Equivalent Limit Research Articles

Cataractogenesis following high-LET radiation exposure.

Biological effectiveness of ionizing radiation differs with its linear energy transfer (LET) such that high-LET radiation is more effective for various biological endpoints than low-LET radiation. Human exposure to high-LET radiation occurs in cancer patients, nuclear workers, aviators, astronauts and other space travellers. From the radiation protection viewpoint, the ocular lens is among the most radiosensitive tissues in the body, and cataract (a clouding of the normally transparent lens) is classified as tissue reactions (formerly called nonstochastic or deterministic effects) with a threshold below which no effect would occur. To prevent radiation cataracts, the International Commission on Radiological Protection (ICRP) has recommended an equivalent dose limit for the lens according to the threshold for vision-impairing cataracts. ICRP recommended the threshold of >8Gy in 1984 and an occupational dose limit of 150mSv/year in 1980. These remained unchanged until 2011, when ICRP recommended lowering the threshold to 0.5Gy and the dose limit to 20mSv/year (averaged over 5 years with no single year exceeding 50mSv). Although such reduction of the threshold was based on findings from low-LET radiation, the dose limit was recommended in Sv. Historically, the lens is the exceptional tissue for which ICRP had assigned a special factor in addition to a general radiation weighting factor, predicated on a belief that the lens is more vulnerable to high-LET radiation than other tissues. Considering such radiosensitive nature of the lens, a deeper understanding of a cataractogenic potential of high-LET radiation is indispensable. This review is thus designed to provide an update on the current knowledge as to high-LET radiation cataractogenesis. To this end, changes in ICRP recommendations on lenticular radiation protection, epidemiological and biological findings on high-LET cataractogenesis are reviewed, and future research needs are then discussed.

Indicators of Evidence for Bioequivalence

Some equivalence tests are based on two one-sided tests, where in many applications the test statistics are approximately normal. We define and find evidence for equivalence in Z-tests and then one- and two-sample binomial tests as well as for t-tests. Multivariate equivalence tests are typically based on statistics with non-central chi-squared or non-central F distributions in which the non-centrality parameter λ is a measure of heterogeneity of several groups. Classical tests of the null λ ≥ λ 0 versus the equivalence alternative λ < λ 0 are available, but simple formulae for power functions are not. In these tests, the equivalence limit λ 0 is typically chosen by context. We provide extensions of classical variance stabilizing transformations for the non-central chi-squared and F distributions that are easy to implement and which lead to indicators of evidence for equivalence. Approximate power functions are also obtained via simple expressions for the expected evidence in these equivalence tests.

The Limits of Physical Equivalence in Algebraic Quantum Field Theory

AbstractSome physicists and philosophers argue that unitarily inequivalent representations (UIRs) in quantum field theory (QFT) are mathematical surplus structure. Support for that view, sometimes ...

Ionizing radiation induced cataracts: Recent biological and mechanistic developments and perspectives for future research.

The lens of the eye has long been considered as a radiosensitive tissue, but recent research has suggested that the radiosensitivity is even greater than previously thought. The 2012 recommendation of the International Commission on Radiological Protection (ICRP) to substantially reduce the annual occupational equivalent dose limit for the ocular lens has now been adopted in the European Union and is under consideration around the rest of the world. However, ICRP clearly states that the recommendations are chiefly based on epidemiological evidence because there are a very small number of studies that provide explicit biological, mechanistic evidence at doses <2Gy. This paper aims to present a review of recently published information on the biological and mechanistic aspects of cataracts induced by exposure to ionizing radiation (IR). The data were compiled by assessing the pertinent literature in several distinct areas which contribute to the understanding of IR induced cataracts, information regarding lens biology and general processes of cataractogenesis. Results from cellular and tissue level studies and animal models, and relevant human studies, were examined. The main focus was the biological effects of low linear energy transfer IR, but dosimetry issues and a number of other confounding factors were also considered. The results of this review clearly highlight a number of gaps in current knowledge. Overall, while there have been a number of recent advances in understanding, it remains unknown exactly how IR exposure contributes to opacification. A fuller understanding of how exposure to relatively low doses of IR promotes induction and/or progression of IR-induced cataracts will have important implications for prevention and treatment of this disease, as well as for the field of radiation protection.

