056). In genotype 2/3 patients, rates were not significantly different (61.8% and 59.5%, respectively) regardless of treatment duration. Besides greater hemoglobin reductions with weight-based RBV, safety profiles were similar across RBV dosing groups, including the 1400-mg/day group. PEG-IFN alfa-2b plus weight-based RBV is more effective than flat-dose RBV, particularly in genotype 1 patients, providing equivalent efficacy across all weight groups. RBV 1400 mg/day is appropriate for patients 105 to 125 kg. For genotype 2/3 patients, 24 weeks of treatment with flat-dose RBV is adequate; no evidence of additional benefit of extending treatment to 48 weeks was demonstrated.

Dexamethasone and High-Dose Methotrexate Improve Outcome for Children and Young Adults With High-Risk B-Acute Lymphoblastic Leukemia: A Report From Children’s Oncology Group Study AALL0232

PubMed Central

Devidas, Meenakshi; Chen, Si; Salzer, Wanda L.; Raetz, Elizabeth A.; Loh, Mignon L.; Mattano, Leonard A.; Cole, Catherine; Eicher, Alisa; Haugan, Maureen; Sorenson, Mark; Heerema, Nyla A.; Carroll, Andrew A.; Gastier-Foster, Julie M.; Borowitz, Michael J.; Wood, Brent L.; Willman, Cheryl L.; Winick, Naomi J.; Hunger, Stephen P.; Carroll, William L.

2016-01-01

Purpose Survival for children and young adults with high-risk B-acute lymphoblastic leukemia has improved significantly, but 20% to 25% of patients are not cured. Children’s Oncology Group study AALL0232 tested two interventions to improve survival. Patients and Methods Between January 2004 and January 2011, AALL0232 enrolled 3,154 participants 1 to 30 years old with newly diagnosed high-risk B-acute lymphoblastic leukemia. By using a 2 × 2 factorial design, 2,914 participants were randomly assigned to receive dexamethasone (14 days) versus prednisone (28 days) during induction and high-dose methotrexate versus Capizzi escalating-dose methotrexate plus pegaspargase during interim maintenance 1. Results Planned interim monitoring showed the superiority of the high-dose methotrexate regimens, which exceeded the predefined boundary and led to cessation of enrollment in January 2011. At that time, participants randomly assigned to high-dose methotrexate during interim maintenance 1 versus those randomly assigned to Capizzi methotrexate had a 5-year event-free survival (EFS) of 82% versus 75.4% (P = .006). Mature final data showed 5-year EFS rates of 79.6% for high-dose methotrexate and 75.2% for Capizzi methotrexate (P = .008). High-dose methotrexate decreased both marrow and CNS recurrences. Patients 1 to 9 years old who received dexamethasone and high-dose methotrexate had a superior outcome compared with those who received the other three regimens (5-year EFS, 91.2% v 83.2%, 80.8%, and 82.1%; P = .015). Older participants derived no benefit from dexamethasone during induction and experienced excess rates of osteonecrosis. Conclusion High-dose methotrexate is superior to Capizzi methotrexate for the treatment of high-risk B-acute lymphoblastic leukemia, with no increase in acute toxicity. Dexamethasone given during induction benefited younger children but provided no benefit and was associated with a higher risk of osteonecrosis among participants 10 years and older. PMID:27114587

Primaquine to reduce transmission of Plasmodium falciparum malaria in Mali: a single-blind, dose-ranging, adaptive randomised phase 2 trial.

PubMed

Dicko, Alassane; Brown, Joelle M; Diawara, Halimatou; Baber, Ibrahima; Mahamar, Almahamoudou; Soumare, Harouna M; Sanogo, Koualy; Koita, Fanta; Keita, Sekouba; Traore, Sekou F; Chen, Ingrid; Poirot, Eugenie; Hwang, Jimee; McCulloch, Charles; Lanke, Kjerstin; Pett, Helmi; Niemi, Mikko; Nosten, François; Bousema, Teun; Gosling, Roly

2016-06-01

Single low doses of primaquine, when added to artemisinin-based combination therapy, might prevent transmission of Plasmodium falciparum malaria to mosquitoes. We aimed to establish the activity and safety of four low doses of primaquine combined with dihydroartemisinin-piperaquine in male patients in Mali. In this phase 2, single-blind, dose-ranging, adaptive randomised trial, we enrolled boys and men with uncomplicated P falciparum malaria at the Malaria Research and Training Centre (MRTC) field site in Ouelessebougou, Mali. All participants were confirmed positive carriers of gametocytes through microscopy and had normal function of glucose-6-phosphate dehydrogenase (G6PD) on colorimetric quantification. In the first phase, participants were randomly assigned (1:1:1) to one of three primaquine doses: 0 mg/kg (control), 0·125 mg/kg, and 0·5 mg/kg. Randomisation was done with a computer-generated randomisation list (in block sizes of six) and concealed with sealed, opaque envelopes. In the second phase, different participants were sequentially assigned (1:1) to 0·25 mg/kg primaquine or 0·0625 mg/kg primaquine. Primaquine tablets were dissolved into a solution and administered orally in a single dose. Participants were also given a 3 day course of dihydroartemisinin-piperaquine, administered by weight (320 mg dihydroartemisinin and 40 mg piperaquine per tablet). Outcome assessors were masked to treatment allocation, but participants were permitted to find out group assignment. Infectivity was assessed through membrane-feeding assays, which were optimised through the beginning part of phase one. The primary efficacy endpoint was the mean within-person percentage change in mosquito infectivity 2 days after primaquine treatment in participants who completed the study after optimisation of the infectivity assay, had both a pre-treatment infectivity measurement and at least one follow-up infectivity measurement, and who were given the correct primaquine dose. The safety endpoint was the mean within-person change in haemoglobin concentration during 28 days of study follow-up in participants with at least one follow-up visit. This study is registered with ClinicalTrials.gov, number NCT01743820. Between Jan 2, 2013, and Nov 27, 2014, we enrolled 81 participants. In the primary analysis sample (n=71), participants in the 0·25 mg/kg primaquine dose group (n=15) and 0·5 mg/kg primaquine dose group (n=14) had significantly lower mean within-person reductions in infectivity at day 2-92·6% (95% CI 78·3-100; p=0·0014) for the 0·25 mg/kg group; and 75·0% (45·7-100; p=0·014) for the 0·5 mg/kg primaquine group-compared with those in the control group (n=14; 11·3% [-27·4 to 50·0]). Reductions were not significantly different from control for participants assigned to the 0·0625 mg/kg dose group (n=16; 41·9% [1·4-82·5]; p=0·16) and the 0·125 mg/kg dose group (n=12; 54·9% [13·4-96·3]; p=0·096). No clinically meaningful or statistically significant drops in haemoglobin were recorded in any individual in the haemoglobin analysis (n=70) during follow-up. No serious adverse events were reported and adverse events did not differ between treatment groups. A single dose of 0·25 mg/kg primaquine, given alongside dihydroartemisinin-piperaquine, was safe and efficacious for the prevention of P falciparum malaria transmission in boys and men who are not deficient in G6PD. Future studies should assess the safety of single-dose primaquine in G6PD-deficient individuals to define the therapeutic range of primaquine to enable the safe roll-out of community interventions with primaquine. Bill & Melinda Gates Foundation. Copyright © 2016 Elsevier Ltd. All rights reserved.

SU-F-J-109: Generate Synthetic CT From Cone Beam CT for CBCT-Based Dose Calculation

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

Wang, H; Barbee, D; Wang, W

Purpose: The use of CBCT for dose calculation is limited by its HU inaccuracy from increased scatter. This study presents a method to generate synthetic CT images from CBCT data by a probabilistic classification that may be robust to CBCT noise. The feasibility of using the synthetic CT for dose calculation is evaluated in IMRT for unilateral H&N cancer. Methods: In the training phase, a fuzzy c-means classification was performed on HU vectors (CBCT, CT) of planning CT and registered day-1 CBCT image pair. Using the resulting centroid CBCT and CT values for five classified “tissue” types, a synthetic CTmore » for a daily CBCT was created by classifying each CBCT voxel to obtain its probability belonging to each tissue class, then assigning a CT HU with a probability-weighted summation of the classes’ CT centroids. Two synthetic CTs from a CBCT were generated: s-CT using the centroids from classification of individual patient CBCT/CT data; s2-CT using the same centroids for all patients to investigate the applicability of group-based centroids. IMRT dose calculations for five patients were performed on the synthetic CTs and compared with CT-planning doses by dose-volume statistics. Results: DVH curves of PTVs and critical organs calculated on s-CT and s2-CT agree with those from planning-CT within 3%, while doses calculated with heterogeneity off or on raw CBCT show DVH differences up to 15%. The differences in PTV D95% and spinal cord max are 0.6±0.6% and 0.6±0.3% for s-CT, and 1.6±1.7% and 1.9±1.7% for s2-CT. Gamma analysis (2%/2mm) shows 97.5±1.6% and 97.6±1.6% pass rates for using s-CTs and s2-CTs compared with CT-based doses, respectively. Conclusion: CBCT-synthesized CTs using individual or group-based centroids resulted in dose calculations that are comparable to CT-planning dose for unilateral H&N cancer. The method may provide a tool for accurate dose calculation based on daily CBCT.« less

SU-E-J-228: MRI-Based Planning: Dosimetric Feasibility of Dose Painting for ADCDefined Intra-Prostatic Tumor

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

Chen, X; Dalah, E; Prior, P

Purpose: Apparent diffusion coefficient (ADC) map may help to delineate the gross tumor volume (GTV) in prostate gland. Dose painting with external beam radiotherapy for GTV might increase the local tumor control. The purpose of this study is to explore the maximum boosting dose on GTV using VMAT without sacrificing sparing of organs at risk (OARs) in MRI based planning. Methods: VMAT plans for 5 prostate patients were generated following the commonly used dose volume (DV) criteria based on structures contoured on T2 weighted MRI with bulk electron density assignment using electron densities derived from ICRU46. GTV for each patientmore » was manually delineated based on ADC maps and fused to T2-weighted image set for planning study. A research planning system with Monte Carlo dose engine (Monaco, Elekta) was used to generate the VMAT plans with boosting dose on GTV gradually increased from 85Gy to 100Gy. DV parameters, including V(boosting-dose) (volume covered by boosting dose) for GTV, V75.6Gy for PTV, V45Gy, V70Gy, V72Gy and D1cc (Maximum dose to 1cc volume) for rectum and bladder, were used to measure plan quality. Results: All cases achieve at least 99.0% coverage of V(boosting-dose) on GTV and 95% coverage of V75.6Gy to the PTV. All the DV criteria, V45Gy≤50% and V70Gy≤15% for bladder and rectum, D1cc ≤77Gy (Rectum) and ≤80Gy (Bladder), V72Gy≤5% (rectum and bladder) were maintained when boosting GTV to 95Gy for all cases studied. Except for two patients, all the criteria were also met when the boosting dose goes to 100Gy. Conclusion: It is dosimetrically feasible safe to boost the dose to at least 95Gy to ADC defined GTV in prostate cancer using MRI guided VMAT delivery. Conclusion: It is dosimetrically feasible safe to boost the dose to at least 95Gy to ADC defined GTV in prostate cancer using MRI guided VMAT delivery. This research is partially supported by Elekta Inc.« less

Risk ranking of LANL nuclear material storage containers for repackaging prioritization.

PubMed

Smith, Paul H; Jordan, Hans; Hoffman, Jenifer A; Eller, P Gary; Balkey, Simon

2007-05-01

Safe handling and storage of nuclear material at U.S. Department of Energy facilities relies on the use of robust containers to prevent container breaches and subsequent worker contamination and uptake. The U.S. Department of Energy has no uniform requirements for packaging and storage of nuclear materials other than those declared excess and packaged to DOE-STD-3013-2000. This report describes a methodology for prioritizing a large inventory of nuclear material containers so that the highest risk containers are repackaged first. The methodology utilizes expert judgment to assign respirable fractions and reactivity factors to accountable levels of nuclear material at Los Alamos National Laboratory. A relative risk factor is assigned to each nuclear material container based on a calculated dose to a worker due to a failed container barrier and a calculated probability of container failure based on material reactivity and container age. This risk-based methodology is being applied at LANL to repackage the highest risk materials first and, thus, accelerate the reduction of risk to nuclear material handlers.

Exposing exposure: automated anatomy-specific CT radiation exposure extraction for quality assurance and radiation monitoring.

PubMed

Sodickson, Aaron; Warden, Graham I; Farkas, Cameron E; Ikuta, Ichiro; Prevedello, Luciano M; Andriole, Katherine P; Khorasani, Ramin

2012-08-01

To develop and validate an informatics toolkit that extracts anatomy-specific computed tomography (CT) radiation exposure metrics (volume CT dose index and dose-length product) from existing digital image archives through optical character recognition of CT dose report screen captures (dose screens) combined with Digital Imaging and Communications in Medicine attributes. This institutional review board-approved HIPAA-compliant study was performed in a large urban health care delivery network. Data were drawn from a random sample of CT encounters that occurred between 2000 and 2010; images from these encounters were contained within the enterprise image archive, which encompassed images obtained at an adult academic tertiary referral hospital and its affiliated sites, including a cancer center, a community hospital, and outpatient imaging centers, as well as images imported from other facilities. Software was validated by using 150 randomly selected encounters for each major CT scanner manufacturer, with outcome measures of dose screen retrieval rate (proportion of correctly located dose screens) and anatomic assignment precision (proportion of extracted exposure data with correctly assigned anatomic region, such as head, chest, or abdomen and pelvis). The 95% binomial confidence intervals (CIs) were calculated for discrete proportions, and CIs were derived from the standard error of the mean for continuous variables. After validation, the informatics toolkit was used to populate an exposure repository from a cohort of 54 549 CT encounters; of which 29 948 had available dose screens. Validation yielded a dose screen retrieval rate of 99% (597 of 605 CT encounters; 95% CI: 98%, 100%) and an anatomic assignment precision of 94% (summed DLP fraction correct 563 in 600 CT encounters; 95% CI: 92%, 96%). Patient safety applications of the resulting data repository include benchmarking between institutions, CT protocol quality control and optimization, and cumulative patient- and anatomy-specific radiation exposure monitoring. Large-scale anatomy-specific radiation exposure data repositories can be created with high fidelity from existing digital image archives by using open-source informatics tools.

Modeling the economic and health consequences of managing chronic osteoarthritis pain with opioids in Germany: comparison of extended-release oxycodone and OROS hydromorphone.

PubMed

Ward, Alexandra; Bozkaya, Duygu; Fleischmann, Jochen; Dubois, Dominique; Sabatowski, Rainer; Caro, J Jaime

2007-10-01

The Osmotic controlled-Release Oral delivery System (OROS) hydromorphone ensures continuous release of hydromorphone over 24 hours. It is anticipated that this will facilitate optimal pain relief, improve quality of sleep and compliance. This simulation compared managing chronic osteoarthritis pain with once-daily OROS hydromorphone with an equianalgesic dose of extended-release (ER) oxycodone administered two or three times a day. This discrete event simulation follows patients for a year after initiating opioid treatment. Pairs of identical patients are created; one receives OROS hydromorphone the other ER oxycodone; undergo dose adjustments and after titration can be dissatisfied or satisfied, suffer adverse events, pain recurrence, or discontinue the opioid. Each is assigned an initial sleep problems score, and an improved score from a treatment dependent distribution at the end of titration; these are translated to a utility value. Utilities are assigned pre-treatment, updated until the patient reaches the optimal dose or is non-compliant or dissatisfied. The OROS hydromorphone and ER oxycodone doses are converted to equianalgesic morphine doses using the following ratios: hydromorphone to morphine ratio; 1:5, oxycodone to morphine ratio; 1:2. Sensitivity analyses explored uncertainty in the conversion ratios and other key parameters. Direct medical costs are in 2005 euros. Over 1 year on a mean daily morphine-equivalent dose of 90 mg, 14% were estimated to be dissatisfied with each opioid. OROS hydromorphone was predicted to yield 0.017 additional quality-adjusted life years (QALYs)/patient for a small additional annual cost (E141/patient), yielding an incremental cost-effectiveness ratio (ICER) of E8343/QALY gained. Changing the assumed conversion ratio for oxycodone:morphine to 1:1.5 led to lower net costs of E68 per patient, E3979/QALY, and for hydromorphone to 1:7.5 to savings. Based on these analyses, OROS hydromorphone is expected to yield health benefits at reasonable cost in Germany.

Effects of Dose Frequency of Early Communication Intervention in Young Children with and without Down Syndrome

ERIC Educational Resources Information Center

Yoder, Paul; Woynaroski, Tiffany; Fey, Marc; Warren, Steven

2014-01-01

Children with intellectual disability were randomly assigned to receive Milieu Communication Teaching (MCT) at one 1-hr session per week (low dose frequency, LDF) or five 1-hr sessions per week (high dose frequency, HDF) over 9 months (Fey, Yoder, Warren, & Bredin-Oja, 2013. Non-Down syndrome (NDS) and Down syndrome (DS) subgroups were matched…

Standard and reduced radiation dose liver CT images: adaptive statistical iterative reconstruction versus model-based iterative reconstruction-comparison of findings and image quality.

PubMed

Shuman, William P; Chan, Keith T; Busey, Janet M; Mitsumori, Lee M; Choi, Eunice; Koprowicz, Kent M; Kanal, Kalpana M

2014-12-01

To investigate whether reduced radiation dose liver computed tomography (CT) images reconstructed with model-based iterative reconstruction ( MBIR model-based iterative reconstruction ) might compromise depiction of clinically relevant findings or might have decreased image quality when compared with clinical standard radiation dose CT images reconstructed with adaptive statistical iterative reconstruction ( ASIR adaptive statistical iterative reconstruction ). With institutional review board approval, informed consent, and HIPAA compliance, 50 patients (39 men, 11 women) were prospectively included who underwent liver CT. After a portal venous pass with ASIR adaptive statistical iterative reconstruction images, a 60% reduced radiation dose pass was added with MBIR model-based iterative reconstruction images. One reviewer scored ASIR adaptive statistical iterative reconstruction image quality and marked findings. Two additional independent reviewers noted whether marked findings were present on MBIR model-based iterative reconstruction images and assigned scores for relative conspicuity, spatial resolution, image noise, and image quality. Liver and aorta Hounsfield units and image noise were measured. Volume CT dose index and size-specific dose estimate ( SSDE size-specific dose estimate ) were recorded. Qualitative reviewer scores were summarized. Formal statistical inference for signal-to-noise ratio ( SNR signal-to-noise ratio ), contrast-to-noise ratio ( CNR contrast-to-noise ratio ), volume CT dose index, and SSDE size-specific dose estimate was made (paired t tests), with Bonferroni adjustment. Two independent reviewers identified all 136 ASIR adaptive statistical iterative reconstruction image findings (n = 272) on MBIR model-based iterative reconstruction images, scoring them as equal or better for conspicuity, spatial resolution, and image noise in 94.1% (256 of 272), 96.7% (263 of 272), and 99.3% (270 of 272), respectively. In 50 image sets, two reviewers (n = 100) scored overall image quality as sufficient or good with MBIR model-based iterative reconstruction in 99% (99 of 100). Liver SNR signal-to-noise ratio was significantly greater for MBIR model-based iterative reconstruction (10.8 ± 2.5 [standard deviation] vs 7.7 ± 1.4, P < .001); there was no difference for CNR contrast-to-noise ratio (2.5 ± 1.4 vs 2.4 ± 1.4, P = .45). For ASIR adaptive statistical iterative reconstruction and MBIR model-based iterative reconstruction , respectively, volume CT dose index was 15.2 mGy ± 7.6 versus 6.2 mGy ± 3.6; SSDE size-specific dose estimate was 16.4 mGy ± 6.6 versus 6.7 mGy ± 3.1 (P < .001). Liver CT images reconstructed with MBIR model-based iterative reconstruction may allow up to 59% radiation dose reduction compared with the dose with ASIR adaptive statistical iterative reconstruction , without compromising depiction of findings or image quality. © RSNA, 2014.

Analyser-based mammography using single-image reconstruction.

PubMed

Briedis, Dahliyani; Siu, Karen K W; Paganin, David M; Pavlov, Konstantin M; Lewis, Rob A

2005-08-07

We implement an algorithm that is able to decode a single analyser-based x-ray phase-contrast image of a sample, converting it into an equivalent conventional absorption-contrast radiograph. The algorithm assumes the projection approximation for x-ray propagation in a single-material object embedded in a substrate of approximately uniform thickness. Unlike the phase-contrast images, which have both directional bias and a bias towards edges present in the sample, the reconstructed images are directly interpretable in terms of the projected absorption coefficient of the sample. The technique was applied to a Leeds TOR[MAM] phantom, which is designed to test mammogram quality by the inclusion of simulated microcalcifications, filaments and circular discs. This phantom was imaged at varying doses using three modalities: analyser-based synchrotron phase-contrast images converted to equivalent absorption radiographs using our algorithm, slot-scanned synchrotron imaging and imaging using a conventional mammography unit. Features in the resulting images were then assigned a quality score by volunteers. The single-image reconstruction method achieved higher scores at equivalent and lower doses than the conventional mammography images, but no improvement of visualization of the simulated microcalcifications, and some degradation in image quality at reduced doses for filament features.

Antisense oligonucleotides targeting apolipoprotein(a) in people with raised lipoprotein(a): two randomised, double-blind, placebo-controlled, dose-ranging trials.

PubMed

Viney, Nicholas J; van Capelleveen, Julian C; Geary, Richard S; Xia, Shuting; Tami, Joseph A; Yu, Rosie Z; Marcovina, Santica M; Hughes, Steven G; Graham, Mark J; Crooke, Rosanne M; Crooke, Stanley T; Witztum, Joseph L; Stroes, Erik S; Tsimikas, Sotirios

2016-11-05

Elevated lipoprotein(a) (Lp[a]) is a highly prevalent (around 20% of people) genetic risk factor for cardiovascular disease and calcific aortic valve stenosis, but no approved specific therapy exists to substantially lower Lp(a) concentrations. We aimed to assess the efficacy, safety, and tolerability of two unique antisense oligonucleotides designed to lower Lp(a) concentrations. We did two randomised, double-blind, placebo-controlled trials. In a phase 2 trial (done in 13 study centres in Canada, the Netherlands, Germany, Denmark, and the UK), we assessed the effect of IONIS-APO(a) Rx , an oligonucleotide targeting apolipoprotein(a). Participants with elevated Lp(a) concentrations (125-437 nmol/L in cohort A; ≥438 nmol/L in cohort B) were randomly assigned (in a 1:1 ratio in cohort A and in a 4:1 ratio in cohort B) with an interactive response system to escalating-dose subcutaneous IONIS-APO(a) Rx (100 mg, 200 mg, and then 300 mg, once a week for 4 weeks each) or injections of saline placebo, once a week, for 12 weeks. Primary endpoints were mean percentage change in fasting plasma Lp(a) concentration at day 85 or 99 in the per-protocol population (participants who received more than six doses of study drug) and safety and tolerability in the safety population. In a phase 1/2a first-in-man trial, we assessed the effect of IONIS-APO(a)-L Rx , a ligand-conjugated antisense oligonucleotide designed to be highly and selectively taken up by hepatocytes, at the BioPharma Services phase 1 unit (Toronto, ON, Canada). Healthy volunteers (Lp[a] ≥75 nmol/L) were randomly assigned to receive a single dose of 10-120 mg IONIS-APO(a)L Rx subcutaneously in an ascending-dose design or placebo (in a 3:1 ratio; single-ascending-dose phase), or multiple doses of 10 mg, 20 mg, or 40 mg IONIS-APO(a)L Rx subcutaneously in an ascending-dose design or placebo (in an 8:2 ratio) at day 1, 3, 5, 8, 15, and 22 (multiple-ascending-dose phase). Primary endpoints were mean percentage change in fasting plasma Lp(a) concentration, safety, and tolerability at day 30 in the single-ascending-dose phase and day 36 in the multiple-ascending-dose phase in participants who were randomised and received at least one dose of study drug. In both trials, the randomised allocation sequence was generated by Ionis Biometrics or external vendor with a permuted-block randomisation method. Participants, investigators, sponsor personnel, and clinical research organisation staff who analysed the data were all masked to the treatment assignments. Both trials are registered with ClinicalTrials.gov, numbers NCT02160899 and NCT02414594. From June 25, 2014, to Nov 18, 2015, we enrolled 64 participants to the phase 2 trial (51 in cohort A and 13 in cohort B). 35 were randomly assigned to IONIS-APO(a) Rx and 29 to placebo. At day 85/99, participants assigned to IONIS-APO(a) Rx had mean Lp(a) reductions of 66·8% (SD 20·6) in cohort A and 71·6% (13·0) in cohort B (both p<0·0001 vs pooled placebo). From April 15, 2015, to Jan 11, 2016, we enrolled 58 healthy volunteers to the phase 1/2a trial of IONIS-APO(a)-L Rx . Of 28 participants in the single-ascending-dose phase, three were randomly assigned to 10 mg, three to 20 mg, three to 40 mg, six to 80 mg, six to 120 mg, and seven to placebo. Of 30 participants in the multiple-ascending-dose phase, eight were randomly assigned to 10 mg, eight to 20 mg, eight to 40 mg, and six to placebo. Significant dose-dependent reductions in mean Lp(a) concentrations were noted in all single-dose IONIS-APO(a)-L Rx groups at day 30. In the multidose groups, IONIS-APO(a)-L Rx resulted in mean reductions in Lp(a) of 66% (SD 21·8) in the 10 mg group, 80% (SD 13·7%) in the 20 mg group, and 92% (6·5) in the 40 mg group (p=0·0007 for all vs placebo) at day 36. Both antisense oligonucleotides were safe. There were two serious adverse events (myocardial infarctions) in the IONIS-APO(a) Rx phase 2 trial, one in the IONIS-APO(a) Rx and one in the placebo group, but neither were thought to be treatment related. 12% of injections with IONIS-APO(a) Rx were associated with injection-site reactions. IONIS-APO(a)-L Rx was associated with no injection-site reactions. IONIS-APO(a)-L Rx is a novel, tolerable, potent therapy to reduce Lp(a) concentrations. IONIS-APO(a)-L Rx might mitigate Lp(a)-mediated cardiovascular risk and is being developed for patients with elevated Lp(a) concentrations with existing cardiovascular disease or calcific aortic valve stenosis. Ionis Pharmaceuticals. Copyright © 2016 Elsevier Ltd. All rights reserved.

A voxel-based investigation for MRI-only radiotherapy of the brain using ultra short echo times

NASA Astrophysics Data System (ADS)

Edmund, Jens M.; Kjer, Hans M.; Van Leemput, Koen; Hansen, Rasmus H.; Andersen, Jon AL; Andreasen, Daniel

2014-12-01

Radiotherapy (RT) based on magnetic resonance imaging (MRI) as the only modality, so-called MRI-only RT, would remove the systematic registration error between MR and computed tomography (CT), and provide co-registered MRI for assessment of treatment response and adaptive RT. Electron densities, however, need to be assigned to the MRI images for dose calculation and patient setup based on digitally reconstructed radiographs (DRRs). Here, we investigate the geometric and dosimetric performance for a number of popular voxel-based methods to generate a so-called pseudo CT (pCT). Five patients receiving cranial irradiation, each containing a co-registered MRI and CT scan, were included. An ultra short echo time MRI sequence for bone visualization was used. Six methods were investigated for three popular types of voxel-based approaches; (1) threshold-based segmentation, (2) Bayesian segmentation and (3) statistical regression. Each approach contained two methods. Approach 1 used bulk density assignment of MRI voxels into air, soft tissue and bone based on logical masks and the transverse relaxation time T2 of the bone. Approach 2 used similar bulk density assignments with Bayesian statistics including or excluding additional spatial information. Approach 3 used a statistical regression correlating MRI voxels with their corresponding CT voxels. A similar photon and proton treatment plan was generated for a target positioned between the nasal cavity and the brainstem for all patients. The CT agreement with the pCT of each method was quantified and compared with the other methods geometrically and dosimetrically using both a number of reported metrics and introducing some novel metrics. The best geometrical agreement with CT was obtained with the statistical regression methods which performed significantly better than the threshold and Bayesian segmentation methods (excluding spatial information). All methods agreed significantly better with CT than a reference water MRI comparison. The mean dosimetric deviation for photons and protons compared to the CT was about 2% and highest in the gradient dose region of the brainstem. Both the threshold based method and the statistical regression methods showed the highest dosimetrical agreement. Generation of pCTs using statistical regression seems to be the most promising candidate for MRI-only RT of the brain. Further, the total amount of different tissues needs to be taken into account for dosimetric considerations regardless of their correct geometrical position.

Iron absorption from oral iron supplements given on consecutive versus alternate days and as single morning doses versus twice-daily split dosing in iron-depleted women: two open-label, randomised controlled trials.

PubMed

Stoffel, Nicole U; Cercamondi, Colin I; Brittenham, Gary; Zeder, Christophe; Geurts-Moespot, Anneke J; Swinkels, Dorine W; Moretti, Diego; Zimmermann, Michael B

2017-11-01

Current guidelines to treat iron deficiency recommend daily provision of ferrous iron divided through the day to increase absorption. However, daily dosing and split dosing might increase serum hepcidin and decrease iron absorption from subsequent doses. Our study aim was to compare iron absorption from oral iron supplements given on consecutive versus alternate days and given as single morning doses versus twice-daily split dosing. We did two prospective, open-label, randomised controlled trials assessing iron absorption using ( 54 Fe)-labelled, ( 57 Fe)-labelled, or ( 58 Fe)-labelled ferrous sulfate in iron-depleted (serum ferritin ≤25 μg/L) women aged 18-40 years recruited from ETH Zurich and the University of Zurich, Switzerland. In study 1, women were randomly assigned (1:1) to two groups. One group was given 60 mg iron at 0800 h (±1 h) on consecutive days for 14 days, and the other group was given the same doses on alternate days for 28 days. In study 2, women were assigned to two groups, stratified by serum ferritin so that two groups with similar iron statuses could be formed. One group was given 120 mg iron at 0800 h (±1 h) and the other was given the dose split into two divided doses of 60 mg at 0800 h (±1 h) and 1700 h (±1 h) for three consecutive days. 14 days after the final dose, the groups were each crossed over to the other regimen. Within-individual comparisons were done. The co-primary outcomes in both studies were iron bioavailability (total and fractional iron absorption), assessed by measuring the isotopic label abundance in erythrocytes 14 days after administration, and serum hepcidin. Group allocations in both studies were not masked and primary and safety analyses were done on an intention-to-treat basis. The studies were registered at ClinicalTrials.gov, numbers NCT02175888 (study 1) and NCT02177851 (study 2) and are complete. For study 1, 40 women were enrolled on Oct 15-29, 2015. 21 women were assigned to the consecutive-day group and 19 to the alternate-day group. At the end of treatment (14 days for the consecutive-day group and 28 days for the alternate-day group), geometric mean (-SD, +SD) cumulative fractional iron absorptions were 16·3% (9·3, 28·8) in the consecutive-day group versus 21·8% (13·7, 34·6) in the alternate-day group (p=0·0013), and cumulative total iron absorption was 131·0 mg (71·4, 240·5) versus 175·3 mg (110·3, 278·5; p=0·0010). During the first 14 days of supplementation in both groups, serum hepcidin was higher in the consecutive-day group than the alternate-day group (p=0·0031). In study 2, 20 women were enrolled between Aug 13 and 18, 2015. Ten women were assigned to receive once-daily dosing and ten were assigned to receive twice-daily divided dosing. No significant differences were seen in fractional (day 1-3 geometric mean: 11·8% [7·1, 19·4] once daily vs 13·1% [8·2, 20·7] twice daily; p=0·33) or total iron absorption (day 1-3: 44·3 mg [29·4, 66·7] once daily vs 49·4 [35·2, 69·4] twice daily; p=0·33) between the two dosing regimens. Twice-daily divided doses resulted in a higher serum hepcidin concentration than once-daily dosing (p=0·013). No grade 3 or 4 adverse events were reported in either study. In iron-depleted women, providing iron supplements daily as divided doses increases serum hepcidin and reduces iron absorption. Providing iron supplements on alternate days and in single doses optimises iron absorption and might be a preferable dosing regimen. These findings should be confirmed in iron-deficient anaemic patients. Swiss National Science Foundation, Bern, Switzerland. Copyright © 2017 Elsevier Ltd. All rights reserved.

Adaptive, dose-finding phase 2 trial evaluating the safety and efficacy of ABT-089 in mild to moderate Alzheimer disease.

PubMed

Lenz, Robert A; Pritchett, Yili L; Berry, Scott M; Llano, Daniel A; Han, Shu; Berry, Donald A; Sadowsky, Carl H; Abi-Saab, Walid M; Saltarelli, Mario D

2015-01-01

ABT-089, an α4β2 neuronal nicotinic receptor partial agonist, was evaluated for efficacy and safety in mild to moderate Alzheimer disease patients receiving stable doses of acetylcholinesterase inhibitors. This phase 2 double-blind, placebo-controlled, proof-of-concept, and dose-finding study adaptively randomized patients to receive ABT-089 (5, 10, 15, 20, 30, or 35 mg once daily) or placebo for 12 weeks. The primary efficacy endpoint was the Alzheimer's Disease Assessment Scale, cognition subscale (ADAS-Cog) total score. A Bayesian response-adaptive randomization algorithm dynamically assigned allocation probabilities based on interim ADAS-Cog total scores. A normal dynamic linear model for dose-response relationships and a longitudinal model for predicting final ADAS-cog score were employed in the algorithm. Stopping criteria for futility or success were defined. The futility stopping criterion was met, terminating the study with 337 patients randomized. No dose-response relationship was observed and no dose demonstrated statistically significant improvement over placebo on ADAS-Cog or any secondary endpoint. ABT-089 was well tolerated at all dose levels. When administered as adjunctive therapy to acetylcholinesterase inhibitors, ABT-089 was not efficacious in mild to moderate Alzheimer disease. The adaptive study design enabled the examination of a broad dose range, enabled rapid determination of futility, and reduced patient exposure to nonefficacious doses of the investigational compound.

Poster — Thur Eve — 14: Improving Tissue Segmentation for Monte Carlo Dose Calculation using DECT

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

Di Salvio, A.; Bedwani, S.; Carrier, J-F.

2014-08-15

Purpose: To improve Monte Carlo dose calculation accuracy through a new tissue segmentation technique with dual energy CT (DECT). Methods: Electron density (ED) and effective atomic number (EAN) can be extracted directly from DECT data with a stoichiometric calibration method. Images are acquired with Monte Carlo CT projections using the user code egs-cbct and reconstructed using an FDK backprojection algorithm. Calibration is performed using projections of a numerical RMI phantom. A weighted parameter algorithm then uses both EAN and ED to assign materials to voxels from DECT simulated images. This new method is compared to a standard tissue characterization frommore » single energy CT (SECT) data using a segmented calibrated Hounsfield unit (HU) to ED curve. Both methods are compared to the reference numerical head phantom. Monte Carlo simulations on uniform phantoms of different tissues using dosxyz-nrc show discrepancies in depth-dose distributions. Results: Both SECT and DECT segmentation methods show similar performance assigning soft tissues. Performance is however improved with DECT in regions with higher density, such as bones, where it assigns materials correctly 8% more often than segmentation with SECT, considering the same set of tissues and simulated clinical CT images, i.e. including noise and reconstruction artifacts. Furthermore, Monte Carlo results indicate that kV photon beam depth-dose distributions can double between two tissues of density higher than muscle. Conclusions: A direct acquisition of ED and the added information of EAN with DECT data improves tissue segmentation and increases the accuracy of Monte Carlo dose calculation in kV photon beams.« less

Phenobarbitone versus phenytoin for treatment of neonatal seizures: an open-label randomized controlled trial.

PubMed

Pathak, Garima; Upadhyay, Amit; Pathak, Umesh; Chawla, Deepak; Goel, Sneh P

2013-08-01

To compare the efficacy of phenobarbitone and phenytoin for treatment of neonatal seizures in term and near-term neonates. Open labeled randomized controlled trial. Neonatal intensive care unit of a level II unit from India, from November 2008 to September 2009. All term and late pre-term neonates admitted with clinically apparent seizures and not having any transient metabolic disorders (hypoglycemia or hypocalcemia) were randomly assigned. Phenobarbitone (n=54) or phenytoin (n=55) intravenously 20 mg/kg/dose over 20-30 min. Neonates whose seizures were not controlled by the assigned drug were then crossed over to be treated with other drug in same dose. Clinical control of seizures (seizure free period of 24 hours after giving anticonvulsant). Baseline characteristics including mean birthweight, gestation age and sex were comparable in both groups. Seizures were controlled in 8 of the 55 (14.5%) neonates who received phenytoin, as compared to 39 of 54 (72.2%) neonates who received phenobarbitone (P <0.001). In babies not responding to assigned drugs, after cross-over to the other drug, seizure control was achieved in 44/55 (80%) of the neonates assigned to receive phenytoin first as compared to 49/54 (91%) of those assigned to receive phenobarbitone first (P=0.014). After maximum dose of phenobarbitone seizures were controlled in 49/55(89%) in phenytoin group and 52/54 (96%) in phenobarbitone group (P<0.05). Phenobarbitone is more efficacious than phenytoin in control of clinical seizures in term or near-term neonates, irrespective of etiology. To evaluate serum vascular endothelial growth factor (VEGF) levels in children with acute lymphoblastic leukemia (ALL) during the induction phase of chemotherapy.

Evaluation of a plasmid DNA-based anthrax vaccine in rabbits, nonhuman primates and healthy adults.

PubMed

Keitel, Wendy A; Treanor, John J; El Sahly, Hana M; Evans, Thomas G; Kopper, Scott; Whitlow, Vanessa; Selinsky, Cheryl; Kaslow, David C; Rolland, Alain; Smith, Larry R; Lalor, Peggy A

2009-08-01

VCL-AB01, a cationic lipid-formulated plasmid DNA (pDNA)-based vaccine that contains genes encoding genetically detoxified Bacillus anthracis protective antigen (PA) and lethal factor (LF), was assessed in a Phase 1, dose-escalating clinical trial in healthy adults for safety and immunogenicity, and in nonhuman primates for immunogenicity and efficacy against challenge with a lethal dose of B. anthracis spores. Healthy 18-45 year old subjects were randomly assigned to receive either the investigational vaccine containing 0.2 mg, 0.6 mg, or 2 mg of total pDNA per dose, or saline placebo, administered at 0, 1 and 2 months. The 0.2 mg and 0.6 mg dose levels were generally well tolerated; however, dose-limiting reactogenicity was observed among subjects given the first 2 mg dose and the remaining two injections in the 2 mg group were reduced to 0.6 mg. Dose-related increases in seroconversion frequencies were observed. Overall, 10%, 33.3% and 80% of subjects in the 0.2, 0.6 and 2 mg groups, respectively, developed antibodies to PA and/or LF as measured by ELISA; however, antibodies with toxin neutralizing activity (TNA) were detected in only one subject. In monkeys that received a 0.6 mg dose three times at 2 week intervals, low levels of antibodies were detected by ELISA but not by the TNA assay in all animals just prior to challenge. Despite the absence of TNA, 75% animals survived the lethal challenge. In summary, VCL-AB01 was generally well tolerated in humans at a dose that provided immunity in monkeys despite the lack of robust TNA titers in either species.

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.

40 CFR 799.9620 - TSCA neurotoxicity screening battery.

Code of Federal Regulations, 2012 CFR

2012-07-01

... dose and control group for behavioral testing. At least five males and five females should be used in each dose and control group for terminal neuropathology. If interim neuropathological evaluations are... of the study. Animals shall be randomly assigned to treatment and control groups. (3) Control groups...

40 CFR 799.9620 - TSCA neurotoxicity screening battery.

Code of Federal Regulations, 2014 CFR

2014-07-01

... dose and control group for behavioral testing. At least five males and five females should be used in each dose and control group for terminal neuropathology. If interim neuropathological evaluations are... of the study. Animals shall be randomly assigned to treatment and control groups. (3) Control groups...

40 CFR 799.9620 - TSCA neurotoxicity screening battery.

Code of Federal Regulations, 2013 CFR

2013-07-01

... dose and control group for behavioral testing. At least five males and five females should be used in each dose and control group for terminal neuropathology. If interim neuropathological evaluations are... of the study. Animals shall be randomly assigned to treatment and control groups. (3) Control groups...

SU-E-I-57: Estimating the Occupational Eye Lens Dose in Interventional Radiology Using Active Personal Dosimeters Worn On the Chest

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

Omar, A; Marteinsdottir, M; Kadesjo, N

Purpose: To provide a general formalism for determination of occupational eye lens dose based on the response of an active personal dosimeter (APD) worn at chest level above the radiation protection apron. Methods: The formalism consists of three factors: (1) APD conversion factor converting the reading at chest level (APDchest) to the corresponding personal dose equivalent at eye level, (2) Dose conversion factor transferring the measured dose quantity, Hp(10), into a dose quantity relevant for the eye lens dose, (3) Correction factor accounting for differences in exposure of the eye(s) compared to the exposure at chest level (e.g., due tomore » protective lead glasses).The different factors were investigated and evaluated based on phantom and clinical measurements performed in an x-ray angiography suite for interventional cardiology. Results: The eye lens dose can be conservatively estimated by assigning an appropriate numerical value to each factor entering the formalism that in most circumstances overestimates the dose. Doing so, the eye lens dose to the primary operator and assisting staff was estimated in this work as D-eye,primary = 2.0 APDchest and D-eye,assisting = 1.0 APDchest, respectively.The annual eye lens dose to three nurses and one cardiologist was estimated to be 2, 2, 2, and 13 mSv (Hp(0.07)), respectively, using a TLD dosimeter worn at eye level. In comparison, using the formalism and APDchest measurements, the respective doses were 2, 2, 2, and 16 mSv (Hp(3)). Conclusion: The formalism outlined in this work can be used to estimate the occupational eye lens dose from the response of an APD worn on the chest. The formalism is general and could be applied also to other types of dosimeters. However, the numerical value of the different factors may differ from those obtained with the APD’s used in this work due to differences in dosimeter properties.« less

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

Thomas, S; Yuen, C; Huang, V

Purpose: In this abstract we implement and validate a 4D VMAT Acuros XB dose calculation using Gafchromic film. Special attention is paid to the physical material assignment in the CT dataset and to reported dose to water and dose to medium. Methods: A QUASAR phantom with a 3 cm sinusoidal tumor motion and 5 second period was scanned using 4D computed tomography. A CT was also obtained of the static QUASAR phantom with the tumor at the central position. A VMAT plan was created on the average CT dataset and was delivered on a Varian TrueBeam linear accelerator. The trajectorymore » log file from this treatment was acquired and used to create 10 VMAT subplans (one for each portion of the breathing cycle). Motion for each subplan was simulated by moving the beam isocentre in the superior/inferior direction in the Treatment Planning System on the static CT scan. The 10 plans were calculated (both dose to medium and dose to water) and summed for 1) the original HU values from the static CT scan and 2) the correct physical material assignment in the CT dataset. To acquire a breathing phase synchronized film measurements the trajectory log was used to create a VMAT delivery plan which includes dynamic couch motion using the Developer Mode. Three different treatment start phases were investigated (mid inhalation, full inhalation and full exhalation). Results: For each scenario the coronal dose distributions were measured using Gafchromic film and compared to the corresponding calculation with Film QA Pro Software using a Gamma test with a 3%/3mm distance to agreement criteria. Good agreement was found between calculation and measurement. No statistically significant difference in agreement was found between calculations to original HU values vs calculations to over-written (material-assigned) HU values. Conclusion: The investigated 4D dose calculation method agrees well with measurement.« less

Safety and immunogenicity of a recombinant adenovirus type-5 vector-based Ebola vaccine in healthy adults in Sierra Leone: a single-centre, randomised, double-blind, placebo-controlled, phase 2 trial.

PubMed

Zhu, Feng-Cai; Wurie, Alie H; Hou, Li-Hua; Liang, Qi; Li, Yu-Hua; Russell, James B W; Wu, Shi-Po; Li, Jing-Xin; Hu, Yue-Mei; Guo, Qiang; Xu, Wen-Bo; Wurie, Abdul R; Wang, Wen-Juan; Zhang, Zhe; Yin, Wen-Jiao; Ghazzawi, Manal; Zhang, Xu; Duan, Lei; Wang, Jun-Zhi; Chen, Wei

2017-02-11

A recombinant adenovirus type-5 vector-based vaccine expressing the glycoprotein of Ebola Zaire Makona variant showed good safety and immunogenicity in a phase 1 trial of healthy Chinese adults. We aimed to assess the safety and immunogenicity of this vaccine in healthy adults in Sierra Leone and to determine the optimal dose. We did a single-centre, randomised, double-blind, placebo-controlled, phase 2 clinical trial at Sierra Leone-China Friendship Hospital, Freetown, Sierra Leone. We recruited healthy adults aged 18-50 years who were HIV negative, had no history of Ebola virus infection, and had no previous immunisation with other Ebola vaccine candidates. Participants were sequentially enrolled and randomly assigned (2:1:1), by computer-generated block randomisation (block size of eight), to receive the high-dose vaccine (1·6 × 10 11 viral particles), low-dose vaccine (8·0 × 10 10 viral particles), or placebo (containing only vaccine excipients, with no viral particles). Participants, investigators, and study staff (except two study pharmacists) were masked from treatment allocation. The primary safety outcome was occurrence of solicited adverse reactions within 7 days of vaccination, analysed by intention to treat. The primary immunogenicity outcome was glycoprotein-specific antibody responses at days 14, 28, and 168 after vaccination, analysed in all vaccinated participants who had blood samples drawn for antibody tests. The trial is registered with the Pan African Clinical Trials Registry, number PACTR201509001259869, and is completed. During Oct 10-28, 2015, 500 participants were enrolled and randomly assigned to receive the high-dose vaccine (n=250), low-dose vaccine (n=125), or placebo (n=125). 132 (53%) participants in the high-dose group, 60 (48%) in the low-dose group, and 54 (43%) in the placebo group reported at least one solicited adverse reaction within 7 days of vaccination. Most adverse reactions were mild and self-limiting. Solicited injection-site adverse reactions were significantly more frequent in vaccine recipients (65 [26%] in high-dose group and 31 [25%] in low-dose group) than in those receiving placebo (17 [14%]; p=0·0169). Glycoprotein-specific antibody responses were detected from day 14 onwards (geometric mean titre 1251·0 [95% CI 976·6-1602·5] in low-dose group and 1728·4 [1459·4-2047·0] in high-dose group) and peaked at day 28 (1471·8 [1151·0-1881·8] and 2043·1 [1762·4-2368·4]), but declined quickly in the following months (223·3 [148·2-336·4] and 254·2 [185·0-349·5] at day 168). Geometric mean titres in the placebo group remained around 6·0-6·8 throughout the study period. Three serious adverse events (malaria, gastroenteritis, and one fatal asthma episode) were reported in the high-dose vaccine group, but none was deemed related to the vaccine. The recombinant adenovirus type-5 vector-based Ebola vaccine was safe and highly immunogenic in healthy Sierra Leonean adults, and 8·0 × 10 10 viral particles was the optimal dose. Chinese Ministry of Science and Technology and the National Health and Family Planning Commission, Beijing Institute of Biotechnology, and Tianjin CanSino Biotechnology. Copyright © 2017 Elsevier Ltd. All rights reserved.

[Effectiveness and safety of losartan and its combination with hydrochlorothiazide in patients with hypertension: in result study].

PubMed

Glezer, M G; Saĭgitov, R T

2012-01-01

There are limited data on the results of Russia's use of losartan in clinical practice for the treatment of patients with arterial hypertension (AH). The purpose of the study was to assess the efficacy and safety of losartan and its fixed combination with hydrochlorothiazide (HCTZ) in patients with hypertension. Primary care physicians (n=644) for 8 weeks evaluated outcomes of treatment of hypertensive patients who were assigned to losartan monotherapy (12.5, 25, 50 or 100 mg) or a fixed combination with hydrochlorothiazide (losartan 50 mg/hydrochlorothiazide 12.5 mg , losartan 100 mg/hydrochlorothiazide 25 mg). The effectiveness of treatment was assessed by size reduction of systolic/diastolic blood pressure (SBP/DBP), and the frequency of achieving target blood pressure (<140/90 or <130/80 mm Hg in patients with diabetes). Losartan at a dose 12.5 mg was assigned to 382 (3.8%), at a dose of 25 mg - to 1061 (10.7%), at a dose of 50 mg - to 3545 (35.6%), at a dose of 100 mg - to 3247 (32.6%), at a dose of 50 mg / hydrochlorothiazide 12.5 mg - to 893 (9.0%), at a dose of 100 mg / hydrochlorothiazide 25 mg - to 820 (8.2%) of 9948 patients included in the study. According to multivariate analysis, dose selection of losartan was determined by an attending physician, mainly (85% according to the estimate of the explained variance), based on the baseline SBP. As a result of treatment (41 to 53% of patients received losartan only or in combination with HCTZ) SBP decrease in the groups ranged from 20 to 38 mm Hg, DBP - from 10 to 17 mm Hg, the target blood pressure is achieved in 29-66% of patients. At least one adverse event occurred in 141 (1.4%) patients, with lower frequency in patients receiving losartan 50 mg (adjusted odds ratio 0.34, 95% confidence interval 0.19 to 0.63; the reference group - patients receiving losartan 100 mg/hydrochlorothiazide 25 mg). Thus losartan as monotherapy or in fixed combination with HCTZ for hypertensive patients is characterized by high antihypertensive efficacy and safety.

Recommended de minimis radiation dose rates for Canada. Report No. INFO-0355

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

Not Available

1990-01-01

A de minimis dose or dose rate as used in this report represents a level of risk which is generally accepted as being of no significance to an individual, or in the case of a population, of no significance to society. The report describes the risk of biological effects from radiation; radiation from natural and man-made sources; normal incidences of cancer and genetic defects; initiatives by other agencies in the U.S., the U.K. and internationally; the importance of collective dose and dose rate; assigning values to the de minimis dose rates; and application of the de minimis dose rates.

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

Klüter, Sebastian, E-mail: sebastian.klueter@med.uni-heidelberg.de; Schubert, Kai; Lissner, Steffen

Purpose: The dosimetric verification of treatment plans in helical tomotherapy usually is carried out via verification measurements. In this study, a method for independent dose calculation of tomotherapy treatment plans is presented, that uses a conventional treatment planning system with a pencil kernel dose calculation algorithm for generation of verification dose distributions based on patient CT data. Methods: A pencil beam algorithm that directly uses measured beam data was configured for dose calculation for a tomotherapy machine. Tomotherapy treatment plans were converted into a format readable by an in-house treatment planning system by assigning each projection to one static treatmentmore » field and shifting the calculation isocenter for each field in order to account for the couch movement. The modulation of the fluence for each projection is read out of the delivery sinogram, and with the kernel-based dose calculation, this information can directly be used for dose calculation without the need for decomposition of the sinogram. The sinogram values are only corrected for leaf output and leaf latency. Using the converted treatment plans, dose was recalculated with the independent treatment planning system. Multiple treatment plans ranging from simple static fields to real patient treatment plans were calculated using the new approach and either compared to actual measurements or the 3D dose distribution calculated by the tomotherapy treatment planning system. In addition, dose–volume histograms were calculated for the patient plans. Results: Except for minor deviations at the maximum field size, the pencil beam dose calculation for static beams agreed with measurements in a water tank within 2%/2 mm. A mean deviation to point dose measurements in the cheese phantom of 0.89% ± 0.81% was found for unmodulated helical plans. A mean voxel-based deviation of −0.67% ± 1.11% for all voxels in the respective high dose region (dose values >80%), and a mean local voxel-based deviation of −2.41% ± 0.75% for all voxels with dose values >20% were found for 11 modulated plans in the cheese phantom. Averaged over nine patient plans, the deviations amounted to −0.14% ± 1.97% (voxels >80%) and −0.95% ± 2.27% (>20%, local deviations). For a lung case, mean voxel-based deviations of more than 4% were found, while for all other patient plans, all mean voxel-based deviations were within ±2.4%. Conclusions: The presented method is suitable for independent dose calculation for helical tomotherapy within the known limitations of the pencil beam algorithm. It can serve as verification of the primary dose calculation and thereby reduce the need for time-consuming measurements. By using the patient anatomy and generating full 3D dose data, and combined with measurements of additional machine parameters, it can substantially contribute to overall patient safety.« less

SU-C-210-05: Evaluation of Robustness: Dosimetric Effects of Anatomical Changes During Fractionated Radiation Treatment of Pancreatic Cancer Patients

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

Horst, A van der; Houweling, A C; Bijveld, M M C

2015-06-15

Purpose: Pancreatic tumors show large interfractional position variations. In addition, changes in gastrointestinal air volume and body contour take place during treatment. We aim to investigate the robustness of the clinical treatment plans by quantifying the dosimetric effects of these anatomical changes. Methods: Calculations were performed for up to now 3 pancreatic cancer patients who had intratumoral fiducials for daily CBCT-based positioning during their 3-week treatment. For each patient, deformable image registration of the planning CT was used to assign Hounsfield Units to each of the 13—15 CBCTs; air volumes and body contour were copied from CBCT. The clinical treatmentmore » plan was used (CTV-PTV margin = 10 mm; 36Gy; 10MV; 1 arc VMAT). Fraction dose distributions were calculated and accumulated. The V95% of the clinical target volume (CTV) and planning target volume (PTV) were analyzed, as well as the dose to stomach, duodenum and liver. Dose accumulation was done for patient positioning based on the fiducials (as clinically used) as well as for positioning based on bony anatomy. Results: For all three patients, the V95% of the CTV remained 100%, for both fiducial- and bony anatomy-based positioning. For fiducial-based positioning, dose to duodenum en stomach showed no discernable differences with planned dose. For bony anatomy-based positioning, the PTV V95% of the patient with the largest systematic difference in tumor position (patient 1) decreased to 85%; the liver Dmax increased from 33.5Gy (planned) to 35.5Gy. Conclusion: When using intratumoral fiducials, CTV dose coverage was only mildly affected by the daily anatomical changes. When using bony anatomy for patient positioning, we found a decline in PTV dose coverage due to the interfractional tumor position variations. Photon irradiation treatment plans for pancreatic tumors are robust to variations in body contour and gastrointestinal gas, but the use of fiducial-based daily position verification is imperative. This work was supported by the foundation Bergh in het Zadel through the Dutch Cancer Society (KWF Kankerbestrijding) project No. UVA 2011-5271.« less

Dosing Strategies for Lithium Monotherapy in Children and Adolescents with Bipolar I Disorder

PubMed Central

Kafantaris, Vivian; Pavuluri, Mani; McNamara, Nora K.; McClellan, Jon; Frazier, Jean A.; Sikich, Linmarie; Kowatch, Robert; Lingler, Jacqui; Faber, Jon; Rowles, Brieana M.; Clemons, Traci E.; Taylor-Zapata, Perdita

2011-01-01

Abstract Objective The primary goal of this exploratory study was to obtain data that could lead to evidence-based dosing strategies for lithium in children and adolescents suffering from bipolar I disorder. Methods Outpatients aged 7–17 years meeting Diagnostic and Statistical Manual of Mental Disorders, 4th edition, diagnostic criteria for bipolar I disorder (manic or mixed) were eligible for 8 weeks of open label treatment with lithium in one of three dosing arms. In Arm I, participants began treatment at a dose of 300 mg of lithium twice daily. The starting dose of lithium in Arms II and III was 300 mg thrice daily. Patients in Arms I and II could have their dose increased by 300 mg/day, depending on clinical response, at weekly visits. Patients in Arm III also had mid-week telephone interviews after which they could also have their dose of lithium increased by 300 mg per day. Youths weighing <30 kg were automatically assigned to Arm I, whereas youths weighing ≥30 kg were randomly assigned to Arm I, II, or III. Randomization was balanced by age (7–11 years, 12–17 years) and sex in approximately equal numbers. A priori response criteria were defined as a Clinical Global Impressions-Improvement scale score of ≤2 and a 50% decrease from baseline on the Young Mania Rating Scale. Results Of the 61 youths [32 males (52.5%)] who received open-label lithium, 60 youths completed at least 1 week of treatment and returned for a postbaseline assessment. Most patients had a ≥50% improvement in Young Mania Rating Scale score, and more than half of the patients (58%) achieved response. Overall, lithium was well tolerated. All three treatment arms had similar effectiveness, side effect profiles, and tolerability of lithium. Conclusions On the basis of these results, a dosing strategy in which pediatric patients begin lithium at a dose of 300 mg thrice daily (with an additional 300 mg increase during the first week), followed by 300 mg weekly increases until a priori stopping criteria are met, will be used in an upcoming randomized, placebo-controlled trial. PMID:21663422

Efficacy of pentavalent rotavirus vaccine against severe rotavirus gastroenteritis in infants in developing countries in sub-Saharan Africa: a randomised, double-blind, placebo-controlled trial.

PubMed

Armah, George E; Sow, Samba O; Breiman, Robert F; Dallas, Michael J; Tapia, Milagritos D; Feikin, Daniel R; Binka, Fred N; Steele, A Duncan; Laserson, Kayla F; Ansah, Nana A; Levine, Myron M; Lewis, Kristen; Coia, Michele L; Attah-Poku, Margaret; Ojwando, Joel; Rivers, Stephen B; Victor, John C; Nyambane, Geoffrey; Hodgson, Abraham; Schödel, Florian; Ciarlet, Max; Neuzil, Kathleen M

2010-08-21

Rotavirus gastroenteritis causes many deaths in infants in sub-Saharan Africa. Because rotavirus vaccines have proven effective in developed countries but had not been tested in developing countries, we assessed efficacy of a pentavalent rotavirus vaccine against severe disease in Ghana, Kenya, and Mali between April, 2007, and March, 2009. In our multicentre, double-blind, placebo-controlled trial, undertaken in rural areas of Ghana and Kenya and an urban area of Mali, we randomly assigned infants aged 4-12 weeks without symptoms of gastrointestinal disorders in a 1:1 ratio to receive three oral doses of pentavalent rotavirus vaccine 2 mL or placebo at around 6 weeks, 10 weeks, and 14 weeks of age. Infants with HIV infection were not excluded. Randomisation was done by computer-generated randomisation sequence in blocks of six. We obtained data for gastrointestinal symptoms from parents on presentation to health-care facilities and clinical data were obtained prospectively by clinicians. The primary endpoint was severe rotavirus gastroenteritis (Vesikari score >or=11), detected by enzyme immunoassay, arising 14 days or more after the third dose of placebo or vaccine to end of study (March 31, 2009; around 21 months of age). Analysis was per protocol; infants who received scheduled doses of vaccine or placebo without intervening laboratory-confirmed naturally occurring rotavirus disease earlier than 14 days after the third dose and had complete clinical and laboratory results were included in the analysis. This study is registered with ClinicalTrials.gov, number NCT00362648. 5468 infants were randomly assigned to receive pentavalent rotavirus vaccine (n=2733) or placebo (n=2735). 2357 infants assigned to vaccine and 2348 assigned to placebo were included in the per-protocol analysis. 79 cases of severe rotavirus gastroenteritis were reported in 2610.6 person-years in the vaccine group, compared with 129 cases in 2585.9 person-years in the placebo group, resulting in a vaccine efficacy against severe rotavirus gastroenteritis of 39.3% (95% CI 19.1-54.7, p=0.0003 for efficacy >0%). Median follow-up in both groups was 527 days starting 14 days after the third dose of vaccine or placebo was given. 42 (1.5%) of 2723 infants assigned to receive vaccine and 45 (1.7%) of 2724 infants assigned to receive placebo had a serious adverse event within 14 days of any dose. The most frequent serious adverse event was gastroenteritis (vaccine 17 [0.6%]; placebo 17 [0.6%]). Pentavalent rotavirus vaccine is effective against severe rotavirus gastroenteritis in the first 2 years of life in African countries with high mortality in infants younger than 5 years. We support WHO's recommendation for adoption of rotavirus vaccine into national expanded programmes on immunisation in Africa. PATH (GAVI Alliance grant) and Merck. Copyright 2010 Elsevier Ltd. All rights reserved.

Pharmacokinetic Profile and Tolerability of Liposomal Bupivacaine Following a Repeated Dose via Local Subcutaneous Infiltration in Healthy Volunteers.

PubMed

Rice, David; Heil, Justin W; Biernat, Lukasz

2017-03-01

Liposomal bupivacaine is indicated for administration into the surgical site to produce post-surgical analgesia. The objectives of this study were to characterize the pharmacokinetic and safety profiles of liposomal bupivacaine following a repeated dose in healthy volunteers. Healthy adults were assigned to receive liposomal bupivacaine via subcutaneous infiltration in a single 266 mg dose (cohort 1) or in two 266 mg doses, with the second dose given immediately, 24, 48, or 72 h after the first dose (cohorts 2-5). Pharmacokinetic parameters were estimated from blood samples collected up to day 14. Subjects were monitored for adverse events and assessed for neurologic function, cardiac function, and infiltration area abnormalities. Twelve subjects were assigned to each cohort. The mean ± standard deviation maximum observed plasma concentration (C max ) of bupivacaine after a single dose was 129 ± 47 ng/mL. The mean C max after the second dose was higher, but always less than double the C max for cohort 1. The highest individual C max (589 ng/mL) was observed in a subject who received the second dose 24 h after the first dose (cohort 4), but was well below the reported thresholds for neurotoxicity and cardiac toxicity (2000 and 4000 ng/mL, respectively). A single and repeated dose were well-tolerated, and there were no clinically meaningful findings regarding neurologic examinations and electrocardiography. The mean C max following a repeated dose of liposomal bupivacaine remained well below accepted values for central nervous system and cardiac toxicity. Liposomal bupivacaine was well-tolerated and revealed no clinically important safety signals. CLINICALTRIALS. NCT02210247.

Impact of Number of Human Papillomavirus Vaccine Doses on Genital Warts Diagnoses Among a National Cohort of U.S. Adolescents.

PubMed

Perkins, Rebecca B; Lin, Mengyun; Wallington, Sherrie F; Hanchate, Amresh

2017-06-01

The impact of fewer than 3 doses of human papillomavirus (HPV) vaccine on genital warts is uncertain. Using the Truven Health Analytics Marketscan administrative database, we compared rates of genital warts among women receiving 0, 1, 2, or 3 doses of HPV vaccine. Females aged 9 to 18 years on January 1, 2007, who were continuously enrolled in the database through December 31, 2013, were included. Patients were assigned an HPV dose state (0, 1, 2, or 3) based on the last recorded dose. The exposure period began on January 1, 2007, or the date of the final HPV dose, and lasted until the first diagnosis of genital warts or December 31, 2013. Multivariable Poisson regression was performed to determine the risk of genital warts associated with vaccine doses. Among 387,906 subjects, mean age and exposure period were 14.73 and 5.64 years, respectively. The proportions of doses received were: 52.1%, 7.8%, 9.4%, and 30.7% for 0, 1, 2, and 3 doses, respectively. The rate of genital warts was 1.97/1000 person-years. Receipt of 0 or 1 dose was associated with more genital warts than 3 doses. The effectiveness of 2 doses following current Centers for Disease Control and Prevention guidelines was similar to 3 doses. The risk of genital warts rose with age. Prevention of genital warts is higher with completion of 3 vaccine doses than with 1 dose, though 2-dose recommendations appear to provide similar protection. Prospective effectiveness studies of recommended 2-dose schedules against clinical endpoints including persistent infection, genital warts, and cervical dysplasia are necessary to ensure long-term protection of vaccinated cohorts.

Plane of nutrition during the preweaned period and Mannheimia haemolytica dose influence metabolic responses in post-weaned Holstein calves challenged with bovine herpesvirus-1 and Mannheimia haemolytica

USDA-ARS?s Scientific Manuscript database

To determine whether previous plane of milk replacer nutrition (PON) and M. haemolytica (MH) dose influences metabolic responses to a combined viral-bacterial respiratory challenge, Holstein calves (1 day of age; n=30) were assigned to treatments in a 2 x 3 factorial with preweaned PON and dose of M...

Plane of nutrition during the preweaned period and Mannheimia haemolytica dose influences inflammatory responses to a combined bovine herpesvirus-1 and Mannheimia haemolytica challenge in post-weaned Holstein calves

USDA-ARS?s Scientific Manuscript database

To determine whether previous plane of milk replacer nutrition (PON) and M. haemolytica (MH) dose influences inflammatory responses to a combined viral-bacterial respiratory challenge, Holstein calves (1 day of age; n=30) were assigned to treatments in a 2 x 3 factorial with preweaned PON and dose o...

The complexity of intestinal permeability: Assigning the correct BCS classification through careful data interpretation.

PubMed

Zur, Moran; Hanson, Allison S; Dahan, Arik

2014-09-30

While the solubility parameter is fairly straightforward when assigning BCS classification, the intestinal permeability (Peff) is more complex than generally recognized. In this paper we emphasize this complexity through the analysis of codeine, a commonly used antitussive/analgesic drug. Codeine was previously classified as a low-permeability compound, based on its lower LogP compared to metoprolol, a marker for the low-high permeability class boundary. In contrast, high fraction of dose absorbed (Fabs) was reported for codeine, which challenges the generally recognized Peff-Fabs correlation. The purpose of this study was to clarify this ambiguity through elucidation of codeine's BCS solubility/permeability class membership. Codeine's BCS solubility class was determined, and its intestinal permeability throughout the small intestine was investigated, both in vitro and in vivo in rats. Codeine was found to be unequivocally a high-solubility compound. All in vitro studies indicated that codeine's permeability is higher than metoprolol's. In vivo studies in rats showed similar permeability for both drugs throughout the entire small-intestine. In conclusion, codeine was found to be a BCS Class I compound. No Peff-Fabs discrepancy is involved in its absorption; rather, it reflects the risk of assigning BCS classification based on merely limited physicochemical characteristics. A thorough investigation using multiple experimental methods is prudent before assigning a BCS classification, to avoid misjudgment in various settings, e.g., drug discovery, formulation design, drug development and regulation. Copyright © 2013 Elsevier B.V. All rights reserved.

A CONCEPTUAL FRAMEWORK FOR MANAGING RADIATION DOSE TO PATIENTS IN DIAGNOSTIC RADIOLOGY USING REFERENCE DOSE LEVELS.

PubMed

Almén, Anja; Båth, Magnus

2016-06-01

The overall aim of the present work was to develop a conceptual framework for managing radiation dose in diagnostic radiology with the intention to support optimisation. An optimisation process was first derived. The framework for managing radiation dose, based on the derived optimisation process, was then outlined. The outset of the optimisation process is four stages: providing equipment, establishing methodology, performing examinations and ensuring quality. The optimisation process comprises a series of activities and actions at these stages. The current system of diagnostic reference levels is an activity in the last stage, ensuring quality. The system becomes a reactive activity only to a certain extent engaging the core activity in the radiology department, performing examinations. Three reference dose levels-possible, expected and established-were assigned to the three stages in the optimisation process, excluding ensuring quality. A reasonably achievable dose range is also derived, indicating an acceptable deviation from the established dose level. A reasonable radiation dose for a single patient is within this range. The suggested framework for managing radiation dose should be regarded as one part of the optimisation process. The optimisation process constitutes a variety of complementary activities, where managing radiation dose is only one part. This emphasises the need to take a holistic approach integrating the optimisation process in different clinical activities. © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

SU-E-J-193: Feasibility of MRI-Only Based IMRT Planning for Pancreatic Cancer

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

Prior, P; Botros, M; Chen, X

2014-06-01

Purpose: With the increasing use of MRI simulation and the advent of MRI-guided delivery, it is desirable to use MRI only for treatment planning. In this study, we assess the dosimetric difference between MRI- and CTbased IMRT planning for pancreatic cancer. Methods: Planning CTs and MRIs acquired for a representative pancreatic cancer patient were used. MRI-based planning utilized forced relative electron density (rED) assignment of organ specific values from IRCU report 46, where rED = 1.029 for PTV and a rED = 1.036 for non-specified tissue (NST). Six IMRT plans were generated with clinical dose-volume (DV) constraints using a researchmore » Monaco planning system employing Monte Carlo dose calculation with optional perpendicular magnetic field (MF) of 1.5T. The following five plans were generated and compared with the planning CT: 1.) CT plan with MF and dose recalculation without optimization; 2.) MRI (T2) plan with target and OARs redrawn based on MRI, forced rED, no MF, and recalculation without optimization; 3.) Similar as in 2 but with MF; 4.) MRI plan with MF but without optimization; and 5.) Similar as in 4 but with optimization. Results: Generally, noticeable differences in PTV point doses and DV parameters (DVPs) between the CT-and MRI-based plans with and without the MF were observed. These differences between the optimized plans were generally small, mostly within 2%. Larger differences were observed in point doses and mean doses for certain OARs between the CT and MRI plan, mostly due to differences between image acquisition times. Conclusion: MRI only based IMRT planning for pancreatic cancer is feasible. The differences observed between the optimized CT and MRI plans with or without the MF were practically negligible if excluding the differences between MRI and CT defined structures.« less

Exposing Exposure: Automated Anatomy-specific CT Radiation Exposure Extraction for Quality Assurance and Radiation Monitoring

PubMed Central

Warden, Graham I.; Farkas, Cameron E.; Ikuta, Ichiro; Prevedello, Luciano M.; Andriole, Katherine P.; Khorasani, Ramin

2012-01-01

Purpose: To develop and validate an informatics toolkit that extracts anatomy-specific computed tomography (CT) radiation exposure metrics (volume CT dose index and dose-length product) from existing digital image archives through optical character recognition of CT dose report screen captures (dose screens) combined with Digital Imaging and Communications in Medicine attributes. Materials and Methods: This institutional review board–approved HIPAA-compliant study was performed in a large urban health care delivery network. Data were drawn from a random sample of CT encounters that occurred between 2000 and 2010; images from these encounters were contained within the enterprise image archive, which encompassed images obtained at an adult academic tertiary referral hospital and its affiliated sites, including a cancer center, a community hospital, and outpatient imaging centers, as well as images imported from other facilities. Software was validated by using 150 randomly selected encounters for each major CT scanner manufacturer, with outcome measures of dose screen retrieval rate (proportion of correctly located dose screens) and anatomic assignment precision (proportion of extracted exposure data with correctly assigned anatomic region, such as head, chest, or abdomen and pelvis). The 95% binomial confidence intervals (CIs) were calculated for discrete proportions, and CIs were derived from the standard error of the mean for continuous variables. After validation, the informatics toolkit was used to populate an exposure repository from a cohort of 54 549 CT encounters; of which 29 948 had available dose screens. Results: Validation yielded a dose screen retrieval rate of 99% (597 of 605 CT encounters; 95% CI: 98%, 100%) and an anatomic assignment precision of 94% (summed DLP fraction correct 563 in 600 CT encounters; 95% CI: 92%, 96%). Patient safety applications of the resulting data repository include benchmarking between institutions, CT protocol quality control and optimization, and cumulative patient- and anatomy-specific radiation exposure monitoring. Conclusion: Large-scale anatomy-specific radiation exposure data repositories can be created with high fidelity from existing digital image archives by using open-source informatics tools. ©RSNA, 2012 Supplemental material: http://radiology.rsna.org/lookup/suppl/doi:10.1148/radiol.12111822/-/DC1 PMID:22668563

TH-A-9A-01: Active Optical Flow Model: Predicting Voxel-Level Dose Prediction in Spine SBRT

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

Liu, J; Wu, Q.J.; Yin, F

2014-06-15

Purpose: To predict voxel-level dose distribution and enable effective evaluation of cord dose sparing in spine SBRT. Methods: We present an active optical flow model (AOFM) to statistically describe cord dose variations and train a predictive model to represent correlations between AOFM and PTV contours. Thirty clinically accepted spine SBRT plans are evenly divided into training and testing datasets. The development of predictive model consists of 1) collecting a sequence of dose maps including PTV and OAR (spinal cord) as well as a set of associated PTV contours adjacent to OAR from the training dataset, 2) classifying data into fivemore » groups based on PTV's locations relative to OAR, two “Top”s, “Left”, “Right”, and “Bottom”, 3) randomly selecting a dose map as the reference in each group and applying rigid registration and optical flow deformation to match all other maps to the reference, 4) building AOFM by importing optical flow vectors and dose values into the principal component analysis (PCA), 5) applying another PCA to features of PTV and OAR contours to generate an active shape model (ASM), and 6) computing a linear regression model of correlations between AOFM and ASM.When predicting dose distribution of a new case in the testing dataset, the PTV is first assigned to a group based on its contour characteristics. Contour features are then transformed into ASM's principal coordinates of the selected group. Finally, voxel-level dose distribution is determined by mapping from the ASM space to the AOFM space using the predictive model. Results: The DVHs predicted by the AOFM-based model and those in clinical plans are comparable in training and testing datasets. At 2% volume the dose difference between predicted and clinical plans is 4.2±4.4% and 3.3±3.5% in the training and testing datasets, respectively. Conclusion: The AOFM is effective in predicting voxel-level dose distribution for spine SBRT. Partially supported by NIH/NCI under grant #R21CA161389 and a master research grant by Varian Medical System.« less

Robust EM Continual Reassessment Method in Oncology Dose Finding

PubMed Central

Yuan, Ying; Yin, Guosheng

2012-01-01

The continual reassessment method (CRM) is a commonly used dose-finding design for phase I clinical trials. Practical applications of this method have been restricted by two limitations: (1) the requirement that the toxicity outcome needs to be observed shortly after the initiation of the treatment; and (2) the potential sensitivity to the prespecified toxicity probability at each dose. To overcome these limitations, we naturally treat the unobserved toxicity outcomes as missing data, and use the expectation-maximization (EM) algorithm to estimate the dose toxicity probabilities based on the incomplete data to direct dose assignment. To enhance the robustness of the design, we propose prespecifying multiple sets of toxicity probabilities, each set corresponding to an individual CRM model. We carry out these multiple CRMs in parallel, across which model selection and model averaging procedures are used to make more robust inference. We evaluate the operating characteristics of the proposed robust EM-CRM designs through simulation studies and show that the proposed methods satisfactorily resolve both limitations of the CRM. Besides improving the MTD selection percentage, the new designs dramatically shorten the duration of the trial, and are robust to the prespecification of the toxicity probabilities. PMID:22375092

TH-E-BRF-02: 4D-CT Ventilation Image-Based IMRT Plans Are Dosimetrically Comparable to SPECT Ventilation Image-Based Plans

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

Kida, S; University of Tokyo Hospital, Bunkyo, Tokyo; Bal, M

Purpose: An emerging lung ventilation imaging method based on 4D-CT can be used in radiotherapy to selectively avoid irradiating highly-functional lung regions, which may reduce pulmonary toxicity. Efforts to validate 4DCT ventilation imaging have been focused on comparison with other imaging modalities including SPECT and xenon CT. The purpose of this study was to compare 4D-CT ventilation image-based functional IMRT plans with SPECT ventilation image-based plans as reference. Methods: 4D-CT and SPECT ventilation scans were acquired for five thoracic cancer patients in an IRB-approved prospective clinical trial. The ventilation images were created by quantitative analysis of regional volume changes (amore » surrogate for ventilation) using deformable image registration of the 4D-CT images. A pair of 4D-CT ventilation and SPECT ventilation image-based IMRT plans was created for each patient. Regional ventilation information was incorporated into lung dose-volume objectives for IMRT optimization by assigning different weights on a voxel-by-voxel basis. The objectives and constraints of the other structures in the plan were kept identical. The differences in the dose-volume metrics have been evaluated and tested by a paired t-test. SPECT ventilation was used to calculate the lung functional dose-volume metrics (i.e., mean dose, V20 and effective dose) for both 4D-CT ventilation image-based and SPECT ventilation image-based plans. Results: Overall there were no statistically significant differences in any dose-volume metrics between the 4D-CT and SPECT ventilation imagebased plans. For example, the average functional mean lung dose of the 4D-CT plans was 26.1±9.15 (Gy), which was comparable to 25.2±8.60 (Gy) of the SPECT plans (p = 0.89). For other critical organs and PTV, nonsignificant differences were found as well. Conclusion: This study has demonstrated that 4D-CT ventilation image-based functional IMRT plans are dosimetrically comparable to SPECT ventilation image-based plans, providing evidence to use 4D-CT ventilation imaging for clinical applications. Supported in part by Free to Breathe Young Investigator Research Grant and NIH/NCI R01 CA 093626. The authors thank Philips Radiation Oncology Systems for the Pinnacle3 treatment planning systems.« less

Efficacy and safety of dupilumab in adults with moderate-to-severe atopic dermatitis inadequately controlled by topical treatments: a randomised, placebo-controlled, dose-ranging phase 2b trial.

PubMed

Thaçi, Diamant; Simpson, Eric L; Beck, Lisa A; Bieber, Thomas; Blauvelt, Andrew; Papp, Kim; Soong, Weily; Worm, Margitta; Szepietowski, Jacek C; Sofen, Howard; Kawashima, Makoto; Wu, Richard; Weinstein, Steven P; Graham, Neil M H; Pirozzi, Gianluca; Teper, Ariel; Sutherland, E Rand; Mastey, Vera; Stahl, Neil; Yancopoulos, George D; Ardeleanu, Marius

2016-01-02

Data from early-stage studies suggested that interleukin (IL)-4 and IL-13 are requisite drivers of atopic dermatitis, evidenced by marked improvement after treatment with dupilumab, a fully-human monoclonal antibody that blocks both pathways. We aimed to assess the efficacy and safety of several dose regimens of dupilumab in adults with moderate-to-severe atopic dermatitis inadequately controlled by topical treatments. In this randomised, placebo-controlled, double-blind study, we enrolled patients aged 18 years or older who had an Eczema Area and Severity Index (EASI) score of 12 or higher at screening (≥16 at baseline) and inadequate response to topical treatments from 91 study centres, including hospitals, clinics, and academic institutions, in Canada, Czech Republic, Germany, Hungary, Japan, Poland, and the USA. Patients were randomly assigned (1:1:1:1:1:1), stratified by severity (moderate or severe, as assessed by Investigator's Global Assessment) and region (Japan vs rest of world) to receive subcutaneous dupilumab: 300 mg once a week, 300 mg every 2 weeks, 200 mg every 2 weeks, 300 mg every 4 weeks, 100 mg every 4 weeks, or placebo once a week for 16 weeks. We used a central randomisation scheme, provided by an interactive voice response system. Drug kits were coded, providing masking to treatment assignment, and allocation was concealed. Patients on treatment every 2 weeks and every 4 weeks received volume-matched placebo every week when dupilumab was not given to ensure double blinding. The primary outcome was efficacy of dupilumab dose regimens based on EASI score least-squares mean percentage change (SE) from baseline to week 16. Analyses included all randomly assigned patients who received one or more doses of study drug. This trial is registered with ClinicalTrials.gov, number NCT01859988. Between May 15, 2013, and Jan 27, 2014, 452 patients were assessed for eligibility, and 380 patients were randomly assigned. 379 patients received one or more doses of study drug (300 mg once a week [n=63], 300 mg every 2 weeks [n=64], 200 mg every 2 weeks [n=61], 300 mg every 4 weeks [n=65], 100 mg every 4 weeks [n=65]; placebo [n=61]). EASI score improvements favoured all dupilumab regimens versus placebo (p<0·0001): 300 mg once a week (-74% [SE 5·16]), 300 mg every 2 weeks (-68% [5·12]), 200 mg every 2 weeks (-65% [5·19]), 300 mg every 4 weeks (-64% [4·94]), 100 mg every 4 weeks (-45% [4·99]); placebo (-18% [5·20]). 258 (81%) of 318 patients given dupilumab and 49 (80%) of 61 patients given placebo reported treatment-emergent adverse events; nasopharyngitis was the most frequent (28% and 26%, respectively). Dupilumab improved clinical responses in adults with moderate-to-severe atopic dermatitis in a dose-dependent manner, without significant safety concerns. Our findings show that IL-4 and IL-13 are key drivers of atopic dermatitis. Sanofi and Regeneron Pharmaceuticals. Copyright © 2016 Elsevier Ltd. All rights reserved.

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.

Determination of the median lethal dose of botulinum serotype E in channel catfish fingerlings

USDA-ARS?s Scientific Manuscript database

The median lethal dose of botulinum serotype E in 5.3-g channel catfish Ictalurus punctatus fingerlings was determined. Five tanks (five fish/tank) were assigned to each of the following treatment groups: 70, 50, 35, 25, or 15 pg of purified botulinum serotype E. Fish were injected intracoelomically...

Immunogenicity of type 2 monovalent oral and inactivated poliovirus vaccines for type 2 poliovirus outbreak response: an open-label, randomised controlled trial.

PubMed

Zaman, Khalequ; Estívariz, Concepción F; Morales, Michelle; Yunus, Mohammad; Snider, Cynthia J; Gary, Howard E; Weldon, William C; Oberste, M Steven; Wassilak, Steven G; Pallansch, Mark A; Anand, Abhijeet

2018-06-01

Monovalent type 2 oral poliovirus vaccine (mOPV2) and inactivated poliovirus vaccine (IPV) are used to respond to type 2 poliovirus outbreaks. We aimed to assess the effect of two mOPV2 doses on the type 2 immune response by varying the time interval between mOPV2 doses and IPV co-administration with mOPV2. We did a randomised, controlled, parallel, open-label, non-inferiority, inequality trial at two study clinics in Dhaka, Bangladesh. Healthy infants aged 6 weeks (42-48 days) at enrolment were randomly assigned (1:1:1:1) to receive two mOPV2 doses (each dose consisting of two drops [0·1 mL in total] of about 10 5 50% cell culture infectious dose of type 2 Sabin strain) at intervals of 1 week, 2 weeks, 4 weeks (standard or control group), or 4 weeks with IPV (0·5 mL of type 1 [Mahoney, 40 D-antigen units], type 2 [MEF-1, 8 D-antigen units], and type 3 [Saukett, 32 D-antigen units]) administered intramuscularly with the first mOPV2 dose. We used block randomisation, randomly selecting blocks of sizes four, eight, 12, or 16 stratified by study sites. We concealed randomisation assignment from staff managing participants in opaque, sequentially numbered, sealed envelopes. Parents and clinic staff were unmasked to assignment after the randomisation envelope was opened. Laboratory staff analysing sera were masked to assignment, but investigators analysing data and assessing outcomes were not. The primary outcome was type 2 immune response measured 4 weeks after mOPV2 administration. The primary modified intention-to-treat analysis included participants with testable serum samples before and after vaccination. A non-inferiority margin of 10% and p=0·05 (one-tailed) was used. This trial is registered at ClinicalTrials.gov, number NCT02643368, and is closed to accrual. Between Dec 7, 2015, and Jan 5, 2016, we randomly assigned 760 infants to receive two mOPV2 doses at intervals of 1 week (n=191), 2 weeks (n=191), 4 weeks (n=188), or 4 weeks plus IPV (n=190). Immune responses after two mOPV2 doses were observed in 161 (93%) of 173 infants with testable serum samples in the 1 week group, 169 (96%) of 177 in the 2 week group, and 176 (97%) of 181 in the 4 week group. 1 week and 2 week intervals between two mOPV2 doses were non-inferior to 4 week intervals because the lower bound of the absolute differences in the percentage of immune responses were greater than -10% (-4·2% [90% CI -7·9 to -0·4] in the 1 week group and -1·8% [-5·0 to 1·5] in the 2 week group vs the 4 week group). The immune response elicited by two mOPV2 doses 4 weeks apart was not different when IPV was added to the first dose (176 [97%] of 182 infants with IPV vs 176 [97%] of 181 without IPV; p=1·0). During the trial, two serious adverse events (pneumonia; one [1%] of 186 patients in the 1 week group and one [1%] of 182 in the 4 week group) and no deaths were reported; the adverse events were not attributed to the vaccines. Administration of mOPV2 at short intervals does not interfere with its immunogenicity. The addition of IPV to the first mOPV2 dose did not improve poliovirus type 2 immune response. US Centers for Disease Control and Prevention. Copyright © 2018 Elsevier Ltd. All rights reserved.

MO-F-CAMPUS-I-04: Patient Eye-Lens Dose Reduction in Routine Brain CT Examinations Using Organ-Based Tube Current Modulation and In-Plane Bismuth Shielding

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

Tsai, Hui-Yu; Liao, Ying-Lan; Chang Gung University / Chang Gung Memorial Hospital, Taoyun, Taiwan

Purpose: The purpose of this study is to assess eye-lens dose for patients who underwent brain CT examinations using two dose reduction Methods: organ-based tube current modulation (OBTCM) and in-plane bismuth shielding method. Methods: This study received institutional review board approval; written informed consent to participate was obtained from all patients. Ninety patients who underwent the routine brain CT examination were randomly assigned to three groups, ie. routine, OBTCM, and bismuth shield. The OBTCM technique reduced the tube current when the X-ray tube rotates in front of patients’ eye-lens region. The patients in the bismuth shield group were covered one-plymore » bismuth shield in the eyes’ region. Eye-lens doses were measured using TLD-100H chips and the total effective doses were calculated using CT-Expo according to the CT scanning parameters. The surface doses for patients at off-center positions were assessed to evaluate the off-centering effect. Results: Phantom measurements indicates that OBTCM technique could reduced by 26% to 28% of the surface dose to the eye lens, and increased by 25% of the surface dose at the opposed incident direction at the angle of 180°. Patients’ eye-lens doses were reduced 16.9% and 30.5% dose of bismuth shield scan and OBTCM scan, respectively compared to the routine scan. The eye-lens doses were apparently increased when the table position was lower than isocenter. Conclusion: Reducing the dose to the radiosensitive organs, such as eye lens, during routine brain CT examinations could lower the radiation risks. The OBTCM technique and in-plane bismuth shielding could be used to reduce the eye-lens dose. The eye-lens dose could be effectively reduced using OBTCM scan without interfering the diagnostic image quality. Patient position relative the CT gantry also affects the dose level of the eye lens. This study was supported by the grants from the Ministry of Science and Technology of Taiwan (MOST103-2314-B-182-009-MY2), and Chang Gung Memorial Hospital (CMRPD1C0682)« less

Differential pattern of response in mood symptoms and suicide risk measures in severely ill depressed patients assigned to citalopram with placebo or citalopram combined with lithium: role of lithium levels.

PubMed

Khan, Arif; Khan, Shirin R F; Hobus, Joy; Faucett, James; Mehra, Vishaal; Giller, Earl L; Rudolph, Richard L

2011-11-01

The assumption that antidepressants may reduce suicide risk by reducing depressive symptoms is not based on data. Further, it is unclear if the retrospectively based anti-suicidal effects of lithium can be prospectively evaluated using lithium as an augmenting agent to antidepressants. To verify our hypothesis, we designed and conducted an exploratory proof of concept trial of four weeks duration using a randomized, double-blind, parallel group method. Forty patients were assigned to citalopram + lithium and 40 were assigned to citalopram + placebo. The primary dependent measures were the Sheehan-Suicidality Tracking Scale (S-STS) and the Montgomery-Asberg Depression Rating Scale (MADRS). The reduction of S-STS scores was large (43%) and twice that seen in MADRS scores (25%) among the eighty patients included in the trial. Both response (χ(2) = 8.8, p < 0.01) and remission (χ(2) = 4.6, p = 0.03) rates showed similar patterns. There were no significant differences in mean total S-STS change scores among patients assigned to citalopram with placebo (4.8 ± 5.1) and patients assigned to citalopram with lithium (5.1 ± 5.2). When explored further, a subgroup of the patients assigned to citalopram and lithium achieved therapeutic serum levels and had significantly higher S-STS remission rates (45% compared to 19%, p < 0.05). There were no deaths by suicide or other causes indicating that trials enrolling acutely suicidal patients are feasible. These results suggest that citalopram may have a direct therapeutic effect on suicidal thoughts and behaviors. Further, lithium when used in therapeutic doses may augment such effects. These data warrant further exploration of lithium and an antidepressant combination for anti-suicidal effects. Copyright © 2011 Elsevier Ltd. All rights reserved.

[New calculation algorithms in brachytherapy for iridium 192 treatments].

PubMed

Robert, C; Dumas, I; Martinetti, F; Chargari, C; Haie-Meder, C; Lefkopoulos, D

2018-05-18

Since 1995, the brachytherapy dosimetry protocols follow the methodology recommended by the Task Group 43. This methodology, which has the advantage of being fast, is based on several approximations that are not always valid in clinical conditions. Model-based dose calculation algorithms have recently emerged in treatment planning stations and are considered as a major evolution by allowing for consideration of the patient's finite dimensions, tissue heterogeneities and the presence of high atomic number materials in applicators. In 2012, a report from the American Association of Physicists in Medicine Radiation Therapy Task Group 186 reviews these models and makes recommendations for their clinical implementation. This review focuses on the use of model-based dose calculation algorithms in the context of iridium 192 treatments. After a description of these algorithms and their clinical implementation, a summary of the main questions raised by these new methods is performed. Considerations regarding the choice of the medium used for the dose specification and the recommended methodology for assigning materials characteristics are especially described. In the last part, recent concrete examples from the literature illustrate the capabilities of these new algorithms on clinical cases. Copyright © 2018 Société française de radiothérapie oncologique (SFRO). Published by Elsevier SAS. All rights reserved.

Cost-benefit of a clinical services integrated with a decentralized unit dose system.

PubMed

Warrian, K; Irvine-Meek, J

1988-06-01

Clinical pharmacy services are believed to be beneficial to patient care and to have the potential to reduce drug costs. This study was designed to apply cost-benefit analysis techniques to selected clinical pharmacy services provided by staff pharmacists assigned to a mobile decentralized unit-dose drug distribution system. Pharmacists' interventions were identified and recorded by the pharmacists and the investigator over an eight-week period. Interventions, to which a monetary value could be assigned, included non-formulary drug use, drug regimen adjustments, and the duration of drug therapy. A total of 543 interventions were recorded or observed. Of these, 174 (32 percent) fit the criteria for inclusion in the study. Those interventions accepted by physicians (87 percent) were assigned a dollar value and tabulated. Costs to provide the service were the pharmacists' salaries. Benefit to cost ratios of 1.08 and 1.59 demonstrated that the benefits accrued from selected clinical pharmacy services exceeded the costs to the hospital.

Location Modification Factors for Potential Dose Estimation

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

Snyder, Sandra F.; Barnett, J. Matthew

2017-01-01

A Department of Energy facility must comply with the National Emission Standard for Hazardous Air Pollutants for radioactive air emissions. The standard is an effective dose of less than 0.1 mSv yr-1 to the maximum public receptor. Additionally, a lower dose level may be assigned to a specific emission point in a State issued permit. A method to efficiently estimate the expected dose for future emissions is described. This method is most appropriately applied to a research facility with several emission points with generally low emission levels of numerous isotopes.

Determination of florfenicol dose rate in feed for control of mortality in nile tilapia Oreochromis nilotica infected with streptococcus iniae

USDA-ARS?s Scientific Manuscript database

A dose titration study was conducted to determine the dosage of florfenicol (FFC) in feed to control Streptococcus iniae-associated mortality in Nile tilapia Oreochromis niloticus. Six tanks were assigned to each of five treatments: (1) not challenged with S. iniae and fed unmedicated feed; (2) chal...

Pharmacological dose of alpha-tocopherol induces cardiotoxicity in Wistar rats determined by echocardiography and histology

USDA-ARS?s Scientific Manuscript database

The effect of pharmacological dose of alpha-tocopherol on heart health was determined in Wistar rats. Animals were randomly assigned to either C (control, n = 11) or E (alpha-tocopherol, n = 11) group. Animals received corn oil (C) or alpha-tocopherol dissolved in corn oil (250 mg alpha-tocopherol/[...

Safety, Adherence and Acceptability of Intermittent Tenofovir/Emtricitabine as HIV Pre-Exposure Prophylaxis (PrEP) among HIV-Uninfected Ugandan Volunteers Living in HIV-Serodiscordant Relationships: A Randomized, Clinical Trial

PubMed Central

Kibengo, Freddie M.; Ruzagira, Eugene; Katende, David; Bwanika, Agnes N.; Bahemuka, Ubaldo; Haberer, Jessica E.; Bangsberg, David R.; Barin, Burc; Rooney, James F.; Mark, David; Chetty, Paramesh; Fast, Patricia; Kamali, Anatoli; Priddy, Frances H.

2013-01-01

Background Efficacy of oral pre-exposure prophylaxis (PrEP) in prevention of HIV acquisition has been evaluated using a daily regimen. However, adherence to long term daily medication is rarely perfect. Intermittent regimen may be a feasible alternative. Preclinical studies have demonstrated effectiveness of intermittent PrEP in SHIV prevention among animals. However, little is known about intermittent PrEP regimens. Design Seventy two HIV-uninfected volunteers in HIV serodiscordant couple relationships in Uganda were randomly assigned to receive daily oral Tenofovir/Emtricitabine (TDF/FTC-Truvada) or placebo, or intermittent (Monday, Friday and within 2 hours after sex, not to exceed one dose per day) oral TDF/FTC or placebo in a 2:1:2:1 ratio. Volunteers and study staff were blinded to drug assignment, but not to regimen assignment. Methods Volunteers were followed for 4 months after randomization, with monthly clinical and laboratory safety assessments and comprehensive HIV risk reduction services. Adherence was monitored using medication event monitoring system (MEMS) and self-report. Sexual activity data were collected via daily short text message (SMS) and self-report. HIV-specific immune responses were assessed by IFN-γ ELISPOT. Results Both daily and intermittent oral TDF/FTC regimens were well tolerated. Median MEMS adherence rates were 98% (IQR: 93-100) for daily PrEP regimen, 91% (IQR: 73-97) for fixed intermittent dosing and 45% (IQR: 20-63) for post-coital dosing. SMS response rate was 74%, but increased to 80% after excluding server outages; results may have been affected by the novelty of this measure. The majority of volunteers expressed willingness with no particular preference for either regimen. Conclusions Both daily and intermittent oral PrEP dosing regimens were safe. Adherence was high for daily and fixed intermittent dosing; post-coital dosing was associated with poor adherence. Fixed intermittent PrEP regimens may be feasible especially if a minimum effective drug concentration correlating with HIV prevention can be achieved with this dosing. Registration Clinicaltrials.gov number NCT00931346 PMID:24086333

Multidonor intensive faecal microbiota transplantation for active ulcerative colitis: a randomised placebo-controlled trial.

PubMed

Paramsothy, Sudarshan; Kamm, Michael A; Kaakoush, Nadeem O; Walsh, Alissa J; van den Bogaerde, Johan; Samuel, Douglas; Leong, Rupert W L; Connor, Susan; Ng, Watson; Paramsothy, Ramesh; Xuan, Wei; Lin, Enmoore; Mitchell, Hazel M; Borody, Thomas J

2017-03-25

The intestinal microbiota is implicated in the pathogenesis of ulcerative colitis. Faecal microbiota transplantation is a novel form of therapeutic microbial manipulation, but its efficacy in ulcerative colitis is uncertain. We aimed to establish the efficacy of intensive-dosing, multidonor, faecal microbiota transplantation in active ulcerative colitis. We conducted a multicentre, double-blind, randomised, placebo-controlled trial at three hospitals in Australia. We randomly allocated patients with active ulcerative colitis (Mayo score 4-10) in a 1:1 ratio, using a pre-established randomisation list, to either faecal microbiota transplantation or placebo colonoscopic infusion, followed by enemas 5 days per week for 8 weeks. Patients, treating clinicians, and other study staff were unaware of the assigned treatment. Faecal microbiota transplantation enemas were each derived from between three and seven unrelated donors. The primary outcome was steroid-free clinical remission with endoscopic remission or response (Mayo score ≤2, all subscores ≤1, and ≥1 point reduction in endoscopy subscore) at week 8. Analysis was by modified intention-to-treat and included all patients receiving one study dose. We performed 16S rRNA stool analysis to assess associated microbial changes. This trial is registered with ClinicalTrials.gov, number NCT01896635. The trial has ended; this report presents the final analysis. From November, 2013, to May, 2015, 85 patients were enrolled to our trial, of whom 42 were randomly assigned faecal microbiota transplantation and 43 were allocated placebo. One patient assigned faecal microbiota transplantation and three allocated placebo did not receive study treatment and were excluded from the analysis. The primary outcome was achieved in 11 (27%) of 41 patients allocated faecal microbiota transplantation versus three (8%) of 40 who were assigned placebo (risk ratio 3·6, 95% CI 1·1-11·9; p=0·021). Adverse events were reported by 32 (78%) of 41 patients allocated faecal microbiota transplantation and 33 (83%) of 40 who were assigned placebo; most were self-limiting gastrointestinal complaints, with no significant difference in number or type of adverse events between treatment groups. Serious adverse events occurred in two patients assigned faecal microbiota transplantation and in one allocated placebo. Microbial diversity increased with and persisted after faecal microbiota transplantation. Several bacterial taxa were associated with clinical outcome; in particular, the presence of Fusobacterium spp was associated with lack of remission. Intensive-dosing, multidonor, faecal microbiota transplantation induces clinical remission and endoscopic improvement in active ulcerative colitis and is associated with distinct microbial changes that relate to outcome. Faecal microbiota transplantation is, thus, a promising new therapeutic option for ulcerative colitis. Future work should focus on precisely defining the optimum treatment intensity and the role of donor-recipient matching based on microbial profiles. Broad Medical Research Program, Gastroenterological Society of Australia, Mount Sinai (New York) SUCCESS fund, University of New South Wales. Copyright © 2017 Elsevier Ltd. All rights reserved.

SU-F-T-53: Treatment Planning with Inhomogeneity Correction for Intraoperative Radiotherapy Using KV X-Ray Beams

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

Chen, Y; Ghaly, M; Souri, S

Purpose: The current standard in dose calculation for intraoperative radiotherapy (IORT) using the ZEISS Intrabeam 50 kV x-ray system is based on depth dose measurements in water and no heterogeneous tissue effect has been taken into account. We propose an algorithm for pre-treatment planning including inhomogeneity correction based on data of depth dose measurements in various tissue phantoms for kV x-rays. Methods: Direct depth dose measurements were made in air, water, inner bone and cortical bone phantoms for the Intrabeam 50 kV x-rays with a needle applicator. The data were modelled by a function of power law combining exponential withmore » different parameters. Those phantom slabs used in the measurements were scanned to obtain CT numbers. The x-ray beam initiated from the source isocenter is ray-traced through tissues. The corresponding doses will be deposited/assigned at different depths. On the boundary of tissue/organ changes, the x-ray beam will be re-traced in new tissue/organ starting at an equivalent depth with the same dose. In principle, a volumetric dose distribution can be generated if enough directional beams are traced. In practice, a several typical rays traced may be adequate in providing estimates of maximum dose to the organ at risk and minimum dose in the target volume. Results: Depth dose measurements and modeling are shown in Figure 1. The dose versus CT number is shown in Figure 2. A computer program has been written for Kypho-IORT planning using those data. A direct measurement through 2 mm solid water, 2 mm inner bone, and 1 mm solid water yields a dose rate of 7.7 Gy/min. Our calculation shows 8.1±0.4 Gy/min, consistent with the measurement within 5%. Conclusion: The proposed method can be used to more accurately calculate the dose by taking into account the heterogeneous effect. The further validation includes comparison with Monte Carlo simulation.« less

A randomized phase II trial of personalized peptide vaccine plus low dose estramustine phosphate (EMP) versus standard dose EMP in patients with castration resistant prostate cancer.

PubMed

Noguchi, Masanori; Kakuma, Tatsuyuki; Uemura, Hirotsugu; Nasu, Yasutomo; Kumon, Hiromi; Hirao, Yasuhiko; Moriya, Fukuko; Suekane, Shigetaka; Matsuoka, Kei; Komatsu, Nobukazu; Shichijo, Shigeki; Yamada, Akira; Itoh, Kyogo

2010-07-01

Personalized peptide vaccination (PPV) combined with chemotherapy could be a novel approach for many cancer patients. In this randomized study, we evaluated the anti-tumor effect and safety of PPV plus low-dose estramustine phosphate (EMP) as compared to standard-dose EMP for HLA-A2- or -A24-positive patients with castration resistant prostate cancer. Patients were randomized into groups receiving either PPV plus low-dose EMP (280 mg/day) or standard-dose EMP (560 mg/day). After disease progression, patients were switched to the opposite regime. The primary end point was progression-free survival (PFS). We randomly assigned 28 patients to receive PPV plus low-dose EMP and 29 patients to receive standard-dose EMP. Nineteen events in the PPV group and 20 events in the EMP group occurred during the first treatment. Median PFS for the first treatment was 8.5 months in the PPV group and 2.8 months in the EMP group with a hazard ratio (HR) of 0.28 (95% CI, 0.14-0.61; log-rank P = 0.0012), while there was no difference for median PFS for the second treatment. The HR for overall survival was 0.3 (95% CI, 0.1-0.91) in favor of the PPV plus low-dose EMP group (log-rank, P = 0.0328). The PPV plus low-dose EMP was well tolerated without major adverse effects and with increased levels of IgG and cytotoxic-T cell responses to the vaccinated peptides. PPV plus low-dose EMP was associated with an improvement in PSA-based PFS as compared to the standard-dose EMP alone.

