Cumulative or delayed nephrotoxicity after cisplatin (DDP) treatment.

PubMed

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

1986-04-30

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

Single-dose pharmacokinetic properties of esomeprazole in children aged 1 - 11 years with endoscopically proven GERD: a randomized, open-label study.

PubMed

Youssef, Nader N; Tron, Eduardo; Tolia, Vasundhara; Hamer-Maansson, Jennifer E; Lundborg, Per; Illueca, Marta

2014-11-01

To assess the overall exposure after a single dose of esomeprazole in children with gastroesophageal reflux disease (GERD). Oral esomeprazole administered as an intact capsule with 30 - 180 mL of water, or as an opened capsule mixed with as much as 1 tablespoon of applesauce followed by 30 - 180 mL of water. In this randomized, open-label study of children aged 1 - 11 years with endoscopically proven GERD, patients weighing 8 - < 20 kg were randomized to a single 5- or 10-mg oral dose of esomeprazole, and patients weighing >= 20 kg were randomized to a single 10- or 20-mg oral dose of esomeprazole. Esomeprazole exposure (AUC(0-∞)), AUC from zero to last measurable concentration (AUC(0-t)), maximum plasma concentration (C(max)), time to C(max) (t(max)), terminal-phase half-life, apparent oral clearance, and apparent volume of distribution were determined. 28 patients were randomized to receive esomeprazole: 14 patients weighing 8 to < 20 kg received esomeprazole 5 mg (n = 7) or 10 mg (n = 7), and 14 patients weighing ≥20 kg received esomeprazole 10 mg (n = 6) or 20 mg (n = 8). Children weighing 8 - < 20 kg had a 1.8-fold higher exposure with the 10-mg vs. 5-mg dose (AUC(0-∞), 1.32 vs. 0.73 μmol·h/L, respectively); children weighing ≥ 20 kg had a 4.4-fold higher exposure with the 20-mg vs. 10-mg dose (AUC(0-∞), 3.06 vs. 0.69 μmol·h/L). C(max) was 2.2-fold higher for the 10-mg vs. 5-mg dose (8 to < 20 kg) and 2.4-fold higher for the 20-mg vs.10-mg dose (>= 20 kg). The pharmacokinetics of single-dose esomeprazole were dose-dependent in children weighing >= 20 kg but not in children weighing 8 to < 20 kg.

High Dose Vitamin D Therapy for Chronic Pain in Children and Adolescents with Sickle Cell Disease: Results of a Randomized Double Blind Pilot Study

PubMed Central

I, Osunkwo; TR, Ziegler; J, Alvarez; C, McCracken; K, Cherry; CE, Osunkwo; SF, Ofori-Acquah; S, Ghosh; A, Ogunbobode; J, Rhodes; JR, Eckman; CD, Dampier; V, Tangpricha

2012-01-01

Summary We report results of a pilot study of high-dose vitamin D in sickle cell disease (SCD). Subjects were followed for 6 months after receiving a six-week course of oral high-dose cholecalciferol or placebo. Vitamin D insufficiency and deficiency was present at baseline in 82.5% and 52.5% of subjects, respectively. Subjects who received high-dose vitamin D achieved higher serum 25-hydroxyvitamin D, experienced fewer pain days per week, and had higher physical activity quality-of-life scores. These findings suggest a potential benefit of vitamin D in reducing the number of pain days in SCD. Larger prospective studies with longer duration are needed to confirm these effects. PMID:22924607

Methylene Blue Facilitates Memory Retention in Zebrafish in a Dose-Dependent Manner.

PubMed

Echevarria, David J; Caramillo, Erika M; Gonzalez-Lima, Francisco

2016-12-01

Methylene blue (MB) is an FDA-grandfathered drug with memory-enhancing effects at low doses, but opposite effects at high doses. We investigated the effects of four MB doses (0.1, 0.5, 5.0, or 10.0 μM) on zebrafish memory retention in the T-maze task. After training fish to swim into a certain arm of the T-maze, the fish were placed into a tank containing one of the four MB doses or a control tank containing blue food dye. Subsequently, fish were placed into the T-maze for memory retention testing. Results indicated that MB produced hormetic dose-response effects on memory. Fish that received the 0.5 μM dose performed significantly better at the T-maze than those that received higher doses. Fish who received 5.0 μM did not exhibit a significant difference in performance from control fish, and the fish that received the 10.0 μM dose performed significantly worse than lower doses. These findings support the utility of zebrafish in comparative research and their potential value for testing of MB and other neuropsychopharmacological treatments in animal models of memory disorders.

Sickle Trait in African-American Hemodialysis Patients and Higher Erythropoiesis-Stimulating Agent Dose

PubMed Central

Lacson, Eduardo K.; Kshirsagar, Abhijit V.; Key, Nigel S.; Hogan, Susan L.; Hakim, Raymond M.; Mooney, Ann; Jani, Chinu M.; Johnson, Curtis; Hu, Yichun; Falk, Ronald J.; Lazarus, J. Michael

2014-01-01

African Americans require higher doses of erythropoiesis-stimulating agents (ESAs) during dialysis to manage anemia, but the influence of sickle cell trait and other hemoglobinopathy traits on anemia in dialysis patients has not been adequately evaluated. We performed a cross-sectional study of a large cohort of adult African-American hemodialysis patients in the United States to determine the prevalence of hemoglobinopathy traits and quantify their influence on ESA dosing. Laboratory and clinical data were obtained over 6 months in 2011. Among 5319 African-American patients, 542 (10.2%) patients had sickle cell trait, and 129 (2.4%) patients had hemoglobin C trait; no other hemoglobinopathy traits were present. Sickle cell trait was more common in this cohort than the general African-American population (10.2% versus 6.5%–8.7%, respectively, P<0.05). Among 5002 patients (10.3% sickle cell trait and 2.4% hemoglobin C trait) receiving ESAs, demographic and clinical variables were similar across groups, with achieved hemoglobin levels being nearly identical. Patients with hemoglobinopathy traits received higher median doses of ESA than patients with normal hemoglobin (4737.4 versus 4364.1 units/treatment, respectively, P=0.02). In multivariable analyses, hemoglobinopathy traits associated with 13.2% more ESA per treatment (P=0.001). Within subgroups, sickle cell trait patients received 13.2% (P=0.003) higher dose and hemoglobin C trait patients exhibited a similar difference (12.9%, P=0.12). Sensitivity analyses using weight-based dosing definitions and separate logistic regression models showed comparable associations. Our findings suggest that the presence of sickle cell trait and hemoglobin C trait may explain, at least in part, prior observations of greater ESA doses administered to African-American dialysis patients relative to Caucasian patients. PMID:24459231

Hematological toxicity and therapeutic efficacy of lomustine in 20 tumor-bearing cats: critical assessment of a practical dosing regimen.

PubMed

Fan, Timothy M; Kitchell, Barbara E; Dhaliwal, Ravinder S; Jones, Pamela D; Hintermeister, John G; Paria, Biman C

2002-01-01

Twenty cats with spontaneously arising tumors received oral lomustine at a dose range of 32 to 59 mg/m2 every 21 days. Due to biohazard concerns associated with lomustine capsule reformulation, a standardized 10-mg capsule dosage was used for all cats regardless of body weight. Severe hematological toxicity was infrequent, with the incidence of either grade III or IV neutropenia and thrombocytopenia being 4.1% and 1.0%, respectively. Cats receiving higher cumulative doses of lomustine trended toward a greater likelihood for progressive neutropenia (P=0.07). Two cats with lymphoma, two cats with fibrosarcoma, and one cat with multiple myeloma achieved a measurable partial response to lomustine therapy. Cats treated with higher dosages of lomustine trended toward statistically significant higher response rates (P=0.07).

Inpatient management of sickle cell pain: a 'snapshot' of current practice.

PubMed

Miller, Scott T; Kim, Hae-Young; Weiner, Debra; Wager, Carrie G; Gallagher, Dianne; Styles, Lori; Dampier, Carlton D

2012-03-01

The Sickle Cell Disease Clinical Research Network (SCDCRN) designed the PROACTIVE Feasibility Study (ClinicalTrials.gov NCT00951808) to determine whether elevated serum levels of secretory phospholipase A2 (sPLA2) during hospitalization for pain would permit preemptive therapy of sickle cell acute chest syndrome (ACS) by blood transfusion. While PROACTIVE was not designed to assess pain management and was terminated early due to inadequate patient accrual, collection of clinical data allowed a "snapshot" of current care by expert providers. Nearly half the patients admitted for pain were taking hydroxyurea; hydroxyurea did not affect length of stay. Providers commonly administered parenteral opioid analgesia, usually morphine or hydromorphone, to adults and children, generally by patient-controlled analgesia (PCA). Adult providers were more likely to prescribe hydromorphone and did so at substantially higher morphine equivalent doses than were given to adults receiving morphine; the latter received doses similar to children who received either medication. All subjects treated with PCA received higher daily doses of opioids than those treated by time-contingent dosing. Physicians often restricted intravenous fluids to less than a maintenance rate and underutilized incentive spirometry, which reduces ACS in patients hospitalized for pain.

Inpatient Management of Sickle Cell Pain: a Snapshot of Current Practice

PubMed Central

Miller, Scott T.; Kim, Hae-Young; Weiner, Debra; Wager, Carrie G.; Gallagher, Dianne; Styles, Lori; Dampier, Carlton D.

2012-01-01

The Sickle Cell Disease Clinical Research Network (SCDCRN) designed the PROACTIVE Feasibility Study (ClinicalTrials.gov NCT00951808) to determine whether elevated serum levels of secretory phospholipase A2 (sPLA2) during hospitalization for pain would permit preemptive therapy of sickle cell acute chest syndrome (ACS) by blood transfusion. [1, 2] While PROACTIVE was not designed to assess pain management and terminated early due to inadequate patient accrual, collection of clinical data allowed a “snapshot” of current care by expert providers. Nearly half the patients admitted for pain were taking hydroxyurea; hydroxyurea did not affect length of stay. Providers commonly administered parenteral opioid analgesia, usually morphine or hydromorphone, to adults and children, generally by patient-controlled analgesia (PCA). Adult providers were more likely to prescribe hydromorphone and did so at substantially higher morphine equivalent doses than were given to adults receiving morphine; the latter received doses similar to children who received either medication. All subjects treated with PCA received higher daily doses of opioids than those treated by time-contingent dosing. Physicians often restricted intravenous fluids to less than a maintenance rate and underutilized incentive spirometry, which reduces ACS in patients hospitalized for pain. [3] PMID:22231150

TLD measurements of in vivo mammographic exposures and the calculated mean glandular dose across the United States.

PubMed

Gentry, J R; DeWerd, L A

1996-06-01

An analysis is presented of the exposures received by TLDs placed on the breasts of 4400 women obtaining mammograms at 170 institutions across the United States. Mean glandular dose and exposure were examined as a function of compressed breast thickness. The exposure and mean glandular dose were found to increase linearly with breast thickness. The mean glandular dose typically delivered by the institutions was well below the limit of 3.0 mGy for the 4.5-cm breast. However, some institutions tend to uniformly give higher doses. In such institutions approximately 25% of 4.5-cm-thick breasts received a mean glandular dose exceeding 3.0 mGy.

Dose escalation of definitive radiation is not associated with improved survival for cervical esophageal cancer: a National Cancer Data Base (NCDB) analysis.

PubMed

De, B; Rhome, R; Doucette, J; Buckstein, M

2017-04-01

For cervical esophageal cancer (CEC), National Comprehensive Cancer Network guidelines support RT to 50-50.4 Gy with chemotherapy but acknowledge higher doses may be appropriate. This study uses the National Cancer Database (NCDB) to characterize RT practices and identify if a dose-response relationship exists for overall survival (OS) for definitive treatment of CEC. We queried the NCDB for patients diagnosed with Stage I-III CEC from 2004 to 2013, and selected patients receiving definitive RT with doses between 50 and 74 Gy. Using multivariate logistic regression, the database was analyzed to determine factors associated with use of RT > 50.4 Gy. Patients were then stratified into three dose categories. Predictors of OS were analyzed with univariate and multivariate methods using the Kaplan-Meier curves, the log-rank test, and the Cox proportional hazards analysis. We stratified 789 patients with CEC who were treated with definitive radiation ± chemotherapy: 50-50.4 Gy ('standard'), >50.4 and <66 Gy ('medium'), and 66-74 Gy ('high'). Of these patients, 215 (27%) received standard doses, 375 (48%) received medium doses, and 199 (25%) received high doses. Patients with Medicaid insurance and those with Stage II disease were less likely (P < 0.05) to receive >50.4 Gy. Sex, histology, distance to treatment facility, and academic/community facility type were not significantly associated with receipt of >50.4 Gy. There was no association between dose and OS for the medium or high groups when using univariate analysis or analysis adjusted for demographic, facility, and clinical attributes. Stage III disease and the Charlson-Deyo scores of 1 or 2 were associated with higher mortality (P < 0.05), while female sex and use of chemotherapy were associated with lower mortality (P < 0.01). Nearly three-fourths of CEC patients in the United States are treated with RT > 50.4 Gy. Higher radiation doses were not associated with increased OS in CEC patients in the NCDB. © The Authors 2017. Published by Oxford University Press on behalf of International Society for Diseases of the Esophagus. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Serum tocopherol levels in very preterm infants after a single dose of vitamin E at birth.

PubMed

Bell, Edward F; Hansen, Nellie I; Brion, Luc P; Ehrenkranz, Richard A; Kennedy, Kathleen A; Walsh, Michele C; Shankaran, Seetha; Acarregui, Michael J; Johnson, Karen J; Hale, Ellen C; Messina, Lynn A; Crawford, Margaret M; Laptook, Abbot R; Goldberg, Ronald N; Van Meurs, Krisa P; Carlo, Waldemar A; Poindexter, Brenda B; Faix, Roger G; Carlton, David P; Watterberg, Kristi L; Ellsbury, Dan L; Das, Abhik; Higgins, Rosemary D

2013-12-01

Our aim was to examine the impact of a single enteral dose of vitamin E on serum tocopherol levels. The study was undertaken to see whether a single dose of vitamin E soon after birth can rapidly increase the low α-tocopherol levels seen in very preterm infants. If so, this intervention could be tested as a means of reducing the risk of intracranial hemorrhage. Ninety-three infants <27 weeks' gestation and <1000 g were randomly assigned to receive a single dose of vitamin E or placebo by gastric tube within 4 hours of birth. The vitamin E group received 50 IU/kg of vitamin E as dl-α-tocopheryl acetate (Aquasol E). The placebo group received sterile water. Blood samples were taken for measurement of serum tocopherol levels by high-performance liquid chromatography before dosing and 24 hours and 7 days after dosing. Eighty-eight infants received the study drug and were included in the analyses. The α-tocopherol levels were similar between the groups at baseline but higher in the vitamin E group at 24 hours (median 0.63 mg/dL vs. 0.42 mg/dL, P = .003) and 7 days (2.21 mg/dL vs 1.86 mg/dL, P = .04). There were no differences between groups in γ-tocopherol levels. At 24 hours, 30% of vitamin E infants and 62% of placebo infants had α-tocopherol levels <0.5 mg/dL. A 50-IU/kg dose of vitamin E raised serum α-tocopherol levels, but to consistently achieve α-tocopherol levels >0.5 mg/dL, a higher dose or several doses of vitamin E may be needed.

Reconstruction of paediatric organ doses from axial CT scans performed in the 1990s - range of doses as input to uncertainty estimates.

PubMed

Olerud, Hilde M; Toft, Benthe; Flatabø, Silje; Jahnen, Andreas; Lee, Choonsik; Thierry-Chef, Isabelle

2016-09-01

To assess the range of doses in paediatric CT scans conducted in the 1990s in Norway as input to an international epidemiology study: the EPI-CT study, http://epi-ct.iarc.fr/ . National Cancer Institute dosimetry system for Computed Tomography (NCICT) program based on pre-calculated organ dose conversion coefficients was used to convert CT Dose Index to organ doses in paediatric CT in the 1990s. Protocols reported from local hospitals in a previous Norwegian CT survey were used as input, presuming these were used without optimization for paediatric patients. Large variations in doses between different scanner models and local scan parameter settings are demonstrated. Small children will receive a factor of 2-3 times higher doses compared with adults if the protocols are not optimized for them. For common CT examinations, the doses to the active bone marrow, breast tissue and brain may have exceeded 30 mGy, 60 mGy and 100 mGy respectively, for the youngest children in the 1990s. The doses children received from non-optimised CT examinations during the 1990s are of such magnitude that they may provide statistically significant effects in the EPI-CT study, but probably do not reflect current practice. • Some organ doses from paediatric CT in the 1990s may have exceeded 100 mGy. • Small children may have received doses 2-3 times higher compared with adults. • Different scanner models varied by a factor of 2-3 in dose to patients. • Different local scan parameter settings gave dose variations of a factor 2-3. • Modern CTs and age-adjusted protocols will give much lower paediatric doses.

Possible benefit of consolidation therapy with high-dose cytarabine on overall survival of adults with non-promyelocytic acute myeloid leukemia.

PubMed

Azevedo, M C; Velloso, E D R P; Buccheri, V; Chamone, D A F; Dorlhiac-Llacer, P E

2015-02-01

In adults with non-promyelocytic acute myeloid leukemia (AML), high-dose cytarabine consolidation therapy has been shown to influence survival in selected patients, although the appropriate doses and schemes have not been defined. We evaluated survival after calculating the actual dose of cytarabine that patients received for consolidation therapy and divided them into 3 groups according to dose. We conducted a single-center, retrospective study involving 311 non-promyelocytic AML patients with a median age of 36 years (16-79 years) who received curative treatment between 1978 and 2007. The 131 patients who received cytarabine consolidation were assigned to study groups by their cytarabine dose protocol. Group 1 (n=69) received <1.5 g/m2 every 12 h on 3 alternate days for up to 4 cycles. The remaining patients received high-dose cytarabine (≥1.5 g/m2 every 12 h on 3 alternate days for up to 4 cycles). The actual dose received during the entire consolidation period in these patients was calculated, allowing us to divide these patients into 2 additional groups. Group 2 (n=27) received an intermediate-high-dose (<27 g/m2), and group 3 (n=35) received a very-high-dose (≥27 g/m2). Among the 311 patients receiving curative treatment, the 5-year survival rate was 20.2% (63 patients). The cytarabine consolidation dose was an independent determinant of survival in multivariate analysis; age, karyotype, induction protocol, French-American-British classification, and de novo leukemia were not. Comparisons showed that the risk of death was higher in the intermediate-high-dose group 2 (hazard ratio [HR]=4.51; 95% confidence interval [CI]: 1.81-11.21) and the low-dose group 1 (HR=4.43; 95% CI: 1.97-9.96) than in the very-high-dose group 3, with no significant difference between those two groups. Our findings indicated that very-high-dose cytarabine during consolidation in adults with non-promyelocytic AML may improve survival.

Possible benefit of consolidation therapy with high-dose cytarabine on overall survival of adults with non-promyelocytic acute myeloid leukemia

PubMed Central

Azevedo, M.C.; Velloso, E.D.R.P.; Buccheri, V.; Chamone, D.A.F.; Dorlhiac-Llacer, P.E.

2014-01-01

In adults with non-promyelocytic acute myeloid leukemia (AML), high-dose cytarabine consolidation therapy has been shown to influence survival in selected patients, although the appropriate doses and schemes have not been defined. We evaluated survival after calculating the actual dose of cytarabine that patients received for consolidation therapy and divided them into 3 groups according to dose. We conducted a single-center, retrospective study involving 311 non-promyelocytic AML patients with a median age of 36 years (16-79 years) who received curative treatment between 1978 and 2007. The 131 patients who received cytarabine consolidation were assigned to study groups by their cytarabine dose protocol. Group 1 (n=69) received <1.5 g/m2 every 12 h on 3 alternate days for up to 4 cycles. The remaining patients received high-dose cytarabine (≥1.5 g/m2 every 12 h on 3 alternate days for up to 4 cycles). The actual dose received during the entire consolidation period in these patients was calculated, allowing us to divide these patients into 2 additional groups. Group 2 (n=27) received an intermediate-high-dose (<27 g/m2), and group 3 (n=35) received a very-high-dose (≥27 g/m2). Among the 311 patients receiving curative treatment, the 5-year survival rate was 20.2% (63 patients). The cytarabine consolidation dose was an independent determinant of survival in multivariate analysis; age, karyotype, induction protocol, French-American-British classification, and de novo leukemia were not. Comparisons showed that the risk of death was higher in the intermediate-high-dose group 2 (hazard ratio [HR]=4.51; 95% confidence interval [CI]: 1.81-11.21) and the low-dose group 1 (HR=4.43; 95% CI: 1.97-9.96) than in the very-high-dose group 3, with no significant difference between those two groups. Our findings indicated that very-high-dose cytarabine during consolidation in adults with non-promyelocytic AML may improve survival. PMID:25517921

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

Pirlepesov, F.; Shin, J.; Moskvin, V. P.

Purpose: Dose weighted Linear Energy Transfer (LETd) analysis of critical structures may be useful in understanding the side effects of the proton therapy. The objective is to analyze the differences between LETd and dose distributions in brain tumor patients receiving double scattering proton therapy, to quantify LETd variation in critical organs, and to identify beam arrangements contributing to high LETd in critical organs. Methods: Monte Carlo simulations of 9 pediatric brain tumor patients were performed. The treatment plans were reconstructed with the TOPAS Monte Carlo code to calculate LETd and dose. The beam data were reconstructed proximal to the aperturemore » of the double scattering nozzle. The dose and LETd to target and critical organs including brain stem, optic chiasm, lens, optic nerve, pituitary gland, and hypothalamus were computed for each beam. Results: Greater variability in LETd compared to dose was observed in the brainstem for patients with a variety of tumor types including 5 patients with tumors located in the posterior fossa. Approximately 20%–44% brainstem volume received LETd of 5kev/µm or greater from beams within gantry angles 180°±30° for 5 patients treated with a 3 beam arrangement. Critical organs received higher LETd when located in the vicinity of the beam distal edge. Conclusion: This study presents a novel strategy in the evaluation of the proton treatment impact on critical organs. While the dose to critical organs is confined below the required limits, the LETd may have significant variation. Critical organs in the vicinity of beam distal edge receive higher LETd and depended on beam arrangement, e.g. in posterior fossa tumor treatment, brainstem receive higher LETd from posterior-anterior beams. This study shows importance of the LETd analysis of the radiation impact on the critical organs in proton therapy and may be used to explain clinical imaging observations after therapy.« less

Real-life GH dosing patterns in children with GHD, TS or born SGA: a report from the NordiNet® International Outcome Study

PubMed Central

Snajderova, Marta; Blair, Jo; Pournara, Effie; Pedersen, Birgitte Tønnes; Petit, Isabelle Oliver

2017-01-01

Objective To describe real-life dosing patterns in children with growth hormone deficiency (GHD), born small for gestational age (SGA) or with Turner syndrome (TS) receiving growth hormone (GH) and enrolled in the NordiNet International Outcome Study (IOS; Nbib960128) between 2006 and 2016. Design This non-interventional, multicentre study included paediatric patients diagnosed with GHD (isolated (IGHD) or multiple pituitary hormone deficiency (MPHD)), born SGA or with TS and treated according to everyday clinical practice from the Czech Republic (IGHD/MPHD/SGA/TS: n = 425/61/316/119), France (n = 1404/188/970/206), Germany (n = 2603/351/1387/411) and the UK (n = 259/60/87/35). Methods GH dosing was compared descriptively across countries and indications. Proportions of patients by GH dose group (low/medium/high) or GH dose change (decrease/increase/no change) during years 1 and 2 were also evaluated across countries and indications. Results In the Czech Republic, GH dosing was generally within recommended levels. In France, average GH doses were higher for patients with IGHD, MPHD and SGA than in other countries. GH doses in TS tended to be at the lower end of the recommended label range, especially in Germany and the UK; the majority of patients were in the low-dose group. A significant inverse association between baseline height standard deviation score and GH dose was shown (P < 0.05); shorter patients received higher doses. Changes in GH dose, particularly increases, were more common in the second (40%) than in the first year (25%). Conclusions GH dosing varies considerably across countries and indications. In particular, almost half of girls with TS received GH doses below practice guidelines and label recommendations. PMID:28522645

Do Patients Receiving Whole-Brain Radiotherapy for Brain Metastases From Renal Cell Carcinoma Benefit From Escalation of the Radiation Dose?

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

Rades, Dirk, E-mail: Rades.Dirk@gmx.ne; Department of Radiation Oncology, University Hospital Hamburg-Eppendorf, Hamburg; Heisterkamp, Christine

2010-10-01

Purpose: Whole-brain radiotherapy (WBRT) is the most common treatment for brain metastases from renal cell carcinoma (RCC). Most patients cannot receive more aggressive therapies including surgery or radiosurgery. The standard WBRT regimen, 30 Gy/10 fractions (10 x 3 Gy), has resulted in poor survival (OS). This study investigates whether escalation of the WBRT dose improves treatment outcomes. Methods and Materials: Data from 60 patients receiving WBRT for brain metastases from RCC were retrospectively analyzed. A dose of 10 x 3 Gy (n = 31) was compared with higher doses (40 Gy/20 fractions or 45 Gy/15 fractions; n = 29) formore » OS and local control (LC). Additional factors evaluated were patient age, sex, performance status, number of metastases, interval from diagnosis of RCC to WBRT, extracerebral metastases, recursive partitioning analysis (RPA) class, and year of WBRT. Results: The OS at 6 months was 29% after 10 x 3 Gy and 52% after higher doses (p = 0.003). The OS at 12 months was 13% and 47%, respectively. On multivariate analysis, higher WBRT doses (p = 0.022), Karnofsky performance status score {>=}70 (p = 0.017), fewer than four brain metastases (p = 0.035), and RPA Class 1 (p = 0.003) resulted in better OS. The LC at 6 months was 21% after 10 x 3 Gy and 57% after higher doses (p = 0.013). The LC at 12 months was 7% and 35%, respectively. On multivariate analysis, fewer than four brain metastases (p < 0.001) were associated with LC. A trend was found for WBRT regimen (p = 0.06) and RPA class (p = 0.06). Conclusions: The findings suggest that escalation of the WBRT dose beyond 10 x 3 Gy improves outcomes in patients with brain metastases from RCC. The results should be confirmed in a randomized trial stratifying for significant prognostic factors.« less

Effect of Two Different Doses of Dexmedetomidine on Stress Response in Laparoscopic Pyeloplasty: A Randomized Prospective Controlled Study.

PubMed

Shamim, Rafat; Srivastava, Shashi; Rastogi, Amit; Kishore, Kamal; Srivastava, Aneesh

2017-01-01

Clonidine, opioids, β-blockers, and dexmedetomidine have been tried to attenuate stress responses during laparoscopic surgery. We evaluated the efficacy of dexmedetomidine in two different doses in attenuating stress responses on patients undergoing laparoscopic pyeloplasty. Ninety patients were assigned to one of the three groups: Group A, Group B, and Group C. Group B received dexmedetomidine 1 mcg/kg as loading dose, followed by 0.7 mcg/kg/h for maintenance; Group C received dexmedetomidine 0.7 mcg/kg as a loading dose, followed by 0.5 mcg/kg/h for maintenance. Group A received normal saline. Stress responses were assessed by the variations in heart rate (HR), mean arterial pressure (MAP), blood glucose levels, and serum cortisol levels. One-way analysis of variance test was applied. Multiple comparisons between groups were done with post hoc Bonferroni test. The HR and MAP were found to be higher in Group A. The difference was statistically significant ( P < 0.05) during intubation, carbon dioxide insufflation, and extubation when compared with Groups B and C. Blood glucose levels at postintubation and at extubation were higher in Group A and statistically significant ( P < 0.05) when compared with Groups B and C. Serum cortisol levels at postintubation, during midsurgery, and 2 h after extubation were higher in Group A and statistically significant ( P < 0.05) when compared with Groups B and C. However, HR, MAP, blood glucose levels, and serum cortisol levels were similar in dexmedetomidine groups. Dexmedetomidine decreases stress response and provides good condition for maintenance of anesthesia. Dexmedetomidine when used in lower dose in Group C decreases stress response comparable to higher dose in Group B.

A phase I study of different doses and frequencies of pegylated recombinant human granulocyte-colony stimulating factor (PEG rhG-CSF) in patients with standard-dose chemotherapy-induced neutropenia

PubMed Central

Qin, Yan; Han, Xiaohong; Wang, Lin; Du, Ping; Yao, Jiarui; Wu, Di; Song, Yuanyuan; Zhang, Shuxiang; Tang, Le; Shi, Yuankai

2017-01-01

Objective The recommended dose of prophylactic pegylated recombinant human granulocyte-colony stimulating factor (PEG rhG-CSF) is 100 μg/kg once per cycle for patients receiving intense-dose chemotherapy. However, few data are available on the proper dose for patients receiving less-intense chemotherapy. The aim of this phase I study is to explore the proper dose and administration schedule of PEG rhG-CSF for patients receiving standard-dose chemotherapy. Methods Eligible patients received 3-cycle chemotherapy every 3 weeks. No PEG rhG-CSF was given in the first cycle. Patients experienced grade 3 or 4 neutropenia would then enter the cycle 2 and 3. In cycle 2, patients received a single subcutaneous injection of prophylactic PEG rhG-CSF on d 3, and received half-dose subcutaneous injection in cycle 3 on d 3 and d 5, respectively. Escalating doses (30, 60, 100 and 200 μg/kg) of PEG rhG-CSF were investigated. Results A total of 26 patients were enrolled and received chemotherapy, in which 24 and 18 patients entered cycle 2 and cycle 3 treatment, respectively. In cycle 2, the incidence of grade 3 or 4 neutropenia for patients receiving single-dose PEG rhG-CSF of 30, 60, 100 and 200 μg/kg was 66.67%, 33.33%, 22.22% and 0, respectively, with a median duration less than 1 (0–2) d. No grade 3 or higher neutropenia was noted in cycle 3 in all dose cohorts. Conclusions The pharmacokinetic and pharmacodynamic profiles of PEG rhG-CSF used in cancer patients were similar to those reported, as well as the safety. Double half dose administration model showed better efficacy result than a single dose model in terms of grade 3 neutropenia and above. The single dose of 60 μg/kg, 100 μg/kg and double half dose of 30 μg/kg were recommended to the phase II study, hoping to find a preferable method for neutropenia treatment. PMID:29142459

A phase I study of different doses and frequencies of pegylated recombinant human granulocyte-colony stimulating factor (PEG rhG-CSF) in patients with standard-dose chemotherapy-induced neutropenia.

PubMed

Qin, Yan; Han, Xiaohong; Wang, Lin; Du, Ping; Yao, Jiarui; Wu, Di; Song, Yuanyuan; Zhang, Shuxiang; Tang, Le; Shi, Yuankai

2017-10-01

The recommended dose of prophylactic pegylated recombinant human granulocyte-colony stimulating factor (PEG rhG-CSF) is 100 μg/kg once per cycle for patients receiving intense-dose chemotherapy. However, few data are available on the proper dose for patients receiving less-intense chemotherapy. The aim of this phase I study is to explore the proper dose and administration schedule of PEG rhG-CSF for patients receiving standard-dose chemotherapy. Eligible patients received 3-cycle chemotherapy every 3 weeks. No PEG rhG-CSF was given in the first cycle. Patients experienced grade 3 or 4 neutropenia would then enter the cycle 2 and 3. In cycle 2, patients received a single subcutaneous injection of prophylactic PEG rhG-CSF on d 3, and received half-dose subcutaneous injection in cycle 3 on d 3 and d 5, respectively. Escalating doses (30, 60, 100 and 200 μg/kg) of PEG rhG-CSF were investigated. A total of 26 patients were enrolled and received chemotherapy, in which 24 and 18 patients entered cycle 2 and cycle 3 treatment, respectively. In cycle 2, the incidence of grade 3 or 4 neutropenia for patients receiving single-dose PEG rhG-CSF of 30, 60, 100 and 200 μg/kg was 66.67%, 33.33%, 22.22% and 0, respectively, with a median duration less than 1 (0-2) d. No grade 3 or higher neutropenia was noted in cycle 3 in all dose cohorts. The pharmacokinetic and pharmacodynamic profiles of PEG rhG-CSF used in cancer patients were similar to those reported, as well as the safety. Double half dose administration model showed better efficacy result than a single dose model in terms of grade 3 neutropenia and above. The single dose of 60 μg/kg, 100 μg/kg and double half dose of 30 μg/kg were recommended to the phase II study, hoping to find a preferable method for neutropenia treatment.

Application of the Extended Health Control Belief Model to Predict Hepatitis A and B Vaccinations.

PubMed

Reynolds, Grace L; Nguyen, Hannah H; Singh-Carlson, Savitri; Fisher, Dennis G; Odell, Anne; Xandre, Pamela

2016-09-01

Adult vaccination compliance rates vary according to sample and type of vaccine administered (influenza, pneumococcal). This study looked at vaccination of a community sample of low-income, minority adults. Nurses offered free vaccination for hepatitis A and B in the form of the combined Twinrix vaccine to adults on a walk-in basis. In addition to dosing information, participants completed the Risk Behavior Assessment, the Coping Strategies Indicator and the Cardiovascular Risk Assessment. Skaff's extended Health Belief Model was used as the theoretical framework. Count regression was used to model receipt of one, two, or three doses. The majority of participants were male with a mean age of 40 years. The distribution of doses was: 173 individuals (27.6%) received one dose only, 261 (41.7%) received two doses, and 191 (30.5%) received three doses of vaccine. The multivariate count regression model including being male, having previously been told by a health care provider that one has syphilis, having severe negative emotions, and perceived social support were associated with participants' receiving fewer doses of hepatitis vaccine. A greater problem-solving score was associated with a higher number of vaccine doses received. Despite free vaccinations offered in an easily accessible community setting, the majority of participants failed to complete the hepatitis vaccine series. More effort is needed to get adult men to participate in hepatitis vaccination clinics. Additional research is necessary to understand barriers other than cost to adults receiving vaccination. © 2016 Wiley Periodicals, Inc.

Vitamin A-first dose supplement coverage evaluation amongst children aged 12–23 months residing in slums of Delhi, India

PubMed Central

Sachdeva, Sandeep; Datta, Utsuk

2009-01-01

Objective: To determine vitamin A-first dose supplement coverage in children aged 12–23 months and to find out its correlates with selected variables. Materials and Methods: The 30-cluster sampling technique based on probability proportional to size advocated by the World Health Organization was used to assess vitamin A-first dose supplement amongst 210 children in the age group of 12–23 months residing in slums of a randomly selected municipal zone of Delhi during October to November 2005. Results: Only 79 (37.6%) children out of 210 had received vitamin A-first dose supplement. Further analysis of 79 children was carried out with regard to selected variables like religion, gender, birth order, place of birth, immunization status and literacy of mother. These analyses showed that 71 (89.9%) were Hindu and eight (10.1%) were non-Hindu (P = 0.04). Nearly 44 (55.7%) males and 35 (44.3%) females had received vitamin A (P = 0.74). The proportion of children born in a health institution who received first dose (57%) of vitamin A supplementation was significantly higher than of those who were born at home (43%) (P < 0.001). Similarly, higher proportion of children with birth order-one (48.1%) in comparison to birth order-three or above (26.6%) received vitamin A (P < 0.001). Thirty children though fully immunized for vaccine-preventable disease up to the age-of-one year had not received vitamin A-first dose supplement, suggesting that an opportunity had been missed. The association between receipt of vitamin A by the child and literacy status of mother was found to be significant (P < 0.001). Conclusion: The study reflects low coverage of Vitamin A supplement. PMID:19574699

131I-tositumomab myeloablative radioimmunotherapy for non-Hodgkin’s lymphoma: radiation dose to the testes

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

Hattori, Naoya; Gopal, Ajay K.; Shields, Andrew T.

Purpose: To investigate radiation doses to the testes delivered by a radiolabeled anti-CD20 antibody and its effects on male sex hormone levels. Materials and methods: Testicular uptake and retention of 131I-tositumomab were measured, and testicular absorbed doses were calculated for 67 male patients (54+/-11 years of age) with non-Hodgkin's lymphoma who had undergone myeloablative radioimmunotherapy (RIT) using 131I-tositumomab. Time-activity curves for the major organs, testes, and whole body were generated from planar imaging studies. In a subset of patients, male sex hormones were measured before and 1 year after the therapy. Results: The absorbed dose to the testes showed considerablemore » variability (range=4.4-70.2 Gy). Pretherapy levels of total testosterone were below the lower limit of the reference range, and post-therapy evaluation demonstrated further reduction [4.6+/-1.8 nmol/l (pre-RIT) vs. 3.8+/-2.9 nmol/l (post-RIT), P<0.05]. Patients receiving higher radiation doses to the testes (>=25 Gy) showed a greater reduction [4.7+/-1.6 nmol/l (pre-RIT) vs. 3.3+/-2.7 nmol/l (post-RIT), P<0.05] compared with patients receiving lower doses (<25 Gy), who showed no significant change in total testosterone levels. Conclusion: The testicular radiation absorbed dose varied highly among individual patients. Finally, patients receiving higher doses to the testes were more likely to show post-RIT suppression of testosterone levels.« less

Effect of Age at Vaccination on Rotavirus Vaccine Effectiveness in Bolivian Infants.

PubMed

Burke, Rachel M; Tate, Jacqueline E; Pringle, Kimberly D; Patel, Manish; De Oliveira, Lucia H; Parashar, Umesh D

2018-01-16

Rotavirus vaccines are less effective in developing countries versus developed countries. One hypothesis for this difference in performance is that higher levels of maternal antibodies in developing countries may interfere with vaccine response, suggesting that delayed dosing could be beneficial. The present analysis aims to assess whether rotavirus vaccine effectiveness (VE) varies by age at vaccination during routine use in Bolivia. Data were merged from two post-licensure evaluations of monovalent rotavirus vaccine (RV1) in Bolivia, where two doses of RV1 are recommended at two and four months of age. For each dose, children were classified as receiving each dose "early," "on-time," or "late." Stratified unconditional logistic regression models were used to estimate VE, using unvaccinated children as the referent. VE was calculated as (1 - odds ratio) x 100%. Models were adjusted for hospital, age, and time since RV1 introduction (via including terms for month and year of birth). VE for two doses of RV1 tended to be higher in infants receiving the first dose early (VE 92%; 95% confidence interval [CI] [70%, 98%]), when compared to infants receiving their first dose on time (72% [62%, 81%]) or late (68% [51%, 79%]). Estimates of VE were not substantially different when comparing children by age at second dose (early: VE 76% [50%, 89%]; on time: VE 70% [50%, 89%]; late: VE 75% [60%, 84%]), including all children. Our results indicate that early administration may improve VE and support the current WHO recommendations for the RV1 schedule.

High-dose octreotide acetate for management of gastroenteropancreatic neuroendocrine tumors.

PubMed

Chadha, Manpreet K; Lombardo, Jeffrey; Mashtare, Terry; Wilding, Gregory E; Litwin, Alan; Raczyk, Cheryl; Gibbs, John F; Kuvshinoff, Boris; Javle, Milind M; Iyer, Renuka V

2009-10-01

Long-acting sandostatin (S-LAR; octreotide acetate) is well tolerated and effective for symptom control and possibly disease control in gastroenteropancreatic neuroendocrine tumors (GEP-NETs). We undertook a retrospective analysis to study the efficacy and tolerability of higher doses (more than 20-30 mg/month) of S-LAR in GEP-NETs. With IRB approval, charts of all patients with GEP-NET who received S-LAR between June 2002 to September 2007 at Roswell Park Cancer Institute were reviewed and their data analyzed. Fifty-four patients with GEP-NET received S-LAR; thirty required dose escalation. Patients received a median of 5 doses of S-LAR at conventional dose followed by up-titration of the dose for symptom control (20) and radiological progression (17). Median high dose of S-LAR was 40 mg (range: 40-90 mg) with a median of 8.5 high doses received. No treatment related toxicities were seen. The estimated 1-year survival for patients on conventional dose alone was 0.77 (95% CI of 0.50 to 0.91) and those on high-dose was 0.88 (95% CI of 0.68 to 0.96) (p=0.4777) while median time to any other intervention was 2.9 months versus 17.7 months (p=0.12). Dose escalation of S-LAR is well tolerated and may provide longer disease control.

Efficacy and Safety of Escalation of Adalimumab Therapy to Weekly Dosing in Pediatric Patients with Crohn's Disease.

PubMed

Dubinsky, Marla C; Rosh, Joel; Faubion, William A; Kierkus, Jaroslaw; Ruemmele, Frank; Hyams, Jeffrey S; Eichner, Samantha; Li, Yao; Huang, Bidan; Mostafa, Nael M; Lazar, Andreas; Thakkar, Roopal B

2016-04-01

The efficacy of adalimumab in inducing and maintaining remission in children with moderately to severely active Crohn's disease was shown in the IMAgINE 1 trial (NCT00409682). As per protocol, nonresponders or patients experiencing flare(s) on every other week (EOW) maintenance dosing could escalate to weekly dosing; we aimed to determine the therapeutic benefits of weekly dose escalation in this subpopulation. Week 52 remission and response rates were assessed in patients who escalated to weekly dosing from their previous EOW schedule, which was according to randomized treatment dose (higher dose [HD] adalimumab [≥40 kg, 40 mg EOW; <40 kg, 20 mg EOW] or lower dose [LD; ≥40 kg, 20 mg EOW; <40 kg, 10 mg EOW]). Adverse events were reported for patients remaining on EOW dosing and patients receiving weekly dosing. Escalation to weekly dosing occurred in 48/95 (50.5%) patients randomized to LD and 35/93 (37.6%) patients randomized to HD adalimumab (P = 0.076). Week 52 remission and response rates were 18.8% and 47.9% for patients receiving LD adalimumab weekly and 31.4% and 57.1% for patients receiving HD adalimumab weekly, respectively (LD versus HD, P = 0.19 for remission; P = 0.41 for response). Adverse event rates were similar for patients receiving EOW and weekly adalimumab. Weekly adalimumab dosing was clinically beneficial for children with Crohn's disease who experienced nonresponse or flare on EOW dosing. No increased safety risks were observed with weekly dosing.

Serum and tissue concentrations of gallium after oral administration of gallium nitrate and gallium maltolate to neonatal calves.

PubMed

Monk, Caroline S; Sweeney, Raymond W; Bernstein, Lawrence R; Fecteau, Marie-Eve

2016-02-01

To determine serum and tissue concentrations of gallium (Ga) after oral administration of gallium nitrate (GaN) and gallium maltolate (GaM) to neonatal calves. 8 healthy neonatal calves. Calves were assigned to 1 of 2 groups (4 calves/group). Gallium (50 mg/kg) was administered as GaN or GaM (equivalent to 13.15 mg of Ga/kg for GaN and 7.85 mg of Ga/kg for GaM) by oral gavage once daily for 5 days. Blood samples were collected 0, 0.25, 0.5, 1, 2, 4, 8, 12, and 24 hours after Ga administration on day 1; 4 and 24 hours after Ga administration on days 2, 3, and 4; and 4, 12, and 24 hours after Ga administration on day 5. On day 6, calves were euthanized and tissue samples were obtained. Serum and tissue Ga concentrations were measured by use of mass spectrometry. Data were adjusted for total Ga dose, and comparisons were made between the 2 groups. Calves receiving GaM had a significantly higher dose-adjusted area under the curve and dose-adjusted maximum serum Ga concentration than did calves receiving GaN. Despite receiving less Ga per dose, calves receiving GaM had tissue Ga concentrations similar to those for calves receiving GaN. In this study, calves receiving GaM had significantly higher Ga absorption than did calves receiving GaN. These findings suggested that GaM might be useful as a prophylactic agent against Mycobacterium avium subsp paratuberculosis infection in neonatal calves.

Effectiveness of Jeryl Lynn-containing vaccine in Spanish children.

PubMed

Castilla, Jesús; García Cenoz, Manuel; Arriazu, Maite; Fernández-Alonso, Mirian; Martínez-Artola, Víctor; Etxeberria, Jaione; Irisarri, Fátima; Barricarte, Aurelio

2009-03-26

We evaluated the effectiveness of the Jeryl Lynn strain vaccine in a large outbreak of mumps in Navarre, Spain, 2006-2008. Each of the 241 cases of mumps occurring in children over 15 months of age born between 1998 and 2005 was compared with 5 controls individually matched by sex, birth date, district of residence and paediatrician. Vaccination history was obtained blindly from clinical records. Conditional logistic regression was used to obtain the matched odds ratios (ORs), and effectiveness was calculated as 1-OR. Some 70% of cases had received one dose of measles-mumps-rubella vaccine, and 24% had received two doses. Overall vaccine effectiveness was 72% (95% CI, 39-87%). Two doses were more effective (83%; 54-94%) than a single dose (66%; 25-85%). Among vaccinated children, risk was higher in those who had received the first dose after 36 months of age (OR=3.1; 1.2-8.4) and those who had received the second dose 3 or more years before study enrolment (OR=10.2; 1.5-70.7). Early waning of immunity in children after the second dose may contribute to reduced vaccine effectiveness for mumps prevention.

Overdose and prescribed opioids: Associations among chronic non-cancer pain patients

PubMed Central

Dunn, Kate M; Saunders, Kathleen W; Rutter, Carolyn M; Banta-Green, Caleb J; Merrill, Joseph O; Sullivan, Mark D; Weisner, Constance M; Silverberg, Michael J; Campbell, Cynthia I; Psaty, Bruce M; Von Korff, Michael

2010-01-01

Background Chronic opioid therapy for chronic non-cancer pain (CNCP) is increasingly common in community practice. Concomitant with this practice change, rates of fatal opioid overdose have increased. It is not known to what extent overdose risks are elevated among patients receiving medically prescribed chronic opioid therapy. Objective To estimate rates of opioid overdose and their association with average prescribed daily opioid dose among patients receiving medically prescribed chronic opioid therapy. Design Cox proportional hazards models were used to estimate overdose risk as a function of average daily opioid dose (morphine equivalents) received at time of overdose. Setting Health maintenance organization. Patients Individuals (n=9940) who received 3+ opioid prescriptions within 90-days for CNCP between 1997 and 2005. Measurements Average daily opioid dose over the previous 90 days from automated pharmacy data. Primary outcomes, non-fatal and fatal overdoses, were identified through diagnostic codes from inpatient and outpatient care and death certificates and confirmed by medical record review. Results Fifty-one opioid-related overdoses were identified, including six deaths. Compared to patients receiving 1-20mg of opioids per day (0.2% annual overdose rate), patients receiving 50-99 mg had a 3.7 fold increase in overdose risk (95% C.I. 1.5, 9.5) and a 0.7% annual overdose rate. Patients receiving 100mg or more per day had an 8.9 fold increase in overdose risk (95% C.I. 4.0, 19.7) and a 1.8% annual overdose rate. Limitations Increased overdose risk among patients on higher dose regimens may be due to confounding by patient differences and by use of opioids in ways not intended by prescribing physicians. The small number of overdoses in the study cohort is also a limitation. Conclusions Patients receiving higher doses of prescribed opioids are at increased risk of opioid overdose, underscoring the need for close supervision of these patients. PMID:20083827

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

PubMed

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

2017-10-01

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

Risk of a Second Malignant Neoplasm After Cancer in Childhood Treated With Radiotherapy: Correlation With the Integral Dose Restricted to the Irradiated Fields

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

Nguyen, France; Institut Gustave Roussy, Villejuif; Universite Paris XI, Villejuif

2008-03-01

Purpose: After successful treatment of cancers in childhood, the occurrence of second malignant neoplasm (SMN) came to the fore. Few studies have considered the relationship between the radiation dose received and the risk of developing an SMN. To take into account the heterogeneity of the dose distribution so as to evaluate the overall risk of an SMN after a childhood cancer, we therefore focused on the integral dose restricted to the irradiated fields. Methods and Materials: The study was performed in a cohort of 4,401 patients who were 3-year survivors of all types of childhood cancer treated between 1947 andmore » 1986 in France and Great Britain. For each patient, the integral dose was estimated for the volume inside the beam edges. Results: We found a significant dose-response relationship between the overall risk of an SMN and the estimated integral dose. The excess relative risk for each incremental unit of the integral dose was only 0.008 in a linear model and 0.017 when a negative exponential term was considered, when adjusted for chemotherapy. The risk of SMN occurrence was 2.6 times higher in the case of irradiation. However among patients who had received radiotherapy, only those who had received the highest integral dose actually had a higher risk. Conclusions: The integral dose in our study cannot be considered as a good predictor of later risks. However other studies with the same study design are obviously needed to evaluate the use of the integral dose as a tool for decision making concerning different radiotherapy techniques.« less

Effects of the Chemical Defense Antidote Atropine Sulfate on Helicopter Pilot Performance: An In-Flight Study

DTIC Science & Technology

1991-06-01

reported minor hallucinations . Digging ;,rt -,-,7in -e wis degraded overall and number facility was impaired en the aiernoon of the atropine day...at higher doses; 4) loss of coordination with doses higher than 10 mg; and 5) hallucinations with very large doses of atropine. Longo’s (1966) review...diopter of refractive error, possessed normal hearing , and was between the ages of 24 and 32 (mean=29.1). Each one received a complete physical

A Pharmacovigilance Study in First Episode of Psychosis: Psychopharmacological Interventions and Safety Profiles in the PEPs Project

PubMed Central

Bioque, Miquel; Llerena, Adrián; Cabrera, Bibiana; Mezquida, Gisela; Lobo, Antonio; González-Pinto, Ana; Díaz-Caneja, Covadonga M.; Corripio, Iluminada; Aguilar, Eduardo J.; Bulbena, Antoni; Castro-Fornieles, Josefina; Vieta, Eduard; Lafuente, Amàlia; Mas, Sergi; Parellada, Mara; Saiz-Ruiz, Jerónimo; Cuesta, Manuel J.

2016-01-01

Background: The characterization of the first episode of psychosis and how it should be treated are principal issues in actual research. Realistic, naturalistic studies are necessary to represent the entire population of first episode of psychosis attended in daily practice. Methods: Sixteen participating centers from the PEPs project recruited 335 first episode of psychosis patients, aged 7 to 35 years. This article describes and discusses the psychopharmacological interventions and safety profiles at baseline and during a 60-day pharmacovigilance period. Results: The majority of first episode of psychosis patients received a second-generation antipsychotic (96.3%), orally (95%), and in adjusted doses according to the product specifications (87.2%). A total of 24% were receiving an antipsychotic polytherapy pattern at baseline, frequently associated with lower or higher doses of antipsychotics than the recommended ones. Eight patients were taking clozapine, all in monotherapy. Males received higher doses of antipsychotic (P=.043). A total of 5.2% of the patients were being treated with long-acting injectable antipsychotics; 12.2% of the patients received anticholinergic drugs, 12.2% antidepressants, and 13.7% mood stabilizers, while almost 40% received benzodiazepines; and 35.52% reported at least one adverse drug reaction during the pharmacovigilance period, more frequently associated with higher antipsychotic doses and antipsychotic polytherapy (85.2% vs 45.5%, P<.001). Conclusions: These data indicate that the overall pharmacologic prescription for treating a first episode of psychosis in Spain follows the clinical practice guideline recommendations, and, together with security issues, support future research of determinate pharmacological strategies for the treatment of early phases of psychosis, such as the role of clozapine, long-acting injectable antipsychotics, antipsychotic combination, and the use of benzodiazepines. PMID:26506856

Decreased Risk of Radiation Pneumonitis With Incidental Concurrent Use of Angiotensin-Converting Enzyme Inhibitors and Thoracic Radiation Therapy

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

Kharofa, Jordan; Cohen, Eric P.; Tomic, Rade

2012-09-01

Purpose: Angiotensin-converting enzyme (ACE) inhibitors have been shown to mitigate radiation-induced lung injury in preclinical models. The aim of this study was to evaluate whether ACE inhibitors decrease the risk of radiation pneumonitis in lung cancer patients receiving thoracic irradiation. Methods and Materials: Patients with Stage I through III small-cell and non-small-cell lung cancer treated definitively with radiation from 2004-2009 at the Clement J. Zablocki Veterans Affairs Medical Center were retrospectively reviewed. Acute pulmonary toxicity was quantified within 6 months of completion of treatment according to the Common Terminology Criteria for Adverse Events version 4. The use of ACE inhibitors,more » nonsteroidal anti-inflammatory drugs, inhaled glucocorticosteroids, statins, and angiotensin receptor blockers; dose-volume histogram parameters; and patient factors were assessed for association with Grade 2 or higher pneumonitis. Results: A total of 162 patients met the criteria for inclusion. The majority of patients had Stage III disease (64%) and received concurrent chemotherapy (61%). Sixty-two patients were identified as ACE inhibitor users (38%). All patients had acceptable radiation plans based on dose-volume histogram constraints (V20 [volume of lung receiving at least 20 Gy] {<=}37% and mean lung dose {<=}20 Gy) with the exception of 2 patients who did not meet both criteria. Grade 2 or higher pulmonary toxicity occurred in 12 patients (7.4%). The rate of Grade 2 or higher pneumonitis was lower in ACE inhibitor users vs. nonusers (2% vs. 11%, p = 0.032). Rates of Grade 2 or higher pneumonitis were significantly increased in patients aged greater than 70 years (16% vs. 2%, p = 0.005) or in whom V5 (volume of lung receiving at least 5 Gy) was 50% or greater (13% vs. 4%, p = 0.04). V10 (volume of lung receiving at least 10 Gy), V20, V30 (volume of lung receiving at least 30 Gy), and mean lung dose were not independently associated with Grade 2 or higher pneumonitis. Conclusion: ACE inhibitors may decrease the incidence of radiation pneumonitis in patients receiving thoracic radiation for lung cancer. These findings are consistent with preclinical evidence and should be prospectively evaluated.« less

Is It All about the Higher Dose? Why Psychoanalytic Therapy Is an Effective Treatment for Major Depression.

PubMed

Zimmermann, Johannes; Löffler-Stastka, Henriette; Huber, Dorothea; Klug, Günther; Alhabbo, Sarah; Bock, Astrid; Benecke, Cord

2015-01-01

Empirical evidence for the effectiveness of long-term psychodynamic psychotherapy (LTPP) in patients with mood disorders is growing. However, it is unclear whether the effectiveness of LTPP is due to distinctive features of psychodynamic/psychoanalytic techniques or to a higher number of sessions. We tested these rival hypotheses in a quasi-experimental study comparing psychoanalytic therapy (i.e., high-dose LTPP) with psychodynamic therapy (i.e., low-dose LTPP) and cognitive-behavioural therapy (CBT) for depression. Analyses were based on a subsample of 77 subjects, with 27 receiving psychoanalytic therapy, 26 receiving psychodynamic therapy and 24 receiving CBT. Depressive symptoms, interpersonal problems and introject affiliation were assessed prior to treatment, after treatment and at the 1-, 2- and 3-year follow-ups. Psychoanalytic techniques were assessed from three audiotaped middle sessions per treatment using the Psychotherapy Process Q-Set. Subjects receiving psychoanalytic therapy reported having fewer interpersonal problems, treated themselves in a more affiliative way directly after treatment and tended to improve in depressive symptoms and interpersonal problems during follow-up as compared with patients receiving psychodynamic therapy and/or CBT. Multilevel mediation analyses suggested that post-treatment differences in interpersonal problems and introject affiliation were mediated by the higher number of sessions, and follow-up differences in depressive symptoms were mediated by the more pronounced application of psychoanalytic techniques. We also found some evidence for indirect treatment effects via psychoanalytic techniques on changes in introject affiliation during follow-up. These results provide support for the prediction that both a high dose and the application of psychoanalytic techniques facilitate therapeutic change in patients with major depression. Psychoanalytic therapy is an effective treatment for major depression, especially in the long run. The differential effectiveness of psychoanalytic therapy cannot be fully explained by its higher dose. Distinctive features of psychoanalytic technique (e.g., focusing on patients' dreams, fantasies, sexual experiences or childhood memories) may play an important role in establishing sustained therapeutic change. Copyright © 2014 John Wiley & Sons, Ltd.

Risk of Radiation Retinopathy in Patients With Orbital and Ocular Lymphoma

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

Kaushik, Megha; Pulido, Jose S.; Schild, Steven E.

2012-12-01

Purpose: Radiation retinopathy is a potential long-term complication of radiation therapy to the orbit. The risk of developing this adverse effect is dose dependent; however, the threshold is unclear. The aim of this study was to identify the risk of developing radiation retinopathy at increasing radiation doses. Methods and Materials: A 40-year retrospective review was performed of patients who received external beam radiation therapy for ocular/orbital non-Hodgkin lymphoma (NHL). Results: Sixty-seven patients who had at least one ophthalmic follow-up examination were included in this study. Most patients (52%) were diagnosed with NHL involving the orbit. Patients received external beam radiationmore » therapy at doses between 1886 and 5400 cGy (mean, 3033 {+-} 782 cGy). Radiation retinopathy developed in 12% of patients, and the median time to diagnosis was 27 months (range, 15-241months). The mean prescribed radiation dose in patients with retinopathy was 3309 {+-} 585 cGy, and the estimated retinal dose (derived by reviewing the dosimetry) was 3087 {+-} 1030 cGy. The incidence of retinopathy increased with dose. The average prescribed daily fractionated dose was higher in patients who developed retinopathy than in patients who did not (mean, 202 cGy vs 180 cGy, respectively; P = .04). More patients with radiation retinopathy had comorbid diabetes mellitus type 2 than patients without retinopathy (P = .015). In our study, the mean visual acuity of the eyes that received radiation was worse than that of the eyes that did not (P = .027). Other postradiotherapy ocular findings included keratitis (6%), dry eyes (39%), and cataract (33%). Conclusions: Radiation retinopathy, a known complication of radiotherapy for orbital tumors, relates to vascular comorbidities and dose. Higher total doses and larger daily fractions (>180 cGy) appear to be related to higher rates of retinopathy. Future larger studies are required to identify a statistically significant threshold for the development of retinopathy.« less

Solar UV exposure of primary schoolchildren in Valencia, Spain.

PubMed

Serrano, María-Antonia; Cañada, Javier; Moreno, Juan Carlos

2011-04-01

To quantify schoolchildren's exposure to ultraviolet erythemal radiation (UVER), personal dosimeters (VioSpor) were used to measure biologically effective ultraviolet (UV) radiation received in the course of their daily school activities. The study took place in two primary schools in Valencia (39°28'N), Spain, for several weeks from March 2008 until May 2009, with two age groups (6-8 years and 10-11 years) and involved about 47 schoolchildren. The median daily UV exposure values for all age groups and solar height intervals considered in the study ranged from 1.31 to 2.11 standard erythemal doses (SEDs). Individual UV exposure was analyzed as a function of age, gender and dosimeter position. Significant statistical differences were found between different age groups, with the younger age group receiving higher statistically significant UVER exposure. It was also found that boys received significantly higher UVER exposure than girls. It was also noted that shoulder dosimeters registered higher readings than wrist dosimeters. Exposure ratio (ER) is defined as the ratio between the personal dose on a selected anatomical site and the corresponding ambient dose on a horizontal plane. The median ER for all age groups and solar height intervals in the study range from 4.5% to 10.7%, with higher values at lower solar heights.

Treatment of Endometriosis-Associated Pain with Elagolix, an Oral GnRH Antagonist.

PubMed

Taylor, Hugh S; Giudice, Linda C; Lessey, Bruce A; Abrao, Mauricio S; Kotarski, Jan; Archer, David F; Diamond, Michael P; Surrey, Eric; Johnson, Neil P; Watts, Nelson B; Gallagher, J Chris; Simon, James A; Carr, Bruce R; Dmowski, W Paul; Leyland, Nicholas; Rowan, Jean P; Duan, W Rachel; Ng, Juki; Schwefel, Brittany; Thomas, James W; Jain, Rita I; Chwalisz, Kristof

2017-07-06

Endometriosis is a chronic, estrogen-dependent condition that causes dysmenorrhea and pelvic pain. Elagolix, an oral, nonpeptide, gonadotropin-releasing hormone (GnRH) antagonist, produced partial to nearly full estrogen suppression in previous studies. We performed two similar, double-blind, randomized, 6-month phase 3 trials (Elaris Endometriosis I and II [EM-I and EM-II]) to evaluate the effects of two doses of elagolix - 150 mg once daily (lower-dose group) and 200 mg twice daily (higher-dose group) - as compared with placebo in women with surgically diagnosed endometriosis and moderate or severe endometriosis-associated pain. The two primary efficacy end points were the proportion of women who had a clinical response with respect to dysmenorrhea and the proportion who had a clinical response with respect to nonmenstrual pelvic pain at 3 months. Each of these end points was measured as a clinically meaningful reduction in the pain score and a decreased or stable use of rescue analgesic agents, as recorded in a daily electronic diary. A total of 872 women underwent randomization in Elaris EM-I and 817 in Elaris EM-II; of these women, 653 (74.9%) and 632 (77.4%), respectively, completed the intervention. At 3 months, a significantly greater proportion of women who received each elagolix dose met the clinical response criteria for the two primary end points than did those who received placebo. In Elaris EM-I, the percentage of women who had a clinical response with respect to dysmenorrhea was 46.4% in the lower-dose elagolix group and 75.8% in the higher-dose elagolix group, as compared with 19.6% in the placebo group; in Elaris EM-II, the corresponding percentages were 43.4% and 72.4%, as compared with 22.7% (P<0.001 for all comparisons). In Elaris EM-I, the percentage of women who had a clinical response with respect to nonmenstrual pelvic pain was 50.4% in the lower-dose elagolix group and 54.5% in the higher-dose elagolix group, as compared with 36.5% in the placebo group (P<0.001 for all comparisons); in Elaris EM-II, the corresponding percentages were 49.8% and 57.8%, as compared with 36.5% (P=0.003 and P<0.001, respectively). The responses with respect to dysmenorrhea and nonmenstrual pelvic pain were sustained at 6 months. Women who received elagolix had higher rates of hot flushes (mostly mild or moderate), higher levels of serum lipids, and greater decreases from baseline in bone mineral density than did those who received placebo; there were no adverse endometrial findings. Both higher and lower doses of elagolix were effective in improving dysmenorrhea and nonmenstrual pelvic pain during a 6-month period in women with endometriosis-associated pain. The two doses of elagolix were associated with hypoestrogenic adverse effects. (Funded by AbbVie; Elaris EM-I and EM-II ClinicalTrials.gov numbers, NCT01620528 and NCT01931670 .).

Analysis of dose-volume parameters predicting radiation pneumonitis in patients with esophageal cancer treated with 3D-conformal radiation therapy or IMRT.

PubMed

Kumar, Gaurav; Rawat, Sheh; Puri, Abhishek; Sharma, Manoj Kumar; Chadha, Pranav; Babu, Anand Giri; Yadav, Girigesh

2012-01-01

Multimodality therapy for esophageal cancer can cause various kinds of treatment-related sequelae, especially pulmonary toxicities. This prospective study aims to investigate the clinical and dosimetric parameters predicting lung injury in patients undergoing radiation therapy for esophageal cancer. Forty-five esophageal cancer patients were prospectively analyzed. The pulmonary toxicities (or sequelae) were evaluated by comparing chest X-ray films, pulmonary function tests and symptoms caused by pulmonary damage before and after treatment. All patients were treated with either three-dimensional radiotherapy (3DCRT) or with intensity-modulated radiotherapy (IMRT). The planning dose volume histogram was used to compute the lung volumes receiving more than 5, 10, 20 and 30 Gy (V5, V10, V20, V30) and mean lung dose. V20 was larger in the IMRT group than in the 3DCRT group (p = 0.002). V20 (>15%) and V30 (>20%) resulted in a statistically significant increase in the occurrence of chronic pneumonitis (p = 0.03) and acute pneumonitis (p = 0.007), respectively. The study signifies that a larger volume of lung receives lower doses because of multiple beam arrangement and a smaller volume of lung receives higher doses because of better dose conformity in IMRT plans. Acute pneumonitis correlates more with V30 values, whereas chronic pneumonitis was predominantly seen in patients with higher V20 values.

RADIATION-INDUCED CHROMOSOME ABERRATIONS IN MAN

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

Sasaki, M.; Ottoman, R.E.; Norman, A.

1963-10-01

A study was made of the production and elimination of radioinduced chromosomal aberrations in leukocytes from the peripheral blood of persons exposed to chronic or acute doses of high-energy radiation. Included in the group were radiologists and laboratory scientists, for whom there were available complete records of the radiation dose received during their working life, and a number of distinguished radiologists who have practiced more than 25 yrs and who may have received substantial doses One of seven leukocytes from a distinguished radiologist contained a pair of chromosomes that could be classified as pseudo- diploid. In laboratory personnel for whommore » the doses received were significantly within the prescribed limits, the incidence of pseudo-diploid cells, of dicentrics, and of other chroNonemosomal aberrations was significantly higher than in a more or less comparable control group. (tr-auth)« less

Effect of simultaneous vaccination with H1N1 and GAD-alum on GAD65-induced immune response.

PubMed

Tavira, Beatriz; Cheramy, Mikael; Axelsson, Stina; Åkerman, Linda; Ludvigsson, Johnny; Casas, Rosaura

2017-07-01

A European Phase III trial of GAD formulated with aluminium hydroxide (GAD-alum) failed to reach its primary endpoint (preservation of stimulated C-peptide secretion from baseline to 15 months in type 1 diabetes patients), but subgroup analysis showed a clinical effect when participants from Nordic countries were excluded, raising concern as to whether the mass vaccination of the Swedish and Finnish populations with the Pandemrix influenza vaccine could have influenced the study outcomes. In the current study, we aimed to assess whether Pandemrix vaccination affects the specific immune responses induced by GAD-alum and the C-peptide response. In this secondary analysis, we analysed data acquired from the Swedish participants in the Phase III GAD-alum trial who received subcutaneous GAD-alum vaccination (two doses, n = 43; four doses, n = 46) or placebo (n = 48). GAD autoantibodies (GADA) and H1N1 autoantibodies, GAD 65 -induced cytokine secretion and change in fasting and stimulated C-peptide levels from baseline to 15 months were analysed with respect to the relative time between H1N1 vaccination and the first injection of GAD-alum. GADA levels at 15 months were associated with the relative time between GAD-alum and Pandemrix administration in participants who received two doses of the GAD-alum vaccine (p = 0.015, r = 0.4). Both in participants treated with two doses and four doses of GAD-alum, GADA levels were higher when the relative time between vaccines was ≥210 days (p < 0.05). In the group that received two doses of GAD-alum, levels of several GAD 65 -induced cytokines were higher in participants who received the H1N1 vaccination and the first GAD-alum injection at least 150 days apart, and the change in fasting and stimulated C-peptide at 15 months was associated with the relative time between vaccines. Neither of these effects were observed in individuals who received four doses of GAD-alum. In individuals who received two doses of GAD-alum, receiving the Pandemrix vaccine closer to the first GAD-alum injection, i.e. <150 days, seemed to affect both GAD 65 -induced immune response and C-peptide preservation. ClinicalTrials.gov NCT00723411.

Azacitidine in the 'real-world': an evaluation of 1101 higher-risk myelodysplastic syndrome/low blast count acute myeloid leukaemia patients in Ontario, Canada.

PubMed

Mozessohn, Lee; Cheung, Matthew C; Fallahpour, Saber; Gill, Tripat; Maloul, Asmaa; Zhang, Liying; Lau, Olivia; Buckstein, Rena

2018-06-01

The outcome of myelodysplastic syndrome (MDS) patients with uniformly higher-risk disease treated with azacitidine (AZA) in the 'real-world' remains largely unknown. We evaluated 1101 consecutive higher-risk MDS patients (International Prognostic Scoring System intermediate-2/high) and low-blast count acute myeloid leukaemia (AML; 21-30% blasts) patients treated in Ontario, Canada. By dosing schedule, 24·7% received AZA for seven consecutive days, 12·4% for six consecutive days and 62·9% by 5-2-2. Overall, median number of cycles was 6 (range 1-67) and 8 (range 6-14) when restricted to the 692 (63%) patients who received at least 4 cycles. The actuarial median survival was 11·6 months [95% confidence interval (CI) 10·7-12·4) for the entire cohort and 18·0 months (landmark analysis; 95% CI 16·6-19·1 months) for those receiving at least 4 cycles. There was no difference in overall survival (OS) between the 3 dosing schedules (P = 0·87). In our large 'real-world' evaluation of AZA in higher-risk MDS/low-blast count AML, we demonstrated a lower than expected OS. Reassuringly, survival did not differ by dosing schedules. The OS was higher in the 2/3 of patients who received at least 4 cycles of treatment, reinforcing the necessity of sustained administration until therapeutic benefits are realised. This represents the largest 'real-world' evaluation of AZA in higher-risk MDS/low-blast count AML. © 2018 John Wiley & Sons Ltd.

Simultaneous integrated vs. sequential boost in VMAT radiotherapy of high-grade gliomas.

PubMed

Farzin, Mostafa; Molls, Michael; Astner, Sabrina; Rondak, Ina-Christine; Oechsner, Markus

2015-12-01

In 20 patients with high-grade gliomas, we compared two methods of planning for volumetric-modulated arc therapy (VMAT): simultaneous integrated boost (SIB) vs. sequential boost (SEB). The investigation focused on the analysis of dose distributions in the target volumes and the organs at risk (OARs). After contouring the target volumes [planning target volumes (PTVs) and boost volumes (BVs)] and OARs, SIB planning and SEB planning were performed. The SEB method consisted of two plans: in the first plan the PTV received 50 Gy in 25 fractions with a 2-Gy dose per fraction. In the second plan the BV received 10 Gy in 5 fractions with a dose per fraction of 2 Gy. The doses of both plans were summed up to show the total doses delivered. In the SIB method the PTV received 54 Gy in 30 fractions with a dose per fraction of 1.8 Gy, while the BV received 60 Gy in the same fraction number but with a dose per fraction of 2 Gy. All of the OARs showed higher doses (Dmax and Dmean) in the SEB method when compared with the SIB technique. The differences between the two methods were statistically significant in almost all of the OARs. Analysing the total doses of the target volumes we found dose distributions with similar homogeneities and comparable total doses. Our analysis shows that the SIB method offers advantages over the SEB method in terms of sparing OARs.

Vaccination coverage according to doses received and timely administered based on an electronic immunization registry, Araraquara-SP, Brazil, 2012-2014.

PubMed

Tauil, Márcia de Cantuária; Sato, Ana Paula Sayuri; Costa, Ângela Aparecida; Inenami, Marta; Ferreira, Vinícius Leati de Rossi; Waldman, Eliseu Alves

2017-01-01

to describe vaccine coverage by type of vaccine at 12 and 24 months of age. descriptive cohort study with children born in 2012, living in Araraquara-SP, Brazil, recorded in the Information System on Live Births (Sinasc); a manual linkage of Sinasc data with an electronic immunization registry (EIR) was performed; the assessment was based on vaccination status according to São Paulo State recommendations, and on doses received and timely administered. 2,740 children were registered on Sinasc and 99.6% of them were included into EIR; among the 2,612 (95.3%) children studied, the triple viral vaccine (measles, mumps and rubella) had the lowest coverage at 12 months for received dose (74.8%) and at 24 months for timely vaccination (53.5%) and received doses (88.0%). coverage was higher than 90% for most vaccines; however, delayed vaccination was observed, which indicates the need to intensify actions aimed at timely vaccination.

The addition of low-dose-rate brachytherapy and androgen-deprivation therapy decreases biochemical failure and prostate cancer death compared with dose-escalated external-beam radiation therapy for high-risk prostate cancer.

PubMed

Shilkrut, Mark; Merrick, Gregory S; McLaughlin, P William; Stenmark, Matthew H; Abu-Isa, Eyad; Vance, Sean M; Sandler, Howard M; Feng, Felix Y; Hamstra, Daniel A

2013-02-01

The objective of this study was to determine whether the addition of low-dose-rate brachytherapy or androgen-deprivation therapy (ADT) improves clinical outcome in patients with high-risk prostate cancer (HiRPCa) who received dose-escalated radiotherapy (RT). Between 1995 and 2010, 958 patients with HiRPCa were treated at Schiffler Cancer Center (n = 484) or at the University of Michigan (n = 474) by receiving either dose-escalated external-beam RT (EBRT) (n = 510; minimum prescription dose, 75 grays [Gy]; median dose, 78 Gy) or combined-modality RT (CMRT) consisting of (103) Pd implants (n = 369) or (125) I implants (n = 79) both with pelvic irradiation (median prescription dose, 45 Gy). The cumulative incidences of biochemical failure (BF) and prostate cancer-specific mortality (PCSM) were estimated by using the Kaplan-Meier method and Fine and Gray regression analysis. The median follow-up was 63.2 months (interquartile range, 35.4-99.0 months), and 250 patients were followed for >8 years. Compared with CMRT, patients who received EBRT had higher prostate-specific antigen levels, higher tumor classification, lower Gleason sum, and more frequent receipt of ADT for a longer duration. The 8-year incidence BF and PCSM among patients who received EBRT was 40% (standard error, 38%-44%) and 13% (standard error, 11%-15%) compared with 14% (standard error, 12%-16%; P < .0001) and 7% (standard error 6%-9%; P = .003) among patients who received CMRT. On multivariate analysis, the hazard ratios (HRs) for BF and PCSM were 0.35 (95% confidence interval [CI], 0.23-0.52; P < .0001) and 0.41 (95% CI, 0.23-0.75; P < .003), favoring CMRT. Increasing duration of ADT predicted decreased BF (P = .04) and PCSM (P = .001), which was greatest with long-term ADT (BF: HR, 0.33; P < .0001; 95% CI, 0.21-0.52; PCSM: HR, 0.30; P = .001; 95% CI, 0.15-0.6) even in the subgroup that received CMRT. In this retrospective comparison, both low-dose-rate brachytherapy boost and ADT were associated with decreased risks of BF and PCSM compared with EBRT. Copyright © 2012 American Cancer Society.

Real-life GH dosing patterns in children with GHD, TS or born SGA: a report from the NordiNet® International Outcome Study.

PubMed

Blankenstein, Oliver; Snajderova, Marta; Blair, Jo; Pournara, Effie; Pedersen, Birgitte Tønnes; Petit, Isabelle Oliver

2017-08-01

To describe real-life dosing patterns in children with growth hormone deficiency (GHD), born small for gestational age (SGA) or with Turner syndrome (TS) receiving growth hormone (GH) and enrolled in the NordiNet International Outcome Study (IOS; Nbib960128) between 2006 and 2016. This non-interventional, multicentre study included paediatric patients diagnosed with GHD (isolated (IGHD) or multiple pituitary hormone deficiency (MPHD)), born SGA or with TS and treated according to everyday clinical practice from the Czech Republic (IGHD/MPHD/SGA/TS: n  = 425/61/316/119), France ( n  = 1404/188/970/206), Germany ( n  = 2603/351/1387/411) and the UK ( n  = 259/60/87/35). GH dosing was compared descriptively across countries and indications. Proportions of patients by GH dose group (low/medium/high) or GH dose change (decrease/increase/no change) during years 1 and 2 were also evaluated across countries and indications. In the Czech Republic, GH dosing was generally within recommended levels. In France, average GH doses were higher for patients with IGHD, MPHD and SGA than in other countries. GH doses in TS tended to be at the lower end of the recommended label range, especially in Germany and the UK; the majority of patients were in the low-dose group. A significant inverse association between baseline height standard deviation score and GH dose was shown ( P  < 0.05); shorter patients received higher doses. Changes in GH dose, particularly increases, were more common in the second (40%) than in the first year (25%). GH dosing varies considerably across countries and indications. In particular, almost half of girls with TS received GH doses below practice guidelines and label recommendations. © 2017 The authors.

Long-Term Dose-Dependent Agalsidase Effects on Kidney Histology in Fabry Disease.

PubMed

Skrunes, Rannveig; Tøndel, Camilla; Leh, Sabine; Larsen, Kristin Kampevold; Houge, Gunnar; Davidsen, Einar Skulstad; Hollak, Carla; van Kuilenburg, André B P; Vaz, Frédéric M; Svarstad, Einar

2017-09-07

Dose-dependent clearing of podocyte globotriaosylceramide has previously been shown in patients with classic Fabry disease treated with enzyme replacement. Our study evaluates the dose-dependent effects of agalsidase therapy in serial kidney biopsies of patients treated for up to 14 years. Twenty patients with classic Fabry disease (12 men) started enzyme replacement therapy at a median age of 21 (range =7-62) years old. Agalsidase- α or - β was prescribed for a median of 9.4 (range =5-14) years. The lower fixed dose group received agalsidase 0.2 mg/kg every other week throughout the follow-up period. The higher dose group received a range of agalsidase doses (0.2-1.0 mg/kg every other week). Dose changes were made due to disease progression, suboptimal effect, or agalsidase- β shortage. Serial kidney biopsies were performed along with clinical assessment and biomarkers and scored according to recommendations from the International Study Group of Fabry Nephropathy. No statistical differences were found in baseline or final GFR or albuminuria. Kidney biopsies showed significant reduction of podocyte globotriaosylceramide in both the lower fixed dose group (-1.39 [SD=1.04]; P =0.004) and the higher dose group (-3.16 [SD=2.39]; P =0.002). Podocyte globotriaosylceramide (Gb3) reduction correlated with cumulative agalsidase dose ( r =0.69; P =0.001). Arterial/arteriolar intima Gb3 cleared significantly in the higher dose group, all seven patients with baseline intimal Gb3 cleared the intima, one patient gained intimal Gb3 inclusions ( P =0.03), and medial Gb3 did not change statistically in either group. Residual plasma globotriaosylsphingosine levels remained higher in the lower fixed dose group (20.1 nmol/L [SD=11.9]) compared with the higher dose group (10.4 nmol/L [SD=8.4]) and correlated with cumulative agalsidase dose in men ( r =0.71; P =0.01). Reduction of podocyte globotriaosylceramide was found in patients with classic Fabry disease treated with long-term agalsidase on different dosing regimens, correlating with cumulative dose. Limited clearing of arterial/arteriolar globotriaosylceramide raises concerns regarding long-term vascular effects of current therapy. Residual plasma globotriaosylsphingosine correlated with cumulative dose in men. Copyright © 2017 by the American Society of Nephrology.

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

PubMed

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

2012-10-01

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

Furosemide Prescription During the Dry State Is a Predictor of Long-Term Survival of Stable, Optimally Medicated Patients With Systolic Heart Failure.

PubMed

Sargento, Luis; Simões, Andre Vicente; Longo, Susana; Lousada, Nuno; Reis, Roberto Palma Dos

2017-05-01

Furosemide is associated with poor prognosis in patients with heart failure and reduced ejection fraction (HFrEF). To evaluate the association between daily furosemide dose prescribed during the dry state and long-term survival in stable, optimally medicated outpatients with HFrEF. Two hundred sixty-six consecutive outpatients with left ventricular ejection fraction <40%, clinically stable in the dry state and on optimal heart failure therapy, were followed up for 3 years in a heart failure unit. The end point was all-cause death. There were no changes in New York Heart Association class and therapeutics, including diuretics, and no decompensation or hospitalization during 6 months. Furosemide doses were categorized as low or none (0-40 mg/d), intermediate (41-80 mg/d), and high (>80 mg). Cox regression was adjusted for significant confounders. The 3-year mortality rate was 33.8%. Mean dose of furosemide was 57.3 ± 21.4 mg/d. A total of 47.6% of patients received the low dose, 42.1% the intermediate dose, and 2.3% the high dose. Receiver operating characteristics for death associated with furosemide dose showed an area under the curve of 0.74 (95% confidence interval [CI]: 0.68-0.79; P < .001), and the best cutoff was >40 mg/d. An increasing daily dose of furosemide was associated with worse prognosis. Those receiving the intermediate dose (hazard ratio [HR] = 4.1; 95% CI: 2.57-6.64; P < .001) or high dose (HR = 19.8; 95% CI: 7.9-49.6; P < .001) had a higher risk of mortality compared to those receiving a low dose. Patients receiving >40 mg/d, in a propensity score-matched cohort, had a greater risk of mortality than those receiving a low dose (HR = 4.02; 95% CI: 1.8-8.8; P = .001) and those not receiving furosemide (HR = 3.9; 95% CI: 0.07-14.2; P = .039). Furosemide administration during the dry state in stable, optimally medicated outpatients with HFrEF is unfavorably associated with long-term survival. The threshold dose was 40 mg/d.

A phase I study of recombinant human leukemia inhibitory factor in patients with advanced cancer.

PubMed

Gunawardana, Dishan H; Basser, Russell L; Davis, Ian D; Cebon, Jonathan; Mitchell, Paul; Underhill, Craig; Kilpatrick, Trevor J; Reardon, Katrina; Green, Michael D; Bardy, Peter; Amor, Pene; Crump, David; Ng, Siobhan; Nation, Roger L; Begley, C Glenn

2003-06-01

Leukemia inhibitory factor (LIF) is a pleiotropic molecule of the interleukin 6 family of cytokines. We aimed to examine the safety, pharmacokinetics, and biological effects of recombinant human LIF (rhLIF, emfilermin) in patients with advanced cancer. In stage 1 of the study, 34 patients received rhLIF or placebo (3:1 ratio) at doses of 0.25-16.0 micro g/kg/day or 4.0 micro g/kg three times daily for 7 days. In stage 2, 40 patients received rhLIF or placebo, either once daily for 14 days commencing the day after chemotherapy (0.25-8.0 micro g/kg/day) or for 7 days commencing the day before chemotherapy (4.0 micro g/kg three times daily). The chemotherapy was cisplatin 75 mg/m(2) and paclitaxel 135 mg/m(2). In stage 1, platelet counts increased in most patients, including those who received placebo. Blood progenitor cells increased in response to rhLIF. In stage 2, platelet recovery to baseline levels was earlier for patients receiving higher doses of rhLIF (>/=4.0 micro g/kg/day; P = 0.02). The neutrophil nadir after chemotherapy was less severe in patients receiving >/=4.0 micro g/kg/day of rhLIF. In stages 1 and 2, increases in C reactive protein were seen at higher doses. Several patients developed evidence of autonomic dysfunction, in particular impotence and episodic hypotension. The dose-limiting toxicities were hypotension and rigors. Pharmacokinetic studies demonstrated a short half-life (1-5 h) independent of dose. We demonstrated a biological effect of rhLIF on blood progenitor cells, C reactive protein levels, and hemopoietic recovery after chemotherapy.

Radiation Doses from the Norwegian Diet.

PubMed

Komperød, Mari; Skuterud, Lavrans

2018-06-13

Ingestion doses between and within countries are expected to vary significantly due to differences in dietary habits and geographical variations in radionuclide concentrations. This paper presents the most comprehensive assessment to date of the effective radiation dose from the Norwegian diet, from natural as well as anthropogenic radionuclides. Ingestion doses to the Norwegian public are calculated using national dietary statistics and the most relevant radionuclide concentration data for the various food products. The age-weighted average effective dose received by the Norwegian population from the diet is estimated at 0.41 mSv y from naturally occurring radionuclides and 0.010 mSv y from anthropogenic radionuclides. This is approximately 50% higher than the estimated world average. Fish and shellfish is the food group that provides the largest dose contribution from the average Norwegian diet. Although the average dose from anthropogenic radionuclides today is low, the exposure may still be significant for certain critical groups-especially persons who consume large amounts of reindeer meat from the regions that received significant radioactive fallout after the Chernobyl accident. Furthermore, persons with high Rn concentrations in their drinking water are among those receiving the highest ingestion doses in Norway.

Immunogenicity Following One, Two, or Three Doses of the 7-valent Pneumococcal Conjugate Vaccine

PubMed Central

Russell, FM; Balloch, A; Tang, MLK; Carapetis, JR; Licciardi, P; Nelson, J; Jenney, AWJ; Tikoduadua, L; Waqatakirewa, L; Pryor, J; Byrnes, GB; Cheung, YB; Mulholland, EK

2009-01-01

The aim was to identify an appropriate infant pneumococcal vaccination strategy for resource poor countries. Fijian infants received 0, 1, 2, or 3 doses of 7-valent pneumococcal conjugate vaccine (PCV) in early infancy. Following 3 PCV doses, geometric mean concentration (GMC) to all 7 serotypes were ≥ 1.0μg/mL, and >85% of children achieved antibody levels ≥0.35μg/mL at 18 weeks. Following 2 doses, GMC were lower for 6B, 14, and 23F, but higher for 19F compared with 3 doses. Following a single dose, significant responses were seen for all serotypes post primary series compared with the unvaccinated. By 12 months, differences between 2 and 3 doses persisted for serotype 14 only. Although GMC following 3 doses are higher than after 2 doses, the differences were small. A single dose may offer some protection for most serotypes. PMID:19616498

Pharmacokinetic profiles of repaglinide in elderly subjects with type 2 diabetes.

PubMed

Hatorp, V; Huang, W C; Strange, P

1999-04-01

Pharmacokinetic profiles of single- and multiple-dose regimens of repaglinide were evaluated in 12 elderly subjects with type 2 diabetes. On day 1, following a 10-hour fast, subjects received a single 2-mg dose of repaglinide. Starting on day 2 and continuing for 7 days, each subject received a 2-mg dose of repaglinide 15 minutes before each of the three main meals. On day 9, subjects received a single 2-mg dose of repaglinide. Pharmacokinetic profiles, including area under the curve (AUC), log(AUC), maximal concentration (Cmax), log(Cmax), time to maximal concentration (Tmax), and half-life (T(1/2)), were determined at completion of the single- and multiple-dose regimens (days 1 and 9, respectively). Trough repaglinide values were collected on days 2 through 7. The mean log(AUC) values after multiple dosing were significantly higher than the values obtained after a single dose. The mean values for log(Cmax), and Tmax were comparable after each dosing regimen. The T(1/2) of repaglinide after multiple dosing was 1.7 hours. The trough values for repaglinide were low. No hypoglycemic events were reported. The pharmacokinetic profiles of repaglinide after single- and multiple-dose regimens were similar, and repaglinide was well tolerated by elderly subjects with type 2 diabetes.

Thyroid Adenomas After Solid Cancer in Childhood

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

Haddy, Nadia; El-Fayech, Chiraz; Guibout, Catherine

Purpose: Very few childhood cancer survivor studies have been devoted to thyroid adenomas. We assessed the role of chemotherapy and the radiation dose to the thyroid in the risk of thyroid adenoma after childhood cancer. Methods and Materials: A cohort of 3254 2-year survivors of a solid childhood cancer treated in 5 French centers before 1986 was established. The dose received by the isthmus and the 2 lobes of the thyroid gland during each course of radiation therapy was estimated after reconstruction of the actual radiation therapy conditions in which each child was treated as well as the dose receivedmore » at other anatomical sites of interest. Results: After a median follow-up of 25 years, 71 patients had developed a thyroid adenoma. The risk strongly increased with the radiation dose to the thyroid up to a few Gray, plateaued, and declined for high doses. Chemotherapy slightly increased the risk when administered alone but also lowered the slope of the dose-response curve for the radiation dose to the thyroid. Overall, for doses up to a few Gray, the excess relative risk of thyroid adenoma per Gray was 2.8 (90% CI: 1.2-6.9), but it was 5.5 (90% CI: 1.9-25.9) in patients who had not received chemotherapy or who had received only 1 drug, and 1.1 (90% CI: 0.4-3.4) in the children who had received more than 1 drug (P=.06, for the difference). The excess relative risk per Gray was also higher for younger children at the time of radiation therapy than for their older counterparts and was higher before attaining 40 years of age than subsequently. Conclusions: The overall pattern of thyroid adenoma after radiation therapy for a childhood cancer appears to be similar to that observed for thyroid carcinoma.« less

Hepatoprotective effect of Crocus sativus (saffron) petals extract against acetaminophen toxicity in male Wistar rats

PubMed Central

Omidi, Arash; Riahinia, Narges; Montazer Torbati, Mohammad Bagher; Behdani, Mohammad-Ali

2014-01-01

Objectives: Acetaminophen (APAP) toxicity is known to be common and potentially fatal. This study aims to investigate the protective effects of hydroalcoholic extract, remaining from Crocus sativus petals (CSP) against APAP-induced hepatotoxicity by measuring the blood parameters and studying the histopathology of liver in male rats. Materials and Methods: Wister rats (24) were randomly assigned into four groups including: I) healthy, receiving normal saline; II) Intoxicated, receiving only APAP (600 mg/kg); III) pre-treated with low dose of CSP (10 mg /kg) and receiving APAP (600 mg/kg); IV) pre-treated with high dose of CSP (20 mg/kg) and receiving APAP (600 mg/kg). Results: The APAP treatment resulted in higher levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), and bilirubin, along with lower total protein and albumin concentration than the control group. The administration of CSP with a dose of 20 mg/kg was found to result in lower levels of AST, ALT and bilirubin, with a significant higher concentration of total protein and albumin. The histopathological results regarding liver pathology, revealed sever conditions including cell swelling, severe inflammation and necrosis in APAP-exposed rats, which was quiet contrasting compared to the control group. The pre-treated rats with low doses of ‍CSP showed hydropic degeneration with mild necrosis in centrilobular areas of the liver, while the same subjects with high doses of ‍CSP appeared to have only mild hepatocyte degeneration. Conclusions: Doses of 20 mg/kg of CSP ameliorates APAP–induced acute liver injury in rats. It was concluded that the antioxidant property of CSP resulted in reducing the oxidative stress complications of toxic levels of APAP in intoxicated rats. PMID:25386395

Portal Hypertension in Children With Wilms' Tumor: A Report From the National Wilms' Tumor Study Group

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

Warwick, Anne B., E-mail: awarwick@mcw.ed; Kalapurakal, John A.; Ou, San-San

Purpose: This analysis was undertaken to determine the cumulative risk of and risk factors for portal hypertension (PHTN) in patients with Wilms' tumor (WT). Methods and Materials: Medical records were reviewed to identify cases of PHTN identified with late liver/spleen/gastric toxicities in a cohort of 5,195 patients treated with National Wilms' Tumor Studies (NWTS) protocols 1 to 4. A nested case control study (5 controls/case) was conducted to determine relationships among doxorubicin, radiation therapy (RT) dose to the liver, patient gender, and PHTN. Conditional logistic regression was used to estimate adjusted hazard ratios (HR) of PHTN associated with these factors.more » Results: Cumulative risk of PHTN at 6 years from WT diagnosis was 0.7% for patients with right-sided tumors vs. 0.1% for those with left-sided tumors (p = 0.002). Seventeen of 19 cases were evaluable for RT. The majority of cases (16/17 [94%]) received right-flank RT either alone or as part of whole-abdomen RT and received >15 Gy to the liver. Fifteen of 17 (88%) patients received a higher dose to the liver than they would have with modern WT protocols. Controlling for RT dose, the HR was 3.0 for patients who received doxorubicin (p = 0.32) and 2.8 for females (p = 0.15). Controlling for doxorubicin, the 95% lower confidence bound on the HR associating PHTN with a minimum liver RT dose of >15 Gy vs. <=15 Gy was 2.5 (p = 0.001); it was 2.4 for a maximum liver dose of >15 Gy vs. <=15 Gy (p = 0.001). Conclusions: There was a strong association between higher doses of liver RT (>15 Gy) and the development of PHTN among WT patients.« less

Evaluation of entrance surface air kerma in pediatric chest radiography

NASA Astrophysics Data System (ADS)

Porto, L.; Lunelli, N.; Paschuk, S.; Oliveira, A.; Ferreira, J. L.; Schelin, H.; Miguel, C.; Denyak, V.; Kmiecik, C.; Tilly, J.; Khoury, H.

2014-11-01

The objective of this study was to evaluate the entrance surface air kerma in pediatric chest radiography. An evaluation of 301 radiographical examinations in anterior-posterior (AP) and posterior-anterior (PA) (166 examinations) and lateral (LAT) (135 examinations) projections was performed. The analyses were performed on patients grouped by age; the groups included ages 0-1 y, 1-5 y, 5-10 y, and 10-15 y. The entrance surface air kerma was determined with DoseCal software (Radiological Protection Center of Saint George's Hospital, London) and thermoluminescent dosimeters. Two different exposure techniques were compared. The doses received by patients who had undergone LAT examinations were 40% higher, on average, those in AP/PA examinations because of the difference in tube voltage. A large high-dose “tail” was observed for children up to 5 y old. An increase in tube potential and corresponding decrease in current lead to a significant dose reduction. The difference between the average dose values for different age ranges was not practically observed, implying that the exposure techniques are still not optimal. Exposure doses received using the higher tube voltage and lower current-time product correspond to the international diagnostic reference levels.

Optimal dose and volume for postoperative radiotherapy in brain oligometastases from lung cancer: a retrospective study.

PubMed

Chung, Seung Yeun; Chang, Jong Hee; Kim, Hye Ryun; Cho, Byoung Chul; Lee, Chang Geol; Suh, Chang-Ok

2017-06-01

To evaluate intracranial control after surgical resection according to the adjuvant treatment received in order to assess the optimal radiotherapy (RT) dose and volume. Between 2003 and 2015, a total of 53 patients with brain oligometastases from non-small cell lung cancer (NSCLC) underwent metastasectomy. The patients were divided into three groups according to the adjuvant treatment received: whole brain radiotherapy (WBRT) ± boost (WBRT ± boost group, n = 26), local RT/Gamma Knife surgery (local RT group, n = 14), and the observation group (n = 13). The most commonly used dose schedule was WBRT (25 Gy in 10 fractions, equivalent dose in 2 Gy fractions [EQD2] 26.04 Gy) with tumor bed boost (15 Gy in 5 fractions, EQD2 16.25 Gy). The WBRT ± boost group showed the lowest 1-year intracranial recurrence rate of 30.4%, followed by the local RT and observation groups, at 66.7%, and 76.9%, respectively (p = 0.006). In the WBRT ± boost group, there was no significant increase in the 1-year new site recurrence rate of patients receiving a lower dose of WBRT (EQD2) <27 Gy compared to that in patients receiving a higher WBRT dose (p = 0.553). The 1-year initial tumor site recurrence rate was lower in patients receiving tumor bed dose (EQD2) of ≥42.3 Gy compared to those receiving <42.3 Gy, although the difference was not significant (p = 0.347). Adding WBRT after resection of brain oligometastases from NSCLC seems to enhance intracranial control. Furthermore, combining lower-dose WBRT with a tumor bed boost may be an attractive option.

Optimal dose and volume for postoperative radiotherapy in brain oligometastases from lung cancer: a retrospective study

PubMed Central

Chung, Seung Yeun; Chang, Jong Hee; Kim, Hye Ryun; Cho, Byoung Chul; Lee, Chang Geol; Suh, Chang-Ok

2017-01-01

Purpose To evaluate intracranial control after surgical resection according to the adjuvant treatment received in order to assess the optimal radiotherapy (RT) dose and volume. Materials and Methods Between 2003 and 2015, a total of 53 patients with brain oligometastases from non-small cell lung cancer (NSCLC) underwent metastasectomy. The patients were divided into three groups according to the adjuvant treatment received: whole brain radiotherapy (WBRT) ± boost (WBRT ± boost group, n = 26), local RT/Gamma Knife surgery (local RT group, n = 14), and the observation group (n = 13). The most commonly used dose schedule was WBRT (25 Gy in 10 fractions, equivalent dose in 2 Gy fractions [EQD2] 26.04 Gy) with tumor bed boost (15 Gy in 5 fractions, EQD2 16.25 Gy). Results The WBRT ± boost group showed the lowest 1-year intracranial recurrence rate of 30.4%, followed by the local RT and observation groups, at 66.7%, and 76.9%, respectively (p = 0.006). In the WBRT ± boost group, there was no significant increase in the 1-year new site recurrence rate of patients receiving a lower dose of WBRT (EQD2) <27 Gy compared to that in patients receiving a higher WBRT dose (p = 0.553). The 1-year initial tumor site recurrence rate was lower in patients receiving tumor bed dose (EQD2) of ≥42.3 Gy compared to those receiving <42.3 Gy, although the difference was not significant (p = 0.347). conclusions Adding WBRT after resection of brain oligometastases from NSCLC seems to enhance intracranial control. Furthermore, combining lower-dose WBRT with a tumor bed boost may be an attractive option. PMID:28712276

Opioid Analgesics and Adverse Outcomes among Hemodialysis Patients.

PubMed

Ishida, Julie H; McCulloch, Charles E; Steinman, Michael A; Grimes, Barbara A; Johansen, Kirsten L

2018-05-07

Patients on hemodialysis frequently experience pain and may be particularly vulnerable to opioid-related complications. However, data evaluating the risks of opioid use in patients on hemodialysis are limited. Using the US Renal Data System, we conducted a cohort study evaluating the association between opioid use (modeled as a time-varying exposure and expressed in standardized oral morphine equivalents) and time to first emergency room visit or hospitalization for altered mental status, fall, and fracture among 140,899 Medicare-covered adults receiving hemodialysis in 2011. We evaluated risk according to average daily total opioid dose (>60 mg, ≤60 mg, and per 60-mg dose increment) and specific agents (per 60-mg dose increment). The median age was 61 years old, 52% were men, and 50% were white. Sixty-four percent received opioids, and 17% had an episode of altered mental status (15,658 events), fall (7646 events), or fracture (4151 events) in 2011. Opioid use was associated with risk for all outcomes in a dose-dependent manner: altered mental status (lower dose: hazard ratio, 1.28; 95% confidence interval, 1.23 to 1.34; higher dose: hazard ratio, 1.67; 95% confidence interval, 1.56 to 1.78; hazard ratio, 1.29 per 60 mg; 95% confidence interval, 1.26 to 1.33), fall (lower dose: hazard ratio, 1.28; 95% confidence interval, 1.21 to 1.36; higher dose: hazard ratio, 1.45; 95% confidence interval, 1.31 to 1.61; hazard ratio, 1.04 per 60 mg; 95% confidence interval, 1.03 to 1.05), and fracture (lower dose: hazard ratio, 1.44; 95% confidence interval, 1.33 to 1.56; higher dose: hazard ratio, 1.65; 95% confidence interval, 1.44 to 1.89; hazard ratio, 1.04 per 60 mg; 95% confidence interval, 1.04 to 1.05). All agents were associated with a significantly higher hazard of altered mental status, and several agents were associated with a significantly higher hazard of fall and fracture. Opioids were associated with adverse outcomes in patients on hemodialysis, and this risk was present even at lower dosing and for agents that guidelines have recommended for use. Copyright © 2018 by the American Society of Nephrology.

Maintenance treatment of duodenal ulceration: ranitidine 300 mg at night is better than 150 mg in cigarette smokers.

PubMed Central

Lee, F I; Hardman, M; Jaderberg, M E

1991-01-01

Two hundred patients received either ranitidine 150 mg or 300 mg at night for 18 months to prevent duodenal ulcer relapse. Recurrence rates were lower in patients receiving the higher dose of ranitidine (3.1% v 9.7%, p = 0.78; 6.5% v 16.7%, p = 0.037; and 8.9% v 17.0%, p = 0.121 at six, 12, and 18 months respectively). In patients receiving ranitidine 150 mg, recurrences were significantly more common in smokers than non-smokers after 12 and 18 months, while in patients receiving ranitidine 300 mg recurrence rates were similar in smokers and non-smokers. Ranitidine 300 mg at night abolishes the adverse effect of smoking observed during maintenance treatment with ranitidine 150 mg at night and may therefore be an appropriate maintenance dose for smokers who relapse during standard dose maintenance treatment. PMID:1864532

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

PubMed

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

2016-01-01

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

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.

Can a single dose of human papillomavirus (HPV) vaccine prevent cervical cancer? Early findings from an Indian study.