Time of maximum cycloplegia after instillation of cyclopentolate 1% in children with brown irises.

PurposeWe aimed to 1) determine the time of maximum cycloplegia after instillation of cyclopentolate 1% in children with brown irises, 2) evaluate the correlation between the pupillary reaction and time of maximum cycloplegia, and 3) identify any side effects of the medication.Patients and methodsThis was a prospective analytical study involving children aged 5 to 14 years who were attending refraction clinic. Cyclopentolate 1% was instilled three times at 10-minute intervals. The spherical equivalent, pupillary reaction, and pupillary diameter were recorded before the first drop and nine times after the last drop at 10-minute intervals. Side effects were assessed. Time of maximum cycloplegia was determined from the time point at which the 95% confidence interval of the differences between the mean spherical equivalent at each point and its final value at 110 minutes was reached and remained within the equivalence limit (±0.25 D).ResultsSixty children were enrolled in this study. Their mean age was 9.8 years (range: 5–4 years). Time of maximum cycloplegia was reached at 30 minutes after the first instillation of cyclopentolate. A poor correlation was observed between the pupillary reaction and the time of maximum cycloplegia (r=−0.07). The mean pupillary diameter at 30 minutes was 3.7±1.3 mm, and further dilation occurred thereafter. No side effects were observed.ConclusionIn most children, maximum cycloplegia was reached 30 minutes after the first instillation of cyclopentolate. The absence of a pupillary reaction should not be used as an indicator of maximum cycloplegia.

Equivalence limits of reference intervals for partitioning of population data. Relevant differences of reference limits

Abstract: Reference limits need to be compared with each other for two main purposes: to evaluate the clinical relevance of a possible difference, if limits are obtained from the same population but at different time periods, or to check if limits derived from two different subpopulations can be considered as identical. The comparison of reference limits required for the periodic reviewing of applied reference limits and for checking the transferability of reference limits adopted from external sources according to international standards is an example for the first case. In the second case, a decision is intended whether the full population has to be partitioned (stratified) into the subpopulations under consideration (e.g. males and females). In both situations, differences may be due either to analytical errors, to biological differences or to both effects. The difference between reference limits may be acceptable if it is within permissible limits. For establishing permissible limits, the concept of equivalence limits was adopted to assess the relevance of differences between two reference limits. The concept bases on the permissible uncertainty at a particular reference limit. The permissible uncertainty is quantified by the permissible analytical standard deviation derived from the empirical biological variation as recently proposed. It is defined separately for lower and upper reference limits. The concept proposed can be condensed to simple equations.

Growth and Tolerance of a Routine Infant Formula with an Alternative DHA Source Fed to Term Infants

BackgroundDocasahexaenoic (DHA) and arachidonic acid (ARA) are long‐chain polyunsaturated fatty acids (LCPUFAs) important for fetal and infant development. When fed at concentrations based on worldwide human milk composition, DHA in infant formula is related to visual and cognitive development in term infants and has resulted in red blood cell (RBC) LCPUFA concentrations comparable to breastfed infants1,2. Commercially available algal‐derived DHA single cell oil (DHASCO) is generally recognized as safe (GRAS) for use in and at certain levels specified for infant formula. DHASCO also has a long history of safe use in infant formula. Recently, a new DHA‐rich single cell oil (DHASCO‐B) from an alternative marine algae source achieved GRAS status for a similar use.ObjectiveThe objective of this study was to establish that the investigational cow's milk‐based formula with an alternative DHA source (DHASCO‐B) compared to the marketed formula with the current DHA source (DHASCO; Control) provides adequate growth and dietary bioequivalence with respect to DHA.MethodsIn this multi‐center, double‐blind, randomized, controlled, parallel‐group, prospective study, infants received one of two study formulas with DHA at 17 mg/100 kcal: Control (n=140) or an investigational formula (DHASCO‐B, n=127). The primary outcome was growth rate from 14 to 120 days. Growth rates were analyzed by gender using ANOVA. A blood sample was collected at 120 days of age in a subset of participants (Control, n =34; DHASCO‐B, n=27). DHA and ARA concentrations in RBC (μg/mL) were assessed by capillary column gas chromatography. A 90% confidence interval (CI) was calculated for the ratio of the group mean (geometric) total RBC DHA concentration.ResultsThere were no group differences in infant demographic or anthropometric characteristics at enrollment or study completion rate. No significant group differences were observed for weight, length, or head circumference growth rates by gender from 14 to 120 days of age. The calculated CI for total RBC DHA concentration for the investigational relative to the Control group (91 to 104%) fell within the pre‐specified equivalence limit (80 to 125%). No statistically significant differences (P&lt;0.05) in total RBC DHA or ARA concentrations (μg/ml) (DHA: Control, 90.2 ±2.31; DHASCO‐B, 88.1 ±2.59 and ARA: Control, 243.6 ±4.68; DHASCO‐B, 240.8 ±5.25) or percent of total fatty acids (wt/wt) (DHA: Control, 5.52 ±0.12; DHASCO‐B, 5.52 ±0.13 and ARA: 14.90 ±0.24, DHASCO‐B: 15.15 ±0.27) were detected.ConclusionsResults of this study demonstrated the investigational formula provided adequate growth and dietary bioequivalence when fed to healthy term infants from 14 to 120 days of age compared to the control formula with the traditional source of DHA.Support or Funding InformationAC Patterson, KH Maditz, J Wampler, C Harris, A Kirchoff, and CL Berseth are full‐time employees of Mead Johnson Nutrition.