Toward an organ based dose prescription method for the improved accuracy of murine dose in orthovoltage x-ray irradiators

PubMed Central

Belley, Matthew D.; Wang, Chu; Nguyen, Giao; Gunasingha, Rathnayaka; Chao, Nelson J.; Chen, Benny J.; Dewhirst, Mark W.; Yoshizumi, Terry T.

2014-01-01

Purpose: Accurate dosimetry is essential when irradiating mice to ensure that functional and molecular endpoints are well understood for the radiation dose delivered. Conventional methods of prescribing dose in mice involve the use of a single dose rate measurement and assume a uniform average dose throughout all organs of the entire mouse. Here, the authors report the individual average organ dose values for the irradiation of a 12, 23, and 33 g mouse on a 320 kVp x-ray irradiator and calculate the resulting error from using conventional dose prescription methods. Methods: Organ doses were simulated in the Geant4 application for tomographic emission toolkit using the MOBY mouse whole-body phantom. Dosimetry was performed for three beams utilizing filters A (1.65 mm Al), B (2.0 mm Al), and C (0.1 mm Cu + 2.5 mm Al), respectively. In addition, simulated x-ray spectra were validated with physical half-value layer measurements. Results: Average doses in soft-tissue organs were found to vary by as much as 23%–32% depending on the filter. Compared to filters A and B, filter C provided the hardest beam and had the lowest variation in soft-tissue average organ doses across all mouse sizes, with a difference of 23% for the median mouse size of 23 g. Conclusions: This work suggests a new dose prescription method in small animal dosimetry: it presents a departure from the conventional approach of assigning a single dose value for irradiation of mice to a more comprehensive approach of characterizing individual organ doses to minimize the error and uncertainty. In human radiation therapy, clinical treatment planning establishes the target dose as well as the dose distribution, however, this has generally not been done in small animal research. These results suggest that organ dose errors will be minimized by calibrating the dose rates for all filters, and using different dose rates for different organs. PMID:24593746

A new tissue segmentation method to calculate 3D dose in small animal radiation therapy.

PubMed

Noblet, C; Delpon, G; Supiot, S; Potiron, V; Paris, F; Chiavassa, S

2018-02-26

In pre-clinical animal experiments, radiation delivery is usually delivered with kV photon beams, in contrast to the MV beams used in clinical irradiation, because of the small size of the animals. At this medium energy range, however, the contribution of the photoelectric effect to absorbed dose is significant. Accurate dose calculation therefore requires a more detailed tissue definition because both density (ρ) and elemental composition (Z eff ) affect the dose distribution. Moreover, when applied to cone beam CT (CBCT) acquisitions, the stoichiometric calibration of HU becomes inefficient as it is designed for highly collimated fan beam CT acquisitions. In this study, we propose an automatic tissue segmentation method of CBCT imaging that assigns both density (ρ) and elemental composition (Z eff ) in small animal dose calculation. The method is based on the relationship found between CBCT number and ρ*Z eff product computed from known materials. Monte Carlo calculations were performed to evaluate the impact of ρZ eff variation on the absorbed dose in tissues. These results led to the creation of a tissue database composed of artificial tissues interpolated from tissue values published by the ICRU. The ρZ eff method was validated by measuring transmitted doses through tissue substitute cylinders and a mouse with EBT3 film. Measurements were compared to the results of the Monte Carlo calculations. The study of the impact of ρZ eff variation over the range of materials, from ρZ eff  = 2 g.cm - 3 (lung) to 27 g.cm - 3 (cortical bone) led to the creation of 125 artificial tissues. For tissue substitute cylinders, the use of ρZ eff method led to maximal and average relative differences between the Monte Carlo results and the EBT3 measurements of 3.6% and 1.6%. Equivalent comparison for the mouse gave maximal and average relative differences of 4.4% and 1.2%, inside the 80% isodose area. Gamma analysis led to a 94.9% success rate in the 10% isodose area with 4% and 0.3 mm criteria in dose and distance. Our new tissue segmentation method was developed for 40kVp CBCT images. Both density and elemental composition are assigned to each voxel by using a relationship between HU and the product ρZ eff . The method, validated by comparing measurements and calculations, enables more accurate small animal dose distribution calculated on low energy CBCT images.

Brief report: Moving prevention into schools: The impact of a trauma-informed school-based intervention.

PubMed

Mendelson, Tamar; Tandon, S Darius; O'Brennan, Lindsey; Leaf, Philip J; Ialongo, Nicholas S

2015-08-01

Adolescents in disadvantaged communities have high rates of exposure to stress and trauma, which can negatively impact emotion regulation and executive functioning, increasing likelihood of school problems. This pilot study evaluated RAP Club, a 12-session school-based trauma-informed group intervention co-facilitated by a mental health counselor and young adult community member that utilizes evidence-based cognitive-behavioral and mindfulness strategies. Seventh and eighth graders at two urban public schools serving low-income communities were assigned to receive RAP Club (n = 29) or regular school programming (n = 20). RAP Club improved teacher-rated emotion regulation, social and academic competence, classroom behavior, and discipline. Higher program dose predicted improvements in several teacher-rated outcomes. Student self-report outcomes, however, did not vary by study group or dose. Even students with low baseline depression showed improvement in teacher-rated outcomes following program participation, supporting a model of universal program delivery to all students. Findings suggest RAP Club merits further study. Copyright © 2015 The Foundation for Professionals in Services for Adolescents. Published by Elsevier Ltd. All rights reserved.

Effect of mipomersen, an apolipoprotein B synthesis inhibitor, on low-density lipoprotein cholesterol in patients with familial hypercholesterolemia.

PubMed

Akdim, Fatima; Visser, Maartje E; Tribble, Diane L; Baker, Brenda F; Stroes, Erik S G; Yu, Rosie; Flaim, Joann D; Su, John; Stein, Evan A; Kastelein, John J P

2010-05-15

A randomized, double-blind, placebo-controlled, dose-escalation study was conducted to examine the efficacy and safety of mipomersen (ISIS 301012), an antisense inhibitor of apolipoprotein B, when added to conventional lipid-lowering therapy for patients with heterozygous familial hypercholesterolemia. A total of 44 patients were enrolled and were separated into 4 cohorts, with doses ranging from 50 to 300 mg (4:1 active treatment/placebo ratio). Patients received 8 doses subcutaneously during a 6-week treatment period. Patients assigned to the 300-mg dose continued for an additional 7 weeks with once-per-week dosing. The primary efficacy end point was the percentage of change from baseline to week 7 in low-density lipoprotein (LDL) cholesterol. Safety was assessed using the laboratory test results and according to the incidence, severity, and relation of adverse events to drug dose. Mipomersen produced significant reductions in LDL cholesterol and other atherogenic apolipoprotein B-containing lipoproteins. After 6 weeks of treatment, the LDL cholesterol level was reduced by 21% from baseline in the 200-mg/week dose group (p <0.05) and 34% from baseline in the 300-mg/week dose group (p <0.01), with a concomitant reduction in apolipoprotein B of 23% (p <0.05) and 33% (p <0.01), respectively. Injection site reactions were the most common adverse event. Elevations in liver transaminase levels (> or =3 times the upper limit of normal) occurred in 4 (11%) of 36 patients assigned to active treatment; 3 of these patients were in the highest dose group. In conclusion, mipomersen has an incremental LDL cholesterol lowering effect when added to conventional lipid-lowering therapy. Copyright 2010 Elsevier Inc. All rights reserved.

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

Zhang, P; Kuo, L; Yorke, E

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

SU-E-T-280: Reconstructed Rectal Wall Dose Map-Based Verification of Rectal Dose Sparing Effect According to Rectum Definition Methods and Dose Perturbation by Air Cavity in Endo-Rectal Balloon

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

Park, J; Research Institute of Biomedical Engineering, The Catholic University of Korea, Seoul; Park, H

Purpose: Dosimetric effect and discrepancy according to the rectum definition methods and dose perturbation by air cavity in an endo-rectal balloon (ERB) were verified using rectal-wall (Rwall) dose maps considering systematic errors in dose optimization and calculation accuracy in intensity-modulated radiation treatment (IMRT) for prostate cancer patients. Methods: When the inflated ERB having average diameter of 4.5 cm and air volume of 100 cc is used for patient, Rwall doses were predicted by pencil-beam convolution (PBC), anisotropic analytic algorithm (AAA), and AcurosXB (AXB) with material assignment function. The errors of dose optimization and calculation by separating air cavity from themore » whole rectum (Rwhole) were verified with measured rectal doses. The Rwall doses affected by the dose perturbation of air cavity were evaluated using a featured rectal phantom allowing insert of rolled-up gafchromic films and glass rod detectors placed along the rectum perimeter. Inner and outer Rwall doses were verified with reconstructed predicted rectal wall dose maps. Dose errors and extent at dose levels were evaluated with estimated rectal toxicity. Results: While AXB showed insignificant difference of target dose coverage, Rwall doses underestimated by up to 20% in dose optimization for the Rwhole than Rwall at all dose range except for the maximum dose. As dose optimization for Rwall was applied, the Rwall doses presented dose error less than 3% between dose calculation algorithm except for overestimation of maximum rectal dose up to 5% in PBC. Dose optimization for Rwhole caused dose difference of Rwall especially at intermediate doses. Conclusion: Dose optimization for Rwall could be suggested for more accurate prediction of rectal wall dose prediction and dose perturbation effect by air cavity in IMRT for prostate cancer. This research was supported by the Leading Foreign Research Institute Recruitment Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Science, ICT and Future Planning (MSIP) (Grant No. 200900420)« less

SU-F-I-14: 3D Breast Digital Phantom for XACT Imaging

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

Tang, S; Laaroussi, R; Chen, J

Purpose: The X-ray induced acoustic computed tomography (XACT) is a new imaging modality which combines X-ray contrast and high ultrasonic resolution in a single modality. Using XACT in breast imaging, a 3D breast volume can be imaged by only one pulsed X-ray radiation, which could dramatically reduce the imaging dose for patients undergoing breast cancer screening and diagnosis. A 3D digital phantom that contains both X-ray properties and acoustic properties of different tissue types is indeed needed for developing and optimizing the XACT system. The purpose of this study is to offer a realistic breast digital phantom as a valuablemore » tool for improving breast XACT imaging techniques and potentially leading to better diagnostic outcomes. Methods: A series of breast CT images along the coronal plane from a patient who has breast calcifications are used as the source images. A HU value based segmentation algorithm is employed to identify breast tissues in five categories, namely the skin tissue, fat tissue, glandular tissue, chest bone and calcifications. For each pixel, the dose related parameters, such as material components and density, and acoustic related parameters, such as frequency-dependent acoustic attenuation coefficient and bandwidth, are assigned based on tissue types. Meanwhile, other parameters which are used in sound propagation, including the sound speed, thermal expansion coefficient, and heat capacity are also assigned to each tissue. Results: A series of 2D tissue type image is acquired first and the 3D digital breast phantom is obtained by using commercial 3D reconstruction software. When giving specific settings including dose depositions and ultrasound center frequency, the X-ray induced initial pressure rise can be calculated accordingly. Conclusion: The proposed 3D breast digital phantom represents a realistic breast anatomic structure and provides a valuable tool for developing and evaluating the system performance for XACT.« less

Dose response effect of NutriTek on leukocyte functionality during a dexamethasone challenge in Holstein steer calves.

USDA-ARS?s Scientific Manuscript database

The objective of this study was to determine the dose response effects of supplementing NutriTek® on leukocyte functionality and ex vivo cytokine production during a dexamethasone (DEX) challenge. Holstein steers (125.1±8.16kg; N=32) were assigned to treatments including 0, 20, 40, or 60g/head/d of ...

Influence of two different doses of infectious bovine rhinotracheitis virus (IBRV) on immune and physiological parameters in steers

USDA-ARS?s Scientific Manuscript database

To evaluate the effects different doses of IBRV and the impact they have on immunological and physiological parameters of cattle, 18 Holstein steers (450.11 ± 75.70 kg) were randomly assigned to either a control group or 1 of 2 IBRV challenged groups. Prior to the challenge, steers were fitted with ...

A random walk rule for phase I clinical trials.

PubMed

Durham, S D; Flournoy, N; Rosenberger, W F

1997-06-01

We describe a family of random walk rules for the sequential allocation of dose levels to patients in a dose-response study, or phase I clinical trial. Patients are sequentially assigned the next higher, same, or next lower dose level according to some probability distribution, which may be determined by ethical considerations as well as the patient's response. It is shown that one can choose these probabilities in order to center dose level assignments unimodally around any target quantile of interest. Estimation of the quantile is discussed; the maximum likelihood estimator and its variance are derived under a two-parameter logistic distribution, and the maximum likelihood estimator is compared with other nonparametric estimators. Random walk rules have clear advantages: they are simple to implement, and finite and asymptotic distribution theory is completely worked out. For a specific random walk rule, we compute finite and asymptotic properties and give examples of its use in planning studies. Having the finite distribution theory available and tractable obviates the need for elaborate simulation studies to analyze the properties of the design. The small sample properties of our rule, as determined by exact theory, compare favorably to those of the continual reassessment method, determined by simulation.

Toxicity studies on agents Gb and Gd (Phase 2): Delayed neuropathy study of soman in SPF white leghorn chickens. Final technical report, July 1985-August 1991

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

Bucci, T.J.; Parker, R.M.; Gosnell, P.A.

1992-05-01

A dose rangefinding study, a delayed neuropathy study, and a neurotoxic esterase study, were performed in White Leghorn chickens using the organophosphate ester Soman. The hens used for the Rangefinding study were dosed once orally with 500, 250, 100, 50, 25, or 0 microns g/Kg GD, on Day 1. They were pretreated and protected daily through Day 7 with atropine. Surviving hens were euthanized with sodium pentobarbital on Day 21. The maximum tolerated dose (MTD) to be used in the Delayed Neuropathy Study was chosen based upon the rangefinding data. Fifty hens were assigned to a Single Dose Delayed Neuropathymore » study. Groups of ten hens were given 14.2 (MTD), 7.1 (MTD/2), 3.5 (MTD/4), 0 (negative control) microns/Kg GD or 51 0 mg/Kg tri-ortho-cresyl phosphate (TOCP) (positive control). Rangefinding study. They were evaluated for signs of neurologic toxicity/ataxia. Necropsy examination was performed on all animals. Sections of cerebellum, medulla, spinal cord (cervical, thoracic, and lumbar), both sciatic nerves and their tibial branch were examined microscopically.... Delayed neuropathy; Agents; Soman; Chickens.« less

Deriving concentrations of oxygen and carbon in human tissues using single- and dual-energy CT for ion therapy applications

NASA Astrophysics Data System (ADS)

Landry, Guillaume; Parodi, Katia; Wildberger, Joachim E.; Verhaegen, Frank

2013-08-01

Dedicated methods of in-vivo verification of ion treatment based on the detection of secondary emitted radiation, such as positron-emission-tomography and prompt gamma detection require high accuracy in the assignment of the elemental composition. This especially concerns the content in carbon and oxygen, which are the most abundant elements of human tissue. The standard single-energy computed tomography (SECT) approach to carbon and oxygen concentration determination has been shown to introduce significant discrepancies in the carbon and oxygen content of tissues. We propose a dual-energy CT (DECT)-based approach for carbon and oxygen content assignment and investigate the accuracy gains of the method. SECT and DECT Hounsfield units (HU) were calculated using the stoichiometric calibration procedure for a comprehensive set of human tissues. Fit parameters for the stoichiometric calibration were obtained from phantom scans. Gaussian distributions with standard deviations equal to those derived from phantom scans were subsequently generated for each tissue for several values of the computed tomography dose index (CTDIvol). The assignment of %weight carbon and oxygen (%wC,%wO) was performed based on SECT and DECT. The SECT scheme employed a HU versus %wC,O approach while for DECT we explored a Zeff versus %wC,O approach and a (Zeff, ρe) space approach. The accuracy of each scheme was estimated by calculating the root mean square (RMS) error on %wC,O derived from the input Gaussian distribution of HU for each tissue and also for the noiseless case as a limiting case. The (Zeff, ρe) space approach was also compared to SECT by comparing RMS error for hydrogen and nitrogen (%wH,%wN). Systematic shifts were applied to the tissue HU distributions to assess the robustness of the method against systematic uncertainties in the stoichiometric calibration procedure. In the absence of noise the (Zeff, ρe) space approach showed more accurate %wC,O assignment (largest error of 2%) than the Zeff versus %wC,O and HU versus %wC,O approaches (largest errors of 15% and 30%, respectively). When noise was present, the accuracy of the (Zeff, ρe) space (DECT approach) was decreased but the RMS error over all tissues was lower than the HU versus %wC,O (SECT approach) (5.8%wC versus 7.5%wC at CTDIvol = 20 mGy). The DECT approach showed decreasing RMS error with decreasing image noise (or increasing CTDIvol). At CTDIvol = 80 mGy the RMS error over all tissues was 3.7% for DECT and 6.2% for SECT approaches. However, systematic shifts greater than ±5HU undermined the accuracy gains afforded by DECT at any dose level. DECT provides more accurate %wC,O assignment than SECT when imaging noise and systematic uncertainties in HU values are not considered. The presence of imaging noise degrades the DECT accuracy on %wC,O assignment but it remains superior to SECT. However, DECT was found to be sensitive to systematic shifts of human tissue HU.

Poster — Thur Eve — 66: Robustness Assessment of a Novel IMRT Planning Method for Lung Radiotherapy

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

Ahanj, M.; Bissonnette, J.-P.; Heath, E.

2014-08-15

Conventional radiotherapy treatment planning for lung cancer accounts for tumour motion by increasing the beam apertures. We recently developed an IMRT planning strategy which uses reduced beam apertures in combination with an edge enhancing boost of 110% of the prescription dose to the volume that corresponds to the portion of the CTV that moves outside of the reduced beam. Previous results showed that this approach ensures target coverage while reducing lung dose. In the current study, we evaluate the robustness of this boost volume approach to changes in respiratory motion, including amplitude and phase weight variations. ITV and boost volumemore » plans were generated for 5 NSCLC patients with respiratory motion amplitudes ranging from 1 to 2 cm. A standard 5mm PTV margin was used for all plans. The ORBIT treatment planning tool was used to plan and accumulate dose over 10 respiratory phases defined by the 4DCT datasets. For the phase weight variation study, dose was accumulated for three scenarios: equally-weighted-phases, higher weight assigned to exhale phases and higher weight assigned to inhale phases. For the amplitude variation study, a numerical phantom was used to generate 4DCT datasets corresponding to 7 mm, 10 mm and 14 mm motion amplitudes. Preliminary results found that delivered plans for all phase weight scenarios were clinically acceptable. When normalized to mean lung dose, the boost volume plan delivered 5% more dose to the CTV which indicates the potential for dose escalation using this approach.« less

Phase III Randomized Study of Rituximab/Carmustine, Etoposide, Cytarabine, and Melphalan (BEAM) Compared With Iodine-131 Tositumomab/BEAM With Autologous Hematopoietic Cell Transplantation for Relapsed Diffuse Large B-Cell Lymphoma: Results From the BMT CTN 0401 Trial

PubMed Central

Vose, Julie M.; Carter, Shelly; Burns, Linda J.; Ayala, Ernesto; Press, Oliver W.; Moskowitz, Craig H.; Stadtmauer, Edward A.; Mineshi, Shin; Ambinder, Richard; Fenske, Timothy; Horowitz, Mary; Fisher, Richard; Tomblyn, Marcie

2013-01-01

Purpose This clinical trial evaluated standard-dose radioimmunotherapy with a chemotherapy-based transplantation regimen followed by autologous hematopoietic cell transplantation versus rituximab with the same regimen in patients with relapsed diffuse large B-cell lymphoma (DLBCL). Patients and Methods Patients with chemotherapy-sensitive persistent or relapsed DLBCL were randomly assigned to receive iodine-131 tositumomab (dosimetric dose of 5 mCi on day −19 and therapeutic dose of 0.75 Gy on day −12), carmustine 300 mg/m2 (day −6), etoposide 100 mg/m2 twice daily (days −5 to −2), cytarabine 100 mg/m2 twice daily (days −5 to −2), and melphalan 140 mg/m2 (day −1; B-BEAM) or rituximab 375 mg/m2 on days −19 and −12 and the same chemotherapy regimen (R-BEAM). Results Two hundred twenty-four patients were enrolled, with 113 patients randomly assigned to R-BEAM and 111 patients assigned to B-BEAM. Two-year progression-free survival (PFS) rates, the primary end point, were 48.6% (95% CI, 38.6% to 57.8%) for R-BEAM and 47.9% (95% CI, 38.2% to 57%; P = .94) for B-BEAM, and the 2-year overall survival (OS) rates were 65.6% (95% CI, 55.3% to 74.1%) for R-BEAM and 61% (95% CI, 50.9% to 69.9%; P = .38) for B-BEAM. The 100-day treatment-related mortality rates were 4.1% (95% CI, 0.2% to 8.0%) for R-BEAM and 4.9% (95% CI, 0.8% to 9.0%; P = .97) for B-BEAM. The maximum mucositis score was higher in the B-BEAM arm (0.72) compared with the R-BEAM arm (0.31; P < .001). Conclusion The B-BEAM and R-BEAM regimens produced similar 2-year PFS and OS rates for patients with chemotherapy-sensitive relapsed DLBCL. No differences in toxicities other than mucositis were noted. PMID:23478060

Use of Severity Grades to Characterize Histopathologic Changes.

PubMed

Schafer, Kenneth A; Eighmy, John; Fikes, James D; Halpern, Wendy G; Hukkanen, Renee R; Long, Gerald G; Meseck, Emily K; Patrick, Daniel J; Thibodeau, Michael S; Wood, Charles E; Francke, Sabine

2018-04-01

The severity grade is an important component of a histopathologic diagnosis in a nonclinical toxicity study that helps distinguish treatment-related effects from background findings and aids in determining adverse dose levels during hazard characterization. Severity grades should be assigned based only on the extent (i.e., amount and complexity) of the morphologic change in the examined tissue section(s) and be clearly defined in the pathology report for critical lesions impacting study interpretation. However, the level of detail provided and criteria by which severity grades are assigned can vary, which can lead to inappropriate comparisons and confusion when evaluating pathology results. To help address this issue, a Working Group of the Society of Toxicologic Pathology's Scientific and Regulatory Policy Committee was formed to provide a "points to consider" article on the assignment and application of pathology severity grades. Overall, the Working Group supports greater transparency and consistency in the reporting of grading scales and provides recommendations to improve selection of diagnoses requiring more detailed severity criteria. This information should enhance the overall understanding by toxicologic pathologists, toxicologists, and regulatory reviewers of pathology findings and thereby improve effective communication in regulatory submissions.

Challenging the FDA black box warning for high aspirin dose with ticagrelor in patients with diabetes.

PubMed

DiNicolantonio, James J; Serebruany, Victor L

2013-03-01

Ticagrelor, a novel reversible antiplatelet agent, has a Food and Drug Administration (FDA) black box warning to avoid maintenance doses of aspirin (ASA) >100 mg/daily. This restriction is based on the hypothesis that ASA doses >100 mg somehow decreased ticagrelor's benefit in the Platelet Inhibition and Patient Outcomes (PLATO) U.S. cohort. However, these data are highly postrandomized, come from a very small subgroup in PLATO (57% of patients in the U.S. site), and make no biological sense. Moreover, the ticagrelor-ASA interaction was not significant by any multivariate Cox regression analyses. The Complete Response Review for ticagrelor indicates that for U.S. PLATO patients, an ASA dose >300 mg was not a significant interaction for vascular outcomes. In the ticagrelor-ASA >300 mg cohort, all-cause and vascular mortality were not significantly increased (hazard ratio [HR] 1.27 [95% CI 0.84-1.93], P = 0.262 and 1.39 [0.87-2.2], P = 0.170), respectively. Furthermore, for major adverse cardiovascular events (MACEs), 30-day all-cause mortality, and 30-day vascular mortality, the strongest interaction is the diabetes-ASA interaction. That is, patients who had diabetes had significantly fewer MACEs through study end (0.49 [0.34-0.63], P < 0.0001), significantly less 30-day all-cause mortality (0.33 [0.20-0.56], P < 0.0001), and significantly less 30-day vascular mortality (0.35 [0.22-0.55], P < 0.0001), respectively, when given high-dose (300-325 mg) ASA, regardless of treatment (clopidogrel or ticagrelor) assignment. The black box warning for the use of maintenance ASA doses >100 mg with ticagrelor is inappropriate for patients with diabetes and not evidence based.

A paired comparison of tuberculin skin test results in health care workers using 5 TU and 10 TU tuberculin

PubMed Central

Stuart, R.; Bennett, N.; Forbes, A.; Grayson, M

2000-01-01

BACKGROUND—Historically, 10 TU has been employed in Australia and the United Kingdom to perform the tuberculin skin test (TST). However, this makes it difficult to compare the rates of TST positivity with other countries such as the USA who use 5 TU. To assess the impact of the dose of tuberculin on the TST a comparison was made of TST responses in health care workers given a TST with both 5 and 10 TU.
METHODS—Two TSTs were performed simultaneously in each health care worker using 5 and 10 TU. Each dose was randomly assigned in a blinded manner to the right or left forearm and read at 48-72 hours by a single nurse who was blinded to the assignment of the 5 and 10 TU doses.
RESULTS—A total of 128 health care workers were enrolled, 119 (93%) of whom had a past history of BCG vaccination. The overall mean difference in paired reaction sizes for the two doses was 1.5 mm with 95% limits of agreement of -3.6 to 6.5 mm.
CONCLUSION—A slightly larger TST reading was seen with 10 TU than with 5 TU. The mean difference of 1.5 mm between the two doses should be considered when comparing rates of TST positivity between countries who use different doses of tuberculin to perform the tuberculin skin test.

 PMID:10899248

[Optimization of ventricular function during anesthesia induction by administering crystalloids and colloids to heart surgery patients].

PubMed

Ballesteros, M; Boldt, J; Zickmann, B; Knothe, C; Hempelmann, G

1995-01-01

To describe the changes in cardiac function after administration of three different solutions infused after anesthetic induction. Thirty-six patients scheduled for elective aortocoronary bypass surgery were randomly distributed into three groups. Over a period of 25 min after anesthetic induction, 12 received 10 ml/kg of Ringer solution (low dose crystalloid group), 12 received 20 ml/kg of Ringer solution (high dose crystalloid group), and 12 received 10 ml/kg of Ringer solution with 10 ml/kg of hydroxi-ethyl-almidon solution 450,000 D, 0.7 substitution grade (group C-HEA). Minute volume, systemic and pulmonary pressures, osmolality of blood and urine, and plasma and urine sodium concentrations were measured before and after infusion of the assigned liquid. In spite of the volume infused, low dose crystalloid group showed a high incidence of oliguria, increased urinary osmolality and decreased sodium in urine. Cardiac and systolic indices and left ventricular work load remained stable after infusion of the assigned liquid in low and high dose crystalloid groups, whereas they increased significantly ion group C-HEA (+23%, +16% and +20%). Administration of restricted doses of crystalloids after anesthetic induction favors the retention of water and sodium. Higher doses of crystalloids weaken this effect. However, neither of these two regimens leads to a more effective cardiac work load. A combination of crystalloids and colloids administered immediately after anesthetic induction temporarily improves cardiac performance during surgery.

Promoting Abstinence from Cocaine and Heroin with a Methadone Dose Increase and a Novel Contingency

PubMed Central

Schmittner, John; Umbricht, Annie; Schroeder, Jennifer R.; Moolchan, Eric T.; Preston, Kenzie L.

2010-01-01

To test whether a combination of contingency management and methadone dose increase would promote abstinence from heroin and cocaine, we conducted a randomized controlled trial using a 2 X 3 (Dose X Contingency) factorial design in which dose assignment was double-blind. Participants were 252 heroin- and cocaine-abusing outpatients on methadone maintenance. They were randomly assigned to methadone dose (70 or 100 mg/day, double blind) and voucher condition (noncontingent, contingent on cocaine-negative urines, or “split”). The “split” contingency was a novel contingency that reinforced abstinence from either drug while doubly reinforcing simultaneous abstinence from both: the total value of incentives was “split” between drugs to contain costs. The main outcome measures were percentages of urine specimens negative for heroin, cocaine, and both simultaneously; these were monitored during a 5-week baseline of standard treatment (to determine study eligibility), a 12-week intervention, and a 10-week maintenance phase (to examine intervention effects in return-to-baseline conditions). DSM-IV criteria for ongoing drug dependence were assessed at study exit. Urine-screen results showed that the methadone dose increase reduced heroin use but not cocaine use. The Split 100mg group was the only group to achieve a longer duration of simultaneous negatives than its same-dose Noncontingent control group. The frequency of DSM-IV opiate and cocaine dependence diagnoses decreased in the active intervention groups. For a split contingency to promote simultaneous abstinence from cocaine and heroin, a relatively high dose of methadone appears necessary but not sufficient; an increase in overall incentive amount may also be required. PMID:19101098

Minoxidil (Mx) as a prophylaxis of doxorubicin--induced alopecia.

PubMed

Rodriguez, R; Machiavelli, M; Leone, B; Romero, A; Cuevas, M A; Langhi, M; Romero Acuña, L; Romero Acuña, J; Amato, S; Barbieri, M

1994-10-01

Minoxidil (Mx) is known to induce hair growth in men with male-pattern baldness. Based on this potential, the effectiveness of Mx 2% topical solution was evaluated in cancer patients (pts) to prevent doxorubicin-induced alopecia. 48 female pts with different types of solid tumors treated with doxorubicin-based chemotherapy in a dose range of 50-60 mg/m2/cycle were randomly assigned to receive Mx 2% topical solution or placebo. 88% and 92% of pts in both arms showed severe alopecia (p = ns). No adverse effects were observed. In this study Mx 2% topical solution was non-toxic but was not effective in the prevention of chemotherapy-induced alopecia.

Three-Month Randomized Clinical Trial of Nasal Calcitonin in Adults with X-linked Hypophosphatemia.

PubMed

Sullivan, Rebecca; Abraham, Alice; Simpson, Christine; Olear, Elizabeth; Carpenter, Thomas; Deng, Yanhong; Chen, Chuqing; Insogna, Karl L

2018-06-01

Previous work has demonstrated that a single subcutaneous dose of salmon calcitonin leads to a transient decline in circulating levels of FGF23 in patients with X-linked hypophosphatemia (XLH). Since the calcitonin receptor is expressed on osteocytes, this raises the possibility that interdicting signals through that receptor could modulate circulating levels of FGF23 in XLH. In the present study, 21 subjects with XLH were randomly assigned to receive either placebo nasal spray or 400 IU of nasal salmon calcitonin daily for three months. On the first and last day of the study, serial measurements of FGF23, 1,25-dihydroxyvitamin D, and TmP/GFR were made over 27 h. At the beginning of Visit 2 (the first day of month 2) and the beginning of Visit 3 (the first day of month 3), single, first-morning, fasting measurements of these same parameters were made before the next administered dose of study drug. Following the initial or final dose of study drug, there were no differences in area under the curve, based on treatment assignment, for the three principal outcome variables. Similarly, there were no differences in the fasting measures taken at the beginning of Visit 2 or Visit 3 compared to the fasting values on either day 2 of Visit 1 or the fasting values on day 2 of Visit 4. There were also no significant changes over time in serum phosphorus, serum calcium, circulating levels of PTH, CTx, or P1NP. The reasons why nasal salmon calcitonin did not recapitulate the findings with subcutaneously administered drug may relate to the kinetics of drug delivery, the bioavailability of drug or peak drug dose achieved. It remains possible, however, that other means of altering calcitonin receptor signaling may still provide an opportunity for regulating FGF23 production.

Fecal hemoglobin excretion in elderly patients with atrial fibrillation: combined aspirin and low-dose warfarin vs conventional warfarin therapy.

PubMed

Blackshear, J L; Baker, V S; Holland, A; Litin, S C; Ahlquist, D A; Hart, R G; Ellefson, R; Koehler, J

1996-03-25

Antithrombotic prophylaxis using combined aspirin and low-dose warfarin is under evaluation in several clinical trials. However, therapy may result in increased gastrointestinal blood loss and clinical bleeding vs conventional single-agent antithrombotic therapy. To assess differences in gastrointestinal blood loss, we measured quantitative fecal hemoglobin equivalents (HemoQuant, Mayo Medical Laboratory, Rochester, Minn) in 117 patients, mean age 71 years, 1 month after initiation of assigned therapy in the Stroke Prevention in Atrial Fibrillation III Study. Sixty-three of these patients who had characteristics for high risk of stroke were randomly assigned to conventional adjusted-dose warfarin therapy (international normalized ratio, 2.0 to 3.0) or low-dose combined therapy (warfarin [international normalization ratio,<1.5] plus 325 mg/d of enteric-coated aspirin). The remaining 54 patients with low risk of stroke received 325 mg/d of enteric-coated aspirin. Among the 63 at high risk of stroke, abnormal values (>2mg of hemoglobin per gram of stool) were detected in 11% and values greater than 4 mg of hemoglobin per gram of stool were found in 8%. Mean ( +/- SD) values were more for those randomly assigned to receive combined therapy (1.7 +/- 3.3 mg of hemoglobin per gram of stool vs adjusted-dose warfarin therapy, 1.0 +/- 1.9 mg/g; P=.003). The 54 nonrandomized patients with low risk of stroke receiving aspirin alone had a mean (+/- SD) HemoQuant value of 0.8 +/- 0.7mg of hemoglobin per gram of stool 1 month after entry in the study. Abnormal levels of fecal hemoglobin excretion were common in elderly patients with high risk of atrial fibrillation 1 month after randomization to prophylactic antithrombotic therapy. Combined warfarin and aspirin therapy was associated with greater fecal hemoglobin excretion than standard warfarin therapy, suggesting the potential for increased gastrointestinal hemorrhage.

SU-E-T-625: Robustness Evaluation and Robust Optimization of IMPT Plans Based on Per-Voxel Standard Deviation of Dose Distributions.

PubMed

Liu, W; Mohan, R

2012-06-01

Proton dose distributions, IMPT in particular, are highly sensitive to setup and range uncertainties. We report a novel method, based on per-voxel standard deviation (SD) of dose distributions, to evaluate the robustness of proton plans and to robustly optimize IMPT plans to render them less sensitive to uncertainties. For each optimization iteration, nine dose distributions are computed - the nominal one, and one each for ± setup uncertainties along x, y and z axes and for ± range uncertainty. SD of dose in each voxel is used to create SD-volume histogram (SVH) for each structure. SVH may be considered a quantitative representation of the robustness of the dose distribution. For optimization, the desired robustness may be specified in terms of an SD-volume (SV) constraint on the CTV and incorporated as a term in the objective function. Results of optimization with and without this constraint were compared in terms of plan optimality and robustness using the so called'worst case' dose distributions; which are obtained by assigning the lowest among the nine doses to each voxel in the clinical target volume (CTV) and the highest to normal tissue voxels outside the CTV. The SVH curve and the area under it for each structure were used as quantitative measures of robustness. Penalty parameter of SV constraint may be varied to control the tradeoff between robustness and plan optimality. We applied these methods to one case each of H&N and lung. In both cases, we found that imposing SV constraint improved plan robustness but at the cost of normal tissue sparing. SVH-based optimization and evaluation is an effective tool for robustness evaluation and robust optimization of IMPT plans. Studies need to be conducted to test the methods for larger cohorts of patients and for other sites. This research is supported by National Cancer Institute (NCI) grant P01CA021239, the University Cancer Foundation via the Institutional Research Grant program at the University of Texas MD Anderson Cancer Center, and MD Anderson’s cancer center support grant CA016672. © 2012 American Association of Physicists in Medicine.

Alternative methods for CYP2D6 phenotyping: comparison of dextromethorphan metabolic ratios from AUC, single point plasma, and urine.

PubMed

Chen, Rui; Wang, Haotian; Shi, Jun; Hu, Pei

2016-05-01

CYP2D6 is a high polymorphic enzyme. Determining its phenotype before CYP2D6 substrate treatment can avoid dose-dependent adverse events or therapeutic failures. Alternative phenotyping methods of CYP2D6 were compared to aluate the appropriate and precise time points for phenotyping after single-dose and ultiple-dose of 30-mg controlled-release (CR) dextromethorphan (DM) and to explore the antimodes for potential sampling methods. This was an open-label, single and multiple-dose study. 21 subjects were assigned to receive a single dose of CR DM 30 mg orally, followed by a 3-day washout period prior to oral administration of CR DM 30 mg every 12 hours for 6 days. Metabolic ratios (MRs) from AUC∞ after single dosing and from AUC0-12h at steady state were taken as the gold standard. The correlations of metabolic ratios of DM to dextrorphan (MRDM/DX) values based on different phenotyping methods were assessed. Linear regression formulas were derived to calculate the antimodes for potential sample methods. In the single-dose part of the study statistically significant correlations were found between MRDM/DX from AUC∞ and from serial plasma points from 1 to 30 hours or from urine (all p-values < 0.001). In the multiple-dose part, statistically significant correlations were found between MRDM/DX from AUC0-12h on day 6 and MRDM/DX from serial plasma points from 0 to 36 hours after the last dosing (all p-values < 0.001). Based on reported urinary antimode and linear regression analysis, the antimodes of AUC and plasma points were derived to profile the trend of antimodes as the drug concentrations changed. MRDM/DX from plasma points had good correlations with MRDM/DX from AUC. Plasma points from 1 to 30 hours after single dose of 30-mg CR DM and any plasma point at steady state after multiple doses of CR DM could potentially be used for phenotyping of CYP2D6.

Ultra-low-dose lung screening CT with model-based iterative reconstruction: an assessment of image quality and lesion conspicuity.

PubMed

Ju, Yun Hye; Lee, Geewon; Lee, Ji Won; Hong, Seung Baek; Suh, Young Ju; Jeong, Yeon Joo

2018-05-01

Background Reducing radiation dose inevitably increases image noise, and thus, it is important in low-dose computed tomography (CT) to maintain image quality and lesion detection performance. Purpose To assess image quality and lesion conspicuity of ultra-low-dose CT with model-based iterative reconstruction (MBIR) and to determine a suitable protocol for lung screening CT. Material and Methods A total of 120 heavy smokers underwent lung screening CT and were randomly and equally assigned to one of five groups: group 1 = 120 kVp, 25 mAs, with FBP reconstruction; group 2 = 120 kVp, 10 mAs, with MBIR; group 3 = 100 kVp, 15 mAs, with MBIR; group 4 = 100 kVp, 10 mAs, with MBIR; and group 5 = 100 kVp, 5 mAs, with MBIR. Two radiologists evaluated intergroup differences with respect to radiation dose, image noise, image quality, and lesion conspicuity using the Kruskal-Wallis test and the Chi-square test. Results Effective doses were 61-87% lower in groups 2-5 than in group 1. Image noises in groups 1 and 5 were significantly higher than in the other groups ( P < 0.001). Overall image quality was best in group 1, but diagnostic acceptability of overall image qualities in groups 1-3 was not significantly different (all P values > 0.05). Lesion conspicuities were similar in groups 1-4, but were significantly poorer in group 5. Conclusion Lung screening CT with MBIR obtained at 100 kVp and 15 mAs enables a ∼60% reduction in radiation dose versus low-dose CT, while maintaining image quality and lesion conspicuity.

Image based Monte Carlo Modeling for Computational Phantom

NASA Astrophysics Data System (ADS)

Cheng, Mengyun; Wang, Wen; Zhao, Kai; Fan, Yanchang; Long, Pengcheng; Wu, Yican

2014-06-01

The evaluation on the effects of ionizing radiation and the risk of radiation exposure on human body has been becoming one of the most important issues for radiation protection and radiotherapy fields, which is helpful to avoid unnecessary radiation and decrease harm to human body. In order to accurately evaluate the dose on human body, it is necessary to construct more realistic computational phantom. However, manual description and verfication of the models for Monte carlo(MC)simulation are very tedious, error-prone and time-consuming. In addiation, it is difficult to locate and fix the geometry error, and difficult to describe material information and assign it to cells. MCAM (CAD/Image-based Automatic Modeling Program for Neutronics and Radiation Transport Simulation) was developed as an interface program to achieve both CAD- and image-based automatic modeling by FDS Team (Advanced Nuclear Energy Research Team, http://www.fds.org.cn). The advanced version (Version 6) of MCAM can achieve automatic conversion from CT/segmented sectioned images to computational phantoms such as MCNP models. Imaged-based automatic modeling program(MCAM6.0) has been tested by several medical images and sectioned images. And it has been applied in the construction of Rad-HUMAN. Following manual segmentation and 3D reconstruction, a whole-body computational phantom of Chinese adult female called Rad-HUMAN was created by using MCAM6.0 from sectioned images of a Chinese visible human dataset. Rad-HUMAN contains 46 organs/tissues, which faithfully represented the average anatomical characteristics of the Chinese female. The dose conversion coefficients(Dt/Ka) from kerma free-in-air to absorbed dose of Rad-HUMAN were calculated. Rad-HUMAN can be applied to predict and evaluate dose distributions in the Treatment Plan System (TPS), as well as radiation exposure for human body in radiation protection.

Use of low-dose oral theophylline as an adjunct to inhaled corticosteroids in preventing exacerbations of chronic obstructive pulmonary disease: study protocol for a randomised controlled trial.

PubMed

Devereux, Graham; Cotton, Seonaidh; Barnes, Peter; Briggs, Andrew; Burns, Graham; Chaudhuri, Rekha; Chrystyn, Henry; Davies, Lisa; De Soyza, Anthony; Fielding, Shona; Gompertz, Simon; Haughney, John; Lee, Amanda J; McCormack, Kirsty; McPherson, Gladys; Morice, Alyn; Norrie, John; Sullivan, Anita; Wilson, Andrew; Price, David

2015-06-10

Chronic obstructive pulmonary disease (COPD) is associated with high morbidity, mortality, and health-care costs. An incomplete response to the anti-inflammatory effects of inhaled corticosteroids is present in COPD. Preclinical work indicates that 'low dose' theophylline improves steroid responsiveness. The Theophylline With Inhaled Corticosteroids (TWICS) trial investigates whether the addition of 'low dose' theophylline to inhaled corticosteroids has clinical and cost-effective benefits in COPD. TWICS is a randomised double-blind placebo-controlled trial conducted in primary and secondary care sites in the UK. The inclusion criteria are the following: an established predominant respiratory diagnosis of COPD (post-bronchodilator forced expiratory volume in first second/forced vital capacity [FEV1/FVC] of less than 0.7), age of at least 40 years, smoking history of at least 10 pack-years, current inhaled corticosteroid use, and history of at least two exacerbations requiring treatment with antibiotics or oral corticosteroids in the previous year. A computerised randomisation system will stratify 1424 participants by region and recruitment setting (primary and secondary) and then randomly assign with equal probability to intervention or control arms. Participants will receive either 'low dose' theophylline (Uniphyllin MR 200 mg tablets) or placebo for 52 weeks. Dosing is based on pharmacokinetic modelling to achieve a steady-state serum theophylline of 1-5 mg/l. A dose of theophylline MR 200 mg once daily (or placebo once daily) will be taken by participants who do not smoke or participants who smoke but have an ideal body weight (IBW) of not more than 60 kg. A dose of theophylline MR 200 mg twice daily (or placebo twice daily) will be taken by participants who smoke and have an IBW of more than 60 kg. Participants will be reviewed at recruitment and after 6 and 12 months. The primary outcome is the total number of participant-reported COPD exacerbations requiring oral corticosteroids or antibiotics during the 52-week treatment period. The demonstration that 'low dose' theophylline increases the efficacy of inhaled corticosteroids in COPD by reducing the incidence of exacerbations is relevant not only to patients and clinicians but also to health-care providers, both in the UK and globally. Current Controlled Trials ISRCTN27066620 was registered on Sept. 19, 2013, and the first subject was randomly assigned on Feb. 6, 2014.

Single- and multiple-dose pharmacokinetics, pharmacodynamics, and safety of apixaban in healthy Chinese subjects

PubMed Central

Cui, Yimin; Song, Yan; Wang, Jessie; Yu, Zhigang; Schuster, Alan; Barrett, Yu Chen; Frost, Charles

2013-01-01

Background The pharmacokinetics (PK), pharmacodynamics (PD), and safety of apixaban were assessed in healthy Chinese subjects in this randomized, placebo-controlled, double-blind, single-sequence, single- and multiple-dose study. Subjects and methods Eighteen subjects 18–45 years of age were randomly assigned (2:1 ratio) to receive apixaban or matched placebo. Subjects received a single 10 mg dose of apixaban or placebo on day 1, followed by 10 mg apixaban or placebo twice daily for 6 days (days 4–9). The PK and PD of apixaban were assessed by collecting plasma samples for 72 hours following the dose on day 1 and the morning dose on day 9, and measuring apixaban concentration and anti-Xa activity. Safety was assessed via physical examinations, vital sign measurements, electrocardiograms, and clinical laboratory evaluations. Results PK analysis showed similar characteristics of apixaban after single and multiple doses, including a median time to maximum concentration of ~3 hours, mean elimination half-life of ~11 hours, and renal clearance of ~1.2 L/hour. The accumulation index was 1.7, consistent with twice-daily dosing and the observed elimination half-life. Single-dose data predict multiple-dose PK, therefore apixaban PK are time-independent. The relationship between anti-Xa activity and plasma apixaban concentrations appears to be linear. Apixaban was safe and well tolerated, with no bleeding-related adverse events reported. Conclusion Apixaban was safe and well tolerated in healthy Chinese subjects. Apixaban PK and PD were predictable and consistent with findings from previous studies in Asian and non-Asian subjects. The administration of apixaban does not require any dose modification based on race. PMID:24353445

Dose response effect of NutriTek on leukocyte functionality and ex vivo cytokine production during a dexamethasone challenge in Holstein steer calves

USDA-ARS?s Scientific Manuscript database

The objective of this study was to determine the dose response effects of supplementing NutriTek on leukocyte functionality and ex vivo cytokine production during a dexamethasone (DEX) challenge. Holstein steers (125.1 ± 8.16 kg; N = 32) were assigned to treatments including 0, 20, 40, or 60 g/head/...

Safety and efficacy of low-dose, subacute exposure of mature ewes to sodium chlorate

USDA-ARS?s Scientific Manuscript database

The objective was to determine the safety and efficacy of low-dose, subacute exposure of mature ewes to NaClO3 in the drinking water. Twenty-five ewes (BW = 62.5 ± 7.3 kg) were placed indoors in individual pens with ad libitum access to water and feed. After 7 d of adaptation, ewes were assigned ran...

A Randomized Intervention Study to Evaluate Whether Electronic Messaging Can Increase Human Papillomavirus Vaccine Completion and Knowledge among College Students

ERIC Educational Resources Information Center

Richman, Alice R.; Maddy, LaDonna; Torres, Essie; Goldberg, Ellen J.

2016-01-01

Objective: To evaluate an intervention aimed at increasing human papillomavirus (HPV) vaccine completion of the 3-dose series and knowledge. Participants: Two hundred sixty-four male and female US college students 18-26 years old who were receiving HPV vaccine dose 1. Methods: Students were randomly assigned to the intervention or control group.…

Description of and link to the I-131 dose/risk calculator

Cancer.gov

This calculator estimates radiation dose received by the thyroid from radionuclides in fallout from nuclear tests conducted at the Nevada Test Site (NTS) and sites outside of the United States (global fallout); estimates risk of developing thyroid cancer from that exposure; and provides an estimate of probability of causation, sometimes called assigned share (PC/AS), for individuals who have been diagnosed with thyroid cancer.

Pharmacokinetics and Safety of Bortezomib in Patients with Advanced Malignancies and Varying Degrees of Liver Dysfunction: Phase 1 NCI Organ Dysfunction Working Group Study NCI-6432

PubMed Central

LoRusso, Patricia M; Venkatakrishnan, Karthik; Ramanathan, Ramesh K; Sarantopoulos, John; Mulkerin, Daniel; Shibata, Stephen I; Hamilton, Anne; Dowlati, Afshin; Mani, Sridhar; Rudek, Michelle A; Takimoto, Chris H; Neuwirth, Rachel; Esseltine, Dixie-Lee; Ivy, Percy

2013-01-01

Purpose The proteasome inhibitor bortezomib undergoes oxidative hepatic metabolism. This study (NCI-6432; NCT00091117) was conducted to evaluate bortezomib pharmacokinetics and safety in patients with varying degrees of hepatic impairment, to inform dosing recommendations in these special populations. Methods Patients received bortezomib on days 1, 4, 8, and 11 of 21-day cycles. Patients were assigned to four hepatic function groups based on the National Cancer Institute Organ Dysfunction Working Group classification. Those with normal function received bortezomib at the 1.3 mg/m2 standard dose. Patients with severe, moderate, and mild impairment received escalating doses from 0.5, 0.7, and 1.0 mg/m2, respectively, up to a 1.3 mg/m2 maximum. Serial blood samples were collected for 24 hours post-dose on days 1 and 8, cycle 1, for bortezomib plasma concentration measurements. Results Sixty-one patients were treated, including 14 with normal hepatic function and 17, 12, and 18 with mild, moderate, and severe impairment, respectively. Mild hepatic impairment did not alter dose-normalized bortezomib exposure (AUC0-tlast) or Cmax compared with patients with normal function. Mean dose-normalized AUC0-tlast was increased by approximately 60% on day 8 in patients with moderate or severe impairment. Conclusions Patients with mild hepatic impairment do not require a starting dose adjustment of bortezomib. Patients with moderate or severe hepatic impairment should be started at a reduced dose of 0.7 mg/m2. PMID:22394984

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

PubMed Central

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

2013-01-01

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

Evaluation of Total Daily Dose and Glycemic Control for Patients on U-500 Insulin Admitted to the Hospital

DTIC Science & Technology

2016-05-20

regular insulin has significantly increased in recent years. These patients are severely insulin resistant requiring high doses of insulin to achieve...on U-500 Insulin Admitted to the Hospital presented at SURF Conference, San Antonio, TX 20 May 201 6 with MDWI 41-108, and has been assigned local...59th CSPG/SGVU) C.201 4 . I 52d PROTOCOL TITLE Evaluation of Total Dai ly Dose and Glycemic Control for Patients on U-500 Insulin Admitted to the

Effects of relationship motivation, partner familiarity, and alcohol on women's risky sexual decision making.

PubMed

Zawacki, Tina; Norris, Jeanette; Hessler, Danielle M; Morrison, Diane M; Stoner, Susan A; George, William H; Davis, Kelly Cue; Abdallah, Devon A

2009-06-01

This experiment examined the effects of women's relationship motivation, partner familiarity, and alcohol consumption on sexual decision making. Women completed an individual difference measure of relationship motivation and then were randomly assigned to partner familiarity condition (low, high) and to alcohol consumption condition (high dose, low dose, no alcohol, placebo). Then women read and projected themselves into a scenario of a sexual encounter. Relationship motivation and partner familiarity interacted with intoxication to influence primary appraisals of relationship potential. Participants' primary and secondary relationship appraisals mediated the effects of women's relationship motivation, partner familiarity, and intoxication on condom negotiation, sexual decision abdication, and unprotected sex intentions. These findings support a cognitive mediation model of women's sexual decision making and identify how individual and situational factors interact to shape alcohol's influences on cognitive appraisals that lead to risky sexual decisions. This knowledge can inform empirically based risky sex interventions.

The Use of BDDCS in Classifying the Permeability of Marketed Drugs1

PubMed Central

Benet, Leslie Z.; Amidon, Gordon L.; Barends, Dirk M.; Lennernäs, Hans; Polli, James E.; Shah, Vinod P.; Stavchansky, Salomon A.; Yu, Lawrence X.

2013-01-01

We recommend that regulatory agencies add the extent of drug metabolism (i.e., ≥90% metabolized) as an alternate method in defining Class 1 marketed drugs suitable for a waiver of in vivo studies of bioequivalence. That is, ≥90% metabolized is an additional methodology that may be substituted for ≥90% absorbed. We propose that the following criteria be used to define ≥ 90% metabolized for marketed drugs: Following a single oral dose to humans, administered at the highest dose strength, mass balance of the Phase 1 oxidative and Phase 2 conjugative drug metabolites in the urine and feces, measured either as unlabeled, radioactive labeled or nonradioactive labeled substances, account for ≥ 90% of the drug dosed. This is the strictest definition for a waiver based on metabolism. For an orally administered drug to be ≥ 90% metabolized by Phase 1 oxidative and Phase 2 conjugative processes, it is obvious that the drug must be absorbed. This proposal, which strictly conforms to the present ≥90% criteria, is a suggested modification to facilitate a number of marketed drugs being appropriately assigned to Class 1. PMID:18236138

Preemptive carprofen for peri-operative analgesia in dogs undergoing Tibial Plateau Leveling Osteotomy (TPLO): a prospective, randomized, blinded, placebo controlled clinical trial.

PubMed

Bufalari, A; Maggio, C; Cerasoli, I; Morath, U; Adami, C

2012-03-01

Eighteen client-owned dogs undergoing Tibial Plateau Leveling Osteotomy (TPLO) were included in this blinded clinical study and randomly assigned to one of two treatment groups. Group C (carprofen) received intravenous (IV) carprofen, 4 mg/kg, prior to anesthesia, whereas group P (placebo) received IV saline. General anesthesia was maintained with isoflurane in oxygen and a constant rate infusion (CRI) of sufentanyl IV. Intra-operatively, assessment of nociception was based on changes in physiological parameters and on the analgesics requirement, whereas in the post-operative period evaluation of pain was performed by using a Hellyer and Gaynor pain score and by comparing the doses of rescue buprenorphine required by the two treatment groups. Although no statistically significant differences in intra-operative sufentanyl doses were found between treatment groups, group C had superior cardiovascular stability, and lower post-operative pain scores and rescue buprenorphine doses than group P. Our results indicate that administration of carprofen prior to surgery was effective in improving peri-operative analgesia in dogs undergoing TPLO.

Dose-response relationship between cumulative physical workload and osteoarthritis of the hip - a meta-analysis applying an external reference population for exposure assignment.

PubMed

Seidler, Andreas; Lüben, Laura; Hegewald, Janice; Bolm-Audorff, Ulrich; Bergmann, Annekatrin; Liebers, Falk; Ramdohr, Christina; Romero Starke, Karla; Freiberg, Alice; Unverzagt, Susanne

2018-06-01

There is consistent evidence from observational studies of an association between occupational lifting and carrying of heavy loads and the diagnosis of hip osteoarthritis. However, due to the heterogeneity of exposure estimates considered in single studies, a dose-response relationship between cumulative physical workload and hip osteoarthritis could not be determined so far. This study aimed to analyze the dose-response relationship between cumulative physical workload and hip osteoarthritis by replacing the exposure categories of the included studies with cumulative exposure values of an external reference population. Our meta-regression analysis was based on a recently conducted systematic review (Bergmann A, Bolm-Audorff U, Krone D, Seidler A, Liebers F, Haerting J, Freiberg A, Unverzagt S, Dtsch Arztebl Int 114:581-8, 2017). The main analysis of our meta-regression comprised six case-control studies for men and five for women. The population control subjects of a German multicentre case-control study (Seidler A, Bergmann A, Jäger M, Ellegast R, Ditchen D, Elsner G, Grifka J, Haerting J, Hofmann F, Linhardt O, Luttmann A, Michaelis M, Petereit-Haack G, Schumann B, Bolm-Audorff U, BMC Musculoskelet Disord 10:48, 2009) served as the reference population. Based on the sex-specific cumulative exposure percentiles of the reference population, we assigned exposure values to each category of the included studies using three different cumulative exposure parameters. To estimate the doubling dose (the amount of physical workload to double the risk of hip osteoarthritis) on the basis of all available case-control-studies, meta-regression analyses were conducted based on the linear association between exposure values of the reference population and the logarithm of reported odds ratios (ORs) from the included studies. In men, the risk to develop hip osteoarthritis was increased by an OR of 1.98 (95% CI 1.20-3.29) per 10,000 tons of weights ≥20 kg handled, 2.08 (95% CI 1.22-3.53) per 10,000 tons handled > 10 times per day and 8.64 (95% CI 1.87-39.91) per 10 6 operations. These estimations result in doubling dosages of 10,100 tons of weights ≥20 kg handled, 9500 tons ≥20 kg handled > 10 times per day and 321,400 operations of weights ≥20 kg. There was no linear association between manual handling of weights at work and risk to develop hip osteoarthritis in women. Under specific conditions, the application of an external reference population allows for the derivation of a dose-response relationship despite high exposure heterogeneities in the pooled studies.

A quantitative three-dimensional dose attenuation analysis around Fletcher-Suit-Delclos due to stainless steel tube for high-dose-rate brachytherapy by Monte Carlo calculations.

PubMed

Parsai, E Ishmael; Zhang, Zhengdong; Feldmeier, John J

2009-01-01

The commercially available brachytherapy treatment-planning systems today, usually neglects the attenuation effect from stainless steel (SS) tube when Fletcher-Suit-Delclos (FSD) is used in treatment of cervical and endometrial cancers. This could lead to potential inaccuracies in computing dwell times and dose distribution. A more accurate analysis quantifying the level of attenuation for high-dose-rate (HDR) iridium 192 radionuclide ((192)Ir) source is presented through Monte Carlo simulation verified by measurement. In this investigation a general Monte Carlo N-Particles (MCNP) transport code was used to construct a typical geometry of FSD through simulation and compare the doses delivered to point A in Manchester System with and without the SS tubing. A quantitative assessment of inaccuracies in delivered dose vs. the computed dose is presented. In addition, this investigation expanded to examine the attenuation-corrected radial and anisotropy dose functions in a form parallel to the updated AAPM Task Group No. 43 Report (AAPM TG-43) formalism. This will delineate quantitatively the inaccuracies in dose distributions in three-dimensional space. The changes in dose deposition and distribution caused by increased attenuation coefficient resulted from presence of SS are quantified using MCNP Monte Carlo simulations in coupled photon/electron transport. The source geometry was that of the Vari Source wire model VS2000. The FSD was that of the Varian medical system. In this model, the bending angles of tandem and colpostats are 15 degrees and 120 degrees , respectively. We assigned 10 dwell positions to the tandem and 4 dwell positions to right and left colpostats or ovoids to represent a typical treatment case. Typical dose delivered to point A was determined according to Manchester dosimetry system. Based on our computations, the reduction of dose to point A was shown to be at least 3%. So this effect presented by SS-FSD systems on patient dose is of concern.

Comparative efficacy of low-dose versus standard-dose azithromycin for patients with yaws: a randomised non-inferiority trial in Ghana and Papua New Guinea.

PubMed

Marks, Michael; Mitjà, Oriol; Bottomley, Christian; Kwakye, Cynthia; Houinei, Wendy; Bauri, Mathias; Adwere, Paul; Abdulai, Abdul A; Dua, Fredrick; Boateng, Laud; Wangi, James; Ohene, Sally-Ann; Wangnapi, Regina; Simpson, Shirley V; Miag, Helen; Addo, Kennedy K; Basing, Laud A; Danavall, Damien; Chi, Kai H; Pillay, Allan; Ballard, Ronald; Solomon, Anthony W; Chen, Cheng Y; Bieb, Sibauk V; Adu-Sarkodie, Yaw; Mabey, David C W; Asiedu, Kingsley

2018-04-01

A dose of 30 mg/kg of azithromycin is recommended for treatment of yaws, a disease targeted for global eradication. Treatment with 20 mg/kg of azithromycin is recommended for the elimination of trachoma as a public health problem. In some settings, these diseases are co-endemic. We aimed to determine the efficacy of 20 mg/kg of azithromycin compared with 30 mg/kg azithromycin for the treatment of active and latent yaws. We did a non-inferiority, open-label, randomised controlled trial in children aged 6-15 years who were recruited from schools in Ghana and schools and the community in Papua New Guinea. Participants were enrolled based on the presence of a clinical lesion that was consistent with infectious primary or secondary yaws and a positive rapid diagnostic test for treponemal and non-treponemal antibodies. Participants were randomly assigned (1:1) to receive either standard-dose (30 mg/kg) or low-dose (20 mg/kg) azithromycin by a computer-generated random number sequence. Health-care workers assessing clinical outcomes in the field were not blinded to the patient's treatment, but investigators involved in statistical or laboratory analyses and the participants were blinded to treatment group. We followed up participants at 4 weeks and 6 months. The primary outcome was cure at 6 months, defined as lesion healing at 4 weeks in patients with active yaws and at least a four-fold decrease in rapid plasma reagin titre from baseline to 6 months in patients with active and latent yaws. Active yaws was defined as a skin lesion that was positive for Treponema pallidum ssp pertenue in PCR testing. We used a non-inferiority margin of 10%. This trial was registered with ClinicalTrials.gov, number NCT02344628. Between June 12, 2015, and July 2, 2016, 583 (65·1%) of 895 children screened were enrolled; 292 patients were assigned a low dose of azithromycin and 291 patients were assigned a standard dose of azithromycin. 191 participants had active yaws and 392 had presumed latent yaws. Complete follow-up to 6 months was available for 157 (82·2%) of 191 patients with active yaws. In cases of active yaws, cure was achieved in 61 (80·3%) of 76 patients in the low-dose group and in 68 (84·0%) of 81 patients in the standard-dose group (difference 3·7%; 95% CI -8·4 to 15·7%; this result did not meet the non-inferiority criterion). There were no serious adverse events reported in response to treatment in either group. The most commonly reported adverse event at 4 weeks was gastrointestinal upset, with eight (2·7%) participants in each group reporting this symptom. In this study, low-dose azithromycin did not meet the prespecified non-inferiority margin compared with standard-dose azithromycin in achieving clinical and serological cure in PCR-confirmed active yaws. Only a single participant (with presumed latent yaws) had definitive serological failure. This work suggests that 20 mg/kg of azithromycin is probably effective against yaws, but further data are needed. Coalition for Operational Research on Neglected Tropical Diseases. © 2018 World Health Organization; licensee Elsevier. This is an Open Access article published under the CC BY 3.0 license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. In any use of this article, there should be no suggestion that WHO endorses any specific organisation, products or services. The use of the WHO logo is not permitted. This notice should be preserved along with the article's original URL.

With adaptation, the WHO guidelines on calcium supplementation for prevention of pre-eclampsia are adopted by pregnant women.

PubMed

Omotayo, Moshood O; Martin, Stephanie L; Stoltzfus, Rebecca J; Ortolano, Stephanie E; Mwanga, Erick; Dickin, Katherine L

2018-04-01

The World Health Organization (WHO) recommends calcium supplementation for prevention of pre-eclampsia, but factors affecting adoption and acceptability of the recommendations among pregnant women have not been examined. We explored adoption of the WHO guidelines in Kenya, using the trials of improved practices. We recruited 38 pregnant women and assigned participants to three regimens representing potential trade-offs among daily dose, bioavailability, and acceptability. Participants were provided with supplements, requested to select preferred product type, counselled on how to take them, and interviewed 4 times over 6 weeks to assess their experiences. We tracked bottle opening with electronic monitors, as proxy for supplement consumption. We analysed interview transcripts thematically. All participants were willing to try the supplements. Average daily consumption ranged from 77 to 1,577 mg/d. Most participants (74%) chose the chewable product. Participants preferred its "sweet taste" and liked the ability to consume it without water. Women in the 2-dose regimen were least likely to switch; however, women assigned to the 3-dose regimen, or who switched to the 3-dose regimen, consumed the most calcium per day. Difficulties with the 4-dose regimen included afternoon doses when women were likely to forget and having to wait hours after supper for last dose. Use of an illustrated calendar, keeping supplements in conspicuous locations and requesting support from relatives were strategies that supported adherence. Pregnant women are likely to adopt Ca supplementation, with appropriate programmatic adaptations. Careful attention to product attributes, regimen complexity, and strategies for reassuring and reminding women are needed to adapt the WHO guidelines. © 2017 John Wiley & Sons Ltd.

Impact of Internal Metallic Ports in Temporary Tissue Expanders on Postmastectomy Radiation Dose Distribution

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

Chen, Susie A.; Ogunleye, Tomiwa; Dhabbaan, Anees

Purpose: Temporary tissue expanders (TTE) with an internal magnetic metal port (IMP) have been increasingly used for breast reconstruction in post-mastectomy patients who receive radiation therapy (XRT). We evaluated XRT plans of patients with IMP to determine its effect on XRT dose distribution. Methods and Materials: Original treatment plans with CT simulation scans of 24 consecutive patients who received XRT (ORI), planned without heterogeneity corrections, to a reconstructed breast containing an IMP were used. Two additional treatment plans were then generated: one treatment plan with the IMP assigned the electron density of the rare earth magnet, nickel plated neodymium-iron-boron (HET),more » and a second treatment plan with the IMP assigned a CT value of 1 to simulate a homogeneous breast without an IMP (BRS). All plans were prescribed 50 Gy to the reconstructed breast (CTV). Results: CTV coverage by 50 Gy was significantly lower in the HET (mean 87.7% CTV) than in either the ORI (mean 99.7% CTV, P<.001) or BRS plans (mean 95.0% CTV, P<.001). The effect of the port was more pronounced on CT slices containing the IMP with prescription dose coverage of the CTV being less in the HET than in either ORI (mean difference 33.6%, P<.01) or BRS plans (mean difference 30.1%, P<.001). HET had a less homogeneous and conformal dose distribution than BRS or ORI. Conclusion: IMPs increase dose heterogeneity and reduce dose to the breast CTV through attenuation of the beam. For optimal XRT treatment, heterogeneity corrections should be used in XRT planning for patients with TTE with IMP, as the IMP impacts dose distribution.« less

Acute personalized habitual caffeine doses improve attention and have selective effects when considering the fractionation of executive functions.

PubMed

Lanini, Juliana; Galduróz, José Carlos Fernandes; Pompéia, Sabine

2016-01-01

Caffeine is widely used, often consumed with food, and improves simple and complex/executive attention under fasting conditions. We investigated whether these cognitive effects are observed when personalized habitual doses of caffeine are ingested by caffeine consumers, whether they are influenced by nutriments and if various executive domains are susceptible to improvement. This was a double-blind, placebo-controlled study including 60 young, healthy, rested males randomly assigned to one of four treatments: placebo fasting, caffeine fasting, placebo meal and caffeine meal. Caffeine doses were individualized for each participant based on their self-reported caffeine consumption at the time of testing (morning). The test battery included measures of simple and sustained attention, executive domains (inhibiting, updating, shifting, dual tasking, planning and accessing long-term memory), control measures of subjective alterations, glucose and insulin levels, skin conductance, heart rate and pupil dilation. Regardless of meal intake, acute habitual doses of caffeine decreased fatigue, and improved simple and sustained attention and executive updating. This executive effect was not secondary to the habitual weekly dose consumed, changes in simple and sustained attention, mood, meal ingestion and increases in cognitive effort. We conclude that the morning caffeine "fix" has positive attentional effects and selectively improved executive updating whether or not caffeine is consumed with food. Copyright © 2015 John Wiley & Sons, Ltd.

Dupilumab Efficacy and Safety in Moderate-to-Severe Uncontrolled Asthma.

PubMed

Castro, Mario; Corren, Jonathan; Pavord, Ian D; Maspero, Jorge; Wenzel, Sally; Rabe, Klaus F; Busse, William W; Ford, Linda; Sher, Lawrence; FitzGerald, J Mark; Katelaris, Constance; Tohda, Yuji; Zhang, Bingzhi; Staudinger, Heribert; Pirozzi, Gianluca; Amin, Nikhil; Ruddy, Marcella; Akinlade, Bolanle; Khan, Asif; Chao, Jingdong; Martincova, Renata; Graham, Neil M H; Hamilton, Jennifer D; Swanson, Brian N; Stahl, Neil; Yancopoulos, George D; Teper, Ariel

2018-05-21

Background Dupilumab is a fully human anti-interleukin-4 receptor α monoclonal antibody that blocks both interleukin-4 and interleukin-13 signaling. We assessed its efficacy and safety in patients with uncontrolled asthma. Methods We randomly assigned 1902 patients 12 years of age or older with uncontrolled asthma in a 2:2:1:1 ratio to receive add-on subcutaneous dupilumab at a dose of 200 or 300 mg every 2 weeks or matched-volume placebos for 52 weeks. The primary end points were the annualized rate of severe asthma exacerbations and the absolute change from baseline to week 12 in the forced expiratory volume in 1 second (FEV 1 ) before bronchodilator use in the overall trial population. Secondary end points included the exacerbation rate and FEV 1 in patients with a blood eosinophil count of 300 or more per cubic millimeter. Asthma control and dupilumab safety were also assessed. Results The annualized rate of severe asthma exacerbations was 0.46 (95% confidence interval [CI], 0.39 to 0.53) among patients assigned to 200 mg of dupilumab every 2 weeks and 0.87 (95% CI, 0.72 to 1.05) among those assigned to a matched placebo, for a 47.7% lower rate with dupilumab than with placebo (P<0.001); similar results were seen with the dupilumab dose of 300 mg every 2 weeks. At week 12, the FEV 1 had increased by 0.32 liters in patients assigned to the lower dose of dupilumab (difference vs. matched placebo, 0.14 liters; P<0.001); similar results were seen with the higher dose. Among patients with a blood eosinophil count of 300 or more per cubic millimeter, the annualized rate of severe asthma exacerbations was 0.37 (95% CI, 0.29 to 0.48) among those receiving lower-dose dupilumab and 1.08 (95% CI, 0.85 to 1.38) among those receiving a matched placebo (65.8% lower rate with dupilumab than with placebo; 95% CI, 52.0 to 75.6); similar results were observed with the higher dose. Blood eosinophilia occurred after the start of the intervention in 52 patients (4.1%) who received dupilumab as compared with 4 patients (0.6%) who received placebo. Conclusions In this trial, patients who received dupilumab had significantly lower rates of severe asthma exacerbation than those who received placebo, as well as better lung function and asthma control. Greater benefits were seen in patients with higher baseline levels of eosinophils. Hypereosinophilia was observed in some patients. (Funded by Sanofi and Regeneron Pharmaceuticals; LIBERTY ASTHMA QUEST ClinicalTrials.gov number, NCT02414854 .).

Intrathecal 2-hydroxypropyl-β-cyclodextrin decreases neurological disease progression in Niemann-Pick disease, type C1: a non-randomised, open-label, phase 1-2 trial.

PubMed

Ory, Daniel S; Ottinger, Elizabeth A; Farhat, Nicole Yanjanin; King, Kelly A; Jiang, Xuntian; Weissfeld, Lisa; Berry-Kravis, Elizabeth; Davidson, Cristin D; Bianconi, Simona; Keener, Lee Ann; Rao, Ravichandran; Soldatos, Ariane; Sidhu, Rohini; Walters, Kimberly A; Xu, Xin; Thurm, Audrey; Solomon, Beth; Pavan, William J; Machielse, Bernardus N; Kao, Mark; Silber, Steven A; McKew, John C; Brewer, Carmen C; Vite, Charles H; Walkley, Steven U; Austin, Christopher P; Porter, Forbes D

2017-10-14

Niemann-Pick disease, type C1 (NPC1) is a lysosomal storage disorder characterised by progressive neurodegeneration. In preclinical testing, 2-hydroxypropyl-β-cyclodextrins (HPβCD) significantly delayed cerebellar Purkinje cell loss, slowed progression of neurological manifestations, and increased lifespan in mouse and cat models of NPC1. The aim of this study was to assess the safety and efficacy of lumbar intrathecal HPβCD. In this open-label, dose-escalation phase 1-2a study, we gave monthly intrathecal HPβCD to participants with NPC1 with neurological manifestation at the National Institutes of Health (NIH), Bethesda, MD, USA. To explore the potential effect of 2-week dosing, three additional participants were enrolled in a parallel study at Rush University Medical Center (RUMC), Chicago, IL, USA. Participants from the NIH were non-randomly, sequentially assigned in cohorts of three to receive monthly initial intrathecal HPβCD at doses of 50, 200, 300, or 400 mg per month. A fifth cohort of two participants received initial doses of 900 mg. Participants from RUMC initially received 200 or 400 mg every 2 weeks. The dose was escalated based on tolerance or safety data from higher dose cohorts. Serum and CSF 24(S)-hydroxycholesterol (24[S]-HC), which serves as a biomarker of target engagement, and CSF protein biomarkers were evaluated. NPC Neurological Severity Scores (NNSS) were used to compare disease progression in HPβCD-treated participants relative to a historical comparison cohort of 21 NPC1 participants of similar age range. Between Sept 21, 2013, and Jan 19, 2015, 32 participants with NPC1 were assessed for eligibility at the National Institutes of Health. 18 patients were excluded due to inclusion criteria not met (six patients), declined to participate (three patients), pursued independent expanded access and obtained the drug outside of the study (three patients), enrolled in the RUMC cohort (one patient), or too late for the trial enrolment (five patients). 14 patients were enrolled and sequentially assigned to receive intrathecal HPβCD at a starting dose of 50 mg per month (three patients), 200 mg per month (three patients), 300 mg per month (three patients), 400 mg per month (three patients), or 900 mg per month (two patients). During the first year, two patients had treatment interrupted for one dose, based on grade 1 ototoxicity. All 14 patients were assessed at 12 months. Between 12 and 18 months, one participant had treatment interrupted at 17 months due to hepatocellular carcinoma, one patient had dose interruption for 2 doses based on caregiver hardship and one patient had treatment interrupted for 1 dose for mastoiditis. 11 patients were assessed at 18 months. Between Dec 11, 2013, and June 25, 2014, three participants were assessed for eligibility and enrolled at RUMC, and were assigned to receive intrathecal HPβCD at a starting dose of 200 mg every 2 weeks (two patients), or 400 mg every two weeks (one patient). There were no dropouts in this group and all 3 patients were assessed at 18 months. Biomarker studies were consistent with improved neuronal cholesterol homoeostasis and decreased neuronal pathology. Post-drug plasma 24(S)-HC area under the curve (AUC 8-72 ) values, an indicator of neuronal cholesterol homoeostasis, were significantly higher than post-saline plasma 24(S)-HC AUC 8-72 after doses of 900 mg (p=0·0063) and 1200 mg (p=0·0037). CSF 24(S)-HC concentrations in three participants given either 600 or 900 mg of HPβCD were increased about two fold (p=0·0032) after drug administration. No drug-related serious adverse events were observed. Mid-frequency to high-frequency hearing loss, an expected adverse event, was documented in all participants. When managed with hearing aids, this did not have an appreciable effect on daily communication. The NNSS for the 14 participants treated monthly increased at a rate of 1·22, SEM 0·34 points per year compared with 2·92, SEM 0·27 points per year (p=0·0002) for the 21 patient comparison group. Decreased progression was observed for NNSS domains of ambulation (p=0·0622), cognition (p=0·0040) and speech (p=0·0423). Patients with NPC1 treated with intrathecal HPβCD had slowed disease progression with an acceptable safety profile. These data support the initiation of a multinational, randomised, controlled trial of intrathecal HPβCD. National Institutes of Health, Dana's Angels Research Trust, Ara Parseghian Medical Research Foundation, Hope for Haley, Samantha's Search for the Cure Foundation, National Niemann-Pick Disease Foundation, Support of Accelerated Research for NPC Disease, Vtesse, Janssen Research and Development, a Johnson & Johnson company, and Johnson & Johnson. Copyright © 2017 Elsevier Ltd. All rights reserved.

Low-Dose, High-Frequency CPR Training Improves Skill Retention of In-Hospital Pediatric Providers

PubMed Central

Niles, Dana; Meaney, Peter A.; Aplenc, Richard; French, Benjamin; Abella, Benjamin S.; Lengetti, Evelyn L.; Berg, Robert A.; Helfaer, Mark A.; Nadkarni, Vinay

2011-01-01

OBJECTIVE: To investigate the effectiveness of brief bedside cardiopulmonary resuscitation (CPR) training to improve the skill retention of hospital-based pediatric providers. We hypothesized that a low-dose, high-frequency training program (booster training) would improve CPR skill retention. PATIENTS AND METHODS: CPR recording/feedback defibrillators were used to evaluate CPR quality during simulated arrest. Basic life support–certified, hospital-based providers were randomly assigned to 1 of 4 study arms: (1) instructor-only training; (2) automated defibrillator feedback only; (3) instructor training combined with automated feedback; and (4) control (no structured training). Each session (time: 0, 1, 3, and 6 months after training) consisted of a pretraining evaluation (60 seconds), booster training (120 seconds), and a posttraining evaluation (60 seconds). Excellent CPR was defined as chest compression (CC) depth ≥ one-third anterior-posterior chest depth, rate ≥ 90 and ≤120 CC per minute, ≤20% of CCs with incomplete release (>2500 g), and no flow fraction ≤ 0.30. MEASUREMENTS AND MAIN RESULTS: Eighty-nine providers were randomly assigned; 74 (83%) completed all sessions. Retention of CPR skills was 2.3 times (95% confidence interval [CI]: 1.1–4.5; P = .02) more likely after 2 trainings and 2.9 times (95% CI: 1.4–6.2; P = .005) more likely after 3 trainings. The automated defibrillator feedback only group had lower retention rates compared with the instructor-only training group (odds ratio: 0.41 [95% CI: 0.17–0.97]; P = .043). CONCLUSIONS: Brief bedside booster CPR training improves CPR skill retention. Our data reveal that instructor-led training improves retention compared with automated feedback training alone. Future studies should investigate whether bedside training improves CPR quality during actual pediatric arrests. PMID:21646262

Effects of Altering Levothyroxine (L-T4) Doses on Quality of Life, Mood, and Cognition in L-T4 Treated Subjects.

PubMed

Samuels, Mary H; Kolobova, Irina; Niederhausen, Meike; Janowsky, Jeri S; Schuff, Kathryn G

2018-05-01

The brain is a critical target organ for thyroid hormone, but it is unclear whether variations in thyroid function within and near the reference range affect quality of life, mood, or cognition. A total of 138 subjects with levothyroxine (L-T4)-treated hypothyroidism and normal thyrotropin (TSH) levels underwent measures of quality of life (36-Item Short Form Health Survey, Underactive Thyroid-Dependent Quality of Life Questionnaire), mood (Profile of Mood States, Affective Lability Scale), and cognition (executive function, memory). They were then randomly assigned to receive an unchanged, higher, or lower L-T4 dose in double-blind fashion, targeting one of three TSH ranges (0.34 to 2.50, 2.51 to 5.60, or 5.61 to 12.0 mU/L). Doses were adjusted every 6 weeks based on TSH levels. Baseline measures were reassessed at 6 months. At the end of the study, by intention to treat, mean L-T4 doses were 1.50 ± 0.07, 1.32 ± 0.07, and 0.78 ± 0.08 μg/kg (P < 0.001), and mean TSH levels were 1.85 ± 0.25, 3.93 ± 0.38, and 9.49 ± 0.80 mU/L (P < 0.001), respectively, in the three arms. There were minor differences in a few outcomes between the three arms, which were no longer significant after correction for multiple comparisons. Subjects could not ascertain how their L-T4 doses had been adjusted (P = 0.55) but preferred L-T4 doses they perceived to be higher (P < 0.001). Altering L-T4 doses in hypothyroid subjects to vary TSH levels in and near the reference range does not affect quality of life, mood, or cognition. L-T4-treated subjects prefer perceived higher L-T4 doses despite a lack of objective benefit. Adjusting L-T4 doses in hypothyroid patients based on symptoms in these areas may not result in significant clinical improvement.

Half doses of PEG-ES and senna vs. high-dose senna for bowel cleansing before colonoscopy: a randomized, investigator-blinded trial.

PubMed

Amato, Arnaldo; Radaelli, Franco; Paggi, Silvia; Terruzzi, Vittorio

2010-03-01

Patients' compliance with and tolerance of large-volume polyethylene glycol electrolyte solution (PEG-ES) have prompted continuous investigation with alternative forms of cleansing. High-dose senna is superior to PEG-ES for the quality of bowel cleansing, patient compliance, and tolerance, but its acceptance may be influenced by the incidence of abdominal pain. We hypothesized that a combination of half doses of PEG-ES and senna could minimize the incidence of abdominal pain without affecting the quality of bowel preparation. This randomized, investigator-blinded trial has been conducted on consecutive outpatients scheduled for elective colonoscopy at a single community-based hospital. Patients were randomly assigned to receive either 12 tablets of 12 mg senna and 2 l of PEG-ES (half-dose group, HDG) or 24 tablets of senna divided in two doses (senna group, SG) the day before colonoscopy. The main outcome measures were the quality of colon cleansing (Aronchick scoring scale) and the incidence of preparation-related abdominal pain. Secondary outcome measures were patients' compliance with the cleansing regimen, overall tolerability, prevalence of predefined side effects, and quality of right colon cleansing. A total of 296 patients were enrolled (HDG=151 and SG=145). Overall cleansing was excellent to good in 90.1 and 88.3% patients in HDG and SG, respectively (P=0.62). Preparation-related moderate-to-severe abdominal pain was reported by 6% patients in HDG and 15.2% in SG (P=0.009). No significant differences were observed for secondary outcomes. The regimen combining half doses of PEG-ES and senna provides high-quality bowel preparation and acceptable patient tolerance, with less abdominal pain compared with high-dose senna.

Patients with Fabry Disease after Enzyme Replacement Therapy Dose Reduction and Switch-2-Year Follow-Up.

PubMed

Lenders, Malte; Canaan-Kühl, Sima; Krämer, Johannes; Duning, Thomas; Reiermann, Stefanie; Sommer, Claudia; Stypmann, Jörg; Blaschke, Daniela; Üçeyler, Nurcan; Hense, Hans-Werner; Brand, Stefan-Martin; Wanner, Christoph; Weidemann, Frank; Brand, Eva

2016-03-01

Because of the shortage of agalsidase-β supply between 2009 and 2012, patients with Fabry disease either were treated with reduced doses or were switched to agalsidase-α. In this observational study, we assessed end organ damage and clinical symptoms with special focus on renal outcome after 2 years of dose-reduction and/or switch to agalsidase-α. A total of 89 adult patients with Fabry disease who had received agalsidase-β (1.0 mg/kg body wt) for >1 year were nonrandomly assigned to continue this treatment regimen (regular-dose group, n=24), to receive a reduced dose of 0.3-0.5 mg/kg and a subsequent switch to 0.2 mg/kg agalsidase-α (dose-reduction-switch group, n=28), or to directly switch to 0.2 mg/kg agalsidase-α (switch group, n=37) and were followed-up for 2 years. We assessed clinical events (death, myocardial infarction, severe arrhythmia, stroke, progression to ESRD), changes in cardiac and renal function, Fabry-related symptoms (pain, hypohidrosis, diarrhea), and disease severity scores. Determination of renal function by creatinine and cystatin C-based eGFR revealed decreasing eGFRs in the dose-reduction-switch group and the switch group. The Mainz Severity Score Index increased significantly in these two groups (P=0.02 and P<0.001, respectively), and higher frequencies of gastrointestinal pain occurred during follow-up. In conclusion, after 2 years of observation, all groups showed a stable clinical disease course with respect to serious clinical events. However, patients under agalsidase-β dose-reduction and switch or a direct switch to agalsidase-α showed a decline of renal function independent of the eGFR formula used. Copyright © 2016 by the American Society of Nephrology.

Patients with Fabry Disease after Enzyme Replacement Therapy Dose Reduction and Switch–2-Year Follow-Up

PubMed Central

Lenders, Malte; Canaan-Kühl, Sima; Krämer, Johannes; Duning, Thomas; Reiermann, Stefanie; Sommer, Claudia; Stypmann, Jörg; Blaschke, Daniela; Üçeyler, Nurcan; Hense, Hans-Werner; Brand, Stefan-Martin; Wanner, Christoph; Weidemann, Frank

2016-01-01

Because of the shortage of agalsidase-β supply between 2009 and 2012, patients with Fabry disease either were treated with reduced doses or were switched to agalsidase-α. In this observational study, we assessed end organ damage and clinical symptoms with special focus on renal outcome after 2 years of dose-reduction and/or switch to agalsidase-α. A total of 89 adult patients with Fabry disease who had received agalsidase-β (1.0 mg/kg body wt) for >1 year were nonrandomly assigned to continue this treatment regimen (regular-dose group, n=24), to receive a reduced dose of 0.3–0.5 mg/kg and a subsequent switch to 0.2 mg/kg agalsidase-α (dose-reduction-switch group, n=28), or to directly switch to 0.2 mg/kg agalsidase-α (switch group, n=37) and were followed-up for 2 years. We assessed clinical events (death, myocardial infarction, severe arrhythmia, stroke, progression to ESRD), changes in cardiac and renal function, Fabry-related symptoms (pain, hypohidrosis, diarrhea), and disease severity scores. Determination of renal function by creatinine and cystatin C–based eGFR revealed decreasing eGFRs in the dose-reduction-switch group and the switch group. The Mainz Severity Score Index increased significantly in these two groups (P=0.02 and P<0.001, respectively), and higher frequencies of gastrointestinal pain occurred during follow-up. In conclusion, after 2 years of observation, all groups showed a stable clinical disease course with respect to serious clinical events. However, patients under agalsidase-β dose-reduction and switch or a direct switch to agalsidase-α showed a decline of renal function independent of the eGFR formula used. PMID:26185201

Daily low-dose subcutaneous interleukin-2 added to single- or dual-nucleoside therapy in HIV infection does not protect against CD4+ T-cell decline or improve other indices of immune function: results of a randomized controlled clinical trial (ACTG 248).

PubMed

Vogler, Mary A; Teppler, Hedy; Gelman, Rebecca; Valentine, Fred; Lederman, Michael M; Pomerantz, Roger J; Pollard, Richard B; Cherng, Deborah Weng; Gonzalez, Charles J; Squires, Kathleen E; Frank, Ian; Mildvan, Donna; Mahon, Laura F; Schock, Barbara

2004-05-01

Approaches to preserve or enhance immune function in HIV-1 infection are needed. To examine the ability of daily low-dose interleukin-2 (IL-2) in combination with antiretroviral therapy to preserve circulating CD4+ T-cell counts, the clinical safety and tolerability of this treatment, and safety with respect to changes in plasma HIV-1 RNA levels. Twenty-four-week, phase 2, multicenter, randomized, open-label trial conducted at 12 AIDS Clinical Trials Units between September 1995 and May 1997. A total of 115 HIV-infected persons with screening CD4+ T-cell counts between 300 and 700 cells/mm who were on stable single- or dual-nucleoside therapy for at least 2 months, 11% of whom were also on a protease inhibitor at study entry. Patients were randomly assigned to receive IL-2 at a dose of 1 million IU subcutaneously once daily plus continued anti-retroviral therapy (ART + IL-2, n = 57) vs. continued ART alone (ART alone, n = 58). IL-2 dose reductions were made for objective or subjective toxicities. All subjects randomly assigned to the IL-2 arm who interrupted ART were also required to discontinue IL-2 for the same period. The primary endpoint was a decrease in CD4 T-cell count from baseline; the safety analysis was based on change in plasma HIV RNA by bDNA; and clinical safety and tolerability were analyzed by standard clinical criteria. Of the patients with a baseline CD4 T-cell count recorded, 15 (27%) of 55 patients randomly assigned to ART alone had a drop of > or =25% in their CD4 T-cell count and 23 (41%) of 56 patients randomly assigned to ART + IL-2 had a drop of > or =25% in their CD4 T-cell count at some time over the 24 weeks of the study. This difference was not statistically significant. There was a statistically significant greater variance in CD4 T-cell counts in the IL-2-treated group. More patients in the IL-2 group had at least a 25% increase in CD4 T-cell counts over baseline (34 vs. 13%, P = 0.007). A comparison of grade 3 or worse toxicity showed no differences between the arms, but IL-2 was associated with significantly more grade 2 or worse general body symptoms, primarily discomfort and fatigue. There was no significant difference between the groups with regard to changes in plasma HIV RNA, lymphocyte proliferation, natural killer cell activity, skin test responses to recall antigens, or antibody responses to immunization. Plasma markers of immune activation all increased significantly in IL-2 recipients. In patients with baseline CD4 T-cell counts > or =300 cells/mm primarily treated with single- or dual-nucleoside ART, subcutaneously administered IL-2 at a dose of 1 million IU daily for up to 24 weeks had low toxicity but showed no consistent benefit in preventing decline in CD4 T-cell counts and minimal evidence of immunologic improvement vs. continued ART alone.

Chromogenic assay for BAY 81-8973 potency assignment has no impact on clinical outcome or monitoring in patient samples.

PubMed

Kitchen, S; Katterle, Y; Beckmann, H; Maas Enriquez, M

2016-06-01

Essentials Discrepancies can exist in factor VIII activity measured by the one-stage or chromogenic assays. LEOPOLD trial data were used to assess clinical impact of BAY 81-8973 potency assignment assay. Efficacy was not affected by the assay used for potency assignment and dosing of BAY 81-8973. Either assay may be used to measure factor VIII activity after BAY 81-8973 infusion. Background Product-specific discrepancies have been reported for factor VIII (FVIII) activity determined with one-stage or chromogenic assays. Objective To assess the clinical impact of potency assignment of BAY 81-8973, a full-length, unmodified, recombinant human FVIII, by use of the chromogenic assay or chromogenic assay adjusted to mimic results obtained with the one-stage assay Patients/methods Patients aged 12-65 years with severe hemophilia A received BAY 81-8973 in LEOPOLD I (20-50 IU kg(-1) two or three times weekly [investigator decision]) and LEOPOLD II (randomized to 20-30 IU kg(-1) twice weekly, 30-40 IU kg(-1) three times weekly, or on-demand treatment). Both trials included two 6-month crossover periods in which potency labeling was determined with the chromogenic substrate assay as per the European Pharmacopoeia (CS/EP) or the chromogenic substrate assay adjusted to mimic results obtained with the one-stage assay (CS/ADJ). The annualized bleeding rate (ABR) and FVIII incremental recovery were assessed by the use of pooled data. Results The analysis was perfomed on 121 patients. Median (quartile [Q] 1; Q3) ABRs during the CS/EP and CS/ADJ periods were 1.98 (0; 5.92) and 1.98 (0; 7.34), respectively. The mean incremental recovery was > 2 IU dL(-1) per IU kg(-1) in both periods with the use of either assay for postinfusion FVIII measurements. The median (Q1; Q3) chromogenic/one-stage assay recovery ratio was 1.054 (0.892; 1.150) for the CS/EP period when a plasma standard was used for calibration. Conclusions No impact on the ABR was observed with chromogenic-based as compared with one-stage assay-based potency and dosing. Either assay may be used to determine FVIII plasma activity after infusion of BAY 81-8973 without the need for a product-specific standard. © 2016 The Authors. Journal of Thrombosis and Haemostasis published by Wiley Periodicals, Inc. on behalf of International Society on Thrombosis and Haemostasis.

Homework "Dose," Type, and Helpfulness as Predictors of Clinical Outcomes in Prolonged Exposure for PTSD.

PubMed

Cooper, Andrew A; Kline, Alexander C; Graham, Belinda; Bedard-Gilligan, Michele; Mello, Patricia G; Feeny, Norah C; Zoellner, Lori A

2017-03-01

Homework is often viewed as central to prolonged exposure (PE) for posttraumatic stress disorder (PTSD), but its relationship with treatment outcome is not well understood. We evaluated homework type, dose, and patients' perceptions of helpfulness as predictors of symptom change and posttreatment outcomes in PE. Patients with chronic PTSD received PE in a randomized clinical trial. Independent evaluators assessed PTSD severity at pre- and posttreatment. Patients reported homework adherence and perceived helpfulness at the beginning of each session, separately for in vivo and imaginal exposure assignments. These variables were examined as predictors of change in PTSD symptoms, PTSD remission, and good end-state functioning (GESF; low PTSD, depression, and anxiety) at posttreatment. Higher imaginal homework adherence predicted greater symptom improvement between sessions and across treatment, as well as twice the odds of achieving remission and GESF. Patients who were at least moderately adherent to imaginal homework assignments (two or more times a week) reported more symptom gains than those who were least adherent but did not differ from those who were most adherent. In vivo adherence was not consistently associated with better outcome, perhaps due to heterogeneity in form and function of weekly assignments. Higher ratings of helpfulness of both types of homework predicted greater symptom improvement from pre- to posttreatment and between sessions. Overall, imaginal exposure homework may complement in-session exposures by enhancing key change processes, though perfect adherence is not necessary. Patients' perceptions of helpfulness may reflect buy-in or perceived match between homework completion and functional impairment. Clinically, in addition to targeting adherence to homework assignments, querying about perceived helpfulness and adjusting assignments appropriately may help augment clinical gains. Copyright © 2016. Published by Elsevier Ltd.

Low-Dose versus Standard-Dose Intravenous Alteplase in Acute Ischemic Stroke.

PubMed

Anderson, Craig S; Robinson, Thompson; Lindley, Richard I; Arima, Hisatomi; Lavados, Pablo M; Lee, Tsong-Hai; Broderick, Joseph P; Chen, Xiaoying; Chen, Guofang; Sharma, Vijay K; Kim, Jong S; Thang, Nguyen H; Cao, Yongjun; Parsons, Mark W; Levi, Christopher; Huang, Yining; Olavarría, Verónica V; Demchuk, Andrew M; Bath, Philip M; Donnan, Geoffrey A; Martins, Sheila; Pontes-Neto, Octavio M; Silva, Federico; Ricci, Stefano; Roffe, Christine; Pandian, Jeyaraj; Billot, Laurent; Woodward, Mark; Li, Qiang; Wang, Xia; Wang, Jiguang; Chalmers, John

2016-06-16

Thrombolytic therapy for acute ischemic stroke with a lower-than-standard dose of intravenous alteplase may improve recovery along with a reduced risk of intracerebral hemorrhage. Using a 2-by-2 quasi-factorial open-label design, we randomly assigned 3310 patients who were eligible for thrombolytic therapy (median age, 67 years; 63% Asian) to low-dose intravenous alteplase (0.6 mg per kilogram of body weight) or the standard dose (0.9 mg per kilogram); patients underwent randomization within 4.5 hours after the onset of stroke. The primary objective was to determine whether the low dose would be noninferior to the standard dose with respect to the primary outcome of death or disability at 90 days, which was defined by scores of 2 to 6 on the modified Rankin scale (range, 0 [no symptoms] to 6 [death]). Secondary objectives were to determine whether the low dose would be superior to the standard dose with respect to centrally adjudicated symptomatic intracerebral hemorrhage and whether the low dose would be noninferior in an ordinal analysis of modified Rankin scale scores (testing for an improvement in the distribution of scores). The trial included 935 patients who were also randomly assigned to intensive or guideline-recommended blood-pressure control. The primary outcome occurred in 855 of 1607 participants (53.2%) in the low-dose group and in 817 of 1599 participants (51.1%) in the standard-dose group (odds ratio, 1.09; 95% confidence interval [CI], 0.95 to 1.25; the upper boundary exceeded the noninferiority margin of 1.14; P=0.51 for noninferiority). Low-dose alteplase was noninferior in the ordinal analysis of modified Rankin scale scores (unadjusted common odds ratio, 1.00; 95% CI, 0.89 to 1.13; P=0.04 for noninferiority). Major symptomatic intracerebral hemorrhage occurred in 1.0% of the participants in the low-dose group and in 2.1% of the participants in the standard-dose group (P=0.01); fatal events occurred within 7 days in 0.5% and 1.5%, respectively (P=0.01). Mortality at 90 days did not differ significantly between the two groups (8.5% and 10.3%, respectively; P=0.07). This trial involving predominantly Asian patients with acute ischemic stroke did not show the noninferiority of low-dose alteplase to standard-dose alteplase with respect to death and disability at 90 days. There were significantly fewer symptomatic intracerebral hemorrhages with low-dose alteplase. (Funded by the National Health and Medical Research Council of Australia and others; ENCHANTED ClinicalTrials.gov number, NCT01422616.).

SU-E-T-599: The Variation of Hounsfield Unit and Relative Electron Density Determination as a Function of KVp and Its Effect On Dose Calculation Accuracy

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

Ohl, A; Boer, S De

Purpose: To investigate the differences in relative electron density for different energy (kVp) settings and the effect that these differences have on dose calculations. Methods: A Nuclear Associates 76-430 Mini CT QC Phantom with materials of known relative electron densities was imaged by one multi-slice (16) and one single-slice computed tomography (CT) scanner. The Hounsfield unit (HU) was recorded for each material with energies ranging from 80 to 140 kVp and a representative relative electron density (RED) curve was created. A 5 cm thick inhomogeneity was created in the treatment planning system (TPS) image at a depth of 5 cm.more » The inhomogeneity was assigned HU for various materials for each kVp calibration curve. The dose was then calculated with the analytical anisotropic algorithm (AAA) at points within and below the inhomogeneity and compared using the 80 kVp beam as a baseline. Results: The differences in RED values as a function of kVp showed the largest variations of 580 and 547 HU for the Aluminum and Bone materials; the smallest differences of 0.6 and 3.0 HU were observed for the air and lung inhomogeneities. The corresponding dose calculations for the different RED values assigned to the 5 cm thick slab revealed the largest differences inside the aluminum and bone inhomogeneities of 2.2 to 6.4% and 4.3 to 7.0% respectively. The dose differences beyond these two inhomogeneities were between 0.4 to 1.6% for aluminum and 1.9 to 2.2 % for bone. For materials with lower HU the calculated dose differences were less than 1.0%. Conclusion: For high CT number materials the dose differences in the phantom calculation as high as 7.0% are significant. This result may indicate that implementing energy specific RED curves can increase dose calculation accuracy.« less

SU-F-T-443: Quantification of Dosimetric Effects of Dental Metallic Implant On VMAT Plans

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

Lin, C; Jiang, W; Feng, Y

Purpose: To evaluate the dosimetric impact of metallic implant that correlates with the size of targets and metallic implants and distance in between on volumetric-modulated arc therapy (VMAT) plans for head and neck (H&N) cancer patients with dental metallic implant. Methods: CT images of H&N cancer patients with dental metallic implant were used. Target volumes with different sizes and locations were contoured. Metal artifact regions excluding surrounding critical organs were outlined and assigned with CT numbers close to water (0HU). VMAT plans with half-arc, one-full-arc and two-full-arcs were constructed and same plans were applied to structure sets with and withoutmore » CT number assignment of metal artifact regions and compared. D95% was utilized to investigate PTV dose coverage and SNC Patient− Software was used for the analysis of dose distribution difference slice by slice. Results: For different targets sizes, variation of PTV dose coverage (Delta-D95%) with and without CT number replacement reduced with larger target volume for all half-arc, one-arc and two-arc VMAT plans even though there were no clinically significant differences. Additionally, there were no significant variations of the maximum percent difference (max.%diff) of dose distribution. With regard to the target location, Delta-D95% and max. %diff dropped with increasing distance between target and metallic implant. Furthermore, half-arc plans showed greater impact than one-arc plans, and two-arc plans had smallest influence for PTV dose coverage and dose distribution. Conclusion: The target size has less correlation of doseimetric impact than the target location relative to metallic implants. Plans with more arcs alleviate the dosimetric effect of metal artifact because of less contribution to the target dose from beams going through the regions with metallic artifacts. Incorrect CT number causes inaccurate dose distribution, therefore appropriately overwriting metallic artifact regions with reasonable CT numbers is recommended. More patient data are collected and under further analysis.« less

SU-F-T-300: Impact of Electron Density Modeling of ArcCHECK Cylindricaldiode Array On 3DVH Patient Specific QA Software Tool Analysis

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

Patwe, P; Mhatre, V; Dandekar, P

Purpose: 3DVH software is a patient specific quality assurance tool which estimates the 3D dose to the patient specific geometry with the help of Planned Dose Perturbation algorithm. The purpose of this study is to evaluate the impact of HU value of ArcCHECK phantom entered in Eclipse TPS on 3D dose & DVH QA analysis. Methods: Manufacturer of ArcCHECK phantom provides CT data set of phantom & recommends considering it as a homogeneous phantom with electron density (1.19 gm/cc or 282 HU) close to PMMA. We performed this study on Eclipse TPS (V13, VMS) & trueBEAM STx VMS Linac &more » ArcCHECK phantom (SNC). Plans were generated for 6MV photon beam, 20cm×20cm field size at isocentre & SPD (Source to phantom distance) of 86.7 cm to deliver 100cGy at isocentre. 3DVH software requires patients DICOM data generated by TPS & plan delivered on ArcCHECK phantom. Plans were generated in TPS by assigning different HU values to phantom. We analyzed gamma index & the dose profile for all plans along vertical down direction of beam’s central axis for Entry, Exit & Isocentre dose. Results: The global gamma passing rate (2% & 2mm) for manufacturer recommended HU value 282 was 96.3%. Detector entry, Isocentre & detector exit Doses were 1.9048 (1.9270), 1.00(1.0199) & 0.5078(0.527) Gy for TPS (Measured) respectively.The global gamma passing rate for electron density 1.1302 gm/cc was 98.6%. Detector entry, Isocentre & detector exit Doses were 1.8714 (1.8873), 1.00(0.9988) & 0.5211(0.516) Gy for TPS (Measured) respectively. Conclusion: Electron density value assigned by manufacturer does not hold true for every user. Proper modeling of electron density of ArcCHECK in TPS is essential to avoid systematic error in dose calculation of patient specific QA.« less

First-In-Human, Double-Blind, Placebo-Controlled, Randomized, Dose-Escalation Study of BG00010, a Glial Cell Line-Derived Neurotrophic Factor Family Member, in Subjects with Unilateral Sciatica.