PubMed

Sankaranarayanan, Rengaswamy; Joshi, Smita; Muwonge, Richard; Esmy, Pulikottil Okkuru; Basu, Partha; Prabhu, Priya; Bhatla, Neerja; Nene, Bhagwan M; Shaw, Janmesh; Poli, Usha Rani Reddy; Verma, Yogesh; Zomawia, Eric; Pimple, Sharmila; Tommasino, Massimo; Pawlita, Michael; Gheit, Tarik; Waterboer, Tim; Sehr, Peter; Pillai, Madhavan Radhakrishna

2018-03-15

Human papillomavirus (HPV) vaccination is a major strategy for preventing cervical and other ano-genital cancers. Worldwide HPV vaccination introduction and coverage will be facilitated if a single dose of vaccine is as effective as two or three doses or demonstrates significant protective effect compared to 'no vaccination'. In a multi-centre cluster randomized trial of two vs three doses of quadrivalent HPV vaccination (Gardasil™) in India, suspension of the vaccination due to events unrelated to the study led to per protocol and partial vaccination of unmarried 10-18 year old girls leading to four study groups, two by design and two by default. They were followed up for the primary outcomes of immunogenicity in terms of L1 genotype-specific binding antibody titres, neutralising antibody titres, and antibody avidity for the vaccine-targeted HPV types and HPV infections. Analysis was per actual number of vaccine doses received. This study is registered with ISRCTN, number ISRCTN98283094; and with ClinicalTrials.gov, number NCT00923702. Of the 17,729 vaccinated girls, 4348 (25%) received three doses on days 1, 60, 180 or later, 4979 (28%) received two doses on days 1 and 180 or later, 3452 (19%) received two doses on days 1 and 60, and 4950 (28%) received one dose. One dose recipients demonstrated a robust and sustained immune response against HPV 16 and 18, albeit inferior to that of 3- or 2-doses and the antibody levels were stable over a 4 year period. The frequencies of cumulative incident and persistent HPV 16 and 18 infections up to 7 years of follow-up were similar and uniformly low in all the vaccinated study groups; the frequency of HPV 16 and 18 infections were significantly higher in unvaccinated age-matched control women than among vaccine recipients. The frequency of vaccine non-targeted HPV types was similar in the vaccinated groups but higher in the unvaccinated control women. Our results indicate that a single dose of quadrivalent HPV vaccine is immunogenic and provides lasting protection against HPV 16 and 18 infections similar to the three- and two-dose vaccine schedules, although the study suffer from some limitations. Data on long term protection beyond 7 years against HPV infection and cervical precancerous lesions are needed before policy guidelines regarding a single dose can be formulated and implemented. Significant and long-lasting protective effect of a single dose can be a strong argument to introduce one dose of the HPV vaccine in many low income countries where the current standard of care for cervical cancer prevention is 'no intervention'. Copyright © 2018 The Authors. Published by Elsevier Ltd.. All rights reserved.

The effects of crude aqueous and alcohol extracts of Aloe vera on growth and abdominal viscera of suckling rats.

PubMed

Beya, Wabeya; Davidson, Bruce; Erlwanger, Kennedy H

2012-01-01

The gastrointestinal tract of neonates is sensitive to dietary manipulations. When nursing mothers use Aloe vera, their babies are at risk of indirect exposure to Aloe vera via breast feeding or directly as health supplements. The effects of orally administered extracts of Aloe vera in unweaned rats were investigated. Six day old Sprague-Dawley rats were gavaged with aqueous or alcohol extracts of Aloe vera (low dose 50mg. kg⁻¹ or high dose 500mg. kg⁻¹) daily for eight days. All data were expressed as mean ± SD and analyzed by one way ANOVA. Pups receiving high doses of either extract had a significantly higher body mass gain than the group receiving lower dose (p < 0.05). Tibial length was significantly increased in the high dose aqueous extract group (15-26%). The differences in growth could not be attributed to circulating insulin-like growth factor-1 as the levels were not significantly different. The caecum was significantly enlarged in the rats that received the high doses of both extracts. Although, there was no significant difference in the non-fasting plasma concentration of glucose and triglycerides, the hepatic lipid and glycogen content were significantly higher (p < 0.001) for the high dose aqueous extract group. The plasma alanine transaminase was not affected by the treatments, however the high doses of the extracts significantly increased plasma alkaline phosphatase activity. Short term administration of Aloe vera extracts resulted in growth promotion, enhanced hepatic storage of metabolic substrates, increased ALP possibly in relation to bone growth and caused hypertrophy of the caecum of neonatal rats. These effects need to be explored further to enhance animal production and health.

Dose delivered from Varian's CBCT to patients receiving IMRT for prostate cancer.

PubMed

Wen, Ning; Guan, Huaiqun; Hammoud, Rabih; Pradhan, Deepak; Nurushev, T; Li, Shidong; Movsas, Benjamin

2007-04-21

With the increased use of cone beam CT (CBCT) for daily patient setup, the accumulated dose from CBCT may be significantly higher than that from simulation CT or portal imaging. The objective of this work is to measure the dose from daily pelvic scans with fixed technical settings and collimations. CBCT scans were acquired in half-fan mode using a half bowtie and x-rays were delivered in pulsed-fluoro mode. The skin doses for seven prostate patients were measured on an IRB-approved protocol. TLD capsules were placed on the patient's skin at the central axis of three beams: AP, left lateral (Lt Lat) and right lateral (Rt Lat). To avoid the ring artefacts centred in the prostate, the treatment couch was dropped 3 cm from the patient's tattoo (central axis). The measured AP skin doses ranged 3-6 cGy for 20-33 cm separation. The larger the patient size the less the AP skin dose. Lateral doses did not change much with patient size. The Lt Lat dose was approximately 4.0 cGy, which was approximately 40% higher than the Rt Lat dose of approximately 2.6 cGy. To verify this dose asymmetry, surface doses on an IMRT QA phantom (oval shaped, 30 cm x 20 cm) were measured at the same three sites using TLD capsules with 3 cm table-drop. The dose asymmetry was due to: (1) kV source rotation which always starts from the patient's Lt Lat and ends at Lt Lat. Gantry rotation gets much slower near the end of rotation but dose rate stays constant and (2) 370 degrees scan rotation (10 degrees scan overlap on the Lt Lat side). In vivo doses were measured inside a Rando pelvic heterogeneous phantom using TLDs. The left hip (femoral head and neck) received the highest doses of approximately 10-11 cGy while the right hip received approximately 6-7 cGy. The surface and in vivo doses were also measured for phantoms at the central-axis setup. The difference was less than approximately 12% to the table-drop setup.

Dose delivered from Varian's CBCT to patients receiving IMRT for prostate cancer

NASA Astrophysics Data System (ADS)

Wen, Ning; Guan, Huaiqun; Hammoud, Rabih; Pradhan, Deepak; Nurushev, T.; Li, Shidong; Movsas, Benjamin

2007-04-01

With the increased use of cone beam CT (CBCT) for daily patient setup, the accumulated dose from CBCT may be significantly higher than that from simulation CT or portal imaging. The objective of this work is to measure the dose from daily pelvic scans with fixed technical settings and collimations. CBCT scans were acquired in half-fan mode using a half bowtie and x-rays were delivered in pulsed-fluoro mode. The skin doses for seven prostate patients were measured on an IRB-approved protocol. TLD capsules were placed on the patient's skin at the central axis of three beams: AP, left lateral (Lt Lat) and right lateral (Rt Lat). To avoid the ring artefacts centred in the prostate, the treatment couch was dropped 3 cm from the patient's tattoo (central axis). The measured AP skin doses ranged 3-6 cGy for 20-33 cm separation. The larger the patient size the less the AP skin dose. Lateral doses did not change much with patient size. The Lt Lat dose was ~4.0 cGy, which was ~40% higher than the Rt Lat dose of ~2.6 cGy. To verify this dose asymmetry, surface doses on an IMRT QA phantom (oval shaped, 30 cm × 20 cm) were measured at the same three sites using TLD capsules with 3 cm table-drop. The dose asymmetry was due to: (1) kV source rotation which always starts from the patient's Lt Lat and ends at Lt Lat. Gantry rotation gets much slower near the end of rotation but dose rate stays constant and (2) 370° scan rotation (10° scan overlap on the Lt Lat side). In vivo doses were measured inside a Rando pelvic heterogeneous phantom using TLDs. The left hip (femoral head and neck) received the highest doses of ~10-11 cGy while the right hip received ~6-7 cGy. The surface and in vivo doses were also measured for phantoms at the central-axis setup. The difference was less than ~12% to the table-drop setup.

Low muscle mass is associated with chemotherapy-induced haematological toxicity in advanced non-small cell lung cancer.

PubMed

Sjøblom, Bjørg; Grønberg, Bjørn H; Benth, Jūratė Šaltytė; Baracos, Vickie E; Fløtten, Øystein; Hjermstad, Marianne J; Aass, Nina; Jordhøy, Marit

2015-10-01

Recent research suggests a significant relationship between lean body mass (LBM) and toxicity from chemotherapeutic agents. We investigated if higher drug doses per kg LBM were associated with increased toxicity in stage IIIB/IV non-small cell lung cancer (NSCLC) patients receiving a first-line chemotherapy regimen dosed according to body surface area (BSA). Data from patients randomised to receive intravenous gemcitabine 1000 mg/m(2) plus orally vinorelbine 60 mg/m(2) days 1 and 8 in a phase III trial comparing two chemotherapy regimens were analysed. LBM was estimated from assessment of the cross-sectional muscle area at the third lumbar level (L3) on computed tomography images obtained before chemotherapy commenced. Common terminology criteria for adverse events (CTCAE) grade 3-4 haematological toxicity and dose reduction and/or stop of treatment after the first course of chemotherapy were defined as primary and secondary toxicity outcomes. The study sample included 153 patients, mean age was 66 years, 55% were men, 87% had disease stage IV and 75% had performance status (PS) 0-1. Gemcitabine doses per kg LBM varied from 23.2 to 53.1 mg/kg LBM, and vinorelbine doses from 1.5 to 3.3 mg/kg LBM. Higher doses of gemcitabine per kg LBM were significantly associated with grade 3-4 haematological toxicity in bivariate (OR=1.12, 95% CI 1.03-1.23, p=0.008) and multivariate analyses (OR=1.15, 95% CI 1.01-1.29, p=0.018), as were also higher doses of vinorelbine per kg LBM. No significant association was found between drug doses per kg LBM and dose reduction and/or stop of treatment. The study showed that dose estimates according to BSA lead to a substantial variation in drug dose per kg LBM, and higher doses per kg LBM are a significant predictor for chemotherapy-induced haematological toxicity. The results indicate that taking LBM into account may lead to a better dose individualisation of chemotherapy. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

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

PubMed Central

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

2017-01-01

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

Cisplatin neuropathy. Risk factors, prognosis, and protection by WR-2721

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

Mollman, J.E.; Glover, D.J.; Hogan, W.M.

1988-06-01

A prospective study of patients receiving cis-diaminedichloroplatin II (DDP) was carried out to determine if risk factors could be identified related to the patient's living habits or past medical history that would predict in which patients DDP neuropathy might develop. Sixty-nine patients receiving six different combinations of chemotherapeutic agents, including DDP were examined. Twenty-eight of these patients received DDP in combination with the radioprotective agent S-2-(3-aminopropylamino)-ethylphosporothioic acid (WR 2721). No risk factors were identified relating to personal habits or past medical history of the patients. However, patients receiving DDP (40 mg/m2) on 5 consecutive days had a significantly higher incidencemore » of neuropathy. Patients receiving DDP in combination with WR 2721 had a significantly lower incidence of neuropathy, and the mean dose at onset was significantly higher than the mean dose at onset of neuropathy for all other groups. In addition, five of six patients who were available for long-term follow-up demonstrated nearly complete reversal of the signs and symptoms of neuropathy.« less

Dose-Response Relationship between Radiation Dose and Loco-regional Control in Patients with Stage II-III Esophageal Cancer Treated with Definitive Chemoradiotherapy.

PubMed

Kim, Hyun Ju; Suh, Yang-Gun; Lee, Yong Chan; Lee, Sang Kil; Shin, Sung Kwan; Cho, Byung Chul; Lee, Chang Geol

2017-07-01

The correlation between radiation dose and loco-regional control (LRC) was evaluated in patients with stage II-III esophageal cancer treated with definitive concurrent chemoradiotherapy (CRT). Medical records of 236 stage II-III esophageal cancer patients treated with definitive CRT at Yonsei Cancer Center between 1994 and 2013 were retrospectively reviewed. Among these, 120 received a radiation dose of < 60 Gy (standard-dose group), while 116 received ≥ 60 Gy (high-dose group). The median doses of radiation in the standard- and high-dose groups were 50.4 and 63 Gy, respectively. Concurrent 5-fluorouracil/cisplatin chemotherapy was administered to most patients. There were no differences in patient characteristics between the two groups except for high Karnofsky performance status and lower-thoracic lesions being more prevalent in the standard-dose group. The median progression-free survival (PFS) and overall survival (OS) times were 13.2 months and 26.2 months, respectively. Patients in the high-dose group had significantly better 2-year LRC (69.1% vs. 50.3%, p=0.002), median PFS (16.7 months vs. 11.7 months, p=0.029), and median OS (35.1 months vs. 22.3 months, p=0.043). Additionally, LRC exhibited a dose-response relationship and the complete response rate was significantly higher in the high-dose group (p=0.006). There were no significant differences in treatment-related toxicities between the groups. A higher radiation dose (> 60 Gy) is associated with increased LRC, PFS, and OS in patients with stage II-III esophageal cancer treated with definitive CRT.

Immunological mechanism of low-dose priming radiation resistance in walker-256 tumor model mice

PubMed Central

Feng, Li; Qin, Ling; Guo, Dan; Deng, Daping; Lu, Feng; Li, Hailiang; Bao, Narisu; Yang, Xiting; Ding, Hongyu; Li, Jianguo

2017-01-01

The aim of the present study was to investigate whether low-dose priming radiation induces antitumor immunity that can be augmented by the modulation of natural killer (NK) cell and cytokine activity using a mouse tumor model. Walker-256 cells were injected into the right flank of male BALB/c mice. At 7 days after inoculation, mice were divided into three groups, including group 1,2,3. In group 1 the mice were without radiation, in group 2 the mice were received 2 Gy radiation only, and in group 3 the mice were radiated with a priming dose of 75 mGy followed by 2 Gy radiation after 24 h. On day 21 following the radiation, the tumors were removed and the tumor index (tumor weight as a percentage of body weight) was calculated. At 1, 7, 14 and 21 days following the 2 Gy radiation, mouse splenocytes were isolated to analyze the NK activity and measure the production of the cytokines interleukin-1β, interferon-γ and tumor necrosis factor-α by ELISA. Apoptosis was also measured by flow cytometry. The results demonstrated that priming radiation significantly delayed the tumor growth and prolonged the median survival time to 38 days compared with the 31-day survival in the 2 Gy radiation group. The percentage of apoptotic cells was significantly higher in the mice that received 75 mGy + 2 Gy radiation compared with that in the mice that received 2 Gy alone; by contrast, mice that were not irradiated exhibited a relatively low level of apoptosis. The primed mice had a higher level of NK activity as compared with the mice exposed to 2 Gy radiation only or mice that were not irradiated. Furthermore, cytokine expression remained at a higher level in mice receiving priming dose of radiation compared that in the mice receiving only 2 Gy radiation. In conclusion, the results indicated that low-dose priming X-ray radiation may enhance the NK activity and the levels of cytokines, and that the immune response serves an important role in anticancer therapy, including radiotherapy. PMID:29042994

Does motivational interviewing counseling time influence HIV-positive persons' self-efficacy to practice safer sex?

PubMed

Chariyeva, Zulfiya; Golin, Carol E; Earp, Jo Anne; Suchindran, Chirayath

2012-04-01

This study examined the impact of motivational interviewing (MI) counseling time on self-efficacy to practice safer sex for people living with HIV/AIDS (PLWHA). In 4 month intervals we followed a cohort of 490 PLWHA for 12 months. We conducted hierarchical linear regression models to examine changes in safer sex self-efficacy when participants received zero, low to moderate (5-131 min) and high (132-320 min) doses of MI time. We conducted a similar analysis using number of counseling sessions as the predictor variable. Participants with low to moderate doses of MI counseling had 0.26 higher self-efficacy scores than participants with zero MI time (p=0.01). Also, they had 0.26 lower self-efficacy scores than participants with high amounts of MI time (p=0.04). Participants with high doses of MI had a 0.5 higher self-efficacy score than participants with zero amount of MI time (p<0.0001). Participants who received 3-4 counseling sessions had 0.41 greater self-efficacy scores than participants who did not receive any sessions (p<0.0001) but did not differ from participants receiving 1-2 sessions. MI time is a key to enhancing safer sex self-efficacy among PLWHA. Safer sex self-efficacy improves the more MI counseling time and sessions PLWHA receive. Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.

Differences in botulinum toxin dosing between patients with adductor spasmodic dysphonia and essential voice tremor.

PubMed

Orbelo, Diana M; Duffy, Joseph R; Hughes Borst, Becky J; Ekbom, Dale; Maragos, Nicolas E

2014-01-01

To explore possible dose differences in average botulinum toxin (BTX) given to patients with adductor spasmodic dysphonia (ADSD) compared with patients with essential voice tremor (EVT). A retrospective study compared the average BTX dose injected in equal doses to the thyroarytenoid (TA) muscles of 51 patients with ADSD with 52 patients with EVT. Those with ADSD received significantly higher total doses (6.80 ± 2.79 units) compared with those with EVT (5.02 ± 1.65 units). Dose at time of first injection, age at time of first injection, gender, year of first injection, and average time between injections were included in multivariate analysis but did not interact with total average dose findings. Patients with ADSD may need relatively higher doses of BTX injections to bilateral TA muscles compared with patients with EVT. Copyright © 2014 The Voice Foundation. Published by Mosby, Inc. All rights reserved.

Higher rate of severe toxicities in obese patients receiving dose-dense (dd) chemotherapy according to unadjusted body surface area: results of the prospectively randomized GAIN study.

PubMed

Furlanetto, J; Eiermann, W; Marmé, F; Reimer, T; Reinisch, M; Schmatloch, S; Stickeler, E; Thomssen, C; Untch, M; Denkert, C; von Minckwitz, G; Lederer, B; Nekljudova, V; Weber, K; Loibl, S; Möbus, V

2016-11-01

In routine clinical practice, chemotherapy doses are frequently capped at a body surface area (BSA) of 2.0 m 2 or adjusted to an ideal weight for obese patients due to safety reasons. Between August 2004 and July 2008, a total of 3023 patients were enrolled in the GAIN study, a randomized phase III adjuvant trial, comparing two types of dose-dense (dd) regimen [epirubicin, docetaxel and cyclophosphamide (iddETC) versus epirubicin and cyclophosphamide (EC) followed by docetaxel (T) plus capecitabine (X)]. We retrospectively evaluated a total of 555 patients with a BMI of ≥30 for safety and outcome. Eighteen percent of all patients were obese: 31% of those received chemotherapy according to an unadjusted BSA. For the remaining patients, BSA was adjusted to ideal weight or was capped at 2.0 m 2 . A total of 15% of obese patients receiving full (unadjusted) dose of chemotherapy versus 6% of obese patients with an adjusted BSA experienced febrile neutropenia (P = 0.003) and 9% versus 3% high-grade thrombopenia (P = 0.002). Overall, 17% versus 10% had a thromboembolic event (P = 0.017), which was high grade in 13% versus 6%, respectively (P = 0.019), and 3% versus 0.3% high-grade hot flushes (P = 0.013). Dizziness (5% versus 11%; P = 0.016), diarrhea (19% versus 27%; P = 0.033) and an increase in serum creatinine (7% versus 14%; P = 0.019) were higher in the adjusted group. However, no differences in disease-free survival (DFS) and overall survival (OS) were observed between non-obese patients, obese patients receiving full-dose chemotherapy or according to an adjusted BSA [5-year DFS 81% (confidence interval 79% to 83%) versus 82% (75% to 87%) versus 81% (76% to 84%); P = 0.761; 5-year OS 90% (88% to 91%) versus 86% (80% to 91%) versus 88% (84% to 91%); P = 0.143]. Obese patients receiving dd chemotherapy according to their real BSA have a higher risk of developing severe toxicities without influencing survival. Therefore, a dose adjustment of intense dd chemotherapy should be carried out to avoid life-threatening complications. © The Author 2016. 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.

Radiation dose in neoadjuvant chemoradiation therapy for esophageal cancer: patterns of care and outcomes from the National Cancer Data Base.

PubMed

Haque, Waqar; Verma, Vivek; Butler, E Brian; Teh, Bin S

2018-02-01

Neoadjuvant chemoradiotherapy (CRT) for locally advanced esophageal cancer (EC) may utilize a wide variety of RT doses, without clear consensus to date. This study evaluated national practice patterns between lower dose (LD) (40-41.4 Gy) or higher dose (HD) (50-50.4 Gy) therapy, in addition to differences in survival and postoperative events. The National Cancer Data Base (NCDB) was queried [2004-2013] for patients with newly-diagnosed cT1a-T4aN0/N+M0 EC that received neoadjuvant CRT followed by esophagectomy. Multivariable logistic regression determined factors predictive of receiving LD RT. Kaplan-Meier analysis evaluated overall survival (OS), and Cox proportional hazards modeling determined variables associated with OS. Propensity score matching assessed groups in a balanced manner while reducing indication biases. Altogether, 5,025 patients met inclusion criteria; 257 (5%) received LD RT, while 4,768 (95%) received HD RT. LD RT was more likely delivered at academic centers (P=0.038), in more recent years (2009-2013, P=0.011), and to squamous cell carcinomas (P=0.001). HD RT tended to be administered with higher T stage as well as node-positive disease (P<0.05). The median OS in the LD and HD cohorts was 39.0 vs. 35.6 months (P=0.072), and 39.0 vs. 42.7 months after propensity matching (P=0.812). Dose did not independently correlate with OS on multivariate analysis (P=0.069), but treatment at academic centers correlated with improved OS (P=0.028). There were no differences between groups in the rates of 30-day readmission (P=0.182), 30-day mortality (P=0.314), or length of postoperative hospital stay (P=0.665), but the LD group experienced lower 90-day mortality (P=0.007). Although neoadjuvant LD CRT has been underutilized for EC in the United States, it is rising in more recent years. Dose did not significantly impact survival before or after propensity matching, nor did it independently predict for survival. Treatment at academic facilities independently correlated with higher survival, which has implications for patient counseling.

Vorapaxar and optimal aspirin dose: The FDA outlook.

PubMed

Serebruany, Victor L; Fortmann, Seth D; Kim, Moo Hyun

2016-01-15

Vorapaxar, a novel thrombin PAR-1 inhibitor, approved for post-myocardial infarction, and peripheral artery disease indications has been tested in 2 major clinical trials. In the successful TRA2P, antecedent aspirin (ASA) has been used in 94% of patients, and in failed TRACER in over 96% of patients. However, both trial publications were silent on the impact of ASA dose on clinical outcomes after voraparax. We determined which ASA dose range should be used in combination with voraparax based on the TRA2P and TRACER secondary FDA review. The data suggest that for both voraparax trials, younger patients, males, and diabetics received higher ASA doses. The interactions between voraparax efficacy and ASA dose ≥ 300 mg was marginally significant by Cox regressions for TRA2P (CI=1.00-1.61; p=0.048) and strongly trended in TRACER (CI=0.98-1.47; p=0.073). Bleeding rates were overall slightly higher with voraparax than with placebo, and were the highest in patients receiving ASA dosages ≥ 300 mg. However, there were no interactions between ASA dose and GUSTO moderate/severe bleeding. In conclusion, the efficacy of voraparax in TRA2P and TRACER, was slightly worse while bleeding was substantially worse with the higher over 300 mg/day of ASA dosages. Voraparax label should recommend ASA daily use in 75 to 100mg range for concomitant use. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Somatotype, the risk of hydroxychloroquine retinopathy, and safe daily dosing guidelines.

PubMed

Browning, David J; Lee, Chong

2018-01-01

The aim of this study was to determine whether somatotype influences the risk of hydroxychloroquine (HC) retinopathy (HCR) and whether dosing by real body weight (RBW), ideal body weight (IBW), or the lesser of these better predicts the risk of HCR. A total of 565 patients taking HC for whom height and weight were recorded and a sensitive ancillary testing modality was used including 10-2 visual fields, spectral domain optical coherence tomography, fundus autofluorescence imaging, and multifocal electroretinography were enrolled. Body mass index (BMI) was compared for patients without and with HCR. Logistic regression models of age, cumulative dose, and daily dosing based on RBW, IBW, or lesser of these were compared. Area under the curve (AUC) of receiver operating characteristic plots was used to assess the diagnostic accuracy of RBW, IBW, and lesser of these guidelines for safe dosing. Probability plots for the risk of retinopathy versus BMI were compared for the different recommended guidelines on safe dosing. A total of 41 patients had HCR. The median BMI was 27.6 (interquartile range [IQR] 24.3, 32.6) and 24.0 (IQR 21.0, 31.6) for patients without and with HCR ( P =0.0102), respectively. AUC for univariate receiver operating characteristic plots of retinopathy versus dosing by RBW, IBW, and lesser of these was 0.71, 0.72, and 0.76, respectively. AUC for multivariate receiver operating characteristic plots of retinopathy versus models incorporating gender, age, cumulative dose, and BMI and differing by including dosing by RBW, IBW, and lesser of these was 0.82, 0.82, and 0.83, respectively. For all of the multivariate logistic models, the risk of retinopathy was higher for lower BMIs. Short, asthenic women are at higher risk for HCR. The 2011 American Academy of Ophthalmology (AAO) guidelines are safer for short, obese women. The 2016 AAO guidelines are safer for short, asthenic patients. Choosing daily dosing based on the lesser of the RBW and IBW guidelines is safer for all patients.

A Phase IIb Study of ABT‐494, a Selective JAK‐1 Inhibitor, in Patients With Rheumatoid Arthritis and an Inadequate Response to Anti–Tumor Necrosis Factor Therapy

PubMed Central

Emery, Paul; Camp, Heidi S.; Friedman, Alan; Wang, Li; Othman, Ahmed A.; Khan, Nasser; Pangan, Aileen L.; Jungerwirth, Steven; Keystone, Edward C.

2016-01-01

Objective To compare the efficacy and safety of ABT‐494, a novel selective JAK‐1 inhibitor, with placebo in patients with moderate‐to‐severe rheumatoid arthritis (RA) and an inadequate response or intolerance to at least 1 anti–tumor necrosis factor (anti‐TNF) agent. Methods In this 12‐week, double‐blind, placebo‐controlled, dose‐ranging study, 276 RA patients receiving a stable dose of methotrexate (MTX) who had previously received treatment with at least 1 anti‐TNF agent were randomized equally to receive immediate‐release ABT‐494 at 3, 6, 12, or 18 mg twice daily or matching placebo twice daily. The primary end point was the proportion of patients meeting the American College of Rheumatology 20% improvement criteria (achieving an ACR20 response) at week 12. Results At week 12, significantly more patients receiving ABT‐494 (53–71%) than those receiving placebo (34%) achieved an ACR20 response (by nonresponder imputation analysis) (P < 0.05), with a dose‐response relationship among all ABT‐494 doses (P < 0.001). ACR50 and ACR70 response rates were significantly higher in those receiving ABT‐494 (36–42% and 22–26%, respectively) than in those receiving placebo (16% and 4%, respectively). Changes from baseline in the Disease Activity Score in 28 joints using the C‐reactive protein level (DAS28‐CRP) were significantly greater for all doses of ABT‐494 than for placebo (P ≤ 0.01). Onset of action of ABT‐494 was rapid, with significant differences from placebo at week 2 both in ACR20 response rate (for 12 and 18 mg) and in change in the DAS28‐CRP (P < 0.001 for 6–18 mg). The most frequent adverse events (AEs) were headache, nausea, upper respiratory tract infection, and urinary tract infection. Infection rates were higher at higher doses of ABT‐494, but no infections were serious. No deaths were reported among those receiving ABT‐494. Conclusion In patients with an inadequate response or intolerance to anti‐TNF agents, ABT‐494 added to MTX showed rapid, dose‐dependent improvements in RA signs and symptoms, with safety and tolerability similar to those of other drugs of this class. No new AEs were identified. PMID:27389975

[Estimation of effective doses derived from radon in selected SPA centers that use geothermal waters based on the information of radon concentrations].

PubMed

Walczak, Katarzyna; Zmyślony, Marek

2013-01-01

Geothermal waters contain, among other components, soluble radon gas. Alpha radioactive radon is a health hazard to humans, especially when it gets into the respiratory tract. SPA facilities that use geothermal water can be a source of an increased radiation dose to people who stay there. Based on the available literature concerning radon concentrations, we assessed exposure to radon among people - workers and visitors of Spa centers that use geothermal waters. Radon concentrations were analyzed in 17 geothermal centers: in Greece (3 centers), Iran (5), China (4) and India (5). Doses recived by people in the SPA were estimated using the formula that 1 hour exposure to 1 Bq/m3 of radon concentration and equilibrium factor F = 0.4 corresponds to an effective dose of 3.2 nSv. We have found that radon levels in SPAs are from a few to several times higher than those in confined spaces, where geothermal waters are not used (e.g., residential buildings). In 82% of the analyzed SPAs, workers may receive doses above 1 mSv/year. According to the relevant Polish regulations, people receiving doses higher than 1 mSv/year are included in category B of radiation exposure and require regular dosimetric monitoring. Doses received by SPA visitors are much lower because the time of their exposure to radon released from geothermal water is rather short. The analysis of radon concentration in SPA facilities shows that the radiological protection of people working with geothermal waters plays an important role. It seems reasonable to include SPA workers staying close to geotermal waters into a dosimetric monitoring program.

The Effects of Nanoparticles Containing Iron on Blood and Inflammatory Markers in Comparison to Ferrous Sulfate in Anemic Rats

PubMed Central

Shafie, Elaheh Honarkar; Keshavarz, Seyed Ali; Kefayati, Mohammad Esmaiel; Taheri, Fatemeh; Sarbakhsh, Parvin; Vafa, Mohammad Reza

2016-01-01

Background: Ferrous sulfate is the most used supplement for treating anemia, but it can result in unfavorable side effects. Nowadays, nanotechnology is used as a way to increase bioavailability and decrease the side effects of drugs and nutrients. This study investigates the effects of nanoparticles containing iron on blood and inflammatory markers in comparison to ferrous sulfate in anemic rats. Methods: To induce the model of hemolytic anemia, 50 mg/kg bw phenylhydrazine was injected intraperitoneally in rats on the 1st day and 25 mg/kg bw for the four following days. Then, rats were randomly divided into five groups. No material was added to the nipple of the Group 1 (control). Group 2 received 0.4 mg/day nanoparticles of iron; Group 3 received 0.4 mg/day ferrous sulfate, and Groups 4 and 5 received double dose of iron nanoparticle and ferrous sulfate, respectively for ten days. Results: Hemoglobin and red blood cell (RBC) in Group 2 were significantly higher than Group 3 (P < 0.05). In addition, hemoglobin and RBC in Group 4 and 5 were significantly higher than Group 3 (P < 0.05). The average level of serum iron in Groups 2 and 4 was remarkably more than the groups received ferrous sulfate with similar doses (P < 0.05). C-reactive protein in Group 3 was more than Group 2 and in Group 5 was more compare to all other groups. Conclusions: Single dose of nanoparticles had more bioavailability compare to ferrous sulfate, but this did not occur for the double dose. Furthermore, both doses of nanoparticles caused lower inflammation than ferrous sulfate. PMID:27857830

Antibiotic dosing in critically ill patients receiving CRRT: underdosing is overprevalent.

PubMed

Lewis, Susan J; Mueller, Bruce A

2014-01-01

Published CRRT drug dosing algorithms and other dosing guidelines appear to result in underdosed antibiotics, leading to failure to attain pharmacodynamic targets. High mortality rates persist with inadequate antibiotic therapy as the most important risk factor for death. Reasons for unintended antibiotic underdosing in patients receiving CRRT are many. Underdosing may result from lack of the recognition that better hepatic function in AKI patients yields higher nonrenal antibiotic clearance compared to ESRD patients. Other factors include the variability in body size and fluid composition of patients, the serious consequence of delayed achievement of antibiotic pharmacodynamic targets in septic patients, potential subtherapeutic antibiotic concentrations at the infection site, and the influence of RRT intensity on antibiotic concentrations. Too often, clinicians weigh the benefits of overcautious antibiotic dosing to avoid antibiotic toxicity too heavily against the benefits of rapid attainment of therapeutic antibiotic concentrations in critically ill patients receiving CRRT. We urge clinicians to prescribe antibiotics aggressively for these vulnerable patients. © 2014 Wiley Periodicals, Inc.

Patterns of diagnostic imaging and associated radiation exposure among long-term survivors of young adult cancer: a population-based cohort study.

PubMed

Daly, Corinne; Urbach, David R; Stukel, Thérèse A; Nathan, Paul C; Deitel, Wayne; Paszat, Lawrence F; Wilton, Andrew S; Baxter, Nancy N

2015-09-03

Survivors of young adult malignancies are at risk of accumulated exposures to radiation from repetitive diagnostic imaging. We designed a population-based cohort study to describe patterns of diagnostic imaging and cumulative diagnostic radiation exposure among survivors of young adult cancer during a survivorship time period where surveillance imaging is not typically warranted. Young adults aged 20-44 diagnosed with invasive malignancy in Ontario from 1992-1999 who lived at least 5 years from diagnosis were identified using the Ontario Cancer Registry and matched 5 to 1 to randomly selected cancer-free persons. We determined receipt of 5 modalities of diagnostic imaging and associated radiation dose received by survivors and controls from years 5-15 after diagnosis or matched referent date through administrative data. Matched pairs were censored six months prior to evidence of recurrence. 20,911 survivors and 104,524 controls had a median of 13.5 years observation. Survivors received all modalities of diagnostic imaging at significantly higher rates than controls. Survivors received CT at a 3.49-fold higher rate (95% Confidence Interval [CI]:3.37, 3.62) than controls in years 5 to 15 after diagnosis. Survivors received a mean radiation dose of 26 miliSieverts solely from diagnostic imaging in the same time period, a 4.57-fold higher dose than matched controls (95% CI: 4.39, 4.81). Long-term survivors of young adult cancer have a markedly higher rate of diagnostic imaging over time than matched controls, imaging associated with substantial radiation exposure, during a time period when surveillance is not routinely recommended.

Comparison of the Pharmacoeconomics of Calfactant and Poractant Alfa in Surfactant Replacement erapy.

PubMed

Zayek, Michael M; Eyal, Fabien G; Smith, Robert C

2018-01-01

To compare the pharmacy costs of calfactant (Infasurf, ONY, Inc.) and poractant alfa (Curosurf, Chiesi USA, Inc., Cary, NC). The University of South Alabama Children's and Women's Hospital switched from calfactant to poractant alfa in 2013 and back to calfactant in 2015. Retrospectively, we used deidentified data from pharmacy records that provided type of surfactant administered, gestational age, birth weight, and number of doses on each patient. We examined differences in the number of doses by gestational ages and the differences in costs by birth weight cohorts because cost per dose is based on weight. There were 762 patients who received calfactant and 432 patients who received poractant alfa. The average number of doses required per patient was 1.6 administrations for calfactant-treated patients and 1.7 administrations for poractant alfa-treated patients, p = 0.03. A higher percentage of calfactant patients needed only 1 dose (53%) than poractant alfa patients (47%). The distribution of the number of doses for calfactant-treated patients was significantly lower than for the poractant alfa-patients, p < 0.001. Gestational age had no consistent effect on the number of doses required for either calfactant or poractant alfa. Per patient cost was higher for poractant alfa than for calfactant in all birth weight cohorts. Average per patient cost was $1160.62 for poractant alfa, 38% higher than the average per patient cost for calfactant ($838.34). Using poractant alfa for 22 months is estimated to have cost $202,732.75 more than it would have cost if the hospital had continued using calfactant. Our experience showed a strong pharmacoeconomic advantage for the use of calfactant compared to the use of poractant alfa because of similar average dosing and lower per patient drug costs.

Hepatic effects of orally administered styrene in rats.

PubMed

Srivastava, S P; Das, M; Mushtaq, M; Chandra, S V; Seth, P K

1982-08-01

Adult male rats receiving styrene by gavage (200 or 400 mg kg-1, 6 days a week) for 100 days exhibited a significant dose-dependent increase in hepatic benzo[a]pyrene hydroxylase and aminopyrine-N-demethylase, a decrease in glutathione-S-transferase and no change in glucose-6-phosphatase. A decrease in the activity of mitochondrial succinic dehydrogenase and beta-glucuronidase was also observed. Activity of acid phosphatase was decreased only at the higher dose level. Levels of serum glutamic oxaloacetic transaminase and glutamic pyruvic transaminase were elevated only at the higher dose level. The absolute and relative weights of the liver of control and treated animals showed no significant difference. Histopathological studies of the liver tissue revealed tiny areas of focal necrosis, consisting of few degenerated hepatocytes and inflammatory cells at the higher dose level only.

INADEQUACY OF THORON DOSE CALCULATIONS FROM THORON PROGENY MEASUREMENT ALONE.

PubMed

Lane-Smith, D; Wong, F K

2016-10-01

To determine the dose received by thoron ( 220 Rn) domestically, conventional methods measure the activity concentration of thoron progeny only (namely the 212 Pb atoms) and calculate the dose by using a set of conversion factors. This may be due to the measurement of progeny being simpler since it is longer lived and will be evenly spread throughout the room, whereas the thoron gas, with its short half-life, will exist only near the source and hence will not be of major concern for the majority of the room. However, concrete walls are a source of thoron, and spending prolonged amounts of time near them may lead to greatly increased radiation exposure, the degree of which is not revealed through progeny activity alone. The present paper compares the energy received from the ionising radiation of both thoron gas and thoron progeny near its source. Converting the energy dose to radiation dose is not within the scope of this paper. The results suggest a difference of an order of magnitude higher when taking into account the dose received by thoron gas. © The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Estradiol promotes the rewarding effects of nicotine in female rats.

PubMed

Flores, Rodolfo J; Pipkin, Joseph A; Uribe, Kevin P; Perez, Adriana; O'Dell, Laura E

2016-07-01

It is presently unclear whether ovarian hormones, such as estradiol (E2), promote the rewarding effects of nicotine in females. Thus, we compared extended access to nicotine intravenous self-administration (IVSA) in intact male, intact female, and OVX female rats (Study 1) as well as OVX females that received vehicle or E2 supplementation (Study 2). The E2 supplementation procedure involved a 4-day injection regimen involving 2 days of vehicle and 2 days of E2 administration. Two doses of E2 (25 or 250μg) were assessed in separate groups of OVX females in order to examine the dose-dependent effects of this hormone on the rewarding effects of nicotine. The rats were given 23-hour access to nicotine IVSA using an escalating dose regimen (0.015, 0.03, and 0.06mg/kg/0.1mL). Each dose was self-administered for 4 days with 3 intervening days of nicotine abstinence. The results revealed that intact females displayed higher levels of nicotine intake as compared to males. Also, intact females displayed higher levels of nicotine intake versus OVX females. Lastly, our results revealed that OVX rats that received E2 supplementation displayed a dose-dependent increase in nicotine intake as compared to OVX rats that received vehicle. Together, our results suggest that the rewarding effects of nicotine are enhanced in female rats via the presence of the ovarian hormone, E2. Copyright © 2016 Elsevier B.V. All rights reserved.

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 .).

Dosimetric quality endpoints for low-dose-rate prostate brachytherapy using biological effective dose (bed) vs. conventional dose

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

Singh, Rachana; Al-Hallaq, Hania; Pelizzari, Charles A.

2003-12-31

The purpose of this study was to compare conventional low-dose-rate prostate brachytherapy dosimetric quality parameters with their biological effective dose (BED) counterparts. To validate a model for transformation from conventional dose to BED, the postimplant plans of 31 prostate brachytherapy patients were evaluated using conventional dose-volume histogram (DVH) quality endpoints and analogous BED-DVH endpoints. Based on CT scans obtained 4 weeks after implantation, DVHs were computed and standard dosimetric endpoints V100 (volume receiving 100% of the prescribed dose), V150, V200, HI (1-[V150/V100]), and D90 (dose that 90% of the target volume received) were obtained for quality analysis. Using known andmore » reported transformations, dose grids were transformed to BED-early ({alpha}/{beta} = 10 Gy) and BED-late ({alpha}/{beta} = 3 Gy) grids, and the same dosimetric endpoints were analyzed. For conventional, BED-early and BED-late DVHs, no differences in V100 were seen (0.896, 0.893, and 0.894, respectively). However, V150 and V200 were significantly higher for both BED-early (0.582 and 0.316) and BED-late (0.595 and 0.337), compared with the conventional (0.539 and 0.255) DVHs. D90 was significantly lower for the BED-early (103.1 Gy) and BED-late transformations (106.9 Gy) as compared with the conventional (119.5 Gy) DVHs. The conventional prescription parameter V100 is the same for the corresponding BED-early and BED-late transformed DVHs. The toxicity parameters V150 and V200 are slightly higher using the BED transformations, suggesting that the BED doses are somewhat higher than predicted using conventional DVHs. The prescription/quality parameter D90 is slightly lower, implying that target coverage is lower than predicted using conventional DVHs. This methodology can be applied to analyze BED dosimetric endpoints to improve clinical outcome and reduce complications of prostate brachytherapy.« less

Thyroid Radiation Dose and Other Risk Factors of Thyroid Carcinoma Following Childhood Cancer.

PubMed

de Vathaire, Florent; Haddy, Nadia; Allodji, Rodrigue S; Hawkins, Mike; Guibout, Catherine; El-Fayech, Chiraz; Teinturier, Cécile; Oberlin, Odile; Pacquement, Hélène; Diop, Fara; Kalhouche, Amar; Benadjaoud, Mohamedamine; Winter, David; Jackson, Angela; Bezin Mai-Quynh, Giao; Benabdennebi, Aymen; Llanas, Damien; Veres, Cristina; Munzer, Martine; Nguyen, Tan Dat; Bondiau, Pierre-Yves; Berchery, Delphine; Laprie, Anne; Deutsch, Eric; Lefkopoulos, Dimitri; Schlumberger, Martin; Diallo, Ibrahima; Rubino, Carole

2015-11-01

Thyroid carcinoma is a frequent complication of childhood cancer radiotherapy. The dose response to thyroid radiation dose is now well established, but the potential modifier effect of other factors requires additional investigation. This study aimed to investigate the role of potential modifiers of the dose response. We followed a cohort of 4338 5-year survivors of solid childhood cancer treated before 1986 over an average of 27 years. The dose received by the thyroid gland and some other anatomical sites during radiotherapy was estimated after reconstruction of the actual conditions in which irradiation was delivered. Fifty-five patients developed thyroid carcinoma. The risk of thyroid carcinoma increased with a radiation dose to the thyroid of up to two tenths of Gy, then leveled off for higher doses. When taking into account the thyroid radiation dose, a surgical or radiological splenectomy (>20 Gy to the spleen) increased thyroid cancer risk (relative risk [RR] = 2.3; 95% confidence interval [CI], 1.3-4.0), high radiation doses (>5 Gy) to pituitary gland lowered this risk (RR = 0.2; 95% CI, 0.1-0.6). Patients who received nitrosourea chemotherapy had a 6.6-fold (95% CI, 2.5-15.7) higher risk than those who did not. The excess RR per Gy of radiation to the thyroid was 4.7 (95% CI, 1.7-22.6). It was 7.6 (95% CI, 1.6-33.3) if body mass index at time of interview was equal or higher than 25 kg/m(2), and 4.1 (95% CI, 0.9-17.7) if not (P for interaction = .1). Predicting thyroid cancer risk following childhood cancer radiation therapy probably requires the assessment of more than just the radiation dose to the thyroid. Chemotherapy, splenectomy, radiation dose to pituitary gland, and obesity also play a role.

Randomized trial of betahistine mesilate tablets as augmentation for oxcarbazepine and carbamazepine in treating vestibular paroxysmia.

PubMed

Xue, Hui; Xiang, Wenping; Yu, Yichuan; Liu, Guorong; Chong, Yi; Zhou, Jiying

2018-01-01

Vestibular paroxysmia (VP) is a rare episodic peripheral vestibular disorder. This study was conducted to compare the efficacy and acceptability of carbamazepine (CBZ) plus betahistine mesilate tablets (BMT) (CBZ+BMT) and oxcarbazepine (OXC) plus BMT (OXC+BMT) in treating VP, and investigated whether the synergistic effect could be increased along with the increased dose of BMT. VP patients were recruited and randomly assigned to receive CBZ+BMT or OXC+BMT. The doses of CBZ and OXC were set to 200 and 300 mg/time, twice daily, respectively. The doses of BMT were set to 12 and 18 mg/time, twice daily. Half of the patients in each group received BMT 12 mg/time and the other half received BMT 18 mg/time. The treatment was continued for 12 weeks. The vertigo frequency, vertigo score, vertigo duration, response rate, and drug-related side effects were analyzed. In total, 92 patients in the CBZ+BMT group and 93 patients in the OXC+BMT group completed this trial. After 12 weeks of treatment, the two groups had similar average vertigo frequency, average vertigo score, average vertigo duration, and response rate. But the incidence of side effects was significantly higher in the CBZ+BMT group than in the OXC+BMT group ( p =0.04). Subgroup analysis found that patients receiving BMT (18 mg) had greater reductions in average vertigo frequency, average vertigo duration, and average vertigo score, and higher response rates than patients receiving BMT (12 mg). These results demonstrated that OXC+BMT may be suitable as an alternative method in VP patients with CBZ hypersensitivity, and the synergistic effect could be increased along with the increased dose of BMT.

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

PubMed

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

2017-01-01

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

A summary of evidence on radiation exposures received near to the Semipalatinsk nuclear weapons test site in Kazakhstan.

PubMed

Simon, Steven L; Baverstock, Keith F; Lindholm, Carita

2003-06-01

The presently available evidence about the magnitude of doses received by members of the public living in villages in the vicinity of Semipalatinsk nuclear test in Kazakhstan, particularly with respect to external radiation, while preliminary, is conflicting. The village of Dolon, in particular, has been identified for many years as the most highly exposed location in the vicinity of the test site. Previous publications cited external doses of more than 2 Gy to residents of Dolon while an expert group assembled by the WHO in 1997 estimated that external doses were likely to have been less than 0.5 Gy. In 2001, a larger expert group workshop was held in Helsinki jointly by the WHO, the National Cancer Institute of the United States, and the Radiation and Nuclear Safety Authority of Finland, with the expressed purpose to acquire data to evaluate the state of knowledge concerning doses received in Kazakhstan. This paper summarizes evidence presented at that workshop. External dose estimates from calculations based on sparse physical measurements and bio-dosimetric estimates based on chromosome abnormalities and electron paramagnetic resonance from a relatively small sample of teeth do not agree well. The physical dose estimates are generally higher than the biodosimetric estimates (1 Gy or more compared to 0.5 Gy or less). When viewed in its entirety, the present body of evidence does not appear to support external doses greater than 0.5 Gy; however, research is continuing to try and resolve the difference in dose estimates from the different methods. Thyroid doses from internal irradiation, which can only be estimated via calculation, are expected to have been several times greater than the doses from external irradiation, especially where received by small children.

Aminocaproic Acid (amicar) as an alternative to aprotinin (trasylol) in liver transplantation.

PubMed

Mangus, R S; Kinsella, S B; Fridell, J A; Kubal, C A; Lahsaei, P; Mark, L O; Tector, A J

2014-06-01

This study compared clinical outcomes for a large number of liver transplant patients receiving intraoperative epsilon-aminocaproic acid (EACA), aprotinin, or no antifibrinolytic agent over an 8-year period. Records for deceased donor liver transplants were reviewed. Data included antifibrinolytic agent, blood loss, early graft function, and postoperative complications. Study groups included low-dose aprotinin, high-dose aprotinin, EACA (25 mg/kg, 1-hour infusion), or no antifibrinolytic agent. Data were included for 1170 consecutive transplants. Groups included low-dose aprotinin (n = 324 [28%]), high-dose aprotinin (n = 308 [26%]), EACA (n = 216 [18%]), or no antifibrinolytic (n = 322 [28%]). EACA had the lowest intraoperative blood loss and required the fewest transfusions of plasma. Patients receiving no agent required the most blood transfusions. Early graft loss was lowest in the EACA group, and 90-day and 1-year patient survival rates were significantly higher for the low-dose aprotinin and EACA groups according to Cox regression. Complications were similar, but there were more episodes of deep vein thrombosis in patients receiving EACA. These results suggest that transitioning from aprotinin to EACA did not result in worse outcomes. In addition to decreased intraoperative blood loss, a trend toward improved graft and patient survival was seen in patients receiving EACA. Copyright © 2014 Elsevier Inc. All rights reserved.

Effective Dose of Radon 222 Bottled Water in Different Age Groups Humans: Bandar Abbas City, Iran.

PubMed

Fakhri, Yadolah; Mahvi, Amir Hossein; Langarizadeh, Ghazaleh; Zandsalimi, Yahya; Amirhajeloo, Leila Rasouli; Kargosha, Morteza; Moradi, Mahboobeh; Moradi, Bigard; Mirzaei, Maryam

2015-06-04

Radon 222 is a natural radioactive element with a half-life of 3.8 days. It is odorless and colorless as well as water-soluble. Consuming waters which contain high concentration of 222Rn would increase the effective dose received by different age groups. It would also be followed by an increased prevalence of cancer. In this research, 72 samples of the most commonly used bottled water in Bandar Abbas were collected in 3 consecutive months, May, June and July of 2013. Concentration 222Rn of was measured by radon-meter model RTM166-2. The effective dose received by the 4 age groups, male and female adults as well as children and infants was estimated using the equation proposed by UNSCEAR. The results revealed that the mean and range concentration of 222Rn in bottled waters were 641±9 Bq/m3 and 0-901 Bq/m3, respectively. The mean concentration of 222Rn in the well-known Marks followed this Zam Zam>Bishe>Koohrng>Dassani>Christal>Polour>Damavand>Sivan. Infants were observed to receive a higher effective dose than children. The highest and lowest effective dose received was found to belong to male adults and children, respectively.

Effective Dose of Radon 222 Bottled Water in Different Age Groups Humans: Bandar Abbas City, Iran

PubMed Central

Fakhri, Yadolah; Mahvi, Amir Hossein; Langarizadeh, Ghazaleh; Zandsalimi, Yahya; Amirhajeloo, Leila Rasouli; Kargosha, Morteza; Moradi, Mahboobeh; Moradi, Bigard; Mirzaei, Maryam

2016-01-01

Radon 222 is a natural radioactive element with a half-life of 3.8 days. It is odorless and colorless as well as water-soluble. Consuming waters which contain high concentration of 222Rn would increase the effective dose received by different age groups. It would also be followed by an increased prevalence of cancer. In this research, 72 samples of the most commonly used bottled water in Bandar Abbas were collected in 3 consecutive months, May, June and July of 2013. Concentration 222Rn of was measured by radon-meter model RTM166-2. The effective dose received by the 4 age groups, male and female adults as well as children and infants was estimated using the equation proposed by UNSCEAR. The results revealed that the mean and range concentration of 222Rn in bottled waters were 641±9 Bq/m3 and 0-901 Bq/m3, respectively. The mean concentration of 222Rn in the well-known Marks followed this Zam Zam>Bishe>Koohrng>Dassani>Christal>Polour>Damavand>Sivan. Infants were observed to receive a higher effective dose than children. The highest and lowest effective dose received was found to belong to male adults and children, respectively. PMID:26383192

High-dose versus standard-dose radiotherapy with concurrent chemotherapy in stages II-III esophageal cancer.

PubMed

Suh, Yang-Gun; Lee, Ik Jae; Koom, Wong Sub; Cha, Jihye; Lee, Jong Young; Kim, Soo Kon; Lee, Chang Geol

2014-06-01

In this study, we investigated the effects of radiotherapy ≥60 Gy in the setting of concurrent chemo-radiotherapy for treating patients with Stages II-III esophageal cancer. A total of 126 patients treated with 5-fluorouracilbased concurrent chemo-radiotherapy between January 1998 and February 2008 were retrospectively reviewed. Among these patients, 49 received a total radiation dose of <60 Gy (standard-dose group), while 77 received a total radiation dose of ≥60 Gy (high-dose group). The median doses in the standard- and high-dose groups were 54 Gy (range, 45-59.4 Gy) and 63 Gy (range, 60-81 Gy), respectively. The high-dose group showed significantly improved locoregional control (2-year locoregional control rate, 69 versus 32%, P < 0.01) and progression-free survival (2-year progression-free survival, 47 versus 20%, P = 0.01) than the standard-dose group. Median overall survival in the high- and the standard-dose groups was 28 and 18 months, respectively (P = 0.26). In multivariate analysis, 60 Gy or higher radiotherapy was a significant prognostic factor for improved locoregional control, progression-free survival and overall survival. No significant differences were found in frequencies of late radiation pneumonitis, post-treatment esophageal stricture or treatment-related mortality between the two groups. High-dose radiotherapy of 60 Gy or higher with concurrent chemotherapy improved locoregional control and progression-free survival without a significant increase of in treatment-related toxicity in patients with Stages II-III esophageal cancer. Our study could provide the basis for future randomized clinical trials. © The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

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

PubMed Central

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

2016-01-01

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

Hematologic Toxicity in RTOG 0418: A Phase 2 Study of Postoperative IMRT for Gynecologic Cancer

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

Klopp, Ann H., E-mail: aklopp@mdanderson.org; Moughan, Jennifer; Portelance, Lorraine

2013-05-01

Purpose: Intensity modulated radiation therapy (IMRT), compared with conventional 4-field treatment, can reduce the volume of bone marrow irradiated. Pelvic bone marrow sparing has produced a clinically significant reduction in hematologic toxicity (HT). This analysis investigated HT in Radiation Therapy Oncology Group (RTOG) 0418, a prospective study to test the feasibility of delivering postoperative IMRT for cervical and endometrial cancer in a multiinstitutional setting. Methods and Materials: Patients in the RTOG 0418 study were treated with postoperative IMRT to 50.4 Gy to the pelvic lymphatics and vagina. Endometrial cancer patients received IMRT alone, whereas patients with cervical cancer received IMRTmore » and weekly cisplatin (40 mg/m{sup 2}). Pelvic bone marrow was defined within the treatment field by using a computed tomography density-based autocontouring algorithm. The volume of bone marrow receiving 10, 20, 30, and 40 Gy and the median dose to bone marrow were correlated with HT, graded by Common Terminology Criteria for Adverse Events, version 3.0, criteria. Results: Eighty-three patients were eligible for analysis (43 with endometrial cancer and 40 with cervical cancer). Patients with cervical cancer treated with weekly cisplatin and pelvic IMRT had grades 1-5 HT (23%, 33%, 25%, 0%, and 0% of patients, respectively). Among patients with cervical cancer, 83% received 5 or more cycles of cisplatin, and 90% received at least 4 cycles of cisplatin. The median percentage volume of bone marrow receiving 10, 20, 30, and 40 Gy in all 83 patients, respectively, was 96%, 84%, 61%, and 37%. Among cervical cancer patients with a V40 >37%, 75% had grade 2 or higher HT compared with 40% of patients with a V40 less than or equal to 37% (P =.025). Cervical cancer patients with a median bone marrow dose of >34.2 Gy also had higher rates of grade ≥2 HT than did those with a dose of ≤34.2 Gy (74% vs 43%, P=.049). Conclusions: Pelvic IMRT with weekly cisplatin is associated with low rates of HT and high rates of weekly cisplatin use. The volume of bone marrow receiving 40 Gy and the median dose to bone marrow correlated with higher rates of grade ≥2 toxicity among patients receiving weekly cisplatin (cervical cancer patients). Evaluation and limitation of the volume of bone marrow treated with pelvic IMRT is warranted in patients receiving concurrent chemotherapy.« less

Older adults and high-risk medication administration in the emergency department.

PubMed

Kim, Mitchell; Mitchell, Steven H; Gatewood, Medley; Bennett, Katherine A; Sutton, Paul R; Crawford, Carol A; Bentov, Itay; Damodarasamy, Mamatha; Kaplan, Stephen J; Reed, May J

2017-01-01

Older adults are susceptible to adverse effects from opioids, nonsteroidal anti-inflammatory drugs (NSAIDs), and benzodiazepines (BZDs). We investigated factors associated with the administration of elevated doses of these medications of interest to older adults (≥65 years old) in the emergency department (ED). ED records were queried for the administration of medications of interest to older adults at two academic medical center EDs over a 6-month period. Frequency of recommended versus elevated ("High doses" were defined as doses that ranged between 1.5 and 3 times higher than the recommended starting doses; "very high doses" were defined as higher than high doses) starting doses of medications, as determined by geriatric pharmacy/medicine guidelines and expert consensus, was compared by age groups (65-69, 70-74, 75-79, 80-84, and ≥85 years), gender, and hospital. There were 17896 visits representing 11374 unique patients >65 years of age (55.3% men, 44.7% women). A total of 3394 doses of medications of interest including 1678 high doses and 684 very high doses were administered to 1364 different patients. Administration of elevated doses of medications was more common than that of recommended doses. Focusing on opioids and BZDs, the 65-69-year age group was much more likely to receive very high doses (1481 and 412 doses, respectively) than the ≥85-year age groups (relative risk [RR] 5.52, 95% CI 2.56-11.90), mainly reflecting elevated opioid dosing (RR 8.28, 95% CI 3.69-18.57). Men were more likely than women to receive very high doses (RR 1.47, 95% CI 1.26-1.72), primarily due to BZDs (RR 2.12, 95% CI 2.07-2.16). Administration of elevated doses of opioids and BZDs in the older population occurs frequently in the ED, especially to the 65-69-year age group and men. Further attention to potentially unsafe dosing of high-risk medications to older adults in the ED is warranted.

Clinical and Immune Responses to Inactivated Influenza A(H1N1)pdm09 Vaccine in Children

PubMed Central

Kotloff, Karen L.; Halasa, Natasha B.; Harrison, Christopher J.; Englund, Janet A.; Walter, Emmanuel B.; King, James C.; Creech, C. Buddy; Healy, Sara A.; Dolor, Rowena J.; Stephens, Ina; Edwards, Kathryn M.; Noah, Diana L.; Hill, Heather; Wolff, Mark

2014-01-01

Background As the influenza AH1N1 pandemic emerged in 2009, children were found to experience high morbidity and mortality and were prioritized for vaccination. This multicenter, randomized, double-blind, age-stratified trial assessed the safety and immunogenicity of inactivated influenza A(H1N1)pdm09 vaccine in healthy children aged 6 months to 17 years. Methods Children received two doses of approximately 15 μg or 30 μg hemagglutin antigen 21 days apart. Reactogenicity was assessed for 8 days after each dose, adverse events through day 42, and serious adverse events or new-onset chronic illnesses through day 201. Serum hemagglutination inhibition (HAI) titers were measured on days 0 (pre-vaccination), 8, 21, 29, and 42. Results A total of 583 children received the first dose and 571 received the second dose of vaccine. Vaccinations were generally well-tolerated and no related serious adverse events were observed. The 15 μg dosage elicited a seroprotective HAI (≥1:40) in 20%, 47%, and 93% of children in the 6-35 month, 3-9 year, and 10-17 year age strata 21 days after dose 1 and in 78%, 82%, and 98% of children 21 days after dose 2, respectively. The 30 μg vaccine dosage induced similar responses. Conclusions The inactivated influenza A(H1N1)pdm09 vaccine exhibited a favorable safety profile at both dosage levels. While a single 15 or 30 μg dose induced seroprotective antibody responses in most 10-17 year olds, younger children required 2 doses, even when receiving dosages 4-6 fold higher than recommended. Well-tolerated vaccines are needed that induce immunity after a single dose for use in young children during influenza pandemics. PMID:25222307

Durable responses and reversible toxicity of high-dose interleukin-2 treatment of melanoma and renal cancer in a Community Hospital Biotherapy Program.

PubMed

Payne, Roxanne; Glenn, Lyn; Hoen, Helena; Richards, Beverley; Smith, John W; Lufkin, Robert; Crocenzi, Todd S; Urba, Walter J; Curti, Brendan D

2014-01-01

High-dose interleukin-2 (IL-2) has been FDA-approved for over 20 years, but it is offered only at a small number of centers with expertise in its administration. We analyzed the outcomes of patients receiving high-dose IL-2 in relation to the severity of toxicity to ascertain if response or survival were adversely affected. A retrospective analysis of the outcomes of 500 patients with metastatic renal cell carcinoma (RCC) (n = 186) or melanoma (n = 314) treated with high-dose IL-2 between 1997 and 2012 at Providence Cancer Center was performed. IL-2 was administered at a dose of 600,000 international units per kg by IV bolus every 8 hours for up to 14 doses. A second cycle was administered 16 days after the first and patients with tumor regression could receive additional cycles. Survival and anti-tumor response were analyzed by diagnosis, severity of toxicity, number of IL-2 cycles and subsequent therapy. The objective response rate in melanoma was 28% (complete 12% and partial 16%), and in RCC was 24% (complete 7% and partial 17%). The 1-, 2- and 3-year survivals were 59%, 41% and 31%, for melanoma and 75%, 56% and 44%, for RCC, respectively. The proportion of patients with complete or partial response in both melanoma and RCC was higher in patients who a) required higher phenylephrine doses to treat hypotension (p < 0.003), b) developed acidosis (bicarbonate < 19 mmol (p < 0.01)), or c) thrombocytopenia (<50, 50-100, >100,000 platelets; p < 0.025). The proportion achieving a complete or partial response was greater in patients with melanoma who received 5 or more compared with 4 or fewer IL-2 cycles (p < 0.0001). The incidence of death from IL-2 was less than 1% and was not higher in patients who required phenylephrine. High-dose IL-2 can be administered safely; severe toxicity including hypotension is reversible and can be managed in a community hospital. The tumor response and survival reported here are superior to the published literature and support treating patients to their individualized maximum tolerated dose. IL-2 should remain part of the treatment paradigm in selected patients with melanoma and RCC.

Acute toxicity of ibogaine and noribogaine.

PubMed

Kubiliene, Asta; Marksiene, Rūta; Kazlauskas, Saulius; Sadauskiene, Ilona; Razukas, Almantas; Ivanov, Leonid

2008-01-01

To evaluate acute toxic effect of ibogaine and noribogaine on the survival of mice and determine median lethal doses of the substances mentioned. White laboratory mice were used for the experiments. Ibogaine and noribogaine were administered intragastrically to mice via a stomach tube. Control animals received the same volume of saline. The median lethal dose was calculated with the help of a standard formula. To determine the median lethal dose of ibogaine, the doses of 100, 300, 400, and 500 mg/kg were administered intragastrically to mice. The survival time of mice after the drug administration was recorded, as well as the number of survived mice in each group. Upon administration of ibogaine at a dose of 500 mg/kg, all mice in this dose group died. Three out of four mice died in the group, which received 300 mg/kg of ibogaine. No mouse deaths were observed in the group, which received 100 mg/kg of ibogaine. The determined LD(50) value of ibogaine equals to 263 mg/kg of body mass. In order to determine the median lethal dose of noribogaine, the doses of 300, 500, 700, and 900 mg/kg were administered to mice intragastrically. Noribogaine given at a dose of 500 mg/kg had no impact on the mouse survival. The increase of noribogaine dose to 700 mg/kg of mouse body mass led to the death of three out of four mice in the group. Upon administration of noribogaine at a dose of 900 mg/kg, all mice in this group died. The LD(50) value of noribogaine in mice determined on the basis of the number of dead mice and the size of the doses used equals to 630 mg/kg of mouse body mass. The behavior of mice was observed upon administration of ibogaine or noribogaine. Low doses of ibogaine and noribogaine had no impact on the mouse behavior. External effects (convulsions, nervous behaviour, limb paralysis) were observed only when substances were administrated at higher doses. It has been determined that the median lethal dose of ibogaine and noribogaine equals to 263 mg and 630 mg/kg of mouse body mass, respectively. The toxicity of ibogaine is 2.4 times higher than that of noribogaine.

Volumetric tumor burden and its effect on brachial plexus dosimetry in head and neck intensity-modulated radiotherapy

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

Romesser, Paul B.; Qureshi, Muhammad M.; Kovalchuk, Nataliya

2014-07-01

To determine the effect of gross tumor volume of the primary (GTV-P) and nodal (GTV-N) disease on planned radiation dose to the brachial plexus (BP) in head and neck intensity-modulated radiotherapy (IMRT). Overall, 75 patients underwent definitive IMRT to a median total dose of 69.96 Gy in 33 fractions. The right BP and left BP were prospectively contoured as separate organs at risk. The GTV was related to BP dose using the unpaired t-test. Receiver operating characteristics curves were constructed to determine optimized volumetric thresholds of GTV-P and GTV-N corresponding to a maximum BP dose cutoff of > 66 Gy.more » Multivariate analyses were performed to account for factors associated with a higher maximal BP dose. A higher maximum BP dose (> 66 vs ≤ 66 Gy) correlated with a greater mean GTV-P (79.5 vs 30.8 cc; p = 0.001) and ipsilateral GTV-N (60.6 vs 19.8 cc; p = 0.014). When dichotomized by the optimized nodal volume, patients with an ipsilateral GTV-N ≥ 4.9 vs < 4.9 cc had a significant difference in maximum BP dose (64.2 vs 59.4 Gy; p = 0.001). Multivariate analysis confirmed that an ipsilateral GTV-N ≥ 4.9 cc was an independent predictor for the BP to receive a maximal dose of > 66 Gy when adjusted individually for BP volume, GTV-P, the use of a low anterior neck field technique, total planned radiation dose, and tumor category. Although both the primary and the nodal tumor volumes affected the BP maximal dose, the ipsilateral nodal tumor volume (GTV-N ≥ 4.9 cc) was an independent predictor for high maximal BP dose constraints in head and neck IMRT.« less

Effect of esomeprazole and rabeprazole on intragastric pH in healthy Chinese: an open, randomized crossover trial.

PubMed

Li, Zhao-Shen; Zhan, Xian-Bao; Xu, Guo-Ming; Cheng, Neng-Neng; Liao, Zhuan

2007-06-01

Esomeprazole is the S-isomer of omeprazole, with a stronger acid suppressive effect than omeprazole. This open, randomized crossover study was designed to evaluate the effect of esomeprazole and another proton-pump inhibitor, rabeprazole, on intragastric pH in healthy Chinese. Thirty-six healthy volunteers (26 men and 10 women, aged between 20 and 31 years) were enrolled. Subjects were given either esomeprazole 40 mg (n = 18) or rabeprazole 10 mg (n = 18) orally once daily for 5 days during the first dosing period, then the other medicine at the set dosage for the second dosing period. The two periods were separated by a 14-day washout phase. The doses were chosen according to the State Food and Drug Administration of China for the treatment of acid-related diseases. Intragastric pH was continuously monitored for 24 h on days 1 and 5 of each dosing period. CYP2C19 genotypes were analyzed to identify the extensive metabolizers (EM) and poor metabolizers (PM). The percentage of time with intragastric pH >4 was significantly higher (P < 0.001) in subjects receiving esomeprazole than in those receiving rabeprazole in the first 4 h after administration of the first dose (70.65% vs 44.87%), at 24 h on day 1 (73.7% vs 54.8%) and at 24 h on day 5 (84.2% vs 76.2%). The median intragastric pH was also higher in subjects receiving esomeprazole than in those receiving rabeprazole in the first 6 h, day 1 and day 5 (P 4 for at least 16 h on day 1 (63.9% vs 33.3%) and on day 5 (88.9% vs 61.1%) was higher after administration of esomeprazole than after rabeprazole (both P < 0.05). On genotype analysis, 28 of the subjects were EM and eight were PM. Those who were PM tended to have a higher, albeit not statistically significant, percentage of time with intragastric pH >4 and the median 24-h intragastric pH than those who were EM. Both drugs were well tolerated. Esomeprazole 40 mg orally once daily is more effective and faster in increasing intragastric pH than rabeprazole 10 mg orally once daily, and thus offers a potential for improved efficacy in acid-related diseases.

Postoperative radiotherapy dose requirement in standard combined-modality practice for head and neck squamous cell carcinoma: Analysis of salient surgical and radiotherapy parameters in 2 cohorts.

PubMed

Mohanti, Bidhu K; Thakar, Alok; Kaur, Jaspreet; Bahadur, Sudhir; Malik, Monica; Gandhi, Ajeet K; Bhasker, Suman; Sharma, Atul

2017-09-01

This study compared 2 sequential cohorts to identify the postoperative radiotherapy (PORT) dose requirement for head and neck squamous cell carcinoma (HNSCC). Two distinct PORT dose regimens were prescribed over 11 years; group 1 received 56 Gy or less, and group 2 received 60 Gy or more. The 2D and 3D techniques were used. Two sequential cohorts consisted of 478 patients, with mean and median follow-up for group 1 and 2 as: 37.0 versus 28.5 months and 13.8 versus 13.1 months, respectively. Grades 3-4 mucosal toxicities (11.4% vs 28.3%), hospitalization (3.2% vs 17.4%), and nasogastric feeding (11.9% vs 29.7%) were higher in group 2. The 2-year disease-free survival (DFS) was higher with PORT >60 Gy for the following factors: age ≤ 50 years (P = .041); ≥ 4 positive nodes (P = .029); and overall treatment time (OTT) ≥ 100 days (P = .042). Except for the benefit of doses >60 Gy for limited parameters, a lower PORT dose did not compromise the results and can potentially reduce the morbidities and healthcare costs. © 2017 Wiley Periodicals, Inc.

A randomized, double-blind, active control, multicenter, dose-finding study of lipegfilgrastim (XM22) in breast cancer patients receiving myelosuppressive therapy.

PubMed

Buchner, Anton; Elsässer, Reiner; Bias, Peter

2014-11-01

This dose-ranging study was conducted to identify the optimal fixed dose of lipegfilgrastim compared with pegfilgrastim 6.0 mg for the provision of neutrophil support during myelosuppressive chemotherapy in patients with breast cancer. A phase 2 study was conducted in which 208 chemotherapy-naive patients were randomized to receive lipegfilgrastim 3.0, 4.5, or 6.0 mg or pegfilgrastim 6.0 mg. Study drugs were administered as a single subcutaneous injection on day 2 of each chemotherapy cycle (doxorubicin/docetaxel on day 1 for four 3-week cycles). The primary outcome measure was duration of severe neutropenia (DSN) in cycle 1. Patients treated with lipegfilgrastim experienced shorter DSN in cycle 1 with higher doses. The mean DSN was 0.76 days in the lipegfilgrastim 6.0-mg group and 0.87 days in the pegfilgrastim 6.0-mg group, with no significant differences between treatment groups. Treatment with lipegfilgrastim 6.0 mg was consistently associated with a higher absolute neutrophil count (ANC) at nadir, shorter ANC recovery time, and a similar safety and tolerability profile compared with pegfilgrastim. This phase 2 study demonstrated that lipegfilgrastim 6.0 mg is the optimal dose for patients with breast cancer and provides neutrophil support that is at least equivalent to the standard 6.0-mg fixed dose of pegfilgrastim.

Severity of mumps disease is related to MMR vaccination status and viral shedding.

PubMed

Gouma, Sigrid; Hahné, Susan J M; Gijselaar, Daphne B; Koopmans, Marion P G; van Binnendijk, Rob S

2016-04-07

During recent years, various mumps outbreaks have occurred among measles, mumps, and rubella (MMR) vaccinated persons in various countries worldwide, including the Netherlands. We studied mumps virus shedding in MMR vaccinated and unvaccinated mumps patients and related these findings to clinical data. In this study, we included 1112 mumps patients of whom diagnostic samples were tested positive in our laboratory between 1 January 2007 and 31 December 2014. We compared mumps virus shedding and severity of disease between patients who had received 2 doses of MMR (n=592) and unvaccinated mumps patients (n=195). Mumps virus shedding in saliva and urine specimens was measured by qPCR. Severity of disease was studied in a subset of patients with clinical data available. Mumps patients who had received 2 MMR doses shed less often mumps virus in their urine than unvaccinated patients. Salivary viral loads were higher at day of onset of disease in twice MMR vaccinated patients with viruria than in twice MMR vaccinated patients without viruria. However, salivary viral loads did not significantly differ between patients who had received 2 MMR doses and unvaccinated patients. Bilateral parotitis and orchitis were less often reported in patients who had received 2 MMR doses than in unvaccinated patients. Furthermore, the prevalence of bilateral parotitis and orchitis was higher among twice MMR vaccinated patients with viruria than among twice MMR vaccinated patients without viruria. MMR vaccination was associated with less severe disease among mumps patients. Systemic spread of virus was associated with more severe disease. The elevated salivary viral loads in patients with systemic mumps disease suggest that these patients pose a higher risk for mumps virus transmission. Our study contributes to the understanding of mumps virus pathogenesis and shows the protective effect of MMR vaccination on severity of disease. Copyright © 2016 Elsevier Ltd. All rights reserved.

A current and historical perspective on disparities in US childhood pneumococcal conjugate vaccine adherence and in rates of invasive pneumococcal disease: Considerations for the routinely-recommended, pediatric PCV dosing schedule in the United States

PubMed Central

McLaughlin, John M; Utt, Eric A; Hill, Nina M; Welch, Verna L; Power, Edward; Sylvester, Gregg C

2016-01-01

Previous research has suggested that reducing the US 4-dose PCV13 schedule to a 3-dose schedule may provide cost savings, despite more childhood pneumococcal disease. The study also stressed that dose reduction should be coupled with improved PCV adherence, however, US PCV uptake has leveled-off since 2008. An estimated 24–36% of US children aged 5–19 months are already receiving a reduced PCV schedule (i.e., missing ≥1 dose). This raises a practical concern that, under a reduced, 3-dose schedule, a similar proportion of children may receive ≤2 doses. It is also unknown if a reduced, 3-dose PCV schedule in the United States will afford the same disease protection as 3-dose schedules used elsewhere, given lower US PCV adherence. Finally, more assurance is needed that, under a reduced schedule, racial, socioeconomic, and geographic disparities in PCV adherence will not correspond with disproportionately higher rates of pneumococcal disease among poor or minority children. PMID:26376039

Leukemia risk associated with chronic external exposure to ionizing radiation in a French cohort of nuclear workers.

PubMed

Metz-Flamant, C; Samson, E; Caër-Lorho, S; Acker, A; Laurier, D

2012-11-01

Leukemia is one of the earliest cancer effects observed after acute exposure to relatively high doses of ionizing radiation. Leukemia mortality after external exposure at low doses and low-dose rates has been investigated at the French Atomic Energy Commission (CEA) and Nuclear Fuel Company (AREVA NC) after an additional follow-up of 10 years. The cohort included radiation-monitored workers employed for at least one year during 1950-1994 at CEA or AREVA NC and followed during 1968-2004. Association between external exposure and leukemia mortality was estimated with excess relative risk (ERR) models and time-dependent modifying factors were investigated with time windows. The cohort included 36,769 workers, followed for an average of 28 years, among whom 73 leukemia deaths occurred. Among the workers with a positive recorded dose, the mean cumulative external dose was 21.7 mSv. Results under a 2-year lag assumption suggested that the risk of leukemia (except chronic lymphatic leukemia) increased significantly by 8% per 10 mSv. The magnitude of the association for myeloid leukemia was larger. The higher ERR/Sv for doses received 2-14 years earlier suggest that time since exposure modifies the effect. The ERR/Sv also appeared higher for doses received at exposure rates ≥20 mSv per year. These results are consistent with those found in other studies of nuclear workers. However, confidence intervals are still wide. Further analyses should be conducted in pooled cohorts of nuclear workers.

Radiation dose in neoadjuvant chemoradiation therapy for esophageal cancer: patterns of care and outcomes from the National Cancer Data Base

PubMed Central

Haque, Waqar; Verma, Vivek; Butler, E. Brian

2018-01-01

Background Neoadjuvant chemoradiotherapy (CRT) for locally advanced esophageal cancer (EC) may utilize a wide variety of RT doses, without clear consensus to date. This study evaluated national practice patterns between lower dose (LD) (40–41.4 Gy) or higher dose (HD) (50–50.4 Gy) therapy, in addition to differences in survival and postoperative events. Methods The National Cancer Data Base (NCDB) was queried [2004–2013] for patients with newly-diagnosed cT1a-T4aN0/N+M0 EC that received neoadjuvant CRT followed by esophagectomy. Multivariable logistic regression determined factors predictive of receiving LD RT. Kaplan-Meier analysis evaluated overall survival (OS), and Cox proportional hazards modeling determined variables associated with OS. Propensity score matching assessed groups in a balanced manner while reducing indication biases. Results Altogether, 5,025 patients met inclusion criteria; 257 (5%) received LD RT, while 4,768 (95%) received HD RT. LD RT was more likely delivered at academic centers (P=0.038), in more recent years (2009–2013, P=0.011), and to squamous cell carcinomas (P=0.001). HD RT tended to be administered with higher T stage as well as node-positive disease (P<0.05). The median OS in the LD and HD cohorts was 39.0 vs. 35.6 months (P=0.072), and 39.0 vs. 42.7 months after propensity matching (P=0.812). Dose did not independently correlate with OS on multivariate analysis (P=0.069), but treatment at academic centers correlated with improved OS (P=0.028). There were no differences between groups in the rates of 30-day readmission (P=0.182), 30-day mortality (P=0.314), or length of postoperative hospital stay (P=0.665), but the LD group experienced lower 90-day mortality (P=0.007). Conclusions Although neoadjuvant LD CRT has been underutilized for EC in the United States, it is rising in more recent years. Dose did not significantly impact survival before or after propensity matching, nor did it independently predict for survival. Treatment at academic facilities independently correlated with higher survival, which has implications for patient counseling. PMID:29564174

Pedestrians in Traffic Environments: Ultrafine Particle Respiratory Doses

PubMed Central

Manigrasso, Maurizio; Natale, Claudio; Vitali, Matteo; Protano, Carmela; Avino, Pasquale

2017-01-01

Particulate matter has recently received more attention than other pollutants. PM10 and PM2.5 have been primarily monitored, whereas scientists are focusing their studies on finer granulometric sizes due both to their high number concentration and their high penetration efficiency into the respiratory system. The purpose of this study is to investigate the population exposure to UltraFine Particles (UFP, submicrons in general) in outdoor environments. The particle number doses deposited into the respiratory system have been compared between healthy individuals and persons affected by Chronic Obstructive Pulmonary Disease (COPD). Measurements were performed by means of Dust Track and Nanoscan analyzers. Forty minute walking trails through areas with different traffic densities in downtown Rome have been considered. Furthermore, particle respiratory doses have been estimated for persons waiting at a bus stop, near a traffic light, or along a high-traffic road, as currently occurs in a big city. Large differences have been observed between workdays and weekdays: on workdays, UFP number concentrations are much higher due to the strong contribution of vehicular exhausts. COPD-affected individuals receive greater doses than healthy individuals due to their higher respiratory rate. PMID:28282961

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

PubMed

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

2018-01-20

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

Immune response and reactogenicity of intradermal administration versus subcutaneous administration of varicella-zoster virus vaccine: an exploratory, randomised, partly blinded trial.

PubMed

Beals, Chan R; Railkar, Radha A; Schaeffer, Andrea K; Levin, Yotam; Kochba, Efrat; Meyer, Brian K; Evans, Robert K; Sheldon, Eric A; Lasseter, Kenneth; Lang, Nancy; Weinberg, Adriana; Canniff, Jennifer; Levin, Myron J

2016-08-01

The licensed live, attenuated varicella-zoster virus vaccine prevents herpes zoster in adults older than 50 years. We aimed to determine whether intradermal administration of zoster vaccine could enhance vaccine immunogenicity compared with conventional needle subcutaneous administration. In this randomised, dose-ranging study, adults aged 50 years or older who had a history of varicella or who had resided in a country with endemic varicella-zoster virus infection for 30 years or more were eligible. Participants received the approved full or a 1/3 dose of zoster vaccine given subcutaneously or one of four intradermal doses (full, 1/3, 1/10, or 1/27 dose) using the MicronJet600 device. The two subcutaneous doses and the four intradermal doses were randomised (1·5:1:1:1:1:1) by computer generated sequence with randomisation stratified by age (50-59 years or 60 years or older). The primary immunogenicity endpoint was the change from baseline in IgG antibody to varicella-zoster virus-specific glycoproteins (gpELISA) measured at 6 weeks. All patients were included in the primary and safety analyses. This study is registered with ClinicalTrials.gov, number NCT01385566. Between Sept 2, 2011, and Jan 13, 2012, 224 participants were enrolled from three clinics in the USA and 223 were randomly assigned: 52 to receive the full dose subcutaneous zoster vaccine, 34 to receive the 1/3 dose subcutaneous zoster vaccine, 34 to receive the full dose intradermal zoster vaccine, 35 to receive the 1/3 dose intradermal zoster vaccine, 34 to receive the 1/10 dose intradermal zoster vaccine, and 34 to receive the 1/27 dose intradermal zoster vaccine. Full dose zoster vaccine given subcutaneously resulted in a gpELISA geometric mean fold-rise (GMFR) of 1·74 (90% CI 1·48-2·04) at 6 weeks post-vaccination compared with intradermal administration which resulted in a significantly higher gpELISA GMFR of 3·25 (2·68-3·94; p<0·0001), which also remained high at 18 months. An apparent dose-response relation was observed with intradermal administration (1/3 dose subcutaneous GMFR 1·64 [90% CI 1·36-1·99], 1/3 dose intradermal 2·58 (2·13-3·13), 1/10 dose intradermal 2·22 [1·83-2·69], and 1/27 dose intradermal 1·64 [1·35-2·00]). Each partial dose of zoster vaccine given intradermaly had a gpELISA GMFR comparable to that of full dose zoster vaccine given subcutaneously. Transient erythema and induration were more common after intradermal administration (31% erythema for full subcutaneous dose and 77% for intradermal dose). Intradermal zoster vaccine showed a greater increase in varicella-zoster virus gpELISA antibody compared with subcutaneous zoster vaccine at comparable doses. Larger and longer studies of intradermal administration of live, attenuated zoster vaccine are needed to provide convincing evidence of improved cell mediated immunity. Merck & Co Inc. Copyright © 2016 Elsevier Ltd. All rights reserved.

Efficacy of topotecan treatment on antioxidant enzymes and TBA-RS levels in submandibular glands of rabbits: an experimental study.

PubMed

Muluk, Nuray Bayar; Kisa, Uçler; Kaçmaz, Murat; Apan, Alpaslan; Koç, Can

2005-01-01

The aim of this study was to investigate the effects of topotecan (Hycamtin), a topoisomerase I inhibiting anticancer agent, on antioxidant enzymes (SOD, CAT, and GSH-Px) and TBA-RS values of the submandibular glands of the rabbits. The study was conveyed in two groups (Group I, II) and control with a total of 24 rabbits. Eight rabbits in group I received intravenous (i.v.) topotecan (0.25 mg/kg once daily) for 3 days. Eight rabbits in group II received i.v. topotecan (0.5 mg/kg once daily) for 3 days. On the 15th day after administration of topotecan, submandibular glands were removed and levels of the SOD, CAT, and GSH-Px and the TBA-RS in the submandibular glands of the rabbits were examined. SOD, CAT, and GSH-Px values were significantly higher in high-dose topotecan group compared to control group (P < 0.05). SOD and TBA-RS values were significantly higher in high-dose topotecan group compared to low-dose topotecan group (P < 0.05). It was concluded that, to prevent the hazardous effects of oxygen free radicals due to topotecan, antioxidant enzymes SOD, CAT, and GSH-Px were increased. The higher levels of the TBA-RS values in group II showed that permanent damage was present because of high-dose topotecan administration in the submandibular glands of the rabbits.

Attenuating the defibrillation dosage decreases postresuscitation myocardial dysfunction in a swine model of pediatric ventricular fibrillation

PubMed Central

Berg, Marc D.; Banville, Isabelle L.; Chapman, Fred W.; Walker, Robert G.; Gaballa, Mohammed A.; Hilwig, Ronald W.; Samson, Ricardo A.; Kern, Karl B.; Berg, Robert A.

2009-01-01

Objective The optimal biphasic defibrillation dose for children is unknown. Postresuscitation myocardial dysfunction is common and may be worsened by higher defibrillation doses. Adult-dose automated external defibrillators are commonly available; pediatric doses can be delivered by attenuating the adult defibrillation dose through a pediatric pads/cable system. The objective was to investigate whether unattenuated (adult) dose biphasic defibrillation results in greater postresuscitation myocardial dysfunction and damage than attenuated (pediatric) defibrillation. Design Laboratory animal experiment. Setting University animal laboratory. Subjects Domestic swine weighing 19 ± 3.6 kg. Interventions Fifty-two piglets were randomized to receive biphasic defibrillation using either adult-dose shocks of 200, 300, and 360 J or pediatric-dose shocks of ~50, 75, and 85 J after 7 mins of untreated ventricular fibrillation. Contrast left ventriculograms were obtained at baseline and then at 1, 2, 3, and 4 hrs postresuscitation. Postresuscitation left ventricular ejection fraction and cardiac troponins were evaluated. Measurements and Main Results By design, piglets in the adult-dose group received shocks with more energy (261 ± 65 J vs. 72 ± 12 J, p < .001) and higher peak current (37 ± 8 A vs. 13 ± 2 A, p < .001) at the largest defibrillation dose needed. In both groups, left ventricular ejection fraction was reduced significantly at 1, 2, and 4 hrs from baseline and improved during the 4 hrs postresuscitation. The decrease in left ventricular ejection fraction from baseline was greater after adult-dose defibrillation. Plasma cardiac troponin levels were elevated 4 hrs postresuscitation in 11 of 19 adult-dose piglets vs. four of 20 pediatric-dose piglets (p = .02). Conclusions Unattenuated adult-dose defibrillation results in a greater frequency of myocardial damage and worse postresuscitation myocardial function than pediatric doses in a swine model of prolonged out-of-hospital pediatric ventricular fibrillation cardiac arrest. These data support the use of pediatric attenuating electrodes with adult biphasic automated external defibrillators to defibrillate children. PMID:18496405

A Voxel-Based Approach to Explore Local Dose Differences Associated With Radiation-Induced Lung Damage

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

Palma, Giuseppe; Monti, Serena; D'Avino, Vittoria

Purpose: To apply a voxel-based (VB) approach aimed at exploring local dose differences associated with late radiation-induced lung damage (RILD). Methods and Materials: An interinstitutional database of 98 patients who were Hodgkin lymphoma (HL) survivors treated with postchemotherapy supradiaphragmatic radiation therapy was analyzed in the study. Eighteen patients experienced late RILD, classified according to the Radiation Therapy Oncology Group scoring system. Each patient's computed tomographic (CT) scan was normalized to a single reference case anatomy (common coordinate system, CCS) through a log-diffeomorphic approach. The obtained deformation fields were used to map the dose of each patient into the CCS. Themore » coregistration robustness and the dose mapping accuracy were evaluated by geometric and dose scores. Two different statistical mapping schemes for nonparametric multiple permutation inference on dose maps were applied, and the corresponding P<.05 significance lung subregions were generated. A receiver operating characteristic (ROC)-based test was performed on the mean dose extracted from each subregion. Results: The coregistration process resulted in a geometrically robust and accurate dose warping. A significantly higher dose was consistently delivered to RILD patients in voxel clusters near the peripheral medial-basal portion of the lungs. The area under the ROC curves (AUC) from the mean dose of the voxel clusters was higher than the corresponding AUC derived from the total lung mean dose. Conclusions: We implemented a framework including a robust registration process and a VB approach accounting for the multiple comparison problem in dose-response modeling, and applied it to a cohort of HL survivors to explore a local dose–RILD relationship in the lungs. Patients with RILD received a significantly greater dose in parenchymal regions where low doses (∼6 Gy) were delivered. Interestingly, the relation between differences in the high-dose range and RILD seems to lack a clear spatial signature.« less

High-Dose Ursodeoxycholic Acid Is Associated With the Development of Colorectal Neoplasia in Patients With Ulcerative Colitis and Primary Sclerosing Cholangitis

PubMed Central

Eaton, John E.; Silveira, Marina G.; Pardi, Darrell S.; Sinakos, Emmanouil; Kowdley, Kris V.; Luketic, Velimir A.C.; Harrison, M. Edwyn; McCashland, Timothy; Befeler, Alex S.; Harnois, Denise; Jorgensen, Roberta; Petz, Jan; Lindor, Keith D.

2011-01-01

OBJECTIVES Some studies have suggested that ursodeoxycholic acid (UDCA) may have a chemopreventive effect on the development of colorectal neoplasia in patients with ulcerative colitis (UC) and primary sclerosing cholangitis (PSC). We examined the effects of high-dose (28–30 mg/kg/day) UDCA on the development of colorectal neoplasia in patients with UC and PSC. METHODS Patients with UC and PSC enrolled in a prior, multicenter randomized placebo-controlled trial of high-dose UDCA were evaluated for the development of colorectal neoplasia. Patients with UC and PSC who received UDCA were compared with those who received placebo. We reviewed the pathology and colonoscopy reports for the development of low-grade or high-grade dysplasia or colorectal cancer. RESULTS Fifty-six subjects were followed for a total of 235 patient years. Baseline characteristics (including duration of PSC and UC, medications, patient age, family history of colorectal cancer, and smoking status) were similar for both the groups. Patients who received high-dose UDCA had a significantly higher risk of developing colorectal neoplasia (dysplasia and cancer) during the study compared with those who received placebo (hazard ratio: 4.44, 95% confidence interval: 1.30–20.10, P=0.02). CONCLUSIONS Long-term use of high-dose UDCA is associated with an increased risk of colorectal neoplasia in patients with UC and PSC. PMID:21556038

Mortality associated with administration of high-dose tranexamic acid and aprotinin in primary open-heart procedures: a retrospective analysis.

PubMed

Sander, Michael; Spies, Claudia D; Martiny, Viktoria; Rosenthal, Christoph; Wernecke, Klaus-Dieter; von Heymann, Christian

2010-01-01

Antifibrinolytic agents are commonly used during cardiac surgery to minimize bleeding. Because of safety concerns, aprotinin was withdrawn from the market in 2007. Since then, tranexamic acid (TXA) has become the antifibrinolytic treatment of choice in many heart centers. The safety profile of TXA has not been extensively studied. Therefore, the aim of this study was to evaluate safety and efficiency of TXA compared with aprotinin in cardiac surgery. Since July 1, 2006, TXA has been administered at a dose of 50 mg/kg tranexamic acid before cardiopulmonary bypass (CPB) and 50 mg/kg into the priming fluid of the CPB. Prior to this, all patients were treated with aprotinin at a dose of 50,000 KIU per kilogram body weight. Safety was evaluated with mortality, biomarkers, and the diagnosis of myocardial infarction, ischemic stroke, convulsive seizures, and acute renal failure in the intensive care unit (ICU), intermediate care unit (IMCU), and hospital stay. Efficiency was evaluated by the need for transfusion of blood products and total postoperative blood loss. After informed consent, 893 patients were included in our database (557 consecutive patients receiving aprotinin and 336 patients receiving TXA). A subgroup of 320 patients undergoing open-heart procedures (105 receiving TXA and 215 receiving aprotinin) was analyzed separately. In the aprotinin group, a higher rate of late events of ischemic stroke (3.4% versus 0.9%; P = 0.02) and neurologic disability (5.8% versus 2.4%; P = 0.02) was found. The rate of postoperative convulsive seizures was increased in tendency in patients receiving TXA (2.7% versus 0.9%; P = 0.05). The use of TXA was associated with higher cumulative drainage losses (PANOVA < 0.01; Ptime < 0.01) and a higher rate of repeated thoracotomy for bleeding (6.9% versus 2.4%; P < 0.01). In the subgroup of patients with open-chamber procedures, mortality was higher in the TXA group (16.2% TXA versus 7.5% aprotinin; P = 0.02). Multivariate logistic regression identified EURO score II and CPB time as additional risk factors for this increased mortality. The use of high-dose TXA is questioned, as our data suggest an association between higher mortality and minor efficiency while the safety profile of this drug is not consistently improved. Further confirmatory prospective studies evaluating the efficacy and safety profile of TXA are urgently needed to find a safe dosage for this antifibrinolytic drug.

TU-AB-201-06: Evaluation of Electromagnetically Guided High- Dose Rate Brachytherapy for Ablative Treatment of Lung Metastases

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

Pinkham, D.W.; Shultz, D.; Loo, B.W.

Purpose: The advent of electromagnetic navigation bronchoscopy has enabled minimally invasive access to peripheral lung tumors previously inaccessible by optical bronchoscopes. As an adjunct to Stereotactic Ablative Radiosurgery (SABR), implantation of HDR catheters can provide focal treatments for multiple metastases and sites of retreatments. The authors evaluate a procedure to deliver ablative doses via Electromagnetically-Guided HDR (EMG-HDR) to lung metastases, quantify the resulting dosimetry, and assess its role in the comprehensive treatment of lung cancer. Methods: A retrospective study was conducted on ten patients, who, from 2009 to 2011, received a hypo-fractionated SABR regimen with 6MV VMAT to lesions inmore » various lobes ranging from 1.5 to 20 cc in volume. A CT visible pathway was delineated for EM guided placement of an HDR applicator (catheter) and dwell times were optimized to ensure at least 98% prescription dose coverage of the GTV. Normal tissue doses were calculated using inhomogeneity corrections via a grid-based Boltzmann solver (Acuros-BV-1.5.0). Results: With EMG-HDR, an average of 83% (+/−9% standard deviation) of each patient’s GTV received over 200% of the prescription dose, as compared to SABR where the patients received an average maximum dose of 125% (+/−5%). EMG-HDR enabled a 59% (+/−12%) decrease in the aorta maximum dose, a 63% (+/−26%) decrease in the spinal cord max dose, and 57% (+/−23%) and 70% (+/−17%) decreases in the volume of the body receiving over 50% and 25% of the prescription dose, respectively. Conclusion: EMG-HDR enables delivery of higher ablative doses to the GTV, while concurrently reducing surrounding normal tissue doses. The single catheter approach shown here is limited to targets smaller than 20 cc. As such, the technique enables ablation of small lesions and a potentially safe and effective retreatment option in situations where external beam utility is limited by normal tissue constraints.« less

Quantifying the impact of immediate reconstruction in postmastectomy radiation: a large, dose-volume histogram-based analysis.

PubMed

Ohri, Nisha; Cordeiro, Peter G; Keam, Jennifer; Ballangrud, Ase; Shi, Weiji; Zhang, Zhigang; Nerbun, Claire T; Woch, Katherine M; Stein, Nicholas F; Zhou, Ying; McCormick, Beryl; Powell, Simon N; Ho, Alice Y

2012-10-01

To assess the impact of immediate breast reconstruction on postmastectomy radiation (PMRT) using dose-volume histogram (DVH) data. Two hundred forty-seven women underwent PMRT at our center, 196 with implant reconstruction and 51 without reconstruction. Patients with reconstruction were treated with tangential photons, and patients without reconstruction were treated with en-face electron fields and customized bolus. Twenty percent of patients received internal mammary node (IMN) treatment. The DVH data were compared between groups. Ipsilateral lung parameters included V20 (% volume receiving 20 Gy), V40 (% volume receiving 40 Gy), mean dose, and maximum dose. Heart parameters included V25 (% volume receiving 25 Gy), mean dose, and maximum dose. IMN coverage was assessed when applicable. Chest wall coverage was assessed in patients with reconstruction. Propensity-matched analysis adjusted for potential confounders of laterality and IMN treatment. Reconstruction was associated with lower lung V20, mean dose, and maximum dose compared with no reconstruction (all P<.0001). These associations persisted on propensity-matched analysis (all P<.0001). Heart doses were similar between groups (P=NS). Ninety percent of patients with reconstruction had excellent chest wall coverage (D95 >98%). IMN coverage was superior in patients with reconstruction (D95 >92.0 vs 75.7%, P<.001). IMN treatment significantly increased lung and heart parameters in patients with reconstruction (all P<.05) but minimally affected those without reconstruction (all P>.05). Among IMN-treated patients, only lower lung V20 in those without reconstruction persisted (P=.022), and mean and maximum heart doses were higher than in patients without reconstruction (P=.006, P=.015, respectively). Implant reconstruction does not compromise the technical quality of PMRT when the IMNs are untreated. Treatment technique, not reconstruction, is the primary determinant of target coverage and normal tissue doses. Published by Elsevier Inc.

Efficacy of Common Analgesics for Postsurgical Pain in Rats

PubMed Central

Waite, Megan E; Tomkovich, Ashleigh; Quinn, Tammie L; Schumann, Alan P; Dewberry, L Savannah; Totsch, Stacie K; Sorge, Robert E

2015-01-01

Each year, millions of rats undergo surgery for research purposes and receive analgesics to alleviate pain. We sought to evaluate the efficacy of common analgesics in tests of hot-plate nociception and postsurgical pain by using the Rat Grimace Scale. Rats received a single dose of one of several drug–dose combinations and were tested by using the hot-plate test (acute pain) or after laparotomy (with either prophylactic or intraoperative analgesic). The efficacy of analgesics for hot-plate pain was generally not predictive of efficacy for surgical pain. Carprofen and ketoprofen were rarely effective in any of the conditions tested. With the exception of the opioid buprenorphine, several of the drugs we tested required higher-than-recommended doses to alleviate pain. Taken together, our data suggest that current analgesic use frequently is insufficient, and many rats may experience significant postsurgical pain even when analgesics are used in commonly recommended doses. PMID:26224443

An experimental measurement of galactic cosmic radiation dose in conventional aircraft between San Francisco and London compared to theoretical values for conventional and supersonic aircraft

NASA Technical Reports Server (NTRS)

Wallace, R.; Boyer, M. F.

1972-01-01

These direct measurements are in fair agreement with computations made using a program which considers both basic cosmic ray atmospheric physics and the focusing effect of the earth's magnetic field. These measurements also agree with those made at supersonic jet aircraft altitudes in Rb-57 aircraft. It is concluded that experiments and theory show that the doses received at conventional jet aircraft altitudes are slightly higher than those encountered in supersonic flights at much higher altitudes.

Dosage effects of histamine-2 receptor antagonist on the primary prophylaxis of non-steroidal anti-inflammatory drug (NSAID)-associated peptic ulcers: a retrospective cohort study.

PubMed

He, Ying; Chan, Esther W; Man, Kenneth K C; Lau, Wallis C Y; Leung, Wai K; Ho, Lai M; Wong, Ian C K

2014-09-01

A histamine-2 receptor antagonist (H2RA) is one of the common gastroprotective co-therapies used with non-steroidal anti-inflammatory drugs (NSAIDs) for the prevention or treatment of peptic ulcers (PUs). To date, no study has directly compared the prophylactic effectiveness between high-dose and low-dose H2RA. Our objective was to compare the effectiveness of high-dose versus low-dose H2RAs in the primary prophylaxis of PUs among short-term NSAID users. A retrospective cohort study was conducted using the Clinical Data Analysis and Reporting System (CDARS) in Hong Kong. Patients aged 18 years or above who received a single prescription of oral NSAID with oral H2RA were identified within the study period (1 January 2009-31 December 2012). Patients with a history of or risk factors for PU in the corresponding 2 years prior to the index date (of the first NSAID prescription) were excluded. Log binomial regression analysis was used to calculate the relative risk of PU among NSAID users with high-dose H2RA versus low-dose H2RA exposure. Among the NSAID cohort (n = 102,042), 77,509 (76 %) were on low-dose H2RA and 24,533 (24 %) were on high-dose H2RA. Of the total 69 PU cases identified during the drug exposure period, 64 (0.08 %) received low-dose-H2RA and five (0.02 %) received high-dose H2RA. The overall absolute risk of PUs for NSAID users whilst on H2RA was approximately 1 per 1,479 patients. The adjusted relative risk for NSAID users receiving high-dose H2RA versus low-dose H2RA was 0.32 (95 % confidence interval [CI] 0.13-0.79). Patients aged ≥65 years, receiving a longer duration of treatment, or with concomitant use of antiplatelet agents were found to be at higher risk of PU. High-dose H2RA showed greater effectiveness than low-dose H2RA in the primary prophylaxis of NSAID-associated PUs in short-term new users.

Process evaluation of a randomised controlled trial of a diabetes prevention intervention in Dutch primary health care: the SLIMMER study.

PubMed

van Dongen, Ellen Ji; Duijzer, Geerke; Jansen, Sophia C; Ter Beek, Josien; Huijg, Johanna M; Leerlooijer, Joanne N; Hiddink, Gerrit J; Feskens, Edith Jm; Haveman-Nies, Annemien

2016-11-01

To investigate (i) how the SLIMMER intervention was delivered and received in Dutch primary health care and (ii) how this could explain intervention effectiveness. A randomised controlled trial was conducted and subjects were randomly allocated to the intervention (10-month combined dietary and physical activity intervention) or the control group. A process evaluation including quantitative and qualitative methods was conducted. Data on process indicators (recruitment, reach, dose received, acceptability, implementation integrity and applicability) were collected via semi-structured interviews with health-care professionals (n 45) and intervention participant questionnaires (n 155). SLIMMER was implemented in Dutch primary health care in twenty-five general practices, eleven dietitians, nine physiotherapist practices and fifteen sports clubs. Subjects at increased risk of developing type 2 diabetes were included. It was possible to recruit the intended high-risk population (response rate 54 %) and the SLIMMER intervention was very well received by both participants and health-care professionals (mean acceptability rating of 82 and 80, respectively). The intervention programme was to a large extent implemented as planned and was applicable in Dutch primary health care. Higher dose received and participant acceptability were related to improved health outcomes and dietary behaviour, but not to physical activity behaviour. The present study showed that it is feasible to implement a diabetes prevention intervention in Dutch primary health care. Higher dose received and participant acceptability were associated with improved health outcomes and dietary behaviour. Using an extensive process evaluation plan to gain insight into how an intervention is delivered and received is a valuable way of identifying intervention components that contribute to implementation integrity and effective prevention of type 2 diabetes in primary health care.