An analysis of personnel dose reports in medical radiation occupational workers from an oncology center

Background: To evaluate the risk involved, there is need to know the quantum of personnel exposures in whole service. Dose reports from an Oncology Centre over 7 block periods, 5 years each from 1979 $ll 2013 are analyzed. Materials and Methods: Personnel monitoring (PM) reports $ll 1990s with film badges and later thermoluminescent (TL) badges (CaSo4.Dy) were evaluated. 35 years total service was taken to represent total professional service of staff superannua$ng at age 60 years. Results: Mean personnel equivalent dose for 5 year block period is 3.30±0.43 mSv (n=7 blocks). Maximum dose in any block period was 30-60 mSv. Equivalent doses 22% were zero, 64.3% within 5 mSv. 2.1% were above 30 mSv in 5 year periods. Doses were decreasing order 11.8 mSv (radiopharmaceu$cal prepara$on), 4.3 mSv (nuclear medicine), 4.1 mSv (medical physics), 2.2 mSv (brachytherapy); 1.2 mSv (radiodiagnosis), 1.1 mSv (external beam radiotherapy) and 0.73 mSv (radia$on steriliza$on plant). Conclusion: The whole body personnel dose in are much lower than recommended annual dose equivalent limits of 100 mSv/ 5 years. The magnitude of recorded doses to staff show that the risk is negligible and the principle of ALARA is being prac$ced in the work areas.

The featureless and non-variable optical spectral energy distribution of AXP 4U 0142+61

Abstract We present GTC-10.4 m spectroscopy and multiband photometry of the faint (r ∼ 26) optical counterpart of the anomalous X-ray pulsar 4U 0142+61. The 5000–9000 Å spectrum – the first obtained for a magnetar – is featureless, allowing us to set an equivalent width upper limit EW &amp;lt; 25 Å to the presence of emission lines in the H α region. Multiband photometry in the g, r, i, z Sloan Digital Sky Survey (SDSS) bands obtained at different epochs over 12 yr shows no significant variability from minutes-to-years time-scales. The photometry has been calibrated, for the first time, against the SDSS itself, resulting in solid upper limits to variability ranging from ∼0.2 mag in i (over 12 yr) to 0.05 mag in z (over 1.5 yr). The shape of the optical + near-infrared (literature values) spectral energy distribution is not well constrained due to the high extinction along the line of sight. Using a Markov Chain Monte Carlo analysis, we find that it can be described by a power law with a spectral index β = −0.7 ± 0.5 and E(B − V) = 1.5 ± 0.4. We also discuss on the implications of adding hard X-ray flux values from literature to the spectral fitting.