PubMed

Rolan, Paul E; O'Neill, Gilmore; Versage, Eve; Rana, Jitesh; Tang, Yongqiang; Galluppi, Gerald; Aycardi, Ernesto

2015-01-01

To evaluate the safety, tolerability, and pharmacokinetics of single doses of BG00010 (neublastin, artemin, enovin) in subjects with unilateral sciatica. This was a single-center, blinded, placebo-controlled, randomized Phase 1 sequential-cohort, dose-escalation study (ClinicalTrials.gov identifier NCT00961766; funded by Biogen Idec). Adults with unilateral sciatica were enrolled at The Royal Adelaide Hospital, Australia. Four subjects were assigned to each of eleven cohorts (intravenous BG00010 0.3, 1, 3, 10, 25, 50, 100, 200, 400, or 800 μg/kg, or subcutaneous BG00010 50 μg/kg) and were randomized 3:1 to receive a single dose of BG00010 or placebo. The primary safety and tolerability assessments were: adverse events; clinical laboratory parameters and vital signs; pain as measured by a Likert rating scale; intra-epidermal nerve fiber density; and longitudinal assessment of quantitative sensory test parameters. Blood, serum, and plasma samples were collected for pharmacokinetic and pharmacodynamic assessments. Subjects were blinded to treatment assignment throughout the study. The investigator was blinded to treatment assignment until the Data Safety Review Committee review of unblinded data, which occurred after day 28. Beyond the planned enrollment of 44 subjects, four additional subjects were enrolled into to the intravenous BG00010 200 μg/kg cohort after one original subject experienced mild generalized pruritus. Therefore, a total of 48 subjects were enrolled between August 2009 and December 2011; all were included in the safety analyses. BG00010 was generally well tolerated: in primary analyses, the most common treatment-emergent adverse events were changes in temperature perception, pruritus, rash, or headache; no trends were observed in clinical laboratory parameters, vital signs, intra-epidermal nerve fiber density, or quantitative sensory testing. BG00010 was not associated with any clear, dose-dependent trends in Likert pain scores. BG00010 was rapidly distributed, with a prolonged terminal elimination phase. These data support the development of BG00010 for the treatment of neuropathic pain. ClinicalTrials.gov NCT00961766.

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

Efficacy and safety of ABP 980 compared with reference trastuzumab in women with HER2-positive early breast cancer (LILAC study): a randomised, double-blind, phase 3 trial.

PubMed

von Minckwitz, Gunter; Colleoni, Marco; Kolberg, Hans-Christian; Morales, Serafin; Santi, Patricia; Tomasevic, Zorica; Zhang, Nan; Hanes, Vladimir

2018-06-04

ABP 980 (Amgen Inc, Thousand Oaks, CA, USA) is a biosimilar of trastuzumab, with analytical, functional, and pharmacokinetic similarities. We compared the clinical safety and efficacy of ABP 980 with that of trastuzumab in women with HER2-positive early breast cancer. We did a randomised, multicentre, double-blind, active-controlled equivalence trial at 97 study centres in 20 countries, mainly in Europe and South America. Eligible women were aged 18 years or older, had histologically confirmed HER2-positive invasive early breast cancer, an Eastern Cooperative Oncology Group performance status score of 0 or 1, and were planning to have surgical resection of the breast tumour with sentinel or axillary lymph node dissection and neoadjuvant chemotherapy. After four cycles of run-in anthracycline-based chemotherapy, patients were assigned 1:1 to receive ABP 980 or trastuzumab with a permuted block design (blocks of four) computer-generated randomisation schedule. Patients received neoadjuvant therapy with a loading dose (8 mg/kg) of ABP 980 or trastuzumab plus paclitaxel 175 mg/m 2 in a 90 min intravenous infusion, followed by three cycles of 6 mg/kg intravenous ABP 980 or trastuzumab plus paclitaxel 175 mg/m 2 every 3 weeks in 30 min intravenous infusions (or 80 mg/m 2 paclitaxel once per week for 12 cycles if that was the local standard of care). Randomisation was stratified by T stage, node status, hormone receptor status, planned paclitaxel dosing schedule, and geographical region. Surgery was completed 3-7 weeks after the last dose of neoadjuvant treatment, after which adjuvant treatment with ABP 980 or trastuzumab was given every 3 weeks for up to 1 year after the first dose in the study. Patients had been randomly assigned at baseline to continue APB 980, continue trastuzumab, or switch from trastuzumab to APB 980 as their adjuvant treatment. The co-primary efficacy endpoints were risk difference and risk ratio (RR) of pathological complete response in breast tissue and axillary lymph nodes assessed at a local laboratory in all patients who were randomly assigned and received any amount of neoadjuvant investigational product and underwent surgery. We assessed safety in all patients who were randomly assigned and received any amount of investigational product. This trial is registered with ClinicalTrials.gov, number NCT01901146 and Eudra, number CT 2012-004319-29. Of 827 patients enrolled, 725 were randomly assigned to receive ABP 980 (n=364) or trastuzumab (n=361). The primary endpoint was assessable in 696 patients (358 who received ABP 980 and 338 who received trastuzumab). Pathological complete response was recorded in 172 (48%, 95% CI 43-53) of 358 patients in the ABP 980 group and 137 (41%, 35-46) of 338 in the trastuzumab group (risk difference 7·3%, 90% CI 1·2-13·4; RR 1·188, 90% CI 1·033-1·366), with the upper bounds of the CIs exceeding the predefined equivalence margins of 13% and 1·318, respectively. Pathological complete response in the central laboratory assessment was seen in 162 (48%) of 339 patients assigned to ABP 980 at baseline and 138 (42%) of 330 assigned to trastuzumab at baseline (risk difference 5·8%, 90% CI -0·5 to 12·0, and RR 1·142, 90% CI 0·993 to 1·312). Grade 3 or worse adverse events during the neoadjuvant phase occurred in 54 (15%) of 364 patients in the ABP 980 group and 51 (14%) of 361 patients in the trastuzumab group, of which the most frequent grade 3 or worse event of interest was neutropenia, occurring in 21 (6%) patients in both groups. In the adjuvant phase, grade 3 or worse adverse events occurred in 30 (9%) of 349 patients continuing ABP 980, 11 (6%) of 171 continuing trastuzumab, and 13 (8%) of 171 who switched from trastuzumab to ABP 980, the most frequent grade 3 or worse events of interest were infections and infestations (four [1%], two [1%], and two [1%]), neutropenia (three [1%], two [1%], and one [1%]), and infusion reactions (two [1%], two [1%], and three [2%]). Two patients died from adverse events judged to be unrelated to the investigational products: one died from pneumonia while receiving neoadjuvant ABP 980 and one died from septic shock while receiving adjuvant ABP 980 after trastuzumab. Although the lower bounds of the 90% CIs for RR and risk difference showed non-inferiority, the upper bounds exceeded the predefined equivalence margins when based on local laboratory review of tumour samples, meaning that non-superiority was non-conclusive. In our sensitivity analyses based on central laboratory evaluation of tumour samples, estimates for the two drugs were contained within the predefined equivalence margins, indicating similar efficacy. ABP 980 and trastuzumab had similar safety outcomes in both the neoadjuvant and adjuvant phases of the study. Amgen. Copyright © 2018 Elsevier Ltd. All rights reserved.

Efficacy and Safety of Morphine and Low Dose Ketamine for Pain Control of Patients with Long Bone Fractures: A Randomized, Double-Blind, Clinical Trial

PubMed Central

Jahanian, Fatemeh; Hosseininejad, Seyed Mohammad; Amini Ahidashti, Hamed; Bozorgi, Farzad; Goli Khatir, Iraj; Montazar, Seyyed Hosein; Azarfar, Vahideh

2018-01-01

Objective: To compare the effects of intravenous morphine and a low dose of ketamine on pain intensity of patients with traumatic fractures of the long bones. Methods: This randomized, controlled, double-blinded, clinical trial was conducted in the adult emergency department (ED) of Emam Khomeini hospital, a tertiary general hospital affiliated with Mazandaran University of Medical Sciences, in Northern Iran, during a 6-month period. Patients were randomly assigned to receive intravenous morphine (0.1 mg/kg) or low dose ketamine (0.5 mg/kg) for control of the pain in the emergency room. The pain intensity was checked by a nurse using the visual analogue scale (VAS) at 30, 60, 90, 120, 180 and 240, minutes after the intervention. Results: Overall we included a total number of 156 patients with mean age of 35.87±3.38 years. There were 111 (71.2%) men and 4 (28.8%) women among the patients. Patients were randomly assigned to receive intravenous morphine (n=78) or low dose ketamine (n=78). The pain intensity decreased significantly in both study groups after 240 minutes of intervention. However, there was no significant difference between the two study groups regarding the pain intensity at 30 (p=0.378), 60 (p=0.927), 90 (p=0.434), 120 (p=0.557), 180 (p=0.991) and 240 (p=0.829) minutes. The side effects were comparable while low dose ketamine was associated with higher need for rescue analgesic (p=0.036).    Conclusion: The results of the current study demonstrates that the intravenous low dose ketamine leads to successful pain control in patients with long bone fractures and the effects are comparable with intravenous morphine. PMID:29379807

SU-E-T-493: Accelerated Monte Carlo Methods for Photon Dosimetry Using a Dual-GPU System and CUDA.

PubMed

Liu, T; Ding, A; Xu, X

2012-06-01

To develop a Graphics Processing Unit (GPU) based Monte Carlo (MC) code that accelerates dose calculations on a dual-GPU system. We simulated a clinical case of prostate cancer treatment. A voxelized abdomen phantom derived from 120 CT slices was used containing 218×126×60 voxels, and a GE LightSpeed 16-MDCT scanner was modeled. A CPU version of the MC code was first developed in C++ and tested on Intel Xeon X5660 2.8GHz CPU, then it was translated into GPU version using CUDA C 4.1 and run on a dual Tesla m 2 090 GPU system. The code was featured with automatic assignment of simulation task to multiple GPUs, as well as accurate calculation of energy- and material- dependent cross-sections. Double-precision floating point format was used for accuracy. Doses to the rectum, prostate, bladder and femoral heads were calculated. When running on a single GPU, the MC GPU code was found to be ×19 times faster than the CPU code and ×42 times faster than MCNPX. These speedup factors were doubled on the dual-GPU system. The dose Result was benchmarked against MCNPX and a maximum difference of 1% was observed when the relative error is kept below 0.1%. A GPU-based MC code was developed for dose calculations using detailed patient and CT scanner models. Efficiency and accuracy were both guaranteed in this code. Scalability of the code was confirmed on the dual-GPU system. © 2012 American Association of Physicists in Medicine.

Efficacy of alfaxalone for intravascular anesthesia and euthanasia in blue crabs (Callinectes sapidus).

PubMed

Minter, Larry J; Harms, Craig A; Archibald, Kate E; Broadhurst, Heather; Bailey, Kate M; Christiansen, Emily F; Lewbart, Gregory A; Posner, Lysa P

2013-09-01

The objective of this study was to characterize the behavioral effects and changes in heart rate of four doses of alfaxalone delivered by intravascular injection to blue crabs (Callinectes sapidus). Thirty (male, n = 27; female, n = 3) blue crabs were randomly assigned to one of four treatment groups of alfaxalone: eight animals were assigned to each of the 5-, 10-, and 15-mg/kg treatment groups, and the remaining six animals were assigned to the 100-mg/kg group. Times for anesthetic induction and recovery periods were recorded. Righting reflex, defensive posturing, and heart rate were evaluated before, during, and after the anesthetic trial. Anesthesia was induced in all 14 animals consolidated into the high-dosage group (15 mg/kg [n = 8] and 100 mg/kg [n = 6]), which was significantly greater than 8 of 16 animals in the low-dosage group (5 mg/kg [n = 2] and 10 mg/kg [n = 6]). Median anesthesia induction time for all crabs was 0.4 min, with no significant difference in induction time between groups observed. Median recovery time was 9.4 min (n = 2), 6.1 min (n = 5), 11.3 min (n = 8), and 66.1 min (n = 5) for the 5-, 10-, 15-, and 100-mg/kg groups, respectively. Recovery times were significantly longer for crabs exposed to an induction dose of 100 mg/kg compared with the 10- and 15-mg/kg induction doses. A significant decrease in the median heart rate was observed between the baseline value and that observed at both induction and 5 min postinjection in the 100-mg/kg dose trial. Two mortalities were observed during the anesthesia trials (n = 1, 10 mg/kg; n = 1, 100 mg/kg), both associated with the autotomization of limbs. In summary, the intravascular administration of alfaxalone at 15 mg/kg provided rapid and reliable sedation, whereas alfaxalone administered at 100 mg/kg produced rapid and long lasting anesthesia.

Gabapentin for hot flashes in 420 women with breast cancer: a randomised double-blind placebo-controlled trial

PubMed Central

Pandya, K J; Morrow, G R; Roscoe, J A; Hickok, J T; Zhao, H; Pajon, E; Sweeney, T J; Banerjee, T K; Flynn, P J

2005-01-01

Summary Background Most women receiving systemic therapy for breast cancer experience hot flashes. We undertook a randomised, double-blind, placebo-controlled, multi-institutional trial to assess the efficacy of gabapentin in controlling hot flashes in women with breast cancer. Methods 420 women with breast cancer who were having two or more hot flashes per day were randomly assigned placebo, gabapentin 300 mg/day, or gabapentin 900 mg/day by mouth in three divided doses for 8 weeks. Each patient kept a 1-week, self-report diary on the frequency, severity, and duration of hot flashes before the start of the study and during weeks 4 and 8 of treatment. Analyses were by intention to treat. Findings Evaluable data were available on 371 participants at 4 weeks (119 placebo, 123 gabapentin 300 mg, and 129 gabapentin 900 mg) and 347 at 8 weeks (113 placebo, 114 gabapentin 300 mg, and 120 gabapentin 900 mg). The percentage decreases in hot-flash severity score between baseline and weeks 4 and 8, respectively were: 21% (95% CI 12 to 30) and 15% (1 to 29) in the placebo group; 33% (23 to 43) and 31% (16 to 46) in the group assigned gabapentin 300 mg; and 49% (42 to 56) and 46% (34 to 58) in the group assigned gabapentin 900 mg. The differences between the groups were significant (p=0.0001 at 4 weeks and p=0.007 at 8 weeks by ANCOVA for overall treatment effect, adjusted for baseline values); only the higher dose of gabapentin was associated with significant decreases in hot-flash frequency and severity. Interpretation Gabapentin is effective in the control of hot flashes at a dose of 900 mg/day, but not at a dose of 300 mg/day. This drug should be considered for treatment of hot flashes in women with breast cancer. PMID:16139656

Toxicological profile of ultrapure 2,2',3,4,4',5,5'-heptachlorbiphenyl (PCB 180) in adult rats.

PubMed

Viluksela, Matti; Heikkinen, Päivi; van der Ven, Leo T M; Rendel, Filip; Roos, Robert; Esteban, Javier; Korkalainen, Merja; Lensu, Sanna; Miettinen, Hanna M; Savolainen, Kari; Sankari, Satu; Lilienthal, Hellmuth; Adamsson, Annika; Toppari, Jorma; Herlin, Maria; Finnilä, Mikko; Tuukkanen, Juha; Leslie, Heather A; Hamers, Timo; Hamscher, Gerd; Al-Anati, Lauy; Stenius, Ulla; Dervola, Kine-Susann; Bogen, Inger-Lise; Fonnum, Frode; Andersson, Patrik L; Schrenk, Dieter; Halldin, Krister; Håkansson, Helen

2014-01-01

PCB 180 is a persistent non-dioxin-like polychlorinated biphenyl (NDL-PCB) abundantly present in food and the environment. Risk characterization of NDL-PCBs is confounded by the presence of highly potent dioxin-like impurities. We used ultrapure PCB 180 to characterize its toxicity profile in a 28-day repeat dose toxicity study in young adult rats extended to cover endocrine and behavioral effects. Using a loading dose/maintenance dose regimen, groups of 5 males and 5 females were given total doses of 0, 3, 10, 30, 100, 300, 1000 or 1700 mg PCB 180/kg body weight by gavage. Dose-responses were analyzed using benchmark dose modeling based on dose and adipose tissue PCB concentrations. Body weight gain was retarded at 1700 mg/kg during loading dosing, but recovered thereafter. The most sensitive endpoint of toxicity that was used for risk characterization was altered open field behavior in females; i.e. increased activity and distance moved in the inner zone of an open field suggesting altered emotional responses to unfamiliar environment and impaired behavioral inhibition. Other dose-dependent changes included decreased serum thyroid hormones with associated histopathological changes, altered tissue retinoid levels, decreased hematocrit and hemoglobin, decreased follicle stimulating hormone and luteinizing hormone levels in males and increased expression of DNA damage markers in liver of females. Dose-dependent hypertrophy of zona fasciculata cells was observed in adrenals suggesting activation of cortex. There were gender differences in sensitivity and toxicity profiles were partly different in males and females. PCB 180 adipose tissue concentrations were clearly above the general human population levels, but close to the levels in highly exposed populations. The results demonstrate a distinct toxicological profile of PCB 180 with lack of dioxin-like properties required for assignment of WHO toxic equivalency factor. However, PCB 180 shares several toxicological targets with dioxin-like compounds emphasizing the potential for interactions.

Toxicological Profile of Ultrapure 2,2′,3,4,4′,5,5′-Heptachlorbiphenyl (PCB 180) in Adult Rats

PubMed Central

Viluksela, Matti; Heikkinen, Päivi; van der Ven, Leo T. M.; Rendel, Filip; Roos, Robert; Esteban, Javier; Korkalainen, Merja; Lensu, Sanna; Miettinen, Hanna M.; Savolainen, Kari; Sankari, Satu; Lilienthal, Hellmuth; Adamsson, Annika; Toppari, Jorma; Herlin, Maria; Finnilä, Mikko; Tuukkanen, Juha; Leslie, Heather A.; Hamers, Timo; Hamscher, Gerd; Al-Anati, Lauy; Stenius, Ulla; Dervola, Kine-Susann; Bogen, Inger-Lise; Fonnum, Frode; Andersson, Patrik L.; Schrenk, Dieter; Halldin, Krister; Håkansson, Helen

2014-01-01

PCB 180 is a persistent non-dioxin-like polychlorinated biphenyl (NDL-PCB) abundantly present in food and the environment. Risk characterization of NDL-PCBs is confounded by the presence of highly potent dioxin-like impurities. We used ultrapure PCB 180 to characterize its toxicity profile in a 28-day repeat dose toxicity study in young adult rats extended to cover endocrine and behavioral effects. Using a loading dose/maintenance dose regimen, groups of 5 males and 5 females were given total doses of 0, 3, 10, 30, 100, 300, 1000 or 1700 mg PCB 180/kg body weight by gavage. Dose-responses were analyzed using benchmark dose modeling based on dose and adipose tissue PCB concentrations. Body weight gain was retarded at 1700 mg/kg during loading dosing, but recovered thereafter. The most sensitive endpoint of toxicity that was used for risk characterization was altered open field behavior in females; i.e. increased activity and distance moved in the inner zone of an open field suggesting altered emotional responses to unfamiliar environment and impaired behavioral inhibition. Other dose-dependent changes included decreased serum thyroid hormones with associated histopathological changes, altered tissue retinoid levels, decreased hematocrit and hemoglobin, decreased follicle stimulating hormone and luteinizing hormone levels in males and increased expression of DNA damage markers in liver of females. Dose-dependent hypertrophy of zona fasciculata cells was observed in adrenals suggesting activation of cortex. There were gender differences in sensitivity and toxicity profiles were partly different in males and females. PCB 180 adipose tissue concentrations were clearly above the general human population levels, but close to the levels in highly exposed populations. The results demonstrate a distinct toxicological profile of PCB 180 with lack of dioxin-like properties required for assignment of WHO toxic equivalency factor. However, PCB 180 shares several toxicological targets with dioxin-like compounds emphasizing the potential for interactions. PMID:25137063

An oral carcinogenicity and toxicity study of senna (Tinnevelly senna fruits) in the rat.

PubMed

Mitchell, J M; Mengs, U; McPherson, S; Zijlstra, J; Dettmar, P; Gregson, R; Tigner, J C

2006-01-01

Senna (Tinnevelly senna fruits), a known laxative derived from plants, was administered by gavage to Sprague-Dawley (Crl:CD (SD) BR) rats once daily at dose levels of 0, 25, 100 and 300 mg/kg/day for up to 104 consecutive weeks. Based upon clinical signs related to the laxation effect of senna, the highest dose (300 mg/kg/day) was considered to be a maximum tolerated dose. Sixty animals per sex were assigned to the control and dose groups. Assessments included clinical chemistry, hematology, full histology (control and high-dose groups; in addition, low and mid dose: intestinal tract, adrenals, liver, kidneys, brain and gross lesions) and toxicokinetics. The primary treatment-related clinical observation was mucoid feces seen at 300 mg/kg/day. When compared to controls, animals administered 300 mg/kg/day had slightly reduced body weights, increased water consumption and notable changes in electrolytes in serum (increases in potassium and chloride) and urine (decreases in sodium, potassium and chloride). The changes in electrolytes are most likely physiologic adaptations to the laxative effect of senna. At necropsy, dark discoloration of the kidneys was observed in animals in all treated groups. Histological changes were seen in the kidneys of animals from all treated groups and included slight to moderate tubular basophilia and tubular pigment deposits. In addition, for all treated groups, minimal to slight hyperplasia was evident in the colon and cecum. These histological changes, together with the changes seen in the evaluation of clinical chemistry and urine parameters, have been shown to be reversible in a previous 13-week rat study of senna. No treatment-related neoplastic changes were observed in any of the examined organs. Based upon these data, it is concluded that senna is not carcinogenic even after daily administration for 2 years at dosages of up to 300 mg/kg/day in Sprague-Dawley rats.

SU-E-J-141: Comparison of Dose Calculation On Automatically Generated MRBased ED Maps and Corresponding Patient CT for Clinical Prostate EBRT Plans

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

Schadewaldt, N; Schulz, H; Helle, M

2014-06-01

Purpose: To analyze the effect of computing radiation dose on automatically generated MR-based simulated CT images compared to true patient CTs. Methods: Six prostate cancer patients received a regular planning CT for RT planning as well as a conventional 3D fast-field dual-echo scan on a Philips 3.0T Achieva, adding approximately 2 min of scan time to the clinical protocol. Simulated CTs (simCT) where synthesized by assigning known average CT values to the tissue classes air, water, fat, cortical and cancellous bone. For this, Dixon reconstruction of the nearly out-of-phase (echo 1) and in-phase images (echo 2) allowed for water andmore » fat classification. Model based bone segmentation was performed on a combination of the DIXON images. A subsequent automatic threshold divides into cortical and cancellous bone. For validation, the simCT was registered to the true CT and clinical treatment plans were re-computed on the simCT in pinnacle{sup 3}. To differentiate effects related to the 5 tissue classes and changes in the patient anatomy not compensated by rigid registration, we also calculate the dose on a stratified CT, where HU values are sorted in to the same 5 tissue classes as the simCT. Results: Dose and volume parameters on PTV and risk organs as used for the clinical approval were compared. All deviations are below 1.1%, except the anal sphincter mean dose, which is at most 2.2%, but well below clinical acceptance threshold. Average deviations are below 0.4% for PTV and risk organs and 1.3% for the anal sphincter. The deviations of the stratifiedCT are in the same range as for the simCT. All plans would have passed clinical acceptance thresholds on the simulated CT images. Conclusion: This study demonstrated the clinical usability of MR based dose calculation with the presented Dixon acquisition and subsequent fully automatic image processing. N. Schadewaldt, H. Schulz, M. Helle and S. Renisch are employed by Phlips Technologie Innovative Techonologies, a subsidiary of Royal Philips NV.« less

Phase I trial of capecitabine rapidly disintegrating tablets and concomitant radiation therapy in children with newly diagnosed brainstem gliomas and high-grade gliomas

PubMed Central

Kilburn, Lindsay B.; Kocak, Mehmet; Schaedeli Stark, Franziska; Meneses-Lorente, Georgina; Brownstein, Carrie; Hussain, Sazzad; Chintagumpala, Murali; Thompson, Patrick A.; Gururangan, Sri; Banerjee, Anuradha; Paulino, Arnold C.; Kun, Larry; Boyett, James M.; Blaney, Susan M.

2013-01-01

Background We conducted a phase I study to estimate the maximum tolerated dose and describe the dose-limiting toxicities and pharmacokinetics of oral capecitabine rapidly disintegrating tablets given concurrently with radiation therapy to children with newly diagnosed brainstem or high-grade gliomas. Methods Children 3–21 y with newly diagnosed intrinsic brainstem or high-grade gliomas were eligible for enrollment. The starting dose was 500 mg/m2, given twice daily, with subsequent cohorts enrolled at 650 mg/m2 and 850 mg/m2 using a 3 + 3 phase I design. Children received capecitabine at the assigned dose daily for 9 wks starting from the first day of radiation therapy (RT). Following a 2-wk break, patients received 3 courses of capecitabine 1250 mg/m2 twice daily for 14 days followed by a 7-day rest. Pharmacokinetic sampling was performed in consenting patients. Six additional patients with intrinsic brainstem gliomas were enrolled at the maximum tolerated dose to further characterize the pharmacokinetic and toxicity profiles. Results Twenty-four patients were enrolled. Twenty were fully assessable for toxicity. Dose-limiting toxicities were palmar plantar erythroderma (grades 2 and 3) and elevation of alanine aminotransferase (grades 2 and 3). Systemic exposure to capecitabine and metabolites was similar to or slightly lower than predicted based on adult data. Conclusions Capecitabine with concurrent RT was generally well tolerated. The recommended phase II capecitabine dose when given with concurrent RT is 650 mg/m2, administered twice daily. A phase II study to evaluate the efficacy of this regimen in children with intrinsic brainstem gliomas is in progress (PBTC-030). PMID:23592571

Significant and safe reduction of propofol sedation dose for geriatric population undergoing pacemaker implantation: randomized clinical trial.

PubMed

Hernandez-Perez, Ana Luisa; Gallardo-Hernandez, Ana Gabriela; Ordoñez-Espinosa, German; Martinez-Carrillo, Beatriz; Bermudez-Ochoa, Manuel Gerardo; Revilla-Monsalve, Cristina; Sanchez-Lopez, Jose Antonio; Saturno-Chiu, Guillemo; Leder, Ronald

2018-02-21

A previous multidisciplinary pilot study based on computer simulations for the geriatric population showed that a dose of 0.5 mg/kg/h of propofol could sedate patients older than 65 for pacemaker implantation. The present study validates that the pacemaker implantation can be done in the elderly using 0.5-1 mg/kg/h of propofol with hemodynamic stability. 66 patients from 65 to 88 years old scheduled for pacemaker implantation were randomly assigned one of three doses of propofol. The first group received 2 mg/kg/h of propofol (P2) that is within normal range of the sedation dose. The second group received 1 mg/kg/h (P1) dose and the third group received the dose of 0.5 mg/kg/h (P0.5) according to the simulation-predicted dose for geriatric populations. All patients kept MAP between 76 and 85 mmHg, with no hypotension episodes in any of the groups; therefore, they were all hemodynamically stable during the procedure. BIS was between 80 and 65 during the pacemaker implantation for the three groups, BIS of group P2 was significantly lower than the other groups. BIS in groups P1 and P0.5 was within the appropriated range for moderate sedation. Brice was positive for auditory recalls only when there was arousing noise in the operating room. Moderate sedation, adequate for pacemaker implantation, can be achieved infusing 0.5-1 mg/kg/h of propofol in elderly patients when the patient has proper analgesia management at the device implantation site. The second important condition is to avoid unnecessary and alerting auditory and mechanical stimuli in the operating room, so that the patient will remain calm.

Mesalamine Dose Escalation Reduces Fecal Calprotectin In Patients With Quiescent Ulcerative Colitis

PubMed Central

Osterman, Mark T.; Aberra, Faten N; Cross, Raymond; Liakos, Steven; McCabe, Robert; Shafran, Ira; Wolf, Douglas; Hardi, Robert; Nessel, Lisa; Brensinger, Colleen; Gilroy, Erin; Lewis, James D.

2014-01-01

Background & Aims Among patients with quiescent ulcerative colitis (UC), lower fecal concentrations of calprotectin are associated with lower rates of relapse. We performed an open-label, randomized, controlled trial to investigate whether increasing doses mesalamine reduce concentrations of fecal calprotectin (FC) in patients with quiescent UC. Methods We screened 119 patients with UC in remission, based on Simple Clinical Colitis Activity Index scores, FC >50 mcg/g, and intake of no more than 3g/day of mesalamine. Participants taking mesalamine formulations other than multimatrix mesalamine were switched to multimatrix mesalamine (2.4 g/day) for 6 weeks; 52 participants were then randomly assigned (1:1) to a group that continued its current dose of mesalamine (controls, n=26) or a group that increased its dose by 2.4 g/day for 6 weeks (n=26). The primary outcome was continued remission with FC<50 mcg/g. Secondary outcomes were continued remission with FC<100 mcg/g or <200 mcg/g (among patients with pre-randomization values above these levels). Results The primary outcome was achieved by 3.8% of controls and 26.9% of the dose escalation group (P=.0496). More patients in the dose escalation group reduced FC to below 100 mcg/g (P=.04) and 200 mcg/g (P=.005). Among the patients who were still in remission after the randomization phase, clinical relapse occurred sooner in patients with FC >200 mcg/g compared to those with FC <200 mcg/g (P=.01). Conclusion Among patients with quiescent UC and increased levels of FC, increasing the dose of mesalamine by 2.4 g/day reduced fecal concentrations of calprotectin to those associated with lower rates of relapse. Clinicaltrials.gov: NCT00652145 PMID:24793028

Disposition of a long-acting oxytetracycline formulation in Thai swamp buffaloes (Bubalus bubalis).

PubMed

Poapolathep, S; Wongpanit, K; Imsilp, K; Tanhan, P; Klangkaew, N; Giorgi, M; Poapolathep, A

2017-04-01

The present study aimed to characterize the pharmacokinetic profile of oxytetracycline long-acting formulation (OTC-LA) in Thai swamp buffaloes, Bubalus bubalis, following single intramuscular administration at two dosages of 20 and 30 mg/kg body weight (b.w.). Blood samples were collected at assigned times up to 504 h. The plasma concentrations of OTC were measured by high-performance liquid chromatography (HPLC). The concentrations of OTC in the plasma were determined up to 264 h and 432 h after i.m. administration at doses of 20 and 30 mg/kg b.w., respectively. The C max values of OTC were 12.11 ± 1.87 μg/mL and 12.27 ± 1.92 μg/mL at doses of 20 and 30 mg/kg, respectively. The AUC last values increased in a dose-dependent fashion. The half-life values were 52.00 ± 14.26 h and 66.80 ± 10.91 h at doses of 20 and 30 mg/kg b.w, respectively. Based on the pharmacokinetic data and PK-PD index (T > MIC), i.m. administration of OTC at a dose of 30 mg/kg b.w once per week might be appropriate for the treatment of susceptible bacterial infection in Thai swamp buffaloes. © 2016 John Wiley & Sons Ltd.

Reporting the national antimicrobial consumption in Danish pigs: influence of assigned daily dosage values and population measurement.

PubMed

Dupont, Nana; Fertner, Mette; Kristensen, Charlotte Sonne; Toft, Nils; Stege, Helle

2016-05-03

Transparent calculation methods are crucial when investigating trends in antimicrobial consumption over time and between populations. Until 2011, one single standardized method was applied when quantifying the Danish pig antimicrobial consumption with the unit "Animal Daily Dose" (ADD). However, two new methods for assigning values for ADDs have recently emerged, one implemented by DANMAP, responsible for publishing annual reports on antimicrobial consumption, and one by the Danish Veterinary and Food Administration (DVFA), responsible for the Yellow Card initiative. In addition to new ADD assignment methods, Denmark has also experienced a shift in the production pattern, towards a larger export of live pigs. The aims of this paper were to (1) describe previous and current ADD assignment methods used by the major Danish institutions and (2) to illustrate how ADD assignment method and choice of population and population measurement affect the calculated national antimicrobial consumption in pigs (2007-2013). The old VetStat ADD-values were based on SPCs in contrast to the new ADD-values, which were based on active compound, concentration and administration route. The new ADD-values stated by both DANMAP and DVFA were only identical for 48 % of antimicrobial products approved for use in pigs. From 2007 to 2013, the total number of ADDs per year increased by 9 % when using the new DVFA ADD-values, but decreased by 2 and 7 % when using the new DANMAP ADD-values or the old VetStat ADD-values, respectively. Through 2007 to 2013, the production of pigs increased from 26.1 million pigs per year with 18 % exported live to 28.7 million with 34 % exported live. In the same time span, the annual pig antimicrobial consumption increased by 22.2 %, when calculated using the new DVFA ADD-values and pigs slaughtered per year as population measurement (13.0 ADDs/pig/year to 15.9 ADDs/pig/year). However, when based on the old VetStat ADD values and pigs produced per year (including live export), a 10.9 % decrease was seen (10.6 ADDs/pig/year to 9.4 ADDs/pig/year). The findings of this paper clearly highlight that calculated national antimicrobial consumption is highly affected by chosen population measurement and the applied ADD-values.

Searching for moderators and mediators of pharmacological treatment effects in children and adolescents with anxiety disorders.

PubMed

Walkup, John T; Labellarte, Michael J; Riddle, Mark A; Pine, Daniel; Greenhill, Laurence; Klein, Rachel; Davies, Mark; Sweeney, Michael; Fu, Caifeng; Abikoff, Howard; Hack, Sabine; Klee, Brain; McCracken, James; Bergman, Lindsey; Piacentini, John; March, John; Compton, Scott; Robinson, James; O'Hara, Thomas; Baker, Sheryl; Vitiello, Benedetto; Ritz, Louise; Roper, Margaret

2003-01-01

To examine whether age, gender, ethnicity, type of anxiety disorder, severity of illness, comorbidity, intellectual level, family income, or parental education may function as moderators and whether treatment adherence, medication dose, adverse events, or blinded rater's guess of treatment assignment may function as mediators of pharmacological treatment effect in children and adolescents with anxiety disorders. The database of a recently reported double-blind placebo-controlled trial of fluvoxamine in 128 youths was analyzed. With a mixed-model random-effects regression analysis of the Pediatric Anxiety Rating Scale total score, moderators and mediators were searched by testing for a three-way interaction (strata by treatment by time). A two-way interaction (strata by time) identified predictors of treatment outcome. No significant moderators of efficacy were identified, except for lower baseline depression scores, based on parent's (but not child's) report, being associated with greater improvement (p < .001). Patients with social phobia (p < .05) and greater severity of illness (p < .001) were less likely to improve, independently of treatment assignment. Blinded rater's guess of treatment assignment acted as a possible mediator (p < .001), but improvement was attributed to fluvoxamine, regardless of actual treatment assignment. Treatment adherence tended to be associated (p = .05) with improvement. In this exploratory study, patient demographics, illness characteristics, family income, and parental education did not function as moderators of treatment effect. Social phobia and severity of illness predicted less favorable outcome. Attribution analyses indicated that study blindness remained intact. The presence of concomitant depressive symptoms deserves attention in future treatment studies of anxious children.

Study on store-space assignment based on logistic AGV in e-commerce goods to person picking pattern

NASA Astrophysics Data System (ADS)

Xu, Lijuan; Zhu, Jie

2017-10-01

This paper studied on the store-space assignment based on logistic AGV in E-commerce goods to person picking pattern, and established the store-space assignment model based on the lowest picking cost, and design for store-space assignment algorithm after the cluster analysis based on similarity coefficient. And then through the example analysis, compared the picking cost between store-space assignment algorithm this paper design and according to item number and storage according to ABC classification allocation, and verified the effectiveness of the design of the store-space assignment algorithm.

Effect of low doses of dietary rare earth elements on growth performance of broilers.

PubMed

He, M L; Wehr, U; Rambeck, W A

2010-02-01

The present study was designed to investigate effect of dietary rare earth elements (REE), including both organic and inorganic compounds, on growth performance of broilers. In experiment 1, a total of 180 male Ross broiler chicks were allocated to 72 pens with different assignment: four chicks per pen or individually. The following three treatment diets were applied: control, REE-chlorides at a dose of 40 mg/kg and REE-citrate at a dose of 70 mg/kg. Each treatment group had 24 pens containing both assignments (12 pens each). In experiment 2, a total of 72 male 3-day-old Ross broiler chicks were separated to four groups: control, REE-chlorides at a dose of 70 mg/kg and REE-citrate at doses of 70 mg/kg and 100 mg/kg. In experiment 1, dietary REE-citrate improved body weight gain during the overall period by 5.0% (p < 0.05) while the increase with REE-chloride was not significant. In experiment 2, growth effects (p < 0.05) were only found in the period from day 21 to slaughter with all REE forms, and feed conversion ratio was improved by 3.4% (p < 0.05) with REE-citrate. No significant effects of REE were found on chill weight, percentages of breast meat, thigh weight, drumstick weight and wing weight. Concentrations of La and Ce in the liver and muscles were very low, accounting for 0.11-0.76 and 0.02-0.30 mg/kg respectively. There was weak tendency for a dose-response relationship especially in the groups supplemented with REE-chlorides. The main blood serum biochemical parameters were not significantly affected by REE in the diets. The results suggest that dietary supplementation of low doses of REE-citrates might improve growth performance of broilers without affecting carcass composition and health of the broilers.

Bitemporal Versus High-Dose Unilateral Twice-Weekly Electroconvulsive Therapy for Depression (EFFECT-Dep): A Pragmatic, Randomized, Non-Inferiority Trial.

PubMed

Semkovska, Maria; Landau, Sabine; Dunne, Ross; Kolshus, Erik; Kavanagh, Adam; Jelovac, Ana; Noone, Martha; Carton, Mary; Lambe, Sinead; McHugh, Caroline; McLoughlin, Declan M

2016-04-01

ECT is the most effective treatment for severe depression. Previous efficacy studies, using thrice-weekly brief-pulse ECT, reported that high-dose (6× seizure threshold) right unilateral ECT is similar to bitemporal ECT but may have fewer cognitive side effects. The authors aimed to assess the effectiveness and cognitive side effects of twice-weekly moderate-dose (1.5× seizure threshold) bitemporal ECT with high-dose unilateral ECT in real-world practice. This was a pragmatic, patient- and rater-blinded, noninferiority trial of patients with major depression (N=138; 63% female; age=56.7 years [SD=14.8]) in a national ECT service with a 6-month follow-up. Participants were independently randomly assigned to bitemporal or high-dose unilateral ECT. The primary outcome was change in the 24-item Hamilton Depression Rating Scale (HAM-D) score after the ECT course; the prespecified noninferiority margin was 4.0 points. Secondary outcomes included response and remission rates, relapse status after 6 months, and cognition. Of the eligible patients, 69 were assigned to bitemporal ECT and 69 to unilateral ECT. High-dose unilateral ECT was noninferior to bitemporal ECT regarding the 24-item HAM-D scores after the ECT course (mean difference=1.08 points in favor of unilateral ECT [95% CI=-1.67 to 3.84]). There were no significant differences for response and remission or 6-month relapse status. Recovery of orientation was quicker following unilateral ECT (median=19.1 minutes versus 26.4 minutes). Bitemporal ECT was associated with a lower percent recall of autobiographical information (odds ratio=0.66) that persisted for 6 months. Twice-weekly high-dose unilateral ECT is not inferior to bitemporal ECT for depression and may be preferable because of its better cognitive side-effect profile.

Antimicrobial usage and risk of retreatment for mild to moderate clinical mastitis cases on dairy farms following on-farm bacterial culture and selective therapy.

PubMed

McDougall, S; Niethammer, J; Graham, E M

2018-03-01

To assess antimicrobial usage for treatment of mild to moderate clinical mastitis, and risk of retreatment, following implementation of an on-farm bacterial culture system and selective therapy based on culture results, and to assess compliance with treatment decision tree protocols and the level of agreement between results from on-farm culture and laboratory-based microbiology methods. Herdowners from seven dairy herds were asked to collect milk samples from cases of mild to moderate clinical mastitis between July 2015 and May 2016. All samples were cultured on-farm using a commercially available selective media and were also submitted for laboratory-based culture. Within sequential pairs of cows with mastitis, half were assigned to be treated without regard to culture results (Blanket group), and half were treated based on the on-farm culture results (Selective group) according to decision tree diagrams provided to the farmers. Culture results, treatments, and retreatments for clinical mastitis were recorded. The sum of the daily doses of antimicrobials used per cow, the number of retreatments and interval to first retreatment were compared between treatment groups. The geometric mean sum of daily doses for quarters assigned to the Selective (1.72 (95% CI=1.55-1.90)) group was lower than for the Blanket (2.38 (95% CI=2.17-2.60)) group (p=0.005). The percentage of cows retreated for clinical mastitis did not differ between the Selective (21.7 (95% CI=10.5-25.9)%) and Blanket (26.1 (95% CI=20.9-31.3)%) groups (p=0.13), and there was no difference between groups in the hazard that cows would be retreated within 60 days of enrolment (hazard ratio=0.82 (95% CI=0.39-1.69); p=0.59). Compliance with the treatment protocols was higher amongst quarters assigned to the Selective (199/233; 85.4%) compared with the Blanket (171/249; 68.7%) group (p<0.001), and varied between farms from 64-94%. The overall agreement between results from on-farm and laboratory culture was 188/331 (56.9%; kappa=0.31; p<0.001), but varied between farms from 44.7-88.2% (p<0.001). Use of on-farm culture with selective antimicrobial therapy resulted in approximately 25% lower antimicrobial usage, but was not associated with an increase in the proportion of cows retreated for clinical mastitis. This study has demonstrated that on-farm culture and selective therapy based on culture results can be implemented on-farm. However, farms varied in their implementation of both the treatment protocols and microbiology procedures. Where such systems are to be used on-farm, specific training and on-going monitoring is required.

Over the counter drugs (and dietary supplement) exercise: a team-based introduction to biochemistry for health professional students.

PubMed

Phadtare, Sangita; Abali, Emine; Brodsky, Barbara

2013-01-01

For successful delivery of basic science topics for health-professional students, it is critical to reduce apprehension and illustrate relevance to clinical settings and everyday life. At the beginning of the Biochemistry course for Physician Assistants, a team-based assignment was designed to develop an understanding of the mechanism of action, effectiveness, and toxicity of five common over the counter (OTC) drugs and dietary supplements, and place these familiar medicines in a political and historical context. The objectives of this exercise were to stimulate interest in biochemistry; to provide basic information on enzymes and enzyme inhibitors related to these drugs to be expanded upon later in the course; and to encourage active and interactive learning. Teams of five students were formed, and each student was given an information sheet on aspirin, alpha-galactosidase, orlistat, dextromethorphan, or simvastatin, a low dose statin, which was previously available without prescription at pharmacies in the UK. After each member of the team acquired information on one OTC drug/dietary supplement by reading an assigned information sheet, the team was asked to go through a series of questions, and then submit answers to a quiz as a group. A high rate of success on the quiz, an overwhelmingly positive response on formal course evaluations, and enthusiastic exchanges during class suggested this team-based session accomplished its goals. Copyright © 2013 Wiley-Liss, Inc.

Synthetic CT for MRI-based liver stereotactic body radiotherapy treatment planning

NASA Astrophysics Data System (ADS)

Bredfeldt, Jeremy S.; Liu, Lianli; Feng, Mary; Cao, Yue; Balter, James M.

2017-04-01

A technique for generating MRI-derived synthetic CT volumes (MRCTs) is demonstrated in support of adaptive liver stereotactic body radiation therapy (SBRT). Under IRB approval, 16 subjects with hepatocellular carcinoma were scanned using a single MR pulse sequence (T1 Dixon). Air-containing voxels were identified by intensity thresholding on T1-weighted, water and fat images. The envelope of the anterior vertebral bodies was segmented from the fat image and fuzzy-C-means (FCM) was used to classify each non-air voxel as mid-density, lower-density, bone, or marrow in the abdomen, with only bone and marrow classified within the vertebral body envelope. MRCT volumes were created by integrating the product of the FCM class probability with its assigned class density for each voxel. MRCTs were deformably aligned with corresponding planning CTs and 2-ARC-SBRT-VMAT plans were optimized on MRCTs. Fluence was copied onto the CT density grids, dose recalculated, and compared. The liver, vertebral bodies, kidneys, spleen and cord had median Hounsfield unit differences of less than 60. Median target dose metrics were all within 0.1 Gy with maximum differences less than 0.5 Gy. OAR dose differences were similarly small (median: 0.03 Gy, std:0.26 Gy). Results demonstrate that MRCTs derived from a single abdominal imaging sequence are promising for use in SBRT dose calculation.

Efficacy and safety of a medication dose reminder feature in a digital health offering with the use of sensor-enabled medicines.

PubMed

Moorhead, Penjit; Zavala, Ana; Kim, Yoona; Virdi, Naunihal S

Over one-half of patients with chronic diseases, such as hypertension and type 2 diabetes (DM), do not take medicines as prescribed. This study assessed the efficacy and safety of "seeing" versus "not seeing" medication dose reminders regarding medication adherence and risk for overdose. Post hoc analysis. Outpatient setting. Adult subjects (18 years of age or older) with uncontrolled hypertension and DM. Subjects enrolled in this institutional review board-approved study were assigned to either use digital health (DH) with the use of sensor-enabled medicines (coencapsulated medicines with an ingestible sensor) for 4 or 12 weeks or receive usual care based on a cluster-randomized design. All subjects were followed for 12 weeks. Subjects using DH were included in the post hoc study consisting of an efficacy analysis and a safety analysis. A main efficacy outcome of comparison of subjects taking medicine with or without "seeing" DH medication dose reminders was assessed. Safety analysis assessed risk of overdosing after DH medication dose reminders. In 57 subjects included in the efficacy analysis, DH device reminder messages were associated with a 16 ± 16% increase (75 ± 18% when seeing vs. 59 ± 24% when not seeing mobile dose reminders) in medication taking if not taken before dose reminder. The mean overall adherence for all subjects was 86 ± 12%; the mean on-time adherence was 69.7 ± 19.7%. Subjects with lower adherence benefited more from seeing DH reminder messages. In the safety study (n = 74 subjects and 24,426 medication ingestions), no events of overdoses related to DH medication dose reminders occurred. This study demonstrates benefits of DH medication dose reminders to improve medication adherence, especially in patients with lower adherence; DH medication dose reminders also appear to be safe. Copyright © 2017 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.

Differences in carbachol dose, pain condition, and sex following lateral hypothalamic stimulation.

PubMed

Holden, J E; Wang, E; Moes, J R; Wagner, M; Maduko, A; Jeong, Y

2014-06-13

Lateral hypothalamic (LH) stimulation produces antinociception in female rats in acute, nociceptive pain. Whether this effect occurs in neuropathic pain or whether male-female sex differences exist is unknown. We examined the effect of LH stimulation in male and female rats using conditions of nociceptive and neuropathic pain. Neuropathic groups received chronic constriction injury (CCI) to induce thermal hyperalgesia, a sign of neuropathic pain. Nociceptive rats were naive for CCI, but received the same thermal stimulus following LH stimulation. To demonstrate that CCI ligation produced thermal hyperalgesia, males and females received either ligation or sham surgery for control. Both males and females demonstrated significant thermal hyperalgesia following CCI ligation (p<0.05), but male sham surgery rats also showed a significant left-right difference not present in female sham rats. In the second experiment, rats randomly assigned to CCI or nociceptive groups were given one of three doses of the cholinergic agonist carbachol (125, 250, or 500 nmol) or normal saline for control, microinjected into the left LH. Paw withdrawal from a thermal stimulus (paw withdrawal latency; PWL) was measured every 5 min for 45 min. Linear mixed models analysis showed that males and females in both pain conditions demonstrated significant antinociception, with the 500-nmol dose producing the greatest effect across groups compared with controls for the left paw (p<0.05). Female CCI rats showed equivalent responses to the three doses, while male CCI rats showed more variability for dose. However, nociceptive females responded only to the 500-nmol dose, while nociceptive males responded to all doses (p<0.05). For right PWL, only nociceptive males showed a significant carbachol dose response. These findings are suggestive that LH stimulation produces antinociception in male and female rats in both nociceptive and neuropathic pain, but dose response differences exist based on sex and pain condition. Copyright © 2014 IBRO. Published by Elsevier Ltd. All rights reserved.

Categorical regression dose-response modeling

EPA Science Inventory

The goal of this training is to provide participants with training on the use of the U.S. EPA’s Categorical Regression soft¬ware (CatReg) and its application to risk assessment. Categorical regression fits mathematical models to toxicity data that have been assigned ord...

Rationale and design of a randomized trial to evaluate an evidence-based prescription drug label on actual medication use.

PubMed

Shrank, William H; Parker, Ruth; Davis, Terry; Pandit, Anjali U; Knox, Joann P; Moraras, Pear; Rademaker, Alfred; Wolf, Michael S

2010-11-01

Medication errors are an important public health concern, and poor understanding of medication labels are a root cause. Research shows that labels are variable, of poor quality, and not patient-centered. No real-world trials have evaluated whether improved medication labels can affect appropriate medication use, adherence or health outcomes. We developed an evidence-based prescription label that addresses both content and format. The enhanced label includes a universal medication schedule (UMS) that standardizes the directions for use incorporating 1) standard time periods for administration (morning, noon, evening, and bedtime), 2) numeric vs. alpha characters, 3) 'carriage returns' to separate daily dose and 4) a graphic aid to visually depict dose and frequency. We will evaluate the effect of providing this label to randomly sampled patients who receive their care from free clinics, mobile vans and federally qualified health centers (FQHCs) in Northern Virginia. We will recruit patients with diabetes or hypertension; these patients will be randomly assigned to receive all of their medications with improved labels or to receive prescriptions with standard labels. The primary outcome will be the patient's ability to correctly demonstrate dosing instructions. Other outcomes include adherence, error rates and health outcomes. To our knowledge, this trial is the first to evaluate the effect of prescription label improvement on understanding, medication use and outcomes in a clinical setting. If successful, these findings could be implemented broadly to promote safe and appropriate medication use and to support evidence-based standards in the development of labels. Copyright © 2010 Elsevier Inc. All rights reserved.

TU-AB-BRC-11: Moving a GPU-OpenCL-Based Monte Carlo (MC) Dose Engine Towards Routine Clinical Use: Automatic Beam Commissioning and Efficient Source Sampling

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

Tian, Z; Folkerts, M; Jiang, S

Purpose: We have previously developed a GPU-OpenCL-based MC dose engine named goMC with built-in analytical linac beam model. To move goMC towards routine clinical use, we have developed an automatic beam-commissioning method, and an efficient source sampling strategy to facilitate dose calculations for real treatment plans. Methods: Our commissioning method is to automatically adjust the relative weights among the sub-sources, through an optimization process minimizing the discrepancies between calculated dose and measurements. Six models built for Varian Truebeam linac photon beams (6MV, 10MV, 15MV, 18MV, 6MVFFF, 10MVFFF) were commissioned using measurement data acquired at our institution. To facilitate dose calculationsmore » for real treatment plans, we employed inverse sampling method to efficiently incorporate MLC leaf-sequencing into source sampling. Specifically, instead of sampling source particles control-point by control-point and rejecting the particles blocked by MLC, we assigned a control-point index to each sampled source particle, according to MLC leaf-open duration of each control-point at the pixel where the particle intersects the iso-center plane. Results: Our auto-commissioning method decreased distance-to-agreement (DTA) of depth dose at build-up regions by 36.2% averagely, making it within 1mm. Lateral profiles were better matched for all beams, with biggest improvement found at 15MV for which root-mean-square difference was reduced from 1.44% to 0.50%. Maximum differences of output factors were reduced to less than 0.7% for all beams, with largest decrease being from1.70% to 0.37% found at 10FFF. Our new sampling strategy was tested on a Head&Neck VMAT patient case. Achieving clinically acceptable accuracy, the new strategy could reduce the required history number by a factor of ∼2.8 given a statistical uncertainty level and hence achieve a similar speed-up factor. Conclusion: Our studies have demonstrated the feasibility and effectiveness of our auto-commissioning approach and new efficient source sampling strategy, implying the potential of our GPU-based MC dose engine goMC for routine clinical use.« less

CT scans for pulmonary surveillance may be overused in lower-grade sarcoma.

PubMed

Miller, Benjamin J; Carmody Soni, Emily E; Reith, John D; Gibbs, C Parker; Scarborough, Mark T

2012-01-01

Chest CT scans are often used to monitor patients after excision of a sarcoma. Although sensitive, CT scans are more expensive than chest radiographs and are associated with possible health risks from a higher radiation dose. We hypothesized that a program based upon limited CT scans in lower-grade sarcoma could be efficacious and less expensive. We retrospectively assigned patients to a high-risk or low-risk hypothetical protocol. Eighty-three low- or intermediate-grade soft tissue sarcomas met our inclusion criteria. Eight patients had pulmonary metastasis. A protocol based on selective CT scans for high-risk patients would have identified seven out of eight lesions. The incremental cost-effectiveness ratio for routine CT scans was $731,400. A program based upon selective CT scans for higher-risk patients is accurate, spares unnecessary radiation to many patients, and is less expensive.

Eltrombopag for the treatment of children with persistent and chronic immune thrombocytopenia (PETIT): a randomised, multicentre, placebo-controlled study.

PubMed

Bussel, James B; de Miguel, Purificación Garcia; Despotovic, Jenny M; Grainger, John D; Sevilla, Julián; Blanchette, Victor S; Krishnamurti, Lakshmanan; Connor, Philip; David, Michèle; Boayue, Koh B; Matthews, Dana C; Lambert, Michele P; Marcello, Lisa M; Iyengar, Malini; Chan, Geoffrey W; Chagin, Karen D; Theodore, Dickens; Bailey, Christine K; Bakshi, Kalpana K

2015-08-01

The oral thrombopoietin receptor agonist eltrombopag is approved for treatment of adults with chronic immune thrombocytopenia. In the PETIT trial, we aimed to investigate the efficacy and safety of eltrombopag in children with persistent or chronic immune thrombocytopenia. PETIT was a three-part, randomised, multicentre, placebo-controlled study done at 22 centres in the USA, UK, Canada, Spain, France, and the Netherlands. Patients aged 1-17 years with immune thrombocytopenia lasting for 6 months or longer and platelets less than 30 × 10(9) per L who had received at least one previous treatment were enrolled. We enrolled patients into three cohorts consisting of patients aged 12-17, 6-11, and 1-5 years. We established patients' starting doses with an open-label, dose-finding phase with five patients in each cohort. During the dose-finding phase, patients aged 6-17 years started eltrombopag at 25 mg once per day (12·5 mg for those weighing <27 kg) and patients aged 1-5 years received 0·7 mg/kg per day to a maximum of 2 mg/kg unless otherwise approved. We permitted dose adjustments on the basis of platelet response up to a maximum dosage of 75 mg per day. Additional patients were then recruited and randomly assigned (2:1) to receive either eltrombopag or placebo tablets (or oral suspension formulation if aged 1-5 years) once per day for 7 weeks at the previously established doses. Starting doses for the double-blind phase were 37·5 mg/day for patients aged 12-17 years; 50 mg/day for patients weighing 27 kg or more (25 mg for east Asian patients) and 25 mg/day for patients weighing less than 27 kg (12·5 mg once per day for east Asian patients) for patients aged 6-11 years; and 1·5 mg/kg once per day (0·8 mg/kg once per day for east Asian patients) for patients aged 1-5 years. Randomisation was done by the GlaxoSmithKline Registration/Medication Ordering System and both patients and study personnel were masked to treatment assignments. Patients who completed treatment were then enrolled into an open-label phase and all patients could receive up to 24 weeks of eltrombopag. The primary outcome was the proportion of patients achieving a platelet count of 50 × 10(9) per L or more at least once from weeks 1-6 (days 8 to 43) of the randomised phase of the study in the absence of rescue therapy. We assessed efficacy in the intent-to-treat population, which consisted of all patients assigned to treatment, and we assessed safety in all patients who received at least one dose of study treatment. This trial is registered with ClinicalTrials.gov, number NCT00908037. Between Oct 2, 2009, and June 22, 2011, we recruited 15 patients, with five patients in each age cohort, into the open-label dose-finding phase who did not progress into the double-blind phase. From March 17, 2010, to Jan 15, 2013, we randomly assigned 67 patients to treatment, with 45 patients assigned to receive eltrombopag (16 children aged 12-17 years, 19 aged 6-11 years, and ten aged 1-5 years) and 22 to receive placebo (eight children aged 12-17 years, nine aged 6-11 years, and five aged 1-5 years). However, two patients assigned to receive eltrombopag did not receive the study drug and one was lost to follow-up, and one patient assigned to receive placebo was given eltrombopag. From weeks 1 to 6, 28 (62%) patients who received eltrombopag, compared with seven (32%) who received placebo, achieved the primary endpoint of platelet count 50 × 10(9) per L or more at least once without rescue (odds ratio 4·31, 95% CI 1·39-13·34, p=0·011). The most common adverse events with eltrombopag were headache (13 [30%] patients receiving eltrombopag vs nine [43%] patients receiving placebo), upper respiratory tract infection (11 [25%] patients vs two [10%] patients), and diarrhoea (seven [16%] patients vs one [5%] patient). Grade 3 or 4 adverse events occurred in five (11%) patients receiving eltrombopag and four (19%) patients receiving placebo, and serious adverse events (four [9%] patients receiving eltrombopag and two (10%) patients receiving placebo) were similarly infrequent in both groups. No thrombotic events or malignancies occurred. Increased alanine aminotransferase concentrations caused two (3%) of 65 patients to discontinue eltrombopag in the open-label phase. Our results showed that eltrombopag could be used to increase platelet counts and reduce clinically significant bleeding in children with persistent or chronic immune thrombocytopenia. Prevalence of increased liver laboratory values was similar to that seen in adults. GlaxoSmithKline. Copyright © 2015 Elsevier Ltd. All rights reserved.

A phase III, randomized, open-label study to assess the tolerability and immunogenicity of an H5N1 influenza vaccine administered to healthy adults with a 1-, 2-, 3-, or 6-week interval between first and second doses.

PubMed

Beran, Jiri; Abdel-Messih, Ibrahim A; Raupachova, Jolana; Hobzova, Lenka; Fragapane, Elena

2010-12-01

Preparedness for an H5N1 influenza pre-pandemic requires effective and well-tolerated emergency vaccination strategies that provide both pandemic strain-specific and heterologous protection. This was a pivotal study for the regulatory approval process for a candidate MF59-adjuvanted H5N1 vaccine. Its goals were to identify the preferred primary 2-dose vaccination schedule in adults and to assess whether the vaccine met European Committee for Medicinal Products for Human Use (CHMP) licensure criteria. Healthy volunteers aged 18 to 60 years received 1 of 4 randomized schedules in which the 2 doses of vaccine were separated by a 1-, 2-, 3-, or 6-week interval. Three blood samples (~20 mL(-1)) were obtained from each subject: the first sample, immediately before administration of the first dose of vaccine; the second, immediately before administration of the second dose; and the third, 21 days after administration of the second dose. Hemagglutination inhibition (HI), microneutralization (MN), and single radial hemolysis (SRH) were assayed after each dose. Immunogenicity was assessed based on the CHMP licensure criteria for annual influenza vaccines (number of seroconversions or significant increase in HI titer >40%; mean geometric increase >2.5; and proportion of subjects achieving an HI titer ≥40 or SRH titer >25 mm(2) should be >70% [seroprotection]). Subjects recorded all adverse events occurring within 7 days of vaccine administration; information on any serious adverse events was collected throughout the study (duration, 202 days). All study participants (N = 240) were white, with a mean age of 33 years and a mean body mass index of 24.6 kg/m(2). Equal numbers of men and women were assigned to each vaccination schedule. The CHMP criterion for seroprotection was achieved when the 2 doses of vaccine were separated by 2 (76%), 3 (72%), and 6 (79%) weeks; similar results were obtained on MN and SRH analysis. On the SRH analysis, the candidate vaccine showed a heterologous immune response to the H5N1/turkey/Turkey/1/05 (NIBRG-23; clade 2) influenza antigen. The vaccine met 2 of the 3 European licensure criteria, with seroconversion rates of 69% and 65% in the groups assigned to a 2- and 3-week interval between doses, respectively, and geometric mean ratios of 4.3 and 4.5. There were no serious adverse events related to vaccination. The most common adverse events reported within 7 days of the first and second doses of vaccine were mild to moderate injection-site pain (63%-73% and 34%-48%, respectively) and fatigue (25%-30% and 13%-24%). Two 7.5-μg doses of MF59-adjuvanted H5N1 influenza vaccine given 2, 3, or 6 weeks apart afforded H5N1-specific immunity and met the CHMP licensure criterion for seroprotection in these healthy volunteers. Clinically relevant levels of heterologous immunity were observed when the 2 doses of vaccine were administered either 2 or 3 weeks apart; however, the licensure criterion for seroprotection was not met in this case. Copyright © 2010 Elsevier HS Journals, Inc. Published by EM Inc USA.. All rights reserved.

Towards Automated Structure-Based NMR Resonance Assignment

NASA Astrophysics Data System (ADS)

Jang, Richard; Gao, Xin; Li, Ming

We propose a general framework for solving the structure-based NMR backbone resonance assignment problem. The core is a novel 0-1 integer programming model that can start from a complete or partial assignment, generate multiple assignments, and model not only the assignment of spins to residues, but also pairwise dependencies consisting of pairs of spins to pairs of residues. It is still a challenge for automated resonance assignment systems to perform the assignment directly from spectra without any manual intervention. To test the feasibility of this for structure-based assignment, we integrated our system with our automated peak picking and sequence-based resonance assignment system to obtain an assignment for the protein TM1112 with 91% recall and 99% precision without manual intervention. Since using a known structure has the potential to allow one to use only N-labeled NMR data and avoid the added expense of using C-labeled data, we work towards the goal of automated structure-based assignment using only such labeled data. Our system reduced the assignment error of Xiong-Pandurangan-Bailey-Kellogg's contact replacement (CR) method, which to our knowledge is the most error-tolerant method for this problem, by 5 folds on average. By using an iterative algorithm, our system has the added capability of using the NOESY data to correct assignment errors due to errors in predicting the amino acid and secondary structure type of each spin system. On a publicly available data set for Ubiquitin, where the type prediction accuracy is 83%, we achieved 91% assignment accuracy, compared to the 59% accuracy that was obtained without correcting for typing errors.

Moving beyond "Bookish Knowledge": Using Film-Based Assignments to Promote Deep Learning

ERIC Educational Resources Information Center

Olson, Joann S.; Autry, Linda; Moe, Jeffry

2016-01-01

This article investigates the effectiveness of a film-based assignment given to adult learners in a graduate-level group counseling class. Semi-structured interviews were conducted with four students; data analysis suggested film-based assignments may promote deep approaches to learning (DALs). Participants indicated the assignment helped them…

Continuous phase and amplitude holographic elements

NASA Technical Reports Server (NTRS)

Maker, Paul D. (Inventor); Muller, Richard E. (Inventor)

1995-01-01

A method for producing a phase hologram using e-beam lithography provides n-ary levels of phase and amplitude by first producing an amplitude hologram on a transparent substrate by e-beam exposure of a resist over a film of metal by exposing n is less than or equal to m x m spots of an array of spots for each pixel, where the spots are randomly selected in proportion to the amplitude assigned to each pixel, and then after developing and etching the metal film producing a phase hologram by e-beam lithography using a low contrast resist, such as PMMA, and n-ary levels of low doses less than approximately 200 micro-C/sq cm and preferably in the range of 20-200 micro-C/sq cm, and aggressive development using pure acetone for an empirically determined time (about 6 s) controlled to within 1/10 s to produce partial development of each pixel in proportion to the n-ary level of dose assigned to it.

Efficacy and safety of Lian-Ju-Gan-Mao capsules for treating the common cold with wind-heat syndrome: study protocol for a randomized controlled trial.

PubMed

Wang, Shengjun; Jiang, Hongli; Yu, Qin; She, Bin; Mao, Bing

2017-01-05

The common cold is a common and frequent respiratory disease mainly caused by viral infection of the upper respiratory tract. Chinese herbal medicine has been increasingly prescribed to treat the common cold; however, there is a lack of evidence to support the wide utility of this regimen. This protocol describes an ongoing phase II randomized controlled clinical trial, based on the theory of traditional Chinese medicine (TCM), with the objective of evaluating the efficacy and safety of Lian-Ju-Gan-Mao capsules (LJGMC), a Chinese patent medicine, compared with placebo in patients suffering from the common cold with wind-heat syndrome (CCWHS). This is a multicenter, randomized, double-blind, placebo-controlled phase II clinical trial. A total of 240 patients will be recruited and randomly assigned to a high-dose group, medium-dose group, low-dose group, and placebo-matched group in a 1:1:1:1 ratio. The treatment course is 3 consecutive days, with a 5-day follow-up. The primary outcome is time to all symptoms' clearance. Secondary outcomes include time to the disappearance of primary symptoms and each secondary symptom, time to fever relief, time to fever clearance, and change in TCM symptom and sign scores. This trial is a well-designed study according to principles and regulations issued by the China Food and Drug Administration (CFDA). The results will provide high-quality evidence on the efficacy and safety of LJGMC in treating CCWHS and help to optimize the dose for the next phase III clinical trial. Moreover, the protocol presents a detailed and practical methodology for future clinical trials of drugs developed based on TCM. Chinese Clinical Trial Registry, ChiCTR-IPR-15006504 . Registered on 4 June 2015.

Effects of choline on blood metabolites associated with lipid metabolism and digestion by steers fed corn-based diets.

PubMed

Bindel, D J; Titgemeyer, E C; Drouillard, J S; Ives, S E

2005-07-01

Ruminally cannulated steers (281 +/- 18 kg) were used to evaluate effects of choline on digestion and metabolism. Four steers were implanted with 24 mg of estradiol and 120 mg of trenbolone acetate, and four steers were not implanted. Cattle were assigned to concurrent 4 x 4 Latin squares. Dietary treatments were a 2 x 2 factorial: 0 or 4% tallow (DM basis) in corn-based diets, and 0 or 5 g/d supplemental choline administered abomasally. Blood collected before and 6 h after the initial choline infusion was used to assess acute responses to choline. Digestibility and blood metabolites were measured after adaptation to choline, as well as after an abomasal dose of 100 g of lipid. Digestibilities of dietary DM (P = 0.29) and of dietary total fatty acids (P = 0.42) were not affected by choline. Apparent digestibilities of C18:0 and C18:1 fatty acids were greater (P < 0.05) when diets contained 4% tallow. Digestibilities of fatty acids in the lipid dose were less than those in the diet, and no biologically important differences in fatty acid disappearance resulted from the treatments. No significant acute responses to choline were detected. After adaptation to choline, no important differences in plasma metabolites occurred in response to choline infusion. Plasma urea was less (P < 0.05) for implanted cattle, reflecting increased deposition of protein. Plasma cholesterol was greater (P < 0.05) for steers fed 4% tallow. Changes in plasma triglycerides in response to an abomasal lipid dose were less (P < 0.05) for steers fed 4% tallow, probably due to greater triglyceride concentrations at the time of lipid dosing. In summary, few responses to abomasally infused choline were observed in either digestion or plasma metabolites.

Combined extracts of Urtica dioica and Pygeum africanum in the treatment of benign prostatic hyperplasia: double-blind comparison of two doses.

PubMed

Krzeski, T; Kazón, M; Borkowski, A; Witeska, A; Kuczera, J

1993-01-01

The 134 patients (aged 53 to 84 years) with symptoms of benign prostatic hyperplasia were drawn from two medical centers in Warsaw. The patients were randomly assigned to receive two capsules of the standard dose of an urtica/pygeum preparation (300 mg of Urtica dioica root extract combined with 25 mg of Pygeum africanum bark extract) or two capsules containing half the standard dose twice daily for 8 weeks. After 28 days' treatment, urine flow, residual urine, and nycturia were significantly reduced in both treatment groups. After 56 days' treatment, further significant decreases were found in residual urine (half-dose group) and in nycturia (both groups). There were no between-group differences in these measures of efficacy. Five patients reported adverse effects of treatment; treatment was not discontinued in any patient because of side effects. It is concluded that half doses of the urtica/pygeum extract are as safe and effective as the recommended full doses.

The impact of using different doses of progesterone on memory performance.

PubMed

Roozbehi, A; Sharafi, M T; Karimi, F; Kamali, A M

2017-01-01

Progesterone is a sex hormone and its receptors are expressed throughout the hippocampus. This study was aimed at evaluating the effects of different doses of progesterone on memory. Male rats were arbitrarily assigned to nine groups, namely Group I: control, Group II: control-cannula, Group III received 0.5 μl of saline by cannula, Groups IV , V, VI, VII and VIII received progesterone in doses of 0.5, 1, 1.5, 2, and 3 μg/ 0.5 μl by cannula, respectively. Group IX received 0.5 μl almond oil by cannula. Memory performance was tested in form of passive avoidance task. Our results indicated that progesterone at doses of 1.5 and 2 µg (p < 0.05) significantly increased the memory performance while at a dose of 3 µg (p < 0.05), it significantly decreased memory as compared to the control group. The current study revealed that the influence of progesterone on memory is related to its dose (Fig. 1, Ref. 25).

A Multi-Center Controlled Study of the Acute and Chronic Effects of Cooling Therapy for MS

NASA Technical Reports Server (NTRS)

Luna, Bernadette; Schwid, Steven W.; Cutter, Gary; Murray, Ronald; Bowen, James; Pellegrino, Richard; Guisado, Raul; Webbon, Bruce W.; DeVincenzi, Donald (Technical Monitor)

2000-01-01

To determine the acute and chronic effects of cooling therapy on patients with MS using objective functional performance measures and self-assessed measures of fatigue. Cooling demyelinated nerves can reduce conduction block, potentially improving symptoms of MS. Significant acute and chronic effects of cooling have not been demonstrated in a multi-center, controlled, blinded study using objective measures of neurologic function. Patients (N=84) with definite MS, mild to moderate disability (EDSS less than 6.0), and self-reported heat sensitivity were enrolled at 5 study sites. Acute effects of cooling were assessed by randomly assigning subjects to high-dose or low-dose cooling for one hour using an active cooling vest and cap (Life Enhancement Technologies, Santa Clara, CA). Settings were individualized to maintain the cooling garments at 55 F for the high-dose treatment and 70 F for the low-dose treatment. Both patients and examining investigators were blinded to treatment assignments. The MSFC and visual acuity/contrast sensitivity were assessed before and 30 minutes after treatment. The following week, subjects had an identical visit with the alternate cooling treatment. Chronic effects of cooling were assessed by randomly assigning the same subjects to unblinded daily home cooling or observation for 4 weeks. All subjects completed the Rochester Fatigue Diary (RFD) twice weekly and subjective measures of strength, cognition, and energy level daily. At the end of the period, subjects completed the Modified Fatigue Impact Scale (MFIS) and underwent another high-dose cooling session with assessment of the MSFC and vision. After a one-week washout period, subjects crossed over to the alternate 4-week treatment. Oral temperatures were reduced with both acute treatments (0.8 +/- .06 F, high and 0.5 +/- .06 F, low). While mean MSFC did not change significantly during individual cooling sessions, post hoc analysis pooling the 3 high-dose cooling sessions revealed an improvement in MSFC scores (acute phase 0.064 +/- 0.020, p = 0.0013; chronic phase 0.044 +/- 0.021, p = 0.0368) from before to after cooling. The change in MSFC scores during the acute cooling sessions was not related to the extent of change in oral temperatures. Both the RFD score and the MFIS indicate a significantly lower fatigue level during the cooling month compared to observation (RFD, 2.53 +/- 0.83,p = 0.0033; MFIS 7.63 +/- 1.56, p = 0.0001).

Results of initial low-dose computed tomographic screening for lung cancer.

PubMed

Church, Timothy R; Black, William C; Aberle, Denise R; Berg, Christine D; Clingan, Kathy L; Duan, Fenghai; Fagerstrom, Richard M; Gareen, Ilana F; Gierada, David S; Jones, Gordon C; Mahon, Irene; Marcus, Pamela M; Sicks, JoRean D; Jain, Amanda; Baum, Sarah

2013-05-23

Lung cancer is the largest contributor to mortality from cancer. The National Lung Screening Trial (NLST) showed that screening with low-dose helical computed tomography (CT) rather than with chest radiography reduced mortality from lung cancer. We describe the screening, diagnosis, and limited treatment results from the initial round of screening in the NLST to inform and improve lung-cancer-screening programs. At 33 U.S. centers, from August 2002 through April 2004, we enrolled asymptomatic participants, 55 to 74 years of age, with a history of at least 30 pack-years of smoking. The participants were randomly assigned to undergo annual screening, with the use of either low-dose CT or chest radiography, for 3 years. Nodules or other suspicious findings were classified as positive results. This article reports findings from the initial screening examination. A total of 53,439 eligible participants were randomly assigned to a study group (26,715 to low-dose CT and 26,724 to chest radiography); 26,309 participants (98.5%) and 26,035 (97.4%), respectively, underwent screening. A total of 7191 participants (27.3%) in the low-dose CT group and 2387 (9.2%) in the radiography group had a positive screening result; in the respective groups, 6369 participants (90.4%) and 2176 (92.7%) had at least one follow-up diagnostic procedure, including imaging in 5717 (81.1%) and 2010 (85.6%) and surgery in 297 (4.2%) and 121 (5.2%). Lung cancer was diagnosed in 292 participants (1.1%) in the low-dose CT group versus 190 (0.7%) in the radiography group (stage 1 in 158 vs. 70 participants and stage IIB to IV in 120 vs. 112). Sensitivity and specificity were 93.8% and 73.4% for low-dose CT and 73.5% and 91.3% for chest radiography, respectively. The NLST initial screening results are consistent with the existing literature on screening by means of low-dose CT and chest radiography, suggesting that a reduction in mortality from lung cancer is achievable at U.S. screening centers that have staff experienced in chest CT. (Funded by the National Cancer Institute; NLST ClinicalTrials.gov number, NCT00047385.).

High-dose senna compared with conventional PEG-ES lavage as bowel preparation for elective colonoscopy: a prospective, randomized, investigator-blinded trial.

PubMed

Radaelli, Franco; Meucci, Gianmichele; Imperiali, Gianni; Spinzi, Giancarlo; Strocchi, Enrico; Terruzzi, Vittorio; Minoli, Giorgio

2005-12-01

To compare the efficacy and patient acceptance of an oral high dose of senna to conventional polyethylene glycol-electrolyte lavage solution (PEG-ES) in adults undergoing elective colonoscopy. Consecutive outpatients referred for elective colonoscopy were prospectively randomly assigned to receive, the day before the procedure, either 24 tablets of 12 mg senna, divided into two doses at 1 p.m. and 9 p.m. (senna group, n=191), or standard 4-L PEG-ES (PEG-ES group, n=92). The overall quality of colon cleansing (primary outcome measure) and cleansing in the right colon were evaluated using the Aronchick scoring scale (1=excellent to 4=inadequate) by the investigator/endoscopist who was blinded to the treatment assignment. Patient acceptance and the safety of the preparation were assessed by a nurse, using a structured questionnaire covering compliance with the dosing, overall tolerance of the preparation (1=none or mild discomfort to 4=severely distressing), and adverse events. The quality of colon cleansing, overall tolerance of the preparation, and compliance were significantly better with senna; overall cleansing was excellent or good in 90.6% of patients in the senna group and in 79.7% in the PEG-ES group (p= 0.003). The percentage of procedures rescheduled because of insufficient colon cleansing was 7.3% in the PEG-ES group and 2.6% in the senna group (p=0.035). Multivariate logistic regression modeling showed the PEG-ES preparation as negative independent predictor of unsuccessful bowel cleansing. The incidence of adverse reactions was similar in the two groups; patients who received senna experienced significantly less nausea and vomiting, but more abdominal pain. An oral high dose of senna is a valid alternative to standard PEG-ES for outpatient colonoscopy preparation.

Efficacy of high doses of penicillin versus amoxicillin in the treatment of uncomplicated community acquired pneumonia in adults. A non-inferiority controlled clinical trial.

PubMed

Llor, Carl; Pérez, Almudena; Carandell, Eugenia; García-Sangenís, Anna; Rezola, Javier; Llorente, Marian; Gestoso, Salvador; Bobé, Francesc; Román-Rodríguez, Miguel; Cots, Josep M; Hernández, Silvia; Cortés, Jordi; Miravitlles, Marc; Morros, Rosa

2017-10-20

Community-acquired pneumonia (CAP) is treated with penicillin in some northern European countries. To evaluate whether high-dose penicillin V is as effective as high-dose amoxicillin for the treatment of non-severe CAP. Multicentre, parallel, double-blind, controlled, randomized clinical trial. 31 primary care centers in Spain. Patients from 18 to 75 years of age with no significant associated comorbidity and with symptoms of lower respiratory tract infection and radiological confirmation of CAP were randomized to receive either penicillin V 1.6 million units, or amoxicillin 1000mg three times per day for 10 days. The main outcome was clinical cure at 14 days, and the primary hypothesis was that penicillin V would be non-inferior to amoxicillin with regard to this outcome, with a margin of 15% for the difference in proportions. EudraCT register 2012-003511-63. A total of 43 subjects (amoxicillin: 28; penicillin: 15) were randomized. Clinical cure was observed in 10 (90.9%) patients assigned to penicillin and in 25 (100%) patients assigned to amoxicillin with a difference of -9.1% (95% CI, -41.3% to 6.4%; p=.951) for non-inferiority. In the intention-to-treat analysis, amoxicillin was found to be 28.6% superior to penicillin (95% CI, 7.3-58.1%; p=.009 for superiority). The number of adverse events was similar in both groups. There was a trend favoring high-dose amoxicillin versus high-dose penicillin in adults with uncomplicated CAP. The main limitation of this trial was the low statistical power due to the low number of patients included. Copyright © 2017 Elsevier España, S.L.U. All rights reserved.

Assessment of medical radiation exposure to patients and ambient doses in several diagnostic radiology departments

NASA Astrophysics Data System (ADS)

Sulieman, A.; Elhadi, T.; Babikir, E.; Alkhorayef, M.; Alnaaimi, M.; Alduaij, M.; Bradley, D. A.

2017-11-01

In many countries diagnostic medical exposures typically account for a very large fraction of the collective effective dose that can be assigned to anthropological sources and activities. This in part flags up the question of whether sufficient steps are being taken in regard to potential dose saving from such medical services. As a first step, one needs to survey doses to compare against those of best practice. The present study has sought evaluation of the radiation protection status and patient doses for certain key radiological procedures in four film-based radiology departments within Sudan. The radiation exposure survey, carried out using a survey meter and quality control test tools, involved a total of 299 patients their examinations being carried out at one or other of these four departments. The entrance surface air kerma (ESAK) was determined from exposure settings using DosCal software and an Unfors -Xi-meter. The mean ESAK for x-ray examination of the chest was 0.30±0.1 mGy, for the skull it was 0.96±0.7 mGy, for the abdomen 0.85±0.01 mGy, for spinal procedures 1.30±0.6 mGy and for procedures involving the limbs it was 0.43±0.3 mGy. Ambient dose-rates in the reception area, at the closed door of the x-ray room, recorded instantaneous values of up to 100 μSv/h. In regard to protection, the associated levels were found to be acceptable in three of the four departments, corrective action being required for one department, regular quality control also being recommended.

Improving medication titration in heart failure by embedding a structured medication titration plan.

PubMed

Hickey, Annabel; Suna, Jessica; Marquart, Louise; Denaro, Charles; Javorsky, George; Munns, Andrew; Mudge, Alison; Atherton, John J

2016-12-01

To improve up-titration of medications to target dose in heart failure patients by improving communication from hospital to primary care. This quality improvement project was undertaken within three heart failure disease management (HFDM) services in Queensland, Australia. A structured medication plan was collaboratively designed and implemented in an iterative manner, using methods including awareness raising and education, audit and feedback, integration into existing work practice, and incentive payments. Evaluation was undertaken using sequential audits, and included process measures (use of the titration plan, assignment of responsibility) and outcome measures (proportion of patients achieving target dose) in HFDM service patients with reduced left ventricular ejection fraction. Comparison of the three patient cohorts (pre-intervention cohort A n=96, intervention cohort B n=95, intervention cohort C n=89) showed increase use of the titration plan, a shift to greater primary care responsibility for titration, and an increase in the proportion of patients achieving target doses of angiotensin converting enzyme inhibitors/angiotensin receptor blockers (ACEI/ARB) (A 37% vs B 48% vs C 55%, p=0.051) and beta-blockers (A 38% vs B 33% vs C 51%, p=0.045). Combining all three cohorts, patients not on target doses when discharged from hospital were more likely to achieve target doses of ACEI/ARB (p<0.0001) and beta blockers (p<0.0001) within six months if they received a medication titration plan. A medication titration plan was successfully implemented in three HFDM services and improved transitional communication and achievement of target doses of evidence-based therapies within six months of hospital discharge. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

High-dose baclofen for the treatment of alcohol dependence (BACLAD study): a randomized, placebo-controlled trial.

PubMed

Müller, Christian A; Geisel, Olga; Pelz, Patricia; Higl, Verena; Krüger, Josephine; Stickel, Anna; Beck, Anne; Wernecke, Klaus-Dieter; Hellweg, Rainer; Heinz, Andreas

2015-08-01

Previous randomized, placebo-controlled trials (RCTs) assessing the efficacy of the selective γ-aminobutyric acid (GABA)-B receptor agonist baclofen in the treatment of alcohol dependence have reported divergent results, possibly related to the low to medium dosages of baclofen used in these studies (30-80mg/d). Based on preclinical observations of a dose-dependent effect and positive case reports in alcohol-dependent patients, the present RCT aimed to assess the efficacy and safety of individually titrated high-dose baclofen for the treatment of alcohol dependence. Out of 93 alcohol-dependent patients initially screened, 56 were randomly assigned to a double-blind treatment with individually titrated baclofen or placebo using dosages of 30-270mg/d. The multiple primary outcome measures were (1) total abstinence and (2) cumulative abstinence duration during a 12-week high-dose phase. More patients of the baclofen group maintained total abstinence during the high-dose phase than those receiving placebo (15/22, 68.2% vs. 5/21, 23.8%, p=0.014). Cumulative abstinence duration was significantly higher in patients given baclofen compared to patients of the placebo group (mean 67.8 (SD 30) vs. 51.8 (SD 29.6) days, p=0.047). No drug-related serious adverse events were observed during the trial. Individually titrated high-dose baclofen effectively supported alcohol-dependent patients in maintaining alcohol abstinence and showed a high tolerability, even in the event of relapse. These results provide further evidence for the potential of baclofen, thereby possibly extending the current pharmacological treatment options in alcohol dependence. Copyright © 2015 Elsevier B.V. and ECNP. All rights reserved.

Correlation between prescribed daily dose, seizure freedom and defined daily dose in antiepileptic drug treatment.

PubMed

Horváth, László; Fekete, Klára; Márton, Sándor; Fekete, István

2017-04-01

Background Although defined daily doses (DDD) for antiepileptic drugs (AED) have been assigned only in combination therapy, based on the literature, most patients take them in monotherapy. Furthermore, discrepancies between DDD and prescribed daily dose (PDD) were observed. Objective First, to determine PDDs of AEDs and to reveal PDD/DDD ratio among seizure free versus not seizure free patients in everyday clinical practice. Second, to test the applicability of 75% cut-off of DDD to achieve seizure freedom. Furthermore, to find out what factors might influence PDD. Setting Outpatient data files at a Hungarian university hospital were studied. Methods A retrospective, 20-year cross-sectional database was compiled from 1282 epileptic outpatients' files. Main outcome measure Seizure freedom and PDD were used as outcome measures. Results The mean DDD% of all prescribed AEDs increased steadily from monotherapy, through bitherapy towards polytherapy (p < 0.0001). Most seizure free patients took AEDs in doses in the range of ≤75% of DDDs in monotherapy and bitherapy. Older AEDs (carbamazepine and valproate) were given in a significantly higher mean dose in bitherapy in the seizure free group. Among the newer types, only levetiracetam and lamotrigine had a significantly higher DDD% in mono-, bi-, and polytherapy. Confirmed by logistic regression analysis, gender, age, type of epilepsy, and number of AEDs had a significant impact on the value of 75% DDD. Conclusion No significant unfavourable impact of the lower ratio of PDD/DDD on the outcome of achieving seizure freedom has been confirmed. As a measure of seizure freedom, 75% of DDD may be used, although individual therapy must be emphasised. Precisely quantified DDD would provide a more accurate calculation of other derived values.

A Web-based Tool to Aid the Identification of Chemicals Potentially Posing a Health Risk through Percutaneous Exposure.

PubMed

Gorman Ng, Melanie; Milon, Antoine; Vernez, David; Lavoué, Jérôme

2016-04-01

Occupational hygiene practitioners typically assess the risk posed by occupational exposure by comparing exposure measurements to regulatory occupational exposure limits (OELs). In most jurisdictions, OELs are only available for exposure by the inhalation pathway. Skin notations are used to indicate substances for which dermal exposure may lead to health effects. However, these notations are either present or absent and provide no indication of acceptable levels of exposure. Furthermore, the methodology and framework for assigning skin notation differ widely across jurisdictions resulting in inconsistencies in the substances that carry notations. The UPERCUT tool was developed in response to these limitations. It helps occupational health stakeholders to assess the hazard associated with dermal exposure to chemicals. UPERCUT integrates dermal quantitative structure-activity relationships (QSARs) and toxicological data to provide users with a skin hazard index called the dermal hazard ratio (DHR) for the substance and scenario of interest. The DHR is the ratio between the estimated 'received' dose and the 'acceptable' dose. The 'received' dose is estimated using physico-chemical data and information on the exposure scenario provided by the user (body parts exposure and exposure duration), and the 'acceptable' dose is estimated using inhalation OELs and toxicological data. The uncertainty surrounding the DHR is estimated with Monte Carlo simulation. Additional information on the selected substances includes intrinsic skin permeation potential of the substance and the existence of skin notations. UPERCUT is the only available tool that estimates the absorbed dose and compares this to an acceptable dose. In the absence of dermal OELs it provides a systematic and simple approach for screening dermal exposure scenarios for 1686 substances. © The Author 2015. Published by Oxford University Press on behalf of the British Occupational Hygiene Society.

Statistical controversies in clinical research: building the bridge to phase II-efficacy estimation in dose-expansion cohorts.

PubMed

Boonstra, P S; Braun, T M; Taylor, J M G; Kidwell, K M; Bellile, E L; Daignault, S; Zhao, L; Griffith, K A; Lawrence, T S; Kalemkerian, G P; Schipper, M J

2017-07-01

Regulatory agencies and others have expressed concern about the uncritical use of dose expansion cohorts (DECs) in phase I oncology trials. Nonetheless, by several metrics-prevalence, size, and number-their popularity is increasing. Although early efficacy estimation in defined populations is a common primary endpoint of DECs, the types of designs best equipped to identify efficacy signals have not been established. We conducted a simulation study of six phase I design templates with multiple DECs: three dose-assignment/adjustment mechanisms multiplied by two analytic approaches for estimating efficacy after the trial is complete. We also investigated the effect of sample size and interim futility analysis on trial performance. Identifying populations in which the treatment is efficacious (true positives) and weeding out inefficacious treatment/populations (true negatives) are competing goals in these trials. Thus, we estimated true and false positive rates for each design. Adaptively updating the MTD during the DEC improved true positive rates by 8-43% compared with fixing the dose during the DEC phase while maintaining false positive rates. Inclusion of an interim futility analysis decreased the number of patients treated under inefficacious DECs without hurting performance. A substantial gain in efficiency is obtainable using a design template that statistically models toxicity and efficacy against dose level during expansion. Design choices for dose expansion should be motivated by and based upon expected performance. Similar to the common practice in single-arm phase II trials, cohort sample sizes should be justified with respect to their primary aim and include interim analyses to allow for early stopping. © The Author 2017. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com.

Low-dose metabolism of benzene in humans: science and obfuscation

PubMed Central

Rappaport, Stephen M.

2013-01-01

Benzene is a ubiquitous air pollutant that causes human leukemia and hematotoxic effects. Although the mechanism by which benzene causes toxicity is unclear, metabolism is required. A series of articles by Kim et al. used air and biomonitoring data from workers in Tianjin, China, to investigate the dose-specific metabolism (DSM) of benzene over a wide range of air concentrations (0.03–88.9 p.p.m.). Kim et al. concluded that DSM of benzene is greatest at air concentrations <1 p.p.m. This provocative finding motivated the American Petroleum Institute to fund a study by Price et al. to reanalyze the original data. Although their formal ‘reanalysis’ reproduced Kim’s finding of enhanced DSM at sub-p.p.m. benzene concentrations, Price et al. argued that Kim’s methods were inappropriate for assigning benzene exposures to low exposed subjects (based on measurements of urinary benzene) and for adjusting background levels of metabolites (based on median values from the 60 lowest exposed subjects). Price et al. then performed uncertainty analyses under alternative approaches, which led them to conclude that ‘… the Tianjin data appear to be too uncertain to support any conclusions …’ regarding the DSM of benzene. They also argued that the apparent low-dose metabolism of benzene could be explained by ‘lung clearance.’ In addressing these criticisms, we show that the methods and arguments presented by Price et al. are scientifically unsound and that their results are unreliable. PMID:23222815

Influence of genetic polymorphisms on the effect of high- and standard-dose clopidogrel after percutaneous coronary intervention: the GIFT (Genotype Information and Functional Testing) study.

PubMed

Price, Matthew J; Murray, Sarah S; Angiolillo, Dominick J; Lillie, Elizabeth; Smith, Erin N; Tisch, Rebecca L; Schork, Nicholas J; Teirstein, Paul S; Topol, Eric J

2012-05-29

This study sought to evaluate the influence of single nucleotide polymorphisms (SNPs) on the pharmacodynamic effect of high- or standard-dose clopidogrel after percutaneous coronary intervention (PCI). There is a lack of prospective, multicenter data regarding the effect of different genetic variants on clopidogrel pharmacodynamics over time in patients undergoing PCI. The GRAVITAS (Gauging Responsiveness with A VerifyNow assay-Impact on Thrombosis And Safety) trial screened patients with platelet function testing after PCI and randomly assigned those with high on-treatment reactivity (OTR) to either high- or standard-dose clopidogrel; a cohort of patients without high OTR were also followed. DNA samples obtained from 1,028 patients were genotyped for 41 SNPs in 17 genes related to platelet reactivity. After adjusting for clinical characteristics, the associations between the SNPs and OTR using linear regression were evaluated. CYP2C19*2 was significantly associated with OTR at 12 to 24 h (R(2) = 0.07, p = 2.2 × 10(-15)), 30 days (R(2) = 0.10, p = 1.3 × 10(-7)), and 6 months after PCI (R(2) = 0.07, p = 1.9 × 10(-11)), whereas PON1, ABCB1 3435 C→T, and other candidate SNPs were not. Carriers of 1 and 2 reduced-function CYP2C19 alleles were significantly more likely to display persistently high OTR at 30 days and 6 months, irrespective of treatment assignment. The portion of the risk of persistently high OTR at 30 days attributable to reduced-function CYP2C19 allele carriage was 5.2% in the patients randomly assigned to high-dose clopidogrel. CYP2C19, but not PON1 or ABCB1, is a significant determinant of the pharmacodynamic effects of clopidogrel, both early and late after PCI. In patients with high OTR identified by platelet function testing, the CYP2C19 genotype provides limited incremental information regarding the risk of persistently high reactivity with clopidogrel 150-mg maintenance dosing. (Genotype Information and Functional Testing Study [GIFT]; NCT00992420). Copyright © 2012 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

There Is No Correlation Between Erectile Dysfunction and Dose to Penile Bulb and Neurovascular Bundles Following Real-Time Low-Dose-Rate Prostate Brachytherapy

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

Solan, Amy N.; Cesaretti, Jamie A.; Stone, Nelson N.

2009-04-01

Purpose: We evaluated the relationship between the onset of erectile dysfunction and dose to the penile bulb and neurovascular bundles (NVBs) after real-time ultrasound-guided prostate brachytherapy. Methods and Materials: One hundred forty-seven patients who underwent prostate brachytherapy met the following eligibility criteria: (1) treatment with {sup 125}I brachytherapy to a prescribed dose of 160 Gy with or without hormones without supplemental external beam radiation therapy, (2) identification as potent before the time of implantation based on a score of 2 or higher on the physician-assigned Mount Sinai Erectile Function Score and a score of 16 or higher on the abbreviatedmore » International Index of Erectile Function patient assessment, and (3) minimum follow-up of 12 months. Median follow-up was 25.7 months (range, 12-47 months). Results: The 3-year actuarial rate of impotence was 23% (34 of 147 patients). An additional 43% of potent patients (49 of 113 patients) were using a potency aid at last follow-up. The penile bulb volume receiving 100% of the prescription dose (V{sub 100}) ranged from 0-0.05 cc (median, 0 cc), with a dose to the hottest 5% (D{sub 5}) range of 12.5-97.9 Gy (median, 40.8 Gy). There was no correlation between penile bulb D{sub 5} or V{sub 100} and postimplantation impotency on actuarial analysis. For the combined right and left NVB structures, V{sub 100} range was 0.3-5.1 cc (median, 1.8 cc), and V{sub 150} range was 0-1.5 cc (median, 0.31 cc). There was no association between NVB V{sub 100} or V{sub 150} and postimplantation impotency on actuarial analysis. Conclusion: Penile bulb doses are low after real-time ultrasound-guided prostate brachytherapy. We found no correlation between dose to either the penile bulb or NVBs and the development of postimplantation impotency.« less

10 CFR 36.55 - Personnel monitoring.

Code of Federal Regulations, 2012 CFR

2012-01-01

... REGULATORY COMMISSION LICENSES AND RADIATION SAFETY REQUIREMENTS FOR IRRADIATORS Operation of Irradiators... accident dose ranges (see 10 CFR 20.1501(c)). Each personnel dosimeter must be assigned to and worn by only... processed at least quarterly. (b) Other individuals who enter the radiation room of a panoramic irradiator...

10 CFR 36.55 - Personnel monitoring.

Code of Federal Regulations, 2011 CFR

2011-01-01

... REGULATORY COMMISSION LICENSES AND RADIATION SAFETY REQUIREMENTS FOR IRRADIATORS Operation of Irradiators... accident dose ranges (see 10 CFR 20.1501(c)). Each personnel dosimeter must be assigned to and worn by only... processed at least quarterly. (b) Other individuals who enter the radiation room of a panoramic irradiator...

10 CFR 36.55 - Personnel monitoring.

Code of Federal Regulations, 2014 CFR

2014-01-01

... REGULATORY COMMISSION LICENSES AND RADIATION SAFETY REQUIREMENTS FOR IRRADIATORS Operation of Irradiators... accident dose ranges (see 10 CFR 20.1501(c)). Each personnel dosimeter must be assigned to and worn by only... processed at least quarterly. (b) Other individuals who enter the radiation room of a panoramic irradiator...

10 CFR 36.55 - Personnel monitoring.

Code of Federal Regulations, 2010 CFR

2010-01-01

... REGULATORY COMMISSION LICENSES AND RADIATION SAFETY REQUIREMENTS FOR IRRADIATORS Operation of Irradiators... accident dose ranges (see 10 CFR 20.1501(c)). Each personnel dosimeter must be assigned to and worn by only... processed at least quarterly. (b) Other individuals who enter the radiation room of a panoramic irradiator...

10 CFR 36.55 - Personnel monitoring.

Code of Federal Regulations, 2013 CFR

2013-01-01

... REGULATORY COMMISSION LICENSES AND RADIATION SAFETY REQUIREMENTS FOR IRRADIATORS Operation of Irradiators... accident dose ranges (see 10 CFR 20.1501(c)). Each personnel dosimeter must be assigned to and worn by only... processed at least quarterly. (b) Other individuals who enter the radiation room of a panoramic irradiator...

Some Considerations for Chelation Treatment and Surgical Excision Following Incorporation of Plutonium in Wounds

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

Poudel, Deepesh; Bertelli, Luiz; Klumpp, John A.

After a plutonium-contaminated wound, the role of an internal dosimetrist is to inform the patient and the physician of the dosimetric considerations. The doses averted due to medical treatments (excision or chelation) are higher if the treatments are administered early; therefore, the internal dosimetrist needs to rely on limited information on wound counts and process knowledge for advising the physician. For this study, several wound cases in the literature were reviewed to obtain estimates of the efficacies of surgical excision and chelation treatment after plutonium-contaminated wounds. The dose coefficients calculated by coupling the NCRP 156 wound model with the systemicmore » model were used to derive the decision guidelines that may indicate medical treatment based on 1) the concept of saved doses proposed by the NCRP 156 wound model, 2) the limits recommended by the CEC/DOE guidebook, and 3) the Clinical Decision Guidelines proposed in NCRP Report No. 161. These guidelines by themselves, however, are of limited use for several reasons, including 1) large uncertainties associated with wound measurements, 2) exposure to forms of radionuclides that cannot be assigned to a single category in the NCRP 156 framework, 3) inability of the NCRP 156 model to explain some of the wound cases in the literature, 4) neglect of the local doses to the wound site and the pathophysiological response of the tissue, 5) poorly understood relationship between effective doses and risks of late health effects, and 6) disregard of the psychological aspects of radionuclide intake.« less

Some Considerations for Chelation Treatment and Surgical Excision Following Incorporation of Plutonium in Wounds

DOE PAGES

Poudel, Deepesh; Bertelli, Luiz; Klumpp, John A.; ...

2018-03-01

After a plutonium-contaminated wound, the role of an internal dosimetrist is to inform the patient and the physician of the dosimetric considerations. The doses averted due to medical treatments (excision or chelation) are higher if the treatments are administered early; therefore, the internal dosimetrist needs to rely on limited information on wound counts and process knowledge for advising the physician. For this study, several wound cases in the literature were reviewed to obtain estimates of the efficacies of surgical excision and chelation treatment after plutonium-contaminated wounds. The dose coefficients calculated by coupling the NCRP 156 wound model with the systemicmore » model were used to derive the decision guidelines that may indicate medical treatment based on 1) the concept of saved doses proposed by the NCRP 156 wound model, 2) the limits recommended by the CEC/DOE guidebook, and 3) the Clinical Decision Guidelines proposed in NCRP Report No. 161. These guidelines by themselves, however, are of limited use for several reasons, including 1) large uncertainties associated with wound measurements, 2) exposure to forms of radionuclides that cannot be assigned to a single category in the NCRP 156 framework, 3) inability of the NCRP 156 model to explain some of the wound cases in the literature, 4) neglect of the local doses to the wound site and the pathophysiological response of the tissue, 5) poorly understood relationship between effective doses and risks of late health effects, and 6) disregard of the psychological aspects of radionuclide intake.« less

Training software using virtual-reality technology and pre-calculated effective dose data.