Dose of Prophylactic Platelet Transfusions and Prevention of Hemorrhage

PubMed Central

Slichter, Sherrill J.; Kaufman, Richard M.; Assmann, Susan F.; McCullough, Jeffrey; Triulzi, Darrell J.; Strauss, Ronald G.; Gernsheimer, Terry B.; Ness, Paul M.; Brecher, Mark E.; Josephson, Cassandra D.; Konkle, Barbara A.; Woodson, Robert D.; Ortel, Thomas L.; Hillyer, Christopher D.; Skerrett, Donna L.; McCrae, Keith R.; Sloan, Steven R.; Uhl, Lynne; George, James N.; Aquino, Victor M.; Manno, Catherine S.; McFarland, Janice G.; Hess, John R.; Leissinger, Cindy; Granger, Suzanne

2010-01-01

BACKGROUND We conducted a trial of prophylactic platelet transfusions to evaluate the effect of platelet dose on bleeding in patients with hypoproliferative thrombocytopenia. METHODS We randomly assigned hospitalized patients undergoing hematopoietic stem-cell transplantation or chemotherapy for hematologic cancers or solid tumors to receive prophylactic platelet transfusions at a low dose, a medium dose, or a high dose (1.1×1011, 2.2×1011, or 4.4×1011 platelets per square meter of body-surface area, respectively), when morning platelet counts were 10,000 per cubic millimeter or lower. Clinical signs of bleeding were assessed daily. The primary end point was bleeding of grade 2 or higher (as defined on the basis of World Health Organization criteria). RESULTS In the 1272 patients who received at least one platelet transfusion, the primary end point was observed in 71%, 69%, and 70% of the patients in the low-dose group, the medium-dose group, and the high-dose group, respectively (differences were not significant). The incidences of higher grades of bleeding, and other adverse events, were similar among the three groups. The median number of platelets transfused was significantly lower in the low-dose group (9.25×1011) than in the medium-dose group (11.25×1011) or the high-dose group (19.63×1011) (P = 0.002 for low vs. medium, P<0.001 for high vs. low and high vs. medium), but the median number of platelet transfusions given was significantly higher in the low-dose group (five, vs. three in the medium-dose and three in the high-dose group; P<0.001 for low vs. medium and low vs. high). Bleeding occurred on 25% of the study days on which morning platelet counts were 5000 per cubic millimeter or lower, as compared with 17% of study days on which platelet counts were 6000 to 80,000 per cubic millimeter (P<0.001). CONCLUSIONS Low doses of platelets administered as a prophylactic transfusion led to a decreased number of platelets transfused per patient but an increased number of transfusions given. At doses between 1.1×1011 and 4.4×1011 platelets per square meter, the number of platelets in the prophylactic transfusion had no effect on the incidence of bleeding. (ClinicalTrials.gov number, NCT00128713.) PMID:20164484

Relationships between thermal dose parameters and the efficacy of definitive chemoradiotherapy plus regional hyperthermia in the treatment of locally advanced cervical cancer: data from a multicentre randomised clinical trial.

PubMed

Ohguri, Takayuki; Harima, Yoko; Imada, Hajime; Sakurai, Hideyuki; Ohno, Tatsuya; Hiraki, Yoshiyuki; Tuji, Koh; Tanaka, Masahiro; Terashima, Hiromi

2018-06-01

To evaluate the contribution of the thermal dose parameters during regional hyperthermia (HT) treatment to the clinical outcomes in patients with cervical carcinoma (CC) who received chemoradiotherapy (CRT) plus HT. Data from a multicentre randomised clinical trial of concurrent CRT + HT vs. CRT alone were used to evaluate the efficacy and safety of this combination therapy in the CC patients. The intrarectal temperatures of patients undergoing HT were recorded. The complete thermal data of 47 (92%) of the 51 patients in the CRT + HT group were available for the thermal analysis. Thus, 47 patients who received CRT + HT were included in the present study. Among the patients who received CRT + HT, a higher CEM43T90 (≥1 min) value (a thermal dose parameter) was significantly associated with better local relapse-free survival in both univariate (p = 0.024) and multivariate (p = 0.0097) analyses. The disease-free survival of the patients with higher CEM43T90 (≥1 min) values tended to be better in comparison to patients with lower CEM43T90 (<1 min) value (p = 0.071). A complete response tended to be associated with the CEM43T90 (p = 0.056). Disease-free survival, local relapse-free survival and complete response rate for patients with higher CEM43T90 (≥1) were significantly better than those for patients with CRT alone (p = 0.036, p = 0.036 and p = 0.048). Dose-effect relationships between thermal dose parameters and clinical outcomes were confirmed in the CC patients treated with a combination of CRT + HT. This study also confirmed that HT with lower CEM43T90 is insufficient to achieve a significant hyperthermic sensitisation to CRT.

The effects of two different doses of hydrocortisone on cognition in patients with secondary adrenal insufficiency--results from a randomized controlled trial.

PubMed

Werumeus Buning, Jorien; Brummelman, Pauline; Koerts, Janneke; Dullaart, Robin P F; van den Berg, Gerrit; van der Klauw, Melanie M; Tucha, Oliver; Wolffenbuttel, Bruce H R; van Beek, André P

2015-05-01

A wide variety in hydrocortisone (HC) substitution dose-regimens are considered physiological for patients with secondary adrenal insufficiency (SAI). However, it is likely that cognition is negatively influenced by higher cortisol exposure to the brain. To examine the effects of a high physiological HC dose in comparison to a low physiological HC dose on cognition. This study was a randomized double blind cross-over study at the University Medical Center Groningen. This study is registered with ClinicalTrials.gov, number NCT01546922. Forty-seven patients (29 males, 18 females; mean [SD] age, 51 [14] years, range 19-73) with SAI participated. Patients randomly received first a low dose of HC (0.2-0.3 mg/kg body weight/day) during 10 weeks followed by a high dose (0.4-0.6 mg/kg body weight/day) for another 10 weeks, or vice versa. HC substitution was given in three divided doses with the highest dose in the morning. Cognitive performance (memory, attention, executive functioning and social cognition) of patients was measured at baseline and after each treatment period using a battery of 12 standardized cognitive tests. The higher dose of HC resulted in significantly higher systemic cortisol exposure for example measured at 1h after first dose ingestion (mean [SD], low dose: 653 [281] nmol/L; high dose: 930 [148] nmol/L; P<0.001). No differences in cognitive performance were found between the two dose regimens. No negative influence on memory, attention, executive functioning and social cognition was observed after 10 weeks of treatment with a higher physiological dose of HC in patients with SAI when compared to a lower dose. Copyright © 2015 Elsevier Ltd. All rights reserved.

Comparative evaluation of two-dimensional radiography and three dimensional computed tomography based dose-volume parameters for high-dose-rate intracavitary brachytherapy of cervical cancer: a prospective study.

PubMed

Madan, Renu; Pathy, Sushmita; Subramani, Vellaiyan; Sharma, Seema; Mohanti, Bidhu Kalyan; Chander, Subhash; Thulkar, Sanjay; Kumar, Lalit; Dadhwal, Vatsla

2014-01-01

Dosimetric comparison of two dimensional (2D) radiography and three-dimensional computed tomography (3D-CT) based dose distributions with high-dose-rate (HDR) intracavitry radiotherapy (ICRT) for carcinoma cervix, in terms of target coverage and doses to bladder and rectum. Sixty four sessions of HDR ICRT were performed in 22 patients. External beam radiotherapy to pelvis at a dose of 50 Gray in 27 fractions followed by HDR ICRT, 21 Grays to point A in 3 sessions, one week apart was planned . All patients underwent 2D-orthogonal and 3D-CT simulation for each session. Treatment plans were generated using 2D-orthogonal images and dose prescription was made at point A. 3D plans were generated using 3D-CT images after delineating target volume and organs at risk. Comparative evaluation of 2D and 3D treatment planning was made for each session in terms of target coverage (dose received by 90%, 95% and 100% of the target volume: D90, D95 and D100 respectively) and doses to bladder and rectum: ICRU-38 bladder and rectum point dose in 2D planning and dose to 0.1cc, 1cc, 2cc, 5cc, and 10cc of bladder and rectum in 3D planning. Mean doses received by 100% and 90% of the target volume were 4.24 ± 0.63 and 4.9 ± 0.56 Gy respectively. Doses received by 0.1cc, 1cc and 2cc volume of bladder were 2.88 ± 0.72, 2.5 ± 0.65 and 2.2 ± 0.57 times more than the ICRU bladder reference point. Similarly, doses received by 0.1cc, 1cc and 2cc of rectum were 1.80 ± 0.5, 1.48 ± 0.41 and 1.35 ± 0.37 times higher than ICRU rectal reference point. Dosimetric comparative evaluation of 2D and 3D CT based treatment planning for the same brachytherapy session demonstrates underestimation of OAR doses and overestimation of target coverage in 2D treatment planning.

Randomized Phase II Study of Azacitidine Alone or in Combination With Lenalidomide or With Vorinostat in Higher-Risk Myelodysplastic Syndromes and Chronic Myelomonocytic Leukemia: North American Intergroup Study SWOG S1117.

PubMed

Sekeres, Mikkael A; Othus, Megan; List, Alan F; Odenike, Olatoyosi; Stone, Richard M; Gore, Steven D; Litzow, Mark R; Buckstein, Rena; Fang, Min; Roulston, Diane; Bloomfield, Clara D; Moseley, Anna; Nazha, Aziz; Zhang, Yanming; Velasco, Mario R; Gaur, Rakesh; Atallah, Ehab; Attar, Eyal C; Cook, Elina K; Cull, Alyssa H; Rauh, Michael J; Appelbaum, Frederick R; Erba, Harry P

2017-08-20

Purpose Azacitidine is standard, first-line therapy in higher-risk myelodysplastic syndromes (MDS). Whether azacitidine-based combinations with lenalidomide or vorinostat produce superior overall response rates (ORRs) to azacitidine is not known. Patients and Methods North American Intergroup Study S1117 is a phase II/III trial that randomly assigned patients with higher-risk MDS and chronic myelomonocytic leukemia (CMML) 1:1:1 to azacitidine (75 mg/m 2 /day on days 1 to 7 of a 28-day cycle); azacitidine plus lenalidomide (10 mg/day on days 1 to 21); or azacitidine plus vorinostat (300 mg twice daily on days 3 to 9). The primary phase II end point was improved ORR. Results Of 277 patients from 90 centers, 92 received azacitidine, 93 received azacitidine plus lenalidomide, and 92 received azacitidine plus vorinostat. Median age was 70 years (range, 28 to 93 years), 85 patients (31%) were female, and 53 patients (19%) had CMML. Serious adverse events were similar across arms, although combination-arm patients were more likely to undergo nonprotocol-defined dose modifications ( P < .001).With a median follow-up of 23 months (range, 1 to 43 months), the ORR was 38% for patients receiving azacitidine, 49% for azacitidine plus lenalidomide ( P = .14 v azacitidine), and 27% for azacitidine plus vorinostat ( P = .16 v azacitidine). For patients with CMML, ORR was higher for azacitidine plus lenalidomide versus azacitidine (68% v 28%, P = .02) but similar for all arms across cytogenetic subgroups, as was remission duration and overall survival. ORR was higher with mutations in DNMT3A and lower for SRSF2, whereas ORR duration improved with fewer mutations. Lenalidomide dose reduction was associated with worse overall survival (hazard ratio, 1.30; P = .05). Conclusion Patients with higher-risk MDS treated with azacitidine-based combinations had similar ORR to azacitidine monotherapy, although patients with CMML benefitted from azacitidine plus lenalidomide. The efficacy of combination regimens may have been affected by dose modifications.

The administration of a loading dose of aspirin to patients presenting with acute myocardial infarction while receiving chronic aspirin treatment reduces thromboxane A2-dependent platelet reactivity.

PubMed

Santos, Maria Teresa; Madrid, Isabel; Moscardo, Antonio; Latorre, Ana M; Bonastre, Juan; Ruano, Miguel; Valles, Juana

2014-01-01

Abstract The optimal dose of aspirin for patients presenting with acute myocardial infarction (AMI) while receiving chronic aspirin therapy has not been clearly established. We evaluated whether continued treatment with 100 mg of aspirin or a loading dose (200-500 mg) influences thromboxane A2 (TX) suppression or platelet reactivity. Sixty-four consecutive patients with AMI and 98 healthy subjects (82 aspirin-free and 16 receiving 100 mg daily for a week) were evaluated. Treatment was at the discretion of the attending physician. Collagen (1 µg/ml)-induced TX synthesis, (14)C-serotonin-release, platelet aggregation, and the PFA-100 assay were evaluated. The platelet TX synthesis of patients receiving a loading dose of aspirin was sixfold lower than that of patients receiving 100 mg of aspirin (p<0.005). This was associated with marked reductions in (14)C-serotonin-release and arachidonic-acid-induced aggregation and an increase in the PFA-100 closure time (p<0.01). Categorization of patients according to their TX synthesis (<95% or ≥ 95% inhibition vs. healthy aspirin-free subjects) revealed that 8% of the patients treated with loading doses had a poor response (<95% inhibition) vs. 53% of those treated with 100 mg (p<0.001). Patients with lower TX inhibition had higher serum NT-Pro-BNP (p<0.005), a marker of poor left ventricular systolic function. Administration of a loading dose of aspirin to patients with AMI during existing chronic aspirin treatment induced greater reductions in platelet TX synthesis and TX-dependent platelet reactivity than the continued treatment alone.

Eye doses to staff in a nuclear medicine department.

PubMed

Summers, Elizabeth C; Brown, Janis L E; Bownes, Peter J; Anderson, Shona E

2012-05-01

Occupational radiation doses to the Nuclear Medicine Department staff at Mount Vernon Hospital are routinely measured using optically stimulated luminescence dosemeters for whole-body effective dose and ring thermoluminescence dosemeters (TLDs) for finger dose. In 2002, a project was carried out using LiF:Mg,Cu,P Chinese TLDs to measure the dose to the lens of the eye received by staff during normal working procedures. Separate pairs of TLDs were worn by staff on their forehead between their eyes while dispensing and releasing in the radiopharmacy, injecting, and when administering I-131 capsules to patients. The dose received was calculated using calibration data from identical TLDs irradiated with Tc-99m, I-131, and the Ir-192 source of a Gammamed High Dose Rate (HDR) treatment unit. Data were collected over a 5-month period and the mean dose to the eye was calculated for each procedure. Using a typical yearly workload, the annual dose to the eye for a single member of staff was calculated and found to be 4.5 mSv. The occupational eye dose limit was, at the time, 150 mSv; therefore, staff were well below the level (3/10th of this limit) that would have required them to be classified. However, there have been large increases in radiopharmacy production and I-131 therapies administered at Mount Vernon in subsequent years. It is therefore expected that the eye dose received by staff will have increased to be significantly higher than 4.5 mSv and will in fact be greater than 6 mSv, which is 3/10th of the proposed new dose limit and would require these staff to become classified workers.

What dose of tranexamic acid is most effective and safe for adult patients undergoing cardiac surgery?

PubMed

Hodgson, Sam; Larvin, Joseph T; Dearman, Charles

2015-09-01

A best evidence topic in cardiac surgery was written according to a structured protocol. The question addressed was: what dose of tranexamic acid is most effective and safe for adult patients undergoing cardiac surgery? Altogether 586 papers were found using the reported search, of which 12 represented the best evidence to answer the clinical question. The authors, journal, date and country of publication, patient group studied, study type, relevant outcomes and results of these papers are tabulated. Current evidence shows clinical benefit of using high-dose tranexamic acid (>80 mg/kg total dose) as opposed to low-dose tranexamic acid (<50 mg/kg total dose) in cardiac surgery with cardiopulmonary bypass. Evidence from a large randomized controlled trial shows that patients receiving high-dose tranexamic acid lose less blood postoperatively than patients receiving low-dose tranexamic acid (590 vs 820 ml, P = 0.01). Patients receiving high-dose tranexamic acid also require fewer units of blood product transfusion (2.5 units vs 4.1 units; P = 0.02) and are less likely to undergo repeat surgery to achieve haemostasis. This effect is larger in those who are at high risk of bleeding. Several prospective studies comparing doses found no difference in clinical outcomes between high- and low-dose regimens, but excluded patients at high risk of bleeding. However, data from numerous observational studies demonstrate that tranexamic acid use is associated with an increased risk of postoperative seizure; one analysis showed tranexamic acid use to be a very strong independent predictor (odds ratio = 14.3, P < 0.001). There is also evidence that this risk of seizure is dose-dependent, with the greatest risk at higher doses of tranexamic acid. We conclude that, in general, patients with a high risk of bleeding should receive high-dose tranexamic acid, while those at low risk of bleeding should receive low-dose tranexamic acid with consideration given to potential dose-related seizure risk. We recommend the regimens of high-dose (30 mg kg(-1) bolus + 16 mg kg(-1) h(-1) + 2 mg kg(-1) priming) and low-dose (10 mg kg(-1) bolus + 1 mg kg(-1) h(-1) + 1 mg kg(-1) priming) tranexamic acid, as these are well established in terms of safety profile and have the strongest evidence for efficacy. © The Author 2015. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.

Intravitreally-administered dopamine D2-like (and D4), but not D1-like, receptor agonists reduce form-deprivation myopia in tree shrews.

PubMed

Ward, Alexander H; Siegwart, John T; Frost, Michael R; Norton, Thomas T

2017-01-01

We examined the effect of intravitreal injections of D1-like and D2-like dopamine receptor agonists and antagonists and D4 receptor drugs on form-deprivation myopia (FDM) in tree shrews, mammals closely related to primates. In eleven groups (n = 7 per group), we measured the amount of FDM produced by monocular form deprivation (FD) over an 11-day treatment period. The untreated fellow eye served as a control. Animals also received daily 5 µL intravitreal injections in the FD eye. The reference group received 0.85% NaCl vehicle. Four groups received a higher, or lower, dose of a D1-like receptor agonist (SKF38393) or antagonist (SCH23390). Four groups received a higher, or lower, dose of a D2-like receptor agonist (quinpirole) or antagonist (spiperone). Two groups received the D4 receptor agonist (PD168077) or antagonist (PD168568). Refractions were measured daily; axial component dimensions were measured on day 1 (before treatment) and day 12. We found that in groups receiving the D1-like receptor agonist or antagonist, the development of FDM and altered ocular component dimensions did not differ from the NaCl group. Groups receiving the D2-like receptor agonist or antagonist at the higher dose developed significantly less FDM and had shorter vitreous chambers than the NaCl group. The D4 receptor agonist, but not the antagonist, was nearly as effective as the D2-like agonist in reducing FDM. Thus, using intravitreally-administered agents, we did not find evidence supporting a role for the D1-like receptor pathway in reducing FDM in tree shrews. The reduction of FDM by the dopamine D2-like agonist supported a role for the D2-like receptor pathway in the control of FDM. The reduction of FDM by the D4 receptor agonist, but not the D4 antagonist, suggests an important role for activation of the dopamine D4 receptor in the control of axial elongation and refractive development.

Intravitreally-administered dopamine D2-like (and D4), but not D1-like, receptor agonists reduce form-deprivation myopia in tree shrews

PubMed Central

Ward, Alexander H.; Siegwart, John T.; Frost, Michael R.; Norton, Thomas T.

2017-01-01

We examined the effect of intravitreal injections of D1-like and D2-like dopamine receptor agonists and antagonists and D4 receptor drugs on form-deprivation myopia (FDM) in tree shrews, mammals closely related to primates. In eleven groups (n = 7 per group), we measured the amount of FDM produced by monocular form deprivation (FD) over an 11-day treatment period. The untreated fellow eye served as a control. Animals also received daily 5 μL intravitreal injections in the FD eye. The reference group received 0.85% NaCl vehicle. Four groups received a higher, or lower, dose of a D1-like receptor agonist (SKF38393) or antagonist (SCH23390). Four groups received a higher, or lower, dose of a D2-like receptor agonist (quinpirole) or antagonist (spiperone). Two groups received the D4 receptor agonist (PD168077) or antagonist (PD168568). Refractions were measured daily; axial component dimensions were measured on day 1 (before treatment) and day 12. We found that in groups receiving the D1-like receptor agonist or antagonist, the development of FDM and altered ocular component dimensions did not differ from the NaCl group. Groups receiving the D2-like receptor agonist or antagonist at the higher dose developed significantly less FDM and had shorter vitreous chambers than the NaCl group. The D4 receptor agonist, but not the antagonist, was nearly as effective as the D2-like agonist in reducing FDM. Thus, using intravitreally-administered agents, we did not find evidence supporting a role for the D1-like receptor pathway in reducing FDM in tree shrews. The reduction of FDM by the dopamine D2-like agonist supported a role for the D2-like receptor pathway in the control of FDM. The reduction of FDM by the D4 receptor agonist, but not the D4 antagonist, suggests an important role for activation of the dopamine D4 receptor in the control of axial elongation and refractive development. PMID:28304244

Dosimetric impact in the dose-volume histograms of rectal and vesical wall contouring in prostate cancer IMRT treatments.

PubMed

Gómez, Laura; Andrés, Carlos; Ruiz, Antonio

2017-01-01

The main purpose of this study was to evaluate the differences in dose-volume histograms of IMRT treatments for prostate cancer based on the delineation of the main organs at risk (rectum and bladder) as solid organs or by contouring their wall. Rectum and bladder have typically been delineated as solid organs, including the waste material, which, in practice, can lead to an erroneous assessment of the risk of adverse effects. A retrospective study was made on 25 patients treated with IMRT radiotherapy for prostate adenocarcinoma. 76.32 Gy in 36 fractions was prescribed to the prostate and seminal vesicles. In addition to the delineation of the rectum and bladder as solid organs (including their content), the rectal and bladder wall were also delineated and the resulting dose-volume histograms were analyzed for the two groups of structures. Data analysis shows statistically significant differences in the main parameters used to assess the risk of toxicity of a prostate radiotherapy treatment. Higher doses were received on the rectal and bladder walls compared to doses received on the corresponding solid organs. The observed differences in terms of received doses to the rectum and bladder based on the method of contouring could gain greater importance in inverse planning treatments, where the treatment planning system optimizes the dose in these volumes. So, one should take into account the method of delineating of these structures to make a clinical decision regarding dose limitation and risk assessment of chronic toxicity.

Comparison of 2 doses of recombinant human thyrotropin for thyroid function testing in healthy and suspected hypothyroid dogs.

PubMed

Boretti, F S; Sieber-Ruckstuhl, N S; Wenger-Riggenbach, B; Gerber, B; Lutz, H; Hofmann-Lehmann, R; Reusch, C E

2009-01-01

Various protocols using different doses of recombinant human thyrotropin (rhTSH) in TSH stimulation testing have been described. However, the influence of TSH dosage on thyroxine (T4) concentration has not yet been evaluated in suspected hypothyroid dogs. To evaluate the effectiveness of 2 doses of rhTSH. Fifteen dogs with clinical signs consistent with hypothyroidism and abnormal stimulation results with 75 microg rhTSH and 18 clinically healthy dogs. All dogs were stimulated with 75 and 150 microg rhTSH IV in a 1st and 2nd stimulation test, respectively. Blood samples were taken before and 6 hours after rhTSH administration for determination of total T4 concentration. Using the higher dose led to a normal test interpretation in 9 of the 15 dogs, in which stimulation had been abnormal using the lower dose. Based on follow-up information, hypothyroidism was excluded in 7 of these 9 dogs. In all 6 dogs with a blunted response to the higher dose, hypothyroidism could be confirmed. Healthy dogs showed significantly higher post-TSH T4 concentrations with the higher compared with the lower dose. Post-TSH T4 concentrations after TSH stimulation were not related to dogs' body weight in either healthy or diseased dogs. TSH dose significantly influenced test interpretation in suspected hypothyroid dogs. Differentiation between primary hypothyroidism and nonthyroidal disease was improved with 150 microg rhTSH. Because this effect was independent of the dogs' body weight, the higher dose is recommended in dogs that have concurrent disease or are receiving medication.

Extrapolating theoretical efficacy of inactivated influenza A/H5N1 virus vaccine from human immunogenicity studies

PubMed Central

Feldstein, Leora R.; Matrajt, Laura; Halloran, M. Elizabeth; Keitel, Wendy A.; Longini, Ira M.

2016-01-01

Influenza A virus subtype H5N1 has been a public health concern for almost 20 years due to its potential ability to become transmissible among humans. Phase I and II clinical trials have assessed safety, reactogenicity and immunogenicity of inactivated influenza A/H5N1 virus vaccines. A shortage of vaccine is likely to occur during the first months of a pandemic. Hence, determining whether to give one dose to more people or two doses to fewer people to best protect the population is essential. We use hemagglutination-inhibition antibody titers as an immune correlate for avian influenza vaccines. Using an established relationship to obtain a theoretical vaccine efficacy from immunogenicity data from thirteen arms of six phase I and phase II clinical trials of inactivated influenza A/H5N1 virus vaccines, we assessed: 1) the proportion of theoretical vaccine efficacy achieved after a single dose (defined as primary response level), and 2) whether theoretical efficacy increases after a second dose, with and without adjuvant. Participants receiving vaccine with AS03 adjuvant had higher primary response levels (range: 0.48–0.57) compared to participants receiving vaccine with MF59 adjuvant (range: 0.32–0.47), with no observed trends in primary response levels by antigen dosage. After the first and second doses, vaccine with AS03 at dosage levels 3.75, 7.5 and 15 mcg had the highest estimated theoretical vaccine efficacy: Dose 1) 45% (95%CI: 36–57%), 53% (95%CI: 42–63%) and 55% (95%CI: 44–64%), respectively and Dose 2) 93% (95%CI: 89–96%), 97% (95%CI: 95–98%) and 97% (95%CI: 96–100%), respectively. On average, the estimated theoretical vaccine efficacy of lower dose adjuvanted vaccines (AS03 and MF59) was 17% higher than that of higher dose unadjuvanted vaccines, suggesting that including an adjuvant is dose-sparing. These data indicate adjuvanted inactivated influenza A/H5N1 virus vaccine produces high theoretical efficacy after two doses to protect individuals against a potential avian influenza pandemic. PMID:27268778

Hypothyroidism as a Consequence of Intensity-Modulated Radiotherapy With Concurrent Taxane-Based Chemotherapy for Locally Advanced Head-and-Neck Cancer

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

Diaz, Roberto; Jaboin, Jerry J.; Morales-Paliza, Manuel

Purpose: To conduct a retrospective review of 168 consecutively treated locally advanced head-and-neck cancer (LAHNC) patients treated with intensity-modulated radiotherapy (IMRT)/chemotherapy, to determine the rate and risk factors for developing hypothyroidism. Methods and Materials: Intensity-modulated radiotherapy was delivered in 33 daily fractions to 69.3 Gy to gross disease and 56.1 Gy to clinically normal cervical nodes. Dose-volume histograms (DVHs) of IMRT plans were used to determine radiation dose to thyroid and were compared with DVHs using conventional three-dimensional radiotherapy (3D-RT) in 10 of these same patients randomly selected for replanning and with DVHs of 16 patients in whom the thyroidmore » was intentionally avoided during IMRT. Weekly paclitaxel (30 mg/m{sup 2}) and carboplatin area under the curve-1 were given concurrently with IMRT. Results: Sixty-one of 128 evaluable patients (47.7%) developed hypothyroidism after a median of 1.08 years after IMRT (range, 2.4 months to 3.9 years). Age and volume of irradiated thyroid were associated with hypothyroidism development after IMRT. Compared with 3D-RT, IMRT with no thyroid dose constraints resulted in significantly higher minimum, maximum, and median dose (p < 0.0001) and percentage thyroid volume receiving 10, 20, and 60 Gy (p < 0.05). Compared with 3D-RT, IMRT with thyroid dose constraints resulted in lower median dose and percentage thyroid volume receiving 30, 40, and 50 Gy (p < 0.005) but higher minimum and maximum dose (p < 0.005). Conclusions: If not protected, IMRT for LAHNC can result in higher radiation to the thyroid than with conventional 3D-RT. Techniques to reduce dose and volume of radiation to thyroid tissue with IMRT are achievable and recommended.« less

The antiplatelet effect of higher loading and maintenance dose regimens of clopidogrel: the PRINC (Plavix Response in Coronary Intervention) trial.

PubMed

Gladding, Patrick; Webster, Mark; Zeng, Irene; Farrell, Helen; Stewart, Jim; Ruygrok, Peter; Ormiston, John; El-Jack, Seif; Armstrong, Guy; Kay, Patrick; Scott, Douglas; Gunes, Arzu; Dahl, Marja-Liisa

2008-12-01

This study evaluated the antiplatelet effect of a higher loading and maintenance dose regimen of clopidogrel and a possible drug interaction with verapamil. Clopidogrel loading doses above 600 mg have not resulted in more rapid or complete platelet inhibition. Higher maintenance dosages may be more effective than 75 mg/day. A double-blind, randomized, placebo-controlled trial was undertaken in 60 patients undergoing percutaneous coronary intervention. All patients received clopidogrel 600 mg at the start of the procedure. Using a 2 x 2 design, patients were allocated to clopidogrel 600 mg given 2 h later or matching placebo, and to verapamil 5 mg intra-arterial or placebo. Platelet function was measured using the VerifyNow P2Y12 analyzer (Accumetrics Ltd., San Diego, California) at 2, 4, and 7 h. Patients were further randomized to receive a clopidogrel 75 or 150 mg once daily, with platelet function assessed after 1 week. Two hours after the second dose of clopidogrel or placebo, platelet inhibition was 42 +/- 27% with clopidogrel, compared with 24 +/- 22% with placebo (p = 0.0006). By 5 h after the second dose, platelet inhibition was 49 +/- 30% with clopidogrel, compared with 29 +/- 22% with placebo (p = 0.01). No drug interaction was seen with verapamil. A clopidogrel maintenance dosage of 150 mg daily for 1 week resulted in greater platelet inhibition than 75 mg daily (50 +/- 28% vs. 29 +/- 19%, p = 0.01). In an unselected population undergoing percutaneous coronary intervention a clopidogrel 1,200-mg loading dose, given as two 600-mg doses 2 h apart, results in more rapid and complete platelet inhibition than a single 600-mg dose. A maintenance dosage of 150 mg daily produces greater platelet inhibition than 75 mg daily. (The PRINC trial; ACTRN12606000129583).

Opioid doses required for pain management in lung cancer patients with different cholesterol levels: negative correlation between opioid doses and cholesterol levels.

PubMed

Huang, Zhenhua; Liang, Lining; Li, Lingyu; Xu, Miao; Li, Xiang; Sun, Hao; He, Songwei; Lin, Lilong; Zhang, Yixin; Song, Yancheng; Yang, Man; Luo, Yuling; Loh, Horace H; Law, Ping-Yee; Zheng, Dayong; Zheng, Hui

2016-03-08

Pain management has been considered as significant contributor to broad quality-of-life improvement for cancer patients. Modulating serum cholesterol levels affects analgesia abilities of opioids, important pain killer for cancer patients, in mice system. Thus the correlation between opioids usages and cholesterol levels were investigated in human patients with lung cancer. Medical records of 282 patients were selected with following criteria, 1) signed inform consent, 2) full medical records on total serum cholesterol levels and opioid administration, 3) opioid-naïve, 4) not received/receiving cancer-related or cholesterol lowering treatment, 5) pain level at level 5-8. The patients were divided into different groups basing on their gender and cholesterol levels. Since different opioids, morphine, oxycodone, and fentanyl, were all administrated at fixed low dose initially and increased gradually only if pain was not controlled, the percentages of patients in each group who did not respond to the initial doses of opioids and required higher doses for pain management were determined and compared. Patients with relative low cholesterol levels have larger percentage (11 out of 28 in female and 31 out of 71 in male) to not respond to the initial dose of opioids than those with high cholesterol levels (0 out of 258 in female and 8 out of 74 in male). Similar differences were obtained when patients with different opioids were analyzed separately. After converting the doses of different opioids to equivalent doses of oxycodone, significant correlation between opioid usages and cholesterol levels was also observed. Therefore, more attention should be taken to those cancer patients with low cholesterol levels because they may require higher doses of opioids as pain killer.

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

PubMed

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

2015-12-01

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

Effect of high doses of 2-CdA on Schwann cells of mouse peripheral nerve.

PubMed

Djaldetti, R; Hart, J; Alexandrova, S; Cohen, S; Beilin, B; Djaldetti, M; Bessler, H

1996-07-01

The present study was undertaken to examine the effect of 2-CdA (Leustatin) on the Schwann cells of myelinated and unmyelinated fibers of peripheral mouse nerve. Two groups of mice were injected intravenously for seven days with 2-CdA: one group received daily doses of 1 mg/kg and the other 0.5 mg/kg. Both doses exceeded those accepted in clinical practice. Mice injected with saline served as controls. The sciatic nerve was then dissected and examined with a transmission electron microscope. The Schwann cells of both the myelinated and unmyelinated nerve fibers of the animals receiving the higher doses of 2-CdA showed nuclear and nucleolus damage, loss of heterochromatin, vacuolization and disorganization of the myelin sheaths. The mesaxons and the axons were also damaged. The Schwann cells of the animals treated with the lower doses appeared undamaged. The results indicate that in contrast to other anticancer drugs known to produce peripheral neuropathy, 2-CdA may cause damage to the Schwann cells only at doses exceeding the therapeutic ones.

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

Pokhrel, D; Sood, S; Badkul, R

Purpose: To compare dose distributions calculated using PB-hete vs. XVMC algorithms for SRT treatments of cavernous sinus tumors. Methods: Using PB-hete SRT, five patients with cavernous sinus tumors received the prescription dose of 25 Gy in 5 fractions for planning target volume PTV(V100%)=95%. Gross tumor volume (GTV) and organs at risk (OARs) were delineated on T1/T2 MRI-CT-fused images. PTV (range 2.1–84.3cc, mean=21.7cc) was generated using a 5mm uniform-margin around GTV. PB-hete SRT plans included a combination of non-coplanar conformal arcs/static beams delivered by Novalis-TX consisting of HD-MLCs and a 6MV-SRS(1000 MU/min) beam. Plans were re-optimized using XVMC algorithm with identicalmore » beam geometry and MLC positions. Comparison of plan specific PTV(V99%), maximal, mean, isocenter doses, and total monitor units(MUs) were evaluated. Maximal dose to OARs such as brainstem, optic-pathway, spinal cord, and lenses as well as normal tissue volume receiving 12Gy(V12) were compared between two algorithms. All analysis was performed using two-tailed paired t-tests of an upper-bound p-value of <0.05. Results: Using either algorithm, no dosimetrically significant differences in PTV coverage (PTVV99%,maximal, mean, isocenter doses) and total number of MUs were observed (all p-values >0.05, mean ratios within 2%). However, maximal doses to optic-chiasm and nerves were significantly under-predicted using PB-hete (p=0.04). Maximal brainstem, spinal cord, lens dose and V12 were all comparable between two algorithms, with exception of one patient with the largest PTV who exhibited 11% higher V12 with XVMC. Conclusion: Unlike lung tumors, XVMC and PB-hete treatment plans provided similar PTV coverage for cavernous sinus tumors. Majority of OARs doses were comparable between two algorithms, except for small structures such as optic chiasm/nerves which could potentially receive higher doses when using XVMC algorithm. Special attention may need to be paid on a case-by-case basis when planning for sinus SRT based on tumor size and location to OARs particularly the optic apparatus.« less

IMRT delivers lower radiation doses to dental structures than 3DRT in head and neck cancer patients.

PubMed

Fregnani, Eduardo Rodrigues; Parahyba, Cláudia Joffily; Morais-Faria, Karina; Fonseca, Felipe Paiva; Ramos, Pedro Augusto Mendes; de Moraes, Fábio Yone; da Conceição Vasconcelos, Karina Gondim Moutinho; Menegussi, Gisela; Santos-Silva, Alan Roger; Brandão, Thais B

2016-09-07

Radiotherapy (RT) is frequently used in the treatment of head and neck cancer, but different side-effects are frequently reported, including a higher frequency of radiation-related caries, what may be consequence of direct radiation to dental tissue. The intensity-modulated radiotherapy (IMRT) was developed to improve tumor control and decrease patient's morbidity by delivering radiation beams only to tumor shapes and sparing normal tissue. However, teeth are usually not included in IMRT plannings and the real efficacy of IMRT in the dental context has not been addressed. Therefore, the aim of this study is to assess whether IMRT delivers lower radiation doses to dental structures than conformal 3D radiotherapy (3DRT). Radiation dose delivery to dental structures of 80 patients treated for head and neck cancers (oral cavity, tongue, nasopharynx and oropharynx) with IMRT (40 patients) and 3DRT (40 patients) were assessed by individually contouring tooth crowns on patients' treatment plans. Clinicopathological data were retrieved from patients' medical files. The average dose of radiation to teeth delivered by IMRT was significantly lower than with 3DRT (p = 0.007); however, only patients affected by nasopharynx and oral cavity cancers demonstrated significantly lower doses with IMRT (p = 0.012 and p = 0.011, respectively). Molars received more radiation with both 3DRT and IMRT, but the latter delivered significantly lower radiation in this group of teeth (p < 0.001), whereas no significant difference was found for the other dental groups. Maxillary teeth received lower doses than mandibular teeth, but only IMRT delivered significantly lower doses (p = 0.011 and p = 0.003). Ipsilateral teeth received higher doses than contralateral teeth with both techniques and IMRT delivered significantly lower radiation than 3DRT for contralateral dental structures (p < 0.001). IMRT delivered lower radiation doses to teeth than 3DRT, but only for some groups of patients and teeth, suggesting that this decrease was more likely due to the protection of other high risk organs, and was not enough to remove teeth from the zone of high risk for radiogenic disturbance (>30Gy).

Intrathecal Baclofen Dosing Regimens: A Retrospective Chart Review.

PubMed

Clearfield, Jacob S; Nelson, Mary Elizabeth S; McGuire, John; Rein, Lisa E; Tarima, Sergey

2016-08-01

To examine dosing patterns in patients receiving baclofen via intrathecal baclofen pumps to assess for common patterns by diagnosis, ambulation ability, and affected limbs distribution. This trial study included 25 patients with baclofen pumps selected from the 356 patients enrolled in our center's baclofen pump program. Selection was done by splitting all patients into diagnostic categories of stroke, multiple sclerosis, traumatic/anoxic brain injury, cerebral palsy, and spinal cord injury, and then, five patients were randomly selected from each diagnosis.A systematic chart review was then conducted for each patient from Jan 1, 2008, through September 16, 2013, to look at factors including mean daily dose at end of study, and among those implanted during the study mean initial stable dose and time to initial stable dose. Analysis of mean daily dose across diagnoses found significant differences, with brain injury, cerebral palsy, and spinal cord injury patients having higher doses while multiple sclerosis and stroke patients required lower doses. Nonambulatory patients strongly trended to have higher daily doses than ambulatory patients. Similar trends of mean initial stable dose being higher in a similar pattern as that of end mean daily dose were seen according to diagnoses and ambulatory status, although statistical significance could not be achieved with the small sample size. Significant differences in dosing were found between diagnoses and trended to differ by ambulatory status at the end of the study, and similar trends could be observed in achieving initial stable dose. © 2015 International Neuromodulation Society.

Fluoroscopically guided transforaminal epidural steroid injections at a quaternary-care teaching institution: effect of trainee involvement and patient body mass index on fluoroscopy time and patient dose.

PubMed

Tiegs-Heiden, C A; Murthy, N S; Geske, J R; Diehn, F E; Schueler, B A; Wald, J T; Kaufmann, T J; Lehman, V T; Carr, C M; Amrami, K K; Morris, J M; Thielen, K R; Maus, T P

2016-01-01

To investigate whether there are differences in fluoroscopy time and patient dose for fluoroscopically guided lumbar transforaminal epidural steroid injections (TFESIs) performed by staff radiologists versus with trainees and to evaluate the effect of patient body mass index (BMI) on fluoroscopy time and patient dose, including their interactions with other variables. Single-level lumbar TFESIs (n=1844) between 1 January 2011 and 31 December 2013 were reviewed. Fluoroscopy time, reference point air kerma (Ka,r), and kerma area product (KAP) were recorded. BMI and trainee involvement were examined as predictors of fluoroscopy time, Ka,r, and KAP in models adjusted for age and gender in multivariable linear models. Stratified models of BMI groups by trainee presence were performed. Increased age was the only significant predictor of increased fluoroscopy time (p<0.0001). Ka,r and KAP were significantly higher in patients with a higher BMI (p<0.0001 and p=0.0009). When stratified by BMI, longer fluoroscopy time predicted increased Ka,r and KAP in all groups (p<0.0001). Trainee involvement was not a statistically significant predictor of fluoroscopy time or Ka,r in any BMI category. KAP was lower with trainees in the overweight group (p=0.0009) and higher in male patients for all BMI categories (p<0.02). Trainee involvement did not result in increased fluoroscopy time or patient dose. BMI did not affect fluoroscopy time; however, overweight and obese patients received significantly higher Ka,r and KAP. Male patients received a higher KAP in all BMI categories. Limiting fluoroscopy time and good collimation practices should be reinforced in these patients. Copyright © 2015 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.

Bowel sparing in pediatric cranio-spinal radiotherapy: a comparison of combined electron and photon and helical TomoTherapy techniques to a standard photon method

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

Harron, Elizabeth, E-mail: elizabeth.harron@nuh.nhs.uk; Lewis, Joanne

2012-07-01

The aim of this study was to compare the dose to organs at risk (OARs) from different craniospinal radiotherapy treatment approaches available at the Northern Centre for Cancer Care (NCCC), with a particular emphasis on sparing the bowel. Method: Treatment plans were produced for a pediatric medulloblastoma patient with inflammatory bowel disease using 3D conformal 6-MV photons (3DCP), combined 3D 6-MV photons and 18-MeV electrons (3DPE), and helical photon TomoTherapy (HT). The 3DPE plan was a modification of the standard 3DCP technique, using electrons to treat the spine inferior to the level of the diaphragm. The plans were compared inmore » terms of the dose-volume data to OARs and the nontumor integral dose. Results: The 3DPE plan was found to give the lowest dose to the bowel and the lowest nontumor integral dose of the 3 techniques. However, the coverage of the spine planning target volume (PTV) was least homogeneous using this technique, with only 74.6% of the PTV covered by 95% of the prescribed dose. HT was able to achieve the best coverage of the PTVs (99.0% of the whole-brain PTV and 93.1% of the spine PTV received 95% of the prescribed dose), but delivered a significantly higher integral dose. HT was able to spare the heart, thyroid, and eyes better than the linac-based techniques, but other OARs received a higher dose. Conclusions: Use of electrons was the best method for reducing the dose to the bowel and the integral dose, at the expense of compromised spine PTV coverage. For some patients, HT may be a viable method of improving dose homogeneity and reducing selected OAR doses.« less

SU-C-207A-07: Cumulative 18F-FDG Uptake Histogram Relative to Radiation Dose Volume Histogram of Lung After IMRT Or PSPT and Their Association with Radiation Pneumonitis

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

Shusharina, N; Choi, N; Bortfeld, T

2016-06-15

Purpose: To determine whether the difference in cumulative 18F-FDG uptake histogram of lung treated with either IMRT or PSPT is associated with radiation pneumonitis (RP) in patients with inoperable stage II and III NSCLC. Methods: We analyzed 24 patients from a prospective randomized trial to compare IMRT (n=12) with vs. PSPT (n=12) for inoperable NSCLC. All patients underwent PET-CT imaging between 35 and 88 days post-therapy. Post-treatment PET-CT was aligned with planning 4D CT to establish a voxel-to-voxel correspondence between post-treatment PET and planning dose images. 18F-FDG uptake as a function of radiation dose to normal lung was obtained formore » each patient. Distribution of the standard uptake value (SUV) was analyzed using a volume histogram method. The image quantitative characteristics and DVH measures were correlated with clinical symptoms of pneumonitis. Results: Patients with RP were present in both groups: 5 in the IMRT and 6 in the PSPT. The analysis of cumulative SUV histograms showed significantly higher relative volumes of the normal lung having higher SUV uptake in the PSPT patients for both symptomatic and asymptomatic cases (VSUV=2: 10% for IMRT vs 16% for proton RT and VSUV=1: 10% for IMRT vs 23% for proton RT). In addition, the SUV histograms for symptomatic cases in PSPT patients exhibited a significantly longer tail at the highest SUV. The absolute volume of the lung receiving the dose >70 Gy was larger in the PSPT patients. Conclusion: 18F-FDG uptake – radiation dose response correlates with RP in both groups of patients by means of the linear regression slope. SUV is higher for the PSPT patients for both symptomatic and asymptomatic cases. Higher uptake after PSPT patients is explained by larger volumes of the lung receiving high radiation dose.« less

HPV Vaccination Coverage of Male Adolescents in the United States

PubMed Central

Lu, Peng-jun; Yankey, David; Jeyarajah, Jenny; O’Halloran, Alissa; Elam-Evans, Laurie D.; Smith, Philip J.; Stokley, Shannon; Singleton, James A.; Dunne, Eileen F.

2018-01-01

Background In 2011, the Advisory Committee for Immunization Practices (ACIP) recommended routine use HPV vaccine for male adolescents. Methods We used the 2013 National Immunization Survey-Teen (NIS-Teen) data to assess HPV vaccine uptake (≥1 dose) and series completion (≥3 doses). Multivariable logistic regression analysis and a predictive marginal model were conducted to identify independent predictors of vaccination among adolescent males aged 13–17 years. Results HPV vaccination coverage with ≥1 dose was 34.6% while series completion (≥3 doses) was 13.9%. Coverage was significantly higher among non-Hispanic blacks and Hispanics compared with non-Hispanic white males. Multivariable logistic regression showed that characteristics independently associated with a higher likelihood of HPV vaccination (≥1 dose) included: being non-Hispanic black race or Hispanic ethnicity, having mothers who were widowed, divorced, or separated, having 1–3 physician contacts in the past 12 months, a well-child visit at age 11–12 years, having one or two vaccination providers, living in urban or suburban areas, and receiving vaccinations from more than one type of facility (p<0.05). Having mothers with some college or college education, having a higher family income to poverty ratio, living in South or Midwest, and receiving vaccinations from all STD/school/teen clinics or other facilities were independently associated with a lower likelihood of HPV vaccination (p<0.05). Conclusions Following recommendations for routine HPV vaccination among male adolescents, uptake in 2013 was low in males. Increased efforts are needed to improve vaccination coverage, especially for those who are least likely to be vaccinated. PMID:26504124

[Pretreatment doses of antithymocyte globubin-fresenius for allogeneic hematopoietic stem cell transplantation for beta-thalassemia major].

PubMed

Li, Chunfu; Wang, Yanhua; Wu, Xuedong; Pei, Fuyu; He, Yuelin; Feng, Xiaoqin; Liu, Huaying

2012-05-01

To investigate the effects of different doses of antithymocyte globubin-fresenius (ATG-F) for allogeneic hematopoietic stem cell transplantation (allo-HSCT) in patients with beta-thalassemia Major. Sixty-four children with beta-thalassemia major undergoing allo-HSCT were divided into two equal groups to receive ATG-F pretreatments at high (30 mg/kg) or low (15 mg/kg) doses as part of the conditioning regimen including mainly cyclophosphamide, busulfan, fludarabine, and thiotepa. The outcomes of the patients were compared between the two groups. No obvious difference were noted in the time to leukocyte and platelet engraftment between the two groups. The incidence of grade II-IV acute graft-versus-host disease (aGVHD) appeared to be higher in the low-dose group than in the high-dose group (12.5% vs 9.4%). The incidence of grade III-IV aGVHD was also higher in the low dose group (12.5% vs 6.3%), but the difference was not statistically significant. Application of high-dose ATG-F was associated with a higher rate of probable and possible fungal infection (P<0.05). The two doses of ATG-F is feasible as a part of the conditioning regimen for allo-HSCT in children with beta-thalassemia major.

Single and Multiple Ascending-dose Studies of Oral Delafloxacin: Effects of Food, Sex, and Age.

PubMed

Hoover, Randall; Hunt, Thomas; Benedict, Michael; Paulson, Susan K; Lawrence, Laura; Cammarata, Sue; Sun, Eugene

2016-01-01

The objective of this report is describe the results of 2 studies that examined the pharmacokinetic parameters, safety profile, and tolerability of single and multiple ascending doses of oral delafloxacin and the effects of food, sex, and age on oral delafloxacin pharmacokinetic parameters, safety profile, and tolerability. The first study contained 3 parts and used unformulated delafloxacin in a capsule. Part 1 was a randomized, double-blind, placebo-controlled, single (50, 100, 200, 400, 800, 1200, and 1600 mg) ascending-dose study of oral delafloxacin in healthy men. Part 2 was a single-dose crossover study in which 20 men received 250 mg delafloxacin with or without food. Part 2 also included a parallel group, double-blind, placebo-controlled study in 16 women and 16 elderly men and women who were randomized (3:1) to receive 250 mg delafloxacin or placebo. Part 3 was a randomized, double-blind, placebo-controlled, multiple (100, 200, 400, 800, 1200 mg once daily for 5 days) ascending-dose study of oral delafloxacin in healthy men. The second study was a single-dose, randomized, 3-period crossover study in which participants received 900 mg delafloxacin (2 × 450-mg tablets) under fasted conditions, with a high-fat meal, or fasted with a high-fat meal 2 hours after dosing. Serial blood samples were collected, and plasma pharmacokinetic parameters of delafloxacin were determined. Delafloxacin Cmax and AUC0-∞ increased with increasing oral dose over the dose range of 50 to 1600 mg. The increases in delafloxacin AUC0-∞ were dose proportional at doses of ≥200 mg. Steady state was reached by day 3 of dosing with minimal accumulation of delafloxacin. The Cmax of delafloxacin was decreased slightly in the presence of food. No sex difference in delafloxacin pharmacokinetic parameters was observed. In the elderly men and women, mean delafloxacin Cmax and AUC0-∞ were 35% higher than observed for young adults, which could be partially explained by a decrease in the creatinine clearance in the elderly men and women. Delafloxacin was well tolerated at the tested doses, with gastrointestinal adverse effects observed more commonly at doses ≥1200 mg. Delafloxacin exhibits linear pharmacokinetic parameters that reached steady state after 3 days of daily oral dosing with minimal accumulation. Delafloxacin was well tolerated throughout both studies, with gastrointestinal effects observed at the higher doses (≥1200 mg). Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

Patient dose estimation from CT scans at the Mexican National Neurology and Neurosurgery Institute

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

Alva-Sánchez, Héctor, E-mail: halva@ciencias.unam.mx; Reynoso-Mejía, Alberto; Casares-Cruz, Katiuzka

In the radiology department of the Mexican National Institute of Neurology and Neurosurgery, a dedicated institute in Mexico City, on average 19.3 computed tomography (CT) examinations are performed daily on hospitalized patients for neurological disease diagnosis, control scans and follow-up imaging. The purpose of this work was to estimate the effective dose received by hospitalized patients who underwent a diagnostic CT scan using typical effective dose values for all CT types and to obtain the estimated effective dose distributions received by surgical and non-surgical patients. Effective patient doses were estimated from values per study type reported in the applications guidemore » provided by the scanner manufacturer. This retrospective study included all hospitalized patients who underwent a diagnostic CT scan between 1 January 2011 and 31 December 2012. A total of 8777 CT scans were performed in this two-year period. Simple brain scan was the CT type performed the most (74.3%) followed by contrasted brain scan (6.1%) and head angiotomography (5.7%). The average number of CT scans per patient was 2.83; the average effective dose per patient was 7.9 mSv; the mean estimated radiation dose was significantly higher for surgical (9.1 mSv) than non-surgical patients (6.0 mSv). Three percent of the patients had 10 or more brain CT scans and exceeded the organ radiation dose threshold set by the International Commission on Radiological Protection for deterministic effects of the eye-lens. Although radiation patient doses from CT scans were in general relatively low, 187 patients received a high effective dose (>20 mSv) and 3% might develop cataract from cumulative doses to the eye lens.« less

Patient dose estimation from CT scans at the Mexican National Neurology and Neurosurgery Institute

NASA Astrophysics Data System (ADS)

Alva-Sánchez, Héctor; Reynoso-Mejía, Alberto; Casares-Cruz, Katiuzka; Taboada-Barajas, Jesús

2014-11-01

In the radiology department of the Mexican National Institute of Neurology and Neurosurgery, a dedicated institute in Mexico City, on average 19.3 computed tomography (CT) examinations are performed daily on hospitalized patients for neurological disease diagnosis, control scans and follow-up imaging. The purpose of this work was to estimate the effective dose received by hospitalized patients who underwent a diagnostic CT scan using typical effective dose values for all CT types and to obtain the estimated effective dose distributions received by surgical and non-surgical patients. Effective patient doses were estimated from values per study type reported in the applications guide provided by the scanner manufacturer. This retrospective study included all hospitalized patients who underwent a diagnostic CT scan between 1 January 2011 and 31 December 2012. A total of 8777 CT scans were performed in this two-year period. Simple brain scan was the CT type performed the most (74.3%) followed by contrasted brain scan (6.1%) and head angiotomography (5.7%). The average number of CT scans per patient was 2.83; the average effective dose per patient was 7.9 mSv; the mean estimated radiation dose was significantly higher for surgical (9.1 mSv) than non-surgical patients (6.0 mSv). Three percent of the patients had 10 or more brain CT scans and exceeded the organ radiation dose threshold set by the International Commission on Radiological Protection for deterministic effects of the eye-lens. Although radiation patient doses from CT scans were in general relatively low, 187 patients received a high effective dose (>20 mSv) and 3% might develop cataract from cumulative doses to the eye lens.

Incidence of cerebral infarction after radiotherapy for pituitary adenoma

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

Flickinger, J.C.; Nelson, P.B.; Taylor, F.H.

1989-06-15

The incidence of cerebral infarction was studied in 156 patients irradiated for treatment of pituitary adenomas. Seven patients experienced strokes at intervals of 3.2 to 14.6 years after irradiation. The observed incidence was not significantly greater than the expected value of 3.5 strokes (P = 0.078). Six strokes occurred in patients receiving equivalent doses (ED) of 1070 ret or more (observed to expected ratio 3.87, significantly elevated; P less than 0.001). Univariate log-rank analysis showed that the risk of stroke was significantly higher (P = 0.010) in patients receiving an ED of 1070 ret or more (4180 cGy/22 fractions) thanmore » those receiving lower doses. Multivariate analysis, however, demonstrated that the increased risk of stroke was associated only with increasing age (P less than 0.0001), not ED (P = 0.148). Due to these inconsistent statistical results, no definitive conclusions could be reached about the relationship between radiation dose to the pituitary and subsequent cerebral infarction.« less

A toddler PCV booster dose following 3 infancy priming doses increases circulating serotype-specific IGG levels but does not increase protection against carriage.

PubMed

Dagan, Ron; Ben-Shimol, Shalom; Simell, Birgit; Greenberg, David; Porat, Nurith; Käyhty, Helena; Givon-Lavi, Noga

2018-05-11

We compared PCV7 serological response and protection against carriage in infants receiving 3 doses (2, 4, 6 months; 3+0 schedule) to those receiving a booster (12 months; 3+1). A prospective, randomized controlled study, conducted between 2005 and 2008, before PCVs were implemented in Israel. Healthy infants were randomized 1:1:1 to receive 3+1, 3+0 and 0+2 (control group; 12, 18 months doses). Nasopharyngeal/oropharyngeal swabs were obtained at all visits. Serum serotype-specific IgG concentrations and opsonic activities (OPA) were measured at 2, 7, 13 and 19 months. This study was registered with Current Controlled Trials, Ltd. ISRCTN28445844. Overall, 544 infants were enrolled: 3+1 (n = 178), 3+0 (n = 178) and 0+2 (n = 188). Post-priming (7 months), antibody concentrations were similar in both groups, except for serotype 18C (higher in 3+0). Post-booster (13, 19 months), ELISA and OPA levels were significantly higher in 3+1 than in 3+0 group. Nasopharyngeal/oropharyngeal cultures were positive for Streptococcus pneumoniae in 2673 (54.3%) visits. Acquisition rates (vaccine and non-vaccine serotypes) were similar for 3+1 and 3+0 groups at 7-30 months and for 0+2 group at 19-30 months. PCV7 booster after 3 priming doses increased substantially IgG concentrations but did not further reduced vaccine-serotype nasopharyngeal acquisition, suggesting that protection from pneumococcal carriage does not depend primarily on serum IgG. Copyright © 2018 Elsevier Ltd. All rights reserved.

Facial exposure to ultraviolet radiation: Predicted sun protection effectiveness of various hat styles.

PubMed

Backes, C; Religi, A; Moccozet, L; Vuilleumier, L; Vernez, D; Bulliard, J-L

2018-04-23

Solar ultraviolet radiation (UVR) doses received by individuals are highly influenced by behavioural and environmental factors. This study aimed at quantifying hats' sun protection effectiveness in various exposure conditions, by predicting UVR exposure doses and their anatomical distributions. A well-defined three-dimensional head morphology and four hat styles (a cap, a helmet, a middle- and a wide-brimmed hat) were added to a previously published model. Midday (12:00-14:00) and daily (08:00 - 17:00) seasonal UVR doses were estimated at various facial skin zones, with and without hat-wear, accounting for each UVR component. Protection effectiveness was calculated by the relative reduction of predicted UVR dose, expressed as a predictive protection factor (PPF). The unprotected entire face received 2.5 times higher UVR doses during a summer midday compared to a winter midday (3.3 vs. 1.3 SED) with highest doses received at the nose (6.1 SED). During a cloudless summer day, the lowest mean UVR dose is received by the entire face protected by a wide-brimmed hat (1.7 SED). No hat reached 100% protection at any facial skin zone (PPF max : 76%). Hats' sun protection effectiveness varied highly with environmental conditions and were mainly limited by the high contribution of diffuse UVR, irrespective of hat style. Larger brim sizes afforded greater facial protection than smaller brim sizes except around midday when the sun position is high. Consideration of diffuse and reflected UVR in sun educational messages could improve sun protection effectiveness. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

Effect of low-dose versus higher-dose antenatal iron supplementation on child health outcomes at 36 months of age in Viet Nam: longitudinal follow-up of a cluster randomised controlled trial.

PubMed

Hanieh, Sarah; Ha, Tran T; Simpson, Julie A; Braat, Sabine; Thuy, Tran T; Tran, Thach D; King, Janet; Tuan, Tran; Fisher, Jane; Biggs, Beverley-Ann

2017-01-01

Intermittent iron-folic acid supplementation (IFA) is currently recommended for pregnant women in populations where anaemia prevalence among pregnant women is <20% or if daily iron is not acceptable. The effect of providing lower doses of antenatal elemental iron through intermittent regimes on longer-term health outcomes in childhood is unclear. A prospective cohort study conducted between May 2012 and May 2014 in Viet Nam among children of 36 months of age, born to women previously enrolled in a cluster randomised controlled trial of antenatal micronutrient supplementation (daily IFA (60 mg elemental iron) vs twice-weekly IFA (60 mg elemental iron) vs twice-weekly multiple micronutrient (MMN) supplementation (60 mg elemental iron)). Primary outcomes were height-for-age z-scores (HAZ), according to WHO growth standards and cognitive composite scores (Bayley Scales of Infant and Toddler Development, third edition) at 36 months of age. A total of 1017 children born to mothers enrolled in the cluster randomised trial were assessed at 36 months of age. Adjusted mean differences (MDs) in HAZ were -0.14 (95% CI -0.28 to -0.01) and -0.15 (95% CI -0.29 to -0.01) in children born to mothers who received twice-weekly IFA or MMN compared with those who received daily IFA. Children born to mothers who received twice-weekly MMN had lower composite motor scores compared with those who received daily IFA (MD -2.07, 95% CI -4.11 to -0.03). There were no differences in composite cognitive scores in the twice-weekly compared with daily regimens. Low-dose antenatal IFA supplementation (120 mg elemental iron per week) resulted in lower HAZ and motor composite scores in children compared with higher-dose antenatal IFA supplementation (420 mg elemental iron per week). This highlights the importance of adequate iron stores during pregnancy and the need for careful monitoring when lower-dose antenatal iron regimens are used. Australia New Zealand Clinical Trials Registry: 12610000944033.

Comparison of dose volume parameters evaluated using three forward planning – optimization techniques in cervical cancer brachytherapy involving two applicators

PubMed Central

Basu-Roy, Somapriya; Kar, Sanjay Kumar; Das, Sounik; Lahiri, Annesha

2017-01-01

Purpose This study is intended to compare dose-volume parameters evaluated using different forward planning- optimization techniques, involving two applicator systems in intracavitary brachytherapy for cervical cancer. It looks for the best applicator-optimization combination to fulfill recommended dose-volume objectives in different high-dose-rate (HDR) fractionation schedules. Material and methods We used tandem-ring and Fletcher-style tandem-ovoid applicator in same patients in two fractions of brachytherapy. Six plans were generated for each patient utilizing 3 forward optimization techniques for each applicator used: equal dwell weight/times (‘no optimization’), ‘manual dwell weight/times’, and ‘graphical’. Plans were normalized to left point A and dose of 8 Gy was prescribed. Dose volume and dose point parameters were compared. Results Without graphical optimization, maximum width and thickness of volume enclosed by 100% isodose line, dose to 90%, and 100% of clinical target volume (CTV); minimum, maximum, median, and average dose to both rectum and bladder are significantly higher with Fletcher applicator. Even if it is done, dose to both points B, minimum dose to CTV, and treatment time; dose to 2 cc (D2cc) rectum and rectal point etc.; D2cc, minimum, maximum, median, and average dose to sigmoid colon; D2cc of bladder remain significantly higher with this applicator. Dose to bladder point is similar (p > 0.05) between two applicators, after all optimization techniques. Conclusions Fletcher applicator generates higher dose to both CTV and organs at risk (2 cc volumes) after all optimization techniques. Dose restriction to rectum is possible using graphical optimization only during selected HDR fractionation schedules. Bladder always receives dose higher than recommended, and 2 cc sigmoid colon always gets permissible dose. Contrarily, graphical optimization with ring applicators fulfills all dose volume objectives in all HDR fractionations practiced. PMID:29204164

Primate paneth cell degeneration following methylmercury hydroxide ingestion.

PubMed Central

Mottet, N. K.; Body, R. L.

1976-01-01

The effects of methylmercury on the intestinal epithelium were studied in 14 adolescent male Macaca mulatta monkeys weighing 3 to 5 kg. They were divided into three groups: two controls received daily applesauce vehicle without methylmercury. Nine chronic low-dose animals received 0.2 to 1.0 mg of methylmercury per day for 80 to 491 days. Three acute high-dose animals received 2.0 mg methylmercury for 17 to 18 days, when they became terminally ill. Light and electron microscopic observations were made on samples of duodenum and ileum following perfusion and immersion fixation in a glutaraldehyde-paraformaldehyde fixative. Numerous uniquely structured inclusions were prominent in the Paneth cells of the chronic low-dose animals and some necrotic Paneth cells were seen, especially in the most chronic and higher dosed animals of the group. Acute high-dose treatment produced some inclusions in the Paneth cells similar to those of the chronic low-dose group, but degenerative and necrotic cells were more frequently seen. These alterations were not seen in other intestinal epithelial cells. Paneth cells are selectively altered. These findings suggest that a function of Paneth cells may be to eliminate metals from the body. Images Figure 11 Figure 12 Figure 13 Figure 1 Figure 2 Figure 3 Figures 4 and 5 Figure 14 Figure 15 Figures 16-18 Figures 6-10 PMID:820204

TH-A-9A-04: Incorporating Liver Functionality in Radiation Therapy Treatment Planning

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

Wu, V; Epelman, M; Feng, M

2014-06-15

Purpose: Liver SBRT patients have both variable pretreatment liver function (e.g., due to degree of cirrhosis and/or prior treatments) and sensitivity to radiation, leading to high variability in potential liver toxicity with similar doses. This work aims to explicitly incorporate liver perfusion into treatment planning to redistribute dose to preserve well-functioning areas without compromising target coverage. Methods: Voxel-based liver perfusion, a measure of functionality, was computed from dynamic contrast-enhanced MRI. Two optimization models with different cost functions subject to the same dose constraints (e.g., minimum target EUD and maximum critical structure EUDs) were compared. The cost functions minimized were EUDmore » (standard model) and functionality-weighted EUD (functional model) to the liver. The resulting treatment plans delivering the same target EUD were compared with respect to their DVHs, their dose wash difference, the average dose delivered to voxels of a particular perfusion level, and change in number of high-/low-functioning voxels receiving a particular dose. Two-dimensional synthetic and three-dimensional clinical examples were studied. Results: The DVHs of all structures of plans from each model were comparable. In contrast, in plans obtained with the functional model, the average dose delivered to high-/low-functioning voxels was lower/higher than in plans obtained with its standard counterpart. The number of high-/low-functioning voxels receiving high/low dose was lower in the plans that considered perfusion in the cost function than in the plans that did not. Redistribution of dose can be observed in the dose wash differences. Conclusion: Liver perfusion can be used during treatment planning potentially to minimize the risk of toxicity during liver SBRT, resulting in better global liver function. The functional model redistributes dose in the standard model from higher to lower functioning voxels, while achieving the same target EUD and satisfying dose limits to critical structures. This project is funded by MCubed and grant R01-CA132834.« less

The influence of angiotensin converting enzyme inhibitors on lipid peroxidation in sera and aorta of rabbits in diet-induced hypercholesterolemia.

PubMed

Wojakowski, W; Gminski, J; Siemianowicz, K; Goss, M; Machalski, M

2000-11-01

In hypercholesterolemia increased lipid and lipoprotein peroxidation occurs. The renin-angiotensin system plays an important role in atherogenesis. Angiotensin II induces smooth muscle cells proliferation and stimulates oxidation of LDL particles and foam cell accumulation. Inhibition of ang II production leads to decrease in lipid peroxide production. The aim of this study was to assess the lipid peroxidation expressed as concentration of thiobarbituric acid reactive species (TBARS) in sera and aorta homogenates after administration of two doses of angiotensin-converting enzyme (ACE) inhibitors (captopril, enalapril and quinapril) in diet-induced hypercholesterolemia in rabbits. Sixty-four New Zealand rabbits were used. Animals were fed with standard fodder, special diet (1% cholesterol content) or special diet + tested ACEI. Two doses of ACE inhibitors were used: i), equivalent to applied to humans, ii), dose 10 times higher. The animals were divided into 8 groups: control, standard fodder; B, special diet; C1, C2, special diet + captopril in doses 2.5 and 25 mg/kg/24 h, respectively; E1, E2, special diet + enalapril in doses 0.75 and 7.5 mg/kg/24 h, respectively; Q1 and Q2, special diet + quinapril in doses 0.75 and 7.5 mg/kg per day, respectively. In cholesterol-fed rabbits and in groups receiving lower doses of tested ACE inhibitors, the serum TBARS concentration at 6 months was significantly higher in comparison to the control. The higher doses of enalapril, quinapril and captopril, prevented the cholesterol-induced rise in TBARS concentration. Lower dose of captopril attenuated the rise in TBARS concentration, it was significantly lower in comparison to group B, but higher than in the control group. In animals from groups B, E1, C1, Q1 TBARS concentration in aortae was significantly higher as compared to control group. Both doses of captopril and higher doses of enalapril and quinapril inhibited the rise of lipid peroxides concentration induced by cholesterol-rich diet.

Effect of Admission Oral Diuretic Dose on Response to Continuous versus Bolus Intravenous Diuretics in Acute Heart Failure: An Analysis from DOSE-AHF

PubMed Central

Shah, Ravi V.; McNulty, Steven; O'Connor, Christopher M.; Felker, G. Michael; Braunwald, Eugene; Givertz, Michael M.

2014-01-01

Background Results from the Diuretic Optimization Strategies in Acute Heart Failure (DOSE-AHF) study suggest that an initial continuous infusion of loop diuretics is not superior to bolus dosing with regard to clinical endpoints in AHF. We hypothesized that outpatient furosemide dose was associated with congestion and poorer renal function, and explored the hypothesis that a continuous infusion may be more effective in patients on higher outpatient diuretic doses. Methods DOSE-AHF randomized 308 patients within 24 hours of admission to high vs. low initial intravenous diuretic dose given as either a continuous infusion or bolus. We compared baseline characteristics and assessed associations between mode of administration (bolus vs. continuous) and outcomes in patients receiving high-dose (≥120 mg furosemide equivalent, n=177) versus low-dose (<120 mg furosemide equivalent, n=131) outpatient diuretics. Results Patients on higher doses of furosemide were less frequently on renin-angiotensin system inhibitors (P=.01), and had worse renal function and more advanced symptoms. There was a significant interaction between outpatient dose and mode of therapy (P=0.01) with respect to net fluid loss at 72 hours after adjusting for creatinine and intensification strategy. Admission diuretic dose was associated with an increased risk of death or rehospitalization at 60 days (adjusted HR=1.08 per 20-mg increment in dose, 95% CI 1.01–1.16, P=.03). Conclusions In acute HF, patients on higher diuretic doses have greater disease severity, and may benefit from an initial bolus strategy. PMID:23194486

Pharmacokinetics, pharmacodynamics, tolerability, and safety of exenatide in Japanese patients with type 2 diabetes mellitus.

PubMed

Kothare, Prajakti A; Linnebjerg, Helle; Isaka, Yoshitaka; Uenaka, Kazunori; Yamamura, Ayuko; Yeo, Kwee Poo; de la Peña, Amparo; Teng, Choo Hua; Mace, Kenneth; Fineman, Mark; Shigeta, Hirofumi; Sakata, Yukikuni; Irie, Shin

2008-12-01

In this single-blind, parallel, placebo-controlled study, the pharmacokinetics, pharmacodynamics, tolerability, and safety of subcutaneous exenatide were evaluated in 40 Japanese patients with type 2 diabetes. Patients were allocated to 4 groups and randomized to receive exenatide (n = 8/group) or placebo (n = 2/group), with all receiving placebo on day 1. On day 2, patients received single-dose exenatide (2.5 microg [group A] or 5 microg [groups B, C, and D]) or placebo and then bid on days 3 to 5. On days 6 to 10, groups A and B continued on 2.5 and 5 microg bid; groups C and D received 10 and 15 microg bid, respectively. The last dose was given on the morning of day 10. All adverse events were mild or moderate in severity. Exenatide was generally well tolerated up to 10 microg. Exenatide was well absorbed with a median t(max) of 1.5 hours and mean t((1/2)) of 1.6 hours; exposure increased with dose. Up to 10 microg, exenatide reduced postprandial glucose concentrations in a dose-dependent fashion compared with placebo; decreases were similar for 10 and 15 microg. An E(max) model demonstrated that doses higher than 2.5 microg were necessary for adequate glycemic response. Based on tolerability and pharmacokinetic/pharmacodynamic relationships, 5 and 10 microg exenatide may be considered for further clinical development in Japanese patients with type 2 diabetes.

Use of fentanyl and midazolam in mechanically ventilated children--Does the method of infusion matter?

PubMed

da Silva, Paulo Sérgio Lucas; Reis, Maria Eunice; de Aguiar, Vânia Euzébio; Fonseca, Marcelo Cunio Machado

2016-04-01

Benzodiazepines and opioids are commonly used in pediatric intensive care unit. However, there is no previous study assessing the use of administering these drugs combined (single solution) or separately. We sought to evaluate the impact of these 2 different methods of providing sedation/analgesia in pediatric intensive care unit. One hundred twelve patients mechanically ventilated for more than 48 hours were randomized to receive a protocolized sedation regime comprising midazolam and fentanyl either separately (group 1, 57 patients) or combined as a single solution (group 2, 55 patients). Primary end point variable was the cumulated dose of midazolam and fentanyl. The median cumulated doses of both fentanyl (0.19 vs 0.37 mg/kg, P < .05) and midazolam (28.8 vs 45.6 mg/kg, P < .05) required in group 2 were higher when compared with those of group 1. Moreover, group 2 patients had a significantly longer time of vasopressor drugs requirement and a higher number of patients developing tolerance. Patients who received a single solution of midazolam and fentanyl had a higher cumulated dose of compared with those patients who did not. The potential risk for long-term neurologic effects on developing brains associated with this finding should be considered. Copyright © 2015 Elsevier Inc. All rights reserved.

A simple low-cost of liquid I-131 dispenser for routine radiopharmaceutical dispensing at nuclear medicine department, Institut Kanser Negara

NASA Astrophysics Data System (ADS)

Said, M. A.; Ashhar, Z. N.; Suhaimi, N. E. F.; Zainon, R.

2016-01-01

In routine radiopharmaceutical Iodine-131 (131I) dispensing, the amount of radiation dose received by the personnel depends on the distance between the personnel and the source, the time spent manipulating the source and the amount of shielding used to reduce the dose rate from the source. The novel iRAD-I131 dispenser using recycle 131I liquid lead pot will lead into low cost production, less maintenance and low dose received by the personnel that prepared the 131I. The new fabricated of low cost 131I dispenser was tested and the dose received by personnel were evaluated. The body of lead material is made from 2.5 cm lead shielded coated with epoxy paint to absorb the radiation dose up to 7.4 GBq of 131 I. The lead pot was supported with two stainless steel rod. The Optically Stimulated Luminescence (OSL) nanodot was used in this study to measure the dose rate at both extremities for every personnel who prepared the 131I. Each OSL nanodot was attached at the fingertip. Three different personnel (experienced between one to ten years above in preparing the radiopharmaceuticals) were participated in this study. The average equivalent dose at right and left hand were 122.694 ± 121.637 µSv/GBq and 77.281 ± 62.146 µSv/GBq respectively. This study found that the dose exposure received using iRAD-I131 was less up to seven times compared to the conventional method. The comparison of experimental data using iRAD-I131 and established radiopharmaceutical dispenser was also discussed. The innovation of 131I dispenser is highly recommended in a small radiopharmaceutical facility with limited budget. The novel iRAD-I131 enables implementation of higher output liquid dispensing with low radiation dose to the personnel.

A simple low-cost of liquid I-131 dispenser for routine radiopharmaceutical dispensing at nuclear medicine department, Institut Kanser Negara

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

Said, M. A.; Suhaimi, N. E. F.; Ashhar, Z. N., E-mail: aminhpj@gmail.com

In routine radiopharmaceutical Iodine-131 ({sup 131}I) dispensing, the amount of radiation dose received by the personnel depends on the distance between the personnel and the source, the time spent manipulating the source and the amount of shielding used to reduce the dose rate from the source. The novel iRAD-I131 dispenser using recycle {sup 131}I liquid lead pot will lead into low cost production, less maintenance and low dose received by the personnel that prepared the {sup 131}I. The new fabricated of low cost {sup 131}I dispenser was tested and the dose received by personnel were evaluated. The body of leadmore » material is made from 2.5 cm lead shielded coated with epoxy paint to absorb the radiation dose up to 7.4 GBq of {sup 131} I. The lead pot was supported with two stainless steel rod. The Optically Stimulated Luminescence (OSL) nanodot was used in this study to measure the dose rate at both extremities for every personnel who prepared the {sup 131}I. Each OSL nanodot was attached at the fingertip. Three different personnel (experienced between one to ten years above in preparing the radiopharmaceuticals) were participated in this study. The average equivalent dose at right and left hand were 122.694 ± 121.637 µSv/GBq and 77.281 ± 62.146 µSv/GBq respectively. This study found that the dose exposure received using iRAD-I131 was less up to seven times compared to the conventional method. The comparison of experimental data using iRAD-I131 and established radiopharmaceutical dispenser was also discussed. The innovation of {sup 131}I dispenser is highly recommended in a small radiopharmaceutical facility with limited budget. The novel iRAD-I131 enables implementation of higher output liquid dispensing with low radiation dose to the personnel.« less

A Phase I Study of Sunitinib plus Bevacizumab in Advanced Solid Tumors

PubMed Central

Rini, Brian I.; Garcia, Jorge A.; Cooney, Matthew M.; Elson, Paul; Tyler, Allison; Beatty, Kristi; Bokar, Joseph; Mekhail, Tarek; Bukowski, R.M.; Budd, G. Thomas; Triozzi, Pierre; Borden, Ernest; Ivy, Percy; Chen, Helen X.; Dolwati, Afshin; Dreicer, Robert

2009-01-01

Purpose Bevacizumab is an antibody against vascular endothelial growth factor (VEGF); sunitinib is an inhibitor of VEGF and related receptors. The safety and maximum tolerated dose (MTD) of sunitinib plus bevacizumab was assessed in this phase I trial. Experimental Design Patients with advanced solid tumors were treated on a 3+3 trial design. Patients received sunitinib daily (starting dose level 25 mg) for 4 weeks on followed by 2 weeks off and bevacizumab (starting dose level 5 mg/kg) on days 1, 15 and 29 of a 42-day cycle. Dose-limiting toxicities (DLTs) during the first 6-week cycle were used to determine the MTD. Results Thirty-eight patients were enrolled. Pts received a median of 3 cycles of treatment (range, 1–17+). There was one DLT (grade 4 hypertension) at 37.5 mg sunitinib and 5 mg/kg bevacizumab. Grade 3 or greater toxicity was observed in 87% of patients including hypertension (47%), fatigue (24%), thrombocytopenia (18%), proteinuria (13%), and hand-foot syndrome (13%). Dose modifications and delays were common at higher dose levels. No clinical or laboratory evidence of microangiopathic hemolytic anemia was observed. Seven patients had a confirmed RECIST-defined PR (18%; 95% confidence interval: 8–34%). Nineteen of the 32 patients with a post-baseline scan (59%) had at least some reduction in overall tumor burden (median 32%, range 3–73%). Conclusions The combination of sunitinib and bevacizumab in patients with advanced solid tumors is feasible, albeit with toxicity at higher dose levels and requiring dose modification with continued therapy. Anti-tumor activity was observed across multiple solid tumors. PMID:19773375

Higher pain scores, similar opioid doses and side effects associated with antipyretic analgesics in specialised tertiary pain care.

PubMed

Lötsch, Jörn; Freynhagen, Rainer; von Hentig, Nils; Griessinger, Norbert; Zimmermann, Michael; Sittl, Reinhard; Geisslinger, Gerd

2010-11-01

To evaluate whether non-opioid antipyretic analgesics are associated with lower pain scores, opioid doses and side effects in pain patients in tertiary care. In a cross-sectional observational study, data from 519 Caucasians (197 men, 322 women; mean age 55.6 ± 15 years) who had undertaken pain therapy for various causes for 77.5 ± 90.8 months, obtained in three separate study centres, was analysed for actual 24-h pain scores, daily opioid doses and the occurrence of side effects. Of the 519 patients, 352 received opioids and 260 antipyretic analgesics, from whom 154 received both classes and 304 only either class. The administration of non-opioid antipyretic analgesics was associated with higher average pain scores (4.6 ± 2.5 vs 3.9 ± 2.6; P = 0.01), tendentially higher average oral morphine equivalent doses (121.8 ± 162.2 vs 146.7 ± 242.4 mg/d; P = 0.25) and a similar incidence of side effects (P = 0.21). These results were correspondingly seen when analysing the three study centres separately as independent cohorts. With the caution advised for cross-sectional data, the results dispute a clinical benefit of non-opioid antipyretic analgesics for most chronic pain patients in tertiary care and draw attention towards prospectively re-evaluating the utility of non-opioid antipyretic analgesics in tertiary pain care in a randomised placebo controlled trial.

Non-CD34+ cells, especially CD8+ cytotoxic T cells and CD56+ natural killer cells, rather than CD34 cells, predict early engraftment and better transplantation outcomes in patients with hematologic malignancies after allogeneic peripheral stem cell transplantation.

PubMed

Kim, Dong Hwan; Won, Dong Il; Lee, Nan Young; Sohn, Sang Kyun; Suh, Jang Soo; Lee, Kyu Bo

2006-07-01

The effect of the transplant dose of each cell subset on engraftment kinetics and transplantation outcomes was evaluated in HLA-identical allogeneic peripheral blood stem cell transplantation (PBSCT). Sixty-nine patients were included in this retrospective study. Engraftment kinetics, transplantation outcomes, and immune reconstitution up to 1 year after transplantation were analyzed according to the transplant dose of CD34+ and non-CD34+ cells, including natural killer (NK) cells and CD8+ cytotoxic T (Tc) cells. An accelerated neutrophil engraftment was strongly associated with a higher transplant dose of NK cells (12 versus 16 days, P < .001) and Tc cells (13 versus 16 days, P < .001) but not CD34+ cells (P = .442). Survival analyses revealed a favorable prognosis for patients who received a higher dose of non-CD34+ cell subsets, rather than CD34+ cells, in terms of overall survival (OS; P = .024 for NK cells and .050 for Tc cells) and nonrelapse mortality (NRM; P = .005 for NK cells, .060 for Tc cells). In addition, a higher transplant dose of NK and Tc cells was correlated with a faster lymphoid reconstitution. In multivariate analyses, rapid neutrophil engraftment was correlated with a higher transplant dose of NK cells (P = .001) and Tc cells (P = .004). Moreover, an increased OS was associated with the NK cell dose (P = .007) and chronic graft-versus-host disease (P = .009), whereas a decreased NRM was associated with the NK dose (P = .024). In conclusion, in a PBSCT setting, a higher transplant dose of NK and Tc cells accelerated neutrophil engraftment, improved the immune reconstitution, and decreased NRM, thereby increasing OS after allogeneic PBSCT.

High-dose Versus Low-dose Tranexamic Acid to Reduce Transfusion Requirements in Pediatric Scoliosis Surgery.

PubMed

Johnson, Daniel J; Johnson, Christine C; Goobie, Susan M; Nami, Nina; Wetzler, Joshua A; Sponseller, Paul D; Frank, Steven M

2017-12-01

Our objective was to quantify blood loss and transfusion requirements for high-dose and low-dose tranexamic acid (TXA) dosing regimens in pediatric patients undergoing spinal fusion for correction of idiopathic scoliosis. Previous investigators have established the efficacy of TXA in pediatric scoliosis surgery; however, the dosing regimens vary widely and the optimal dose has not been established. We retrospectively analyzed electronic medical records for 116 patients who underwent spinal fusion surgery for idiopathic scoliosis by a single surgeon and were treated with TXA. In total, 72 patients received a 10 mg/kg loading dose with a 1 mg/kg/h maintenance dose (low-dose) and 44 patients received 50 mg/kg loading dose with a 5 mg/kg/h maintenance dose (high-dose). Estimated blood loss and transfusion requirements were compared between dosing groups. Patient characteristics were nearly identical between the 2 groups. Compared with the low-dose TXA group, the high-dose TXA group had decreased estimated blood loss (695 vs. 968 mL, P=0.01), and a decrease in both intraoperative (0.3 vs. 0.9 units, P=0.01) and whole hospitalization (0.4 vs. 1.0 units, P=0.04) red blood cell transfusion requirements. The higher-dose TXA was associated with decreased intraoperative (P=0.01), and whole hospital transfusion (P=0.01) requirements, even after risk-adjustment for potential confounding variables. High-dose TXA is more effective than low-dose TXA in reducing blood loss and transfusion requirements in pediatric idiopathic scoliosis patients undergoing surgery. Level-III, retrospective cohort study.

The impact of a novel franchise clinic network on access to medicines and vaccinations in Kenya: a cross-sectional study

PubMed Central

Adhvaryu, Achyuta

2012-01-01

Objectives To study the impact of a new franchise health clinic model (The HealthStore Foundation's CFWShops) on access to vaccinations and treatment for acute illnesses in a nationally representative sample of children in Kenya. Design The authors used multivariate linear and count regressions to examine associations between receipt of vaccinations or treatment and proximity to a franchise health clinic, adjusting for individual, household and clinic attributes as well as region fixed effects. Setting Demographic and Health Survey data from Kenya, 2008–2009. Participants 6079 Kenyan children younger than 5 years, of whom 2310 reported recent acute illness. Main outcome measures Outcomes for all children were number of polio doses received, number of DPT doses received, receipt of BCG vaccine, receipt of measles vaccine and number of total vaccinations received. Outcomes for acutely ill children were receipt of any medical treatment, treatment for fever, treatment for malaria and treatments specifically stocked by CFWShops. Results Children living within 30 km of a CFWShop received 0.129 (p=0.017) and 0.113 (p=0.025) more DPT and polio doses, respectively; and 0.285 more total vaccinations (p=0.023). Among acutely ill children, CFWShop proximity was associated with significant increases in the probabilities of receiving any medical treatment (0.142; p<0.001), treatment for fever (0.117; p=0.007) and treatments specifically stocked by CFWShops (0.064; p=0.015). Use of CFWShop services was not significantly different for lower-income vis-a-vis higher-income households. Conclusions The franchise health clinic model could substantially increase access to essential vaccinations and treatments in low-income countries. Moreover, the model's benefits may accrue to lesser- and higher-income households alike. PMID:22786948

The impact of a novel franchise clinic network on access to medicines and vaccinations in Kenya: a cross-sectional study.

PubMed

Berk, Justin; Adhvaryu, Achyuta

2012-01-01

To study the impact of a new franchise health clinic model (The HealthStore Foundation's CFWShops) on access to vaccinations and treatment for acute illnesses in a nationally representative sample of children in Kenya. The authors used multivariate linear and count regressions to examine associations between receipt of vaccinations or treatment and proximity to a franchise health clinic, adjusting for individual, household and clinic attributes as well as region fixed effects. Demographic and Health Survey data from Kenya, 2008-2009. 6079 Kenyan children younger than 5 years, of whom 2310 reported recent acute illness. Outcomes for all children were number of polio doses received, number of DPT doses received, receipt of BCG vaccine, receipt of measles vaccine and number of total vaccinations received. Outcomes for acutely ill children were receipt of any medical treatment, treatment for fever, treatment for malaria and treatments specifically stocked by CFWShops. Children living within 30 km of a CFWShop received 0.129 (p=0.017) and 0.113 (p=0.025) more DPT and polio doses, respectively; and 0.285 more total vaccinations (p=0.023). Among acutely ill children, CFWShop proximity was associated with significant increases in the probabilities of receiving any medical treatment (0.142; p<0.001), treatment for fever (0.117; p=0.007) and treatments specifically stocked by CFWShops (0.064; p=0.015). Use of CFWShop services was not significantly different for lower-income vis-a-vis higher-income households. The franchise health clinic model could substantially increase access to essential vaccinations and treatments in low-income countries. Moreover, the model's benefits may accrue to lesser- and higher-income households alike.

Older adults and high-risk medication administration in the emergency department

PubMed Central

Kim, Mitchell; Mitchell, Steven H; Gatewood, Medley; Bennett, Katherine A; Sutton, Paul R; Crawford, Carol A; Bentov, Itay; Damodarasamy, Mamatha; Kaplan, Stephen J; Reed, May J

2017-01-01

Background Older adults are susceptible to adverse effects from opioids, nonsteroidal anti-inflammatory drugs (NSAIDs), and benzodiazepines (BZDs). We investigated factors associated with the administration of elevated doses of these medications of interest to older adults (≥65 years old) in the emergency department (ED). Patients and methods ED records were queried for the administration of medications of interest to older adults at two academic medical center EDs over a 6-month period. Frequency of recommended versus elevated (“High doses” were defined as doses that ranged between 1.5 and 3 times higher than the recommended starting doses; “very high doses” were defined as higher than high doses) starting doses of medications, as determined by geriatric pharmacy/medicine guidelines and expert consensus, was compared by age groups (65–69, 70–74, 75–79, 80–84, and ≥85 years), gender, and hospital. Results There were 17896 visits representing 11374 unique patients >65 years of age (55.3% men, 44.7% women). A total of 3394 doses of medications of interest including 1678 high doses and 684 very high doses were administered to 1364 different patients. Administration of elevated doses of medications was more common than that of recommended doses. Focusing on opioids and BZDs, the 65–69-year age group was much more likely to receive very high doses (1481 and 412 doses, respectively) than the ≥85-year age groups (relative risk [RR] 5.52, 95% CI 2.56–11.90), mainly reflecting elevated opioid dosing (RR 8.28, 95% CI 3.69–18.57). Men were more likely than women to receive very high doses (RR 1.47, 95% CI 1.26–1.72), primarily due to BZDs (RR 2.12, 95% CI 2.07–2.16). Conclusion Administration of elevated doses of opioids and BZDs in the older population occurs frequently in the ED, especially to the 65–69-year age group and men. Further attention to potentially unsafe dosing of high-risk medications to older adults in the ED is warranted. PMID:29184448

Safety and immunogenicity of a Vi polysaccharide-tetanus toxoid conjugate vaccine (Typbar-TCV) in healthy infants, children, and adults in typhoid endemic areas: a multicenter, 2-cohort, open-label, double-blind, randomized controlled phase 3 study.

PubMed

Mohan, Vadrevu Krishna; Varanasi, Vineeth; Singh, Anit; Pasetti, Marcela F; Levine, Myron M; Venkatesan, Ramasamy; Ella, Krishna M

2015-08-01

Enteric fever caused by Salmonella Typhi remains a major public health problem in developing countries. Typbar-TCV is a single-dose typhoid Vi polysaccharide-tetanus toxoid conjugate vaccine for persons ≥6 months of age. Six hundred fifty-four healthy subjects aged 2-45 years enrolled in a double-blind, randomized controlled trial (RCT) received a single dose of Typbar-TCV or comparator "Vi polysaccharide" (Typbar), and 327 healthy subjects aged 6-23 months received a single dose of Typbar-TCV in an open-label trial (OLT); both received single- or multidose presentations from different lots. After 2 years, subsets in each group received a booster dose. The primary objective included analysis of geometric mean titer (GMTs) and 4-fold rise of anti-Vi serum immunoglobulin G (IgG) enzyme-linked immunosorbent assay titers over baseline (seroconversion [SCN]) 42 days after immunization. Typbar-TCV recipients in the RCT attained higher anti-Vi IgG GMTs 42 days after immunization (SCN, 97%; GMT, 1293 [95% confidence interval {CI}, 1153-1449]) than recipients of Typbar (SCN, 93%; GMT, 411 [95% CI, 359-471]) (P < .001). Typbar-TCV was highly immunogenic in the OLT (SCN, 98%; GMT, 1937 [95% CI, 1785-2103]). Two years after vaccination, anti-Vi titers remained higher in Typbar-TCV subjects (GMT, 82 [95% CI, 73-92]); and exhibited higher avidity (geometric mean avidity index [GMAI], 60%) than in Typbar recipients (GMT, 46 [95% CI, 40-53]; GMAI 46%) in the RCT (P < .001). OLT Typbar-TCV recipients achieved GMT of 48 (95% CI, 42-55) and GMAI of 57%. Typbar-TCV induced multiple IgG subclasses and strong booster responses in all ages. No serious vaccine-attributable adverse events were observed. Single-dose Typbar-TCV is well tolerated and induces robust and long-lasting serum anti-Vi IgG across age groups. CTRI/2011/08/001957, CTRI/2014/01/004341. © 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.

On the mutagenicity of methadone hydrochloride. Induced dominant lethal mutation and spermatocyte chromosomal aberrations in treated males.

PubMed

Badr, F M; Rabouh, S A; Badr, R S

1979-11-01

The mutagenicity of methadone hydrochloride was tested in male mice using the dominant lethal mutation technique and the spermatocyte test of treated mice. Male mice of C3H inbred strain received one of the following doses, 1, 2, 4 or 6 mg/kg body weight once a day for 3 consecutive days. Another group of mice served as control and received saline instead. Treated males were then mated to virgin females at 3-day intervals for a period of 45 days. Pregnant females were dissected at mid-term and the corpora lutea and intrauterine contents were recorded. The spermatocytes of treated males were examined 45-50 d after treatments with methadone and abnormal pairing configurations were scored. The methadone treatment was found to increase the rate of preimplantation deaths consistently in all post-meiotic stages with all doses used. In addition, the higher doses, 4 and 6 mg, affected spermatogonia stages. Quantitatively, the dose-response relationship cannot be demonstrated though the spectrum of effect increased with higher doses as more spermatogenesis stages became more sensitive to the treatment. In many cases the frequency of live implants showed a positive correlation with preimplantation deaths in contrast with the frequency of early deaths which showed only sporadic variation. The mutation indices based on total embryonic death indicate that methadone hydrochloride affected several stages of germ-cell maturation namely, spermatozoa (M.I. 14-35), late spermatids (M.I. 15-48), early spermatids (M.I. 14-50), late spermatocytes (M.I. 15-43) and spermatogonial stages (M.I. 12-63). Chromosome analysis at diakinesis-metaphase 1 revealed significant increase in the frequency of sex chromosome and autosome univalents with different doses of methadone. The smallest dose applied was quite effective and the data represent direct dose-response relationship. Of the multivalent configuration, the most frequent type was chain quadrivalents. The frequencies of total translocations per cell were estimated as 0.1, 0.16 and 0.2 for the 4 applied doses illustrating a dose-response relationship for the doses: 1, 2 and 4 mg, whereas with the higher dose, 6 mg, an abrupt decrease was apparent (0.05). This study calls for concern regarding the possible genetic hazards this drug may impose upon human populations.

First-in-human study of the toxicity, pharmacokinetics, and pharmacodynamics of CG200745, a pan-HDAC inhibitor, in patients with refractory solid malignancies.

PubMed

Kim, Kyu-pyo; Park, Seong Joon; Kim, Jeong-Eun; Hong, Yong Sang; Lee, Jae-Lyun; Bae, Kyun-Seop; Cha, Hyunju; Kwon, Sool-Ki; Ro, Seonggu; Cho, JoongMyung; Kim, Tae Won

2015-10-01

The aim of the present study was to assess the safety, maximum tolerated dose (MTD), pharmacokinetics, pharmacodynamics, and efficacy of single and multiple doses of intravenous CG200745, a novel histone deacetylase (HDAC) inhibitor, in patients with advanced solid malignancies. Two to six patients received intravenous CG200745 according to the 2 + 4 dose-escalating method. This first-in-human trial was comprised of two parts: Part 1 was a single ascending dose, and Part 2 was multiple ascending doses weekly for 3 weeks, and then 1 week off. For the first cycle, pharmacokinetic sampling for CG200745 and pharmacodynamic sampling for acetylated histone H4 in peripheral blood mononuclear cells (PBMCs) were performed on day 1 for Part 1 and on days 1 and 15 for Part 2. Examination of acetylated histone H4 in pre- and post-biopsy samples was performed in accessible patients. In all, 28 patients were treated at 13 dose levels (1.8-250 mg/m(2)) and received a total of 71 cycles of CG200745. Hematologic toxicities included grade 3/4 neutropenia (22.2 %) that did not last a week and non-hematologic toxicities included fatigue (22.2 %) and anorexia (16.7 %) that did not exceed grade 2. No dose-limiting toxic effects were noted. Dose proportionality was observed for both the maximum concentration and area under the curve. The elimination half-life was 5.67 ± 2.69 h (mean ± standard deviation). An increase in PBMC acetylated histone H4 was observed at dose levels up to 51 mg/m(2), which plateaued at higher dose levels. At 24 h, 75 % of patients (6/8) showed higher relative acetylation in tumor tissue compared to PBMCs. Although there was no partial or complete response, 57.1 % of patients (16/28) had stable disease that lasted at least 6 weeks. CG200745 can be safely administered at effective dose levels that inhibit HDAC in PBMCs and tumor tissue. Although MTD was not reached, further escalation was not performed because acetylated histone H4 plateaued at dose levels higher than 51 mg/m(2). Additional phase II trials are recommended at 250 mg/m(2).

Race- and gender-related differences in clinical characteristics and quality of life among outpatients with psychotic disorders.

PubMed

Nejtek, Vicki A; Allison, Nanette; Hilburn, Craig

2012-09-01

Historically, the literature suggests that African Americans with mental illness are diagnosed with psychotic disorders at a higher rate and receive higher doses of antipsychotic medications than other racial groups. However, few studies have compared clinical characteristics and quality of life among African-American (AA) and white men and women. Thus, research is needed to examine potential race and gender differences in clinical characteristics, prescribing practices, and quality of life. This exploratory, hypothesis-generating study examined current and past diagnoses, current pharmacotherapy, failed psychotropic medications, and quality of life among 23 AA and 31 white men and women receiving outpatient treatment for psychosis. Depression and psychotic depression were common complaints in the sample, yet only a third of the patients received antidepressants. We found that AA men received an antidepressant for depression symptoms less often, received higher antipsychotic doses, and rated their overall quality of life as poorer than any other group. White men and AA women had a history of more years of mental illness and had experienced 57% and 69% more psychotropic medication failures, respectively, than AA men or white women. Quality of life scores were significantly related to years of mental illness, number of past diagnoses, and number of failed medications. Our data suggest that clinicians could significantly enhance prognostic outcomes in outpatients with psychotic disorders by routinely re-evaluating depressive symptomatology and prescribing practices and considering adding psychosocial interventions to avert deterioration in quality of life. Further investigation of race and gender differences in quality of life and satisfaction as a function of diagnoses and treatment is warranted.

Radiation exposure of German aircraft crews under the impact of solar cycle 23 and airline business factors.

PubMed

Frasch, Gerhard; Kammerer, Lothar; Karofsky, Ralf; Schlosser, Andrea; Stegemann, Ralf

2014-12-01

The exposure of German aircraft crews to cosmic radiation varies both with solar activity and operational factors of airline business. Data come from the German central dose registry and cover monthly exposures of up to 37,000 German aircraft crewmembers that were under official monitoring. During the years 2004 to 2009 of solar cycle 23 (i.e., in the decreasing phase of solar activity), the annual doses of German aircraft crews increased by an average of 20%. Decreasing solar activity allows more galactic radiation to reach the atmosphere, increasing high-altitude doses. The rise results mainly from the less effective protection from the solar wind but also from airline business factors. Both cockpit and cabin personnel differ in age-dependent professional and social status. This status determines substantially the annual effective dose: younger cabin personnel and the elder pilots generally receive higher annual doses than their counterparts. They also receive larger increases in their annual dose when the solar activity decreases. The doses under this combined influence of solar activity and airline business factors result in a maximum of exposure for German aircrews for this solar cycle. With the increasing solar activity of the current solar cycle 24, the doses are expected to decrease again.

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

PubMed

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

2011-03-01

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

Ozanimod Induction and Maintenance Treatment for Ulcerative Colitis.

PubMed

Sandborn, William J; Feagan, Brian G; Wolf, Douglas C; D'Haens, Geert; Vermeire, Severine; Hanauer, Stephen B; Ghosh, Subrata; Smith, Heather; Cravets, Matthew; Frohna, Paul A; Aranda, Richard; Gujrathi, Sheila; Olson, Allan

2016-05-05

Ozanimod (RPC1063) is an oral agonist of the sphingosine-1-phosphate receptor subtypes 1 and 5 that induces peripheral lymphocyte sequestration, potentially decreasing the number of activated lymphocytes circulating to the gastrointestinal tract. We conducted a double-blind, placebo-controlled phase 2 trial of ozanimod in 197 adults with moderate-to-severe ulcerative colitis. Patients were randomly assigned, in a 1:1:1 ratio, to receive ozanimod at a dose of 0.5 mg or 1 mg or placebo daily for up to 32 weeks. The Mayo Clinic score was used to measure disease activity on a scale from 0 to 12, with higher scores indicating more severe disease; subscores range from 0 to 3, with higher scores indicating more severe disease. The primary outcome was clinical remission (Mayo Clinic score ≤2, with no subscore >1) at 8 weeks. The primary outcome occurred in 16% of the patients who received 1 mg of ozanimod and in 14% of those who received 0.5 mg of ozanimod, as compared with 6% of those who received placebo (P=0.048 and P=0.14, respectively, for the comparison of the two doses of ozanimod with placebo). Differences in the primary outcome between the group that received 0.5 mg of ozanimod and the placebo group were not significant; therefore, the hierarchical testing plan deemed the analyses of secondary outcomes exploratory. Clinical response (decrease in Mayo Clinic score of ≥3 points and ≥30% and decrease in rectal-bleeding subscore of ≥1 point or a subscore ≤1) at 8 weeks occurred in 57% of those receiving 1 mg of ozanimod and 54% of those receiving 0.5 mg, as compared with 37% of those receiving placebo. At week 32, the rate of clinical remission was 21% in the group that received 1 mg of ozanimod, 26% in the group that received 0.5 mg of ozanimod, and 6% in the group that received placebo; the rate of clinical response was 51%, 35%, and 20%, respectively. At week 8, absolute lymphocyte counts declined 49% from baseline in the group that received 1 mg of ozanimod and 32% from baseline in the group that received 0.5 mg. The most common adverse events overall were anemia and headache. In this preliminary trial, ozanimod at a daily dose of 1 mg resulted in a slightly higher rate of clinical remission of ulcerative colitis than placebo. The trial was not large enough or of sufficiently long duration to establish clinical efficacy or assess safety. (Funded by Receptos; TOUCHSTONE ClinicalTrials.gov number, NCT01647516.).

Radiation Dose-Volume Effects in the Stomach and Small Bowel

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

Kavanagh, Brian D., E-mail: Brian.Kavanagh@ucdenver.ed; Pan, Charlie C.; Dawson, Laura A.