Supergravity background of λ-deformed model for AdS2 × S2 supercoset

Starting with the Fˆ/G supercoset model corresponding to the AdSn×Sn superstring one can define the λ-model of arXiv:1409.1538 either as a deformation of the Fˆ/Fˆ gauged WZW model or as an integrable one-parameter generalisation of the non-abelian T-dual of the AdSn×Sn superstring sigma model with respect to the whole supergroup Fˆ. Here we consider the case of n=2 and find the explicit form of the 4d target space background for the λ-model for the PSU(1,1|2)/SO(1,1)×SO(2) supercoset. We show that this background represents a solution of type IIB 10d supergravity compactified on a 6-torus with only metric, dilaton Φ and the RR 5-form (represented by a 2-form F in 4d) being non-trivial. This implies that the λ-model is Weyl invariant at the quantum level and thus defines a consistent superstring sigma model. The supergravity solution we find is different from the one in arXiv:1410.1886 which should correspond to a version of the λ-model where only the bosonic subgroup of Fˆ is gauged. Still, the two solutions have equivalent scaling limit of arXiv:1504.07213 leading to the isometric background for the metric and eΦF which is related to the η-deformed AdS2×S2 sigma model of arXiv:1309.5850. Similar results are expected in the AdS3×S3 and AdS5×S5 cases.

Generic-to-generic lamotrigine switches in people with epilepsy: the randomised controlled EQUIGEN trial

Patients and clinicians share concerns that generic drug substitution might lead to loss of efficacy or emergence of adverse events. In this trial, we assessed US Food and Drug Administration (FDA) bioequivalence standards by studying the effects of switching between two disparate generic immediate-release lamotrigine products in patients with epilepsy. The Equivalence among Generic Antiepileptic Drugs (EQUIGEN) chronic-dose study was a randomised, double-blind, crossover study that enrolled adults (aged ≥18 years) with epilepsy from six epilepsy centres at academic institutions across the USA who were receiving immediate-release lamotrigine dosed at 100 mg, 200 mg, 300 mg, or 400 mg twice daily. Eligible patients were randomly allocated (1:1) to one of two treatment sequences (sequence 1 or sequence 2), comprising four study periods of 14 days each. During each 14-day treatment period, patients received balanced doses of an oral generic lamotrigine product every 12 h (200-800 mg total, identical to lamotrigine dose prior to study enrolment); after each 14-day period, patients were crossed over to receive the other generic product. Computer-based randomisation was done using random permuted blocks of size two or four for each site to prevent sequence predictability. Both patients and study personnel were masked to the generic products selected, their predicted exposure (ie, "high" vs "low"), and their group allocation. The primary outcome of this trial was bioequivalence between the generic products, which was assessed at the end of the study through a comparison of maximum plasma concentration (Cmax) and area under the concentration-time curve (AUC) for each product in the analysis population (all patients who completed all four treatment periods). Bioequivalence was established if the 90% CIs of the ratios of these two parameters for the two products were within equivalence limits (80-125%) in the analysis population. This study is registered with ClinicalTrials.gov\, number NCT01713777. Between April 25, 2013, and Aug 12, 2014, 35 eligible patients were enrolled and randomly assigned to treatment sequence 1 (n=15) or treatment sequence 2 (n=20). 33 patients completed all four treatment periods and were included in the primary outcome analysis. The 90% CIs of the ratios of both Cmax and AUC were within equivalence limits (AUC 90% CI 98-103, Cmax 90% CI 99-105), showing that lamotrigine exposures were equivalent between the generic products. No significant changes in seizure frequency or adverse events were recorded. No deaths, study-related serious adverse events, or changes in clinical laboratory values or vital signs occurred during this study. Disparate generic lamotrigine products in patients with epilepsy showed bioequivalence with no detectable difference in clinical effects, confirming that US Food and Drug Administration bioequivalence standards are appropriate. American Epilepsy Society, Epilepsy Foundation, and US Food and Drug Administration.

Non-Contact Photoacoustic Imaging Using a Commercial Heterodyne Interferometer.

