Prospective, non-randomized phase 2 clinical trial of carboplatin plus paclitaxel with sequential radical pelvic radiotherapy for uterine papillary serous carcinoma

Objective Uterine Papillary Serous Carcinoma (UPSC) is uncommon and accounts for less than 5% of all uterine cancers. Therefore the majority of evidence about the benefits of adjuvant treatment comes from retrospective case series. We conducted a prospective multi-centre non-randomized phase 2 clinical trial using four cycles of adjuvant paclitaxel plus carboplatin chemotherapy followed by pelvic radiotherapy, in order to evaluate the tolerability and safety of this approach. Methods This trial enrolled patients with newly diagnosed, previously untreated patients with stage 1b-4 (FIGO-1988) UPSC with a papillary serous component of at least 30%. Paclitaxel (175 mg/m2) and carboplatin (AUC 6) were administered on day 1 of each 3-week cycle for 4 cycles. Chemotherapy was followed by external beam radiotherapy to the whole pelvis (50.4 Gy over 5.5 weeks). Completion and toxicity of treatment (Common Toxicity Criteria, CTC) and quality of life measures were the primary outcome indicators. Results Twenty-nine of 31 patients completed treatment as planned. Dose reduction was needed in 9 patients (29%), treatment delay in 7 (23%), and treatment cessation in 2 patients (6.5%). Hematologic toxicity, grade 3 or 4 occurred in 19% (6/31) of patients. Patients' self-reported quality of life remained stable throughout treatment. Thirteen of the 29 patients with stages 1–3 disease (44.8%) recurred (average follow up 28.1 months, range 8–60 months). Conclusion This multimodal treatment is feasible, safe and tolerated reasonably well and would be suitable for use in multi-institutional prospective randomized clinical trials incorporating novel therapies in patients with UPSC.

Computed success rates of various carrier phase integer estimation solutions and their comparison with statistical success rates

The success rate of carrier phase ambiguity resolution (AR) is the probability that the ambiguities are successfully fixed to their correct integer values. In existing works, an exact success rate formula for integer bootstrapping estimator has been used as a sharp lower bound for the integer least squares (ILS) success rate. Rigorous computation of success rate for the more general ILS solutions has been considered difficult, because of complexity of the ILS ambiguity pull-in region and computational load of the integration of the multivariate probability density function. Contributions of this work are twofold. First, the pull-in region mathematically expressed as the vertices of a polyhedron is represented by a multi-dimensional grid, at which the cumulative probability can be integrated with the multivariate normal cumulative density function (mvncdf) available in Matlab. The bivariate case is studied where the pull-region is usually defined as a hexagon and the probability is easily obtained using mvncdf at all the grid points within the convex polygon. Second, the paper compares the computed integer rounding and integer bootstrapping success rates, lower and upper bounds of the ILS success rates to the actual ILS AR success rates obtained from a 24 h GPS data set for a 21 km baseline. The results demonstrate that the upper bound probability of the ILS AR probability given in the existing literatures agrees with the actual ILS success rate well, although the success rate computed with integer bootstrapping method is a quite sharp approximation to the actual ILS success rate. The results also show that variations or uncertainty of the unit–weight variance estimates from epoch to epoch will affect the computed success rates from different methods significantly, thus deserving more attentions in order to obtain useful success probability predictions.

Mechanical conditions in the initial phase of bone healing

Background: Bone healing is sensitive to the initial mechanical conditions with tissue differentiation being determined within days of trauma. Whilst axial compression is regarded as stimulatory, the role of interfragmentary shear is controversial. The purpose of this study was to determine how the initial mechanical conditions produced by interfragmentary shear and torsion differ from those produced by axial compressive movements. ----- ----- Methods: The finite element method was used to estimate the strain, pressure and fluid flow in the early callus tissue produced by the different modes of interfragmentary movement found in vivo. Additionally, tissue formation was predicted according to three principally different mechanobiological theories. ----- ----- Findings: Large interfragmentary shear movements produced comparable strains and less fluid flow and pressure than moderate axial interfragmentary movements. Additionally, combined axial and shear movements did not result in overall increases in the strains and the strain magnitudes were similar to those produced by axial movements alone. Only when axial movements where applied did the non-distortional component of the pressure–deformation theory influence the initial tissue predictions. ----- ----- Interpretation: This study found that the mechanical stimuli generated by interfragmentary shear and torsion differed from those produced by axial interfragmentary movements. The initial tissue formation as predicted by the mechanobiological theories was dominated by the deformation stimulus.