2010-03-01

Published data suggest that the risk of moderately severe (>=Grade 3) radiation-induced acute small-bowel toxicity can be predicted with a threshold model whereby for a given dose level, D, if the volume receiving that dose or greater (VD) exceeds a threshold quantity, the risk of toxicity escalates. Estimates of VD depend on the means of structure segmenting (e.g., V15 = 120 cc if individual bowel loops are outlined or V45 = 195 cc if entire peritoneal potential space of bowel is outlined). A similar predictive model of acute toxicity is not available for stomach. Late small-bowel/stomach toxicity is likely relatedmore » to maximum dose and/or volume threshold parameters qualitatively similar to those related to acute toxicity risk. Concurrent chemotherapy has been associated with a higher risk of acute toxicity, and a history of abdominal surgery has been associated with a higher risk of late toxicity.« less

High dose vitamin D therapy for chronic pain in children and adolescents with sickle cell disease: results of a randomized double blind pilot study.

PubMed

Osunkwo, Ifeyinwa; Ziegler, Thomas R; Alvarez, Jessica; McCracken, Courtney; Cherry, Korin; Osunkwo, Chinyere E; Ofori-Acquah, Solomon F; Ghosh, Samit; Ogunbobode, Adeolu; Rhodes, Jim; Eckman, James R; Dampier, Carlton; Tangpricha, Vin

2012-10-01

We report results of a pilot study of high-dose vitamin D in sickle cell disease (SCD). Subjects were given a 6-week course of oral high-dose cholecalciferol (4000-100 000 IU per week) or placebo and monitored prospectively for a period of six months. Vitamin D insufficiency and deficiency was present at baseline in 82·5% and 52·5% of subjects, respectively. Subjects who received high-dose vitamin D achieved higher serum 25-hydroxyvitamin D, experienced fewer pain days per week, and had higher physical activity quality-of-life scores. These findings suggest a potential benefit of vitamin D in reducing the number of pain days in SCD. Larger prospective studies with longer duration are needed to confirm these effects. © 2012 Blackwell Publishing Ltd.

A search for new CYP3A4 variants as determinants of tacrolimus dose requirements in renal-transplanted patients.

PubMed

Tavira, Beatriz; Coto, Eliecer; Diaz-Corte, Carmen; Alvarez, Victoria; López-Larrea, Carlos; Ortega, Francisco

2013-08-01

The CYP3A5*3 and CYP3A4*1B alleles have been related with tacrolimus (Tac) dose requirements. The rare CYP3A4*22 variant has also been associated with a significantly lower Tac dose. We genotyped the three single-nucleotide polymorphisms in 206 kidney-transplanted patients who received Tac as the primary immunosuppressor. CYP3A5*1 and CYP3A4*1B allele carriers received a significantly higher Tac dose (P<0.01) compared with wild-type homozygotes. We did not find significant differences between the CYP3A4*22 genotypes, either nominally or according to the CYP3A5 genotype (expressers vs. nonexpressers). Sequencing of CYP3A4 coding exons in a total of 15 patients revealed only one nonreported missense change (p.P227>T) in one patient. We concluded that CYP3A5*3 and CYP3A4*1B were the main determinants of the Tac dose-adjusted blood concentration in our cohort of renal-transplanted patients.

A retrospective analysis of outcomes of dalteparin use in pediatric patients: a single institution experience.

PubMed

Warad, Deepti; Rao, Amulya Nageswara; Mullikin, Trey; Graner, Kevin; Shaughnessy, William J; Pruthi, Rajiv K; Rodriguez, Vilmarie

2015-08-01

Dalteparin is a commonly used low molecular weight heparin (LMWH) with extensive safety data in adults. With distinct advantages of once daily dosing and relative safety in renal impairment, it has been used off-label in pediatric practice; however, age-based dosing guidelines, safety and efficacy data in children are evolving. To report our institutional experience with the use of dalteparin in the treatment and prophylaxis of venous thromboembolism (VTE) in pediatric patients. Retrospective chart review of all children (0-18years) that received dalteparin from December 1, 2000 through December 31, 2011. Doses per unit body weight per day (units/kg/day) were calculated for age-based group comparisons. Of 166 patients identified, 116 (70%) received prophylactic doses while 50 (30%) received therapeutic doses of dalteparin. Infants (<1year) required significantly higher weight-based dosing to achieve therapeutic anti-Xa levels compared to children (1-10years) or adolescents (>10-18years) (mean dose units/kg/day; 396.6 versus 236.7 and 178.8 respectively, p<0.0001). Overall response rate, including complete and partial thrombus resolution, was 83%. Bleeding complications were minor and the rates were similar in therapeutic and prophylaxis patients. No significant differences in dosing or bleeding events were noted based on obesity or malignancy. In our experience, dalteparin is effective for prophylaxis and therapy of VTE in pediatric patients. Dosing should be customized in an age-based manner with close monitoring of anti-Xa activity in order to achieve optimal levels, prevent bleeding complications, and to allow full benefit of prevention or therapy of thrombotic complications. Copyright © 2015 Elsevier Ltd. All rights reserved.

Can we avoid high levels of dose escalation for high-risk prostate cancer in the setting of androgen deprivation?

PubMed Central

Shakespeare, Thomas P; Wilcox, Shea W; Aherne, Noel J

2016-01-01

Aim Both dose-escalated external beam radiotherapy (DE-EBRT) and androgen deprivation therapy (ADT) improve outcomes in patients with high-risk prostate cancer. However, there is little evidence specifically evaluating DE-EBRT for patients with high-risk prostate cancer receiving ADT, particularly for EBRT doses >74 Gy. We aimed to determine whether DE-EBRT >74 Gy improves outcomes for patients with high-risk prostate cancer receiving long-term ADT. Patients and methods Patients with high-risk prostate cancer were treated on an institutional protocol prescribing 3–6 months neoadjuvant ADT and DE-EBRT, followed by 2 years of adjuvant ADT. Between 2006 and 2012, EBRT doses were escalated from 74 Gy to 76 Gy and then to 78 Gy. We interrogated our electronic medical record to identify these patients and analyzed our results by comparing dose levels. Results In all, 479 patients were treated with a 68-month median follow-up. The 5-year biochemical disease-free survivals for the 74 Gy, 76 Gy, and 78 Gy groups were 87.8%, 86.9%, and 91.6%, respectively. The metastasis-free survivals were 95.5%, 94.5%, and 93.9%, respectively, and the prostate cancer-specific survivals were 100%, 94.4%, and 98.1%, respectively. Dose escalation had no impact on any outcome in either univariate or multivariate analysis. Conclusion There was no benefit of DE-EBRT >74 Gy in our cohort of high-risk prostate patients treated with long-term ADT. As dose escalation has higher risks of radiotherapy-induced toxicity, it may be feasible to omit dose escalation beyond 74 Gy in this group of patients. Randomized studies evaluating dose escalation for high-risk patients receiving ADT should be considered. PMID:27274277

Can we avoid high levels of dose escalation for high-risk prostate cancer in the setting of androgen deprivation?

PubMed

Shakespeare, Thomas P; Wilcox, Shea W; Aherne, Noel J

2016-01-01

Both dose-escalated external beam radiotherapy (DE-EBRT) and androgen deprivation therapy (ADT) improve outcomes in patients with high-risk prostate cancer. However, there is little evidence specifically evaluating DE-EBRT for patients with high-risk prostate cancer receiving ADT, particularly for EBRT doses >74 Gy. We aimed to determine whether DE-EBRT >74 Gy improves outcomes for patients with high-risk prostate cancer receiving long-term ADT. Patients with high-risk prostate cancer were treated on an institutional protocol prescribing 3-6 months neoadjuvant ADT and DE-EBRT, followed by 2 years of adjuvant ADT. Between 2006 and 2012, EBRT doses were escalated from 74 Gy to 76 Gy and then to 78 Gy. We interrogated our electronic medical record to identify these patients and analyzed our results by comparing dose levels. In all, 479 patients were treated with a 68-month median follow-up. The 5-year biochemical disease-free survivals for the 74 Gy, 76 Gy, and 78 Gy groups were 87.8%, 86.9%, and 91.6%, respectively. The metastasis-free survivals were 95.5%, 94.5%, and 93.9%, respectively, and the prostate cancer-specific survivals were 100%, 94.4%, and 98.1%, respectively. Dose escalation had no impact on any outcome in either univariate or multivariate analysis. There was no benefit of DE-EBRT >74 Gy in our cohort of high-risk prostate patients treated with long-term ADT. As dose escalation has higher risks of radiotherapy-induced toxicity, it may be feasible to omit dose escalation beyond 74 Gy in this group of patients. Randomized studies evaluating dose escalation for high-risk patients receiving ADT should be considered.

Evaluation of contralateral breast skin doses by thermoluminescent dosimeters of patients receiving adjuvant radiotherapy for breast cancer.

PubMed

Gorken, I B; Kentli, S; Alanyali, H; Karagüler, Z; Kinay, M

2002-01-01

It is reported that low dose radiation received by the contralateral breast (CLB) during adjuvant radiotherapy (RT) is carcinogenic. This trial was planned to evaluate the CLB skin doses received during adjuvant RT of breast carcinoma. Twenty-four breast carcinoma patients treated locally or locoregionally with adjuvant RT were included. RT was performed with only tangential fields (TA) in 6 patients whereas 9 patients had an extra internal mammary (IM) field (TAIM). The remaining 9 patients received 5-field locoregional RT (5FLR). All patients were treated with wedge filters except for 3 TA patients. Of 9 5FLR patients IM fields were treated with Co60 in 5 and with electrons in the remaining 4 patients. LiF(2)-based Ribbon type thermoluminescent dosimeters (TLD) were used for dose evaluation. An average of 10 TLD's, placed with 1 cm gaps beginning from the medial border of the treatment field along the central axis were used to obtain dose measurements. Median measure of TLD's between 2-8 cm and maximum dose point (MDP) values in the same range were used to evaluate the CLB dose. In TA patients the CLB skin received 6.3% of the total dose in patients treated with wedge filters and 7.13% with half-beam blocks. For 6 TAIM patients with IM fields treated with Co60, the CLB dose was 7.24%. In 5 of 9 5FLR patients, whose IM fields were treated with Co60 the CLB skin received 8.8% of the total dose, while for electron beam therapy the CLB dose was 5.44%. CLB median MDP values were as follows: 12.76% in TA patients treated with wedge filters and 11.45% with half-beam blocking; 11.89% in TAIM patients with IM fields treated with Co60 and 7.83% with electron beams; 12.29% in 5FLR patients of whose IM fields were treated with Co60 and 8.94% with electron beams. When compared to wedge filters, halfbeam blocks caused 13% increase in CLB doses. If IM fields were added, 27.5% and 62% increases at CLB doses were established with Co60 when compared to electron beam RT in 3-field and 5-field treatments, respectively. CLB doses increased by 15-40% with the increased number of treatment fields. MDP values were also found to be higher with IM fields treated with Co60, but the number of treatment fields and accessories used seemed to have no effect on MDP doses. We conclude that by using wedge filters instead of half-beam blocks and by increasing the number of fractions treated with electron energies for IM fields, apparent decreases in CLB doses can be obtained. Large number of cases is needed to statistically establish the significant differences between subgroups.

Randomized clinical trial comparing high versus standard dose of ribavirin plus peginterferon alfa-2a in hepatitis C genotype 3 and high viral load. Dargen-3 study.

PubMed

Fernández-Rodríguez, Conrado M; Morillas, Rosa María; Masnou, Helena; Navarro, José María; Bárcena, Rafael; González, José Manuel; Martín-Martín, Leticia; Poyato, Antonio; Miquel-Planas, Mireia; Jorquera, Francisco; Casanovas, Teresa; Salmerón, Javier; Calleja, José Luis; Solà, Ricard; Alonso, Sonia; Planas, Ramón; Romero-Gomez, Manuel

2014-01-01

Less than half of patients with chronic hepatitis C genotype 3 (G3) and high viral load (HVL) without a rapid virological response (RVR) achieve a sustained virological response (SVR) when treated with peginterferon plus ribavirin (RBV). To assess the impact of high doses of RBV on SVR in patients with G3 and HVL. Ninety-seven patients were randomized to receive peginterferon α-2a+RBV 800 mg/day (A; n=42) or peginterferon α-2a+RBV 1600 mg/day+epoetin β 400 IU/kg/week SC (B; n=55). Patients allocated to group B who achieved RVR continued on RBV (800mg/day) for a further 20 weeks (B1; n=42) while non-RVR patients received a higher dose of RBV (1600 mg/day)+epoetin β (B2; n=13). RVR was observed in 64.3% of patients in A and in 76.4% in B (p=0.259). Intention-to-treat (ITT) analysis showed SVR rates of 64.3% (A) and 61.8% (B), with a reduction of -2.5% (-21.8% to 16.9%) (p=0.835). The SVR rate was 61.9% in arm B1 and 61.5% in arm B2. No serious adverse events were reported, and the rate of moderate adverse events was < 5%. G3 patients with high viral load without RVR did not obtain a benefit from a higher dose of RBV. Higher doses of RBV plus epoetin β were safe and well tolerated (Clin Trials Gov NCT00830609). Copyright © 2013 Elsevier España, S.L. and AEEH y AEG. All rights reserved.

Frequency of booster injections of allergoids.

PubMed

Norman, P S; Creticos, P S; Marsh, D G

1990-01-01

In 1982, 43 ragweed-sensitive patients receiving maintenance injections of full doses of ragweed allergoid were selected for a study of the immunologic and clinical efficacy of booster injections only four times a year. These patients had participated for 2 to 7 years as part of a trial of mixes of up to four allergoids to common pollens in the mid-Atlantic area tailored to each patient's skin test sensitivity. They were divided into a group (21 patients) to receive injections every 3 months and a group (22 patients) to receive injections about every 6 weeks (eight injections per year). Patients were rerandomized after 1 year so that half of each original group switched to the alternate treatment, and this program was continued until after the ragweed season of 1985. Thirty-four patients were still under study the last year. Doses, per injection, were 100 allergoid units (1 allergoid unit equals 100 PNU) of each allergen in the mixture. Symptom scores during the 8 weeks of each of the four ragweed seasons were not significantly higher in the 3-month treated group. IgG antibody levels to Amb a I (antigen E) were followed until early 1984 and were not significantly different in the two groups, even though the 6-week treated patients received a two times higher cumulative dose per year. Rates of local and systemic reactions (percent of injections eliciting reactions) were not different in the groups, which means that the 3-month treated group had about half as many reactions by virtue of taking half as many injections.(ABSTRACT TRUNCATED AT 250 WORDS)

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

Wang Shulian; Liao Zhongxing; Vaporciyan, Ara A.

Purpose: To assess the association of clinical and especially dosimetric factors with the incidence of postoperative pulmonary complications among esophageal cancer patients treated with concurrent chemoradiation therapy followed by surgery. Method and Materials: Data from 110 esophageal cancer patients treated between January 1998 and December 2003 were analyzed retrospectively. All patients received concurrent chemoradiotherapy followed by surgery; 72 patients also received irinotecan-based induction chemotherapy. Concurrent chemotherapy was 5-fluorouracil-based and in 97 cases included taxanes. Radiotherapy was delivered to a total dose of 41.4-50.4 Gy at 1.8-2.0 Gy per fraction with a three-dimensional conformal technique. Surgery (three-field, Ivor-Lewis, or transhiatal esophagectomy)more » was performed 27-123 days (median, 45 days) after completion of radiotherapy. The following dosimetric parameters were generated from the dose-volume histogram (DVH) for total lung: lung volume, mean dose to lung, relative and absolute volumes of lung receiving more than a threshold dose (relative V{sub dose} and absolute V{sub dose}), and absolute volume of lung receiving less than a threshold dose (volume spared, or VS{sub dose}). Occurrence of postoperative pulmonary complications, defined as pneumonia or acute respiratory distress syndrome (ARDS) within 30 days after surgery, was the endpoint for all analyses. Fisher's exact test was used to investigate the relationship between categorical factors and incidence of postoperative pulmonary complications. Logistic analysis was used to analyze the relationship between continuous factors (e.g., V{sub dose} or VS{sub dose}) and complication rate. Logistic regression with forward stepwise inclusion of factors was used to perform multivariate analysis of those factors having univariate significance (p < 0.05). The Mann-Whitney test was used to compare length of hospital stay in patients with and without lung complications and to compare lung volumes, VS5 values, and absolute and relative V5 values in male vs. female patients. Pearson correlation analysis was used to determine correlations between dosimetric factors. Results: Eighteen (16.4%) of the 110 patients developed postoperative pulmonary complications. Two of these died of progressive pneumonia. Hospitalizations were significantly longer for patients with postoperative pulmonary complications than for those without (median, 15 days vs. 11 days, p = 0.003). On univariate analysis, female gender (p = 0.017), higher mean lung dose (p = 0.036), higher relative volume of lung receiving {>=}5 Gy (V5) (p = 0.023), and smaller volumes of lung spared from doses {>=}5-35 Gy (VS5-VS35) (p < 0.05) were all significantly associated with an increased incidence of postoperative pulmonary complications. No other clinical factors were significantly associated with the incidence of postoperative pulmonary complications in this cohort. On multivariate analysis, the volume of lung spared from doses {>=}5 Gy (VS5) was the only significant independent factor associated with postoperative pulmonary complications (p = 0.005). Conclusions: Dosimetric factors but not clinical factors were found to be strongly associated with the incidence of postoperative pulmonary complications in this cohort of esophageal cancer patients treated with concurrent chemoradiation plus surgery. The volume of the lung spared from doses of {>=}5 Gy was the only independent dosimetric factor in multivariate analysis. This suggests that ensuring an adequate volume of lung unexposed to radiation might reduce the incidence of postoperative pulmonary complications.« less

Investigation of clinical and dosimetric factors associated with postoperative pulmonary complications in esophageal cancer patients treated with concurrent chemoradiotherapy followed by surgery.

PubMed

Wang, Shu-lian; Liao, Zhongxing; Vaporciyan, Ara A; Tucker, Susan L; Liu, Helen; Wei, Xiong; Swisher, Stephen; Ajani, Jaffer A; Cox, James D; Komaki, Ritsuko

2006-03-01

To assess the association of clinical and especially dosimetric factors with the incidence of postoperative pulmonary complications among esophageal cancer patients treated with concurrent chemoradiation therapy followed by surgery. Data from 110 esophageal cancer patients treated between January 1998 and December 2003 were analyzed retrospectively. All patients received concurrent chemoradiotherapy followed by surgery; 72 patients also received irinotecan-based induction chemotherapy. Concurrent chemotherapy was 5-fluorouracil-based and in 97 cases included taxanes. Radiotherapy was delivered to a total dose of 41.4-50.4 Gy at 1.8-2.0 Gy per fraction with a three-dimensional conformal technique. Surgery (three-field, Ivor-Lewis, or transhiatal esophagectomy) was performed 27-123 days (median, 45 days) after completion of radiotherapy. The following dosimetric parameters were generated from the dose-volume histogram (DVH) for total lung: lung volume, mean dose to lung, relative and absolute volumes of lung receiving more than a threshold dose (relative V(dose) and absolute V(dose)), and absolute volume of lung receiving less than a threshold dose (volume spared, or VS(dose)). Occurrence of postoperative pulmonary complications, defined as pneumonia or acute respiratory distress syndrome (ARDS) within 30 days after surgery, was the endpoint for all analyses. Fisher's exact test was used to investigate the relationship between categorical factors and incidence of postoperative pulmonary complications. Logistic analysis was used to analyze the relationship between continuous factors (e.g., V(dose) or VS(dose)) and complication rate. Logistic regression with forward stepwise inclusion of factors was used to perform multivariate analysis of those factors having univariate significance (p < 0.05). The Mann-Whitney test was used to compare length of hospital stay in patients with and without lung complications and to compare lung volumes, VS5 values, and absolute and relative V5 values in male vs. female patients. Pearson correlation analysis was used to determine correlations between dosimetric factors. Eighteen (16.4%) of the 110 patients developed postoperative pulmonary complications. Two of these died of progressive pneumonia. Hospitalizations were significantly longer for patients with postoperative pulmonary complications than for those without (median, 15 days vs. 11 days, p = 0.003). On univariate analysis, female gender (p = 0.017), higher mean lung dose (p = 0.036), higher relative volume of lung receiving > or = 5 Gy (V5) (p = 0.023), and smaller volumes of lung spared from doses > or = 5-35 Gy (VS5-VS35) (p < 0.05) were all significantly associated with an increased incidence of postoperative pulmonary complications. No other clinical factors were significantly associated with the incidence of postoperative pulmonary complications in this cohort. On multivariate analysis, the volume of lung spared from doses > or = 5 Gy (VS5) was the only significant independent factor associated with postoperative pulmonary complications (p = 0.005). Dosimetric factors but not clinical factors were found to be strongly associated with the incidence of postoperative pulmonary complications in this cohort of esophageal cancer patients treated with concurrent chemoradiation plus surgery. The volume of the lung spared from doses of > or = 5 Gy was the only independent dosimetric factor in multivariate analysis. This suggests that ensuring an adequate volume of lung unexposed to radiation might reduce the incidence of postoperative pulmonary complications.

Long-term persistence of humoral and cellular immune responses induced by an AS03A-adjuvanted H1N1 2009 influenza vaccine: an open-label, randomized study in adults aged 18-60 years and older.

PubMed

Van Damme, Pierre; Kafeja, Froukje; Bambure, Vinod; Hanon, Emmanuel; Moris, Philippe; Roman, François; Gillard, Paul

2013-07-01

This manuscript presents data on the persistence of Hemagglutination Inhibition (HI) immune response against the A/California/7/2009 strain, six and 12 mo after adults received one dose (n = 138) or two doses (n = 102; 21 d apart) of a 3.75 µg Hemagglutinin antigen AS03-adjuvanted H1N1 2009 vaccine (NCT00968526). Two hundred forty subjects (18-60 y: 120;>60 y: 120) were vaccinated. Immunogenicity end points were based on the European licensure criteria for pandemic influenza vaccines. Exploratory analyses assessed the cell-mediated immune response (CMI) up to Month 12 and the influence of previous influenza vaccination on persistence of immune response. At Month 6, the CHMP criteria were met in subjects aged 18-60 y who received one or two vaccine doses and in subjects aged>60 y who received two vaccine doses. At Month 12, the CHMP criteria were met only in subjects aged 18-60 y who received two vaccine doses. Persistence of HI immune response against the vaccine strain was higher in subjects without prior influenza vaccination. Exploratory analyses showed that two doses of the H1N1 2009 vaccine induced persistence of H1N1-specific CD4+ T cells up to Month 6 and memory B cells up to Month 12. In conclusion, HI immune responses persisted up to 12 mo after vaccination with one-dose and two-dose regimens of the AS03-adjuvanted 3.75 µg HA H1N1 2009 pandemic influenza vaccine, although not all three CHMP guidance criteria for both groups were met at Month 6 and Month 12. The CD4+ T cell and B cell responses also persisted up to Month 12.

Maximum dose rate is a determinant of hypothyroidism after 131I therapy of Graves' disease but the total thyroid absorbed dose is not.

PubMed

Krohn, Thomas; Hänscheid, Heribert; Müller, Berthold; Behrendt, Florian F; Heinzel, Alexander; Mottaghy, Felix M; Verburg, Frederik A

2014-11-01

The determinants of successful (131)I therapy of Graves' disease (GD) are unclear. To relate dosimetry parameters to outcome of therapy to identify significant determinants eu- and/or hypothyroidism after (131)I therapy in patients with GD. A retrospective study in which 206 Patients with GD treated in University Hospital between November 1999 and January 2011. All received (131)I therapy aiming at a total absorbed dose to the thyroid of 250 Gy based on pre-therapeutic dosimetry. Post-therapy dosimetric thyroid measurements were performed twice daily until discharge. From these measurements, thyroid (131)I half-life, the total thyroid absorbed dose, and the maximum dose rate after (131)I administration were calculated. In all, 48.5% of patients were hypothyroid and 28.6% of patients were euthyroid after (131)I therapy. In univariate analysis, nonhyperthyroid and hyperthyroid patients only differed by sex. A lower thyroid mass, a higher activity per gram thyroid tissue, a shorter effective thyroidal (131)I half-life, and a higher maximum dose rate, but not the total thyroid absorbed dose, were significantly associated with hypothyroidism. In multivariate analysis, the maximum dose rate remained the only significant determinant of hypothyroidism (P < .001). Maximum dose rates of 2.2 Gy/h and higher were associated with a 100% hypothyroidism rate. Not the total thyroid absorbed dose, but the maximum dose rate is a determinant of successfully achieving hypothyroidism in Graves' disease. Dosimetric concepts aiming at a specific total thyroid absorbed dose will therefore require reconsideration if our data are confirmed prospectively.

Antibody persistence and booster responses 24-36 months after different 4CMenB vaccination schedules in infants and children: A randomised trial.

PubMed

Martinón-Torres, Federico; Carmona Martinez, Alfonso; Simkó, Róbert; Infante Marquez, Pilar; Arimany, Josep-Lluis; Gimenez-Sanchez, Francisco; Couceiro Gianzo, José Antonio; Kovács, Éva; Rojo, Pablo; Wang, Huajun; Bhusal, Chiranjiwi; Toneatto, Daniela

2018-03-01

This phase IIIb, open-label, multicentre, extension study (NCT01894919) evaluated long-term antibody persistence and booster responses in participants who received a reduced 2 + 1 or licensed 3 + 1 meningococcal serogroup B vaccine (4CMenB)-schedule (infants), or 2-dose catch-up schedule (2-10-year-olds) in parent study NCT01339923. Children aged 35 months to 12 years (N = 851) were enrolled. Follow-on participants (N = 646) were randomised 2:1 to vaccination and non-vaccination subsets; vaccination subsets received an additional 4CMenB dose. Newly enrolled vaccine-naïve participants (N = 205) received 2 catch-up doses, 1 month apart (accelerated schedule). Antibody levels were determined using human serum bactericidal assay (hSBA) against MenB indicator strains for fHbp, NadA, PorA and NHBA. Safety was also evaluated. Antibody levels declined across follow-on groups at 24-36 months versus 1 month post-vaccination. Antibody persistence and booster responses were similar between infants receiving the reduced or licensed 4CMenB-schedule. An additional dose in follow-on participants induced higher hSBA titres than a first dose in vaccine-naïve children. Two catch-up doses in vaccine-naïve participants induced robust antibody responses. No safety concerns were identified. Antibody persistence, booster responses, and safety profiles were similar with either 2 + 1 or 3 + 1 vaccination schedules. The accelerated schedule in vaccine-naïve children induced robust antibody responses. Copyright © 2017 GlaxoSmithKline SA. Published by Elsevier Ltd.. All rights reserved.

Safety and reactogenicity of an MSP-1 malaria vaccine candidate: a randomized phase Ib dose-escalation trial in Kenyan children.

PubMed

Withers, Mark R; McKinney, Denise; Ogutu, Bernhards R; Waitumbi, John N; Milman, Jessica B; Apollo, Odika J; Allen, Otieno G; Tucker, Kathryn; Soisson, Lorraine A; Diggs, Carter; Leach, Amanda; Wittes, Janet; Dubovsky, Filip; Stewart, V Ann; Remich, Shon A; Cohen, Joe; Ballou, W Ripley; Holland, Carolyn A; Lyon, Jeffrey A; Angov, Evelina; Stoute, José A; Martin, Samuel K; Heppner, D Gray

2006-11-24

Our aim was to evaluate the safety, reactogenicity, and immunogenicity of an investigational malaria vaccine. This was an age-stratified phase Ib, double-blind, randomized, controlled, dose-escalation trial. Children were recruited into one of three cohorts (dosage groups) and randomized in 2:1 fashion to receive either the test product or a comparator. The study was conducted in a rural population in Kombewa Division, western Kenya. Subjects were 135 children, aged 12-47 mo. Subjects received 10, 25, or 50 microg of falciparum malaria protein 1 (FMP1) formulated in 100, 250, and 500 microL, respectively, of AS02A, or they received a comparator (Imovax (rabies vaccine). We performed safety and reactogenicity parameters and assessment of adverse events during solicited (7 d) and unsolicited (30 d) periods after each vaccination. Serious adverse events were monitored for 6 mo after the last vaccination. Both vaccines were safe and well tolerated. FMP1/AS02A recipients experienced significantly more pain and injection-site swelling with a dose-effect relationship. Systemic reactogenicity was low at all dose levels. Hemoglobin levels remained stable and similar across arms. Baseline geometric mean titers were comparable in all groups. Anti-FMP1 antibody titers increased in a dose-dependent manner in subjects receiving FMP1/AS02A; no increase in anti-FMP1 titers occurred in subjects who received the comparator. By study end, subjects who received either 25 or 50 microg of FMP1 had similar antibody levels, which remained significantly higher than that of those who received the comparator or 10 microg of FMP1. A longitudinal mixed effects model showed a statistically significant effect of dosage level on immune response (F(3,1047) = 10.78, or F(3, 995) = 11.22, p < 0.001); however, the comparison of 25 microg and 50 microg recipients indicated no significant difference (F(1,1047) = 0.05; p = 0.82). The FMP1/AS02A vaccine was safe and immunogenic in malaria-exposed 12- to 47-mo-old children and the magnitude of immune response of the 25 and 50 microg doses was superior to that of the 10 microg dose.

Safety and Reactogenicity of an MSP-1 Malaria Vaccine Candidate: A Randomized Phase Ib Dose-Escalation Trial in Kenyan Children

PubMed Central

Withers, Mark R; McKinney, Denise; Ogutu, Bernhards R; Waitumbi, John N; Milman, Jessica B; Apollo, Odika J; Allen, Otieno G; Tucker, Kathryn; Soisson, Lorraine A; Diggs, Carter; Leach, Amanda; Wittes, Janet; Dubovsky, Filip; Stewart, V. Ann; Remich, Shon A; Cohen, Joe; Ballou, W. Ripley; Holland, Carolyn A; Lyon, Jeffrey A; Angov, Evelina; Stoute, José A; Martin, Samuel K; Heppner, D. Gray

2006-01-01

Objective: Our aim was to evaluate the safety, reactogenicity, and immunogenicity of an investigational malaria vaccine. Design: This was an age-stratified phase Ib, double-blind, randomized, controlled, dose-escalation trial. Children were recruited into one of three cohorts (dosage groups) and randomized in 2:1 fashion to receive either the test product or a comparator. Setting: The study was conducted in a rural population in Kombewa Division, western Kenya. Participants: Subjects were 135 children, aged 12–47 mo. Interventions: Subjects received 10, 25, or 50 μg of falciparum malaria protein 1 (FMP1) formulated in 100, 250, and 500 μL, respectively, of AS02A, or they received a comparator (Imovax® rabies vaccine). Outcome Measures: We performed safety and reactogenicity parameters and assessment of adverse events during solicited (7 d) and unsolicited (30 d) periods after each vaccination. Serious adverse events were monitored for 6 mo after the last vaccination. Results: Both vaccines were safe and well tolerated. FMP1/AS02A recipients experienced significantly more pain and injection-site swelling with a dose-effect relationship. Systemic reactogenicity was low at all dose levels. Hemoglobin levels remained stable and similar across arms. Baseline geometric mean titers were comparable in all groups. Anti-FMP1 antibody titers increased in a dose-dependent manner in subjects receiving FMP1/AS02A; no increase in anti-FMP1 titers occurred in subjects who received the comparator. By study end, subjects who received either 25 or 50 μg of FMP1 had similar antibody levels, which remained significantly higher than that of those who received the comparator or 10 μg of FMP1. A longitudinal mixed effects model showed a statistically significant effect of dosage level on immune response (F3,1047 = 10.78, or F3, 995 = 11.22, p < 0.001); however, the comparison of 25 μg and 50 μg recipients indicated no significant difference (F1,1047 = 0.05; p = 0.82). Conclusions: The FMP1/AS02A vaccine was safe and immunogenic in malaria-exposed 12- to 47-mo-old children and the magnitude of immune response of the 25 and 50 μg doses was superior to that of the 10 μg dose. PMID:17124529

Effects of Radiation Exposure From Cardiac Imaging: How Good Are the Data?

PubMed Central

Einstein, Andrew J.

2012-01-01

Concerns about medical exposure to ionizing radiation have become heightened in recent years due to rapid growth in procedure volumes and the high radiation doses incurred from some procedures. This article summarizes the evidence base undergirding concerns about radiation exposure in cardiac imaging. After classifying radiation effects, explaining terminology used to quantify the radiation received by patients, and describing typical doses from cardiac imaging procedures, I address the major epidemiological studies having bearing on radiation effects at doses comparable to those received by patients undergoing cardiac imaging. These include studies of atomic bomb survivors, nuclear industry workers, and children exposed in utero to x-rays, all of which have evidenced increased cancer risks at low doses. Additional higher dose epidemiological studies of cohorts exposed to radiation in the context of medical treatment are described and found to be generally compatible with these cardiac-dose-level studies, albeit with exceptions. Using risk projection models developed by the US National Academies that incorporate these data and reflect several evidence-based assumptions, cancer risk from cardiac imaging can be estimated and compared to benefits from imaging. Several ongoing epidemiological studies will provide better understanding of radiation-associated cancer risks. PMID:22300689

A longitudinal study of depression among middle-aged and senior patients initiating chronic opioid therapy.

PubMed

Von Korff, Michael; Shortreed, Susan M; LeResche, Linda; Saunders, Kathleen; Thielke, Stephen; Thakral, Manu; Rosenberg, Dori; Turner, Judith A

2017-03-15

Improved understanding how depressive symptoms change with sustained opioid use is needed. We prospectively assessed patients 45 years or older initiating chronic opioid therapy (COT) at baseline and at 4 and 12 months, differentiating recent COT initiators (n=748) and continuing users (n=468). Level of opioid use before 12-month follow-up was classified as regular/higher-dose, intermittent/lower-dose, or minimal/no use. Depressive symptoms were assessed using the Patient Health Questionnaire-8 (PHQ-8). Depressive symptoms decreased, on average, from baseline to 12 months regardless of level of opioid use. COT patients with regular/higher-dose compared to those with intermittent/lower-dose opioid use (who had similar pain outcomes) did not differ in PHQ-8 scores at 12 months (adjusted mean difference -0.14, 95% CI, -1.07, 0.78 for COT initiators). At 12 months, COT patients with intermittent/lower-dose use had higher adjusted PHQ-8 scores than did those with minimal/no opioid use (adjusted mean difference 0.77, 95% CI, 0.03-1.52 for COT initiators). However, 77% of patients who discontinued opioids cited improved pain as a reason for discontinuation, while 21% cited negative emotional effects of opioids as a reason for discontinuation. Discontinuation was more common among persons who, at baseline, attributed 3 or more depressive symptoms to opioid use. Results are relevant to older COT patients receiving low to moderate opioid doses. Depressive symptoms did not increase with sustained opioid use. Depressive symptoms were not higher with regular/higher-dose compared to intermittent/lower-dose use. Persons who perceived negative effects of opioids on emotions more often discontinued their use. Copyright © 2017. Published by Elsevier B.V.

Red Marrow-Absorbed Dose for Non-Hodgkin Lymphoma Patients Treated with 177Lu-Lilotomab Satetraxetan, a Novel Anti-CD37 Antibody-Radionuclide Conjugate.

PubMed

Blakkisrud, Johan; Løndalen, Ayca; Dahle, Jostein; Turner, Simon; Holte, Harald; Kolstad, Arne; Stokke, Caroline

2017-01-01

Red marrow (RM) is often the primary organ at risk in radioimmunotherapy; irradiation of marrow may induce short- and long-term hematologic toxicity. 177 Lu-lilotomab satetraxetan is a novel anti-CD37 antibody-radionuclide conjugate currently in phase 1/2a. Two predosing regimens have been investigated, one with 40 mg of unlabeled lilotomab antibody (arm 1) and one without (arm 2). The aim of this work was to compare RM-absorbed doses for the two arms and to correlate absorbed doses with hematologic toxicity. Eight patients with relapsed CD37+ indolent B-cell non-Hodgkin lymphoma were included for RM dosimetry. Hybrid SPECT and CT images were used to estimate the activity concentration in the RM of L2-L4. Pharmacokinetic parameters were calculated after measurement of the 177 Lu-lilotomab satetraxetan concentration in blood samples. Adverse events were graded according to the Common Terminology Criteria for Adverse Events, version 4.0. The mean absorbed doses to RM were 0.9 mGy/MBq for arm 1 (lilotomab+) and 1.5 mGy/MBq for arm 2 (lilotomab-). There was a statistically significant difference between arms 1 and 2 (Student t test, P = 0.02). Total RM-absorbed doses ranged from 67 to 127 cGy in arm 1 and from 158 to 207 cGy in arm 2. For blood, the area under the curve was higher with lilotomab predosing than without (P = 0.001), whereas the volume of distribution and the clearance of 177 Lu-lilotomab satetraxetan was significantly lower (P = 0.01 and P = 0.03, respectively). Patients with grade 3/4 thrombocytopenia had received significantly higher radiation doses to RM than patients with grade 1/2 thrombocytopenia (P = 0.02). A surrogate, non-imaging-based, method underestimated the RM dose and did not show any correlation with toxicity. Predosing with lilotomab reduces the RM-absorbed dose for 177 Lu-lilotomab satetraxetan patients. The decrease in RM dose could be explained by the lower volume of distribution. Hematologic toxicity was more severe for patients receiving higher absorbed radiation doses, indicating that adverse events possibly can be predicted by the calculation of absorbed dose to RM from SPECT/CT images. © 2017 by the Society of Nuclear Medicine and Molecular Imaging.

The effect of perioperative dexamethasone dosing on post-tonsillectomy hemorrhage risk.

PubMed

Yiu, Yin; Mahida, Justin B; Cooper, Jennifer N; Elsey, Nicole M; Deans, Katherine J; Minneci, Peter C; Merrill, Tyler B; Tobias, Joseph D; Elmaraghy, Charles A

2017-07-01

Dexamethasone is currently recommended for routine prophylaxis against postoperative nausea and vomiting after tonsillectomy procedures. However, some studies have raised concern that dexamethasone use may lead to higher rates of post-tonsillectomy hemorrhage. Our objective was to determine whether higher doses of dexamethasone administered perioperatively during tonsillectomy procedures are associated with an increased risk of secondary post-tonsillectomy hemorrhage. We conducted a retrospective review of 9843 patients who underwent tonsillectomy and received dexamethasone at our institution from January 2010 to October 2014. We compared the dose of dexamethasone administered to patients who did and did not develop secondary post-tonsillectomy hemorrhage using Mann Whitney U tests. Multivariable logistic regression models were used to evaluate the association between dexamethasone dose and post-tonsillectomy hemorrhage after adjustment for demographic and clinical characteristics. A total of 280 (2.8%) patients developed secondary post-tonsillectomy hemorrhage. Patients who developed hemorrhage tended to be older (median (interquartile range) 7 (4-11) vs. 5 (3-8) years), p < 0.001) and had undergone tonsillectomy more often for chronic tonsillitis but less often for tonsillar or adenotonsillar hypertrophy or sleep disturbances. Dexamethasone dose was significantly lower on average in patients who experienced secondary post-tonsillectomy hemorrhage (median (interquartile range) 0.19 (0.14, 0.23) mg/kg vs. 0.21 (0.17, 0.30), p < 0.001). Multivariable modeling demonstrated that the dose of dexamethasone was not significantly associated with post-tonsillectomy hemorrhage after adjustment for age. There does not appear to be a dose-related increase in the risk of post-tonsillectomy hemorrhage for patients receiving dexamethasone during tonsillectomy procedures. Copyright © 2017 Elsevier B.V. All rights reserved.

Predictors of Excess Patient Radiation Exposure During Chronic Total Occlusion Coronary Intervention: Insights from a Contemporary Multicenter Registry

PubMed Central

Christakopoulos, Georgios E.; Christopoulos, Georgios; Karmpaliotis, Dimitri; Alaswad, Khaldoon; Yeh, Robert W.; Jaffer, Farouc A.; Wyman, Michael R.; Lombardi, William L.; Tarar, Muhammad Nauman J.; Grantham, J. Aaron; Kandzari, David; Lembo, Nicholas; Moses, Jeffrey W.; Kirtane, Ajay; Parikh, Manish; Green, Philip; Finn, Matthew; Garcia, Santiago; Doing, Anthony; Hatem, Raja; Thompson, Craig A.; Banerjee, Subhash; Brilakis, Emmanouil S.

2016-01-01

Background High patient radiation dose during chronic total occlusion (CTO) percutaneous coronary intervention (PCI) may lead to procedural failure and radiation skin injury. Methods We examined the association between several clinical and angiographic variables on patient air kerma (AK) radiation dose among 748 consecutive CTO PCIs performed at 9 experienced US centers between May 2012 and May 2015. Results Mean age was 65±10 years, 87% of patients were men, and 35% had prior coronary artery bypass graft surgery (CABG). Technical and procedural success was 92% and 90%, respectively. The median patient AK dose was 3.40 (2.00, 5.40) Gray and 34% of the patients received >4.8 Gray (high radiation exposure). On univariable analysis male gender (p=0.016), high body mass index (p<0.001), history of hyperlipidemia (p=0.023), prior CABG (p<0.001), moderate or severe calcification (p<0.001), tortuosity (p<0.001), proximal cap ambiguity (p=0.001), distal cap at a bifurcation (p=0.006), longer CTO occlusion length (p<0.001), blunt/no blunt stump (p<0.001), and center (<0.001) were associated with higher patient AK dose. On multivariable analysis high body mass index (p<0.001), prior CABG (p=0.005), moderate or severe calcification (p=0.005), longer CTO occlusion length (p<0.001), and center (p<0.001) were independently associated with higher patient AK dose. Conclusions Approximately 1 in 3 patients undergoing CTO PCI receives high AK radiation dose (>4.8 Gray). Several baseline clinical and angiographic characteristics can help predict the likelihood of high radiation dose and assist with intensifying efforts to reduce radiation exposure for the patient and the operator. PMID:28169091

Immunogenicity and safety of investigational vaccine formulations against meningococcal serogroups A, B, C, W, and Y in healthy adolescents

PubMed Central

Saez-Llorens, Xavier; Aguilera Vaca, Diana Catalina; Abarca, Katia; Maho, Emmanuelle; Graña, Maria Gabriela; Heijnen, Esther; Smolenov, Igor; Dull, Peter M

2015-01-01

This phase 2 study assessed the immunogenicity, safety, and reactogenicity of investigational formulations of meningococcal ABCWY vaccines, consisting of recombinant proteins (rMenB) and outer membrane vesicle (OMV) components of a licensed serogroup B vaccine, combined with components of a licensed quadrivalent meningococcal glycoconjugate vaccine (MenACWY-CRM). A total of 495 healthy adolescents were randomized to 6 groups to receive 2 doses (Months 0, 2) of one of 4 formulations of rMenB antigens, with or without OMV, combined with MenACWY-CRM, or 2 doses of rMenB alone or one dose of MenACWY-CRM then a placebo. Immunogenicity was assessed by serum bactericidal assay with human complement (hSBA) against serogroups ACWY and serogroup B test strains; solicited reactions and any adverse events (AEs) were assessed. Two MenABCWY vaccinations elicited robust ACWY immune responses, with higher seroresponse rates than one dose of MenACWY-CRM. Bactericidal antibody responses against the rMenB antigens and OMV components were highest in subjects who received 2 doses of OMV-containing MenABCWY formulations, with ≥68% of subjects achieving hSBA titers ≥5 against each of the serogroup B test strains. After the first dose, solicited local reaction rates were higher in the MenABCWY or rMenB groups than the MenACWY-CRM group, but similar across groups after the second dose, consisting mainly of transient injection site pain. Fever (≥38.0°C) was rare and there were no vaccine-related serious AEs. In conclusion, investigational MenABCWY formulations containing OMV components elicited highly immunogenic responses against meningococcal serogroups ACWY, as well as serogroup B test strains, with an acceptable safety profile. [NCT01210885] PMID:25969894

Impact of weight-based ribavirin with peginterferon alfa-2b in African Americans with hepatitis C virus genotype 1.

PubMed

Jacobson, Ira M; Brown, Robert S; McCone, Jonathan; Black, Martin; Albert, Clive; Dragutsky, Michael S; Siddiqui, Firdous A; Hargrave, Thomas; Kwo, Paul Y; Lambiase, Louis; Galler, Greg W; Araya, Victor; Freilich, Bradley; Harvey, Joann; Griffel, Louis H; Brass, Clifford A

2007-10-01

WIN-R (Weight-based dosing of pegINterferon alfa-2b and Ribavirin) was a multicenter, randomized, open-label, investigator-initiated trial involving 236 community and academic sites in the United States, comparing response to pegylated interferon (PEG-IFN) alfa-2b plus a flat or weight-based dose of ribavirin (RBV) in treatment-naive patients with chronic hepatitis C and compensated liver disease. Patients were randomized to receive PEG-IFN alfa-2b at 1.5 microg/kg/week plus flat-dose (800 mg/day) or weight-based-dose RBV (800 mg/day for weight <65 kg, 1000 mg/day for 65-85 kg, 1200 mg/day for >85-105 kg, or 1400 mg/day for >105-<125 kg). Sustained virologic response (SVR; undetectable [<125 IU/mL] hepatitis C virus [HCV] RNA at end of follow-up) in patients > or =65 kg was the primary end point. Low SVR rates have been reported among African American individuals, in whom there is a preponderance of HCV genotype 1. This subanalysis of WIN-R was conducted to evaluate the efficacy of weight-based dosing among African American individuals with genotype 1 infection enrolled in the trial. Of 362 African American patients in the primary efficacy analysis, 188 received RBV flat dosing and 174 received weight-based dosing. SVR rates were higher (21% versus 10%; P = 0.0006) and relapse rates were lower (22% versus 30%) in the weight-based-dose group than in the flat-dose group. Safety and rates of drug discontinuation were similar between the 2 groups. Weight-based dosing of RBV is more effective than flat dosing in combination with PEG-IFN alfa-2b in African American individuals with HCV genotype 1. Even with weight-based dosing, response rates in African American individuals are lower than reported in other ethnic groups.

A randomized controlled trial of preprocedure administration of parecoxib for therapeutic endoscopic retrograde cholangiopancreatography.

PubMed

Amornyotin, Somchai; Chalayonnawin, Wiyada; Kongphlay, Siriporn

2012-01-01

Parecoxib is occasionally used for analgesia in postprocedural patients. The clinical efficacy of parecoxib used for endoscopic retrograde cholangiopancreatography (ERCP) is controversial. The aim of the study was to determine the clinical efficacy of preprocedure administration of parecoxib for therapeutic ERCP patients. Eighty-five patients who underwent therapeutic ERCP in a single year were randomly assigned to normal saline group (C, n = 43) and parecoxib group (P, n = 42). Patients in group C received normal saline and those in group P received 40 mg of parecoxib intravenously in equivalent volume. Patients in both groups received the saline or parecoxib 60 seconds before administration of the sedative agents. All patients were monitored for the depth of sedation by using the Narcotrend(TM) monitor, maintaining stage D0-E0 during ERCP. All patients were oxygenated with 100% O(2) via nasal cannula and sedated with 0.03 mg/kg of intravenous midazolam and 1 μg/kg of intravenous fentanyl as well as the titration of intravenous propofol. After the ERCP procedure, pethidine in an intramuscular dose of 0.5-1.0 mg/kg was used as rescue medication. The pain scores (visual analog scale [VAS], 0-10) at 2, 12, and 24 hours post-ERCP, the total number of doses of pethidine used, the dose volume of pethidine used, patient satisfaction, endoscopist satisfaction, and complications were recorded. There were no significant differences in sedative and analgesic agents used during the procedure, pain at 24 hours post-ERCP, endoscopist satisfaction, and complications in both groups. The total number of doses of pethidine used post-ERCP in group C was significantly higher than in group P. Additionally, the mean pain score at 2 and 12 hours post-ERCP in group C was significantly greater than in group P. Patient satisfaction in group P was higher than in group C. Preprocedure administration of parecoxib for therapeutic ERCP patients was clinically effective. The analgesic efficacy of a standard dose of parecoxib was clearly demonstrated during the first 12 hours postprocedure. Additionally, patient satisfaction in the parecoxib group was also higher than in the control group.

[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.

Sex Differences in Dose Escalation and Overdose Death during Chronic Opioid Therapy: A Population-Based Cohort Study

PubMed Central

Kaplovitch, Eric; Gomes, Tara; Camacho, Ximena; Dhalla, Irfan A.; Mamdani, Muhammad M.; Juurlink, David N.

2015-01-01

Background The use of opioids for noncancer pain is widespread, and more than 16,000 die of opioid-related causes in the United States annually. The patients at greatest risk of death are those receiving high doses of opioids. Whether sex influences the risk of dose escalation or opioid-related mortality is unknown. Methods and Findings We conducted a cohort study using healthcare records of 32,499 individuals aged 15 to 64 who commenced chronic opioid therapy for noncancer pain between April 1, 1997 and December 31, 2010 in Ontario, Canada. Patients were followed from their first opioid prescription until discontinuation of therapy, death from any cause or the end of the study period. Among patients receiving chronic opioid therapy, 589 (1.8%) escalated to high dose therapy and n = 59 (0.2%) died of opioid-related causes while on treatment. After multivariable adjustment, men were more likely than women to escalate to high-dose opioid therapy (adjusted hazard ratio 1.44; 95% confidence interval 1.21 to 1.70) and twice as likely to die of opioid-related causes (adjusted hazard ratio 2.04; 95% confidence interval 1.18 to 3.53). These associations were maintained in a secondary analysis of 285,520 individuals receiving any opioid regardless of the duration of therapy. Conclusions Men are at higher risk than women for escalation to high-dose opioid therapy and death from opioid-related causes. Both outcomes were more common than anticipated. PMID:26291716

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

Lin, M; Saboury, B

Purpose: Selective-internal-radiation-therapy (SIRT) and transarterial-chemoembolization (TACE) are commonly used for treatment of liver tumors. The use of TACE, which is macroembolic, prior to SIRT may cause hemodynamic changes in tumor vasculature that impair yttrium-90 (90Y) microsphere delivery to the targeted lesions. This work aims to quantify dosimetric tumor coverage using 90Y positron emission tomography (PET) dosimetry after SIRT alone compared to TACE followed by SIRT. Methods: A total of 40 consecutive hepatocellular carcinoma (HCC) SIRT patients who had a post-SIRT 90Y PET/CT scan were evaluated. The patient-specific-3D-dose was reconstructed from the PET images. Patients were categorized into two groups: patientsmore » received TACE prior SIRT procedure (n=18) and patient received SIRT alone (n=22). The lesions and liver were delineated by a senior radiologist. We evaluated both the lesion-specific dose-volume-histogram (DVH) and the selectivity index (SI) defined as the ratio of the average dose inside the total lesion(s) and the average dose of the normal liver. The SI values of patients were compared based on whether TACE was previously used. Results: A wide spectrum was observed in the lesion-specific DVH-evaluation and SI appeared to be suitable of evaluating the quality of each SIRT infusion. The average SI of the entire patient group was 3.0, i.e. targeted lesion receiving three times higher dose than normal liver. The average SI was 1.8 for patients who had prior TACE and 3.9 for patients who did not have prior TACE (p=0.008). 85% of the patients with prior TACE demonstrated poor 90Y-microsphere delivery (SI <2) while none demonstrated excellent delivery (SI >4). On the other hand, the incidence SI >4 among patients with no prior TACE was 37%. Conclusion: 3D dose evaluation using post-SIRT PET suggests that 90Y microsphere delivery to liver tumors is impaired among patients who received prior TACE compared to those who receive SIRT alone.« less

Effective doses in children: association with common complex imaging techniques used during interventional radiology procedures.

PubMed

Lai, Priscilla; McNeil, Sarah M; Gordon, Christopher L; Connolly, Bairbre L

2014-12-01

The purpose of this study was to determine the range of effective doses associated with imaging techniques used during interventional radiology procedures on children. A pediatric phantom set (1, 5, and 10 years) coupled with high-sensitivity metal oxide semiconductor field effect transistor (MOSFET) dosimeters was used to calculate effective doses. Twenty MOSFETs were inserted into each phantom at radiosensitive organ locations. The phantoms were exposed to mock head, chest, and abdominal interventional radiology procedures performed with different geometries and magnifications. Fluoroscopy, digital subtraction angiography (DSA), and spin angiography were simulated on each phantom. Road mapping was conducted only on the 5-year-old phantom. International Commission on Radiological Protection publication 103 tissue weights were applied to the organ doses recorded with the MOSFETs to determine effective dose. For easy application to clinical cases, doses were normalized per minute of fluoroscopy and per 10 frames of DSA or spin angiography. Effective doses from DSA, angiography, and fluoroscopy were higher for younger ages because of magnification use and were largest for abdominal procedures. DSA of the head, chest, and abdomen (normalized per 10 frames) imparted doses 2-3 times as high as corresponding doses per minute of fluoroscopy while all other factors remained unchanged (age, projection, collimation, magnification). Three to five frames of DSA imparted an effective dose equal to doses from 1 minute of fluoroscopy. Doses from spin angiography were almost one-half the doses received from an equivalent number of frames of DSA. Patient effective doses during interventional procedures vary substantially depending on procedure type but tend to be higher because of magnification use in younger children and higher in the abdomen.

Skin-sparing Helical Tomotherapy vs 3D-conformal Radiotherapy for Adjuvant Breast Radiotherapy: In Vivo Skin Dosimetry Study

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

Capelle, Lisa; Warkentin, Heather; MacKenzie, Marc

Purpose: We investigated whether treatment-planning system (TPS)-calculated dose accurately reflects skin dose received for patients receiving adjuvant breast radiotherapy (RT) with standard three-dimensional conformal RT (3D-CRT) or skin-sparing helical tomotherapy (HT). Methods and Materials: Fifty patients enrolled in a randomized controlled trial investigating acute skin toxicity from adjuvant breast RT with 3D-CRT compared to skin-sparing HT, where a 5-mm strip of ipsilateral breast skin was spared. Thermoluminescent dosimetry or optically stimulated luminescence measurements were made in multiple locations and were compared to TPS-calculated doses. Skin dosimetric parameters and acute skin toxicity were recorded in these patients. Results: With HT theremore » was a significant correlation between calculated and measured dose in the medial and lateral ipsilateral breast (r = 0.67, P<.001; r = 0.44, P=.03, respectively) and the medial and central contralateral breast (r = 0.73, P<.001; r = 0.88, P<.001, respectively). With 3D-CRT there was a significant correlation in the medial and lateral ipsilateral breast (r = 0.45, P=.03; r = 0.68, P<.001, respectively); the medial and central contralateral breast (r = 0.62, P=.001; r = 0.86, P<.001, respectively); and the mid neck (r = 0.42, P=.04, respectively). On average, HT-calculated dose overestimated the measured dose by 14%; 3D-CRT underestimated the dose by 0.4%. There was a borderline association between highest measured skin dose and moist desquamation (P=.05). Skin-sparing HT had greater skin homogeneity (homogeneity index of 1.39 vs 1.65, respectively; P=.005) than 3D-CRT plans. HT plans had a lower skin{sub V50} (1.4% vs 5.9%, respectively; P=.001) but higher skin{sub V40} and skin{sub V30} (71.7% vs 64.0%, P=.02; and 99.0% vs 93.8%, P=.001, respectively) than 3D-CRT plans. Conclusion: The 3D-CRT TPS more accurately reflected skin dose than the HT TPS, which tended to overestimate dose received by 14% in patients receiving adjuvant breast RT.« less

A Recombinant Vesicular Stomatitis Virus Ebola Vaccine.

PubMed

Regules, Jason A; Beigel, John H; Paolino, Kristopher M; Voell, Jocelyn; Castellano, Amy R; Hu, Zonghui; Muñoz, Paula; Moon, James E; Ruck, Richard C; Bennett, Jason W; Twomey, Patrick S; Gutiérrez, Ramiro L; Remich, Shon A; Hack, Holly R; Wisniewski, Meagan L; Josleyn, Matthew D; Kwilas, Steven A; Van Deusen, Nicole; Mbaya, Olivier Tshiani; Zhou, Yan; Stanley, Daphne A; Jing, Wang; Smith, Kirsten S; Shi, Meng; Ledgerwood, Julie E; Graham, Barney S; Sullivan, Nancy J; Jagodzinski, Linda L; Peel, Sheila A; Alimonti, Judie B; Hooper, Jay W; Silvera, Peter M; Martin, Brian K; Monath, Thomas P; Ramsey, W Jay; Link, Charles J; Lane, H Clifford; Michael, Nelson L; Davey, Richard T; Thomas, Stephen J

2017-01-26

The worst Ebola virus disease (EVD) outbreak in history has resulted in more than 28,000 cases and 11,000 deaths. We present the final results of two phase 1 trials of an attenuated, replication-competent, recombinant vesicular stomatitis virus (rVSV)-based vaccine candidate designed to prevent EVD. We conducted two phase 1, placebo-controlled, double-blind, dose-escalation trials of an rVSV-based vaccine candidate expressing the glycoprotein of a Zaire strain of Ebola virus (ZEBOV). A total of 39 adults at each site (78 participants in all) were consecutively enrolled into groups of 13. At each site, volunteers received one of three doses of the rVSV-ZEBOV vaccine (3 million plaque-forming units [PFU], 20 million PFU, or 100 million PFU) or placebo. Volunteers at one of the sites received a second dose at day 28. Safety and immunogenicity were assessed. The most common adverse events were injection-site pain, fatigue, myalgia, and headache. Transient rVSV viremia was noted in all the vaccine recipients after dose 1. The rates of adverse events and viremia were lower after the second dose than after the first dose. By day 28, all the vaccine recipients had seroconversion as assessed by an enzyme-linked immunosorbent assay (ELISA) against the glycoprotein of the ZEBOV-Kikwit strain. At day 28, geometric mean titers of antibodies against ZEBOV glycoprotein were higher in the groups that received 20 million PFU or 100 million PFU than in the group that received 3 million PFU, as assessed by ELISA and by pseudovirion neutralization assay. A second dose at 28 days after dose 1 significantly increased antibody titers at day 56, but the effect was diminished at 6 months. This Ebola vaccine candidate elicited anti-Ebola antibody responses. After vaccination, rVSV viremia occurred frequently but was transient. These results support further evaluation of the vaccine dose of 20 million PFU for preexposure prophylaxis and suggest that a second dose may boost antibody responses. (Funded by the National Institutes of Health and others; rVSV∆G-ZEBOV-GP ClinicalTrials.gov numbers, NCT02269423 and NCT02280408 .).

Does Maternal Buprenorphine Dose Affect Severity or Incidence of Neonatal Abstinence Syndrome?

PubMed

Wong, Jacqueline; Saver, Barry; Scanlan, James M; Gianutsos, Louis Paul; Bhakta, Yachana; Walsh, James; Plawman, Abigail; Sapienza, David; Rudolf, Vania

2018-06-13

To measure the incidence, onset, duration, and severity of neonatal abstinence syndrome (NAS) in infants born to mothers receiving buprenorphine and to assess the association between buprenorphine dose and NAS outcomes. We reviewed charts of all mother-infant pairs maintained on buprenorphine who delivered in our hospital from January 1, 2000 to April 1, 2016. In 89 infants, NAS incidence requiring morphine was 43.8%. Means for morphine-treated infants included: 55.2 hours to morphine start, 15.9 days on morphine, and 20 days hospital stay. NAS requiring morphine treatment occurred in 48.5% and 41.4% of infants of mothers receiving ≤8 mg/d buprenorphine versus >8 mg/d, respectively (P = 0.39). We found no significant associations of maternal buprenorphine dose with peak NAS score, NAS severity requiring morphine, time to morphine start, peak morphine dose, or days on morphine. Among the other factors examined, only exclusive breastfeeding was significantly associated with neonatal outcomes, specifically lower odds of morphine treatment (odds ratio 0.24, P = 0.003). These findings suggest higher buprenorphine doses can be prescribed to pregnant women receiving medication therapy for addiction without increasing NAS severity. Our finding of reduced risk of NAS requiring morphine treatment also suggests breastfeeding is both safe and beneficial for these infants and should be encouraged.

Association between bortezomib dose intensity and overall survival in mantle cell lymphoma patients on frontline VR-CAP in the phase 3 LYM-3002 study.

PubMed

Robak, Tadeusz; Huang, Huiqiang; Jin, Jie; Zhu, Jun; Liu, Ting; Samoilova, Olga; Pylypenko, Halyna; Verhoef, Gregor; Siritanaratkul, Noppadol; Osmanov, Evgenii; Pereira, Juliana; Mayer, Jiri; Hong, Xiaonan; Okamoto, Rumiko; Pei, Lixia; Rooney, Brendan; van de Velde, Helgi; Cavalli, Franco

2017-06-05

The pivotal LYM-3002 study compared frontline rituximab plus cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP) with bortezomib, rituximab, cyclophosphamide, doxorubicin and prednisone (VR-CAP) in newly diagnosed mantle cell lymphoma (MCL) patients for whom stem cell transplantation was not an option. This post hoc subanalysis of the VR-CAP data from LYM-3002 evaluated the effect of bortezomib dose intensity on OS in patients who completed ≥6 cycles of treatment. From the end of cycle 6, patients receiving ≥4.6 mg/m 2 /cycle of bortezomib had significantly longer OS (but not PFS) compared with those receiving <4.6 mg/m 2 /cycle by univariate analysis (HR 0.43 [95% CI: 0.23-0.80]; p = .0059). This association remained significant in multivariate analysis adjusting for baseline patient and disease characteristics (HR 0.40 [95% CI: 0.20-0.79]; p = .008]. Higher bortezomib dose intensity was the strongest predictor of OS in newly diagnosed MCL patients receiving VR-CAP. Clinicaltrials.gov identifier: NCT00722137.

Circulating Myeloid‐Related Protein–8/14 is Related to Thromboxane‐Dependent Platelet Activation in Patients With Acute Coronary Syndrome, With and Without Ongoing Low‐Dose Aspirin Treatment

PubMed Central

Santilli, Francesca; Paloscia, Leonardo; Liani, Rossella; Di Nicola, Marta; Di Marco, Massimo; Lattanzio, Stefano; La Barba, Sara; Pascale, Silvia; Mascellanti, Marco; Davì, Giovanni

2014-01-01

Background Platelet activation is involved in acute coronary syndromes (ACS). Incomplete suppression by low‐dose aspirin treatment of thromboxane (TX) metabolite excretion (urinary 11‐dehydro‐TXB2) is predictive of vascular events in high‐risk patients. Myeloid‐related protein (MRP)‐8/14 is a heterodimer secreted on activation of platelets, monocytes, and neutrophils, regulating inflammation and predicting cardiovascular events. Among platelet transcripts, MRP‐14 has emerged as a powerful predictor of ACS. Methods and Results We enrolled 68 stable ischemic heart disease (IHD) and 63 ACS patients, undergoing coronary angiography, to evaluate whether MRP‐8/14 release in the circulation is related to TX‐dependent platelet activation in ACS and IHD patients and to residual TX biosynthesis in low‐dose aspirin–treated ACS patients. In ACS patients, plasma MRP‐8/14 and urinary 11‐dehydro‐TXB2 levels were linearly correlated (r=0.651, P<0.001) but significantly higher than those in IHD patients (P=0.012, P=0.044) only among subjects not receiving aspirin. In aspirin‐treated ACS patients, MRP‐8/14 and 11‐dehydro‐TXB2 were lower versus those not receiving aspirin (P<0.001) and still significantly correlated (r=0.528, P<0.001). Higher 11‐dehydro‐TXB2 significantly predicted higher MRP‐8/14 in both all ACS patients and ACS receiving aspirin (P<0.001, adj R2=0.463 and adj R2=0.497) after multivariable adjustment. Conversely, plasma MRP‐8/14 (P<0.001) and higher urinary 8‐iso‐prostaglandin F2α (P=0.050) levels were significant predictors of residual, on‐aspirin, TX biosynthesis in ACS (adjusted R2=0.384). Conclusions Circulating MRP‐8/14 is associated with TX‐dependent platelet activation in ACS, even during low‐dose aspirin treatment, suggesting a contribution of residual TX to MRP‐8/14 shedding, which may further amplify platelet activation. Circulating MRP‐8/14 may be a target to test different antiplatelet strategies in ACS. PMID:25037196

Adenoid cystic salivary gland carcinoma: treatment with irradiation and surgery

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

Simpson, J.R.; Thawley, S.E.; Matsuba, H.M.

1984-05-01

The recrods of 71 patients with adenoid cystic carcinoma of the salivary glands were reviewed to determine the dose response relationships for this aggressive tumor. Local control after treament was determined for all patients and analyzed with respect to extent of surgery and dose of radiation. Of 70 patients who were available for evaluation of local control, 28 (40%) had a local recurrence and 42 (60%) did not. The highest control rates were found in patients who underwent both radiation therapy and surgery. Patients who received a dose equal to or greater than 6,000 rad (60 Gy) in addition tomore » surgery had significantly higher local control rates than those who received less than 6,000 rad (60 Gy). Distant metastases developed in 50% of patients regardless of local control, with the following distribution: 39% lung, 19% bone, and 10% disseminated soft-tissue metastases.« less

Radiation therapy dose is associated with improved survival for unresected anaplastic thyroid carcinoma: Outcomes from the National Cancer Data Base.

PubMed

Pezzi, Todd A; Mohamed, Abdallah S R; Sheu, Tommy; Blanchard, Pierre; Sandulache, Vlad C; Lai, Stephen Y; Cabanillas, Maria E; Williams, Michelle D; Pezzi, Christopher M; Lu, Charles; Garden, Adam S; Morrison, William H; Rosenthal, David I; Fuller, Clifton D; Gunn, G Brandon

2017-05-01

The outcomes of patients with unresected anaplastic thyroid carcinoma (ATC) from the National Cancer Data Base (NCDB) were assessed, and potential correlations were explored between radiation therapy (RT) dose and overall survival (OS). The study cohort was comprised of patients who underwent either no surgery or grossly incomplete resection. Correlates of OS were explored using univariate analysis and multivariable analysis (MVA). In total, 1288 patients were analyzed. The mean patient age was 70.2 years, 59.7% of patients were women, and 47.6% received neck RT. The median OS was 2.27 months, and 11% of patients remained alive at 1 year. A positive RT dose-survival correlation was observed for the entire study cohort, for those who received systemic therapy, and for those with stage IVA/IVB and IVC disease. On MVA, older age (hazard ratio [HR], 1.317; 95% confidence interval [CI], 1.137-1.526), ≥ 1 comorbidity (HR, 1.587; 95% CI, 1.379-1.827), distant metastasis (HR, 1.385; 95% CI, 1.216-1.578), receipt of systemic therapy (HR, 0.637; 95% CI, 0.547-0.742), and receipt of RT compared with no RT (<45 grays [Gy]:HR, 0.843; 95% CI, 0.718-0.988; 45-59.9 Gy: HR, 0.596; 95% CI, 0.479-0.743; 60-75 Gy: HR, 0.419; 95% CI, 0.339-0.517) correlated with OS. The RT dose-survival correlation for patients who received higher (60-75 Gy) versus lower (45-59.9 Gy) therapeutic doses was confirmed by propensity-score matching. Survival was poor in this cohort of patients with unresected ATC, and more effective therapies are needed. However, the association of RT dose with OS highlights the importance of identifying patients with unresected ATC who may still yet benefit from multimodal locoregional treatment that incorporates higher dose RT. Cancer 2017;123:1653-1661. © 2017 American Cancer Society. © 2016 American Cancer Society.

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

PubMed

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

2017-07-01

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

[Do poor-responder patients benefit from increasing the daily gonadotropin dose from 300 to 450 IU during controlled ovarian hyperstimulation for IVF?].

PubMed

Haas, Jigal; Zilberberg, Eran; Kedem, Alon; Dar, Shir; Orvieto, Raoul

2015-02-01

We aim to evaluate the IVF-ET outcome in patients receiving a high daily dose (300 IU) of gonadotropins during controlled ovarian hyperstimulation (COH) for IVF and to assess the role of increasing the daily dose to 450 IU on improving outcome. All consecutive women admitted to our IVF unit during an 11 year period who underwent COH consisting of daily gonadotropin dose of 300 IU were included in the study. The ovarian stimulation characteristics, number of oocytes retrieved, number of embryo transferred and pregnancy rate were assessed. We also evaluated the subsequent cycle, using daily gonadotropin doses of 450 IU, among those patients who did not conceive using the 300 IU daily gonadotropin dose. Nine hundred and forty-nine consecutive IVF cycles were evaluated. Patients who conceived using the daily gonadotropin dose of 300 IU (n = 133, 14% pregnancy rate) had significantly longer stimulation, yielded higher numbers of oocytes retrieved, fertilization rate and number of embryos transferred, compared to those who did not conceive. Moreover, while comparing IVF cycles using daily gonadotropin doses of 300 IU to 450 IU (n = 117), no in-between group differences were observed, except for significantly higher yields of oocytes retrieved. Moreover, cycles using daily gonadotropin doses of 450 IU resulted in a 7.7 live-birth rate. In poor responders undergoing COH with a daily gonadotropin dose of 300 IU, increasing the dose to 450 IU resulted in significantly higher oocyte yields and a reasonable live birth rate.

Inhaled Corticosteroids in Lung Diseases

PubMed Central

Raissy, Hengameh H.; Kelly, H. William; Harkins, Michelle

2013-01-01

Inhaled corticosteroids (ICSs) are used extensively in the treatment of asthma and chronic obstructive pulmonary disease (COPD) due to their broad antiinflammatory effects. They improve lung function, symptoms, and quality of life and reduce exacerbations in both conditions but do not alter the progression of disease. They decrease mortality in asthma but not COPD. The available ICSs vary in their therapeutic index and potency. Although ICSs are used in all age groups, younger and smaller children may be at a greater risk for adverse systemic effects because they can receive higher mg/kg doses of ICSs compared with older children. Most of the benefit from ICSs occurs in the low to medium dose range. Minimal additional improvement is seen with higher doses, although some patients may benefit from higher doses. Although ICSs are the preferred agents for managing persistent asthma in all ages, their benefit in COPD is more controversial. When used appropriately, ICSs have few adverse events at low to medium doses, but risk increases with high-dose ICSs. Although several new drugs are being developed and evaluated, it is unlikely that any of these new medications will replace ICSs as the preferred initial long-term controller therapy for asthma, but more effective initial controller therapy could be developed for COPD. PMID:23370915

Local Control With Reduced-Dose Radiotherapy for Low-Risk Rhabdomyosarcoma: A Report From the Children's Oncology Group D9602 Study

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

Breneman, John, E-mail: john.breneman@uchealth.com; Meza, Jane; Donaldson, Sarah S.

2012-06-01

Purpose: To analyze the effect of reduced-dose radiotherapy on local control in children with low-risk rhabdomyosarcoma (RMS) treated in the Children's Oncology Group D9602 study. Methods and Materials: Patients with low-risk RMS were nonrandomly assigned to receive radiotherapy doses dependent on the completeness of surgical resection of the primary tumor (clinical group) and the presence of involved regional lymph nodes. After resection, most patients with microscopic residual and uninvolved nodes received 36 Gy, those with involved nodes received 41.4 to 50.4 Gy, and those with orbital primary tumors received 45 Gy. All patients received vincristine and dactinomycin, with cyclophosphamide addedmore » for patient subsets with a higher risk of relapse in Intergroup Rhabdomyosarcoma Study Group III and IV studies. Results: Three hundred forty-two patients were eligible for analysis; 172 received radiotherapy as part of their treatment. The cumulative incidence of local/regional failure was 15% in patients with microscopic involved margins when cyclophosphamide was not part of the treatment regimen and 0% when cyclophosphamide was included. The cumulative incidence of local/regional failure was 14% in patients with orbital tumors. Protocol-specified omission of radiotherapy in girls with Group IIA vaginal tumors (n = 5) resulted in three failures for this group. Conclusions: In comparison with Intergroup Rhabdomyosarcoma Study Group III and IV results, reduced-dose radiotherapy does not compromise local control for patients with microscopic tumor after surgical resection or with orbital primary tumors when cyclophosphamide is added to the treatment program. Girls with unresected nonbladder genitourinary tumors require radiotherapy for postsurgical residual tumor for optimal local control to be achieved.« less

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

PubMed

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

2016-04-01

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

[Analysis of the cumulative solar ultraviolet radiation in Mexico].

PubMed

Castanedo-Cázares, Juan Pablo; Torres-Álvarez, Bertha; Portales-González, Bárbara; Martínez-Rosales, Karla; Hernández-Blanco, Diana

2016-01-01

The incidence of skin cancer has increased in Mexico in recent years. Ultraviolet radiation is the main risk factor associated. Due to the need to develop strategies to prevent skin cancer, the aim of the study was to estimate the UV intensity in several representative regions of Mexico, the average annual UV dose of these populations, and the potential benefit of applying sunscreen at different ages. The intensity of UV radiation was quantified by remote and terrestrial radiometry. The dose of UV exposure was measured in minimal erythema doses using validated models for face and arms. The benefit of using a sunscreen was calculated with the use of a sunscreen with SPF 15 from birth to age 70. The UV radiation is lower in December and greater in the period from May to July. The region with a lower annual dose is Tijuana; and the higher annual dose is in the Mexico City area. The annual difference between these regions was 58 %. Through life, a low SPF sunscreen can reduce up to 66 % of the received UV dose. The geographical location is a risk factor for accumulation of UV radiation in Mexico. Since childhood, people receive high amounts of it; however, most of this dose can be reduced using any commercially available sunscreen, if applied strategically.

Comparison of testicular dose delivered by intensity-modulated radiation therapy (IMRT) and volumetric-modulated arc therapy (VMAT) in patients with prostate cancer

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

Martin, Jeffrey M.; Handorf, Elizabeth A.; Price, Robert A.

A small decrease in testosterone level has been documented after prostate irradiation, possibly owing to the incidental dose to the testes. Testicular doses from prostate external beam radiation plans with either intensity-modulated radiation therapy (IMRT) or volumetric-modulated arc therapy (VMAT) were calculated to investigate any difference. Testicles were contoured for 16 patients being treated for localized prostate cancer. For each patient, 2 plans were created: 1 with IMRT and 1 with VMAT. No specific attempt was made to reduce testicular dose. Minimum, maximum, and mean doses to the testicles were recorded for each plan. Of the 16 patients, 4 receivedmore » a total dose of 7800 cGy to the prostate alone, 7 received 8000 cGy to the prostate alone, and 5 received 8000 cGy to the prostate and pelvic lymph nodes. The mean (range) of testicular dose with an IMRT plan was 54.7 cGy (21.1 to 91.9) and 59.0 cGy (25.1 to 93.4) with a VMAT plan. In 12 cases, the mean VMAT dose was higher than the mean IMRT dose, with a mean difference of 4.3 cGy (p = 0.019). There was a small but statistically significant increase in mean testicular dose delivered by VMAT compared with IMRT. Despite this, it unlikely that there is a clinically meaningful difference in testicular doses from either modality.« less

Evaluation of 16 genotype-guided Warfarin Dosing Algorithms in 310 Korean Patients Receiving Warfarin Treatment: Poor Prediction Performance in VKORC1 1173C Carriers.

PubMed

Yang, Mina; Choi, Rihwa; Kim, June Soo; On, Young Keun; Bang, Oh Young; Cho, Hyun-Jung; Lee, Soo-Youn

2016-12-01

The purpose of this study was to evaluate the performance of 16 previously published warfarin dosing algorithms in Korean patients. The 16 algorithms were selected through a literature search and evaluated using a cohort of 310 Korean patients with atrial fibrillation or cerebral infarction who were receiving warfarin therapy. A large interindividual variation (up to 11-fold) in warfarin dose was observed (median, 25 mg/wk; range, 7-77 mg/wk). Estimated dose and actual maintenance dose correlated well overall (r range, 0.52-0.73). Mean absolute error (MAE) of the 16 algorithms ranged from -1.2 to -20.1 mg/wk. The percentage of patients whose estimated dose fell within 20% of the actual dose ranged from 1.0% to 49%. All algorithms showed poor accuracy with increased MAE in a higher dose range. Performance of the dosing algorithms was worse in patients with VKORC1 1173TC or CC than in total (r range, 0.38-0.61 vs 0.52-0.73; MAE range, -2.6 to -28.0 mg/wk vs -1.2 to -20.1 mg/wk). The algorithms had comparable prediction abilities but showed limited accuracy depending on ethnicity, warfarin dose, and VKORC1 genotype. Further studies are needed to develop genotype-guided warfarin dosing algorithms with greater accuracy in the Korean population. Copyright © 2016 Elsevier HS Journals, Inc. All rights reserved.

Planning comparison between intensity modulated radiation therapy and intensity modulated proton therapy in a case of head and neck cancer

NASA Astrophysics Data System (ADS)

Nguyen, T. T. C.; Nguyen, B. T.; Mai, N. V.

2018-03-01

In this work, we made the comparison between IMRT plan and IMPT plan for a head and neck case. We used Prowess Panther to perform IMRT plan and LAP- CERR for IMPT plan. The result showed that IMPT plan had better coverage than IMRT plan. In the IMRT plan, normal structures received higher dose with higher volume. Especially, the maximum dose of spinal cord is 31.5 Gy (RBE) using IMRT technique compared to 13.5 Gy (RBE) using IMPT technique. These results showed that IMPT is beneficial for head and neck cancer compared to IMRT technique.

L-Boronophenylalanine-Mediated Boron Neutron Capture Therapy for Malignant Glioma Progressing After External Beam Radiation Therapy: A Phase I Study

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

Kankaanranta, Leena; Seppaelae, Tiina; Koivunoro, Hanna

Purpose: To investigate the safety of boronophenylalanine-mediated boron neutron capture therapy (BNCT) in the treatment of malignant gliomas that progress after surgery and conventional external beam radiation therapy. Methods and Materials: Adult patients who had histologically confirmed malignant glioma that had progressed after surgery and external beam radiotherapy were eligible for this Phase I study, provided that >6 months had elapsed from the last date of radiation therapy. The first 10 patients received a fixed dose, 290 mg/kg, of L-boronophenylalanine-fructose (L-BPA-F) as a 2-hour infusion before neutron irradiation, and the remaining patients were treated with escalating doses of L-BPA-F, eithermore » 350 mg/kg, 400 mg/kg, or 450 mg/kg, using 3 patients on each dose level. Adverse effects were assessed using National Cancer Institute Common Toxicity Criteria version 2.0. Results: Twenty-two patients entered the study. Twenty subjects had glioblastoma, and 2 patients had anaplastic astrocytoma, and the median cumulative dose of prior external beam radiotherapy was 59.4 Gy. The maximally tolerated L-BPA-F dose was reached at the 450 mg/kg level, where 4 of 6 patients treated had a grade 3 adverse event. Patients who were given >290 mg/kg of L-BPA-F received a higher estimated average planning target volume dose than those who received 290 mg/kg (median, 36 vs. 31 Gy [W, i.e., a weighted dose]; p = 0.018). The median survival time following BNCT was 7 months. Conclusions: BNCT administered with an L-BPA-F dose of up to 400 mg/kg as a 2-hour infusion is feasible in the treatment of malignant gliomas that recur after conventional radiation therapy.« less

Study design and early result of a phase I study of SABR for early-stage glottic cancer.

PubMed

Yu, Tosol; Wee, Chan Woo; Choi, Noorie; Wu, Hong-Gyun; Kang, Hyun-Cheol; Park, Jong Min; Kim, Jung-In; Kim, Jin Ho; Kwon, Tack-Kyun; Chung, Eun-Jae

2018-05-14

Avoidance of organs at risk has become possible with advances in image-guided volumetric-modulated arc therapy (VMAT) techniques. This study was designed to evaluate the safety and feasibility of stereotactic ablative radiotherapy (SABR) for early stage glottic cancer. This report presents the preliminary result of the first and second dose level. Fraction size was increased from 3.5 gray (Gy) (total dose 59.5 Gy) to 9 Gy (total dose 45 Gy). Dose-limiting toxicities were defined as grade 3 or higher treatment-related toxicities. Voice outcome was assessed with electroglottography, and quality of life (QoL) was measured with the Head and Neck Cancer Inventory (HNCI). Seven patients received 59.5 Gy at 3.5 Gy per fraction as the first dose level, and five patients received 55 Gy at 5 Gy per fraction as the second dose level. None of the patients developed grade 3+ toxicity throughout a median follow-up of 17.5 months (range, 1.7-30.6 months). One patient in the second dose level recurred in the primary site at 4 months after radiotherapy (RT) and received total laryngectomy. The rest of participants were disease-free at locoregional and distant sites. Jitter, shimmer, mean phonation time, and noise-to-harmony ratio did not change significantly at 6 months after RT. HNCI scores between pretreatment and posttreatment were not significantly different (P = 0.221). This study revealed acceptable toxicity, voice outcome, and QoL in patients treated with hypofractionated VMAT of 3.5 Gy and 5 Gy per fraction. This phase I study is currently ongoing with a dose of 55 Gy in 11 fractions and 45 Gy in five fractions. 2b. Laryngoscope, 2018. © 2018 The American Laryngological, Rhinological and Otological Society, Inc.

Propofol dose and incidence of dreaming during sedation.

PubMed

Eer, Audrey Singyi; Padmanabhan, Usha; Leslie, Kate

2009-10-01

Dreaming is commonly reported after propofol-based sedation. We measured the incidence of dreaming and bispectral index (BIS) values in colonoscopy patients sedated with combinations of propofol, midazolam and fentanyl. Two hundred patients presenting for elective outpatient colonoscopy were sedated with combinations of propofol, midazolam and fentanyl. BIS was monitored throughout the procedure. Patients were interviewed immediately after they emerged from sedation. The primary end point was a report of dreaming during sedation. Ninety-seven patients were administered propofol alone, 44 were administered propofol and fentanyl, 16 were administered propofol and midazolam and 43 were administered propofol, midazolam and fentanyl. Dreaming was reported by 19% of patients. Dreamers received higher doses of propofol and had lower BIS values during sedation. Age of 50 years or less, preoperative quality of recovery score of less than 14, higher home dream recall, propofol dose of more than 300 mg and time to Observers' Assessment of Alertness/Sedation score equalling 5 of 8 min or less were independent predictors of dreaming. Dreaming during sedation is associated with higher propofol dose and lower BIS values.

Risk Factors for Neovascular Glaucoma After Proton Beam Therapy of Uveal Melanoma: A Detailed Analysis of Tumor and Dose–Volume Parameters

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

Mishra, Kavita K., E-mail: kmishra@radonc.ucsf.edu; Daftari, Inder K.; Weinberg, Vivian

2013-10-01

Purpose: To determine neovascular glaucoma (NVG) incidence and identify contributing tumor and dosing factors in uveal melanoma patients treated with proton beam radiation therapy (PBRT). Methods and Materials: A total of 704 PBRT patients treated by a single surgeon (DHC) for uveal melanoma (1996-2010) were reviewed for NVG in our prospectively maintained database. All patients received 56 GyE in 4 fractions. Median follow-up was 58.3 months. Analyses included the Kaplan-Meier method to estimate NVG distributions, univariate log–rank tests, and Cox's proportional hazards multivariate analysis using likelihood ratio tests to identify independent risk factors of NVG among patient, tumor, and dose–volumemore » histogram parameters. Results: The 5-year PBRT NVG rate was 12.7% (95% confidence interval [CI] 10.2%-15.9%). The 5-year rate of enucleation due to NVG was 4.9% (95% CI 3.4%-7.2%). Univariately, the NVG rate increased significantly with larger tumor diameter (P<.0001), greater height (P<.0001), higher T stage (P<.0001), and closer proximity to the disc (P=.002). Dose–volume histogram analysis revealed that if >30% of the lens or ciliary body received ≥50% dose (≥28 GyE), there was a higher probability of NVG (P<.0001 for both). Furthermore, if 100% of the disc or macula received ≥28 GyE, the NVG rate was higher (P<.0001 and P=.03, respectively). If both anterior and posterior doses were above specified cut points, NVG risk was highest (P<.0001). Multivariate analysis confirmed significant independent risk factors to include tumor height (P<.0001), age (P<.0001), %disc treated to ≥50% Dose (<100% vs 100%) (P=.0007), larger tumor diameter (P=.01), %lens treated to ≥90% Dose (0 vs >0%-30% vs >30%) (P=.01), and optic nerve length treated to ≥90% Dose (≤1 mm vs >1 mm) (P=.02). Conclusions: Our current PBRT patients experience a low rate of NVG and resultant enucleation compared with historical data. The present analysis shows that tumor height, diameter, and anterior as well as posterior critical structure dose–volume parameters may be used to predict NVG risk.« less

Secukinumab in Active Rheumatoid Arthritis: A Phase III Randomized, Double-Blind, Active Comparator- and Placebo-Controlled Study.

PubMed

Blanco, Francisco J; Möricke, Rüdiger; Dokoupilova, Eva; Codding, Christine; Neal, Jeffrey; Andersson, Mats; Rohrer, Susanne; Richards, Hanno

2017-06-01

To evaluate the efficacy and safety of secukinumab in patients with active rheumatoid arthritis (RA) who had an inadequate response to or intolerance of tumor necrosis factor (TNF) inhibitors. In this phase III study, 551 patients were randomized (1:1:1:1) to receive intravenous secukinumab at a dose of 10 mg/kg (at baseline and weeks 2 and 4) followed by subcutaneous secukinumab at a dose of either 150 mg or 75 mg every 4 weeks or, alternatively, abatacept or placebo on the same dosing schedule. The primary end point was the proportion of patients achieving 20% improvement in disease activity according to the American College of Rheumatology response criteria (ACR20) at week 24 in the secukinumab 150 mg or 75 mg treatment groups as compared with placebo. Key secondary end points included change from baseline to week 24 in the Disease Activity Score in 28 joints using C-reactive protein level (DAS28-CRP) and the Health Assessment Questionnaire disability index (HAQ DI), as well as the ACR 50% improvement (ACR50) response rate at week 24. The primary efficacy end point was met in patients receiving 150 mg secukinumab, in whom the ACR20 response rate at week 24 was significantly higher than that in the placebo group. The ACR20 response rates at week 24 were 30.7% in patients receiving 150 mg secukinumab (P = 0.0305), 28.3% in those receiving 75 mg secukinumab (P = 0.0916), and 42.8% in those receiving abatacept, compared with 18.1% in the placebo group. A significant reduction in the DAS28-CRP was seen in patients treated with 150 mg secukinumab (P = 0.0495), but not in patients treated with 75 mg secukinumab. Improvements in the HAQ DI and ACR50 response rates were not significant in the 2 secukinumab dose groups compared with the placebo group. The overall safety profile was similar across all treatment groups. Secukinumab at a dose of 150 mg resulted in improvement in signs and symptoms and reduced disease activity in patients with active RA who had an inadequate response to TNF inhibitors. Improvements observed with abatacept were numerically higher than with secukinumab. There were no new or unexpected safety signals with secukinumab in this study. © 2017, American College of Rheumatology.

Comparing proton treatment plans of pediatric brain tumors in two pencil beam scanning nozzles with different spot sizes

PubMed Central

Kralik, John C.; Xi, Liwen; Solberg, Timothy D.; Simone, Charles B.

2015-01-01

Target coverage and organ‐at‐risk sparing were compared for 22 pediatric patients with primary brain tumors treated using two distinct nozzles in pencil beam scanning (PBS) proton therapy. Consecutive patients treated at our institution using a PBS‐dedicated nozzle (DN) were replanned using a universal nozzle (UN) beam model and the original DN plan objectives. Various cranial sites were treated among the patients to prescription doses ranging from 45 to 54 Gy. Organs at risk (OARs) evaluated were patient‐dependent; 15 unique OARs were analyzed, all of which were assessed in at least 10 patients. Clinical target volume (CTV) coverage and organ sparing were compared for the two nozzles using dose‐volume histogram data. Statistical analysis using a confidence‐interval approach demonstrates that CTV coverage is equivalent for UN and DN plans within ±5% equivalence bounds. In contrast, average mean and maximum doses are significantly higher for nearly all 15 OARs in the UN plans. The average median increase over all OARs and patients is approximately 1.7 Gy, with an increase in the 25%–75% of 1.0–2.3 Gy; the median increase to the pituitary gland, temporal lobes, eyes and cochleas are 1.8, 1.7, 0.7, and 2.7 Gy, respectively. The CTV dose distributions fall off slower for UN than for the DN plans; hence, normal tissue structures in close proximity to CTVs receive higher doses in UN plans than in DN plans. The higher OAR doses in the UN plans are likely due to the larger spot profile in plans created with UN beams. In light of the high rates of toxicities in pediatric patients receiving cranial irradiation and in light of selected brain tumor types having high cure rates, this study suggests the smaller DN beam profile is preferable for the advantage of reducing dose to OARs. PACS number: 87.55.D‐ PMID:26699553

Impact of cyclophosphamide dose of conditioning on the outcome of allogeneic hematopoietic stem cell transplantation for aplastic anemia from human leukocyte antigen-identical sibling.

PubMed

Mori, Takehiko; Koh, Hideo; Onishi, Yasushi; Kako, Shinichi; Onizuka, Makoto; Kanamori, Heiwa; Ozawa, Yukiyasu; Kato, Chiaki; Iida, Hiroatsu; Suzuki, Ritsuro; Ichinohe, Tatsuo; Kanda, Yoshinobu; Maeda, Tetsuo; Nakao, Shinji; Yamazaki, Hirohito

2016-04-01

The standard conditioning regimen in allogeneic hematopoietic stem cell transplantation (HSCT) for aplastic anemia from a human leukocyte antigen (HLA)-identical sibling has been high-dose cyclophosphamide (CY 200 mg/kg). In the present study, results for 203 patients with aplastic anemia aged 16 years or older who underwent allogeneic HSCT from HLA-identical siblings were retrospectively analyzed using the registry database of Japan Society for Hematopoietic Cell Transplantation. Conditioning regimens were defined as a (1) high-dose CY (200 mg/kg or greater)-based (n = 117); (2) reduced-dose CY (100 mg/kg or greater, but less than 200 mg/kg)-based (n = 38); and (3) low-dose CY (less than 100 mg/kg)-based (n = 48) regimen. Patient age and the proportion of patients receiving fludarabine were significantly higher in the reduced- and low-dose CY groups than the high-dose CY group. Engraftment was comparable among the groups. Five-year overall survival (OS) tended to be higher in the low-dose CY group [93.0 % (95 % CI 85.1-100.0 %)] than the high-dose CY [84.2 % (95 % CI 77.1-91.3 %)] or reduced-dose CY groups [83.8 % (95 % CI 71.8-95.8 %); P = 0.214]. Age-adjusted OS was higher in the low-dose CY group than the high- and reduced-dose CY groups with borderline significance (P = 0.067). These results suggest that CY dose can safely be reduced without increasing graft rejection by adding fludarabine in allogeneic HSCT for aplastic anemia from an HLA-identical sibling.

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

Correlation between measles vaccine doses: implications for the maintenance of elimination.

PubMed

McKee, A; Ferrari, M J; Shea, K

2018-03-01

Measles eradication efforts have been successful at achieving elimination in many countries worldwide. Such countries actively work to maintain this elimination by continuing to improve coverage of two routine doses of measles vaccine following measles elimination. While improving measles vaccine coverage is always beneficial, we show, using a steady-state analysis of a dynamical model, that the correlation between populations receiving the first and second routine dose also has a significant impact on the population immunity achieved by a specified combination of first and second dose coverage. If the second dose is administered to people independently of whether they had the first dose, high second-dose coverage improves the proportion of the population receiving at least one dose, and will have a large effect on population immunity. If the second dose is administered only to people who have had the first dose, high second-dose coverage reduces the rate of primary vaccine failure, but does not reach people who missed the first dose; this will therefore have a relatively small effect on population immunity. When doses are administered dependently, and assuming the first dose has higher coverage, increasing the coverage of the first dose has a larger impact on population immunity than does increasing the coverage of the second. Correlation between vaccine doses has a significant impact on the level of population immunity maintained by current vaccination coverage, potentially outweighing the effects of age structure and, in some cases, recent improvements in vaccine coverage. It is therefore important to understand the correlation between vaccine doses as such correlation may have a large impact on the effectiveness of measles vaccination strategies.

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.

Effect of gender on treatment outcomes in type 2 diabetes mellitus.

PubMed

McGill, J B; Vlajnic, A; Knutsen, P G; Recklein, C; Rimler, M; Fisher, S J

2013-12-01

To evaluate the effect of gender on clinical outcomes in people with type 2 diabetes mellitus (T2DM) receiving antidiabetes therapy. This is a pooled analysis from nine similarly designed phase 3 and 4 randomized, controlled studies evaluating insulin glargine and an active comparator (NPH insulin, insulin lispro, premixed insulin, oral antidiabetes drugs, dietary intervention) in adults with T2DM. Impact of gender on outcomes including HbA1c, fasting plasma glucose (FPG), weight-adjusted insulin dose, and hypoglycemia incidence was evaluated after 24 weeks of treatment. Overall, 1651 male and 1287 female individuals were included; 49.8% and 50.2% were treated with insulin glargine or comparators, respectively. Females receiving insulin glargine were less likely than males to achieve a glycemic target of HbA1c≤7.0% (53mmol/mol) (54.3% vs 60.8%, respectively, p=0.0162); there was no difference between females and males receiving comparators (52.7% vs 51.3%, respectively, p=0.4625). Females had significantly greater reductions in FPG (3.1mg/dL, p=0.0458), required significantly higher insulin doses (0.03IU/kg, p=0.0071), and had significantly higher annual rates of symptomatic (p<0.0001), glucose-confirmed (<50 and <70mg/dL) symptomatic (p=0.0005 and p<0.0001), and severe hypoglycemia (p=0.0020) than males. Females in this analysis had smaller reductions in HbA1c and were less likely to reach glycemic goals despite higher insulin doses and more hypoglycemic events than males. Differences in gender responses to therapy should be considered when individualizing treatment for people with T2DM. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

Polysaccharides from Cordyceps sinensis mycelium ameliorate exhaustive swimming exercise-induced oxidative stress.

PubMed

Yan, Feng; Wang, Beibei; Zhang, Yan

2014-02-01

Cordyceps sinensis (Berk.) Sacc. (Clavicipitaceae) is a famous medicinal fungus (mushroom) in Chinese herbal medicine. Polysaccharides from Cordyceps sinensis (CSP) have been identified as active ingredients responsible for its biological activities. Although many pharmacological actions of CSP have received a great deal of attention, research in this area continues. The current study was designed to investigate the effects of CSP on exhaustive exercise-induced oxidative stress. The mice were divided into four groups: control (C), low-dose CSP treated (LC), intermediate-dose CSP treated (IC) and high-dose CSP treated (HC). The treated groups received CSP (100, 200 and 400 mg/kg, ig), while the control group received drinking water for 28 days, followed by being forced to undergo exhaustive swimming exercise, and some biochemical parameters including superoxide dismutase (SOD), glutathione peroxidase (GPx), catalase (CAT), malondialdehyde (MDA) and 8-hydroxy-2'-deoxyguanosine (8-OHdG) were measured using detection kits according to the manufacturers' instructions. Compared with the C group, exhaustive swimming time was significantly prolonged in the LC, IC and HC groups (p < 0.05); SOD activities in serum, liver and muscle were significantly higher in the IC and HC groups (p < 0.05); GPx activities in serum, liver and muscle were significantly higher in the LC, IC and HC groups (p < 0.05); CAT activities in serum, liver and muscle were significantly higher in the HC groups (p < 0.05); MDA and 8-OHdG levels in serum, liver and muscle were significantly lower in the LC, IC and HC groups (p < 0.05). The results obtained herein indicate that CSP could ameliorate exhaustive exercise-induced oxidative stress.

Immune tolerance improves the efficacy of enzyme replacement therapy in canine mucopolysaccharidosis I

PubMed Central

Dickson, Patricia; Peinovich, Maryn; McEntee, Michael; Lester, Thomas; Le, Steven; Krieger, Aimee; Manuel, Hayden; Jabagat, Catherine; Passage, Merry; Kakkis, Emil D.

2008-01-01

Mucopolysaccharidoses (MPSs) are lysosomal storage diseases caused by a deficit in the enzymes needed for glycosaminoglycan (GAG) degradation. Enzyme replacement therapy with recombinant human α-l-iduronidase successfully reduces lysosomal storage in canines and humans with iduronidase-deficient MPS I, but therapy usually also induces antibodies specific for the recombinant enzyme that could reduce its efficacy. To understand the potential impact of α-l-iduronidase–specific antibodies, we studied whether inducing antigen-specific immune tolerance to iduronidase could improve the effectiveness of recombinant iduronidase treatment in canines. A total of 24 canines with MPS I were either tolerized to iduronidase or left nontolerant. All canines received i.v. recombinant iduronidase at the FDA-approved human dose or a higher dose for 9–44 weeks. Nontolerized canines developed iduronidase-specific antibodies that proportionally reduced in vitro iduronidase uptake. Immune-tolerized canines achieved increased tissue enzyme levels at either dose in most nonreticular tissues and a greater reduction in tissue GAG levels, lysosomal pathology, and urinary GAG excretion. Tolerized MPS I dogs treated with the higher dose received some further benefit in the reduction of GAGs in tissues, urine, and the heart valve. Therefore, immune tolerance to iduronidase improved the efficacy of enzyme replacement therapy with recombinant iduronidase in canine MPS I and could potentially improve outcomes in patients with MPS I and other lysosomal storage diseases. PMID:18654665

G-CSF plus preemptive plerixafor vs hyperfractionated CY plus G-CSF for autologous stem cell mobilization in multiple myeloma: effectiveness, safety and cost analysis.

PubMed

Antar, A; Otrock, Z K; Kharfan-Dabaja, M A; Ghaddara, H A; Kreidieh, N; Mahfouz, R; Bazarbachi, A

2015-06-01

The optimal stem cell mobilization regimen for patients with multiple myeloma (MM) remains undefined. We retrospectively compared our experience in hematopoietic cell mobilization in 83 MM patients using fractionated high-dose CY and G-CSF with G-CSF plus preemptive plerixafor. All patients in the CY group (n=56) received fractionated high-dose CY (5 g/m(2) divided into five doses of 1 g/m(2) every 3 h) with G-CSF. All patients in the plerixafor group (n=27) received G-CSF and plerixafor preemptively based on an established algorithm. Compared with plerixafor, CY use was associated with higher total CD34+ cell yield (7.5 × 10(6) vs 15.5 × 10(6) cells/kg, P=0.005). All patients in both groups yielded ⩾4 × 10(6) CD34+ cells/kg. Conversely, CY use was associated with high frequency of febrile neutropenia, blood and platelet transfusions need and hospitalizations. The average total cost of mobilization in Lebanon was slightly higher in the plerixafor group ($7886 vs $7536; P=0.16). Our data indicate robust stem cell mobilization in MM patients with either fractionated high-dose CY and G-CSF or G-CSF alone with preemptive plerixafor. The chemo-mobilization approach was associated with twofold stem cell yield, slightly lower cost but significantly increased toxicity.

Single-Dose and Multiple-Dose Pharmacokinetics of Nicotine 6 mg Gum.

PubMed

Hansson, Anna; Rasmussen, Thomas; Kraiczi, Holger

2017-04-01

Under-dosing is a recognized problem with current nicotine replacement therapy (NRT). Therefore, a new 6mg nicotine gum has been developed. To compare the nicotine uptake from the 6mg gum versus currently available NRT products, two pharmacokinetic studies were performed. In one randomized crossover study, 44 healthy adult smokers received single doses of 6, 4, and 2mg nicotine gum, and 4mg nicotine lozenge on separate occasions. In a separate randomized crossover multiple-dose study over 11 hours, 50 healthy adult smokers received one 6mg gum every hour and 90 minutes, respectively, one 4mg gum every hour, and one 4mg lozenge every hour. In both studies, blood samples were collected over 12 hours to determine single-dose and multiple-dose pharmacokinetic variables. In the single-dose study, the amount of nicotine released from the 2, 4, and 6mg gums (1.44, 3.36, and 4.94mg) as well as the resulting maximum concentration and area under the curve (5.9, 10.1, and 13.8ng/mL, and 17.1, 30.7, 46.2ng/mL × h, respectively) increased with dose. The maximum concentration and area under the curve of the 6mg gum were 44% and 30% greater, respectively, than those for 4mg lozenge. Upon hourly administration, the steady-state average plasma nicotine concentration with 6mg gum (37.4ng/mL) was significantly higher than those for 4mg lozenge (28.3ng/mL) and 4mg gum (27.1ng/mL). Nicotine delivery via the 6mg gum results in higher plasma nicotine concentrations after a single dose and at steady state than with currently available oral NRT. Under-dosing is a recognized problem with current NRT. Therefore, a new 6mg nicotine gum has been developed. Our studies show that upon single-dose and multiple-dose administration, the 6mg gum releases and delivers more nicotine to the systemic circulation than 2mg gum, 4mg gum, and 4mg lozenge. Thus, each 6mg nicotine gum provides a higher degree of nicotine substitution and/or lasts for a longer period of time than currently available nicotine gums and lozenges. © The Author 2016. Published by Oxford University Press on behalf of the Society for Research on Nicotine and Tobacco. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Peripheral photon and neutron doses from prostate cancer external beam irradiation.