Most current photoacoustic imaging (PAI) systems employ piezoelectric transducers to receive photoacoustic signals, which requires coupling medium to facilitate photoacoustic wave propagation and are not favored in many applications. Here, we report an all-optical non-contact PAI system based on a commercial heterodyne interferometer working at 1550 nm. The interferometer remotely detects ultrasound-induced surface vibration and does not involve any physical contact with the sample. The theoretically predicated and experimentally measured noise equivalent detection limits of the optical sensor are about 4.5 and 810 Pa over 1.2 MHz bandwidth. Using a raster-scan PAI system equipped with the non-contact design, stereotactic boundaries of an artificial tumor in a pig brain were accurately delineated. The non-contact design also enables the tomographic PAI of biological tissue samples in a non-invasive manner. The preliminary results and analyses reveal that the heterodyne interferometer-based non-contact PAI system holds good potential in biomedical imaging.

Novel MOEMS Lorentz Force Transducer for Magnetic Fields

This contribution describes a novel magnetic field transducer based on a MOEMS (micro-opto-electo-mechanical-system) readout. The silicon structure is deflected in a static magnetic field due to the Lorentz force This deflection is measured with the mechano-optical transducer [1]. The transduction method is based on the modulation of a perpendicularly introduced light flux. The modulation is achieved by one movable optical grating on a suspended structure and a second grating that is fixed to the foundation of the system. The proof-of-concept device was characterized at ambient pressure exhibiting a sensitivity of 200 mV/T. The noise equivalent magnetic resolution limit is 1.5 μT/√Hz which results mainly from the opto-electrical evaluation circuit. By introducing advanced opto-electronics and using improved MEMS devices it is feasible to reduce this value down to 1 nT/√Hz which is equivalent to the fundamental mechanical Brownian noise limit.

The constrained referrals: How dependence and structural equivalence limit referrals’ performance

Referrals--new employees who are hired by the firm through a job referral practice--have advantages in achieving greater performance compared to non-referrals, because referrals can mobilize on-goi...

Nanostructured cupric oxide electrode: An alternative to amperometric detection of carbohydrates in anion-exchange chromatography

In this paper, a new and low cost copper/cupric oxide nanostructured electrode is presented as an alternative to the amperometric detection of carbohydrates in high-performance anion exchange chromatography. The modified copper electrodes were prepared by a simple and fast method which resulted in the obtainment of homogeneously distributed nanostructures adhered to the surface with controlled chemical nature. The results, when compared to conventional copper electrodes, exhibited considerable improvements in analytical results, including: 1) Better repeatability in consecutive glucose detections, in which the percent relative standard deviation improved from 15.1% to 0.279%. 2) Significant improvements in the stability of the baseline and a decrease of the stabilization time, going from several hours to approximately 15 min. 3) Considerable increase in the sensitivity towards glucose, from 5.02 nA min mg L−1 to 25.5 nA min mg L−1. 4) Improvements in the detectability with limits as low as 1.09 pmol. 5) Wide working range of concentrations (1 × 10−2 to 1 × 104 mg L−1). 6) Good linearity with correlation coefficients greater than 0.998. 7) Possibility of detecting different molecules of carbohydrates (lactose, maltose, sucrose cellobiose, sorbitol, fructose, glucose, galactose, manose, arabitol, xylose, ribose and arabnose). In comparison to the electrode that is more employed for this type of application (gold electrode), the low cost, the possibility of detection at constant potential and the equivalent detection limits presented by the new electrode material introduced in this work emerge as characteristics that make this material a powerful alternative considering the detection of carbohydrates in anion exchange chromatography.

Abstract B153: Effect of food and gastric pH modifiers on the pharmacokinetics of AZD9291