Antiretroviral therapy (ART) adherence among people living with HIV/AIDS (PLHIV) in the north of Vietnam : a multi-method approach

The antiretroviral therapy (ART) program for People Living with HIV/AIDS (PLHIV) in Vietnam has been scaled up rapidly in recent years (from 50 clients in 2003 to almost 38,000 in 2009). ART success is highly dependent on the ability of the patients to fully adhere to the prescribed treatment regimen. Despite the remarkable extension of ART programs in Vietnam, HIV/AIDS program managers still have little reliable data on levels of ART adherence and factors that might promote or reduce adherence. Several previous studies in Vietnam estimated extremely high levels of ART adherence among their samples, although there are reasons to question the veracity of the conclusion that adherence is nearly perfect. Further, no study has quantitatively assessed the factors influencing ART adherence. In order to reduce these gaps, this study was designed to include several phases and used a multi-method approach to examine levels of ART non-adherence and its relationship to a range of demographic, clinical, social and psychological factors. The study began with an exploratory qualitative phase employing four focus group discussions and 30 in-depth interviews with PLHIV, peer educators, carers and health care providers (HCPs). Survey interviews were completed with 615 PLHIV in five rural and urban out-patient clinics in northern Vietnam using an Audio Computer Assisted Self-Interview (ACASI) and clinical records extraction. The survey instrument was carefully developed through a systematic procedure to ensure its reliability and validity. Cultural appropriateness was considered in the design and implementation of both the qualitative study and the cross sectional survey. The qualitative study uncovered several contrary perceptions between health care providers and HIV/AIDS patients regarding the true levels of ART adherence. Health care providers often stated that most of their patients closely adhered to their regimens, while PLHIV and their peers reported that “it is not easy” to do so. The quantitative survey findings supported the PLHIV and their peers’ point of view in the qualitative study, because non-adherence to ART was relatively common among the study sample. Using the ACASI technique, the estimated prevalence of onemonth non-adherence measured by the Visual Analogue Scale (VAS) was 24.9% and the prevalence of four-day not-on-time-adherence using the modified Adult AIDS Clinical Trials Group (AACTG) instrument was 29%. Observed agreement between the two measures was 84% and kappa coefficient was 0.60 (SE=0.04 and p<0.0001). The good agreement between the two measures in the current study is consistent with those found in previous research and provides evidence of cross-validation of the estimated adherence levels. The qualitative study was also valuable in suggesting important variables for the survey conceptual framework and instrument development. The survey confirmed significant correlations between two measures of ART adherence (i.e. dose adherence and time adherence) and many factors identified in the qualitative study, but failed to find evidence of significant correlations of some other factors and ART adherence. Non-adherence to ART was significantly associated with untreated depression, heavy alcohol use, illicit drug use, experiences with medication side-effects, chance health locus of control, low quality of information from HCPs, low satisfaction with received support and poor social connectedness. No multivariate association was observed between ART adherence and age, gender, education, duration of ART, the use of adherence aids, disclosure of ART, patients’ ability to initiate communication with HCPs or distance between clinic and patients’ residence. This is the largest study yet reported in Asia to examine non-adherence to ART and its possible determinants. The evidence strongly supports recent calls from other developing nations for HIV/AIDS services to provide screening, counseling and treatment for patients with depressive symptoms, heavy use of alcohol and substance use. Counseling should also address fatalistic beliefs about chance or luck determining health outcomes. The data suggest that adherence could be enhanced by regularly providing information on ART and assisting patients to maintain social connectedness with their family and the community. This study highlights the benefits of using a multi-method approach in examining complex barriers and facilitators of medication adherence. It also demonstrated the utility of the ACASI interview method to enhance open disclosure by people living with HIV/AIDS and thus, increase the veracity of self-reported data.

Instantaneous phase of the autocorrelation and robustness to signal-dependent noise

The phase of an analytic signal constructed from the autocorrelation function of a signal contains significant information about the shape of the signal. Using Bedrosian's (1963) theorem for the Hilbert transform it is proved that this phase is robust to multiplicative noise if the signal is baseband and the spectra of the signal and the noise do not overlap. Higher-order spectral features are interpreted in this context and shown to extract nonlinear phase information while retaining robustness. The significance of the result is that prior knowledge of the spectra is not required.