PubMed

Bezak, Eva; Takam, Rundgham; Marcu, Loredana G

2015-12-01

Peripheral photon and neutron doses from external beam radiotherapy (EBRT) are associated with increased risk of carcinogenesis in the out-of-field organs; thus, dose estimations of secondary radiation are imperative. Peripheral photon and neutron doses from EBRT of prostate carcinoma were measured in Rando phantom. (6)LiF:Mg,Cu,P and (7)LiF:Mg,Cu,P glass-rod thermoluminescence dosemeters (TLDs) were inserted in slices of a Rando phantom followed by exposure to 80 Gy with 18-MV photon four-field 3D-CRT technique. The TLDs were calibrated using 6- and 18-MV X-ray beam. Neutron dose equivalents measured with CR-39 etch-track detectors were used to derive readout-to-neutron dose conversion factor for (6)LiF:Mg,Cu,P TLDs. Average neutron dose equivalents per 1 Gy of isocentre dose were 3.8±0.9 mSv Gy(-1) for thyroid and 7.0±5.4 mSv Gy(-1) for colon. For photons, the average dose equivalents per 1 Gy of isocentre dose were 0.2±0.1 mSv Gy(-1) for thyroid and 8.1±9.7 mSv Gy(-1) for colon. Paired (6)LiF:Mg,Cu,P and (7)LiF:Mg,Cu,P TLDs can be used to measure photon and neutron doses simultaneously. Organs in close proximity to target received larger doses from photons than those from neutrons whereas distally located organs received higher neutron versus photon dose. © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Ultra-low dose of intravitreal bevacizumab in retinopathy of prematurity.

PubMed

Şahin, A; Gürsel-Özkurt, Z; Şahin, M; Türkcü, F M; Yıldırım, A; Yüksel, H

2018-05-01

We aimed to investigate the effectivity of the 0.0625 mg dose of bevacizumab in patients with retinopathy of prematurity (ROP) and compare the results with 0.625 mg dose of intravitreal bevacizumab (IVB) injection. The medical records of the patients with type 1 ROP who received IVB monotherapy were retrospectively reviewed. Demographic and clinical characteristics of the patients were recorded. The patients were classified into two groups with respect to received dose of bevacizumab as follows: group F (n = 46) (full dose of bevacizumab-0.625 mg/0.025 ml) and group L (n = 45) (low dose (one tenth) of bevacizumab-0.0625 mg/0.025 ml). Both treatment dose regimens have similar outcomes. Moreover, the mean retinal vascularization time seemed to be significantly higher in group F compared to group L, 168 ± 65 and 97 ± 29 days, respectively (p < 0.001). Disappearance of plus sign is observed earlier in group F (2.45 ± 1.7 vs 3.66 ± 2.46 days, respectively, p = 0.03). The low dose (0.0625 mg) of IVB treatment was effective as full (0.625 mg) dose in ROP treatment. Moreover, our results showed that low-dose treatment might provide faster retinal vascularization than the regular used dose. On the other hand, disappearance of the plus sign takes longer time in patients treated with low dose compared to eyes treated with full dose of IVB that should be taken into account.

Sirolimus and tacrolimus trough concentrations and dose requirements after kidney transplantation in relation to CYP3A5 and MDR1 polymorphisms and steroids.

PubMed

Mourad, Michel; Mourad, Georges; Wallemacq, Pierre; Garrigue, Valérie; Van Bellingen, Christophe; Van Kerckhove, Valérie; De Meyer, Martine; Malaise, Jacques; Eddour, Djamila Chaib; Lison, Dominique; Squifflet, Jean Paul; Haufroid, Vincent

2005-10-15

CYP3A5 and MDR1 polymorphisms have been shown to influence tacrolimus blood concentrations and dose requirements. The aim is to determine whether these polymorphisms also affect sirolimus trough concentrations and dose requirements after kidney transplantation. Eighty-five renal transplant recipients receiving sirolimus were included. Twenty-four were treated with a combined sirolimus-tacrolimus regimen. Eighty-one patients received steroids. Sirolimus and tacrolimus were adjusted to a target therapeutic window. CYP3A5 (intron 3) and MDR1 (exons 12, 21, 26) genotypes were correlated to the adjusted trough concentrations and dose requirements for both sirolimus and tacrolimus. There were no significant correlation between adjusted sirolimus trough concentrations or dose requirements and genetic polymorphisms. In a multiple regression model, adjusted-prednisone dose was involved with a positive or negative effect when considering sirolimus dose requirements or adjusted concentrations, respectively. In the subgroup of patients treated by tacrolimus and sirolimus, adjusted tacrolimus doses were higher in patients carrying at least one CYP3A5 *1 allele (median 0.083 vs. 0.035 mg/kg for CYP3A5*3/*3 patients, P<0.05). Adjusted-prednisolone dose and CYP3A5 polymorphism explained up to 61% of the variability in tacrolimus dose requirements. Unlike tacrolimus, sirolimus adjusted trough concentrations and dose requirements seem not affected by CYP3A5 and MDR1 polymorphisms. Adjusted-prednisone dose has a significant impact on tacrolimus and sirolimus dose requirements.

Do Asian renal transplant patients need another mycophenolate mofetil dose compared with Caucasian or African American patients?

PubMed

Li, Pengmei; Shuker, Nauras; Hesselink, Dennis A; van Schaik, Ron H N; Zhang, Xianglin; van Gelder, Teun

2014-10-01

Mycophenolate mofetil (MMF) is used to prevent acute rejection following solid organ transplantation in transplant centers all over the world. Patients from different ethnic backgrounds are treated with this drug, for which therapeutic drug monitoring (TDM) has not become the standard of practice in most centers. Whether or not some ethnic groups require a different MMF dose has been a topic of debate in recent years. In this review, it is shown that Asian patients, compared with Caucasian patients, with a comparable MMF dose reach higher mycophenolic acid (MPA) exposure. Also clinical experience points toward more adverse events in case of treatment with 1 g MMF bid in Asian patients, and therefore, for this ethnic group, a lower maintenance dose seems justified. In contrast, African American patients reach similar drug concentrations as Caucasians patients receiving the same MMF dose, but due to immunological reasons, they require a higher MMF dose to reach comparable acute rejection incidences. When TDM is performed, clinicians can correct the dose and compensate for interethnic differences in drug exposure. Otherwise, it is important to choose the right dose. This optimal dose is 20-46% lower in Asian transplant recipients than in Caucasian or African American patients. © 2014 Steunstichting ESOT.

Comparison of Risperidone and Olanzapine in Bipolar and Schizoaffective Disorders

PubMed Central

Masand, Prakash S.; Wang, Xiaohong; Gupta, Sanjay; Schwartz, Thomas L.; Virk, Subhdeep; Hameed, Ahmad

2002-01-01

Objective: To compare risperidone and olanzapine for efficacy, tolerability, need for concomitant mood stabilizers, and cost of treatment in bipolar and schizoaffective disorders. Method: We conducted a retrospective chart review of 36 consecutive outpatients with DSM-IV bipolar or schizoaffective disorder seen in 3 settings who received risperidone or olanzapine for at least 1 month between May and August 1997. Results: The mean ± SD doses were 3.7 ± 3.5 mg/day of risperidone and 12.0 ± 5.4 mg/day of olanzapine. Between-treatment differences in patient characteristics, psychiatric history, Clinical Global Impressions scale ratings, and duration of treatment were not significant. Similar proportions of patients in the 2 groups reported side effects, including extrapyramidal symptoms, akathisia, tardive dyskinesia, and precipitation of mania by the respective drug. Patients in the olanzapine group received a significantly higher dose of concomitant lithium than those receiving risperidone (mean daily lithium doses: risperidone group, 750 ± 150 mg; olanzapine group, 1211 ± 186 mg; p = .006). The total daily acquisition cost per patient was $11.84 for olanzapine versus $5.81 for risperidone. Conclusion: Olanzapine and risperidone were equally efficacious and safe in the treatment of patients with bipolar or schizoaffective disorder, but treatment costs and dose of concomitant lithium were lower in risperidone-treated patients. PMID:15014747

Implant breast reconstruction followed by radiotherapy: Can helical tomotherapy become a standard irradiation treatment?

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

Massabeau, Carole, E-mail: cmassabeau@hotmail.com; Fournier-Bidoz, Nathalie; Wakil, Georges

2012-01-01

To evaluate the benefits and limitations of helical tomotherapy (HT) for loco-regional irradiation of patients after a mastectomy and immediate implant-based reconstruction. Ten breast cancer patients with retropectoral implants were randomly selected for this comparative study. Planning target volumes (PTVs) 1 (the volume between the skin and the implant, plus margin) and 2 (supraclavicular, infraclavicular, and internal mammary nodes, plus margin) were 50 Gy in 25 fractions using a standard technique and HT. The extracted dosimetric data were compared using a 2-tailed Wilcoxon matched-pair signed-rank test. Doses for PTV1 and PTV2 were significantly higher with HT (V95 of 98.91 andmore » 97.91%, respectively) compared with the standard technique (77.46 and 72.91%, respectively). Similarly, the indexes of homogeneity were significantly greater with HT (p = 0.002). HT reduced ipsilateral lung volume that received {>=}20 Gy (16.7 vs. 35%), and bilateral lungs (p = 0.01) and neighboring organs received doses that remained well below tolerance levels. The heart volume, which received 25 Gy, was negligible with both techniques. HT can achieve full target coverage while decreasing high doses to the heart and ipsilateral lung. However, the low doses to normal tissue volumes need to be reduced in future studies.« less

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

PubMed

Fredericks, Trinity; Kwan, Kellie; Mak, Donna

2010-10-01

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

[Oral loading dose of phenytoin in the treatment of serial seizures, prevention of seizure recurrence and rapid drug substitution].

PubMed

Sokić, D; Janković, S M

1994-01-01

Over a period of nine months twenty-five epileptic patients were treated with the oral loading dose of phenytoin. The dose ranged from 12 to 23 mg/kg body weight during 1 to 12 hours. In 20 patients with serial seizures or intolerance to other antiepileptic drugs this treatment was effective. Seizures also stopped in 2 of 4 patients with serial partial motor seizures. These 2 patients required both higher loading dose and faster rate of administration than the other patients. A patient with epilepsia partialis continua failed to respond to the treatment. Patients that received phenytoin through the naso-gastric tube, in respect to oral administration, required higher doses to obtain therapeutic plasma levels of phenytoin. One patient had mild nausea, 3 mild dizziness, and 1 tinitus on the first day of the treatment. There was no correlation between a given dose and the achieved phenytoin plasma levels. In our opinion the therapy with oral loading dose of phenytoin is highly effective in the treatment of serial generalized seizures and rapid antiepileptic drug substitution, and partially effective in the prevention of partial motor seizures. It produces only mild and transient side-effects.

Factors associated with higher oxytocin requirements in labor.

PubMed

Frey, Heather A; Tuuli, Methodius G; England, Sarah K; Roehl, Kimberly A; Odibo, Anthony O; Macones, George A; Cahill, Alison G

2015-09-01

To identify clinical characteristics associated with high maximum oxytocin doses in women who achieve complete cervical dilation. A retrospective nested case-control study was performed within a cohort of all term women at a single center between 2004 and 2008 who reached the second stage of labor. Cases were defined as women who had a maximum oxytocin dose during labor >20 mu/min, while women in the control group had a maximum oxytocin dose during labor of ≤20 mu/min. Exclusion criteria included no oxytocin administration during labor, multiple gestations, major fetal anomalies, nonvertex presentation, and prior cesarean delivery. Multiple maternal, fetal, and labor factors were evaluated with univariable analysis and multivariable logistic regression. Maximum oxytocin doses >20 mu/min were administered to 108 women (3.6%), while 2864 women received doses ≤20 mu/min. Factors associated with higher maximum oxytocin dose after adjusting for relevant confounders included maternal diabetes, birthweight >4000 g, intrapartum fever, administration of magnesium, and induction of labor. Few women who achieve complete cervical dilation require high doses of oxytocin. We identified maternal, fetal and labor factors that characterize this group of parturients.

Febrile events including convulsions following the administration of four brands of 2010 and 2011 inactivated seasonal influenza vaccine in NZ infants and children: the importance of routine active safety surveillance.

PubMed

Petousis-Harris, Helen; Poole, Tracey; Turner, Nikki; Reynolds, Gary

2012-07-13

To evaluate and compare rates of febrile events, including febrile convulsion, following immunisation with four brands of inactivated 2010 and 2011 influenza vaccine in NZ infants and children. Retrospective telephone surveys of parents of infants and children who received at least one dose of the vaccines of interest. 184 NZ General Practices who received the vaccines of interest. Recipients of 4088 doses of trivalent inactivated vaccines Fluvax(®), Vaxigrip(®), Influvac(®) and Fluarix(®) and/or monovalent Celvapan. Vaccinees were identified via the electronic Practice Management System and contacted consecutively. Primary outcome was febrile convulsive seizure. Secondary outcomes were presence of fever plus other organ system specific symptoms. The parental response rate was 99%. Of 4088 doses given, 865 were Fluvax(®), 2571 Vaxigrip(®), 204 Influvac(®), 438 Fluarix(®) and 10 Celvapan. Three febrile convulsions followed Fluvax(®), a rate of 35 per 10,000 doses. No convulsions occurred following any dose of the other vaccines. There were nine febrile events that included rigors, all following Fluvax(®). Fever occurred significantly more frequently following administration of Fluvax(®) compared with the other brands of vaccines (p<0.0001) and Fluvax recipients were more likely to seek medical attention. Influvac(®) also had higher rates of febrile reactions (OR 0.54, 0.36-0.81) than the other two brands Vaxigrip(®) (OR 0.21, 0.16-0.27) and Fluarix(®) (OR 0.10, 0.05-0.20). After multivariable analysis vaccine, European ethnicity and second dose of vaccine were significantly associated with reporting of fever within 24h of vaccination. Influenza vaccines have different rates of reactogenicity in children which varies between ethnic groups. High rates of febrile convulsions and reactions in children receiving Fluvax(®) and to a lesser extent the higher fever rates in those receiving Influvac(®) compared with the other two brands of influenza vaccines in this study suggests that reactogenicity profiles need to be considered prior to national policy advice each season. The risk-benefit profile in children might not be equally favourable for all licensed paediatric influenza vaccines. More attention needs to be given to comparative research for all trivalent seasonal vaccines, and with all strain changes. Copyright © 2012 Elsevier Ltd. All rights reserved.

Advanced proton beam dosimetry part II: Monte Carlo vs. pencil beam-based planning for lung cancer.

PubMed

Maes, Dominic; Saini, Jatinder; Zeng, Jing; Rengan, Ramesh; Wong, Tony; Bowen, Stephen R

2018-04-01

Proton pencil beam (PB) dose calculation algorithms have limited accuracy within heterogeneous tissues of lung cancer patients, which may be addressed by modern commercial Monte Carlo (MC) algorithms. We investigated clinical pencil beam scanning (PBS) dose differences between PB and MC-based treatment planning for lung cancer patients. With IRB approval, a comparative dosimetric analysis between RayStation MC and PB dose engines was performed on ten patient plans. PBS gantry plans were generated using single-field optimization technique to maintain target coverage under range and setup uncertainties. Dose differences between PB-optimized (PBopt), MC-recalculated (MCrecalc), and MC-optimized (MCopt) plans were recorded for the following region-of-interest metrics: clinical target volume (CTV) V95, CTV homogeneity index (HI), total lung V20, total lung V RX (relative lung volume receiving prescribed dose or higher), and global maximum dose. The impact of PB-based and MC-based planning on robustness to systematic perturbation of range (±3% density) and setup (±3 mm isotropic) was assessed. Pairwise differences in dose parameters were evaluated through non-parametric Friedman and Wilcoxon sign-rank testing. In this ten-patient sample, CTV V95 decreased significantly from 99-100% for PBopt to 77-94% for MCrecalc and recovered to 99-100% for MCopt (P<10 -5 ). The median CTV HI (D95/D5) decreased from 0.98 for PBopt to 0.91 for MCrecalc and increased to 0.95 for MCopt (P<10 -3 ). CTV D95 robustness to range and setup errors improved under MCopt (ΔD95 =-1%) compared to MCrecalc (ΔD95 =-6%, P=0.006). No changes in lung dosimetry were observed for large volumes receiving low to intermediate doses (e.g., V20), while differences between PB-based and MC-based planning were noted for small volumes receiving high doses (e.g., V RX ). Global maximum patient dose increased from 106% for PBopt to 109% for MCrecalc and 112% for MCopt (P<10 -3 ). MC dosimetry revealed a reduction in target dose coverage under PB-based planning that was regained under MC-based planning along with improved plan robustness. MC-based optimization and dose calculation should be integrated into clinical planning workflows of lung cancer patients receiving actively scanned proton therapy.

Advanced proton beam dosimetry part II: Monte Carlo vs. pencil beam-based planning for lung cancer

PubMed Central

Maes, Dominic; Saini, Jatinder; Zeng, Jing; Rengan, Ramesh; Wong, Tony

2018-01-01

Background Proton pencil beam (PB) dose calculation algorithms have limited accuracy within heterogeneous tissues of lung cancer patients, which may be addressed by modern commercial Monte Carlo (MC) algorithms. We investigated clinical pencil beam scanning (PBS) dose differences between PB and MC-based treatment planning for lung cancer patients. Methods With IRB approval, a comparative dosimetric analysis between RayStation MC and PB dose engines was performed on ten patient plans. PBS gantry plans were generated using single-field optimization technique to maintain target coverage under range and setup uncertainties. Dose differences between PB-optimized (PBopt), MC-recalculated (MCrecalc), and MC-optimized (MCopt) plans were recorded for the following region-of-interest metrics: clinical target volume (CTV) V95, CTV homogeneity index (HI), total lung V20, total lung VRX (relative lung volume receiving prescribed dose or higher), and global maximum dose. The impact of PB-based and MC-based planning on robustness to systematic perturbation of range (±3% density) and setup (±3 mm isotropic) was assessed. Pairwise differences in dose parameters were evaluated through non-parametric Friedman and Wilcoxon sign-rank testing. Results In this ten-patient sample, CTV V95 decreased significantly from 99–100% for PBopt to 77–94% for MCrecalc and recovered to 99–100% for MCopt (P<10−5). The median CTV HI (D95/D5) decreased from 0.98 for PBopt to 0.91 for MCrecalc and increased to 0.95 for MCopt (P<10−3). CTV D95 robustness to range and setup errors improved under MCopt (ΔD95 =−1%) compared to MCrecalc (ΔD95 =−6%, P=0.006). No changes in lung dosimetry were observed for large volumes receiving low to intermediate doses (e.g., V20), while differences between PB-based and MC-based planning were noted for small volumes receiving high doses (e.g., VRX). Global maximum patient dose increased from 106% for PBopt to 109% for MCrecalc and 112% for MCopt (P<10−3). Conclusions MC dosimetry revealed a reduction in target dose coverage under PB-based planning that was regained under MC-based planning along with improved plan robustness. MC-based optimization and dose calculation should be integrated into clinical planning workflows of lung cancer patients receiving actively scanned proton therapy. PMID:29876310

Effect of extended-release dexmethylphenidate and mixed amphetamine salts on sleep: a double-blind, randomized, crossover study in youth with attention-deficit hyperactivity disorder.

PubMed

Santisteban, J A; Stein, M A; Bergmame, L; Gruber, R

2014-09-01

We sought to determine the dose-response effects of extended-release (ER) dexmethylphenidate (d-MPH) and ER mixed amphetamine salts (MAS) on objective measures of sleep. This was an 8-week, double-blind, placebo-controlled, randomized, two period, crossover study of youth with attention-deficit hyperactivity disorder (ADHD) as confirmed by the Kiddie Schedule for Affective Disorders for School-Age Children-Present and Lifetime version (K-SADS-PL). Children aged 10-17 years were recruited from clinical practice, colleague referrals, and flyers. Participants were randomized to initially receive either d-MPH or MAS. During each 4-week drug period, children received three dose levels (10, 20, and 25/30 mg) in ascending order, with placebo substituted for active medication in a randomized fashion during 1 week of the study. After 4 weeks, participants were switched to the alternative medication for another 4 weeks of treatment. The main outcome measure was sleep duration as measured by actigraphy. Children, parents, and researchers were blinded to drug, dose, and placebo status. Sixty-five participants met the inclusion criteria and were enrolled in the study. Of these, 37 participants with sufficient sleep data for analysis were included. Sleep schedule measures showed a significant effect for dose on sleep start time (F(1,36) = 6.284; p < 0.05), with a significantly later sleep start time when children were receiving 20- or 30-mg doses, compared with placebo (p < 0.05). A significant dose effect was found on actual sleep duration (F(1,36) = 8.112; p < 0.05), with significantly shorter actual sleep duration for subjects receiving 30 mg compared with those receiving placebo (p < 0.05). There were no significant differences on sleep duration or sleep schedule between the two stimulant medications. The trial is complete and closed to follow-up. Higher stimulant doses were associated with reduced sleep duration and later sleep start times, regardless of medication class. ClinicalTrials.gov: NCT00393042.

Spinal Cord Tolerance to Reirradiation With Single-Fraction Radiosurgery: A Swine Model

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

Medin, Paul M., E-mail: Paul.medin@utsouthwestern.edu; Foster, Ryan D.; Kogel, Albert J. van der

2012-07-01

Purpose: This study was performed to determine swine spinal cord tolerance to single-fraction, partial-volume irradiation 1 year after receiving uniform irradiation to 30 Gy in 10 fractions. Methods and Materials: A 10-cm length of spinal cord (C3-T1) was uniformly irradiated to 30 Gy in 10 consecutive fractions and reirradiated 1 year later with a single radiosurgery dose centered within the previously irradiated segment. Radiosurgery was delivered to a cylindrical volume approximately 5 cm in length and 2 cm in diameter, which was positioned laterally to the cervical spinal cord, resulting in a dose distribution with the 90%, 50%, and 10%more » isodose lines traversing the ipsilateral, central, and contralateral spinal cord, respectively. Twenty-three pigs were stratified into six dose groups with mean maximum spinal cord doses of 14.9 {+-} 0.1 Gy (n = 2), 17.1 {+-} 0.3 Gy (n = 3), 19.0 {+-} 0.1 Gy (n = 5), 21.2 {+-} 0.1 Gy (n = 5), 23.4 {+-} 0.2 Gy (n = 5), and 25.4 {+-} 0.4 Gy (n = 3). The mean percentage of spinal cord volumes receiving {>=}10 Gy for the same groups were 34% {+-} 1%, 40% {+-} 1%, 46% {+-} 3%, 52% {+-} 1%, 56 {+-} 3%, and 57% {+-} 1%. The study endpoint was motor neurologic deficit as determined by a change in gait during a 1- year follow-up period. Results: A steep dose-response curve was observed with a 50% incidence of paralysis (ED{sub 50}) for the maximum point dose of 19.7 Gy (95% confidence interval, 17.4-21.4). With two exceptions, histology was unremarkable in animals with normal neurologic status, while all animals with motor deficits showed some degree of demyelination and focal white matter necrosis on the irradiated side, with relative sparing of gray matter. Histologic comparison with a companion study of de novo irradiated animals revealed that retreatment responders had more extensive tissue damage, including infarction of gray matter, only at prescription doses >20 Gy. Conclusion: Pigs receiving spinal radiosurgery 1 year after receiving 30 Gy in 10 fractions were not at significantly higher risk of developing motor deficits than pigs that received radiosurgery alone.« less

Outcomes Associated with Reducing the Urine Alkalinization Threshold in Patients Receiving High-Dose Methotrexate.

PubMed

Drost, Sarah A; Wentzell, Jason R; Giguère, Pierre; McLurg, Darcy L; Sabloff, Mitchell; Kanji, Salmaan; Nguyen, Tiffany T

2017-06-01

Urine alkalinization increases methotrexate (MTX) solubility and reduces the risk of nephrotoxicity. The objectives of this study were to determine whether a reduction in the urine pH threshold from 8 to 7 in patients receiving high-dose methotrexate (HDMTX) results in a shorter length of hospital stay, delayed MTX clearance, or higher rates of nephrotoxicity; and to determine whether specific factors were associated with prolonged MTX clearance. Retrospective cohort study. Hematology service of a large university-affiliated teaching hospital in Ottawa, Canada. Sixty-five adults with 150 HDMTX exposures who had elective admissions for HDMTX between September 1, 2014, and December 18, 2015, were included. Thirty-four patients (with 79 HDMTX exposures) had their urine alkalinized to a pH of 8 or higher, and 31 patients (with 71 HDMTX exposures) had their urine alkalinized to a pH of 7 or higher, after an institutional change in the urine pH threshold from 8 to 7 was implemented on May 1, 2015. Data related to patient demographics, urine alkalinization, MTX serum concentration monitoring, hospital length of stay, and renal function were collected retrospectively from patients' electronic health records. Lowering the urine pH threshold from 8 to 7 did not significantly affect hospital length of stay (absolute difference 3.5 hrs, 95% confidence interval -4.0 to 10.9) or clearance of MTX (elimination rate constant 0.058 in the pH of 7 or higher group vs 0.064 in the pH of 8 or higher group, p=0.233). Nephrotoxicity rates were similar between groups (15.5% in the pH of 7 or higher group vs 10.1% in the pH of 8 or higher group, p=0.34). Higher MTX dose and interacting medications (e.g., proton pump inhibitors and sulfonamide antibiotics) were significantly associated with delayed MTX elimination. No significant differences in HDMTX-associated hospital length of stay, MTX clearance, or rates of nephrotoxicity were noted between patients in the urine pH of 7 or higher and 8 or higher groups. Interacting medications and higher MTX dose were associated with delayed MTX elimination, suggesting that a closer review of interacting medications before HDMTX administration may be warranted. © 2017 Pharmacotherapy Publications, Inc.

SU-F-T-444: Quality Improvement Review of Radiation Therapy Treatment Planning in the Presence of Dental Implants

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

Parenica, H; Ford, J; Mavroidis, P

Purpose: To quantify and compare the effect of metallic dental implants (MDI) on dose distributions calculated using Collapsed Cone Convolution Superposition (CCCS) algorithm or a Monte Carlo algorithm (with and without correcting for the density of the MDI). Methods: Seven previously treated patients to the head and neck region were included in this study. The MDI and the streaking artifacts on the CT images were carefully contoured. For each patient a plan was optimized and calculated using the Pinnacle3 treatment planning system (TPS). For each patient two dose calculations were performed, a) with the densities of the MDI and CTmore » artifacts overridden (12 g/cc and 1 g/cc respectively) and b) without density overrides. The plans were then exported to the Monaco TPS and recalculated using Monte Carlo dose calculation algorithm. The changes in dose to PTVs and surrounding Regions of Interest (ROIs) were examined between all plans. Results: The Monte Carlo dose calculation indicated that PTVs received 6% lower dose than the CCCS algorithm predicted. In some cases, the Monte Carlo algorithm indicated that surrounding ROIs received higher dose (up to a factor of 2). Conclusion: Not properly accounting for dental implants can impact both the high dose regions (PTV) and the low dose regions (OAR). This study implies that if MDI and the artifacts are not appropriately contoured and given the correct density, there is potential significant impact on PTV coverage and OAR maximum doses.« less

Effects of Hydrocortisone on the Regulation of Blood Pressure: Results From a Randomized Controlled Trial.

PubMed

Werumeus Buning, Jorien; van Faassen, Martijn; Brummelman, Pauline; Dullaart, Robin P F; van den Berg, Gerrit; van der Klauw, Melanie M; Kerstens, Michiel N; Stegeman, Coen A; Muller Kobold, Anneke C; Kema, Ido P; Wolffenbuttel, Bruce H R; van Beek, André P

2016-10-01

Cardiovascular risk is increased in patients with secondary adrenal insufficiency, which may be ascribed to an unfavorable metabolic profile consequent to a relatively high hydrocortisone replacement dose. We determined the effects of a higher versus a lower glucocorticoid replacement dose on blood pressure (BP), the renin-angiotensin-aldosterone system, 11β-hydroxysteroid dehydrogenase enzyme activity and circulating (nor)metanephrines. Forty-seven patients with secondary adrenal insufficiency from the University Medical Center Groningen participated in this randomized double-blind crossover study. Patients randomly received 0.2-0.3 mg hydrocortisone/kg body weight followed by 0.4-0.6 mg hydrocortisone/kg body weight, or vice versa, each during 10 weeks. BP and regulating hormones were measured. The higher hydrocortisone dose resulted in an increase in systolic BP of 5 (12) mm Hg (P = .011), diastolic BP of 2 (9) mm Hg (P = .050), and a median [interquartile range] drop in plasma potassium of -0.1 [-0.3; 0.1] nmol/liter (P = .048). The higher hydrocortisone dose led to decreases in serum aldosterone of -28 [-101; 9] pmol/liter (P = .020) and plasma renin of -1.3 [-4.5; 1.2 ] pg/mL (P = .051), and increased the ratio of plasma and urinary cortisol to cortisone (including their metabolites) (P < .001 for all). Furthermore, on the higher dose, plasma and urinary normetanephrine decreased by -0.101 [-0.242; 0.029] nmol/liter (P < .001) and -1.48 [-4.06; 0.29] μmol/mol creatinine (P < .001) respectively. A higher dose of hydrocortisone increased systolic and diastolic BP and was accompanied by changes in the renin-angiotensin-aldosterone system, 11β-hydroxysteroid dehydrogenase enzyme activity, and circulating normetanephrine. This demonstrates that hydrocortisone dose even within the physiological range affects several pathways involved in BP regulation.

Maximizing the biological effect of proton dose delivered with scanned beams via inhomogeneous daily dose distributions

PubMed Central

Zeng, Chuan; Giantsoudi, Drosoula; Grassberger, Clemens; Goldberg, Saveli; Niemierko, Andrzej; Paganetti, Harald; Efstathiou, Jason A.; Trofimov, Alexei

2013-01-01

Purpose: Biological effect of radiation can be enhanced with hypofractionation, localized dose escalation, and, in particle therapy, with optimized distribution of linear energy transfer (LET). The authors describe a method to construct inhomogeneous fractional dose (IFD) distributions, and evaluate the potential gain in the therapeutic effect from their delivery in proton therapy delivered by pencil beam scanning. Methods: For 13 cases of prostate cancer, the authors considered hypofractionated courses of 60 Gy delivered in 20 fractions. (All doses denoted in Gy include the proton's mean relative biological effectiveness (RBE) of 1.1.) Two types of plans were optimized using two opposed lateral beams to deliver a uniform dose of 3 Gy per fraction to the target by scanning: (1) in conventional full-target plans (FTP), each beam irradiated the entire gland, (2) in split-target plans (STP), beams irradiated only the respective proximal hemispheres (prostate split sagittally). Inverse planning yielded intensity maps, in which discrete position control points of the scanned beam (spots) were assigned optimized intensity values. FTP plans preferentially required a higher intensity of spots in the distal part of the target, while STP, by design, employed proximal spots. To evaluate the utility of IFD delivery, IFD plans were generated by rearranging the spot intensities from FTP or STP intensity maps, separately as well as combined using a variety of mixing weights. IFD courses were designed so that, in alternating fractions, one of the hemispheres of the prostate would receive a dose boost and the other receive a lower dose, while the total physical dose from the IFD course was roughly uniform across the prostate. IFD plans were normalized so that the equivalent uniform dose (EUD) of rectum and bladder did not increase, compared to the baseline FTP plan, which irradiated the prostate uniformly in every fraction. An EUD-based model was then applied to estimate tumor control probability (TCP) and normal tissue complication probability (NTCP). To assess potential local RBE variations, LET distributions were calculated with Monte Carlo, and compared for different plans. The results were assessed in terms of their sensitivity to uncertainties in model parameters and delivery. Results: IFD courses included equal number of fractions boosting either hemisphere, thus, the combined physical dose was close to uniform throughout the prostate. However, for the entire course, the prostate EUD in IFD was higher than in conventional FTP by up to 14%, corresponding to the estimated increase in TCP to 96% from 88%. The extent of gain depended on the mixing factor, i.e., relative weights used to combine FTP and STP spot weights. Increased weighting of STP typically yielded a higher target EUD, but also led to increased sensitivity of dose to variations in the proton's range. Rectal and bladder EUD were same or lower (per normalization), and the NTCP for both remained below 1%. The LET distributions in IFD also depended strongly on the mixing weights: plans using higher weight of STP spots yielded higher LET, indicating a potentially higher local RBE. Conclusions: In proton therapy delivered by pencil beam scanning, improved therapeutic outcome can potentially be expected with delivery of IFD distributions, while administering the prescribed quasi-uniform dose to the target over the entire course. The biological effectiveness of IFD may be further enhanced by optimizing the LET distributions. IFD distributions are characterized by a dose gradient located in proximity of the prostate's midplane, thus, the fidelity of delivery would depend crucially on the precision with which the proton range could be controlled. PMID:23635256

Maximizing the biological effect of proton dose delivered with scanned beams via inhomogeneous daily dose distributions.

PubMed

Zeng, Chuan; Giantsoudi, Drosoula; Grassberger, Clemens; Goldberg, Saveli; Niemierko, Andrzej; Paganetti, Harald; Efstathiou, Jason A; Trofimov, Alexei

2013-05-01

Biological effect of radiation can be enhanced with hypofractionation, localized dose escalation, and, in particle therapy, with optimized distribution of linear energy transfer (LET). The authors describe a method to construct inhomogeneous fractional dose (IFD) distributions, and evaluate the potential gain in the therapeutic effect from their delivery in proton therapy delivered by pencil beam scanning. For 13 cases of prostate cancer, the authors considered hypofractionated courses of 60 Gy delivered in 20 fractions. (All doses denoted in Gy include the proton's mean relative biological effectiveness (RBE) of 1.1.) Two types of plans were optimized using two opposed lateral beams to deliver a uniform dose of 3 Gy per fraction to the target by scanning: (1) in conventional full-target plans (FTP), each beam irradiated the entire gland, (2) in split-target plans (STP), beams irradiated only the respective proximal hemispheres (prostate split sagittally). Inverse planning yielded intensity maps, in which discrete position control points of the scanned beam (spots) were assigned optimized intensity values. FTP plans preferentially required a higher intensity of spots in the distal part of the target, while STP, by design, employed proximal spots. To evaluate the utility of IFD delivery, IFD plans were generated by rearranging the spot intensities from FTP or STP intensity maps, separately as well as combined using a variety of mixing weights. IFD courses were designed so that, in alternating fractions, one of the hemispheres of the prostate would receive a dose boost and the other receive a lower dose, while the total physical dose from the IFD course was roughly uniform across the prostate. IFD plans were normalized so that the equivalent uniform dose (EUD) of rectum and bladder did not increase, compared to the baseline FTP plan, which irradiated the prostate uniformly in every fraction. An EUD-based model was then applied to estimate tumor control probability (TCP) and normal tissue complication probability (NTCP). To assess potential local RBE variations, LET distributions were calculated with Monte Carlo, and compared for different plans. The results were assessed in terms of their sensitivity to uncertainties in model parameters and delivery. IFD courses included equal number of fractions boosting either hemisphere, thus, the combined physical dose was close to uniform throughout the prostate. However, for the entire course, the prostate EUD in IFD was higher than in conventional FTP by up to 14%, corresponding to the estimated increase in TCP to 96% from 88%. The extent of gain depended on the mixing factor, i.e., relative weights used to combine FTP and STP spot weights. Increased weighting of STP typically yielded a higher target EUD, but also led to increased sensitivity of dose to variations in the proton's range. Rectal and bladder EUD were same or lower (per normalization), and the NTCP for both remained below 1%. The LET distributions in IFD also depended strongly on the mixing weights: plans using higher weight of STP spots yielded higher LET, indicating a potentially higher local RBE. In proton therapy delivered by pencil beam scanning, improved therapeutic outcome can potentially be expected with delivery of IFD distributions, while administering the prescribed quasi-uniform dose to the target over the entire course. The biological effectiveness of IFD may be further enhanced by optimizing the LET distributions. IFD distributions are characterized by a dose gradient located in proximity of the prostate's midplane, thus, the fidelity of delivery would depend crucially on the precision with which the proton range could be controlled.

Dose escalation using conformal high-dose-rate brachytherapy improves outcome in unfavorable prostate cancer.

PubMed

Martinez, Alvaro A; Gustafson, Gary; Gonzalez, José; Armour, Elwood; Mitchell, Chris; Edmundson, Gregory; Spencer, William; Stromberg, Jannifer; Huang, Raywin; Vicini, Frank

2002-06-01

To overcome radioresistance for patients with unfavorable prostate cancer, a prospective trial of pelvic external beam irradiation (EBRT) interdigitated with dose-escalating conformal high-dose-rate (HDR) prostate brachytherapy was performed. Between November 1991 and August 2000, 207 patients were treated with 46 Gy pelvic EBRT and increasing HDR brachytherapy boost doses (5.50-11.5 Gy/fraction) during 5 weeks. The eligibility criteria were pretreatment prostate-specific antigen level >or=10.0 ng/mL, Gleason score >or=7, or clinical Stage T2b or higher. Patients were divided into 2 dose levels, low-dose biologically effective dose <93 Gy (58 patients) and high-dose biologically effective dose >93 Gy (149 patients). No patient received hormones. We used the American Society for Therapeutic Radiology and Oncology definition for biochemical failure. The median age was 69 years. The mean follow-up for the group was 4.4 years, and for the low and high-dose levels, it was 7.0 and 3.4 years, respectively. The actuarial 5-year biochemical control rate was 74%, and the overall, cause-specific, and disease-free survival rate was 92%, 98%, and 68%, respectively. The 5-year biochemical control rate for the low-dose group was 52%; the rate for the high-dose group was 87% (p <0.001). Improvement occurred in the cause-specific survival in favor of the brachytherapy high-dose level (p = 0.014). On multivariate analysis, a low-dose level, higher Gleason score, and higher nadir value were associated with increased biochemical failure. The Radiation Therapy Oncology Group Grade 3 gastrointestinal/genitourinary complications ranged from 0.5% to 9%. The actuarial 5-year impotency rate was 51%. Pelvic EBRT interdigitated with transrectal ultrasound-guided real-time conformal HDR prostate brachytherapy boost is both a precise dose delivery system and a very effective treatment for unfavorable prostate cancer. We demonstrated an incremental beneficial effect on biochemical control and cause-specific survival with higher doses. These results, coupled with the low risk of complications, the advantage of not being radioactive after implantation, and the real-time interactive planning, define a new standard for treatment.

Dosimetric comparison between VMAT with different dose calculation algorithms and protons for soft-tissue sarcoma radiotherapy.

PubMed

Fogliata, Antonella; Scorsetti, Marta; Navarria, Piera; Catalano, Maddalena; Clivio, Alessandro; Cozzi, Luca; Lobefalo, Francesca; Nicolini, Giorgia; Palumbo, Valentina; Pellegrini, Chiara; Reggiori, Giacomo; Roggio, Antonella; Vanetti, Eugenio; Alongi, Filippo; Pentimalli, Sara; Mancosu, Pietro

2013-04-01

To appraise the potential of volumetric modulated arc therapy (VMAT, RapidArc) and proton beams to simultaneously achieve target coverage and enhanced sparing of bone tissue in the treatment of soft-tissue sarcoma with adequate target coverage. Ten patients presenting with soft-tissue sarcoma of the leg were collected for the study. Dose was prescribed to 66.5 Gy in 25 fractions to the planning target volume (PTV) while significant maximum dose to the bone was constrained to 50 Gy. Plans were optimised according to the RapidArc technique with 6 MV photon beams or for intensity modulated protons. RapidArc photon plans were computed with: 1) AAA; 2) Acuros XB as dose to medium; and 3) Acuros XB as dose to water. All plans acceptably met the criteria of target coverage (V95% >90-95%) and bone sparing (D(1 cm3) <50 Gy). Significantly higher PTV dose homogeneity was found for proton plans. Near-to-maximum dose to bone was similar for RapidArc and protons, while volume receiving medium/low dose levels was minimised with protons. Similar results were obtained for the remaining normal tissue. Dose distributions calculated with the dose to water option resulted ~5% higher than corresponding ones computed as dose to medium. High plan quality was demonstrated for both VMAT and proton techniques when applied to soft-tissue sarcoma.

A comparison between simplified and intensive dose-titration algorithms using AIR inhaled insulin for insulin-naive patients with type 2 diabetes in a randomized noninferiority trial.

PubMed

Mathieu, C; Cuddihy, R; Arakaki, R F; Belin, R M; Planquois, J-M; Lyons, J N; Heilmann, C R

2009-09-01

Insulin initiation and optimization is a challenge for patients with type 2 diabetes. Our objective was to determine whether safety and efficacy of AIR inhaled insulin (Eli Lilly and Co., Indianapolis, IN) (AIR is a registered trademark of Alkermes, Inc., Cambridge, MA) using a simplified regimen was noninferior to an intensive regimen. This was an open-label, randomized study in insulin-naive adults not optimally controlled by oral antihyperglycemic medications. Simplified titration included a 6 U per meal AIR insulin starting dose. Individual doses were adjusted at mealtime in 2-U increments from the previous day's four-point self-monitored blood glucose (SMBG) (total < or =6 U). Starting Air insulin doses for intensive titration were based on fasting blood glucose, gender, height, and weight. Patients conducted four-point SMBG daily for the study duration. Insulin doses were titrated based on the previous 3 days' mean SMBG (total < or =8 U). End point hemoglobin A1C (A1C) was 7.07 +/- 0.09% and 6.87 +/- 0.09% for simplified (n = 178) and intensive (n = 180) algorithms, respectively. Noninferiority between algorithms was not established. The fasting blood glucose (least squares mean +/- standard error) values for the simplified (137.27 +/- 3.42 mg/dL) and intensive (133.13 +/- 3.42 mg/dL) algorithms were comparable. Safety profiles were comparable. The hypoglycemic rate at 4, 8, 12, and 24 weeks was higher in patients receiving intensive titration (all P < .0001). The nocturnal hypoglycemic rate for patients receiving intensive titration was higher than for those receiving simplified titration at 8 (P < 0.015) and 12 weeks (P < 0.001). Noninferiority between the algorithms, as measured by A1C, was not demonstrated. This finding re-emphasizes the difficulty of identifying optimal, simplified insulin regimens for patients.

Efficacy and safety of different doses of tirofiban combined with ticagrelor on diabetic patients with AMI receiving in emergency percutaneous coronary intervention (PCI)

PubMed Central

Liu, Yang; Liu, Hengliang; Hao, Zhenxuan; Geng, Guoying; Chen, Qi; Han, Wenjie; Jia, Kailong; Zhou, Yuxin

2015-01-01

Objective: The aim of this study was to investigate the efficacy and safety of dual antiplatelet drugs combined with different doses of tirofiban on diabetic patients with acute myocardial infarction (AMI) receiving emergency percutaneous coronary intervention (PCI). Methods: 158 diabetic patients with AMI undergone emergency PCI were randomly divided into three groups: Group A (53 cases) as the control group-dual anti-platelet agents (aspirin + ticagrelor); Group B (52 cases)-dual anti-platelet agents + conventional dose of tirofiban [10 μg/kg by PCI and 0.15 μg/(kg·min) by continue venous pump for 24 h]; Group C (53 cases)-dual antiplatelet agents + half-dose tirofiban [10 μg/kg by PCI and 0.075 μg/(kg·min) by continue venous pump for 24 h]. Results: Compared with group A, thrombolysis in myocardial infarction 3 (TIMI3) blood flow and TIMI myocardial perfusion grade 3 (TMPG3) myocardial perfusion of patients in group B and group C after PCI was significantly higher (P < 0.05), the average day of hospitalization was significantly shorter (P < 0.05), reinfarction during hospitalization, post-infarction angina, severe arrhythmia, the incidence of cardiac function above KillipIII level was significantly lower (P < 0.05). And the differences between group B and C was not statistically significant (P > 0.05). Severe bleeding and moderate incidence of bleeding in group B was significantly higher than that in group A and group C (P < 0.05). Conclusions: Based on combination of dual the anti-platelet agents and ticagrelor for diabetic patients with AMI receiving PCI, the combination of half-dose tirofiban can effectively improve TIMI flow and TMPG myocardial tissue perfusion, and reduce the incidence of major adverse cardiac events (MACE) and severe bleeding. PMID:26379951

High-dose thalidomide increases the risk of peripheral neuropathy in the treatment of ankylosing spondylitis.

PubMed

Xue, Hong-Xia; Fu, Wen-Yi; Cui, Hua-Dong; Yang, Li-Li; Zhang, Ning; Zhao, Li-Juan

2015-05-01

Thalidomide is an effective drug for the treatment of ankylosing spondylitis but might induce peripheral neuropathy. This major adverse reaction has attracted much concern. The current study aimed to observe the incidence of thalidomide-induced peripheral neuropathy among ankylosing spondylitis patients for 1 year after treatment. In this study, 207 ankylosing spondylitis cases received thalidomide treatment, while 116 ankylosing spondylitis cases received other treatments. Results showed that the incidence of thalidomide-induced peripheral neuropathy in the thalidomide group was higher than that in the non-thalidomide group. There was no significant difference in the incidence of neuropathy between the < 6 months medication and ≥ 6 months medication groups. There were no differences in the mean age, gender, or daily dose between the two groups. The incidence of peripheral neuropathy among patients receiving 25, 50, 75, or 100 mg thalidomide per day was 4.6%, 8.5%, 17.1%, 21.7%, respectively. The incidence was significantly different between the groups receiving 25 mg and 100 mg thalidomide. In conclusion, thalidomide can induce peripheral neuropathy within 1 year after treatment of ankylosing spondylitis; however, age and gender have no obvious impact on the incidence of peripheral neuropathy. The incidence of peripheral neuropathy is associated with increasing daily doses of thalidomide.

High-dose thalidomide increases the risk of peripheral neuropathy in the treatment of ankylosing spondylitis

PubMed Central

Xue, Hong-xia; Fu, Wen-yi; Cui, Hua-dong; Yang, Li-li; Zhang, Ning; Zhao, Li-juan

2015-01-01

Thalidomide is an effective drug for the treatment of ankylosing spondylitis but might induce peripheral neuropathy. This major adverse reaction has attracted much concern. The current study aimed to observe the incidence of thalidomide-induced peripheral neuropathy among ankylosing spondylitis patients for 1 year after treatment. In this study, 207 ankylosing spondylitis cases received thalidomide treatment, while 116 ankylosing spondylitis cases received other treatments. Results showed that the incidence of thalidomide-induced peripheral neuropathy in the thalidomide group was higher than that in the non-thalidomide group. There was no significant difference in the incidence of neuropathy between the < 6 months medication and ≥ 6 months medication groups. There were no differences in the mean age, gender, or daily dose between the two groups. The incidence of peripheral neuropathy among patients receiving 25, 50, 75, or 100 mg thalidomide per day was 4.6%, 8.5%, 17.1%, 21.7%, respectively. The incidence was significantly different between the groups receiving 25 mg and 100 mg thalidomide. In conclusion, thalidomide can induce peripheral neuropathy within 1 year after treatment of ankylosing spondylitis; however, age and gender have no obvious impact on the incidence of peripheral neuropathy. The incidence of peripheral neuropathy is associated with increasing daily doses of thalidomide. PMID:26109960

Protective effect of Ginkgo biloba L. leaf extract against glyphosate toxicity in Swiss albino mice.

PubMed

Cavuşoğlu, Kültiğin; Yapar, Kürşad; Oruç, Ertan; Yalçın, Emine

2011-10-01

The aim of the present study was to investigate the protective role of Ginkgo biloba L. leaf extract against the active agent of Roundup® herbicide (Monsanto, Creve Coeur, MO, USA). The Swiss Albino mice were randomly divided into six groups, with each group consisting of six animals: Group I (control) received an intraperitoneal injection of dimethyl sulfoxide (0.2 mL, once only), Group II received glyphosate at a dose of 50 mg/kg of body weight, Group III received G. biloba at a dose of 50 mg/kg of body weight, Group IV received G. biloba at a dose of 150 mg/kg of body weight, Group V received G. biloba (50 mg/kg of body weight) and glyphosate (50 mg/kg of body weight), and Group VI received G. biloba (150 mg/kg of body weight) and glyphosate (50 mg/kg of body weight). The single dose of glyphosate was given intraperitoneally. Animals from all the groups were sacrificed at the end of 72 hours, and their blood, bone marrow, and liver and kidney tissues were analyzed for aspartate aminotransferase (AST), alanine aminotransferase (ALT), blood urea nitrogen (BUN), creatinine, malondialdehyde (MDA), and glutathione (GSH) levels and the presence of micronucleus (MN), chromosomal aberrations (CAs), and pathological damages. The results indicated that serum AST, ALT, BUN, and creatinine levels significantly increased in mice treated with glyphosate alone compared with the other groups (P<.05). Besides, glyphosate-induced oxidative damage caused a significant decrease in GSH levels and a significant increase in MDA levels of the liver and kidney tissues. Moreover, glyphosate alone-treated mice presented higher frequencies of CAs, MNs, and abnormal metaphases compared with the controls (P<.05). These mice also displayed a lower mean mitotic index than the controls (P<.05). Treatment with G. biloba produced amelioration in indices of hepatotoxicity, nephrotoxicity, lipid peroxidation, and genotoxicity relative to Group II. Each dose of G. biloba provided significant protection against glyphosate-induced toxicity, and the strongest effect was observed at a dose of 150 mg/kg of body weight. Thus, in vivo results showed that G. biloba extract is a potent protector against glyphosate-induced toxicity, and its protective role is dose-dependent.

Effect of feeding isolates of anaerobic fungus Neocallimastix sp. CF 17 on growth rate and fibre digestion in buffalo calves.

PubMed

Paul, Shyam S; Deb, Sitangshu M; Punia, Balbir S; Das, Kalyan S; Singh, Ghansham; Ashar, Manisha N; Kumar, Rajiv

2011-06-01

In this investigation, the effects of feeding encapsulated cells (rhizomycelia and zoospores) of a fibrolytic isolate from an anaerobic fungus (Neocallimastix sp. CF 17) on nutrient digestion, ruminal fermentation, microbial populations, enzyme profile and growth performance were evaluated in buffaloes. In three in vitro studies, the true digestibility of wheat straw was increased after addition of CF 17 to buffalo rumen fluid (p < 0.05). In Exp. 1, three groups of six buffaloes each (initial BW [body weight] 148 +/- 12.0 kg) were allotted to three dosing regimes: Group 1 received 200 ml of liquid culture of Neocallimastix sp. CF 17 (about 10(6) TFU [thallus-forming units]/ml); Group 2 received an encapsulated culture of the same fungi prepared from 200 ml liquid culture; Group 3: received 200 ml of autoclaved culture (Control). The supplementations were given weekly for four weeks (on days 1,7, 14 and 21). During the dosing period, the average daily gain of Group 2 was higher than in the Control group (444 g/d compared with 264 g/d; p < 0.05). Furthermore, the digestibility of organic matter increased in Group 1 and 2 compared with the Control (64.8, 64.0 and 60.4% respectively; p < 0.05), resulting in an increase in the total digestible nutrient (TDN) percent of ration (p < 0.05). But these effects disappeared post-dosing. There were also an increase in concentration of volatile fatty acids, trichloroacetic acid precipitable N and number of fibrolytic microbes in the rumen during the dosing period (p < 0.05), but these effects declined post-dosing. Results of Exp 2., where the encapsulated culture was applied at intervals of 4 d or 8 d for 120 d, showed that a shorter dosing frequency did not improve growth performance or feed intake. However, independent of the dosing frequency the growth rate of both groups fed the encapsulated culture were about 20% higher than in the Control group (p < 0.05). The present study showed that encapsulated fungi have a high potential to be used as feed additive at the farmers' level and that weekly dosing can increase growth performance of wheat straw based diets.

Addition of cyclophosphamide and higher doses of dexamethasone do not improve outcomes of patients with AL amyloidosis treated with bortezomib.

PubMed

Kastritis, E; Gavriatopoulou, M; Roussou, M; Fotiou, D; Ziogas, D C; Migkou, M; Eleutherakis-Papaiakovou, E; Panagiotidis, I; Kanellias, N; Psimenou, E; Papadopoulou, E; Pamboucas, C; Manios, E; Gakiopoulou, H; Ntalianis, A; Tasidou, A; Giannouli, S; Terpos, E; Dimopoulos, M A

2017-06-16

Bortezomib, in combination with dexamethasone (VD) or with the addition of cyclophosphamide (VCD), is highly effective in patients with amyloid light-chain (AL) amyloidosis. Currently, VCD is considered as a primary regimen for patients with AL, but it is not clear whether the addition of cyclophosphamide to VD further and significantly improves efficacy, given the substantial activity of bortezomib itself. We retrospectively compared the outcomes of 101 patients with AL amyloidosis who received VD (n=59) or VCD (n=42) in two consecutive periods. Early mortality after adjustment for Mayo stage was similar. On intent to treat, a hematologic response rate was 68% for patients treated with VD and 78% for VCD (P=0.26), while complete response+very good partial response (CR+VGPR) rate was 47.5% and 35%, respectively. Higher doses of dexamethasone or twice-weekly bortezomib were not associated with significantly higher CR+VGPR rates. Organ responses occurred in similar rates between the two groups. Median survival was similar (33 vs 36 months, P=0.45) even after adjustment for Mayo stage and dose and schedule of bortezomib and dexamethasone. In conclusion, bortezomib even with low doses of dexamethasone is effective for the treatment of AL amyloidosis; higher doses of dexamethasone and addition of cyclophosphamide do not seem to have a profound effect on efficacy and survival.

Immunogenicity and immunologic memory after hepatitis B virus booster vaccination in HIV-infected children receiving highly active antiretroviral therapy.

PubMed

Abzug, Mark J; Warshaw, Meredith; Rosenblatt, Howard M; Levin, Myron J; Nachman, Sharon A; Pelton, Stephen I; Borkowsky, William; Fenton, Terence

2009-09-15

Hepatitis B virus (HBV) is an important cause of comorbidity in human immunodeficiency virus (HIV)-infected individuals. The immunogenicity of HBV vaccination in children receiving highly active antiretroviral therapy (HAART) was investigated. HIV-infected children receiving HAART who had low to moderate HIV loads and who had previously received 3 doses of HBV vaccine were given an HBV vaccine booster. Concentrations of antibody to hepatitis B surface antigen (anti-HBs) were determined before vaccination and at weeks 8, 48, and 96. A subset of subjects was administered a subsequent dose, and anti-HBs was measured before and 1 and 4 weeks later. At entry, 24% of 204 subjects were seropositive. Vaccine response occurred in 46% on the basis of seropositivity 8 weeks after vaccination and in 37% on the basis of a 4-fold rise in antibody concentration. Of 69 subjects given another vaccination 4-5 years later, immunologic memory was exhibited by 45% on the basis of seropositivity 1 week after vaccination and by 29% on the basis of a 4-fold rise in antibody concentration at 1 week. Predictors of response and memory included higher nadir and current CD4 cell percentage, higher CD19 cell percentage, and undetectable HIV load. HIV-infected children frequently lack protective levels of anti-HBs after previous HBV vaccination, and a significant proportion of them do not respond to booster vaccination or demonstrate memory despite receiving HAART, leaving this population insufficiently protected from infection with HBV.

FAILURE OF RADIOACTIVE IODINE IN TREATMENT OF HYPERTHYROIDISM

PubMed Central

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

2015-01-01

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

Pharmacokinetics of a single dose of intravenous and oral meloxicam in red-tailed hawks (Buteo jamaicensis) and great horned owls (Bubo virginianus).

PubMed

Lacasse, Claude; Gamble, Kathryn C; Boothe, Dawn M

2013-09-01

Pharmacokinetic data were determined after a single dose of meloxicam in red-tailed hawks (RTH; Buteo jamaicensis) and great horned owls (GHO; Bubo virginianus). In a nonrandomized crossover design, individual birds of each species received 1 dose of intravenous meloxicam (0.5 mg/kg i.v.; n = 7 for each species) followed by a 2-week washout period, and then each received 1 dose of oral meloxicam (0.5 mg/kg PO; n = 5 for each species). Blood samples were collected intermittently after administration, and meloxicam was detected in plasma by high-performance liquid chromatography. Time versus plasma concentration data were subjected to noncompartmental analysis. Red-tailed hawks were determined to have the shortest elimination half-life for meloxicam (0.49 +/- 0.5 hours) of any species documented. Great horned owls also eliminated meloxicam very rapidly (0.78 +/- 0.52 hours). Great horned owls achieved higher plasma concentrations (368 +/- 87 ng/mL) of meloxicam than RTH (182 +/- 167 ng/mL) after oral administration, although RTH had a markedly higher volume of distribution (832 +/- 711 mL/kg) than GHO (137.6 +/- 62.7 mL/kg). The differences in meloxicam pharmacokinetics between these 2 raptor species supports the need for species-dependent studies and underlines the challenges of extrapolating drug dosages between species. Results of this study suggest that the current recommended once-daily dosing interval of oral meloxicam is unlikely to maintain plasma concentrations anticipated to be therapeutic in either RTH or GHO, and practical dosing options are questionable for this nonsteriodal anti-inflammatory drug in these raptor species.

Failure of radioactive iodine in the treatment of hyperthyroidism.

PubMed

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

2014-12-01

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

Earlier therapeutic effects associated with high dose (2.0 mg) Ranibizumab for treatment of vascularized pigment epithelial detachments in age-related macular degeneration

PubMed Central

Chan, C K; Abraham, P; Sarraf, D; Nuthi, A S D; Lin, S G; McCannel, C A

2015-01-01

Summary statement Intravitreal high dose (2 mg) ranibizumab may lead to quicker resolution of choroidal neovascularization (CNV) and associated retinal pigment epithelial detachment in eyes with exudative age-related macular degeneration, although it may possibly correlate with RPE tears in certain cases. Purpose This prospective study compared the outcomes of 0.5 vs 2.0 mg intravitreal ranibizumab injections (RI) for treating vascularized pigment epithelial detachment (vPED) due to age-related macular degeneration. Methods Patients with vPED were randomized to receive 2.0 vs 0.5 mg RI monthly for 12 months or for 4 months and then repeated on a pro-re nata basis. Optical coherence tomography, fundus photography, and fluorescein and indocyanine-green angiography were obtained at baseline and subsequent specific intervals. Outcome measures were best-corrected standardized visual acuities, central 1-mm thickness, surface area (SA), greatest linear diameter (GLD), heights (PED and CNV), and amount of subretinal fluid (SRF) and cystoid macular edema (CME). Results Both groups yielded reductions of the central 1-mm thickness, PED and CNV SA and PED height and GLD, SRF, and CME. Vision improvement and reduction in SRF and PED height occurred earlier for eyes receiving the 2.0 mg dose. Cataract progression was similar but RPE tears developed more often with the 2.0 mg dose. Conclusions There were similar visual and anatomical outcomes at the end of the study; however, the higher dose yielded more rapid reductions and more complete resolution of the PED, although there was possible increased tendency for an RPE tear with the higher dose. PMID:25277305

Patients with Posttraumatic Stress Disorder with Comorbid Major Depressive Disorder Require a Higher Dose of Psychotropic Drugs.

PubMed

Chiba, Hiromi; Oe, Misari; Uchimura, Naohisa

2016-01-01

Major depressive disorder (MDD) has been associated with stressful life events and with posttraumatic stress disorder (PTSD). PTSD and MDD comorbidity was also reported to be associated with greater symptom severity and lower levels of functioning. However, the characteristics of pharmacotherapy for PTSD with MDD are not fully understood. To understand this relationship, we conducted a retrospective review using medical charts at the Department of Neuropsychiatry, Kurume University Hospital. Information from 55 patients with PTSD was analyzed. Five cases were excluded after re-evaluation of the PTSD diagnosis. A higher rate of type II trauma was observed in the PTSD with MDD group (50.0%) than in the PTSD-only group [13.6%; χ(2) (1, n =50) = 7.26, p<0.01]. Patients with comorbid MDD were significantly older, had more severe PTSD symptomatology, and a longer duration of treatment. They also received higher doses of psychotropic drugs, regardless of the type (antidepressants, antipsychotics, benzodiazepines), than the PTSD-only group. Our results showed that comorbid MDD is associated with higher doses of psychotropic drugs, suggesting difficulties in treatment.

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

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

Bruner, A.

1976-09-01

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

Dose-ranging pharmacokinetics of colistin methanesulphonate (CMS) and colistin in rats following single intravenous CMS doses.

PubMed

Marchand, Sandrine; Lamarche, Isabelle; Gobin, Patrice; Couet, William

2010-08-01

The aim of this study was to evaluate the effect of colistin methanesulphonate (CMS) dose on CMS and colistin pharmacokinetics in rats. Three rats per group received an intravenous bolus of CMS at a dose of 5, 15, 30, 60 or 120 mg/kg. Arterial blood samples were drawn at 0, 5, 15, 30, 60, 90, 120, 150 and 180 min. CMS and colistin plasma concentrations were determined by liquid chromatography-tandem mass spectrometry (LC-MS/MS). The pharmacokinetic parameters of CMS and colistin were calculated by non-compartmental analysis. Linear relationships were observed between CMS and colistin AUCs to infinity and CMS doses, as well as between CMS and colistin C(max) and CMS doses. CMS and colistin pharmacokinetics were linear for a range of colistin concentrations covering the range of values encountered and recommended in patients even during treatment with higher doses.

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

PubMed

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

2018-01-01

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

The pharmacological effects of the anesthetic alfaxalone after intramuscular administration to dogs.

PubMed

Tamura, Jun; Ishizuka, Tomohito; Fukui, Sho; Oyama, Norihiko; Kawase, Kodai; Miyoshi, Kenjiro; Sano, Tadashi; Pasloske, Kirby; Yamashita, Kazuto

2015-03-01

The pharmacological effects of the anesthetic alfaxalone were evaluated after intramuscular (IM) administration to 6 healthy beagle dogs. The dogs received three IM doses each of alfaxalone at increasing dose rates of 5 mg/kg (IM5), 7.5 mg/kg (IM7.5) and 10 mg/kg (IM10) every other day. Anesthetic effect was subjectively evaluated by using an ordinal scoring system to determine the degree of neuro-depression and the quality of anesthetic induction and recovery from anesthesia. Cardiorespiratory variables were measured using noninvasive methods. Alfaxalone administered IM produced dose-dependent neuro-depression and lateral recumbency (i.e., 36 ± 28 min, 87 ± 26 min and 115 ± 29 min after the IM5, IM7.5 and IM10 treatments, respectively). The endotracheal tube was tolerated in all dogs for 46 ± 20 and 58 ± 21 min after the IM7.5 and IM10 treatments, respectively. It was not possible to place endotracheal tubes in 5 of the 6 dogs after the IM5 treatment. Most cardiorespiratory variables remained within clinically acceptable ranges, but hypoxemia was observed by pulse oximetry for 5 to 10 min in 2 dogs receiving the IM10 treatment. Dose-dependent decreases in rectal temperature, respiratory rate and arterial blood pressure also occurred. The quality of recovery was considered satisfactory in all dogs receiving each treatment; all the dog exhibited transient muscular tremors and staggering gait. In conclusion, IM alfaxalone produced a dose-dependent anesthetic effect with relatively mild cardiorespiratory depression in dogs. However, hypoxemia may occur at higher IM doses of alfaxalone.

The pharmacological effects of the anesthetic alfaxalone after intramuscular administration to dogs

PubMed Central

TAMURA, Jun; ISHIZUKA, Tomohito; FUKUI, Sho; OYAMA, Norihiko; KAWASE, Kodai; MIYOSHI, Kenjiro; SANO, Tadashi; PASLOSKE, Kirby; YAMASHITA, Kazuto

2014-01-01

The pharmacological effects of the anesthetic alfaxalone were evaluated after intramuscular (IM) administration to 6 healthy beagle dogs. The dogs received three IM doses each of alfaxalone at increasing dose rates of 5 mg/kg (IM5), 7.5 mg/kg (IM7.5) and 10 mg/kg (IM10) every other day. Anesthetic effect was subjectively evaluated by using an ordinal scoring system to determine the degree of neuro-depression and the quality of anesthetic induction and recovery from anesthesia. Cardiorespiratory variables were measured using noninvasive methods. Alfaxalone administered IM produced dose-dependent neuro-depression and lateral recumbency (i.e., 36 ± 28 min, 87 ± 26 min and 115 ± 29 min after the IM5, IM7.5 and IM10 treatments, respectively). The endotracheal tube was tolerated in all dogs for 46 ± 20 and 58 ± 21 min after the IM7.5 and IM10 treatments, respectively. It was not possible to place endotracheal tubes in 5 of the 6 dogs after the IM5 treatment. Most cardiorespiratory variables remained within clinically acceptable ranges, but hypoxemia was observed by pulse oximetry for 5 to 10 min in 2 dogs receiving the IM10 treatment. Dose-dependent decreases in rectal temperature, respiratory rate and arterial blood pressure also occurred. The quality of recovery was considered satisfactory in all dogs receiving each treatment; all the dog exhibited transient muscular tremors and staggering gait. In conclusion, IM alfaxalone produced a dose-dependent anesthetic effect with relatively mild cardiorespiratory depression in dogs. However, hypoxemia may occur at higher IM doses of alfaxalone. PMID:25428797

Variation in diurnal sedation in mechanically ventilated patients who are managed with a sedation protocol alone or a sedation protocol and daily interruption.

PubMed

Mehta, Sangeeta; Meade, Maureen; Burry, Lisa; Mallick, Ranjeeta; Katsios, Christina; Fergusson, Dean; Dodek, Peter; Burns, Karen; Herridge, Margaret; Devlin, John W; Tanios, Maged; Fowler, Robert; Jacka, Michael; Skrobik, Yoanna; Olafson, Kendiss; Cook, Deborah

2016-08-01

Mechanically ventilated patients may receive more sedation during the night than during the day, potentially delaying extubation. We compared nighttime and daytime benzodiazepine and opioid administration in adult patients enrolled in a multicenter sedation trial comparing protocolized sedation alone or protocolized sedation combined with daily sedation interruption; and we evaluated whether nighttime and daytime doses were associated with liberation from mechanical ventilation. This is a secondary analysis of a randomized trial which was conducted in 16 North American medical-surgical ICUs. In all 423 patients, nurses applied a validated sedation scale hourly to titrate benzodiazepine and opioid infusions to achieve a light level of sedation. Using fentanyl equivalents and midazolam equivalents, we compared dosages administered during night (19:00 to 07:00) and day (07:00 to 19:00) shifts. Using multivariable logistic regression we evaluated the association between nighttime and daytime opioid and sedative doses, and spontaneous breathing trial (SBT) conduct, SBT success, and extubation. Nighttime benzodiazepine and opioid doses were significantly higher than daytime doses (mean difference midazolam equivalents 23.3 mg, 95 % CI 12.9, 33.8, p < 0.0001; mean difference fentanyl equivalents 356 mcg, 95 % CI 130, 582, p = 0.0021). Mean Sedation Agitation Scale score was similar between night and day, and was at target (3.2 vs 3.3, 95 % CI -0.05, 0.02, p = 0.35). Self-reported nurse workload was similar during the night and day. Patients were more often restrained during day shifts (76.3 % vs 73.7 %, p < 0.0001), and there were more unintentional device removals during the day compared with night (15.9 % vs 9.1 %, p < 0.0001). Increases in nighttime drug doses were independently associated with failure to meet SBT screening criteria, SBT failure, and the decision not to extubate the patient despite successful SBT. Patients received higher doses of opioids and benzodiazepines at night. Higher nighttime doses were associated with SBT failure and delayed extubation. ClinicalTrials.gov NCT00675363 . Registered 7 May 2008.

The Bad Berka dose protocol: comparative results of dosimetry in peptide receptor radionuclide therapy using (177)Lu-DOTATATE, (177)Lu-DOTANOC, and (177)Lu-DOTATOC.

PubMed

Schuchardt, Christiane; Kulkarni, Harshad R; Prasad, Vikas; Zachert, Carolin; Müller, Dirk; Baum, Richard P

2013-01-01

The objective of this study is to analyze the in vivo behavior of the (177)Lu-labeled peptides DOTATATE, DOTANOC, and DOTATOC used for peptide receptor radionuclide therapy (PRRNT) of neuroendocrine tumors (NETs), by measuring organ and tumor kinetics and by performing dosimetric calculations. Two hundred fifty-three patients (group 1) with metastasized NET who underwent PRRNT were examined. Out of these, 185 patients received (177)Lu-DOTATATE, 9 were treated with (177)Lu-DOTANOC, and 59 with (177)Lu-DOTATOC. Additionally, 25 patients receiving, in consecutive PRRNT cycles, DOTATATE followed by DOTATOC (group 2) and 3 patients receiving DOTATATE and DOTANOC (group 3) were analyzed. Dosimetric calculations (according to MIRD scheme) were performed using OLINDA software. In group 1, DOTATOC exhibited the lowest and DOTANOC the highest uptake and therefore mean absorbed dose in normal organs (whole body, kidney, and spleen). In group 2, there was a significant difference between DOTATATE and DOTATOC concerning kinetics and normal organ doses. (177)Lu-DOTATOC had the lowest uptake/dose delivered to normal organs and highest tumor-to-kidney ratio. There were no significant differences between the three peptides concerning tumor kinetics and mean absorbed tumor dose. The study demonstrates a correlation between high affinity of DOTANOC in vitro and high uptake in normal organs/whole body in vivo, resulting in a higher whole-body dose. DOTATOC exhibited the lowest uptake and dose delivered to normal tissues and the best tumor-to-kidney ratio. Due to large interpatient variability, individual dosimetry should be performed for each therapy cycle.

A Phase II Dose-Ranging Study Evaluating the Efficacy and Safety of the Orexin Receptor Antagonist Filorexant (MK-6096) in Patients with Primary Insomnia

PubMed Central

Mahoney, Erin; Jackson, Saheeda; Hutzelmann, Jill; Zhao, Xin; Jia, Nan; Snyder, Ellen; Snavely, Duane; Michelson, David; Roth, Thomas; Herring, W. Joseph

2016-01-01

Background: Filorexant (MK-6096) is an orexin receptor antagonist; here, we evaluate the efficacy of filorexant in the treatment of insomnia in adults. Methods: A double-blind, placebo-controlled, randomized, two 4-week–period, adaptive crossover polysomnography study was conducted at 51 sites worldwide. Patients (18 to <65 years) with insomnia received 1 of 4 doses of oral filorexant (2.5, 5, 10, 20mg) once daily at bedtime during one period and matching placebo in the other period in 1 of 8 possible treatment sequences. Polysomnography was performed on night 1 and end of week 4 of each period. The primary endpoint was sleep efficiency at night 1 and end of week 4. Secondary endpoints included wakefulness after persistent sleep onset and latency to onset of persistent sleep. Results: A total of 324 patients received study treatment, 315 received ≥1 dose of placebo, and 318 ≥1 dose of filorexant (2.5mg, n=79; 5mg, n=78; 10mg, n=80; 20mg, n=81). All filorexant doses (2.5/5/10/20mg) were significantly superior to placebo in improving sleep among patients with insomnia as measured by sleep efficiency and wakefulness after persistent sleep onset on night 1 and end of week 4. The 2 higher filorexant doses (10/20mg) were also significantly more effective than placebo in improving sleep onset as measured by latency to onset of persistent sleep at night 1 and end of week 4. Filorexant was generally well tolerated. Conclusions: Orexin receptor antagonism by filorexant significantly improved sleep efficiency in nonelderly patients with insomnia. Dose-related improvements in sleep onset and maintenance outcomes were also observed with filorexant. PMID:26979830

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

PubMed

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

2006-08-01

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

Inhaled corticosteroids and asthma control in adult-onset asthma: 12-year follow-up study.

PubMed

Vähätalo, Iida; Ilmarinen, Pinja; Tuomisto, Leena E; Niemelä, Onni; Kankaanranta, Hannu

2018-04-01

Prescribed inhaled corticosteroid (ICS) doses in asthma have been studied in cross-sectional settings whereas long-term follow-up studies have not been carried out. To evaluate prescribed medication longitudinally by calculating cumulative ICS doses and dose changes in a cohort of new-onset adult asthma during 12 years and in different groups of asthma control. A total of 203 patients were followed for 12 years as part of Seinäjoki Adult Asthma Study (SAAS). All asthma-related visits and prescribed medication over the study period were collected from medical records. Total cumulative ICS dose for the 12-year follow-up period was 3.4g (±SEM 0.1) per patient. Both respiratory specialists and GPs prescribed step-ups and step-downs in ICS treatment and in total 649 dose changes were noted during the follow-up (median 3(1-5) per patient). Patients with uncontrolled asthma received higher ICS doses throughout the follow-up period, and therefore, cumulative 12-year ICS dose (3.8g ± SEM 0.2) in this group was higher than that in those with partially controlled (3.4g ± SEM 0.2) or controlled disease (2.9g ± SEM 0.2) (p = 0.0001). Patients with uncontrolled asthma were also prescribed a higher number of ICS dose changes than patients with controlled disease. Despite frequent dose changes and high ICS doses during the 12-year follow-up, the level of asthma control remained poor in patients with uncontrolled asthma. This suggests that high ICS doses may not be effective enough for management of disease in patients with uncontrolled adult-onset asthma and novel targeted treatments are required. Copyright © 2018 Elsevier Ltd. All rights reserved.

Quality of harvest and role of cell dose in unrelated bone marrow transplantation: an Italian Bone Marrow Donor Registry-Gruppo Italiano Trapianto di Midollo Osseo Study.

PubMed

Fagioli, Franca; Quarello, Paola; Pollichieni, Simona; Lamparelli, Teresa; Berger, Massimo; Benedetti, Fabio; Barat, Veronica; Marciano, Renato; Rambaldi, Alessandro; Bacigalupo, Andrea; Sacchi, Nicoletta

2014-01-01

In this study, we investigated the factors affecting cell dose harvest and the role of cell dose on outcome. We analysed data from a cohort of 703 patients who underwent unrelated bone marrow transplantation facilitated by IBMDR in GITMO centers between 2002 and 2008. The median-infused cell doses is 3.7 × 10(8)/kg, the correlation between the nucleated cells requested from transplant centers and those harvested by collection centers was adequate. A harvested/requested cells ratio lower than 0.5 was observed only in 3% of harvests. A volume of harvested marrow higher than the median value of 1270 ml was related to a significant lower infused cell dose (χ(2): 44.4; P < 0.001). No patient- or donor-related variables significantly influenced the cell dose except for the recipient younger age (χ(2): 95.7; P < 0.001) and non-malignant diseases (χ(2): 33.8; P < 0.001). The cell dose resulted an independent predictor factor for a better outcome in patients affected by non-malignant disease (P = 0.05) while early disease malignant patients receiving a lower cell dose showed a higher risk of relapse (P = 0.05).

Association between peak neutrophil count, clopidogrel loading dose, and left ventricular systolic function in patients with primary percutaneous coronary intervention.

PubMed

Wang, Xinyu; Yu, Haiyi; Li, Zhaoping; Li, Liuning; Zhang, Youyi; Gao, Wei

2014-01-01

Inflammation plays an important role in plaque development and left ventricular remodeling during acute myocardial infarction (AMI). Clopidogrel may exhibit some anti-inflammatory properties and high loading dose of clopidogrel results in improved clinical outcomes in patients with AMI. 357 patients who received successful primary percutaneous coronary intervention from January 2008 to March 2011 in Peking University Third Hospital were included in this study. Different loading dose of clopidogrel (300 mg, 450 mg, or 600 mg) was given at the discretion of the clinician. Neutrophils reached their peak values on the first day after AMI. Higher levels of peak neutrophil and lower left ventricular ejection fraction (LVEF) were found in patients of low clopidogrel loading dose group (300 mg or 450 mg). After adjusting for the related confounders, a logistic regression model showed that low clopidogrel loading dose remained an independent predictor of low LVEF (LVEF ≤ 50%) [OR: 1.97, 95% CI: 1.03-3.79, P = 0.04]. Low clopidogrel loading dose was associated with higher peak neutrophil count and poor left ventricular systolic function, suggesting an important role of clopidogrel loading dose in the improvement of left ventricular function and high loading dose may exhibit better anti-inflammatory properties.

Effects of radiation exposure from cardiac imaging: how good are the data?

PubMed

Einstein, Andrew J

2012-02-07

Concerns about medical exposure to ionizing radiation have become heightened in recent years as a result of rapid growth in procedure volumes and the high radiation doses incurred from some procedures. This paper summarizes the evidence base undergirding concerns about radiation exposure in cardiac imaging. After classifying radiation effects, explaining terminology used to quantify the radiation received by patients, and describing typical doses from cardiac imaging procedures, this paper will address the major epidemiological studies having bearing on radiation effects at doses comparable to those received by patients undergoing cardiac imaging. These include studies of atomic bomb survivors, nuclear industry workers, and children exposed in utero to x-rays, all of which have evidenced increased cancer risks at low doses. Additional higher-dose epidemiological studies of cohorts exposed to radiation in the context of medical treatment are described and found to be generally compatible with these cardiac dose-level studies, albeit with exceptions. Using risk projection models developed by the U.S. National Academies that incorporate these data and reflect several evidence-based assumptions, cancer risk from cardiac imaging can be estimated and compared with the benefits from imaging. Several ongoing epidemiological studies will provide better understanding of radiation-associated cancer risks. Copyright © 2012 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

Effect of amphetamine on human macronutrient intake.

PubMed

Foltin, R W; Kelly, T H; Fischman, M W

1995-11-01

Six male subjects participated in a 15-day residential study examining the effects of amphetamine on macronutrient intake. During the first 11 days, carbohydrate intake was manipulated by providing lunch meals high (155 g) or low (25 g) in carbohydrate. Subjects received oral d-amphetamine (5, 10 mg/70 kg, BID) or placebo. Total daily caloric intake was similar under both lunch conditions (approximately 3400/Kcal), but carbohydrate contributed more energy under the high-carbohydrate condition. Both doses of amphetamine decreased total caloric intake to approximately 2600 Kcal, by decreasing the number of eating bouts, without affecting macronutrient selection. During the last four days subjects received a higher daily dose of amphetamine (30 mg/70 kg in four doses) or placebo, and were allowed to self-select lunch. Although 30 mg amphetamine decreased intake of all macronutrients, the relative contribution of carbohydrate to total caloric intake was increased from 54% to 62%, while the contribution of fat was decreased from 32% to 26% and the contribution of protein was decreased from 14% to 12%. Thus, at a high dose, amphetamine altered the relative contribution of specific macronutrients to total caloric intake.

The role of single-shot metronidazole in the prevention of Clostridium difficile infection following ileostomy reversal surgery.

PubMed

Fernandes, Roland; Robinson, Paul; Rangarajan, Karan; Scott, Sophie; Angco, Laura

2017-05-01

Symptomatic infection with Clostridium difficile is strongly linked to antibiotic use and rates are higher for colorectal surgery. In February 2015, trust policy for antibiotic prophylaxis of ileostomy reversal surgery was changed from three doses of metronidazole plus cefuroxime to single-dose metronidazole, in a bid to reduce rates of Clostridium difficile infection. A retrospective cohort study was conducted at a single, large hospital trust between February 2014 and February 2016, before and after change in antimicrobial policy. Theatre data, clinical notes and pathology results were all reviewed. Outcome data, patient age, gender, length of operation and hospital stay were extracted. One hundred three patients underwent ileostomy reversal surgery between February 2014 and February 2015. All received cefuroxime together with metronidazole at induction of anaesthesia followed by two further post-operative doses as operative prophylaxis. Ninety-six patients underwent ileostomy reversal surgery between February 2015 and February 2016. All received single-dose metronidazole at induction as prophylaxis. Post-operative diarrhoea was significantly reduced in patients given single-dose metronidazole compared with patients managed with multiple dose, dual antibiotic therapy (32 vs 12.5%, P 0.001). Rates of CDI were also significantly reduced in patients given single-dose metronidazole (6.8 vs 1%, P 0.038). Single-dose, pre-operative metronidazole is effective at reducing post-operative diarrhoea and CDI in ileostomy reversal surgery compared with multiple-dose cefuroxime plus metronidazole. Metronidazole may be effective as a prophylactic antibiotic against CDI in colonic surgery.

Irradiation doses on thyroid gland during the postoperative irradiation for breast cancer.

PubMed

Akın, Mustafa; Ergen, Arzu; Unal, Aysegul; Bese, Nuran

2014-01-01

Thyroid gland is one of the radiosensitive endocrine organs in the body. It has been shown that direct irradiation of thyroid with total doses of 26 to 30 Gy can lead to functional abnormalities. In this study, irradiation doses on thyroid gland of the patients who received postoperative chest-wall/breast and regional nodal irradiation were assessed. Retrospective analyses of treatment plans from 122 breast cancer patients who were treated with 3D conformal radiotherapy (3D CRT) planning was performed. All patients received irradiation to supraclavicular/level III lymph nodes in addition to chest-wall/breast. A total dose of 46 Gy was delivered in 25 days to supraclavicular/level III lymph node region while a total dose of 50 Gy was delivered to whole breast/chest-wall. Thyroid gland was contoured on 2-5 mm thickness of computed tomography scans. Absolute thyroid volume, mean thyroid doses were calculated. The mean thyroid volume of all patients was 16.7 cc (min: 1.9 cc, max: 41.6 cc). The mean irradiation dose on was 22.5 Gy (0.32 Gy-46.5 Gy). The level of dose was higher than 26 Gy in 44% of the patients. In majority of the node-positive breast cancer patients treated with 3D CRT, the thyroid gland was exposed to considerable doses. On the other hand, for 44% of the patients are at risk for developing thyroid function abnormalities which should be considered during the routine follow-up.

Effect of stimulus intensity and number of treatments on ECS-related seizure duration and retrograde amnesia in rats.

PubMed

Andrade, Chittaranjan; Thyagarajan, S; Vinod, P S; Srikanth, S N; Rao, N S K; Chandra, J Suresh

2002-12-01

Animal models are frequently used to generate and test hypotheses about amnesia resulting from electroconvulsive therapy (ECT). Although many predictors of ECT-induced amnesia are known, their relative effects have been inadequately researched in the context of the animal models. We sought to determine the relative retrograde amnestic effects of electroconvulsive shock (ECS) stimulus intensity (dose) and number on strong memories in rats. We also sought to identify dose-dependent ceiling amnestic effects, if any. Adult rats (n = 144) were overtrained in a passive avoidance task using a step down apparatus. The rats were then randomized in a factorial design to receive one, two, or three once-daily bilateral ECS at 0-mC (sham ECS), 30-mC, 60-mC, 120-mC, or 180-mC doses. Recall of the pre-ECS training was assessed 1 day after the last ECS. Retrograde amnesia was observed only in rats that received 3 ECS; dose-dependent amnestic effects did not emerge. Higher stimulus intensity was associated with a small (13%) but significant increase in motor seizure duration, but only at the first ECS; stimulus intensity did not influence the attenuation of seizure duration across repeated occasions of ECS. With bilateral ECS, the number of ECSs administered is a more important variable than the ECS dose in weakening a strong, recently acquired, noxious memory; this finding may have important clinical implications. Higher stimulus intensity marginally increases motor seizure duration at the first ECS but does not influence the decrease in seizure duration across repeated ECSs.

Postlumpectomy Focal Brachytherapy for Simultaneous Treatment of Surgical Cavity and Draining Lymph Nodes

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

Hrycushko, Brian A.; Li Shihong; Shi Chengyu

2011-03-01

Purpose: The primary objective was to investigate a novel focal brachytherapy technique using lipid nanoparticle (liposome)-carried {beta}-emitting radionuclides (rhenium-186 [{sup 186}Re]/rhenium-188 [{sup 188}Re]) to simultaneously treat the postlumpectomy surgical cavity and draining lymph nodes. Methods and Materials: Cumulative activity distributions in the lumpectomy cavity and lymph nodes were extrapolated from small animal imaging and human lymphoscintigraphy data. Absorbed dose calculations were performed for lumpectomy cavities with spherical and ellipsoidal shapes and lymph nodes within human subjects by use of the dose point kernel convolution method. Results: Dose calculations showed that therapeutic dose levels within the lumpectomy cavity wall can covermore » 2- and 5-mm depths for {sup 186}Re and {sup 188}Re liposomes, respectively. The absorbed doses at 1 cm sharply decreased to only 1.3% to 3.7% of the doses at 2 mm for {sup 186}Re liposomes and 5 mm for {sup 188}Re liposomes. Concurrently, the draining sentinel lymph nodes would receive a high focal therapeutic absorbed dose, whereas the average dose to 1 cm of surrounding tissue received less than 1% of that within the nodes. Conclusions: Focal brachytherapy by use of {sup 186}Re/{sup 188}Re liposomes was theoretically shown to be capable of simultaneously treating the lumpectomy cavity wall and draining sentinel lymph nodes with high absorbed doses while significantly lowering dose to surrounding healthy tissue. In turn, this allows for dose escalation to regions of higher probability of containing residual tumor cells after lumpectomy while reducing normal tissue complications.« less

Estimated UV doses to psoriasis patients during climate therapy at Gran Canaria in March 2006

NASA Astrophysics Data System (ADS)

Nilsen, L. T. N.; Søyland, E.; Krogstad, A. L.

2008-01-01

Psoriasis is a chronic inflammatory disease involving about 2-3% of the Norwegian population. Sun exposure has a positive effect on most psoriasis lesions, but ultraviolet (UV) radiation also causes a direct DNA damage in the skin cells and comprises a carcinogenic potential. UV exposure on the skin causes a local as well as a systemic immune suppressive effect, but the relation between sun exposure and these biological effects is not well known. In March 2006 a study was carried out to investigate possible therapeutic outcome mechanisms in 20 psoriasis patients receiving climate therapy at Gran Canaria. This paper presents estimates of their individual skin UV-doses based on UV measurements and the patients' diaries with information on time spent in the sun. On the first day of exposure the patients received on average 5.1 Standard Erythema Doses (SED: median=4.0 SED, range 2.6-10.3 SED) estimated to the skin. During the 15 days study they received 165.8 SED (range 104.3-210.1 SED). The reduction in PASI score was 72.8% on average, but there was no obvious relation between the improvement and the UV dose. The UV doses were higher than those found from climate therapy studies at other locations. It seems beneficial to use more strict exposure schedules that consider the available UV irradiance, depending on time of the day, time of the year and weather conditions.

Impact of Vitamin D Supplementation on Gross Motor Development of Healthy Term Infants: A Randomized Dose-Response Trial.

PubMed

Wicklow, Brandy; Gallo, Sina; Majnemer, Annette; Vanstone, Catherine; Comeau, Kathryn; Jones, Glenville; L'Abbe, Mary; Khamessan, Ali; Sharma, Atul; Weiler, Hope; Rodd, Celia

2016-08-01

In addition to benefits for bone health, vitamin D is implicated in muscle function in children and adults. To determine if vitamin D dosage positively correlated with gross motor development at 3 and 6 months of age. We hypothesized that higher doses would be associated with higher scores for gross motor skills. A consecutive sample of 55 healthy, term, and breastfed infants from Montreal, Canada were recruited from a randomized trial of vitamin D supplementation between 2009 and 2012. Infants were randomized to 400 International Units (IU) (n = 19), 800 IU (n = 18) or 1,200 IU (n = 18) vitamin D3/day. Motor performance at 3 and 6 months was quantified by the Alberta Infant Motor Scale (AIMS). Plasma vitamin D3 metabolites were measured by tandem mass spectrometry. AIMS scores did not differ at 3 months. However, total AIMS scores and sitting subscores were significantly higher at 6 months in infants receiving 400 IU/day compared to 800 IU/day and 1,200 IU/day groups (p < .05). There were weak negative correlations with length and C-3 epimer of 25(OH)D. In contrast to our hypothesis, gross motor achievements were significantly higher in infants receiving 400 IU/day vitamin D. Our findings also support longer infants being slightly delayed.

External Beam Radiotherapy for Prostate Cancer Patients on Anticoagulation Therapy: How Significant is the Bleeding Toxicity?

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

Choe, Kevin S.; Jani, Ashesh B.; Liauw, Stanley L., E-mail: sliauw@radonc.uchicago.ed

Purpose: To characterize the bleeding toxicity associated with external beam radiotherapy for prostate cancer patients receiving anticoagulation (AC) therapy. Methods and Materials: The study cohort consisted of 568 patients with adenocarcinoma of the prostate who were treated with definitive external beam radiotherapy. Of these men, 79 were receiving AC therapy with either warfarin or clopidogrel. All patients were treated with three-dimensional conformal radiotherapy or intensity-modulated radiotherapy. Bleeding complications were recorded during treatment and subsequent follow-up visits. Results: With a median follow-up of 48 months, the 4-year actuarial risk of Grade 3 or worse bleeding toxicity was 15.5% for those receivingmore » AC therapy compared with 3.6% among those not receiving AC (p < .0001). On multivariate analysis, AC therapy was the only significant factor associated with Grade 3 or worse bleeding (p < .0001). For patients taking AC therapy, the crude rate of bleeding was 39.2%. Multivariate analysis within the AC group demonstrated that a higher radiotherapy dose (p = .0408), intensity-modulated radiotherapy (p = 0.0136), and previous transurethral resection of the prostate (p = .0001) were associated with Grade 2 or worse bleeding toxicity. Androgen deprivation therapy was protective against bleeding, with borderline significance (p = 0.0599). Dose-volume histogram analysis revealed that Grade 3 or worse bleeding was minimized if the percentage of the rectum receiving >=70 Gy was <10% or the rectum receiving >=50 Gy was <50%. Conclusion: Patients taking AC therapy have a substantial risk of bleeding toxicity from external beam radiotherapy. In this setting, dose escalation or intensity-modulated radiotherapy should be used judiciously. With adherence to strict dose-volume histogram criteria and minimizing hotspots, the risk of severe bleeding might be reduced.« less

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

Coverage and cost of a large oral cholera vaccination program in a high-risk cholera endemic urban population in Dhaka, Bangladesh.

PubMed

Khan, Iqbal Ansary; Saha, Amit; Chowdhury, Fahima; Khan, Ashraful Islam; Uddin, Md Jasim; Begum, Yasmin A; Riaz, Baizid Khoorshid; Islam, Sanjida; Ali, Mohammad; Luby, Stephen P; Clemens, John D; Cravioto, Alejandro; Qadri, Firdausi

2013-12-09

A feasibility study of an oral cholera vaccine was carried out to test strategies to reach high-risk populations in urban Mirpur, Dhaka, Bangladesh. The study was cluster randomized, with three arms: vaccine, vaccine plus safe water and hand washing practice, and no intervention. High risk people of age one year and above (except pregnant woman) from the two intervention arms received two doses of the oral cholera vaccine, Shanchol™. Vaccination was conducted between 17th February and 16th April 2011, with a minimum interval of fourteen days between two doses. Interpersonal communication preceded vaccination to raise awareness amongst the target population. The number of vaccine doses used, the population vaccinated, left-out, drop out, vaccine wastage and resources required were documented. Fixed outreach site vaccination strategy was adopted as the mode of vaccine delivery. Additionally, mobile vaccination sites and mop-up activities were carried out to reach the target communities. Of the 172,754 target population, 141,839 (82%) and 123,666 (72%) received complete first and second doses of the vaccine, respectively. Dropout rate from the first to the second dose was 13%. Two complete doses were received by 123,661 participants. Vaccine coverage in children was 81%. Coverage was significantly higher in females than in males (77% vs. 66%, P<0.001). Vaccine wastage for delivering the complete doses was 1.2%. The government provided cold-chain related support at no cost to the project. Costs for two doses of vaccine per-person were US$3.93, of which US$1.63 was spent on delivery. Cost for delivering a single dose was US$0.76. We observed no serious adverse events. Mass vaccination with oral cholera vaccine is feasible for reaching high risk endemic population through the existing national immunization delivery system employed by the government. Copyright © 2013 The Authors. Published by Elsevier Ltd.. All rights reserved.

Focal Radiation Therapy Dose Escalation Improves Overall Survival in Locally Advanced Pancreatic Cancer Patients Receiving Induction Chemotherapy and Consolidative Chemoradiation

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

Krishnan, Sunil, E-mail: skrishnan@mdanderson.org; Chadha, Awalpreet S.; Suh, Yelin

2016-03-15

Purpose: To review outcomes of locally advanced pancreatic cancer (LAPC) patients treated with dose-escalated intensity modulated radiation therapy (IMRT) with curative intent. Methods and Materials: A total of 200 patients with LAPC were treated with induction chemotherapy followed by chemoradiation between 2006 and 2014. Of these, 47 (24%) having tumors >1 cm from the luminal organs were selected for dose-escalated IMRT (biologically effective dose [BED] >70 Gy) using a simultaneous integrated boost technique, inspiration breath hold, and computed tomographic image guidance. Fractionation was optimized for coverage of gross tumor and luminal organ sparing. A 2- to 5-mm margin around the gross tumor volume wasmore » treated using a simultaneous integrated boost with a microscopic dose. Overall survival (OS), recurrence-free survival (RFS), local-regional and distant RFS, and time to local-regional and distant recurrence, calculated from start of chemoradiation, were the outcomes of interest. Results: Median radiation dose was 50.4 Gy (BED = 59.47 Gy) with a concurrent capecitabine-based (86%) regimen. Patients who received BED >70 Gy had a superior OS (17.8 vs 15.0 months, P=.03), which was preserved throughout the follow-up period, with estimated OS rates at 2 years of 36% versus 19% and at 3 years of 31% versus 9% along with improved local-regional RFS (10.2 vs 6.2 months, P=.05) as compared with those receiving BED ≤70 Gy. Degree of gross tumor volume coverage did not seem to affect outcomes. No additional toxicity was observed in the high-dose group. Higher dose (BED) was the only predictor of improved OS on multivariate analysis. Conclusion: Radiation dose escalation during consolidative chemoradiation therapy after induction chemotherapy for LAPC patients improves OS and local-regional RFS.« less

Switch from epoetin to darbepoetin alfa in hemodialysis: dose equivalence and hemoglobin stability.

PubMed

Arrieta, Javier; Moina, Iñigo; Molina, José; Gallardo, Isabel; Muñiz, María Luisa; Robledo, Carmen; García, Oscar; Vidaur, Fernando; Muñoz, Rosa Inés; Iribar, Izaskun; Aguirre, Román; Maza, Antonio

2014-01-01

The objective of the study reported here was to describe dose equivalence and hemoglobin (Hb) stability in a cohort of unselected hemodialysis patients who were switched simultaneously from epoetin alfa to darbepoetin alfa. This was a multicenter, observational, retrospective study in patients aged ≥18 years who switched from intravenous (IV) epoetin alfa to IV darbepoetin alfa in October 2007 (Month 0) and continued on hemodialysis for at least 24 months. The dose was adjusted to maintain Hb within 1.0 g/dL of baseline. We included 125 patients (59.7% male, mean [standard deviation (SD)] age 70.4 [13.4] years). No significant changes were observed in Hb levels (mean [SD] 11.9 [1.3] g/dL, 12.0 [1.5], 12.0 [1.5], and 12.0 [1.7] at Months -12, 0, 12 and 24, respectively, P=0.409). After conversion, the erythropoiesis-stimulating agent (ESA) dose decreased significantly (P<0.0001), with an annual mean of 174.7 (88.7) international units (IU)/kg/week for epoetin versus 95.7 (43.4) (first year) and 91.4 (42.7) IU/kg/week (second year) for darbepoetin (65% and 64% reduction, respectively). The ESA resistance index decreased from 15.1 (8.5) IU/kg/week/g/dL with epoetin to 8.1 (3.9) (first year) and 7.9 (4.0) (second year) with darbepoetin (P<0.0001). The conversion rate was 354:1 in patients requiring high (>200 IU/kg/week) doses of epoetin and 291:1 in patients requiring low doses. In patients on hemodialysis receiving ESAs, conversion from epoetin alfa to darbepoetin alfa was associated with an approximate and persistent reduction of 65% of the required dose. To maintain Hb stability, a conversion rate of 300:1 seems to be appropriate for most patients receiving low doses of epoetin alfa (≤200 IU/kg/week), while 350:1 would be better for patients receiving higher doses.

H1N1 antibody persistence 1 year after immunization with an adjuvanted or whole-virion pandemic vaccine and immunogenicity and reactogenicity of subsequent seasonal influenza vaccine: a multicenter follow-on study.

PubMed

Walker, Woolf T; de Whalley, Philip; Andrews, Nick; Oeser, Clarissa; Casey, Michelle; Michaelis, Louise; Hoschler, Katja; Harrill, Caroline; Moulsdale, Phoebe; Thompson, Ben; Jones, Claire; Chalk, Jem; Kerridge, Simon; John, Tessa M; Okike, Ifeanyichukwu; Ladhani, Shamez; Tomlinson, Richard; Heath, Paul T; Miller, Elizabeth; Faust, Saul N; Snape, Matthew D; Finn, Adam; Pollard, Andrew J

2012-03-01

We investigated antibody persistence in children 1 year after 2 doses of either an AS03(B)-adjuvanted split-virion or nonadjuvanted whole-virion monovalent pandemic influenza vaccine and assessed the immunogenicity and reactogenicity of a subsequent dose of trivalent influenza vaccine (TIV). Children previously immunized at age 6 months to 12 years in the original study were invited to participate. After a blood sample was obtained to assess persistence of antibody against swine influenza A/H1N1(2009) pandemic influenza, children received 1 dose of 2010/2011 TIV, reactogenicity data were collected for 7 days, and another blood sample was obtained 21 days after vaccination. Of 323 children recruited, 302 received TIV. Antibody persistence (defined as microneutralization [MN] titer ≥1:40) 1 year after initial vaccination was significantly higher in the AS03(B)-adjuvanted compared with the whole-virion vaccine group, 100% (95% confidence interval [CI], 94.1%-100%) vs 32.4% (95% CI, 21.5%-44.8%) in children immunized <3 years old and 96.9% (95% CI, 91.3%-99.4%) vs 65.9% (95% CI, 55.3%-75.5%) in those 3-12 years old at immunization, respectively (P < .001 for both groups). All children receiving TIV had post-vaccination MN titers ≥1:40. Although TIV was well tolerated in all groups, reactogenicity in children <5 years old was slightly greater in those who originally received AS03(B)-adjuvanted vaccine. This study provides serological evidence that 2 doses of AS03(B)-adjuvanted pandemic influenza vaccine may be sufficient to maintain protection across 2 influenza seasons. Administration of TIV to children who previously received 2 doses of either pandemic influenza vaccine is safe and is immunogenic for the H1N1 strain.

H1N1 Antibody Persistence 1 Year After Immunization With an Adjuvanted or Whole-Virion Pandemic Vaccine and Immunogenicity and Reactogenicity of Subsequent Seasonal Influenza Vaccine: A Multicenter Follow-on Study

PubMed Central

Walker, Woolf T.; de Whalley, Philip; Andrews, Nick; Oeser, Clarissa; Casey, Michelle; Michaelis, Louise; Hoschler, Katja; Harrill, Caroline; Moulsdale, Phoebe; Thompson, Ben; Jones, Claire; Chalk, Jem; Kerridge, Simon; John, Tessa M.; Okike, Ifeanyichukwu; Ladhani, Shamez; Tomlinson, Richard; Heath, Paul T.; Miller, Elizabeth; Snape, Matthew D.; Finn, Adam; Pollard, Andrew J.

2012-01-01

Background. We investigated antibody persistence in children 1 year after 2 doses of either an AS03B-adjuvanted split-virion or nonadjuvanted whole-virion monovalent pandemic influenza vaccine and assessed the immunogenicity and reactogenicity of a subsequent dose of trivalent influenza vaccine (TIV). Methods. Children previously immunized at age 6 months to 12 years in the original study were invited to participate. After a blood sample was obtained to assess persistence of antibody against swine influenza A/H1N1(2009) pandemic influenza, children received 1 dose of 2010/2011 TIV, reactogenicity data were collected for 7 days, and another blood sample was obtained 21 days after vaccination. Results. Of 323 children recruited, 302 received TIV. Antibody persistence (defined as microneutralization [MN] titer ≥1:40) 1 year after initial vaccination was significantly higher in the AS03B-adjuvanted compared with the whole-virion vaccine group, 100% (95% confidence interval [CI], 94.1%–100%) vs 32.4% (95% CI, 21.5%–44.8%) in children immunized <3 years old and 96.9% (95% CI, 91.3%–99.4%) vs 65.9% (95% CI, 55.3%–75.5%) in those 3–12 years old at immunization, respectively (P < .001 for both groups). All children receiving TIV had post-vaccination MN titers ≥1:40. Although TIV was well tolerated in all groups, reactogenicity in children <5 years old was slightly greater in those who originally received AS03B-adjuvanted vaccine. Conclusions. This study provides serological evidence that 2 doses of AS03B-adjuvanted pandemic influenza vaccine may be sufficient to maintain protection across 2 influenza seasons. Administration of TIV to children who previously received 2 doses of either pandemic influenza vaccine is safe and is immunogenic for the H1N1 strain. PMID:22267719

Immunogenicity and safety of a high-dose hepatitis B vaccine among patients receiving methadone maintenance treatment: A randomized, double-blinded, parallel-controlled trial.