PubMed

Ding, Aiping; Zhang, Di; Xu, X George

2009-05-01

This paper describes the development of a software package, called VR Dose Simulator, which aims to provide interactive radiation safety and ALARA training to radiation workers using virtual-reality (VR) simulations. Combined with a pre-calculated effective dose equivalent (EDE) database, a virtual radiation environment was constructed in VR authoring software, EON Studio, using 3-D models of a real nuclear power plant building. Models of avatars representing two workers were adopted with arms and legs of the avatar being controlled in the software to simulate walking and other postures. Collision detection algorithms were developed for various parts of the 3-D power plant building and avatars to confine the avatars to certain regions of the virtual environment. Ten different camera viewpoints were assigned to conveniently cover the entire virtual scenery in different viewing angles. A user can control the avatar to carry out radiological engineering tasks using two modes of avatar navigation. A user can also specify two types of radiation source: Cs and Co. The location of the avatar inside the virtual environment during the course of the avatar's movement is linked to the EDE database. The accumulative dose is calculated and displayed on the screen in real-time. Based on the final accumulated dose and the completion status of all virtual tasks, a score is given to evaluate the performance of the user. The paper concludes that VR-based simulation technologies are interactive and engaging, thus potentially useful in improving the quality of radiation safety training. The paper also summarizes several challenges: more streamlined data conversion, realistic avatar movement and posture, more intuitive implementation of the data communication between EON Studio and VB.NET, and more versatile utilization of EDE data such as a source near the body, etc., all of which needs to be addressed in future efforts to develop this type of software.

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

Ma, Y; Lacroix, F; Lavallee, M

Purpose: To evaluate the commercially released Collapsed Cone convolution-based(CCC) dose calculation module of the Elekta OncentraBrachy(OcB) treatment planning system(TPS). Methods: An allwater phantom was used to perform TG43 benchmarks with single source and seventeen sources, separately. Furthermore, four real-patient heterogeneous geometries (chestwall, lung, breast and prostate) were used. They were selected based on their clinical representativity of a class of clinical anatomies that pose clear challenges. The plans were used as is(no modification). For each case, TG43 and CCC calculations were performed in the OcB TPS, with TG186-recommended materials properly assigned to ROIs. For comparison, Monte Carlo simulation was runmore » for each case with the same material scheme and grid mesh as TPS calculations. Both modes of CCC (standard and high quality) were tested. Results: For the benchmark case, the CCC dose, when divided by that of TG43, yields hot-n-cold spots in a radial pattern. The pattern of the high mode is denser than that of the standard mode and is representative of angular dicretization. The total deviation ((hot-cold)/TG43) is 18% for standard mode and 11% for high mode. Seventeen dwell positions help to reduce “ray-effect”, with the total deviation to 6% (standard) and 5% (high), respectively. For the four patient cases, CCC produces, as expected, more realistic dose distributions than TG43. A close agreement was observed between CCC and MC for all isodose lines, from 20% and up; the 10% isodose line of CCC appears shifted compared to that of MC. The DVH plots show dose deviations of CCC from MC in small volume, high dose regions (>100% isodose). For patient cases, the difference between standard and high modes is almost undiscernable. Conclusion: OncentraBrachy CCC algorithm marks a significant dosimetry improvement relative to TG43 in real-patient cases. Further researches are recommended regarding the clinical implications of the above observations. Support provided by a CIHR grant and CCC system provided by Elekta-Nucletron.« less

Anxiety and Health-Related Quality of Life Among Patients With Low–Tumor Burden Non-Hodgkin Lymphoma Randomly Assigned to Two Different Rituximab Dosing Regimens: Results From ECOG Trial E4402 (RESORT)

PubMed Central

Wagner, Lynne I.; Zhao, Fengmin; Hong, Fangxin; Williams, Michael E.; Gascoyne, Randy D.; Krauss, John C.; Advani, Ranjana H.; Go, Ronald S.; Habermann, Thomas M.; Leach, Joseph W.; O'Connor, Brian; Schuster, Stephen J.; Cella, David; Horning, Sandra J.; Kahl, Brad S.

2015-01-01

Purpose The purpose of this study was to compare illness-related anxiety among participants in the Rituximab Extended Schedule or Retreatment Trial (RESORT) randomly assigned to maintenance rituximab (MR) versus rituximab re-treatment (RR). A secondary objective was to examine whether the superiority of MR versus RR on anxiety depended on illness-related coping style. Patients and Methods Patients (N = 253) completed patient-reported outcome (PRO) measures at random assignment to MR or RR (baseline); at 3, 6, 12, 24, 36, and 48 months after random assignment; and at rituximab failure. PRO measures assessed illness-related anxiety and coping style, and secondary end points including general anxiety, worry and interference with emotional well-being, depression, and health-related quality of life (HRQoL). Patients were classified as using an active or avoidant illness-related coping style. Independent sample t tests and linear mixed-effects models were used to identify treatment arm differences on PRO end points and differences based on coping style. Results Illness-related anxiety was comparable between treatment arms at all time points (P > .05), regardless of coping style (active or avoidant). Illness-related anxiety and general anxiety significantly decreased over time on both arms. HRQoL scores were relatively stable and did not change significantly from baseline for both arms. An avoidant coping style was associated with significantly higher anxiety (18% and 13% exceeded clinical cutoff points at baseline and 6 months, respectively) and poorer HRQoL compared with an active coping style (P < .001), regardless of treatment arm assignment. Conclusion Surveillance until RR at progression was not associated with increased anxiety compared with MR, regardless of coping style. Avoidant coping was associated with higher anxiety and poorer HRQoL. PMID:25605841

Preliminary calculation of solar cosmic ray dose to the female breast in space mission

NASA Technical Reports Server (NTRS)

Shavers, Mark; Poston, John W.; Atwell, William; Hardy, Alva C.; Wilson, John W.

1991-01-01

No regulatory dose limits are specifically assigned for the radiation exposure of female breasts during manned space flight. However, the relatively high radiosensitivity of the glandular tissue of the breasts and its potential exposure to solar flare protons on short- and long-term missions mandate a priori estimation of the associated risks. A model for estimating exposure within the breast is developed for use in future NASA missions. The female breast and torso geometry is represented by a simple interim model. A recently developed proton dose-buildup procedure is used for estimating doses. The model considers geomagnetic shielding, magnetic-storm conditions, spacecraft shielding, and body self-shielding. Inputs to the model include proton energy spectra, spacecraft orbital parameters, STS orbiter-shielding distribution at a given position, and a single parameter allowing for variation in breast size.

A phase 1 trial of 2 dose schedules of ABT-510, an antiangiogenic, thrombospondin-1-mimetic peptide, in patients with advanced cancer.

PubMed

Gordon, Michael S; Mendelson, David; Carr, Robert; Knight, Raymond A; Humerickhouse, Rod A; Iannone, Maria; Stopeck, Alison T

2008-12-15

ABT-510 is a substituted nonapeptide that mimics the antiangiogenic activity of the endogenous protein thrombospondin-1 (TSP-1). The current study was designed to establish the safety of ABT-510 in the treatment of patients with advanced malignancies on a once-daily (QD) and twice-daily dosing schedule. Patients were randomly assigned to 1 of 6 dosing regimens: 20 mg, 50 mg, or 100 mg QD or 10 mg, 25 mg, or 50 mg twice daily. ABT-510 was administered by subcutaneous bolus injection in cycles of 28 days. Tumor response and disease progression were monitored at 8-week intervals by computed tomography scan or magnetic resonance imaging. Thirty-six patients were randomly assigned in equal numbers to the 6 study regimens, with an additional 13 patients randomized to the 10-mg-twice-daily and 50-mg-twice-daily ABT-510 regimens. The expected pharmacokinetic target was achieved at all dose levels tested. The majority of adverse events were grade 1 or 2 (according to National Cancer Institute Common Toxicity Criteria [version 2]) and were not found to be dose related. The most frequently reported adverse events that were possibly related to ABT-510 included injection site reactions, asthenia, headache, and nausea. Grade 3 events considered to possibly be related included nausea, dyspnea, bone pain, constipation, vomiting, asthenia, and chills and tremors. One partial response was observed in a patient with carcinosarcoma who received 20 mg QD. The 6-month progression-free survival rate was 6%. Approximately 42% of patients (21 of 50 patients) had stable disease for > or =3 months. ABT-510 can be administered at doses of 20 mg/day to 100 mg/day without significant toxicity. In the current study, minimal antitumor activity was observed, which was similar to observations in other single-agent antiangiogenic trials.

Evaluation of a High Concentrated Contrast Media Injection Protocol in Combination with Low Tube Current for Dose Reduction in Coronary Computed Tomography Angiography: A Randomized, Two-center Prospective Study.

PubMed

Sun, Yibo; Hua, Yanqing; Wang, Mingpeng; Mao, Dingbiao; Jin, Xiu; Li, Cheng; Shi, Kailei; Xu, Jianrong

2017-12-01

The study aimed to prospectively evaluate the radiation dose reduction potential and image quality (IQ) of a high-concentration contrast media (HCCM) injection protocol in combination with a low tube current (mAs) in coronary computed tomography angiography. Eighty-one consecutive patients (mean age: 62 years; 34 females; body mass index: 18-31) were included and randomized-assigned into two groups. All computed tomography (CT) examinations were performed in two groups with the same tube voltage (100 kV), flow rate of contrast medium (5.0 mL/s), and iodine dose (22.8 g). An automatic mAs and low concentration contrast medium (300 mgI/mL) were used in group A, whereas effective mAs was reduced by a factor 0.6 along with HCCM (400 mgI/mL) in group B. Radiation dose was assessed (CT dose index [CTDI vol ] and dose length product), and vessel-based objective IQ for various regions of interest (enhancement, noise, signal-to-noise ratio, and contrast-to-noise ratio), subjective IQ, noise, and motion artifacts were analyzed overall and vessel-based with a 5-point Likert scale. The CT attenuation of coronary arteries and image noise in group B were significantly higher than those in group A (ranges: 507.5-548.1 Hounsfield units vs 407.5-444.5 Hounsfield units; and 20.3 ± 8.6 vs 17.7 ± 8.0) (P ≤ 0.0166). There was no significant difference between the two groups in signal-to-noise ratio, contrast-to-noise ratio, and subjective IQ of coronary arteries (29.4-31.7, 30.0-37.0, and medium score of 5 in group A vs 29.4-32.4, 27.7-36.3, and medium score of 5 in group B, respectively, P ≥ 0.1859). Both mean CTDI vol and dose length product in group B were 58% of those of group A. HCCM combined with low tube current allows dose reduction in coronary computed tomography angiography and does not compromise IQ. Copyright © 2017 The Association of University Radiologists. Published by Elsevier Inc. All rights reserved.

Efficacy and safety of three antiretroviral regimens for initial treatment of HIV-1: a randomized clinical trial in diverse multinational settings.

PubMed

Campbell, Thomas B; Smeaton, Laura M; Kumarasamy, N; Flanigan, Timothy; Klingman, Karin L; Firnhaber, Cynthia; Grinsztejn, Beatriz; Hosseinipour, Mina C; Kumwenda, Johnstone; Lalloo, Umesh; Riviere, Cynthia; Sanchez, Jorge; Melo, Marineide; Supparatpinyo, Khuanchai; Tripathy, Srikanth; Martinez, Ana I; Nair, Apsara; Walawander, Ann; Moran, Laura; Chen, Yun; Snowden, Wendy; Rooney, James F; Uy, Jonathan; Schooley, Robert T; De Gruttola, Victor; Hakim, James Gita

2012-01-01

Antiretroviral regimens with simplified dosing and better safety are needed to maximize the efficiency of antiretroviral delivery in resource-limited settings. We investigated the efficacy and safety of antiretroviral regimens with once-daily compared to twice-daily dosing in diverse areas of the world. 1,571 HIV-1-infected persons (47% women) from nine countries in four continents were assigned with equal probability to open-label antiretroviral therapy with efavirenz plus lamivudine-zidovudine (EFV+3TC-ZDV), atazanavir plus didanosine-EC plus emtricitabine (ATV+DDI+FTC), or efavirenz plus emtricitabine-tenofovir-disoproxil fumarate (DF) (EFV+FTC-TDF). ATV+DDI+FTC and EFV+FTC-TDF were hypothesized to be non-inferior to EFV+3TC-ZDV if the upper one-sided 95% confidence bound for the hazard ratio (HR) was ≤1.35 when 30% of participants had treatment failure. An independent monitoring board recommended stopping study follow-up prior to accumulation of 472 treatment failures. Comparing EFV+FTC-TDF to EFV+3TC-ZDV, during a median 184 wk of follow-up there were 95 treatment failures (18%) among 526 participants versus 98 failures among 519 participants (19%; HR 0.95, 95% CI 0.72-1.27; p = 0.74). Safety endpoints occurred in 243 (46%) participants assigned to EFV+FTC-TDF versus 313 (60%) assigned to EFV+3TC-ZDV (HR 0.64, CI 0.54-0.76; p<0.001) and there was a significant interaction between sex and regimen safety (HR 0.50, CI 0.39-0.64 for women; HR 0.79, CI 0.62-1.00 for men; p = 0.01). Comparing ATV+DDI+FTC to EFV+3TC-ZDV, during a median follow-up of 81 wk there were 108 failures (21%) among 526 participants assigned to ATV+DDI+FTC and 76 (15%) among 519 participants assigned to EFV+3TC-ZDV (HR 1.51, CI 1.12-2.04; p = 0.007). EFV+FTC-TDF had similar high efficacy compared to EFV+3TC-ZDV in this trial population, recruited in diverse multinational settings. Superior safety, especially in HIV-1-infected women, and once-daily dosing of EFV+FTC-TDF are advantageous for use of this regimen for initial treatment of HIV-1 infection in resource-limited countries. ATV+DDI+FTC had inferior efficacy and is not recommended as an initial antiretroviral regimen. www.ClinicalTrials.gov NCT00084136. Please see later in the article for the Editors' Summary.

Treatment of adult chronic indeterminate Chagas disease with benznidazole and three E1224 dosing regimens: a proof-of-concept, randomised, placebo-controlled trial.

PubMed

Torrico, Faustino; Gascon, Joaquim; Ortiz, Lourdes; Alonso-Vega, Cristina; Pinazo, María-Jesús; Schijman, Alejandro; Almeida, Igor C; Alves, Fabiana; Strub-Wourgaft, Nathalie; Ribeiro, Isabela

2018-04-01

Chagas disease is a major neglected vector-borne disease. In this study, we investigated the safety and efficacy of three oral E1224 (a water-soluble ravuconazole prodrug) regimens and benznidazole versus placebo in adult chronic indeterminate Chagas disease. In this proof-of-concept, double-blind, randomised phase 2 clinical trial, we recruited adults (18-50 years) with confirmed diagnosis of Trypanosoma cruzi infection from two outpatient units in Bolivia. Patients were randomised with a computer-generated randomisation list, which was stratified by centre and used a block size of ten. Patients were randomly assigned (1:1:1:1:1) to five oral treatment groups: high-dose E1224 (duration 8 weeks, total dose 4000 mg), low-dose E1224 (8 weeks, 2000 mg), short-dose E1224 (4 weeks + 4 weeks placebo, 2400 mg), benznidazole (60 days, 5 mg/kg per day), or placebo (8 weeks, E1224-matched tablets). Double-blinding was limited to the E1224 and placebo arms, and assessors were masked to all treatment allocations. The primary efficacy endpoint was parasitological response to E1224 at the end of treatment, assessed by PCR. The secondary efficacy endpoints were parasitological response to benznidazole at end of treatment, assessed by PCR; sustainability of parasitological response until 12 months; parasite clearance and changes in parasite load; incidence of conversion to negative response in conventional and non-conventional (antigen trypomastigote chemiluminescent ELISA [AT CL-ELISA]) serological response; changes in levels of biomarkers; and complete response. The primary analysis population consisted of all randomised patients by their assigned treatment arms. This trial is registered with ClinicalTrials.gov, number NCT01489228. Between July 19, 2011, and July 26, 2012, we screened 560 participants with confirmed Chagas disease, of whom 231 were enrolled and assigned to high-dose E1224 (n=45), low-dose E1224 (n=48), short-dose E1224 (n=46), benznidazole (n=45), or placebo (n=47). Parasite clearance was observed with E1224 during the treatment phase, but no sustained response was seen with low-dose and short-dose regimens, whereas 13 patients (29%, 95% CI 16·4-44·3) had sustained response with the high-dose regimen compared with four (9%, 2·4-20·4) in the placebo group (p<0·0001). Benznidazole had a rapid and sustained effect on parasite clearance, with 37 patients (82%, 67·9-92·0) with sustained response at 12-month follow-up. After 1 week of treatment, mean quantitative PCR repeated measurements showed a significant reduction in parasite load in all treatment arms versus placebo. Parasite levels in the low-dose and short-dose E1224 groups gradually returned to placebo levels. Both treatments were well tolerated. Reversible, dose-dependent liver enzyme increases were seen with E1224 and benznidazole. 187 (81%) participants developed treatment-emergent adverse events and six (3%) developed treatment-emergent serious adverse events. Treatment-emergent adverse events were headaches, nausea, pruritus, peripheral neuropathy, and hypersensitivity. E1224 is the first new chemical entity developed for Chagas disease in decades. E1224 displayed a transient, suppressive effect on parasite clearance, whereas benznidazole showed early and sustained efficacy until 12 months of follow-up. Despite PCR limitations, our results support increased diagnosis and access to benznidazole standard regimen, and provide a development roadmap for novel benznidazole regimens in monotherapy and in combinations with E1224. Drugs for Neglected Diseases initiative. Copyright © 2018 Elsevier Ltd. All rights reserved.

A phase I study of muscadine grape skin extract in men with biochemically recurrent prostate cancer: Safety, tolerability, and dose determination.

PubMed

Paller, Channing J; Rudek, Michelle A; Zhou, Xian C; Wagner, William D; Hudson, Tamaro S; Anders, Nicole; Hammers, Hans J; Dowling, Donna; King, Serina; Antonarakis, Emmanuel S; Drake, Charles G; Eisenberger, Mario A; Denmeade, Samuel R; Rosner, Gary L; Carducci, Michael A

2015-10-01

New therapies are being explored as therapeutic options for men with biochemically recurrent prostate cancer (BRPC) who wish to defer androgen deprivation therapy. MPX is pulverized muscadine grape (Vitis rotundifolia) skin that contains ellagic acid, quercetin, and resveratrol and demonstrates preclinical activity against prostate cancer cells in vitro. In the phase I portion of this phase I/II study, non-metastatic BRPC patients were assigned to increasing doses of MPX (Muscadine Naturals. Inc., Clemmons, NC) in cohorts of two patients, with six patients at the highest dose, using a modified continual reassessment method. Initial dose selection was based on preclinical data showing the equivalent of 500 to 4,000 mg of MPX to be safe in mouse models. The primary endpoint was the recommended phase II dosing regimen. The cohort (n = 14, 71% Caucasian, 29% black) had a median follow-up of 19.2 (6.2-29.7) months, median age of 61 years, and median Gleason score of 7. Four patients had possibly related gastrointestinal symptoms, including grade 1 flatulence, grade 1 soft stools, and grade 1 eructation. No other related adverse events were reported and one patient reported improvement of chronic constipation. Six of 14 patients came off study for disease progression (five metastatic, one rising PSA) after exposure for a median of 15 months. One patient came off for myasthenia gravis that was unrelated to treatment. Seven patients remain on study. The lack of dose-limiting toxicities led to the selection of 4,000 mg/d as the highest dose for further study. Median within-patient PSADT increased by 5.3 months (non-significant, P = 0.17). No patients experienced a maintained decline in serum PSA from baseline. These data suggest that 4,000 mg of MPX is safe, and exploratory review of a lengthening in PSADT of a median of 5.3 months supports further exploration of MPX. Both low-dose (500 mg) and high-dose (4,000 mg) MPX are being further investigated in a randomized, multicenter, placebo-controlled, dose-evaluating phase II trial. © 2015 Wiley Periodicals, Inc.

Safety and efficacy of eculizumab in anti-acetylcholine receptor antibody-positive refractory generalised myasthenia gravis (REGAIN): a phase 3, randomised, double-blind, placebo-controlled, multicentre study.

PubMed

Howard, James F; Utsugisawa, Kimiaki; Benatar, Michael; Murai, Hiroyuki; Barohn, Richard J; Illa, Isabel; Jacob, Saiju; Vissing, John; Burns, Ted M; Kissel, John T; Muppidi, Srikanth; Nowak, Richard J; O'Brien, Fanny; Wang, Jing-Jing; Mantegazza, Renato

2017-12-01

Complement is likely to have a role in refractory generalised myasthenia gravis, but no approved therapies specifically target this system. Results from a phase 2 study suggested that eculizumab, a terminal complement inhibitor, produced clinically meaningful improvements in patients with anti-acetylcholine receptor antibody-positive refractory generalised myasthenia gravis. We further assessed the efficacy and safety of eculizumab in this patient population in a phase 3 trial. We did a phase 3, randomised, double-blind, placebo-controlled, multicentre study (REGAIN) in 76 hospitals and specialised clinics in 17 countries across North America, Latin America, Europe, and Asia. Eligible patients were aged at least 18 years, with a Myasthenia Gravis-Activities of Daily Living (MG-ADL) score of 6 or more, Myasthenia Gravis Foundation of America (MGFA) class II-IV disease, vaccination against Neisseria meningitides, and previous treatment with at least two immunosuppressive therapies or one immunosuppressive therapy and chronic intravenous immunoglobulin or plasma exchange for 12 months without symptom control. Patients with a history of thymoma or thymic neoplasms, thymectomy within 12 months before screening, or use of intravenous immunoglobulin or plasma exchange within 4 weeks before randomisation, or rituximab within 6 months before screening, were excluded. We randomly assigned participants (1:1) to either intravenous eculizumab or intravenous matched placebo for 26 weeks. Dosing for eculizumab was 900 mg on day 1 and at weeks 1, 2, and 3; 1200 mg at week 4; and 1200 mg given every second week thereafter as maintenance dosing. Randomisation was done centrally with an interactive voice or web-response system with patients stratified to one of four groups based on MGFA disease classification. Where possible, patients were maintained on existing myasthenia gravis therapies and rescue medication was allowed at the study physician's discretion. Patients, investigators, staff, and outcome assessors were masked to treatment assignment. The primary efficacy endpoint was the change from baseline to week 26 in MG-ADL total score measured by worst-rank ANCOVA. The efficacy population set was defined as all patients randomly assigned to treatment groups who received at least one dose of study drug, had a valid baseline MG-ADL assessment, and at least one post-baseline MG-ADL assessment. The safety analyses included all randomly assigned patients who received eculizumab or placebo. This trial is registered with ClinicalTrials.gov, number NCT01997229. Between April 30, 2014, and Feb 19, 2016, we randomly assigned and treated 125 patients, 62 with eculizumab and 63 with placebo. The primary analysis showed no significant difference between eculizumab and placebo (least-squares mean rank 56·6 [SEM 4·5] vs 68·3 [4·5]; rank-based treatment difference -11·7, 95% CI -24·3 to 0·96; p=0·0698). No deaths or cases of meningococcal infection occurred during the study. The most common adverse events in both groups were headache and upper respiratory tract infection (ten [16%] for both events in the eculizumab group and 12 [19%] for both in the placebo group). Myasthenia gravis exacerbations were reported by six (10%) patients in the eculizumab group and 15 (24%) in the placebo group. Six (10%) patients in the eculizumab group and 12 (19%) in the placebo group required rescue therapy. The change in the MG-ADL score was not statistically significant between eculizumab and placebo, as measured by the worst-rank analysis. Eculizumab was well tolerated. The use of a worst-rank analytical approach proved to be an important limitation of this study since the secondary and sensitivity analyses results were inconsistent with the primary endpoint result; further research into the role of complement is needed. Alexion Pharmaceuticals. Copyright © 2017 Elsevier Ltd. All rights reserved.

A Randomized Trial of a Multicomponent Intervention to Promote Medication Adherence: The Teen Adherence in Kidney Transplant Effectiveness of Intervention Trial (TAKE-IT).

PubMed

Foster, Bethany J; Pai, Ahna L H; Zelikovsky, Nataliya; Amaral, Sandra; Bell, Lorraine; Dharnidharka, Vikas R; Hebert, Diane; Holly, Crystal; Knauper, Baerbel; Matsell, Douglas; Phan, Veronique; Rogers, Rachel; Smith, Jodi M; Zhao, Huaqing; Furth, Susan L

2018-07-01

Poor adherence to immunosuppressive medications is a major cause of premature graft loss among children and young adults. Multicomponent interventions have shown promise but have not been fully evaluated. Unblinded parallel-arm randomized trial to assess the efficacy of a clinic-based adherence-promoting intervention. Prevalent kidney transplant recipients 11 to 24 years of age and 3 or more months posttransplantation at 8 kidney transplantation centers in Canada and the United States (February 2012 to May 2016) were included. Adherence was electronically monitored in all participants during a 3-month run-in, followed by a 12-month intervention. Participants assigned to the TAKE-IT intervention could choose to receive text message, e-mail, and/or visual cue dose reminders and met with a coach at 3-month intervals when adherence data from the prior 3 months were reviewed with the participant. "Action-Focused Problem Solving" was used to address adherence barriers selected as important by the participant. Participants assigned to the control group met with coaches at 3-month intervals but received no feedback about adherence data. The primary outcomes were electronically measured "taking" adherence (the proportion of prescribed doses of immunosuppressive medications taken) and "timing" adherence (the proportion of doses of immunosuppressive medications taken between 1 hour before and 2 hours after the prescribed time of administration) on each day of observation. Secondary outcomes included the standard deviation of tacrolimus trough concentrations, self-reported adherence, acute rejection, and graft failure. 81 patients were assigned to intervention (median age, 15.5 years; 57% male) and 88 to the control group (median age, 15.8 years; 61% male). Electronic adherence data were available for 64 intervention and 74 control participants. Participants in the intervention group had significantly greater odds of taking prescribed medications (OR, 1.66; 95% CI, 1.15-2.39) and taking medications at or near the prescribed time (OR, 1.74; 95% CI, 1.21-2.50) than controls. Lack of electronic adherence data for some participants may have introduced bias. There was low statistical power for clinical outcomes. The multicomponent TAKE-IT intervention resulted in significantly better medication adherence than the control condition. Better medication adherence may result in improved graft outcomes, but this will need to be demonstrated in larger studies. Registered at ClinicalTrials.gov with study number NCT01356277. Copyright © 2018 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.

Prospective pilot trial of PerMIT versus standard anticoagulation service management of patients initiating oral anticoagulation.

PubMed

Borgman, Mark P; Pendleton, Robert C; McMillin, Gwendolyn A; Reynolds, Kristen K; Vazquez, Sara; Freeman, Andrew; Wilson, Andrew; Valdes, Roland; Linder, Mark W

2012-09-01

We performed a randomised pilot trial of PerMIT, a novel decision support tool for genotype-based warfarin initiation and maintenance dosing, to assess its efficacy for improving warfarin management. We prospectively studied 26 subjects to compare PerMIT-guided management with routine anticoagulation service management. CYP2C9 and VKORC1 genotype results for 13 subjects randomly assigned to the PerMIT arm were recorded within 24 hours of enrolment. To aid in INR interpretation, PerMIT calculates estimated loading and maintenance doses based on a patient's genetic and clinical characteristics and displays calculated S-warfarin plasma concentrations based on planned or administered dosages. In comparison to control subjects, patients in the PerMIT study arm demonstrated a 3.6-day decrease in the time to reach a stabilised INR within the target therapeutic range (4.7 vs. 8.3 days, p = 0.015); a 12.8% increase in time spent within the therapeutic interval over the first 25 days of therapy (64.3% vs. 55.3%, p = 0.180); and a 32.9% decrease in the frequency of warfarin dose adjustments per INR measurement (38.3% vs. 57.1%, p = 0.007). Serial measurements of plasma S-warfarin concentrations were also obtained to prospectively evaluate the accuracy of the pharmacokinetic model during induction therapy. The PerMIT S-warfarin plasma concentration model estimated 62.8% of concentrations within 0.15 mg/l. These pilot data suggest that the PerMIT method and its incorporation of genotype/phenotype information may help practitioners increase the safety, efficacy, and efficiency of warfarin therapeutic management.

Electric cell-substrate impedance sensing (ECIS) based real-time measurement of titer dependent cytotoxicity induced by adenoviral vectors in an IPI-2I cell culture model.

PubMed

Müller, Jakob; Thirion, Christian; Pfaffl, Michael W

2011-01-15

Recombinant viral vectors are widespread tools for transfer of genetic material in various modern biotechnological applications like for example RNA interference (RNAi). However, an accurate and reproducible titer assignment represents the basic step for most downstream applications regarding a precise multiplicity of infection (MOI) adjustment. As necessary scaffold for the studies described in this work we introduce a quantitative real-time PCR (qPCR) based approach for viral particle measurement. Still an implicated problem concerning physiological effects is that the appliance of viral vectors is often attended by toxic effects on the individual target. To determine the critical viral dose leading to cell death we developed an electric cell-substrate impedance sensing (ECIS) based assay. With ECIS technology the impedance change of a current flow through the cell culture medium in an array plate is measured in a non-invasive manner, visualizing effects like cell attachment, cell-cell contacts or proliferation. Here we describe the potential of this online measurement technique in an in vitro model using the porcine ileal epithelial cell line IPI-2I in combination with an adenoviral transfection vector (Ad5-derivate). This approach shows a clear dose-depending toxic effect, as the amount of applied virus highly correlates (p<0.001) with the level of cell death. Thus this assay offers the possibility to discriminate the minimal non-toxic dose of the individual transfection method. In addition this work suggests that the ECIS-device bears the feasibility to transfer this assay to multiple other cytotoxicological questions. Copyright © 2010 Elsevier B.V. All rights reserved.

Pilot study to assess toxicity and pharmacokinetics of docetaxel in patients with metastatic breast cancer and impaired liver function secondary to hepatic metastases.

PubMed

Eckmann, Karen; Michaud, Laura B; Rivera, Edgardo; Madden, Timothy L; Esparza-Guerra, Laura; Kawedia, Jitesh; Booser, Daniel J; Green, Marjorie C; Hortobagyi, Gabriel N; Valero, Vicente

2014-04-01

Limited clinical data are available regarding the safety of docetaxel in metastatic breast cancer patients with liver dysfunction. Eligible patients had breast cancer with impaired liver function secondary to hepatic metastases and were candidates for docetaxel therapy. They were assigned to one of five groups on the basis of total bilirubin, alanine aminotransferase, aspartate aminotransferase, and alkaline phosphatase levels. All other causes of liver dysfunction were excluded, and bile duct obstruction was corrected, if possible, prior to study entry. Patients received docetaxel every three weeks. The chemotherapy dose was chosen on the basis of the patient's level of hepatic dysfunction and escalated as tolerated. The primary outcome of this study was safety. The secondary outcomes were pharmacokinetic data and efficacy in terms of time to disease progression. Twenty-three patients were enrolled. No unexpected toxicities occurred. Grade 3/4 fatigue (65%), neutropenia (30%), myalgias (26%), neutropenic fever (26%), vomiting (9%), and rash (9%) were the most common serious adverse events. The median time to progression was three months (range 1-18 months). Pharmacokinetic results indicated that patients with more severe hepatic dysfunction may have been underdosed based on our conservative dosing strategy. Docetaxel can be administered to patients with metastatic breast cancer and liver dysfunction after dose attenuation. However, because of a narrow therapeutic index in this clinical setting, therapy should be closely monitored with subsequent dose escalation when possible.

Effect of naltrexone plus bupropion on weight loss in overweight and obese adults (COR-I): a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial.

PubMed

Greenway, Frank L; Fujioka, Ken; Plodkowski, Raymond A; Mudaliar, Sunder; Guttadauria, Maria; Erickson, Janelle; Kim, Dennis D; Dunayevich, Eduardo

2010-08-21

Despite increasing public health concerns regarding obesity, few safe and effective drug treatments are available. Combination treatment with sustained-release naltrexone and bupropion was developed to produce complementary actions in CNS pathways regulating bodyweight. The Contrave Obesity Research I (COR-I) study assessed the effect of such treatment on bodyweight in overweight and obese participants. Men and women aged 18-65 years who had a body-mass index (BMI) of 30-45 kg/m(2) and uncomplicated obesity or BMI 27-45 kg/m(2) with dyslipidaemia or hypertension were eligible for enrolment in this randomised, double-blind, placebo-controlled, phase 3 trial undertaken at 34 sites in the USA. Participants were prescribed mild hypocaloric diet and exercise and were randomly assigned in a 1:1:1 ratio to receive sustained-release naltrexone 32 mg per day plus sustained-release bupropion 360 mg per day combined in fixed-dose tablets (also known as NB32), sustained-release naltrexone 16 mg per day plus sustained-release bupropion 360 mg per day combined in fixed-dose tablets (also known as NB16), or matching placebo twice a day, given orally for 56 weeks. The trial included a 3-week dose escalation. Randomisation was done by use of a centralised, computer-generated, web-based system and was stratified by study centre. Co-primary efficacy endpoints at 56 weeks were percentage change in bodyweight and proportion of participants who achieved a decrease in bodyweight of 5% or more. The primary analysis included all randomised participants with a baseline weight measurement and a post-baseline weight measurement while on study drug (last observation carried forward). This study is registered with ClinicalTrials.gov, number NCT00532779. 1742 participants were enrolled and randomised to double-blind treatment (naltrexone 32 mg plus bupropion, n=583; naltrexone 16 mg plus bupropion, n=578; placebo, n=581). 870 (50%) participants completed 56 weeks of treatment (n=296; n=284; n=290, respectively) and 1453 (83%) were included in the primary analysis (n=471; n=471; n=511). Mean change in bodyweight was -1.3% (SE 0.3) in the placebo group, -6.1% (0.3) in the naltrexone 32 mg plus bupropion group (p<0.0001 vs placebo) and -5.0% (0.3) in the naltrexone 16 mg plus bupropion group (p<0.0001 vs placebo). 84 (16%) participants assigned to placebo had a decrease in bodyweight of 5% or more compared with 226 (48%) assigned to naltrexone 32 mg plus bupropion (p<0.0001 vs placebo) and 186 (39%) assigned to naltrexone 16 mg plus bupropion (p<0.0001 vs placebo). The most frequent adverse event in participants assigned to combination treatment was nausea (naltrexone 32 mg plus bupropion, 171 participants [29.8%]; naltrexone 16 mg plus bupropion, 155 [27.2%]; placebo, 30 [5.3%]). Headache, constipation, dizziness, vomiting, and dry mouth were also more frequent in the naltrexone plus bupropion groups than in the placebo group. A transient increase of around 1.5 mm Hg in mean systolic and diastolic blood pressure was followed by a reduction of around 1 mm Hg below baseline in the naltrexone plus bupropion groups. Combination treatment was not associated with increased depression or suicidality events compared with placebo. A sustained-release combination of naltrexone plus bupropion could be a useful therapeutic option for treatment of obesity. Orexigen Therapeutics. Copyright 2010 Elsevier Ltd. All rights reserved.

Female pelvic synthetic CT generation based on joint intensity and shape analysis

NASA Astrophysics Data System (ADS)

Liu, Lianli; Jolly, Shruti; Cao, Yue; Vineberg, Karen; Fessler, Jeffrey A.; Balter, James M.

2017-04-01

Using MRI for radiotherapy treatment planning and image guidance is appealing as it provides superior soft tissue information over CT scans and avoids possible systematic errors introduced by aligning MR to CT images. This study presents a method that generates Synthetic CT (MRCT) volumes by performing probabilistic tissue classification of voxels from MRI data using a single imaging sequence (T1 Dixon). The intensity overlap between different tissues on MR images, a major challenge for voxel-based MRCT generation methods, is addressed by adding bone shape information to an intensity-based classification scheme. A simple pelvic bone shape model, built from principal component analysis of pelvis shape from 30 CT image volumes, is fitted to the MR volumes. The shape model generates a rough bone mask that excludes air and covers bone along with some surrounding soft tissues. Air regions are identified and masked out from the tissue classification process by intensity thresholding outside the bone mask. A regularization term is added to the fuzzy c-means classification scheme that constrains voxels outside the bone mask from being assigned memberships in the bone class. MRCT image volumes are generated by multiplying the probability of each voxel being represented in each class with assigned attenuation values of the corresponding class and summing the result across all classes. The MRCT images presented intensity distributions similar to CT images with a mean absolute error of 13.7 HU for muscle, 15.9 HU for fat, 49.1 HU for intra-pelvic soft tissues, 129.1 HU for marrow and 274.4 HU for bony tissues across 9 patients. Volumetric modulated arc therapy (VMAT) plans were optimized using MRCT-derived electron densities, and doses were recalculated using corresponding CT-derived density grids. Dose differences to planning target volumes were small with mean/standard deviation of 0.21/0.42 Gy for D0.5cc and 0.29/0.33 Gy for D99%. The results demonstrate the accuracy of the method and its potential in supporting MRI only radiotherapy treatment planning.

Effect of Clopidogrel on Early Failure of Arteriovenous Fistulas for Hemodialysis

PubMed Central

Dember, Laura M.; Beck, Gerald J.; Allon, Michael; Delmez, James A.; Dixon, Bradley S.; Greenberg, Arthur; Himmelfarb, Jonathan; Vazquez, Miguel A.; Gassman, Jennifer J.; Greene, Tom; Radeva, Milena K.; Braden, Gregory L.; Ikizler, T. Alp; Rocco, Michael V.; Davidson, Ingemar J.; Kaufman, James S.; Meyers, Catherine M.; Kusek, John W.; Feldman, Harold I.

2016-01-01

Context The arteriovenous fistula is the preferred type of vascular access for hemodialysis because of lower thrombosis and infection rates and lower health care expenditures compared with synthetic grafts or central venous catheters. Early failure of fistulas due to thrombosis or inadequate maturation is a barrier to increasing the prevalence of fistulas among patients treated with hemodialysis. Small, inconclusive trials have suggested that antiplatelet agents may reduce thrombosis of new fistulas. Objective To determine whether clopidogrel reduces early failure of hemodialysis fistulas. Design, Setting, and Participants Randomized, double-blind, placebo-controlled trial conducted at 9 US centers composed of academic and community nephrology practices in 2003–2007. Eight hundred seventy-seven participants with end-stage renal disease or advanced chronic kidney disease were followed up until 150 to 180 days after fistula creation or 30 days after initiation of dialysis, whichever occurred later. Intervention Participants were randomly assigned to receive clopidogrel (300-mg loading dose followed by daily dose of 75 mg; n = 441) or placebo (n = 436) for 6 weeks starting within 1 day after fistula creation. Main Outcome Measures The primary outcome was fistula thrombosis, determined by physical examination at 6 weeks. The secondary outcome was failure of the fistula to become suitable for dialysis. Suitability was defined as use of the fistula at a dialysis machine blood pump rate of 300 mL/min or more during 8 of 12 dialysis sessions. Results Enrollment was stopped after 877 participants were randomized based on a stopping rule for intervention efficacy. Fistula thrombosis occurred in 53 (12.2%) participants assigned to clopidogrel compared with 84 (19.5%) participants assigned to placebo (relative risk, 0.63; 95% confidence interval, 0.46–0.97; P = .018). Failure to attain suitability for dialysis did not differ between the clopidogrel and placebo groups (61.8% vs 59.5%, respectively; relative risk, 1.05; 95% confidence interval, 0.94–1.17; P = .40). Conclusion Clopidogrel reduces the frequency of early thrombosis of new arteriovenous fistulas but does not increase the proportion of fistulas that become suitable for dialysis. Trial Registration clinicaltrials.gov Identifier: NCT00067119 PMID:18477783

Axitinib with or without dose titration for first-line metastatic renal-cell carcinoma: a randomised double-blind phase 2 trial.

PubMed

Rini, Brian I; Melichar, Bohuslav; Ueda, Takeshi; Grünwald, Viktor; Fishman, Mayer N; Arranz, José A; Bair, Angel H; Pithavala, Yazdi K; Andrews, Glen I; Pavlov, Dmitri; Kim, Sinil; Jonasch, Eric

2013-11-01

Population pharmacokinetic data suggest axitinib plasma exposure correlates with efficacy in metastatic renal-cell carcinoma. Axitinib dose titration might optimise exposure and improve outcomes. We prospectively assessed the efficacy and safety of axitinib dose titration in previously untreated patients with metastatic renal-cell carcinoma. In this randomised, double-blind, multicentre, phase 2 study, patients were enrolled from 49 hospitals and outpatient clinics in the Czech Republic, Germany, Japan, Russia, Spain, and USA. Patients with treatment-naive metastatic renal-cell carcinoma received axitinib 5 mg twice daily during a 4 week lead-in period. Those patients with blood pressure 150/90 mm Hg or lower, no grade 3 or 4 treatment-related toxic effects, no dose reductions, and no more than two antihypertensive drugs for 2 consecutive weeks were stratified by Eastern Cooperative Oncology Group performance status (0 vs 1), and then randomly assigned (1:1) to either masked titration with axitinib to total twice daily doses of 7 mg, and then 10 mg, if tolerated, or placebo titration. Patients who did not meet these criteria continued without titration. The primary objective was comparison of the proportion of patients achieving an objective response between randomised groups. Safety analyses were based on all patients who received at least one dose of axitinib. Between Sept 2, 2009, and Feb 28, 2011, we enrolled 213 patients, of whom 112 were randomly assigned to either the axitinib titration group (56 patients) or the placebo titration group (56 patients). 91 were not eligible for titration, and ten withdrew during the lead-in period. 30 patients (54%, 95% CI 40-67) in the axitinib titration group had an objective response, as did 19 patients (34%, 22-48]) in the placebo titration group (one-sided p=0·019). 54 (59%, 95% CI 49-70) of non-randomised patients achieved an objective response. Common grade 3 or worse, all-causality adverse events in treated patients were hypertension (ten [18%] of 56 in the axitinib titration group vs five [9%] of 56 in the placebo titration group vs 45 [49%] of 91 in the non-randomised group), diarrhoea (seven [13%] vs two [4%] vs eight [9%]), and decreased weight (four [7%] vs three [5%] vs six [7%]). One or more all-causality serious adverse events were reported in 15 (27%) patients in the axitinib titration group, 13 (23%) patients in the placebo titration group, and 35 (38%) non-randomised patients. The most common serious adverse events in all 213 patients were disease progression and dehydration (eight each [4%]), and diarrhoea, vomiting, pneumonia, and decreased appetite (four each [2%]). The greater proportion of patients in the axitinib titration group achieving an objective response supports the concept of individual axitinib dose titration in selected patients with metastatic renal-cell carcinoma. Axitinib shows clinical activity with a manageable safety profile in treatment-naive patients with this disease. Copyright © 2013 Elsevier Ltd. All rights reserved.

Effect of quantity and route of administration of manganese monoxide on feed intake and serum manganese in ruminants

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

Black, J.R.; Ammerman, C.B.; Henry, P.R.

1985-02-01

The experiment investigated effects of high quantities of manganese and route of administration (diet versus capsule-dosed) on feed intake and blood characteristics in sheep. Twenty-four Florida native or Florida native by St. Croix crossbred wethers, 47 kg initially, were assigned randomly to eight treatments including basal diet supplemented with 0, 3000, 6000, or 9000 ppm manganese as a reagent grade manganese monoxide or basal diet plus gelatin capsules containing the equivalent of 0, 3000, 6000, or 9000 ppm manganese based on intake of the previous day. Three sheep per treatment were provided feed and tap water for ad libitum intake.more » Sheep were fed basal diet for 7 days followed by a 21-day experimental period, then placed back on the basal diet for 7 days. Average daily feed intake was reduced by increasing supplemental manganese, regardless of route. Animals dosed by capsule consumed less feed than those administered manganese in the diet. Serum manganese increased as manganese supplementation increased, but route of administration had no effect.« less

Gene therapy with recombinant adeno-associated vectors for neovascular age-related macular degeneration: 1 year follow-up of a phase 1 randomised clinical trial.

PubMed

Rakoczy, Elizabeth P; Lai, Chooi-May; Magno, Aaron L; Wikstrom, Matthew E; French, Martyn A; Pierce, Cora M; Schwartz, Steven D; Blumenkranz, Mark S; Chalberg, Thomas W; Degli-Esposti, Mariapia A; Constable, Ian J

2015-12-12

Neovascular, or wet, age-related macular degeneration causes central vision loss and represents a major health problem in elderly people, and is currently treated with frequent intraocular injections of anti-VEGF protein. Gene therapy might enable long-term anti-VEGF therapy from a single treatment. We tested the safety of rAAV.sFLT-1 in treatment of wet age-related macular degeneration with a single subretinal injection. In this single-centre, phase 1, randomised controlled trial, we enrolled patients with wet age-related macular degeneration at the Lions Eye Institute and the Sir Charles Gairdner Hospital (Nedlands, WA, Australia). Eligible patients had to be aged 65 years or older, have age-related macular degeneration secondary to active subfoveal choroidal neovascularisation, with best corrected visual acuity (BCVA) of 3/60-6/24 and 6/60 or better in the other eye. Patients were randomly assigned (3:1) to receive either 1 × 10(10) vector genomes (vg; low-dose rAAV.sFLT-1 group) or 1 × 10(11) vg (high-dose rAAV.sFLT-1 group), or no gene-therapy treatment (control group). Randomisation was done by sequential group assignment. All patients and investigators were unmasked. Staff doing the assessments were masked to the study group at study visits. All patients received ranibizumab at baseline and week 4, and rescue treatment during follow-up based on prespecified criteria including BCVA measured on the Early Treatment Diabetic Retinopathy Study (EDTRS) scale, optical coherence tomography, and fluorescein angiography. The primary endpoint was ocular and systemic safety. This trial is registered with ClinicalTrials.gov, number NCT01494805. From Dec 16, 2011, to April 5, 2012, we enrolled nine patients of whom eight were randomly assigned to receive either intervention (three patients in the low-dose rAAV.sFLT-1 group and three patients in the high-dose rAAV.sFLT-1 group) or no treatment (two patients in the control group). Subretinal injection of rAAV.sFLT-1 was highly reproducible. No drug-related adverse events were noted; procedure-related adverse events (subconjunctival or subretinal haemorrhage and mild cell debris in the anterior vitreous) were generally mild and self-resolving. There was no evidence of chorioretinal atrophy. Clinical laboratory assessments generally remained unchanged from baseline. Four (67%) of six patients in the treatment group required zero rescue injections, and the other two (33%) required only one rescue injection each. rAAV.sFLT-1 was safe and well tolerated. These results support ocular gene therapy as a potential long-term treatment option for wet age-related macular degeneration. National Health and Medical Research Council of Australia, Richard Pearce Bequest, Lions Save Sight Foundation, Brian King Fellowship, and Avalanche Biotechnologies, Inc. Copyright © 2015 Elsevier Ltd. All rights reserved.

Comparison of Physician-, Biomarker-, and Symptom-Based Strategies for Adjustment of Inhaled Corticosteroid Therapy in Adults With Asthma

PubMed Central

Calhoun, William J.; Ameredes, Bill T.; King, Tonya S.; Icitovic, Nikolina; Bleecker, Eugene R.; Castro, Mario; Cherniack, Reuben M.; Chinchilli, Vernon M.; Craig, Timothy; Denlinger, Loren; DiMango, Emily A.; Engle, Linda L.; Fahy, John V.; Grant, J. Andrew; Israel, Elliot; Jarjour, Nizar; Kazani, Shamsah D.; Kraft, Monica; Kunselman, Susan J.; Lazarus, Stephen C.; Lemanske, Robert F.; Lugogo, Njira; Martin, Richard J.; Meyers, Deborah A.; Moore, Wendy C.; Pascual, Rodolfo; Peters, Stephen P.; Ramsdell, Joe; Sorkness, Christine A.; Sutherland, E. Rand; Szefler, Stanley J.; Wasserman, Stephen I.; Walter, Michael J.; Wechsler, Michael E.; Boushey, Homer A.

2013-01-01

Context No consensus exists for adjusting inhaled corticosteroid therapy in patients with asthma. Approaches include adjustment at outpatient visits guided by physician assessment of asthma control (symptoms, rescue therapy, pulmonary function), based on exhaled nitric oxide, or on a day-to-day basis guided by symptoms. Objective To determine if adjustment of inhaled corticosteroid therapy based on exhaled nitric oxide or day-to-day symptoms is superior to guideline-informed, physician assessment–based adjustment in preventing treatment failure in adults with mild to moderate asthma. Design, Setting, and Participants A randomized, parallel, 3-group, placebo-controlled, multiply-blinded trial of 342 adults with mild to moderate asthma controlled by low-dose inhaled corticosteroid therapy (n=114 assigned to physician assessment–based adjustment [101 completed], n=115 to biomarker-based [exhaled nitric oxide] adjustment [92 completed], and n=113 to symptom-based adjustment [97 completed]), the Best Adjustment Strategy for Asthma in the Long Term (BASALT) trial was conducted by the Asthma Clinical Research Network at 10 academic medical centers in the United States for 9 months between June 2007 and July 2010. Interventions For physician assessment–based adjustment and biomarker-based (exhaled nitric oxide) adjustment, the dose of inhaled corticosteroids was adjusted every 6 weeks; for symptom-based adjustment, inhaled corticosteroids were taken with each albuterol rescue use. Main Outcome Measure The primary outcome was time to treatment failure. Results There were no significant differences in time to treatment failure. The 9-month Kaplan-Meier failure rates were 22% (97.5% CI, 14%-33%; 24 events) for physician assessment–based adjustment, 20% (97.5% CI, 13%-30%; 21 events) for biomarker-based adjustment, and 15% (97.5% CI, 9%-25%; 16 events) for symptom-based adjustment. The hazard ratio for physician assessment–based adjustment vs biomarker-based adjustment was 1.2 (97.5% CI, 0.6-2.3). The hazard ratio for physician assessment–based adjustment vs symptom-based adjustment was 1.6 (97.5% CI, 0.8-3.3). Conclusion Among adults with mild to moderate persistent asthma controlled with low-dose inhaled corticosteroid therapy, the use of either biomarker-based or symptom-based adjustment of inhaled corticosteroids was not superior to physician assessment–based adjustment of inhaled corticosteroids in time to treatment failure. Trial Registration clinicaltrials.gov Identifier: NCT00495157 PMID:22968888

Stochastic dosimetry model for radon progeny in the rat lung.

PubMed

Winkler-HeiI, R; Hofmann, W; Hussain, M

2014-07-01

The stochastic dosimetry model presented here considers the distinctly asymmetric, stochastic branching pattern reported in morphometric measurements. This monopodial structure suggests that an airway diameter is a more appropriate morphometric parameter to classify bronchial dose distributions for inhaled radon progeny than the commonly assigned airway generation numbers. Bronchial doses were calculated for the typical exposure conditions reported for the Pacific Northwest National Laboratory rat inhalation studies, yielding an average bronchial dose of 7.75 mGy WLM(-1). If plotted as functions of airway generations, the resulting dose distributions are highest in the central bronchial airways, while significantly decreasing towards peripheral generations. However, if plotted as functions of airway diameters, doses are much more uniformly distributed among bronchial airways. The comparison between rat and human lungs indicates that dose conversion coefficients for the rat lung are higher than the corresponding values for the human lung by a factor of 1.34 for the experimental PNNL exposure conditions, and of 1.25 for typical human indoor conditions. © The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Comparisons of node-based and element-based approaches of assigning bone material properties onto subject-specific finite element models.

PubMed

Chen, G; Wu, F Y; Liu, Z C; Yang, K; Cui, F

2015-08-01

Subject-specific finite element (FE) models can be generated from computed tomography (CT) datasets of a bone. A key step is assigning material properties automatically onto finite element models, which remains a great challenge. This paper proposes a node-based assignment approach and also compares it with the element-based approach in the literature. Both approaches were implemented using ABAQUS. The assignment procedure is divided into two steps: generating the data file of the image intensity of a bone in a MATLAB program and reading the data file into ABAQUS via user subroutines. The node-based approach assigns the material properties to each node of the finite element mesh, while the element-based approach assigns the material properties directly to each integration point of an element. Both approaches are independent from the type of elements. A number of FE meshes are tested and both give accurate solutions; comparatively the node-based approach involves less programming effort. The node-based approach is also independent from the type of analyses; it has been tested on the nonlinear analysis of a Sawbone femur. The node-based approach substantially improves the level of automation of the assignment procedure of bone material properties. It is the simplest and most powerful approach that is applicable to many types of analyses and elements. Copyright © 2015 IPEM. Published by Elsevier Ltd. All rights reserved.

SU-F-BRF-14: Increasing the Accuracy of Dose Calculation On Cone-Beam Imaging Using Deformable Image Registration in the Case of Prostate Translation

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

Fillion, O; Gingras, L; Departement de physique, de genie physique et d'optique, Universite Laval, Quebec, Quebec

2014-06-15

Purpose: Artifacts can reduce the quality of dose re-calculations on CBCT scans during a treatment. The aim of this project is to correct the CBCT images in order to allow for more accurate and exact dose calculations in the case of a translation of the tumor in prostate cancer. Methods: Our approach is to develop strategies based on deformable image registration algorithms using the elastix software (Klein et al., 2010) to register the treatment planning CT on a daily CBCT scan taken during treatment. Sets of images are provided by a 3D deformable phantom and comprise two CT and twomore » CBCT scans: one of both with the reference anatomy and the others with known deformations (i.e. translations of the prostate). The reference CT is registered onto the deformed CBCT and the deformed CT serves as the control for dose calculation accuracy. The planned treatment used for the evaluation of dose calculation is a 2-Gy fraction prescribed at the location of the reference prostate and assigned to 7 rectangular fields. Results: For a realistic 0.5-cm translation of the prostate, the relative dose discrepancy between the CBCT and the CT control scan at the prostate's centroid is 8.9 ± 0.8 % while dose discrepancy between the registered CT and the control scan lessens to −2.4 ± 0.8 %. For a 2-cm translation, clinical indices like the V90 and the D100 are more accurate by 0.7 ± 0.3 % and 8.0 ± 0.5 cGy respectively when using registered CT than when using CBCT for dose calculation. Conclusion: The results show that this strategy gives doses in agreement within a few percents with those from calculations on actual CT scans. In the future, various deformations of the phantom anatomy will allow a thorough characterization of the registration strategies needed for more complex anatomies.« less

Adapting Parent-Child Interaction Therapy to Foster Care

ERIC Educational Resources Information Center

Mersky, Joshua P.; Topitzes, James; Grant-Savela, Stacey D.; Brondino, Michael J.; McNeil, Cheryl B.

2016-01-01

Objective: This study presents outcomes from a randomized trial of a novel Parent-Child Interaction Therapy (PCIT) model for foster families. Differential effects of two intervention doses on child externalizing and internalizing symptoms are examined. Method: A sample of 102 foster children was assigned to one of three conditions--brief PCIT,…

Is More Better? Milieu Communication Teaching in Toddlers with Intellectual Disabilities

ERIC Educational Resources Information Center

Fey, Marc E.; Yoder, Paul J.; Warren, Steven F.; Bredin-Oja, Shelley L.

2013-01-01

Purpose: The authors sought to determine whether a program of 5 weekly doses of milieu communication teaching (MCT) would yield improvements in children's communication and word use compared with a once-weekly delivery of the same treatment. Method: Sixty-four children with intellectual and communication delay were randomly assigned to receive…

CHRONIC DOSE RESPONSE STUDY OF LEAD TOXICITY IN RATS: ASSIGNMENT OF A LOWEST OBSERVED EFFECT LEVEL IN A DRINKING WATER STUDY. (R827161)

EPA Science Inventory

The perspectives, information and conclusions conveyed in research project abstracts, progress reports, final reports, journal abstracts and journal publications convey the viewpoints of the principal investigator and may not represent the views and policies of ORD and EPA. Concl...

Comparison of propofol with pentobarbital/midazolam/fentanyl sedation for magnetic resonance imaging of the brain in children.

PubMed

Pershad, Jay; Wan, Jim; Anghelescu, Doralina L

2007-09-01

Propofol and pentobarbital, alone or combined with other agents, are frequently used to induce deep sedation in children for MRI. However, we are unaware of a previous comparison of these 2 agents as part of a randomized, controlled trial. We compared the recovery time of children after deep sedation with single-agent propofol with a pentobarbital-based regimen for MRI and considered additional variables of safety and efficacy. This prospective, randomized trial at a tertiary children's hospital enrolled 60 patients 1 to 17 years old who required intravenous sedation for elective cranial MRI. Patients were assigned randomly to receive a loading dose of propofol followed by continuous intravenous infusion of propofol or to receive sequential doses of midazolam, pentobarbital, and fentanyl until a modified Ramsay score of >4 was attained. A nurse who was blind to group assignment assessed discharge readiness (Aldrete score > 8) and administered a follow-up questionnaire. We compared recovery time, time to induction of sedation, total sedation time, quality of imaging, number of repeat-image sequences, adverse events, caregiver satisfaction, and time to return to presedation functional status. The groups were similar in age, gender, race, American Society of Anesthesiology physical status class, and frequency of cognitive impairment. No sedation failure or significant adverse events were observed. Propofol offered significantly shorter sedation induction time, recovery time, total sedation time, and time to return to baseline functional status. Caregiver satisfaction scores were also significantly higher in the patients in the propofol group. Propofol permits faster onset and recovery than, and comparable efficacy to, a pentobarbital/midazolam/fentanyl regimen for sedation of children for MRI.

Superior long-term outcome with idarubicin compared with high-dose daunorubicin in patients with acute myeloid leukemia age 50 years and older.

PubMed

Gardin, Claude; Chevret, Sylvie; Pautas, Cécile; Turlure, Pascal; Raffoux, Emmanuel; Thomas, Xavier; Quesnel, Bruno; de Revel, Thierry; de Botton, Stéphane; Gachard, Nathalie; Renneville, Aline; Boissel, Nicolas; Preudhomme, Claude; Terré, Christine; Fenaux, Pierre; Bordessoule, Dominique; Celli-Lebras, Karine; Castaigne, Sylvie; Dombret, Hervé

2013-01-20

Although standard chemotherapy remains associated with a poor outcome in older patients with acute myeloid leukemia (AML), it is unclear which patients can survive long enough to be considered as cured. This study aimed to identify factors influencing the long-term outcome in these patients. The study included 727 older patients with AML (median age, 67 years) treated in two idarubicin (IDA) versus daunorubicin (DNR) Acute Leukemia French Association trials. Prognostic analysis was based on standard univariate and multivariate models and also included a cure fraction model to focus on long-term outcome. Age, WBC count, secondary AML, Eastern Cooperative Oncology Group (ECOG) performance status (PS), and adverse-risk and favorable-risk AML subsets (European LeukemiaNet classification) all influenced complete remission (CR) rate and overall survival (OS). IDA random assignment was associated with higher CR rate, but not with longer OS (P = .13). The overall cure rate was 13.3%. Older age and ECOG-PS more than 1 negatively influenced cure rate, which was higher in patients with favorable-risk AML (39.1% v 8.0% in adverse-risk AML; P < .001) and those treated with IDA (16.6% v 9.8% with DNR; P = .018). The long-term impact of IDA was still observed in patients younger than age 65 years, although all of the younger patients in the DNR control arm received high DNR doses (cure rate, 27.4% for IDA v 15.9% for DNR; P = .049). In multivariate analysis, IDA random assignment remained associated with a higher cure rate (P = .04), together with younger age and favorable-risk AML, despite not influencing OS (P = .11). In older patients with AML, younger age, favorable-risk AML, and IDA treatment predict a better long-term outcome.

Dabigatran versus warfarin in patients with mechanical heart valves.

PubMed

Eikelboom, John W; Connolly, Stuart J; Brueckmann, Martina; Granger, Christopher B; Kappetein, Arie P; Mack, Michael J; Blatchford, Jon; Devenny, Kevin; Friedman, Jeffrey; Guiver, Kelly; Harper, Ruth; Khder, Yasser; Lobmeyer, Maximilian T; Maas, Hugo; Voigt, Jens-Uwe; Simoons, Maarten L; Van de Werf, Frans

2013-09-26

Dabigatran is an oral direct thrombin inhibitor that has been shown to be an effective alternative to warfarin in patients with atrial fibrillation. We evaluated the use of dabigatran in patients with mechanical heart valves. In this phase 2 dose-validation study, we studied two populations of patients: those who had undergone aortic- or mitral-valve replacement within the past 7 days and those who had undergone such replacement at least 3 months earlier. Patients were randomly assigned in a 2:1 ratio to receive either dabigatran or warfarin. The selection of the initial dabigatran dose (150, 220, or 300 mg twice daily) was based on kidney function. Doses were adjusted to obtain a trough plasma level of at least 50 ng per milliliter. The warfarin dose was adjusted to obtain an international normalized ratio of 2 to 3 or 2.5 to 3.5 on the basis of thromboembolic risk. The primary end point was the trough plasma level of dabigatran. The trial was terminated prematurely after the enrollment of 252 patients because of an excess of thromboembolic and bleeding events among patients in the dabigatran group. In the as-treated analysis, dose adjustment or discontinuation of dabigatran was required in 52 of 162 patients (32%). Ischemic or unspecified stroke occurred in 9 patients (5%) in the dabigatran group and in no patients in the warfarin group; major bleeding occurred in 7 patients (4%) and 2 patients (2%), respectively. All patients with major bleeding had pericardial bleeding. The use of dabigatran in patients with mechanical heart valves was associated with increased rates of thromboembolic and bleeding complications, as compared with warfarin, thus showing no benefit and an excess risk. (Funded by Boehringer Ingelheim; ClinicalTrials.gov numbers, NCT01452347 and NCT01505881.).

Pharmacodynamic effects of a new fixed-dose clopidogrel-aspirin combination compared with separate administration of clopidogrel and aspirin in patients treated with coronary stents: The ACCEL-COMBO trial.

PubMed

Koh, Jin-Sin; Park, Yongwhi; Tantry, Udaya S; Ahn, Jong-Hwa; Kang, Min Gyu; Kim, Kyehwan; Jang, Jeong Yoon; Park, Hyun Woong; Park, Jeong Rang; Hwang, Seok-Jae; Kwak, Choong Hwan; Hwang, Jin-Yong; Gurbel, Paul A; Jeong, Young-Hoon

2017-03-01

Dual antiplatelet therapy (DAPT) with clopidogrel and aspirin is a widely prescribed regimen to prevent ischemic events in patients undergoing percutaneous coronary intervention (PCI). A fixed-dose combination (FDC) capsule (HCP0911) has been developed to provide dosing convenience and improve adherence. We compared the antiplatelet effects of single daily dose HCP0911 with separate treatment with daily 75 mg clopidogrel plus 100 mg aspirin. This was a randomized, open-label, two-period, crossover, non-inferiority study conducted in stented patients who had been treated for at least 6 months with clopidogrel and aspirin. Thirty patients were randomly assigned to receive either daily 75 mg clopidogrel plus 100 mg aspirin treatment or HCP0911 for 2 weeks and then were crossed over to the other treatment for 2 weeks. Pharmacodynamic effects were measured with VerifyNow, light transmittance aggregometry (LTA), and thromboelastography (TEG ® ). The primary endpoint was P2Y12 Reaction Units (PRU) measured by VerifyNow. PRUs during treatment with HCP0911 were not inferior to those during separate treatment (202 ± 52 vs. 207 ± 60 PRU; mean difference, -5 PRU; 90% confidence interval of difference, -23 to 13 PRU; P for non-inferiority = 0.015 for predetermined limit). "BASE" and Aspirin Reaction Units by VerifyNow did not differ between the two treatments. During each treatment, there were no differences in maximal and final platelet aggregations by LTA (all P values ≥0.822) and TEG ® measurements. In conclusion, in stented patients, the antiplatelet effect of a fixed-dose clopidogrel-aspirin combination, HCP0911, was not inferior to separate administration of clopidogrel and aspirin.

Frequency, predictors, and economic impact of upward dose adjustment of infliximab in managed care patients with rheumatoid arthritis.

PubMed

Ollendorf, Daniel A; Massarotti, Elena; Birbara, Charles; Burgess, Somali Misra

2005-06-01

To examine dosing patterns and costs among rheumatoid arthritis (RA) patients newly treated with infliximab in a large national health care claims database. Using data from a proprietary database of pharmacy and medical claims for 75 U.S. health plans, RA patients newly treated with infliximab between June 2000 and June 2002 were selected and assigned an .index date. based on the first infusion. A pretreatment period of 6 months was created; patients were also followed for a minimum of 6 months after the initial infusion. Follow-up was allowed to vary beyond this minimum 6 months in order to preserve all available patient data. A maintenance number of infliximab vials was determined as of the second infusion; patients with 1 subsequent increase in vials used or 2 intervals between infusions of <49 days were considered to have had an upward dose adjustment. Differences (i.e., between those with upward dose adjustment and those with no upward dose) in patient characteristics were examined using descriptive statistics. In addition, time to upward dose adjustment and factors influencing its likelihood were analyzed using Kaplan-Meier and Cox proportional hazards techniques. Finally, differences in RA-related and unrelated costs (medication, outpatient, inpatient, and total, expressed in 2003 dollars) were examined using Wilcoxon rank-sum tests and were also stratified by a number of patient characteristics found to differ between the 2 groups. A total of 1,236 patients met all study entry criteria and were included in these analyses. One or more upward dose adjustments were experienced by 61.7% (N=762) of patients during an average of 15 months of follow-up (median =13 months, range=6 to 31 months). The majority (63.3%) of upward dose adjustments were due to increases in the number of billed vials. Median time to upward dose adjustment was 254 days and declined steadily based on year of initiation (from 330 days in 2000 to 224 days in 2002). Factors significantly influencing upward dose adjustment included pretreatment use of leflunomide, comorbid Crohn.s disease, and pretreatment liver function testing. During followup, patients in the upward dose adjustment group used a mean (SD) of 30.28 (20.90) vials of infliximab, compared with 15.90 (14.28) among those not adjusting dose (P<0.001). Annualized (i.e., standardized to a 365-day rate) RA-related costs were higher by more than 50% among patients with upward dose adjustment (SD $22,283 [$20,517] versus $14,425 [$10,828] for those without upward dose adjustment; P<0.001); differences were driven almost entirely by the costs of infliximab itself ($16,336 [$9,490] versus $9,573 [$6,790], P<0.001). In a cohort of managed care members with RA, upward dose adjustment with infliximab was frequent and appeared to occur earlier in the drug therapy in 2002 compared with 2000. Upward dose adjustment was associated with significant increases in drug treatment costs; therefore, payers and providers should consider the impact of current dosing trends when monitoring the use of biologics for autoimmune diseases.

Effectiveness of Aquaflor (50% florfenicol) administered in feed to control mortality associated with Streptococcus iniae in tilapia at a commercial tilapia production facility

USGS Publications Warehouse

Gaikowski, Mark P.; Schleis, Susan M.; Leis, Eric; Lasee, Becky A.; Endris, Richard G.

2014-01-01

The efficacy of Aquaflor (florfenicol; FFC) to control mortality caused by Streptococcus iniae in tilapia was evaluated under field conditions. The trial was initiated following presumptive diagnosis of S. iniae infection in a mixed group of fingerling (mean, 4.5 g) Nile Tilapia Oreochromis niloticus and a hybrid of Nile Tilapia×Blue Tilapia O. aureus. Diagnoses included mortality in source tank; examination of clinical signs and presence or absence of gram-positive cocci in brain, and collection of samples for microbiological review and disease confirmation of 60 moribund fish. Following presumptive diagnosis, tilapia (83/tank) were randomly transferred to each of 20 test tanks receiving the same water as the source tank (test tank water was not reused). Tilapia were offered either nonmedicated control feed or FFC-medicated feed (FFC at 15 mg/kg body weight/d; 10 tanks per regimen) for 10 consecutive days followed by a 14-d observation period during which only the nonmedicated control feed was offered. Streptococcus iniae was presumptively identified during pretreatment necropsy and confirmed by polymerase chain reaction assay; S. iniae was confirmed in samples taken during the dosing period but was not detected during the postdosing period. The FFC disk diffusion zone of inhibition ranged from 29 to 32 mm, while the minimum inhibitory concentration of FFC ranged from 2 to 4 μg/mL for the S. iniae isolates collected. Survival of tilapia assigned to the FFC-dose group was significantly greater at 14 d posttreatment than that of the nonmedicated controls. The odds of tilapia assigned to the FFC-dose group surviving to the end of the postdosing period were 1.34 times the odds of survival of tilapia assigned to the nonmedicated control group. There were no clinically apparent adverse effects associated with the administration of FFC-medicated feed in this study.

Personalised chemotherapy based on tumour marker decline in poor prognosis germ-cell tumours (GETUG 13): a phase 3, multicentre, randomised trial.

PubMed

Fizazi, Karim; Pagliaro, Lance; Laplanche, Agnes; Fléchon, Aude; Mardiak, Josef; Geoffrois, Lionnel; Kerbrat, Pierre; Chevreau, Christine; Delva, Remy; Rolland, Frederic; Theodore, Christine; Roubaud, Guilhem; Gravis, Gwenaëlle; Eymard, Jean-Christophe; Malhaire, Jean-Pierre; Linassier, Claude; Habibian, Muriel; Martin, Anne-Laure; Journeau, Florence; Reckova, Maria; Logothetis, Christopher; Culine, Stephane

2014-12-01

Poor prognosis germ-cell tumours are only cured in about half of patients. We aimed to assess whether treatment intensification based on an early tumour marker decline will improve progression-free survival for patients with germ-cell tumours. In this phase 3, multicentre, randomised trial, patients were enrolled from France (20 centres), USA (one centre), and Slovakia (one centre). Patients were eligible if they were older than 16 years, had evidence of testicular, retroperitoneal, or mediastinal non-seminomatous germ cell tumours based on histological findings or clinical evidence and highly elevated serum human chorionic gonadotropin or alfa-fetoprotein concentrations that matched International Germ Cell Cancer Consensus Group poor prognosis criteria. After one cycle of BEP (intravenous cisplatin [20 mg/m(2) per day for 5 days], etoposide [100 mg/m(2) per day for 5 days], and intramuscular or intravenous bleomycin [30 mg per day on days 1, 8, and 15]), patients' human chorionic gonadotropin and alfa-fetoprotein concentrations were measured at day 18-21. Patients with a favourable decline in human chorionic gonadotropin and alfa-fetoprotein continued BEP (Fav-BEP group) for 3 additonal cycles, whereas patients with an unfavourable decline were randomly assigned (1:1) to receive either BEP (Unfav-BEP group) or a dose-dense regimen (Unfav-dose-dense group), consisting of intravenous paclitaxel (175 mg/m(2) over 3 h on day 1) before BEP plus intravenous oxaliplatin (130 mg/m(2) over 3 h on day 10; two cycles), followed by intravenous cisplatin (100 mg/m(2) over 2 h on day 1), intravenous ifosfamide (2 g/m(2) over 3 h on days 10, 12, and 14), plus mesna (500 mg/m(2) at 0, 3, 7 and 11 h), and bleomycin (25 units per day, by continuous infusion for 5 days on days 10-14; two cycles), with granulocyte-colony stimulating factor (lenograstim) support. Centrally blocked computer-generated randomisation stratified by centre was used. The primary endpoint was progression-free survival and the efficacy analysis was done in the intention-to-treat population. The planned trial accrual was completed in May, 2012, and follow-up is ongoing. This study is registered with ClinicalTrials.gov, number NCT00104676. Between Nov 28, 2003, and May 16, 2012, 263 patients were enrolled and 254 were available for tumour marker assessment. Of these 51 (20%) had a favourable marker assessment, and 203 (80%) had an unfavourable tumour marker decline; 105 were randomly assigned to the Unfav-dose-dense group and 98 to the Unfav-BEP group. 3-year progression-free survival was 59% (95% CI 49-68) in the Unfav-dose-dense group versus 48% (38-59) in the Unfav-BEP group (HR 0·66, 95% CI 0·44-1·00, p=0·05). 3-year progression-free survival was 70% (95% CI 57-81) in the Fav-BEP group (HR 0·66, 95% CI 0·49-0·88, p=0·01 for progression-free survival compared with the Unfav-BEP group). More grade 3-4 neurotoxic events (seven [7%] vs one [1%]) and haematotoxic events occurred in the Unfav-dose-dense group compared with in the Unfav-BEP group; there was no difference in grade 1-2 febrile neutropenia (18 [17%] vs 18 [18%]) or toxic deaths (one [1%] in both groups). Salvage high-dose chemotherapy plus a stem-cell transplant was required in six (6%) patients in the Unfav-dose-dense group and 16 (16%) in the Unfav-BEP group. Personalised treatment with chemotherapy intensification reduces the risk of progression or death in patients with poor prognosis germ-cell tumours and an unfavourable tumour marker decline. Institut National du Cancer (Programme Hospitalier de Recherche Clinique). Copyright © 2014 Elsevier Ltd. All rights reserved.

Monovalent type-1 oral poliovirus vaccine given at short intervals in Pakistan: a randomised controlled, four-arm, open-label, non-inferiority trial.

PubMed

Mir, Fatima; Quadri, Farheen; Mach, Ondrej; Ahmed, Imran; Bhatti, Zaid; Khan, Asia; Rehman, Najeeb Ur; Durry, Elias; Salama, Maha; Oberste, Steven M; Weldon, William C; Sutter, Roland W; Zaidi, Anita K M

2015-08-01

Supplementary immunisation activities with oral poliovirus vaccines (OPVs) are usually separated by 4 week intervals; however, shorter intervals have been used in security-compromised areas and for rapid outbreak responses. We assessed the immunogenicity of monovalent type-1 oral poliovirus vaccine (mOPV1) given at shorter than usual intervals in Karachi, Pakistan. This was a multicentre, randomised, controlled, four-arm, open-label, non-inferiority trial done at five primary health-care centres in low-income communities in and around Karachi, Pakistan. Eligible participants were healthy newborn babies with a birthweight of at least 2·5 kg, for whom informed consent was provided by their parent or guardian, and lived less than 30 km from the study clinic. After receiving a birth dose of trivalent OPV, we enrolled and randomly assigned newborn babies (1:1:1:1) to receive two doses of mOPV1 with an interval of 1 week (mOPV1-1 week), 2 weeks (mOPV1-2 weeks), or 4 weeks (mOPV1-4 weeks) between doses, or two doses of bivalent OPV (bOPV) with an interval of 4 weeks between doses (bOPV-4 weeks). We gave the first study dose of OPV at age 6 weeks. We did the randomisation with a centrally generated, computerised allocation sequence with blocks of 16; participants' families and study physicians could not feasibly be masked to the allocations. Trial participants were excluded from local supplementary immunisation activities during the study period. The primary outcome was non-inferiority (within a 20% margin) between groups in seroconversion to type-1 poliovirus. The primary and safety analyses were done in the per-protocol population of infants who received all three doses of vaccine. This trial is registered with ClinicalTrials.gov, number NCT01586572, and is closed to new participants. Between March 1, 2012, and May 31, 2013, we enrolled 1009 newborn babies, and randomly assigned 829 (82%) to treatment. 554 (67%) of the 829 babies were included in the per-protocol analysis. Proportions of seroconversion to type-1 poliovirus were 107/135 (79%, 95% CI 72·4-86·1) with mOPV1-1 week, 108/135 (80%, 73·2-86·8) with mOPV1-2 weeks, 129/148 (87%, 80·9-92·0) with mOPV1-4 weeks, and 107/136 (79%, 71·8-85·6) with bOPV-4 weeks. Non-inferiority was shown between groups and no significant differences were noted. Ten participants died during the trial. Seven of these deaths occurred during the lead-in period before randomisation (two from diarrhoea, five from unknown causes). Three infants died from sepsis after random assignment. No deaths were attributed to the procedures or vaccines. Additionally, we noted no events of vaccine-associated paralysis. We identified no significant differences in responses to mOPV1 given with shorter intervals between doses than with the standard 4 week intervals. The short-interval strategy could be particularly beneficial when temporary windows of opportunity for safe access can be granted in areas of conflict--eg, during cease-fire periods. In such situations, we recommend shortening the interval between OPV doses to 7 days. World Health Organization. Copyright © 2015 World Health Organization. Published by Elsevier Ltd/Inc/BV. All rights reserved. Published by Elsevier Ltd.. All rights reserved.

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

PubMed

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

2014-05-31

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

41 CFR 102-79.20 - What standard must Executive agencies promote when assigning space?

Code of Federal Regulations, 2013 CFR

2013-07-01

... quality workspace that is delivered and occupied in a timely manner, and assign space based on mission... Executive agencies promote when assigning space? 102-79.20 Section 102-79.20 Public Contracts and Property... PROPERTY 79-ASSIGNMENT AND UTILIZATION OF SPACE Assignment and Utilization of Space Assignment of Space...

41 CFR 102-79.20 - What standard must Executive agencies promote when assigning space?

Code of Federal Regulations, 2012 CFR

2012-01-01

... quality workspace that is delivered and occupied in a timely manner, and assign space based on mission... Executive agencies promote when assigning space? 102-79.20 Section 102-79.20 Public Contracts and Property... PROPERTY 79-ASSIGNMENT AND UTILIZATION OF SPACE Assignment and Utilization of Space Assignment of Space...

41 CFR 102-79.20 - What standard must Executive agencies promote when assigning space?

Code of Federal Regulations, 2010 CFR

2010-07-01

... quality workspace that is delivered and occupied in a timely manner, and assign space based on mission... Executive agencies promote when assigning space? 102-79.20 Section 102-79.20 Public Contracts and Property... PROPERTY 79-ASSIGNMENT AND UTILIZATION OF SPACE Assignment and Utilization of Space Assignment of Space...

41 CFR 102-79.20 - What standard must Executive agencies promote when assigning space?

Code of Federal Regulations, 2011 CFR

2011-01-01

... quality workspace that is delivered and occupied in a timely manner, and assign space based on mission... Executive agencies promote when assigning space? 102-79.20 Section 102-79.20 Public Contracts and Property... PROPERTY 79-ASSIGNMENT AND UTILIZATION OF SPACE Assignment and Utilization of Space Assignment of Space...

41 CFR 102-79.20 - What standard must Executive agencies promote when assigning space?

Code of Federal Regulations, 2014 CFR

2014-01-01

... quality workspace that is delivered and occupied in a timely manner, and assign space based on mission... Executive agencies promote when assigning space? 102-79.20 Section 102-79.20 Public Contracts and Property... PROPERTY 79-ASSIGNMENT AND UTILIZATION OF SPACE Assignment and Utilization of Space Assignment of Space...

A Multicenter, Randomized, Open-Label, Pharmacokinetics and Safety Study of Pantoprazole Tablets in Children and Adolescents Aged 6 Through 16 Years With GERD

PubMed Central

Ward, Robert M.; Kearns, Gregory L.; Tammara, Brinda; Bishop, Phyllis; O’Gorman, Molly A.; James, Laura P.; Katz, Mitchell H.; Maguire, Mary K.; Rath, Natalie; Meng, Xu; Comer, Gail M.

2011-01-01

SUMMARY Children with GERD may benefit from gastric acid suppression with proton pump inhibitors such as pantoprazole. Effective treatment with pantoprazole requires correct dosing and understanding of the drug’s kinetic profile in children. The aim of these studies was to characterize the pharmacokinetic (PK) profile of single and multiple doses of pantoprazole delayed-release tablets in pediatric patients with GERD aged ≥6 through 11 years (study 1) and 12 through 16 years (study 2). Patients were randomly assigned to receive pantoprazole 20 or 40 mg once daily. Plasma pantoprazole concentrations were obtained at intervals through 12 hours after the single dose, and at 2 and 4 hours after multiple doses for PK evaluation. PK parameters were derived by standard noncompartmental methods and examined as a function of both drug dose and patient age. Safety was also monitored. Pantoprazole PK was dose independent (when dose normalized) and similar toPK reported from adult studies. There was no evidence of accumulation with multiple dosing or reports of serious drug-associated adverse events. In children aged 6 to 16 years with GERD, currently available pantoprazole delayed-release tablets can be used to provide systemic exposure similar to that in adults. PMID:20852004

Measles virus antibody responses in children randomly assigned to receive standard-titer edmonston-zagreb measles vaccine at 4.5 and 9 months of age, 9 months of age, or 9 and 18 months of age.

PubMed

Martins, Cesario; Garly, May-Lill; Bale, Carlitos; Rodrigues, Amabelia; Njie-Jobe, Jainaba; Benn, Christine S; Whittle, Hilton; Aaby, Peter

2014-09-01

The World Health Organization recommends administration of measles vaccine (MV) at age 9 months in low-income countries. We tested the measles virus antibody response at 4.5, 9, 18, and 24 months of age for children randomly assigned to receive standard-titer Edmonston-Zagreb MV at 4.5 and 9 months, at 9 months, or at 9 and 18 months of age. At 4.5 months of age, 75% had nonprotective measles virus antibody levels. Following receipt of MV at 4.5 months of age, 77% (316/408) had protective antibody levels at 9 months of age; after a second dose at 9 months of age, 97% (326/337) had protective levels at 24 months of age. In addition, the response at both 9 and 24 months of age was inversely correlated with the antibody level at receipt of the first dose of MV, and the second dose of MV, received at 9 months of age, provided a significant boost in antibody level to children who had low antibody levels. In the group of 318 children who received MV at 9 months of age, with or without a second dose at 18 months of age, 99% (314) had protective levels at 24 months of age. The geometric mean titer at 24 months of age was significantly lower in the group that received MV at 4.5 and 9 months of age than in the group that received MV at 9 months of age (P = .0001). In conclusion, an early 2-dose MV schedule was associated with protective measles virus antibody levels at 24 months of age in nearly all children. Clinical Trials Registration. NCT00168558. © The Author 2014. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

Efficacy and safety of Gantong Granules in the treatment of common cold with wind-heat syndrome: study protocol for a randomized controlled trial.

PubMed

Min, Jie; Li, Xiao-qiang; She, Bin; Chen, Yan; Mao, Bing

2015-05-19

Although the common cold is generally mild and self-limiting, it is a leading cause of consultations with doctors and missed days from school and work. In light of its favorable effects of relieving symptoms and minimal side-effects, Traditional Chinese Medicine (TCM) has been widely used to treat the common cold. However, there is a lack of robust evidence to support the clinical utility of such a treatment. This study is designed to evaluate the efficacy and safety of Gantong Granules compared with placebo in patients with the common cold with wind-heat syndrome (CCWHS). This is a multicenter, phase IIb, double-blind, placebo-controlled and randomized clinical trial. A total of 240 patients will be recruited, from 5 centers across China and randomly assigned to the high-dose group, medium-dose group, low-dose group or placebo control group in a 1:1:1:1 ratio. All subjects will receive the treatment for 3 to 5 days, followed by a 7-day follow-up period. The primary outcome is the duration of all symptoms. Secondary outcomes include the duration of primary symptoms and each symptom, time to fever relief and time to fever clearance, change in TCM symptom score, and change in Symptom and Sign Score. This trial will provide high-quality evidence on the efficacy and safety of Gantong Granules in treating CCWHS, and help to optimize the dose selection for a phase III clinical trial. The registration number is ChiCTR-TRC-14004255 , which was assigned by the Chinese Clinical Trial Registry on 12 February 2014.

Efficacy of osmotic-release oral system (OROS) methylphenidate for mothers with attention-deficit/hyperactivity disorder (ADHD): preliminary report of effects on ADHD symptoms and parenting.

PubMed

Chronis-Tuscano, Andrea; Seymour, Karen E; Stein, Mark A; Jones, Heather A; Jiles, Cynthia D; Rooney, Mary E; Conlon, Charles J; Efron, Lisa A; Wagner, Stephanie A; Pian, Jessica; Robb, Adelaide S

2008-12-01

A preliminary study to examine the efficacy of osmotic-release oral system (OROS) methylphenidate for attention-deficit/hyperactivity disorder (ADHD) symptoms and parenting behaviors in mothers with ADHD who had children with ADHD. Participants included 23 mother-child dyads in which both were diagnosed with DSM-IV ADHD. Mothers underwent a 5-week, double-blind titration (placebo, 36 mg/day, 54 mg/day, 72 mg/day, 90 mg/day) to an optimal dose of OROS methylphenidate, followed by random assignment to 2 weeks of placebo or their maximally effective dose. Primary outcome measures included maternal ADHD symptoms (Conners' Adult ADHD Rating Scale) and parenting (Alabama Parenting Questionnaire). Secondary outcomes included side effects ratings. Data were collected from December 2004 until August 2006. During Phase 1, mothers reported significant decreases in inattention (p < .001) and hyperactivity/impulsivity (p < .01) with increases in OROS methylphenidate dose. As dose increased, significant reductions in inconsistent discipline (p < .01) and corporal punishment use (p < .005) were also demonstrated. During Phase 2, small effects on inattention (d = 0.46) and hyperactivity/impulsivity (d = 0.38) were found for those randomly assigned to medication versus placebo. In addition, medium to large medication effects were found on maternal involvement (d = 0.52), poor monitoring/supervision (d = 0.70), and inconsistent discipline (d = 0.71), with small effects on corporal punishment (d = 0.42). During both phases, few adverse effects were noted. OROS methylphenidate was well tolerated and was associated with significant improvement in maternal ADHD symptoms and parenting. Variable effects on parenting suggest that behavioral interventions may be necessary to address impairments in parenting among adults with ADHD. clinicaltrials.gov Identifier: NCT00318981. Copyright 2008 Physicians Postgraduate Press, Inc.

Long-Acting Injectable Naltrexone Induction: A Randomized Trial of Outpatient Opioid Detoxification With Naltrexone Versus Buprenorphine.

PubMed

Sullivan, Maria; Bisaga, Adam; Pavlicova, Martina; Choi, C Jean; Mishlen, Kaitlyn; Carpenter, Kenneth M; Levin, Frances R; Dakwar, Elias; Mariani, John J; Nunes, Edward V

2017-05-01

At present there is no established optimal approach for transitioning opioid-dependent adults to extended-release injection naltrexone (XR-naltrexone) while preventing relapse. The authors conducted a trial examining the efficacy of two methods of outpatient opioid detoxification for induction to XR-naltrexone. Participants were 150 opioid-dependent adults randomly assigned 2:1 to one of two outpatient detoxification regimens, naltrexone-assisted detoxification or buprenorphine-assisted detoxification, followed by an injection of XR-naltrexone. Naltrexone-assisted detoxification lasted 7 days and included a single day of buprenorphine followed by ascending doses of oral naltrexone along with clonidine and other adjunctive medications. Buprenorphine-assisted detoxification included a 7-day buprenorphine taper followed by a week-long delay before administration of XR-naltrexone, consistent with official prescribing information for XR-naltrexone. Participants from both groups received behavioral therapy focused on medication adherence and a second dose of XR-naltrexone. Compared with participants in the buprenorphine-assisted detoxification condition, participants assigned to naltrexone-assisted detoxification were significantly more likely to be successfully inducted to XR-naltrexone (56.1% compared with 32.7%) and to receive the second injection at week 5 (50.0% compared with 26.9%). Both models adjusted for primary type of opioid use, route of opioid administration, and morphine equivalents at baseline. These results demonstrate the safety, efficacy, and tolerability of low-dose naltrexone, in conjunction with single-day buprenorphine dosing and adjunctive nonopioid medications, for initiating adults with opioid dependence to XR-naltrexone. This strategy offers a promising alternative to the high rates of attrition and relapse currently observed with agonist tapers in both inpatient and outpatient settings.

Safety of tenofovir gel, a vaginal microbicide, in South African women: results of the CAPRISA 004 Trial.

PubMed

Sokal, David C; Karim, Quarraisha Abdool; Sibeko, Sengeziwe; Yende-Zuma, Nonhlanhla; Mansoor, Leila E; Baxter, Cheryl; Grobler, Anneke; Frolich, Janet; Kharsany, Ayesha Bm; Miya, Nomsa; Mlisana, Koleka; Maarshalk, Silvia; Karim, Salim S Abdool

2013-01-01

Tenofovir gel, used vaginally before and after coitus, reduced women's acquisition of HIV by 39%. This is a safety assessment of tenofovir gel, including renal, bone, gastrointestinal, genital and haematological parameters. In the Centre for the AIDS Programme of Research in South Africa (CAPRISA) 004, a double-blind, randomized placebo-controlled trial, 445 of the 889 eligibly enrolled women were assigned to tenofovir gel. All participants were advised to use the gel vaginally only, with one dose of gel within 12 h before and a second dose as soon as possible after sex, with no more than two doses in 24 h. Clinical and laboratory safety data were collected at monthly and quarterly visits, respectively. Genital assessments were undertaken at enrolment and quarterly thereafter, or as indicated. Women assigned to tenofovir gel were exposed to an average monthly vaginal dose of 240 mg of tenofovir (six applications). In total, six women, three in each group, had mild creatinine elevations, all of which occurred in July/August 2008. The incidence of anaemia was 3.5 and 3.8 per 100 women-years in tenofovir and placebo groups, respectively (P=0.80). Of the six women (four tenofovir and two placebo) experiencing bone fractures, none were associated with abnormal phosphate or calcium values. The proportion of women with diarrhoea was higher in the tenofovir gel group (17% versus 11%; P=0.026). There was no significant increase of any genital adverse event in the tenofovir group. No significant renal, haematological, genital or bone effects were associated with the use of tenofovir gel. Aside from a puzzling increase in diarrhoea, tenofovir gel has an excellent safety profile.

Nivolumab for Metastatic Renal Cell Carcinoma: Results of a Randomized Phase II Trial

PubMed Central

Motzer, Robert J.; Rini, Brian I.; McDermott, David F.; Redman, Bruce G.; Kuzel, Timothy M.; Harrison, Michael R.; Vaishampayan, Ulka N.; Drabkin, Harry A.; George, Saby; Logan, Theodore F.; Margolin, Kim A.; Plimack, Elizabeth R.; Lambert, Alexandre M.; Waxman, Ian M.; Hammers, Hans J.

2015-01-01

Purpose Nivolumab is a fully human immunoglobulin G4 programmed death–1 immune checkpoint inhibitor antibody that restores T-cell immune activity. This phase II trial assessed the antitumor activity, dose-response relationship, and safety of nivolumab in patients with metastatic renal cell carcinoma (mRCC). Patients and Methods Patients with clear-cell mRCC previously treated with agents targeting the vascular endothelial growth factor pathway were randomly assigned (blinded ratio of 1:1:1) to nivolumab 0.3, 2, or 10 mg/kg intravenously once every 3 weeks. The primary objective was to evaluate the dose-response relationship as measured by progression-free survival (PFS); secondary end points included objective response rate (ORR), overall survival (OS), and safety. Results A total of 168 patients were randomly assigned to the nivolumab 0.3- (n = 60), 2- (n = 54), and 10-mg/kg (n = 54) cohorts. One hundred eighteen patients (70%) had received more than one prior systemic regimen. Median PFS was 2.7, 4.0, and 4.2 months, respectively (P = .9). Respective ORRs were 20%, 22%, and 20%. Median OS was 18.2 months (80% CI, 16.2 to 24.0 months), 25.5 months (80% CI, 19.8 to 28.8 months), and 24.7 months (80% CI, 15.3 to 26.0 months), respectively. The most common treatment-related adverse event (AE) was fatigue (24%, 22%, and 35%, respectively). Nineteen patients (11%) experienced grade 3 to 4 treatment-related AEs. Conclusion Nivolumab demonstrated antitumor activity with a manageable safety profile across the three doses studied in mRCC. No dose-response relationship was detected as measured by PFS. These efficacy and safety results in mRCC support study in the phase III setting. PMID:25452452

Nivolumab for Metastatic Renal Cell Carcinoma: Results of a Randomized Phase II Trial.

PubMed

Motzer, Robert J; Rini, Brian I; McDermott, David F; Redman, Bruce G; Kuzel, Timothy M; Harrison, Michael R; Vaishampayan, Ulka N; Drabkin, Harry A; George, Saby; Logan, Theodore F; Margolin, Kim A; Plimack, Elizabeth R; Lambert, Alexandre M; Waxman, Ian M; Hammers, Hans J

2015-05-01

Nivolumab is a fully human immunoglobulin G4 programmed death-1 immune checkpoint inhibitor antibody that restores T-cell immune activity. This phase II trial assessed the antitumor activity, dose-response relationship, and safety of nivolumab in patients with metastatic renal cell carcinoma (mRCC). Patients with clear-cell mRCC previously treated with agents targeting the vascular endothelial growth factor pathway were randomly assigned (blinded ratio of 1:1:1) to nivolumab 0.3, 2, or 10 mg/kg intravenously once every 3 weeks. The primary objective was to evaluate the dose-response relationship as measured by progression-free survival (PFS); secondary end points included objective response rate (ORR), overall survival (OS), and safety. A total of 168 patients were randomly assigned to the nivolumab 0.3- (n = 60), 2- (n = 54), and 10-mg/kg (n = 54) cohorts. One hundred eighteen patients (70%) had received more than one prior systemic regimen. Median PFS was 2.7, 4.0, and 4.2 months, respectively (P = .9). Respective ORRs were 20%, 22%, and 20%. Median OS was 18.2 months (80% CI, 16.2 to 24.0 months), 25.5 months (80% CI, 19.8 to 28.8 months), and 24.7 months (80% CI, 15.3 to 26.0 months), respectively. The most common treatment-related adverse event (AE) was fatigue (24%, 22%, and 35%, respectively). Nineteen patients (11%) experienced grade 3 to 4 treatment-related AEs. Nivolumab demonstrated antitumor activity with a manageable safety profile across the three doses studied in mRCC. No dose-response relationship was detected as measured by PFS. These efficacy and safety results in mRCC support study in the phase III setting. © 2014 by American Society of Clinical Oncology.

Dose-Response Effects of Aerobic Exercise on Quality of Life in Postmenopausal Women: Results from the Breast Cancer and Exercise Trial in Alberta (BETA).

PubMed

Courneya, Kerry S; McNeil, Jessica; O'Reilly, Rachel; Morielli, Andria R; Friedenreich, Christine M

2017-06-01

Exercise generally improves quality of life (QoL) and psychosocial functioning in adult populations but few randomized trials have examined dose-response effects. The purpose of the present study was to report the QoL and psychosocial outcomes from the Breast Cancer and Exercise Trial in Alberta (BETA). Healthy but inactive postmenopausal women at risk for breast cancer were randomized to a year-long aerobic exercise intervention consisting of either 150 min/week (moderate volume group, n = 200) or 300 min/week (high volume group, n = 200). QoL was assessed at baseline and 1 year using the short form-36 health survey. Sleep quality, depression, anxiety, stress, self-esteem, and happiness were also assessed. Participant preference for group assignment (i.e., exercise volume) was assessed at baseline and tested as a moderator. There were no statistically significant dose-response effects of aerobic exercise on any QoL, sleep quality, or psychosocial outcome. Participant preference for group assignment did not moderate any QoL, sleep quality, or psychosocial responses. Marital status was a significant moderator (p for interaction = 0.01) and obesity showed a trend towards being a moderator (p for interaction = 0.08) of the dose-response effects of aerobic exercise on global sleep quality such that unmarried and obese women improved sleep quality with the higher volume of aerobic exercise. A higher volume of aerobic exercise, approximately double the minimum public health guideline, did not provide additional QoL or psychosocial benefits compared to the minimum public health guideline in inactive postmenopausal women, even for women who preferred the higher volume of exercise at baseline. Trial Registration clinicaltrials.gov identifier: NCT1435005.

MO-F-16A-04: Case Study: Estimation of Peak Skin Dose Following a Physician Reported “High Dose” Case and Sentinel Event Considerations

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

Supanich, M; Chu, J; Wehmeyer, A

2014-06-15

Purpose: This work offers as a teaching example a reported high dose fluoroscopy case and the workflow the institution followed to self-report a radiation overdose sentinel event to the Joint Commission. Methods: Following the completion of a clinical case in a hybrid OR room with a reported air kerma of >18 Gy at the Interventional Reference Point (IRP) the physicians involved in the case referred study to the institution's Radiation Safety Committee (RSC) for review. The RSC assigned a Diagnostic Medical Physicist (DMP) to estimate the patient's Peak Skin Dose (PSD) and analyze the case. Following the DMP's analysis andmore » estimate of a PSD of >15 Gy the institution's adverse event committee was convened to discuss the case and to self-report the case as a radiation overdose sentinel event to the Joint Commission. The committee assigned a subgroup to perform the root cause analysis and develop institutional responses to the event. Results: The self-reporting of the sentinel event and the associated root cause analysis resulted in several institutional action items that are designed to improve process and safety. A formal reporting and analysis mechanism was adopted to review fluoroscopy cases with air kerma greater than 6 Gy at the IRP. An improved and formalized radiation safety training program for physicians using fluoroscopy equipment was implemented. Additionally efforts already under way to monitor radiation exposure in the Radiology department were expanded to include all fluoroscopy equipment capable of automated dose reporting. Conclusion: The adverse event review process and the root cause analysis following the self-reporting of the sentinel event resulted in policies and procedures that are expected to improve the quality and safe usage of fluoroscopy throughout the institution.« less

Long-term results of children with acute myeloid leukemia: a report of three consecutive Phase III trials by the Children's Cancer Group: CCG 251, CCG 213 and CCG 2891.

PubMed

Smith, F O; Alonzo, T A; Gerbing, R B; Woods, W G; Arceci, R J

2005-12-01

The Children's Cancer Group (CCG) conducted three Phase III prospective clinical trials for children with de novo acute myeloid leukemia between the years 1979 and 1995. A total of 1903 eligible children ages birth to 21 years of age were enrolled on CCG 251 (n=485), CCG 213 (n=532) and CCG 2891 (n=886). Follow-up is ongoing, with medians of 7.9, 10.9 and 8.6 years, respectively. These three clinical trials developed dose- and time-intensive induction regimens based upon high-dose cytarabine and daunomycin and randomly assigned patients to allogeneic bone marrow transplantation in first remission if an HLA-matched related donor was identified. Despite dose- and time-intensive induction regimens, remission induction rates remained relatively stable at 77-78%. However, overall survival, event-free survival and disease-free survival (DFS) increased for patients receiving intensive-timing induction therapy in comparison to patients who received standard-timing induction, regardless of the type of postremission therapy. Outcomes were best for patients receiving intensive-timing induction followed by matched related donor allogeneic transplantation with DFS of 65+/-9% at 6 years. These three clinical trials have established a strong foundation for the development of future studies focusing on further risk group stratification and the development of novel, molecularly-targeted therapies.

Cholesterol reduction and lack of genotoxic or toxic effects in mice after repeated 21-day oral intake of lemongrass (Cymbopogon citratus) essential oil.

PubMed

Costa, Celso A R A; Bidinotto, Lucas T; Takahira, Regina K; Salvadori, Daisy M F; Barbisan, Luís F; Costa, Mirtes

2011-09-01

Cymbopogon citratus (lemongrass) is currently used in traditional folk medicine. Although this species presents widespread use, there are no scientific data on its efficacy or safety after repeated treatments. Therefore, this work investigated the toxicity and genotoxicity of this lemongrass's essential oil (EO) in male Swiss mice. The single LD(50) based on a 24h acute oral toxicity study was found to be around 3500 mg/kg. In a repeated-dose 21-day oral toxicity study, mice were randomly assigned to two control groups, saline- or Tween 80 0.01%-treated groups, or one of the three experimental groups receiving lemongrass EO (1, 10 or 100mg/kg). No significant changes in gross pathology, body weight, absolute or relative organ weights, histology (brain, heart, kidneys, liver, lungs, stomach, spleen and urinary bladder), urinalysis or clinical biochemistry were observed in EO-treated mice relative to the control groups. Additionally, blood cholesterol was reduced after EO-treatment at the highest dose tested. Similarly, data from the comet assay in peripheral blood cells showed no genotoxic effect from the EO. In conclusion, our findings verified the safety of lemongrass intake at the doses used in folk medicine and indicated the beneficial effect of reducing the blood cholesterol level. Copyright © 2011 Elsevier Ltd. All rights reserved.

Bovine acute-phase response following different doses of corticotrophin-releasing hormone (CRH) challenge

USDA-ARS?s Scientific Manuscript database

Fourteen weaned, halter-trained Angus steers (BW = 191 ± 2.1 kg) were fitted with indwelling jugular catheter and rectal temperature monitoring device on d -1 of the study. On d 0, steers were ranked by body weight and randomly assigned to receive 1 of 3 infusion treatments (i.v.): 1) 0.1 micrograms...

