Dose and sample size determination for multi-drug combination studies

Preclinical experiment on multi-drug combination has an increasingly important role in (especially cancer) drug development because of the need to reduce development time and costs. Despite recent progress in statistical methods for assessing drug interaction, there is a lack of general methods for determining the doses comprising the combinations and the sample sizes to detect departures from additivity, especially in the case of more than two drugs. We propose a general method for dose and sample size determination for detecting departures from additivity of multiple drugs based on a semiparametric statistical model applicable to both in vivo and in vitro experiments. We show that selecting doses that comprise the combinations uniformly scattered in the experimental domain maximizes the minimum power of the F-test for detecting departures from additivity. In addition, the method applies to drugs whose relative potency is not constant. With both analytic proof and a simulation, we show the proposed design has optimal properties that are not shared by the classic designs such as the fixed ratio (ray) and the checkerboard designs. Furthermore, we show the method is dependent upon the shape of the single drug dose-response curve; therefore, different classes of drugs have to be dealt with separately. To our surprise, such an extension to multi-drug case with three or more drugs is far more difficult than it appears. Using the general methodology, we derive the dose selection and sample size specifically for a common class of drugs to derive the experimental design. We illustrate the method with the SAHA and Ara-C and Etoposide combination study.postprin

Epilepsy Is a Risk Factor for Sudden Cardiac Arrest in the General Population

Background People with epilepsy are at increased risk for sudden death. The most prevalent cause of sudden death in the general population is sudden cardiac arrest (SCA) due to ventricular fibrillation (VF). SCA may contribute to the increased incidence of sudden death in people with epilepsy. We assessed whether the risk for SCA is increased in epilepsy by determining the risk for SCA among people with active epilepsy in a community-based study. Methods and Results This investigation was part of the Amsterdam Resuscitation Studies (ARREST) in the Netherlands. It was designed to assess SCA risk in the general population. All SCA cases in the study area were identified and matched to controls (by age, sex, and SCA date). A diagnosis of active epilepsy was ascertained in all cases and controls. Relative risk for SCA was estimated by calculating the adjusted odds ratios using conditional logistic regression (adjustment was made for known risk factors for SCA). We identified 1019 cases of SCA with ECG-documented VF, and matched them to 2834 controls. There were 12 people with active epilepsy among cases and 12 among controls. Epilepsy was associated with a three-fold increased risk for SCA (adjusted OR 2.9 [95%CI 1.1–8.0.], p = 0.034). The risk for SCA in epilepsy was particularly increased in young and females. Conclusion Epilepsy in the general population seems to be associated with an increased risk for SCA

Colossal Pressure-Induced Softening in Scandium Fluoride

The counter-intuitive phenomenon of pressure-induced softening in materials is likely to be caused by the same dynamical behaviour that produces negative thermal expansion. Through a combination of molecular dynamics simulation on an idealised model and neutron diffraction at variable temperature and pressure, we show the existence of extraordinary and unprecedented pressure-induced softening in the negative thermal expansion material scandium fluoride, ScF$_3$, with values of the pressure-derivative of the bulk modulus $B$, $B^\prime = \partial B / \partial P$, reaching as low as $-40 \pm 1$

Education Center di Kabupaten Sleman dengan Pendekatan Arsitektur Bioklomatik

Sleman Regency has 1860 school facilities ranging from early childhood to high school levels spread across various regions, with 192,283 students and 865 teaching staff. The Sleman Regency Government continues to strive to improve the quality of formal and non-formal education, focusing on non-formal education because this education can support children's potential in increasing learning achievement outside of formal education. The large number of education-based communities, from children to adults, still do not have a good forum in the form of an education center that can exchange ideas and thoughts creatively between communities and young people in Sleman Regency. Based on the problems described, an education center is required. The purpose of designing the education center is to provide a forum for education-based communities that are educative and recreational in nature and provide education center designs that are in accordance with the application of the concept of bioclimatic architecture. In the application of bioclimatic architecture, several indicators are fulfilled, namely building orientation, laying sun-shading on buildings, placing openings in buildings, and selecting building materials. The concept of planning and design is obtaining areas that can support education in Sleman Regency, creating educational facilities as a means of adding insight and skills for the people of Sleman Regency, as well as raising awareness and fostering an appreciation for the people of Sleman Regency for the importance of both formal and non-formal educatio

Association of proinflammatory cytokines and chemotherapy-associated cognitive impairment in breast cancer patients: a multi-centered, prospective, cohort study.