PubMed

Shi, Jing; Feng, Yongliang; Gao, Linying; Feng, Dan; Yao, Tian; Shi, Shan; Zhang, Yawei; Liang, Xiaofeng; Wang, Suping

2017-04-25

To explore whether the immunization with high-dose (60μg) hepatitis B vaccines in patients receiving methadone maintenance treatment (MMT) could yield a superior protection against hepatitis B infection than did the standard dose (20μg). We conducted a randomized, double-blinded, parallel-controlled trial in MMT patients. Patients with serologically negative hepatitis B surface antigen (HBsAg) and hepatitis B surface antibody (anti-HBs) were randomized in a ratio of 1:1 to receive three intramuscular injections of 20μg or 60μg recombinant hepatitis B vaccine at months 0, 1, and 6. Serum HBsAg and anti-HBs were measured at months 7 and 12 post-vaccination to assess the immunogenicity. A total of 196 MMT patients were randomized and 195 received at least one injection (98 and 97 in 20 and 60μg vaccine groups, respectively). The 60μg vaccine group showed a seroconversion of anti-HBs of 87.3%, high-level response rate of 56.3%, and GMC of 742.9mIU/mL at month 7. While these results were numerically higher than the 20μg group, a statistical difference was not found. HIV infection and concomitant drug abuse were negatively associated with the robust immune responses. 7.7% of MMT patients receiving at least one dose of vaccine reported solicited adverse reactions within 7days after vaccination, 2.6% reported unsolicited adverse reactions within 28days after vaccination. None of the MMT patients reported serious adverse events or became HBsAg positive during the follow-up. The three-dose regimen of 60μg recombinant hepatitis B vaccine at months 0, 1, and 6 can yield a similar immunogenicity among MMT patients as compared to the 20μg vaccine. ClinicalTrials.gov identifier: NCT02991599. Copyright © 2017. Published by Elsevier Ltd.

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

PubMed

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

2009-06-15

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

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

PubMed

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

2009-01-01

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

Role of clinical and laboratory parameters for treatment choice in patients with inherited FVII deficiency undergoing surgical procedures: evidence from the STER registry.

PubMed

Di Minno, Matteo N D; Napolitano, Mariasanta; Dolce, Alberto; Mariani, Guglielmo

2018-02-01

Perioperative bleeding is a major concern in patients with factor VII (FVII) deficiency. Evaluating data of 95 FVII-deficient patients undergoing 110 surgical procedures (61 major, 49 minor), we assessed the impact of type of surgery, bleeding phenotype and FVII coagulant activity (FVII:C) levels on perioperative replacement therapy (RT). Compared to those with higher FVII:C levels, patients with <3% FVII:C received a higher number of RT doses (8 vs. 2, P = 0·003) for a longer RT duration (3 days vs. 1 day, P = 0·001), with no difference in RT dose. Similarly, patients with a history of major bleeds received a higher number of RT doses (8·5 vs. 2-3, P = 0·013) for a longer RT duration (2 days vs. 1 day, P = 0·005) as compared to those with a history of minor bleeds or to asymptomatic patients. No difference in RT was found among major and minor surgical procedures. Overall, multivariate analysis showed that history of major bleeding was the only independent predictor of number of RT doses (β = 0·352, P = 0·001) and RT duration (β = 0·405, P = 0·018). Overall, a ≈20 μg/kg perioperative RT was efficacious in 95·5% of cases. The infusion should be repeated ≈8 times in high-risk subsets (i.e. patients with a history of major bleeding). © 2017 John Wiley & Sons Ltd.

Fractionated Radioimmunotherapy With 90Y-Clivatuzumab Tetraxetan and Low-Dose Gemcitabine Is Active in Advanced Pancreatic Cancer

PubMed Central

Ocean, Allyson J.; Pennington, Kenneth L.; Guarino, Michael J.; Sheikh, Arif; Bekaii-Saab, Tanios; Serafini, Aldo N.; Lee, Daniel; Sung, Max W.; Gulec, Seza A.; Goldsmith, Stanley J.; Manzone, Timothy; Holt, Michael; O’Neil, Bert H.; Hall, Nathan; Montero, Alberto J.; Kauh, John; Gold, David V.; Horne, Heather; Wegener, William A.; Goldenberg, David M.

2014-01-01

BACKGROUND It has been demonstrated that the humanized clivatuzumab tetraxetan (hPAM4) antibody targets pancreatic ductal carcinoma selectively. After a trial of radioimmunotherapy that determined the maximum tolerated dose of single-dose yttrium-90-labeled hPAM4 (90Y-hPAM4) and produced objective responses in patients with advanced pancreatic ductal carcinoma, the authors studied fractionated radioimmunotherapy combined with low-dose gemcitabine in this disease. METHODS Thirty-eight previously untreated patients (33 patients with stage IV disease and 5 patients with stage III disease) received gemcitabine 200 mg/m2 weekly for 4 weeks with 90Y-hPAM4 given weekly in Weeks 2, 3, and 4 (cycle 1), and the same cycle was repeated in 13 patients (cycles 2–4). In the first part of the study, 19 patients received escalating weekly 90Y doses of 6.5 mCi/m2, 9.0 mCi/m2, 12.0 mCi/m2, and 15.0 mCi/m2. In the second portion, 19 additional patients received weekly doses of 9.0 mCi/m2 or 12.0 mCi/m2. RESULTS Grade 3/4 thrombocytopenia or neutropenia (according to version 3.0 of the National Cancer Institute’s Common Terminology Criteria for Adverse Events) developed in 28 of 38 patients after cycle 1 and in all retreated patients; no grade >3 nonhematologic toxicities occurred. Fractionated dosing of cycle 1 allowed almost twice the radiation dose compared with single-dose radioimmunotherapy. The maximum tolerated dose of 90Y-hPAM4 was 12.0 mCi/m2 weekly for 3 weeks for cycle 1, with ≤9.0 mCi/m2 weekly for 3 weeks for subsequent cycles, and that dose will be used in future trials. Six patients (16%) had partial responses according to computed tomography-based Response Evaluation Criteria in Solid Tumors, and 16 patients (42%) had stabilization as their best response (58% disease control). The median overall survival was 7.7 months for all 38 patients, including 11.8 months for those who received repeated cycles (46% [6 of 13 patients] ≥1 year), with improved efficacy at the higher radioimmunotherapy doses. CONCLUSIONS Fractionated radioimmunotherapy with 90Y-hPAM4 and low-dose gemcitabine demonstrated promising therapeutic activity and manageable myelosuppression in patients with advanced pancreatic ductal carcinoma. PMID:22569804

A clinical trial of injectable testosterone undecanoate as a potential male contraceptive in normal Chinese men.

PubMed

Zhang, G Y; Gu, Y Q; Wang, X H; Cui, Y G; Bremner, W J

1999-10-01

This is a pilot dose-finding study of spermatogenic suppression using testosterone undecanoate (TU) injections alone in normal Chinese men. Thirty-two healthy men were recruited. Volunteers underwent pretreatment evaluation, then a treatment period in which group I (n = 13) received 500 mg TU, group II (n = 12) received 1000 mg TU, and group III (n = 7) received placebo, respectively, at monthly intervals during the treatment period (or until azoospermia was achieved). Thereafter, they underwent a recovery period until all parameters returned to pretreatment levels. Eleven of 12 volunteers in the 500-mg TU group, and all volunteers in the 1000-mg TU group became azoospermic. Faster suppression of spermatogenesis was achieved in the 1000-mg TU group. Serum testosterone increased significantly in the higher dose group at weeks 8 and 12, but remained within the normal range. Mean serum LH and FSH were profoundly suppressed by both doses to undetectable levels at week 16. TU injections did not cause a significant change in high density lipoprotein cholesterol levels. No serious side-effects were found. We conclude that both dosages of TU can effectively, safely, and reversibly suppress spermatogenesis in normal Chinese men.

[Therapeutic efficacy of nootropil different doses in attention deficit hyperactivity disorder].

PubMed

Zavadenko, N N; Suvorinova, S Iu

2004-01-01

Attention Deficit Hyperactivity Disorder (ADHD) is the most common cause of behavioral and learning problems in childhood. Therapeutic efficiency of nootropil (piracetam) in two different doses has been evaluated in the open control study of 80 children with ADHD, 70 boys and 10 girls, aged 6-11 years, being divided into 3 groups. Two groups received nootropil, as a monotherapy, for a month: 1st group (30 patients)--in the dosage of 70 mg/kg daily and 2nd group (30 patients)--40 mg/kg daily orally. The control group of 20 patients did not receive any treatment. All children were examined twice with one month interval. A procedure of assessment included of structured questionnaire to parents, neurological examination with scored evaluation of subtle signs and psychological testing. Nootropil therapy in ADHD children resulted in the improvement of behavioral characteristics, motor coordination as well as continuous, selective and divided attention. A response rate was 60% in patients received 70 mg/kg of nootropil and 43% for nootropil dosage of 40 mg/kg. The results of the study suggest more considerable positive therapeutic effects of nootropil higher dose on behavioral, motor and attention characteristics in children with ADHD.

Assessing the use of school public address systems to deliver nutrition messages to children: Shape up Somerville--audio adventures.

PubMed

Folta, Sara C; Goldberg, Jeanne P; Economos, Christina; Bell, Rick; Landers, Stewart; Hyatt, Raymond

2006-11-01

Given the current childhood obesity epidemic, it is especially important to find effective ways to promote healthful foods to children. School public address (PA) systems represent an inexpensive and a replicable way of reaching children with health messages. To test the effectiveness of this channel, messages were created to promote 2 dried bean (legume) dishes that had been added to the school lunch menu. Six elementary schools were pair matched, and 1 school from each pair was randomly chosen to play the messages. The impact of the intervention on choice of the 2 new entrees was assessed. Results indicate that for all schools combined, choice was not significantly affected. However, compared to their matched control schools, choice was significantly higher in the school that received the highest dose of the intervention and was significantly lower in the school that received the lowest dose. Choice was not changed in the school that received an intermediate dose. These results suggest that PA systems show promise as an effective and appropriate communications channel but only in schools that are able to play messages frequently.

Breast Radiation Dose With CESM Compared With 2D FFDM and 3D Tomosynthesis Mammography.

PubMed

James, Judy R; Pavlicek, William; Hanson, James A; Boltz, Thomas F; Patel, Bhavika K

2017-02-01

We aimed to compare radiation dose received during contrast-enhanced spectral mammography (CESM) using high- and low-energy projections with radiation dose received during 2D full field digital mammography (FFDM) and 3D tomosynthesis on phantoms and patients with varying breast thickness and density. A single left craniocaudal projection was chosen to determine the doses for 6214 patients who underwent 2D FFDM, 3662 patients who underwent 3D tomosynthesis, and 173 patients who underwent CESM in this retrospective study. Dose measurements were also collected in phantoms with composition mimicking nondense and dense breast tissue. Average glandular dose (AGD) ± SD was 3.0 ± 1.1 mGy for CESM exposures at a mean breast thickness of 63 mm. At this thickness, the dose was 2.1 mGy from 2D FFDM and 2.5 mGy from 3D tomosynthesis. The nondense phantom had a mean AGD of 1.0 mGy with 2D FFDM, 1.3 mGy with 3D tomosynthesis, and 1.6 mGy with CESM. The dense breast phantom had a mean AGD of 1.3 mGy with 2D FFDM, 1.4 mGy with 3D tomosynthesis, and 2.1 mGy with CESM. At a compressed thickness of 4.5 cm, radiation exposure from CESM was approximately 25% higher in dense breast phantoms than in nondense breast phantoms. The dose in the dense phantom at a compressed thickness of 6 cm was approximately 42% higher than the dose in the nondense phantom at a compressed thickness of 4.5 cm. CESM was found to increase AGD at a mean breast thickness of 63 mm by approximately 0.9 mGy and 0.5 mGy compared with 2D FFDM and 3D tomosynthesis, respectively. Of note, CESM provides a standard image (similar to 2D FFDM) that is obtained using the low-energy projection. Overall, the AGD from CESM falls below the dose limit of 3 mGy set by Mammography Quality Standards Act regulations.

Comparative pharmacokinetics and bioavailability of albendazole sulfoxide in sheep and goats, and dose-dependent plasma disposition in goats.

PubMed

Aksit, Dilek; Yalinkilinc, Hande Sultan; Sekkin, Selim; Boyacioğlu, Murat; Cirak, Veli Yilgor; Ayaz, Erol; Gokbulut, Cengiz

2015-05-27

The aims of this study were to compare the pharmacokinetics of albendazole sulfoxide (ABZ-SO, ricobendazole) in goats and sheep at a dose of 5 g/kg bodyweight (BW), after intravenous (IV) and subcutaneous (SC) administrations, and to investigate the effects of increased doses (10 and 15 mg/kg BW) on the plasma disposition of ABZ-SO in goats following SC administration. A total of 16 goats (Capra aegagrus hircus, eight males and eight females) and 8 sheep (Ovis aries, four males and four females) 12-16 months old and weighing 20-32 kg, were used. The study was designed according to two-phase crossover study protocol. In Phase-1, eight sheep were assigned as Group I and 16 goats were allocated into two groups (Group II and Group III). ABZ-SO was applied to Group I (sheep) and Group II (goats) animals subcutaneously, and to Group III (goats) animals intravenously, all at a dose rate of 5 mg/kg BW. In Phase-2, the sheep in the Group I received ABZ-SO intravenously in a dose of 5 mg/kg BW; the goats in Group II and Group III received ABZ-SO subcutaneously at a dose of 10 mg/kg and 15 mg/kg BW, respectively. Blood samples were collected from the jugular vein at different times between 1 and 120 h after drug administrations. The plasma concentrations of ABZ-SO and its metabolites were analysed by high performance liquid chromatography. In goats, the area under the curve, terminal half-life and plasma persistence of ABZ-SO were significantly smaller and shorter, respectively, compared with those observed in sheep following both IV and SC administrations at a dose of 5 mg/kg BW. On the other side, dose-dependent plasma dispositions of ABZ-SO were observed following SC administration at increased doses (10 and 15 mg/kg) in goats. Consequently, ABZ-SO might be used at higher doses to provide higher plasma concentration and thus to achieve greater efficacy against the target parasites.

The Effect of p53 Status of Tumor Cells on Radiosensitivity of Irradiated Tumors With Carbon-Ion Beams Compared With γ-Rays or Reactor Neutron Beams.

PubMed

Masunaga, Shin-Ichiro; Uzawa, Akiko; Hirayama, Ryoichi; Matsumoto, Yoshitaka; Sakurai, Yoshinori; Tanaka, Hiroki; Tano, Keizo; Sanada, Yu; Suzuki, Minoru; Maruhashi, Akira; Ono, Koji

2015-08-01

The aim of the study was to clarify the effect of p53 status of tumor cells on radiosensitivity of solid tumors following accelerated carbon-ion beam irradiation compared with γ-rays or reactor neutron beams, referring to the response of intratumor quiescent (Q) cells. Human head and neck squamous cell carcinoma cells transfected with mutant TP53 (SAS/mp53) or with neo vector (SAS/neo) were injected subcutaneously into hind legs of nude mice. Tumor-bearing mice received 5-bromo-2'-deoxyuridine (BrdU) continuously to label all intratumor proliferating (P) cells. They received γ-rays or accelerated carbon-ion beams at a high or reduced dose-rate. Other tumor-bearing mice received reactor thermal or epithermal neutrons at a reduced dose-rate. Immediately or 9 hours after the high dose-rate irradiation (HDRI), or immediately after the reduced dose-rate irradiation (RDRI), the tumor cells were isolated and incubated with a cytokinesis blocker, and the micronucleus (MN) frequency in cells without BrdU labeling (Q cells) was determined using immunofluorescence staining for BrdU. The difference in radiosensitivity between the total (P + Q) and Q cells after γ-ray irradiation was markedly reduced with reactor neutron beams or carbon-ion beams, especially with a higher linear energy transfer (LET) value. Following γ-ray irradiation, SAS/neo tumor cells, especially intratumor Q cells, showed a marked reduction in sensitivity due to the recovery from radiation-induced damage, compared with the total or Q cells within SAS/mp53 tumors that showed little repair capacity. In both total and Q cells within both SAS/neo and SAS/mp53 tumors, carbon-ion beam irradiation, especially with a higher LET, showed little recovery capacity through leaving an interval between HDRI and the assay or decreasing the dose-rate. The recovery from radiation-induced damage after γ-ray irradiation was a p53-dependent event, but little recovery was found after carbon-ion beam irradiation. With RDRI, the radiosensitivity to reactor thermal and epithermal neutron beams was slightly higher than that to carbon-ion beams. For tumor control, including intratumor Q-cell control, accelerated carbon-ion beams, especially with a higher LET, and reactor thermal and epithermal neutron beams were very useful for suppressing the recovery from radiation-induced damage irrespective of p53 status of tumor cells.

The Effect of p53 Status of Tumor Cells on Radiosensitivity of Irradiated Tumors With Carbon-Ion Beams Compared With γ-Rays or Reactor Neutron Beams

PubMed Central

Masunaga, Shin-ichiro; Uzawa, Akiko; Hirayama, Ryoichi; Matsumoto, Yoshitaka; Sakurai, Yoshinori; Tanaka, Hiroki; Tano, Keizo; Sanada, Yu; Suzuki, Minoru; Maruhashi, Akira; Ono, Koji

2015-01-01

Background The aim of the study was to clarify the effect of p53 status of tumor cells on radiosensitivity of solid tumors following accelerated carbon-ion beam irradiation compared with γ-rays or reactor neutron beams, referring to the response of intratumor quiescent (Q) cells. Methods Human head and neck squamous cell carcinoma cells transfected with mutant TP53 (SAS/mp53) or with neo vector (SAS/neo) were injected subcutaneously into hind legs of nude mice. Tumor-bearing mice received 5-bromo-2’-deoxyuridine (BrdU) continuously to label all intratumor proliferating (P) cells. They received γ-rays or accelerated carbon-ion beams at a high or reduced dose-rate. Other tumor-bearing mice received reactor thermal or epithermal neutrons at a reduced dose-rate. Immediately or 9 hours after the high dose-rate irradiation (HDRI), or immediately after the reduced dose-rate irradiation (RDRI), the tumor cells were isolated and incubated with a cytokinesis blocker, and the micronucleus (MN) frequency in cells without BrdU labeling (Q cells) was determined using immunofluorescence staining for BrdU. Results The difference in radiosensitivity between the total (P + Q) and Q cells after γ-ray irradiation was markedly reduced with reactor neutron beams or carbon-ion beams, especially with a higher linear energy transfer (LET) value. Following γ-ray irradiation, SAS/neo tumor cells, especially intratumor Q cells, showed a marked reduction in sensitivity due to the recovery from radiation-induced damage, compared with the total or Q cells within SAS/mp53 tumors that showed little repair capacity. In both total and Q cells within both SAS/neo and SAS/mp53 tumors, carbon-ion beam irradiation, especially with a higher LET, showed little recovery capacity through leaving an interval between HDRI and the assay or decreasing the dose-rate. The recovery from radiation-induced damage after γ-ray irradiation was a p53-dependent event, but little recovery was found after carbon-ion beam irradiation. With RDRI, the radiosensitivity to reactor thermal and epithermal neutron beams was slightly higher than that to carbon-ion beams. Conclusion For tumor control, including intratumor Q-cell control, accelerated carbon-ion beams, especially with a higher LET, and reactor thermal and epithermal neutron beams were very useful for suppressing the recovery from radiation-induced damage irrespective of p53 status of tumor cells. PMID:28983338

The Effect of High Dose Folic Acid throughout Pregnancy on Homocysteine (Hcy) Concentration and Pre-Eclampsia: A Randomized Clinical Trial

PubMed Central

Sayyah-Melli, Manizheh; Ghorbanihaghjo, Amir; Alizadeh, Mahasti; Kazemi-Shishvan, Maryamalsadat; Ghojazadeh, Morteza; Bidadi, Sanam

2016-01-01

Pre-eclampsia is a pregnancy-related multi-systemic hypertensive disorder and affects at least 5% of pregnancies. This randomized clinical trial aimed at assessing the effect of low doses and high doses of folic acid on homocysteine (Hcy) levels, blood pressure, urea, creatinine and neonatal outcome. A randomized clinical trial was done at Alzahra Teaching Hospital, Tabriz University of Medical Sciences from April 2008 to March 2013. Four-hundred and sixty nulliparous pregnant women were randomly assigned into two groups. Group 1 (n = 230) received 0.5 mg of folic acid and group 2 (n = 230) received 5 mg of folic acid per daily. They were followed until delivery. Blood pressure and laboratory changes, including plasma Hcy levels, were measured and compared between the groups. Homocysteine concentrations were significantly higher at the time of delivery in group 1 (13.17±3.89 μmol/l) than in group 2 (10.31±3.54, μmol/l) (p<0.001). No statistically significant differences were observed in systolic and diastolic blood pressure (p = 0.84 and 0.15, respectively). Birth weight was significantly higher in group 2 (p = 0.031) and early abortion was significantly higher in group 1 than group 2 (p = 0.001). This study has provided evidence that a high dosage of folic acid supplements throughout pregnancy reduces Hcy concentrations at the time of delivery. Trial Registration: Iranian Registry of Clinical Trials IRCT201402175283N9 PMID:27166794

Physiologic and biochemical effects of electroacupuncture combined with intramuscular administration of dexmedetomidine to provide analgesia in goats.

PubMed

Shah, Zahir; Hu, Man L; Qiu, Zheng Y; Zhou, Fei Y; Zeng, Jie; Wan, Juan; Wang, Shao W; Zhang, Wei; Ding, Ming X

2016-03-01

To investigate physiologic and biochemical effects of electroacupuncture and dexmedetomidine administration to goats. 30 healthy adult goats. Goats were allotted to 5 groups (6 goats/group) and received electroacupuncture, dexmedetomidine (5 or 20 μg/kg, IM), electroacupuncture plus dexmedetomidine (5 μg/kg, IM), or saline (0.9% NaCl) solution (IM [control treatment]). Pain threshold, cardiorespiratory effects, rectal temperature, and hematologic and biochemical variables were assessed. Dexmedetomidine (20 μg/kg) increased pain threshold and decreased heart rate, respiratory rate, and rectal temperature. Pain threshold of goats receiving electroacupuncture plus dexmedetomidine (5 μg/kg) was higher than that of goats receiving electroacupuncture or of goats receiving dexmedetomidine at 5 μg/kg at 30 minutes, but did not differ from that of goats receiving dexmedetomidine at 20 μg/kg. Compared with goats administered dexmedetomidine at 20 μg/kg, goats receiving electroacupuncture plus dexmedetomidine at 5 μg/kg had a higher heart rate from 30 to 60 minutes and a higher respiratory rate from 5 to 60 minutes. Electroacupuncture plus dexmedetomidine (5 μg/kg) did not affect rectal temperature. Serum glucose concentrations of goats receiving electroacupuncture plus dexmedetomidine (5 μg/kg) were higher than for goats receiving dexmedetomidine at 5 μg/kg at 30 minutes but not for goats receiving dexmedetomidine at 20 μg/kg. Creatinine and BUN concentrations, alanine or aspartate aminotransferase activities, and hematologic variables of treated goats did not change. Electroacupuncture in combination with a low dose of dexmedetomidine (5 μg/kg, IM) administered to goats provided antinociception.

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

PubMed

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

2013-04-01

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

Immunogenicity and Safety of a Combination of Two Serogroup B Meningococcal Outer Membrane Vesicle Vaccines▿

PubMed Central

Sandbu, Synne; Feiring, Berit; Oster, Philipp; Helland, Oddveig S.; Bakke, Hilde S. W.; Næss, Lisbeth M.; Aase, Audun; Aaberge, Ingeborg S.; Kristoffersen, Anne-Cathrine; Rydland, Kjersti M.; Tilman, Sandrine; Nøkleby, Hanne; Rosenqvist, Einar

2007-01-01

MenBvac and MeNZB are safe and efficacious vaccines against serogroup B meningococcal disease. MenBvac is prepared from a B:15:P1.7,16 meningococcal strain (strain 44/76), and MeNZB is prepared from a B:4:P1.7-2,4 strain (strain NZ98/254). At 6-week intervals, healthy adults received three doses of MenBvac (25 μg), MeNZB (25 μg), or the MenBvac and MeNZB (doses of 12.5 μg of each vaccine) vaccines combined, followed by a booster 1 year later. Two-thirds of the subjects who received a monovalent vaccine in the primary schedule received the other monovalent vaccine as a booster dose. The immune responses to the combined vaccine were of the same magnitude as the homologous responses to each individual vaccine observed. At 6 weeks after the third dose, 77% and 87% of the subjects in the combined vaccine group achieved serum bactericidal titers of ≥4 against strains 44/76 and NZ98/254, respectively, and 97% and 93% of the subjects achieved a fourfold or greater increase in opsonophagocytic activity against strains 44/76 and NZ98/254, respectively. For both strains, a trend of higher responses after the booster dose was observed in all groups receiving at least one dose of the respective strain-specific vaccine. Local and systemic reactions were common in all vaccine groups. Most reactions were mild or moderate in intensity, and there were no vaccine-related serious adverse events. The safety profile of the combined vaccine was not different from those of the separate monovalent vaccines. In conclusion, use of either of the single vaccines or the combination of MenBvac and MeNZB may have a considerable impact on the serogroup B meningococcal disease situation in many countries. PMID:17634513

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

PubMed

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

2005-02-01

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

Hydrocortisone at stress-associated concentrations helps maintain human heart rate variability during subsequent endotoxin challenge.

PubMed

Rassias, Athos J; Guyre, Paul M; Yeager, Mark P

2011-12-01

We evaluated the differential impact of stress-associated vs high pharmacologic concentrations of hydrocortisone pretreatment on heart rate variability (HRV) during a subsequent systemic inflammatory stimulus. Healthy volunteers were randomized to receive placebo (Control) and hydrocortisone at 1.5 μg/kg per minute (STRESS) or at 3.0 μg/kg per minute (PHARM) as a 6-hour infusion. The STRESS dose was chosen to replicate the condition of physiologic adrenal cortical output during acute systemic stress. The PHARM dose was chosen to induce a supraphysiologic concentration of cortisol. The next day, all subjects received 2 ng/kg Escherichia coli endotoxin (lipopolysaccharide). Heart rate variability was analyzed with the statistic approximate entropy (ApEn). A lower ApEn correlates with decreased HRV. At the 3-hour nadir, the decrease in ApEn in the STRESS group was significantly less compared to placebo (P < .03), whereas ApEn in the PHARM group was not statistically different. We also found that the maximal decrease in ApEn preceded maximal increase in heart rate in all groups. The decrease in R-R interval was maximal at 4 hours, whereas the ApEn nadir was 1 hour earlier at 3 hours. Pretreatment with a stress dose of hydrocortisone but not a higher pharmacologic dose maintained a significantly higher ApEn after endotoxin exposure when compared to a placebo. In addition, decreases in ApEn preceded increases in heart rate. Copyright © 2011 Elsevier Inc. All rights reserved.

Clinical Outcomes With Dose-Escalated Adaptive Radiation Therapy for Urinary Bladder Cancer: A Prospective Study

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

Murthy, Vedang, E-mail: vmurthy@actrec.gov.in; Masodkar, Renuka; Kalyani, Nikhil

Purpose: The purpose of this study was to assess feasibility, clinical outcomes, and toxicity in patients with bladder cancer treated with adaptive, image guided radiation therapy (IGRT) for bladder preservation as a part of trimodality treatment. The role of dose escalation was also studied. Methods and Materials: Forty-four patients with localized bladder cancer were enrolled in a prospective study. They underwent maximal safe resection of bladder tumor and concurrent platinum-based chemotherapy. Patients with large tumors were offered induction chemotherapy. Radiation therapy planning was done using either 3 (n=34) or 6 (n=10) concentrically grown planning target volumes (PTV). Patients received 64 Gymore » in 32 fractions to the whole bladder and 55 Gy to the pelvic nodes and, if appropriate, a simultaneous integrated boost to the tumor bed to 68 Gy (equivalent dose for 2-Gy fractions assuming α/β of 10 [EQD2]{sub 10} = 68.7 Gy). Daily megavoltage (MV) imaging helped to choose the most appropriate PTV encompassing bladder for the particular day (using plan-of-the-day approach). Results: Most patients (88%) had T2 disease. Sixteen patients (36%) received neoadjuvant chemotherapy. A majority of the patients (73%) received prophylactic nodal irradiation, whereas 55% of the patients received escalated dose to the tumor bed. With a median follow-up of 30 months, the 3-year locoregional control (LRC), disease-free survival, and overall survival (OS) were 78%, 66%, and 67%, respectively. The bladder preservation rate was 83%. LRC (87% vs 68%, respectively, P=.748) and OS (74% vs 60%, respectively, P=.36) rates were better in patients receiving dose escalation. Instances of acute and late Radiation Therapy Oncology Group (RTOG) grade 3 genitourinary toxicity was seen in 5 (11%) and 2 (4%) patients, respectively. There was no acute or late RTOG grade 3 or higher gastrointestinal toxicity. Conclusions: Adaptive IGRT using plan-of-the-day approach for bladder preservation is clinically feasible, with good oncological outcomes and low rates of acute and late toxicities. Dose escalation is safe and possibly improves outcomes in bladder preservation.« less

Impact of dose reductions on efficacy outcome in heart transplant patients receiving enteric-coated mycophenolate sodium or mycophenolate mofetil at 12 months post-transplantation.

PubMed

Segovia, Javier; Gerosa, Gino; Almenar, Luis; Livi, Ugolino; Viganò, Mario; Arizón, Jose Maria; Yonan, Nizar; Di Salvo, Thomas G; Renlund, Dale G; Kobashigawa, Jon A

2008-01-01

Mycophenolic acid (MPA) dose reduction is associated with increased risk of rejection and graft loss in renal transplantation. This analysis investigated the impact of MPA dose changes with enteric-coated mycophenolate sodium (EC-MPS) or mycophenolate mofetil (MMF) in de novo heart transplant recipients. In a 12-month, single-blind trial, 154 patients (EC-MPS, 78; MMF, 76) were randomized to either EC-MPS (1080 mg bid) or MMF (1500 mg bid) in combination with cyclosporine and steroids. The primary efficacy variable was the incidence of treatment failure, comprising a composite of biopsy-proven (BPAR) and treated acute rejection, graft loss or death. Significantly fewer patients receiving EC-MPS required > or =2 dose reductions than patients on MMF (26.9% vs. 42.1% of patients, p = 0.048). Accordingly, the average daily dose of EC-MPS as a percentage of the recommended dose was significantly higher than for MMF (88.4% vs. 79.0%, p = 0.016). Among patients requiring > or =1 dose reduction, the incidence of treated BPAR grade > or =3A was significantly lower with EC-MPS compared with MMF (23.4% vs. 44.0%, p = 0.032). These data suggest that EC-MPS-treated heart transplant patients are less likely to require multiple dose reductions than those on MMF which may be associated with a significantly lower risk of treated BPAR > or =3A.

Effectiveness of a Third Dose of MMR Vaccine for Mumps Outbreak Control.

PubMed

Cardemil, Cristina V; Dahl, Rebecca M; James, Lisa; Wannemuehler, Kathleen; Gary, Howard E; Shah, Minesh; Marin, Mona; Riley, Jacob; Feikin, Daniel R; Patel, Manisha; Quinlisk, Patricia

2017-09-07

The effect of a third dose of the measles-mumps-rubella (MMR) vaccine in stemming a mumps outbreak is unknown. During an outbreak among vaccinated students at the University of Iowa, health officials implemented a widespread MMR vaccine campaign. We evaluated the effectiveness of a third dose for outbreak control and assessed for waning immunity. Of 20,496 university students who were enrolled during the 2015-2016 academic year, mumps was diagnosed in 259 students. We used Fisher's exact test to compare unadjusted attack rates according to dose status and years since receipt of the second MMR vaccine dose. We used multivariable time-dependent Cox regression models to evaluate vaccine effectiveness, according to dose status (three vs. two doses and two vs. no doses) after adjustment for the number of years since the second dose. Before the outbreak, 98.1% of the students had received at least two doses of MMR vaccine. During the outbreak, 4783 received a third dose. The attack rate was lower among the students who had received three doses than among those who had received two doses (6.7 vs. 14.5 cases per 1000 population, P<0.001). Students had more than nine times the risk of mumps if they had received the second MMR dose 13 years or more before the outbreak. At 28 days after vaccination, receipt of the third vaccine dose was associated with a 78.1% lower risk of mumps than receipt of a second dose (adjusted hazard ratio, 0.22; 95% confidence interval, 0.12 to 0.39). The vaccine effectiveness of two doses versus no doses was lower among students with more distant receipt of the second vaccine dose. Students who had received a third dose of MMR vaccine had a lower risk of mumps than did those who had received two doses, after adjustment for the number of years since the second dose. Students who had received a second dose of MMR vaccine 13 years or more before the outbreak had an increased risk of mumps. These findings suggest that the campaign to administer a third dose of MMR vaccine improved mumps outbreak control and that waning immunity probably contributed to propagation of the outbreak. (Funded by the Centers for Disease Control and Prevention.).

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.

The process evaluation of two alternative participatory ergonomics intervention strategies for construction companies.

PubMed

Visser, Steven; van der Molen, Henk F; Sluiter, Judith K; Frings-Dresen, Monique H W

2018-03-26

To gain insight into the process of applying two guidance strategies - face-to-face (F2F) or e-guidance strategy (EC) - of a Participatory Ergonomics (PE) intervention and whether differences between these guidance strategies occur, 12 construction companies were randomly assigned to a strategy. The process evaluation contained reach, dose delivered, dose received, precision, competence, satisfaction and behavioural change of individual workers. Data were assessed by logbooks, and questionnaires and interviews at baseline and/or after six months. Reach was low (1%). Dose delivered (F2F: 63%; EC: 44%), received (F2F: 42%; EC: 16%) were not sufficient. The precision and competence were sufficient for both strategies and satisfaction was strongly affected by dose received. For behavioural change, knowledge (F2F) and culture (EC) changed positively within companies. Neither strategy was delivered as intended. Compliance to the intervention was low, especially for EC. Starting with a face-to-face meeting might lead to higher compliance, especially in the EC group. Practitioner Summary: This study showed that compliance to a face-to-face and an e-guidance strategy is low. To improve the compliance, it is advised to start with a face-to-face meeting to see which parts of the intervention are needed and which guidance strategy can be used for these parts. ISRCTN73075751.

Lipid metabolism abnormalities in alcohol-treated rabbits: a morphometric and haematologic study comparing high and low alcohol doses.

PubMed

Ikemura, Satoshi; Yamamoto, Takuaki; Motomura, Goro; Iwasaki, Kenyu; Yamaguchi, Ryosuke; Zhao, Garida; Iwamoto, Yukihide

2011-08-01

The pathogenesis of alcohol-induced osteonecrosis remains unclear. The purpose of the present study was to evaluate the morphological changes in bone marrow fat cells and the changes in the serum lipid levels in alcohol-treated rabbits. Fifteen rabbits were randomly assigned into three groups: Four rabbits intragastrically received low-dose alcohol (LDA) (15 ml/kg per day) containing 15% ethanol for 4 weeks, five rabbits received high-dose alcohol (HDA) (30 ml/kg per day) for 4 weeks and six rabbits received physiologic saline for 4 weeks as a control group. Six weeks after the initial alcohol administration, all rabbits were sacrificed. The mean size of the bone marrow fat cells in rabbits treated with HDA was significantly larger than that in the control group (P = 0.0001). Haematologically, the levels of triglycerides and free fatty acids in the rabbits treated with both low-dose and HDA were significantly higher than those in the control group (P = 0.001 for both comparisons). The results of this study are that there are lipid metabolism abnormalities, both morphologically and haematologically, after alcohol administration. Also these findings were more apparent in rabbits treated with HDA than those treated with LDA. © 2011 The Authors. International Journal of Experimental Pathology © 2011 International Journal of Experimental Pathology.

Platelet Aggregation Inhibitory Effects and Pharmacokinetics of Prasugrel Used in Combination With Aspirin in Healthy Japanese Subjects.

PubMed

Umemura, Kazuo; Ikeda, Yasuhiko; Matsushima, Nobuko; Kondo, Kazunao

2017-07-01

We evaluated the pharmacokinetics and pharmacodynamics of prasugrel used in combination with aspirin in healthy Japanese subjects. All subjects received aspirin 100 mg/day. Subsequently, in the single-administration study, 23 subjects also received prasugrel 20 or 30 mg, and in the multiple-administration study, 20 subjects received a loading dose of prasugrel 20 or 30 mg on day 1, followed by a maintenance dose of prasugrel 5 or 7.5 mg/day, respectively, on days 2-5. In both studies, the plasma concentration of the active metabolite of prasugrel, R-138727, reached a maximum 0.5 hours after administration and rapidly decreased within 4 hours. In the single-administration study, the inhibitory effect on adenosine diphosphate-induced platelet aggregation was significantly higher in the prasugrel 20- and 30-mg groups than in the placebo group at all times (1-144 hours) after administration. In the multiple-administration study, a similar antiplatelet effect was found after both the loading dose and the maintenance dose and was maintained for 3-6 days after the last administration. There were study drug-related adverse events; however, all were mild, and none was clinically significant. © 2016 The Authors. Clinical Pharmacology in Drug Development Published by Wiley Periodicals, Inc. on behalf of The American College of Clinical Pharmacology.

Extending Prednisolone Treatment Does Not Reduce Relapses in Childhood Nephrotic Syndrome

PubMed Central

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

2012-01-01

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

Clinical application of a nomogram based on age, serum FSH and AMH to select the FSH starting dose in IVF/ICSI cycles: a retrospective two-centres study.

PubMed

Papaleo, Enrico; Zaffagnini, Stefano; Munaretto, Maria; Vanni, Valeria Stella; Rebonato, Giorgia; Grisendi, Valentina; Di Paola, Rossana; La Marca, Antonio

2016-12-01

To externally validate a nomogram based on ovarian reserve markers as a tool to optimize the FSH starting dose in IVF/ICSI cycles. A two-centres retrospective study including 398 infertile women undergoing their first IVF/ICSI cycle (June 2013-June 2014). IVF data were retrieved from two independent IVF centres in Italy (San Raffaele Hospital, Centre 1; Verona Hospital, Centre 2). A central lab for the routine measurement of AMH and FSH was used for both centres. All women were treated based on physical and hormonal characteristics according to locally adopted protocols. The nomogram was then retrospectively applied to the patients comparing the calculated starting dose to the one actually given. In Centre 1, 64/131 women (48.8%) had an ovarian response below the target. While 45 of these patients were treated with a maximal FSH starting dose (≥225 IU), n=19/131 (14.5%) were treated with a submaximal dose. The vast majority of them (n=17/19) would have received a higher FSH starting dose by using the nomogram. Seventeen patients (n=17/131) had hyper response and about half of them would have been treated with a reduced FSH starting dose according to the nomogram. In Centre 2, 142/267 patients (53.2%) had an ovarian response below the target. While 136 of these were treated with a maximal FSH starting dose (≥225 IU), n=6/267 were treated with a submaximal dose. The majority of them (n=5/6) would have received a higher FSH starting dose. Thirty-two (n=32/267) patients had hyper response and more than half of them would have been treated with a reduced FSH dose. In both Centres, applying the nomogram would have resulted in more appropriate FSH starting doses compared to the the ones actually given based on clinicians choices. The use of an objective algorithm based on patient's age, serum FSH and AMH levels may thus be an effective advice on the selection of the tailored FSH starting dose. Hence, the use of this easily available nomogram could increase the proportion of patients achieving the optimal ovarian response. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Cumulative effective dose associated with radiography and CT of adolescents with spinal injuries.

PubMed

Lemburg, Stefan P; Peters, Soeren A; Roggenland, Daniela; Nicolas, Volkmar; Heyer, Christoph M

2010-12-01

The purpose of this study was to analyze the quantity and distribution of cumulative effective doses in diagnostic imaging of adolescents with spinal injuries. At a level 1 trauma center from July 2003 through June 2009, imaging procedures during initial evaluation and hospitalization and after discharge of all patients 10-20 years old with spinal fractures were retrospectively analyzed. The cumulative effective doses for all imaging studies were calculated, and the doses to patients with spinal injuries who had multiple traumatic injuries were compared with the doses to patients with spinal injuries but without multiple injuries. The significance level was set at 5%. Imaging studies of 72 patients (32 with multiple injuries; average age, 17.5 years) entailed a median cumulative effective dose of 18.89 mSv. Patients with multiple injuries had a significantly higher total cumulative effective dose (29.70 versus 10.86 mSv, p < 0.001) mainly owing to the significantly higher CT-related cumulative effective dose to multiple injury patients during the initial evaluation (18.39 versus 2.83 mSv, p < 0.001). Overall, CT accounted for 86% of the total cumulative effective dose. Adolescents with spinal injuries receive a cumulative effective dose equal to that of adult trauma patients and nearly three times that of pediatric trauma patients. Areas of focus in lowering cumulative effective dose should be appropriate initial estimation of trauma severity and careful selection of CT scan parameters.

[Absorbed dose and the effective dose of panoramic temporo mandibular joint radiography].

PubMed

Matsuo, Ayae; Okano, Tsuneichi; Gotoh, Kenichi; Yokoi, Midori; Hirukawa, Akiko; Okumura, Shinji; Koyama, Syuji

2011-01-01

This study measured the radiation doses absorbed by the patient during Panoramic temporo mandibular joint radiography (Panoramic TMJ), Schüllers method and Orbitoramus projection. The dose of the frontal view in Panoramic TMJ was compared to that with Orbitoramus projection and the lateral view in Panoramic TMJ was compared to that with Schüllers method. We measured the doses received by various organs and calculated the effective doses using the guidelines of the International Commission on Radiological Protection in Publication 103. Organ absorbed doses were measured using an anthropomorphic phantom, loaded with thermoluminescent dosimeters (TLD), located at 160 sensitive sites. The dose shows the sum value of irradiation on both the right and left sides. In addition, we set a few different exposure field sizes. The effective dose for a frontal view in Panoramic TMJ was 11 µSv, and that for the lateral view was 14 µSv. The lens of the Orbitoramus projection was 40 times higher than the frontal view in Panoramic TMJ. Although the effective dose of the lateral view in Panoramic TMJ was 3 times higher than that of the small exposure field (10×10 cm on film) in Schüller's method, it was the same as that of a mid-sized exposure field. When the exposure field in the inferior 1/3 was reduced during panoramic TMJ, the effective doses could be decreased. Therefore we recommend that the size of the exposure field in Panoramic TMJ be decreased.

Impact of hemodialysis dose and frequency on survival of patients on chronic hemodialysis in Lithuania during 1998-2005.

PubMed

Stankuvienė, Asta; Ziginskienė, Edita; Kuzminskis, Vytautas; Bumblytė, Inga Arūnė

2010-01-01

The question of the targets of dialysis dosing remains controversial since the beginning of the long-term dialysis treatment era. It is still uncertain if higher dialysis dose is better. The aim of our study was to investigate issues of dialysis dose in Lithuania during the period of 1998-2005 and to determine associations between hemodialysis dose and survival of patients on chronic hemodialysis. We analyzed data of all patients who started hemodialysis due to end-stage renal disease in Lithuania between January 1, 1998, and December 31, 2005. The information about hemodialysis frequency, duration, and adequacy (according to Kt/V) was obtained from medical documentation. The overall survival rate was estimated using the Kaplan-Meier method. Survival comparisons were made using the log-rank or Breslow tests. Univariate Cox proportional hazards analysis was used to select variables significantly associated with the risk of death; then these variables were included in multivariate Cox proportional hazards models. During the study period, from 2428 patients who started chronic hemodialysis, 58.5% of patients started hemodialysis three times a week. More than one-third (36.2%) of patients were dialyzed twice weekly, and 5.3% of patients started hemodialysis once weekly. Survival analysis revealed that patients dialyzed less than three times per week survived shorter than patients receiving a higher dialysis dose. Duration of HD session of ≤8 hours per week was an independent risk factor for mortality. A higher mean Kt/V was associated with better survival of patients on chronic hemodialysis. Dialysis frequency and weekly duration of HD sessions were dependent on HD accessibility in Lithuania during the period of 1998-2005. Better survival of patients on chronic hemodialysis was associated with a higher hemodialysis dose.

Proton irradiation and endometriosis

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

Wood, D.H.; Yochmowitz, M.G.; Salmon, Y.L.

1983-08-01

Female rhesus monkeys given single total-body exposures of protons of varying energies developed endometriosis at a frequency significantly higher than that of nonirradiated animals of the same age. The minimum latency period was 7 years after exposure. The doses and energies of the radiation received were within the range that could be received by an aircrew member in near-earth orbit during a random solar flare event, leading to the conclusion that endometriosis should be a consideration in assessing the risk of delayed radiation effects in female crewmembers.

Does Digital Video Advertising Increase Population-Level Reach of Multimedia Campaigns? Evidence From the 2013 Tips From Former Smokers Campaign

PubMed Central

Shafer, Paul R; Rodes, Robert; Kim, Annice; Hansen, Heather; Patel, Deesha; Coln, Caryn; Beistle, Diane

2016-01-01

Background Federal and state public health agencies in the United States are increasingly using digital advertising and social media to promote messages from broader multimedia campaigns. However, little evidence exists on population-level campaign awareness and relative cost efficiencies of digital advertising in the context of a comprehensive public health education campaign. Objective Our objective was to compare the impact of increased doses of digital video and television advertising from the 2013 Tips From Former Smokers (Tips) campaign on overall campaign awareness at the population level. We also compared the relative cost efficiencies across these media platforms. Methods We used data from a large national online survey of approximately 15,000 US smokers conducted in 2013 immediately after the conclusion of the 2013 Tips campaign. These data were used to compare the effects of variation in media dose of digital video and television advertising on population-level awareness of the Tips campaign. We implemented higher doses of digital video among selected media markets and randomly selected other markets to receive similar higher doses of television ads. Multivariate logistic regressions estimated the odds of overall campaign awareness via digital or television format as a function of higher-dose media in each market area. All statistical tests used the .05 threshold for statistical significance and the .10 level for marginal nonsignificance. We used adjusted advertising costs for the additional doses of digital and television advertising to compare the cost efficiencies of digital and television advertising on the basis of costs per percentage point of population awareness generated. Results Higher-dose digital video advertising was associated with 94% increased odds of awareness of any ad online relative to standard-dose markets (P<.001). Higher-dose digital advertising was associated with a marginally nonsignificant increase (46%) in overall campaign awareness regardless of media format (P=.09). Higher-dose television advertising was associated with 81% increased odds of overall ad awareness regardless of media format (P<.001). Increased doses of television advertising were also associated with significantly higher odds of awareness of any ad on television (P<.001) and online (P=.04). The adjusted cost of each additional percentage point of population-level reach generated by higher doses of advertising was approximately US $440,000 for digital advertising and US $1 million for television advertising. Conclusions Television advertising generated relatively higher levels of overall campaign awareness. However, digital video was relatively more cost efficient for generating awareness. These results suggest that digital video may be used as a cost-efficient complement to traditional advertising modes (eg, television), but digital video should not replace television given the relatively smaller audience size of digital video viewers. PMID:27627853

Does Digital Video Advertising Increase Population-Level Reach of Multimedia Campaigns? Evidence From the 2013 Tips From Former Smokers Campaign.

PubMed

Davis, Kevin C; Shafer, Paul R; Rodes, Robert; Kim, Annice; Hansen, Heather; Patel, Deesha; Coln, Caryn; Beistle, Diane

2016-09-14

Federal and state public health agencies in the United States are increasingly using digital advertising and social media to promote messages from broader multimedia campaigns. However, little evidence exists on population-level campaign awareness and relative cost efficiencies of digital advertising in the context of a comprehensive public health education campaign. Our objective was to compare the impact of increased doses of digital video and television advertising from the 2013 Tips From Former Smokers (Tips) campaign on overall campaign awareness at the population level. We also compared the relative cost efficiencies across these media platforms. We used data from a large national online survey of approximately 15,000 US smokers conducted in 2013 immediately after the conclusion of the 2013 Tips campaign. These data were used to compare the effects of variation in media dose of digital video and television advertising on population-level awareness of the Tips campaign. We implemented higher doses of digital video among selected media markets and randomly selected other markets to receive similar higher doses of television ads. Multivariate logistic regressions estimated the odds of overall campaign awareness via digital or television format as a function of higher-dose media in each market area. All statistical tests used the .05 threshold for statistical significance and the .10 level for marginal nonsignificance. We used adjusted advertising costs for the additional doses of digital and television advertising to compare the cost efficiencies of digital and television advertising on the basis of costs per percentage point of population awareness generated. Higher-dose digital video advertising was associated with 94% increased odds of awareness of any ad online relative to standard-dose markets (P<.001). Higher-dose digital advertising was associated with a marginally nonsignificant increase (46%) in overall campaign awareness regardless of media format (P=.09). Higher-dose television advertising was associated with 81% increased odds of overall ad awareness regardless of media format (P<.001). Increased doses of television advertising were also associated with significantly higher odds of awareness of any ad on television (P<.001) and online (P=.04). The adjusted cost of each additional percentage point of population-level reach generated by higher doses of advertising was approximately US $440,000 for digital advertising and US $1 million for television advertising. Television advertising generated relatively higher levels of overall campaign awareness. However, digital video was relatively more cost efficient for generating awareness. These results suggest that digital video may be used as a cost-efficient complement to traditional advertising modes (eg, television), but digital video should not replace television given the relatively smaller audience size of digital video viewers.

Safety and Efficacy of Stereotactic Ablative Radiation Therapy for Renal Cell Carcinoma Extracranial Metastases

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

Wang, Chiachien Jake; Department of Radiation Oncology, University of Texas Southwestern Medical Center, Dallas, Texas; Christie, Alana

Purpose: Renal cell carcinoma is refractory to conventional radiation therapy but responds to higher doses per fraction. However, the dosimetric data and clinical factors affecting local control (LC) are largely unknown. We aimed to evaluate the safety and efficacy of stereotactic ablative radiation therapy (SAbR) for extracranial renal cell carcinoma metastases. Methods and Materials: We reviewed 175 metastatic lesions from 84 patients treated with SAbR between 2005 and 2015. LC and toxicity after SAbR were assessed with Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 and Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. Predictors of local failure weremore » analyzed with χ{sup 2}, Kaplan-Meier, and log-rank tests. Results: In most cases (74%), SAbR was delivered with total doses of 40 to 60 Gy, 30 to 54 Gy, and 20 to 40 Gy in 5 fractions, 3 fractions, and a single fraction, respectively. The median biologically effective dose (BED) using the universal survival model was 134.5 Gy. The 1-year LC rate after SAbR was 91.2% (95% confidence interval, 84.9%-95.0%; median follow-up, 16.7 months). Local failures were associated with prior radiation therapy (hazard ratio [HR], 10.49; P<.0001), palliative-intent radiation therapy (HR, 4.63; P=.0189), spinal location (HR, 5.36; P=.0041), previous systemic therapy status (0-1 vs >1; HR, 3.52; P=.0217), and BED <115 Gy (HR, 3.45; P=.0254). Dose received by 99% of the target volume was the strongest dosimetric predictor for LC. Upon multivariate analysis, dose received by 99% of the target volume greater than BED of 98.7 Gy and systemic therapy status remained significant (HR, 0.12 and 3.64, with P=.0014 and P=.0472, respectively). Acute and late grade 3 toxicities attributed to SAbR were observed in 3 patients (1.7%) and 5 patients (2.9%), respectively. Conclusions: SAbR demonstrated excellent LC of metastatic renal cell carcinoma with a favorable safety profile when an adequate dose and coverage were applied. Multimodality treatment with surgery should be considered for reirradiation or vertebral metastasis. A higher radiation dose may be required in patients who received previous systemic therapies.« less

Massive paracetamol overdose: an observational study of the effect of activated charcoal and increased acetylcysteine dose (ATOM-2).

PubMed

Chiew, Angela L; Isbister, Geoffrey K; Kirby, Katharine A; Page, Colin B; Chan, Betty S H; Buckley, Nicholas A

2017-12-01

Paracetamol is commonly taken in overdose, with increasing concerns that those taking "massive" overdoses have higher rates of hepatotoxicity and may require higher doses of acetylcysteine. The objective was to describe the clinical characteristics and outcomes of "massive" (≥ 40 g) paracetamol overdoses. Patients were identified through the Australian Paracetamol Project, a prospective observational study through Poisons Information Centres in NSW and Queensland, over 3 and 1.5 years, respectively, and retrospectively from three clinical toxicology unit databases (over 2.5 to 20 years). Included were immediate-release paracetamol overdoses ≥ 40 g ingested over ≤ 8 h. Outcomes measured included paracetamol ratio[defined as the ratio of the first paracetamol concentration taken 4-16 h post-ingestion to the standard (150 mg/L at 4 h) nomogram line at that time] and hepatotoxicity (ALT >1000 U/L). Two hundred paracetamol overdoses were analysed, reported median dose ingested was 50 g (interquartile range (IQR): 45-60 g) and median paracetamol ratio 1.9 (IQR: 1.4-2.9, n = 173). One hundred and ninety-three received acetylcysteine at median time of 6.3 h (IQR: 4-9.3 h) post-ingestion. Twenty-eight (14%) developed hepatotoxicity, including six treated within 8 h of ingestion. Activated charcoal was administered to 49(25%), at median of 2 h post-ingestion (IQR:1.5-5 h). Those receiving activated charcoal (within 4 h of ingestion), had significantly lower paracetamol ratio versus those who did not: 1.4 (n = 33, IQR: 1.1-1.6) versus 2.2 (n = 140, IQR: 1.5-3.0) (p < .0001) (paracetamol concentration measured ≥ 1 h after charcoal). Furthermore, they had lower rates of hepatotoxicity [unadjusted OR: 0.12 (95% CI: <0.001-0.91); adjusted for time to acetylcysteine OR: 0.20 (95%CI: 0.002-1.74)]. Seventy-nine had a paracetamol ratio ≥2, 43 received an increased dose of acetylcysteine in the first 21 h; most commonly a double dose in the last bag (100 to 200 mg/kg/16 h). Those receiving increased acetylcysteine had a significant decrease risk of hepatotoxicity [OR:0.27 (95% CI: 0.08-0.94)]. The OR remained similar after adjustment for time to acetylcysteine and paracetamol ratio. Massive paracetamol overdose can result in hepatotoxicity despite early treatment. Paracetamol concentrations were markedly reduced in those receiving activated charcoal within 4 h. In those with high paracetamol concentrations, treatment with increased acetylcysteine dose within 21 h was associated with a significant reduction in hepatotoxicity.

Prospective study of inner ear radiation dose and hearing loss in head-and-neck cancer patients

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

Pan, Charlie C.; Eisbruch, Avraham; Lee, Julia S.

Purpose: To determine the relationship between the radiation dose to the inner ear and long-term hearing loss. Methods and Materials: Eligible patients included those receiving curative radiotherapy (RT) for head-and-neck cancer. After enrollment, patients underwent three-dimensional conformal RT planning and delivery (180-200 cGy/fraction) appropriate for their disease site and stage. The inner ear was contoured on axial CT planning images. Dose-volume histograms, as well as the mean and maximal dose for each structure, were calculated. Patients underwent pure tone audiometry at baseline (before treatment) and 1, 6, 12, 24, and 36 months after RT. The threshold level (the greater themore » value, the more hearing loss) in decibels was recorded for 250, 500, 1000, 2000, 4000, and 8000 Hz. For patients receiving predominantly unilateral RT, the contralateral ear served as the de facto control. The differences in threshold level between the ipsilateral and contralateral ears were calculated, and the temporal pattern and dose-response relation of hearing loss were analyzed using statistical methods that take into account the correlation between two ears in the same subject and repeated, sequential measurements of each subject. Results: Of the 40 patients enrolled in this study, 35 qualified for analysis. Four patients who received concurrent chemotherapy and RT were analyzed separately. The 31 unilaterally treated patients received a median dose of 47.4 Gy (range, 14.1-68.8 Gy) to the ipsilateral inner ear and 4.2 Gy (range, 0.5-31.3 Gy) to the contralateral inner ear. Hearing loss was associated with the radiation dose received by the inner ear (loss of 210dB was observed in ears receiving {>=}45 Gy) and was most appreciable in the higher frequencies ({>=}2000 Hz). For a 60-year-old patient with no previous hearing loss in either ear, after receiving 45 Gy, the ipsilateral ear, according to our clinical model, would have a 19.3-dB (95% confidence interval [CI], 15.5-23.0) and 5.4-dB (95% CI, 3.5-7.5) hearing decrement compared with the contralateral ear for 8000 Hz and 1000 Hz, respectively. Age and an initial hearing difference within an ear pair also affected hearing loss. The baseline hearing threshold was inversely related to radiation-induced hearing loss. The degree of hearing loss was dependent on the frequency tested, age, baseline hearing, and baseline difference in hearing between a patient's two ears. Conclusion: High-frequency ({>=}2000 Hz) hearing acuity worsens significantly after RT in a dose-dependent fashion. A larger number of patients needs to be studied to validate these results. This knowledge can be applied to create guidelines regarding future dose limits to the auditory apparatus for patients undergoing head-and-neck RT.« less

Preventing radiation retinopathy with hyperfractionation

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

Monroe, Alan T.; Bhandare, Niranjan; Morris, Christopher G.

2005-03-01

Purpose: The purpose of this study was to determine factors associated with the development of radiation retinopathy in a large series of patients with head-and-neck cancer. In particular, we addressed whether the use of hyperfractionated radiation therapy was effective in reducing the risk of retinopathy. Methods and materials: One hundred eighty-six patients received a significant dose to the retina as part of curative radiotherapy. Primary sites included: nasopharynx, 46; paranasal sinus, 64; nasal cavity, 69; and palate, 7. Prescription doses varied depending on primary site and histology. Hyperfractionated (twice-daily) radiation was delivered to 42% of the patients in this study,more » typically at 1.10 to 1.20 Gy per fraction. The remainder were treated once-daily. Retinal doses were determined from computerized dosimetry plans when available. For all other patients, retinal doses were retrospectively calculated using reconstructed off-axis dosimetry taken from contours through the center of the globes. Retinal dose was defined as the minimum dose received by at least 25% of the globe. The median retinal dose was 56.85 Gy. Patients were followed for a median of 7.6 years. Results: Thirty-one eyes in 30 patients developed radiation retinopathy, resulting in monocular blindness in 25, bilateral blindness in 1, and decreased visual acuity in 4. The median time to the diagnosis of retinopathy was 2.6 years (range, 11 months to 5.3 years). The actuarial incidence of developing radiation retinopathy was 20% at both 5 and 10 years. The incidence of developing ipsilateral blindness due to retinopathy was 16% at 5 years and 17% at 10 years. Site-specific incidences varied considerably, with ethmoid sinus (9 of 25, 36%), nasal cavity (13 of 69, 19%), and maxillary sinus (6 of 35, 17%) being the most common sites associated with radiation retinopathy. Three of 72 patients (4%) receiving retinal doses less than 50 Gy developed retinopathy. Higher retinal doses resulted in a steady increase in the incidence of retinopathy, with 25 of the 30 cases occurring after 60 Gy or more. Of the patients receiving more than 50 Gy to the retina, hyperfractionation was associated with a significantly lower incidence of radiation retinopathy (37% vs. 13%; p = 0.0037). On multivariate analysis, retinal dose (p < 0.0001), fractionation schedule (p = 0.0003), age (p = 0.0365), and prolonged overall treatment time (p = 0.0213) were significant predictors of radiation retinopathy. Conclusion: The incidence of ipsilateral radiation retinopathy after treatment of nasal cavity/paranasal tumors is 20% at 5 and 10 years. Retinal dose and fractionation schedule are the strongest predictors of retinopathy. Hyperfractionated radiotherapy is associated with a significant reduction in the incidence of radiation retinopathy, especially when the retina receives more than 50 Gy.« less

Vitamin D in newborns. A randomised controlled trial comparing daily and single oral bolus vitamin D in infants.

PubMed

Huynh, Julie; Lu, Thao; Liew, Danny; Doery, James Cg; Tudball, Ronald; Jona, Madeleine; Bhamjee, Roisin; Rodda, Christine P

2017-02-01

There are no published data to demonstrate the efficacy of bolus dose vitamin D in newborn infants. The study sought to evaluate this alternative approach of supplementation. This single centre, open randomised controlled trial was conducted from August 2013 to May 2014. It compared the efficacy and safety of daily (400 IU) versus a bolus dose (50 000 IU) of cholecalciferol in newborn infants of vitamin D deficient mothers. The primary outcome measure was the rate of 25 hydroxyvitamin D (25OHD) repletion-defined as 25OHD greater than 50 nmol/L. The secondary objective was determining safety using adjusted total serum calcium. Of 70 eligible infants, 36 received a daily dose and 34 received a single high-dose cholecalciferol. Mean 25OHD in the bolus group (154 nmol/L, 95% confidence interval (CI) 131-177) was higher than the daily group (48 nmol/L, 95% CI 42-54) at 1-2 weeks of age. This was reversed at 3-4 months, (65 nmol/L, 95% CI 59-71) compared with the daily group (81 nmol/L, 95% CI 77-85). More infants in the single bolus group achieved vitamin D repletion (100 vs. 31%) at 1-2 weeks. By 3-4 months, both groups achieved similar vitamin D repletion rates (91 vs. 89%). Mean adjusted total serum calcium in the bolus group were normal at 1-2 weeks (2.73 mmol/L) and 3-4 months (2.55 mmol/L). Single bolus dosing of 50 000 IU cholecalciferol achieves higher 25OHD repletion rates at 1-2 weeks of age compared with daily dosing, but repletion rates were similar by 3-4 months. There was no hypercalcaemia documented with single bolus dosing in this study. © 2016 Paediatrics and Child Health Division (The Royal Australasian College of Physicians).

Brief Report: The Euro-Lupus Low-Dose Intravenous Cyclophosphamide Regimen Does Not Impact the Ovarian Reserve, as Measured by Serum Levels of Anti-Müllerian Hormone.

PubMed

Tamirou, Farah; Husson, Séverine Nieuwland; Gruson, Damien; Debiève, Frédéric; Lauwerys, Bernard R; Houssiau, Frédéric A

2017-06-01

The Euro-Lupus regimen of low-dose intravenous cyclophosphamide (IV CYC) (cumulative dose of 3 gm) was developed to reduce gonadal toxicity. To address the possibility of a marginal effect on the ovarian reserve, we measured serum titers of anti-Müllerian hormone (AMH) in patients with systemic lupus erythematosus (SLE) treated with the Euro-Lupus regimen and compared them with those measured in patients who were treated with higher doses of IV CYC or were never treated with IV CYC. Serum AMH levels were measured by enzyme-linked immunosorbent assay in a cohort of 155 premenopausal SLE patients; 30 of these patients had been treated with the Euro-Lupus regimen, and 24 had received higher doses of IV CYC. None had received oral CYC. AMH levels were age-adjusted using a slope computed from levels measured across the group of SLE patients who had not been treated with IV CYC. Demographic and clinical data were collected. Serum titers of AMH measured in SLE patients treated with the Euro-Lupus IV CYC regimen (median dose 1.46 ng/ml) did not differ from those measured in patients never treated with the cytotoxic drug (median 1.85 ng/ml). As expected, patients given >6 gm of IV CYC had significantly lower serum titers of AMH (median 0.83 ng/ml) compared with those never treated with IV CYC (P = 0.047). Median serum AMH titers did not change before (1.24 ng/ml) and after (2.50 ng/ml) treatment with the Euro-Lupus IV CYC regimen in the subset of patients for whom paired samples could be tested (P = 0.43). The Euro-Lupus regimen of low-dose IV CYC does not impact the ovarian reserve of SLE patients and can therefore be proposed as treatment in patients seeking to become pregnant. © 2017, American College of Rheumatology.

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

PubMed

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

2012-02-01

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

Assessment of topical versus oral ivermectin as a treatment for head lice.

PubMed

Ahmad, Hesham M; Abdel-Azim, Eman S; Abdel-Aziz, Rasha T

2014-01-01

Many medications are available for treatment of pediculosis capitis including ivermectin. Our aim is to compare the efficacy and safety of topical versus oral ivermectin in treatment of pediculosis capitis. Sixty-two patients with proved head lice infestation were included and divided into group I (31 patients; received single topical application of 1% ivermectin) and group II (31 patients; received single dose of oral ivermectin). Treatment was repeated after 1 week for nonresponders. At 1 week after treatment, the eradication rates and improvement of pruritus were significantly higher among patients who received topical than oral ivermectin. When a second treatment, topical or oral, was given to nonresponders, the cure rates of infestation and pruritus was 100% and 97% among patients treated with topical and oral ivermectin, respectively with no significant difference between the two groups. This study suggests that both topical and oral ivermectin demonstrate high efficacy and tolerability in treatment of pediculosis capitis. However, a single treatment with topical ivermectin provides significantly higher cure of infestation and faster relief of pruritus than oral ivermectin. In addition, whether topical or oral ivermectin is used to treat head lice, a second dose is required in some cases to ensure complete eradication. © 2014 Wiley Periodicals, Inc.

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

PubMed Central

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

2016-01-01

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

RESISTANCE PRODUCED IN MICE BY EXPOSURE TO IRRADIATED SCHISTOSOMA MANSONI CERCARIAE

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

Radke, M.G.; Sadun, E.H.

1963-04-01

Studies were undertaken to determine whether gamma irradiation of cercariae might provide a means of investigating some of the mechanisms involved in the acquired resistance to schistosomiasis. Control mice received 200 nonirradiated cercariae, and other groups received the same number of cercariae that had been exposed to 6 different doses of Co/sup 60/ gamma irradiation varying from 1000--20000 rep. Eight weeks later the worms recovered were counted. Doses of 4000 rep or higher completely inhibited the development of schistosomes. A few stunted and underdeveloped worms were found in some of the mice receiving cercariae irradiated at 2500 and 3000 rep.more » Some adult schistosomes were observed in the groups receiving 1500 and 2000 rep and eggs were found in the liver but not in the stools of some mice. However, all of the mice exposed to cercariae irradiated with 1000 rep had eggs in liver and stools. The worm burden decreased regularly with increasing dosages up to 3000 rep, beyond which no worms were found at necropsy. The decrease in the number of worms mice acquired was linear only when cercariae were exposed from 1000to 2000 rep, however, even beyond such dosages, it followed a straight line when the logarithm of irradiation dose was plotied. Acquired resistance to S. mansoni was observed in mice following a previous exposure to irradiated cercariae. (TCO)« less

Immunogenicity and safety of primary and booster vaccination with 2 investigational formulations of diphtheria, tetanus and Haemophilus influenzae type b antigens in a hexavalent DTPa-HBV-IPV/Hib combination vaccine in comparison with the licensed Infanrix hexa.

PubMed

Vesikari, Timo; Rivera, Luis; Korhonen, Tiina; Ahonen, Anitta; Cheuvart, Brigitte; Hezareh, Marjan; Janssens, Winnie; Mesaros, Narcisa

2017-07-03

Safety and immunogenicity of 2 investigational formulations of diphtheria, tetanus and Haemophilus influenzae type b antigens of the combined diphtheria-tetanus-acellular pertussis-hepatitis B-inactivated poliomyelitis-Hib vaccine (DTPa-HBV-IPV/Hib) were evaluated in a Primary (NCT01248884) and a Booster vaccination (NCT01453998) study. In the Primary study, 721 healthy infants (randomized 1:1:1) received 3 doses of DTPa-HBV-IPV/Hib formulation A (D A T A Pa-HBV-IPV/Hib), or B (D B T B Pa-HBV-IPV/Hib) or the licensed DTPa-HBV-IPV/Hib vaccine (Infanrix hexa, GSK; control group) at 2, 3, 4 months of age. Infants were planned to receive a booster dose at 12-15 months of age with the same formulation received in the Primary study; however, following high incidence of fever associated with the investigational formulations in the Primary study, the Booster study protocol was amended and all infants yet to receive a booster dose (N = 385) received the licensed vaccine. In the Primary study, non-inferiority of 3-dose vaccination with investigational formulations compared with the licensed vaccine was not demonstrated due to anti-pertactin failing to meet the non-inferiority criterion. Post-primary vaccination, most infants had seroprotective levels of anti-diphtheria (100% of infants), anti-tetanus antigens (100%), against hepatitis B (≥ 97.5% across groups), polyribosyl-ribitol-phosphate (≥ 88.0%) and poliovirus types 1-3 (≥ 90.5%). Seropositivity rates for each pertussis antigen were 100% in all groups. Higher incidence of fever (> 38°C) was reported in infants receiving the investigational formulations (Primary study: 75.0% [A] and 72.1% [B] vs 58.8% [control]; Booster study, before amendment: 49.4% and 46.6% vs 37.4%, respectively). The development of the investigational formulations was not further pursued.

Immunogenicity and safety of primary and booster vaccination with 2 investigational formulations of diphtheria, tetanus and Haemophilus influenzae type b antigens in a hexavalent DTPa-HBV-IPV/Hib combination vaccine in comparison with the licensed Infanrix hexa

PubMed Central

Vesikari, Timo; Rivera, Luis; Korhonen, Tiina; Ahonen, Anitta; Cheuvart, Brigitte; Hezareh, Marjan; Janssens, Winnie; Mesaros, Narcisa

2017-01-01

ABSTRACT Safety and immunogenicity of 2 investigational formulations of diphtheria, tetanus and Haemophilus influenzae type b antigens of the combined diphtheria-tetanus-acellular pertussis-hepatitis B-inactivated poliomyelitis-Hib vaccine (DTPa-HBV-IPV/Hib) were evaluated in a Primary (NCT01248884) and a Booster vaccination (NCT01453998) study. In the Primary study, 721 healthy infants (randomized 1:1:1) received 3 doses of DTPa-HBV-IPV/Hib formulation A (DATAPa-HBV-IPV/Hib), or B (DBTBPa-HBV-IPV/Hib) or the licensed DTPa-HBV-IPV/Hib vaccine (Infanrix hexa, GSK; control group) at 2, 3, 4 months of age. Infants were planned to receive a booster dose at 12–15 months of age with the same formulation received in the Primary study; however, following high incidence of fever associated with the investigational formulations in the Primary study, the Booster study protocol was amended and all infants yet to receive a booster dose (N = 385) received the licensed vaccine. In the Primary study, non-inferiority of 3-dose vaccination with investigational formulations compared with the licensed vaccine was not demonstrated due to anti-pertactin failing to meet the non-inferiority criterion. Post-primary vaccination, most infants had seroprotective levels of anti-diphtheria (100% of infants), anti-tetanus antigens (100%), against hepatitis B (≥ 97.5% across groups), polyribosyl-ribitol-phosphate (≥ 88.0%) and poliovirus types 1–3 (≥ 90.5%). Seropositivity rates for each pertussis antigen were 100% in all groups. Higher incidence of fever (> 38°C) was reported in infants receiving the investigational formulations (Primary study: 75.0% [A] and 72.1% [B] vs 58.8% [control]; Booster study, before amendment: 49.4% and 46.6% vs 37.4%, respectively). The development of the investigational formulations was not further pursued. PMID:28340322

A Live Attenuated Influenza A(H5N1) Vaccine Induces Long-Term Immunity in the Absence of a Primary Antibody Response

PubMed Central

Talaat, Kawsar R.; Luke, Catherine J.; Khurana, Surender; Manischewitz, Jody; King, Lisa R.; McMahon, Bridget A.; Karron, Ruth A.; Lewis, Kristen D. C.; Qin, Jing; Follmann, Dean A.; Golding, Hana; Neuzil, Kathleen M.; Subbarao, Kanta

2014-01-01

Background. Highly pathogenic avian influenza A(H5N1) causes severe infections in humans. We generated 2 influenza A(H5N1) live attenuated influenza vaccines for pandemic use (pLAIVs), but they failed to elicit a primary immune response. Our objective was to determine whether the vaccines primed or established long-lasting immunity that could be detected by administration of inactivated subvirion influenza A(H5N1) vaccine (ISIV). Methods. The following groups were invited to participate in the study: persons who previously received influenza A(H5N1) pLAIV; persons who previously received an irrelevant influenza A(H7N3) pLAIV; and community members who were naive to influenza A(H5N1) and LAIV. LAIV-experienced subjects received a single 45-μg dose of influenza A(H5N1) ISIV. Influenza A(H5N1)– and LAIV-naive subjects received either 1 or 2 doses of ISIV. Results. In subjects who had previously received antigenically matched influenza A(H5N1) pLAIV followed by 1 dose of ISIV compared with those who were naive to influenza A(H5N1) and LAIV and received 2 doses of ISIV, we observed an increased frequency of antibody response (82% vs 50%, by the hemagglutination inhibition assay) and a significantly higher antibody titer (112 vs 76; P = .04). The affinity of antibody and breadth of cross-clade neutralization was also enhanced in influenza A(H5N1) pLAIV–primed subjects. Conclusions. ISIV administration unmasked long-lasting immunity in influenza A(H5N1) pLAIV recipients, with a rapid, high-titer, high-quality antibody response that was broadly cross-reactive across several influenza A(H5N1) clades. Clinical Trials Registration. NCT01109329. PMID:24604819

A study of the time of hospital discharge of differentiated thyroid cancer patients after receiving iodine-131 for thyroid remnant ablation treatment.

PubMed

Azizmohammadi, Zahra; Tabei, Faraj; Shafiei, Babak; Babaei, Ali Akbar; Jukandan, Seyed Mohsen Qutbi; Naghshine, Reza; Javadi, Hamid; Nabipour, Iraj; Assadi, Majid; Asli, Isa Neshandar

2013-01-01

The aim of this study was to measure the radiation exposure rate from differentiated thyroid carcinoma (DTC) patients who had received iodine-131 ((131)I) treatment, and to evaluate hospital discharge planning in relation to three different sets of regulations. We studied 100 patients, 78 females and 22 males, aged 13 to 79 years (mean 44.40±15.83 years) with DTC, in three Groups who were treated with 3.7, 5.5 or 7.4GBq of (131)I, respectively. The external whole-body dose rates following oral administration of (131)I were measured after each one of the first three hospitalization days. A multivariant linear analysis was performed, considering exposure rates as dependent variables to the administered dose for treatment, age, gender, regional and/or distant metastases, thyroglobulin (Tg), antibodies to Tg and thyroid remnant in the three dose groups. We found that the exposure rates after each of the three first days of hospitalization were 30, 50 and 70μSvh-1 at 1m. All our DTC patients had an acceptable dose rate on days 2 and 3 that allowed their hospital discharge. After only 1 day of hospitalization, just 3/11 cases showed not permissible exposure rates above 70μSvh-1. In conclusion, it is the opinion of the authors that after measuring the exposure rates, most treated, DTC patients could be discharged after only one day of hospitalization, even some of those treated with high doses of (131)I (7.4GBq). Patients, who received the higher doses of (131)I, should not be released before their individual exposure rate is measured.

Hemolytic Potential of Tafenoquine in Female Volunteers Heterozygous for Glucose-6-Phosphate Dehydrogenase (G6PD) Deficiency (G6PD Mahidol Variant) versus G6PD-Normal Volunteers.

PubMed

Rueangweerayut, Ronnatrai; Bancone, Germana; Harrell, Emma J; Beelen, Andrew P; Kongpatanakul, Supornchai; Möhrle, Jörg J; Rousell, Vicki; Mohamed, Khadeeja; Qureshi, Ammar; Narayan, Sushma; Yubon, Nushara; Miller, Ann; Nosten, François H; Luzzatto, Lucio; Duparc, Stephan; Kleim, Jörg-Peter; Green, Justin A

2017-09-01

Tafenoquine is an 8-aminoquinoline under investigation for the prevention of relapse in Plasmodium vivax malaria. This open-label, dose-escalation study assessed quantitatively the hemolytic risk with tafenoquine in female healthy volunteers heterozygous for the Mahidol 487A glucose-6-phosphate dehydrogenase (G6PD)-deficient variant versus G6PD-normal females, and with reference to primaquine. Six G6PD-heterozygous subjects (G6PD enzyme activity 40-60% of normal) and six G6PD-normal subjects per treatment group received single-dose tafenoquine (100, 200, or 300 mg) or primaquine (15 mg × 14 days). All participants had pretreatment hemoglobin levels ≥ 12.0 g/dL. Tafenoquine dose escalation stopped when hemoglobin decreased by ≥ 2.5 g/dL (or hematocrit decline ≥ 7.5%) versus pretreatment values in ≥ 3/6 subjects. A dose-response was evident in G6PD-heterozygous subjects ( N = 15) receiving tafenoquine for the maximum decrease in hemoglobin versus pretreatment values. Hemoglobin declines were similar for tafenoquine 300 mg (-2.65 to -2.95 g/dL [ N = 3]) and primaquine (-1.25 to -3.0 g/dL [ N = 5]). Two further cohorts of G6PD-heterozygous subjects with G6PD enzyme levels 61-80% ( N = 2) and > 80% ( N = 5) of the site median normal received tafenoquine 200 mg; hemolysis was less pronounced at higher G6PD enzyme activities. Tafenoquine hemolytic potential was dose dependent, and hemolysis was greater in G6PD-heterozygous females with lower G6PD enzyme activity levels. Single-dose tafenoquine 300 mg did not appear to increase the severity of hemolysis versus primaquine 15 mg × 14 days.

Comparison and Efficacy of Low-Dose and Standard-Dose Tamsulosin and Alfuzosin in Medical Expulsive Therapy for Lower Ureteral Calculi: Prospective, Randomized, Comparative Study

PubMed Central

Cha, Woo Heon; Choi, Jae Duck; Seo, Young Jin; Lee, Kyungseop

2012-01-01

Purpose Typically in Korea, for a standard dose (0.4 mg) of tamsulosin, two low doses (0.2 mg) are administered. The aim of this study was to evaluate and compare the efficacy of tamsulosin (0.2 mg and 0.4 mg) and alfuzosin (10 mg) in the treatment of lower ureteral stones. Materials and Methods A total of 141 patients presenting with a single 4- to 10-mm sized lower ureteral stone were randomly assigned to 4 groups. Patients in group 1 (n=41) and group 2 (n=30) received an oral dose of 0.2 mg tamsulosin once and twice daily, respectively, and patients in group 3 (n=36) received a daily oral dose of 10 mg alfuzosin. Patients in group 4 (n=34) received trospium chloride only. The spontaneous passage of stones, the stone expulsion time, and adverse effects were evaluated. Results There were no significant differences in patient background, including age, sex, BMI, stone size, stone side, and symptom duration. The spontaneous stone passage rate through the ureter was higher and the stone expulsion time was faster in groups 1, 2, and 3 than in group 4. There were no statistically different changes in groups 1, 2, and 3. The adverse effects observed in all groups were comparable and were mild. Conclusions Tamsulosin at 0.2 mg and 0.4 mg and alfuzosin (10 mg) proved to be safe and effective. A first cycle of medical expulsive therapy with tamsulosin 0.2 mg could be considered as an option in the management of single lower ureteral stone. PMID:22670195

Prevalence of risk factors for acquiring measles during the 2011 outbreak in Quebec and impact of the province-wide school-based vaccination campaign on population immunity.

PubMed

Billard, Marie-Noëlle; De Serres, Gaston; Gariépy, Marie-Claude; Boulianne, Nicole; Toth, Eveline; Landry, Monique; Skowronski, Danuta M

2017-01-01

A large measles outbreak occurred in Quebec, Canada, in 2011. Although nearly two-thirds of the cases occurred in only two health districts, a mass vaccination campaign targeting all Quebec elementary and high school students without valid two-dose history was undertaken to prevent future outbreaks. We compared rates of non-vaccination and age at first measles vaccine dose among students in the two most-affected districts and the rest of the province and estimated the improvement in overall student measles immunity due to the mass school-based vaccination campaign. Data were extracted from the provincial vaccination registry for students in kindergarten to grade 11 during the 2011/2012 school year. A telephone survey was conducted in three sub-groups: students whose first measles vaccine dose recorded in the vaccination registry was received during the 2011 school vaccination campaign; students with no dose recorded in the registry whose parents refused receipt during the school campaign; and students with no dose recorded in the registry and no information about parental consent/refusal during the school campaign. Neither the prevalence of being non-vaccinated nor a younger age at first pediatric dose were higher in the two most-affected districts versus the rest of the province. The school campaign vaccinated nearly 8% of all students including 7% who previously received at least one dose. Before the outbreak, 3% of students were not vaccinated and one-third of these (1%/3%) were vaccinated during the campaign. The campaign likely increased the absolute school population immunity by just 1.7%. The concentration of measles cases in the two most-affected health districts during the large Quebec outbreak is not explained by more students who were unvaccinated or who had received their first vaccine dose at a younger age. The vaccination campaign reached one-third of unvaccinated students and only marginally improved population immunity.

Recent Update on Radiation Dose Assessment for the State-of-the-Art Coronary Computed Tomography Angiography Protocols.

PubMed

Tan, Sock Keow; Yeong, Chai Hong; Ng, Kwan Hoong; Abdul Aziz, Yang Faridah; Sun, Zhonghua

2016-01-01

This study aimed to measure the absorbed doses in selected organs for prospectively ECG-triggered coronary computed tomography angiography (CCTA) using five different generations CT scanners in a female adult anthropomorphic phantom and to estimate the effective dose (HE). Prospectively ECG-triggered CCTA was performed using five commercially available CT scanners: 64-detector-row single source CT (SSCT), 2 × 32-detector-row-dual source CT (DSCT), 2 × 64-detector-row DSCT and 320-detector-row SSCT scanners. Absorbed doses were measured in 34 organs using pre-calibrated optically stimulated luminescence dosimeters (OSLDs) placed inside a standard female adult anthropomorphic phantom. HE was calculated from the measured organ doses and compared to the HE derived from the air kerma-length product (PKL) using the conversion coefficient of 0.014 mSv∙mGy-1∙cm-1 for the chest region. Both breasts and lungs received the highest radiation dose during CCTA examination. The highest HE was received from 2 × 32-detector-row DSCT scanner (6.06 ± 0.72 mSv), followed by 64-detector-row SSCT (5.60 ± 0.68 and 5.02 ± 0.73 mSv), 2 × 64-detector-row DSCT (1.88 ± 0.25 mSv) and 320-detector-row SSCT (1.34 ± 0.48 mSv) scanners. HE calculated from the measured organ doses were about 38 to 53% higher than the HE derived from the PKL-to-HE conversion factor. The radiation doses received from a prospectively ECG-triggered CCTA are relatively small and are depending on the scanner technology and imaging protocols. HE as low as 1.34 and 1.88 mSv can be achieved in prospectively ECG-triggered CCTA using 320-detector-row SSCT and 2 × 64-detector-row DSCT scanners.

Recent Update on Radiation Dose Assessment for the State-of-the-Art Coronary Computed Tomography Angiography Protocols

PubMed Central

Tan, Sock Keow; Yeong, Chai Hong; Ng, Kwan Hoong; Abdul Aziz, Yang Faridah; Sun, Zhonghua

2016-01-01

Objectives This study aimed to measure the absorbed doses in selected organs for prospectively ECG-triggered coronary computed tomography angiography (CCTA) using five different generations CT scanners in a female adult anthropomorphic phantom and to estimate the effective dose (HE). Materials and Methods Prospectively ECG-triggered CCTA was performed using five commercially available CT scanners: 64-detector-row single source CT (SSCT), 2 × 32-detector-row-dual source CT (DSCT), 2 × 64-detector-row DSCT and 320-detector-row SSCT scanners. Absorbed doses were measured in 34 organs using pre-calibrated optically stimulated luminescence dosimeters (OSLDs) placed inside a standard female adult anthropomorphic phantom. HE was calculated from the measured organ doses and compared to the HE derived from the air kerma-length product (PKL) using the conversion coefficient of 0.014 mSv∙mGy-1∙cm-1 for the chest region. Results Both breasts and lungs received the highest radiation dose during CCTA examination. The highest HE was received from 2 × 32-detector-row DSCT scanner (6.06 ± 0.72 mSv), followed by 64-detector-row SSCT (5.60 ± 0.68 and 5.02 ± 0.73 mSv), 2 × 64-detector-row DSCT (1.88 ± 0.25 mSv) and 320-detector-row SSCT (1.34 ± 0.48 mSv) scanners. HE calculated from the measured organ doses were about 38 to 53% higher than the HE derived from the PKL-to-HE conversion factor. Conclusion The radiation doses received from a prospectively ECG-triggered CCTA are relatively small and are depending on the scanner technology and imaging protocols. HE as low as 1.34 and 1.88 mSv can be achieved in prospectively ECG-triggered CCTA using 320-detector-row SSCT and 2 × 64-detector-row DSCT scanners. PMID:27552224

Antimalarial Activity of KAF156 in Falciparum and Vivax Malaria.

PubMed

White, Nicholas J; Duong, Tran T; Uthaisin, Chirapong; Nosten, François; Phyo, Aung P; Hanboonkunupakarn, Borimas; Pukrittayakamee, Sasithon; Jittamala, Podjanee; Chuthasmit, Kittiphum; Cheung, Ming S; Feng, Yiyan; Li, Ruobing; Magnusson, Baldur; Sultan, Marc; Wieser, Daniela; Xun, Xiaolei; Zhao, Rong; Diagana, Thierry T; Pertel, Peter; Leong, F Joel

2016-09-22

KAF156 belongs to a new class of antimalarial agents (imidazolopiperazines), with activity against asexual and sexual blood stages and the preerythrocytic liver stages of malarial parasites. We conducted a phase 2, open-label, two-part study at five centers in Thailand and Vietnam to assess the antimalarial efficacy, safety, and pharmacokinetic profile of KAF156 in adults with acute Plasmodium vivax or P. falciparum malaria. Assessment of parasite clearance rates in cohorts of patients with vivax or falciparum malaria who were treated with multiple doses (400 mg once daily for 3 days) was followed by assessment of the cure rate at 28 days in a separate cohort of patients with falciparum malaria who received a single dose (800 mg). Median parasite clearance times were 45 hours (interquartile range, 42 to 48) in 10 patients with falciparum malaria and 24 hours (interquartile range, 20 to 30) in 10 patients with vivax malaria after treatment with the multiple-dose regimen and 49 hours (interquartile range, 42 to 54) in 21 patients with falciparum malaria after treatment with the single dose. Among the 21 patients who received the single dose and were followed for 28 days, 1 had reinfection and 7 had recrudescent infections (cure rate, 67%; 95% credible interval, 46 to 84). The mean (±SD) KAF156 terminal elimination half-life was 44.1±8.9 hours. There were no serious adverse events in this small study. The most common adverse events included sinus bradycardia, thrombocytopenia, hypokalemia, anemia, and hyperbilirubinemia. Vomiting of grade 2 or higher occurred in 2 patients, 1 of whom discontinued treatment because of repeated vomiting after receiving the single 800-mg dose. More adverse events were reported in the single-dose cohort, which had longer follow-up, than in the multiple-dose cohorts. KAF156 showed antimalarial activity without evident safety concerns in a small number of adults with uncomplicated P. vivax or P. falciparum malaria. (Funded by Novartis and others; ClinicalTrials.gov number, NCT01753323 .).

Dose--effect relationships for femoral fractures after multimodality limb-sparing therapy of soft-tissue sarcomas of the proximal lower extremity.

PubMed

Pak, Daniel; Vineberg, Karen A; Griffith, Kent A; Sabolch, Aaron; Chugh, Rashmi; Ben-Josef, Edgar; Biermann, Janet Sybil; Feng, Mary

2012-07-15

We investigated the clinical and dosimetric predictors for radiation-associated femoral fractures in patients with proximal lower extremity soft tissue sarcomas (STS). We examined 131 patients with proximal lower extremity STS who received limb-sparing surgery and external-beam radiation therapy between 1985 and 2006. Five (4%) patients sustained pathologic femoral fractures. Dosimetric analysis was limited to 4 fracture patients with full three-dimensional dose information, who were compared with 59 nonfracture patients. The mean doses and volumes of bone (V(d)) receiving specified doses (≥30 Gy, 45 Gy, 60 Gy) at the femoral body, femoral neck, intertrochanteric region, and subtrochanteric region were compared. Clinical predictive factors were also evaluated. Of 4 fracture patients in our dosimetric series, there were three femoral neck fractures with a mean dose of 57.6 ± 8.9 Gy, V30 of 14.5 ± 2.3 cc, V45 of 11.8 ± 1.1 cc, and V60 of 7.2 ± 2.2 cc at the femoral neck compared with 22.9 ± 20.8 Gy, 4.8 ± 5.6 cc, 2.5 ± 3.9 cc, and 0.8 ± 2.7 cc, respectively, for nonfracture patients (p < 0.03 for all). The femoral neck fracture rate was higher than at the subtrochanteric region despite lower mean doses at these subregions. All fracture sites received mean doses greater than 40 Gy. Also, with our policy of prophylactic femoral intramedullary nailing for high-risk patients, there was no significant difference in fracture rates between patients with and without periosteal excision. There were no significant differences in age, sex, tumor size, timing of radiation therapy, and use of chemotherapy between fracture and nonfracture patients. These dose-volume toxicity relationships provide RT optimization goals to guide future efforts for reducing pathologic fracture rates. Prophylactic femoral intramedullary nailing may also reduce fracture risk for susceptible patients. Copyright © 2012 Elsevier Inc. All rights reserved.

Immunogenicity and Immunologic Memory after Hepatitis B Virus Booster Vaccination in HIV-Infected Children Receiving Highly Active Antiretroviral Therapy

PubMed Central

Abzug, Mark J.; Warshaw, Meredith; Rosenblatt, Howard M.; Levin, Myron J.; Nachman, Sharon A.; Pelton, Stephen I.; Borkowsky, William; Fenton, Terence

2010-01-01

Background Hepatitis B virus (HBV) is an important cause of comorbidity in human immunodeficiency virus (HIV)–infected individuals. The immunogenicity of HBV vaccination in children receiving highly active antiretroviral therapy (HAART) was investigated. Methods HIV-infected children receiving HAART who had low to moderate HIV loads and who had previously received ≥3 doses of HBV vaccine were given an HBV vaccine booster. Concentrations of antibody to hepatitis B surface antigen (anti-HBs) were determined before vaccination and at weeks 8, 48, and 96. A subset of subjects was administered a subsequent dose, and anti-HBs was measured before and 1 and 4 weeks later. Results At entry, 24% of 204 subjects were seropositive. Vaccine response occurred in 46% on the basis of seropositivity 8 weeks after vaccination and in 37% on the basis of a ≥4-fold rise in antibody concentration. Of 69 subjects given another vaccination 4–5 years later, immunologic memory was exhibited by 45% on the basis of seropositivity 1 week after vaccination and by 29% on the basis of a ≥4-fold rise in antibody concentration at 1 week. Predictors of response and memory included higher nadir and current CD4 cell percentage, higher CD19 cell percentage, and undetectable HIV load. Conclusions HIV-infected children frequently lack protective levels of anti-HBs after previous HBV vaccination, and a significant proportion of them do not respond to booster vaccination or demonstrate memory despite receiving HAART, leaving this population insufficiently protected from infection with HBV. PMID:19663708

Immunogenicity of the 9-Valent HPV Vaccine Using 2-Dose Regimens in Girls and Boys vs a 3-Dose Regimen in Women.

PubMed

Iversen, Ole-Erik; Miranda, Maria Jose; Ulied, Angels; Soerdal, Terje; Lazarus, Erica; Chokephaibulkit, Kulkanya; Block, Stan L; Skrivanek, Ales; Nur Azurah, Abdul Ghani; Fong, Siew Moy; Dvorak, Vladimir; Kim, Kyung-Hyo; Cestero, Ramon M; Berkovitch, Matitiahu; Ceyhan, Mehmet; Ellison, Misoo C; Ritter, Michael A; Yuan, Shuai S; DiNubile, Mark J; Saah, Alfred J; Luxembourg, Alain

2016-12-13

Human papillomavirus (HPV) infections cause anogenital cancers and warts. The 9-valent HPV vaccine provides protection against 7 high-risk types of HPV responsible for 90% of cervical cancers and 2 other HPV types accounting for 90% of genital warts. To determine whether HPV type-specific antibody responses would be noninferior among girls and boys aged 9 to 14 years after receiving 2 doses of the 9-valent HPV vaccine compared with adolescent girls and young women aged 16 to 26 years receiving 3 doses. Open-label, noninferiority, immunogenicity trial conducted at 52 ambulatory care sites in 15 countries. The study was initiated on December 16, 2013, with the last participant visit for this report on June 19, 2015. Five cohorts were enrolled: (1) girls aged 9 to 14 years to receive 2 doses 6 months apart (n = 301); (2) boys aged 9 to 14 years to receive 2 doses 6 months apart (n = 301); (3) girls and boys aged 9 to 14 years to receive 2 doses 12 months apart (n = 301); (4) girls aged 9 to 14 years to receive 3 doses over 6 months (n = 301); and (5) a control group of adolescent girls and young women aged 16 to 26 years to receive 3 doses over 6 months (n = 314). Two doses of the 9-valent HPV vaccine administered 6 or 12 months apart or 3 doses administered over 6 months. The primary end point was prespecified as the antibody response against each HPV type assessed 1 month after the last dose using a competitive immunoassay. Each of the three 2-dose regimens was compared with the standard 3-dose schedule in adolescent girls and young women using a noninferiority margin of 0.67 for the ratio of the antibody geometric mean titers. Of the 1518 participants (753 girls [mean age, 11.4 years]; 451 boys [mean age, 11.5 years]; and 314 adolescent girls and young women [mean age, 21.0 years]), 1474 completed the study and data from 1377 were analyzed. At 4 weeks after the last dose, HPV antibody responses in girls and boys given 2 doses were noninferior to HPV antibody responses in adolescent girls and young women given 3 doses (P < .001 for each HPV type). Compared with adolescent girls and young women who received 3 doses over 6 months, the 1-sided 97.5% CIs for the ratio of HPV antibody geometric mean titers at 1 month after the last dose across the 9 HPV subtypes ranged from 1.36 to ∞ to 2.50 to ∞ for girls who received 2 doses 6 months apart; from 1.37 to ∞ to 2.55 to ∞ for boys who received 2 doses 6 months apart; and from 1.61 to ∞ to 5.36 to ∞ for girls and boys who received 2 doses 12 months apart. Among girls and boys aged 9 to 14 years receiving 2-dose regimens of a 9-valent HPV vaccine separated by 6 or 12 months, immunogenicity 4 weeks after the last dose was noninferior to a 3-dose regimen in a cohort of adolescent girls and young women. Further research is needed to assess persistence of antibody responses and effects on clinical outcomes. clinicaltrials.gov Identifier: NCT01984697.

Dose finding study of granisetron in patients receiving high-dose cisplatin chemotherapy. The Granisetron Study Group.

PubMed Central

Riviere, A.

1994-01-01

The efficacy and safety of three different doses of granisetron (2 micrograms kg-1, group A; 10 micrograms kg-1, group B; 40 micrograms kg-1, group C) were compared in a randomised, double-blind study of 157 patients due to receive high-dose cisplatin therapy (mean dose > 97 mg m-2). In each group, up to two 3 mg rescue doses of granisetron were allowed if more than mild nausea or vomiting occurred. In group A 30.8%, in group B 61.5% and in group C 67.9% of patients were complete responders (i.e. no vomiting or nothing worse than mild nausea) during the first 24 h. These differences are significant between groups A and B, and A and C. There were no statistically significant differences in any efficacy variable between the 10 micrograms kg-1 and 40 micrograms kg-1 groups, although in each case the trend favoured the higher dose. Additional rescue doses resulted in resolved or improved symptoms in 95.3% for the first rescue dose and 93.3% for the second. Over the 7 days of the study, 82.7%, 82.7% and 86.8% of patients in groups A, B and C respectively were treated with granisetron alone. Headache was the most common side-effect, reported by 9.6% of patients; the majority of headaches were mild. There was no difference between the treatment groups regarding the adverse event rate. We concluded that prophylactic doses of 10 or 40 micrograms kg-1 lead to a safe and satisfactory degree of control of nausea and vomiting induced by high-dose cisplatin. PMID:8180032

Thermal Dose is Related to Duration of Local Control in Canine Sarcomas Undergoing Thermoradiotherapy

PubMed Central

Thrall, Donald E.; LaRue, Susan M.; Yu, Daohai; Samulski, Thaddeus; Sanders, Linda; Case, Beth; Rosner, Gary; Azuma, Chieko; Poulson, Jeannie; Pruitt, Amy F.; Stanley, Wilma; Hauck, Marlene L.; Williams, Laurel; Hess, Paul; Dewhirst, Mark W.

2009-01-01

Purpose To test that prospective delivery of higher thermal dose is associated with longer tumor control duration. Experimental Design 122 dogs with a heatable soft tissue sarcoma were randomized to receive a low (2–5 CEM43°CT90) or high (20–50 CEM43°CT90) thermal dose in combination with radiotherapy. Most dogs (90%) received 4–6 hyperthermia treatments over 5 weeks. Results In the primary analysis, median (95% CI) duration of local control in the low dose group was 1.2 (0.7–2.1) years versus 1.9 (1.4–3.2) years in the high dose group (logrank p=0.28). The probability (95% CI) of tumor control at one year in the low vs. high dose groups was 0.57 (0.43–0.70) vs. 0.74 (0.62–0.86), respectively. Using multivariable procedure, thermal dose group (p=0.023), total duration of heating (p=0.008), tumor volume (p=0.041) and tumor grade (p=0.027) were significantly related to duration of local tumor control. When correcting for volume, grade and duration of heating, dogs in the low dose group were 2.3 times as likely to experience local failure. Conclusions Thermal dose is directly related to local control duration in irradiated canine sarcomas. Longer heating being associated with shorter local tumor control was unexpected. However, the effect of thermal dose on tumor control was stronger than for heating duration. The heating duration effect is possibly mediated through deleterious effects on tumor oxygenation. These results are the first to show the value of prospectively controlled thermal dose in achieving local tumor control with thermoradiotherapy, and they establish a paradigm for prescribing thermoradiotherapy and writing a thermal prescription. PMID:16033838

The current status of eye lens dose measurement in interventional cardiology personnel in Thailand.

PubMed

Krisanachinda, Anchali; Srimahachota, Suphot; Matsubara, Kosuke

2017-06-01

Workers involved in interventional cardiology procedures receive high eye lens doses if radiation protection tools are not properly utilized. Currently, there is no suitable method for routine measurement of eye dose. In Thailand, the eye lens equivalent doses in terms of Hp(3) of the interventional cardiologists, nurses, and radiographers participating in interventional cardiology procedures have been measured at 12 centers since 2015 in the pilot study. The optically stimulated luminescence (OSL) dosimeter was used for measurement of the occupational exposure and the eye lens dose of 42 interventional cardiology personnel at King Chulalongkorn Memorial Hospital as one of the pilot centers. For all personnel, it is recommended that a first In Light OSL badge is placed at waist level and under the lead apron for determination of Hp(10); a second badge is placed at the collar for determination of Hp(0.07) and estimation of Hp(3). Nano Dots OSL dosimeter has been used as an eye lens dosimeter for 16 interventional cardiology personnel, both with and without lead-glass eyewear. The mean effective dose at the body, equivalent dose at the collar, and estimated eye lens dose were 0.801, 5.88, and 5.70 mSv per year, respectively. The mean eye lens dose measured by the Nano Dots dosimeter was 8.059 mSv per year on the left eye and 3.552 mSv per year on the right eye. Two of 16 interventional cardiologists received annual eye lens doses on the left side without lead glass that were higher than 20 mSv per year, the new eye lens dose limit as recommended by ICRP with the risk of eye lens opacity and cataract.