Efficacy and Safety of Three Antiretroviral Regimens for Initial Treatment of HIV-1: A Randomized Clinical Trial in Diverse Multinational Settings

PubMed Central

Campbell, Thomas B.; Smeaton, Laura M.; Kumarasamy, N.; Flanigan, Timothy; Klingman, Karin L.; Firnhaber, Cynthia; Grinsztejn, Beatriz; Hosseinipour, Mina C.; Kumwenda, Johnstone; Lalloo, Umesh; Riviere, Cynthia; Sanchez, Jorge; Melo, Marineide; Supparatpinyo, Khuanchai; Tripathy, Srikanth; Martinez, Ana I.; Nair, Apsara; Walawander, Ann; Moran, Laura; Chen, Yun; Snowden, Wendy; Rooney, James F.; Uy, Jonathan; Schooley, Robert T.; De Gruttola, Victor; Hakim, James Gita; Swann, Edith; Barnett, Ronald L.; Brizz, Barbara; Delph, Yvette; Gettinger, Nikki; Mitsuyasu, Ronald T.; Eshleman, Susan; Safren, Steven; Fiscus, Susan A.; Andrade, Adriana; Haas, David W.; Amod, Farida; Berthaud, Vladimir; Bollinger, Robert C.; Bryson, Yvonne; Celentano, David; Chilongozi, David; Cohen, Myron; Collier, Ann C.; Currier, Judith Silverstein; Cu-Uvin, Susan; Eron, Joseph; Flexner, Charles; Gallant, Joel E.; Gulick, Roy M.; Hammer, Scott M.; Hoffman, Irving; Kazembe, Peter; Kumwenda, Newton; Lama, Javier R.; Lawrence, Jody; Maponga, Chiedza; Martinson, Francis; Mayer, Kenneth; Nielsen, Karin; Pendame, Richard B.; Ramratnam, Bharat; Sanne, Ian; Severe, Patrice; Sirisanthana, Thira; Solomon, Suniti; Tabet, Steve; Taha, Taha; van der Horst, Charles; Wanke, Christine; Gormley, Joan; Marcus, Cheryl J.; Putnam, Beverly; Loeliger, Edde; Pappa, Keith A.; Webb, Nancy; Shugarts, David L.; Winters, Mark A.; Descallar, Renard S.; Steele, Joseph; Wulfsohn, Michael; Said, Farideh; Chen, Yue; Martin, John C; Bischofberger, Norbert; Cheng, Andrew; Jaffe, Howard; Sharma, Jabin; Poongulali, S.; Cardoso, Sandra Wagner; Faria, Deise Lucia; Berendes, Sima; Burke, Kelly; Mngqibisa, Rosie; Kanyama, Cecelia; Kayoyo, Virginia; Samaneka, Wadzanai P.; Chisada, Anthony; Faesen, Sharla; Chariyalertsak, Suwat; Santos, Breno; Lira, Rita Alves; Joglekar, Anjali A.; Rosa, Alberto La; Infante, Rosa; Jain, Mamta; Petersen, Tianna; Godbole, Sheela; Dhayarkar, Sampada; Feinberg, Judith; Baer, Jenifer; Pollard, Richard B.; Asmuth, David; Gangakhedkar, Raman R; Gaikwad, Asmita; Ray, M. Graham; Basler, Cathi; Para, Michael F.; Watson, Kathy J.; Taiwo, Babafemi; McGregor, Donna; Balfour, Henry H.; Mullan, Beth; Kim, Ge-Youl; Klebert, Michael K.; Cox, Gary Matthew; Silberman, Martha; Mildvan, Donna; Revuelta, Manuel; Tashima, Karen T.; Patterson, Helen; Geiseler, P. Jan; Santos, Bartolo; Daar, Eric S; Lopez, Ruben; Frarey, Laurie; Currin, David; Haas, David H.; Bailey, Vicki L.; Tebas, Pablo; Zifchak, Larisa; Noel-Connor, Jolene; Torres, Madeline; Sha, Beverly E.; Fritsche, Janice M.; Cespedes, Michelle; Forcht, Janet; O'Brien, William A.; Mogridge, Cheryl; Hurley, Christine; Corales, Roberto; Palmer, Maria; Adams, Mary; Luque, Amneris; Lopez-Detres, Luis; Stroberg, Todd

2012-01-01

Background Antiretroviral regimens with simplified dosing and better safety are needed to maximize the efficiency of antiretroviral delivery in resource-limited settings. We investigated the efficacy and safety of antiretroviral regimens with once-daily compared to twice-daily dosing in diverse areas of the world. Methods and Findings 1,571 HIV-1-infected persons (47% women) from nine countries in four continents were assigned with equal probability to open-label antiretroviral therapy with efavirenz plus lamivudine-zidovudine (EFV+3TC-ZDV), atazanavir plus didanosine-EC plus emtricitabine (ATV+DDI+FTC), or efavirenz plus emtricitabine-tenofovir-disoproxil fumarate (DF) (EFV+FTC-TDF). ATV+DDI+FTC and EFV+FTC-TDF were hypothesized to be non-inferior to EFV+3TC-ZDV if the upper one-sided 95% confidence bound for the hazard ratio (HR) was ≤1.35 when 30% of participants had treatment failure. An independent monitoring board recommended stopping study follow-up prior to accumulation of 472 treatment failures. Comparing EFV+FTC-TDF to EFV+3TC-ZDV, during a median 184 wk of follow-up there were 95 treatment failures (18%) among 526 participants versus 98 failures among 519 participants (19%; HR 0.95, 95% CI 0.72–1.27; p = 0.74). Safety endpoints occurred in 243 (46%) participants assigned to EFV+FTC-TDF versus 313 (60%) assigned to EFV+3TC-ZDV (HR 0.64, CI 0.54–0.76; p<0.001) and there was a significant interaction between sex and regimen safety (HR 0.50, CI 0.39–0.64 for women; HR 0.79, CI 0.62–1.00 for men; p = 0.01). Comparing ATV+DDI+FTC to EFV+3TC-ZDV, during a median follow-up of 81 wk there were 108 failures (21%) among 526 participants assigned to ATV+DDI+FTC and 76 (15%) among 519 participants assigned to EFV+3TC-ZDV (HR 1.51, CI 1.12–2.04; p = 0.007). Conclusion EFV+FTC-TDF had similar high efficacy compared to EFV+3TC-ZDV in this trial population, recruited in diverse multinational settings. Superior safety, especially in HIV-1-infected women, and once-daily dosing of EFV+FTC-TDF are advantageous for use of this regimen for initial treatment of HIV-1 infection in resource-limited countries. ATV+DDI+FTC had inferior efficacy and is not recommended as an initial antiretroviral regimen. Trial Registration www.ClinicalTrials.gov NCT00084136 Please see later in the article for the Editors' Summary. PMID:22936892

Comparing errors in ED computer-assisted vs conventional pediatric drug dosing and administration.

PubMed

Yamamoto, Loren; Kanemori, Joan

2010-06-01

Compared to fixed-dose single-vial drug administration in adults, pediatric drug dosing and administration requires a series of calculations, all of which are potentially error prone. The purpose of this study is to compare error rates and task completion times for common pediatric medication scenarios using computer program assistance vs conventional methods. Two versions of a 4-part paper-based test were developed. Each part consisted of a set of medication administration and/or dosing tasks. Emergency department and pediatric intensive care unit nurse volunteers completed these tasks using both methods (sequence assigned to start with a conventional or a computer-assisted approach). Completion times, errors, and the reason for the error were recorded. Thirty-eight nurses completed the study. Summing the completion of all 4 parts, the mean conventional total time was 1243 seconds vs the mean computer program total time of 879 seconds (P < .001). The conventional manual method had a mean of 1.8 errors vs the computer program with a mean of 0.7 errors (P < .001). Of the 97 total errors, 36 were due to misreading the drug concentration on the label, 34 were due to calculation errors, and 8 were due to misplaced decimals. Of the 36 label interpretation errors, 18 (50%) occurred with digoxin or insulin. Computerized assistance reduced errors and the time required for drug administration calculations. A pattern of errors emerged, noting that reading/interpreting certain drug labels were more error prone. Optimizing the layout of drug labels could reduce the error rate for error-prone labels. Copyright (c) 2010 Elsevier Inc. All rights reserved.

Interaction Between Low-Dose Methotrexate and Nonsteroidal Anti-inflammatory Drugs, Penicillins, and Proton Pump Inhibitors.

PubMed

Hall, Jill J; Bolina, Monika; Chatterley, Trish; Jamali, Fakhreddin

2017-02-01

To review the potential drug interactions between low-dose methotrexate (LD-MTX) and nonsteroidal anti-inflammatory drugs (NSAIDs), penicillins, and proton-pump inhibitors (PPIs) given the disparity between interactions reported for high-dose and low-dose MTX to help guide clinicians. A literature search was performed in MEDLINE (1946 to September 2016), EMBASE (1974 to September 2016), and International Pharmaceutical Abstracts (1970 to January 2015) to identify reports describing potential drug interactions between LD-MTX and NSAIDS, penicillins, or PPIs. Reference lists of included articles were reviewed to find additional eligible articles. All English-language observational, randomized, and pharmacokinetic (PK) studies assessing LD-MTX interactions in humans were analyzed to determine clinical relevance in making recommendations to clinicians. Clinical case reports were assigned a Drug Interaction Probability Scale score. A total of 32 articles were included (28 with NSAIDs, 3 with penicillins, and 2 with PPIs [1 including both PPI and NSAID]). Although there are some PK data to describe increased LD-MTX concentrations when NSAIDs are used concomitantly, the clinical relevance remains unclear. Based on the limited data on LD-MTX with penicillins and PPIs, no clinically meaningful interaction was identified. Given the available evidence, the clinical importance of the interaction between LD-MTX and NSAIDs, penicillins, and PPIs cannot be substantiated. Health care providers should assess the benefit and risk of LD-MTX regardless of concomitant drug use, including factors known to predispose patients to MTX toxicity, and continue to monitor clinical and laboratory parameters per guideline recommendations.

Whole-brain radiotherapy or autologous stem-cell transplantation as consolidation strategies after high-dose methotrexate-based chemoimmunotherapy in patients with primary CNS lymphoma: results of the second randomisation of the International Extranodal Lymphoma Study Group-32 phase 2 trial.

PubMed

Ferreri, Andrés J M; Cwynarski, Kate; Pulczynski, Elisa; Fox, Christopher P; Schorb, Elisabeth; La Rosée, Paul; Binder, Mascha; Fabbri, Alberto; Torri, Valter; Minacapelli, Eleonora; Falautano, Monica; Ilariucci, Fiorella; Ambrosetti, Achille; Roth, Alexander; Hemmaway, Claire; Johnson, Peter; Linton, Kim M; Pukrop, Tobias; Sønderskov Gørløv, Jette; Balzarotti, Monica; Hess, Georg; Keller, Ulrich; Stilgenbauer, Stephan; Panse, Jens; Tucci, Alessandra; Orsucci, Lorella; Pisani, Francesco; Levis, Alessandro; Krause, Stefan W; Schmoll, Hans J; Hertenstein, Bernd; Rummel, Mathias; Smith, Jeffery; Pfreundschuh, Michael; Cabras, Giuseppina; Angrilli, Francesco; Ponzoni, Maurilio; Deckert, Martina; Politi, Letterio S; Finke, Jürgen; Reni, Michele; Cavalli, Franco; Zucca, Emanuele; Illerhaus, Gerald

2017-11-01

The International Extranodal Lymphoma Study Group-32 (IELSG32) trial is an international randomised phase 2 study that addresses two key clinical questions in the treatment of patients with newly diagnosed primary CNS lymphoma. Results of the first randomisation have demonstrated that methotrexate, cytarabine, thiotepa, and rituximab (called the MATRix regimen) is the induction combination associated with significantly better outcome compared with the other induction combinations tested. Here, we report the results of the second randomisation that addresses the efficacy of myeloablative chemotherapy supported by autologous stem-cell transplantation (ASCT), as an alternative to whole-brain radiotherapy (WBRT), as consolidation after high-dose-methotrexate-based chemoimmunotherapy. HIV-negative patients (aged 18-70 years) with newly diagnosed primary CNS lymphoma and an Eastern Cooperative Oncology Group performance status of 0-3 were randomly assigned to receive four courses of methotrexate 3·5 g/m 2 on day 1 plus cytarabine 2 g/m 2 twice daily on days 2 and 3 (group A); or the same combination plus two doses of rituximab 375 mg/m 2 on days -5 and 0 (group B); or the same methotrexate-cytarabine-rituximab combination plus thiotepa 30 mg/m 2 on day 4 (group C), with the three groups repeating treatment every 3 weeks. Patients with responsive or stable disease after induction treatment, with adequate autologous peripheral blood stem-cell collection, and without persistent iatrogenic side-effects, were eligible for the second randomisation between WBRT (photons of 4-10 MeV; five fractions per week; fraction size 180 cGy; started within 4 weeks from the last induction course; group D) and carmustine-thiotepa conditioned ASCT (carmustine 400 mg/m 2 on day -6, and thiotepa 5 mg/kg every 12 h on days -5 and -4, followed by reinfusion of autologous peripheral blood stem cells; group E). A permuted block randomised design was adopted for both randomisations, and a computer-generated randomisation list was used within each stratum. No masking after assignment to intervention was adopted. The primary endpoint was 2-year progression-free survival, with induction group and response to induction chemotherapy as stratification parameters. Analyses were done on a modified intention-to-treat basis. This study is registered with ClinicalTrials.gov, number NCT01011920. Between Feb 19, 2010, and Aug 27, 2014, 227 patients were recruited from 53 centres in five countries. 219 of 227 enrolled patients were assessable. Of the 122 patients eligible for the second randomisation, 118 patients were randomly assigned to WBRT or ASCT (59 patients per group) and constitute the study population. WBRT and ASCT were both effective, and achieved the predetermined efficacy threshold of at least 40 progression-free survivors at 2 years among the first 52 patients in both groups D and E. There were no significant differences in 2-year progression-free survival between WBRT and ASCT: 80% (95% CI 70-90) in group D and 69% (59-79) in group E (hazard ratio 1·50, 95% CI 0·83-2·71; p=0·17). Both consolidation therapies were well tolerated. Grade 4 non-haematological toxicity was uncommon; as expected, haematological toxicity was more common in patients treated with ASCT than in those who received WBRT. Two toxic deaths (infections) were recorded, both in patients who received ASCT. WBRT and ASCT are both feasible and effective as consolidation therapies after high-dose methotrexate-based chemoimmunotherapy in patients aged 70 years or younger with primary CNS lymphoma. The risks and implications of cognitive impairment after WBRT should be considered at the time of therapeutic decision. Agenzia Italiana del Farmaco, Cancer Research UK, Oncosuisse, and Swiss National Science Foundation. Copyright © 2017 Elsevier Ltd. All rights reserved.

Effect of human rotavirus vaccine on severe diarrhea in African infants.

PubMed

Madhi, Shabir A; Cunliffe, Nigel A; Steele, Duncan; Witte, Desirée; Kirsten, Mari; Louw, Cheryl; Ngwira, Bagrey; Victor, John C; Gillard, Paul H; Cheuvart, Brigitte B; Han, Htay H; Neuzil, Kathleen M

2010-01-28

Rotavirus is the most common cause of severe gastroenteritis among young children worldwide. Data are needed to assess the efficacy of the rotavirus vaccine in African children. We conducted a randomized, placebo-controlled, multicenter trial in South Africa (3166 infants; 64.1% of the total) and Malawi (1773 infants; 35.9% of the total) to evaluate the efficacy of a live, oral rotavirus vaccine in preventing severe rotavirus gastroenteritis. Healthy infants were randomly assigned in a 1:1:1 ratio to receive two doses of vaccine (in addition to one dose of placebo) or three doses of vaccine--the pooled vaccine group--or three doses of placebo at 6, 10, and 14 weeks of age. Episodes of gastroenteritis caused by wild-type rotavirus during the first year of life were assessed through active follow-up surveillance and were graded with the use of the Vesikari scale. A total of 4939 infants were enrolled and randomly assigned to one of the three groups; 1647 infants received two doses of the vaccine, 1651 infants received three doses of the vaccine, and 1641 received placebo. Of the 4417 infants included in the per-protocol efficacy analysis, severe rotavirus gastroenteritis occurred in 4.9% of the infants in the placebo group and in 1.9% of those in the pooled vaccine group (vaccine efficacy, 61.2%; 95% confidence interval, 44.0 to 73.2). Vaccine efficacy was lower in Malawi than in South Africa (49.4% vs. 76.9%); however, the number of episodes of severe rotavirus gastroenteritis that were prevented was greater in Malawi than in South Africa (6.7 vs. 4.2 cases prevented per 100 infants vaccinated per year). Efficacy against all-cause severe gastroenteritis was 30.2%. At least one serious adverse event was reported in 9.7% of the infants in the pooled vaccine group and in 11.5% of the infants in the placebo group. Human rotavirus vaccine significantly reduced the incidence of severe rotavirus gastroenteritis among African infants during the first year of life. (ClinicalTrials.gov number, NCT00241644.) 2010 Massachusetts Medical Society

Oral arsenic plus retinoic acid versus intravenous arsenic plus retinoic acid for non-high-risk acute promyelocytic leukaemia: a non-inferiority, randomised phase 3 trial.

PubMed

Zhu, Hong-Hu; Wu, De-Pei; Du, Xin; Zhang, Xi; Liu, Lin; Ma, Jun; Shao, Zong-Hong; Ren, Han-Yun; Hu, Jian-Da; Xu, Kai-Lin; Wang, Jing-Wen; Song, Yong-Ping; Fang, Mei-Yun; Li, Juan; Yan, Xiao-Yan; Huang, Xiao-Jun

2018-06-05

Intravenous arsenic trioxide plus all-trans retinoic acid (ATRA) without chemotherapy is the standard of care for non-high-risk acute promyelocytic leukaemia (white blood cell count ≤10 × 10 9 per L), resulting in cure in more than 95% of cases. However, a pilot study of treatment with oral arsenic realgar-Indigo naturalis formula (RIF) plus ATRA without chemotherapy, which has a more convenient route of administration than the standard intravenous regimen, showed high efficacy. In this study, we compare an oral RIF plus ATRA treatment regimen with the standard intravenous arsenic trioxide plus ATRA treatment regimen in patients with non-high-risk acute promyelocytic leukaemia. We did a multicentre, non-inferiority, open-label, randomised, controlled phase 3 trial at 14 centres in China. Patients aged 18-70 years with newly diagnosed (within 7 days) non-high-risk acute promyelocytic leukaemia, and a WHO performance status of 2 or less were eligible. Patients were randomly assigned (2:1) to receive treatment with RIF-ATRA or arsenic trioxide-ATRA as the induction and consolidation therapy. Randomisation was done centrally with permuted blocks and stratification according to trial centre and was implemented through an interactive web response system. RIF (60 mg/kg bodyweight daily in an oral divided dose) or arsenic trioxide (0·15 mg/kg daily in an intravenous dose) and ATRA (25 mg/m 2 daily in an oral divided dose) were used until complete remission was achieved. The home-based consolidation therapy was RIF (60 mg/kg daily in an oral divided dose) or intravenous arsenic trioxide (0·15 mg/kg daily in an intravenous dose) in a 4-week on 4-week off regimen for four cycles and ATRA (25 mg/m 2 daily in an oral divided dose) in a 2-week on 2-week off regimen for seven cycles. Patients and treating physicians were not masked to treatment allocation. The primary outcome was event-free survival at 2 years. A non-inferiority margin of -10% was used to assess non-inferiority. Primary analyses were done in a modified intention-to-treat population of all patients who received at least one dose of their assigned treatment and the per-protocol population. This study was registered with the Chinese Clinical Trial Registry (ChiCTR-TRC-13004054), and the trial is complete. Between Feb 13, 2014, and Aug 31, 2015, 109 patients were enrolled and assigned to RIF-ATRA (n=72) or arsenic trioxide-ATRA (n=37). Three patients in the RIF-ATRA and one in the arsenic trioxide-ATRA did not receive their assigned treatment. After a median follow-up of 32 months (IQR 27-36), 67 (97%) of 69 patients in the RIF-ATRA group and 34 (94%) of 36 in the arsenic trioxide-ATRA group had achieved 2-year event-free survival in the modified intention-to-treat population. The percentage difference in event-free survival was 2·7% (95% CI, -5·8 to 11·1). The lower limit of the 95% CI for the difference in event-free survival was greater than the -10% non-inferiority margin, confirming non-inferiority (p=0·0017). Non-inferiority was also confirmed in the per-protocol population. During induction therapy, grade 3-4 hepatic toxic effects (ie, increased liver aspartate aminotransferase or alanine transaminase concentrations) were reported in six (9%) of 69 patients in the RIF-ATRA group versus five (14%) of 36 patients in the arsenic trioxide-ATRA group; grade 3-4 infection was reported in 15 (23%) of 64 versus 15 (42%) of 36 patients. Two patients in the arsenic trioxide-ATRA group died during induction therapy (one from haemorrhage and one from thrombocytopenia). Oral RIF plus ATRA is not inferior to intravenous arsenic trioxide plus ATRA for the treatment of patients with non-high-risk acute promyelocytic leukaemia. This study suggests that a completely oral, chemotherapy-free model might be an alternative to the standard intravenous treatment for patients with non-high-risk acute promyelocytic leukaemia. Foundation for innovative research group of the National Natural Science Foundation of China, the Beijing Municipal Science and Technology Commission, the National Key R&D Program of China, and the National Natural Science Foundation of China. Copyright © 2018 Elsevier Ltd. All rights reserved.

Savings from the use of a probiotic formula in the prophylaxis of antibiotic-associated diarrhea.

PubMed

Kamdeu Fansi, Alvine Adrienne; Guertin, Jason Robert; LeLorier, Jacques

2012-01-01

Antibiotic-associated diarrhea (AAD) and particularly Clostridium difficile-associated diarrhea (CDAD) are the most common causes of healthcare associated infectious diarrhea. A double-blind, dose response, placebo-controlled trial of the probiotic formula (Bio-K+ Lactobacillus acidophilus CL1285 and Lactobacillus casei LBC80R formula) for prophylaxis of AAD and CDAD was published in 2010. The Bio-K+ Lactobacillus acidophilus CL1285 and Lactobacillus casei LBC80R formula is a registered trademark of Bio-K Plus International Inc. (Laval, Québec, Canada). Results indicated that the incidence of AAD and CDAD were lower for patients assigned to the probiotic formula compared with the placebo option. The present study aims to estimate the savings in direct medical costs that might result from the use of two different doses of the probiotic formula vs placebo. A cost-consequence analysis was conducted to compare the two doses of the probiotic formula compared to placebo. The analysis was based upon published data and adjusted to the North American context. Economic analyses showed that the use of the probiotic formula would result in estimated mean per patients savings of US$1968 for the single dose and US$2661 for the double dose compared with the placebo option if used an average of 13 days by all patients at risk of developing AAD and CDAD. Several key parameters considered within the economic model were not captured within the Gao et al. study. Numerous sensitivity analyses were conducted to address this issue. The use of the probiotic formula in prophylaxis of AAD and CDAD would lead to estimated savings in direct medical costs that would substantially offset its acquisition cost. Treating 1000 hospitalized patients on antibiotics with the double dose of the product compared to current practice would save a single payer system the sum of $2,661,218.

Intraoperative ketamine for prevention of postoperative delirium or pain after major surgery in older adults: an international, multicentre, double-blind, randomised clinical trial.

PubMed

Avidan, Michael S; Maybrier, Hannah R; Abdallah, Arbi Ben; Jacobsohn, Eric; Vlisides, Phillip E; Pryor, Kane O; Veselis, Robert A; Grocott, Hilary P; Emmert, Daniel A; Rogers, Emma M; Downey, Robert J; Yulico, Heidi; Noh, Gyu-Jeong; Lee, Yonghun H; Waszynski, Christine M; Arya, Virendra K; Pagel, Paul S; Hudetz, Judith A; Muench, Maxwell R; Fritz, Bradley A; Waberski, Witold; Inouye, Sharon K; Mashour, George A

2017-07-15

Delirium is a common and serious postoperative complication. Subanaesthetic ketamine is often administered intraoperatively for postoperative analgesia, and some evidence suggests that ketamine prevents delirium. The primary purpose of this trial was to assess the effectiveness of ketamine for prevention of postoperative delirium in older adults. The Prevention of Delirium and Complications Associated with Surgical Treatments [PODCAST] study is a multicentre, international randomised trial that enrolled adults older than 60 years undergoing major cardiac and non-cardiac surgery under general anaesthesia. Using a computer-generated randomisation sequence we randomly assigned patients to one of three groups in blocks of 15 to receive placebo (normal saline), low-dose ketamine (0·5 mg/kg), or high dose ketamine (1·0 mg/kg) after induction of anaesthesia, before surgical incision. Participants, clinicians, and investigators were blinded to group assignment. Delirium was assessed twice daily in the first 3 postoperative days using the Confusion Assessment Method. We did analyses by intention-to-treat and assessed adverse events. This trial is registered with clinicaltrials.gov, number NCT01690988. Between Feb 6, 2014, and June 26, 2016, 1360 patients were assessed, and 672 were randomly assigned, with 222 in the placebo group, 227 in the 0·5 mg/kg ketamine group, and 223 in the 1·0 mg/kg ketamine group. There was no difference in delirium incidence between patients in the combined ketamine groups and the placebo group (19·45% vs 19·82%, respectively; absolute difference 0·36%, 95% CI -6·07 to 7·38, p=0·92). There were more postoperative hallucinations (p=0·01) and nightmares (p=0·03) with increasing ketamine doses compared with placebo. Adverse events (cardiovascular, renal, infectious, gastrointestinal, and bleeding), whether viewed individually (p value for each >0·40) or collectively (36·9% in placebo, 39·6% in 0·5 mg/kg ketamine, and 40·8% in 1·0 mg/kg ketamine groups, p=0·69), did not differ significantly across groups. A single subanaesthetic dose of ketamine did not decrease delirium in older adults after major surgery, and might cause harm by inducing negative experiences. National Institutes of Health and Cancer Center Support. Copyright © 2017 Elsevier Ltd. All rights reserved.

Increasing the Vegetable Intake Dose Is Associated with a Rise in Plasma Carotenoids without Modifying Oxidative Stress or Inflammation in Overweight or Obese Postmenopausal Women123

PubMed Central

Crane, Tracy E.; Kubota, Chieri; West, Julie L.; Kroggel, Mark A.; Wertheim, Betsy C.; Thomson, Cynthia A.

2011-01-01

The optimal amount of vegetable consumption required to reduce chronic disease risk is widely debated. Intervention trials evaluating biological activity of vegetables at various doses are limited. We conducted a 3-dose, crossover feeding trial to test the hypothesis that vegetable intake is associated in a dose-dependent manner with increased plasma carotenoids and subsequently reduced oxidative stress and inflammation in 49 overweight, postmenopausal women. Participants were assigned in random order to 2 (130 g), 5 (287 g), and 10 (614 g) daily servings of fresh, greenhouse-grown vegetables for 3-wk intervals with a 4-wk washout period between treatments. Plasma total carotenoids significantly increased from 1.63 to 2.07 μmol/L with a dose of 2 vegetable servings, from 1.49 to 2.84 μmol/L with a dose of 5 vegetable servings, and from 1.40 to 4.42 μmol/L with a dose of 10 vegetable servings (pre-post paired ttests, all P < 0.001). The change during each feeding period increased with each dose level (P < 0.001). Urine concentrations of 8-isoprostane F2α, hexanoyl lysine, and serum high sensitivity C-reactive protein were not affected by any administered vegetable dose. In this variable-dose vegetable study, a dose-response for plasma carotenoids was demonstrated without significant change in oxidative stress and inflammation in overweight, postmenopausal women. PMID:21865569

Impact of angiotensin-converting enzyme gene polymorphism on neurohormonal responses to high- versus low-dose enalapril in advanced heart failure.

PubMed

Tang, W H Wilson; Vagelos, Randall H; Yee, Yin-Gail; Fowler, Michael B

2004-11-01

The impact of angiotensin-converting enzyme (ACE) gene polymorphism on neurohormonal dose response to ACE inhibitor therapy is unclear. ACE Insertion (I) or Deletion (D) genotype was determined in 74 patients with chronic heart failure who were randomly assigned to receive either high-dose or low-dose enalapril over a period of 6 months. Monthly pre-enalapril and post-enalapril neurohormone levels (serum ACE activity (sACE), plasma angiotensin II (A-II), plasma renin activity (PRA), and serum aldosterone (ALDO) were compared between genotype subgroups and between patients who received high- or low-dose enalapril within each genotype subgroup. At baseline, predose/postdose sACE and postdose PRA were significantly higher in the DD genotype. At 6-month follow-up, postdose sACE was reduced in a dose-dependent fashion in all three genotypes (P < .05). However, predose and postdose ALDO and A-II levels did not differ between each genotype subgroup at baseline or by enalapril dose within each genotype subgroup. ALDO escape and A-II reactivation were not affected by ACE genotype or enalapril dosage. Predose sACE were consistently higher in the DD genotype when compared with ID or II subgroups. Despite a dose-dependent suppression of sACE, there were no observed statistically significant differences in ALDO and A-II suppression or escape with escalating doses of enalapril within each subgroup.

The dosimetric impact of gadolinium-based contrast media in GBM brain patient plans for a MRI-Linac

NASA Astrophysics Data System (ADS)

Bilal Ahmad, Syed; Paudel, Moti Raj; Sarfehnia, Arman; Kim, Anthony; Pang, Geordi; Ruschin, Mark; Sahgal, Arjun; Keller, Brian M.

2017-08-01

Dosimetric effects of gadolinium based contrast media (Gadovist) were evaluated for the Elekta MRI linear accelerator using the research version of the Monaco treatment planning system (TPS). In order to represent a gadolinium uptake, the contrast was manually assigned to a phantom as well as to the gross tumour volume (GTV) of 6 glioblastoma multiforme (GBM) patients. A preliminary estimate of the dose enhancement, due to gadolinium, was performed using the phantom irradiated with a single beam. A more complicated assessment was performed for the GBM patients using a 7 field IMRT technique. The material table in Monaco was modified in order to identify the presence of a non-biological material. The dose distribution was modelled using GPUMCD (MC algorithm in Monaco) for an unmodified (or default) material table (DMT) as well as for a modified (or custom) material table (CMT) for both the phantom and patients. Various concentrations ranging between 8 and 157 mg ml-1 were used to represent the gadolinium uptake in the patient’s GTV. It was assumed that the gadolinium concentration remained the same for the entire course of radiation treatment. Results showed that at the tissue-Gadovist interface, inside the phantom, dose scored using the DMT was 7% lower compared to that using the CMT for 157 mg ml-1 concentration of gadolinium. Dosimetric differences in the case of the patient study were measured using the DVH parameters. D 50% was higher by 6% when the DMT was used compared to the CMT for dose modelling for a gadolinium concentration of 157 mg ml-1. This difference decreased gradually with decreasing concentration of gadolinium. It was concluded that dosimetric differences can be quantified in Monaco if the tumour-gadolinium concentration is more than 23 mg ml-1. If the gadolinium concentration is lower than 23 mg ml-1, then a correction for the presence of gadolinium may not be necessary in the TPS.

The dosimetric impact of gadolinium-based contrast media in GBM brain patient plans for a MRI-Linac.

PubMed

Ahmad, Syed Bilal; Paudel, Moti Raj; Sarfehnia, Arman; Kim, Anthony; Pang, Geordi; Ruschin, Mark; Sahgal, Arjun; Keller, Brian M

2017-08-01

Dosimetric effects of gadolinium based contrast media (Gadovist) were evaluated for the Elekta MRI linear accelerator using the research version of the Monaco treatment planning system (TPS). In order to represent a gadolinium uptake, the contrast was manually assigned to a phantom as well as to the gross tumour volume (GTV) of 6 glioblastoma multiforme (GBM) patients. A preliminary estimate of the dose enhancement, due to gadolinium, was performed using the phantom irradiated with a single beam. A more complicated assessment was performed for the GBM patients using a 7 field IMRT technique. The material table in Monaco was modified in order to identify the presence of a non-biological material. The dose distribution was modelled using GPUMCD (MC algorithm in Monaco) for an unmodified (or default) material table (DMT) as well as for a modified (or custom) material table (CMT) for both the phantom and patients. Various concentrations ranging between 8 and 157 mg ml -1 were used to represent the gadolinium uptake in the patient's GTV. It was assumed that the gadolinium concentration remained the same for the entire course of radiation treatment. Results showed that at the tissue-Gadovist interface, inside the phantom, dose scored using the DMT was 7% lower compared to that using the CMT for 157 mg ml -1 concentration of gadolinium. Dosimetric differences in the case of the patient study were measured using the DVH parameters. D 50% was higher by 6% when the DMT was used compared to the CMT for dose modelling for a gadolinium concentration of 157 mg ml -1 . This difference decreased gradually with decreasing concentration of gadolinium. It was concluded that dosimetric differences can be quantified in Monaco if the tumour-gadolinium concentration is more than 23 mg ml -1 . If the gadolinium concentration is lower than 23 mg ml -1 , then a correction for the presence of gadolinium may not be necessary in the TPS.

The 'Harmonizing Optimal Strategy for Treatment of coronary artery stenosis - sAfety & effectiveneSS of drug-elUting stents & antiplatelet REgimen' (HOST-ASSURE) trial: study protocol for a randomized controlled trial

PubMed Central

2012-01-01

Background Second-generation drug-eluting stents (DES) have raised the bar of clinical performance. These stents are mostly made from cobalt chromium alloy. A newer generation DES has been developed from platinum chromium alloy, but clinical data regarding the efficacy and safety of the platinum chromium-based everolimus-eluting stent (PtCr-EES) is limited, with no comparison data against the cobalt chromium-based zotarolimus-eluting stent (CoCr-ZES). In addition, an antiplatelet regimen is an integral component of medical therapy after percutaneous coronary intervention (PCI). A 1-week duration of doubling the dose of clopidogrel (double-dose antiplatelet therapy (DDAT)) was shown to improve outcome at 1 month compared with conventional dose in acute coronary syndrome (ACS) patients undergoing PCI. However in Asia, including Korea, the addition of cilostazol (triplet antiplatelet therapy (TAT)) is used more commonly than doubling the dose of clopidogrel in high-risk patients. Methods In the 'Harmonizing Optimal Strategy for Treatment of coronary artery stenosis - sAfety & effectiveneSS of drug-elUting stents & antiplatelet REgimen' (HOST-ASSURE) trial, approximately 3,750 patients are being prospectively and randomly assigned in a 2 × 2 factorial design according to the type of stent (PtCr-EES vs CoCr-ZES) and antiplatelet regimen (TAT vs DDAT). The first primary endpoint is target lesion failure at 1 year for the stent comparison, and the second primary endpoint is net clinical outcome at 1 month for comparison of antiplatelet therapy regimen. Discussion The HOST-ASSURE trial is the largest study yet performed to directly compare the efficacy and safety of the PtCr-EES versus CoCr-ZES in an 'all-comers' population. In addition, this study will also compare the clinical outcome of TAT versus DDAT for 1-month post PCI. Trial registration ClincalTrials.gov number NCT01267734. PMID:22463698

The In Vivo Quantitation of Diazinon, chlorpyrifos, and Their Major Metabolites in Rat Blood for the Refinement of a Physiologically-Based Pharmacokinetic/Pharmacodynamic Models

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

Busby, A.; Kousba, A.; Timchalk, C.

2004-01-01

Chlorpyrifos (CPF)(O,O-diethyl-O-[3,5,6-trichloro-2-pyridyl]-phosphorothioate, CAS 2921-88-2), and diazinon (DZN)(O,O-diethyl-O-2-isopropyl-4-methyl-6-pyrimidyl thiophosphate, CAS 333-41-5) are commonly encountered organophosphorus insecticides whose oxon metabolites (CPF-oxon and DZN-oxon) have the ability to strongly inhibit acetylcholinesterase, an enzyme responsible for the breakdown of acetylcholine at nerve synapses. Chlorpyrifos-oxon and DZN-oxon are highly unstable compounds that degrade via hepatic, peripheral blood, and intestinal metabolism to the more stable metabolites, TCP (3,5,6-trichloro-2-pyridinol, CAS not assigned) and IMHP (2-isopropyl-6-methyl-4-pyrimidinol, CAS 2814-20-2), respectively. Studies have been performed to understand and model the chronic and acute toxic effects of CPF and DZN individually but little is known about their combined effects. The purposemore » of this study was to improve physiologically based pharmacokinetic/ pharmacodynamic (PBPK/PD) computational models by quantifying concentrations of CPF and DZN and their metabolites TCP and IMHP in whole rat blood, following exposure to the chemicals individually or as a mixture. Male Sprague-Dawley rats were orally dosed with 60 mg/kg of CPF, DZN, or a mixture of these two pesticides. When administered individually DZN and CPF were seen to reach their maximum concentration at ~3 hours post-dosing. When given as a mixture, both DZN and CPF peak blood concentrations were not achieved until ~6 hours post-dosing and the calculated blood area under the curve (AUC) for both chemicals exceeded those calculated following the single dose. Blood concentrations of IMHP and TCP correlated with these findings. It is proposed that the higher AUC obtained for both CPF and DZN as a mixture resulted from competition for the same metabolic enzyme systems.« less

Absolute configuration of podophyllotoxone and its inhibitory activity against human prostate cancer cells.

PubMed

Li, Juan; Feng, Juan; Luo, Cheng; Herman, Ho-Yung Sung; Jiang, Ren-Wang

2015-01-01

Podophyllotoxone (1) was isolated from the roots of Dysosma versipellis. The structure was determined by spectroscopic analysis in combination with single-crystal X-ray analysis. The absolute configuration of compound 1 was assigned based on the Flack parameter. It showed significant inhibitory activities against human prostate cancer cells PC3 and DU145 with IC50 values being 14.7 and 20.6 μmol·L(-1), respectively. It also arrested the cells at G2/M phase. Tubulin polymerization assay showed that it inhibited the tubulin polymerization in a dose-dependent manner, and molecular docking analysis revealed a different binding mode with tubulin as compared with those known tubulin inhibitors. Copyright © 2015 China Pharmaceutical University. Published by Elsevier B.V. All rights reserved.

Applying mathematical modeling to create job rotation schedules for minimizing occupational noise exposure.

PubMed

Tharmmaphornphilas, Wipawee; Green, Benjamin; Carnahan, Brian J; Norman, Bryan A

2003-01-01

This research developed worker schedules by using administrative controls and a computer programming model to reduce the likelihood of worker hearing loss. By rotating the workers through different jobs during the day it was possible to reduce their exposure to hazardous noise levels. Computer simulations were made based on data collected in a real setting. Worker schedules currently used at the site are compared with proposed worker schedules from the computer simulations. For the worker assignment plans found by the computer model, the authors calculate a significant decrease in time-weighted average (TWA) sound level exposure. The maximum daily dose that any worker is exposed to is reduced by 58.8%, and the maximum TWA value for the workers is reduced by 3.8 dB from the current schedule.

A randomized, double-blind, placebo-controlled, dose-ranging study of lisdexamfetamine dimesylate augmentation for major depressive disorder in adults with inadequate response to antidepressant therapy

PubMed Central

Richards, Cynthia; Iosifescu, Dan V; Mago, Rajnish; Sarkis, Elias; Reynolds, James; Geibel, Brooke; Dauphin, Matthew

2017-01-01

Background: This randomized, double-blind, placebo-controlled study evaluated dose-response relationships of lisdexamfetamine dimesylate when used as augmentation for major depressive disorder in individuals exhibiting inadequate responses to antidepressant monotherapy. Methods: Eligible adults (18–65 years) were assigned to antidepressant monotherapy (escitalopram or venlafaxine extended-release) plus lisdexamfetamine dimesylate-matching placebo during an eight-week single-blind lead-in phase. Participants meeting randomization criteria were randomized (1:1:1:1:1) to eight weeks of lisdexamfetamine dimesylate (10, 30, 50, or 70 mg) or placebo while maintaining antidepressant therapy. Dose-responses for changes from augmentation baseline to week 16/early termination for Montgomery-Åsberg Depression Rating Scale total score (primary efficacy endpoint) and vital signs (systolic and diastolic blood pressure and pulse) were assessed using multiple comparisons procedures with modeling. Results: For Montgomery-Åsberg Depression Rating Scale total score change, no significant dose-responses were observed for any candidate dose-response curve (all p>0.10). In the dose-response evaluable population, least squares mean (90% confidence interval) treatment differences versus placebo for Montgomery-Åsberg Depression Rating Scale total score change at week 16 were −1.4 (−3.9, 1.2), 0.1 (−2.5, 2.7), −0.7 (−3.4, 2.0), and −0.9 (−3.5, 1.6) with 10, 30, 50, and 70 mg lisdexamfetamine dimesylate, respectively. For all vital sign parameters, lisdexamfetamine dimesylate exhibited significant dose-responses for all candidate dose-response curves (all p<0.10), with increases observed as lisdexamfetamine dimesylate dose increased; a linear relationship provided the best fit. Mean±standard deviation changes from augmentation baseline for systolic and diastolic blood pressure and pulse at week 16/early termination were −0.7±9.90 and −0.3±7.24 mm Hg and 0.2±10.57 bpm with placebo and were 1.9±9.47 and 0.8±7.40 mm Hg and 3.6±9.74 bpm with lisdexamfetamine dimesylate (all doses combined). The safety and tolerability profile of lisdexamfetamine dimesylate was consistent with previous studies. Conclusions: Lisdexamfetamine dimesylate augmentation did not provide benefit over placebo in adults with inadequate responses to antidepressant monotherapy based on the assessed efficacy measures. PMID:28857719

SPIDERplan: A tool to support decision-making in radiation therapy treatment plan assessment.

PubMed

Ventura, Tiago; Lopes, Maria do Carmo; Ferreira, Brigida Costa; Khouri, Leila

2016-01-01

In this work, a graphical method for radiotherapy treatment plan assessment and comparison, named SPIDERplan, is proposed. It aims to support plan approval allowing independent and consistent comparisons of different treatment techniques, algorithms or treatment planning systems. Optimized plans from modern radiotherapy are not easy to evaluate and compare because of their inherent multicriterial nature. The clinical decision on the best treatment plan is mostly based on subjective options. SPIDERplan combines a graphical analysis with a scoring index. Customized radar plots based on the categorization of structures into groups and on the determination of individual structures scores are generated. To each group and structure, an angular amplitude is assigned expressing the clinical importance defined by the radiation oncologist. Completing the graphical evaluation, a global plan score, based on the structures score and their clinical weights, is determined. After a necessary clinical validation of the group weights, SPIDERplan efficacy, to compare and rank different plans, was tested through a planning exercise where plans had been generated for a nasal cavity case using different treatment planning systems. SPIDERplan method was applied to the dose metrics achieved by the nasal cavity test plans. The generated diagrams and scores successfully ranked the plans according to the prescribed dose objectives and constraints and the radiation oncologist priorities, after a necessary clinical validation process. SPIDERplan enables a fast and consistent evaluation of plan quality considering all targets and organs at risk.

Methadone continuation versus forced withdrawal on incarceration in a combined US prison and jail: a randomised, open-label trial.

PubMed

Rich, Josiah D; McKenzie, Michelle; Larney, Sarah; Wong, John B; Tran, Liem; Clarke, Jennifer; Noska, Amanda; Reddy, Manasa; Zaller, Nickolas

2015-07-25

Methadone is an effective treatment for opioid dependence. When people who are receiving methadone maintenance treatment for opioid dependence are incarcerated in prison or jail, most US correctional facilities discontinue their methadone treatment, either gradually, or more often, abruptly. This discontinuation can cause uncomfortable symptoms of withdrawal and renders prisoners susceptible to relapse and overdose on release. We aimed to study the effect of forced withdrawal from methadone upon incarceration on individuals' risk behaviours and engagement with post-release treatment programmes. In this randomised, open-label trial, we randomly assigned (1:1) inmates of the Rhode Island Department of Corrections (RI, USA) who were enrolled in a methadone maintenance-treatment programme in the community at the time of arrest and wanted to remain on methadone treatment during incarceration and on release, to either continuation of their methadone treatment or to usual care--forced tapered withdrawal from methadone. Participants could be included in the study only if their incarceration would be more than 1 week but less than 6 months. We did the random assignments with a computer-generated random permutation, and urn randomisation procedures to stratify participants by sex and race. Participants in the continued-methadone group were maintained on their methadone dose at the time of their incarceration (with dose adjustments as clinically indicated). Patients in the forced-withdrawal group followed the institution's standard withdrawal protocol of receiving methadone for 1 week at the dose at the time of their incarceration, then a tapered withdrawal regimen (for those on a starting dose >100 mg, the dose was reduced by 5 mg per day to 100 mg, then reduced by 3 mg per day to 0 mg; for those on a starting dose >100 mg, the dose was reduced by 3 mg per day to 0 mg). The main outcomes were engagement with a methadone maintenance-treatment clinic after release from incarceration and time to engagement with methadone maintenance treatment, by intention-to-treat and as-treated analyses, which we established in a follow-up interview with the participants at 1 month after their release from incarceration. Our study paid for 10 weeks of methadone treatment after release if participants needed financial help. This trial is registered with ClinicalTrials.gov, number NCT01874964. Between June 14, 2011, and April 3, 2013, we randomly assigned 283 prisoners to our study, 142 to continued methadone treatment, and 141 to forced withdrawal from methadone. Of these, 60 were excluded because they did not fit the eligibility criteria, leaving 114 in the continued-methadone group and 109 in the forced-withdrawal group (usual care). Participants assigned to continued methadone were more than twice as likely than forced-withdrawal participants to return to a community methadone clinic within 1 month of release (106 [96%] of 110 in the continued-methadone group compared with 68 [78%] of 87 in the forced-withdrawal group; adjusted hazard ratio [HR] 2·04, 95% CI 1·48-2·80). We noted no differences in serious adverse events between groups. For the continued-methadone and forced-withdrawal groups, the number of deaths were one and zero, non-fatal overdoses were one and two, admissions to hospital were one and four; and emergency-room visits were 11 and 16, respectively. Although our study had several limitations--eg, it only included participants incarcerated for fewer than 6 months, we showed that forced withdrawal from methadone on incarceration reduced the likelihood of prisoners re-engaging in methadone maintenance after their release. Continuation of methadone maintenance during incarceration could contribute to greater treatment engagement after release, which could in turn reduce the risk of death from overdose and risk behaviours. National Institute on Drug Abuse and the Lifespan/Tufts/Brown Center for AIDS Research from the National Institutes of Health. Copyright © 2015 Elsevier Ltd. All rights reserved.

Methadone continuation versus forced withdrawal on incarceration in a combined US prison and jail: a randomised, open-label trial

PubMed Central

Rich, Josiah D; McKenzie, Michelle; Larney, Sarah; Wong, John B; Tran, Liem; Clarke, Jennifer; Noska, Amanda; Reddy, Manasa; Zaller, Nickolas

2015-01-01

Summary Background Methadone is an effective treatment for opioid dependence. When people who are receiving methadone maintenance treatment for opioid dependence are incarcerated in prison or jail, most US correctional facilities discontinue their methadone treatment, either gradually, or more often, abruptly. This discontinuation can cause uncomfortable symptoms of withdrawal and renders prisoners susceptible to relapse and overdose on release. We aimed to study the effect of forced withdrawal from methadone upon incarceration on individuals’ risk behaviours and engagement with post-release treatment programmes. Methods In this randomised, open-label trial, we randomly assigned (1:1) inmates of the Rhode Island Department of Corrections (RI, USA) who were enrolled in a methadone maintenance-treatment programme in the community at the time of arrest and wanted to remain on methadone treatment during incarceration and on release, to either continuation of their methadone treatment or to usual care—forced tapered withdrawal from methadone. Participants could be included in the study only if their incarceration would be more than 1 week but less than 6 months. We did the random assignments with a computer-generated random permutation, and urn randomisation procedures to stratify participants by sex and race. Participants in the continued-methadone group were maintained on their methadone dose at the time of their incarceration (with dose adjustments as clinically indicated). Patients in the forced-withdrawal group followed the institution’s standard withdrawal protocol of receiving methadone for 1 week at the dose at the time of their incarceration, then a tapered withdrawal regimen (for those on a starting dose >100 mg, the dose was reduced by 5 mg per day to 100 mg, then reduced by 3 mg per day to 0 mg; for those on a starting dose ≤100 mg, the dose was reduced by 3 mg per day to 0 mg). The main outcomes were engagement with a methadone maintenance-treatment clinic after release from incarceration and time to engagement with methadone maintenance treatment, by intention-to-treat and as-treated analyses, which we established in a follow-up interview with the participants at 1 month after their release from incarceration. Our study paid for 10 weeks of methadone treatment after release if participants needed financial help. This trial is registered with ClinicalTrials.gov, number NCT01874964. Findings Between June 14, 2011, and April 3, 2013, we randomly assigned 283 prisoners to our study, 142 to continued methadone treatment, and 141 to forced withdrawal from methadone. Of these, 60 were excluded because they did not fit the eligibility criteria, leaving 114 in the continued-methadone group and 109 in the forced-withdrawal group (usual care). Participants assigned to continued methadone were more than twice as likely than forced-withdrawal participants to return to a community methadone clinic within 1 month of release (106 [96%] of 110 in the continued-methadone group compared with 68 [78%] of 87 in the forced-withdrawal group; adjusted hazard ratio [HR] 2·04, 95% CI 1·48–2·80). We noted no differences in serious adverse events between groups. For the continued-methadone and forced-withdrawal groups, the number of deaths were one and zero, non-fatal overdoses were one and two, admissions to hospital were one and four; and emergency-room visits were 11 and 16, respectively. Interpretation Although our study had several limitations—eg, it only included participants incarcerated for fewer than 6 months, we showed that forced withdrawal from methadone on incarceration reduced the likelihood of prisoners re-engaging in methadone maintenance after their release. Continuation of methadone maintenance during incarceration could contribute to greater treatment engagement after release, which could in turn reduce the risk of death from overdose and risk behaviours. PMID:26028120

Monte Carlo proton dose calculations using a radiotherapy specific dual-energy CT scanner for tissue segmentation and range assessment

NASA Astrophysics Data System (ADS)

Almeida, Isabel P.; Schyns, Lotte E. J. R.; Vaniqui, Ana; van der Heyden, Brent; Dedes, George; Resch, Andreas F.; Kamp, Florian; Zindler, Jaap D.; Parodi, Katia; Landry, Guillaume; Verhaegen, Frank

2018-06-01

Proton beam ranges derived from dual-energy computed tomography (DECT) images from a dual-spiral radiotherapy (RT)-specific CT scanner were assessed using Monte Carlo (MC) dose calculations. Images from a dual-source and a twin-beam DECT scanner were also used to establish a comparison to the RT-specific scanner. Proton ranges extracted from conventional single-energy CT (SECT) were additionally performed to benchmark against literature values. Using two phantoms, a DECT methodology was tested as input for GEANT4 MC proton dose calculations. Proton ranges were calculated for different mono-energetic proton beams irradiating both phantoms; the results were compared to the ground truth based on the phantom compositions. The same methodology was applied in a head-and-neck cancer patient using both SECT and dual-spiral DECT scans from the RT-specific scanner. A pencil-beam-scanning plan was designed, which was subsequently optimized by MC dose calculations, and differences in proton range for the different image-based simulations were assessed. For phantoms, the DECT method yielded overall better material segmentation with  >86% of the voxel correctly assigned for the dual-spiral and dual-source scanners, but only 64% for a twin-beam scanner. For the calibration phantom, the dual-spiral scanner yielded range errors below 1.2 mm (0.6% of range), like the errors yielded by the dual-source scanner (<1.1 mm, <0.5%). With the validation phantom, the dual-spiral scanner yielded errors below 0.8 mm (0.9%), whereas SECT yielded errors up to 1.6 mm (2%). For the patient case, where the absolute truth was missing, proton range differences between DECT and SECT were on average in  ‑1.2  ±  1.2 mm (‑0.5%  ±  0.5%). MC dose calculations were successfully performed on DECT images, where the dual-spiral scanner resulted in media segmentation and range accuracy as good as the dual-source CT. In the patient, the various methods showed relevant range differences.

Use of Transportable Radiation Detection Instruments to Assess Internal Contamination from Intakes of Radionuclides Part II: Calibration Factors and ICAT Computer Program.

PubMed

Anigstein, Robert; Olsher, Richard H; Loomis, Donald A; Ansari, Armin

2016-12-01

The detonation of a radiological dispersion device or other radiological incidents could result in widespread releases of radioactive materials and intakes of radionuclides by affected individuals. Transportable radiation monitoring instruments could be used to measure radiation from gamma-emitting radionuclides in the body for triaging individuals and assigning priorities to their bioassay samples for in vitro assessments. The present study derived sets of calibration factors for four instruments: the Ludlum Model 44-2 gamma scintillator, a survey meter containing a 2.54 × 2.54-cm NaI(Tl) crystal; the Captus 3000 thyroid uptake probe, which contains a 5.08 × 5.08-cm NaI(Tl) crystal; the Transportable Portal Monitor Model TPM-903B, which contains two 3.81 × 7.62 × 182.9-cm polyvinyltoluene plastic scintillators; and a generic instrument, such as an ionization chamber, that measures exposure rates. The calibration factors enable these instruments to be used for assessing inhaled or ingested intakes of any of four radionuclides: Co, I, Cs, and Ir. The derivations used biokinetic models embodied in the DCAL computer software system developed by the Oak Ridge National Laboratory and Monte Carlo simulations using the MCNPX radiation transport code. The three physical instruments were represented by MCNP models that were developed previously. The affected individuals comprised children of five ages who were represented by the revised Oak Ridge National Laboratory pediatric phantoms, and adult men and adult women represented by the Adult Reference Computational Phantoms described in Publication 110 of the International Commission on Radiological Protection. These calibration factors can be used to calculate intakes; the intakes can be converted to committed doses by the use of tabulated dose coefficients. These calibration factors also constitute input data to the ICAT computer program, an interactive Microsoft Windows-based software package that estimates intakes of radionuclides and cumulative and committed effective doses, based on measurements made with these instruments. This program constitutes a convenient tool for assessing intakes and doses without consulting tabulated calibration factors and dose coefficients.

USE OF TRANSPORTABLE RADIATION DETECTION INSTRUMENTS TO ASSESS INTERNAL CONTAMINATION FROM INTAKES OF RADIONUCLIDES PART II: CALIBRATION FACTORS AND ICAT COMPUTER PROGRAM

PubMed Central

Anigstein, Robert; Olsher, Richard H.; Loomis, Donald A.; Ansari, Armin

2017-01-01

The detonation of a radiological dispersion device or other radiological incidents could result in widespread releases of radioactive materials and intakes of radionuclides by affected individuals. Transportable radiation monitoring instruments could be used to measure radiation from gamma-emitting radionuclides in the body for triaging individuals and assigning priorities to their bioassay samples for in vitro assessments. The present study derived sets of calibration factors for four instruments: the Ludlum Model 44-2 gamma scintillator, a survey meter containing a 2.54 × 2.54-cm NaI(Tl) crystal; the Captus 3000 thyroid uptake probe, which contains a 5.08 × 5.08-cm NaI(Tl) crystal; the Transportable Portal Monitor Model TPM-903B, which contains two 3.81 × 7.62 × 182.9-cm polyvinyltoluene plastic scintillators; and a generic instrument, such as an ionization chamber, that measures exposure rates. The calibration factors enable these instruments to be used for assessing inhaled or ingested intakes of any of four radionuclides: 60Co, 131I, 137Cs, and 192Ir. The derivations used biokinetic models embodied in the DCAL computer software system developed by the Oak Ridge National Laboratory and Monte Carlo simulations using the MCNPX radiation transport code. The three physical instruments were represented by MCNP models that were developed previously. The affected individuals comprised children of five ages who were represented by the revised Oak Ridge National Laboratory pediatric phantoms, and adult men and adult women represented by the Adult Reference Computational Phantoms described in Publication 110 of the International Commission on Radiological Protection. These calibration factors can be used to calculate intakes; the intakes can be converted to committed doses by the use of tabulated dose coefficients. These calibration factors also constitute input data to the ICAT computer program, an interactive Microsoft Windows-based software package that estimates intakes of radionuclides and cumulative and committed effective doses, based on measurements made with these instruments. This program constitutes a convenient tool for assessing intakes and doses without consulting tabulated calibration factors and dose coefficients. PMID:27798478

Molindone and haloperidol in tardive dyskinesia.

PubMed

Glazer, W M; Hafez, H M; Benarroche, C L

1985-08-01

Preliminary results are described from a study of 11 outpatients manifesting exacerbated tardive dyskinesia after tapering and withdrawal of neuroleptic medications. Patients were randomly assigned to molindone or haloperidol under double-blind placebo-controlled conditions to compare the masking effects of the two drugs. Haloperidol treatment masked withdrawal-exacerbated tardive dyskinesia more than molindone did; this difference (measured by percent change in AIMS scores) was significant (p = .04) when the dose was 200% but not 100% of the prestudy neuroleptic dose. Despite several limitations to the study, the results suggest that molindone may have less dyskinetogenic potential than haloperidol. Further research in the area of site-specificity of molindone is indicated.

Wheel running decreases the positive reinforcing effects of heroin.

PubMed

Smith, Mark A; Pitts, Elizabeth G

2012-01-01

The purpose of this study was to examine the effects of voluntary wheel running on the positive reinforcing effects of heroin in rats with an established history of drug self-administration. Rats were assigned to sedentary (no wheel) and exercise (wheel) conditions and trained to self-administer cocaine under positive reinforcement contingencies. Rats acquiring cocaine self-administration were then tested with various doses of heroin during daily test sessions. Sedentary rats self-administered more heroin than exercising rats, and this effect was greatest at low and moderate doses of heroin. These data suggest that voluntary wheel running decreases the positive reinforcing effects of heroin.

Critical periods for marihuana-induced intrauterine growth retardation in the rat.

PubMed

Abel, E L; Bush, R; Dintcheff, B A; Ernst, C A

1981-01-01

Pregnant rats were intubated with marihuana extract (20, 200 mg/kg) throughout gestation. Control animals were intubated with vehicle (olive oil). Control animals and animals treated with the lower dose of drug were pair-fed and pair-watered to animals treated with the high dose. At parturition, pups were counted, weighed, culled, and assigned to nondrug-treated dams. Marihuana reduced food and water consumption and maternal weight gain. Pup weight at birth was reduced and neonatal mortality was increased in offspring exposed during the third week of gestation or throughout gestation. Litter size, postnatal mortality and weight at weaning were not significantly affected.

Oral MSG administration alters hepatic expression of genes for lipid and nitrogen metabolism in suckling piglets.

PubMed

Chen, Gang; Zhang, Jun; Zhang, Yuzhe; Liao, Peng; Li, Tiejun; Chen, Lixiang; Yin, Yulong; Wang, Jinquan; Wu, Guoyao

2014-01-01

This experiment was conducted to investigate the effects of oral administration of monosodium glutamate (MSG) on expression of genes for hepatic lipid and nitrogen metabolism in piglets. A total of 24 newborn pigs were assigned randomly into one of four treatments (n = 6/group). The doses of oral MSG administration, given at 8:00 and 18:00 to sow-reared piglets between 0 and 21 days of age, were 0 (control), 0.06 (low dose), 0.5 (intermediate dose), and 1 (high dose) g/kg body weight/day. At the end of the 3-week treatment, serum concentrations of total protein and high-density lipoprotein cholesterol in the intermediate dose group were elevated than those in the control group (P < 0.05). Hepatic mRNA levels for fatty acid synthase, acetyl-coA carboxylase, insulin-like growth factor-1, glutamate-oxaloacetate transaminase, and glutamate-pyruvate transaminase were higher in the middle-dose group (P < 0.05), compared with the control group. MSG administration did not affect hepatic mRNA levels for hormone-sensitive lipase or carnitine palmitoyl transferase-1. We conclude that oral MSG administration alters hepatic expression of certain genes for lipid and nitrogen metabolism in suckling piglets.

Efficacy of Single-dose and 2-dose Intravenous Administration of Ramosetron in Preventing Postoperative Nausea and Vomiting After Laparoscopic Gynecologic Operation: A Randomized, Double-blind, Placebo-controlled, Phase 2 Trial.

PubMed

Lee, Banghyun; Kim, Kidong; Suh, Dong Hoon; Shin, Hyun-Jung; No, Jae Hong; Lee, Jung Ryeol; Jee, Byung Chul; Hwang, Jung Won; Do, Sang Hwan; Kim, Yong Beom

2017-06-01

This randomized trial investigated whether a 2-dose administration of intravenous ramosetron (5-hydroxytryptamine type 3 receptor antagonist) is more effective than a single-dose administration in preventing postoperative nausea and vomiting (PONV) in 89 patients who were scheduled to undergo laparoscopic operation for benign gynecologic diseases and to receive intravenous patient-controlled analgesia for relief of postoperative pain. After assignment at a ratio of 1:1, intravenous ramosetron (0.3 mg) was initially administered at the end of skin closure in all patients. Thereafter, ramosetron (0.3 mg) and placebo were administered to the study and control groups, respectively, at 4 hours after the operation. The baseline and operative characteristics were similar between the groups. The incidence of PONV during the 24-hour period after operation which was assessed as the primary endpoint did not differ between the groups. No serious adverse events occurred in either group. A 2-dose administration of intravenous ramosetron may not be superior to a single-dose administration in preventing PONV in patients undergoing laparoscopic operation for benign gynecologic diseases.

A study of cycle control, side effects and client's satisfaction of a low dose combined contraceptive containing ethinylestradiol/drospirenone (24/4 regimen).

PubMed

Chaiyasit, Noppadol; Taneepanichskul, Surasak

2010-05-01

To study cycle control, side effects, and satisfaction of low dose 24-day combined contraceptive containing 20 microg of Ethinylestradiol and 3 mg of Drospirenone. This was an open label, non-comparative study. The healthy females from the family planning clinic at King Chulalongkorn Memorial Hospital were assigned to receive six cycles of combined oral contraceptive containing 20 microg of ethinylestradiol and 3 mg of drospirenone administered daily for 24 days followed by 4-day hormone-free interval. Data were collected on cycle control, side effects, and satisfaction. Data were analyzed using descriptive statistics for descriptive data and Paired t test for comparison. One hundred fifty four women were assigned the study medication, including one (0.64%) who did not start medication. In the second reference period, the occurrence of frequent and infrequent bleeding was low (2.1% and 4.9%). Only one woman (0.65%) discontinued medication because of irregular bleeding. There was no pregnancy reported during the present study. Overall, the study medication was well tolerated and five subjects (3.24%) discontinued study because of side effects. No serious side effects related to the study medication were reported. The majority of women (84.2%) were satisfied and very satisfied with the treatment and most (73.3%) would continue the medication if it were available. The low dose combined contraceptive containing Ethinylestradiol/Drospirenone (24/4 regimen) has acceptable cycle control and good tolerability.

Vitamin A and cancer prevention II: comparison of the effects of retinol and beta-carotene.

PubMed

de Klerk, N H; Musk, A W; Ambrosini, G L; Eccles, J L; Hansen, J; Olsen, N; Watts, V L; Lund, H G; Pang, S C; Beilby, J; Hobbs, M S

1998-01-30

Former blue asbestos workers known to be at high risk of asbestos-related diseases, particularly malignant mesothelioma and lung cancer, were enrolled in a chemo-prevention program using vitamin A. Our aims were to compare rates of disease and death in subjects randomly assigned to beta-carotene or retinol. Subjects were assigned randomly to take 30 mg/day beta-carotene (512 subjects) or 25,000 IU/day retinol (512 subjects) and followed up through death and cancer registries from the start of the study in June 1990 till May 1995. Comparison between groups was by Cox regression in both intention-to-treat analyses and efficacy analyses based on treatment actually taken. Median follow-up time was 232 weeks. Four cases of lung cancer and 3 cases of mesothelioma were observed in subjects randomised to retinol and 6 cases of lung cancer and 12 cases of mesothelioma in subjects randomised to beta-carotene. The relative rate of mesothelioma (the most common single cause of death in our study) for those on retinol compared with those on beta-carotene was 0.24 (95% CI 0.07-0.86). In the retinol group, there was also a significantly lower rate for death from all causes but a higher rate of ischaemic heart disease mortality. Similar results were found with efficacy analyses. Our results confirm other findings of a lack of any benefit from administration of large doses of synthetic beta-carotene. The finding of significantly lower rates of mesothelioma among subjects assigned to retinol requires further investigation.

German adjuvant intergroup node-positive study: a phase III trial to compare oral ibandronate versus observation in patients with high-risk early breast cancer.

PubMed

von Minckwitz, Gunter; Möbus, Volker; Schneeweiss, Andreas; Huober, Jens; Thomssen, Christoph; Untch, Michael; Jackisch, Christian; Diel, Ingo J; Elling, Dirk; Conrad, Bettina; Kreienberg, Rolf; Müller, Volkmar; Lück, Hans-Joachim; Bauerfeind, Ingo; Clemens, Michael; Schmidt, Marcus; Noeding, Stefanie; Forstbauer, Helmut; Barinoff, Jana; Belau, Antje; Nekljudova, Valentina; Harbeck, Nadia; Loibl, Sibylle

2013-10-01

Bisphosphonates prevent skeletal-related events in patients with metastatic breast cancer. Their effect in early breast cancer is controversial. Ibandronate is an orally and intravenously available amino-bisphosphonate with a favorable toxicity profile. It therefore qualifies as potential agent for adjuvant use. The GAIN (German Adjuvant Intergroup Node-Positive) study was an open-label, randomized, controlled phase III trial with a 2 × 2 factorial design. Patients with node-positive early breast cancer were randomly assigned 1:1 to two different dose-dense chemotherapy regimens and 2:1 to ibandronate 50 mg per day orally for 2 years or observation. In all, 2,640 patients and 728 events were estimated to be required to demonstrate an increase in disease-free survival (DFS) by ibandronate from 75% to 79.5% by using a two-sided α = .05 and 1-β of 80%. We report here the efficacy analysis for ibandronate, which was released by the independent data monitoring committee because the futility boundary was not crossed after 50% of the required DFS events were observed. Between June 2004 and August 2008, 2,015 patients were randomly assigned to ibandronate and 1,008 to observation. Patients randomly assigned to ibandronate showed no superior DFS or overall survival (OS) compared with patients randomly assigned to observation (DFS: hazard ratio, 0.945; 95% CI, 0.768 to 1.161; P = .589; OS: HR, 1.040; 95% CI, 0.763 to 1.419; P = .803). DFS was numerically longer if ibandronate was used in patients younger than 40 years or older than 60 years compared with patients age 40 to 59 years (test for interaction P = .093). Adjuvant treatment with oral ibandronate did not improve outcome of patients with high-risk early breast cancer who received dose-dense chemotherapy.

Sequential multiple-assignment randomized trial design of neurobehavioral treatment for patients with metastatic malignant melanoma undergoing high-dose interferon-alpha therapy.

PubMed

Auyeung, S Freda; Long, Qi; Royster, Erica Bruce; Murthy, Smitha; McNutt, Marcia D; Lawson, David; Miller, Andrew; Manatunga, Amita; Musselman, Dominique L

2009-10-01

Interferon-alpha therapy, which is used to treat metastatic malignant melanoma, can cause patients to develop two distinct neurobehavioral symptom complexes: a mood syndrome and a neurovegetative syndrome. Interferon-alpha effects on serotonin metabolism appear to contribute to the mood and anxiety syndrome, while the neurovegetative syndrome appears to be related to interferon-alpha effects on dopamine. Our goal is to propose a design for utilizing a sequential, multiple assignment, randomized trial design for patients with malignant melanoma to test the relative efficacy of drugs that target serotonin versus dopamine metabolism during 4 weeks of intravenous, then 8 weeks of subcutaneous, interferon-alpha therapy. Patients will be offered participation in a double-blinded, randomized, controlled, 14-week trial involving two treatment phases. During the first month of intravenous interferon-alpha therapy, we will test the hypotheses that escitalopram will be more effective in reducing depressed mood, anxiety, and irritability, whereas methylphenidate will be more effective in diminishing interferon-alpha-induced neurovegetative symptoms, such as fatigue and psychomotor slowing. During the next 8 weeks of subcutaneous interferon therapy, participants whose symptoms do not improve significantly will be randomized to the alternate agent alone versus escitalopram and methylphenidate together. We present a prototype for a single-center, sequential, multiple assignment, randomized trial, which seeks to determine the efficacy of sequenced and targeted treatment for the two distinct symptom complexes suffered by patients treated with interferon-alpha. Because we cannot completely control for external factors, a relevant question is whether or not 'short-term' neuropsychiatric interventions can increase the number of interferon-alpha doses tolerated and improve long-term survival. This sequential, multiple assignment, randomized trial proposes a framework for developing optimal treatment strategies; however, additional studies are needed to determine the best strategy for treating or preventing neurobehavioral symptoms induced by the immunotherapy interferon-alpha.

SU-E-T-367: Optimization of DLG Using TG-119 Test Cases and a Weighted Mean Approach

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

Sintay, B; Vanderstraeten, C; Terrell, J

2014-06-01

Purpose: Optimization of the dosimetric leaf gap (DLG) is an important step in commissioning the Eclipse treatment planning system for sliding window intensity-modulated radiation therapy (SW-IMRT) and RapidArc. Often the values needed for optimal dose delivery differ markedly from those measured at commissioning. We present a method to optimize this value using the AAPM TG-119 test cases. Methods: For SW-IMRT and RapidArc, TG-119 based test plans were created using a water-equivalent phantom. Dose distributions measured on film and ion chamber (IC) readings taken in low-gradient regions within the targets were analyzed separately. Since DLG is a single value per energy,more » SW-IMRT and RapidArc must be considered simultaneously. Plans were recalculated using a linear sweep from 0.02cm (the minimum DLG) to 0.3 cm. The calculated point doses were compared to the measured doses for each plan, and based on these comparisons an optimal DLG value was computed for each plan. TG-119 cases are designed to push the system in various ways, thus, a weighted mean of the DLG was computed where the relative importance of each type of plan was given a score from 0.0 to 1.0. Finally, SW-IMRT and RapidArc are assigned an overall weight based on clinical utilization. Our routine patient-QA (PQA) process was performed as independent validation. Results: For a Varian TrueBeam, the optimized DLG varied with σ = 0.044cm for SW-IMRT and σ = 0.035cm for RapidArc. The difference between the weighted mean SW-IMRT and RapidArc value was 0.038cm. We predicted utilization of 25% SW-IMRT and 75% RapidArc. The resulting DLG was ~1mm different than that found by commissioning and produced an average error of <1% for SW-IMRT and RapidArc PQA test cases separately. Conclusion: The weighted mean method presented is a useful tool for determining an optimal DLG value for commissioning Eclipse.« less

Optimization of rotational arc station parameter optimized radiation therapy.

PubMed

Dong, P; Ungun, B; Boyd, S; Xing, L

2016-09-01

To develop a fast optimization method for station parameter optimized radiation therapy (SPORT) and show that SPORT is capable of matching VMAT in both plan quality and delivery efficiency by using three clinical cases of different disease sites. The angular space from 0° to 360° was divided into 180 station points (SPs). A candidate aperture was assigned to each of the SPs based on the calculation results using a column generation algorithm. The weights of the apertures were then obtained by optimizing the objective function using a state-of-the-art GPU based proximal operator graph solver. To avoid being trapped in a local minimum in beamlet-based aperture selection using the gradient descent algorithm, a stochastic gradient descent was employed here. Apertures with zero or low weight were thrown out. To find out whether there was room to further improve the plan by adding more apertures or SPs, the authors repeated the above procedure with consideration of the existing dose distribution from the last iteration. At the end of the second iteration, the weights of all the apertures were reoptimized, including those of the first iteration. The above procedure was repeated until the plan could not be improved any further. The optimization technique was assessed by using three clinical cases (prostate, head and neck, and brain) with the results compared to that obtained using conventional VMAT in terms of dosimetric properties, treatment time, and total MU. Marked dosimetric quality improvement was demonstrated in the SPORT plans for all three studied cases. For the prostate case, the volume of the 50% prescription dose was decreased by 22% for the rectum and 6% for the bladder. For the head and neck case, SPORT improved the mean dose for the left and right parotids by 15% each. The maximum dose was lowered from 72.7 to 71.7 Gy for the mandible, and from 30.7 to 27.3 Gy for the spinal cord. The mean dose for the pharynx and larynx was reduced by 8% and 6%, respectively. For the brain case, the doses to the eyes, chiasm, and inner ears were all improved. SPORT shortened the treatment time by ∼1 min for the prostate case, ∼0.5 min for brain case, and ∼0.2 min for the head and neck case. The dosimetric quality and delivery efficiency presented here indicate that SPORT is an intriguing alternative treatment modality. With the widespread adoption of digital linac, SPORT should lead to improved patient care in the future.

Optimization of rotational arc station parameter optimized radiation therapy

PubMed Central

Dong, P.; Ungun, B.; Boyd, S.; Xing, L.

2016-01-01

Purpose: To develop a fast optimization method for station parameter optimized radiation therapy (SPORT) and show that SPORT is capable of matching VMAT in both plan quality and delivery efficiency by using three clinical cases of different disease sites. Methods: The angular space from 0° to 360° was divided into 180 station points (SPs). A candidate aperture was assigned to each of the SPs based on the calculation results using a column generation algorithm. The weights of the apertures were then obtained by optimizing the objective function using a state-of-the-art GPU based proximal operator graph solver. To avoid being trapped in a local minimum in beamlet-based aperture selection using the gradient descent algorithm, a stochastic gradient descent was employed here. Apertures with zero or low weight were thrown out. To find out whether there was room to further improve the plan by adding more apertures or SPs, the authors repeated the above procedure with consideration of the existing dose distribution from the last iteration. At the end of the second iteration, the weights of all the apertures were reoptimized, including those of the first iteration. The above procedure was repeated until the plan could not be improved any further. The optimization technique was assessed by using three clinical cases (prostate, head and neck, and brain) with the results compared to that obtained using conventional VMAT in terms of dosimetric properties, treatment time, and total MU. Results: Marked dosimetric quality improvement was demonstrated in the SPORT plans for all three studied cases. For the prostate case, the volume of the 50% prescription dose was decreased by 22% for the rectum and 6% for the bladder. For the head and neck case, SPORT improved the mean dose for the left and right parotids by 15% each. The maximum dose was lowered from 72.7 to 71.7 Gy for the mandible, and from 30.7 to 27.3 Gy for the spinal cord. The mean dose for the pharynx and larynx was reduced by 8% and 6%, respectively. For the brain case, the doses to the eyes, chiasm, and inner ears were all improved. SPORT shortened the treatment time by ∼1 min for the prostate case, ∼0.5 min for brain case, and ∼0.2 min for the head and neck case. Conclusions: The dosimetric quality and delivery efficiency presented here indicate that SPORT is an intriguing alternative treatment modality. With the widespread adoption of digital linac, SPORT should lead to improved patient care in the future. PMID:27587028

Optimization of rotational arc station parameter optimized radiation therapy

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

Dong, P.; Ungun, B.

Purpose: To develop a fast optimization method for station parameter optimized radiation therapy (SPORT) and show that SPORT is capable of matching VMAT in both plan quality and delivery efficiency by using three clinical cases of different disease sites. Methods: The angular space from 0° to 360° was divided into 180 station points (SPs). A candidate aperture was assigned to each of the SPs based on the calculation results using a column generation algorithm. The weights of the apertures were then obtained by optimizing the objective function using a state-of-the-art GPU based proximal operator graph solver. To avoid being trappedmore » in a local minimum in beamlet-based aperture selection using the gradient descent algorithm, a stochastic gradient descent was employed here. Apertures with zero or low weight were thrown out. To find out whether there was room to further improve the plan by adding more apertures or SPs, the authors repeated the above procedure with consideration of the existing dose distribution from the last iteration. At the end of the second iteration, the weights of all the apertures were reoptimized, including those of the first iteration. The above procedure was repeated until the plan could not be improved any further. The optimization technique was assessed by using three clinical cases (prostate, head and neck, and brain) with the results compared to that obtained using conventional VMAT in terms of dosimetric properties, treatment time, and total MU. Results: Marked dosimetric quality improvement was demonstrated in the SPORT plans for all three studied cases. For the prostate case, the volume of the 50% prescription dose was decreased by 22% for the rectum and 6% for the bladder. For the head and neck case, SPORT improved the mean dose for the left and right parotids by 15% each. The maximum dose was lowered from 72.7 to 71.7 Gy for the mandible, and from 30.7 to 27.3 Gy for the spinal cord. The mean dose for the pharynx and larynx was reduced by 8% and 6%, respectively. For the brain case, the doses to the eyes, chiasm, and inner ears were all improved. SPORT shortened the treatment time by ∼1 min for the prostate case, ∼0.5 min for brain case, and ∼0.2 min for the head and neck case. Conclusions: The dosimetric quality and delivery efficiency presented here indicate that SPORT is an intriguing alternative treatment modality. With the widespread adoption of digital linac, SPORT should lead to improved patient care in the future.« less

Phase 1 first-in-human studies of the reactogenicity and immunogenicity of a recombinant meningococcal NspA vaccine in healthy adults.

PubMed

Halperin, Scott A; Langley, Joanne M; Smith, Bruce; Wunderli, Peter; Kaufman, Lisa; Kimura, Alan; Martin, Denis

2007-01-05

Neisserial surface protein A (NspA) is a highly conserved, surface-exposed outer membrane protein of Neisseria meningitidis that has been shown to induce a bactericidal immune response in animals against all pathogenic Neisserial serogroups. Healthy 18-50-year-old adults were assigned to receive, in a dose escalating manner, 3 doses of 1 of 5 formulations of an experimental, unfolded, recombinant NspA (rNspA) vaccine or placebo, or 1 dose of commercially available quadravalent (A, C, Y, W-135) meningococcal polysaccharide vaccine (Menomune((R))). Adverse events were collected during the first week post-immunization, prior to the next dose and 1 month after the last dose. Serum for measurement of hematological and biochemical parameters and antibodies by enzyme immunoassay and bactericidal assay were measured before the first dose, prior to the second dose and 1 month after the last dose of vaccine. The rNspA vaccine was well tolerated by recipients. Injection-site pain was reported more frequently by recipients of the three highest doses of rNspA compared to placebo but at similar rates to the licensed meningococcal polysaccharide vaccine. Adverse events were reported less frequently after subsequent doses in the three-dose series. An antibody rise measured by enzyme immunoassay was elicited with a dose-related increase that reached a maximum with the 125mug dose. Prolongation of the dosing interval between the second and third dose appeared to be associated with increased antibody levels. No bactericidal antibodies were detected after any of the rNspA formulations. The unfolded rNspA meningococcal vaccine was well tolerated and immunogenic in healthy adult volunteers but did not elicit bactericidal antibodies.

Expanding the Parameters for Excellence in Patient Assignments: Is Leveraging an Evidence-Data-Based Acuity Methodology Realistic?

PubMed

Gray, Joel; Kerfoot, Karlene

2016-01-01

Finding the balance of equitable assignments continues to be a challenge for health care organizations seeking to leverage evidence-based leadership practices. Ratios and subjective acuity strategies for nurse-patient staffing continue to be the dominant approach in health care organizations. In addition to ratio-based assignments and acuity-based assignment models driven by financial targets, more emphasis on using evidence-based leadership strategies to manage and create science for effective staffing is needed. In particular, nurse leaders are challenged to increase the sophistication of management of patient turnover (admissions, discharges, and transfers) and integrate tools from Lean methodologies and quality management strategies to determine the effectiveness of nurse-patient staffing.

Axitinib with or without dose titration for first-line metastatic renal-cell carcinoma: a randomised double-blind phase 2 trial

PubMed Central

Rini, Brian I; Melichar, Bohuslav; Ueda, Takeshi; GrÜnwald, Viktor; Fishman, Mayer N; Arranz, José A; Bair, Angel H; Pithavala, Yazdi K; Andrews, Glen I; Pavlov, Dmitri; Kim, Sinil; Jonasch, Eric

2014-01-01

Summary Background Population pharmacokinetic data suggest axitinib plasma exposure correlates with efficacy in metastatic renal-cell carcinoma. Axitinib dose titration might optimise exposure and improve outcomes. We prospectively assessed the efficacy and safety of axitinib dose titration in previously untreated patients with metastatic renal-cell carcinoma. Methods In this randomised, double-blind, multicentre, phase 2 study, patients were enrolled from 49 hospitals and outpatient clinics in the Czech Republic, Germany, Japan, Russia, Spain, and USA. Patients with treatment-naive metastatic renal-cell carcinoma received axitinib 5 mg twice daily during a 4 week lead-in period. Those patients with blood pressure 150/90 mm Hg or lower, no grade 3 or 4 treatment-related toxic effects, no dose reductions, and no more than two antihypertensive drugs for 2 consecutive weeks were stratified by Eastern Cooperative Oncology Group performance status (0 vs 1), and then randomly assigned (1:1) to either masked titration with axitinib to total twice daily doses of 7 mg, and then 10 mg, if tolerated, or placebo titration. Patients who did not meet these criteria continued without titration. The primary objective was comparison of the proportion of patients achieving an objective response between randomised groups. Safety analyses were based on all patients who received at least one dose of axitinib. This ongoing trial is registered with ClinicalTrials.gov, number NCT00835978. Findings Between Sept 2, 2009, and Feb 28, 2011, we enrolled 213 patients, of whom 112 were randomly assigned to either the axitinib titration group (56 patients) or the placebo titration group (56 patients). 91 were not eligible for titration, and ten withdrew during the lead-in period. 30 patients (54%, 95% CI 40–67) in the axitinib titration group had an objective response, as did 19 patients (34%, 22–48]) in the placebo titration group (one-sided p=0·019). 54 (59%, 95% CI 49–70) of non-randomised patients achieved an objective response. Common grade 3 or worse, all-causality adverse events in treated patients were hypertension (ten [18%] of 56 in the axitinib titration group vs five [9%] of 56 in the placebo titration group vs 45 [49%] of 91 in the non-randomised group), diarrhoea (seven [13%] vs two [4%] vs eight [9%]), and decreased weight (four [7%] vs three [5%] vs six [7%]). One or more all-causality serious adverse events were reported in 15 (27%) patients in the axitinib titration group, 13 (23%) patients in the placebo titration group, and 35 (38%) non-randomised patients. The most common serious adverse events in all 213 patients were disease progression and dehydration (eight each [4%]), and diarrhoea, vomiting, pneumonia, and decreased appetite (four each [2%]). Interpretation The greater proportion of patients in the axitinib titration group achieving an objective response supports the concept of individual axitinib dose titration in selected patients with metastatic renal-cell carcinoma. Axitinib shows clinical activity with a manageable safety profile in treatment-naive patients with this disease. Funding Pfizer Inc. PMID:24140184

Safety and immunogenicity of the rVSV∆G-ZEBOV-GP Ebola virus vaccine candidate in healthy adults: a phase 1b randomised, multicentre, double-blind, placebo-controlled, dose-response study.

PubMed

Heppner, D Gray; Kemp, Tracy L; Martin, Brian K; Ramsey, William J; Nichols, Richard; Dasen, Emily J; Link, Charles J; Das, Rituparna; Xu, Zhi Jin; Sheldon, Eric A; Nowak, Teresa A; Monath, Thomas P

2017-08-01

The 2014 Zaire Ebola virus outbreak highlighted the need for a safe, effective vaccine with a rapid onset of protection. We report the safety and immunogenicity of the recombinant vesicular stomatitis virus-Zaire Ebola virus envelope glycoprotein vaccine (rVSV∆G-ZEBOV-GP) across a 6 log 10 dose range in two sequential cohorts. In this phase 1b double-blind, placebo-controlled, dose-response study we enrolled and randomly assigned healthy adults (aged 18-61 years) at eight study sites in the USA to receive a single injection of vaccine or placebo, administered by intramuscular injection. In cohort 1, participants were assigned to receive 3 × 10 3 , 3 × 10 4 , 3 × 10 5 , or 3 × 10 6 PFU doses of rVSV∆G-ZEBOV-GP or placebo. In cohort 2, participants were assigned to receive 3 × 10 6 , 9 × 10 6 , 2 × 10 7 , or 1 × 10 8 PFU doses of rVSV∆G-ZEBOV-GP or placebo. Participants were centrally allocated by the study statistician to vaccine groups or placebo through computer-generated randomisation lists. The primary safety outcome was incidence of adverse events within 14 days in the modified intention-to-treat population (all randomly assigned participants who received vaccine or placebo), and the primary outcome for immunogenicity was IgG ELISA antibody titres at day 28 in the per-protocol population. Surveillance was enhanced for arthritis and dermatitis through to day 56. This study is registered with ClinicalTrials.gov, number NCT02314923. Between Dec 26, 2014, and June 8, 2015, 513 participants were enrolled and randomly assigned; one was not immunised because of unsuccessful phlebotomy. In cohort 1, 256 participants received vaccine (3 × 10 3 [n=64], 3 × 10 4 [n=64], 3 × 10 5 [n=64], or 3 × 10 6 PFU [n=64]) and 74 received placebo. In cohort 2, 162 participants received vaccine (3 × 10 6 [n=20], 9 × 10 6 [n=47], 2 × 10 7 [n=47], or 1 × 10 8 PFU [n=48]) and 20 received placebo. Most adverse events occurred in the first day after vaccination, and were mild to moderate in intensity, of a short duration, and more frequent at high vaccine doses (9 × 10 6 PFU and greater). At the 2 × 10 7 PFU dose (used in phase 3 trials), the most common local adverse events versus placebo within the first 14 days were arm pain (57·4% [27 of 47] vs 7·4% [seven of 94]) and local tenderness (59·6% [28 of 47] vs 8·5% [eight of 94]). The most common systemic adverse events at the 2 × 10 7 PFU dose versus placebo, occurring in the first 14 days, were headache (46·8% [22 of 47] vs 27·7% [26 of 94]), fatigue (38·3% [18 of 47] vs 19·1% [18 of 94]), myalgia (34·0% [16 of 47] vs 10·6% [10 of 94]), subjective fever (29·8% [14 of 47] vs 2·1% [two of 94]), shivering or chills (27·7% [13 of 47] vs 7·4% [seven of 94]), sweats (23·4% [11 of 47] vs 3·2% [three of 94]), joint aches and pain (19·1% [nine of 47] vs 7·4% [seven of 94]), objective fever (14·9% [seven of 47] vs 1·1% [one of 94]), and joint tenderness or swelling (14·9% [seven of 47] vs 2·1% [two of 94]). Self-limited, post-vaccination arthritis occurred in 4·5% (19 of 418) of vaccinees (median onset 12·0 days [IQR 10-14]; median duration 8·0 days [6-15]) versus 3·2% (three of 94) of controls (median onset 15·0 days [6-20]; median duration 47·0 days [37-339]), with no apparent dose relationship. Post-vaccination dermatitis occurred in 5·7% (24 of 418) of vaccinees (median onset 9·0 days [IQR 2-12]; median duration 7·0 days [4-9]) versus 3·2% (three of 94) of controls (median onset 5·0 days [3-53]; median duration 33·0 days [5-370]). A low-level, transient, dose-dependent viraemia occurred in concert with early reactogenicity. Antibody responses were observed in most participants by day 14. IgG and neutralising antibody titres were dose-related (p=0·0003 for IgG ELISA and p<0·0001 for the 60% plaque-reduction neutralisation test [PRNT60] by linear trend). On day 28 at the 2 × 10 7 PFU dose, the geometric mean IgG ELISA endpoint titre was 1624 (95% CI 1146-2302) and seroconversion was 95·7% (95% CI 85·5-98·8); the geometric mean neutralising antibody titre by PRNT60 was 250 (176-355) and seroconversion was 95·7% (85·5-98·8). These robust immunological responses were sustained for 1 year. rVSV∆G-ZEBOV-GP was well tolerated and stimulated a rapid onset of binding and neutralising antibodies, which were maintained through to day 360. The immunogenicity results support selection of the 2 × 10 7 PFU dose. Biomedical Advanced Research and Development Authority, US Department of Health and Human Services. Copyright © 2017 Elsevier Ltd. All rights reserved.

Randomized dose-ranging study of the safety and efficacy of WR 238605 (Tafenoquine) in the prevention of relapse of Plasmodium vivax malaria in Thailand.

PubMed

Walsh, D S; Looareesuwan, S; Wilairatana, P; Heppner, D G; Tang, D B; Brewer, T G; Chokejindachai, W; Viriyavejakul, P; Kyle, D E; Milhous, W K; Schuster, B G; Horton, J; Braitman, D J; Brueckner, R P

1999-10-01

WR 238605 is an 8-aminoquinoline developed for the radical cure of Plasmodium vivax. Forty-four P. vivax-infected patients were randomly assigned to 1 of 4 treatment regimens: 3 groups received a blood schizonticidal dose of chloroquine followed by WR 238605: group A (n=15) received 300 mg daily for 7 days; group B (n=11), 500 mg daily for 3 days, repeated 1 week after the initial dose; group C (n=9), 1 dose of 500 mg. A fourth group (D; n=9) received chloroquine only. Among patients who completed 2-6 months of follow-up (n=23), there was 1 relapse in group B (day 120) and 1 in group C (day 112). Among patients treated with chloroquine only, there were 4 relapses (days 40, 43, 49, and 84). WR 238605 was safe, well tolerated, and effective in preventing P. vivax relapse.

[Comparative study on the tolerance and efficacy of high doses of metoclopramide and clebopride in vomiting induced by cisplatin].

PubMed

Martín, M; Díaz-Rubio, E

1989-06-10

Forty-one patients treated with cisplatin (100-120 mg/m2), alone or associated with vindesine (3 mg/m2), were included in a randomized crossover pilot study which compared 3 different doses of intravenous clebopride with intravenous metoclopramide. The patients were randomly assigned to receive clebopride in the first chemotherapy course in one of the three dose levels used (0.5 mg/kg, 21 patients; 0.75 mg/kg, 11 patients; 1 mg/kg, 10 patients) or metoclopramide (10 mg/kg). In the second course of the same chemotherapy the patients received the alternative antiemetic, and thus each patient was his own control. The total dose of both antiemetic drugs was infused in 5 intravenous fractions given every 2 hours. The antiemetic activity of clebopride was moderately lower to that of metoclopramide with the first two tested doses (overall doses of 0.5 and 0.75 mg/kg) and similar with the last dose (1 mg/kg). Clebopride was reasonably well tolerated at the used dosages, inducing sedation in 20% of cases (versus 24% with metoclopramide) and diarrhea in 37% (versus 20% with metoclopramide). Extrapyramidal reactions developed in 17% of the courses which included metoclopramide and in none including clebopride. This difference was statistically significant.

Comparing Looping Teacher-Assigned and Traditional Teacher-Assigned Student Achievement Scores

ERIC Educational Resources Information Center

Lloyd, Melissa C.

2014-01-01

A problem in many elementary schools is determining which teacher assignment strategy best promotes the academic progress of students. To find and implement educational practices that address the academic needs of all learners, schools need research-based data focusing on the 2 teacher assignment strategies: looping assignment (LA) and traditional…

Effects of Fresh Yellow Onion Consumption on CEA, CA125 and Hepatic Enzymes in Breast Cancer Patients: A Double- Blind Randomized Controlled Clinical Trial.

PubMed

Jafarpour-Sadegh, Farnaz; Montazeri, Vahid; Adili, Ali; Esfehani, Ali; Rashidi, Mohammad-Reza; Mesgari, Mehran; Pirouzpanah, Saeed

2015-01-01

Onion (Allium cepa) consumption has been remarked in folk medicine which has not been noted to be administered so far as an adjunct to conventional doxorubicin-based chemotherapy in breast cancer patients. To our knowledge, this is the first study aimed to investigate the effects of consuming fresh yellow onions on hepatic enzymes and cancer specific antigens compared with a low-onion containing diet among breast cancer (BC) participants treated with doxorubicin. This parallel design randomized controlled clinical trial was conducted on 56 BC patients whose malignancy was confirmed with histopathological examination. Subjects were assigned in a stratified-random allocation into either group received body mass index dependent 100-160 g/d of onion as high onion group (HO; n=28) or 30-40 g/d small onion in low onion group (LO; n=28) for eight weeks intervention. Participants, care givers and laboratory assessor were blinded to the assignments (IRCT registry no: IRCT2012103111335N1). The compliance of participants in the analysis was appropriate (87.9%). Comparing changes throughout pre- and post-dose treatments indicated significant controls on carcinoembryonic antigen, cancer antigen-125 and alkaline phosphatase levels in the HO group (P<0.05). Our findings for the first time showed that regular onion administration could be effective for hepatic enzyme conveying adjuvant chemotherapy relevant toxicity and reducing the tumor markers in BC during doxorubicin-based chemotherapy.

Reduction of Sulfonylurea with the Initiation of Basal Insulin in Patients with Inadequately Controlled Type 2 Diabetes Mellitus Undergoing Long-Term Sulfonylurea-Based Treatment.

PubMed

Yang, Yeoree; Shin, Jeong Ah; Yang, Hae Kyung; Lee, Seung Hwan; Ko, Seung Hyun; Ahn, Yu Bae; Yoon, Kun Ho; Cho, Jae Hyoung

2016-12-01

There were a limited number of studies about β-cell function after insulin initiation in patients exposed to long durations of sulfonylurea treatment. In this study, we aimed to evaluate the recovery of β-cell function and the efficacy of concurrent sulfonylurea use after the start of long-acting insulin. In this randomized controlled study, patients with type 2 diabetes mellitus (T2DM), receiving sulfonylurea for at least 2 years with glycosylated hemoglobin (HbA1c) >7%, were randomly assigned to two groups: sulfonylurea maintenance (SM) and sulfonylurea reduction (SR). Following a 75-g oral glucose tolerance test (OGTT), we administered long-acting basal insulin to the two groups. After a 6-month follow-up, we repeated the OGTT. Among 69 enrolled patients, 57 completed the study and were analyzed: 31 in the SM and 26 in the SR group. At baseline, there was no significant difference except for the longer duration of diabetes and lower triglycerides in the SR group. After 6 months, the HbA1c was similarly reduced in both groups, but there was little difference in the insulin dose. In addition, insulin secretion during OGTT was significantly increased by 20% to 30% in both groups. A significant weight gain was observed in the SM group only. The insulinogenic index was more significantly improved in the SR group. Long-acting basal insulin replacement could improve the glycemic status and restore β-cell function in the T2DM patients undergoing sulfonylurea-based treatment, irrespective of the sulfonylurea dose reduction. The dose reduction of the concurrent sulfonylurea might be beneficial with regard to weight grain.

Progressive Staging of Pilot Studies to Improve Phase III Trials for Motor Interventions

PubMed Central

Dobkin, Bruce H.

2014-01-01

Based on the suboptimal research pathways that finally led to multicenter randomized clinical trials (MRCTs) of treadmill training with partial body weight support and of robotic assistive devices, strategically planned successive stages are proposed for pilot studies of novel rehabilitation interventions Stage 1, consideration-of-concept studies, drawn from animal experiments, theories, and observations, delineate the experimental intervention in a small convenience sample of participants, so the results must be interpreted with caution. Stage 2, development-of-concept pilots, should optimize the components of the intervention, settle on most appropriate outcome measures, and examine dose-response effects. A well-designed study that reveals no efficacy should be published to counterweight the confirmation bias of positive trials. Stage 3, demonstration-of-concept pilots, can build out from what has been learned to test at least 15 participants in each arm, using random assignment and blinded outcome measures. A control group should receive an active practice intervention aimed at the same primary outcome. A third arm could receive a substantially larger dose of the experimental therapy or a combinational intervention. If only 1 site performed this trial, a different investigative group should aim to reproduce positive outcomes based on the optimal dose of motor training. Stage 3 studies ought to suggest an effect size of 0.4 or higher, so that approximately 50 participants in each arm will be the number required to test for efficacy in a stage 4, proof-of-concept MRCT. By developing a consensus around acceptable and necessary practices for each stage, similar to CONSORT recommendations for the publication of phase III clinical trials, better quality pilot studies may move quickly into better designed and more successful MRCTs of experimental interventions. PMID:19240197

Linking implementation process to intervention outcomes in a middle school obesity prevention curriculum, ‘Choice, Control and Change’

PubMed Central

Gray, Heewon Lee; Contento, Isobel R.; Koch, Pamela A.

2015-01-01

This study investigates the link between process evaluation components and the outcomes of a school-based nutrition curriculum intervention, ‘Choice, Control and Change’. Ten New York City public middle schools were recruited and randomly assigned into intervention or control condition. The curriculum was to improve sixth to seventh grade students’ energy balance related behaviors, based on social cognitive and self-determination theories, and implemented during the 2006–2007 school year (n = 1136). Behaviors and psychosocial variables were measured by self-reported questionnaires. Process components were evaluated with classroom observations, teacher interviews, and a student questionnaire. Using ‘Teacher Implementation’ (dose delivered) and ‘Student Reception’ (dose received) process data; intervention group was further categorized into medium- and high-implementation groups. Analysis of covariance revealed that, compared with control group, only high-implementation group showed significant improvement in students’ behavior and psychosocial outcomes. Hierarchical linear models showed that ‘Teacher Implementation’ and ‘Student Reception’ significantly predicted students’ sweetened beverage outcomes (P < 0.05). ‘Student Satisfaction’ was also greater when these implementation components were higher, and significantly associated with behavior and psychosocial outcomes (P < 0.05). Implementation process influenced the effectiveness of the ‘Choice, Control and Change’ intervention study. It is important to take into account the process components when interpreting the results of such research. PMID:25700557

Boron.

PubMed

2008-01-01

To evaluate the scientific evidence on boron including expert opinion, folkloric precedent, history, pharmacology, kinetics/dynamics, interactions, adverse effects, toxicology, and dosing. This review serves as a clinical support tool. Electronic searches were conducted in nine databases, 20 additional journals (not indexed in common databases), and bibliographies from 50 selected secondary references. No restrictions were placed on language or quality of publications. All literature collected pertained to efficacy in humans, dosing, precautions, adverse effects, use in pregnancy/lactation, interactions, alteration of laboratory assays, and mechanisms of action. Standardized inclusion/exclusion criteria are utilized for selection. Grades were assigned using an evidence-based grading rationale. There was a lack of systematic study on the safety and effectiveness of boron in humans. However, based on popular use and supportive scientific data, nine indications are discussed in this review: hormone regulation, improving cognitive function, osteoarthritis, osteoporosis, vaginitis (topical), bodybuilding aid (increasing testosterone), menopausal symptoms, prevention of blood clotting (coagulation effects), and psoriasis (topical). Although studies assessing the use of boron for osteoarthritis and osteoporosis are in preliminary stages, reports are promising. There is conflicting evidence to support the use of boron in hormonal regulation and cognitive function. Future randomized controlled trials are warranted. There is fair negative evidence regarding the use of boron as an anticoagulant, a bodybuilding aid, for menopausal symptoms, or for psoriasis. Excessive use may be harmful, and caution is advised.

T cells expressing CD19 chimeric antigen receptors for acute lymphoblastic leukaemia in children and young adults: a phase 1 dose-escalation trial.

PubMed

Lee, Daniel W; Kochenderfer, James N; Stetler-Stevenson, Maryalice; Cui, Yongzhi K; Delbrook, Cindy; Feldman, Steven A; Fry, Terry J; Orentas, Rimas; Sabatino, Marianna; Shah, Nirali N; Steinberg, Seth M; Stroncek, Dave; Tschernia, Nick; Yuan, Constance; Zhang, Hua; Zhang, Ling; Rosenberg, Steven A; Wayne, Alan S; Mackall, Crystal L

2015-02-07

Chimeric antigen receptor (CAR) modified T cells targeting CD19 have shown activity in case series of patients with acute and chronic lymphocytic leukaemia and B-cell lymphomas, but feasibility, toxicity, and response rates of consecutively enrolled patients treated with a consistent regimen and assessed on an intention-to-treat basis have not been reported. We aimed to define feasibility, toxicity, maximum tolerated dose, response rate, and biological correlates of response in children and young adults with refractory B-cell malignancies treated with CD19-CAR T cells. This phase 1, dose-escalation trial consecutively enrolled children and young adults (aged 1-30 years) with relapsed or refractory acute lymphoblastic leukaemia or non-Hodgkin lymphoma. Autologous T cells were engineered via an 11-day manufacturing process to express a CD19-CAR incorporating an anti-CD19 single-chain variable fragment plus TCR zeta and CD28 signalling domains. All patients received fludarabine and cyclophosphamide before a single infusion of CD19-CAR T cells. Using a standard 3 + 3 design to establish the maximum tolerated dose, patients received either 1 × 10(6) CAR-transduced T cells per kg (dose 1), 3 × 10(6) CAR-transduced T cells per kg (dose 2), or the entire CAR T-cell product if sufficient numbers of cells to meet the assigned dose were not generated. After the dose-escalation phase, an expansion cohort was treated at the maximum tolerated dose. The trial is registered with ClinicalTrials.gov, number NCT01593696. Between July 2, 2012, and June 20, 2014, 21 patients (including eight who had previously undergone allogeneic haematopoietic stem-cell transplantation) were enrolled and infused with CD19-CAR T cells. 19 received the prescribed dose of CD19-CAR T cells, whereas the assigned dose concentration could not be generated for two patients (90% feasible). All patients enrolled were assessed for response. The maximum tolerated dose was defined as 1 × 10(6) CD19-CAR T cells per kg. All toxicities were fully reversible, with the most severe being grade 4 cytokine release syndrome that occurred in three (14%) of 21 patients (95% CI 3·0-36·3). The most common non-haematological grade 3 adverse events were fever (nine [43%] of 21 patients), hypokalaemia (nine [43%] of 21 patients), fever and neutropenia (eight [38%] of 21 patients), and cytokine release syndrome (three [14%) of 21 patients). CD19-CAR T cell therapy is feasible, safe, and mediates potent anti-leukaemic activity in children and young adults with chemotherapy-resistant B-precursor acute lymphoblastic leukaemia. All toxicities were reversible and prolonged B-cell aplasia did not occur. National Institutes of Health Intramural funds and St Baldrick's Foundation. Copyright © 2015 Elsevier Ltd. All rights reserved.