Abstract Background AZD9291 is a potent, oral, irreversible epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) selective for sensitizing (EGFRm) and T790M resistance mutations. Clinical activity has been demonstrated in patients with advanced EGFR T790M positive non-small cell lung cancer (NSCLC). We report results from two Phase I clinical studies, one investigating the effect of food, and another on the impact of increased gastric pH, on the pharmacokinetics (PK) of AZD9291. Design The studies were conducted in accordance with ICH/GCP guidance; protocols were reviewed and approved by IEC and IRB prior to implementation. The likely commercial formulation of AZD9291 80 mg film-coated tablet was used. The Food effect study (NCT02163733) had two parts: A and B. Part A was an open-label randomized two-period crossover design where the primary objective was to evaluate the effect of food on AZD9291 PK following oral dosing of 80 mg tablet in patients with EGFRm+ NSCLC, whose disease had progressed following treatment with a prior EGFR-TKI. Part B is an ongoing extension phase where patients may receive continuous AZD9291 80 mg dosing, if they continue to derive benefit, with safety monitoring conducted for up to 1 year. The Gastric pH interaction study (NCT02224053) was an open-label, two-fixed-period study with primary objective to evaluate the effect of omeprazole 40 mg on AZD9291 exposure in healthy, male volunteers. In Period 1, subjects received omeprazole on Days 1-4 and on Day 5 they received AZD9291 and omeprazole after a 10-hour fast. In Period 2, after a washout of at least 21 days, subjects received AZD9291 alone after a 10-hour fast. After Period 1 the AZD9291 AUC0-72 exposure was assessed and subjects with exposures exceeding set limits were withdrawn and replaced. In both studies, blood samples were taken serially post dose in each treatment period to determine concentrations of AZD9291 and its active metabolites (AZ5104 and AZ7550). The safety and tolerability of AZD9291 was a secondary objective in the Food effect (fed and fasted state) and Gastric pH interaction studies (AZD9291±omeprazole). Results Food effect study (Part A only): 38 patients were assigned to treatment. Geometric LS mean ratios comparing fed to fasted treatments for AZD9291 Cmax and AUC0-72 were 92.75% (81.40, 105.68) and 106.05% (94.82, 118.60), respectively and 90% confidence intervals were contained within the predefined equivalence limits of 70% to 143%. Gastric pH interaction study: 68 subjects were assigned to treatment and 47 subjects completed both study periods. The geometric LS mean ratios comparing AZD9291 Cmax and AUC when given with omeprazole compared to administration of AZD9291 alone were 101.65% (94.65, 109.16) and 106.66% (100.26, 113.46), respectively and 90% confidence intervals were within the equivalence limits of 80% to 125%. In addition, neither food nor co-administration of AZD9291 with omeprazole had a clinically relevant effect on exposure (Cmax and AUC) for the AZD9291 metabolites AZ5104 and AZ7550. Oral administration of 80 mg AZD9291 was well tolerated, with no deaths or discontinuations due to AE in either study. Conclusions These studies suggest that AZD9291 can be administered without regard to food and no restrictions are necessary when administered with gastric pH modifying agents. AZD9291 was well tolerated under fed or fasted conditions, and when co-dosed with omeprazole. Citation Format: Karthick Vishwanathan, Paul A. Dickinson, Khanh Bui, Doris K. Weilert, Karen So, Karen Thomas, Eleanor A. Lisbon, Ruth Plummer. Effect of food and gastric pH modifiers on the pharmacokinetics of AZD9291. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr B153.

WHAT IS THE REDSHIFT OF THE GAMMA-RAY BL LAC SOURCE S4 0954+65?

High signal-to-noise ratio spectroscopic observations of the BL Lac object S4 0954+65 at the alleged redshift z = 0.367 are presented. This source was detected at gamma frequencies by MAGIC (TeV) and FERMI (GeV) telescopes during a remarkable outburst that occurred in February 2015, making the determination of its distance particularly relevant for our understanding of the properties of the Extragalactic Background Light. Contrary to previous reports on the redshift, we found that the optical spectrum is featureless at an equivalent width limit of \sim 0.1 Ang. A critical analysis of the existing observations indicates that the redshift is still unknown. Based on the new data we estimate a lower limit to the redshift at z \geq 0.45.

A comparison between radiation therapists and medical specialists in the use of kilovoltage cone-beam computed tomography scans for potential lung cancer radiotherapy target verification and adaptation