SU-E-T-122: Anisotropic Analytical Algorithm (AAA) Vs. Acuros XB (AXB) in Stereotactic Treatment Planning

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

Mynampati, D; Scripes, P Godoy; Kuo, H

2015-06-15

Purpose: To evaluate dosimetric differences between superposition beam model (AAA) and determinant photon transport solver (AXB) in lung SBRT and Cranial SRS dose computations. Methods: Ten Cranial SRS and ten Lung SBRT plans using Varian, AAA -11.0 were re-planned using Acuros -XB-11.0 with fixed MU. 6MV photon Beam model with HD120-MLC used for dose calculations. Four non-coplanar conformal arcs used to deliver 21Gy or 18Gy to SRS targets (0.4 to 6.2cc). 54Gy (3Fractions) or 50Gy (5Fractions) was planned for SBRT targets (7.3 to 13.9cc) using two VAMT non-coplanar arcs. Plan comparison parameters were dose to 1% PTV volume (D1), dosemore » to 99% PTV volume( D99), Target mean (Dmean), Conformity index (ratio of prescription isodose volume to PTV), Homogeneity Index [ (D2%-D98%)/Dmean] and R50 (ratio of 50% of prescription isodose volume to PTV). OAR parameters were Brain volume receiving 12Gy dose (V12Gy) and maximum dose (D0.03) to Brainstem for SRS. For lung SBRT, maximum dose to Heart and Cord, Mean lung dose (MLD) and volume of lung receiving 20Gy (V20Gy) were computed. PTV parameters compared by percentage difference between AXB and AAA parameters. OAR parameters and HI compared by absolute difference between two calculations. For analysis, paired t-test performed over the parameters. Results: Compared to AAA, AXB SRS plans have on average 3.2% lower D99, 6.5% lower CI and 3cc less Brain-V12. However, AXB SBRT plans have higher D1, R50 and Dmean by 3.15%, 1.63% and 2.5%. For SRS and SBRT, AXB plans have average HI 2 % and 4.4% higher than AAA plans. In both techniques, all other parameters vary within 1% or 1Gy. In both sets only two parameters have P>0.05. Conclusion: Even though t-test results signify difference between AXB and AAA plans, dose differences in dose estimations by both algorithms are clinically insignificant.« less

Can we avoid dose escalation for intermediate-risk prostate cancer in the setting of short-course neoadjuvant androgen deprivation?

PubMed

Shakespeare, Thomas P; Wilcox, Shea W; Aherne, Noel J

2016-01-01

Both dose-escalated external beam radiotherapy (DE-EBRT) and androgen deprivation therapy (ADT) improve the outcomes in patients with intermediate-risk prostate cancer. Despite this, there are only few reports evaluating DE-EBRT for patients with intermediate-risk prostate cancer receiving neoadjuvant ADT, and virtually no studies investigating dose escalation >74 Gy in this setting. We aimed to determine whether DE-EBRT >74 Gy improved the outcomes for patients with intermediate-risk prostate cancer who received neoadjuvant ADT. In our institution, patients with intermediate-risk prostate cancer were treated with neoadjuvant ADT and DE-EBRT, with doses sequentially increasing from 74 Gy to 76 Gy and then to 78 Gy between 2006 and 2012. We identified 435 patients treated with DE-EBRT and ADT, with a median follow-up of 70 months. For the 74 Gy, 76 Gy, and 78 Gy groups, five-year biochemical disease-free survival rates were 95.0%, 97.8%, and 95.3%, respectively; metastasis-free survival rates were 99.1%, 100.0%, and 98.6%, respectively; and prostate cancer-specific survival rate was 100% for all three dose levels. There was no significant benefit for dose escalation either on univariate or multivariate analysis for any outcome. There was no benefit for DE-EBRT >74 Gy in our cohort of intermediate-risk prostate cancer patients treated with neoadjuvant ADT. Given the higher risks of toxicity associated with dose escalation, it may be feasible to omit dose escalation in this group of patients. Randomized studies evaluating dose de-escalation should be considered.

Can we avoid dose escalation for intermediate-risk prostate cancer in the setting of short-course neoadjuvant androgen deprivation?

PubMed Central

Shakespeare, Thomas P; Wilcox, Shea W; Aherne, Noel J

2016-01-01

Background Both dose-escalated external beam radiotherapy (DE-EBRT) and androgen deprivation therapy (ADT) improve the outcomes in patients with intermediate-risk prostate cancer. Despite this, there are only few reports evaluating DE-EBRT for patients with intermediate-risk prostate cancer receiving neoadjuvant ADT, and virtually no studies investigating dose escalation >74 Gy in this setting. We aimed to determine whether DE-EBRT >74 Gy improved the outcomes for patients with intermediate-risk prostate cancer who received neoadjuvant ADT. Findings In our institution, patients with intermediate-risk prostate cancer were treated with neoadjuvant ADT and DE-EBRT, with doses sequentially increasing from 74 Gy to 76 Gy and then to 78 Gy between 2006 and 2012. We identified 435 patients treated with DE-EBRT and ADT, with a median follow-up of 70 months. For the 74 Gy, 76 Gy, and 78 Gy groups, five-year biochemical disease-free survival rates were 95.0%, 97.8%, and 95.3%, respectively; metastasis-free survival rates were 99.1%, 100.0%, and 98.6%, respectively; and prostate cancer-specific survival rate was 100% for all three dose levels. There was no significant benefit for dose escalation either on univariate or multivariate analysis for any outcome. Conclusion There was no benefit for DE-EBRT >74 Gy in our cohort of intermediate-risk prostate cancer patients treated with neoadjuvant ADT. Given the higher risks of toxicity associated with dose escalation, it may be feasible to omit dose escalation in this group of patients. Randomized studies evaluating dose de-escalation should be considered. PMID:27073327

Concomitant Imaging Dose and Cancer Risk in Image Guided Thoracic Radiation Therapy

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

Zhang, Yibao; Wu, Hao; Chen, Zhe

Purpose: Kilovoltage cone beam computed tomography (CT) (kVCBCT) imaging guidance improves the accuracy of radiation therapy but imposes an extra radiation dose to cancer patients. This study aimed to investigate concomitant imaging dose and associated cancer risk in image guided thoracic radiation therapy. Methods and Materials: The planning CT images and structure sets of 72 patients were converted to CT phantoms whose chest circumferences (C{sub chest}) were calculated retrospectively. A low-dose thorax protocol on a Varian kVCBCT scanner was simulated by a validated Monte Carlo code. Computed doses to organs and cardiac substructures (for 5 selected patients of various dimensions)more » were regressed as empirical functions of C{sub chest}, and associated cancer risk was calculated using the published models. The exposures to nonthoracic organs in children were also investigated. Results: The structural mean doses decreased monotonically with increasing C{sub chest}. For all 72 patients, the median doses to the heart, spinal cord, breasts, lungs, and involved chest were 1.68, 1.33, 1.64, 1.62, and 1.58 cGy/scan, respectively. Nonthoracic organs in children received 0.6 to 2.8 cGy/scan if they were directly irradiated. The mean doses to the descending aorta (1.43 ± 0.68 cGy), left atrium (1.55 ± 0.75 cGy), left ventricle (1.68 ± 0.81 cGy), and right ventricle (1.85 ± 0.84 cGy) were significantly different (P<.05) from the heart mean dose (1.73 ± 0.82 cGy). The blade shielding alleviated the exposure to nonthoracic organs in children by an order of magnitude. Conclusions: As functions of patient size, a series of models for personalized estimation of kVCBCT doses to thoracic organs and cardiac substructures have been proposed. Pediatric patients received much higher doses than did the adults, and some nonthoracic organs could be irradiated unexpectedly by the default scanning protocol. Increased cancer risks and disease adverse events in the thorax were strongly related to higher imaging doses and smaller chest dimensions.« less

Evaluation of hyperglycaemic response to intra-operative dexamethasone administration in patients undergoing elective intracranial surgery: A randomised, prospective study.

PubMed

Sethi, Rakesh; Naqash, Imtiaz A; Bajwa, Sukhminder Jit Singh; Dutta, Vikas; Ramzan, Altaf Umar; Zahoor, Syed Amir

2016-01-01

The glucocorticoid dexamethasone in a bolus dose of 8-10 mg followed by quarterly dose of 4 mg is commonly used during intracranial surgery so as to reduce oedema and vascular permeability. However, the detrimental hyperglycaemic effects of dexamethasone may override its potentially beneficial effects. The present prospective, randomised study aimed at comparing the degree and magnitude of hyperglycaemia induced by prophylactic administration of dexamethasone in patients undergoing elective craniotomy. Sixty American Society of Anaesthesiologist (ASA) grade-I and II patients were randomly assigned to three groups of 20 patients each. Group-I received dexamethasone during surgery for the first time. Group-II received dexamethasone in addition to receiving it pre-operatively, whereas Group-III (control group) patients were administered normal saline as placebo. Baseline blood glucose (BG) was measured in all the three groups before induction of anaesthesia and thereafter after every hour for 4 h and then two-hourly. Besides intra- and intergroup comparison of BG, peak BG concentration was also recorded for each patient. Statistical analysis was carried out with analysis of variance (ANOVA) and Student's t-test and value of P < 0.05 was considered statistically significant. Baseline BG reading were higher and statistically significant in Group-II as compared with Group-I and Group-III (P < 0.05). However, peak BG levels were significantly higher in Group-I than in Group-II and III (P < 0.05). Similarly, the magnitude of change in peak BG was significantly higher in Group-I as compared to Group-II and III (P < 0.05). Peri-operative administration of dexamethasone during neurosurgical procedures can cause significant increase in BG concentration especially in patients who receive dexamethasone intra-operatively only.

Evaluation of hyperglycaemic response to intra-operative dexamethasone administration in patients undergoing elective intracranial surgery: A randomised, prospective study

PubMed Central

Sethi, Rakesh; Naqash, Imtiaz A.; Bajwa, Sukhminder Jit Singh; Dutta, Vikas; Ramzan, Altaf Umar; Zahoor, Syed Amir

2016-01-01

Background and Aim: The glucocorticoid dexamethasone in a bolus dose of 8-10 mg followed by quarterly dose of 4 mg is commonly used during intracranial surgery so as to reduce oedema and vascular permeability. However, the detrimental hyperglycaemic effects of dexamethasone may override its potentially beneficial effects. The present prospective, randomised study aimed at comparing the degree and magnitude of hyperglycaemia induced by prophylactic administration of dexamethasone in patients undergoing elective craniotomy. Materials and Methods: Sixty American Society of Anaesthesiologist (ASA) grade-I and II patients were randomly assigned to three groups of 20 patients each. Group-I received dexamethasone during surgery for the first time. Group-II received dexamethasone in addition to receiving it pre-operatively, whereas Group-III (control group) patients were administered normal saline as placebo. Baseline blood glucose (BG) was measured in all the three groups before induction of anaesthesia and thereafter after every hour for 4 h and then two-hourly. Besides intra- and intergroup comparison of BG, peak BG concentration was also recorded for each patient. Statistical analysis was carried out with analysis of variance (ANOVA) and Student's t-test and value of P < 0.05 was considered statistically significant. Results: Baseline BG reading were higher and statistically significant in Group-II as compared with Group-I and Group-III (P < 0.05). However, peak BG levels were significantly higher in Group-I than in Group-II and III (P < 0.05). Similarly, the magnitude of change in peak BG was significantly higher in Group-I as compared to Group-II and III (P < 0.05). Conclusion: Peri-operative administration of dexamethasone during neurosurgical procedures can cause significant increase in BG concentration especially in patients who receive dexamethasone intra-operatively only. PMID:27057213

Vaccination coverage among social and healthcare workers in ten countries of Samu-social international sites.

PubMed

Marshall, Esaie; Salmon, Dominique; Bousfiha, Nadia; Togola, Yacouba; Ouedraogo, François; Santantonio, Maud; Dieng, Coumba Khadidja; Tartière, Suzanne; Emmanuelli, Xavier

2017-09-18

We aim to determine the vaccination coverage of social and healthcare workers in International sites of Samusocial, providing emergency care to homeless people, and to assess factors associated with having received necessary doses at adulthood. Data on immunization coverage of social and healthcare workers were provided by a cross-sectional survey, conducted from February to April 2015 among 252 Samusocial workers in 10 countries. Vaccination status and characteristics of participants were collected through a self-administered questionnaire. Prevalence rate ratio (PRR) of vaccination status was calculated using Poisson regression models. Among 252 Samusocial social and health workers who felt a questionnaire, median age was 39years, 42.1% were female, 88.9% were in contact with homeless beneficiaries (19.1% health workers). Overall, 90.1% of Samusocial staff felt adult vaccinations was useful and 70.2% wished to receive booster doses in future. Vaccination coverage at adulthood was satisfactory for diphtheria and poliomyelitis (96%), but low for influenza (20.8%), meningococcus (50.5%), hepatitis B (56.3%), yellow fever (58.1%), measles (81.3%) and pertussis (90.7%). The main reasons for not having received vaccination booster doses were forgetting the dates of booster doses (38.4%) and not having received the information (13.5%). In adjusted analysis, prevalence of up-to-date for vaccination schedule was 35% higher among health workers than among social workers (aPRR=1.35, 95%CI: 1.01-1.82, P=0.05) and was 56% higher among workers who had a documentary evidence of vaccination than in those who did not (aPRR=1.56, 95%CI: 1.19-2.02, P=0.001). The Samusocial International workers vaccine coverage at adulthood was insufficient and disparate by region. It is necessary to strengthen the outreach of this staff and increase immunization policy for hepatitis B, diphtheria, tetanus, and measles, as well as for yellow fever, rabies and meningococcal ACYW135 vaccines in at risk regions. Copyright © 2017 Elsevier Ltd. All rights reserved.

[Continued Use of Rotigotine Transdermal Patches for Parkinson Disease].

PubMed

Yasutaka, Yuki; Fujioka, Shinsuke; Shibaguchi, Hirotomo; Imakyure, Osamu; Washiyama, Atsushi; Tsuboi, Yoshio; Futagami, Koujiro

2016-06-01

Transdermal patches containing rotigotine, a dopamine agonist (DA) for treatment of Parkinson disease, continuously exert stable effects when applied once daily. Therefore, they are expected to reduce the patient burdens due to complications such as wearing-off and dysphagia. However, dosing is occasionally reduced or discontinued after application because of several reasons such as skin reactions or unsatisfactory efficacy. To identify the risk factors involved in the reduced or discontinued use of rotigotine patches, a retrospective study was conducted with reference to the medical records of patients with Parkinson disease who received rotigotine patches in our hospital. 85 patients were involved in this study. Dosing of rotigotine was reduced or discontinued in 53 patients during the study period. The factors associated with charges in treatment included combination therapy with clonazepam and oral administration of another DA before the application of rotigotine. The reduction or discontinuation rate of rotigotine patches in patients who reduced the equivalent dose of DA on the introduction of rotigotine patches was 94.7%, showing a significantly higher rate compared with 61.3% in the increased dose group. To improve adherence to rotigotine patch therapy, physicians need to carefully consider concomitant drugs and total dose of DAs. (Received December 7, 2015; Accepted February 22, 2016; Published June 1, 2016).

Impact of BMI on clinical outcomes of NOAC therapy in daily care - Results of the prospective Dresden NOAC Registry (NCT01588119).

PubMed

Tittl, L; Endig, S; Marten, S; Reitter, A; Beyer-Westendorf, I; Beyer-Westendorf, J

2018-07-01

Direct acting non-Vitamin K antagonist oral anticoagulants (NOAC) are characterized by a fixed dosing regimen. Despite the potential for relative underdosing due to large distribution volumes, dose adjustments for patients with high body mass index (BMI) are not recommended. Since efficacy and safety data in obese patients are scarce, we evaluated the impact of BMI on clinical outcomes in daily care patients treated with NOAC for stroke prevention in atrial fibrillation or venous thromboembolism. Using prospectively collected data from a non-interventional registry, cardiovascular (CV), major bleeding events (MB) and all-cause mortality were evaluated according to BMI classes. All outcome events were centrally adjudicated using standard scientific definitions. Between November 1st 2011 and December 31st 2016, 3432 patients were enrolled into the registry (61.3% rivaroxaban; 20% apixaban; 10.1% dabigatran, 8.6% edoxaban; mean follow-up 998.1 ± 542.9 days; median 1004 days). With increasing BMI (range 13.7-57.2 kg/m 2 ), the proportion of patients receiving standard (vs. reduced) NOAC dose increased from 64.7% (underweight) to 78.9% (obesity). Although obese patients had more cardiovascular risk factors compared to normal weight patients, on-treatment rates of clinical outcomes (CV, MB, all-cause-mortality) were lowest in overweight and obese patients. In a large set of real-life NOAC recipients we found no indication that high BMI is associated with inferior NOAC effectiveness or safety, which is in line with recent epidemiological data of a "BMI paradox" that indicates a somewhat protective effect of higher BMI regarding unfavourable outcomes also in patients receiving fixed dose NOAC anticoagulation without dose adjustment for higher BMI. Copyright © 2018 Elsevier B.V. All rights reserved.

Identifying risk factors for L'Hermitte's sign after IMRT for head and neck cancer.

PubMed

Laidley, Hannah M; Noble, David J; Barnett, Gill C; Forman, Julia R; Bates, Amy M; Benson, Richard J; Jefferies, Sarah J; Jena, Rajesh; Burnet, Neil G

2018-05-04

L'Hermitte's sign (LS) after chemoradiotherapy for head and neck cancer appears related to higher spinal cord doses. IMRT plans limit spinal cord dose, but the incidence of LS remains high. One hundred seventeen patients treated with TomoTherapy™ between 2008 and 2015 prospectively completed a side-effect questionnaire (VoxTox Trial Registration: UK CRN ID 13716). Baseline patient and treatment data were collected. Radiotherapy plans were analysed; mean and maximum spinal cord dose and volumes receiving 10, 20, 30 and 40 Gy were recorded. Dose variation across the cord was examined. These data were included in a logistic regression model. Forty two patients (35.9%) reported LS symptoms. Concurrent weekly cisplatin did not increase LS risk (p = 0.70, OR = 1.23 {95% CI 0.51-2.34}). Of 13 diabetic participants (9 taking metformin), only 1 developed LS (p = 0.025, OR = 0.13 {95% CI 0.051-3.27}). A refined binary logistic regression model showed that patients receiving unilateral radiation (p = 0.019, OR = 2.06 {95% CI 0.15-0.84}) were more likely to develop LS. Higher V 40Gy (p = 0.047, OR = 1.06 {95% CI 1.00-1.12}), and younger age (mean age 56.6 vs 59.7, p = 0.060, OR = 0.96 {95% CI 0.92-1.00}) were associated with elevated risk of LS, with borderline significance. In this cohort, concomitant cisplatin did not increase risk, and LS incidence was lower in diabetic patients. Patient age and dose gradients across the spinal cord may be important factors.

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

PubMed

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

2018-04-13

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

Immune parameters to p67C antigen adjuvanted with ISA206VG correlate with protection against East Coast fever.

PubMed

Lacasta, Anna; Mwalimu, Stephen; Kibwana, Elisabeth; Saya, Rosemary; Awino, Elias; Njoroge, Thomas; Poole, Jane; Ndiwa, Nicholas; Pelle, Roger; Nene, Vishvanath; Steinaa, Lucilla

2018-03-07

East Coast fever (ECF) is a lymphoproliferative disease caused by the tick-transmitted protozoan parasite Theileria parva. ECF is one of the most serious cattle tick-borne diseases in Sub-Saharan Africa. We have previously demonstrated that three doses of the C-terminal part of the sporozoite protein p67 (p67C) adjuvanted with ISA206VG confers partial protection against ECF at a herd level. We have tested the efficacy of two doses of this experimental vaccine, as reducing the vaccination regimen would facilitate its deployment in the field. We reconfirm that three antigen doses gave a significant level of protection to severe disease (46%, ECF score < 6) when compared with the control group, while two doses did not (23%). Animals receiving three doses of p67C developed higher antibody titers and CD4 + T-cell proliferation indices, than those which received two doses. A new panel of immune parameters were tested in order to identify factors correlating with protection: CD4 + proliferation index, total IgG, IgG1, IgG2 and IgM half maximal titers and neutralization capacity of the sera with and without complement. We show that some of the cellular and humoral immune responses provide preliminary correlates of protection. Copyright © 2018 The Authors. Published by Elsevier Ltd.. All rights reserved.

Cost-effectiveness of single dose cefotaxime plus metronidazole compared with three doses each of cefuroxime plus metronidazole for the prevention of wound infection after colorectal surgery.

PubMed

Davey, P; Lynch, B; Malek, M; Byrne, D; Thomas, P

1992-12-01

The cost-effectiveness of prophylaxis for colonic surgery with single dose cefotaxime plus metronidazole has been compared with that of three doses each of cefuroxime plus metronidazole, by analysing data from a previously published study supplemented with additional data on the hospital and community costs of wound infection after colonic surgery. The original trial included 942 patients having elective colonic surgery in 14 hospitals. The data on costs of wound infection were collected from a further 124 patients undergoing elective colonic surgery at Ninewells Hospital. All these patients received a three dose regimen of cefuroxime plus metronidazole. The Dundee patients received three injections of 0.75 g cefuroxime at 8-hourly intervals whereas the trial patients received a single dose of 1.5 g followed by two further doses of 0.75 g at 8-hourly intervals. The cefuroxime prophylaxis regimen used in the trial cost 24.16 pounds per patient more than the cefotaxime regimen. The components of the excess cost were drugs (15.18 pounds), equipment (6.14 pounds) and staff time (2.84 pounds). The median cost to the hospital of a wound infection was 978.04 pounds (95% CI 482.04 pounds to 1521.22 pounds). The components of the hospital cost of wound infection were: hotel costs 858 pounds (88%), dressing costs 83.02 pounds (8%) and drug costs (excluding prophylaxis) 37.02 pounds (4%). Only five patients received additional antibiotic treatment in the community, and only one required home visits from the District Nurse. Applying the difference in costs of prophylaxis as 21 pounds (costs of drugs plus equipment) and the cost per wound infection as 1000 pounds to the observed wound infection rate of 7% in the cefuroxime group, the wound infection rate in the cefotaxime group would have to be 2.1% higher for the two regimens to be equally cost-effective. The probability that such a difference in efficacy exists is 0.088. A model was developed to calculate the probability of equal cost-effectiveness over a range of costs of wound infection.

Incidence of leukopenia and cytomegalovirus disease in kidney transplants treated with mycophenolate mofetil combined with low cyclosporine and steroid doses.

PubMed

Moreso, F; Serón, D; Morales, J M; Cruzado, J M; Gil-Vernet, S; Pérez, J L; Fulladosa, X; Andrés, A; Grinyó, J M

1998-06-01

Mycophenolate mofetil (MMF) combined with conventional cyclosporine and steroids doses efficiently prevents acute rejection in kidney transplants. However, this regimen has been associated with an increased incidence of cytomegalovirus (CMV) disease and leukopenia, specially in patients receiving MMF at 3 g/d, suggesting that the combination of two powerful immunosuppressants carries the risk of overimmunosuppression. For this reason, we treated a group of patients with MMF 3 g/d combined with low cyclosporine and steroids doses. Eighty-two kidney transplants performed at two centers and enrolled in the European Mycophenolate Mofetil Cooperative Study were randomized to receive: A) placebo (n = 27); B) MMF 2 g/d (n = 27); and C) MMF 3 g/d (n = 28). In this double blind study all patients received cyclosporine and steroids at conventional doses. Fifteen kidney transplants enrolled in an MMF open pharmacokinetic study were treated with MMF 3 g/day combined with low cyclosporine and steroid doses (group D). Efficacy was evaluated as the incidence of biopsy proven acute rejection, and safety focused on CMV disease and leukopenia. Patients receiving MMF showed a low incidence of biopsy proven rejection (B) 18.5%; C) 10.7%; and D) 13.3%). Patients of group C had a high incidence of CMV disease (35.7%) when compared with the other groups (lower than 8%). Incidence of leukopenia was higher in patients treated with MMF (B) 25.9%; C) 39.3%; and D) 40%) than in placebo treated patients (7.4%). Patients in group (C) displayed leukopenia mainly in the context of CMV disease, while patients of group (D) had leukopenia not related to CMV infection. All patients of group (D) who presented leukopenia recovered after MMF reduction dose, while in group (C) there were 5 out of 28 patients who required MMF withdrawal. We propose that a reasonable approach to take advantage of a powerful non-nephrotoxic immunosuppressant such as MMF, could be the administration of this drug at 3 g/d from the time of transplantation combined with low CsA and steroid doses.

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

NASA Astrophysics Data System (ADS)

Velec, Michael

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

Simultaneous integrated boost with intensity modulated radiation therapy in brain oligometastases: A feasible technique for developing countries

PubMed Central

Tiwari, Vivek; Pande, Subodh C.; Verma, Kamal; Goel, Sandeep

2015-01-01

Introduction: To analyze the pattern of brain metastasis (BM), and to use intensity modulated radiation therapy (IMRT) for target dose escalation in cases with ≤3 metastatic lesions (oligometastases). Materials and Methods: Thirty-two consecutive cases of BM treated during September 2009 to August 2012 were analyzed retrospectively. Results: The study comprised 13 males (40.62%) and 19 females (59.37%). Thirteen (40%) patients presented with disseminated intracranial metastases, while 19 (60%) had ≤3 foci. In 25 cases (78%), the primary was located either in the breast (14 cases) or lung (11 cases). The 13 patients with disseminated intracranial metastases received whole brain radiation therapy to a dose of 30 Gy/10-12 daily fractions (Group A) while the 19 cases with ≤3 lesions received an additional dose of 6-10 Gy to gross lesions using a simultaneous integrated boost (SIB) with IMRT thus receiving a total dose of 36-40 Gy/12-15 fractions (Group B). Overall survival (OS) for the breast primary was 6.3 and lung primary was 5.3 months, respectively. The mean OS for breast cases in Group B was higher (9.5 months) as compared to Group A cases (1.9 months) and was statistically significant (P = 0.0056). Similarly, primary lung cancer cases in Group B showed a mean OS of 8.75 months versus 2.6 months for Group A cases (P = 0.213). Conclusions: IMRT is a safe and effective technique in cases with oligometastases for dose escalation in the form of SIB. PMID:25839012

Dialysis Dose Scaled to Body Surface Area and Size-Adjusted, Sex-Specific Patient Mortality

PubMed Central

Kapke, Alissa; Port, Friedrich K.; Wolfe, Robert A.; Saran, Rajiv; Pearson, Jeffrey; Hirth, Richard A.; Messana, Joseph M.; Daugirdas, John T.

2012-01-01

Summary Background and objectives When hemodialysis dose is scaled to body water (V), women typically receive a greater dose than men, but their survival is not better given a similar dose. This study sought to determine whether rescaling dose to body surface area (SA) might reveal different associations among dose, sex, and mortality. Design, setting, participants, & measurements Single-pool Kt/V (spKt/V), equilibrated Kt/V, and standard Kt/V (stdKt/V) were computed using urea kinetic modeling on a prevalent cohort of 7229 patients undergoing thrice-weekly hemodialysis. Data were obtained from the Centers for Medicare & Medicaid Services 2008 ESRD Clinical Performance Measures Project. SA-normalized stdKt/V (SAN-stdKt/V) was calculated as stdKt/V × ratio of anthropometric volume to SA/17.5. Patients were grouped into sex-specific dose quintiles (reference: quintile 1 for men). Adjusted hazard ratios (HRs) for 1-year mortality were calculated using Cox regression. Results spKt/V was higher in women (1.7±0.3) than in men (1.5±0.2; P<0.001), but SAN-stdKt/V was lower (women: 2.3±0.2; men: 2.5±0.3; P<0.001). For both sexes, mortality decreased as spKt/V increased, until spKt/V was 1.6–1.7 (quintile 4 for men: HR, 0.62; quintile 3 for women: HR, 0.64); no benefit was observed with higher spKt/V. HR for mortality decreased further at higher SAN-stdKt/V in both sexes (quintile 5 for men: HR, 0.69; quintile 5 for women: HR, 0.60). Conclusions SA-based dialysis dose results in dose-mortality relationships substantially different from those with volume-based dosing. SAN-stdKt/V analyses suggest women may be relatively underdosed when treated by V-based dosing. SAN-stdKt/V as a measure for dialysis dose may warrant further study. PMID:22977208

Abuse potential assessment of propofol by its subjective effects after sedation.

PubMed

Tezcan, Aysu Hayriye; Ornek, Dilsen Hatice; Ozlu, Onur; Baydar, Mustafa; Yavuz, Nurcan; Ozaslan, Nihal Gokbulut; Dilek, Kevser; Keske, Aylin

2014-01-01

In this study, we examined the euphoric effect of propofol and its high satisfaction ratio regarding its liability to be abused, particularly in painless procedures, such as colonoscopy. Fifty subjects aged between 18 and 65 years who fulfilled the criteria for ASA 1-2 and were prepared for colonoscopy were enrolled into this study. For intravenous sedation induction, 2 mg/kg propofol was used, and additional injections were administered according to BIS values. After colonoscopy, the subjects were taken to a recovery room and observed for 30 minutes. Patients were interviewed with the modified Brice questionnare regarding the incidence and the content of dreams. A 5-point Likert scale was used to classify their dreams, and the content of the dreams was also recorded. To assess the subjective effects of propofol, the patients were asked to use the Hall and Van der Castle emotion scale; their biological states were also assessed. The patients' feelings regarding propofol were each rated as absent or present. We used the Morphine-Benzedrine Group scale to measure the euphoric effects of propofol. At the end of the study, subjects scored their satisfaction on a five-point scale. There were no statistically significant differences in sex age, weight, propofol dose, or satisfaction ratio (p>0.05) in the groups, although male patients received a higher dose of propofol and had higher satisfaction ratio. Patients reported no residual after-effects. The incidence of dreaming was 42%. There was no statistically significant difference in dreaming between the sexes, but male patients had a higher dreaming ratio. Dreamers received higher propofol doses and had a higher satisfaction ratio (p>0.05). All dreamers reported happy dreams regarding daily life, and their mean MBG score was 10.5. There was no correlation between MBG scores and propofol doses (r= -0.044, p= 0.761). We conclude that propofol functions as a reward; that patients enjoy its acute effects; and that no residual after-effects should arise. We suggest that propofol may carry potential for abuse, and further abuse liability testing is indicated.

Abuse potential assessment of propofol by its subjective effects after sedation

PubMed Central

Tezcan, Aysu Hayriye; Ornek, Dilsen Hatice; Ozlu, Onur; Baydar, Mustafa; Yavuz, Nurcan; Ozaslan, Nihal Gokbulut; Dilek, Kevser; Keske, Aylin

2014-01-01

Objective: In this study, we examined the euphoric effect of propofol and its high satisfaction ratio regarding its liability to be abused, particularly in painless procedures, such as colonoscopy. Methods: Fifty subjects aged between 18 and 65 years who fulfilled the criteria for ASA 1-2 and were prepared for colonoscopy were enrolled into this study. For intravenous sedation induction, 2 mg/kg propofol was used, and additional injections were administered according to BIS values. After colonoscopy, the subjects were taken to a recovery room and observed for 30 minutes. Patients were interviewed with the modified Brice questionnare regarding the incidence and the content of dreams. A 5-point Likert scale was used to classify their dreams, and the content of the dreams was also recorded. To assess the subjective effects of propofol, the patients were asked to use the Hall and Van der Castle emotion scale; their biological states were also assessed. The patients’ feelings regarding propofol were each rated as absent or present. We used the Morphine-Benzedrine Group scale to measure the euphoric effects of propofol. At the end of the study, subjects scored their satisfaction on a five-point scale. Results: There were no statistically significant differences in sex age, weight, propofol dose, or satisfaction ratio (p>0.05) in the groups, although male patients received a higher dose of propofol and had higher satisfaction ratio. Patients reported no residual after-effects. The incidence of dreaming was 42%. There was no statistically significant difference in dreaming between the sexes, but male patients had a higher dreaming ratio. Dreamers received higher propofol doses and had a higher satisfaction ratio (p>0.05). All dreamers reported happy dreams regarding daily life, and their mean MBG score was 10.5. There was no correlation between MBG scores and propofol doses (r= -0.044, p= 0.761). Conclusions: We conclude that propofol functions as a reward; that patients enjoy its acute effects; and that no residual after-effects should arise. We suggest that propofol may carry potential for abuse, and further abuse liability testing is indicated. PMID:25674117

Impact of dose size in single fraction spatially fractionated (grid) radiotherapy for melanoma

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

Zhang, Hualin, E-mail: hualin.zhang@northwestern.edu, E-mail: hualinzhang@yahoo.com; Zhong, Hualiang; Barth, Rolf F.

2014-02-15

Purpose: To evaluate the impact of dose size in single fraction, spatially fractionated (grid) radiotherapy for selectively killing infiltrated melanoma cancer cells of different tumor sizes, using different radiobiological models. Methods: A Monte Carlo technique was employed to calculate the 3D dose distribution of a commercially available megavoltage grid collimator in a 6 MV beam. The linear-quadratic (LQ) and modified linear quadratic (MLQ) models were used separately to evaluate the therapeutic outcome of a series of single fraction regimens that employed grid therapy to treat both acute and late responding melanomas of varying sizes. The dose prescription point was atmore » the center of the tumor volume. Dose sizes ranging from 1 to 30 Gy at 100% dose line were modeled. Tumors were either touching the skin surface or having their centers at a depth of 3 cm. The equivalent uniform dose (EUD) to the melanoma cells and the therapeutic ratio (TR) were defined by comparing grid therapy with the traditional open debulking field. The clinical outcomes from recent reports were used to verify the authors’ model. Results: Dose profiles at different depths and 3D dose distributions in a series of 3D melanomas treated with grid therapy were obtained. The EUDs and TRs for all sizes of 3D tumors involved at different doses were derived through the LQ and MLQ models, and a practical equation was derived. The EUD was only one fifth of the prescribed dose. The TR was dependent on the prescribed dose and on the LQ parameters of both the interspersed cancer and normal tissue cells. The results from the LQ model were consistent with those of the MLQ model. At 20 Gy, the EUD and TR by the LQ model were 2.8% higher and 1% lower than by the MLQ, while at 10 Gy, the EUD and TR as defined by the LQ model were only 1.4% higher and 0.8% lower, respectively. The dose volume histograms of grid therapy for a 10 cm tumor showed different dosimetric characteristics from those of conventional radiotherapy. A significant portion of the tumor volume received a very large dose in grid therapy, which ensures significant tumor cell killing in these regions. Conversely, some areas received a relatively small dose, thereby sparing interspersed normal cells and increasing radiation tolerance. The radiobiology modeling results indicated that grid therapy could be useful for treating acutely responding melanomas infiltrating radiosensitive normal tissues. The theoretical model predictions were supported by the clinical outcomes. Conclusions: Grid therapy functions by selectively killing infiltrating tumor cells and concomitantly sparing interspersed normal cells. The TR depends on the radiosensitivity of the cell population, dose, tumor size, and location. Because the volumes of very high dose regions are small, the LQ model can be used safely to predict the clinical outcomes of grid therapy. When treating melanomas with a dose of 15 Gy or higher, single fraction grid therapy is clearly advantageous for sparing interspersed normal cells. The existence of a threshold fraction dose, which was found in the authors’ theoretical simulations, was confirmed by clinical observations.« less

Radon exposure assessment for underground workers: a case of Seoul Subway Police officers in Korea.

PubMed

Song, Myeong Han; Chang, Byung-Uck; Kim, Yongjae; Cho, Kun-Woo

2011-11-01

The objective of this study is the systematic and individual assessment of the annual effective dose due to inhaled radon for the Seoul Subway Police officers, Korea. The annual average radon concentrations were found to be in the range of 18.9-114 Bq·m(-3) in their workplaces. The total annual effective doses which may likely to be received on duty were assessed to be in the range of 0.41-1.64 mSv·y(-1). These were well below the recommended action level 10 mSv·y(-1) by ICRP. However, the effective doses were higher than subway station staff in Seoul, Korea.

Repeated restraint stress lowers the threshold for response to third ventricle CRF administration.

PubMed

Harris, Ruth B S

2017-03-01

Rats and mice exposed to repeated stress or a single severe stress exhibit a sustained increase in energetic, endocrine, and behavioral response to subsequent novel mild stress. This study tested whether the hyper-responsiveness was due to a lowered threshold of response to corticotropin releasing factor (CRF) or an exaggerated response to a standard dose of CRF. Male Sprague-Dawley rats were subjected to 3h of restraint on each of 3 consecutive days (RRS) or were non-restrained controls. RRS caused a temporary hypophagia but a sustained reduction in body weight. Eight days after the end of restraint, rats received increasing third ventricle doses of CRF (0-3.0μg). The lowest dose of CRF (0.25μg) increased corticosterone release in RRS, but not control rats. Higher doses caused the same stimulation of corticosterone in the two groups of rats. Fifteen days after the end of restraint, rats were food deprived during the light period and received increasing third ventricle doses of CRF at the start of the dark period. The lowest dose of CRF inhibited food intake during the first hour following infusion in RRS, but not control rats. All other doses of CRF inhibited food intake to the same degree in both RRS and control rats. The lowered threshold of response to central CRF is consistent with the chronic hyper-responsiveness to CRF and mild stress in RRS rats during the post-restraint period. Copyright © 2016 Elsevier Inc. All rights reserved.

Lubiprostone, a locally acting chloride channel activator, in adult patients with chronic constipation: a double-blind, placebo-controlled, dose-ranging study to evaluate efficacy and safety.

PubMed

Johanson, J F; Ueno, R

2007-06-01

Lubiprostone, a locally acting type-2 chloride channel activator, induces intestinal fluid secretion. To assess efficacy and safety of oral lubiprostone at multiple doses for the treatment of chronic constipation. A total of 129 patients with chronic constipation were randomized to receive lubiprostone (24, 48 or 72 mcg/day) or placebo for 3 weeks. Spontaneous bowel movement (SBM) frequency, rescue medication use, symptom assessments and adverse events (AEs) were tracked. Over the double-blinded period, mean SBM frequencies were higher for lubiprostone groups (5.1-6.1) vs. placebo (3.8) and the overall difference was statistically significant (P = 0.046). SBM frequencies at week 1 were significantly higher in patients taking lubiprostone 48 or 72 mcg/day (P < or = 0.003) and, at week 2, all three lubiprostone doses yielded significantly higher SBM rates vs. placebo (P < or = 0.020). Significantly larger proportions of patients taking lubiprostone 48 and 72 mcg/day also experienced a SBM on the first treatment day (P < or = 0.009). The most common AEs were nausea, headache and diarrhoea. Lubiprostone improved SBM rates in a dose-dependent manner. AEs were tolerable for most patients. Increased AE severity at 72 mcg/day did not provide a clear risk-to-benefit advantage compared with lubiprostone 48 mcg/day, the dose chosen for subsequent Phase 3 studies.

Effects of artificial sweeteners on breath alcohol concentrations in male and female social drinkers.

PubMed

Stamates, Amy L; Maloney, Sarah F; Marczinski, Cecile A

2015-12-01

Alcohol is often mixed with various nonalcoholic beverages. While consumption of food with alcohol will decrease peak breath alcohol concentrations (BrAC), recent evidence has suggested that mixing alcohol with diet beverages can result in higher BrAC when compared with mixing the same amount of alcohol with sweetened beverages. The purpose of this study was to examine this phenomenon using two different moderate alcohol doses. Twenty participants (10 males) attended five sessions where they received 1 of 5 doses (0.91 ml/kg vodka+3.64 ml/kg of diet soda, 0.91 ml/kg vodka+3.64 of regular soda, 1.82 ml/kg vodka+7.28 ml/kg diet soda, 1.82 ml/kg vodka+7.28 ml/kg regular soda, and a placebo beverage). BrAC was recorded repeatedly up to 180 min after dose administration. Participants had significantly higher BrAC when the mixer was diet as compared to regular for both alcohol dose conditions. No gender differences were observed. Mixing alcohol with diet beverages can result in higher BrAC when compared to the same amount of alcohol administered with a similar sweetened beverage. Individuals who consume diet mixers with alcohol may reduce caloric intake but increase the harms associated with higher BrACs. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Knowledge of appropriate acetaminophen doses and potential toxicities in an adult clinic population.

PubMed

Stumpf, Janice L; Skyles, Amy J; Alaniz, Cesar; Erickson, Steven R

2007-01-01

To evaluate the knowledge of appropriate doses and potential toxicities of acetaminophen and assess the ability to recognize products containing acetaminophen in an adult outpatient setting. Cross-sectional, prospective study. University adult general internal medicine (AGIM) clinic. 104 adult patients presenting to the clinic over consecutive weekdays in December 2003. Three-page, written questionnaire. Ability of patients to identify maximum daily doses and potential toxicities of acetaminophen and recognize products that contain acetaminophen. A large percentage of participants (68.3%) reported pain on a daily or weekly basis, and 78.9% reported use of acetaminophen in the past 6 months. Only 2 patients correctly identified the maximum daily dose of regular acetaminophen, and just 3 correctly identified the maximum dose of extra-strength acetaminophen. Furthermore, 28 patients were unsure of the maximum dose of either product. Approximately 63% of participants either had not received or were unsure whether information on the possible danger of high doses of acetaminophen had been previously provided to them. When asked to identify potential problems associated with high doses of acetaminophen, 43.3% of patients noted the liver would be affected. The majority of the patients (71.2%) recognized Tylenol as containing acetaminophen, but fewer than 15% correctly identified Vicodin, Darvocet, Tylox, Percocet, and Lorcet as containing acetaminophen. Although nearly 80% of this AGIM population reported recent acetaminophen use, their knowledge of the maximum daily acetaminophen doses and potential toxicities associated with higher doses was poor and appeared to be independent of education level, age, and race. This indicates a need for educational efforts to all patients receiving acetaminophen-containing products, especially since the ability to recognize multi-ingredient products containing acetaminophen was likewise poor.

Factors Associated With Chest Wall Toxicity After Accelerated Partial Breast Irradiation Using High-Dose-Rate Brachytherapy

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

Brown, Sheree, E-mail: shereedst32@hotmail.com; Vicini, Frank; Vanapalli, Jyotsna R.

2012-07-01

Purpose: The purpose of this analysis was to evaluate dose-volume relationships associated with a higher probability for developing chest wall toxicity (pain) after accelerated partial breast irradiation (APBI) by using both single-lumen and multilumen brachytherapy. Methods and Materials: Rib dose data were available for 89 patients treated with APBI and were correlated with the development of chest wall/rib pain at any point after treatment. Ribs were contoured on computed tomography planning scans, and rib dose-volume histograms (DVH) along with histograms for other structures were constructed. Rib DVH data for all patients were sampled at all volumes {>=}0.008 cubic centimeter (cc)more » (for maximum dose related to pain) and at volumes of 0.5, 1, 2, and 3 cc for analysis. Rib pain was evaluated at each follow-up visit. Patient responses were marked as yes or no. No attempt was made to grade responses. Eighty-nine responses were available for this analysis. Results: Nineteen patients (21.3%) complained of transient chest wall/rib pain at any point in follow-up. Analysis showed a direct correlation between total dose received and volume of rib irradiated with the probability of developing rib/chest wall pain at any point after follow-up. The median maximum dose at volumes {>=}0.008 cc of rib in patients who experienced chest wall pain was 132% of the prescribed dose versus 95% of the prescribed dose in those patients who did not experience pain (p = 0.0035). Conclusions: Although the incidence of chest wall/rib pain is quite low with APBI brachytherapy, attempts should be made to keep the volume of rib irradiated at a minimum and the maximum dose received by the chest wall as low as reasonably achievable.« less

Tolerance to 3,4-Methylenedioxymethamphetamine (MDMA) in Rats Exposed to Single High-Dose Binges

PubMed Central

Baumann, Michael H.; Clark, Robert D.; Franken, Frederick H.; Rutter, John J.; Rothman, Richard B.

2008-01-01

3,4-Methylenedioxymethamphetamine (MDMA or Ecstasy) stimulates the transporter-mediated release of monoamines, including serotonin (5-HT). High-dose exposure to MDMA causes persistent 5-HT deficits (e.g., depletion of brain 5-HT) in animals, yet the functional and clinical relevance of such deficits are poorly defined. Here we examine functional consequences of MDMA-induced 5-HT depletions in rats. Male rats received binges of 3 ip injections of MDMA or saline, one injection every 2 h; MDMA was given at a threshold pharmacological dose (1.5 mg/kg × 3, low dose) or at a 5-fold higher amount (7.5 mg/kg × 3, high dose). One week later, jugular catheters and intracerebral guide cannulae were implanted. Two weeks after binges, rats received acute iv challenge injections of 1 and 3 mg/kg MDMA. Neuroendocrine effects evoked by iv MDMA (prolactin and corticosterone secretion) were assessed via serial blood sampling, while neurochemical effects (5-HT and dopamine release) were assessed via microdialysis in brain. MDMA binges elevated core temperatures only in the high-dose group, with these same rats exhibiting ~50% loss of forebrain 5-HT two weeks later. Prior exposure to MDMA did not alter baseline plasma hormones or dialysate monoamines, and effects of iv MDMA were similar in saline and low-dose groups. By contrast, rats pretreated with high-dose MDMA displayed significant reductions in evoked hormone secretion and 5-HT release when challenged with iv MDMA. As tolerance developed only in rats exposed to high-dose binges, hyperthermia and 5-HT depletion are implicated in this phenomenon. Our results suggest that MDMA tolerance in humans may reflect 5-HT deficits which could contribute to further dose escalation. PMID:18313226

Once daily dolutegravir (S/GSK1349572) in combination therapy in antiretroviral-naive adults with HIV: planned interim 48 week results from SPRING-1, a dose-ranging, randomised, phase 2b trial.

PubMed

van Lunzen, Jan; Maggiolo, Franco; Arribas, José R; Rakhmanova, Aza; Yeni, Patrick; Young, Benjamin; Rockstroh, Jürgen K; Almond, Steve; Song, Ivy; Brothers, Cindy; Min, Sherene

2012-02-01

Dolutegravir (S/GSK1349572) is a new HIV-1 integrase inhibitor that has antiviral activity with once daily, unboosted dosing. SPRING-1 is an ongoing study designed to select a dose for phase 3 assessment. We present data from preplanned primary and interim analyses. In a phase 2b, multicentre, dose-ranging study, treatment-naive adults were randomly assigned (1:1:1:1) to receive 10 mg, 25 mg, or 50 mg dolutegravir or 600 mg efavirenz. Dose but not drug allocation was masked. Randomisation was by a central integrated voice-response system according to a computer-generated code. Study drugs were given with either tenofovir plus emtricitabine or abacavir plus lamivudine. Our study was done at 34 sites in France, Germany, Italy, Russia, Spain, and the USA beginning on July 9, 2009. Eligible participants were seropositive for HIV-1, aged 18 years or older, and had plasma HIV RNA viral loads of at least 1000 copies per mL and CD4 counts of at least 200 cells per μL. Our primary endpoint was the proportion of participants with viral load of less than 50 copies per mL at week 16 and we present data to week 48. Analyses were done on the basis of allocation group and included all participants who received at least one dose of study drug. This study is registered with ClinicalTrials.gov, number NCT00951015. 205 patients were randomly allocated and received at least one dose of study drug: 53, 51, and 51 to receive 10 mg, 25 mg, and 50 mg dolutegravir, respectively, and 50 to receive efavirenz. Week 16 response rates to viral loads of at most 50 copies per mL were 93% (144 of 155 participants) for all doses of dolutegravir (with little difference between dose groups) and 60% (30 of 50) for efavirenz; week 48 response rates were 87% (139 of 155) for all doses of dolutegravir and 82% (41 of 50) for efavirenz. Response rates between nucleoside reverse transcriptase inhibitor subgroups were similar. We identified three virological failures in the dolutegravir groups and one in the efavirenz group-we did not identify any integrase inhibitor mutations. We did not identify any dose-related clinical or laboratory toxic effects, with more drug-related adverse events of moderate-or-higher intensity in the efavirenz group (20%) than the dolutegravir group (8%). We did not judge that any serious adverse events were related to dolutegravir. Dolutegravir was effective when given once daily without a pharmacokinetic booster and was well tolerated at all assessed doses. Our findings support the assessment of once daily 50 mg dolutegravir in phase 3 trials. Copyright © 2012 Elsevier Ltd. All rights reserved.

Factors Related to Blood Hydroxychloroquine Concentration in Patients With Systemic Lupus Erythematosus.

PubMed

Yeon Lee, Ji; Lee, Jennifer; Ki Kwok, Seung; Hyeon Ju, Ji; Su Park, Kyung; Park, Sung-Hwan

2017-04-01

To identify factors associated with blood concentrations of hydroxychloroquine (HCQ) and its major metabolite, N-desethylhydroxychloroquine (DHCQ), in patients with systemic lupus erythematosus (SLE; lupus) receiving long-term oral HCQ treatment. SLE patients who had been taking HCQ for more than 3 months were recruited. Various clinical characteristics, laboratory values, and SLE Disease Activity Index (SLEDAI) scores were examined. The concentrations of HCQ and DHCQ ([HCQ] and [DHCQ]) were measured by liquid chromatography mass spectrometry, and the relationship between [HCQ], [DHCQ], and [HCQ]:[DHCQ] ratio to various factors was investigated. In total, 189 SLE patients receiving long-term HCQ treatment were included in the analysis. The median (interquartile range [IQR]) [HCQ] was 515 (IQR 353-720) ng/ml, the median [DHCQ] was 417 (IQR 266-591) ng/ml, and the median [HCQ]:[DHCQ] ratio was 1.3 (range 1.0-1.7). [HCQ] was closely associated with [DHCQ] (r = 0.81, P < 0.0001). The weight-adjusted oral HCQ dose was strongly associated with both [HCQ] (P < 0.001) and [DHCQ] (P < 0.001). Time since last dose was associated with [HCQ] (P < 0.001). No statistically significant association was found between renal function or smoking and [HCQ] or [DHCQ]. Use of additional immunosuppressants increased both [HCQ] and [DHCQ] after adjusting for possible confounders (P = 0.04 and P = 0.03, respectively). The lower SLEDAI score was significantly related to higher [HCQ], after adjusting for age, sex, weight-adjusted HCQ dose, time since last dose, number of other immunosuppressants, and smoking status (P = 0.007). Various factors affected blood levels of [HCQ], [DHCQ], or the [HCQ]:[DHCQ] ratio of SLE patients receiving long-term oral HCQ treatment. Notably, higher [HCQ] was associated with a lower SLEDAI score in our typical outpatient clinic population with lupus. © 2016, American College of Rheumatology.

Treatment of tinea capitis - griseofulvin versus fluconazole - a comparative study.

PubMed

Shemer, Avner; Plotnik, Ira Bernstein; Davidovici, Batya; Grunwald, Marcelo H; Magun, Ronen; Amichai, Boaz

2013-08-01

To compare the efficacy and safety of fluconazole and griseofulvin in the treatment of tinea capitis. Patients with tinea capitis (n = 113) with positive fungal cultures entered the study. The patients were divided into four groups with different treatment regimes. Two groups received griseofulvin 15 or 25 mg/kg/day and two groups received fluconazole 4 or 6 mg/kg/day, all for up to 12 weeks. Griseofulvin was found to be slightly better than fluconazole. The lower doses for both griseofulvin and fluconazole required significantly longer treatment duration until mycological cure than the higher doses, independent of the fungus type. Since no significant difference was found between the drugs, it is suggested that the choice should be based on tolerability, availability and cost of the drugs. © The Authors • Journal compilation © Blackwell Verlag GmbH, Berlin.

Effects of intra-aortic balloon counterpulsation in a model of septic shock.

PubMed

Solomon, Steven B; Minneci, Peter C; Deans, Katherine J; Feng, Jing; Eichacker, Peter Q; Banks, Steven M; Danner, Robert L; Natanson, Charles; Solomon, Michael A

2009-01-01

Fluid refractory septic shock can develop into a hypodynamic cardiovascular state in both children and adults. Despite management of these patients with empirical inotropic therapy (with or without a vasodilator), mortality remains high. The effect of cardiovascular support using intra-aortic balloon counterpulsation was investigated in a hypodynamic, mechanically ventilated canine sepsis model in which cardiovascular and pulmonary support were titrated based on treatment protocols. Each week, three animals (n = 33, 10-12 kg) were administered intrabronchial Staphylococcus aureus challenge and then randomized to receive intra-aortic balloon counterpulsation for 68 hrs or no intra-aortic balloon counterpulsation (control). Bacterial doses were increased over the study (4-8 x 10(9) cfu/kg) to assess the effects of intra-aortic balloon counterpulsation during sepsis with increasing risk of death. Compared with lower bacterial doses (4-7 x 10(9) colony-forming units/kg), control animals challenged with the highest dose (8 x 10(9) colony-forming units/kg) had a greater risk of death (mortality rate 86% vs. 17%), with worse lung injury ([A - a]O2), and renal dysfunction (creatinine). These sicker animals required higher norepinephrine infusion rates to maintain blood pressure (and higher FIO2) and positive end-expiratory pressure levels to maintain oxygenation (p < or = 0.04 for all). In animals receiving the highest bacterial dose, intra-aortic balloon counterpulsation improved survival time (23.4 +/- 10 hrs longer; p = 0.003) and lowered norepinephrine requirements (0.43 +/- 0.17 microg/kg/min; p = 0.002) and systemic vascular resistance index (1.44 +/- 0.57 dynes/s/cm5/kg; p = 0.0001) compared with controls. Despite these beneficial effects, intra-aortic balloon counterpulsation was associated with an increase in blood urea nitrogen (p = 0.002) and creatinine (p = 0.12). In animals receiving lower doses of bacteria, intra-aortic balloon counterpulsation had no significant effects on survival or renal function. In a canine model of severe septic shock with a low cardiac index, intra-aortic balloon counterpulsation prolongs survival time and lowers vasopressor requirements.

Activated Prothrombin Complex Concentrate Versus 4-Factor Prothrombin Complex Concentrate for Vitamin K-Antagonist Reversal.

PubMed

Rowe, A Shaun; Dietrich, Scott K; Phillips, John W; Foster, Kaci E; Canter, Joshua R

2018-06-01

To compare the international normalized ratio normalization efficacy of activated prothrombin complex concentrates and 4-factor prothrombin complex concentrates and to evaluate the thrombotic complications in patients treated with these products for warfarin-associated hemorrhage. Retrospective, Multicenter Cohort. Large, Community, Teaching Hospital. Patients greater than 18 years old and received either activated prothrombin complex concentrate or 4-factor prothrombin complex concentrate for the treatment of warfarin-associated hemorrhage. We excluded those patients who received either agent for an indication other than warfarin-associated hemorrhage, pregnant, had a baseline international normalized ratio of less than 2, received a massive transfusion as defined by hospital protocol, received plasma for treatment of warfarin-associated hemorrhage, or were treated for an acute warfarin ingestion. Patients in the activated prothrombin complex concentrate group (enrolled from one hospital) with an international normalized ratio of less than 5 received 500 IU and those with an international normalized ratio greater than 5 received 1,000 IU. Patients in the 4-factor prothrombin complex concentrate (enrolled from a separate hospital) group received the Food and Drug Administration approved dosing algorithm. A total of 158 patients were included in the final analysis (activated prothrombin complex concentrate = 118; 4-factor prothrombin complex concentrate = 40). Those in the 4-factor prothrombin complex concentrate group had a higher pretreatment international normalized ratio (2.7 ± 1.8 vs 3.5 ± 2.9; p = 0.0164). However, the posttreatment international normalized ratio was similar between the groups. In addition, even when controlling for differences in the pretreatment international normalized ratio, there was no difference in the ability to achieve a posttreatment international normalized ratio of less than 1.4 (odds ratio, 0.753 [95% CI, 0.637-0.890]; p = 0.0009). Those in the activated prothrombin complex concentrate group did have higher odds of achieving a posttreatment international normalized ratio of less than 1.2 (odds ratio, 3.23 [95% CI, 1.34-7.81]; p = 0.0088). There was only one posttreatment thrombotic complication reported. A low, fixed dose of activated prothrombin complex concentrate was as effective as standard dose 4-factor prothrombin complex concentrate for normalization of international normalized ratio. In addition, we did not see an increase in thrombotic events.

Prescription order risk factors for pediatric dosing alerts.

PubMed

Stultz, J S; Porter, K; Nahata, M C

2015-02-01

To determine dosing alert rates based on prescription order characteristics and identify prescription order risk factors for the occurrence of dosing alerts. A retrospective analysis of inpatient medication orders and dosing alerts occurring during October 2011 and January, April, and July 2012 at a pediatric institution. Prescription orders and alerts were categorized by: medication class, patient age, route of administration, and month of the year. There were 228,259 orders during the studied period, with 11,072 alerted orders (4.9%). The most frequently alerted medication class was the non-analgesic central nervous system agent class (14% of alerts). Age, route, medication class, and month all independently affected dosing alert rates. The alert rate was highest for immunosuppressive agents (54%), neonates (6.7%), and orders for rectal administration (9.5%). The alert rate was higher in adult patients receiving their care at a pediatric institution (5.7%) compared to children (4.7%), but after multivariate analysis, pediatric orders had higher odds for an alert (OR 1.1, 95% CI 1.05-1.16). Mercaptopurine had the highest alert rate when categorized by active ingredient (73.9%). Albuterol 2.5mg/mL continuous aerosol and heparin 1000 units in 0.9% sodium chloride injection solution were the unique medications with the highest alert rates (100.0% and 97.7%, respectively). Certain types of prescription orders have a higher risk for causing dosing alerts than others. Patient age, medication class, route of administration, and the month of year can affect dosing alert rates. Design and customization efforts should focus on these medications and prescription order characteristics that increase the risk for dosing alerts. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

Memory immune response and safety of a booster dose of Japanese encephalitis chimeric virus vaccine (JE-CV) in JE-CV-primed children

PubMed Central

Feroldi, Emmanuel; Capeding, Maria Rosario; Boaz, Mark; Gailhardou, Sophia; Meric, Claude; Bouckenooghe, Alain

2013-01-01

Japanese encephalitis chimeric virus vaccine (JE-CV) is a licensed vaccine indicated in a single dose administration for primary immunization. This controlled phase III comparative trial enrolled children aged 36–42 mo in the Philippines. 345 children who had received one dose of JE-CV in a study two years earlier, received a JE-CV booster dose. 105 JE-vaccine-naïve children in general good health were randomized to receive JE-CV (JE-vaccine naïve group; 46 children) or varicella vaccine (safety control group; 59 children). JE neutralizing antibody titers were assessed using PRNT50. Immunological memory was observed in children who had received the primary dose of JE-CV before. Seven days after the JE-CV booster dose administration, 96.2% and 66.8% of children were seroprotected and had seroconverted, respectively, and the geometric mean titer (GMT) was 231 1/dil. Twenty-eight days after the JE-CV booster dose seroprotection and seroconversion were achieved in 100% and 95.3% of children, respectively, and the GMT was 2,242 1/dil. In contrast, only 15.4% of JE-CV-vaccine naïve children who had not received any prior JE vaccine were seroprotected seven days after they received JE-CV. One year after receiving the JE-CV booster dose, 99.4% of children remained seroprotected. We conclude that JE-CV is effective and safe, both as a single dose and when administrated as a booster dose. A booster dose increases the peak GMT above the peak level reached after primary immunization and the antibody persistence is maintained at least one year after the JE-CV booster dose administration. Five year follow up is ongoing. PMID:23442823

Memory immune response and safety of a booster dose of Japanese encephalitis chimeric virus vaccine (JE-CV) in JE-CV-primed children.

PubMed

Feroldi, Emmanuel; Capeding, Maria Rosario; Boaz, Mark; Gailhardou, Sophia; Meric, Claude; Bouckenooghe, Alain

2013-04-01

Japanese encephalitis chimeric virus vaccine (JE-CV) is a licensed vaccine indicated in a single dose administration for primary immunization. This controlled phase III comparative trial enrolled children aged 36-42 mo in the Philippines. 345 children who had received one dose of JE-CV in a study two years earlier, received a JE-CV booster dose. 105 JE-vaccine-naïve children in general good health were randomized to receive JE-CV (JE-vaccine naïve group; 46 children) or varicella vaccine (safety control group; 59 children). JE neutralizing antibody titers were assessed using PRNT50. Immunological memory was observed in children who had received the primary dose of JE-CV before. Seven days after the JE-CV booster dose administration, 96.2% and 66.8% of children were seroprotected and had seroconverted, respectively, and the geometric mean titer (GMT) was 231 1/dil. Twenty-eight days after the JE-CV booster dose seroprotection and seroconversion were achieved in 100% and 95.3% of children, respectively, and the GMT was 2,242 1/dil. In contrast, only 15.4% of JE-CV-vaccine naïve children who had not received any prior JE vaccine were seroprotected seven days after they received JE-CV. One year after receiving the JE-CV booster dose, 99.4% of children remained seroprotected. We conclude that JE-CV is effective and safe, both as a single dose and when administrated as a booster dose. A booster dose increases the peak GMT above the peak level reached after primary immunization and the antibody persistence is maintained at least one year after the JE-CV booster dose administration. Five year follow up is ongoing.

Timing of HPV vaccine intervals among United States teens with consideration to the current ACIP schedule and the WHO 2-dose schedule

PubMed Central

Cloessner, Emily A.; Stokley, Shannon; Yankey, David; Markowitz, Lauri E.

2016-01-01

Abstract The current recommendation for human papillomavirus (HPV) vaccination in the United States is for 3 doses to be administered over a 6 month period. In April 2014, the World Health Organization (WHO) recommended adoption of a 2-dose schedule, with doses spaced a minimum of 6 months apart, for teens who begin the series before age 15. We analyzed data from the 2013 National Immunization Survey-Teen to examine the timing of second and third dose receipt among US adolescents. All analyses were restricted to adolescents age 13–17 y who had adequate provider data. The Wilcoxon–Mann–Whitney test measured differences in time to receive vaccine doses among demographic and socioeconomic groups. Logistic regression identified socioeconomic characteristics associated with receiving the second dose of HPV vaccine at least 6 months after the first dose. The median time for teens to receive the second dose of HPV vaccine was 2.6 months after the first dose, and the median time to receive the third dose was 4.9 months after the second dose. Minority teens and teens living below the poverty level took significantly longer to receive doses. Among teens that initiated the HPV vaccine series before age 15 y, 28.6% received the second dose at least 6 months after the first dose. If these teens, who met the WHO criteria for up-to-date HPV vaccination, were classified as having completed the vaccination series, overall coverage in the US would increase 3.9 percentage points, with African American and Hispanic teens having the greatest increases in coverage. PMID:26587886

Timing of HPV vaccine intervals among United States teens with consideration to the current ACIP schedule and the WHO 2-dose schedule.

PubMed

Cloessner, Emily A; Stokley, Shannon; Yankey, David; Markowitz, Lauri E

2016-06-02

The current recommendation for human papillomavirus (HPV) vaccination in the United States is for 3 doses to be administered over a 6 month period. In April 2014, the World Health Organization (WHO) recommended adoption of a 2-dose schedule, with doses spaced a minimum of 6 months apart, for teens who begin the series before age 15. We analyzed data from the 2013 National Immunization Survey-Teen to examine the timing of second and third dose receipt among US adolescents. All analyses were restricted to adolescents age 13-17 y who had adequate provider data. The Wilcoxon-Mann-Whitney test measured differences in time to receive vaccine doses among demographic and socioeconomic groups. Logistic regression identified socioeconomic characteristics associated with receiving the second dose of HPV vaccine at least 6 months after the first dose. The median time for teens to receive the second dose of HPV vaccine was 2.6 months after the first dose, and the median time to receive the third dose was 4.9 months after the second dose. Minority teens and teens living below the poverty level took significantly longer to receive doses. Among teens that initiated the HPV vaccine series before age 15 y, 28.6% received the second dose at least 6 months after the first dose. If these teens, who met the WHO criteria for up-to-date HPV vaccination, were classified as having completed the vaccination series, overall coverage in the US would increase 3.9 percentage points, with African American and Hispanic teens having the greatest increases in coverage.

Beta-cell response during a meal test: a comparative study of incremental doses of repaglinide in type 2 diabetic patients.

PubMed

Cozma, Lawrence S; Luzio, Stephen D; Dunseath, Gareth J; Underwood, Paul M; Owens, David R

2005-05-01

To assess the effects of incremental doses of repaglinide on postprandial insulin and glucose profiles after a standard 500-kcal test meal. Sixteen diet-treated Caucasians with type 2 diabetes (mean HbA(1c) 8.4%) were enrolled in this randomized, open-label, crossover trial. Subjects received 0.5, 1, 2, and 4 mg repaglinide or placebo in a random fashion, followed by a standard 500-kcal test meal on 5 separate study days, 1 week apart. The insulinogenic index (DeltaI30/DeltaG30) and insulin area under the curve (AUC) from 0 to 30 min (AUC(0-30)) were higher with the 4-mg drug dose compared with the two lower doses and with 2 mg compared with 0.5 mg. On subgroup analysis, the incremental insulin responses were apparent only in the fasting plasma glucose (FPG) < 9-mmol/l subgroup of subjects and not in the FPG >9-mmol/l subgroup. There was a significant dose-related increase in the late postprandial insulin secretion (insulin AUC(120-240)), which resulted in hypoglycemia in four subjects. Proinsulin-to-insulin ratios at 30 and 60 min improved with increasing doses of repaglinide; higher drug doses (2 and 4 mg) were more effective than the 0.5- and 1-mg doses. Significant dose-related increases in early insulin secretion were found only in less advanced diabetic subjects. In advanced diabetic patients, only the maximum dose (4 mg) was significant compared with placebo. Better proinsulin-to-insulin processing was noted with increasing drug doses.

Maximizing the biological effect of proton dose delivered with scanned beams via inhomogeneous daily dose distributions

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

Zeng Chuan; Giantsoudi, Drosoula; Grassberger, Clemens

2013-05-15

Purpose: Biological effect of radiation can be enhanced with hypofractionation, localized dose escalation, and, in particle therapy, with optimized distribution of linear energy transfer (LET). The authors describe a method to construct inhomogeneous fractional dose (IFD) distributions, and evaluate the potential gain in the therapeutic effect from their delivery in proton therapy delivered by pencil beam scanning. Methods: For 13 cases of prostate cancer, the authors considered hypofractionated courses of 60 Gy delivered in 20 fractions. (All doses denoted in Gy include the proton's mean relative biological effectiveness (RBE) of 1.1.) Two types of plans were optimized using two opposedmore » lateral beams to deliver a uniform dose of 3 Gy per fraction to the target by scanning: (1) in conventional full-target plans (FTP), each beam irradiated the entire gland, (2) in split-target plans (STP), beams irradiated only the respective proximal hemispheres (prostate split sagittally). Inverse planning yielded intensity maps, in which discrete position control points of the scanned beam (spots) were assigned optimized intensity values. FTP plans preferentially required a higher intensity of spots in the distal part of the target, while STP, by design, employed proximal spots. To evaluate the utility of IFD delivery, IFD plans were generated by rearranging the spot intensities from FTP or STP intensity maps, separately as well as combined using a variety of mixing weights. IFD courses were designed so that, in alternating fractions, one of the hemispheres of the prostate would receive a dose boost and the other receive a lower dose, while the total physical dose from the IFD course was roughly uniform across the prostate. IFD plans were normalized so that the equivalent uniform dose (EUD) of rectum and bladder did not increase, compared to the baseline FTP plan, which irradiated the prostate uniformly in every fraction. An EUD-based model was then applied to estimate tumor control probability (TCP) and normal tissue complication probability (NTCP). To assess potential local RBE variations, LET distributions were calculated with Monte Carlo, and compared for different plans. The results were assessed in terms of their sensitivity to uncertainties in model parameters and delivery. Results: IFD courses included equal number of fractions boosting either hemisphere, thus, the combined physical dose was close to uniform throughout the prostate. However, for the entire course, the prostate EUD in IFD was higher than in conventional FTP by up to 14%, corresponding to the estimated increase in TCP to 96% from 88%. The extent of gain depended on the mixing factor, i.e., relative weights used to combine FTP and STP spot weights. Increased weighting of STP typically yielded a higher target EUD, but also led to increased sensitivity of dose to variations in the proton's range. Rectal and bladder EUD were same or lower (per normalization), and the NTCP for both remained below 1%. The LET distributions in IFD also depended strongly on the mixing weights: plans using higher weight of STP spots yielded higher LET, indicating a potentially higher local RBE. Conclusions: In proton therapy delivered by pencil beam scanning, improved therapeutic outcome can potentially be expected with delivery of IFD distributions, while administering the prescribed quasi-uniform dose to the target over the entire course. The biological effectiveness of IFD may be further enhanced by optimizing the LET distributions. IFD distributions are characterized by a dose gradient located in proximity of the prostate's midplane, thus, the fidelity of delivery would depend crucially on the precision with which the proton range could be controlled.« less

Risks of high-dose stimulants in the treatment of disorders of excessive somnolence: a case-control study.

PubMed

Auger, R Robert; Goodman, Scott H; Silber, Michael H; Krahn, Lois E; Pankratz, V Shane; Slocumb, Nancy L

2005-06-01

To ascertain complications associated with high-dose stimulant therapy in patients with narcolepsy or idiopathic hypersomnia. Case-control, retrospective chart review. Sleep center in an academic hospital. 116 patients with narcolepsy or idiopathic hypersomnia were individually matched by sex, diagnosis, age of onset, and duration of follow-up from both onset and diagnosis. Members of the high-dose group (n = 58) had received at least 1 stimulant at a dosage > or = 120% of the maximum recommended by the American Academy of Sleep Medicine Standards of Practice Committee. The standard-dose control group (n = 58) had received stimulants at a dosage < or = 100% of the American Academy of Sleep Medicine guidelines. N/A. The prevalence of psychosis (odds ratio = 12.0 [1.6-92.0]), alcohol or polysubstance misuse (odds ratio = 4.3 [1.2-15.2]), and psychiatric hospitalization (odds ratio = 3.2 [1.1-10.0]) was significantly increased in the high-dose group. More high-dose patients also experienced tachyarrhythmias (odds ratio = 3.3 [0.92-12.1] and anorexia or weight loss (odds ratio = 11.0 [1.4-85.2]). The frequency of physician-diagnosed depression, drug-seeking and suicide-related behaviors, hypertension, and cardiovascular disease did not differ significantly between the groups. This study demonstrated a significantly higher occurrence of psychosis, substance misuse, and psychiatric hospitalizations in patients using high-dose stimulants compared to those using standard doses. Tachyarrhythmias and anorexia or weight loss were also more common in this group as compared with controls. Clinicians should be very cautious in prescribing dosages that exceed maximum guidelines.

Characterization of the disposition of fostamatinib in Japanese subjects including pharmacokinetic assessment in dry blood spots: results from two phase I clinical studies.

PubMed

Martin, Paul; Cheung, S Y Amy; Yen, Mark; Han, David; Gillen, Michael

2016-01-01

The aims of the present study were to characterize the pharmacokinetics of fostamatinib in two phase I studies in healthy Japanese subjects after single- and multiple-dose administration, and to evaluate the utility of dried blood spot (DBS) sampling. In study A, 40 Japanese and 16 white subjects were randomized in a double-blind parallel group study consisting of seven cohorts, which received either placebo or a fostamatinib dose between 50 and 200 mg after single and multiple dosing. Pharmacokinetics of R406 (active metabolite of fostamatinib) in plasma and urine was assessed, and safety was intensively monitored. Study B was an open-label study that assessed fostamatinib 100 and 200 mg in 24 Japanese subjects. In addition to plasma and urine sampling (as for study A), pharmacokinetics was also assessed in blood. Mean maximum plasma concentration (C max) and area under total plasma concentration–time curve (AUC) increased with increasing dose in Japanese subjects. Steady state was achieved in 5–7 days for all doses. C max and AUC were both higher in Japanese subjects administered a 150-mg single dose than in white subjects. This difference was maintained for steady state exposure by day 10. Overall, R406 blood concentrations were consistent and ∼2.5-fold higher than in plasma. Minimal (<0.1 %) R406 was excreted in urine. Fostamatinib was well tolerated at all doses. Fostamatinib pharmacokinetics following single- and multiple-dose administration was approximately dose proportional at all doses ≤150 mg and greater than dose proportional at 200 mg in Japanese subjects. Japanese subjects administered fostamatinib 150 mg had higher exposure than white subjects. R406 could be measured in DBS samples and distributed into red blood cells, and DBS sampling was a useful method for assessing R406 pharmacokinetics.

Evaluation of dose-area product of common radiographic examinations towards establishing a preliminary diagnostic reference levels (PDRLs) in Southwestern Nigeria.

PubMed

Jibiri, Nnamdi N; Olowookere, Christopher J

2016-11-08

In Nigeria, a large number of radiographic examinations are conducted yearly for various diagnostic purposes. However, most examinations carried out do not have records of doses received by the patients, and the employed exposure parameters used are not documented; therefore, adequate radiation dose management is hin-dered. The aim of the present study was to estimate the dose-area product (DAP) of patients examined in Nigeria, and to propose regional reference dose levels for nine common examinations (chest PA, abdomen AP, pelvis AP, lumbar AP, skull AP, leg AP, knee AP, hand AP, and thigh AP) undertaken in Nigeria. Measurement of entrance surface dose (ESD) was carried out using thermoluminescent dosimeter (TLD). Measured ESDS were converted into DAP using the beam area of patients in 12 purposely selected hospitals. Results of the study show that the maximum/ minimum ratio ranged from 3 for thigh AP to 57 in abdomen AP. The range of determined mean and 75th percentile DAPs were 0.18-17.16, and 0.25-28.59 Gy cm2, respectively. Data available for comparison show that 75th percentile DAPs in this study (in chest PA, abdomen AP, pelvis AP, lumbar AP) are higher than NRPB-HPE reference values. The DAP in this study is higher by factor of 31.4 (chest PA), 9.9 (abdomen AP), 2.2 (pelvis AP), and 2.1 (lumbar AP) than NRPB-HPE values. The relative higher dose found in this study shows nonoptimization of practice in Nigeria. It is expected that regular dose auditing and dose optimization implementation in Nigeria would lead to lower DAP value, especially in abdomen AP. The 75th percentile DAP distribution reported in this study could be taken as regional diagnostic reference level in the Southwestern Nigeria; however, a more extensive nationwide dose survey is required to establish national reference dose. © 2016 The Authors.

Effect of ketamine versus thiopental sodium anesthetic induction and a small dose of fentanyl on emergence agitation after sevoflurane anesthesia in children undergoing brief ophthalmic surgery.

PubMed

Jung, Hyun Ju; Kim, Jong Bun; Im, Kyong Shil; Oh, Seung Hwa; Lee, Jae Myeong

2010-02-01

Emergence agitation (EA) in children after sevoflurane anesthesia is common. The purpose of this study was to compare the incidences of EA between ketamine and thiopental sodium induction in children underwent sevoflurane anesthesia. We also evaluated if a small dose of fentanyl could reduce the incidence of EA. The patients who were scheduled for strabismus or entropion surgery were divided into 4 groups. The patients in Groups 1 and 2 were induced anesthesia with ketamine 1.5 mg/kg; those in Groups 3 and 4 were induced with thiopental sodium 5 mg/kg. The patients in Groups 1 and 3 received an injection of fentanyl 1.5 microg/kg, whereas the patients in Groups 2 and 4 received IV saline of the same volume. Anesthesia was maintained with sevoflurane. The recovery characteristics and EA in recovery room were assessed. The incidence of EA was significantly higher in Groups 2 and 4 and there was no difference between Groups 2 and 4. Group 2 had almost an eleven-fold higher risk of developing EA than did Group 1, and the incidence of EA in Group 4 was sixty-nine-fold higher than that of Group 1. The risk factor for EA was only the kind of medication. Preoperative anxiety had no significant correlation with EA. The incidence of EA after sevoflurane anesthesia is similar between ketamine and thiopental sodium anesthetic induction in children undergoing pediatric ophthalmic surgery. Also, the addition of a small dose of fentanyl after anesthetic induction decreases the incidence of EA.

Randomised controlled trial comparing oral and intravenous paracetamol (acetaminophen) plasma levels when given as preoperative analgesia.

PubMed

van der Westhuizen, J; Kuo, P Y; Reed, P W; Holder, K

2011-03-01

Gastric absorption of oral paracetamol (acetaminophen) may be unreliable perioperatively in the starved and stressed patient. We compared plasma concentrations of parenteral paracetamol given preoperatively and oral paracetamol when given as premedication. Patients scheduled for elective ear; nose and throat surgery or orthopaedic surgery were randomised to receive either oral or intravenous paracetamol as preoperative medication. The oral dose was given 30 minutes before induction of anaesthesia and the intravenous dose given pre-induction. All patients were given a standardised anaesthetic by the same specialist anaesthetist who took blood for paracetamol concentrations 30 minutes after the first dose and then at 30 minute intervals for 240 minutes. Therapeutic concentrations of paracetamol were reached in 96% of patients who had received the drug parenterally, and 67% of patients who had received it orally. Maximum median plasma concentrations were 19 mg.l(-1) (interquartile range 15 to 23 mg.l(-1)) and 13 mg.l(-1) (interquartile range 0 to 18 mg.l(-1)) for the intravenous and oral group respectively. The difference between intravenous and oral groups was less marked after 150 minutes but the intravenous preparation gave higher plasma concentrations throughout the study period. It can be concluded that paracetamol gives more reliable therapeutic plasma concentrations when given intravenously.

Thrombocyte counts in mice after the administration of papaya leaf suspension.

PubMed

Sathasivam, Kathiresan; Ramanathan, Surash; Mansor, Sharif M; Haris, Mas Rosemal M H; Wernsdorfer, Walther H

2009-10-01

Following up a popular use of crude leaf preparations from Carica papaya for the treatment of dengue infections, a suspension of powdered Carica papaya leaves in palm oil has been investigated for its effect on thrombocyte counts in mice, administering by gavage 15 mg of powdered leaves per kg body weight to 5 mice. Equal numbers of animals received corresponding volumes of either palm oil alone or physiological saline solution. Thrombocyte counts before and at 1, 2, 4, 8, 10, 12, 24, 48 and 72 hours after dosing revealed significantly higher mean counts at 1, 2, 4, 8, 10 and 12 after dosing with the C. papaya leaf formulation as compared to the mean count at hour 0. There was only a non-significant rise of thrombocyte counts in the group having received saline solution, possibly the expression of a normal circadian rhythm in mice. The group having received palm oil only showed a protracted increase of platelet counts that was significant at hours 8 and 48 and obviously the result of a hitherto unknown stimulation of thrombocyte release. The results call for a dose-response investigation and for extending the studies to the isolation and identification of the C. papaya substances responsible for the release and/or production of thrombocytes.

Evaluation of an ultra-low-dose oral contraceptive for dysmenorrhea: a placebo-controlled, double-blind, randomized trial.

PubMed

Harada, Tasuku; Momoeda, Mikio

2016-12-01

To evaluate the efficacy and safety of an ultra-low-dose oral contraceptive (NPC-01; 0.02 mg ethinyl estradiol and 1 mg norethisterone) in subjects with dysmenorrhea. Placebo-controlled, double-blind, randomized trial. Clinical trial sites. Two hundred fifteen subjects with dysmenorrhea. Subjects were randomly assigned to receive NPC-01, placebo, or IKH-01 (0.035 mg ethinyl estradiol and 1 mg norethisterone) for four cycles. Total dysmenorrhea score (verbal rating scale) assessing pain on the basis of limited ability to work and need for analgesics. The reductions of total dysmenorrhea score and visual analog scale score after the treatment were significantly higher in the NPC-01 group than in the placebo group. Furthermore, the efficacy of NPC-01 was comparable to that of IKH-01. The overall incidence of side effects was significantly higher in the NPC-01 group than in the placebo group. All side effects that occurred in the NPC-01 group were previously reported in patients receiving IKH-01. No serious side effects occurred. The ultra-low-dose contraceptive NPC-01 relieved dysmenorrhea as effectively as IKH-01. Thus, NPC-01 could represent a new option for long-term treatment of dysmenorrhea. NCT01129102. Copyright © 2016 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.

High-Risk Prescribing to Medicaid Enrollees Receiving Opioid Analgesics: Individual- and County-Level Factors.

PubMed

Heins, Sara E; Sorbero, Mark J; Jones, Christopher M; Dick, Andrew W; Stein, Bradley D

2018-01-05

Prescription opioid overdoses have increased dramatically in recent years, with the highest rates among Medicaid enrollees. High-risk prescribing includes practices associated with overdoses and a range of additional opioid-related problems. To identify individual- and county-level factors associated with high-risk prescribing among Medicaid enrollees receiving opioids. In a four-states, cross-sectional claims data study, Medicaid enrollees 18-64 years old with a new opioid analgesic treatment episode 2007-2009 were identified. Multivariate regression analyses were conducted to identify factors associated with high-risk prescribing, defined as high-dose opioid prescribing (morphine equivalent daily dose ≥100 mg for >6 days), opioid overlap, opioid-benzodiazepine overlap. High-risk prescribing occurred in 39.4% of episodes. Older age, rural county of residence, white race, and major depression diagnosis were associated with higher rates of all types of high-risk prescribing. Individuals with prior opioid, alcohol, and hypnotic/sedative use disorder diagnoses had lower odds of high-dose opioid prescribing but higher odds of opioid overlap and opioid-benzodiazepine overlap than individuals without such disorders. High-dose opioid prescribing in Massachusetts was less common than in California, Illinois, and New York, whereas the rate of benzodiazepine overlap in Massachusetts was more common than in other states. Conclusions/Importance: High-risk prescribing was common and associated with several important demographic, clinical, and community factors. Findings can be used to inform targeted interventions designed to reduce such prescribing, and given state variation observed, further research is needed to better understand the effects of state policies on high-risk prescribing.

Safety and tolerability of different titration rates of retigabine (ezogabine) in patients with partial-onset seizures.

PubMed

Biton, Victor; Gil-Nagel, Antonio; Brodie, Martin J; Derossett, Sarah E; Nohria, Virinder

2013-11-01

Retigabine (RTG; international nonproprietary name)/ezogabine (EZG; US adopted name) is an antiepileptic drug (AED) that prolongs neuronal voltage-gated potassium-channel KCNQ2-5 (Kv 7.2-7.5) opening. This double-blind study evaluated different RTG/EZG dose-titration rates. Patients (N=73) with partial-onset seizures receiving concomitant AEDs were randomized to one of three titration groups, all of which were initiated at RTG/EZG 300mg/day divided into three equal doses. Fast-, medium-, and slow-titration groups received dose increments of 150mg/day every 2, 4, and 7 days, respectively, achieving the target dose of 1200mg/day after 13, 25, and 43 days, respectively. Safety assessments were performed throughout. Discontinuation rates due to treatment-emergent adverse events (TEAEs) were numerically higher in the fast- (10/23) and medium- (7/22) titration groups than in the slow-titration group (3/23) but statistical significance was achieved only for the high-titration group compared with the low-titration group (p=0.024). Stratified analysis, with concomitant AEDs divided into enzyme inducers (carbamazepine, phenytoin, oxcarbazepine) or noninducers, showed that the risk of discontinuation due primarily to TEAEs was significantly higher in the fast- (p=0.010) but not in the medium-titration group (p=0.078) when compared with the slow-titration group. Overall, the slow-titration rate appeared to be best tolerated and was used in further efficacy and safety studies with RTG/EZG. Copyright © 2013 Elsevier B.V. All rights reserved.

Short-term Androgen-Deprivation Therapy Improves Prostate Cancer-Specific Mortality in Intermediate-Risk Prostate Cancer Patients Undergoing Dose-Escalated External Beam Radiation Therapy

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

Zumsteg, Zachary S.; Spratt, Daniel E.; Pei, Xin

2013-03-15

Purpose: We investigated the benefit of short-term androgen-deprivation therapy (ADT) in patients with intermediate-risk prostate cancer (PC) receiving dose-escalated external beam radiation therapy. Methods and Materials: The present retrospective study comprised 710 intermediate-risk PC patients receiving external beam radiation therapy with doses of ≥81 Gy at a single institution from 1992 to 2005, including 357 patients receiving neoadjuvant and concurrent ADT. Prostate-specific antigen recurrence-free survival (PSA-RFS) and distant metastasis (DM) were compared using the Kaplan-Meier method and Cox proportional hazards models. PC-specific mortality (PCSM) was assessed using competing-risks analysis. Results: The median follow-up was 7.9 years. Despite being more likelymore » to have higher PSA levels, Gleason score 4 + 3 = 7, multiple National Comprehensive Cancer Network intermediate-risk factors, and older age (P≤.001 for all comparisons), patients receiving ADT had improved PSA-RFS (hazard ratio [HR], 0.598; 95% confidence interval [CI], 0.435-0.841; P=.003), DM (HR, 0.424; 95% CI, 0.219-0.819; P=.011), and PCSM (HR, 0.380; 95% CI, 0.157-0.921; P=.032) on univariate analysis. Using multivariate analysis, ADT was an even stronger predictor of improved PSA-RFS (adjusted HR [AHR], 0.516; 95% CI, 0.360-0.739; P<.001), DM (AHR, 0.347; 95% CI, 0.176-0.685; P=.002), and PCSM (AHR, 0.297; 95% CI, 0.128-0.685; P=.004). Gleason score 4 + 3 = 7 and ≥50% positive biopsy cores were other independent predictors of PCSM. Conclusions: Short-term ADT improves PSA-RFS, DM, and PCSM in patients with intermediate-risk PC undergoing dose-escalated external beam radiation therapy.« less

Evaluation of the subchronic toxicity of kefir by oral administration in Wistar rats.

PubMed

Diniz Rosa, Damiana; Gouveia Peluzio, Maria do Carmo; Pérez Bueno, Tania; Vega Cañizares, Ernesto; Sánchez Miranda, Lilian; Mancebo Dorbignyi, Betty; Chong Dubí, Dainé; Espinosa Castaño, Ivette; Marcin Grzes Kowiak, Lukasz; Fortes Ferreira, Célia Lucia de Luces

2014-06-01

Kefir is obtained by fermentation of milk with complex microbial populations present in kefir grains. Several health-promoting benefits have been attributed to kefir consumption. The objective of this work was to conduct a subchronic toxicity study, offering the rats normal or high-doses of kefir and evaluating growth, hematology and blood chemistry, as well as assessing bacterial translocation and the integrity of the intestinal mucosa of animals. Wistar rats were randomly divided into three groups (n = 6/group): control group received 0.7 mL of water, kefir group received 0.7 mL/day of kefir, (normodose), and Hkefir group received 3.5 mL/day of kefir (fivefold higher dose). Feeding was carried out by gavage. The animals were housed in individual cages and maintained under standard conditions for 4 weeks. The normodose and high-dose of kefir supplementation did not harm the animals since growth, hematology and blood chemistry in rats, as well as the potential pathogenicity in tissues were within normal limits, demonstrating that consumption of normodose and highdose of kefir are safe. In addition, administration of the normodose of kefir reduced cholesterol levels and improved the intestinal mucosa of the rats. These results demonstrate that the consumption of kefir is safe. Importantly, while damages are not seen for the high-dose, the normodose consumption is recommended due to the pronounced beneficial effects, as safety is concerned. Copyright AULA MEDICA EDICIONES 2014. Published by AULA MEDICA. All rights reserved.

Double oral esomeprazole after a 3-day intravenous esomeprazole infusion reduces recurrent peptic ulcer bleeding in high-risk patients: a randomised controlled study.

PubMed

Cheng, Hsiu-Chi; Wu, Chung-Tai; Chang, Wei-Lun; Cheng, Wei-Chun; Chen, Wei-Ying; Sheu, Bor-Shyang

2014-12-01

Patients with high Rockall scores have increased risk of ulcer rebleeding after 3-day esomeprazole infusions. To investigate whether double oral esomeprazole given after a 3-day esomeprazole infusion decreases ulcer rebleeding for patients with high Rockall scores. We prospectively enrolled 293 patients with peptic ulcer bleeding who had achieved endoscopic haemostasis. After a 3-day esomeprazole infusion, patients with Rockall scores ≥6 were randomised into the oral double-dose group (n=93) or the oral standard-dose group (n=94) to receive 11 days of oral esomeprazole 40 mg twice daily or once daily, respectively. The patients with Rockall scores <6 served as controls (n=89); they received 11 days of oral esomeprazole 40 mg once daily. Thereafter, all patients received oral esomeprazole 40 mg once daily for two more weeks until the end of the 28-day study period. The primary end point was peptic ulcer rebleeding. Among patients with Rockall scores ≥6, the oral double-dose group had a higher cumulative rebleeding-free proportion than the oral standard-dose group (p=0.02, log-rank test). The proportion of patients free from recurrent bleeding during the 4th-28th day in the oral double-dose group remained lower than that of the group with Rockall scores <6 (p=0.03, log-rank test). Among patients with Rockall scores ≥6, the rebleeding rate was lower in the oral double-dose group than in the oral standard-dose group (4th-28th day: 10.8% vs 28.7%, p=0.002). Double oral esomeprazole at 40 mg twice daily after esomeprazole infusion reduced recurrent peptic ulcer bleeding in high-risk patients with Rockall scores ≥6. NCT01591083. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

Use of gastroprotective agents in recommended doses in hospitalized patients receiving NSAIDs: a drug utilization study.

PubMed

Erdeljic, Viktorija; Francetic, Igor; Macolic Sarinic, Viola; Bilusic, Marinko; Makar Ausperger, Ksenija; Huic, Mirjana; Mercep, Iveta

2006-10-01

In recent years, studies investigated to what extend recommendations for co-prescribing gastroprotective agents in prevention of NSAID-induced gastrointestinal complications are followed in clinical practice. However, only a few studies have also taken into consideration the recommended dose of gastroprotectives prescribed in NSAID-induced ulcer prophylaxis. The aim of our study was to evaluate the prevalence of concomitant use of gastroprotectives with NSAIDs in hospitalized patients, with emphasis on the recommended dose of gastroprotectives for ulcer prophylaxis. This observational, cross-sectional, drug utilization study included all adult patients receiving NSAIDs hospitalized in the Clinical Hospital Center Zagreb on the day of the study. Data on age, sex, comorbidities, indications for NSAID use, type/dose of NSAIDs and gastroprotectives, history of gastrointestinal events, active gastrointestinal symptoms and risk factors were evaluated. Study outcomes were: (1) prevalence of prescription of gastroprotectives among NSAID-users at risk; (2) prevalence of prescription of gastroprotective in recommended dose; (3) association between risk factors and prescription of GPAs. The rates of gastroprotectives prescription were significantly higher in NSAID-users with concomitant risk factors as compared to patients without risk factors [47/70 (67.1%) and 8/22 (36.4%), respectively; p=0.01072]. However, gastroprotection in recommended ulcer-preventive dose was low in both groups [8/70 (11.4%) and 9/92 (9.8%), respectively]. The number of concomitant risk factors did not increase the odds of receiving anti-ulcer therapy (odds ratio 0.7279). Thirty-three percent of patients with concomitant risk factors were not prescribed gastroprotectives. Ibuprofen, NSAID with the lowest risk of inducing gastrointestinal complications, was prescribed in only two patients. The results indicate high awareness among hospital physicians about possible NSAID-induced gastrointestinal complications, but insufficient knowledge about risk factors related to NSAID-induced gastrointestinal toxicity, recommended dose of gastroprotectives in NSAID-induced ulcer prophylaxis and gastrointestinal toxicity of different types of NSAIDs.

Effectiveness of different vaccine schedules for heptavalent and 13-valent conjugate vaccines against pneumococcal disease in the Community of Madrid.

PubMed

Latasa, P; Ordobás, M; Garrido-Estepa, M; Gil de Miguel, A; Sanz, J C; Barranco, M D; Insúa, E; García-Comas, L

2017-09-25

The heptavalent pneumococcal conjugate vaccine (PCV-7) was added to the childhood routine vaccination program in the Community of Madrid in November of 2006 with 3+1 recommended doses and a catch-up for those under 2years old. In June 2010, PCV-7 was replaced by 13-valent vaccine (PCV-13) with 2+1 recommended doses. In July of 2012, the PCV-13 was removed from the funded program and reintroduced again (2+1 recommended doses) in December 2014. In between, children were vaccinated privately with 3+1 recommended doses of PCV-13. The aim of this study was to evaluate the effectiveness of each vaccination schedule used in the Community of Madrid. We included all cases of invasive pneumococcal disease (IPD) reported between 2007 and 2015 to the Notifiable Diseases Surveillance System. Vaccination information was obtained from the Immunization Registry. Vaccine effectiveness (VE) was estimated using the indirect cohort design for cases with serotype information. A total 779 cases were included in the study. Among them 47.6% of the cases were primo-vaccinated with booster, 20% primo-vaccinated, 15.9% incompletely primo-vaccinated and 16.5% not vaccinated. The VE for ≥1 doses of any PCV was 82% (CI 95%: 67.8-89.9%): 91.9% (CI 95%: 76.5-97.2%) for PCV-7 and 77.2% (48.6-89.9%) for PCV-13. VE in those receiving the full 2+1 or 3+1 schedules was 100% for both vaccines. A high number of vaccine failures were reported in children before they had the opportunity to receive the booster dose, especially due to PCV-13-non-PCV-7 serotypes. VE was higher for PCV-7 compared to PCV-13, except for those that received the complete schedule with booster that achieved 100% of VE, which shows the relevance of the vaccines and complying with all doses scheduled. Copyright © 2017 Elsevier Ltd. All rights reserved.

High dose radiation with chemotherapy followed by salvage esophagectomy among patients with locally advanced esophageal squamous cell carcinoma.

PubMed

Lertbutsayanukul, Chawalit; Tharavej, Chadin; Klaikeaw, Naruemon; Prayongrat, Anussara; Lowanitchai, Chutinan; Sriuranpong, Virote

2017-05-01

Locoregional failure is a major problem associated with chemoradiation treatment for squamous cell esophageal carcinoma. The aim of this study was to assess the feasibility, efficacy, and toxicity of preoperative radiation (dose > 50 Gy) with platinum-based chemotherapy followed by esophagectomy in locally advanced squamous cell carcinoma. Data of patients with cT2-cT4 or node positive squamous cell carcinoma of the esophagus who received trimodality treatment between February 2006 and June 2015 were reviewed. Forty-four patients were treated with intensity-modulated radiation therapy, volumetric-modulated arc therapy or three-dimensional radiation therapy. The median radiation dose was 60 Gy. The average volume of the lungs receiving 10 Gy was 48.1%, 20 Gy was 24.5%, and the average mean lung dose was 14 Gy. After chemoradiation, R0 resection was achieved in 31 patients (71%). Patients who received >60 Gy had a higher pathologic complete remission rate than those in the lower dose group (59.1% vs. 36.4%). R0 resection and radiation dose >60 Gy were associated with better overall survival in Cox proportional hazards regression analysis. The median follow-up duration was 22.4 months and median survival was 25.6 months. Two-year overall, progression-free survival and locoregional control rates were 55.9%, 28.6%, and 56%, respectively. The most common grade 3-4 toxicities were esophagitis (63.6%) and neutropenia (25%). Grade 3-4 postoperative morbidities included surgical wound infection (2.3%), acute renal failure (2.3%), and anastomosis stricture (2.3%). Trimodality treatment with a high preoperative radiation dose and chemotherapy yielded a good pathologic complete response rate, and long-term survival with low toxicities. © 2017 The Authors. Thoracic Cancer published by China Lung Oncology Group and John Wiley & Sons Australia, Ltd.

Mannitol for the prevention of cisplatin-induced nephrotoxicity: A retrospective comparison of hydration plus mannitol versus hydration alone in inpatient and outpatient regimens at a large academic medical center.

PubMed

Williams, Robert P; Ferlas, Brandon W; Morales, Paul C; Kurtzweil, Andy J

2017-09-01

Background Cisplatin-induced nephrotoxicity is a dose limiting adverse effect that occurs in nearly one-third of patients. Mannitol administration has been used as a means to negate this toxicity. Data regarding the efficacy of mannitol use in this context are conflicting and limited. Objective The aim of this study is to evaluate the effect of mannitol on renal function and describe the incidence of cisplatin-induced nephrotoxicity. Methods This study is a quasi-experimental retrospective analysis approved by the Institutional Review Board of inpatient and outpatient adults receiving cisplatin doses ≥40 mg/m 2 . The primary outcome was mean change in serum creatinine from baseline. Secondary outcomes included incidences of various grades of nephrotoxicity. Results A total of 313 patients (95 treated with mannitol and 218 without) were evaluated. The average increase in serum creatinine (mg/dL) was lower in patients who received mannitol versus those who did not (0.30 vs. 0.47; 95% confidence interval for difference, 0.03 to 0.31; P = 0.02). Grade 2 or higher nephrotoxicity occurred less frequently in patients who received mannitol versus those who did not (8% vs. 17%; P = 0.04). Non-gynecologic regimens and those who received doses ≥70 mg/m 2 of cisplatin had lower rates of grade 2 or higher nephrotoxicity with mannitol (6% vs. 23%; P = 0.001, and 7% vs. 22%; P = 0.03, respectively). Conclusion The use of mannitol reduces the incidence and severity of nephrotoxicity in patients treated with cisplatin. The results of the study suggest mannitol may be most effective when used with non-gynecologic regimens and with cisplatin doses ≥70 mg/m 2 .

Immunogenicity and safety of 23-valent pneumococcal polysaccharide vaccine as a booster dose in 12- to 18-month-old children primed with 3 doses of 7-valent pneumococcal conjugate vaccine

PubMed Central

Thisyakorn, Usa; Chokephaibulkit, Kulkanya; Kosalaraksa, Pope; Benjaponpitak, Suwat; Pancharoen, Chitsanu; Chuenkitmongkol, Sunate

2014-01-01

The current study examined the safety and immunogenicity of 23-valent pneumococcal capsular polysaccharide vaccine (Pneumo23® [PPV23], Sanofi Pasteur) as a booster dose in 12- to 18-month-old children primed with heptavalent pneumococcal vaccine (PCV7; Prevnar®, Pfizer). This was a randomized, observer-blinded, 2-arm, controlled, multicenter phase III study performed in Thailand to assess and describe the immunogenicity and safety of PPV23 as a booster dose in children who had received the 3 primary doses of PCV7, the pneumococcal vaccine available during the study period. Children primed with 3 doses of PCV7 were randomized 1:1 to receive a booster immunization with PPV23 or PCV7. Pneumococcal antibody concentrations were measured by enzyme-linked immunosorbent assay and functional antibody levels by multiplex opsonophagocytosis assay on day 30. A total of 339 children were enrolled. Geometric mean serum antibody concentrations against serotypes common to PCV7 and PPV23 (4, 6B, 9V, 14, 18C, 19F, and 23F) increased in both groups but they were higher for serotypes 4, 9V, 18C, and 19F in the PPV23 group. Opsonization indices increased in both groups for all measured serotypes (1, 6B, 14, 19A, and 23F) and were higher for serotypes 6B, 14, and 23F in the PCV7 group and for serotypes 1 and 19A in PPV23 group. Solicited reactions and unsolicited adverse events were similar in the 2 groups and generally mild and transient. No treatment-related serious adverse events were reported. These results confirm that boosting with PPV23 is immunogenic and well tolerated in healthy toddlers primed with PCV7. PMID:25424793

Assessment of squalene adjuvanted and non-adjuvanted vaccines against pandemic H1N1 influenza in children 6 months to 17 years of age

PubMed Central

Vesikari, Timo; Pepin, Stéphanie; Kusters, Inca; Hoffenbach, Agnès; Denis, Martine

2012-01-01

Vaccines were urgently needed in 2009 against A/H1N1 pandemic influenza. Based on the H5N1 experience, it was originally thought that 2 doses of an adjuvanted vaccine were needed for adequate immunogenicity. We tested H1N1 vaccines with or without AF03, a squalene-based adjuvant, in children. Two randomized, open-label, trials were conducted. Participants 3–17 y received two injections of 3.8 µg or 7.5 µg hemagglutinin (HA) with adjuvant or 15 µg HA without adjuvant. Participants aged 6–35 mo received two injections of 1.9 µg or 3.8 µg HA with full or half dose adjuvant or 7.5 µg HA without adjuvant. All subjects 3 to 17 y reached seroprotection (hemagglutination inhibition (HI) titer ≥ 40) after the first dose of the adjuvanted vaccine, and 94% and 98% in the 3–8 and 9–17 y groups respectively with the non-adjuvanted vaccine. In children aged 6–35 mo responses were modest after one dose, but after two doses virtually all children were seroprotected regardless of HA or adjuvant dose. In this age group, antibody titers were 5 to 7 times higher after adjuvanted than non-adjuvanted vaccine. The higher responses with the adjuvanted vaccine were also reflected as better antibody persistence. There was no clustering of adverse events that would be suggestive of a safety signal. While a single injection was sufficient in subjects from 3 y, in children aged 6–35 mo two injections of this A/H1N1 pandemic influenza vaccine were required. Formulation of this vaccine with adjuvant provided a significant advantage for immunogenicity in the latter age group. PMID:22906943

Oral and Anal Vaccination Confers Full Protection against Enteric Redmouth Disease (ERM) in Rainbow Trout

PubMed Central

Ohtani, Maki; Strøm, Helene Kragelund; Raida, Martin Kristian

2014-01-01

The effect of oral vaccines against bacterial fish diseases has been a topic for debate for decades. Recently both M-like cells and dendritic cells have been discovered in the intestine of rainbow trout. It is therefore likely that antigens reaching the intestine can be taken up and thereby induce immunity in orally vaccinated fish. The objective of this project was to investigate whether oral and anal vaccination of rainbow trout induces protection against an experimental waterborne infection with the pathogenic enterobacteria Yersinia ruckeri O1 biotype 1 the causative agent of enteric redmouth disease (ERM). Rainbow trout were orally vaccinated with AquaVac ERM Oral (MERCK Animal Health) or an experimental vaccine bacterin of Y. ruckeri O1. Both vaccines were tested with and without a booster vaccination four months post the primary vaccination. Furthermore, two groups of positive controls were included, one group receiving the experimental oral vaccine in a 50 times higher dose, and the other group receiving a single dose administered anally in order to bypass the stomach. Each group was bath challenged with 6.3×108 CFU/ml Y. ruckeri, six months post the primary vaccination. The challenge induced significant mortality in all the infected groups except for the groups vaccinated anally with a single dose or orally with the high dose of bacterin. Both of these groups had 100% survival. These results show that a low dose of Y. ruckeri bacterin induces full protection when the bacterin is administered anally. Oral vaccination also induces full protection, however, at a dose 50 times higher than if the fish were to be vaccinated anally. This indicates that much of the orally fed antigen is digested in the stomach before it reaches the second segment of the intestine where it can be taken up as immunogenic antigens and presented to lymphocytes. PMID:24705460

The implementation and evaluation of an evidence-based statewide prehospital pain management protocol developed using the national prehospital evidence-based guideline model process for emergency medical services.