A randomized controlled trial of interim methadone maintenance.

PubMed

Schwartz, Robert P; Highfield, David A; Jaffe, Jerome H; Brady, Joseph V; Butler, Carol B; Rouse, Charles O; Callaman, Jason M; O'Grady, Kevin E; Battjes, Robert J

2006-01-01

Effective alternatives to long waiting lists for entry into methadone hydrochloride maintenance treatment are needed to reduce the complications of continuing heroin dependence and to increase methadone treatment entry. To compare the effectiveness of interim methadone maintenance with that of the usual waiting list condition in facilitating methadone treatment entry and reducing heroin and cocaine use and criminal behavior. Randomized, controlled, clinical trial using 2 conditions, with treatment assignment on a 3:2 basis to interim maintenance-waiting list control. A methadone treatment program in Baltimore. A total of 319 individuals meeting the criteria for current heroin dependence and methadone maintenance treatment. Participants were randomly assigned to either interim methadone maintenance, consisting of an individually determined methadone dose and emergency counseling only for up to 120 days, or referral to community-based methadone treatment programs. Entry into comprehensive methadone maintenance therapy at 4 months from baseline; self-reported days of heroin use, cocaine use, and criminal behavior; and number of urine drug test results positive for heroin and cocaine at the follow-up interview conducted at time of entry into comprehensive methadone treatment (or at 4 months from baseline for participants who did not enter regular treatment). Significantly more participants assigned to the interim methadone maintenance condition entered comprehensive methadone maintenance treatment by the 120th day from baseline (75.9%) than those assigned to the waiting list control condition (20.8%) (P<.001). Overall, in the past 30 days at follow-up, interim participants reported significantly fewer days of heroin use (P<.001), had a significant reduction in heroin-positive drug test results (P<.001), reported spending less money on drugs (P<.001), and received less illegal income (P<.02) than the waiting list participants. Interim methadone maintenance results in a substantial increase in the likelihood of entry into comprehensive treatment, and is an effective means of reducing heroin use and criminal behavior among opioid-dependent individuals awaiting entry into a comprehensive methadone treatment program.

Proof-of-principle evaluation of the efficacy of fewer than three doses of a bivalent HPV16/18 vaccine.

PubMed

Kreimer, Aimée R; Rodriguez, Ana Cecilia; Hildesheim, Allan; Herrero, Rolando; Porras, Carolina; Schiffman, Mark; González, Paula; Solomon, Diane; Jiménez, Silvia; Schiller, John T; Lowy, Douglas R; Quint, Wim; Sherman, Mark E; Schussler, John; Wacholder, Sholom

2011-10-05

Three-dose regimens for human papillomavirus (HPV) vaccines are expensive and difficult to complete, especially in settings where the need for cervical cancer prevention is greatest. We evaluated the vaccine efficacy of fewer than three doses of the HPV16/18 vaccine Cervarix in our Costa Rica Vaccine Trial. Women were randomly assigned to receive three doses of the HPV16/18 vaccine or to a control vaccine and were followed for incident HPV16 or HPV18 infection that persisted in visits that were 10 or more months apart (median follow-up 4.2 years). After excluding women who had no follow-up or who were HPV16 and HPV18 DNA positive at enrollment, 5967 women received three vaccine doses (2957 HPV vaccine vs 3010 control vaccine), 802 received two doses (422 HPV vs. 380 control), and 384 received one dose (196 HPV vs. 188 control). Reasons for receiving fewer doses and other pre- and post-randomization characteristics were balanced within each dosage group between women receiving the HPV and control vaccines. Incident HPV16 or HPV18 infections that persisted for 1 year were unrelated to dosage of the control vaccine. Vaccine efficacy was 80.9% for three doses of the HPV vaccine (95% confidence interval [CI] = 71.1% to 87.7%; 25 and 133 events in the HPV and control arms, respectively), 84.1% for two doses (95% CI = 50.2% to 96.3%; 3 and 17 events), and 100% for one dose (95% CI = 66.5% to 100%; 0 and 10 events). Four years after vaccination of women who appeared to be uninfected, this nonrandomized analysis suggests that two doses of the HPV16/18 vaccine, and maybe even one dose, are as protective as three doses.

Assessment of pharmacokinetic proportionality of levofloxacin and cyclosporine over a 100-fold dose range in healthy human volunteers.

PubMed

Lim, Mi-sun; Seong, Sook Jin; Park, Jeonghyeon; Seo, Jeong Ju; Lee, Joomi; Yu, Kyung-Sang; Lee, Hae Won; Yoon, Young-Ran

2012-04-01

Levofloxacin and cyclosporine show different pharmacokinetic properties, but are known to be dose proportional within the therapeutic range. The authors evaluated the pharmacokinetic proportionality of levofloxacin and cyclosporine over a 100-fold dose range in healthy human volunteers, by liquid chromatography-tandem mass spectrometry (LC-MS/MS). Two independent, randomized, crossover studies were performed. For levofloxacin, eight volunteers were randomly assigned in a 1:1 ratio to receive a low dose (7.5 mg) orally or intravenously, followed by a 1-week washout period and administration via the alternate route. After another 1-week washout period, a therapeutic dose (750 mg) was administered to all eight subjects. For cyclosporine, another eight volunteers received a low dose (2 mg) or a therapeutic dose (200 mg) orally with a 1-week washout period. Drug concentrations were determined by LC-MS/MS. For levofloxacin, the mean values for dose-normalized C(max) and AUC(last) with the two doses were as follows: therapeutic dose, 15.2 ± 4.6 ng/ml/mg and 103.6 ± 15.5 ng·h/ml/mg, respectively; low dose, 17.1 ± 6.5 ng/ml/mg and 72.6 ± 8.7 ng·h/ml/mg, respectively. For cyclosporine, the mean values for dose-normalized C(max) and AUC(last) were as follows: therapeutic dose, 4.9 ± 1.5 ng/ml/mg and 15.4 ± 4.9 ng·h/ml/mg, respectively; low dose, 1.6 ± 0.6 ng/ml/mg and 9.3 ± 7.3 ng·h/ml/mg, respectively. In this study levofloxacin, which is completely absorbed and primarily eliminated renally without modification, showed better pharmacokinetic proportionality than cyclosporine, which is poorly absorbed and extensively metabolized.

The effects of nitroglycerin, norepinephrine and aminophylline on intrapulmonary arteriovenous anastomoses in healthy humans at rest.

PubMed

Lozo, Mislav; Lojpur, Mihajlo; Madden, Dennis; Lozo, Petar; Banic, Ivana; Dujic, Zeljko

2014-08-01

We have investigated the effects of the intravenous infusion of nitroglycerin (NTG), norepinephrine (NE) and aminophylline (AMP) on the opening and recruitment of intrapulmonary arteriovenous anastomoses (IPAVA) in healthy humans at rest. In ten volunteers saline contrast echocardiography was performed during administration of two doses of the NTG (3μgkg(-1)min(-1) and 6μgkg(-1)min(-1)) and NE (0.1μgkg(-1)min(-1) and 0.25μgkg(-1)min(-1)) as well as 30min following the administration of AMP at rate of 6mgkg(-1). Echocardiography was used to assign bubble scores (0-5) based on the number and spatial distribution of bubbles in the left ventricle. Doppler ultrasound was used to estimate pulmonary artery systolic pressure. Using a Finometer the following hemodynamic parameters were assessed: heart rate, stroke volume, cardiac output, total peripheral resistance as well as systolic, diastolic and mean arterial pressure. The most important finding from the current study was that nitroglycerin, norepinephrine and aminophylline in the applied doses were not found to promote IPAVA opening in healthy humans at rest. Copyright © 2014 Elsevier B.V. All rights reserved.

Efficacy of oxfendazole and fenbendazole against tortoise (Testudo hermanni) oxyurids.

PubMed

Giannetto, S; Brianti, E; Poglayen, G; Sorgi, C; Capelli, G; Pennisi, M G; Coci, G

2007-04-01

Thirty-six tortoises (Testudo hermanni) with naturally acquired oxyurids infections were used to assess the anthelmintic efficacy of oxfendazole (Dolthene; Merial) and fenbendazole (Panacur; Hoechst Roussel Vet). Animals were randomly assigned to three groups (A, B, and C) based on sex and weight. Animals in group A (seven males and six females) were orally treated with oxfendazole at dose rate of 66 mg/kg, group B animals (nine males and eight females) were orally treated with fenbendazole at dose rate of 100 mg/kg, and group C animals (three males and three females) were not treated and served as controls. All animals were individually stabled in plexiglas boxes under controlled conditions of temperature, humidity, and light beginning 7 days pretreatment and continuing for the duration of the trial. Individual tortoises feces were examined daily by the McMaster technique and drugs efficacy was assessed by the fecal eggs count reduction (FECR) test. Both drugs showed 100% of FECR. However, oxfendazole reached this level 12 days after treatment, whereas 31 days after treatment were necessary to obtain the same stable result with fenbendazole. The two drugs were well tolerated by all the animals and no adverse reactions were observed after treatment.

Validity of mini-dose gallium for objective quantification of alveolitis in pulmonary sarcoidosis

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

Vitti, R.; Maurer, A.H.; Siegel, J.A.

1985-05-01

Patents (pts) with pulmonary sarcoidosis will often have frequent gallium (Ga) studies to assess the response of alveolitis to corticosteroid therapy. Since many pts are young and the cumulative radiation burden significant the authors have evaluated the ability of computer based Ga lung imaging to reliably quantify Ga activity using a 0.5 mCi dose of Ga. Twelve pts with biopsy proven pulmonary sarcoidosis received 0.5 mCi of Ga-67 citrate intravenously and had a posterior view of the chest including a portion of the liver obtained at 24 hrs post injection. At 24 hrs the pts received an additional 2.5 mCimore » and were then imaged at 48 and 72 hrs. A gallium score (GS) was computer generated as follows: regions of interest (ROI's) were manually created for the lungs, liver and background. Following a 9 point spatial smooth and background subtraction, the images were scaled so that the liver activity was assigned an arbitrary value of 400 counts per pixel. The resulting average counts per pixel for the lungs were then summed for the GS. Using a paired T-test there was only a borderline significant difference (0.05« less

Immunogenicity and safety of three aluminium hydroxide adjuvanted vaccines with reduced doses of inactivated polio vaccine (IPV-Al) compared with standard IPV in young infants in the Dominican Republic: a phase 2, non-inferiority, observer-blinded, randomised, and controlled dose investigation trial.

PubMed

Rivera, Luis; Pedersen, Rasmus S; Peña, Lourdes; Olsen, Klaus J; Andreasen, Lars V; Kromann, Ingrid; Nielsen, Pernille I; Sørensen, Charlotte; Dietrich, Jes; Bandyopadhyay, Ananda S; Thierry-Carstensen, Birgit

2017-07-01

Cost and supply constraints are key challenges in the use of inactivated polio vaccine (IPV). Dose reduction through adsorption to aluminium hydroxide (Al) is a promising option, and establishing its effectiveness in the target population is a crucial milestone in developing IPV-Al. The aim of this clinical trial was to show the non-inferiority of three IPV-Al vaccines to standard IPV. In this phase 2, non-inferiority, observer-blinded, randomised, controlled, single-centre trial in the Dominican Republic, healthy infants aged 6 weeks, not previously polio vaccinated, were allocated after computer-generated randomisation by block-size of four, to receive one of four IPV formulations (three-times reduced dose [1/3 IPV-Al], five-times reduced dose [1/5 IPV-Al], ten-times reduced dose [1/10 IPV-Al], or IPV) intramuscularly in the thigh at 6, 10, and 14 weeks of age. The primary outcome was seroconversion for poliovirus types 1, 2, and 3 with titres more than or equal to four-fold higher than the estimated maternal antibody titre and more than or equal to 8 after three vaccinations. Non-inferiority was concluded if the lower two-sided 90% CI of the seroconversion rate difference between IPV-Al and IPV was greater than -10%. The safety analyses were based on the safety analysis set (randomly assigned participants who received at least one trial vaccination) and the immunogenicity analyses were based on the per-protocol population. This study is registered with ClinicalTrials.gov registration, number NCT02347423. Between Feb 2, 2015, and Sept 26, 2015, we recruited 824 infants. The per-protocol population included 820 infants; 205 were randomly assigned to receive 1/3 IPV-Al, 205 to receive 1/5 IPV-Al, 204 to receive 1/10 IPV-Al, and 206 to receive IPV. The proportion of individuals meeting the primary endpoint of seroconversion for poliovirus types 1, 2, and 3 was already high for the three IPV-Al vaccines after two vaccinations, but was higher after three vaccinations (ie, after completion of the expanded programme of immunisation schedule): 1/3 IPV-Al 98·5% (n=202, type 1), 97·6% (n=200; type 2), and 99·5% (n=204, type 3); 1/5 IPV-Al: 99·5% (n=204, type 1), 96·1% (n=197, type 2), and 98·5% (n=202, type 3); and 1/10 IPV-Al: 98·5% (n=201, type 1), 94·6% (n=193, type 2), and 99·5% (n=203, type 3). All three IPV-Al were non-inferior to IPV, with absolute differences in percentage seroconversion for each poliovirus type being greater than -10% (1/3 IPV-Al type 1, -1·46 [-3·60 to 0·10], type 2, -0·98 [-3·62 to 1·49], and type 3, -0·49 [-2·16 to 0·86]; 1/5 IPV-Al type 1, -0·49 [-2·16 to 0·86], type 2, -2·45 [-5·47 to 0·27], and type 3, -1·46 [-3·60 to 0·10]; and 1/10 IPV-Al type 1, -1·47 [-3·62 to 0·10], type 2, -3·94 [-7·28 to -0·97], and type 3, -0·49 [-2·17 to 0·86]). Three serious adverse events occurred that were unrelated to the vaccine. The lowest dose (1/10 IPV-Al) of the vaccine performed well both after two and three doses. Based on these results, this new vaccine is under investigation in phase 3 trials. Bill & Melinda Gates Foundation. Copyright © 2017 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.

A Service-Based Program Evaluation Platform for Enhancing Student Engagement in Assignments

ERIC Educational Resources Information Center

Wu, Ye-Chi; Ma, Lee Wei; Jiau, Hewijin Christine

2013-01-01

Programming assignments are commonly used in computer science education to encourage students to practice target concepts and evaluate their learning status. Ensuring students are engaged in such assignments is critical in attracting and retaining students. To this end, WebHat, a service-based program evaluation platform, is introduced in this…

Understanding Test-Type Assignment: Why Do Special Educators Make Unexpected Test-Type Assignments?

ERIC Educational Resources Information Center

Cho, Hyun-Jeong; Kingston, Neal

2014-01-01

We interviewed special educators (a) whose students with disabilities (SWDs) were proficient on the 2008 general education assessment but were assigned to the 2009 alternate assessment based on modified achievement standards (AA-MAS), and (b) whose students with mild disabilities took the 2008 alternate assessment based on alternate achievement…

Can Nonexperimental Estimates Replicate Estimates Based on Random Assignment in Evaluations of School Choice? A Within-Study Comparison

ERIC Educational Resources Information Center

Bifulco, Robert

2012-01-01

The ability of nonexperimental estimators to match impact estimates derived from random assignment is examined using data from the evaluation of two interdistrict magnet schools. As in previous within-study comparisons, nonexperimental estimates differ from estimates based on random assignment when nonexperimental estimators are implemented…

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

PubMed

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

2014-10-28

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

Computer-based coding of free-text job descriptions to efficiently identify occupations in epidemiological studies

PubMed Central

Russ, Daniel E.; Ho, Kwan-Yuet; Colt, Joanne S.; Armenti, Karla R.; Baris, Dalsu; Chow, Wong-Ho; Davis, Faith; Johnson, Alison; Purdue, Mark P.; Karagas, Margaret R.; Schwartz, Kendra; Schwenn, Molly; Silverman, Debra T.; Johnson, Calvin A.; Friesen, Melissa C.

2016-01-01

Background Mapping job titles to standardized occupation classification (SOC) codes is an important step in identifying occupational risk factors in epidemiologic studies. Because manual coding is time-consuming and has moderate reliability, we developed an algorithm called SOCcer (Standardized Occupation Coding for Computer-assisted Epidemiologic Research) to assign SOC-2010 codes based on free-text job description components. Methods Job title and task-based classifiers were developed by comparing job descriptions to multiple sources linking job and task descriptions to SOC codes. An industry-based classifier was developed based on the SOC prevalence within an industry. These classifiers were used in a logistic model trained using 14,983 jobs with expert-assigned SOC codes to obtain empirical weights for an algorithm that scored each SOC/job description. We assigned the highest scoring SOC code to each job. SOCcer was validated in two occupational data sources by comparing SOC codes obtained from SOCcer to expert assigned SOC codes and lead exposure estimates obtained by linking SOC codes to a job-exposure matrix. Results For 11,991 case-control study jobs, SOCcer-assigned codes agreed with 44.5% and 76.3% of manually assigned codes at the 6- and 2-digit level, respectively. Agreement increased with the score, providing a mechanism to identify assignments needing review. Good agreement was observed between lead estimates based on SOCcer and manual SOC assignments (kappa: 0.6–0.8). Poorer performance was observed for inspection job descriptions, which included abbreviations and worksite-specific terminology. Conclusions Although some manual coding will remain necessary, using SOCcer may improve the efficiency of incorporating occupation into large-scale epidemiologic studies. PMID:27102331

Busulfan and melphalan versus carboplatin, etoposide, and melphalan as high-dose chemotherapy for high-risk neuroblastoma (HR-NBL1/SIOPEN): an international, randomised, multi-arm, open-label, phase 3 trial.

PubMed

Ladenstein, Ruth; Pötschger, Ulrike; Pearson, Andrew D J; Brock, Penelope; Luksch, Roberto; Castel, Victoria; Yaniv, Isaac; Papadakis, Vassilios; Laureys, Geneviève; Malis, Josef; Balwierz, Walentyna; Ruud, Ellen; Kogner, Per; Schroeder, Henrik; de Lacerda, Ana Forjaz; Beck-Popovic, Maja; Bician, Pavel; Garami, Miklós; Trahair, Toby; Canete, Adela; Ambros, Peter F; Holmes, Keith; Gaze, Mark; Schreier, Günter; Garaventa, Alberto; Vassal, Gilles; Michon, Jean; Valteau-Couanet, Dominique

2017-04-01

High-dose chemotherapy with haemopoietic stem-cell rescue improves event-free survival in patients with high-risk neuroblastoma; however, which regimen has the greatest patient benefit has not been established. We aimed to assess event-free survival after high-dose chemotherapy with busulfan and melphalan compared with carboplatin, etoposide, and melphalan. We did an international, randomised, multi-arm, open-label, phase 3 cooperative group clinical trial of patients with high-risk neuroblastoma at 128 institutions in 18 countries that included an open-label randomised arm in which high-dose chemotherapy regimens were compared. Patients (age 1-20 years) with neuroblastoma were eligible to be randomly assigned if they had completed a multidrug induction regimen (cisplatin, carboplatin, cyclophosphamide, vincristine, and etoposide with or without topotecan, vincristine, and doxorubicin) and achieved an adequate disease response. Patients were randomly assigned (1:1) to busulfan and melphalan or to carboplatin, etoposide, and melphalan by minimisation, balancing age at diagnosis, stage, MYCN amplification, and national cooperative clinical group between groups. The busulfan and melphalan regimen comprised oral busulfan (150 mg/m 2 given on 4 days consecutively in four equal doses); after Nov 8, 2007, intravenous busulfan was given (0·8-1·2 mg/kg per dose for 16 doses according to patient weight). After 24 h, an intravenous melphalan dose (140 mg/m 2 ) was given. Doses of busulfan and melphalan were modified according to bodyweight. The carboplatin, etoposide, and melphalan regimen consisted of carboplatin continuous infusion of area under the plasma concentration-time curve 4·1 mg/mL per min per day for 4 days, etoposide continuous infusion of 338 mg/m 2 per day for 4 days, and melphalan 70 mg/m 2 per day for 3 days, with doses for all three drugs modified according to bodyweight and glomerular filtration rate. Stem-cell rescue was given after the last dose of high-dose chemotherapy, at least 24 h after melphalan in patients who received busulfan and melphalan and at least 72 h after carboplatin etoposide, and melphalan. All patients received subsequent local radiotherapy to the primary tumour site followed by maintenance therapy. The primary endpoint was 3-year event-free survival, analysed by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT01704716, and EudraCT, number 2006-001489-17. Between June 24, 2002, and Oct 8, 2010, 1347 patients were enrolled and 676 were eligible for random allocation, 598 (88%) of whom were randomly assigned: 296 to busulfan and melphalan and 302 to carboplatin, etoposide, and melphalan. Median follow-up was 7·2 years (IQR 5·3-9·2). At 3 years, 146 of 296 patients in the busulfan and melphalan group and 188 of 302 in the carboplatin, etoposide, and melphalan group had an event; 3-year event-free survival was 50% (95% CI 45-56) versus 38% (32-43; p=0·0005). Nine patients in the busulfan and melphalan group and 11 in the carboplatin, etoposide, and melphalan group had died without relapse by 5 years. Severe life-threatening toxicities occurred in 13 (4%) patients who received busulfan and melphalan and 29 (10%) who received carboplatin, etoposide, and melphalan. The most frequent grade 3-4 adverse events were general condition (74 [26%] of 281 in the busulfan and melphalan group vs 103 [38%] of 270 in the carboplatin, etoposide, and melphalan group), infection (55 [19%] of 283 vs 74 [27%] of 271), and stomatitis (138 [49%] of 284 vs 162 [59%] of 273); 60 (22%) of 267 patients in the busulfan and melphalan group had Bearman grades 1-3 veno-occlusive disease versus 21 (9%) of 239 in the carboplatin, etoposide, and melphalan group. Busulfan and melphalan improved event-free survival in children with high-risk neuroblastoma with an adequate response to induction treatment and caused fewer severe adverse events than did carboplatin, etoposide, and melphalan. Busulfan and melphalan should thus be considered standard high-dose chemotherapy and ongoing randomised studies will continue to aim to optimise treatment for high-risk neuroblastoma. European Commission 5th Framework Grant and the St Anna Kinderkrebsforschung. Copyright © 2017 Elsevier Ltd. All rights reserved.

Angiotensin II receptor blocker-based therapy in Japanese elderly, high-risk, hypertensive patients.

PubMed

Ogawa, Hisao; Kim-Mitsuyama, Shokei; Matsui, Kunihiko; Jinnouchi, Tomio; Jinnouchi, Hideaki; Arakawa, Kikuo

2012-10-01

It is unknown whether high-dose angiotensin II receptor blocker therapy or angiotensin II receptor blocker + calcium channel blocker combination therapy is better in elderly hypertensive patients with high cardiovascular risk. The objective of the study was to compare the efficacy of these treatments in elderly, high-risk Japanese hypertensive patients. The OlmeSartan and Calcium Antagonists Randomized (OSCAR) study was a multicenter, prospective, randomized, open-label, blinded-end point study of 1164 hypertensive patients aged 65 to 84 years with type 2 diabetes or cardiovascular disease. Patients with uncontrolled hypertension during treatment with olmesartan 20 mg/d were randomly assigned to receive 40 mg/d olmesartan (high-dose angiotensin II receptor blocker) or a calcium channel blocker + 20 mg/d olmesartan (angiotensin II receptor blocker + calcium channel blocker). The primary end point was a composite of cardiovascular events and noncardiovascular death. During a 3-year follow-up, blood pressure was significantly lower in the angiotensin II receptor blocker + calcium channel blocker group than in the high-dose angiotensin II receptor blocker group. Mean blood pressure at 36 months was 135.0/74.3 mm Hg in the high-dose angiotensin II receptor blocker group and 132.6/72.6 mm Hg in the angiotensin II receptor blocker + calcium channel blocker group. More primary end points occurred in the high-dose angiotensin II receptor blocker group than in the angiotensin II receptor blocker + calcium channel blocker group (58 vs 48 events, hazard ratio [HR], 1.31, 95% confidence interval, 0.89-1.92; P=.17). In patients with cardiovascular disease at baseline, more primary events occurred in the high-dose angiotensin II receptor blocker group (HR, 1.63, P=.03); in contrast, fewer events were observed in the subgroup without cardiovascular disease (HR, 0.52, P=.14). This treatment-by-subgroup interaction was significant (P=.02). The angiotensin II receptor blocker and calcium channel blocker combination lowered blood pressure more than the high-dose angiotensin II receptor blocker and reduced the incidence of primary end points more than the high-dose angiotensin II receptor blocker in patients with cardiovascular disease. The addition of a second antihypertensive agent is more effective at lowering blood pressure than simply doubling the dose of an existing agent. Copyright © 2012 Elsevier Inc. All rights reserved.

SU-F-J-63: Abdominal Diameter Changes in Children During Volumetric Modulated Arc Therapy (VMAT): Is Re-Planning Needed?

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

Guerreiro, F; Janssens, G; Seravalli, E

Purpose: To investigate the dosimetric impact of daily changes in patient’s diameter, due to weight gain/loss and air in the bowel, based on CBCT information during radiotherapy treatment of pediatric abdominal tumors. Methods: 10 pediatric patients with neuroblastoma (n=6) and Wilms’ (n=4) tumors were included. Available CBCTs were affinely registered to the planning CT for daily set-up variations corrections. A density override approach assigning air-density to the random air pockets and water-density to the remaining anatomy was used to determine the CBCT and CT dose. Clinical VMAT plans, with a PTV prescribed dose ranging between (14.4- 36) Gy, were re-optimizedmore » on the density override CT and re-calculated on each CBCT. Dose-volume statistics of the PTV and kidneys, delineated on each CBCT, were used to compare the daily and cumulative CBCT dose with the reference CT dose. Results: The average patient diameter variation was (0.5 ± 0.7) cm (maximum daily difference of 2.3 cm). The average PTV mean dose difference (MDD) between the CT and the cumulative CBCT plans was (0.1 ± 1.1) % (maximum daily MDD of 2%). A reduction in target coverage up to 3% and 7% was observed for the cumulative and daily CBCT plans, respectively. The average kidneys’ cumulative MDD was (−2.7 ± 3.6) % (maximum daily MDD of −12%), corresponding to an overdosage. Conclusion: Due to patient’s diameter changes, a target underdosage was assessed. Given the high local tumor control of neuroblastoma and Wilms’ diseases, the need of re-planning might be discarded. However, the assessed kidneys overdosage could represent a problem when the normal tissue tolerance is reached. The necessity of re-planning should then be considered to reduce the risk of long-term renal complications. Due to the poor softtissue contrast on CBCT, MRI-guidance is required to obtain a better assessment of the accumulated dose on the remaining OARs.« less

Safety and efficacy of multipotent adult progenitor cells in acute ischaemic stroke (MASTERS): a randomised, double-blind, placebo-controlled, phase 2 trial.

PubMed

Hess, David C; Wechsler, Lawrence R; Clark, Wayne M; Savitz, Sean I; Ford, Gary A; Chiu, David; Yavagal, Dileep R; Uchino, Ken; Liebeskind, David S; Auchus, Alexander P; Sen, Souvik; Sila, Cathy A; Vest, Jeffrey D; Mays, Robert W

2017-05-01

Multipotent adult progenitor cells are a bone marrow-derived, allogeneic, cell therapy product that modulates the immune system, and represents a promising therapy for acute stroke. We aimed to identify the highest, well-tolerated, and safest single dose of multipotent adult progenitor cells, and if they were efficacious as a treatment for stroke recovery. We did a phase 2, randomised, double-blind, placebo-controlled, dose-escalation trial of intravenous multipotent adult progenitor cells in 33 centres in the UK and the USA. We used a computer-generated randomisation sequence and interactive voice and web response system to assign patients aged 18-83 years with moderately severe acute ischaemic stroke and a National Institutes of Health Stroke Scale (NIHSS) score of 8-20 to treatment with intravenous multipotent adult progenitor cells (400 million or 1200 million cells) or placebo between 24 h and 48 h after symptom onset. Patients were ineligible if there was a change in NIHSS of four or more points during at least a 6 h period between screening and randomisation, had brainstem or lacunar infarct, a substantial comorbid disease, an inability to undergo an MRI scan, or had a history of splenectomy. In group 1, patients were enrolled and randomly assigned in a 3:1 ratio to receive 400 million cells or placebo and assessed for safety through 7 days. In group 2, patients were randomly assigned in a 3:1 ratio to receive 1200 million cells or placebo and assessed for safety through the first 7 days. In group 3, patients were enrolled, randomly assigned, and stratified by baseline NIHSS score to receive 1200 million cells or placebo in a 1:1 ratio within 24-48 h. Patients, investigators, and clinicians were masked to treatment assignment. The primary safety outcome was dose-limiting toxicity effects. The primary efficacy endpoint was global stroke recovery, which combines dichotomised results from the modified Rankin scale, change in NIHSS score from baseline, and Barthel index at day 90. Analysis was by intention to treat (ITT) including all patients in groups 2 and 3 who received the investigational agent or placebo. This study is registered with ClinicalTrials.gov, number NCT01436487. The study was done between Oct 24, 2011, and Dec 7, 2015. After safety assessments in eight patients in group 1, 129 patients were randomly assigned (67 to receive multipotent adult progenitor cells and 62 to receive placebo) in groups 2 and 3 (1200 million cells). The ITT populations consisted of 65 patients who received multipotent adult progenitor cells and 61 patients who received placebo. There were no dose-limiting toxicity events in either group. There were no infusional or allergic reactions and no difference in treatment-emergent adverse events between the groups (64 [99%] of 65 patients in the multipotent adult progenitor cell group vs 59 [97%] of 61 in the placebo group). There was no difference between the multipotent adult progenitor cell group and placebo groups in global stroke recovery at day 90 (odds ratio 1·08 [95% CI 0·55-2·09], p=0·83). Administration of multipotent adult progenitor cells was safe and well tolerated in patients with acute ischaemic stroke. Although no significant improvement was observed at 90 days in neurological outcomes with multipotent adult progenitor cells treatment, further clinical trials evaluating the efficacy of the intervention in an earlier time window after stroke (<36 h) are planned. Athersys Inc. Copyright © 2017 Elsevier Ltd. All rights reserved.

Metabarcoding of marine nematodes – evaluation of reference datasets used in tree-based taxonomy assignment approach

PubMed Central

2016-01-01

Abstract Background Metabarcoding is becoming a common tool used to assess and compare diversity of organisms in environmental samples. Identification of OTUs is one of the critical steps in the process and several taxonomy assignment methods were proposed to accomplish this task. This publication evaluates the quality of reference datasets, alongside with several alignment and phylogeny inference methods used in one of the taxonomy assignment methods, called tree-based approach. This approach assigns anonymous OTUs to taxonomic categories based on relative placements of OTUs and reference sequences on the cladogram and support that these placements receive. New information In tree-based taxonomy assignment approach, reliable identification of anonymous OTUs is based on their placement in monophyletic and highly supported clades together with identified reference taxa. Therefore, it requires high quality reference dataset to be used. Resolution of phylogenetic trees is strongly affected by the presence of erroneous sequences as well as alignment and phylogeny inference methods used in the process. Two preparation steps are essential for the successful application of tree-based taxonomy assignment approach. Curated collections of genetic information do include erroneous sequences. These sequences have detrimental effect on the resolution of cladograms used in tree-based approach. They must be identified and excluded from the reference dataset beforehand. Various combinations of multiple sequence alignment and phylogeny inference methods provide cladograms with different topology and bootstrap support. These combinations of methods need to be tested in order to determine the one that gives highest resolution for the particular reference dataset. Completing the above mentioned preparation steps is expected to decrease the number of unassigned OTUs and thus improve the results of the tree-based taxonomy assignment approach. PMID:27932919

Metabarcoding of marine nematodes - evaluation of reference datasets used in tree-based taxonomy assignment approach.

PubMed

Holovachov, Oleksandr

2016-01-01

Metabarcoding is becoming a common tool used to assess and compare diversity of organisms in environmental samples. Identification of OTUs is one of the critical steps in the process and several taxonomy assignment methods were proposed to accomplish this task. This publication evaluates the quality of reference datasets, alongside with several alignment and phylogeny inference methods used in one of the taxonomy assignment methods, called tree-based approach. This approach assigns anonymous OTUs to taxonomic categories based on relative placements of OTUs and reference sequences on the cladogram and support that these placements receive. In tree-based taxonomy assignment approach, reliable identification of anonymous OTUs is based on their placement in monophyletic and highly supported clades together with identified reference taxa. Therefore, it requires high quality reference dataset to be used. Resolution of phylogenetic trees is strongly affected by the presence of erroneous sequences as well as alignment and phylogeny inference methods used in the process. Two preparation steps are essential for the successful application of tree-based taxonomy assignment approach. Curated collections of genetic information do include erroneous sequences. These sequences have detrimental effect on the resolution of cladograms used in tree-based approach. They must be identified and excluded from the reference dataset beforehand.Various combinations of multiple sequence alignment and phylogeny inference methods provide cladograms with different topology and bootstrap support. These combinations of methods need to be tested in order to determine the one that gives highest resolution for the particular reference dataset.Completing the above mentioned preparation steps is expected to decrease the number of unassigned OTUs and thus improve the results of the tree-based taxonomy assignment approach.

Docosahexaenoic Acid and Bronchopulmonary Dysplasia in Preterm Infants.

PubMed

Collins, Carmel T; Makrides, Maria; McPhee, Andrew J; Sullivan, Thomas R; Davis, Peter G; Thio, Marta; Simmer, Karen; Rajadurai, Victor S; Travadi, Javeed; Berry, Mary J; Liley, Helen G; Opie, Gillian F; Tan, Kenneth; Lui, Kei; Morris, Scott A; Stack, Jacqueline; Stark, Michael J; Chua, Mei-Chien; Jayagobi, Pooja A; Holberton, James; Bolisetty, Srinivas; Callander, Ian R; Harris, Deborah L; Gibson, Robert A

2017-03-30

Studies in animals and in humans have suggested that docosahexaenoic acid (DHA), an n-3 long-chain polyunsaturated fatty acid, might reduce the risk of bronchopulmonary dysplasia, but appropriately designed trials are lacking. We randomly assigned 1273 infants born before 29 weeks of gestation (stratified according to sex, gestational age [<27 weeks or 27 to <29 weeks], and center) within 3 days after their first enteral feeding to receive either an enteral emulsion providing DHA at a dose of 60 mg per kilogram of body weight per day or a control (soy) emulsion without DHA until 36 weeks of postmenstrual age. The primary outcome was bronchopulmonary dysplasia, defined on a physiological basis (with the use of oxygen-saturation monitoring in selected infants), at 36 weeks of postmenstrual age or discharge home, whichever occurred first. A total of 1205 infants survived to the primary outcome assessment. Of the 592 infants assigned to the DHA group, 291 (49.1% by multiple imputation) were classified as having physiological bronchopulmonary dysplasia, as compared with 269 (43.9%) of the 613 infants assigned to the control group (relative risk adjusted for randomization strata, 1.13; 95% confidence interval [CI], 1.02 to 1.25; P=0.02). The composite outcome of physiological bronchopulmonary dysplasia or death before 36 weeks of postmenstrual age occurred in 52.3% of the infants in the DHA group and in 46.4% of the infants in the control group (adjusted relative risk, 1.11; 95% CI, 1.00 to 1.23; P=0.045). There were no significant differences between the two groups in the rates of death or any other neonatal illnesses. Bronchopulmonary dysplasia based on a clinical definition occurred in 53.2% of the infants in the DHA group and in 49.7% of the infants in the control group (P=0.06). Enteral DHA supplementation at a dose of 60 mg per kilogram per day did not result in a lower risk of physiological bronchopulmonary dysplasia than a control emulsion among preterm infants born before 29 weeks of gestation and may have resulted in a greater risk. (Funded by the Australian National Health and Medical Research Council and others; Australian New Zealand Clinical Trials Registry number, ACTRN12612000503820 .).

Safety, efficacy and pharmacokinetics of rVIII-SingleChain in children with severe hemophilia A: results of a multicenter clinical trial.

PubMed

Stasyshyn, O; Djambas Khayat, C; Iosava, G; Ong, J; Abdul Karim, F; Fischer, K; Veldman, A; Blackman, N; St Ledger, K; Pabinger, I

2017-04-01

Essentials rVIII-SingleChain is a novel recombinant factor VIII with covalently bonded heavy and light chains. Efficacy, safety and pharmacokinetics were studied in pediatric patients with severe hemophilia A. Across all prophylaxis regimens, the median annualized spontaneous bleeding rate was 0.00. rVIII-SingleChain showed excellent hemostatic efficacy and a favorable safety profile. Background rVIII-SingleChain is a novel B-domain truncated recombinant factor VIII (rFVIII) comprised of covalently bonded FVIII heavy and light chains, demonstrating a high binding affinity to von Willebrand factor. Objectives This phase III study investigated the safety, efficacy and pharmacokinetics of rVIII-SingleChain in previously treated pediatric patients < 12 years of age with severe hemophilia A. Patients/Methods Patients could be assigned to prophylaxis or on-demand therapy by the investigator. For patients assigned to prophylaxis, the treatment regimen and dose were based on the bleeding phenotype. For patients receiving on-demand therapy, dosing was guided by World Federation of Hemophilia recommendations. The primary endpoint was treatment success, defined as a rating of 'excellent' or 'good' on the investigator's clinical assessment of hemostatic efficacy for all treated bleeding events. Results The study enrolled 84 patients (0 to < 6 years, n = 35; ≥ 6 to < 12 years, n = 49); 81 were assigned to prophylaxis and three to an on-demand regimen. Patients accumulated a total of 5239 exposure days (EDs), with 65 participants reaching > 50 EDs. In the 347 bleeds treated and evaluated by the investigator, hemostatic efficacy was rated as excellent or good in 96.3%. The median annualized spontaneous bleeding rate was 0.00 (Q1, Q3: 0.00, 2.20), and the median annualized bleeding rate was 3.69 (Q1, Q3: 0.00, 7.20) across all prophylaxis regimens. No participant developed an inhibitor. Conclusions rVIII-SingleChain is a novel rFVIII molecule showing excellent hemostatic efficacy and a favorable safety profile in a clinical study in children < 12 years of age with severe hemophilia A. © 2017 The Authors. Journal of Thrombosis and Haemostasis published by Wiley Periodicals, Inc. on behalf of International Society on Thrombosis and Haemostasis.

Effect of low-dose valsartan on proteinuria in normotensive immunoglobulin A nephropathy with minimal proteinuria: a randomized trial.

PubMed

Jo, Young-Il; Na, Ha-Young; Moon, Ju-Young; Han, Sang-Woong; Yang, Dong-Ho; Lee, Sang-Ho; Park, Hyeong-Cheon; Choi, Hoon-Young; Lim, So-Dug; Kie, Jeong-Hae; Lee, Yong-Kyu; Shin, Sug-Kyun

2016-03-01

Immunoglobulin A nephropathy (IgAN) is a generally progressive disease, even in patients with favorable prognostic features. In this study, we aimed to investigate the antiproteinuric effect and tolerability of low-dose valsartan (an angiotensin II receptor blocker) therapy in normotensive IgAN patients with minimal proteinuria of less than 0.5 to 1.0 g/day. Normotensive IgAN patients, who had persistent proteinuria with a spot urine protein-to-creatinine ratio of 0.3 to 1.0 mg/mg creatinine, were recruited from five hospitals and randomly assigned to either 40 mg of valsartan as the low-dose group or 80 mg of valsartan as the regular-dose group. Clinical and laboratory data were collected at baseline, and at 4, 8, 12, and 24 weeks after valsartan therapy. Forty-three patients (low-dose group, n = 23; regular-dose group, n = 20) were enrolled in the study. Proteinuria decreased significantly not only in the regular-dose group but also in the low-dose group. The change in urine protein-to-creatinine ratio at week 24 was -41.3% ± 26.1% (p < 0.001) in the regular-dose group and -21.1% ± 45.1% (p = 0.005) in the low-dose group. In the low-dose group, blood pressure was constant throughout the study period, and there was no symptomatic hypotension. In the regular-dose group, blood pressure decreased at weeks 8 and 12. No significant change in glomerular filtration rate, serum creatinine level, or serum potassium level was observed during the study period. Our results suggest that low-dose valsartan can significantly reduce proteinuria without causing any intolerability in normotensive IgAN patients with minimal proteinuria.

Effect of low-dose valsartan on proteinuria in normotensive immunoglobulin A nephropathy with minimal proteinuria: a randomized trial

PubMed Central

Jo, Young-Il; Na, Ha-Young; Moon, Ju-Young; Han, Sang-Woong; Yang, Dong-Ho; Lee, Sang-Ho; Park, Hyeong-Cheon; Choi, Hoon-Young; Lim, So-Dug; Kie, Jeong-Hae; Lee, Yong-Kyu; Shin, Sug-Kyun

2016-01-01

Background/Aims: Immunoglobulin A nephropathy (IgAN) is a generally progressive disease, even in patients with favorable prognostic features. In this study, we aimed to investigate the antiproteinuric effect and tolerability of low-dose valsartan (an angiotensin II receptor blocker) therapy in normotensive IgAN patients with minimal proteinuria of less than 0.5 to 1.0 g/day. Methods: Normotensive IgAN patients, who had persistent proteinuria with a spot urine protein-to-creatinine ratio of 0.3 to 1.0 mg/mg creatinine, were recruited from five hospitals and randomly assigned to either 40 mg of valsartan as the low-dose group or 80 mg of valsartan as the regular-dose group. Clinical and laboratory data were collected at baseline, and at 4, 8, 12, and 24 weeks after valsartan therapy. Results: Forty-three patients (low-dose group, n = 23; regular-dose group, n = 20) were enrolled in the study. Proteinuria decreased significantly not only in the regular-dose group but also in the low-dose group. The change in urine protein-to-creatinine ratio at week 24 was −41.3% ± 26.1% (p < 0.001) in the regular-dose group and −21.1% ± 45.1% (p = 0.005) in the low-dose group. In the low-dose group, blood pressure was constant throughout the study period, and there was no symptomatic hypotension. In the regular-dose group, blood pressure decreased at weeks 8 and 12. No significant change in glomerular filtration rate, serum creatinine level, or serum potassium level was observed during the study period. Conclusions: Our results suggest that low-dose valsartan can significantly reduce proteinuria without causing any intolerability in normotensive IgAN patients with minimal proteinuria. PMID:26874511

Absorbed organ and effective doses from digital intra-oral and panoramic radiography applying the ICRP 103 recommendations for effective dose estimations

PubMed Central

Thilander-Klang, Anne; Ylhan, Betȕl; Lofthag-Hansen, Sara; Ekestubbe, Annika

2016-01-01

Objective: During dental radiography, the salivary and thyroid glands are at radiation risk. In 2007, the International Commission on Radiological Protection (ICRP) updated the methodology for determining the effective dose, and the salivary glands were assigned tissue-specific weighting factors for the first time. The aims of this study were to determine the absorbed dose to the organs and to calculate, applying the ICRP publication 103 tissue-weighting factors, the effective doses delivered during digital intraoral and panoramic radiography. Methods: Thermoluminescent dosemeter measurements were performed on an anthropomorphic head and neck phantom. The organ-absorbed doses were measured at 30 locations, representing different radiosensitive organs in the head and neck, and the effective dose was calculated according to the ICRP recommendations. Results: The salivary glands and the oral mucosa received the highest absorbed doses from both intraoral and panoramic radiography. The effective dose from a full-mouth intraoral examination was 15 μSv and for panoramic radiography, the effective dose was in the range of 19–75 μSv, depending on the panoramic equipment used. Conclusion: The effective dose from a full-mouth intraoral examination is lower and that from panoramic radiography is higher than previously reported. Clinicians should be aware of the higher effective dose delivered during panoramic radiography and the risk–benefit profile of this technique must be assessed for the individual patient. Advances in knowledge: The effective dose of radiation from panoramic radiography is higher than previously reported and there is large variability in the delivered radiation dosage among the different types of equipment used. PMID:27452261

Meta-cognitive student reflections

NASA Astrophysics Data System (ADS)

Barquist, Britt; Stewart, Jim

2009-05-01

We have recently concluded a project testing the effectiveness of a weekly assignment designed to encourage awareness and improvement of meta-cognitive skills. The project is based on the idea that successful problem solvers implement a meta-cognitive process in which they identify the specific concept they are struggling with, and then identify what they understand, what they don't understand, and what they need to know in order to resolve their problem. The assignment required the students to write an email assessing the level of completion of a weekly workbook assignment and to examine in detail their experiences regarding a specific topic they struggled with. The assignment guidelines were designed to coach them through this meta-cognitive process. We responded to most emails with advice for next week's assignment. Our data follow 12 students through a quarter consisting of 11 email assignments which were scored using a rubric based on the assignment guidelines. We found no correlation between rubric scores and final grades. We do have anecdotal evidence that the assignment was beneficial.

Using interviews to understand the assignment mechanism in a nonexperimental study: the case of eighth grade algebra.

PubMed

Rickles, Jordan H

2011-10-01

Many inquiries regarding the causal effects of policies or programs are based on research designs where the treatment assignment process is unknown, and thus valid inferences depend on tenuous assumptions about the assignment mechanism. This article draws attention to the importance of understanding the assignment mechanism in policy and program evaluation studies, and illustrates how information collected through interviews can develop a richer understanding of the assignment mechanism. Focusing on the issue of student assignment to algebra in 8th grade, I show how a preliminary data collection effort aimed at understanding the assignment mechanism is particularly beneficial in multisite observational studies in education. The findings, based on ten interviews and administrative data from a large school district, draw attention to the often ignored heterogeneity in the assignment mechanism across schools. These findings likely extend beyond the current research project in question to related educational policy issues such as ability grouping, tracking, differential course taking, and curricular intensity, as well as other social programs in which the assignment mechanism can differ across sites.

Investigating Students' Use and Adoption of "With-Video Assignments": Lessons Learnt for Video-Based Open Educational Resources

ERIC Educational Resources Information Center

Pappas, Ilias O.; Giannakos, Michail N.; Mikalef, Patrick

2017-01-01

The use of video-based open educational resources is widespread, and includes multiple approaches to implementation. In this paper, the term "with-video assignments" is introduced to portray video learning resources enhanced with assignments. The goal of this study is to examine the factors that influence students' intention to adopt…

Why IEP Teams Assign Low Performers with Mild Disabilities to the Alternate Assessment Based on Alternate Achievement Standards

ERIC Educational Resources Information Center

Cho, Hyun-Jeong; Kingston, Neal

2013-01-01

The purpose of this case study was to determine teachers' rationales for assigning students with mild disabilities to alternate assessment based on alternate achievement standards (AA-AAS). In interviews, special educators stated that their primary considerations in making the assignments were low academic performance, student use of extended…

Evaluation of Pharmacokinetics, and Bioavailability of Higher Doses of Tocotrienols in Healthy Fed Humans.

PubMed

Qureshi, Asaf A; Khan, Dilshad A; Silswal, Neerupma; Saleem, Shahid; Qureshi, Nilofer

2016-04-01

Tocotrienols has been known to lower serum lipid parameters below 500 mg/d, while increase lipid parameters at higher dose of 750 mg/d. δ-Tocotrienol has a novel inflammatory property of concentration-dependent inhibition and activation. Therefore, inhibition (anti-inflammatory) property of tocotrienols at low doses is useful for cardiovascular disease, whereas, activation (pro-inflammatory) property using high dose is found effective for treatments of various types of cancer. We have recently described plasma bioavailability of 125 mg/d, 250 mg/d and 500 mg/d doses of δ-tocotrienol in healthy fed subjects, which showed dose-dependent increases in area under the curve (AUC) and maximum concentration (C max ). Hence, in the current study, higher doses of tocotrienols have used to analyze its effect on plasma pharmacokinetic parameters. To evaluate the safety and bioavailability of higher doses (750 mg and 1000 mg) of annatto-based tocotrienols in healthy fed subjects. All four isomers (α-, β-, γ-, δ-) of tocols (tocotrienols and tocopherols) present in the plasmas of subjects were quantified and analyzed for various pharmacokinetic parameters. An open-label, randomized study was performed to analyze pharmacokinetics and bioavailability of δ-tocotrienol in 6 healthy fed subjects. All subjects (3/dose) were randomly assigned to one of each dose of 750 mg or 1000 mg. Blood samples were collected at 0, 1, 2, 4, 6, 8 h intervals and all isomers of α-,β-,γ-,δ-tocotrienols, and tocopherols in plasmas were quantified by HPLC. Oral administration of 750 and 1000 mg/d of tocotrienols resulted in dose-dependent increases in plasmas (ng/ml) AUCt 0- t 8 6621, 7450; AUCt 0-∞ 8688, 9633; AUMC t 0-∞ 52497, 57199; MRT 6.04, 5.93; C max 1444, 1592 (P<0.05), respectively, of δ-tocotrienol isomer. Moreover, both doses also resulted in plasmas T max 3.33-4 h; elimination half-life (t 1/2 h) 2.74, 2.68; time of clearance (Cl-T, l/h) 0.086, 0.078; volume of distribution (Vd/f, mg/h) 0.34, 0.30; and elimination rate constant (ke; h -1 ) 0.25, 0.17, respectively of δ- tocotrienol isomer. Similar results of these parameters were reported for γ-tocotrienol, β- tocotrienol, α-tocotrienol, δ-tocopherol, γ-tocopherol, and β-tocopherol, except for α- tocopherol. This study has described pharmacokinetics using higher doses of 750 mg/d and 1000 mg/d of δ-tocotrienol. These results confirmed earlier findings that T max was 3-4 h for all isomers of tocotrienols and tocopherols except for α-tocopherol (6 h). These higher doses of tocotrienols were found safe in humans and may be useful for treatments of various types of cancer, diabetes, and Alzheimer's disease.

Relative bioavailability of generic and branded 250-mg and 500-mg oral chlorphenesin carbamate tablets in healthy Korean volunteers: a single-dose, randomized-sequence, open-label, two-period crossover trial.

PubMed

Yu, Ji-young; Song, Hyun Ho; Kim, Bo Gyeom; Park, Hyeon Ju; Choi, Kwang Sik; Kwon, Young Ee

2009-11-01

Chlorphenesin carbamate is a skeletal muscle relaxant approved in Korea for use in the treatment of pain and discomfort related to skeletal muscle trauma and inflammation. The aim of this study was to assess the bioequivalence of a generic formulation of chlorphenesin carbamate at doses of 250 and 500 mg and 2 branded formulations of the same doses in healthy Korean adults. This single-dose, randomized-sequence, open-label, 2-period crossover study was conducted in healthy Korean male and female volunteers. Subjects were assigned to receive, in a randomized sequence, a single dose of the generic (test) and branded (reference) formulations of chlorphenesin carbamate at a dose of 250 or 500 mg. Blood samples were drawn at 0, 0.33, 0.67, 1, 1.5, 2, 3, 4, 6, 9, 12, and 15 hours after administration. Pharmacokinetic properties (C(max), T(max), AUC(0-t) AUC(0-infinity), t(1/2), and ke) were determined using HPLC. The formulations were to be considered bioequivalent if the 90% CIs of the treatment ratios of the geometric means of C(max) and AUC(0-t) were within a predetermined range of log 0.80 to log 1.25 based on regulatory criteria. Tolerability was assessed by monitoring for adverse events (AEs) on physical examination and/or e-mail and personal interview at the beginning and end of each study period. Twenty-eight subjects (22 men, 6 women) received chlorphenesin carbamate at the 250-mg dose, and 24 male subjects received the 500-mg dose. The mean (SD) ages of the subjects were 24.0 (2.6) and 24.0 (1.9) years in the 250- and 500-mg groups, respectively. No significant differences were found between the test and reference formulations (90% CIs: C(max), 1.0048-1.1153 with the 250-mg dose and 0.9630-1.1189 with the 500-mg dose; AUC(0-t), 0.9882-1.0546 and 0.9842-1.0578, respectively). No clinically significant AEs (upper gastric pain, abdominal bloating, pyrexia, edema, nausea, heartburn, constipation, headache, dizziness, drowsiness, or fatigue) were reported throughout the study. In this single-dose study in these healthy Korean subjects, the generic and branded formulations of chlorphenesin carbamate 250 and 500 mg met the regulatory criteria for bioequivalence. All formulations were well tolerated. Copyright 2009 Excerpta Medica Inc. All rights reserved.

Switching to nilotinib versus imatinib dose escalation in patients with chronic myeloid leukaemia in chronic phase with suboptimal response to imatinib (LASOR): a randomised, open-label trial.

PubMed

Cortes, Jorge E; De Souza, Carmino Antonio; Ayala, Manuel; Lopez, Jose Luis; Bullorsky, Eduardo; Shah, Sandip; Huang, Xiaojun; Babu, K Govind; Abdulkadyrov, Kudrat; de Oliveira, José Salvador Rodrigues; Shen, Zhi-Xiang; Sacha, Tomasz; Bendit, Israel; Liang, Zhizhou; Owugah, Tina; Szczudlo, Tomasz; Khanna, Sadhvi; Fellague-Chebra, Rafik; le Coutre, Philipp D

2016-12-01

Optimal management of patients with chronic myeloid leukaemia in chronic phase with suboptimal cytogenetic response remains undetermined. This study aimed to investigate the safety and efficacy of switching to nilotinib vs imatinib dose escalation for patients with suboptimal cytogenetic response on imatinib. We did a phase 3, open-label, randomised trial in patients with chronic myeloid leukaemia in chronic phase with suboptimal cytogenetic response to imatinib according to the 2009 European LeukemiaNet criteria, in Latin America, Europe, and Asia (59 hospitals and care centres in 12 countries). Eligible patients were aged 18 years or older with Philadelphia chromosome-positive chronic myeloid leukaemia in chronic phase and Eastern Cooperative Oncology Group performance status of 0-2. Before enrolment, all patients had received 3-18 months of imatinib 400 mg once daily and had a suboptimal cytogenetic response according to 2009 ELN recommendations, established through bone marrow cytogenetics. By use of an interactive response technology using fixed blocks, we randomly assigned patients (1:1) to switch to nilotinib 400 mg twice per day or an escalation of imatinib dose to 600 mg once per day (block size of 4). Investigators and participants were not blinded to study treatment. Crossover was allowed for loss of response or intolerance at any time, or for patients with no complete cytogenetic response at 6 months. The primary endpoint was complete cytogenetic response at 6 months in the intention-to-treat population. Efficacy endpoints were based on the intention-to-treat population, with all patients assessed according to the treatment group to which they were randomised (regardless of crossover); the effect of crossover was assessed in post-hoc analyses, in which responses achieved after crossover were excluded. We present the final results at 24 months' follow-up. This study is registered with ClinicalTrials.gov (NCT00802841). Between July 7, 2009, and Aug 29, 2012, we enrolled 191 patients. 96 patients were randomly assigned to nilotinib and 95 patients were randomly assigned to imatinib. Complete cytogenetic response at 6 months was achieved by 48 of 96 patients in the nilotinib group (50%, 95·18% CI 40-61) and 40 of 95 in the imatinib group (42%, 32-53%; difference 7·9% in favour of nilotinib; 95% CI -6·2 to 22·0, p=0·31). Excluding responses achieved after crossover, 48 (50%) of 96 patients in the nilotinib group and 34 (36%) of 95 patients in the imatinib group achieved complete cytogenic response at 6 months (nominal p=0·058). Grade 3-4 non-haematological adverse events occurring in more than one patient were headache (nilotinib group, n=2 [2%, including 1 after crossover to imatinib]; imatinib group, n=1 [1%]), blast cell crisis (nilotinib group, n=1 [1%]; imatinib group, n=1 [1%]), and QT prolongation (nilotinib group, n=1 [1%]; imatinib group, n=1 [1%, after crossover to nilotinib]). Serious adverse events on assigned treatment were reported in 11 (11%) of 96 patients in the nilotinib group and nine (10%) of 93 patients in the imatinib group. Seven (7%) of 96 patients died in the nilotinib group and five (5%) of 93 patients died in the imatinib group; no deaths were treatment-related. While longer-term analyses are needed to establish whether the clinical benefits observed with switching to nilotinib are associated with improved long-term survival outcomes, our results suggest that patients with suboptimal cytogenetic response are more likely to achieve improved cytogenetic and molecular responses with switching to nilotinib than with imatinib dose escalation, although the difference was not statistically significant when responses achieved after crossover were included. Novartis Pharmaceuticals. Copyright © 2016 Elsevier Ltd. All rights reserved.

Pediatric Online Evidence-Based Medicine Assignment Is a Novel Effective Enjoyable Undergraduate Medical Teaching Tool

PubMed Central

Kotb, Magd A.; Elmahdy, Hesham Nabeh; Khalifa, Nour El Deen Mahmoud; El-Deen, Mohamed Hamed Nasr; Lotfi, Mohamed Amr N.

2015-01-01

Abstract Evidence-based medicine (EBM) is delivered through a didactic, blended learning, and mixed models. Students are supposed to construct an answerable question in PICO (patient, intervention, comparison, and outcome) framework, acquire evidence through search of literature, appraise evidence, apply it to the clinical case scenario, and assess the evidence in relation to clinical context. Yet these teaching models have limitations especially those related to group work, for example, handling uncooperative students, students who fail to contribute, students who domineer, students who have personal conflict, their impact upon progress of their groups, and inconsistent individual acquisition of required skills. At Pediatrics Department, Faculty of Medicine, Cairo University, we designed a novel undergraduate pediatric EBM assignment online system to overcome shortcomings of previous didactic method and aimed to assess its effectiveness by prospective follow-up during academic years 2012 to 2013 and 2013 to 2014. The novel web-based online interactive system was tailored to provide sequential single and group assignments for each student. Single assignment addressed a specific case scenario question, while group assignment was teamwork that addressed different questions of same case scenario. Assignment comprised scholar content and skills. We objectively analyzed students’ performance by criterion-based assessment and subjectively by anonymous student questionnaire. A total of 2879 were enrolled in 5th year Pediatrics Course consecutively, of them 2779 (96.5%) logged in and 2554 (88.7%) submitted their work. They were randomly assigned to 292 groups. A total of 2277 (89.15%) achieved ≥80% of total mark (4/5), of them 717 (28.1%) achieved a full mark. A total of 2178 (85.27%) and 2359 (92.36%) made evidence-based conclusions and recommendations in single and group assignment, respectively (P < 0.001). A total of 1102 (43.1%) answered student questionnaire, of them 898 (81.48%) found e-educational experience satisfactory, 175 (15.88%) disagreed, and 29 (2.6%) could not decide. A total of 964 (87.47%) found single assignment educational, 913 (82.84%) found group assignment educational, and 794 (72.3%) enjoyed it. Web-based online interactive undergraduate EBM assignment was found effective in teaching medical students and assured individual student acquisition of concepts and skills of pediatric EMB. It was effective in mass education, data collection, and storage essential for system and student assessment. PMID:26200621

Pediatric Online Evidence-Based Medicine Assignment Is a Novel Effective Enjoyable Undergraduate Medical Teaching Tool: A SQUIRE Compliant Study.

PubMed

Kotb, Magd A; Elmahdy, Hesham Nabeh; Khalifa, Nour El Deen Mahmoud; El-Deen, Mohamed Hamed Nasr; Lotfi, Mohamed Amr N

2015-07-01

Evidence-based medicine (EBM) is delivered through a didactic, blended learning, and mixed models. Students are supposed to construct an answerable question in PICO (patient, intervention, comparison, and outcome) framework, acquire evidence through search of literature, appraise evidence, apply it to the clinical case scenario, and assess the evidence in relation to clinical context. Yet these teaching models have limitations especially those related to group work, for example, handling uncooperative students, students who fail to contribute, students who domineer, students who have personal conflict, their impact upon progress of their groups, and inconsistent individual acquisition of required skills. At Pediatrics Department, Faculty of Medicine, Cairo University, we designed a novel undergraduate pediatric EBM assignment online system to overcome shortcomings of previous didactic method and aimed to assess its effectiveness by prospective follow-up during academic years 2012 to 2013 and 2013 to 2014. The novel web-based online interactive system was tailored to provide sequential single and group assignments for each student. Single assignment addressed a specific case scenario question, while group assignment was teamwork that addressed different questions of same case scenario. Assignment comprised scholar content and skills. We objectively analyzed students' performance by criterion-based assessment and subjectively by anonymous student questionnaire. A total of 2879 were enrolled in 5th year Pediatrics Course consecutively, of them 2779 (96.5%) logged in and 2554 (88.7%) submitted their work. They were randomly assigned to 292 groups. A total of 2277 (89.15%) achieved ≥ 80% of total mark (4/5), of them 717 (28.1%) achieved a full mark. A total of 2178 (85.27%) and 2359 (92.36%) made evidence-based conclusions and recommendations in single and group assignment, respectively (P < 0.001). A total of 1102 (43.1%) answered student questionnaire, of them 898 (81.48%) found e-educational experience satisfactory, 175 (15.88%) disagreed, and 29 (2.6%) could not decide. A total of 964 (87.47%) found single assignment educational, 913 (82.84%) found group assignment educational, and 794 (72.3%) enjoyed it. Web-based online interactive undergraduate EBM assignment was found effective in teaching medical students and assured individual student acquisition of concepts and skills of pediatric EMB. It was effective in mass education, data collection, and storage essential for system and student assessment.

The use of dose-response data in a margin of exposure approach to carcinogenic risk assessment for genotoxic chemicals in food.

PubMed

Benford, Diane J

2016-05-01

Genotoxic substances are generally not permitted for deliberate use in food production. However, an appreciable number of known or suspected genotoxic substances occur unavoidably in food, e.g. from natural occurrence, environmental contamination and generation during cooking and processing. Over the past decade a margin of exposure (MOE) approach has increasingly been used in assessing the exposure to substances in food that are genotoxic and carcinogenic. The MOE is defined as a reference point on the dose-response curve (e.g. a benchmark dose lower confidences limit derived from a rodent carcinogenicity study) divided by the estimated human intake. A small MOE indicates a higher concern than a very large MOE. Whilst the MOE cannot be directly equated to risk, it supports prioritisation of substances for further research or for possible regulatory action, and provides a basis for communicating to the public. So far, the MOE approach has been confined to substances for which carcinogenicity data are available. In the absence of carcinogenicity data, evidence of genotoxicity is used only in hazard identification. The challenge to the genetic toxicology community is to develop approaches for characterising risk to human health based on data from genotoxicity studies. In order to achieve wide acceptance, it would be important to further address the issues that have been discussed in the context of dose-response modelling of carcinogenicity data in order to assign levels of concern to particular MOE values, and also whether it is possible to make generic conclusions on how potency in genotoxicity assays relates to carcinogenic potency. © Crown copyright 2015.

IMO-8400, a toll-like receptor 7, 8, and 9 antagonist, demonstrates clinical activity in a phase 2a, randomized, placebo-controlled trial in patients with moderate-to-severe plaque psoriasis.

PubMed

Balak, Deepak M W; van Doorn, Martijn B A; Arbeit, Robert D; Rijneveld, Rianne; Klaassen, Erica; Sullivan, Tim; Brevard, Julie; Thio, Hok Bing; Prens, Errol P; Burggraaf, Jacobus; Rissmann, Robert

2017-01-01

Aberrant toll-like receptors (TLRs) 7, 8, and 9 activation by self-nucleic acids is implicated in immune-mediated inflammatory diseases (IMIDs) such as psoriasis. In preclinical IMID models, blocking TLR-activation reduced disease severity. IMO-8400 is a first-in-class, oligonucleotide-based antagonist of TLRs 7, 8, and 9. We evaluated the short-term safety and proof-of-concept for efficacy of IMO-8400 in a first-in-patient phase 2 trial. Forty-six psoriasis patients were randomly assigned to IMO-8400 in four dose levels or placebo for 12weeks. Post-treatment follow-up was seven weeks. Primary outcome was incidence of adverse events. Secondary, exploratory outcomes included changes in psoriasis area and severity index (PASI). IMO-8400 across all dose levels did not cause any serious or severe adverse events. The most common treatment-related adverse events were dose-dependent injection-site reactions. All IMO-8400 groups showed clinical improvement, but a clear dose-response relationship and statistically significant differences with placebo were not observed (P=0.26). Eleven (38%) of 29 subjects on IMO-8400 achieved ≥50% PASI-reduction, compared to 1 (11%) of 9 subjects on placebo. Five (17%) and 2 (7%) IMO-8400-treated subjects achieved PASI-75 and PASI-90, respectively, compared to none on placebo. Short-term IMO-8400-treatment was well tolerated and reduced psoriasis severity. These findings warrant further investigation of endosomal TLR-antagonism as a therapeutic approach in psoriasis and other TLR-mediated IMIDs. EudraCT 2013-000164-28 and Clinicaltrials.govNCT01899729. Copyright © 2016 Elsevier Inc. All rights reserved.

Caffeine and sleep-deprivation mediated changes in open-field behaviours, stress response and antioxidant status in mice.

PubMed

Onaolapo, J Olakunle; Onaolapo, Y Adejoke; Akanmu, A Moses; Olayiwola, Gbola

2016-01-01

Effects of daily caffeine consumption on open-field behaviours, serum corticosterone and brain antioxidant levels were investigated after six hours of total sleep-deprivation in prepubertal mice. We tested the hypothesis that daily caffeine consumption may significantly alter behaviour, stress and antioxidative response of prepubertal mice to an acute episode of total sleep-deprivation. Prepubertal Swiss mice of both sexes were assigned to two main groups of 120 each (subdivided into 6 groups of 10 each, based on sex), and administered vehicle or graded oral doses of caffeine (10, 20, 40, 80 and 120 mg/kg/day) for 14 days. On day 14, a main group was subjected to 6 h of total sleep-deprivation by 'gentle-handling'. Open-field behaviours were then assessed in both groups, after which animals were euthanized, and levels of corticosterone, superoxide dismutase and glutathione peroxidase assayed. Horizontal locomotion, rearing and grooming increased significantly, compared to control, with sleep-deprived (SD) mice showing stronger caffeine-driven responses at higher doses; and SD female mice showing sustained response to caffeine, compared to respective males. Plasma corticosterone increased with increasing doses of caffeine in both non sleep-deprived (NSD) and SD mice; although SD mice had higher corticosterone levels. Sleep-deprivation and/or higher doses of caffeine were associated with derangements in brain antioxidant levels. Repeated caffeine consumption and/or acute sleep-deprivation led to significant changes in pattern of open-field behaviour and stress/antioxidant response in mice. Responses seen in the study are probably due to modulatory effects of caffeine on the total body response to stressful stimuli.

Dose-dependent effects on sphingoid bases and cytokines in chickens fed diets prepared with fusarium verticillioides culture material containing fumonisins.

PubMed

Grenier, Bertrand; Schwartz-Zimmermann, Heidi E; Caha, Sylvia; Moll, Wulf Dieter; Schatzmayr, Gerd; Applegate, Todd J

2015-04-13

In chickens, the effect of mycotoxins, especially fumonisins (FB), in the gastrointestinal tract (GIT) is not well documented. Thus, this study in broiler chicks determined the effects of consuming diets prepared with Fusarium verticillioides culture material containing FB on intestinal gene expression and on the sphinganine (Sa)/sphingosine (So) ratio (Sa/So; a biomarker of FB effect due to disruption of sphingolipid metabolism). Male broilers were assigned to 6 diets (6 cages/diet; 6 birds/cage) from hatch to 20 days containing 0.4, 5.6, 11.3, 17.5, 47.8, or 104.8 mg FB/kg diet. Exposure to FB altered the Sa/So ratio in all tissues analyzed, albeit to varying extents. Linear dose-responses were observed in the kidney, jejunum and cecum. The liver and the ileum were very sensitive and data fit a cubic and quadratic polynomial model, respectively. Gene expression in the small intestine revealed low but significant upregulations of cytokines involved in the pro-inflammatory, Th1/Th17 and Treg responses, especially at 10 days of age. Interestingly, the cecal tonsils exhibited a biphasic response. Unlike the sphingolipid analysis, the effects seen on gene expression were not dose dependent, even showing more effects when birds were exposed to 11.3 mg FB/kg. In conclusion, this is the first report on the disruption of the sphingolipid metabolism by FB in the GIT of poultry. Further studies are needed to reach conclusions on the biological meaning of the immunomodulation observed in the GIT, but the susceptibility of chickens to intestinal pathogens when exposed to FB, at doses lower than those that would cause overt clinical symptoms, should be addressed.

ORGAN-SPECIFIC EXTERNAL DOSE COEFFICIENTS AND PROTECTIVE APRON TRANSMISSION FACTORS FOR HISTORICAL DOSE RECONSTRUCTION FOR MEDICAL PERSONNEL

PubMed Central

Simon, Steven L.

2014-01-01

While radiation absorbed dose (Gy) to the skin or other organs is sometimes estimated for patients from diagnostic radiologic examinations or therapeutic procedures, rarely is occupationally-received radiation absorbed dose to individual organs/tissues estimated for medical personnel, e.g., radiologic technologists or radiologists. Generally, for medical personnel, equivalent or effective radiation doses are estimated for compliance purposes. In the very few cases when organ doses to medical personnel are reconstructed, the data is usually for the purpose of epidemiologic studies, e.g., a study of historical doses and risks to a cohort of about 110,000 radiologic technologists presently underway at the U.S. National Cancer Institute. While ICRP and ICRU have published organ-specific external dose conversion coefficients (DCCs), i.e., absorbed dose to organs and tissues per unit air kerma and dose equivalent per unit air kerma, those factors have been primarily published for mono-energetic photons at selected energies. This presents two related problems for historical dose reconstruction, both of which are addressed here. It is necessary to derive conversion factors values for (i) continuous distributions of energy typical of diagnostic medical x rays (bremsstrahlung radiation), and (ii) for energies of particular radioisotopes used in medical procedures, neither of which are presented in published tables. For derivation of DCCs for bremsstrahlung radiation, combinations of x-ray tube potentials and filtrations were derived for different time periods based on a review of relevant literature. Three peak tube potentials (70 kV, 80 kV, and 90 kV) with four different amounts of beam filtration were determined to be applicable for historic dose reconstruction. The probability of these machine settings were assigned to each of the four time periods (earlier than 1949, 1949-1954, 1955-1968, and after 1968). Continuous functions were fit to each set of discrete values of the ICRP/ICRU mono-energetic DCCs and the functions integrated over the air-kerma weighted photon fluence of the 12 defined x-ray spectra. The air kerma-weighted DCCs in this work were developed specifically for an irradiation geometry of anterior to posterior (AP) and for the following tissues: thyroid, breast, ovary, lens of eye, lung, colon, testes, heart, skin (anterior side only), red bone marrow (RBM), heart, and brain. In addition, a series of functional relationships to predict DT per Ka values for RBM dependent on body mass index [BMI (kg m−2) ≡ weight per height2] and average photon energy were derived from a published analysis. Factors to account for attenuation of radiation by protective lead aprons were also developed. Because lead protective aprons often worn by radiology personnel not only reduce the intensity of x-ray exposure but also appreciably harden the transmitted fluence of bremsstrahlung x rays, DCCs were separately calculated for organs possibly protected by lead aprons by considering three cases: no apron, 0.25 mm Pb apron, and 0.5 mm Pb apron. For estimation of organ doses from conducting procedures with radioisotopes, continuous functions of the reported mono-energetic values were developed and DCCs were derived by estimation of the function at relevant energies. By considering the temporal changes in primary exposure-related parameters, e.g., energy distribution, the derived DCCs and transmission factors presented here allow for more realistic historical dose reconstructions for medical personnel when monitoring badge readings are the primary data on which estimation of an individual's organ doses are based. PMID:21617389

Organ-specific external dose coefficients and protective apron transmission factors for historical dose reconstruction for medical personnel.

PubMed

Simon, Steven L

2011-07-01

While radiation absorbed dose (Gy) to the skin or other organs is sometimes estimated for patients from diagnostic radiologic examinations or therapeutic procedures, rarely is occupationally-received radiation absorbed dose to individual organs/tissues estimated for medical personnel; e.g., radiologic technologists or radiologists. Generally, for medical personnel, equivalent or effective radiation doses are estimated for compliance purposes. In the very few cases when organ doses to medical personnel are reconstructed, the data is usually for the purpose of epidemiologic studies; e.g., a study of historical doses and risks to a cohort of about 110,000 radiologic technologists presently underway at the U.S. National Cancer Institute. While ICRP and ICRU have published organ-specific external dose conversion coefficients (DCCs) (i.e., absorbed dose to organs and tissues per unit air kerma and dose equivalent per unit air kerma), those factors have been published primarily for mono-energetic photons at selected energies. This presents two related problems for historical dose reconstruction, both of which are addressed here. It is necessary to derive conversion factor values for (1) continuous distributions of energy typical of diagnostic medical x-rays (bremsstrahlung radiation), and (2) energies of particular radioisotopes used in medical procedures, neither of which are presented in published tables. For derivation of DCCs for bremsstrahlung radiation, combinations of x-ray tube potentials and filtrations were derived for different time periods based on a review of relevant literature. Three peak tube potentials (70 kV, 80 kV, and 90 kV) with four different amounts of beam filtration were determined to be applicable for historic dose reconstruction. The probabilities of these machine settings were assigned to each of the four time periods (earlier than 1949, 1949-1954, 1955-1968, and after 1968). Continuous functions were fit to each set of discrete values of the ICRP/ICRU mono-energetic DCCs and the functions integrated over the air-kerma weighted photon fluence of the 12 defined x-ray spectra. The air kerma-weighted DCCs in this work were developed specifically for an irradiation geometry of anterior to posterior (AP) and for the following tissues: thyroid, breast, ovary, lens of eye, lung, colon, testes, heart, skin (anterior side only), red bone marrow (RBM), and brain. In addition, a series of functional relationships to predict DT Ka-1 values for RBM dependent on body mass index [BMI (kg m-2) ≡ weight per height] and average photon energy were derived from a published analysis. Factors to account for attenuation of radiation by protective lead aprons were also developed. Because lead protective aprons often worn by radiology personnel not only reduce the intensity of x-ray exposure but also appreciably harden the transmitted fluence of bremsstrahlung x-rays, DCCs were separately calculated for organs possibly protected by lead aprons by considering three cases: no apron, 0.25 mm Pb apron, and 0.5 mm Pb apron. For estimation of organ doses from conducting procedures with radioisotopes, continuous functions of the reported mono-energetic values were developed, and DCCs were derived by estimation of the function at relevant energies. By considering the temporal changes in primary exposure-related parameters (e.g., energy distribution), the derived DCCs and transmission factors presented here allow for more realistic historical dose reconstructions for medical personnel when monitoring badge readings are the primary data on which estimation of an individual's organ doses are based.

Teriparatide versus low-dose bisphosphonates before and after surgery for adult spinal deformity in female Japanese patients with osteoporosis.

PubMed

Seki, Shoji; Hirano, Norikazu; Kawaguchi, Yoshiharu; Nakano, Masato; Yasuda, Taketoshi; Suzuki, Kayo; Watanabe, Kenta; Makino, Hiroto; Kanamori, Masahiko; Kimura, Tomoatsu

2017-08-01

Complications of adult spinal deformity surgery are problematic in osteoporotic individuals. We compared outcomes between Japanese patients treated perioperatively with teriparatide vs. low-dose bisphosphonates. Fifty-eight osteoporotic adult Japanese female patients were enrolled and assigned to perioperative teriparatide (33 patients) and bisphosphonate (25 patients) groups in non-blinded fashion. Pre- and post-operative X-ray and computed tomography imaging were used to assess outcome, and rates were compared between the groups and according to age. Pain scores and Oswestry Disability Indices (ODI) were calculated before and 2 years after surgery. Adjacent vertebral fractures and implant failure, fusion failure, and poor pain and ODI outcomes were significantly more common in the bisphosphonates group than the teriparatide group. Perioperative administration of teriparatide is more effective than that of low-dose bisphosphonates in preventing complications and maintaining fusion rates in osteoporotic Japanese females with spinal deformities undergoing surgery.

WWC Review of the Report "Increasing Young Children's Contact with Print during Shared Reading: Longitudinal Effects on Literacy Achievement"

ERIC Educational Resources Information Center

What Works Clearinghouse, 2012

2012-01-01

The study examined the impact of the "Project STAR" ("Sit Together and Read") reading program on the literacy skills of preschool students. Researchers randomly assigned 85 preschool classrooms in Ohio to one of three study groups at the start of the 2004-05 or 2005-06 school years: (1) A high-dose intervention group, in which…

A National Coordinating Center for Trauma Research

DTIC Science & Technology

2017-10-01

symptoms of acute stress disorder and depression to prevent syndromal PTSD and depression Related Research Presentations/Publications Posters Annual JHU...Site: Johns Hopkins University School of Medicine HRPO Assigned A-number: A-19299.2 Abstract: Background: Early, effective pain control for acute ...sparing drug for the treatment of acute post-traumatic pain • The side effect profile of ketamine when administered in sub-anesthetic doses • Whether

Oral administration of citrus pulp reduces gasrointestinal recovery of orally dosed Escherichia coli F18 in weaned pigs

USDA-ARS?s Scientific Manuscript database

The effects of citrus pulp (CTP), on the immune and cortisol responses to E. coli F18 inoculation and subsequent E. coli recovery were evaluated in newly weaned pigs (23.3 + 1.8 d of age). Barrows were assigned to 1 of 2 treatment groups; with (CTP; n = 15) and without (Control; n = 15) the in-feed ...

SU-E-T-328: Dosimetric Impact of Cobalt-Chrome Stabilization Hardware in Paraspinal Radiation Therapy

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

Tang, G; LoSasso, T; Saleh, Z

2015-06-15

Purpose: Due to saturation, high density materials Result in an apparent density of 3.2 g/cm{sup 3} in CT images. The true density of traditional titanium stabilization rods (∼4.4 g/cm{sup 3}) is typically ignored in treatment planning. This may not be acceptable for new cobalt-chrome rods with a density of 8.5 g/cm{sup 3}. This study reports the dosimetric impact of cobalt-chrome rods in paraspinal radiotherapy. Methods: For titanium and cobalt-chrome rods, two planning studies were done for both IMRT and VMAT in Varian Eclipse using AAA. 1) The effect of planning without assigning the true rod density was assessed by comparingmore » plans generated with the apparent density and recalculated with the true density for titanium and cobalt-chrome. 2) To test if TPS can compensate for high density rods during optimization. Furthermore, TPS calculation accuracy was verified using MapCheck for a single 20 x 10 cm{sup 2} field. The MapCheck was incrementally shifted to achieve measurement resolution of 1 mm. Results: PTV coverage was ∼0.3% and ∼4.7% lower in plans that were recalculated with the true rod density of titanium and cobalt-chrome, respectively. PTV coverage can be maintained if the correct density is used in optimization. Measurements showed that TPS overestimated the dose locally by up to 11% for cobalt-chrome rods and up to 4% for titanium rods if the density is incorrect. With density corrected, maximum local differences of 6% and 3% were seen for cobalt-chrome and titanium rods, respectively. At 2 cm beneath a rod, electrons scattered from the side of the rod increased the lateral dose and diminished as depth increases. TPS was not able to account for this effect properly even with the true rod density assigned. Conclusion: Neglecting the true density of cobalt-chrome rods can cause under coverage to the PTV. Assigning the correct density during treatment planning can minimize unexpected decrease in PTV dose.« less

Irradiate-anneal screening of total dose effects in semiconductor devices

NASA Technical Reports Server (NTRS)

Stanley, A. G.; Price, W. E.

1976-01-01

Judicious choice of radiation dose and parameter change acceptance criteria, absence of anomalous anneal phenomena, and absence of anomalous reirradiation effects are recognized as essential for a successful irradiation-anneal (IRAN) screening procedure to ensure that no device will fall, upon reirradiation, above parametric limits assigned for the worst case application. Reirradiation and irradiation-anneal behavior of various semiconductor devices are compared and those that do not lend themselves to IRAN screening are singled out. Information needed to judge the suitability of an IRAN type screening program is detailed. Reasons for success of the limited IRAN screening of flight parts for the Mariner Jupiter/Saturn (MJS '77) spacecraft are indicated.

Transient arterial phase respiratory motion-related artifact in MR imaging of the liver: an analysis of four different gadolinium-based contrast agents.

PubMed

Shah, Mansi R; Flusberg, Milana; Paroder, Viktoriya; Rozenblit, Alla M; Chernyak, Victoria

The purpose was to compare hepatic arterial phase (HAP) respiratory motion artifact (RMA) between gadoxetate, gadobutrol, gadopentetate, and gadobenate. Two hundred cases of each gadolinium agent were included. RMA was assigned using 5-point Likert scale (1=no motion, 5=extreme motion) on precontrast and HAP. RMA increase (increase ≥1 on HAP from precontrast) was the outcome in logistic regression. Odds of RMA increase for gadoxetate were 5.5 (P<.001), 3.6 (P=.034), and 9.5 (P<.001) times higher than gadobutrol, gadopentetate, and gadobenate, respectively. Gadolinium volume and dose were not independent predictors of RMA increase. Gadoxetate has increased odds of RMA compared with other gadolinium agents; tight contrast bolus is not a contributor. Copyright © 2016 Elsevier Inc. All rights reserved.

Levosimendan in Patients with Left Ventricular Dysfunction Undergoing Cardiac Surgery.

PubMed

Mehta, Rajendra H; Leimberger, Jeffrey D; van Diepen, Sean; Meza, James; Wang, Alice; Jankowich, Rachael; Harrison, Robert W; Hay, Douglas; Fremes, Stephen; Duncan, Andra; Soltesz, Edward G; Luber, John; Park, Soon; Argenziano, Michael; Murphy, Edward; Marcel, Randy; Kalavrouziotis, Dimitri; Nagpal, Dave; Bozinovski, John; Toller, Wolfgang; Heringlake, Matthias; Goodman, Shaun G; Levy, Jerrold H; Harrington, Robert A; Anstrom, Kevin J; Alexander, John H

2017-05-25

Levosimendan is an inotropic agent that has been shown in small studies to prevent or treat the low cardiac output syndrome after cardiac surgery. In a multicenter, randomized, placebo-controlled, phase 3 trial, we evaluated the efficacy and safety of levosimendan in patients with a left ventricular ejection fraction of 35% or less who were undergoing cardiac surgery with the use of cardiopulmonary bypass. Patients were randomly assigned to receive either intravenous levosimendan (at a dose of 0.2 μg per kilogram of body weight per minute for 1 hour, followed by a dose of 0.1 μg per kilogram per minute for 23 hours) or placebo, with the infusion started before surgery. The two primary end points were a four-component composite of death through day 30, renal-replacement therapy through day 30, perioperative myocardial infarction through day 5, or use of a mechanical cardiac assist device through day 5; and a two-component composite of death through day 30 or use of a mechanical cardiac assist device through day 5. A total of 882 patients underwent randomization, 849 of whom received levosimendan or placebo and were included in the modified intention-to-treat population. The four-component primary end point occurred in 105 of 428 patients (24.5%) assigned to receive levosimendan and in 103 of 421 (24.5%) assigned to receive placebo (adjusted odds ratio, 1.00; 99% confidence interval [CI], 0.66 to 1.54; P=0.98). The two-component primary end point occurred in 56 patients (13.1%) assigned to receive levosimendan and in 48 (11.4%) assigned to receive placebo (adjusted odds ratio, 1.18; 96% CI, 0.76 to 1.82; P=0.45). The rate of adverse events did not differ significantly between the two groups. Prophylactic levosimendan did not result in a rate of the short-term composite end point of death, renal-replacement therapy, perioperative myocardial infarction, or use of a mechanical cardiac assist device that was lower than the rate with placebo among patients with a reduced left ventricular ejection fraction who were undergoing cardiac surgery with the use of cardiopulmonary bypass. (Funded by Tenax Therapeutics; LEVO-CTS ClinicalTrials.gov number, NCT02025621 .).

Gender Differences in the Determinants of the Willingness to Accept an International Assignment

ERIC Educational Resources Information Center

van der Velde, Mandy E. G.; Bossink, Carin J. H.; Jansen, Paul G. W.

2005-01-01

Multinational organisations experience difficulties in finding managers willing to accept international assignments. This study has therefore focused on factors that can predict males' and females' willingness to accept international assignments, or to follow their partners on international assignments. Hypotheses were formulated based on the…

Temporal changes in physiology and haematology in response to high- and micro-doses of recombinant human erythropoietin.

PubMed

Clark, Brad; Woolford, Sarah M; Eastwood, Annette; Sharpe, Ken; Barnes, Peter G; Gore, Christopher J

2017-10-01

There is evidence to suggest athletes have adopted recombinant human erythropoietin (rHuEPO) dosing regimens that diminish the likelihood of being caught by direct detection techniques. However, the temporal response in physiology, performance, and Athlete Biological Passport (ABP) parameters to such regimens is not clearly understood. Participants were assigned to a high-dose only group (HIGH, n = 8, six rHuEPO doses of 250 IU/kg over two weeks), a combined high micro-dose group (COMB, n = 8, high-dose plus nine rHuEPO micro-doses over a further three weeks), or one of two placebo control groups who received saline in the same pattern as the HIGH (HIGH-PLACEBO, n = 4) or COMB (COMB-PLACEBO, n = 4) groups. Temporal changes in physiology and performance were tracked by graded exercise test (GXT) and haemoglobin mass assessment at baseline, after high dose, after micro-dose (COMB and COMB-PLACEBO only) and after a four-week washout. Venous blood samples were collected throughout the baseline, rHuEPO administration, and washout periods to determine the haematological and ABP response to each dosing regimen. Physiological adaptations induced by a two-week rHuEPO high-dose were maintained by rHuEPO micro-dosing for at least three weeks. However, all participants administered rHuEPO registered at least one suspicious ABP value during the administration or washout periods. These results indicate there is sufficient sensitivity in the ABP to detect use of high rHuEPO doping regimens in athletic populations and they provide important empirical examples for use by anti-doping experts. Copyright © 2017 John Wiley & Sons, Ltd. Copyright © 2017 John Wiley & Sons, Ltd.

Effects of alfaxalone administered intravenously to healthy yearling loggerhead sea turtles (Caretta caretta) at three different doses.

PubMed

Phillips, Brianne E; Posner, Lysa P; Lewbart, Gregory A; Christiansen, Emily F; Harms, Craig A

2017-04-15

OBJECTIVE To compare physiologic and anesthetic effects of alfaxalone administered IV to yearling loggerhead sea turtles (Caretta caretta) at 3 different doses. DESIGN Randomized crossover study. ANIMALS 9 healthy yearling loggerhead sea turtles. PROCEDURES Animals received each of 3 doses of alfaxalone (3 mg/kg [1.4 mg/lb], 5 mg/kg [2.3 mg/lb], or 10 mg/kg [4.5 mg/lb]) administered IV in randomly assigned order, with a minimum 7-day washout period between doses. Endotracheal intubation was attempted following anesthetic induction, and heart rate, sedation depth, cloacal temperature, and respirations were monitored. Times to first effect, induction, first voluntary muscle movement, first respiration, and recovery were recorded. Venous blood gas analysis was performed at 0 and 30 minutes. Assisted ventilation was performed if apnea persisted 30 minutes following induction. RESULTS Median anesthetic induction time for all 3 doses was 2 minutes. Endotracheal intubation was accomplished in all turtles following induction. Heart rate significantly increased after the 3- and 5-mg/kg doses were administered. Median intervals from alfaxalone administration to first spontaneous respiration were 16, 22, and 54 minutes for the 3-, 5-, and 10-mg/kg doses, respectively, and median intervals to recovery were 28, 46, and 90 minutes, respectively. Assisted ventilation was required for 1 turtle after receiving the 5-mg/kg dose and for 5 turtles after receiving the 10-mg/kg dose. The 10-mg/kg dose resulted in respiratory acidosis and marked hypoxemia at 30 minutes. CONCLUSIONS AND CLINICAL RELEVANCE IV alfaxalone administration to loggerhead sea turtles resulted in a rapid anesthetic induction and dose-dependent duration of sedation. Assisted ventilation is recommended if the 10 mg/kg dose is administered.

The effects of acute alcohol on psychomotor, set-shifting, and working memory performance in older men and women.

PubMed

Hoffman, Lauren A; Sklar, Alfredo L; Nixon, Sara Jo

2015-05-01

A limited number of publications have documented the effects of acute alcohol administration among older adults. Among these, only a few have investigated sex differences within this population. The current project examined the behavioral effects of acute low- and moderate-dose alcohol on 62 older (ages 55-70) male and female, healthy, light to moderate drinkers. Participants were randomly assigned to one of three dose conditions: placebo (peak breath alcohol concentration [BrAC] of 0 mg/dL), low (peak BrAC of 40 mg/dL), and moderate (peak BrAC of 65 mg/dL). Tasks assessed psychomotor, set-shifting, and working memory performance. Better set-shifting abilities were observed among women, whereas men demonstrated more efficient working memory, regardless of dose. The moderate-dose group did not significantly differ from the placebo group on any task. However, the low-dose group performed better than the moderate-dose group across measures of set shifting and working memory. Relative to the placebo group, the low-dose group exhibited better working memory, specifically for faces. Interestingly, there were no sex by dose interactions. These data suggest that, at least for our study's task demands, low and moderate doses of alcohol do not significantly hinder psychomotor, set-shifting, or working memory performance among older adults. In fact, low-dose alcohol may facilitate certain cognitive abilities. Furthermore, although sex differences in cognitive abilities were observed, these alcohol doses did not differentially affect men and women. Further investigation is necessary to better characterize the effects of sex and alcohol dose on cognition in older adults. Copyright © 2015 Elsevier Inc. All rights reserved.

Ascorbic acid treatment elevates follicle stimulating hormone and testosterone plasma levels and enhances sperm quality in albino Wistar rats.

PubMed

Okon, Uduak Akpan; Utuk, Ikponoabasi Ibanga

2016-01-01

Infertility issues have been linked to the effect of oxidative reaction in the reproductive system. This study evaluated the effect of ascorbic acid, on fertility parameters of male albino Wistar rats was studied. Eighteen albino Wistar rats weighed between 178 g and 241 g were used, randomly assigned into three groups. Group 1 was the control group; oral gavaged 5 ml of distilled water; Groups 2 and 3 were administered medium dose (250 mg/kg) and high dose of ascorbic acid (400 mg/kg), respectively; twice daily for 21 days. Blood samples were obtained by cardiac puncture, and blood serum was obtained for hormonal assay, and the testes were harvested for sperm analysis. Follicle stimulating hormone levels significantly increased in the high-dose group as compared to both the control and medium dose groups. Luteinizing hormone levels in the medium dose group decreased significantly as compared to the control group. Testosterone significantly increased in both the medium- and high-dose groups as compared to the control group. Sperm motility increased significantly in the high-dose group as compared to both control and medium-dose groups. Percentage sperm concentration decreased significantly in the medium-dose group when compared to the control and increased significantly in the high-dose group as compared to the medium-dose group. For percentage normal morphology, there was a dose-dependent increase in the test groups when compared to control group. These results are indicative of a positive influence of ascorbic acid on male fertility modulators and may therefore, serve as a potential adjuvant treatment for male infertility cases.

Modeling adverse event counts in phase I clinical trials of a cytotoxic agent.

PubMed

Muenz, Daniel G; Braun, Thomas M; Taylor, Jeremy Mg

2018-05-01

Background/Aims The goal of phase I clinical trials for cytotoxic agents is to find the maximum dose with an acceptable risk of severe toxicity. The most common designs for these dose-finding trials use a binary outcome indicating whether a patient had a dose-limiting toxicity. However, a patient may experience multiple toxicities, with each toxicity assigned an ordinal severity score. The binary response is then obtained by dichotomizing a patient's richer set of data. We contribute to the growing literature on new models to exploit this richer toxicity data, with the goal of improving the efficiency in estimating the maximum tolerated dose. Methods We develop three new, related models that make use of the total number of dose-limiting and low-level toxicities a patient experiences. We use these models to estimate the probability of having at least one dose-limiting toxicity as a function of dose. In a simulation study, we evaluate how often our models select the true maximum tolerated dose, and we compare our models with the continual reassessment method, which uses binary data. Results Across a variety of simulation settings, we find that our models compare well against the continual reassessment method in terms of selecting the true optimal dose. In particular, one of our models which uses dose-limiting and low-level toxicity counts beats or ties the other models, including the continual reassessment method, in all scenarios except the one in which the true optimal dose is the highest dose available. We also find that our models, when not selecting the true optimal dose, tend to err by picking lower, safer doses, while the continual reassessment method errs more toward toxic doses. Conclusion Using dose-limiting and low-level toxicity counts, which are easily obtained from data already routinely collected, is a promising way to improve the efficiency in finding the true maximum tolerated dose in phase I trials.

Automatic detection of cardiovascular risk in CT attenuation correction maps in Rb-82 PET/CTs

NASA Astrophysics Data System (ADS)

Išgum, Ivana; de Vos, Bob D.; Wolterink, Jelmer M.; Dey, Damini; Berman, Daniel S.; Rubeaux, Mathieu; Leiner, Tim; Slomka, Piotr J.

2016-03-01

CT attenuation correction (CTAC) images acquired with PET/CT visualize coronary artery calcium (CAC) and enable CAC quantification. CAC scores acquired with CTAC have been suggested as a marker of cardiovascular disease (CVD). In this work, an algorithm previously developed for automatic CAC scoring in dedicated cardiac CT was applied to automatic CAC detection in CTAC. The study included 134 consecutive patients undergoing 82-Rb PET/CT. Low-dose rest CTAC scans were acquired (100 kV, 11 mAs, 1.4mm×1.4mm×3mm voxel size). An experienced observer defined the reference standard with the clinically used intensity level threshold for calcium identification (130 HU). Five scans were removed from analysis due to artifacts. The algorithm extracted potential CAC by intensity-based thresholding and 3D connected component labeling. Each candidate was described by location, size, shape and intensity features. An ensemble of extremely randomized decision trees was used to identify CAC. The data set was randomly divided into training and test sets. Automatically identified CAC was quantified using volume and Agatston scores. In 33 test scans, the system detected on average 469mm3/730mm3 (64%) of CAC with 36mm3 false positive volume per scan. The intraclass correlation coefficient for volume scores was 0.84. Each patient was assigned to one of four CVD risk categories based on the Agatston score (0-10, 11-100, 101-400, <400). The correct CVD category was assigned to 85% of patients (Cohen's linearly weighted κ0.82). Automatic detection of CVD risk based on CAC scoring in rest CTAC images is feasible. This may enable large scale studies evaluating clinical value of CAC scoring in CTAC data.

Comparison of the Immunogenicity of Various Booster Doses of Inactivated Polio Vaccine Delivered Intradermally Versus Intramuscularly to HIV-Infected Adults

PubMed Central

Troy, Stephanie B.; Kouiavskaia, Diana; Siik, Julia; Kochba, Efrat; Beydoun, Hind; Mirochnitchenko, Olga; Levin, Yotam; Khardori, Nancy; Chumakov, Konstantin; Maldonado, Yvonne

2015-01-01

Background. Inactivated polio vaccine (IPV) is necessary for global polio eradication because oral polio vaccine can rarely cause poliomyelitis as it mutates and may fail to provide adequate immunity in immunocompromised populations. However, IPV is unaffordable for many developing countries. Intradermal IPV shows promise as a means to decrease the effective dose and cost of IPV, but prior studies, all using 20% of the standard dose used in intramuscular IPV, resulted in inferior antibody titers. Methods. We randomly assigned 231 adults with well-controlled human immunodeficiency virus infection at a ratio of 2:2:2:1 to receive 40% of the standard dose of IPV intradermally, 20% of the standard dose intradermally, the full standard dose intramuscularly, or 40% of the standard dose intramuscularly. Intradermal vaccination was done using the NanoPass MicronJet600 microneedle device. Results. Baseline immunity was 87%, 90%, and 66% against poliovirus serotypes 1, 2, and 3, respectively. After vaccination, antibody titers increased a median of 64-fold. Vaccine response to 40% of the standard dose administered intradermally was comparable to that of the standard dose of IPV administered intramuscularly and resulted in higher (although not significantly) antibody titers. Intradermal administration had higher a incidence of local side effects (redness and itching) but a similar incidence of systemic side effects and was preferred by study participants over intramuscular administration. Conclusions. A 60% reduction in the standard IPV dose without reduction in antibody titers is possible through intradermal administration. PMID:25567841

Safety and immunogenicity of a parenteral P2-VP8-P[8] subunit rotavirus vaccine in toddlers and infants in South Africa: a randomised, double-blind, placebo-controlled trial.

PubMed

Groome, Michelle J; Koen, Anthonet; Fix, Alan; Page, Nicola; Jose, Lisa; Madhi, Shabir A; McNeal, Monica; Dally, Len; Cho, Iksung; Power, Maureen; Flores, Jorge; Cryz, Stanley

2017-08-01

Efficacy of live oral rotavirus vaccines is reduced in low-income compared with high-income settings. Parenteral non-replicating rotavirus vaccines might offer benefits over oral vaccines. We assessed the safety and immunogenicity of the P2-VP8-P[8] subunit rotavirus vaccine at different doses in South African toddlers and infants. This double-blind, randomised, placebo-controlled, dose-escalation trial was done at a single research unit based at a hospital in South Africa in healthy HIV-uninfected toddlers (aged 2 to <3 years) and term infants (aged 6 to <8 weeks, without previous rotavirus vaccination). Block randomisation (computer-generated, electronic allocation) was used to assign eligible toddlers (in a 6:1 ratio) and infants (in a 3:1 ratio) in each dose cohort (10 μg, followed by 30 μg, then 60 μg if doses tolerated) to parenteral P2-VP8-P[8] subunit rotavirus or placebo injection. The two highest tolerated doses were then assessed in an expanded cohort (in a 1:1:1 ratio). Parents of participants and clinical, data, and laboratory staff were masked to treatment assignment. P2-VP8-P[8] vaccine versus placebo was assessed first in toddlers (single injection) and then in infants (three injections 4 weeks apart). The primary safety endpoints were local and systemic reactions within 7 days after each injection, adverse events within 28 days after each injection, and all serious adverse events, assessed in toddlers and infants who received at least one dose. In infants receiving all study injections, primary immunogenicity endpoints were anti-P2-VP8-P[8] IgA and IgG and neutralising antibody seroresponses and geometric mean titres 4 weeks after the third injection. This trial is registered at ClinicalTrials.gov, number NCT02109484. Between March 17, 2014, and Sept 29, 2014, 42 toddlers (36 to vaccine and six to placebo) and 48 infants (36 to vaccine and 12 to placebo) were enrolled in the dose-escalation phase, in which the 30 μg and 60 μg doses where found to be the highest tolerated doses. A further 114 infants were enrolled in the expanded cohort between Nov 3, 2014, and March 20, 2015, and all 162 infants (12 assigned to 10 μg, 50 to 30 μg, 50 to 60 μg, and 50 to placebo) were included in the safety analysis. Serum IgA seroresponses were observed in 38 (81%, 95% CI 67-91) of 47 infants in the 30 μg group and 32 (68%, 53-81) of 47 in the 60 μg group, compared with nine (20%, 10-35) of 45 in the placebo group; adjusted IgG seroresponses were seen in 46 (98%, 89-100) of 47 infants in the 30 μg group and 47 (100%; 92-100) of 47 in the 60 μg group, compared with four (9%, 2·5-21) of 45 in the placebo group; and adjusted neutralising antibody seroresponses against the homologous Wa-strain were seen in 40 (85%, 72-94) of 47 infants in both the 30 μg and 60 μg groups, compared with three (7%, 1·4-18) of 45 participants in the placebo group. Solicited reactions following any injection occurred with similar frequency and severity in participants receiving vaccine and those receiving placebo. Unsolicited adverse events were mostly mild and occurred at a similar frequency between groups. Eight serious adverse events (one with placebo, two with 30 μg, and five with 60 μg) occurred in seven infants within 28 days of any study injection, none of which were deemed related to study treatment. The parenteral P2-VP8-P[8] vaccine was well tolerated and immunogenic in infants, providing a novel approach to vaccination against rotavirus disease. On the basis of these results, a phase 1/2 trial of a trivalent P2-VP8 (P[4], P[6], and P[8]) subunit vaccine is underway at three sites in South Africa. Bill & Melinda Gates Foundation. Copyright © 2017 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.