Target volume matching using cone-beam computed tomography (CBCT) is the preferred treatment verification method for lung cancer in many centers. However, radiation therapists (RTs) are trained in bony matching and not soft tissue matching. The purpose of this study was to determine whether RTs were equivalent to radiation oncologists (ROs) and radiologists (RDs) in alignment of the treatment CBCT with the gross tumor volume (GTV) defined at planning and in delineating the GTV on the treatment CBCT, as may be necessary for adaptive radiotherapy. In this study, 10 RTs, 1 RO, and 1 RD performed a manual tumor alignment and correction of the planning GTV to a treatment CBCT to generate an isocenter correction distance for 15 patient data sets. Participants also contoured the GTV on the same data sets. The isocenter correction distance and the contoured GTVs from the RTs were compared with the RD and RO. The mean difference in isocenter correction distances was 0.40cm between the RO and RD, 0.51cm between the RTs, and RO and 0.42cm between the RTs and RD. The 95% CIs were smaller than the equivalence limit of 0.5cm, indicating that the RTs were equivalent to the RO and RD. For GTV delineation comparisons, the RTs were not found to be equivalent to the RD or RO. The alignment of the planning defined GTV and treatment CBCT using soft tissue matching by the RTs has been shown to be equivalent to those by the RO and RD. However, tumor delineation by the RTs on the treatment CBCT was not equivalent to that of the RO and RD. Thus, it may be appropriate for RTs to undertake soft tissue alignment based on CBCT; however, further investigation may be necessary before RTs undertake delineation for adaptive radiotherapy purposes.

Pharmacokinetics, Pharmacodynamics, Efficacy, and Safety of Albuterol (Salbuterol) Multi-dose Dry-Powder Inhaler and ProAir® Hydrofluoroalkane for the Treatment of Persistent Asthma: Results of Two Randomized Double-Blind Studies

Metered-dose inhalers require patients to coordinate inhalation with actuation. The present albuterol multi-dose dry-powder inhaler (mDPI) does not require patients to coordinate inspiration with actuation, thereby simplifying delivery of albuterol to the lungs. The aim of the present study was to compare the efficacy, pharmacokinetics, pharmacodynamics, extrapulmonary pharmacodynamics, and safety of albuterol (salbuterol) delivered via a ProAir® hydrofluoroalkane (HFA) metered-dose inhaler and an mDPI. Two double-blind, randomized, double-dummy, crossover, multicenter, placebo-controlled studies in persistent asthma patients were conducted. Study 1: 47 adult patients were treated with cumulative doses of albuterol mDPI or ProAir HFA (90 µg/inhalation; 1 + 1 + 2 + 4 + 8 inhalations) or placebo. Study 2: 71 patients aged ≥12 years were randomly assigned to receive 90 or 180 μg of albuterol mDPI or ProAir HFA, or placebo. Primary efficacy endpoints were baseline-adjusted forced expiratory volume in 1 s (FEV1) at 30 min (30-min FEV1) after each cumulative dose (Study 1) and FEV1 area under the effect curve over 6 h (FEV1 AUEC0-6) after dosing (Study 2). Study 1: differences, with corresponding 90% confidence intervals, between albuterol mDPI and ProAir HFA in FEV1 after each cumulative dose and in FEV1 AUEC0-6 after the final dose were within pre-established equivalence limits. The difference in FEV1 at high vs. low doses was significant for both active treatments (p < 0.0001). Active treatments were similar in systemic exposure, extrapulmonary pharmacodynamics, and safety. Study 2: mean FEV1 AUEC0-6 was significantly greater than for placebo for both doses of albuterol mDPI and ProAir HFA (p < 0.0001). Albuterol mDPI was comparable to ProAir HFA at 90 and 180 µg. Both study treatments were generally well tolerated. The bronchodilatory efficacy and pharmacokinetic/pharmacodynamic profiles of albuterol mDPI and ProAir HFA are comparable, with a safety profile consistent with that of inhaled albuterol.

Defect acceptability under full-scale fretting fatigue tests for railway axles

This paper presents a new approach based on the application of a multiaxial high cycle fatigue criterion together with the use of El-Haddad correction for investigation of fretting fatigue in railway axles. Stress path along the axle–wheel contact, determined by the FE analysis, was implemented into different multiaxial fatigue criteria in order to predict critical sites of nucleation. The equivalent fatigue limit expressed by the applied criterion is compared with the crack size dependent fatigue limit described by El-Haddad correction in order to define a defect size acceptability criterion. Verification of the proposed approach was done by post-test failure investigation of the full-scale axle tests conducted as a part of Euraxles project. Scanning electron microscope (SEM) examination of the failed press-fit sections revealed a critical defect size in the order of 200μm in depth for non-propagating cracks. The obtained results were found to be consistent with the estimations made by the proposed approach.