BackgroundExisting evidence suggests that proinflammatory cytokines play an intermediary role in postchemotherapy cognitive impairment. This is one of the largest multicentered, cohort studies conducted in Singapore to evaluate the prevalence and proinflammatory biomarkers associated with cognitive impairment in breast cancer patients.Patients and methodsChemotherapy-receiving breast cancer patients (stages I-III) were recruited. Proinflammatory plasma cytokines concentrations [interleukin (IL)-1β, IL-2, IL-4, IL-6, IL-8, IL-10, granulocyte-macrophage colony-stimulating factor, interferon-γ and tumor necrosis factor-α] were evaluated at 3 time points (before chemotherapy, 6 and 12 weeks after chemotherapy initiation). The FACT-Cog (version 3) was utilized to evaluate patients' self-perceived cognitive disturbances and a computerized neuropsychological assessment (Headminder) was administered to evaluate patients' memory, attention, response speed and processing speed. Changes of cognition throughout chemotherapy treatment were compared against the baseline. Linear mixed-effects models were applied to test the relationships of clinical variables and cytokine concentrations on self-perceived cognitive disturbances and each objective cognitive domain.ResultsNinety-nine patients were included (age 50.5 ± 8.4 years; 81.8% Chinese; mean duration of education = 10.8 ± 3.3 years). Higher plasma IL-1β was associated with poorer response speed performance (estimate: -0.78; 95% confidence interval (CI) -1.34 to -0.03; P = 0.023), and a higher concentration of IL-4 was associated with better response speed performance (P = 0.022). Higher concentrations of IL-1β and IL-6 were associated with more severe self-perceived cognitive disturbances (P = 0.018 and 0.001, respectively). Patients with higher concentrations of IL-4 also reported less severe cognitive disturbances (P = 0.022).ConclusionsWhile elevated concentrations of IL-6 and IL-1β were observed in patients with poorer response speed performance and perceived cognitive disturbances, IL-4 may be protective against chemotherapy-associated cognitive impairment. This study is important because cytokines would potentially be mechanistic mediators of chemotherapy-associated cognitive changes

Importance of Frame Selection in Video Quality Assessment

Video sequences contains multiple frames therefore their quality is estimated by determining individual quality metric of each frame then apply the temporal masking affect. However, the integration of each frame’s quality metric into one score is very important because each video frame has different spatial features hence have different quality metric. There are several methods available to combine the metric into one score like averaging, linear weighting, worst frames averaging etc. Taking the average of each frame’s score is not very useful as humans give more attention to the worst values (most distorted frame) while rating their values. In this paper we evaluated the performance of different integration methods and a different approach is proposed which includes the average of worst selected frames which is discussed in later sections. The work is tested on LIVE video database which consists of 40 video sequences. They have provided the mean opinion scores for each video with the database. The correlation coefficient of 88.21% is achieved when tested with the best model designed

Swimming using surface acoustic waves

Microactuation of free standing objects in fluids is currently dominated by the rotary propeller, giving rise to a range of potential applications in the military, aeronautic and biomedical fields. Previously, surface acoustic waves (SAWs) have been shown to be of increasing interest in the field of microfluidics, where the refraction of a SAW into a drop of fluid creates a convective flow, a phenomenon generally known as SAW streaming. We now show how SAWs, generated at microelectronic devices, can be used as an efficient method of propulsion actuated by localised fluid streaming. The direction of the force arising from such streaming is optimal when the devices are maintained at the Rayleigh angle. The technique provides propulsion without any moving parts, and, due to the inherent design of the SAW transducer, enables simple control of the direction of travel

Anthracycline-Induced Cardiotoxicity: Cardiac Monitoring by Continuous Wave-Doppler Ultrasound Cardiac Output Monitoring and Correlation to Echocardiography

Background: Anthracyclines are agents with a well-known cardiotoxicity. The study sought to evaluate the hemodynamic response to an anthracycline using real-time continuous-wave (CW)-Doppler ultrasound cardiac output monitoring (USCOM) and echocardiography in combination with serum biomarkers. Methods: 50 patients (26 male, 24 female, median age 59 years) suffering from various types of cancer received an anthracycline-based regimen. Patients' responses were measured at different time points (T0 prior to infusion, T1 6 h post infusion, T2 after 1 day, T3 after 7 days, and T4 after 3 months) with CW-Doppler ultrasound (T0-T4) and echocardiography (T1, T4) for hemodynamic parameters such as stroke volume (SV; SVUSCOM ml) and ejection fraction (EF; EFechocardiography%) and with NT-pro-BNP and hs-Troponin T (T0-T4). Results: During the 3-month observation period, the relative decrease in the EF determined by echocardiography was -2.1% (Delta T0-T4, T0 71 +/- 7.8%, T4 69.5 +/- 7%, p = 0.04), whereas the decrease in SV observed using CW-Doppler was -6.5% (Delta T0-T4, T0 54 +/- 19.2 ml, T4 50.5 +/- 20.6 ml, p = 0.14). The kinetics for serum biomarkers were inversely correlated. Conclusions: Combining real-time CW-Doppler USCOM and serum biomarkers is feasible for monitoring the immediate and chronic hemodynamic changes during an anthracycline-based regimen; the results obtained were comparable to those from echocardiography

X-ray total scattering study of regular and magic-size nanoclusters of cadmium sulphide

Four kinds of magic-size CdS clusters and two different regular CdS quantum dots have been studied by x-ray total scattering technique and pair distribution function method. Results for the regular CdS quantum dots could be modelled as a mixed phase of atomic structures based on the two bulk crystalline phases, which is interpreted as representing the effects of stacking disorder. However, the results for the magic-size clusters were significantly different. On one hand, the short-range features in the pair distribution function reflect the bulk, indicating that these structures are based on the same tetrahedral coordination found in the bulk phases (and therefore excluding new types of structures such as cage-like arrangements of atoms). But on the other hand, the longer- range atomic structure clearly does not reflect the layer structures found in the bulk and the regular quantum dots. We compare the effects of two ligands, phenylacetic acid and oleic acid, showing that in two cases the ligand has little effect on the atomic structure of the magic-size nanocluster and in another it has a significant effect