Intervention Fidelity: Aspects of Complementary and Alternative Medicine (CAM) Research

PubMed Central

Wyatt, Gwen; Sikorskii, Alla; Rahbar, Mohammad Hossein; Victorson, David; Adams, Lora

2010-01-01

Background The Treatment Fidelity Workgroup (TFW) established by the National Institutes of Health (NIH) provides a 5-point structure for intervention fidelity: dosing, interventionists’ consistency, intervention delivery, receipt and enactment of the intervention. Using our reflexology trial, we apply the first three points. Objectives Study objectives are to: 1) evaluate key dosage dimensions associated with CAM research; 2) evaluate approaches to interventionists’ consistency of delivery of CAM protocols; and 3) evaluate and discuss data that reflect CAM intervention fidelity. Intervention Women with late stage breast cancer (N=318) were randomly assigned to either 4 weeks of reflexology, placebo, or standard care. Results Dosing consists of three dimensions: frequency (4-sessions), duration (30 minutes), and interval between sessions (5–9 days). Interventionist consistency revealed over a 90% accuracy rate in following the protocol; 84% and 89% completion rate of the 4 session in the reflexology and placebo groups respectively; and no differences in attrition after randomization between reflexology and placebo groups (17% and 15%, respectively). Intervention delivery, examined through debriefing data, indicated a significantly higher rate of correct guesses on group assignment in the reflexology group as compared to the placebo (82% versus 46%, p-value=.0002). Conclusions This study points out the relevance of dosing, interventionists’ consistency, and delivery data within a CAM clinical trial, as well as the challenges of blinding. Implications Monitoring intervention fidelity by using the key areas identified by the BCC ensures that findings from a clinical trial are meaningful and have the potential to be translated to clinical practice. PMID:20467309

Changes in Neuropsychiatric Inventory Associated with Semagacestat Treatment of Alzheimer's Disease.

PubMed

Rosenberg, Paul B; Lanctôt, Krista L; Herrmann, Nathan; Mintzer, Jacobo E; Porsteinsson, Anton P; Sun, Xiaoying; Raman, Rema

2016-08-10

In a recent report, 76 weeks' treatment with a gamma-secretase inhibitor (semagacestat) was associated with poorer cognitive outcomes in Alzheimer's disease (AD). We sought to examine the effect of semagacestat treatment on neuropsychiatric symptoms (NPS). 1,537 participants with mild to moderate AD were randomized to 76 weeks' treatment with placebo versus two doses of semagacestat. NPS were assessed with the Neuropsychiatric Inventory (NPI-Total and subdomains). Cognition was assessed with the Alzheimer's Disease Assessment Scale-Cognitive (first 11 items, ADAS11). Mixed-Model Repeated Measures was used to compare the effects of treatment assignment on change in NPI-total and subdomains over time. Survival analysis was used to assess the treatment effect on time to first worsening of NPS (NPI-Total ≥10 or NPI subdomain ≥4) for subjects with no or minor NPS at baseline. Participants on high dose semagecestat (140 mg) had greater increase in NPI-Total and greater risk of incident first worsening in NPI-Total and in subdomains of aberrant motor behavior, appetite, depression/dysphoria, and sleep. ADAS11 increased more in participants whose NPI-Total increased. In participants with mild to moderate AD, high dose semagacestat treatment was associated with greater severity and faster worsening of NPS in a pattern resembling an agitated depression. Increased NPS was associated with cognitive decline regardless of treatment assignment. These findings suggest that greater NPS may be the result of gamma-secretase treatment and emphasize the importance of monitoring NPS as potential adverse events in trials of novel treatments for AD.

Outcome with lenalidomide plus dexamethasone followed by early autologous stem cell transplantation in patients with newly diagnosed multiple myeloma on the ECOG-ACRIN E4A03 randomized clinical trial: long-term follow-up.

PubMed

Biran, N; Jacobus, S; Vesole, D H; Callander, N S; Fonseca, R; Williams, M E; Abonour, R; Katz, M S; Rajkumar, S V; Greipp, P R; Siegel, D S

2016-09-02

In Eastern Cooperative Oncology Group-ACRIN E4A03, on completion of four cycles of therapy, newly diagnosed multiple myeloma patients had the option of proceeding to autologous peripheral blood stem cell transplant (ASCT) or continuing on their assigned therapy lenalidomide plus low-dose dexamethasone (Ld) or lenalidomide plus high-dose dexamethasone (LD). This landmark analysis compared the outcome of 431 patients surviving their first four cycles of therapy pursuing early ASCT to those continuing on their assigned therapy. Survival distributions were estimated using the Kaplan-Meier method and compared with log-rank test. Ninety patients (21%) opted for early ASCT. The 1-, 2-, 3-, 4- and 5-year survival probability estimates were higher for early ASCT versus no early ASCT at 99, 93, 91, 85 and 80% versus 94, 84, 75, 65 and 57%, respectively. The median overall survival (OS) in the early versus no early ASCT group was not reached (NR) versus 5.78 years. In patients <65 years of age, median OS in the early versus no early ASCT groups was NR in both, hazard ratio 0.79, 95% confidence interval: (0.50, 0.25). In patients ⩾65 years of age, median OS in the early versus no early ASCT was NR versus 5.11 years. ASCT dropped out of statistical significance (P=0.080). Patients opting for ASCT after induction Ld/LD had a higher survival probability and improvement in OS regardless of dexamethasone dose density.

Comparative assessment of efficacy of two different pretreatment single oral doses of betamethasone on inter-appointment and postoperative discomfort: An in vivo clinical evaluation.

PubMed

Gyanani, Hitesh; Chhabra, Naveen; Parmar, Ghanshyam R

2016-01-01

Study aimed to evaluate the efficacy of two different pretreatment single oral doses of betamethasone on the incidence of inter-appointment flare up and postoperative discomfort. Fifty-four patients aged 18-59 years requiring endodontic treatment were selected and randomly assigned to three groups; single pretreatment oral dose of placebo or betamethasone in two different oral doses of 0.5 mg and 1 mg, respectively. Endodontic therapy was completed in two visits using triple antibiotic paste as intracanal medicament. Patients were given a questionnaire to record their pain at 1, 2, 3, and 7 days after treatment. In the second visit, obturation was done, and the patients were again instructed to record their pain scores after treatment and discharged. The verbal rating scale was used for recording the pain scores. Statistical analysis was done using ANOVA and the Friedman test. 0.5 mg betamethasone group showed least mean pain scores among all experimental groups; however, there was no statistically significant difference between any of the groups ( P > 0.05). Pretreatment single oral dose of betamethasone is an effective in managing endodontic flare-ups; however, the results were statistically insignificant.

Clinical evaluation of rosoxacin for the treatment of chancroid.

PubMed Central

Haase, D A; Ndinya-Achola, J O; Nash, R A; D'Costa, L J; Hazlett, D; Lubwama, S; Nsanze, H; Ronald, A R

1986-01-01

One hundred seven men with Haemophilus ducreyi-positive chancroid were assigned to receive 300 mg of rosoxacin as a single dose or 150 mg twice daily for 3 days. Ulcers and buboes were followed clinically and bacteriologically for 1 month. Of 40 evaluable males on the 3-day regimen, 38 (95%) were cured, while only 14 of 23 (61%) males on the single-dose regimen were cured; this regimen was discontinued. There was one ulcer relapse at day 21 in both groups; the one relapse in the single-dose group had a persistent culture-positive bubo. Eight of nine (89%) buboes followed to the endpoint on the 3-day rosoxacin regimen were cured, versus three of six (50%) on the single-dose regimen. Adverse effects were mainly related to the central nervous system but were minor and did not require intervention. None of the treatment failures was due to organisms resistant to rosoxacin, and failure of the single-dose regimen presumably was related to duration of tissue levels rather than to drug resistance. Administration of 150 mg of rosoxacin twice daily for 3 days is an effective regimen for the therapy of chancroid and is a reasonable alternative to other short-course regimens. PMID:3489439

Relative bioavailability of an extemporaneous ondansetron 4-mg capsule formulation versus solution.

PubMed

Lam, Y W Francis; Javors, Martin A; Ait-Daoud, Nassima; Roache, John D; Johnson, Bankole A

2004-04-01

To compare the relative bioavailability of an extemporaneous ondansetron capsule formulation with that of an identical dose of the commercially available solution formulation. Open-label, randomized, two-way crossover study. University-affiliated research laboratory. Sixteen (eight men, eight women) healthy, nonsmoking volunteers. Participants were randomly assigned to receive a 4-mg dose of either the commercially available ondansetron solution or the extemporaneous ondansetron capsule formulation. Blood sampling was performed over 12 hours after dosing. After a washout period of at least 3 days, each participant was switched to the alternate formulation, and blood sampling was repeated. Ondansetron was well absorbed after administration of both formulations, with the solution achieving a faster rate of drug absorption over the first hour of dosing. After the peak plasma concentration was achieved, the plasma concentration-time curves of both formulations declined at a similar steady rate. There were no significant differences in pharmacokinetic parameters between the two formulations, and the relative bioavailability of the capsule versus the solution formulation was 101%. Similar concentration-time curves and pharmacokinetic parameters were achieved with the two formulations. The commercially available solution would be a useful alternative formulation for administration of low-dose ondansetron in research and clinical settings.

Standard and double-dose intravenous proton pump inhibitor injections for prevention of bleeding after endoscopic resection.

PubMed

Jung, Sung Woo; Kim, Seung Young; Choe, Jung Wan; Hyun, Jong Jin; Jung, Young Kul; Koo, Ja Seol; Yim, Hyung Joon; Lee, Sang Woo

2017-04-01

Endoscopic resection is commonly used to remove gastric neoplasms. However, effective dosing or scheduling of proton pump inhibitors for the prevention of delayed bleeding after endoscopic resection remains unclear. One hundred sixty-six patients with gastric adenoma or early gastric cancer were enrolled. After an endoscopic procedure, each subject was randomly assigned to 40 mg every 24 h (standard dose group) or 40 mg every 12 h (double-dose group) of intravenous pantoprazole for 48 h. Second-look endoscopy was performed on day 2 after endoscopic resection to compare signs of rebleeding and ulcer status between the two groups. Eighty-one patients of the standard dose group and 81 of the double-dose group were analyzed. There were no significant differences in the incidence of delayed bleeding events (1.3% vs 6.2%, P = 0.21) and bleeding ulcer at the second-look endoscopy (6.2% vs 3.9%, P = 0.69) between standard and double-dose groups. There were no other significant variables associated with delayed bleeding or bleeding ulcer on second-look endoscopy. Intravenous pantoprazole 40 mg every 24 h or 12 h for 2 days after endoscopic resection was equally effective for the prevention of delayed bleeding. © 2016 Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.

Inhibition of nocturnal acidity is important but not essential for duodenal ulcer healing.

PubMed Central

Bianchi Porro, G; Parente, F; Sangaletti, O

1990-01-01

We have determined the relative importance of day and night time gastric acid inhibition for duodenal ulcer healing by comparing the anti-ulcer efficacy of a single morning with that of a single bedtime dose of ranitidine. One hundred and thirty patients with active duodenal ulcer were randomly assigned to a double-blind therapy with ranitidine 300 mg at 8 am or the same dose at 10 pm for up to eight weeks. The antisecretory effects of these regimens were also assessed by 24 h intragastric pH monitoring in 18 of these patients. At four weeks ulcers had healed in 41/61 (67%) of patients taking the morning dose and in 47/63 (75%) of those receiving the nocturnal dose (95% CI for the difference -0.09 +0.25; p ns). At eight weeks, the corresponding healing rates were 82% and 85.5%, respectively (95% CI for the difference -0.11 +0.17; p ns). Both treatments were significantly superior to placebo in raising 24 h intragastric pH, although the effects of the morning dose were of shorter duration than those of the nocturnal dose. These findings suggest that suppression of nocturnal acidity is important but not essential to promote healing of duodenal ulcers; a prolonged period of acid inhibition during the day (as obtained with a single large morning dose of H2-blockers) may be equally effective. PMID:2186980

Efficacy and safety of guaifenesin for upper back, neck, and shoulder pain: a Phase II proof-of-concept, multicenter, placebo-controlled, repeat-dose, parallel-group study.

PubMed

Collaku, Agron; Yue, Yong; Reed, Kenneth

2017-01-01

Guaifenesin, an over-the-counter (OTC) expectorant, has exhibited muscle relaxant effects preclinically and clinically. This proof-of-principle study explored whether OTC doses of guaifenesin can provide relief from acute upper back, neck, or shoulder muscle spasm and pain. This multicenter, placebo-controlled, repeat-dose, parallel study randomly assigned adults experiencing acute pain and muscle spasm in their upper back, neck, or shoulder to guaifenesin 600 or 1200 mg or matched placebo twice daily (BID) in a 2:2:1:1 ratio for 7 days. The primary end point was the change from baseline in muscle spasm relief, measured using an 11-point numeric rating scale (0=not present to 10=unbearable) recorded twice daily and averaged over the 7-day treatment period. Analyses were performed using a linear mixed model that included treatment as a fixed effect and site as a random effect. A total of 77 subjects were included in the 4 treatment groups. Least squares mean muscle spasm score over 7 days was 1.77 with guaifenesin 1200 mg, 1.42 with its matched placebo, 1.53 with guaifenesin 600 mg, and 1.74 with its matched placebo. Treatment with guaifenesin 1200 mg BID provided 25% greater reduction in mean muscle spasm over its matched placebo and 16% greater reduction than guaifenesin 600 mg BID. These differences were not statistically significant. Based on comparisons of absolute mean values, a consistent directional change in effect was observed, suggesting some benefit from placebo to lower-to-upper doses of guaifenesin with regard to muscle spasm, tension, pain, discomfort, and relaxation. No severe or serious adverse events were reported. Results suggest the potential for OTC dose of guaifenesin 1200 mg BID to provide symptomatic relief of upper back musculoskeletal pain and spasm. Confirmation of this preliminary result in a larger, adequately powered study is needed.

Efficacy and safety of guaifenesin for upper back, neck, and shoulder pain: a Phase II proof-of-concept, multicenter, placebo-controlled, repeat-dose, parallel-group study

PubMed Central

Collaku, Agron; Yue, Yong; Reed, Kenneth

2017-01-01

Background/objective Guaifenesin, an over-the-counter (OTC) expectorant, has exhibited muscle relaxant effects preclinically and clinically. This proof-of-principle study explored whether OTC doses of guaifenesin can provide relief from acute upper back, neck, or shoulder muscle spasm and pain. Methods This multicenter, placebo-controlled, repeat-dose, parallel study randomly assigned adults experiencing acute pain and muscle spasm in their upper back, neck, or shoulder to guaifenesin 600 or 1200 mg or matched placebo twice daily (BID) in a 2:2:1:1 ratio for 7 days. The primary end point was the change from baseline in muscle spasm relief, measured using an 11-point numeric rating scale (0=not present to 10=unbearable) recorded twice daily and averaged over the 7-day treatment period. Analyses were performed using a linear mixed model that included treatment as a fixed effect and site as a random effect. Results A total of 77 subjects were included in the 4 treatment groups. Least squares mean muscle spasm score over 7 days was 1.77 with guaifenesin 1200 mg, 1.42 with its matched placebo, 1.53 with guaifenesin 600 mg, and 1.74 with its matched placebo. Treatment with guaifenesin 1200 mg BID provided 25% greater reduction in mean muscle spasm over its matched placebo and 16% greater reduction than guaifenesin 600 mg BID. These differences were not statistically significant. Based on comparisons of absolute mean values, a consistent directional change in effect was observed, suggesting some benefit from placebo to lower-to-upper doses of guaifenesin with regard to muscle spasm, tension, pain, discomfort, and relaxation. No severe or serious adverse events were reported. Conclusion Results suggest the potential for OTC dose of guaifenesin 1200 mg BID to provide symptomatic relief of upper back musculoskeletal pain and spasm. Confirmation of this preliminary result in a larger, adequately powered study is needed. PMID:28356767

High-dose levofloxacin in community-acquired pneumonia: a randomized, open-label study.

PubMed

Lee, Jin Hwa; Kim, Seo Woo; Kim, Ji Hye; Ryu, Yon Ju; Chang, Jung Hyun

2012-09-01

The conventional treatment for community-acquired pneumonia (CAP) involves combination therapy consisting of a β-lactam penicillin or a cephalosporin with a macrolide. Alternatively, high-dose levofloxacin treatment has been used as single-agent therapy for treating CAP, covering atypical pathogens. This study compared the clinical efficacy and safety of high-dose levofloxacin with combined ceftriaxone and azithromycin for the treatment of CAP. This phase IV, prospective, randomized, open-label trial enrolled patients admitted to a tertiary referral hospital for CAP treatment from 2010 to 2011. Hospital admission was decided based on clinical judgement and the pneumonia severity index. Forty subjects were enrolled and assigned to two treatment arms using a random numbers table. The 20 subjects in the experimental group were given levofloxacin 750 mg intravenously once daily, followed by the same dose of oral levofloxacin at discharge when clinically improved and the 20 subjects in the control group were given ceftriaxone 2.0 g intravenously once daily plus oral azithromycin 500 mg for 3 consecutive days, followed by oral cefpodoxime 200 mg per day at discharge after clinical improvement. The primary outcome was the clinical success rate. Secondary outcomes were the microbiological success rate and adverse events during the study. Of the 40 subjects enrolled, 36 completed the study: 17 in the experimental group and 19 in the control group. The groups did not differ in terms of demographic factors or clinical findings at baseline. The clinical success rate (cured + improved) was 94% in the experimental (levofloxacin) group and 84% in the control group (p > 0.05). The microbiological success rate and overall adverse events were also similar in both groups. Single-agent, high-dose levofloxacin treatment exhibited excellent clinical and microbiological efficacy with a safety profile comparable to that of ceftriaxone plus azithromycin therapy. Large-scale clinical trials are required to verify these results. WHO International Clinical Trials Registry: KCT0000374; Daiichi-Sankyo Korea study code: T11-13-V1.

The Ramazzini Institute 13-week pilot study on glyphosate and Roundup administered at human-equivalent dose to Sprague Dawley rats: effects on the microbiome.

PubMed

Mao, Qixing; Manservisi, Fabiana; Panzacchi, Simona; Mandrioli, Daniele; Menghetti, Ilaria; Vornoli, Andrea; Bua, Luciano; Falcioni, Laura; Lesseur, Corina; Chen, Jia; Belpoggi, Fiorella; Hu, Jianzhong

2018-05-29

Glyphosate-based herbicides (GBHs) are broad-spectrum herbicides that act on the shikimate pathway in bacteria, fungi, and plants. The possible effects of GBHs on human health are the subject of an intense public debate for both its potential carcinogenic and non-carcinogenic effects, including its effects on microbiome. The present pilot study examines whether exposure to GBHs at doses of glyphosate considered to be "safe" (the US Acceptable Daily Intake - ADI - of 1.75 mg/kg bw/day), starting from in utero, may modify the composition of gut microbiome in Sprague Dawley (SD) rats. Glyphosate alone and Roundup, a commercial brand of GBHs, were administered in drinking water at doses comparable to the US glyphosate ADI (1.75 mg/kg bw/day) to F0 dams starting from the gestational day (GD) 6 up to postnatal day (PND) 125. Animal feces were collected at multiple time points from both F0 dams and F1 pups. The gut microbiota of 433 fecal samples were profiled at V3-V4 region of 16S ribosomal RNA gene and further taxonomically assigned and assessed for diversity analysis. We tested the effect of exposure on overall microbiome diversity using PERMANOVA and on individual taxa by LEfSe analysis. Microbiome profiling revealed that low-dose exposure to Roundup and glyphosate resulted in significant and distinctive changes in overall bacterial composition in F1 pups only. Specifically, at PND31, corresponding to pre-pubertal age in humans, relative abundance for Bacteriodetes (Prevotella) was increased while the Firmicutes (Lactobacillus) was reduced in both Roundup and glyphosate exposed F1 pups compared to controls. This study provides initial evidence that exposures to commonly used GBHs, at doses considered safe, are capable of modifying the gut microbiota in early development, particularly before the onset of puberty. These findings warrant future studies on potential health effects of GBHs in early development such as childhood.

Postinduction Dexamethasone and Individualized Dosing of Escherichia Coli L-Asparaginase Each Improve Outcome of Children and Adolescents With Newly Diagnosed Acute Lymphoblastic Leukemia: Results From a Randomized Study—Dana-Farber Cancer Institute ALL Consortium Protocol 00-01

PubMed Central

Vrooman, Lynda M.; Stevenson, Kristen E.; Supko, Jeffrey G.; O'Brien, Jane; Dahlberg, Suzanne E.; Asselin, Barbara L.; Athale, Uma H.; Clavell, Luis A.; Kelly, Kara M.; Kutok, Jeffery L.; Laverdière, Caroline; Lipshultz, Steven E.; Michon, Bruno; Schorin, Marshall; Relling, Mary V.; Cohen, Harvey J.; Neuberg, Donna S.; Sallan, Stephen E.; Silverman, Lewis B.

2013-01-01

Purpose We assessed the toxicity and efficacy of dexamethasone and a novel dosing method of Escherichia coli L-asparaginase (EC-Asnase) in children and adolescents with newly diagnosed acute lymphoblastic leukemia (ALL). Patients and Methods Patients achieving complete remission (CR) on Dana-Farber Cancer Institute ALL Consortium Protocol 00-01 were eligible for random assignment to 1) dexamethasone or prednisone, administered as 5-day pulses, every 3 weeks, and 2) weekly EC-Asnase, administered as a 25,000 IU/m2 fixed dose (FD) or individualized dose (ID) starting at 12,500-IU/m2, adjusted every 3 weeks based on nadir serum asparaginase activity (NSAA) determinations. Results Between 2000 and 2004, 492 evaluable patients (ages 1 to 18 years) enrolled; 473 patients (96%) achieved CR. Four hundred eight patients (86%) participated in the corticosteroid randomization and 384 patients (81%) in the EC-Asnase randomization. With 4.9 years of median follow-up, dexamethasone was associated with superior 5-year event-free survival (EFS; 90% v 81% for prednisone; P = .01) but higher rates of infection (P = .03) and, in older children, higher cumulative incidence of osteonecrosis (P = .02) and fracture (P = .06). ID EC-Asnase had superior 5-year EFS (90% v 82% for FD; P = .04), but did not reduce the frequency of asparaginase-related toxicity. Multivariable analysis identified both dexamethasone and ID EC-Asnase as independent predictors of favorable EFS. Conclusion There was no overall difference in skeletal toxicity by corticosteroid type; dexamethasone was associated with more infections and, in older children, increased incidence of osteonecrosis and fracture. There was no difference in asparaginase-related toxicity by EC-Asnase dosing method. Dexamethasone and ID EC-Asnase were each associated with superior EFS. Monitoring NSAA during treatment with EC-Asnase may be an effective strategy to improve outcome in pediatric ALL. PMID:23358966

Effect of low-dose spironolactone on resistant hypertension in type 2 diabetes mellitus: a randomized controlled trial in a sub-Saharan African population.

PubMed

Djoumessi, Romance Nguetse; Noubiap, Jean Jacques N; Kaze, Francois Folefack; Essouma, Mickael; Menanga, Alain Patrick; Kengne, Andre Pascal; Mbanya, Jean Claude; Sobngwi, Eugene

2016-03-23

Low-dose spironolactone has been proven to be effective for resistant hypertension in the general population, but this has yet to be confirmed in type 2 diabetic (T2DM) patients. We assessed the efficacy of a low-dose spironolactone on resistant hypertension in a sub-Saharan African population of T2DM patients from Cameroon. This was a four-week single blinded randomized controlled trial in 17 subjects presenting with resistant hypertension in specialized diabetes care units in Cameroon. They were randomly assigned to treatment with a daily 25 mg of spironolactone (n = 9) or to an alternative antihypertensive regimen (n = 8), on top of any ongoing regimen and prevailing lifestyle prescriptions. They were seen at the start of the treatment, then 2 and 4 weeks later. The primary outcome was change in office and self-measured blood pressure (BP) during follow-up, and secondary outcomes were changes in serum potassium, sodium, and creatinine levels. Compared with alternative treatment, low-dose spironolactone was associated with significant decrease in office systolic BP (-33 vs. -14 mmHg; p = 0.024), and in diastolic BP (-14 vs. -5 mmHg; p = 0.006). After 1 month of spironolactone, all the patients were controlled based on BP below 130/80 mmHg, with significant office BP reduction from 158 ± 17/86 ± 11 to 125 ± 11/72 ± 8, vs. 158 ± 8/94 ± 8 to 144 ± 17/89 ± 12 mmHg in the alternative treatment group. There was no significant variation in sodium and creatinine levels in both groups, but a mild increase of potassium levels in the spironolactone group. Add-on low-dose spironolactone was effective in reducing BP to optimal levels in T2DM Cameroonian patients despite mild increase in serum potassium. Trial registration ClinicalTrials.gov Identifier NCT02426099. Date of registration April 2015.

Placebo-controlled pilot trial of mecamylamine for treatment of autism spectrum disorders.

PubMed

Arnold, L Eugene; Aman, Michael G; Hollway, Jill; Hurt, Elizabeth; Bates, Bethany; Li, Xiaobai; Farmer, Cristan; Anand, Rene; Thompson, Susan; Ramadan, Yaser; Williams, Craig

2012-06-01

To explore possible benefits of a nicotinic acetylcholine receptor (nAChR) agent for autistic symptoms based on postmortem observation of nAChR abnormalities (deficient α4β2 nAChRs, excess α7 nAChRs) in brains of patients with autism. Mecamylamine, because of its safety record in children with other disorders, was chosen for this first exploration. Twenty children with autism spectrum disorder age 4-12 years were randomly assigned for 14 weeks to placebo (n=8) or mecamylamine (n=12) in ascending fixed doses: 0.5 mg/day for 6 weeks, 2.5 mg for 2 weeks, then 5 mg/day for 6 weeks. Improvement was rated by a blinded independent evaluator. Because of small sample, data analysis was descriptive. Eighteen participants (10 mecamylamine, 8 placebo) completed the study. All doses were well tolerated; the only side effect of note was constipation (50% compared with 25% of placebo group). Three children had clinically nonsignificant electrocardiographic QT prolongation. Both groups showed modest to moderate improvement, but differences between groups were negligible. On the primary outcome measure, the Ohio Autism Clinical Impressions Scale, 90% of the active treatment group showed improvement at some point (but only 40% sustained it), compared with 62% on placebo. Of the four in active treatment that sustained improvement, three had a maximum dose of 0.13-0.15 mg/kg/day, while those who regressed had doses ≥0.18 mg/kg/day. Graphed means suggested better outcome with lower mg/kg and longer medication duration. Four parents spontaneously reported reduced hyperactivity and irritability and better verbalization and continued mecamylamine at their own expense. Mecamylamine appeared to be safe, but not very effective in autism. The suggestion of better results at lower doses and longer exposure warrants consideration for future trials. The next step would be exploration of a more specific α4β2 nAChR agonist, such as varenicline.

SU-F-T-408: On the Determination of Equivalent Squares for Rectangular Small MV Photon Fields

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

Sauer, OA; Wegener, S; Exner, F

Purpose: It is common practice to tabulate dosimetric data like output factors, scatter factors and detector signal correction factors for a set of square fields. In order to get the data for an arbitrary field, it is mapped to an equivalent square, having the same scatter as the field of interest. For rectangular fields both, tabulated data and empiric formula exist. We tested the applicability of such rules for very small fields. Methods: Using the Monte-Carlo method (EGSnrc-doseRZ), the dose to a point in 10cm depth in water was calculated for cylindrical impinging fluence distributions. Radii were from 0.5mm tomore » 11.5mm with 1mm thickness of the rings. Different photon energies were investigated. With these data a matrix was constructed assigning the amount of dose to the field center to each matrix element. By summing up the elements belonging to a certain field, the dose for an arbitrary point in 10cm depth could be determined. This was done for rectangles up to 21mm side length. Comparing the dose to square field results, equivalent squares could be assigned. The results were compared to using the geometrical mean and the 4Xperimeter/area rule. Results: For side length differences less than 2mm, the difference between all methods was in general less than 0.2mm. For more elongated fields, relevant differences of more than 1mm and up to 3mm for the fields investigated occurred. The mean square side length calculated from both empiric formulas fitted much better, deviating hardly more than 1mm and for the very elongated fields only. Conclusion: For small rectangular photon fields, deviating only moderately from square both investigated empiric methods are sufficiently accurate. As the deviations often differ regarding their sign, using the mean improves the accuracy and the useable elongation range. For ratios larger than 2, Monte-Carlo generated data are recommended. SW is funded by Deutsche Forschungsgemeinschaft (SA481/10-1)« less

Randomized control trial of benzydamine HCl versus sodium bicarbonate for prophylaxis of concurrent chemoradiation-induced oral mucositis.

PubMed

Chitapanarux, Imjai; Tungkasamit, Tharatorn; Petsuksiri, Janjira; Kannarunimit, Danita; Katanyoo, Kanyarat; Chakkabat, Chakkapong; Setakornnukul, Jiraporn; Wongsrita, Somying; Jirawatwarakul, Naruemon; Lertbusayanukul, Chawalit; Sripan, Patumrat; Traisathit, Patrinee

2018-03-01

The purpose of the study is to compare the efficacy of benzydamine HCl with sodium bicarbonate in the prevention of concurrent chemoradiation-induced oral mucositis in head and neck cancer patients. Sixty locally advanced head and neck cancer patients treated with high-dose radiotherapy concurrently with platinum-based chemotherapy were randomly assigned to receive either benzydamine HCl or sodium bicarbonate from the first day of treatment to 2 weeks after the completion of treatment. The total score for mucositis, based on the Oral Mucositis Assessment Scale (OMAS), was used for the assessment, conducted weekly during the treatment period and at the fourth week of the follow-up. Pain score, all prescribed medications, and tube feeding needs were also recorded and compared. The median of total OMAS score was statistically significant lower in patients who received benzydamine HCl during concurrent chemo-radiotherapy (CCRT) than in those who received sodium bicarbonate, (p value < 0.001). There was no difference in median pain score, (p value = 0.52). Nineteen percent of patients in sodium bicarbonate arm needed oral antifungal agents whereas none in the benzydamine HCl arm required such medications, (p value = 0.06). Tube feeding needs and the compliance of CCRT were not different between the two study arms. For patients undergoing high-dose radiotherapy concurrently with platinum-based chemotherapy, using benzydamine HCl mouthwash as a preventive approach was superior to basic oral care using sodium bicarbonate mouthwash in terms of reducing the severity of oral mucositis and encouraging trend for the less need of oral antifungal drugs.

Task-Driven Optimization of Fluence Field and Regularization for Model-Based Iterative Reconstruction in Computed Tomography.

PubMed

Gang, Grace J; Siewerdsen, Jeffrey H; Stayman, J Webster

2017-12-01

This paper presents a joint optimization of dynamic fluence field modulation (FFM) and regularization in quadratic penalized-likelihood reconstruction that maximizes a task-based imaging performance metric. We adopted a task-driven imaging framework for prospective designs of the imaging parameters. A maxi-min objective function was adopted to maximize the minimum detectability index ( ) throughout the image. The optimization algorithm alternates between FFM (represented by low-dimensional basis functions) and local regularization (including the regularization strength and directional penalty weights). The task-driven approach was compared with three FFM strategies commonly proposed for FBP reconstruction (as well as a task-driven TCM strategy) for a discrimination task in an abdomen phantom. The task-driven FFM assigned more fluence to less attenuating anteroposterior views and yielded approximately constant fluence behind the object. The optimal regularization was almost uniform throughout image. Furthermore, the task-driven FFM strategy redistribute fluence across detector elements in order to prescribe more fluence to the more attenuating central region of the phantom. Compared with all strategies, the task-driven FFM strategy not only improved minimum by at least 17.8%, but yielded higher over a large area inside the object. The optimal FFM was highly dependent on the amount of regularization, indicating the importance of a joint optimization. Sample reconstructions of simulated data generally support the performance estimates based on computed . The improvements in detectability show the potential of the task-driven imaging framework to improve imaging performance at a fixed dose, or, equivalently, to provide a similar level of performance at reduced dose.

Fully automatic assignment of small molecules' NMR spectra without relying on chemical shift predictions.

PubMed

Castillo, Andrés M; Bernal, Andrés; Patiny, Luc; Wist, Julien

2015-08-01

We present a method for the automatic assignment of small molecules' NMR spectra. The method includes an automatic and novel self-consistent peak-picking routine that validates NMR peaks in each spectrum against peaks in the same or other spectra that are due to the same resonances. The auto-assignment routine used is based on branch-and-bound optimization and relies predominantly on integration and correlation data; chemical shift information may be included when available to fasten the search and shorten the list of viable assignments, but in most cases tested, it is not required in order to find the correct assignment. This automatic assignment method is implemented as a web-based tool that runs without any user input other than the acquired spectra. Copyright © 2015 John Wiley & Sons, Ltd.

Effects of high-dose versus low-dose losartan on clinical outcomes in patients with heart failure (HEAAL study): a randomised, double-blind trial.

PubMed

Konstam, Marvin A; Neaton, James D; Dickstein, Kenneth; Drexler, Helmut; Komajda, Michel; Martinez, Felipe A; Riegger, Gunter A J; Malbecq, William; Smith, Ronald D; Guptha, Soneil; Poole-Wilson, Philip A

2009-11-28

Angiotensin-receptor blockers (ARBs) are effective treatments for patients with heart failure, but the relation between dose and clinical outcomes has not been explored. We compared the effects of high-dose versus low-dose losartan on clinical outcomes in patients with heart failure. This double-blind trial was undertaken in 255 sites in 30 countries. 3846 patients with heart failure of New York Heart Association class II-IV, left-ventricular ejection fraction 40% or less, and intolerance to angiotensin-converting-enzyme (ACE) inhibitors were randomly assigned to losartan 150 mg (n=1927) or 50 mg daily (n=1919). Allocation was by block randomisation stratified by centre and presence or absence of beta-blocker therapy, and all patients and investigators were masked to assignment. The primary endpoint was death or admission for heart failure. Analysis was by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00090259. Six patients in each group were excluded because of poor data quality. With 4.7-year median follow-up in each group (IQR 3.7-5.5 for losartan 150 mg; 3.4-5.5 for losartan 50 mg), 828 (43%) patients in the 150 mg group versus 889 (46%) in the 50 mg group died or were admitted for heart failure (hazard ratio [HR] 0.90, 95% CI 0.82-0.99; p=0.027). For the two primary endpoint components, 635 patients in the 150 mg group versus 665 in the 50 mg group died (HR 0.94, 95% CI 0.84-1.04; p=0.24), and 450 versus 503 patients were admitted for heart failure (0.87, 0.76-0.98; p=0.025). Renal impairment (n=454 vs 317), hypotension (203 vs 145), and hyperkalaemia (195 vs 131) were more common in the 150 mg group than in the 50 mg group, but these adverse events did not lead to significantly more treatment discontinuations in the 150 mg group. Losartan 150 mg daily reduced the rate of death or admission for heart failure in patients with heart failure, reduced left-ventricular ejection fraction, and intolerance to ACE inhibitors compared with losartan 50 mg daily. These findings show the value of up-titrating ARB doses to confer clinical benefit. Merck (USA).

A trichrome beam model for biological dose calculation in scanned carbon-ion radiotherapy treatment planning.

PubMed

Inaniwa, T; Kanematsu, N

2015-01-07

In scanned carbon-ion (C-ion) radiotherapy, some primary C-ions undergo nuclear reactions before reaching the target and the resulting particles deliver doses to regions at a significant distance from the central axis of the beam. The effects of these particles on physical dose distribution are accounted for in treatment planning by representing the transverse profile of the scanned C-ion beam as the superposition of three Gaussian distributions. In the calculation of biological dose distribution, however, the radiation quality of the scanned C-ion beam has been assumed to be uniform over its cross-section, taking the average value over the plane at a given depth (monochrome model). Since these particles, which have relatively low radiation quality, spread widely compared to the primary C-ions, the radiation quality of the beam should vary with radial distance from the central beam axis. To represent its transverse distribution, we propose a trichrome beam model in which primary C-ions, heavy fragments with atomic number Z ≥ 3, and light fragments with Z ≤ 2 are assigned to the first, second, and third Gaussian components, respectively. Assuming a realistic beam-delivery system, we performed computer simulations using Geant4 Monte Carlo code for analytical beam modeling of the monochrome and trichrome models. The analytical beam models were integrated into a treatment planning system for scanned C-ion radiotherapy. A target volume of 20  ×  20  ×  40 mm(3) was defined within a water phantom. A uniform biological dose of 2.65 Gy (RBE) was planned for the target with the two beam models based on the microdosimetric kinetic model (MKM). The plans were recalculated with Geant4, and the recalculated biological dose distributions were compared with the planned distributions. The mean target dose of the recalculated distribution with the monochrome model was 2.72 Gy (RBE), while the dose with the trichrome model was 2.64 Gy (RBE). The monochrome model underestimated the RBE within the target due to the assumption of no radial variations in radiation quality. Conversely, the trichrome model accurately predicted the RBE even in a small target. Our results verify the applicability of the trichrome model for clinical use in C-ion radiotherapy treatment planning.

A trichrome beam model for biological dose calculation in scanned carbon-ion radiotherapy treatment planning

NASA Astrophysics Data System (ADS)

Inaniwa, T.; Kanematsu, N.

2015-01-01

In scanned carbon-ion (C-ion) radiotherapy, some primary C-ions undergo nuclear reactions before reaching the target and the resulting particles deliver doses to regions at a significant distance from the central axis of the beam. The effects of these particles on physical dose distribution are accounted for in treatment planning by representing the transverse profile of the scanned C-ion beam as the superposition of three Gaussian distributions. In the calculation of biological dose distribution, however, the radiation quality of the scanned C-ion beam has been assumed to be uniform over its cross-section, taking the average value over the plane at a given depth (monochrome model). Since these particles, which have relatively low radiation quality, spread widely compared to the primary C-ions, the radiation quality of the beam should vary with radial distance from the central beam axis. To represent its transverse distribution, we propose a trichrome beam model in which primary C-ions, heavy fragments with atomic number Z ≥ 3, and light fragments with Z ≤ 2 are assigned to the first, second, and third Gaussian components, respectively. Assuming a realistic beam-delivery system, we performed computer simulations using Geant4 Monte Carlo code for analytical beam modeling of the monochrome and trichrome models. The analytical beam models were integrated into a treatment planning system for scanned C-ion radiotherapy. A target volume of 20  ×  20  ×  40 mm3 was defined within a water phantom. A uniform biological dose of 2.65 Gy (RBE) was planned for the target with the two beam models based on the microdosimetric kinetic model (MKM). The plans were recalculated with Geant4, and the recalculated biological dose distributions were compared with the planned distributions. The mean target dose of the recalculated distribution with the monochrome model was 2.72 Gy (RBE), while the dose with the trichrome model was 2.64 Gy (RBE). The monochrome model underestimated the RBE within the target due to the assumption of no radial variations in radiation quality. Conversely, the trichrome model accurately predicted the RBE even in a small target. Our results verify the applicability of the trichrome model for clinical use in C-ion radiotherapy treatment planning.

SU-D-BRB-04: Plan Quality Comparison of Intracranial Stereotactic Radiosurgery (SRS) for Gamma Knife and VMAT Treatments

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

Keeling, V; Algan, O; Ahmad, S

2015-06-15

Purpose: To compare treatment plan quality of intracranial stereotactic radiosurgery (SRS) for VMAT (RapidArc) and Gamma Knife (GK) systems. Methods: Ten patients with 24 tumors (seven with 1–2 and three with 4–6 lesions), previously treated with GK 4C (prescription doses ranging from 14–23 Gy) were re-planned for RapidArc. Identical contour sets were kept on MRI images for both plans with tissues assigned a CT number of zero. RapidArc plans were performed using 6 MV flattening-filter-free (FFF) beams with dose rate of 1400 MU/minute using two to eight arcs with the following combinations: 2 full coplanar arcs and the rest non-coplanarmore » half arcs. Beam selection was based on target depth. Areas that penetrated more than 10 cm of tissue were avoided by creating smaller arcs or using avoidance sectors in optimization. Plans were optimized with jaw tracking and a high weighting to the normal-brain-tissue and Normal-Tissue-Objective without compromising PTV coverage. Plans were calculated on a 1 mm grid size using AAA algorithm and then normalized so that 99% of each target volume received the prescription dose. Plan quality was assessed by target coverage using Paddick Conformity Index (PCI), sparing of normal-brain-tissue through analysis of V4, V8, and V12 Gy, and integral dose. Results: In all cases critical structure dose criteria were met. RapidArc had a higher PCI than GK plans for 23 out of 24 lesions. The average PCI was 0.76±0.21 for RapidArc and 0.46±0.20 for GK plans (p≤0.001), respectively. Integral dose and normal-brain-tissue doses for all criteria were lower for RapidArc in nearly all patients. The average ratio of GK to RapidArc plans was 1.28±0.27 (p=0.018), 1.31±0.25 (p=0.017), 1.81±0.43 (p=0.005), and 1.50±0.61 (p=0.006) for V4, V8, and V12 Gy, and integral dose, respectively. Conclusion: VMAT was capable of producing higher quality treatment plans than GK when using optimal beam geometries and proper optimization techniques.« less

Clarithromycin therapy for bacteremic Mycobacterium avium complex disease. A randomized, double-blind, dose-ranging study in patients with AIDS. AIDS Clinical Trials Group Protocol 157 Study Team.

PubMed

Chaisson, R E; Benson, C A; Dube, M P; Heifets, L B; Korvick, J A; Elkin, S; Smith, T; Craft, J C; Sattler, F R

1994-12-15

To determine the antimicrobial activity and tolerability of clarithromycin for treating bacteremic Mycobacterium avium complex disease in patients with the acquired immunodeficiency syndrome (AIDS). A randomized, double-blind, dose-ranging study. Outpatient clinics. 154 patients with human immunodeficiency virus (HIV) infection and blood cultures positive for M. avium complex who had symptomatic disease. Random assignment to clarithromycin at dosages of 500 mg, 1000 mg, or 2000 mg twice daily for 12 weeks. Median number of colony-forming units of M. avium complex per milliliter of blood. Clarithromycin decreased mycobacterial CFUs from 2.7 to 2.8 log 10/mL of blood at baseline to less than 0 log 10/mL during follow-up (P < 0.0001). After 2 weeks, patients receiving 500 mg twice daily were less likely to be culture negative than were patients receiving 1000 or 2000 mg twice daily (11% compared with 33% or 29%; P = 0.08). At 6 weeks, the median number of CFUs of M. avium complex/mL of blood was 0 or 1 for all three groups. Clarithromycin-resistant isolates of M. avium complex developed in 46% of patients at a median of 16 weeks. Median survival was longer in patients assigned to 500 mg twice daily (median, 249 days) than in patients assigned to 1000 mg or 2000 mg. Death in the first 12 weeks was lowest in the 500-mg group (P = 0.007). Clarithromycin therapy acutely decreased M. avium complex bacteremia in patients with HIV infection by more than 99%. Clarithromycin, 500 mg twice daily, was well tolerated and associated with better survival. Emergence of clarithromycin-resistant organisms was an important problem.

Effects of angiotensin-converting enzyme inhibition on transient ischemia: the Quinapril Anti-Ischemia and Symptoms of Angina Reduction (QUASAR) trial.

PubMed

Pepine, Carl J; Rouleau, Jean-Lucien; Annis, Karen; Ducharme, Anique; Ma, Patrick; Lenis, Jacques; Davies, Richard; Thadani, Udho; Chaitman, Bernard; Haber, Harry E; Freedman, S Ben; Pressler, Milton L; Pitt, Bertram

2003-12-17

We sought to determine whether angiotensin-converting enzyme inhibition (ACE-I) (i.e., quinapril) prevents transient ischemia (exertional and spontaneous) in patients with coronary artery disease (CAD). It is known that ACE-I reduces the risk of death, myocardial infarction (MI), and other CAD-related outcomes in high-risk patients. Numerous studies have confirmed that ACE-I improves coronary flow and endothelial function. Whether ACE-I also decreases transient ischemia is unclear, because no studies have been adequately designed or sufficiently powered to evaluate this issue. Using a randomized, double-blinded, placebo-controlled, multicenter design, we enrolled 336 CAD patients with stable angina. None had uncontrolled hypertension, left ventricular (LV) dysfunction, or recent MI, and all developed electrocardiographic (ECG) evidence of ischemia during exercise. They were randomly assigned to one of two groups: 40 mg/day quinapril (n = 177) or placebo (n = 159) for 8 weeks. Patients then entered an additional eight-week treatment phase to examine the full dose range. Those assigned to 40 mg quinapril continued that dose and those assigned to placebo were titrated to 80 mg/day. Treadmill testing, the Seattle Angina Questionnaire, and ambulatory ECG monitoring were used to assess responses at baseline and at 8 and 16 weeks. The groups did not differ significantly at entry or in terms of indexes assessing myocardial ischemia at 8 or 16 weeks of treatment. In this low-risk population, ACE-I was not associated with serious adverse events. Our findings suggest short-term ACE-I in CAD patients without hypertension, LV dysfunction, or acute MI is not associated with significant effects on transient ischemia.

Randomized controlled trial comparing 200μg and 400μg sublingual misoprostol for prevention of primary postpartum hemorrhage.

PubMed

Ugwu, Innocent A; Oluwasola, Timothy A; Enabor, Obehi O; Anayochukwu-Ugwu, Ngozi N; Adeyemi, Abolaji B; Olayemi, Oladapo O

2016-05-01

To compare efficacy and adverse effects of 200μg and 400μg misoprostol for prevention of postpartum hemorrhage (PPH). In a randomized control trial, women with term singleton pregnancies in active labor attending University College Hospital, Ibadan, Nigeria, were enrolled between July 2011 and February 2012. Participants were randomly assigned using random numbers (block size four) to receive 200μg or 400μg sublingual misoprostol after delivery of the anterior shoulder, alongside intravenous oxytocin. Investigators were masked to group assignment, but participants were not. The primary outcomes were blood loss up to 1h after delivery, PPH (blood loss ≥500mL), and adverse effects. Overall, 62 patients were assigned to each group. No significant differences between the 200-μg and 400-μg groups were recorded in mean peripartum blood loss (307±145mL vs 296±151mL; P=0.679) and PPH occurrence (5 [8.1%] vs 6 [9.7%] women; P=0.752). Noticeable adverse effects were reported by 16 (25.8%) women in the 200-μg group and 42 (67.7%) in the 400-μg group (P<0.001). Risk of shivering was significantly lower with 200μg than 400μg (relative risk 0.33, 95% confidence interval 0.19-0.58). Blood loss and PPH occurrence did not differ by misoprostol dose, but a 200-μg dose was associated with a reduction in adverse effects. Pan Africa Clinical Trials Registry: PACTR201505001107182. Copyright © 2016 International Federation of Gynecology and Obstetrics. Published by Elsevier Ireland Ltd. All rights reserved.

47 CFR 90.723 - Selection and assignment of frequencies.

Code of Federal Regulations, 2012 CFR

2012-10-01

... shall specify the number of frequencies requested. All frequencies in this band will be assigned by the... assigned only the number of channels justified to meet their requirements. (d) Phase I base or fixed station receivers utilizing 221-222 MHz frequencies assigned from Sub-band A as designated in § 90.715(b...

47 CFR 90.723 - Selection and assignment of frequencies.

Code of Federal Regulations, 2013 CFR

2013-10-01

... shall specify the number of frequencies requested. All frequencies in this band will be assigned by the... assigned only the number of channels justified to meet their requirements. (d) Phase I base or fixed station receivers utilizing 221-222 MHz frequencies assigned from Sub-band A as designated in § 90.715(b...

47 CFR 90.723 - Selection and assignment of frequencies.

Code of Federal Regulations, 2014 CFR

2014-10-01

... shall specify the number of frequencies requested. All frequencies in this band will be assigned by the... assigned only the number of channels justified to meet their requirements. (d) Phase I base or fixed station receivers utilizing 221-222 MHz frequencies assigned from Sub-band A as designated in § 90.715(b...

High-dose rapid and standard induction chemotherapy for patients aged over 1 year with stage 4 neuroblastoma: a randomised trial.

PubMed

Pearson, Andrew D J; Pinkerton, C Ross; Lewis, Ian J; Imeson, John; Ellershaw, Caroline; Machin, David

2008-03-01

The current standard treatment for patients with high-risk neuroblastoma includes initial induction chemotherapy with a 21-day interval between induction treatments. We aimed to assess whether an intensive chemotherapy protocol that had a 10-day interval between treatments would improve event-free survival (EFS) in patients aged 1 year or over with high-risk neuroblastoma. Between Oct 30, 1990, and March 18, 1999, patients with stage 4 neuroblastoma who had not received previous chemotherapy were enrolled from 29 centres in Europe. Patients were randomly assigned to rapid treatment (cisplatin [C], vincristine [O], carboplatin [J], etoposide [E], and cyclophosphamide [C], known as COJEC) or standard treatment (vincristine [O], cisplatin [P], etoposide [E], and cyclophosphamide [C], ie, OPEC, alternated with vincristine [O], carboplatin [J], etoposide [E], and cyclophosphamide [C], ie, OJEC). Both regimens used the same total cumulative doses of each drug (except vincristine), but the dose intensity of the rapid regimen was 1.8-times higher than that of the standard regimen. The standard regimen was given every 21 days if patients showed haematological recovery, whereas the rapid regimen was given every 10 days irrespective of haematological recovery. Response to chemotherapy was assessed according to the conventional International Neuroblastoma Response Criteria (INRC). In responders, surgical excision of the primary tumour was attempted, followed by myeloablation (with 200 mg/m2 of melphalan) and haemopoietic stem-cell rescue. Primary endpoints were 3-year, 5-year, and 10-year EFS. Data were analysed by intention to treat. This trial is registered on the clinical trials site of the US National Cancer Institute website, number NCT00365755, and also as EU-20592 and CCLG-NB-1990-11. 262 patients, of median age 2.95 years (range 1.03-20.97), were randomly assigned-132 patients to standard and 130 patients to rapid treatment. 111 patients in the standard group and 109 patients in the rapid group completed chemotherapy. Chemotherapy doses were recorded for 123 patients in the standard group and 126 patients in the rapid group. 97 of 123 (79%) patients in the standard group and 84 of 126 (67%) patients in the rapid group received at least 90% of the scheduled chemotherapy, and the relative dose intensity was 1.94 compared with the standard regimen. 3-year EFS was 24.2% for patients in the standard group and 31.0% for those in the rapid group (hazard ratio [HR] 0.86 [95% CI 0.66-1.14], p=0.30. 5-year EFS was 18.2% in the standard group and 30.2% in the rapid group, representing a difference of 12.0% (1.8 to 22.3), p=0.022. 10-year EFS was 18.2% in the standard group and 27.1% in the rapid group, representing a difference of 8.9% (-1.2 to 19.0), p=0.085. Myeloablation was given a median of 55 days earlier in patients assigned rapid treatment than those assigned standard treatment. Infective complications (numbers of patients with febrile neutropenia and septicaemia, and if given, time on antibiotic and antifungal treatment) and time in hospital were greater with rapid treatment. Occurrence of fungal infection was the same in both regimens. Dose intensity can be increased with a rapid induction regimen in patients with high-risk neuroblastoma. There was no significant difference in OS between the rapid and standard regimens at 5 years and 10 years. However, an increasing difference in EFS after 3 years suggests that the efficacy of the rapid regimen is better than the standard regimen. A rapid induction regimen enables myeloablation to be given much earlier, which might contribute to a better outcome.

Regulating exposure of the lens of the eye to ionising radiations.

PubMed

Thorne, M C

2012-06-01

The International Commission on Radiological Protection (ICRP) has reviewed recent epidemiological evidence suggesting that, for the lens of the eye, the threshold in absorbed dose for the induction of deleterious health effects is about 0.5 Gy. On this basis, the Commission recommends that for occupational exposure in planned exposure situations, the equivalent dose limit for the lens of the eye should be 20 mSv in a year, averaged over defined periods of 5 yr, with exposure not exceeding 50 mSv in any single year. This paper summarises the data that have been taken into account by the ICRP and critically examines whether the proposed downward revision of the dose limit is justified. Overall, it is concluded that the accumulating radiobiological and epidemiological evidence makes it more appropriate to treat cataract induction as a stochastic rather than a deterministic effect. Within this framework, it is illogical to have the same dose limit for the lens of the eye as for the whole body irradiated uniformly. This could be addressed either by removing the special dose limit for the lens of the eye, assigning it an appropriate tissue weighting factor and including it in the computation of the effective dose, or through a composite approach involving the use of a tissue weighting factor for effective dose computations together with a special limit on the equivalent dose to the lens of the eye to ensure that no individual was subject to an unacceptably high risk of induction of clinically significant cataracts.

Gestational length assignment based on last menstrual period, first trimester crown-rump length, ovulation, and implantation timing.

PubMed

Mahendru, Amita A; Wilhelm-Benartzi, Charlotte S; Wilkinson, Ian B; McEniery, Carmel M; Johnson, Sarah; Lees, Christoph

2016-10-01

Understanding the natural length of human pregnancy is central to clinical care. However, variability in the reference methods to assign gestational age (GA) confound our understanding of pregnancy length. Assignation from ultrasound measurement of fetal crown-rump length (CRL) has superseded that based on last menstrual period (LMP). Our aim was to estimate gestational length based on LMP, ultrasound CRL, and implantation that were known, compared to pregnancy duration assigned by day of ovulation. Prospective study in 143 women trying to conceive. In 71 ongoing pregnancies, gestational length was estimated from LMP, CRL at 10-14 weeks, ovulation, and implantation day. For each method of GA assignment, the distribution in observed gestational length was derived and both agreement and correlation between the methods determined. Median ovulation and implantation days were 16 and 27, respectively. The gestational length based on LMP, CRL, implantation, and ovulation was similar: 279, 278, 276.5 and 276.5 days, respectively. The distributions for observed gestational length were widest where GA was assigned from CRL and LMP and narrowest when assigned from implantation and ovulation day. The strongest correlation for gestational length assessment was between ovulation and implantation (r = 0.98) and weakest between CRL and LMP (r = 0.88). The most accurate method of predicting gestational length is ovulation day, and this agrees closely with implantation day. Prediction of gestational length from CRL and known LMP are both inferior to ovulation and implantation day. This information could have important implications on the routine assignment of gestational age.

Computer-based coding of free-text job descriptions to efficiently identify occupations in epidemiological studies.

PubMed

Russ, Daniel E; Ho, Kwan-Yuet; Colt, Joanne S; Armenti, Karla R; Baris, Dalsu; Chow, Wong-Ho; Davis, Faith; Johnson, Alison; Purdue, Mark P; Karagas, Margaret R; Schwartz, Kendra; Schwenn, Molly; Silverman, Debra T; Johnson, Calvin A; Friesen, Melissa C

2016-06-01

Mapping job titles to standardised occupation classification (SOC) codes is an important step in identifying occupational risk factors in epidemiological studies. Because manual coding is time-consuming and has moderate reliability, we developed an algorithm called SOCcer (Standardized Occupation Coding for Computer-assisted Epidemiologic Research) to assign SOC-2010 codes based on free-text job description components. Job title and task-based classifiers were developed by comparing job descriptions to multiple sources linking job and task descriptions to SOC codes. An industry-based classifier was developed based on the SOC prevalence within an industry. These classifiers were used in a logistic model trained using 14 983 jobs with expert-assigned SOC codes to obtain empirical weights for an algorithm that scored each SOC/job description. We assigned the highest scoring SOC code to each job. SOCcer was validated in 2 occupational data sources by comparing SOC codes obtained from SOCcer to expert assigned SOC codes and lead exposure estimates obtained by linking SOC codes to a job-exposure matrix. For 11 991 case-control study jobs, SOCcer-assigned codes agreed with 44.5% and 76.3% of manually assigned codes at the 6-digit and 2-digit level, respectively. Agreement increased with the score, providing a mechanism to identify assignments needing review. Good agreement was observed between lead estimates based on SOCcer and manual SOC assignments (κ 0.6-0.8). Poorer performance was observed for inspection job descriptions, which included abbreviations and worksite-specific terminology. Although some manual coding will remain necessary, using SOCcer may improve the efficiency of incorporating occupation into large-scale epidemiological studies. 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/

Apixaban with antiplatelet therapy after acute coronary syndrome.

PubMed

Alexander, John H; Lopes, Renato D; James, Stefan; Kilaru, Rakhi; He, Yaohua; Mohan, Puneet; Bhatt, Deepak L; Goodman, Shaun; Verheugt, Freek W; Flather, Marcus; Huber, Kurt; Liaw, Danny; Husted, Steen E; Lopez-Sendon, Jose; De Caterina, Raffaele; Jansky, Petr; Darius, Harald; Vinereanu, Dragos; Cornel, Jan H; Cools, Frank; Atar, Dan; Leiva-Pons, Jose Luis; Keltai, Matyas; Ogawa, Hisao; Pais, Prem; Parkhomenko, Alexander; Ruzyllo, Witold; Diaz, Rafael; White, Harvey; Ruda, Mikhail; Geraldes, Margarida; Lawrence, Jack; Harrington, Robert A; Wallentin, Lars

2011-08-25

Apixaban, an oral, direct factor Xa inhibitor, may reduce the risk of recurrent ischemic events when added to antiplatelet therapy after an acute coronary syndrome. We conducted a randomized, double-blind, placebo-controlled clinical trial comparing apixaban, at a dose of 5 mg twice daily, with placebo, in addition to standard antiplatelet therapy, in patients with a recent acute coronary syndrome and at least two additional risk factors for recurrent ischemic events. The trial was terminated prematurely after recruitment of 7392 patients because of an increase in major bleeding events with apixaban in the absence of a counterbalancing reduction in recurrent ischemic events. With a median follow-up of 241 days, the primary outcome of cardiovascular death, myocardial infarction, or ischemic stroke occurred in 279 of the 3705 patients (7.5%) assigned to apixaban (13.2 events per 100 patient-years) and in 293 of the 3687 patients (7.9%) assigned to placebo (14.0 events per 100 patient-years) (hazard ratio with apixaban, 0.95; 95% confidence interval [CI], 0.80 to 1.11; P=0.51). The primary safety outcome of major bleeding according to the Thrombolysis in Myocardial Infarction (TIMI) definition occurred in 46 of the 3673 patients (1.3%) who received at least one dose of apixaban (2.4 events per 100 patient-years) and in 18 of the 3642 patients (0.5%) who received at least one dose of placebo (0.9 events per 100 patient-years) (hazard ratio with apixaban, 2.59; 95% CI, 1.50 to 4.46; P=0.001). A greater number of intracranial and fatal bleeding events occurred with apixaban than with placebo. The addition of apixaban, at a dose of 5 mg twice daily, to antiplatelet therapy in high-risk patients after an acute coronary syndrome increased the number of major bleeding events without a significant reduction in recurrent ischemic events. (Funded by Bristol-Myers Squibb and Pfizer; APPRAISE-2 ClinicalTrials.gov number, NCT00831441.).

Patients with Fabry Disease after Enzyme Replacement Therapy Dose Reduction Versus Treatment Switch

PubMed Central

Krämer, Johannes; Duning, Thomas; Lenders, Malte; Canaan-Kühl, Sima; Krebs, Alice; González, Hans Guerrero; Sommer, Claudia; Üçeyler, Nurcan; Niemann, Markus; Störk, Stefan; Schelleckes, Michael; Reiermann, Stefanie; Stypmann, Jörg; Brand, Stefan-Martin; Wanner, Christoph; Brand, Eva

2014-01-01

Because of the shortage of agalsidase-beta in 2009, many patients with Fabry disease were treated with lower doses or were switched to agalsidase-alfa. This observational study assessed end-organ damage and clinical symptoms during dose reduction or switch to agalsidase-alfa. A total of 105 adult patients with Fabry disease who had received agalsidase-beta (1.0 mg/kg body weight) for ≥1 year were nonrandomly assigned to continue this treatment regimen (regular-dose group, n=38), receive a reduced dose of 0.3–0.5 mg/kg (dose-reduction group, n=29), or switch to 0.2 mg/kg agalsidase-alfa (switch group) and were followed prospectively for 1 year. We assessed clinical events (death, myocardial infarction, severe arrhythmia, stroke, progression to ESRD); changes in cardiac, renal, and neurologic function; and Fabry-related symptoms (neuropathic pain, hypohidrosis, diarrhea, and disease severity scores). Organ function and Fabry-related symptoms remained stable in the regular-dose group. In contrast, estimated GFR decreased by about 3 ml/min per 1.73 m2 (P=0.01) in the dose-reduction group, and the median albumin-to-creatinine ratio increased from 114 (0–606) mg/g to 216 (0–2062) mg/g (P=0.03) in the switch group. Furthermore, mean Mainz Severity Score Index scores and frequencies of pain attacks, chronic pain, gastrointestinal pain, and diarrhea increased significantly in the dose-reduction and switch groups. In conclusion, patients receiving regular agalsidase-beta dose had a stable disease course, but dose reduction led to worsening of renal function and symptoms. Switching to agalsidase-alfa is safe, but microalbuminuria may progress and Fabry-related symptoms may deteriorate. PMID:24556354

Patients with Fabry disease after enzyme replacement therapy dose reduction versus treatment switch.

PubMed

Weidemann, Frank; Krämer, Johannes; Duning, Thomas; Lenders, Malte; Canaan-Kühl, Sima; Krebs, Alice; Guerrero González, Hans; Sommer, Claudia; Üçeyler, Nurcan; Niemann, Markus; Störk, Stefan; Schelleckes, Michael; Reiermann, Stefanie; Stypmann, Jörg; Brand, Stefan-Martin; Wanner, Christoph; Brand, Eva

2014-04-01

Because of the shortage of agalsidase-beta in 2009, many patients with Fabry disease were treated with lower doses or were switched to agalsidase-alfa. This observational study assessed end-organ damage and clinical symptoms during dose reduction or switch to agalsidase-alfa. A total of 105 adult patients with Fabry disease who had received agalsidase-beta (1.0 mg/kg body weight) for ≥1 year were nonrandomly assigned to continue this treatment regimen (regular-dose group, n=38), receive a reduced dose of 0.3-0.5 mg/kg (dose-reduction group, n=29), or switch to 0.2 mg/kg agalsidase-alfa (switch group) and were followed prospectively for 1 year. We assessed clinical events (death, myocardial infarction, severe arrhythmia, stroke, progression to ESRD); changes in cardiac, renal, and neurologic function; and Fabry-related symptoms (neuropathic pain, hypohidrosis, diarrhea, and disease severity scores). Organ function and Fabry-related symptoms remained stable in the regular-dose group. In contrast, estimated GFR decreased by about 3 ml/min per 1.73 m(2) (P=0.01) in the dose-reduction group, and the median albumin-to-creatinine ratio increased from 114 (0-606) mg/g to 216 (0-2062) mg/g (P=0.03) in the switch group. Furthermore, mean Mainz Severity Score Index scores and frequencies of pain attacks, chronic pain, gastrointestinal pain, and diarrhea increased significantly in the dose-reduction and switch groups. In conclusion, patients receiving regular agalsidase-beta dose had a stable disease course, but dose reduction led to worsening of renal function and symptoms. Switching to agalsidase-alfa is safe, but microalbuminuria may progress and Fabry-related symptoms may deteriorate.

Switching From Age-Based Stimulus Dosing to Dose Titration Protocols in Electroconvulsive Therapy: Empirical Evidence for Better Patient Outcomes With Lower Peak and Cumulative Energy Doses.

PubMed

O'Neill-Kerr, Alex; Yassin, Anhar; Rogers, Stephen; Cornish, Janie

2017-09-01

The aim of this study was to test the proposition that adoption of a dose titration protocol may be associated with better patient outcomes, at lower treatment dose, and with comparable cumulative dose to that in patients treated using an age-based stimulus dosing protocol. This was an analysis of data assembled from archived records and based on cohorts of patients treated respectively on an age-based stimulus dosing protocol and on a dose titration protocol in the National Health Service in England. We demonstrated a significantly better response in the patient cohort treated with dose titration than with age-based stimulus dosing. Peak doses were less and the total cumulative dose was less in the dose titration group than in the age-based stimulus dosing group. Our findings are consistent with superior outcomes in patients treated using a dose titration protocol when compared with age-based stimulus dosing in a similar cohort of patients.

Rituximab-dose-dense chemotherapy with or without high-dose chemotherapy plus autologous stem-cell transplantation in high-risk diffuse large B-cell lymphoma (DLCL04): final results of a multicentre, open-label, randomised, controlled, phase 3 study.

PubMed

Chiappella, Annalisa; Martelli, Maurizio; Angelucci, Emanuele; Brusamolino, Ercole; Evangelista, Andrea; Carella, Angelo Michele; Stelitano, Caterina; Rossi, Giuseppe; Balzarotti, Monica; Merli, Francesco; Gaidano, Gianluca; Pavone, Vincenzo; Rigacci, Luigi; Zaja, Francesco; D'Arco, Alfonso; Cascavilla, Nicola; Russo, Eleonora; Castellino, Alessia; Gotti, Manuel; Congiu, Angela Giovanna; Cabras, Maria Giuseppina; Tucci, Alessandra; Agostinelli, Claudio; Ciccone, Giovannino; Pileri, Stefano A; Vitolo, Umberto

2017-08-01

The prognosis of young patients with diffuse large B-cell lymphoma at high risk (age-adjusted International Prognostic Index [aa-IPI] score 2 or 3) treated with R-CHOP (rituximab, cyclophosphamide, vincristine, doxorubicin, and prednisone) is poor. The aim of this study was to investigate the possible benefit of intensification with high-dose chemotherapy and autologous stem-cell transplantation as part of first-line treatment in these patients. We did a multicentre, open-label, randomised, controlled, phase 3 trial with a 2 × 2 factorial design to compare, at two different R-CHOP dose levels, a full course of rituximab-dose-dense chemotherapy (no transplantation group) versus an abbreviated course of rituximab-dose-dense chemotherapy followed by consolidation with R-MAD (rituximab plus high-dose cytarabine plus mitoxantrone plus dexamethasone) and high-dose BEAM chemotherapy (carmustine, etoposide, cytarabine, and melphalan) plus autologous stem-cell transplantation (transplantation group) in young patients (18-65 years) with untreated high-risk diffuse large B-cell lymphoma (aa-IPI score 2-3). At enrolment, patients were stratified according to aa-IPI score and randomly assigned (1:1:1:1) to receive R-CHOP (intravenous rituximab 375 mg/m 2 , cyclophosphamide 750 mg/m 2 , doxorubicin 50 mg/m 2 , and vincristine 1·4 mg/m 2 on day 1, plus oral prednisone 100 mg on days 1-5) delivered in a 14-day cycle (R-CHOP-14) for eight cycles; high-dose R-CHOP-14 (R-MegaCHOP-14; R-CHOP-14 except for cyclophosphamide 1200 mg/m 2 and doxorubicin 70 mg/m 2 ) for six cycles; R-CHOP-14 for four cycles followed by R-MAD (intravenous rituximab 375 mg/m 2 on day 1 or 4 plus intravenous cytarabine 2000 mg/m 2 and dexamethasone 4 mg/m 2 every 12 h on days 1-3 plus intravenous mitoxantrone 8 mg/m 2 on days 1-3) plus BEAM (intravenous carmustine 300 mg/m 2 on day -7, intravenous cytarabine 200 mg/m 2 twice a day on days -6 to -3, intravenous etoposide 100 mg/m 2 twice a day on days -6 to -3, plus intravenous melphalan 140 mg/m 2 on day -2) and autologous stem-cell transplantation (day 0); or R-MegaCHOP-14 for four cycles followed by R-MAD plus BEAM and autologous stem-cell transplantation. The primary endpoint was failure-free survival at 2 years in the intention-to-treat population. This study is registered with EudraCT (2005-002181-14; 2007-000275-42) and with ClinicalTrials.gov, number NCT00499018. Between Jan 10, 2006, and Sept 8, 2010, 399 patients were randomly assigned to receive transplantation (n=199) or no transplantation (n=200); 203 patients were assigned to receive R-CHOP-14 and 196 were assigned to receive R-MegaCHOP-14. With a median follow-up of 72 months (IQR 57-88), 2-year failure-free survival was 71% (95% CI 64-77) in the transplantation group versus 62% (95% CI 55-68) in the no transplantation group (hazard ratio [HR] 0·65 [95% CI 0·47-0·91]; stratified log-rank test p=0·012). No difference in 5-year overall survival was observed between these groups (78% [95% CI 71-83] versus 77% [71-83]; HR 0·98 [0·65-1·48]; stratified log-rank test p=0·91). Grade 3 or worse haematological adverse events were reported in 183 (92%) of 199 patients in the transplantation group versus 135 (68%) of 200 patients in the no transplantation group. Grade 3 or worse non-haematological adverse events were reported in 90 (45%) versus 31 (16%); the most common grade 3 or worse non-haematological adverse event was gastrointestinal (49 [25%] vs 19 [10%]). Treatment-related deaths occurred in 13 (3%) patients; eight in the transplantation group and five in the no transplantation group. Abbreviated rituximab-dose-dense chemotherapy plus R-MAD plus BEAM and autologous stem-cell transplantation reduced the risk of treatment failure compared with full course rituximab-dose-dense chemotherapy in young patients with diffuse large B-cell lymphoma at high risk. However, these results might not be clinically meaningful, since this improvement did not reflect an improvement in overall survival. These results do not support further consideration of the use of intensification of R-CHOP as an upfront strategy in patients with diffuse large B-cell lymphoma with poor prognosis. Fondazione Italiana Linfomi. Copyright © 2017 Elsevier Ltd. All rights reserved.

Comparison of ambulatory blood pressure-lowering effects of higher doses of different calcium antagonists in uncontrolled hypertension: the Calcium Antagonist Controlled-Release High-Dose Therapy in Uncontrolled Refractory Hypertensive Patients (CARILLON) Study.

PubMed

Mizuno, Hiroyuki; Hoshide, Satoshi; Tomitani, Naoko; Kario, Kazuomi

2017-10-01

Data are sparse regarding ambulatory blood pressure (BP) reduction of up-titration from a standard dose to a high dose in both nifedipine controlled-release (CR) and amlodipine. This was a prospective, randomized, multicenter, open-label trial. Fifty-one uncontrolled hypertensives medicated by two or more antihypertensive drugs including a renin-angiotensin system inhibitor and a calcium antagonist were randomly assigned to either the nifedipine CR (80 mg)/candesartan (8 mg) group or the amlodipine (10 mg)/candesartan (8 mg) group. The changes in 24-hr BP were comparable between the groups. The nifedipine group demonstrated a significant decrease in their urinary albumin creatinine ratio, whereas the amlodipine group demonstrated a significant decrease in their NTproBNP level. However, there was no significant difference in any biomarkers between the two groups. Nifedipine showed an almost equal effect on ambulatory blood pressure as amlodipine. Their potentially differential effects on renal protection and NTproBNP should be tested in larger samples.

Effects on lung stress of position and different doses of perfluorocarbon in a model of ARDS.

PubMed

López-Aguilar, Josefina; Lucangelo, Umberto; Albaiceta, Guillermo M; Nahum, Avi; Murias, Gastón; Cañizares, Rosario; Oliva, Joan Carles; Romero, Pablo V; Blanch, Lluís

2015-05-01

We determined whether the combination of low dose partial liquid ventilation (PLV) with perfluorocarbons (PFC) and prone positioning improved lung function while inducing minimal stress. Eighteen pigs with acute lung injury were assigned to conventional mechanical ventilation (CMV) or PLV (5 or 10 ml/kg of PFC). Positive end-expiratory pressure (PEEP) trials in supine and prone positions were performed. Data were analyzed by a multivariate polynomial regression model. The interplay between PLV and position depended on the PEEP level. In supine PLV dampened the stress induced by increased PEEP during the trial. The PFC dose of 5 ml/kg was more effective than the dose 10 ml/kg. This effect was not observed in prone. Oxygenation was significantly higher in prone than in supine position mainly at lower levels of PEEP. In conclusion, MV settings should take both gas exchange and stress/strain into account. When protective CMV fails, rescue strategies combining prone positioning and PLV with optimal PEEP should improve gas exchange with minimal stress. Copyright © 2015 Elsevier B.V. All rights reserved.

Cognitive behavioural therapy for adherence and depression in patients with HIV: a three-arm randomised controlled trial.

PubMed

Safren, Steven A; Bedoya, C Andres; O'Cleirigh, Conall; Biello, Katie B; Pinkston, Megan M; Stein, Michael D; Traeger, Lara; Kojic, Erna; Robbins, Gregory K; Lerner, Jonathan A; Herman, Debra S; Mimiaga, Matthew J; Mayer, Kenneth H

2016-11-01

Depression is highly prevalent in people with HIV and has consistently been associated with poor antiretroviral therapy (ART) adherence. Integrating cognitive behavioural therapy (CBT) for depression with adherence counselling using the Life-Steps approach (CBT-AD) has an emerging evidence base. The aim of this study was to test the efficacy of CBT-AD. In this three-arm randomised controlled trial in HIV-positive adults with depression, we compared CBT-AD with information and supportive psychotherapy plus adherence counselling using the Life-Steps approach (ISP-AD), and with enhanced treatment as usual (ETAU) including Life-Steps adherence counselling only. Participants were recruited from three sites in New England, USA (two hospital settings and one community health centre). Patients were randomly assigned (2:2:1) to receive CBT-AD (one Life-Steps session plus 11 weekly integrated sessions lasting up to 1 h each), ISP-AD (one Life-Steps session plus 11 weekly integrated sessions lasting up to 1 h each), or ETAU (one Life-Steps session and five assessment visits roughly every 2 weeks), randomisation was done with allocation software, in pairs, and stratified by three variables: study site, whether or not participants had been prescribed antidepressant medication, and whether or not participants had a history of injection drug use. The primary outcome was ART adherence at the end of treatment (4 month assessment) assessed via electronic pill caps (Medication Event Monitoring System [MEMS]) with correction for pocketed doses, analysed by intention to treat. Patients were recruited from Feb 26, 2009, to June 21, 2012. Patients who were assigned to CBT-AD (94 randomly assigned, 83 completed assessment) had greater improvements in adherence (estimated difference 1·00 percentage point per visit, 95% CI 0·34 to 1·66, p=0·003) and depression (Center for Epidemiological Studies depression [CESD] score estimated difference -0·41, -0·66 to -0·16, p=0·001; Montgomery-Asberg depression rating scale [MADRS] score -4·69, -8·09 to -1·28, p=0·007; clinical global impression [CGI] score -0·66, -1·11 to -0·21, p=0·005) than did patients who had ETAU (49 assigned, 46 completed assessment) after treatment (4 months). No significant differences in adherence were noted between CBT-AD and ISP-AD (97 assigned, 87 completed assessment). No study-related adverse events were reported. Integrating evidenced-based treatment for depression with evidenced-based adherence counselling is helpful for individuals living with HIV/AIDS and depression. Future efforts should examine how to best disseminate effective psychosocial depression treatments such as CBT-AD to people living with HIV/AIDS and examine the cost-effectiveness of such approaches. National Institute of Mental Health, National Institute of Allergy and Infectious Diseases. Copyright © 2016 Elsevier Ltd. All rights reserved.

Oral administration of citrus pulp reduces gastrointestinal recovery of orally dosed Escherichia coli F18 in weaned pigs

USDA-ARS?s Scientific Manuscript database

The effects of citrus pulp (CTP) on the immune and cortisol responses to E. coli F18 inoculation and subsequent E. coli recovery were evaluated in newly weaned pigs (23.3 + 1.8 d of age). Barrows were assigned to 1 of 2 treatment groups; with (CTP; n = 15) and without (Control; n = 15) the in-feed i...

Nurse-patient assignment models considering patient acuity metrics and nurses' perceived workload.

PubMed

Sir, Mustafa Y; Dundar, Bayram; Barker Steege, Linsey M; Pasupathy, Kalyan S

2015-06-01

Patient classification systems (PCSs) are commonly used in nursing units to assess how many nursing care hours are needed to care for patients. These systems then provide staffing and nurse-patient assignment recommendations for a given patient census based on these acuity scores. Our hypothesis is that such systems do not accurately capture workload and we conduct an experiment to test this hypothesis. Specifically, we conducted a survey study to capture nurses' perception of workload in an inpatient unit. Forty five nurses from oncology and surgery units completed the survey and rated the impact of patient acuity indicators on their perceived workload using a six-point Likert scale. These ratings were used to calculate a workload score for an individual nurse given a set of patient acuity indicators. The approach offers optimization models (prescriptive analytics), which use patient acuity indicators from a commercial PCS as well as a survey-based nurse workload score. The models assign patients to nurses in a balanced manner by distributing acuity scores from the PCS and survey-based perceived workload. Numerical results suggest that the proposed nurse-patient assignment models achieve a balanced assignment and lower overall survey-based perceived workload compared to the assignment based solely on acuity scores from the PCS. This results in an improvement of perceived workload that is upwards of five percent. Copyright © 2015 Elsevier Inc. All rights reserved.

Evaluation of a selected lactic acid bacteria-based probiotic on Salmonella enterica serovar Enteritidis colonization and intestinal permeability in broiler chickens.

PubMed

Prado-Rebolledo, Omar F; Delgado-Machuca, Jaime de Jesus; Macedo-Barragan, Rafael J; Garcia-Márquez, Luis J; Morales-Barrera, Jesus E; Latorre, Juan D; Hernandez-Velasco, Xochitl; Tellez, Guillermo

2017-02-01

Two experiments were conducted to evaluate the effect of a lactic acid bacteria-based probiotic (FloraMax-B11 ® ) against Salmonella enterica serovar Enteritidis intestinal colonization and intestinal permeability in broiler chickens. Experiment 1 consisted of two independent trials. In each trial, day-old broiler chicks were assigned to one of two groups: control + S. Enteritidis or probiotic + S. Enteritidis. At 72 h post-S. Enteritidis challenge, haematology and caecal content were evaluated for S. Enteritidis colonization. In Experiment 2, day-old broiler chicks were assigned to one of four groups: negative control; probiotic; control + S. Enteritidis; or probiotic + S. Enteritidis. At 72 h post-S. Enteritidis challenge, chickens in all groups were given an oral gavage dose of fluorescein isothiocyanate dextran (FITC-d). In both trials of Experiment 1, a significant reduction (P < 0.05) in colony-forming units/gram of S. Enteritidis in caecal content and a reduction in the incidence of S. Enteritidis enriched caecal samples were observed in probiotic + S. Enteritidis chickens. In addition, significant heterophilia and lymphopaenia were observed in control + S. Enteritidis chickens. In Experiment 2, a decrease in numbers of S. Enteritidis in caeca were observed in probiotic + S. Enteritidis chickens when compared to control + S. Enteritidis. Also, an increase in serum FITC-d concentration was detected in control + S. Enteritidis. These results suggest that early infection with S. Enteritidis can increase intestinal permeability, but the adverse effects can be prevented by the administration of the probiotic tested.

21 CFR 1271.27 - Will FDA assign me a registration number?

Code of Federal Regulations, 2014 CFR

2014-04-01

... 21 Food and Drugs 8 2014-04-01 2014-04-01 false Will FDA assign me a registration number? 1271.27..., TISSUES, AND CELLULAR AND TISSUE-BASED PRODUCTS Procedures for Registration and Listing § 1271.27 Will FDA assign me a registration number? (a) FDA will assign each location a permanent registration number. (b...

21 CFR 1271.27 - Will FDA assign me a registration number?

Code of Federal Regulations, 2013 CFR

2013-04-01

... 21 Food and Drugs 8 2013-04-01 2013-04-01 false Will FDA assign me a registration number? 1271.27..., TISSUES, AND CELLULAR AND TISSUE-BASED PRODUCTS Procedures for Registration and Listing § 1271.27 Will FDA assign me a registration number? (a) FDA will assign each location a permanent registration number. (b...

21 CFR 1271.27 - Will FDA assign me a registration number?

Code of Federal Regulations, 2010 CFR

2010-04-01

... 21 Food and Drugs 8 2010-04-01 2010-04-01 false Will FDA assign me a registration number? 1271.27..., TISSUES, AND CELLULAR AND TISSUE-BASED PRODUCTS Procedures for Registration and Listing § 1271.27 Will FDA assign me a registration number? (a) FDA will assign each location a permanent registration number. (b...

21 CFR 1271.27 - Will FDA assign me a registration number?

Code of Federal Regulations, 2011 CFR

2011-04-01

... 21 Food and Drugs 8 2011-04-01 2011-04-01 false Will FDA assign me a registration number? 1271.27..., TISSUES, AND CELLULAR AND TISSUE-BASED PRODUCTS Procedures for Registration and Listing § 1271.27 Will FDA assign me a registration number? (a) FDA will assign each location a permanent registration number. (b...

21 CFR 1271.27 - Will FDA assign me a registration number?

Code of Federal Regulations, 2012 CFR

2012-04-01

... 21 Food and Drugs 8 2012-04-01 2012-04-01 false Will FDA assign me a registration number? 1271.27..., TISSUES, AND CELLULAR AND TISSUE-BASED PRODUCTS Procedures for Registration and Listing § 1271.27 Will FDA assign me a registration number? (a) FDA will assign each location a permanent registration number. (b...

Model-based virtual VSB mask writer verification for efficient mask error checking and optimization prior to MDP

NASA Astrophysics Data System (ADS)

Pack, Robert C.; Standiford, Keith; Lukanc, Todd; Ning, Guo Xiang; Verma, Piyush; Batarseh, Fadi; Chua, Gek Soon; Fujimura, Akira; Pang, Linyong

2014-10-01

A methodology is described wherein a calibrated model-based `Virtual' Variable Shaped Beam (VSB) mask writer process simulator is used to accurately verify complex Optical Proximity Correction (OPC) and Inverse Lithography Technology (ILT) mask designs prior to Mask Data Preparation (MDP) and mask fabrication. This type of verification addresses physical effects which occur in mask writing that may impact lithographic printing fidelity and variability. The work described here is motivated by requirements for extreme accuracy and control of variations for today's most demanding IC products. These extreme demands necessitate careful and detailed analysis of all potential sources of uncompensated error or variation and extreme control of these at each stage of the integrated OPC/ MDP/ Mask/ silicon lithography flow. The important potential sources of variation we focus on here originate on the basis of VSB mask writer physics and other errors inherent in the mask writing process. The deposited electron beam dose distribution may be examined in a manner similar to optical lithography aerial image analysis and image edge log-slope analysis. This approach enables one to catch, grade, and mitigate problems early and thus reduce the likelihood for costly long-loop iterations between OPC, MDP, and wafer fabrication flows. It moreover describes how to detect regions of a layout or mask where hotspots may occur or where the robustness to intrinsic variations may be improved by modification to the OPC, choice of mask technology, or by judicious design of VSB shots and dose assignment.

Cancer mortality and occupational exposure to aromatic amines and inhalable aerosols in rubber tire manufacturing in Poland.

PubMed

de Vocht, Frank; Sobala, Wojciech; Wilczynska, Urszula; Kromhout, Hans; Szeszenia-Dabrowska, Neonila; Peplonska, Beata

2009-08-01

Most data on carcinogenic risk in the rubber industry are based on data from Western countries. This study assessed cancer risks in a retrospective cohort in a Polish tire manufacturing plant, relying on quantified exposure to inhalable aerosols and aromatic amines instead of job titles or external comparisons. Cumulative exposure for all exposures was assigned to cohort members based on estimates from a company-specific JEM. Cancer risks associated with cumulative exposure adjusted for co-exposures, gender and year of birth were calculated. Exposure levels were higher for women than for men. Aromatic amine exposure was significantly associated with increased urinary bladder cancer risk (RR=7.32-8.27), depending on exposure level, and prostate cancer at low levels only (RR=5.86). In women, increased risks were found for all cancers (RR=2.50) and of the digestive organs and peritoneum (RR=4.54) at low level only, while an exposure-response association with breast cancer risk was found. Inhalable aerosol exposure was associated with cancers of the liver and intrahepatic bile ducts in a dose-dependent manner, while dose-dependent reduced risks were found for respiratory cancers (most notably the larynx) and cancer of the colon. Increased risks for specific cancer sites in this rubber plant were similar to Western Europe and the US. However, several cancer risks were gender-specific which could relate to higher exposure levels in women or to differences in exposures to chemicals not assessed in this study.

SU-E-T-799: Verification of a Simultaneous Treatment of Multiple Brain Metastases Using VMAT Technique by a Composite Alanine-Gel Dosimeter Phantom

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

Pavoni, J; Silveira, M; Filho, O Baffa

Purpose: This work presents an end-to-end test using a Gel-Alanine phantom to validate the three-dimensional (3D) dose distribution (DD) delivered by a single isocenter VMAT technique on the simultaneous treatment of multiple brain metastases. Methods: Three cylindrical phantons containing MAGIC-f gel dosimeter were used to measure the 3D DD of a VMAT treatment, the first two were filled with the gel dosimeter (Gel 1 and 2) and the third one was filled with gel and 12 alanine dosimeters distributed along it (Gel 3). Gels 1 and 3 were irradiated and gel 2 was used to map the magnetic resonance imagemore » (MRI) scanner field inomogeneities. A CT scan of gel 3 was used for the VMAT treatment planning and 5 alanine pellets were chosen as lesions, around them a PTV was grown and different dose prescriptions were assigned for each one, varying from 5 to 9Gy. Before treatment, the plan was approved in a QA based on an ionization chamber absolute dose measurement, a radiochromic film planar dose measurement and a portal dosimetry per field verification; and also the phantons positioning were verified by ExacTrac 6D correction and OBI kV Cone Beam CT. The gels were irradiated, the MRIs were acquired 24 hours after irradiation and finally, the alanine dosimeters were analysed in a X-band Electron Spin Resonance spectrometer. Results: The association of the two detectors enabled the 3D dose evaluation by gel and punctually inside target volumes by alanine. In the gamma analyses (3%/3mm) comparing the 5 PTVs’ central images DD with TPS expected DD more than 95% of the points were approved. The alanine absolute dose measurements were in agreement with TPS by less than 5%. Conclusion: The gel-alanine phantom enabled the dosimetric validation of multiple brain metastases treatment using VMAT, being an almost ideal tool for this application. This work is partially supported by FAPESP.« less

Theoretical and subjective bit assignments in transform picture

NASA Technical Reports Server (NTRS)

Jones, H. W., Jr.

1977-01-01

It is shown that all combinations of symmetrical input distributions with difference distortion measures give a bit assignment rule identical to the well-known rule for a Gaussian input distribution with mean-square error. Published work is examined to show that the bit assignment rule is useful for transforms of full pictures, but subjective bit assignments for transform picture coding using small block sizes are significantly different from the theoretical bit assignment rule. An intuitive explanation is based on subjective design experience, and a subjectively obtained bit assignment rule is given.

Rapid analysis of protein backbone resonance assignments using cryogenic probes, a distributed Linux-based computing architecture, and an integrated set of spectral analysis tools.

PubMed

Monleón, Daniel; Colson, Kimberly; Moseley, Hunter N B; Anklin, Clemens; Oswald, Robert; Szyperski, Thomas; Montelione, Gaetano T

2002-01-01

Rapid data collection, spectral referencing, processing by time domain deconvolution, peak picking and editing, and assignment of NMR spectra are necessary components of any efficient integrated system for protein NMR structure analysis. We have developed a set of software tools designated AutoProc, AutoPeak, and AutoAssign, which function together with the data processing and peak-picking programs NMRPipe and Sparky, to provide an integrated software system for rapid analysis of protein backbone resonance assignments. In this paper we demonstrate that these tools, together with high-sensitivity triple resonance NMR cryoprobes for data collection and a Linux-based computer cluster architecture, can be combined to provide nearly complete backbone resonance assignments and secondary structures (based on chemical shift data) for a 59-residue protein in less than 30 hours of data collection and processing time. In this optimum case of a small protein providing excellent spectra, extensive backbone resonance assignments could also be obtained using less than 6 hours of data collection and processing time. These results demonstrate the feasibility of high throughput triple resonance NMR for determining resonance assignments and secondary structures of small proteins, and the potential for applying NMR in large scale structural proteomics projects.

Evacuee Compliance Behavior Analysis using High Resolution Demographic Information

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

Lu, Wei; Han, Lee; Liu, Cheng

2014-01-01

The purpose of this study is to examine whether evacuee compliance behavior with route assignments from different resolutions of demographic data would impact the evacuation performance. Most existing evacuation strategies assume that travelers will follow evacuation instructions, while in reality a certain percent of evacuees do not comply with prescribed instructions. In this paper, a comparison study of evacuation assignment based on Traffic Analysis Zones (TAZ) and high resolution LandScan USA Population Cells (LPC) were conducted for the detailed road network representing Alexandria, Virginia. A revised platform for evacuation modeling built on high resolution demographic data and activity-based microscopic trafficmore » simulation is proposed. The results indicate that evacuee compliance behavior affects evacuation efficiency with traditional TAZ assignment, but it does not significantly compromise the efficiency with high resolution LPC assignment. The TAZ assignment also underestimates the real travel time during evacuation, especially for high compliance simulations. This suggests that conventional evacuation studies based on TAZ assignment might not be effective at providing efficient guidance to evacuees. From the high resolution data perspective, traveler compliance behavior is an important factor but it does not impact the system performance significantly. The highlight of evacuee compliance behavior analysis should be emphasized on individual evacuee level route/shelter assignments, rather than the whole system performance.« less

32 CFR 700.721 - Administration and discipline: Staff based ashore.

Code of Federal Regulations, 2011 CFR

2011-07-01

... 32 National Defense 5 2011-07-01 2011-07-01 false Administration and discipline: Staff based... discipline: Staff based ashore. When a staff is based ashore, the enlisted persons serving with the staff... discipline. The staff officers may be similarly assigned. Members of a staff assigned for any purpose to a...

32 CFR 700.721 - Administration and discipline: Staff based ashore.

Code of Federal Regulations, 2013 CFR

2013-07-01

... 32 National Defense 5 2013-07-01 2013-07-01 false Administration and discipline: Staff based... discipline: Staff based ashore. When a staff is based ashore, the enlisted persons serving with the staff... discipline. The staff officers may be similarly assigned. Members of a staff assigned for any purpose to a...

32 CFR 700.721 - Administration and discipline: Staff based ashore.

Code of Federal Regulations, 2010 CFR

2010-07-01

... 32 National Defense 5 2010-07-01 2010-07-01 false Administration and discipline: Staff based... discipline: Staff based ashore. When a staff is based ashore, the enlisted persons serving with the staff... discipline. The staff officers may be similarly assigned. Members of a staff assigned for any purpose to a...

Efficacy and safety of high-dose baclofen for the treatment of alcohol dependence: A multicentre, randomised, double-blind controlled trial.

PubMed

Beraha, Esther M; Salemink, Elske; Goudriaan, Anna E; Bakker, Abraham; de Jong, David; Smits, Natasha; Zwart, Jan Willem; Geest, Dick van; Bodewits, Pieter; Schiphof, Tom; Defourny, Harma; van Tricht, Mirjam; van den Brink, Wim; Wiers, Reinout W

2016-12-01

Previous randomised placebo-controlled trials with low-to-medium doses of baclofen (30-60mg) showed inconsistent results, but case studies suggested a dose-response effect and positive outcomes in patients on high doses of baclofen (up to 270mg). Its prescription was temporary permitted for the treatment of alcohol dependence (AD) in France, and baclofen is now widely prescribed. Recently, a small RCT found a strong effect of a mean dose of 180mg baclofen. In the present study the efficacy and safety of high doses of baclofen was examined in a multicentre, double-blind, placebo-controlled trial. 151 patients were randomly assigned to either six weeks titration and ten weeks high-dose baclofen (N=58; up to 150mg), low-dose baclofen (N=31; 30mg), or placebo (N=62). The primary outcome measure was time to first relapse. Nine of the 58 patients (15.5%) in the high-dose group reached 150mg and the mean baclofen dose in this group was 93.6mg (SD=40.3). No differences between the survival distributions for the three groups were found in the time to first relapse during the ten-weeks high-dose phase (χ 2 =0.41; p=0.813) or the 16-weeks complete medication period (χ 2 =0.04; p=0.982). There were frequent dose-related adverse events in terms of fatigue, sleepiness, and dry mouth. One medication related serious adverse event occurred in the high-dose baclofen group. Neither low nor high doses of baclofen were effective in the treatment of AD. Adverse events were frequent, although generally mild and transient. Therefore, large-scale prescription of baclofen for the treatment of AD seems premature and should be reconsidered. Copyright © 2016 Elsevier B.V. and ECNP. All rights reserved.

Application of dynamic traffic assignment to advanced managed lane modeling.

DOT National Transportation Integrated Search

2013-11-01

In this study, a demand estimation framework is developed for assessing the managed lane (ML) : strategies by utilizing dynamic traffic assignment (DTA) modeling, instead of the traditional : approaches that are based on the static traffic assignment...

A SAS-based solution to evaluate study design efficiency of phase I pediatric oncology trials via discrete event simulation.

PubMed

Barrett, Jeffrey S; Jayaraman, Bhuvana; Patel, Dimple; Skolnik, Jeffrey M

2008-06-01

Previous exploration of oncology study design efficiency has focused on Markov processes alone (probability-based events) without consideration for time dependencies. Barriers to study completion include time delays associated with patient accrual, inevaluability (IE), time to dose limiting toxicities (DLT) and administrative and review time. Discrete event simulation (DES) can incorporate probability-based assignment of DLT and IE frequency, correlated with cohort in the case of DLT, with time-based events defined by stochastic relationships. A SAS-based solution to examine study efficiency metrics and evaluate design modifications that would improve study efficiency is presented. Virtual patients are simulated with attributes defined from prior distributions of relevant patient characteristics. Study population datasets are read into SAS macros which select patients and enroll them into a study based on the specific design criteria if the study is open to enrollment. Waiting times, arrival times and time to study events are also sampled from prior distributions; post-processing of study simulations is provided within the decision macros and compared across designs in a separate post-processing algorithm. This solution is examined via comparison of the standard 3+3 decision rule relative to the "rolling 6" design, a newly proposed enrollment strategy for the phase I pediatric oncology setting.

Effect of gamma-ray irradiation on the device process-induced defects in 4H-SiC epilayers

NASA Astrophysics Data System (ADS)

Miyazaki, T.; Makino, T.; Takeyama, A.; Onoda, S.; Ohshima, T.; Tanaka, Y.; Kandori, M.; Yoshie, T.; Hijikata, Y.

2016-11-01

We investigated the gamma-ray irradiation effect on 4H-SiC device process-induced defects by photoluminescence (PL) imaging and deep level transient spectroscopy (DLTS). We found that basal plane dislocations (BPDs) that were present before the irradiation were eliminated by gamma-ray irradiation of 1 MGy. The reduction mechanism of BPD was discussed in terms of BPD-threading edge dislocation (TED) transformation and shrinkage of stacking faults. In addition, the entire PL image was gradually darkened with increasing absorbed dose, which is presumably due to the point defects generated by gamma-ray irradiation. We obtained DLTS peaks that could be assigned to complex defects, termed RD series, and found that the peaks increased with absorbed dose.

Invited commentary: missing doses in the life span study of Japanese atomic bomb survivors.

PubMed

Ozasa, K; Grant, E J; Cullings, H M; Shore, R E

2013-03-15

The Life Span Study is a long-term epidemiologic cohort study of survivors of the atomic bombs dropped on Hiroshima and Nagasaki, Japan. In this issue of the Journal, Richardson et al. (Am J Epidemiol. 2013;177(6):562-568) suggest that those who died in the earliest years of follow-up were more likely to have a missing dose of radiation exposure assigned, leading to a bias in the radiation risk estimates. We show that nearly all members of the cohort had shielding information recorded before the beginning of follow-up and that much of the alleged bias that Richardson et al. describe simply reflects the geographic distribution of shielding conditions for which reliable dosimetry was impossible.

New botanical drug, HL tablet, reduces hepatic fat as measured by magnetic resonance spectroscopy in patients with nonalcoholic fatty liver disease: A placebo-controlled, randomized, phase II trial.

PubMed

Jeong, Jae Yoon; Sohn, Joo Hyun; Baek, Yang Hyun; Cho, Yong Kyun; Kim, Yongsoo; Kim, Hyeonjin

2017-08-28

To evaluate the efficacy and safety of HL tablet extracted from magnolia officinalis for treating patients with nonalcoholic fatty liver disease (NAFLD). Seventy-four patients with NAFLD diagnosed by ultrasonography were randomly assigned to 3 groups given high dose (400 mg) HL tablet, low dose (133.4 mg) HL tablet and placebo, respectively, daily for 12 wk. The primary endpoint was post-treatment change of hepatic fat content (HFC) measured by magnetic resonance spectroscopy. Secondary endpoints included changes of serum aspartate aminotransferase, alanine aminotransferase (ALT), cholesterol, triglyceride, free fatty acid, homeostasis model assessment-estimated insulin resistance, and body mass index (BMI). The mean HFC of the high dose HL group, but not of the low dose group, declined significantly after 12 wk of treatment (high dose vs placebo, P = 0.033; low dose vs placebo, P = 0.386). The mean changes of HFC from baseline at week 12 were -1.7% ± 3.1% in the high dose group ( P = 0.018), -1.21% ± 4.97% in the low dose group ( P = 0.254) and 0.61% ± 3.87% in the placebo group (relative changes compared to baseline, high dose were: -12.1% ± 23.5%, low dose: -3.2% ± 32.0%, and placebo: 7.6% ± 44.0%). Serum ALT levels also tended to decrease in the groups receiving HL tablet while other factors were unaffected. There were no moderate or severe treatment-related safety issues during the study. HL tablet is effective in reducing HFC without any negative lipid profiles, BMI changes and adverse effects.

New botanical drug, HL tablet, reduces hepatic fat as measured by magnetic resonance spectroscopy in patients with nonalcoholic fatty liver disease: A placebo-controlled, randomized, phase II trial

PubMed Central

Jeong, Jae Yoon; Sohn, Joo Hyun; Baek, Yang Hyun; Cho, Yong Kyun; Kim, Yongsoo; Kim, Hyeonjin

2017-01-01

AIM To evaluate the efficacy and safety of HL tablet extracted from magnolia officinalis for treating patients with nonalcoholic fatty liver disease (NAFLD). METHODS Seventy-four patients with NAFLD diagnosed by ultrasonography were randomly assigned to 3 groups given high dose (400 mg) HL tablet, low dose (133.4 mg) HL tablet and placebo, respectively, daily for 12 wk. The primary endpoint was post-treatment change of hepatic fat content (HFC) measured by magnetic resonance spectroscopy. Secondary endpoints included changes of serum aspartate aminotransferase, alanine aminotransferase (ALT), cholesterol, triglyceride, free fatty acid, homeostasis model assessment-estimated insulin resistance, and body mass index (BMI). RESULTS The mean HFC of the high dose HL group, but not of the low dose group, declined significantly after 12 wk of treatment (high dose vs placebo, P = 0.033; low dose vs placebo, P = 0.386). The mean changes of HFC from baseline at week 12 were -1.7% ± 3.1% in the high dose group (P = 0.018), -1.21% ± 4.97% in the low dose group (P = 0.254) and 0.61% ± 3.87% in the placebo group (relative changes compared to baseline, high dose were: -12.1% ± 23.5%, low dose: -3.2% ± 32.0%, and placebo: 7.6% ± 44.0%). Serum ALT levels also tended to decrease in the groups receiving HL tablet while other factors were unaffected. There were no moderate or severe treatment-related safety issues during the study. CONCLUSION HL tablet is effective in reducing HFC without any negative lipid profiles, BMI changes and adverse effects. PMID:28932090

Efficacy of dosing and re-dosing of two oral fixed combinations of indomethacin, prochlorperazine and caffeine compared with oral sumatriptan in the acute treatment of multiple migraine attacks: a double-blind, double-dummy, randomised, parallel group, multicentre study

PubMed Central

Sandrini, G; Cerbo, R; Del Bene, E; Ferrari, A; Genco, S; Grazioli, I; Martelletti, P; Nappi, G; Pinessi, L; Sarchielli, P; Tamburro, P; Uslenghi, C; Zanchin, G

2007-01-01

Aims and methods: In this double-blind, double-dummy, randomised, parallel group, multicentre study, the efficacy of dosing and re-dosing of a fixed combination of indomethacin, prochlorperazine and caffeine (Indoprocaf) was compared with encapsulated sumatriptan in the acute treatment of two migraine attacks. Additionally, in the group taking Indoprocaf, two different oral formulations were tested: effervescent tablets and encapsulated coated tablets. Results: Of 297 patients randomised (150 assigned to Indoprocaf and 147 to sumatriptan), 281 were included in the intention-to-treat efficacy analysis. The initial dosing of Indoprocaf and sumatriptan was similarly effective with pain-free rates higher than 30% (95% CI of odds-ratio: 0.57–1.28) and headache relief rates of about 60% (95% CI of odds-ratio: 0.82–1.84) with both the drugs. The efficacy of re-dosing of Indoprocaf as rescue medication was more effective than that of sumatriptan with pain-free values of 47% vs. 27% in the total attacks with a statistically significant difference in the first migraine attack in favour of Indoprocaf. The efficacy of re-dosing to treat a recurrence/relapse was very high without differences between the drugs (pain-free: 60% with Indoprocaf and 50% with sumatriptan in the total attacks). Indoprocaf and sumatriptan were well-tolerated. Conclusion: The study demonstrated that the efficacy of the initial dosing of Indoprocaf was not higher than that of sumatriptan, but that the strategy to use the lowest effective dose as soon as the headache occurred, followed by a second dose if the headache has not relieved or to treat a relapse, was very effective, especially with Indoprocaf. PMID:17627707

Immunogenicity study to investigate the interchangeability among three different types of polio vaccine: A cohort study in Japan.