PubMed

Brown, Kathleen M; Hirshon, Jon Mark; Alcorta, Richard; Weik, Tasmeen S; Lawner, Ben; Ho, Shiu; Wright, Joseph L

2014-01-01

In 2008, the National Highway Traffic Safety Administration funded the development of a model process for the development and implementation of evidence-based guidelines (EBGs) for emergency medical services (EMS). We report on the implementation and evaluation of an evidence-based prehospital pain management protocol developed using this model process. An evidence-based protocol for prehospital management of pain resulting from injuries and burns was reviewed by the Protocol Review Committee (PRC) of the Maryland Institute for Emergency Medical Services Systems (MIEMSS). The PRC recommended revisions to the Maryland protocol that reflected recommendations in the EBG: weight-based dosing and repeat dosing of morphine. A training curriculum was developed and implemented using Maryland's online Learning Management System and successfully accessed by 3,941 paramedics and 15,969 BLS providers. Field providers submitted electronic patient care reports to the MIEMSS statewide prehospital database. Inclusion criteria were injured or burned patients transported by Maryland ambulances to Maryland hospitals whose electronic patient care records included data for level of EMS provider training during a 12-month preimplementation period and a 12-month postimplementation period from September 2010 through March 2012. We compared the percentage of patients receiving pain scale assessments and morphine, as well as the dose of morphine administered and the use of naloxone as a rescue medication for opiate use, before and after the protocol change. No differences were seen in the percentage of patients who had a pain score documented or the percent of patients receiving morphine before and after the protocol change, but there was a significant increase in the total dose and dose in mg/kg administered per patient. During the postintervention phase, patients received an 18% higher total morphine dose and a 14.9% greater mg/kg dose. We demonstrated that the implementation of a revised statewide prehospital pain management protocol based on an EBG developed using the National Prehospital Evidence-based Guideline Model Process was associated with an increase in dosing of narcotic pain medication consistent with that recommended by the EBG. No differences were seen in the percentage of patients receiving opiate analgesia or in the documentation of pain scores.

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.

A global quality assurance system for personalized radiation therapy treatment planning for the prostate (or other sites)

NASA Astrophysics Data System (ADS)

Nwankwo, Obioma; Sihono, Dwi Seno K.; Schneider, Frank; Wenz, Frederik

2014-09-01

Introduction: the quality of radiotherapy treatment plans varies across institutions and depends on the experience of the planner. For the purpose of intra- and inter-institutional homogenization of treatment plan quality, we present an algorithm that learns the organs-at-risk (OARs) sparing patterns from a database of high quality plans. Thereafter, the algorithm predicts the dose that similar organs will receive in future radiotherapy plans prior to treatment planning on the basis of the anatomies of the organs. The predicted dose provides the basis for the individualized specification of planning objectives, and for the objective assessment of the quality of radiotherapy plans. Materials and method: one hundred and twenty eight (128) Volumetric Modulated Arc Therapy (VMAT) plans were selected from a database of prostate cancer plans. The plans were divided into two groups, namely a training set that is made up of 95 plans and a validation set that consists of 33 plans. A multivariate analysis technique was used to determine the relationships between the positions of voxels and their dose. This information was used to predict the likely sparing of the OARs of the plans of the validation set. The predicted doses were visually and quantitatively compared to the reference data using dose volume histograms, the 3D dose distribution, and a novel evaluation metric that is based on the dose different test. Results: a voxel of the bladder on the average receives a higher dose than a voxel of the rectum in optimized radiotherapy plans for the treatment of prostate cancer in our institution if both voxels are at the same distance to the PTV. Based on our evaluation metric, the predicted and reference dose to the bladder agree to within 5% of the prescribed dose to the PTV in 18 out of 33 cases, while the predicted and reference doses to the rectum agree to within 5% in 28 out of the 33 plans of the validation set. Conclusion: We have described a method to predict the likely dose that OARs will receive before treatment planning. This prospective knowledge could be used to implement a global quality assurance system for personalized radiation therapy treatment planning.

Tracking Cumulative Radiation Exposure in Orthopaedic Surgeons and Residents: What Dose Are We Getting?

PubMed

Gausden, Elizabeth B; Christ, Alexander B; Zeldin, Roseann; Lane, Joseph M; McCarthy, Moira M

2017-08-02

The purpose of this study was to determine the amount of cumulative radiation exposure received by orthopaedic surgeons and residents in various subspecialties. We obtained dosimeter measures over 12 months on 24 residents and 16 attending surgeons. Monthly radiation exposure was measured over a 12-month period for 24 orthopaedic residents and 16 orthopaedic attending surgeons. The participants wore a Landauer Luxel dosimeter on the breast pocket of their lead apron. The dosimeters were exchanged every rotation (5 to 7 weeks) for the resident participants and every month for the attending surgeon participants. Radiation exposure was compared by orthopaedic subspecialty, level of training, and type of fluoroscopy used (regular C-arm compared with mini C-arm). Orthopaedic residents participating in this study received monthly mean radiation exposures of 0.2 to 79 mrem/month, lower than the dose limits of 5,000 mrem/year recommended by the United States Nuclear Regulatory Commission (U.S. NRC). Senior residents rotating on trauma were exposed to the highest monthly radiation (79 mrem/month [range, 15 to 243 mrem/month]) compared with all other specialty rotations (p < 0.001). Similarly, attending orthopaedic surgeons who specialize in trauma or deformity surgery received the highest radiation exposure of their peers, and the mean exposure was 53 mrem/month (range, 0 to 355 mrem/month). Residents and attending surgeons performing trauma or deformity surgical procedures are exposed to significantly higher doses of radiation compared with all other subspecialties within orthopaedic surgery, but the doses are still within the recommended limits. The use of ionizing radiation in the operating room has become an indispensable part of orthopaedic surgery. Although all surgeons in our study received lower than the yearly recommended dose limit, it is important to be aware of how much radiation we are exposed to as surgeons and to take measures to further limit that exposure.

RADIATION DOSES AND CANCER RISKS IN THE MARSHALL ISLANDS ASSOCIATED WITH EXPOSURE TO RADIOACTIVE FALLOUT FROM BIKINI AND ENEWETAK NUCLEAR WEAPONS TESTS: SUMMARY

PubMed Central

Simon, Steven L.; Bouville, André; Land, Charles E.; Beck, Harold L.

2014-01-01

Nuclear weapons testing conducted at Bikini and Enewetak Atolls during 1946–1958 resulted in exposures of the resident population of the present-day Republic of the Marshall Islands to radioactive fallout. This paper summarizes the results of a thorough and systematic reconstruction of radiation doses to that population, by year, age at exposure, and atoll of residence, and the related cancer risks. Detailed methods and results are presented in a series of companion papers in this volume. From our analysis, we concluded that 20 of the 66 nuclear tests conducted in or near the Marshall Islands resulted in measurable fallout deposition on one or more of the inhabited atolls of the Marshall Islands. In this work, we estimated deposition densities (kBq m−2) of all important dose-contributing radionuclides at each of the 32 atolls and separate reef islands of the Marshall Islands. Quantitative deposition estimates were made for 63 radionuclides from each test at each atoll. Those estimates along with reported measurements of exposure rates at various times after fallout were used to estimate radiation absorbed doses to the red bone marrow, thyroid gland, stomach wall, and colon wall of atoll residents from both external and internal exposure. Annual doses were estimated for six age groups ranging from newborns to adults. We found that the total deposition of 137Cs, external dose, internal organ doses, and cancer risks followed the same geographic pattern with the large population of the southern atolls receiving the lowest doses. Permanent residents of the southern atolls who were of adult age at the beginning of the testing period received external doses ranging from 5 to 12 mGy on average; the external doses to adults at the mid-latitude atolls ranged from 22 to 59 mGy on average, while the residents of the northern atolls received external doses in the hundreds to over 1,000 mGy. Internal doses varied significantly by age at exposure, location, and organ. Except for internal doses to the thyroid gland, external exposure was generally the major contributor to organ doses, particularly for red bone marrow and stomach wall. Internal doses to the stomach wall and red bone marrow were similar in magnitude, about 1 mGy to 7 mGy for permanent residents of the southern and mid-latitude atolls. However, adult residents of Utrik and Rongelap Island, which are part of the northern atolls, received much higher internal doses because of intakes of short-lived radionuclides leading to doses from 20 mGy to more than 500 mGy to red bone marrow and stomach wall. In general, internal doses to the colon wall were four to ten times greater than those to the red bone marrow and internal doses to the thyroid gland were 20 to 30 times greater than to the red bone marrow. Adult internal thyroid doses for the Utrik community and for the Rongelap Island community were about 760 mGy and 7,600 mGy, respectively. The highest doses were to the thyroid glands of young children exposed on Rongelap at the time of the Castle Bravo test of 1 March 1954 and were about three times higher than for adults. Internal doses from chronic intakes, related to residual activities of long-lived radionuclides in the environment, were, in general, low in comparison with acute exposure resulting from the intakes of radionuclides immediately or soon after the deposition of fallout. The annual doses and the population sizes at each atoll in each year were used to develop estimates of cancer risks for the permanent residents of all atolls that were inhabited during the testing period as well as for the Marshallese population groups that were relocated prior to the testing or after it had begun. About 170 excess cancers (radiation-related cases) are projected to occur among more than 25,000 Marshallese, half of whom were born before 1948. All but about 65 of those cancers are estimated to have already been expressed. The 170 excess cancers are in comparison to about 10,600 cancers that would spontaneously arise, unrelated to radioactive fallout, among the same cohort of Marshallese people. PMID:20622547

Radiation doses and cancer risks in the Marshall Islands associated with exposure to radioactive fallout from Bikini and Enewetak nuclear weapons tests: summary.

PubMed

Simon, Steven L; Bouville, André; Land, Charles E; Beck, Harold L

2010-08-01

Nuclear weapons testing conducted at Bikini and Enewetak Atolls during 1946-1958 resulted in exposures of the resident population of the present-day Republic of the Marshall Islands to radioactive fallout. This paper summarizes the results of a thorough and systematic reconstruction of radiation doses to that population, by year, age at exposure, and atoll of residence, and the related cancer risks. Detailed methods and results are presented in a series of companion papers in this volume. From our analysis, we concluded that 20 of the 66 nuclear tests conducted in or near the Marshall Islands resulted in measurable fallout deposition on one or more of the inhabited atolls of the Marshall Islands. In this work, we estimated deposition densities (kBq m(-2)) of all important dose-contributing radionuclides at each of the 32 atolls and separate reef islands of the Marshall Islands. Quantitative deposition estimates were made for 63 radionuclides from each test at each atoll. Those estimates along with reported measurements of exposure rates at various times after fallout were used to estimate radiation absorbed doses to the red bone marrow, thyroid gland, stomach wall, and colon wall of atoll residents from both external and internal exposure. Annual doses were estimated for six age groups ranging from newborns to adults. We found that the total deposition of 137Cs, external dose, internal organ doses, and cancer risks followed the same geographic pattern with the large population of the southern atolls receiving the lowest doses. Permanent residents of the southern atolls who were of adult age at the beginning of the testing period received external doses ranging from 5 to 12 mGy on average; the external doses to adults at the mid-latitude atolls ranged from 22 to 59 mGy on average, while the residents of the northern atolls received external doses in the hundreds to over 1,000 mGy. Internal doses varied significantly by age at exposure, location, and organ. Except for internal doses to the thyroid gland, external exposure was generally the major contributor to organ doses, particularly for red bone marrow and stomach wall. Internal doses to the stomach wall and red bone marrow were similar in magnitude, about 1 mGy to 7 mGy for permanent residents of the southern and mid-latitude atolls. However, adult residents of Utrik and Rongelap Island, which are part of the northern atolls, received much higher internal doses because of intakes of short-lived radionuclides leading to doses from 20 mGy to more than 500 mGy to red bone marrow and stomach wall. In general, internal doses to the colon wall were four to ten times greater than those to the red bone marrow and internal doses to the thyroid gland were 20 to 30 times greater than to the red bone marrow. Adult internal thyroid doses for the Utrik community and for the Rongelap Island community were about 760 mGy and 7,600 mGy, respectively. The highest doses were to the thyroid glands of young children exposed on Rongelap at the time of the Castle Bravo test of 1 March 1954 and were about three times higher than for adults. Internal doses from chronic intakes, related to residual activities of long-lived radionuclides in the environment, were, in general, low in comparison with acute exposure resulting from the intakes of radionuclides immediately or soon after the deposition of fallout. The annual doses and the population sizes at each atoll in each year were used to develop estimates of cancer risks for the permanent residents of all atolls that were inhabited during the testing period as well as for the Marshallese population groups that were relocated prior to the testing or after it had begun. About 170 excess cancers (radiation-related cases) are projected to occur among more than 25,000 Marshallese, half of whom were born before 1948. All but about 65 of those cancers are estimated to have already been expressed. The 170 excess cancers are in comparison to about 10,600 cancers that would spontaneously arise, unrelated to radioactive fallout, among the same cohort of Marshallese people.

Safety, Pharmacokinetic, and Functional Effects of the Nogo-A Monoclonal Antibody in Amyotrophic Lateral Sclerosis: A Randomized, First-In-Human Clinical Trial

PubMed Central

Meininger, Vincent; Pradat, Pierre-François; Corse, Andrea; Al-Sarraj, Safa; Rix Brooks, Benjamin; Caress, James B.; Cudkowicz, Merit; Kolb, Stephen J.; Lange, Dale; Leigh, P. Nigel; Meyer, Thomas; Milleri, Stefano; Morrison, Karen E.; Orrell, Richard W.; Peters, Gary; Rothstein, Jeffrey D.; Shefner, Jeremy; Lavrov, Arseniy; Williams, Nicola; Overend, Phil; Price, Jeffrey; Bates, Stewart; Bullman, Jonathan; Krull, David; Berges, Alienor; Abila, Bams; Meno-Tetang, Guy; Wurthner, Jens

2014-01-01

The neurite outgrowth inhibitor, Nogo-A, has been shown to be overexpressed in skeletal muscle in amyotrophic lateral sclerosis (ALS); it is both a potential biomarker and therapeutic target. We performed a double-blind, two-part, dose-escalation study, in subjects with ALS, assessing safety, pharmacokinetics (PK) and functional effects of ozanezumab, a humanized monoclonal antibody against Nogo-A. In Part 1, 40 subjects were randomized (3∶1) to receive single dose intravenous ozanezumab (0.01, 0.1, 1, 5, or 15 mg/kg) or placebo. In Part 2, 36 subjects were randomized (3∶1) to receive two repeat doses of intravenous ozanezumab (0.5, 2.5, or 15 mg/kg) or placebo, approximately 4 weeks apart. The primary endpoints were safety and tolerability (adverse events [AEs], vital signs, electrocardiogram (ECG), and clinical laboratory tests). Secondary endpoints included PK, immunogenicity, functional endpoints (clinical and electrophysiological), and biomarker parameters. Overall, ozanezumab treatment (0.01–15 mg/kg) was well tolerated. The overall incidence of AEs in the repeat dose 2.5 mg/kg and 15 mg/kg ozanezumab groups was higher than in the repeat dose placebo group and repeat dose 0.5 mg/kg ozanezumab group. The majority were considered not related to study drug by the investigators. Six serious AEs were reported in three subjects receiving ozanezumab; none were considered related to study drug. No study drug-related patterns were identified for ECG, laboratory, or vital signs parameters. One subject (repeat dose 15 mg/kg ozanezumab) showed a weak, positive anti-ozanezumab-antibody result. PK results were generally consistent with monoclonal antibody treatments. No apparent treatment effects were observed for functional endpoints or muscle biomarkers. Immunohistochemical staining showed dose-dependent co-localization of ozanezumab with Nogo-A in skeletal muscle. In conclusion, single and repeat dose ozanezumab treatment was well tolerated and demonstrated co-localization at the site of action. These findings support future studies with ozanezumab in ALS. Trial Registration ClinicalTrials.gov NCT00875446 GSK-ClinicalStudyRegister.com GSK ID 111330 PMID:24841795

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

PubMed Central

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

2013-01-01

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

Evaluation of dose coverage to target volume and normal tissue sparing in the adjuvant radiotherapy of gastric cancers: 3D-CRT compared with dynamic IMRT.

PubMed

Murthy, Kk; Shukeili, Ka; Kumar, Ss; Davis, Ca; Chandran, Rr; Namrata, S

2010-01-01

To assess the potential advantage of intensity-modulated radiotherapy (IMRT) over 3D-conformal radiotherapy (3D-CRT) planning in postoperative adjuvant radiotherapy for patients with gastric carcinoma. In a retrospective study, for plan comparison, dose distribution was recalculated in 15 patients treated with 3D-CRT on the contoured structures of same CT images using an IMRT technique. 3D-conformal plans with three fields and four-fields were compared with seven-field dynamic IMRT plans. The different plans were compared by analyzing the dose coverage of planning target volume using TV(95), D(mean), uniformity index, conformity index and homogeneity index parameters. To assess critical organ sparing, D(mean), D(max), dose to one-third and two-third volumes of the OARs and percentage of volumes receiving more than their tolerance doses were compared. The average dose coverage values of PTV with 3F-CRT and 4F-CRT plans were comparable, where as IMRT plans achieved better target coverage(p<0.001) with higher conformity index value of 0.81±0.07 compared to both the 3D-CRT plans. The doses to the liver and bowel reduced significantly (p<0.001) with IMRT plans compared to other 3D-CRT plans. For all OARs the percentage of volumes receiving more than their tolerance doses were reduced with the IMRT plans. This study showed that a better target coverage and significant dose reduction to OARs could be achieved with the IMRT plans. The IMRT can be preferred with caution for organ motion. The authors are currently studying organ motion in the upper abdomen to use IMRT for patient treatment.

Controlled progressive innate immune stimulation regimen prevents the induction of sickness behavior in the open field test

PubMed Central

Chen, Qun; Tarr, Andrew J; Liu, Xiaoyu; Wang, Yufen; Reed, Nathaniel S; DeMarsh, Cameron P; Sheridan, John F; Quan, Ning

2013-01-01

Peripheral immune activation by bacterial mimics or live replicating pathogens is well known to induce central nervous system activation. Sickness behavior alterations are often associated with inflammation-induced increases in peripheral proinflammatory cytokines (eg, interleukin [IL]-1β and IL-6). However, most researchers have used acute high dose endotoxin/bacterial challenges to observe these outcomes. Using this methodology may pose inherent risks in the translational interpretation of the experimental data in these studies. Studies using Escherichia coli have yet to establish the full kinetics of repeated E. coli peripheral injections. Therefore, we sought to examine the effects of repeated low dose E. coli on sickness behavior and local peripheral inflammation in the open field test. Results from the current experiments showed a behavioral dose response, where increased amounts of E. coli resulted in correspondingly increased sickness behavior. Furthermore, animals that received a subthreshold dose (ie, one that did not cause sickness behavior) of E. coli 24 hours prior were able to withstand a larger dose of E. coli on the second day (a dose that would normally cause sickness behavior in mice without prior exposure) without inducing sickness behavior. In addition, animals that received escalating subthreshold doses of E. coli on days 1 and 2 behaviorally tolerated a dose of E. coli 25 times higher than what would normally cause sickness behavior if given acutely. Lastly, increased levels of E. coli caused increased IL-6 and IL-1β protein expression in the peritoneal cavity, and this increase was blocked by administering a subthreshold dose of E. coli 24 hours prior. These data show that progressive challenges with subthreshold levels of E. coli may obviate the induction of sickness behavior and proinflammatory cytokine expression. PMID:23950656

Controlled progressive innate immune stimulation regimen prevents the induction of sickness behavior in the open field test.

PubMed

Chen, Qun; Tarr, Andrew J; Liu, Xiaoyu; Wang, Yufen; Reed, Nathaniel S; Demarsh, Cameron P; Sheridan, John F; Quan, Ning

2013-01-01

Peripheral immune activation by bacterial mimics or live replicating pathogens is well known to induce central nervous system activation. Sickness behavior alterations are often associated with inflammation-induced increases in peripheral proinflammatory cytokines (eg, interleukin [IL]-1β and IL-6). However, most researchers have used acute high dose endotoxin/bacterial challenges to observe these outcomes. Using this methodology may pose inherent risks in the translational interpretation of the experimental data in these studies. Studies using Escherichia coli have yet to establish the full kinetics of repeated E. coli peripheral injections. Therefore, we sought to examine the effects of repeated low dose E. coli on sickness behavior and local peripheral inflammation in the open field test. Results from the current experiments showed a behavioral dose response, where increased amounts of E. coli resulted in correspondingly increased sickness behavior. Furthermore, animals that received a subthreshold dose (ie, one that did not cause sickness behavior) of E. coli 24 hours prior were able to withstand a larger dose of E. coli on the second day (a dose that would normally cause sickness behavior in mice without prior exposure) without inducing sickness behavior. In addition, animals that received escalating subthreshold doses of E. coli on days 1 and 2 behaviorally tolerated a dose of E. coli 25 times higher than what would normally cause sickness behavior if given acutely. Lastly, increased levels of E. coli caused increased IL-6 and IL-1β protein expression in the peritoneal cavity, and this increase was blocked by administering a subthreshold dose of E. coli 24 hours prior. These data show that progressive challenges with subthreshold levels of E. coli may obviate the induction of sickness behavior and proinflammatory cytokine expression.

Fluence field modulated CT on a clinical TomoTherapy radiation therapy machine

NASA Astrophysics Data System (ADS)

Szczykutowicz, Timothy P.; Hermus, James

2015-03-01

Purpose: The multi-leaf collimator (MLC) assembly present on TomoTherapy (Accuray, Madison WI) radiation therapy (RT) and mega voltage CT machines is well suited to perform fluence field modulated CT (FFMCT). In addition, there is a demand in the RT environment for FFMCT imaging techniques, specifically volume of interest (VOI) imaging. Methods: A clinical TomoTherapy machine was programmed to deliver 30% imaging dose outside predefined VOIs. Four different size ROIs were placed at varying distances from isocenter. Projections intersecting the VOI received "full dose" while those not intersecting the VOI received 30% of the dose (i.e. the incident fluence for non VOI projections was 30% of the incident fluence for projections intersecting the VOI). Additional scans without fluence field modulation were acquired at "full" and 30% dose. The noise (pixel standard deviation) was measured inside the VOI region and compared between the three scans. Results: The VOI-FFMCT technique produced an image noise 1.09, 1.05, 1.05, and 1.21 times higher than the "full dose" scan for ROI sizes of 10 cm, 13 cm, 10 cm, and 6 cm respectively within the VOI region. Conclusions: Noise levels can be almost unchanged within clinically relevant VOIs sizes for RT applications while the integral imaging dose to the patient can be decreased, and/or the image quality in RT can be dramatically increased with no change in dose relative to non-FFMCT RT imaging. The ability to shift dose away from regions unimportant for clinical evaluation in order to improve image quality or reduce imaging dose has been demonstrated. This paper demonstrates that FFMCT can be performed using the MLC on a clinical TomoTherapy machine for the first time.

The effects of recombinant activated factor VII dose on the incidence of thromboembolic events in patients with coagulopathic bleeding.

PubMed

Bucklin, Mason H; Acquisto, Nicole M; Nelson, Catherine

2014-05-01

Previous studies have suggested the used of off-label recombinant factor VII (rFVIIa) increases the risk of thromboembolic events, but the effect of the dose of rFVIIa is not well described in the literature. All adult patients that received off-label rFVIIa from 2005-2012 were included in this single-center, retrospective cohort study. The primary endpoint was the incidence of a thromboembolic event in the low dose (<50 mcg/kg) compared to the high dose (≥50 mcg/kg) cohort. Secondary endpoints compared time to thromboembolic event, incidence of arterial compared to venous events, and mortality. There were 152 patients that received rFVIIa during the study period with 66 in the low dose cohort and 86 in the high dose cohort. Mean total dose of rFVIIa was 30.2 mcg/kg (SD ± 9.5 mcg/kg) in the low dose and 99.8 mcg/kg (SD ± 64.7 mcg/kg) in the high dose cohort (p=0.0001). The overall incidence of thromboembolic events was 12.5%. There were 12 (14%) events in the low dose cohort and seven (10.6%) in the high dose cohort, RR=0.76 (95% CI 0.31-1.82). There were no differences in any of the secondary outcomes. A higher incidence of thromboembolic events in cardiothoracic surgery (20.8%) and penetrating trauma patients (21.4%) was seen compared to the remaining cohort (6.7%). No significant difference in the incidence of thromboembolic events was seen between low dose versus high dose rFVIIa over a seven year period at our institution. However, due to the relatively low overall incidence and a small sample size, type II error may be present. Copyright © 2014 Elsevier Ltd. All rights reserved.

SU-E-T-556: Monte Carlo Generated Dose Distributions for Orbital Irradiation Using a Single Anterior-Posterior Electron Beam and a Hanging Lens Shield

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

Duwel, D; Lamba, M; Elson, H

Purpose: Various cancers of the eye are successfully treated with radiotherapy utilizing one anterior-posterior (A/P) beam that encompasses the entire content of the orbit. In such cases, a hanging lens shield can be used to spare dose to the radiosensitive lens of the eye to prevent cataracts. Methods: This research focused on Monte Carlo characterization of dose distributions resulting from a single A-P field to the orbit with a hanging shield in place. Monte Carlo codes were developed which calculated dose distributions for various electron radiation energies, hanging lens shield radii, shield heights above the eye, and beam spoiler configurations.more » Film dosimetry was used to benchmark the coding to ensure it was calculating relative dose accurately. Results: The Monte Carlo dose calculations indicated that lateral and depth dose profiles are insensitive to changes in shield height and electron beam energy. Dose deposition was sensitive to shield radius and beam spoiler composition and height above the eye. Conclusion: The use of a single A/P electron beam to treat cancers of the eye while maintaining adequate lens sparing is feasible. Shield radius should be customized to have the same radius as the patient’s lens. A beam spoiler should be used if it is desired to substantially dose the eye tissues lying posterior to the lens in the shadow of the lens shield. The compromise between lens sparing and dose to diseased tissues surrounding the lens can be modulated by varying the beam spoiler thickness, spoiler material composition, and spoiler height above the eye. The sparing ratio is a metric that can be used to evaluate the compromise between lens sparing and dose to surrounding tissues. The higher the ratio, the more dose received by the tissues immediately posterior to the lens relative to the dose received by the lens.« less

The Efficacy of Single-Dose versus Double-Dose Praziquantel Treatments on Schistosoma mansoni Infections: Its Implication on Undernutrition and Anaemia among Primary Schoolchildren in Two On-Shore Communities, Northwestern Tanzania

PubMed Central

Buza, Joram; Mpolya, Emmanuel A.; Angelo, Teckla; Kinung'hi, Safari M.

2017-01-01

Administering more than one treatment may increase Praziquantel cure and egg reduction rates, thereby hastening achievement of schistosomiasis transmission control. A total of 431 S. mansoni-infected schoolchildren were randomized to receive either a single or repeated 40 mg/kg Praziquantel dose. Heights, weights, and haemoglobin levels were determined using a stadiometer, weighing scale, and HemoCue, respectively. At 8 weeks, cure rate was higher on repeated dose (93.10%) compared to single dose (68.68%) (p < 0.001). The egg reduction rate was higher on repeated dose (97.54%) compared to single dose (87.27%) (p = 0.0062). Geometric mean egg intensity was lower among those on repeated dose (1.30 epg) compared to single dose (3.18 epg) (p = 0.036) but not at 5 (p > 0.05) and 8 (p > 0.05) months with no difference in reinfection rate. No difference in the prevalence of stunting was observed between the two treatment regimens (p > 0.05) at 8 months, but there was an increase in the prevalence of wasting among those on repeated dose (p < 0.001). There was an increase in the mean haemoglobin levels at 8 months with no difference between the two arms (p > 0.05). To achieve reduction of transmission intensity and disease control in highly endemic areas, repeated treatments alone may not be sufficient. This trial was registered with PACTR201601001416338. PMID:29094048

In vivo tumor targeting of gold nanoparticles: effect of particle type and dosing strategy.

PubMed

Puvanakrishnan, Priyaveena; Park, Jaesook; Chatterjee, Deyali; Krishnan, Sunil; Tunnell, James W

2012-01-01

Gold nanoparticles (GNPs) have gained significant interest as nanovectors for combined imaging and photothermal therapy of tumors. Delivered systemically, GNPs preferentially accumulate at the tumor site via the enhanced permeability and retention effect, and when irradiated with near infrared light, produce sufficient heat to treat tumor tissue. The efficacy of this process strongly depends on the targeting ability of the GNPs, which is a function of the particle's geometric properties (eg, size) and dosing strategy (eg, number and amount of injections). The purpose of this study was to investigate the effect of GNP type and dosing strategy on in vivo tumor targeting. Specifically, we investigated the in vivo tumor-targeting efficiency of pegylated gold nanoshells (GNSs) and gold nanorods (GNRs) for single and multiple dosing. We used Swiss nu/nu mice with a subcutaneous tumor xenograft model that received intravenous administration for a single and multiple doses of GNS and GNR. We performed neutron activation analysis to quantify the gold present in the tumor and liver. We performed histology to determine if there was acute toxicity as a result of multiple dosing. Neutron activation analysis results showed that the smaller GNRs accumulated in higher concentrations in the tumor compared to the larger GNSs. We observed a significant increase in GNS and GNR accumulation in the liver for higher doses. However, multiple doses increased targeting efficiency with minimal effect beyond three doses of GNPs. These results suggest a significant effect of particle type and multiple doses on increasing particle accumulation and on tumor targeting ability.

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

Dexmedetomidine oromucosal gel for noise-associated acute anxiety and fear in dogs-a randomised, double-blind, placebo-controlled clinical study.

PubMed

Korpivaara, M; Laapas, K; Huhtinen, M; Schöning, B; Overall, K

2017-04-08

The aim of this randomised, double-blind, placebo-controlled, clinical-field study was to evaluate the effect of dexmedetomidine oromucosal gel at subsedative doses in alleviation of noise-associated acute anxiety and fear in dogs. On New Year's Eve, 182 dogs with a history of acute anxiety and fear associated with fireworks received treatment as needed up to five times: 89 dogs received dexmedetomidine and 93 dogs received placebo. For the primary efficacy variables, dog owners assessed the overall treatment effect as well as signs and extent of anxiety and fear. The overall treatment effect was statistically significant (P<0.0001). An excellent or good treatment effect was reported for a higher proportion of dogs treated with dexmedetomidine (64/89, 72 per cent) than those receiving placebo (34/93, 37 per cent). Additionally, dexmedetomidine-treated dogs expressed significantly (P<0.0314) fewer signs of fear and anxiety despite the noise of fireworks. No local tolerance or clinical safety concerns occurred during the study. This study demonstrated that oromucosal dexmedetomidine at subsedative doses alleviates noise-associated acute anxiety and fear in dogs. British Veterinary Association.

[Combined therapy for children and adolescents with Ewing tumors (a 25-year experience)].

PubMed

Yukhta, T V; Punanov, Yu A; Kazantsev, I V; Malinin, A P; Safonova, S A; Gafton, G I; Gevorgyan, A G; Morozova, E V; Zubarovskaya, L S; Fanasiev, B V A

2015-01-01

A total of 115 children (median age 10.5 years, range 2-17) with Ewing sarcoma family tumors (ESFT) received therapy in N.N. Petrov Institute of Oncology pediatric department from April 1985 till August 2013. These patients were divided into two groups depending on treatment tactics used: patients treated according to modified T9 protocol (n = 64) and patients treated according to EICESS-92 or Euro-Ewing 99 regimens (n = 51). Twenty four patients from the second group with adverse prognostic factors received high-dose chemotherapy with autologous stem cell transplantation. All patients received surgical treatment and/or irradiation for primary tumor local control. Five-year overall and disease-free survival was 39% and 37,9% in the first group. In the second group these values were significantly higher; 55% and 39.5%, accordingly (p = 0.03 and 0.25). All patients from the first group with primary metastatic ESFT died of disease progression, while in the second group OS and DFS reached 45.8% and 28.9%, accordingly. There was a statistically significant correlation between local relapse rate and irradiation dose biological equivalent (in TDF units). The local relapse cumulative rate was minimal (12,6%) in patients receiving 80 TDF.

Respiratory depression in the intoxicated trauma patient: are opioids to blame?

PubMed

Shenk, Eleni; Barton, Cassie A; Mah, Nathan D; Ran, Ran; Hendrickson, Robert G; Watters, Jennifer

2016-02-01

Providing effective pain management to acutely intoxicated trauma patients represents a challenge of balancing appropriate pain management with the risk of potential respiratory depression from opioid administration. The objective of this study was to quantify the incidence of respiratory depression in trauma patients acutely intoxicated with ethanol who received opioids as compared with those who did not and identify potential risk factors for respiratory depression in this population. Retrospective medical record review was conducted for subjects identified via the trauma registry who were admitted as a trauma activation and had a detectable serum ethanol level upon admission. Risk factors and characteristics compared included demographics, Injury Severity Score, Glasgow Coma Score, serum ethanol level upon arrival, urine drug screen results, incidence of respiratory depression, and opioid and other sedative medication use. A total of 233 patients were included (78.5% male). Patients who received opioids were more likely to have a higher Injury Severity Score and initial pain score on admission as compared with those who did not receive opioids. Blood ethanol content was higher in patients who did not receive opioids (0.205 vs 0.237 mg/dL, P = .015). Patients who did not receive opioids were more likely to be intubated within 4 hours of admission (1.7% vs 12.1%, P = .02). Opioid administration was not associated with increased risk of respiratory depression (19.7% vs 22.4%, P = .606). Increased cumulative fentanyl dose was associated with increased risk of respiratory depression. Increased cumulative fentanyl dose, but not opioid administration alone, was found to be a risk factor for respiratory depression. Copyright © 2015 Elsevier Inc. All rights reserved.

Compliance with vaccination against tick-borne encephalitis virus in Germany.

PubMed

Jacob, L; Kostev, K

2017-07-01

The goal of this study was to analyse patients' compliance with vaccination against tick-borne encephalitis (TBE) virus in Germany. The present study included 7266 patients from 638 general practices and 4194 patients from 114 paediatric practices. Patients were included if they had received the first dose of one of two vaccines against TBE virus (FSME-Immune ® and Encepur ® ). The immunization schedule of these vaccines consisted of three injections. Patients were considered compliant if they received the second and third doses at the recommended time or within a period of ±25% around the recommended time (tolerance period). Of the recruited patients, 28% received both the second and the third injections within the tolerance period. Individuals treated in paediatric practices had a higher likelihood of receiving vaccine doses within the tolerance period compared with individuals treated in general practices (OR 2.15; 95% CI 1.92-2.41). Moreover, patients <18 years old were more likely to be compliant than patients >65 years old (OR 1.22; 95% CI 1.02-1.46), whereas patients aged between 18 and 30 years were least likely to be compliant (OR 0·77; 95% CI 0.61-0.96). Compliance with vaccination against the TBE virus was low. This compliance was significantly associated with age and the type of practices in which patients were treated. Copyright © 2017 European Society of Clinical Microbiology and Infectious Diseases. Published by Elsevier Ltd. All rights reserved.

Cumulative cisplatin dose in concurrent chemoradiotherapy for head and neck cancer: A systematic review.

PubMed

Strojan, Primož; Vermorken, Jan B; Beitler, Jonathan J; Saba, Nabil F; Haigentz, Missak; Bossi, Paolo; Worden, Francis P; Langendijk, Johannes A; Eisbruch, Avraham; Mendenhall, William M; Lee, Anne W M; Harrison, Louis B; Bradford, Carol R; Smee, Robert; Silver, Carl E; Rinaldo, Alessandra; Ferlito, Alfio

2016-04-01

The optimal cumulative dose and timing of cisplatin administration in various concurrent chemoradiotherapy protocols for nonmetastatic head and neck squamous cell carcinoma (HNSCC) has not been determined. The absolute survival benefit at 5 years of concurrent chemoradiotherapy protocols versus radiotherapy alone observed in prospective randomized trials reporting on the use of cisplatin monochemotherapy for nonnasopharyngeal HNSCC was extracted. In the case of nonrandomized studies, the outcome results at 2 years were compared between groups of patients receiving different cumulative cisplatin doses. Eleven randomized trials and 7 nonrandomized studies were identified. In 6 definitive radiotherapy phase III trials, a statistically significant association (p = .027) between cumulative cisplatin dose, independent of the schedule, and overall survival benefit was observed for higher doses. Results support the conclusion that the cumulative dose of cisplatin in concurrent chemoradiation protocols for HNSCC has a significant positive correlation with survival. © 2015 Wiley Periodicals, Inc. Head Neck 38: E2151-E2158, 2016. © 2015 Wiley Periodicals, Inc.

Relationship between Eustachian tube dysfunction and otitis media with effusion in radiotherapy patients.

PubMed

Akazawa, K; Doi, H; Ohta, S; Terada, T; Fujiwara, M; Uwa, N; Tanooka, M; Sakagami, M

2018-02-01

This study evaluated the relationship between radiation and Eustachian tube dysfunction, and examined the radiation dose required to induce otitis media with effusion. The function of 36 Eustachian tubes in 18 patients with head and neck cancer were examined sonotubometrically before, during, and 1, 2 and 3 months after, intensity-modulated radiotherapy. Patients with an increase of 5 dB or less in sound pressure level (dB) during swallowing were categorised as being in the dysfunction group. Additionally, radiation dose distributions were assessed in all Eustachian tubes using three dose-volume histogram parameters. Twenty-two of 25 normally functioning Eustachian tubes before radiotherapy (88.0 per cent) shifted to the dysfunction group after therapy. All ears that developed otitis media with effusion belonged to the dysfunction group. The radiation dose threshold evaluation revealed that ears with otitis media with effusion received significantly higher doses to the Eustachian tubes. The results indicate a relationship between radiation dose and Eustachian tube dysfunction and otitis media with effusion.

Timeliness and risk factors associated with delay for pneumococcal conjugate 10-valent routine immunization in Brazilian children.

PubMed

Sartori, Ana Lucia; Minamisava, Ruth; Afonso, Eliane Terezinha; Policena, Gabriela Moreira; Pessoni, Grécia Carolina; Bierrenbach, Ana Luiza; Andrade, Ana Lucia

2017-02-15

Vaccination coverage is the usual metrics to evaluate the immunization programs performance. For the 10-valent pneumococcal conjugate (PCV10) vaccine, measuring the delay of vaccination is also important, particularly as younger children are at increased risk of disease. Routinely collected administrative data was used to assess the timeliness of PCV10 vaccination, and the factors associated with delay to receive the first and second doses, and the completion of the PCV10 3+1 schedule. A population-based retrospective cohort study was conducted with children born in 2012 in Central Brazil. Children who received the PCV10 first dose in public health services were followed-up until 23months of age. Timeliness of receiving each PCV10 dose at any given age was defined as receiving the dose within 28days grace period from the recommended age by the National Immunization Program. Log-binomial regression models were used to examine risk factors for delays of the first dose and the completion PCV10 3+1 schedule. In total, 14,282 children were included in the cohort of study. Delayed vaccination occurred in 9.4%, 23.8%, 36.8% and 39.9% children for the first, second, third and the booster doses, respectively. A total of 1912 children (12.8% of the cohort) were not adequately vaccinated at the 6months of life; 1,071 (7%) received the second dose after 6months of age, 784 (5.4%) did not receive the second dose, and 57 (0.4%) received the first dose after six months of life. A considerable delay was found in PCV10 third and booster doses. Almost 2 thousand children had not received the recommended PCV10 doses at 6months of age. Timeliness of vaccination is an issue in Brazil although high vaccination coverages. Copyright © 2017 Elsevier Ltd. All rights reserved.

Paraquat detoxication with multiple emulsions.

PubMed

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

2009-10-01

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

Efficacy and safety of rivastigmine in patients with Alzheimer’s disease: international randomised controlled trial

PubMed Central

Rösler, Michael; Anand, Ravi; Cicin-Sain, Ana; Gauthier, Serge; Agid, Yves; Dal-Bianco, Peter; Stähelin, Hannes B; Hartman, Richard; Gharabawi, Marguirguis

1999-01-01

Objectives To assess the effects of rivastigmine on the core domains of Alzheimer’s disease. Design Prospective, randomised, multicentre, double blind, placebo controlled, parallel group trial. Patients received either placebo, 1-4 mg/day (lower dose) rivastigmine, or 6-12 mg/day (higher dose) rivastigmine. Doses were increased in one of two fixed dose ranges (1-4 mg/day or 6-12 mg/day) over the first 12 weeks with a subsequent assessment period of 14 weeks. Setting 45 centres in Europe and North America. Participants 725 patients with mild to moderately severe probable Alzheimer’s disease diagnosed according to the Diagnostic and Statistical Manual of Mental Disorders, fourth edition, and the criteria of the National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer’s Disease and Related Disorders Association. Outcome measures Cognitive subscale of the Alzheimer’s disease assessment scale, rating on the clinician interview based impression of change incorporating caregiver information scale, and the progressive deterioration scale. Results At the end of the study cognitive function had deteriorated among those in the placebo group. Scores on the Alzheimer’s disease assessment scale improved in patients in the higher dose group when compared with patients taking placebo (P<0.05). Significantly more patients in the higher dose group had improved by 4 points or more than had improved in the placebo group (24% (57/242) v 16% (39/238)). Global function as rated by the clinician interview scale had significantly improved among those in the higher dose group compared with those taking placebo (P<0.001), and significantly more patients in the higher dose group showed improvement than did in the placebo group (37% (80/219) v 20% (46/230)). Mean scores on the progressive deterioration scale improved from baseline in patients in the higher dose group but fell in the placebo group. Adverse events were predominantly gastrointestinal, of mild to moderate severity, transient, and occurred mainly during escalation of the dose. 23% (55/242) of those in the higher dose group, 7% (18/242) of those in the lower dose group, and 7% (16/239) of those in the placebo group discontinued treatment because of adverse events. Conclusions Rivastigmine is well tolerated and effective. It improves cognition, participation in activities of daily living, and global evaluation ratings in patients with mild to moderately severe Alzheimer’s disease. This is the first treatment to show compelling evidence of efficacy in a predominantly European population. Key messagesIn a 6 month trial rivastigmine was effective in treating the core cognitive and functional symptoms of patients with mild to moderate Alzheimer’s diseaseRivastigmine at doses of 6-12 mg/day produces clinically relevant and statistically significant improvements in cognitive and global assessments, and in activities of daily livingThe effects of rivastigmine are dose dependentRivastigmine was well tolerated in this population of elderly patients PMID:10066203

Influence of vector dose on factor IX-specific T and B cell responses in muscle-directed gene therapy.

PubMed

Herzog, Roland W; Fields, Paul A; Arruda, Valder R; Brubaker, Jeff O; Armstrong, Elina; McClintock, Darryl; Bellinger, Dwight A; Couto, Linda B; Nichols, Timothy C; High, Katherine A

2002-07-20

Intramuscular injection of an adeno-associated virus (AAV) vector has resulted in vector dose-dependent, stable expression of canine factor IX (cF.IX) in hemophilia B dogs with an F.IX missense mutation (Herzog et al., Nat. Med. 1999;5:56-63). The use of a species-specific transgene allowed us to study risks and characteristics of antibody formation against the therapeutic transgene product. We analyzed seven dogs that had been injected at a single time point at multiple intramuscular sites with varying vector doses (dose per kilogram, dose per animal, dose per site). Comparison of individual animals suggests an increased likelihood of inhibitory anti-cF.IX (inhibitor) development with increased vector doses, with dose per site showing the strongest correlation with the risk of inhibitor formation. In six of seven animals, such immune responses were either absent or transient, and therefore did not prevent sustained systemic expression of cF.IX. Transient inhibitory/neutralizing anti-cF.IX responses occurred at vector doses of 2 x 10(12)/site, whereas a 6-fold higher dose resulted in a longer lasting, higher titer inhibitor. Anti-cF.IX was efficiently blocked in an eighth animal that was injected with a high vector dose per site, but in addition received transient immune suppression. Inhibitor formation was characterized by synthesis of two IgG subclasses and in vitro proliferation of lymphocytes to cF.IX antigen, indicating a helper T cell-dependent mechanism. Anti-cF.IX formation is likely influenced by the extent of local antigen presentation and may be avoided by limited vector doses or by transient immune modulation.

Patient-specific FDG dosimetry for adult males, adult females, and very low birth weight infants

NASA Astrophysics Data System (ADS)

Niven, Erin

Fluorodeoxyglucose is the most commonly used radiopharmaceutical in Positron Emission Tomography, with applications in neurology, cardiology, and oncology. Despite its routine use worldwide, the radiation absorbed dose estimates from FDG have been based primarily on data obtained from two dogs studied in 1977 and 11 adults (most likely males) studied in 1982. In addition, the dose estimates calculated for FDG have been centered on the adult male, with little or no mention of variations in the dose estimates due to sex, age, height, weight, nationality, diet, or pathological condition. Through an extensive investigation into the Medical Internal Radiation Dose schema for calculating absorbed doses, I have developed a simple patient-specific equation; this equation incorporates the parameters necessary for alterations to the mathematical values of the human model to produce an estimate more representative of the individual under consideration. I have used this method to determine the range of absorbed doses to FDG from the collection of a large quantity of biological data obtained in adult males, adult females, and very low birth weight infants. Therefore, a more accurate quantification of the dose to humans from FDG has been completed. My results show that per unit administered activity, the absorbed dose from FDG is higher for infants compared to adults, and the dose for adult women is higher than for adult men. Given an injected activity of approximately 3.7 MBq kg-1, the doses for adult men, adult women, and full-term newborns would be on the order of 5.5, 7.1, and 2.8 mSv, respectively. These absorbed doses are comparable to the doses received from other nuclear medicine procedures.

Estrus synchronization in sheep with synthetic progestagens.

PubMed

Awel, Hayatu; Eshetu, Lisanework; Tadesse, Gebrehiwot; Birhanu, Alemselam; Khar, S K

2009-10-01

Sixteen female sheep of Degua breed were assigned to receive either the full dose of norgestomet ear implant and injectable solution containing norgestomet and estradiol valerate (n = 8) or half the dose (n = 8). The ear implants were removed in both groups on day 12. All ewes received an intramuscular administration of 500 IU PMSG at implant withdrawal. Synchronized ewes were individually hand mated twice at 48 and 60 hours after implant removal. One ewe in each group however refused mating on both occasions. Pregnancy diagnosis was conducted by bimanual external palpation 90 to 100 days post mating. The conception rates (3/7, 42.85%) and (5/7, 71.42%) were recorded in the two treatment groups, respectively. All eight ewes lambed between 145 to 153 days post mating. In group I ewes carried only singletons (prolificity rate 1.0) whereas in group II two ewes delivered twins, producing 7 lambs with prolificity rate of 1.4 (N.S). From this preliminary investigation it appears that the lower dose of norgestomet ear implants offers better option for estrus synchronization accompanied by higher fertility.

Lung deposition and systemic bioavailability of different aerosol devices with and without humidification in mechanically ventilated patients.

PubMed

Moustafa, Islam O F; Ali, Mohammed R A-A; Al Hallag, Moataz; Rabea, Hoda; Fink, James B; Dailey, Patricia; Abdelrahim, Mohamed E A

During mechanical ventilation medical aerosol delivery has been reported to be upto two fold greater with dry inhaled gas than with heated humidity. Urine levels at 0.5 h post dose (URSAL0.5%) has been confirmed as an index of lung deposition and 24 h (URSAL24%) as index of systemic absorption. Our aim was to determine the effect of humidification and aerosol device type on drug delivery to ventilated patients using urine levels. In a randomized crossover design, 36 (18female) mechanically ventilated patients were assigned to one of three groups. Groups 1 and 2 received 5000 μg salbutamol using vibrating mesh (VM) and jet nebulizers (JN), respectively, while group 3 received 1600 μg (16 puffs) of salbutamol via metered dose inhaler with AeroChamber Vent (MDI-AV). All devices were placed in the inspiratory limb of ventilator downstream from the humidifier. Each subject received aerosol with and without humidity at >24 h intervals with >12 h washout periods between salbutamol doses. Patients voided urine 15 min before each study dose and urine samples were collected at 0.5 h post dosing and pooled for the next 24 h. The MDI-AV and VM resulted in a higher percentage of urinary salbutamol levels compared to the JN (p < 0.05). Urine levels were similar between humidity and dry conditions. Our findings suggest that in-vitro reports overestimate the impact of dry vs. heated humidified conditions on the delivery of aerosol during invasive mechanical ventilation. Copyright © 2017 Elsevier Inc. All rights reserved.

Reactogenicity of tetanus, diphtheria, 5-component acellular pertussis vaccine administered as a sixth consecutive acellular pertussis vaccine dose to adolescents.

PubMed

Liese, Johannes G; Rieber, Nikolaus; Malzer, Thomas; Ocak, Marion; Johnson, David R; Decker, Michael D

2010-12-01

Safety of a sixth consecutive dose of acellular pertussis vaccine in adolescents was assessed in a 2-armed, randomized study. Adolescents who had received 5 doses of acellular pertussis vaccine combined with diphtheria and tetanus toxoids (6-dose group) received 1 dose of reduced 5-component acellular pertussis vaccine combined with tetanus toxoid and reduced diphtheria toxoid (Tdap). Adolescents who had received a primary series of 3 doses of whole-cell pertussis and 1 acellular or whole-cell pertussis booster received 1 dose of Tdap vaccine (5-dose group). Of 214 participants, 176 (82%) reported an injection-site reaction with pain (80%), erythema (22%), and swelling (19%) most frequently reported. A systemic reaction was reported by 169 of 214 (79%) with myalgia (66%), headache (42%), malaise (39%), and fever (9%) most frequently reported. The overall rate of solicited reactions was lower in the 6-dose group than in the 5-dose group (for injection-site reactions: 76.1% vs. 89.7%; for systemic reactions 72.6% vs. 86.6%). Significant differences were observed for injection-site pain, erythema, and for grade 1 or grade 2 increases in arm circumference. Fever, myalgia, and headache were reported at a significantly lower rate in the 6-dose group. Swelling >10 cm was observed in 5 patients (2%), 4 in the 5-dose group. Tdap vaccine was safe when given to adolescents who had received 5 prior doses of acellular pertussis vaccine.

Intermittent preventive treatment of malaria during pregnancy in central Mozambique.

PubMed

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

2007-11-01

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

Determination of cytokine protein levels in oral secretions in patients undergoing radiotherapy for head and neck malignancies

PubMed Central

2012-01-01

Background Cytokines may be elevated in tumor and normal tissues following irradiation. Cytokine expression in these tissues may predict for toxicity or tumor control. The purpose of this pilot study was to determine the feasibility of measuring local salivary cytokine levels using buccal sponges in patients receiving chemo-radiation for head and neck malignancies. Patients and methods 11 patients with epithelial malignancies of the head and neck were recruiting to this study. All patients received radiotherapy to the head and neck region with doses ranging between 60 – 67.5 Gy. Chemotherapy was delivered concurrently with radiation in all patients. Salivary samples were obtained from high dose and low dose regions prior to treatment and at three intervals during treatment for assessment of cytokine levels (IL-4, IL-6, IL-8, IL-10, EGF, MCP-1, TNF-α, and VEGF). Results Cytokine levels were detectable in the salivary samples. Salivary cytokine levels of IL-4, IL-6, IL-8, EGF, MCP-1, TNF- α , and VEGF were higher in the high dose region compared to the low dose region at all time points (p < 0.05). A trend toward an increase in cytokine levels as radiation dose increased was observed for IL-6, IL-8, MCP-1, and TNF-α. Conclusion Assessment of salivary cytokine levels may provide a novel method to follow local cytokine levels during radiotherapy and may provide a mechanism to study cytokine levels in a regional manner. PMID:22537315

Occupational Radiation Exposure to the Extremities of Medical Staff during Hysterosalpingography and Radionuclide Bone Scan Procedures in Several Nigerian Hospitals.

PubMed

Jibiri, Nnamdi Norbert; Akintunde, Tawakalitu Oluwatoyin; Dambele, Musa Yusuf; Olowookere, Christopher Jimoh

2016-10-05

The practice of regular dose measurement helps to ascertain the level of occupational dose delivered to the staff involved in diagnostic procedures. This study was carried out to evaluate the dose exposed to the hands of radiologists and a radiologic technologist carrying out HSG and radionuclide bone scan examinations in several hospitals in Nigeria. Radiation doses exposed to the hands of radiologists and a technician carrying out hysterosalpingography (HSG) and bone scan procedures were measured using calibrated thermo-luminescent dosimeters. Five radiologists and a radiologic technologist were included in the study for dose measurement. The study indicates that each radiologist carried out approximately 2 examinations per week with the mean dose ranging between 0.49-0.62 mSv per week, resulting in an annual dose of 191 mSv. Similarly, the occupational dose delivered to both the left and right hands of a radiologic technologist administering 99mTc-methylene diphosphonate (MDP) without cannula and with cannula were 10.68 (720.2) and 13.82 (556.4) mSv per week (and per annum), respectively. It was determined that the left hand of the personnel received higher doses than their right hand. The estimated annual dose during HSG is far below the annual dose limit for deterministic effects, however, it is greater than 10% of the applicable annual dose limit. Hence, routine monitoring is required to ensure adequate protection of the personnel. The total annual dose received during the bone scan exceeds the annual dose limit for both hands, and the dose to either left or right hand is greater than the dose limit of 500 mSv/yr. The radiologists monitored are not expected to incur any deterministic effects during HSG examinations, however, accumulated doses arising from the scattered radiation to the eyes, legs, and neck could be substantial and might lead to certain effects. More staff are required to administer 99mTc-MDP in Nigerian institutions to prevent excessive doses to personnel.

Occupational Radiation Exposure to the Extremities of Medical Staff during Hysterosalpingography and Radionuclide Bone Scan Procedures in Several Nigerian Hospitals

PubMed Central

Jibiri, Nnamdi Norbert; Akintunde, Tawakalitu Oluwatoyin; Dambele, Musa Yusuf; Olowookere, Christopher Jimoh

2016-01-01

Objective: The practice of regular dose measurement helps to ascertain the level of occupational dose delivered to the staff involved in diagnostic procedures. This study was carried out to evaluate the dose exposed to the hands of radiologists and a radiologic technologist carrying out HSG and radionuclide bone scan examinations in several hospitals in Nigeria. Methods: Radiation doses exposed to the hands of radiologists and a technician carrying out hysterosalpingography (HSG) and bone scan procedures were measured using calibrated thermo-luminescent dosimeters. Five radiologists and a radiologic technologist were included in the study for dose measurement. Results: The study indicates that each radiologist carried out approximately 2 examinations per week with the mean dose ranging between 0.49-0.62 mSv per week, resulting in an annual dose of 191 mSv. Similarly, the occupational dose delivered to both the left and right hands of a radiologic technologist administering 99mTc-methylene diphosphonate (MDP) without cannula and with cannula were 10.68 (720.2) and 13.82 (556.4) mSv per week (and per annum), respectively. It was determined that the left hand of the personnel received higher doses than their right hand. Conclusion: The estimated annual dose during HSG is far below the annual dose limit for deterministic effects, however, it is greater than 10% of the applicable annual dose limit. Hence, routine monitoring is required to ensure adequate protection of the personnel. The total annual dose received during the bone scan exceeds the annual dose limit for both hands, and the dose to either left or right hand is greater than the dose limit of 500 mSv/yr. The radiologists monitored are not expected to incur any deterministic effects during HSG examinations, however, accumulated doses arising from the scattered radiation to the eyes, legs, and neck could be substantial and might lead to certain effects. More staff are required to administer 99mTc-MDP in Nigerian institutions to prevent excessive doses to personnel. PMID:27751973

Exposure to radon in the Gadime Cave, Kosovo.

PubMed

Bahtijari, M; Vaupotic, J; Gregoric, A; Stegnar, P; Kobal, I

2008-02-01

Air radon concentration was measured in summer and winter at 11 points along the tourist guided route in the Gadime Cave in Kosovo using alpha scintillation cells and etched track detectors. At two points in summer, values higher than 1700Bqm(-3) were observed; they otherwise were in the range 400-1000Bqm(-3). Values were lower in winter. The effective dose received by a person during a 90min visit is 3.7microSv in summer and 2.5microSv in winter. For a tourist guide the annual effective dose is less than 3.5mSv.

Single dose parenteral hyposensitization to poison ivy urushiol in guinea pigs.

PubMed

Walker, L A; Watson, E S; elSohly, M A

1995-08-01

Studies were carried out in guinea pigs to evaluate the potential for single dose hyposensitization to poison ivy urushiol dermatitis. Sensitization was induced by topical application of 1 mg of poison ivy urushiol to the back of the neck. In the first series of studies, three different analogs of poison ivy urushiol were studied: 1) a mixture of pentadecyl and heptadecyl catechols (PDC/HDC), the saturated side chain analog of the natural urushiol mixture; 2) a mixture of the diacetate esters of PDC and HDC (PDC/HDC Ac), the esterified form of the saturated sidechain analogs; 3) 2-n-pentadecyl hydroquinone diacetate (HQ Ac). Each of these compounds was administered as 5 mg of the free catechol i.m. each week for three weeks. A vehicle group received only corn oil injections. Reactivity to poison ivy urushiol (PIU) challenge was evaluated in skin tests at 1 and 5 weeks post-treatment. PDC/HDC Ac induced a marked reduction in both the incidence and the severity of lesions induced by PIU at both 1 and at 5 weeks post-treatment. Other analogs were ineffective at 5 weeks post-treatment, and were less effective than PDC/HDC Ac at 1 week post-treatment. In a second series of experiments, the efficacy of PDC/HDC Ac was evaluated in both single and multiple dose regiments. One treatment group received 5 mg of PDC/HDC Ac intramuscularly each week for 4 weeks, while another treatment group received a single dose of 20 mg PDC/HDC Ac i.m. Corresponding vehicle control groups were also included. At 1 week post-treatment in the single dose group, the PDC/HDC Ac was only modestly effective, with some reduction of severity of lesions at the higher challenge doses of PIU. However, at 4 and 7 weeks post-treatment, both the incidence and the severity of the lesions at all challenge doses were reduced. In the multiple dose group, the incidence and severity of lesions are reduced at 1 week and 4 weeks post-treatment (4 weeks and 7 weeks after the initial dose) but were not significantly different from the single dose group. These findings indicate that the diacetate ester of PDC/HDC is an effective hyposensitizer to poison ivy urushiol, and that this hyposensitization can be reasonably accomplished in a single dose treatment regimen.

A population-based study of dosing and persistence with anti-dementia medications.

PubMed

Brewer, Linda; Bennett, Kathleen; McGreevy, Cora; Williams, David

2013-07-01

Cholinesterase inhibitors and memantine are the mainstay of pharmacological intervention for the cognitive symptoms of Alzheimer's disease (AD). This study assessed the adequacy of dosing and persistence with AD medications and the predictors of these variables in the 'real world' (outside the clinical trial setting). The Health Service Executive-Primary Care Reimbursement Services prescription claims database in the Republic of Ireland contains prescription information for 1.6 million people. Patients aged >70 years who received at least two prescriptions for donepezil, rivastigmine, galantamine and memantine between January 2006 and December 2010 were included in the study. Rates of dose-maximisation were recorded by examining the initiation dose of each AD drug commenced during the study period and any subsequent dose titrations. Non-persistence was defined by a gap in prescribing of more than 63 consecutive days. Predictors of dose-maximisation and non-persistence were also analysed. Between January 2006 and December 2010, 20,729 patients aged >70 years received a prescription for an AD medication. Despite most patients on donepezil and memantine receiving a prescription for the maximum drug dose, this dose was maintained for 2 consecutive months in only two-thirds of patients. Patients were significantly more likely to have their doses of donepezil and memantine maximised if prescribed in more recent years (2010 vs. 2007). Rates of non-persistence were 30.1 % at 6 months and 43.8 % at 12 months. Older age [75+ vs. <75 years; hazards ratio (HR) 1.16, 95 % confidence interval (CI) 1.06-1.27] and drug type (rivastigmine vs. donepezil; HR 1.15, 95 % CI 1.03-1.27) increased the risk of non-persistence. Non-persistence was lower for those commencing therapy in more recent years (2010 vs. 2007; HR 0.81, 95 % CI 0.73-0.89, p < 0.001) and for those on multiple anti-dementia medications (HR 0.59, 95 % CI 0.54-0.65, p < 0.001). Persistence was significantly higher when memantine was co-prescribed with donepezil (p < 0.0001). Future studies should explore the reasons underlying non-persistence and failure to maintain dose-maximisation in patients on AD medications. There may be scope to improve the dosing and persistence with these medications in the community.

Effect of paricalcitol on mineral bone metabolism in kidney transplant recipients with secondary hyperparathyroidism.

PubMed

Borrego Utiel, Francisco José; Bravo Soto, Juan Antonio; Merino Pérez, María José; González Carmelo, Isabel; López Jiménez, Verónica; García Álvarez, Teresa; Acosta Martínez, Yelenei; Mazuecos Blanca, María Auxiliadora

2015-01-01

Secondary hyperparathyroidism is highly prevalent in kidney transplant recipients, and commonly results in hypercalcaemia; an association to osteopenia and bone fractures has also been observed. Paricalcitol has proved effective to control secondary hyperparathyroidism in chronic kidney disease in both dialysed and non-dialysed patients, with a low hypercalcaemia incidence. Currently available experience on paricalcitol use in kidney transplant recipients is scarce. Our main aim was to show the effect of paricalcitol on mineral bone metabolism in kidney transplant recipients with secondary hyperparathyroidism. A retrospective multicentre study in kidney transplant recipients aged>18 years with a 12-month or longer post-transplantation course, stable renal function, having received paricalcitol for more than 12 months, with available clinical follow-up for a 24-month period. A total of 69 patients with a 120 ± 92-month post-transplantation course were included. Baseline creatinine was 2.2 ± 0.9 mg/dl y GFR-MDRD was 36 ± 20 ml/min/1.73 m(2). Paricalcitol doses were gradually increased during the study: baseline 3.8 ± 1.9 μg/week, 12 months 5.2 ± 2.4 μg/week; 24 months 6.0 ± 2.9 μg/week (P<.001). Serum PTH levels showed a significant fast decline: baseline 288 ± 152 pg/ml; 6 months 226 ± 184 pg/ml; 12 months 207 ± 120; 24 months 193 ± 119 pg/ml (P<.001). Reduction from baseline PTH was ≥30% in 42.4% of patients at 12 months y in 65.2% of patients at 24 months. Alkaline phosphatase showed a significant decrease in first 6 months followed by a plateau: baseline 92 ± 50 IU/l; 6 months 85 ± 36 IU/l, 12 months 81 ± 39 IU/l (P<.001). Overall, no changes were observed in serum calcium and phosphorus, and in urine calcium excretion. PTH decline was larger in patients with higher baseline levels. Patients with lower baseline calcium levels showed significantly increased levels (mean increase was 0.5-0.6 mg/dl) but still within normal range, whereas patients with baseline calcium>10mg/dl showed gradually decreasing levels. Fifteen (21.7%) patients had received prior calcitriol therapy. When shifted to paricalcitol, such patients required paricalcitol doses significantly larger than those not having received calcitriol. Paricalcitol was used concomitantly to cinacalcet in 11 patients with significant PTH reductions being achieved; clinical course was similar to other patients and paricalcitol doses were also similar. Paricalcitol is an effective therapy for secondary hyperparathyroidism in kidney transplant recipients. Overall, no significant changes were observed in calcium and phosphorus levels or urinary excretion. Patients having previously received calcitriol required higher paricalcitol doses. When used in patients receiving cinacalcet, paricalcitol results in a significant PTH fall, with paricalcitol doses being similar to those used in patients not receiving cinacalcet. Copyright © 2015 The Authors. Published by Elsevier España, S.L.U. All rights reserved.

The local and systemic side-effects of venom and inhaled-allergen subcutaneous immunotherapy.

PubMed

Adamic, Katja; Zidarn, Mihaela; Bajrovic, Nissera; Erzen, Renato; Kopac, Peter; Music, Ema

2009-01-01

Although immunotherapy is effective in allergic rhinitis, conjunctivitis, asthma and stinging insect hypersensitivity, it carries a risk of anaphylactic reactions. In a 4-year retrospective survey, we investigated 1257 adult patients who had received venom or inhaled-allergen subcutaneous immunotherapy. The dose-increase phase was performed as the 2-day rush protocol for venom immunotherapy and the 6-week protocol for inhaled-allergen immunotherapy. A total of 904 patients received venom immunotherapy and 353 patients inhaled-allergen immunotherapy. The prevalence of systemic reactions was 13.6%. The frequency of systemic reactions was higher during the maintenance phase than in the dose-increase phase (9.6% vs. 5.9%) and was highest in both phases of treatment with honeybee venom (P < 0.001). The majority of systemic reactions were mild. Five (0.4%) patients had reaction with a fall of blood pressure and were treated with adrenaline. There was no fatal outcome. The systemic side-effects during the dose-increase phase of venom immunotherapy occurred at a median dose of 46 microg (range 2-100 microg). Large local reactions occurred in 13.9% of patients without any significant difference between the allergens. We have shown that systemic reactions are not rare even during maintenance phase in patients with a well tolerated dose-increase phase of treatment. The most prominent risk factor for systemic reactions was immunotherapy with honeybee extract.

Hydrogel-forming microneedle arrays: Potential for use in minimally-invasive lithium monitoring.

PubMed

Eltayib, Eyman; Brady, Aaron J; Caffarel-Salvador, Ester; Gonzalez-Vazquez, Patricia; Zaid Alkilani, Ahlam; McCarthy, Helen O; McElnay, James C; Donnelly, Ryan F

2016-05-01

We describe, for the first time, hydrogel-forming microneedle (s) (MN) arrays for minimally-invasive extraction and quantification of lithium in vitro and in vivo. MN arrays, prepared from aqueous blends of hydrolysed poly(methyl-vinylether-co-maleic anhydride) and crosslinked by poly(ethyleneglycol), imbibed interstitial fluid (ISF) upon skin insertion. Such MN were always removed intact. In vitro, mean detected lithium concentrations showed no significant difference following 30min MN application to excised neonatal porcine skin for lithium citrate concentrations of 0.9 and 2mmol/l. However, after 1h application, the mean lithium concentrations extracted were significantly different, being appropriately concentration-dependent. In vivo, rats were orally dosed with lithium citrate equivalent to 15mg/kg and 30mg/kg lithium carbonate, respectively. MN arrays were applied 1h after dosing and removed 1h later. The two groups, having received different doses, showed no significant difference between lithium concentrations in serum or MN. However, the higher dosed rats demonstrated a lithium concentration extracted from MN arrays equivalent to a mean increase of 22.5% compared to rats which received the lower dose. Hydrogel-forming MN clearly have potential as a minimally-invasive tool for lithium monitoring in outpatient settings. We will now focus on correlation between serum and MN lithium concentrations. Copyright © 2016 The Authors. Published by Elsevier B.V. All rights reserved.

Effects of a Single Dose of Parecoxib on Inflammatory Response and Ischemic Tubular Injury Caused by Hemorrhagic Shock in Rats.

PubMed

Takaku, Mariana; da Silva, Andre Carnevali; Iritsu, Nathalie Izumi; Vianna, Pedro Thadeu Galvao; Castiglia, Yara Marcondes Machado

2018-01-01

Parecoxib, a selective COX-2 inhibitor, is used to improve analgesia in postoperative procedures. Here we evaluated whether pretreatment with a single dose of parecoxib affects the function, cell injury, and inflammatory response of the kidney of rats subjected to acute hemorrhage. Inflammatory response was determined according to serum and renal tissue cytokine levels (IL-1 α , IL-1 β , IL-6, IL-10, and TNF- α ). Forty-four adult Wistar rats anesthetized with sevoflurane were randomized into four groups: placebo/no hemorrhage (Plc/NH); parecoxib/no hemorrhage (Pcx/NH); placebo/hemorrhage (Plc/H); and parecoxib/hemorrhage (Pcx/H). Pcx groups received a single dose of intravenous parecoxib while Plc groups received a single dose of placebo (isotonic saline). Animals in hemorrhage groups underwent bleeding of 30% of blood volume. Renal function and renal histology were then evaluated. Plc/H showed the highest serum levels of cytokines, suggesting that pretreatment with parecoxib reduced the inflammatory response in rats subjected to hemorrhage. No difference in tissue cytokine levels between groups was observed. Plc/H showed higher percentage of tubular dilation and degeneration, indicating that parecoxib inhibited tubular injury resulting from renal hypoperfusion. Our findings indicate that pretreatment with a single dose of parecoxib reduced the inflammatory response and tubular renal injury without altering renal function in rats undergoing acute hemorrhage.

Reduced-dose telaprevir-based triple antiviral therapy for recurrent hepatitis C after living donor liver transplantation.

PubMed

Ikegami, Toru; Yoshizumi, Tomoharu; Kato, Masaki; Yamamoto, Satomi; Fukuhara, Takasuke; Matsuura, Yoshiharu; Nakamura, Shota; Itoh, Shinji; Shirabe, Ken; Maehara, Yoshihiko

2014-11-15

The feasibility of telaprevir-based triple therapy for recurrent hepatitis C after liver transplantation (LT) has not been evaluated in Asian patients. Eleven Japanese patients received reduced-dose telaprevir (1500 mg) and adjusted-dose cyclosporine after LT. Six patients were nonresponders and three were transient responders to dual therapy. Rapid viral response, early viral response, end of treatment response, and sustained viral response were achieved in 27.3%, 90.9%, 90.9%, and 81.8% of patients, respectively. One patient had viral breakthrough at week 8 with a T54A mutation in NS3. Deep sequence analysis showed that the T54A mutation reverted to wild-type after stopping telaprevir administration. Seven patients developed severe anemia, and six received blood transfusions (4-20 U). Their hemoglobin and estimated glomerular filtration rate remained significantly lower than pretreatment values at 36 weeks after treatment. Four patients developed plasma cell hepatitis after completing telaprevir treatment, and it was treated by increasing the immunosuppressants. Although the cyclosporine level/dose ratio was 2.7 times higher at week 4 than before treatment, it was 0.7 times lower at week 36. Reduced-dosed telaprevir-based triple antiviral therapy achieved a high viral clearance rate in Japanese patients after LT. Major adverse events included severe anemia, renal dysfunction, and plasma cell hepatitis.

Higher serotonin transporter occupancy after multiple dose administration of escitalopram compared to citalopram: an [123I]ADAM SPECT study.

PubMed

Klein, Nikolas; Sacher, Julia; Geiss-Granadia, Thomas; Mossaheb, Nilufar; Attarbaschi, Trawat; Lanzenberger, Rupert; Spindelegger, Christoph; Holik, Alexander; Asenbaum, Susanne; Dudczak, Robert; Tauscher, Johannes; Kasper, Siegfried

2007-04-01

Previous studies have investigated the occupancy of the serotonin reuptake transporter (SERT) after clinical doses of citalopram and other selective serotonin reuptake inhibitors. In the present study, the occupancies of SERT after multiple doses of escitalopram and citalopram were compared using the radioligand [(123)I]ADAM and single photon emission computed tomography (SPECT). Fifteen healthy subjects received escitalopram 10 mg/day (n = 6) or citalopram 20 mg/day (n = 9) for a total of 10 days. SERT occupancies in midbrain were determined with SPECT and [(123)I]ADAM at three different time points: at baseline (no medication) and at 6 and 54 h after last drug intake. At 6 h after the last dose, mean SERT occupancies were 81.5 +/- 5.4% (mean+/-SD) for escitalopram and 64.0 +/- 12.7% for citalopram (p < 0.01). At 54 h after the last dose, mean SERT occupancies were 63.3 +/- 12.1% for escitalopram and 49.0 +/- 11.7% for citalopram (p < 0.05). The plasma concentrations of the S-enantiomer were of the same magnitude in both substances. For both drugs, the elimination rate of the S-enantiomer in plasma was markedly higher than the occupancy decline rate in the midbrain. The significantly higher occupancy of SERT after multiple doses of escitalopram compared to citalopram indicates an increased inhibition of SERT by escitalopram. The results can also be explained by an attenuating effect of R-citalopram on the occupancy of S-citalopram at the SERT.

Single ascending oral dose pharmacokinetics and pharmacodynamics study of EV-077: the specific inhibitor of prostanoid- and isoprostane-induced cellular activation.

PubMed

Richardson, A; Sakariassen, K S; Meyer, J-P; Alberts, P; Sorensen, A S

2013-03-01

This study was performed to determine the oral pharmacokinetics (PK) of EV-077 and its effects on pharmacodynamic (PD) markers. EV-077 blocks prostanoid-induced and isoprostane-induced cellular activation, and is in development for the treatment of vascular inflammation and associated complications of type-2 diabetes.. This single-ascending-dose mono-centre study was randomised, placebo-controlled, and double-blinded within each dose group. Seven EV-077 doses were administered sequentially as an oral solution: 0.0125, 0.125, 0.375, 0.75, 1.25, 1.875 and 2.5 mg/kg body weight. PK, platelet aggregation, bleeding time and safety parameters were measured. Seven to eight healthy male subjects were dosed per group: five to six subjects received EV-077 and two subjects received placebo. Tmax was reached rapidly between 0.5 h and 1.0 h. Both Cmax and AUC increased linearly with the dose. The apparent terminal half-life (t½z) increased with the dose, most likely reflecting the increasing last quantifiable concentration with increasing dose; at 2.5 mg/kg, it was 2.7-6.9 h. Measurement of platelet aggregation showed no effect at 0.0125 mg/kg, and a full and reversible inhibition at doses of 0.125-2.5 mg/kg. The average bleeding time was dose-dependently prolonged, but was always below 9 min. The PK/PD profile showed that at plasma concentrations above 20 ng/ml, EV-077 platelet aggregation was completely inhibited (>90 %). All tested doses were well tolerated. Orally administered EV-077 was well tolerated, readily absorbed, reached Cmax within 1 h, with a linear PK based on Cmax and AUC. The inhibition of platelet aggregation was complete and reversible at doses of 0.125 mg/kg and higher, and average bleeding time was below 9 min.

Postmastectomy radiotherapy with integrated scar boost using helical tomotherapy.

PubMed

Rong, Yi; Yadav, Poonam; Welsh, James S; Fahner, Tasha; Paliwal, Bhudatt

2012-01-01

The purpose of this study was to evaluate helical tomotherapy dosimetry in postmastectomy patients undergoing treatment for chest wall and positive nodal regions with simultaneous integrated boost (SIB) in the scar region using strip bolus. Six postmastectomy patients were scanned with a 5-mm-thick strip bolus covering the scar planning target volume (PTV) plus 2-cm margin. For all 6 cases, the chest wall received a total cumulative dose of 49.3-50.4 Gy with daily fraction size of 1.7-2.0 Gy. Total dose to the scar PTV was prescribed to 58.0-60.2 Gy at 2.0-2.5 Gy per fraction. The supraclavicular PTV and mammary nodal PTV received 1.7-1.9 dose per fraction. Two plans (with and without bolus) were generated for all 6 cases. To generate no-bolus plans, strip bolus was contoured and overrode to air density before planning. The setup reproducibility and delivered dose accuracy were evaluated for all 6 cases. Dose-volume histograms were used to evaluate dose-volume coverage of targets and critical structures. We observed reduced air cavities with the strip bolus setup compared with what we normally see with the full bolus. The thermoluminescence dosimeters (TLD) in vivo dosimetry confirmed accurate dose delivery beneath the bolus. The verification plans performed on the first day megavoltage computed tomography (MVCT) image verified that the daily setup and overall dose delivery was within 2% accuracy compared with the planned dose. The hotspot of the scar PTV in no-bolus plans was 111.4% of the prescribed dose averaged over 6 cases compared with 106.6% with strip bolus. With a strip bolus only covering the postmastectomy scar region, we observed increased dose uniformity to the scar PTV, higher setup reproducibility, and accurate dose delivered beneath the bolus. This study demonstrates the feasibility of using a strip bolus over the scar using tomotherapy for SIB dosimetry in postmastectomy treatments. Published by Elsevier Inc.

Postmastectomy radiotherapy with integrated scar boost using helical tomotherapy

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

Rong Yi, E-mail: rong@humonc.wisc.edu; University of Wisconsin Riverview Cancer Center, Wisconsin Rapids, WI; Yadav, Poonam

2012-10-01

The purpose of this study was to evaluate helical tomotherapy dosimetry in postmastectomy patients undergoing treatment for chest wall and positive nodal regions with simultaneous integrated boost (SIB) in the scar region using strip bolus. Six postmastectomy patients were scanned with a 5-mm-thick strip bolus covering the scar planning target volume (PTV) plus 2-cm margin. For all 6 cases, the chest wall received a total cumulative dose of 49.3-50.4 Gy with daily fraction size of 1.7-2.0 Gy. Total dose to the scar PTV was prescribed to 58.0-60.2 Gy at 2.0-2.5 Gy per fraction. The supraclavicular PTV and mammary nodal PTVmore » received 1.7-1.9 dose per fraction. Two plans (with and without bolus) were generated for all 6 cases. To generate no-bolus plans, strip bolus was contoured and overrode to air density before planning. The setup reproducibility and delivered dose accuracy were evaluated for all 6 cases. Dose-volume histograms were used to evaluate dose-volume coverage of targets and critical structures. We observed reduced air cavities with the strip bolus setup compared with what we normally see with the full bolus. The thermoluminescence dosimeters (TLD) in vivo dosimetry confirmed accurate dose delivery beneath the bolus. The verification plans performed on the first day megavoltage computed tomography (MVCT) image verified that the daily setup and overall dose delivery was within 2% accuracy compared with the planned dose. The hotspot of the scar PTV in no-bolus plans was 111.4% of the prescribed dose averaged over 6 cases compared with 106.6% with strip bolus. With a strip bolus only covering the postmastectomy scar region, we observed increased dose uniformity to the scar PTV, higher setup reproducibility, and accurate dose delivered beneath the bolus. This study demonstrates the feasibility of using a strip bolus over the scar using tomotherapy for SIB dosimetry in postmastectomy treatments.« less

Effect of Brain Stem and Dorsal Vagus Complex Dosimetry on Nausea and Vomiting in Head and Neck Intensity-Modulated Radiation Therapy

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

Ciura, Katherine; McBurney, Michelle; Nguyen, Baongoc

Intensity-modulated radiation therapy (IMRT) is becoming the treatment of choice for many head and neck cancer patients. IMRT reduces some toxicities by reducing radiation dose to uninvolved normal tissue near tumor targets; however, other tissues not irradiated using previous 3D techniques may receive clinically significant doses, causing undesirable side effects including nausea and vomiting (NV). Irradiation of the brainstem, and more specifically, the area postrema and dorsal vagal complex (DVC), has been linked to NV. We previously reported preliminary hypothesis-generating dose effects associated with NV in IMRT patients. The goal of this study is to relate brainstem dose to NVmore » symptoms. We retrospectively studied 100 consecutive patients that were treated for oropharyngeal cancer with IMRT. We contoured the brainstem, area postrema, and DVC with the assistance of an expert diagnostic neuroradiologist. We correlated dosimetry for the 3 areas contoured with weekly NV rates during IMRT. NV rates were significantly higher for patients who received concurrent chemotherapy. Post hoc analysis demonstrated that chemoradiation cases exhibited a trend towards the same dose-response relationship with both brainstem mean dose (p = 0.0025) and area postrema mean dose (p = 0.004); however, both failed to meet statistical significance at the p {<=} 0.002 level. Duration of toxicity was also greater for chemoradiation patients, who averaged 3.3 weeks with reported Common Terminology Criteria for Adverse Events (CTC-AE), compared with an average of 2 weeks for definitive RT patients (p = 0.002). For definitive RT cases, no dose-response trend could be ascertained. The mean brainstem dose emerged as a key parameter of interest; however, no one dose parameter (mean/median/EUD) best correlated with NV. This study does not address extraneous factors that would affect NV incidence, including the use of antiemetics, nor chemotherapy dose schedule specifics before and during RT. A prospective study will be required to depict exactly how IMRT dose affects NV.« less

Pre-harvest UV-C irradiation triggers VOCs accumulation with alteration of antioxidant enzymes and phytohormones in strawberry leaves.

PubMed

Xu, Yanqun; Luo, Zisheng; Charles, Marie Thérèse; Rolland, Daniel; Roussel, Dominique

2017-11-01

Recent studies have highlighted the biological and physiological effects of pre-harvest ultraviolet (UV)-C treatment on growing plants. However, little is known about the involvement of volatile organic compounds (VOCs) and their response to this treatment. In this study, strawberry plants were exposed to three different doses of UV-C radiation for seven weeks (a low dose: 9.6kJm -2 ; a medium dose: 15kJm -2 ; and a high-dose: 29.4kJm -2 ). Changes in VOC profiles were investigated and an attempt was made to identify factors that may be involved in the regulation of these alterations. Principle compounds analysis revealed that VOC profiles of UV-C treated samples were significantly altered with 26 VOCs being the major contributors to segregation. Among them, 18 fatty acid-derived VOCs accumulated in plants that received high and medium dose of UV-C treatments with higher lipoxygenase and alcohol dehydrogenase activities. In treated samples, the activity of the antioxidant enzymes catalase and peroxidase was inhibited, resulting in a reduced antioxidant capacity and higher lipid peroxidation. Simultaneously, jasmonic acid level was 74% higher in the high-dose group while abscisic acid content was more than 12% lower in both the medium and high-dose UV-C treated samples. These results indicated that pre-harvest UV-C treatment stimulated the biosynthesis of fatty acid-derived VOCs in strawberry leaf tissue by upregulating the activity of enzymes of the LOX biosynthetic pathway and downregulating antioxidant enzyme activities. It is further suggested that the mechanisms underlying fatty acid-derived VOCs biosynthesis in UV-C treated strawberry leaves are associated with UV-C-induced changes in phytohormone profiles. Crown Copyright © 2017. Published by Elsevier GmbH. All rights reserved.

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

PubMed Central

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

2014-01-01

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

An analysis of timing and frequency of malaria infection during pregnancy in relation to the risk of low birth weight, anaemia and perinatal mortality in Burkina Faso.

PubMed

Valea, Innocent; Tinto, Halidou; Drabo, Maxime K; Huybregts, Lieven; Sorgho, Hermann; Ouedraogo, Jean-Bosco; Guiguemde, Robert T; van Geertruyden, Jean Pierre; Kolsteren, Patrick; D'Alessandro, Umberto

2012-03-16

A prospective study aiming at assessing the effect of adding a third dose sulphadoxine-pyrimethamine (SP) to the standard two-dose intermittent preventive treatment for pregnant women was carried out in Hounde, Burkina Faso, between March 2006 and July 2008. Pregnant women were identified as earlier as possible during pregnancy through a network of home visitors, referred to the health facilities for inclusion and followed up until delivery. Study participants were enrolled at antenatal care (ANC) visits and randomized to receive either two or three doses of SP at the appropriate time. Women were visited daily and a blood slide was collected when there was fever (body temperature > 37.5°C) or history of fever. Women were encouraged to attend ANC and deliver in the health centre, where the new-born was examined and weighed. The timing and frequency of malaria infection was analysed in relation to the risk of low birth weight, maternal anaemia and perinatal mortality. Data on birth weight and haemoglobin were available for 1,034 women. The incidence of malaria infections was significantly lower in women having received three instead of two doses of SP. Occurrence of first malaria infection during the first or second trimester was associated with a higher risk of low birth weight: incidence rate ratios of 3.56 (p < 0.001) and 1.72 (p = 0.034), respectively. After adjusting for possible confounding factors, the risk remained significantly higher for the infection in the first trimester of pregnancy (adjusted incidence rate ratio = 2.07, p = 0.002). The risk of maternal anaemia and perinatal mortality was not associated with the timing of first malaria infection. Malaria infection during first trimester of pregnancy is associated to a higher risk of low birth weight. Women should be encouraged to use long-lasting insecticidal nets before and throughout their pregnancy.

Ultraviolet radiation exposure of children and adolescents in Durban, South Africa.

PubMed

Guy, Caradee; Diab, Roseanne; Martincigh, Bice

2003-03-01

The solar ultraviolet radiation (UVR) exposure of 30 children and adolescents in three age groups (4-6 years, 7-9 years and 13-14 years) was measured for 1 week in late summer (February-March) in Durban, South Africa, using UVR-sensitive polysulfone film badges (PSFB) attached to the lapel region of the body. The mean and median values for all ages over the study period were 2.0 and 1.2 standard erythemal dose (SED) units, respectively, where 1 SED = 100 J x m(-2). Individual PSFB doses were analyzed as a function of age, gender and behavior. No significant statistical differences were found between different age groups; however, there was a statistical difference between males and females, with males generally receiving higher PSFB doses. Subjects completed UVR exposure journals documenting their time outdoors, shade versus sun conditions, nature of their activities, clothing worn and their use of sunscreen for each day of the study. Activity patterns were noted as the most important factor influencing individual UVR dose. Ambient erythemal UVR was measured by a Yankee Environmental Systems UVB pyranometer, and a relationship between ambient UVR and individual UVR dose was derived. On average, subjects received a dose of 4.6% of the total daily erythemal UVR. Based on this factor, the potential dose of an individual over a full annual cycle was estimated. Accordingly, there were 139 days during the year when an individual with skin type I (light skin) would be likely to experience minimal erythema and 97 and 32 days for individuals with skin types II and III, respectively.

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

PubMed Central

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

2017-01-01

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

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

PubMed

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

2017-07-01

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

Radionuclide monitoring in Northern Ireland of the Chernobyl nuclear reactor accident

PubMed Central

Gilmore, B J; Cranley, K

1987-01-01

Northern Ireland received higher radiation doses due to the radionuclide contamination from the Chernobyl nuclear reactor accident than did the south of England. Levels of radioactive iodine (131I) and caesium (137Cs) in cows' milk in Northern Ireland increased to 166 and 120 Bq/l respectively in May 1986, but had decreased by factors of one million, and of twenty-five, respectively, by 1 September 1986. The resultant radiation doses represent less than one per cent of those received by a Northern Ireland individual over a period of 40 years from natural background radiation sources. The added risk to any individual from the Chernobyl accident will therefore be very small and may best be judged in the context of the enormously greater risk of death due to potentially preventable diseases, such as smoking-related lung cancer, and coronary heart disease. PMID:3590387

Impact of high- versus low-dose neuromuscular blocking agent administration on unplanned 30-day readmission rates in retroperitoneal laparoscopic surgery.

PubMed

Boon, Martijn; Martini, Chris; Yang, H Keri; Sen, Shuvayu S; Bevers, Rob; Warlé, Michiel; Aarts, Leon; Niesters, Marieke; Dahan, Albert

2018-01-01

Recent data shows that a neuromuscular block (NMB) induced by administration of high doses of rocuronium improves surgical conditions in certain procedures. However, there are limited data on the effect such practices on postoperative outcomes. We performed a retrospective analysis to compare unplanned 30-day readmissions in patients that received high-dose versus low-dose rocuronium administration during general anesthesia for laparoscopic retroperitoneal surgery. This retrospective cohort study was performed in the Netherlands in an academic hospital where routine high-dose rocuronium NMB has been practiced since July 2015. Charts of patients receiving anesthesia between January 2014 and December 2016 were searched for surgical cases receiving high-dose rocuronium and matched with respect to procedure, age, sex and ASA classification to patients receiving low-dose rocuronium. The primary post-operative outcome was unplanned 30-day readmission rate. There were 130 patients in each cohort. Patients in the high- and low-dose rocuronium cohorts received 217 ± 49 versus 37 ± 5 mg rocuronium, respectively. In the high-dose rocuronium group neuromuscular activity was consistently monitored; matched patients were unreliably monitored. All patients receiving high-dose rocuronium were reversed with sugammadex, while just 33% of matched patients were reversed with sugammadex and 20% with neostigmine; the remaining patients were not reversed. Unplanned 30-day readmission rate was significantly lower in the high-dose compared to the low-dose rocuronium cohort (3.8% vs. 12.7%; p = 0.03; odds ratio = 0.33, 95% C.I. 0.12-0.95). This small retrospective study demonstrates a lower incidence of unplanned readmissions within 30-days following laparoscopic retroperitoneal surgery with high-dose relaxant anesthesia and sugammadex reversal in comparison to low-dose relaxant anesthesia. Further prospective studies are needed in larger samples to corroborate our findings and additionally assess the pharmacoeconomics of high-dose relaxant anesthesia taking into account the benefits (reduced readmissions) and harm (cost of relaxants and reversal agents) of such practice.

Prospective Clinical Trial of Bladder Filling and Three-Dimensional Dosimetry in High-Dose-Rate Vaginal Cuff Brachytherapy

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

Stewart, Alexandra J.; Cormack, Robert A.; Lee, Hang

2008-11-01

Purpose: To investigate the effect of bladder filling on dosimetry and to determine the best bladder dosimetric parameter for vaginal cuff brachytherapy. Methods and Materials: In this prospective clinical trial, a total of 20 women underwent vaginal cylinder high-dose-rate brachytherapy. The bladder was full for Fraction 2 and empty for Fraction 3. Dose-volume histogram and dose-surface histogram values were generated for the bladder, rectum, and urethra. The midline maximal bladder point (MBP) and the midline maximal rectal point were recorded. Paired t tests, Pearson correlations, and regression analyses were performed. Results: The volume and surface area of the irradiated bladdermore » were significantly smaller when the bladder was empty than when full. Of the several dose-volume histogram and dose-surface histogram parameters evaluated, the bladder maximal dose received by 2 cm{sup 3} of tissue, volume of bladder receiving {>=}50% of the dose, volume of bladder receiving {>=}70% of the dose, and surface area of bladder receiving {>=}50% of the dose significantly predicted for the difference between the empty vs. full filling state. The volume of bladder receiving {>=}70% of the dose and the maximal dose received by 2 cm{sup 3} of tissue correlated significantly with the MBP. Bladder filling did not alter the volume or surface area of the rectum irradiated. However, an empty bladder did result in the nearest point of bowel being significantly closer to the vaginal cylinder than when the bladder was full. Conclusions: Patients undergoing vaginal cuff brachytherapy treated with an empty bladder have a lower bladder dose than those treated with a full bladder. The MBP correlated well with the volumetric assessments of bladder dose and provided a noninvasive method for reporting the MBP dose using three-dimensional imaging. The MBP can therefore be used as a surrogate for complex dosimetry in the clinic.« less

Calculation of Dose Deposition in 3D Voxels by Heavy Ions

NASA Technical Reports Server (NTRS)

Plante, Ianik; Cucinotta, Francis A.

2010-01-01

The biological response to high-LET radiation is very different from low-LET radiation, and can be partly attributed to the energy deposition by the radiation. Several experiments, notably detection of gamma-H2AX foci by immunofluorescence, has revealed important differences in the nature and in the spatial distribution of double-strand breaks (DSB) induced by low- and high-LET radiations. Many calculations, most of which are based on amorphous track models with radial dose, have been combined with chromosome models to calculate the number and distribution of DSB within nuclei and chromosome aberrations. In this work, the Monte-Carlo track structure simulation code RITRACKS have been used to calculate directly the energy deposition in voxels (3D pixels). A cubic volume of 5 micrometers of side was irradiated by 1) 450 (1)H+ ions of 300 MeV (LET is approximately 0.3 keV/micrometer) and 2) by 1 (56)Fe26+ ion of 1 GeV/amu (LET is approximately 150 keV/micrometer). In both cases, the dose deposited in the volume is approximately 1 Gy. All energy deposition events are recorded and dose is calculated in voxels of 20 micrometers of side. The voxels are then visualized in 3D by using a color scale to represent the intensity of the dose in a voxel. This simple approach has revealed several important points which may help understand experimental observations. In both simulations, voxels which receive low dose are the most numerous, and those corresponding to electron track ends received a dose which is in the higher range. The dose voxels are distributed randomly and scattered uniformly within the volume irradiated by low-LET radiation. The distribution of the voxels shows major differences for the (56)Fe26+ ion. The track structure can still be seen, and voxels with much higher dose are found in the region corresponding to the track "core". These high-dose voxels are not found in the low-LET irradiation simulation and may be responsible for DSB that are more difficult to repair. By applying a threshold on the dose visualization, voxels corresponding to electron track ends are evidenced and the spatial distribution of voxels is very similar to the distribution of DSB observed in gamma H2AX experiments, even if no chromosomes have been included in the simulation. Furthermore, this work has shown that a significant dose is deposited in voxels corresponding to electron track ends. Since some delta-rays from iron ion can travel several millimeters, they may also be of radiobiological importance.

Failed heart rate control with oral metoprolol prior to coronary CT angiography: effect of additional intravenous metoprolol on heart rate, image quality and radiation dose.

PubMed

Jiménez-Juan, Laura; Nguyen, Elsie T; Wintersperger, Bernd J; Moshonov, Hadas; Crean, Andrew M; Deva, Djeven P; Paul, Narinder S; Torres, Felipe S

2013-01-01

The purpose of this study was to evaluate the effect of intravenous (i.v.) metoprolol after a suboptimal heart rate (HR) response to oral metoprolol (75-150 mg) on HR control, image quality (IQ) and radiation dose during coronary CTA using 320-MDCT. Fifty-three consecutive patients who failed to achieve a target HR of < 60 bpm after an oral dose of metoprolol and required supplementary i.v. metoprolol (5-20 mg) prior to coronary CTA were evaluated. Patients with HR < 60 bpm during image acquisition were defined as responders (R) and those with HR ≥ 60 bpm as non-responders (NR). Two observers assessed IQ using a 3-point scale (1-2, diagnostic and 3, non-diagnostic). Effective dose (ED) was estimated using dose-length product and a 0.014 mSV/mGy.cm conversion factor. Baseline characteristics and HR on arrival were similar in the two groups. 58% of patients didn't achieve the target HR after receiving i.v. metoprolol (NR). R had a significantly higher HR reduction after oral (mean HR 63.9 ± 4.5 bpm vs. 69.6 ± 5.6 bpm) (p < 0.005) and i.v. (mean HR 55.4 ± 3.9 bpm vs. 67.4 ± 5.3 bpm) (p < 0.005) doses of metoprolol. Studies from NR showed a significantly higher ED in comparison to R (8.0 ± 2.9 vs. 6.1 ± 2.2 mSv) (p = 0.016) and a significantly higher proportion of non-diagnostic coronary segments (9.2 vs. 2.5%) (p < 0.001). 58% of patients who do not achieve a HR of <60 bpm prior to coronary CTA with oral fail to respond to additional i.v. metoprolol and have studies with higher radiation dose and worse image quality.

Does initial dosing of levothyroxine in infants with congenital hypothyroidism lead to frequent dose adjustments secondary to iatrogenic hyperthyroidism on follow-up?

PubMed

Craven, Meghan; Frank, Graeme R

2018-06-27

Congenital hypothyroidism (CH) is the most common preventable cause of intellectual disability. The recommended starting dose of levothyroxine (LT4) is between 10 and 15 μg/kg, an extremely wide range. We hypothesized that a sizable proportion of newborns treated for CH at the higher end of the dosage range become biochemically hyperthyroid at a follow-up visit. This study is a retrospective chart review of infants with CH between 2002 and 2012. Of the 104 patients included in this analysis, the average age at diagnosis was 11 days and the average starting dose of LT4 was 12±2.5 μg/kg. At follow-up, 36.5% required a dose reduction because of iatrogenic hyperthyroxinemia, 51% required no dose adjustment and 12.5% required a dose increase due to an elevated thyroid stimulating hormone (TSH). The starting doses of LT4 for those requiring a dose reduction, those not requiring an adjustment and those requiring an increase in the dose were 13.2±2.4, 11.5±2.1 and 10.3±2.6 μg/kg/day, respectively (p≤0.0001). Of the 34% of infants treated with an initial dose of >12.5 μg/day, 57.1% required a dose reduction at follow-up, compared to 26.1% of those whose initial starting dose was ≤12.5 μg/kg/day (p=0.007). Following the guidelines for initiating therapy for CH, 36.5% of the infants required a dose reduction for iatrogenic hyperthyroxinemia. These infants received a higher dose of LT4 than the infants who either required no adjustment or required an increase in the dose. A narrower range for initial dosing in CH may be appropriate.

Efficacy of sacubitril/valsartan vs. enalapril at lower than target doses in heart failure with reduced ejection fraction: the PARADIGM-HF trial.

PubMed

Vardeny, Orly; Claggett, Brian; Packer, Milton; Zile, Michael R; Rouleau, Jean; Swedberg, Karl; Teerlink, John R; Desai, Akshay S; Lefkowitz, Martin; Shi, Victor; McMurray, John J V; Solomon, Scott D

2016-10-01

In this analysis, we utilized data from PARADIGM-HF to test the hypothesis that participants who exhibited any dose reduction during the trial would have similar benefits from lower doses of sacubitril/valsartan relative to lower doses of enalapril. In a post-hoc analysis from PARADIGM-HF, we characterized patients by whether they received the maximal dose (200 mg sacubitril/valsartan or 10 mg enalapril twice daily) throughout the trial or had any dose reduction to lower doses (100/50/0 mg sacubitril/valsartan or 5/2.5/0 mg enalapril twice daily). The treatment effect for the primary outcome was estimated, stratified by dose level using time-updated Cox regression models. In the two treatment arms, participants with a dose reduction (43% of those randomized to enalapril and 42% of those randomized to sacubitril/valsartan) had similar baseline characteristics and similar baseline predictors of the need for dose reduction. In a time-updated analysis, any dose reduction was associated with a higher subsequent risk of the primary event [hazard ratio (HR) 2.5, 95% confidence interval (CI) 2.2-2.7]. However, the treatment benefit of sacubitril/valsartan over enalapril following a dose reduction was similar (HR 0.80, 95% CI 0.70-0.93, P < 0.001) to that observed in patients who had not experienced any dose reduction (HR 0.79, 95% CI 0.71-0.88, P < 0.001). In PARADIGM-HF, study medication dose reduction identified patients at higher risk of a major cardiovascular event. The magnitude of benefit for patients on lower doses of sacubitril/valsartan relative to those on lower doses of enalapril was similar to that of patients who remained on target doses of both drugs. © 2016 The Authors. European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.

Escalation to High Dose Defibrotide in Patients with Hepatic Veno-Occlusive Disease

PubMed Central

Triplett, Brandon M.; Kuttab, Hani I.; Kang, Guolian; Leung, Wing

2015-01-01

Hepatic veno-occlusive disease (VOD) is a serious complication of high-dose chemotherapy regimens, such as those utilized in hematopoietic cell transplantation recipients. Defibrotide is considered a safe and effective treatment when dosed at 25 mg/kg/day. However, patients who develop VOD still have increased mortality despite the use of defibrotide. Data are limited on the use of doses above 60 mg/kg/day for persistent VOD. In this prospective clinical trial, 34 patients received escalating doses of defibrotide. For patients with persistent VOD despite doses of 60 mg/kg/day, doses were increased to a maximum of 110 mg/kg/day. There was no observed increase in toxicity until doses rose beyond 100 mg/kg/day. Patients receiving doses between 10–100 mg/kg/day experienced an average of 3 bleeding episodes per 100 days of treatment, while those receiving doses >100 mg/kg/day experienced 13.2 bleeding episodes per 100 days (p=0.008). Moreover, dose reductions due to toxicity were needed at doses of 110 mg/kg/day more often than at lower doses. Defibrotide may be safely escalated to doses well above the current standard without an increase in bleeding risk. However, the efficacy of this dose escalation strategy remains unclear, as outcomes were similar to published cohorts of patients receiving standard doses of defibrotide for VOD. PMID:26278046