PubMed

Ohfuji, Satoko; Ito, Kazuya; Ishibashi, Motoki; Shindo, Shizuo; Takasaki, Yoshio; Yokoyama, Takashi; Yokoyama, Takato; Yamashita, Yuji; Shibao, Keigo; Nakano, Takashi; Tsuru, Tomomi; Irie, Shin; Hirota, Yoshio

2017-06-01

In Japan, the routine immunization program with oral polio vaccine (OPV) has been suspended since September 2012, when a program with 4 doses of inactivated monovalent polio vaccine (IPV) or quadrivalent vaccine against diphtheria, pertussis, and tetanus with IPV (DTaP-IPV) was introduced. The aim of this study was to examine the interchangeability among these 3 types of polio vaccines.We conducted a prospective cohort study at 5 pediatric clinics in Japan. A total of 153 infants were assigned to 1 of the 4 groups by considering the vaccination history of OPV and trivalent vaccine against DTaP. Eleven infants with a history of OPV received 3 doses of DTaP-IPV; 49 infants with a history of OPV and DTaP received 3 doses of IPV; 50 polio vaccine-naïve infants received 2 doses of IPV followed by 2 doses of DTaP-IPV; and 43 polio vaccine-naive infants received 2 doses of DTaP-IPV followed by IPV. The immunogenicity after polio vaccination was evaluated among these 4 groups.After 2 doses of polio vaccination, more than 80% of the infants exhibited a neutralization antibody titer ≥1:8 for all Sabin strains and wild strains in all groups. After the third dose, the seroprotection proportion (i.e., a neutralization antibody titer ≥1:8) reached about 100%. After the fourth dose, a neutralization antibody titer exceeded the required protective levels (i.e., a neutralization antibody titer ≥1:8) considerably in all groups.Four doses of polio vaccines induced a sufficient level of immunity in Japanese infants, irrespective of vaccine combinations or order.

Comparison of the Immunogenicity of Various Booster Doses of Inactivated Polio Vaccine Delivered Intradermally Versus Intramuscularly to HIV-Infected Adults.

PubMed

Troy, Stephanie B; Kouiavskaia, Diana; Siik, Julia; Kochba, Efrat; Beydoun, Hind; Mirochnitchenko, Olga; Levin, Yotam; Khardori, Nancy; Chumakov, Konstantin; Maldonado, Yvonne

2015-06-15

Inactivated polio vaccine (IPV) is necessary for global polio eradication because oral polio vaccine can rarely cause poliomyelitis as it mutates and may fail to provide adequate immunity in immunocompromised populations. However, IPV is unaffordable for many developing countries. Intradermal IPV shows promise as a means to decrease the effective dose and cost of IPV, but prior studies, all using 20% of the standard dose used in intramuscular IPV, resulted in inferior antibody titers. We randomly assigned 231 adults with well-controlled human immunodeficiency virus infection at a ratio of 2:2:2:1 to receive 40% of the standard dose of IPV intradermally, 20% of the standard dose intradermally, the full standard dose intramuscularly, or 40% of the standard dose intramuscularly. Intradermal vaccination was done using the NanoPass MicronJet600 microneedle device. Baseline immunity was 87%, 90%, and 66% against poliovirus serotypes 1, 2, and 3, respectively. After vaccination, antibody titers increased a median of 64-fold. Vaccine response to 40% of the standard dose administered intradermally was comparable to that of the standard dose of IPV administered intramuscularly and resulted in higher (although not significantly) antibody titers. Intradermal administration had higher a incidence of local side effects (redness and itching) but a similar incidence of systemic side effects and was preferred by study participants over intramuscular administration. A 60% reduction in the standard IPV dose without reduction in antibody titers is possible through intradermal administration. © The Author 2015. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

Optimizing and accelerating the assignation of lineages in Mycobacterium tuberculosis using novel alternative single-tube assays

PubMed Central

Carcelén, María; Abascal, Estefanía; Herranz, Marta; Santantón, Sheila; Zenteno, Roberto; Ruiz Serrano, María Jesús; Bouza, Emilio

2017-01-01

The assignation of lineages in Mycobacterium tuberculosis (MTB) provides valuable information for evolutionary and phylogeographic studies and makes for more accurate knowledge of the distribution of this pathogen worldwide. Differences in virulence have also been found for certain lineages. MTB isolates were initially assigned to lineages based on data obtained from genotyping techniques, such as spoligotyping or MIRU-VNTR analysis, some of which are more suitable for molecular epidemiology studies. However, since these methods are subject to a certain degree of homoplasy, other criteria have been chosen to assign lineages. These are based on targeting robust and specific SNPs for each lineage. Here, we propose two newly designed multiplex targeting methods—both of which are single-tube tests—to optimize the assignation of the six main lineages in MTB. The first method is based on ASO-PCR and offers an inexpensive and easy-to-implement assay for laboratories with limited resources. The other, which is based on SNaPshot, enables more refined standardized assignation of lineages for laboratories with better resources. Both methods performed well when assigning lineages from cultured isolates from a control panel, a test panel, and a problem panel from an unrelated population, Mexico, which included isolates in which standard genotyping was not able to classify lineages. Both tests were also able to assign lineages from stored isolates, without the need for subculture or purification of DNA, and even directly from clinical specimens with a medium-high bacilli burden. Our assays could broaden the contexts where information on lineages can be acquired, thus enabling us to quickly update data from retrospective collections and to merge data with those obtained at the time of diagnosis of a new TB case. PMID:29091913

Treatment assignment guesses by study participants in a double-blind dose escalation clinical trial of saw palmetto.

PubMed

Lee, Jeannette Y; Moore, Page; Kusek, John; Barry, Michael

2014-01-01

This report assesses participant perception of treatment assignment in a randomized, double-blind, placebo-controlled trial of saw palmetto for the treatment of benign prostatic hyperplasia (BCM). Participants randomized to receive saw palmetto were instructed to take one 320 mg gelcap daily for the first 24 weeks, two 320 mg gelcaps daily for the second 24 weeks, and three 320 mg gelcaps daily for the third 24 weeks. Study participants assigned to placebo were instructed to take the same number of matching placebo gelcaps in each time period. At 24, 48, and 72 weeks postrandomization, the American Urological Association Symptom Index (AUA-SI) was administered and participants were asked to guess their treatment assignment. The study was conducted at 11 clinical centers in North America. Study participants were men, 45 years and older, with moderate to low severe BPH symptoms, randomized to saw palmetto (N=151) or placebo (N=155). Treatment arms were compared with respect to the distribution of participant guesses of treatment assignment. For participants assigned to saw palmetto, 22.5%, 24.7%, and 29.8% correctly thought they were taking saw palmetto, and 37.3%, 40.0%, and 44.4% incorrectly thought they were on placebo at 24, 48, and 72 weeks, respectively. For placebo participants, 21.8%, 27.4%, and 25.2% incorrectly thought they were on saw palmetto, and 41.6%, 39.9%, and 42.6% correctly thought they were on placebo at 24, 48, and 72 weeks, respectively. The treatment arms did not vary with respect to the distributions of participants who guessed they were on saw palmetto (p=0.823) or placebo (p=0.893). Participants who experienced an improvement in AUA-SI were 2.16 times more likely to think they were on saw palmetto. Blinding of treatment assignment was successful in this study. Improvement in BPH-related symptoms was associated with the perception that participants were taking saw palmetto.

A New Secondary Structure Assignment Algorithm Using Cα Backbone Fragments

PubMed Central

Cao, Chen; Wang, Guishen; Liu, An; Xu, Shutan; Wang, Lincong; Zou, Shuxue

2016-01-01

The assignment of secondary structure elements in proteins is a key step in the analysis of their structures and functions. We have developed an algorithm, SACF (secondary structure assignment based on Cα fragments), for secondary structure element (SSE) assignment based on the alignment of Cα backbone fragments with central poses derived by clustering known SSE fragments. The assignment algorithm consists of three steps: First, the outlier fragments on known SSEs are detected. Next, the remaining fragments are clustered to obtain the central fragments for each cluster. Finally, the central fragments are used as a template to make assignments. Following a large-scale comparison of 11 secondary structure assignment methods, SACF, KAKSI and PROSS are found to have similar agreement with DSSP, while PCASSO agrees with DSSP best. SACF and PCASSO show preference to reducing residues in N and C cap regions, whereas KAKSI, P-SEA and SEGNO tend to add residues to the terminals when DSSP assignment is taken as standard. Moreover, our algorithm is able to assign subtle helices (310-helix, π-helix and left-handed helix) and make uniform assignments, as well as to detect rare SSEs in β-sheets or long helices as outlier fragments from other programs. The structural uniformity should be useful for protein structure classification and prediction, while outlier fragments underlie the structure–function relationship. PMID:26978354

Automated and assisted RNA resonance assignment using NMR chemical shift statistics

PubMed Central

Aeschbacher, Thomas; Schmidt, Elena; Blatter, Markus; Maris, Christophe; Duss, Olivier; Allain, Frédéric H.-T.; Güntert, Peter; Schubert, Mario

2013-01-01

The three-dimensional structure determination of RNAs by NMR spectroscopy relies on chemical shift assignment, which still constitutes a bottleneck. In order to develop more efficient assignment strategies, we analysed relationships between sequence and 1H and 13C chemical shifts. Statistics of resonances from regularly Watson–Crick base-paired RNA revealed highly characteristic chemical shift clusters. We developed two approaches using these statistics for chemical shift assignment of double-stranded RNA (dsRNA): a manual approach that yields starting points for resonance assignment and simplifies decision trees and an automated approach based on the recently introduced automated resonance assignment algorithm FLYA. Both strategies require only unlabeled RNAs and three 2D spectra for assigning the H2/C2, H5/C5, H6/C6, H8/C8 and H1′/C1′ chemical shifts. The manual approach proved to be efficient and robust when applied to the experimental data of RNAs with a size between 20 nt and 42 nt. The more advanced automated assignment approach was successfully applied to four stem-loop RNAs and a 42 nt siRNA, assigning 92–100% of the resonances from dsRNA regions correctly. This is the first automated approach for chemical shift assignment of non-exchangeable protons of RNA and their corresponding 13C resonances, which provides an important step toward automated structure determination of RNAs. PMID:23921634

Association between edoxaban dose, concentration, anti-Factor Xa activity, and outcomes: an analysis of data from the randomised, double-blind ENGAGE AF-TIMI 48 trial.

PubMed

Ruff, Christian T; Giugliano, Robert P; Braunwald, Eugene; Morrow, David A; Murphy, Sabina A; Kuder, Julia F; Deenadayalu, Naveen; Jarolim, Petr; Betcher, Joshua; Shi, Minggao; Brown, Karen; Patel, Indravadan; Mercuri, Michele; Antman, Elliott M

2015-06-06

New oral anticoagulants for stroke prevention in atrial fibrillation were developed to be given in fixed doses without the need for the routine monitoring that has hindered usage and acceptance of vitamin K antagonists. A concern has emerged, however, that measurement of drug concentration or anticoagulant activity might be needed to prevent excess drug concentrations, which significantly increase bleeding risk. In the ENGAGE AF-TIMI 48 trial, higher-dose and lower-dose edoxaban were compared with warfarin in patients with atrial fibrillation. Each regimen incorporated a 50% dose reduction in patients with clinical features known to increase edoxaban drug exposure. We aim to assess whether adjustment of edoxaban dose in this trial prevented excess drug concentration and the risk of bleeding events. We analysed data from the randomised, double-blind ENGAGE AF-TIMI 48 trial. We correlated edoxaban dose, plasma concentration, and anti-Factor Xa (FXa) activity and compared efficacy and safety outcomes with warfarin stratified by dose reduction status. Patients with atrial fibrillation and at moderate to high risk of stroke were randomly assigned in a 1:1:1 ratio to receive warfarin, dose adjusted to an international normalised ratio of 2·0-3·0, higher-dose edoxaban (60 mg once daily), or lower-dose edoxaban (30 mg once daily). Randomisation was done with use of a central, 24 h, interactive, computerised response system. International normalised ratio was measured using an encrypted point-of-care device. To maintain masking, sham international normalised ratio values were generated for patients assigned to edoxaban. Edoxaban (or placebo-edoxaban in warfarin group) doses were halved at randomisation or during the trial if patients had creatinine clearance 30-50 mL/min, bodyweight 60 kg or less, or concomitant medication with potent P-glycoprotein interaction. Efficacy outcomes included the primary endpoint of all-cause stroke or systemic embolism, ischaemic stroke, and all-cause mortality. Safety outcomes included the primary safety endpoint of major bleeding, fatal bleeding, intracranial haemorrhage, and gastrointestinal bleeding. This trial is registered with ClinicalTrials.gov, number NCT00781391. Between Nov 19, 2008 and Nov 22, 2010, 21 105 patients were recruited. Patients who met clinical criteria for dose reduction at randomisation (n=5356) had higher rates of stroke, bleeding, and death compared with those who did not have a dose reduction (n=15 749). Edoxaban dose ranged from 15 mg to 60 mg, resulting in a two-fold to three fold gradient of mean trough drug exposure (16·0-48·5 ng/mL in 6780 patients with data available) and mean trough anti-FXa activity (0·35-0·85 IU/mL in 2865 patients). Dose reduction decreased mean exposure by 29% (from 48·5 ng/mL [SD 45·8] to 34·6 ng/mL [30·9]) and 35% (from 24·5 ng/mL [22·7] to 16·0 ng/mL [14·5]) and mean anti-FXa activity by 25% (from 0·85 IU/mL [0·76] to 0·64 IU/mL [0·54]) and 20% (from 0·44 IU/mL [0·37] to 0·35 IU/mL [0·28]) in the higher-dose and lower-dose regimens, respectively. Despite the lower anti-FXa activity, dose reduction preserved the efficacy of edoxaban compared with warfarin (stroke or systemic embolic event: higher dose pinteraction=0·85, lower dose pinteraction=0·99) and provided even greater safety (major bleeding: higher dose pinteraction 0·02, lower dose pinteraction=0·002). These findings validate the strategy that tailoring of the dose of edoxaban on the basis of clinical factors alone achieves the dual goal of preventing excess drug concentrations and helps to optimise an individual patient's risk of ischaemic and bleeding events and show that the therapeutic window for edoxaban is narrower for major bleeding than thromboembolism. Daiichi-Sankyo Pharma Development. Copyright © 2015 Elsevier Ltd. All rights reserved.

Evaluation of Pharmacokinetics, and Bioavailability of Higher Doses of Tocotrienols in Healthy Fed Humans

PubMed Central

Qureshi, Asaf A; Khan, Dilshad A; Silswal, Neerupma; Saleem, Shahid; Qureshi, Nilofer

2016-01-01

Background Tocotrienols has been known to lower serum lipid parameters below 500 mg/d, while increase lipid parameters at higher dose of 750 mg/d. δ-Tocotrienol has a novel inflammatory property of concentration-dependent inhibition and activation. Therefore, inhibition (anti-inflammatory) property of tocotrienols at low doses is useful for cardiovascular disease, whereas, activation (pro-inflammatory) property using high dose is found effective for treatments of various types of cancer. We have recently described plasma bioavailability of 125 mg/d, 250 mg/d and 500 mg/d doses of δ-tocotrienol in healthy fed subjects, which showed dose-dependent increases in area under the curve (AUC) and maximum concentration (Cmax). Hence, in the current study, higher doses of tocotrienols have used to analyze its effect on plasma pharmacokinetic parameters. Aims To evaluate the safety and bioavailability of higher doses (750 mg and 1000 mg) of annatto-based tocotrienols in healthy fed subjects. All four isomers (α-, β-, γ-, δ-) of tocols (tocotrienols and tocopherols) present in the plasmas of subjects were quantified and analyzed for various pharmacokinetic parameters. Study design An open-label, randomized study was performed to analyze pharmacokinetics and bioavailability of δ-tocotrienol in 6 healthy fed subjects. All subjects (3/dose) were randomly assigned to one of each dose of 750 mg or 1000 mg. Blood samples were collected at 0, 1, 2, 4, 6, 8 h intervals and all isomers of α-,β-,γ-,δ-tocotrienols, and tocopherols in plasmas were quantified by HPLC. Results Oral administration of 750 and 1000 mg/d of tocotrienols resulted in dose-dependent increases in plasmas (ng/ml) AUCt0-t8 6621, 7450; AUCt0-∞ 8688, 9633; AUMC t0-∞ 52497, 57199; MRT 6.04, 5.93; Cmax 1444, 1592 (P<0.05), respectively, of δ-tocotrienol isomer. Moreover, both doses also resulted in plasmas Tmax 3.33–4 h; elimination half-life (t1/2 h) 2.74, 2.68; time of clearance (Cl-T, l/h) 0.086, 0.078; volume of distribution (Vd/f, mg/h) 0.34, 0.30; and elimination rate constant (ke; h-1) 0.25, 0.17, respectively of δ- tocotrienol isomer. Similar results of these parameters were reported for γ-tocotrienol, β- tocotrienol, α-tocotrienol, δ-tocopherol, γ-tocopherol, and β-tocopherol, except for α- tocopherol. Conclusions This study has described pharmacokinetics using higher doses of 750 mg/d and 1000 mg/d of δ-tocotrienol. These results confirmed earlier findings that Tmax was 3-4 h for all isomers of tocotrienols and tocopherols except for α-tocopherol (6 h). These higher doses of tocotrienols were found safe in humans and may be useful for treatments of various types of cancer, diabetes, and Alzheimer's disease. PMID:27493840

Alcohol Effects on Simulated Driving in Frequent and Infrequent Binge Drinkers

PubMed Central

Bernosky-Smith, Kimberly A.; Shannon, Erin E.; Roth, Alicia J.; Liguori, Anthony

2011-01-01

Objective Compared to non-bingers, binge drinkers are more likely to drive while intoxicated. The extent to which binge frequency impacts confidence in driving and subsequent driving impairment is unknown. This study compared the effects of an experimenter-delivered alcohol binge on subjective impairment and simulated driving ability in female High and Low Frequency bingers. Methods Female drinkers were assigned to High Frequency (n=30) or Low Frequency (n=30) binge groups based on their Alcohol Use Questionnaire responses. At 30-minute intervals within a two-hour period, participants received either a placebo drink (n=15 per group) or a 0.2 g/kg dose of alcohol (n=15 per group; cumulative dose 0.8 g/kg). Self-reported impairment, driving confidence, and simulated driving were then measured. Results Self-reported confidence in driving was significantly lower after alcohol than after placebo in Low Frequency but not High Frequency bingers. Self-reported impairment and collisions during simulated driving were significantly greater after alcohol than after placebo in both Low Frequency and High Frequency bingers. Conclusions The impairing effects of a single alcohol binge on driving ability in females are not influenced by binge frequency. However, high binge frequency may be associated with a less cautious approach to post-binge driving. PMID:21542027

Intervention efficacy and intensity for children with speech sound disorder.

PubMed

Allen, Melissa M

2013-06-01

Clinicians do not have an evidence base they can use to recommend optimum intervention intensity for preschool children who present with speech sound disorder (SSD). This study examined the effect of dose frequency on phonological performance and the efficacy of the multiple oppositions approach. Fifty-four preschool children with SSD were randomly assigned to one of three intervention conditions. Two intervention conditions received the multiple oppositions approach either 3 times per week for 8 weeks (P3) or once weekly for 24 weeks (P1). A control (C) condition received a storybook intervention. Percentage of consonants correct (PCC) was evaluated at 8 weeks and after 24 sessions. PCC gain was examined after a 6-week maintenance period. The P3 condition had a significantly better phonological outcome than the P1 and C conditions at 8 weeks and than the P1 condition after 24 weeks. There were no significant differences between the P1 and C conditions. There was no significant difference between the P1 and P3 conditions in PCC gain during the maintenance period. Preschool children with SSD who received the multiple oppositions approach made significantly greater gains when they were provided with a more intensive dose frequency and when cumulative intervention intensity was held constant.

A comparative study of restricted randomization procedures for multiarm trials with equal or unequal treatment allocation ratios.

PubMed

Ryeznik, Yevgen; Sverdlov, Oleksandr

2018-06-04

Randomization designs for multiarm clinical trials are increasingly used in practice, especially in phase II dose-ranging studies. Many new methods have been proposed in the literature; however, there is lack of systematic, head-to-head comparison of the competing designs. In this paper, we systematically investigate statistical properties of various restricted randomization procedures for multiarm trials with fixed and possibly unequal allocation ratios. The design operating characteristics include measures of allocation balance, randomness of treatment assignments, variations in the allocation ratio, and statistical characteristics such as type I error rate and power. The results from the current paper should help clinical investigators select an appropriate randomization procedure for their clinical trial. We also provide a web-based R shiny application that can be used to reproduce all results in this paper and run simulations under additional user-defined experimental scenarios. Copyright © 2018 John Wiley & Sons, Ltd.

Thiamine for prevention and treatment of Wernicke-Korsakoff Syndrome in people who abuse alcohol.

PubMed

Day, Ed; Bentham, Peter W; Callaghan, Rhiannon; Kuruvilla, Tarun; George, Sanju

2013-07-01

Autopsy studies suggest that Wernicke-Korsakoff syndrome (WKS) is not a rare disorder, particularly in individuals who abuse alcohol. Thiamine has been established as the treatment of choice for over 50 years, but uncertainty remains about appropriate dosage and duration. Current practice guidelines are based on case reports and clinical experience. This is an update of a review first published in 2004 and last updated in 2008. • To assess the efficacy of thiamine in preventing and treating the manifestations of WKS due to excess alcohol consumption. • To determine the optimum form, dose and duration of thiamine treatment for this indication. ALOIS, the Specialized Register of the Cochrane Dementia and Cognitive Improvement Group (CDCIG), The Cochrane Library, MEDLINE, EMBASE, PsycINFO, CINAHL and LILACS were searched on 6 September 2012 using the term thiamine OR aneurine. ALOIS contains records from all major health care databases (The Cochrane Library, MEDLINE, EMBASE, PsycINFO, CINAHL, LILACS) as well as from many trial databases and grey literature sources. Any randomised trials comparing thiamine with alternative interventions or comparing different thiamine regimens (varying in formulation, dose or duration of administration). All abstracts were independently inspected by two reviewers (ED and PWB), and relevant articles were retrieved and assessed for methodological quality using criteria provided in the Cochrane Handbook for Systematic Reviews of Interventions. Two studies were identified that met the inclusion criteria, but only one contained sufficient data for quantitative analysis. Ambrose (2001) randomly assigned participants (n = 107) to one of five doses of intramuscular thiamine and measured outcomes after 2 days of treatment. We compared the lowest dose (5 mg/day) with each of the other four doses. A significant difference favoured 200 mg/day compared with the 5-mg/day dose in determining the number of trials needed to meet inclusion criteria on a delayed alternation test (mean difference (MD) -17.90, 95% confidence interval (CI) -35.4 to -0.40, P = 0.04). No significant differences emerged when the other doses were compared with 5 mg/day. The pattern of results did not reflect a simple dose-response relationship. The study had methodological shortcomings in design and in the presentation of results that limited further analysis. Evidence from randomised controlled clinical trials is insufficient to guide clinicians in determining the dose, frequency, route or duration of thiamine treatment for prophylaxis against or treatment of WKS due to alcohol abuse.

In Vitro and In Vivo Short-Term Pulmonary Toxicity of Differently Sized Colloidal Amorphous SiO2

PubMed Central

Wiemann, Martin; Sauer, Ursula G.; Vennemann, Antje; Bäcker, Sandra; Keller, Johannes-Georg; Ma-Hock, Lan; Wohlleben, Wendel; Landsiedel, Robert

2018-01-01

In vitro prediction of inflammatory lung effects of well-dispersed nanomaterials is challenging. Here, the in vitro effects of four colloidal amorphous SiO2 nanomaterials that differed only by their primary particle size (9, 15, 30, and 55 nm) were analyzed using the rat NR8383 alveolar macrophage (AM) assay. Data were compared to effects of single doses of 15 nm and 55 nm SiO2 intratracheally instilled in rat lungs. In vitro, all four elicited the release of concentration-dependent lactate dehydrogenase, β-glucuronidase, and tumor necrosis factor alpha, and the two smaller materials also released H2O2. All effects were size-dependent. Since the colloidal SiO2 remained well-dispersed in serum-free in vitro conditions, effective particle concentrations reaching the cells were estimated using different models. Evaluating the effective concentration–based in vitro effects using the Decision-making framework for the grouping and testing of nanomaterials, all four nanomaterials were assigned as “active.” This assignment and the size dependency of effects were consistent with the outcomes of intratracheal instillation studies and available short-term rat inhalation data for 15 nm SiO2. The study confirms the applicability of the NR8383 AM assay to assessing colloidal SiO2 but underlines the need to estimate and consider the effective concentration of such well-dispersed test materials. PMID:29534009

Weight-based dosing in medication use: what should we know?

PubMed Central

Pan, Sheng-dong; Zhu, Ling-ling; Chen, Meng; Xia, Ping; Zhou, Quan

2016-01-01

Background Weight-based dosing strategy is still challenging due to poor awareness and adherence. It is necessary to let clinicians know of the latest developments in this respect and the correct circumstances in which weight-based dosing is of clinical relevance. Methods A literature search was conducted using PubMed. Results Clinical indications, physiological factors, and types of medication may determine the applicability of weight-based dosing. In some cases, the weight effect may be minimal or the proper dosage can only be determined when weight is combined with other factors. Medications within similar therapeutic or structural class (eg, anticoagulants, antitumor necrosis factor medications, P2Y12-receptor antagonists, and anti-epidermal growth factor receptor antibodies) may exhibit differences in requirements on weight-based dosing. In some cases, weight-based dosing is superior to currently recommended fixed-dose regimen in adult patients (eg, hydrocortisone, vancomycin, linezolid, and aprotinin). On the contrary, fixed dosing is noninferior to or even better than currently recommended weight-based regimen in adult patients in some cases (eg, cyclosporine microemulsion, recombinant activated Factor VII, and epoetin α). Ideal body-weight-based dosing may be superior to the currently recommended total body-weight-based regimen (eg, atracurium and rocuronium). For dosing in pediatrics, whether weight-based dosing is better than body surface-area-based dosing is dependent on the particular medication (eg, methotrexate, prednisone, prednisolone, zidovudine, didanosine, growth hormone, and 13-cis-retinoic acid). Age-based dosing strategy is better than weight-based dosing in some cases (eg, intravenous busulfan and dalteparin). Dosing guided by pharmacogenetic testing did not show pharmacoeconomic advantage over weight-adjusted dosing of 6-mercaptopurine. The common viewpoint (ie, pediatric patients should be dosed on the basis of body weight) is not always correct. Effective weight-based dosing interventions include standardization of weight estimation, documentation and dosing determination, dosing chart, dosing protocol, order set, pharmacist participation, technological information, and educational measures. Conclusion Although dosing methods are specified in prescribing information for each drug and there are no principal pros and cons to be elaborated, this review of weight-based dosing strategy will enrich the knowledge of medication administration from the perspectives of safety, efficacy, and pharmacoeconomics, and will also provide research opportunities in clinical practice. Clinicians should be familiar with dosage and administration of the medication to be prescribed as well as the latest developments. PMID:27110105

Optimal dose of hyperbaric bupivacaine 0.5% for unilateral spinal anesthesia during diagnostic knee arthroscopy

PubMed Central

Atef, HM; El-Kasaby, AM; Omera, MA; Badr, MD

2010-01-01

Objective To determine the dose of hyperbaric bupivacaine 0.5% required for unilateral spinal anesthesia during diagnostic knee arthroscopy. Patients and methods This prospective, randomized, clinical study was performed in 80 patients who were assigned to four groups to receive different doses of intrathecal hyperbaric bupivacaine (5 mg, 7.5 mg, 10 mg and 12.5 mg in Groups 1, 2, 3, and 4 respectively). Onset of sensory and motor block, hemodynamic changes, regression of motor block, and incidence of complications were recorded. Results Unilateral sensory block was reported in 90% and 85% of patients in Group 1 and Group 2, respectively, but not in any patient in Group 3 and Group 4. Unilateral motor block (modified Bromage scale 0) was reported in 95% of patients in Group 1, 90% in Group 2, and only 5% in Group 3, while no patient in Group 4 showed unilateral motor block. The time required for regression of motor block (Bromage scale 0) was prolonged with higher doses. The incidence of nausea, vomiting, and urine retention was similar in the study groups. Conclusion Unilateral sensory and motor block can be achieved with doses of 5 mg and 7.5 mg hyperbaric bupivacaine 0.5% with a stable hemodynamic state. However, 7.5 mg of hyperbaric bupivacaine 0.5% was the dose required for adequate unilateral spinal anesthesia. PMID:22915874

Influences of mechanical exposure biographies on physical capabilities of workers from automotive industry - a study on possible dose-response relationships and consequences for short and long term job rotation.

PubMed

Rademacher, Holger; Bruder, Ralph; Sinn-Behrendt, Andrea; Landau, Kurt

2012-01-01

This paper describes a field study in production areas of a vehicle manufacturing plant, where 106 male workers (aged from 20 to 63 years) were examined and interviewed by the authors. Aim of study was to identify relationships between specific physical worker capabilities and doses of mechanical exposures using self-developed standardized questionnaires as well as a battery of work-specific tests. The dependent variables are different "physical capabilities", classified using a five-point rating scale with regard to the grade of limitation of the respective capability. Independent variables are "age" and specific "mechanical exposures". Several exposures were combined and multiplied with their respective durations in order to determine doses on three different body regions - back, shoulder-neck and upper limbs. There are significant positive correlations between "age" and "dose of mechanical exposure on back/shoulder-neck/upper limbs region". The analysis of the relationship between dose of exposure and different capabilities to lift or reposition loads (with variable weight) shows weak significant correlations for all three body regions. Data analysis shows no significant correlations between any dose of mechanical exposure and capabilities to work in awkward body postures.These results should be considered in age management programs when scheduling future employee assignments to workplaces, especially for production systems where manual handling tasks are dominant.

Comparative trial of two intravenous doses of granisetron (1 versus 3 mg) in the prevention of chemotherapy-induced acute emesis: a double-blind, randomized, non-inferiority trial.

PubMed

Tsuji, Daiki; Kim, Yong-Il; Taku, Keisei; Nakagaki, Shigeru; Ikematsu, Yoshito; Tsubota, Hiromi; Maeda, Masato; Hashimoto, Naoya; Kimura, Masayuki; Daimon, Takashi

2012-05-01

A single 3 mg or 40 μg/kg intravenous dose of granisetron combined with dexamethasone is routinely used in several countries, although the antiemetic guidelines have recommended granisetron at the dose of 1 mg or 10 μg/kg. A randomized, multicenter trial was conducted to determine the optimal intravenous granisetron dose, 1 or 3 mg, in cancer patients receiving emetogenic chemotherapy. We enrolled 365 patients and randomly assigned them to receive intravenous granisetron 3 mg (3-mg group) or 1 mg (1-mg group), combined with dexamethasone at an adequate dose fixed as per the emetic risk category. The primary end point was the proportion of patients with a complete response during the first 24 h after chemotherapy. The study demonstrated that 1 mg of granisetron was not inferior in effect to 3 mg. For the primary end point, 359 patients were evaluable according to the modified intention-to-treat (ITT) analysis. Complete protection was achieved in the modified ITT population, 90.6% and 88.8% for the 3- and 1-mg groups, respectively (p < 0.01 for non-inferiority). This study showed that 1 mg granisetron is not inferior to 3 mg when both doses are combined with dexamethasone. Therefore, 1-mg dose of intravenous granisetron should be the recommended prophylactic regimen for the prevention of acute emesis.

Pro blood clotting activity of Scoparia dulcis in rats

PubMed Central

Ediriweera, E. R. H. S. S.; Jayakody, J. R. A. C.; Ratnasooriya, W. D.

2011-01-01

Scoparia dulcis Linn (Family: Scrophulariaceae, Sinhala: WalKoththamalli) is a perennial herb growing in many tropical countries including Sri Lanka. Traditional Physicians in rural down south areas apply crushed S. dulcis plant on cuts and bruises to stop bleeding. S. dulcis may also have Rakta Sthambhana property. The study on effect of decoction (water extract) of S. dulcis on blood clotting time in rats was carried out to investigate this. Two groups of rats, 12 males and 42 females were used in this experimental study. Forty-two female rats were assigned into seven equal groups (n = 6/gp). Different doses of DE (25, 50, 100, 1000, 1500 mg/kg) (group 1-5) or 2 ml of distilled water (DW) (group 6) were orally administered. 0.1 ml of vitamin K was injected intramuscularly (group 7) as reference drug to seventh the group. Twelve male rats were assigned into two equal groups (n = 6/gp), 2 ml of distilled water (DW) and doses of DE (1500 mg/kg) were orally administered. Clotting time was determined on the Days 1, 2, and 7 using Lee and White method. In the DE treated groups with all doses, there was no reduction in clotting time on the Day 1 but a significant reduction of clotting time (P < 0.05) was observed on the Days 2 and 7. In the group treated with vitamin K, there was no significant reduction in clotting time on Day 1 or 2, but there was a significant reduction in clotting time on Day 7. It is concluded that S. dulcis has proclotting activity (rakthasthambhana property) and this was faster than vitamin K. PMID:22408315

Pro blood clotting activity of Scoparia dulcis in rats.

PubMed

Ediriweera, E R H S S; Jayakody, J R A C; Ratnasooriya, W D

2011-04-01

Scoparia dulcis Linn (Family: Scrophulariaceae, Sinhala: WalKoththamalli) is a perennial herb growing in many tropical countries including Sri Lanka. Traditional Physicians in rural down south areas apply crushed S. dulcis plant on cuts and bruises to stop bleeding. S. dulcis may also have Rakta Sthambhana property. The study on effect of decoction (water extract) of S. dulcis on blood clotting time in rats was carried out to investigate this. Two groups of rats, 12 males and 42 females were used in this experimental study. Forty-two female rats were assigned into seven equal groups (n = 6/gp). Different doses of DE (25, 50, 100, 1000, 1500 mg/kg) (group 1-5) or 2 ml of distilled water (DW) (group 6) were orally administered. 0.1 ml of vitamin K was injected intramuscularly (group 7) as reference drug to seventh the group. Twelve male rats were assigned into two equal groups (n = 6/gp), 2 ml of distilled water (DW) and doses of DE (1500 mg/kg) were orally administered. Clotting time was determined on the Days 1, 2, and 7 using Lee and White method. In the DE treated groups with all doses, there was no reduction in clotting time on the Day 1 but a significant reduction of clotting time (P < 0.05) was observed on the Days 2 and 7. In the group treated with vitamin K, there was no significant reduction in clotting time on Day 1 or 2, but there was a significant reduction in clotting time on Day 7. It is concluded that S. dulcis has proclotting activity (rakthasthambhana property) and this was faster than vitamin K.

Patient-controlled oral analgesia for postoperative pain management following total knee replacement.

PubMed

Kastanias, Patti; Gowans, Sue; Tumber, Paul S; Snaith, Kianda; Robinson, Sandra

2010-01-01

To investigate whether patient-controlled oral analgesia (PCOA) used by individuals receiving a total knee replacement could reduce pain, increase patient satisfaction, reduce opioid use and/or reduce opioid side effects when compared with traditional nurse (RN)-administered oral analgesia. Patients who underwent an elective total knee replacement at a quaternary care centre (Toronto Western Hospital, Toronto, Ontario) were randomly assigned to either PCOA or RN-administered short-acting oral opioids on postoperative day 2. Subjects in the RN group called the RN to receive their prescribed short-acting opioid. Subjects in the PCOA group kept a single dose of their prescribed oral opioid at their bedside and took this dose when they felt they needed it, to a maximum of one dose every 2 h. Study outcomes, collected on postoperative day 2, included pain (measured by the Brief Pain Inventory - Short Form), patient satisfaction (measured by the Pain Outcome Questionnaire Satisfaction subscale - component II), opioid use (oral morphine equivalents), opioid side effects (nausea, pruritus and/or constipation) and knee measures (maximum passive knee flexion and pain at maximum passive knee flexion, performed on the operative knee). Study outcomes were analyzed twice. First, for a subset of 73 subjects who remained in their randomly assigned group (PCOA group, n=36; RN group, n=37), randomized analyses were performed. Second, for the larger sample of 88 subjects who were categorized by their actual method of receiving oral opioids (PCOA group, n=41; RN group, n=47), as-treated analyses were performed. There were no differences in study outcomes between the PCOA and RN groups in either analysis. PCOA was not superior to RN administration on study outcomes. However, PCOA did not increase opioid use or pain. PCOA remains an important element in the patient-centred care facility.

Ginger (Zingiber officinale) reduces acute chemotherapy-induced nausea: A URCC CCOP study of 576 patients

PubMed Central

Ryan, Julie L.; Heckler, Charles E.; Roscoe, Joseph A.; Dakhil, Shaker R.; Kirshner, Jeffrey; Flynn, Patrick J.; Hickok, Jane T.; Morrow, Gary R.

2012-01-01

Purpose Despite the widespread use of antiemetics, nausea continues to be reported by over 70% of patients receiving chemotherapy. Methods In this double blind, multicenter trial, we randomly assigned 744 cancer patients to four arms: 1) placebo, 2) 0.5g ginger, 3) 1.0g ginger, or 4) 1.5g ginger. Nausea occurrence and severity were assessed at a baseline cycle and the two following cycles during which patients were taking their assigned study medication. All patients received a 5-HT3 receptor antagonist antiemetic on Day 1 of all cycles. Patients took three capsules of ginger (250mg) or placebo twice daily for six days starting three days before the first day of chemotherapy. Patients reported the severity of nausea on a 7-point rating scale (“1” = “Not at all Nauseated” and “7” = “Extremely Nauseated”) for Days 1-4 of each cycle. The primary outcomes were to determine the dose and efficacy of ginger at reducing the severity of chemotherapy-induced nausea on Day 1 of chemotherapy. Results A total of 576 patients were included in final analysis (91% female, mean age = 53). Mixed model analyses demonstrated that all doses of ginger significantly reduced acute nausea severity compared to placebo on Day 1 of chemotherapy (p=0.003). The largest reduction in nausea intensity occurred with 0.5g and 1.0g of ginger (p=0.017 and p=0.036, respectively). Anticipatory nausea was a key factor in acute chemotherapy-induced nausea (p<0.0001). Conclusions Ginger supplementation at daily dose of 0.5g-1.0g significantly aids in reduction of the severity of acute chemotherapy-induced nausea in adult cancer patients. PMID:21818642

Cognitive Behavior Therapy as Augmentation for Sertraline in Treating Patients with Persistent Postural-Perceptual Dizziness.

PubMed

Yu, Yi-Chuan; Xue, Hui; Zhang, Ying-Xin; Zhou, Jiying

2018-01-01

Persistent postural-perceptual dizziness (PPPD) is a common vestibular disorder. This study was conducted to assess whether the addition of cognitive behavior therapy (CBT) could significantly improve the efficacy and acceptability of sertraline in treating PPPD. PPPD patients were recruited and randomly assigned to control and experiment groups. Patients in both groups received sertraline 50-200 mg/day, and only patients in the experiment group received CBT (twice a week, one hour per time). The treatment was continued for eight weeks. At baseline, week 2, week 4, and week 8, the 25-item Dizziness Handicap Inventory (DHI), Hamilton Anxiety Rating Scale (HARS), and Hamilton Depression Rating Scale (HDRS) were used to assess the self-perceived handicapping effects caused by PPPD, anxiety, and depressive symptoms, respectively. The dose of sertraline used and the adverse events in both groups were recorded and analyzed. In total, 91 PPPD patients were randomly assigned to the control group ( n = 45) and experiment group ( n = 46). After eight weeks of treatment, the average DHI scores, HDRS scores, and HARS scores were significantly decreased in both groups. But compared to the control group, the experiment group had significantly lower average DHI score, HDRS score, and HARS score at weeks 4 and 8. Moreover, the dose of sertraline used in the experiment group was significantly lower than that in the control group, and adverse events occurred more frequently in the control group than in the experiment group (48.9% versus 26.1%, p = 0.025). These results demonstrated that the addition of CBT could significantly improve the efficacy and acceptability of sertraline in treating PPPD and reduce the dose of sertraline used.

Comparative study of therapeutic effects of PPI and H2RA on ulcers during continuous aspirin therapy

PubMed Central

Nema, Hiroaki; Kato, Mototsugu

2010-01-01

AIM: To compare the therapeutic effects of proton pump inhibitors (PPI) and histamine 2 receptor antagonists (H2RA) on gastroduodenal ulcers under continuous use of low-dose aspirin. METHODS: Sixty patients who had a gastroduodenal ulcer on screening endoscopy but required continuous use of low-dose aspirin were randomly assigned to receive PPI (lansoprazole 30 mg, n = 30) or H2RA (famotidine 40 mg or if famotidine had been administered before assignment, ranitidine 300 mg, n = 30). The therapeutic effects were evaluated by endoscopy after 8-wk treatment. The presence or absence of Helicobacter pylori (H. pylori) was determined by urea breath test before treatment. Abdominal symptoms were compared with the gastrointestinal symptom rating scale (GSRS) questionnaire before and after treatment. RESULTS: Twenty-six patients in the PPI group and 26 patients in the H2RA group, excluding dropouts, were analyzed. There were no significant differences in median age, sex, underlying disease, smoking status, H. pylori infection, prevalence of ulcers before treatment, and lesion site between the two groups. The therapeutic effects were endoscopically evaluated as healed in 23 patients (88.5%) and not healed in 3 patients in the PPI group and as healed in 22 patients (84.6%) and not healed in 4 patients in the H2RA group. Abdominal symptoms before treatment were uncommon in both groups; the GSRS scores were not significantly reduced after treatment as compared with before treatment. CONCLUSION: The healing rate of gastroduodenal ulcers during continuous use of low-dose aspirin was greater than 80% in both the PPI group and the H2RA group, with no significant difference between the two groups. PMID:21072898

Glossary of Terms--Nuclear Weapon Phenomena and Effects

DTIC Science & Technology

1985-02-15

w".: w~*~ combat ineffective. An individual whose injuries are of such nature that he is no longer capable of carrying out his assigned task...significantly harmful result [39]. That dose of ionizing radiation that is not expected to cause appreciable bodily injury to a person at any time during his...art and science of protecting human beings from injury by radia- tion, and promoting better health through beneficial applications of radiation [39

Space Environmental Effects on Materials and Processes

NASA Technical Reports Server (NTRS)

Sabbann, Leslie M.

2009-01-01

The Materials and Processes (M&P) Branch of the Structural Engineering Division at Johnson Space Center (JSC) seeks to uphold the production of dependable space hardware through materials research, which fits into NASA's purpose of advancing human exploration, use, and development of space. The Space Environmental Effects projects fully support these Agency goals. Two tasks were assigned to support M&P. Both assignments were to further the research of material behavior outside of Earth's atmosphere in order to determine which materials are most durable and safe to use in space for mitigating risks. One project, the Materials on International Space Station Experiments (MISSE) task, was to compile data from International Space Station (ISS) experiments to pinpoint beneficial space hardware. The other project was researching the effects on composite materials of exposure to high doses of radiation for a Lunar habitat project.

Probability Distribution of Dose and Dose-Rate Effectiveness Factor for use in Estimating Risks of Solid Cancers From Exposure to Low-Let Radiation.

PubMed

Kocher, David C; Apostoaei, A Iulian; Hoffman, F Owen; Trabalka, John R

2018-06-01

This paper presents an analysis to develop a subjective state-of-knowledge probability distribution of a dose and dose-rate effectiveness factor for use in estimating risks of solid cancers from exposure to low linear energy transfer radiation (photons or electrons) whenever linear dose responses from acute and chronic exposure are assumed. A dose and dose-rate effectiveness factor represents an assumption that the risk of a solid cancer per Gy at low acute doses or low dose rates of low linear energy transfer radiation, RL, differs from the risk per Gy at higher acute doses, RH; RL is estimated as RH divided by a dose and dose-rate effectiveness factor, where RH is estimated from analyses of dose responses in Japanese atomic-bomb survivors. A probability distribution to represent uncertainty in a dose and dose-rate effectiveness factor for solid cancers was developed from analyses of epidemiologic data on risks of incidence or mortality from all solid cancers as a group or all cancers excluding leukemias, including (1) analyses of possible nonlinearities in dose responses in atomic-bomb survivors, which give estimates of a low-dose effectiveness factor, and (2) comparisons of risks in radiation workers or members of the public from chronic exposure to low linear energy transfer radiation at low dose rates with risks in atomic-bomb survivors, which give estimates of a dose-rate effectiveness factor. Probability distributions of uncertain low-dose effectiveness factors and dose-rate effectiveness factors for solid cancer incidence and mortality were combined using assumptions about the relative weight that should be assigned to each estimate to represent its relevance to estimation of a dose and dose-rate effectiveness factor. The probability distribution of a dose and dose-rate effectiveness factor for solid cancers developed in this study has a median (50th percentile) and 90% subjective confidence interval of 1.3 (0.47, 3.6). The harmonic mean is 1.1, which implies that the arithmetic mean of an uncertain estimate of the risk of a solid cancer per Gy at low acute doses or low dose rates of low linear energy transfer radiation is only about 10% less than the mean risk per Gy at higher acute doses. Data were also evaluated to define a low acute dose or low dose rate of low linear energy transfer radiation, i.e., a dose or dose rate below which a dose and dose-rate effectiveness factor should be applied in estimating risks of solid cancers.

Association Between Early Low-Dose Hydrocortisone Therapy in Extremely Preterm Neonates and Neurodevelopmental Outcomes at 2 Years of Age.

PubMed

Baud, Olivier; Trousson, Clémence; Biran, Valérie; Leroy, Emilie; Mohamed, Damir; Alberti, Corinne

2017-04-04

Dexamethasone to prevent bronchopulmonary dysplasia in very preterm neonates was associated with adverse neurodevelopmental events. Early low-dose hydrocortisone treatment has been reported to improve survival without bronchopulmonary dysplasia but its safety with regard to neurodevelopment remains to be assessed. To assess whether early hydrocortisone therapy in extremely preterm infants is associated with neurodevelopmental impairment at 2 years of age. An exploratory secondary analysis of the PREMILOC (Early Low-Dose Hydrocortisone to Improve Survival without Bronchopulmonary Dysplasia in Extremely Preterm Infants) randomized clinical trial conducted between 2008 and 2014 in 21 French neonatal intensive care units. Randomization was stratified by gestational age groups. Neurodevelopmental assessments were completed from 2010 to 2016. After birth, patients were randomly assigned to receive placebo or hydrocortisone (0.5 mg/kg twice per day for 7 days, followed by 0.5 mg/kg per day for 3 days). The prespecified exploratory secondary outcome of neurodevelopmental impairment was based on a standardized neurological examination and the revised Brunet-Lézine scale (global developmental quotient score and subscores; mean norm, 100 [SD, 15]). The minimal clinically important difference on the global developmental quotient was 5 points. Of 1072 neonates screened, 523 were assigned to hydrocortisone (n = 256) or placebo (n = 267) and 406 survived to 2 years of age. A total of 379 patients (93%; 46% female) were evaluated (194 in the hydrocortisone group and 185 in the placebo group) at a median corrected age of 22 months (interquartile range, 21-23 months). The distribution of patients without neurodevelopmental impairment (73% in the hydrocortisone group vs 70% in the placebo group), with mild neurodevelopmental impairment (20% in the hydrocortisone group vs 18% in the placebo group), or with moderate to severe neurodevelopmental impairment (7% in the hydrocortisone group vs 11% in the placebo group) was not statistically significantly different between groups (P = .33). The mean global developmental quotient score was not statistically significantly different between groups (91.7 in the hydrocortisone group vs 91.4 in the placebo group; between-group difference, 0.3 [95% CI, -2.7 to 3.4]; P = .83). The incidence of cerebral palsy or other major neurological impairments was not significantly different between groups. In this exploratory analysis of secondary outcomes of a randomized clinical trial of extremely preterm infants, early low-dose hydrocortisone was not associated with a statistically significant difference in neurodevelopment at 2 years of age. Further randomized studies are needed to provide definitive assessment of the neurodevelopmental safety of hydrocortisone in extremely preterm infants. clinicaltrials.gov Identifier: NCT00623740.

The selective treatment of clinical mastitis based on on-farm culture results: I. Effects on antibiotic use, milk withholding time, and short-term clinical and bacteriological outcomes.

PubMed

Lago, A; Godden, S M; Bey, R; Ruegg, P L; Leslie, K

2011-09-01

The objective of this multi-state, multi-herd clinical trial was to evaluate the efficacy of using an on-farm culture system to guide strategic treatment decisions in cows with clinical mastitis. The study was conducted in 8 commercial dairy farms ranging in size from 144 to 1,795 cows from Minnesota, Wisconsin, and Ontario, Canada. A total of 422 cows affected with mild or moderate clinical mastitis in 449 quarters were randomly assigned to either (1) a positive-control treatment program or (2) an on-farm, culture-based treatment program. Quarter cases assigned to the positive-control group received immediate on-label intramammary treatment with cephapirin sodium. Quarters assigned to the culture-based treatment program were cultured on-farm and treated with cephapirin sodium after 18 to 24h of incubation if they had gram-positive growth or a mixed infection. Quarters with gram-negative or no growth did not receive intramammary therapy. The proportion of quarter cases assigned to positive-control and culture-based treatments that received intramammary antibiotic therapy because of study assignment was 100 and 44%, respectively; the proportion of cases that received secondary antibiotic therapy was 36 and 19%, respectively; and the proportion of cases that received intramammary antibiotic therapy because of study assignment or secondary therapy was 100 and 51%, respectively. A tendency existed for a decrease in the number of days in which milk was discarded from cows assigned to the culture-based treatment program versus cows assigned to the positive-control group (5.9 vs. 5.2 d). No statistically significant differences existed between cases assigned to the positive-control and cases assigned to the culture-based treatment program in days to clinical cure (2.7 vs. 3.2 d), bacteriological cure risk within 21 d of enrollment (71 vs. 60%), new intramammary infection risk within 21 d of enrollment (50 vs. 50%), and treatment failure risk (presence of infection, secondary treatment, clinical mastitis recurrence, or removal from herd within 21 d after enrollment; 81 vs. 78%). In summary, the use of an on-farm culture system to guide the strategic treatment of clinical mastitis reduced intramammary antibiotic use by half and tended to decrease milk withholding time by 1 d, without significant differences in days to clinical cure, bacteriological cure risk, new intramammary infection risk, and treatment failure risk within 21 d after the clinical mastitis event. Copyright © 2011 American Dairy Science Association. Published by Elsevier Inc. All rights reserved.

Effects of TD-5108 on Gastrointestinal Transit and Bowel Function in Health and Pharmacokinetics in Health and Constipation

PubMed Central

Manini, Mhd Louai; Camilleri, Michael; Goldberg, Michael; Sweetser, Seth; McKinzie, Sanna; Burton, Duane; Wong, Shekman; Kitt, Michael M.; Li, Yu-Ping; Zinsmeister, Alan R.

2010-01-01

Background TD-5108 is a potent, selective high intrinsic activity serotonin 5-HT4 receptor agonist. Aim To assess effects of TD-5108 on gastrointestinal transit and compare its pharmacokinetics (PK) in healthy volunteers (HV) and chronic constipation (CC) patients. Methods 60 HV were randomly assigned, double-blind to placebo, 5, 15, 30 or 50 mg TD-5108 (single and 6-day dosing). Primary endpoints were colonic transit (geometric center at 24 hours, GC24) and ascending colon emptying (ACE) T1/2 after first dose. Secondary endpoints included gastric emptying (GE) T1/2 and colonic filling at 6 h (CF6). Results Single dose TD-5108 significantly accelerated GC24, ACE T1/2, and CF6; 30 and 50°mg TD-5108 accelerated all 3 endpoints. With multiple doses, TD-5108 30 mg accelerated GC24, and overall accelerated GE T1/2 at 15–50 mg. PK studies showed dose proportionality in health, and no significant differences between health and chronic constipation with a 15 mg oral dose of TD-5108. Stimulation of bowel function after15 mg TD-5108 were similar in CC and controls. There were no serious adverse events; notable adverse were the predictable GI effects such as diarrhea or altered bowel movements. Conclusions TD-5108 significantly accelerated intestinal and colonic transit after single dosing and accelerated gastric emptying after multiple dosing. Further studies of its potential as a gastrointestinal and colonic prokinetic are warranted. PMID:19691492

Methadone dose increase and abstinence reinforcement for treatment of continued heroin use during methadone maintenance.

PubMed

Preston, K L; Umbricht, A; Epstein, D H

2000-04-01

Although methadone maintenance is an effective therapy for heroin dependence, some patients continue to use heroin and may benefit from therapeutic modifications. This study evaluated a behavioral intervention, a pharmacological intervention, and a combination of both interventions. Throughout the study all patients received daily methadone hydrochloride maintenance (initially 50 mg/d orally) and weekly counseling. Following baseline treatment patients who continued to use heroin were randomly assigned to 1 of 4 interventions: (1) contingent vouchers for opiate-negative urine specimens (n = 29 patients); (2) methadone hydrochloride dose increase to 70 mg/d (n = 31 patients); (3) combined contingent vouchers and methadone dose increase (n = 32 patients); and (4) neither intervention (comparison standard; n = 28 patients). Methadone dose increases were double blind. Vouchers had monetary value and were exchangeable for goods and services. Groups not receiving contingent vouchers received matching vouchers independent of urine test results. Primary outcome measure was opiate-negative urine specimens (thrice weekly urinalysis). Contingent vouchers and a methadone dose increase each significantly increased the percentage of opiate-negative urine specimens during intervention. Contingent vouchers, with or without a methadone dose increase, increased the duration of sustained abstinence as assessed by urine screenings. Methadone dose increase, with or without contingent vouchers, reduced self-reported frequency of use and self-reported craving. In patients enrolled in a methadone-maintainence program who continued to use heroin, abstinence reinforcement and a methadone dose increase were each effective in reducing use. When combined, they did not dramatically enhance each other's effects on any 1 outcome measure, but they did seem to have complementary benefits.

Tear film concentrations of doxycycline following oral administration in ophthalmologically normal dogs.

PubMed

Collins, Sean P; Labelle, Amber L; Dirikolu, Levent; Li, Zhong; Mitchell, Mark A; Hamor, Ralph E

2016-09-01

OBJECTIVE To determine tear film concentrations of doxycycline in ophthalmologically normal dogs following oral doxycycline administration. DESIGN Crossover study. ANIMALS 10 privately owned dolichocephalic or mesaticephalic dogs free of ophthalmic disease. PROCEDURES Dogs were randomly assigned to receive doxycycline hyclate first at 5 mg/kg (2.3 mg/lb) or 10 mg/kg (4.5 mg/lb), PO, every 12 hours for 5 days, beginning on day 1. Doxycycline was administered 1 hour prior to feeding. Tear samples were collected from days 1 through 10 approximately 3 hours after the morning dose was administered. Following a 3-week washout period, dogs received the alternative dose in the same conditions. Doxycycline concentration in tear samples from 1 eye (same eye used for both sessions) was measured via liquid chromatography-mass spectrometry and compared between the 2 doxycycline doses. RESULTS Doxycycline was detected in tear samples of all dogs from days 1 through 10 for both doxycycline doses. Median peak doxycycline concentrations for the 5 mg/kg and 10 mg/kg doses were 2.19 ng/mL on day 3 and 4.32 ng/mL on day 4, respectively. Concentrations differed significantly with time, but this difference was not influenced by dose, dose order, or eye. A significant positive correlation was identified between doxycycline concentration and body weight (r = 0.22). CONCLUSIONS AND CLINICAL RELEVANCE Detectable doxycycline concentrations were achieved in the tear film of ophthalmologically normal dogs following oral administration of doxycycline at 5 or 10 mg/kg, every 12 hours. Dose had no significant effect on tear film concentration of the drug.

Dose-Dependent Cortical Thinning After Partial Brain Irradiation in High-Grade Glioma

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

Karunamuni, Roshan; Bartsch, Hauke; White, Nathan S.

Purpose: Radiation-induced cognitive deficits may be mediated by tissue damage to cortical regions. Volumetric changes in cortex can be reliably measured using high-resolution magnetic resonance imaging (MRI). We used these methods to study the association between radiation therapy (RT) dose and change in cortical thickness in high-grade glioma (HGG) patients. Methods and Materials: We performed a voxel-wise analysis of MRI from 15 HGG patients who underwent fractionated partial brain RT. Three-dimensional MRI was acquired pre- and 1 year post RT. Cortex was parceled with well-validated segmentation software. Surgical cavities were censored. Each cortical voxel was assigned a change in cortical thicknessmore » between time points, RT dose value, and neuroanatomic label by lobe. Effects of dose, neuroanatomic location, age, and chemotherapy on cortical thickness were tested using linear mixed effects (LME) modeling. Results: Cortical atrophy was seen after 1 year post RT with greater effects at higher doses. Estimates from LME modeling showed that cortical thickness decreased by −0.0033 mm (P<.001) for every 1-Gy increase in RT dose. Temporal and limbic cortex exhibited the largest changes in cortical thickness per Gy compared to that in other regions (P<.001). Age and chemotherapy were not significantly associated with change in cortical thickness. Conclusions: We found dose-dependent thinning of the cerebral cortex, with varying neuroanatomical regional sensitivity, 1 year after fractionated partial brain RT. The magnitude of thinning parallels 1-year atrophy rates seen in neurodegenerative diseases and may contribute to cognitive decline following high-dose RT.« less

Detection of calcification clusters in digital breast tomosynthesis slices at different dose levels utilizing a SRSAR reconstruction and JAFROC

NASA Astrophysics Data System (ADS)

Timberg, P.; Dustler, M.; Petersson, H.; Tingberg, A.; Zackrisson, S.

2015-03-01

Purpose: To investigate detection performance for calcification clusters in reconstructed digital breast tomosynthesis (DBT) slices at different dose levels using a Super Resolution and Statistical Artifact Reduction (SRSAR) reconstruction method. Method: Simulated calcifications with irregular profile (0.2 mm diameter) where combined to form clusters that were added to projection images (1-3 per abnormal image) acquired on a DBT system (Mammomat Inspiration, Siemens). The projection images were dose reduced by software to form 35 abnormal cases and 25 normal cases as if acquired at 100%, 75% and 50% dose level (AGD of approximately 1.6 mGy for a 53 mm standard breast, measured according to EUREF v0.15). A standard FBP and a SRSAR reconstruction method (utilizing IRIS (iterative reconstruction filters), and outlier detection using Maximum-Intensity Projections and Average-Intensity Projections) were used to reconstruct single central slices to be used in a Free-response task (60 images per observer and dose level). Six observers participated and their task was to detect the clusters and assign confidence rating in randomly presented images from the whole image set (balanced by dose level). Each trial was separated by one weeks to reduce possible memory bias. The outcome was analyzed for statistical differences using Jackknifed Alternative Free-response Receiver Operating Characteristics. Results: The results indicate that it is possible reduce the dose by 50% with SRSAR without jeopardizing cluster detection. Conclusions: The detection performance for clusters can be maintained at a lower dose level by using SRSAR reconstruction.

Simultaneous infield boost with helical tomotherapy for patients with 1 to 3 brain metastases.

PubMed

Bauman, Glenn; Yartsev, Slav; Fisher, Barb; Kron, Tomas; Laperriere, Normand; Heydarian, Mostafa; VanDyk, Jake

2007-02-01

We sought to model the feasibility of a simultaneous in field boost (SIB) to individual brain metastases during a course of whole brain radiotherapy (WBXRT) using helical tomotherapy (HT) intensity-modulated radiation therapy. Planning computed tomography data from 14 patients with 1 to 3 brain metastases were used to model an intralesional SIB delivery that yielded a total intralesional dose of 60 Gy with a surrounding whole brain dose of 30 Gy (designed to be isoeffective to WBXRT of 30 Gy with an 18 Gy in 1 fraction radiosurgery boost). Accuracy of treatment of a phantom on the HT unit was measured. Comparisons of HT delivery versus a conventional stereotactic radiotherapy technique for a particularly challenging simulated anatomy were made. In all cases, SIB to 60 Gy with WBXRT to 30 Gy was possible while maintaining critical structures below assigned dose limits. Estimated radiation delivery time for the SIB treatment was approximately 10 minutes per fraction. Planning and treatment of the head phantom was associated with an overall accuracy of 2 mm. Comparison to conventional noncoplanar arc fractionated stereotactic radiotherapy plan demonstrated similar target coverage and improved critical tissue sparing even for a challenging anatomy with multiple lesions in the same plane as the optic apparatus. Based on this study, use of an image guided SIB using HT seemed feasible and a phase I trial initiated at our institution is described. Potential advantages of this approach include frameless stereotaxis through daily megavoltage computed tomography localization, more efficient use of resources and exploitation of radiobiologic advantages of fractionation.

Effects of upper respiratory tract illnesses, ibuprofen and caffeine on reaction time and alertness.

PubMed

Smith, Andrew P; Nutt, David J

2014-05-01

Compared with healthy individuals, those with upper respiratory tract illnesses (URTIs) report reduced alertness and have slower reaction times. It is important to evaluate medication that can remove this behavioural malaise. The aim of this study was to compare the effects of a combination of ibuprofen plus caffeine with ibuprofen and caffeine alone, and placebo on malaise associated with URTIs, as measured by psychomotor performance and mood testing. Volunteers were randomly assigned to one of four medication conditions as follows: 200 mg ibuprofen and 100 mg caffeine; 200 mg ibuprofen; 100 mg caffeine; placebo. A single oral dose was given and testing followed for 3 h. Efficacy variables were based on the volunteers' performance, measured by psychomotor performance and mood. The pre-drug results confirmed that those with an URTI had a more negative mood and impaired performance. Results from the simple reaction time task, at both 55- and 110-min post-dosing, showed that a single-dose of caffeinated products (I200/C100 and CAF100) led to significantly faster reaction times than IBU200 and placebo. These effects were generally confirmed with the other performance tasks. Subjective measures showed that the combination of ibuprofen and caffeine was superior to the other conditions. There were no serious adverse events reported, and study medication was well tolerated. The results from the post-drug assessments suggest that a combination of ibuprofen and caffeine was the optimum treatment for malaise associated with URTIs in that it had significant effects on objective performance and subjective measures.

RNAi therapy targeting KRAS in combination with chemotherapy for locally advanced pancreatic cancer patients

PubMed Central

Golan, Talia; Khvalevsky, Elina Zorde; Hubert, Ayala; Gabai, Rachel Malka; Hen, Naama; Segal, Amiel; Domb, Abraham; Harari, Gil; David, Eliel Ben; Raskin, Stephen; Goldes, Yuri; Goldin, Eran; Eliakim, Rami; Lahav, Maor; Kopleman, Yael; Dancour, Alain; Shemi, Amotz; Galun, Eithan

2015-01-01

Purpose The miniature biodegradable implant siG12D-LODER™ was inserted into a tumor and released a siRNA drug against KRAS(G12D) along four months. This novel siRNA based drug was studied, in combination with chemotherapy, as targeted therapy for Locally Advanced Pancreatic Cancer (LAPC). Methods An open-label Phase 1/2a study in the first-line setting of patients with non-operable LAPC was initiated. In this study patients were assigned to receive a single dose of siG12D-LODERs, in three escalating dose cohorts (0.025mg, 0.75mg and 3.0mg). Gemcitabine was given on a weekly basis, following the siG12D-LODERTM insertion, until disease progression. The recommended dose was further examined with modified FOLFIRINOX. The follow up period was eight weeks and survival until death. Results Fifteen patients with LAPC were enrolled. Among the 15 treated patients, the most frequent adverse events observed were grade 1or 2 in severity (89%); five patients experienced serious adverse events (SAEs). In 12 patients analyzed by CT scans, none showed tumor progression, the majority (10/12) demonstrated stable disease and two showed partial response. Decrease in tumor marker CA19-9 was observed in 70% (7/10) of patients. Median overall survival was 15.12 months; 18 month survival was 38.5%. Conclusions The combination of siG12D-LODER™ and chemotherapy is well tolerated, safe and demonstrated a potential efficacy in patients with LAPC. NCT01188785 PMID:26009994

"The Dose Makes the Poison": Informing Consumers About the Scientific Risk Assessment of Food Additives.

PubMed

Bearth, Angela; Cousin, Marie-Eve; Siegrist, Michael

2016-01-01

Intensive risk assessment is required before the approval of food additives. During this process, based on the toxicological principle of "the dose makes the poison,ˮ maximum usage doses are assessed. However, most consumers are not aware of these efforts to ensure the safety of food additives and are therefore sceptical, even though food additives bring certain benefits to consumers. This study investigated the effect of a short video, which explains the scientific risk assessment and regulation of food additives, on consumers' perceptions and acceptance of food additives. The primary goal of this study was to inform consumers and enable them to construct their own risk-benefit assessment and make informed decisions about food additives. The secondary goal was to investigate whether people have different perceptions of food additives of artificial (i.e., aspartame) or natural origin (i.e., steviolglycoside). To attain these research goals, an online experiment was conducted on 185 Swiss consumers. Participants were randomly assigned to either the experimental group, which was shown a video about the scientific risk assessment of food additives, or the control group, which was shown a video about a topic irrelevant to the study. After watching the video, the respondents knew significantly more, expressed more positive thoughts and feelings, had less risk perception, and more acceptance than prior to watching the video. Thus, it appears that informing consumers about complex food safety topics, such as the scientific risk assessment of food additives, is possible, and using a carefully developed information video is a successful strategy for informing consumers. © 2015 Society for Risk Analysis.

Safety and immunogenicity of pneumococcal protein vaccine candidates: monovalent choline-binding protein A (PcpA) vaccine and bivalent PcpA-pneumococcal histidine triad protein D vaccine.

PubMed

Bologa, Monica; Kamtchoua, Thierry; Hopfer, Robert; Sheng, Xiaohua; Hicks, Bryony; Bixler, Garvin; Hou, Victor; Pehlic, Vildana; Yuan, Tao; Gurunathan, Sanjay

2012-12-14

Pneumococcal vaccines based on protein antigens may provide expanded protection against Streptococcus pneumoniae. To evaluate safety and immunogenicity in adults of pneumococcal vaccine candidates comprising S. pneumoniae pneumococcal histidine triad protein D (PhtD) and pneumococcal choline-binding protein A (PcpA) in monovalent and bivalent formulations. This was a phase I, randomized, observer-blinded, placebo-controlled, step-wise dose-escalation study. Following a pilot safety study in which participants received one intramuscular injection of either aluminum hydroxide (AH)-adjuvanted PcpA (25 μg) or PhtD-PcpA (10 μg each), participants in the main study received AH-adjuvanted PcpA (25 μg), AH-adjuvanted PhtD-PcpA (10, 25, or 50 μg each), unadjuvanted PhtD-PcpA (25 μg each), or placebo as 2 injections 30 days apart. Assignment of successive dose cohorts was made after blinded safety reviews after each dose level. Safety endpoints included rates of solicited injection site and systemic reactions, unsolicited adverse events (AEs), serious AEs (SAEs), and safety laboratory tests. Immunogenicity endpoints included levels of anti-PhtD and anti-PcpA antibodies (ELISA). Six adults 18-50 years of age were included in the pilot study and 125 in the main study. No obvious increases in solicited reactions or unsolicited AEs were reported with escalating doses (adjuvanted vaccine) after either injection, or with repeated administration. Adjuvanted vaccine candidates were associated with a higher incidence of solicited reactions (particularly injection site reactions) than unadjuvanted vaccine candidates. However, no SAE or discontinuation due to an AE occurred. Geometric mean concentrations of anti-PhtD IgG and anti-PcpA IgG increased significantly after injection 2 compared with injection 1 at each dose level. No enhancement of immune responses was shown with adjuvanted vaccine candidates compared with the unadjuvanted vaccine candidate. In the dose-escalating comparison, a plateau effect at the 25 μg dose was observed as measured by geometric mean concentrations and by fold increases. Promising safety profiles and immunogenicity of these monovalent and bivalent protein vaccine candidates were demonstrated in an adult population (ClinicalTrials.gov registry no. NCT01444339). Copyright © 2012 Elsevier Ltd. All rights reserved.

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

Heijst, T C F van; Hoekstra, N; Philippens, M E P

Purpose: The Utrecht MRI-linac (MRL) design enables new MR-guided radiotherapy (RT) approaches. This is a feasibility study for a single-fraction high dose (boost) to individual lymph nodes (LNs) in breast-cancer patients, after breast-conserving surgery (BCS) and hypofractionated whole-breast irradiation (WBI) with conventional axillary RT (AxRT). Methods: After written informed consent, 5 breast-cancer patients (cT1-3N0) were enrolled (NL500460.041.14 trial) and underwent 1.5T MRI in supine RT position, after BCS. Axillary levels, based on ESTRO guidelines, and organs-at-risk (OARs) – including lungs, chest wall, plexus and neurovascular bundle (NVB) – were delineated. Pseudo-CT scans (pCTs) were generated by HU bulk-assignment of water,more » lung, and air. With Monaco treatment-planning software (TPS Elekta), VMAT plans were generated for simultaneous WBI and AxRT, prescribing 16×2.66=42.56Gy (V95%>99% V107%<2cc). Two scenarios were considered: AxRT of levels I–II; AxRT of levels I–IV, depending on boost location. Per patient, 4 LNs with varying axillary locations were selected, delineated, and expanded to PTV with 2-mm margin. Using dedicated MRL TPS, accounting for magnetic-field effects, an IMRT 1×8.5Gy boost was simulated for each LN, to achieve a total target dose of 66Gy EQD2 (α/β=3.5Gy). WBI/ART doses and boost doses were added, and evaluated in EQD2. Results: For all scenarios, 1×8.5Gy boosts could be simulated within clinical constraints for a 66Gy total dose, in addition to WBI/AxRT. LN target coverage was excellent (V95%>95%, mean >8.5Gy). Additional dose to OARs was limited. Conclusion: Our study explored the concept of LN boosting using on-line MRI guidance. It is feasible to boost individual axillary LNs – with 2-mm margin – with an additional 1×8.5Gy, in all axillary levels, within clinical constraints. This may lead to more personalized RT approaches for patients with involved LNs and may reduce RT-induced toxicity, or the need for axillary surgery. Other LN boost strategies, including dose escalation, are under investigation.« less

Bag-of-features based medical image retrieval via multiple assignment and visual words weighting.

PubMed

Wang, Jingyan; Li, Yongping; Zhang, Ying; Wang, Chao; Xie, Honglan; Chen, Guoling; Gao, Xin

2011-11-01

Bag-of-features based approaches have become prominent for image retrieval and image classification tasks in the past decade. Such methods represent an image as a collection of local features, such as image patches and key points with scale invariant feature transform (SIFT) descriptors. To improve the bag-of-features methods, we first model the assignments of local descriptors as contribution functions, and then propose a novel multiple assignment strategy. Assuming the local features can be reconstructed by their neighboring visual words in a vocabulary, reconstruction weights can be solved by quadratic programming. The weights are then used to build contribution functions, resulting in a novel assignment method, called quadratic programming (QP) assignment. We further propose a novel visual word weighting method. The discriminative power of each visual word is analyzed by the sub-similarity function in the bin that corresponds to the visual word. Each sub-similarity function is then treated as a weak classifier. A strong classifier is learned by boosting methods that combine those weak classifiers. The weighting factors of the visual words are learned accordingly. We evaluate the proposed methods on medical image retrieval tasks. The methods are tested on three well-known data sets, i.e., the ImageCLEFmed data set, the 304 CT Set, and the basal-cell carcinoma image set. Experimental results demonstrate that the proposed QP assignment outperforms the traditional nearest neighbor assignment, the multiple assignment, and the soft assignment, whereas the proposed boosting based weighting strategy outperforms the state-of-the-art weighting methods, such as the term frequency weights and the term frequency-inverse document frequency weights.

A randomized clinical trial of the efficacy of single versus double-daily dose of oral iron for prevention of iron deficiency anemia in women with twin gestations.

PubMed

Ali, Mohammed K; Abbas, Ahmed M; Abdelmagied, Ahmed M; Mohammed, Ghada E; Abdalmageed, Osama S

2017-12-01

The study aims to assess the efficacy of single versus double-daily oral iron dose on prevention of iron deficiency anemia in women with twin gestations. A randomized controlled trial (NCT02858505) conducted at Woman's Health Hospital, Assiut, Egypt, between August 2015 and June 2016 included 120 non-anemic pregnant women with twin gestations in the first trimester. Women were randomly assigned to either group I (27 mg elemental iron) or group II (54 mg elemental iron) daily starting from 12 weeks of pregnancy till 36 weeks. The primary outcomes included the mean level of hemoglobin, hematocrit and serum ferritin at 36 weeks' gestation. Both iron doses maintained the mean hemoglobin and hematocrit within the normal level from 12 weeks to 36 weeks (p = 0.378 and p = 0.244, respectively). However, the mean serum ferritin level was higher in group II than group I (p = 0.000) at 36 weeks' gestation. Moreover, women in group II reported more side effects than group I at 36 weeks' gestation. Doubling the prophylactic iron dose is comparable to single dose in the prevention of iron deficiency anemia among women with twin gestations with more side effects.

Comparative assessment of efficacy of two different pretreatment single oral doses of betamethasone on inter-appointment and postoperative discomfort: An in vivo clinical evaluation

PubMed Central

Gyanani, Hitesh; Chhabra, Naveen; Parmar, Ghanshyam R.

2016-01-01

Aim: Study aimed to evaluate the efficacy of two different pretreatment single oral doses of betamethasone on the incidence of inter-appointment flare up and postoperative discomfort. Materials and Methods: Fifty-four patients aged 18–59 years requiring endodontic treatment were selected and randomly assigned to three groups; single pretreatment oral dose of placebo or betamethasone in two different oral doses of 0.5 mg and 1 mg, respectively. Endodontic therapy was completed in two visits using triple antibiotic paste as intracanal medicament. Patients were given a questionnaire to record their pain at 1, 2, 3, and 7 days after treatment. In the second visit, obturation was done, and the patients were again instructed to record their pain scores after treatment and discharged. The verbal rating scale was used for recording the pain scores. Statistical analysis was done using ANOVA and the Friedman test. Results: 0.5 mg betamethasone group showed least mean pain scores among all experimental groups; however, there was no statistically significant difference between any of the groups (P > 0.05). Conclusion: Pretreatment single oral dose of betamethasone is an effective in managing endodontic flare-ups; however, the results were statistically insignificant. PMID:27994320

Monte Carlo dose calculation in dental amalgam phantom

PubMed Central

Aziz, Mohd. Zahri Abdul; Yusoff, A. L.; Osman, N. D.; Abdullah, R.; Rabaie, N. A.; Salikin, M. S.

2015-01-01

It has become a great challenge in the modern radiation treatment to ensure the accuracy of treatment delivery in electron beam therapy. Tissue inhomogeneity has become one of the factors for accurate dose calculation, and this requires complex algorithm calculation like Monte Carlo (MC). On the other hand, computed tomography (CT) images used in treatment planning system need to be trustful as they are the input in radiotherapy treatment. However, with the presence of metal amalgam in treatment volume, the CT images input showed prominent streak artefact, thus, contributed sources of error. Hence, metal amalgam phantom often creates streak artifacts, which cause an error in the dose calculation. Thus, a streak artifact reduction technique was applied to correct the images, and as a result, better images were observed in terms of structure delineation and density assigning. Furthermore, the amalgam density data were corrected to provide amalgam voxel with accurate density value. As for the errors of dose uncertainties due to metal amalgam, they were reduced from 46% to as low as 2% at d80 (depth of the 80% dose beyond Zmax) using the presented strategies. Considering the number of vital and radiosensitive organs in the head and the neck regions, this correction strategy is suggested in reducing calculation uncertainties through MC calculation. PMID:26500401

Dose and time dependent ototoxicity of aspartame in rats.

PubMed

Ozturan, Orhan; Dogan, Remzi; Tugrul, Selahattin; Gedik, Ozge; Sjostrand, Alev Pektas; Yildirim, Yavuz Selim

2017-04-01

Low-dose administration of Aspartame (Ap) did not produce a significant ototoxic effect at the end of the 6th month. However, duration of the ototoxic effect is shortened and severity of the effect is increased as dose and duration of Ap administration is increased. While Ap toxicity has been studied in short- and long-term studies, its effects on hearing have not been investigated. This study was conducted to evaluate the effects of long-term consumption of Ap administered in various doses on hearing status of rats. The study included 54 female Wistar Albino rats. Ap was given for 6 months to the rats. The groups were assigned according to levels of Ap dosage. DPOAE and ABR tests were utilized for serial hearing evaluations. Serial hearing measurement times were designed as baseline, 1st week, 2nd week, 1st, 2nd, 3rd, and 6th months. While audiological parameters deteriorated with 100 mg/kg/day dose after the 3rd month, ABR thresholds were elevated and DPOAE values were significantly decreased in 500 mg/kg/day and 1000 mg/kg/day applications after the 2nd month. In 2000 mg/kg/day and 4000 mg/kg/day applications, deteriorations in audiological parameters were detected as early as the first and second months; respectively.

Effect of aqueous fruit extract of Xylopia aethiopica on intestinal fluid and glucose transfer in rats.

PubMed

Okwari, O O; Nneli, R O; Osim, E E

2010-11-28

Intestinal fluid and glucose absorption was studied in jejunal and ileal segments in Xylopia aethiopica fed rats using inverted sac technique. Thirty male Wistar rats were assigned into three groups of 10 rats each; control, 100mg/kg and 200mg/kg Xylopia aethiopica treated groups. The control group received normal rat chow and water while the low dose and high dose groups received oral administration of Xylopia aethiopica extract at doses of 100mg/kg and 200mg/kg body weight respectively in addition to daily rat chow and water intake for 28 days. The results showed significant reduction and increase in fluid transfer in the jejunum and ileum respectively compared with control. 100mg/kg increased gut fluid uptake in the ileum while 200mg/kg treatment reduced uptake in jejunum compared with control. Both doses had significantly increased jejunal and ileal glucose transfer. Gut glucose uptake was increased in jejunum and ileum of Xylopia aethiopica treated groups. Both doses increased the crypt depth but significantly decreased the villus height in the ileum. In conclusion, increased ileal gut fluid uptake may be beneficial in diarrheal state while an enhanced glucose uptake implies that glucose substrate may be made available to cells for synthesize of ATP for cellular activities.

Safety, tolerability, and cerebrospinal fluid penetration of ursodeoxycholic Acid in patients with amyotrophic lateral sclerosis.

PubMed

Parry, Gareth J; Rodrigues, Cecilia M P; Aranha, Marcia M; Hilbert, Sarah J; Davey, Cynthia; Kelkar, Praful; Low, Walter C; Steer, Clifford J

2010-01-01

Amyotrophic lateral sclerosis is a progressive degenerative disease, which typically leads to death in 3 to 5 years. Neuronal cell death offers a potential target for therapeutic intervention. Ursodeoxycholic acid is a cytoprotective, endogenous bile acid that has been shown to be neuroprotective in experimental Huntington and Alzheimer diseases, retinal degeneration, and ischemic and hemorrhagic stroke. The objective of this research was to study the safety and the tolerability of ursodeoxycholic acid in amyotrophic lateral sclerosis and document effective and dose-dependent cerebrospinal fluid penetration. Eighteen patients were randomly assigned to receive ursodeoxycholic acid at doses of 15, 30, and 50 mg/kg of body weight per day. Serum and cerebrospinal fluid were obtained for analysis after 4 weeks of treatment. Treatment-emergent clinical and laboratory events were monitored weekly. Our data indicated that ursodeoxycholic acid is well tolerated by all subjects at all doses. We also showed that ursodeoxycholic acid is well absorbed after oral administration and crosses the blood-brain barrier in a dose-dependent manner. These results show excellent safety and tolerability of ursodeoxycholic acid. The drug penetrates the cerebrospinal fluid in a dose-dependent manner. A large, placebo-controlled clinical trial is needed to assess the efficacy of ursodeoxycholic acid in treating amyotrophic lateral sclerosis.

Assigning king eiders to wintering regions in the Bering Sea using stable isotopes of feathers and claws

USGS Publications Warehouse

Oppel, S.; Powell, A.N.

2008-01-01

Identification of wintering regions for birds sampled during the breeding season is crucial to understanding how events outside the breeding season may affect populations. We assigned king eiders captured on breeding grounds in northern Alaska to 3 broad geographic wintering regions in the Bering Sea using stable carbon and nitrogen isotopes obtained from head feathers. Using a discriminant function analysis of feathers obtained from birds tracked with satellite transmitters, we estimated that 88 % of feathers were assigned to the region in which they were grown. We then assigned 84 birds of unknown origin to wintering regions based on their head feather isotope ratios, and tested the utility of claws for geographic assignment. Based on the feather results, we estimated that similar proportions of birds in our study area use each of the 3 wintering regions in the Bering Sea. These results are in close agreement with estimates from satellite telemetry and show the usefulness of stable isotope signatures of feathers in assigning marine birds to geographic regions. The use of claws is currently limited by incomplete understanding of claw growth rates. Data presented here will allow managers of eiders, other marine birds, and marine mammals to assign animals to regions in the Bering Sea based on stable isotope signatures of body tissues. ?? Inter-Research 2008.

In vitro dissolution of strontium titanate to estimate clearance rates in human lungs

NASA Astrophysics Data System (ADS)

Anderson, Jeri Lynn

At the In-Tank Precipitation facility (ITP) of the Savannah River Site, strontium and other radionuclides are removed from high-level radioactive waste and sent to the Defense Waste Processing Facility (DWPF). Strontium removal is accomplished by ion-exchange using monosodium titanate slurry which creates a form of strontium titanate with unknown solubility characteristics. In the case of accidental inhalation of a compound containing radioactive strontium, the ICRP, in Publication 66, recommends using default values for rates of absorption into body fluids at the lungs in the absence of reliable human or animal data. The default value depends on whether the absorption is considered to be fast, moderate, or slow (Type F, M, or S). Current dose assessment for an individual upon inadvertent exposure to airborne radioactive strontium assumes that all strontium compounds are Type F (soluble) or Type S (insoluble). Pure high-fired strontium titanate (SrTiOsb3) is considered Type S. The purpose of this project was to determine the solubility of strontium titanate in the form created at the ITP facility. An in vitro dissolution study was done with a precipitate simulant and with several types of strontium titanate and the results were compared. An in vivo study was also performed with high-fired SrTiOsb3 in rats. The data from both studies were used independently to assign the compounds to absorption type based on criteria specified in ICRP 71. Results of the in vitro studies showed that the DWPF simulant should be assigned to Type M and the strontium titanate should be assigned to Type S. It is possible the difference in the DWPF simulant is due to the other chemicals present. Results of the in vivo study verified that SrTiOsb3 should be assigned to Type S. Lung clearance data of SrTiOsb3 from rats showed that 85% cleared within the first 24 hours and the remaining 15% with a half-time of 130 days. The initial rapid clearance is attributed to deposition in airways as compared to the alveolar region.

Positron Emission Tomography-Guided Therapy of Aggressive Non-Hodgkin Lymphomas (PETAL): A Multicenter, Randomized Phase III Trial.

PubMed

Dührsen, Ulrich; Müller, Stefan; Hertenstein, Bernd; Thomssen, Henrike; Kotzerke, Jörg; Mesters, Rolf; Berdel, Wolfgang E; Franzius, Christiane; Kroschinsky, Frank; Weckesser, Matthias; Kofahl-Krause, Dorothea; Bengel, Frank M; Dürig, Jan; Matschke, Johannes; Schmitz, Christine; Pöppel, Thorsten; Ose, Claudia; Brinkmann, Marcus; La Rosée, Paul; Freesmeyer, Martin; Hertel, Andreas; Höffkes, Heinz-Gert; Behringer, Dirk; Prange-Krex, Gabriele; Wilop, Stefan; Krohn, Thomas; Holzinger, Jens; Griesshammer, Martin; Giagounidis, Aristoteles; Raghavachar, Aruna; Maschmeyer, Georg; Brink, Ingo; Bernhard, Helga; Haberkorn, Uwe; Gaska, Tobias; Kurch, Lars; van Assema, Daniëlle M E; Klapper, Wolfram; Hoelzer, Dieter; Geworski, Lilli; Jöckel, Karl-Heinz; Scherag, André; Bockisch, Andreas; Rekowski, Jan; Hüttmann, Andreas

2018-05-11

Purpose Interim positron emission tomography (PET) using the tracer, [ 18 F]fluorodeoxyglucose, may predict outcomes in patients with aggressive non-Hodgkin lymphomas. We assessed whether PET can guide therapy in patients who are treated with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP). Patients and Methods Newly diagnosed patients received two cycles of CHOP-plus rituximab (R-CHOP) in CD20-positive lymphomas-followed by a PET scan that was evaluated using the ΔSUV max method. PET-positive patients were randomly assigned to receive six additional cycles of R-CHOP or six blocks of an intensive Burkitt's lymphoma protocol. PET-negative patients with CD20-positive lymphomas were randomly assigned or allocated to receive four additional cycles of R-CHOP or the same treatment with two additional doses rituximab. The primary end point was event-free survival time as assessed by log-rank test. Results Interim PET was positive in 108 (12.5%) and negative in 754 (87.5%) of 862 patients treated, with statistically significant differences in event-free survival and overall survival. Among PET-positive patients, 52 were randomly assigned to R-CHOP and 56 to the Burkitt protocol, with 2-year event-free survival rates of 42.0% (95% CI, 28.2% to 55.2%) and 31.6% (95% CI, 19.3% to 44.6%), respectively (hazard ratio, 1.501 [95% CI, 0.896 to 2.514]; P = .1229). The Burkitt protocol produced significantly more toxicity. Of 754 PET-negative patients, 255 underwent random assignment (129 to R-CHOP and 126 to R-CHOP with additional rituximab). Event-free survival rates were 76.4% (95% CI, 68.0% to 82.8%) and 73.5% (95% CI, 64.8% to 80.4%), respectively (hazard ratio, 1.048 [95% CI, 0.684 to 1.606]; P = .8305). Outcome prediction by PET was independent of the International Prognostic Index. Results in diffuse large B-cell lymphoma were similar to those in the total group. Conclusion Interim PET predicted survival in patients with aggressive lymphomas treated with R-CHOP. PET-based treatment intensification did not improve outcome.

A comparative study of fluoxetine, moclobemide, and tianeptine in the treatment of posttraumatic stress disorder following an earthquake.

PubMed

Onder, E; Tural, U; Aker, T

2006-04-01

Although antidepressant drugs have been proven as an effective treatment for posttraumatic stress disorder (PTSD), there are few comparative studies of antidepressants that are acting on different neurotransmitters. The main aim of this study is to compare the efficacy of different class of antidepressant drugs on the PTSD. SUBJECTS/MATERIALS AND METHODS: In this open label study, the patients who met DSM-IV criteria for PTSD were randomly assigned to flexible doses of fluoxetine, moclobemide, or tianeptine. After the first assessment, consecutive assessments were performed at the end of weeks 2, 4, 8, and 12 using clinician administered PTSD scale (CAPS) and Clinical Global Impression of Severity (CGI-S). Changes in the total score of CAPS and sub-scale scores of symptom clusters (re-experience, avoidance, and hyperarousal) were the main output of efficacy. All statistics were based on intention-to-treat and last-observation-carried-forward (LOCF) principles. Thirty-eight patients were assigned to fluoxetine, 35 patients were assigned to moclobemide, and 30 patients were assigned to tianeptine group. Gender distributions and mean ages of the treatment groups were not significantly different. Drop-out rates due to an adverse events or unknown reasons were not significantly different among fluoxetine (18.4%), moclobemide (14.3%), and tianeptine (20.0%) groups. All three treatments has led to a significant improvement in PTSD severity assessed with CAPS total score (ANOVA P < 0.001). Similarly, total scores of re-experiencing, avoidance, and hyperarousal clusters that are subscales of CAPS were significantly reduced by all three treatments (with ANOVA all P values < 0.001). There was not significant difference in terms of treatment effect between three groups. Treatment groups showed very similar improvement on all ratings scales. The findings support that fluoxetine, moclobemide, and tianeptine are all effective in the treatment of PTSD. Different mechanisms of action for these antidepressant drugs might result in the same common neurochemical end point. However, further studies using different classes of antidepressant drugs are needed.

The effect of grape seed extract on estrogen levels of postmenopausal women: a pilot study.

PubMed

Wahner-Roedler, Dietlind L; Bauer, Brent A; Loehrer, Laura L; Cha, Stephen S; Hoskin, Tanya L; Olson, Janet E

2014-06-01

The role of estrogens in breast cancer (BC) development is widely accepted, leading to the development of selective estrogen receptor modulators and aromatase inhibitors for BC treatment and prevention. However, because of potential adverse effects, healthy women with high risk of BC are hesitant to take them. Preliminary evidence from animal studies shows that grapes may have an aromatase-inhibiting effect, decreasing estrogen synthesis and increasing androgen precursors. We conducted a randomized, double-blind, dose-finding early-phase trial on the effect of grape seed extract (GSE) on estrogen levels. Postmenopausal women who met study inclusion criteria (N = 46) were randomly assigned to daily GSE at a dose of 200, 400, 600, or 800 mg for 12 weeks. Primary outcome was change in plasma levels of estrogen conjugates from baseline to 12 weeks posttreatment. Thirty-nine participants (84.8%) completed the study. GSE in the 4 daily doses did not significantly decrease estrogen or increase androgen precursors.

Au Colloids Formed by Ion Implantation in Muscovite Mica Studied by Vibrational and Electronic Spectroscopes and Atomic Force Microscopy

NASA Technical Reports Server (NTRS)

Tung, Y. S.; Henderson, D. O.; Mu, R.; Ueda, A.; Collins, W. E.; White, C. W.; Zuhr, R. A.; Zhu, Jane G.

1997-01-01

Au was implanted into the (001) surface of Muscovite mica at an energy of 1.1 MeV and at doses of 1, 3, 6, and 10 x 10(exp 16) ions/cu cm. Optical spectra of the as-implanted samples revealed a peak at 2.28 eV (545 nm) which is attributed to the surface plasmon absorption of Au colloids. The infrared reflectance measurements show a decreasing reflectivity with increasing ion dose in the Si-O stretching region (900-1200 /cm). A new peak observed at 967 /cm increases with the ion dose and is assigned to an Si-O dangling bond. Atomic force microscopy images of freshly cleaved samples implanted with 6 and 10 x 10(exp 16) ions/sq cm indicated metal colloids with diameters between 0.9- 1.5 nm. AFM images of the annealed samples showed irregularly shaped structures with a topology that results from the fusion of smaller colloids.

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

PubMed

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

2000-01-01

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

Subjective and physiological effects after controlled Sativex and oral THC administration.

PubMed

Karschner, E L; Darwin, W D; McMahon, R P; Liu, F; Wright, S; Goodwin, R S; Huestis, M A

2011-03-01

Sativex is a cannabis-plant extract delivering nearly 1:1 Δ(9)-tetrahydrocannabinol (THC) and cannabidiol (CBD) by oromucosal spray. It has been suggested that CBD attenuates THC-induced tachycardia, anxiety, and euphoria. In this study, pharmacodynamic effects were compared over 10.5 h in nine cannabis smokers randomly assigned to receive placebo, 5 and 15 mg oral synthetic THC, and low (5.4 mg THC, 5.0 mg CBD) and high (16.2 mg THC, 15.0 mg CBD) doses of Sativex. At therapeutic doses, no substantial CBD-induced modulation of THC's effects was evident. Oral THC and Sativex produced similar, clinically insignificant increases in heart rate, anxiety, and "good drug effects" with no serious adverse events. Oral and oromucosal THC have slower absorption, lower rate of THC delivery to the brain, and fewer associated adverse events as compared with smoked cannabis. These results indicate that Sativex has a pharmacodynamic safety profile comparable to that of oral THC at low, therapeutic doses.

Subjective and Physiological Effects After Controlled Sativex and Oral THC Administration

PubMed Central

Karschner, EL; Darwin, WD; McMahon, RP; Liu, F; Wright, S; Goodwin, RS; Huestis, MA

2013-01-01

Sativex is a cannabis-plant extract delivering nearly 1:1 Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD) by oromucosal spray. It has been suggested that CBD attenuates THC-induced tachycardia, anxiety, and euphoria. In this study, pharmacodynamic effects were compared over 10.5 h in nine cannabis smokers randomly assigned to receive placebo, 5 and 15 mg oral synthetic THC, and low (5.4 mg THC, 5.0 mg CBD) and high (16.2 mg THC, 15.0 mg CBD) doses of Sativex. At therapeutic doses, no substantial CBD-induced modulation of THC's effects was evident. Oral THC and Sativex produced similar, clinically insignificant increases in heart rate, anxiety, and “good drug effects” with no serious adverse events. Oral and oromucosal THC have slower absorption, lower rate of THC delivery to the brain, and fewer associated adverse events as compared with smoked cannabis. These results indicate that Sativex has a pharmacodynamic safety profile comparable to that of oral THC at low, therapeutic doses. PMID:21289620

Impacts of high resolution data on traveler compliance levels in emergency evacuation simulations

DOE PAGES

Lu, Wei; Han, Lee D.; Liu, Cheng; ...

2016-05-05

In this article, we conducted a comparison study of evacuation assignment based on Traffic Analysis Zones (TAZ) and high resolution LandScan USA Population Cells (LPC) with detailed real world roads network. A platform for evacuation modeling built on high resolution population distribution data and activity-based microscopic traffic simulation was proposed. This platform can be extended to any cities in the world. The results indicated that evacuee compliance behavior affects evacuation efficiency with traditional TAZ assignment, but it did not significantly compromise the performance with high resolution LPC assignment. The TAZ assignment also underestimated the real travel time during evacuation. Thismore » suggests that high data resolution can improve the accuracy of traffic modeling and simulation. The evacuation manager should consider more diverse assignment during emergency evacuation to avoid congestions.« less

Integrated consensus-based frameworks for unmanned vehicle routing and targeting assignment

NASA Astrophysics Data System (ADS)

Barnawi, Waleed T.

Unmanned aerial vehicles (UAVs) are increasingly deployed in complex and dynamic environments to perform multiple tasks cooperatively with other UAVs that contribute to overarching mission effectiveness. Studies by the Department of Defense (DoD) indicate future operations may include anti-access/area-denial (A2AD) environments which limit human teleoperator decision-making and control. This research addresses the problem of decentralized vehicle re-routing and task reassignments through consensus-based UAV decision-making. An Integrated Consensus-Based Framework (ICF) is formulated as a solution to the combined single task assignment problem and vehicle routing problem. The multiple assignment and vehicle routing problem is solved with the Integrated Consensus-Based Bundle Framework (ICBF). The frameworks are hierarchically decomposed into two levels. The bottom layer utilizes the renowned Dijkstra's Algorithm. The top layer addresses task assignment with two methods. The single assignment approach is called the Caravan Auction Algorithm (CarA) Algorithm. This technique extends the Consensus-Based Auction Algorithm (CBAA) to provide awareness for task completion by agents and adopt abandoned tasks. The multiple assignment approach called the Caravan Auction Bundle Algorithm (CarAB) extends the Consensus-Based Bundle Algorithm (CBBA) by providing awareness for lost resources, prioritizing remaining tasks, and adopting abandoned tasks. Research questions are investigated regarding the novelty and performance of the proposed frameworks. Conclusions regarding the research questions will be provided through hypothesis testing. Monte Carlo simulations will provide evidence to support conclusions regarding the research hypotheses for the proposed frameworks. The approach provided in this research addresses current and future military operations for unmanned aerial vehicles. However, the general framework implied by the proposed research is adaptable to any unmanned vehicle. Civil applications that involve missions where human observability would be limited could benefit from the independent UAV task assignment, such as exploration and fire surveillance are also notable uses for this approach.

Beneficial effects of Korean red ginseng on lymphocyte DNA damage, antioxidant enzyme activity, and LDL oxidation in healthy participants: a randomized, double-blind, placebo-controlled trial.

PubMed

Kim, Ji Young; Park, Ju Yeon; Kang, Hee Jung; Kim, Oh Yoen; Lee, Jong Ho

2012-07-17

The reported health benefits of Korean red ginseng (KRG) include antioxidant, antitumor, antimutagenic, and immunomodulatory activities; however, the effects on oxidative stress have not yet been evaluated. Therefore, we assessed the effect of KRG on antioxidant enzymes and oxidative stress markers in humans. We conducted a randomized, double-blind, placebo-controlled study with three groups, including placebo, low-dose (3 g/day), and high-dose (6 g/day), which were randomly assigned to healthy subjects aged 20-65 years. Lymphocyte DNA damage, antioxidative enzyme activity, and lipid peroxidation were assessed before and after the 8-week supplementation. Fifty-seven subjects completed the protocol. Plasma superoxide dismutase (SOD) activity after the 8-week KRG supplementation was significantly higher in the low-and high-dose groups compared to baseline. Plasma glutathione peroxidase (GPx) and catalase activities were also increased after the high-dose supplementation. Furthermore, the DNA tail length and tail moment were significantly reduced after the supplementation (low-dose and high-dose), and plasma oxidized low-density lipoprotein (LDL) levels were reduced in low-dose and high-dose groups, but increased in the placebo group. The net changes in oxidized LDL after the supplementation differed significantly between both KRG supplementation groups and the placebo group. Net changes in GPx, SOD and catalase activities, and DNA tail length and tail moment were significantly different between the high-dose group and the placebo group. Additionally, the net changes in urinary 8-epi-PGF(2α) were significantly different between the KRG supplementation groups and the placebo group. KRG supplementation may attenuate lymphocyte DNA damage and LDL oxidation by upregulating antioxidant enzyme activity.

Race influences warfarin dose changes associated with genetic factors

PubMed Central

Brown, Todd M.; Yan, Qi; Thigpen, Jonathan L.; Shendre, Aditi; Liu, Nianjun; Hill, Charles E.; Arnett, Donna K.; Beasley, T. Mark

2015-01-01

Warfarin dosing algorithms adjust for race, assigning a fixed effect size to each predictor, thereby attenuating the differential effect by race. Attenuation likely occurs in both race groups but may be more pronounced in the less-represented race group. Therefore, we evaluated whether the effect of clinical (age, body surface area [BSA], chronic kidney disease [CKD], and amiodarone use) and genetic factors (CYP2C9*2, *3, *5, *6, *11, rs12777823, VKORC1, and CYP4F2) on warfarin dose differs by race using regression analyses among 1357 patients enrolled in a prospective cohort study and compared predictive ability of race-combined vs race-stratified models. Differential effect of predictors by race was assessed using predictor-race interactions in race-combined analyses. Warfarin dose was influenced by age, BSA, CKD, amiodarone use, and CYP2C9*3 and VKORC1 variants in both races, by CYP2C9*2 and CYP4F2 variants in European Americans, and by rs12777823 in African Americans. CYP2C9*2 was associated with a lower dose only among European Americans (20.6% vs 3.0%, P < .001) and rs12777823 only among African Americans (12.3% vs 2.3%, P = .006). Although VKORC1 was associated with dose decrease in both races, the proportional decrease was higher among European Americans (28.9% vs 19.9%, P = .003) compared with African Americans. Race-stratified analysis improved dose prediction in both race groups compared with race-combined analysis. We demonstrate that the effect of predictors on warfarin dose differs by race, which may explain divergent findings reported by recent warfarin pharmacogenetic trials. We recommend that warfarin dosing algorithms should be stratified by race rather than adjusted for race. PMID:26024874