Collaboration : developing integration in multi-purpose services in rural New South Wales, Australia

Introduction: The Multi-purpose Service (MPS) Program was introduced to rural Australia in 1991 as a solution to poor health outcomes in rural compared with metropolitan populations, difficulty in attracting healthcare staff and a lack of viability and range of health services in rural areas. The aim of this study was to describe the main concerns of participants involved in the development of multi-purpose services in rural New South Wales (NSW). This article is abstracted from a larger study and discusses the extent to which collaboration occurred within the new multi-purpose service. Methods: A constructivist grounded theory methodology was used. Participants were from 13 multi-purpose services in rural NSW and 30 in-depth interviews were conducted with 6 community members, 11 managers and 13 staff members who had been involved in the process of developing a multi-purpose service. Results: The main concern of all participants was their anticipation of risk. This anticipation of risk manifested itself in either trust or suspicion and explained their progression through a phase of collaborating. Participants who had trust in other stakeholders were more likely to embrace an integrated health service identity. Those participants, who were suspicious that they would lose status or power, maintained that the previous hospital services provided a better health service and described a coexistence of services within the multi-purpose service. Conclusions: This study provided an insight into the perceptions of community members, staff members and managers involved in the process of developing a multi-purpose service. It revealed that the anticipation of risk was intrinsic to a process of changing from a traditional hospital service to collaborating in a new model of health care provided at a multi-purpose service.

Free surface flow past topography : a beyond-all-orders approach

The problem of steady subcritical free surface flow past a submerged inclined step is considered. The asymptotic limit of small Froude number is treated, with particular emphasis on the effect that changing the angle of the step face has on the surface waves. As demonstrated by Chapman & Vanden-Broeck (2006), the divergence of a power series expansion in powers of the square of the Froude number is caused by singularities in the analytic continuation of the free surface; for an inclined step, these singularities may correspond to either the corners or stagnation points of the step, or both, depending on the angle of incline. Stokes lines emanate from these singularities, and exponentially small waves are switched on at the point the Stokes lines intersect with the free surface. Our results suggest that for a certain range of step angles, two wavetrains are switched on, but the exponentially subdominant one is switched on first, leading to an intermediate wavetrain not previously noted. We extend these ideas to the problem of flow over a submerged bump or trench, again with inclined sides. This time there may be two, three or four active Stokes lines, depending on the inclination angles. We demonstrate how to construct a base topography such that wave contributions from separate Stokes lines are of equal magnitude but opposite phase, thus cancelling out. Our asymptotic results are complemented by numerical solutions to the fully nonlinear equations.

The development of a multi-segment kinematic model of footwear

In gait analysis, both shoe mounted and skin mounted markers have been used to quantify the movement of the foot inside the shoe. However, these models have not been demonstrated as reliable or accurate in shod conditions. The purpose of this study was to develop an accurate and reliable marker set to describe foot-shoe complex kinematics during stance phase.

Footwear modifies coronal plane forefoot and sagittal plane hallux kinematics during stance phase of walking gait

Footwear is designed to reduce injury, and enhance performance. However, the effect footwear has on foot and ankle kinematics currently remains unknown. Acknowledging the need for improved understanding, multi-segment models of the foot-shoe complex need to be established to both describe and quantify the effect footwear has on the foot and ankle during stance phase of gait. The purpose of this study was to quantify how footwear alters the kinematics of the foot inside the shoe during stance phase of walking gait.

Footwear modifies foot and ankle kinematics during stance phase of walking gait

Footwear is designed to reduce injury and enhance performance. However, the effect footwear has on foot and ankle kinematics currently remains unknown. Acknowledging the need for improved understanding, the aim of this study was to describe the effect footwear has on the kinematics of a multi segment foot during stance phase of walking gait.

Evidence for carbonate platform failure during rapid sea-level rise; ca 14 000 year old bioclastic flow deposits in the Lesser Antilles

Bioclastic flow deposits offshore from the Soufrie`re Hills volcano on Montserrat in the Lesser Antilles were deposited by the largest volume sediment flows near this active volcano in the last 26 kyr. The volume of these deposits exceeds that of the largest historic volcanic dome collapse in the world, which occurred on Montserrat in 2003. These flows were most probably generated by a large submarine slope failure of the carbonate shelf comprising the south west flank of Antigua or the east flank of Redonda; adjacent islands that are not volcanically active. The bioclastic flow deposits are relatively coarse-grained and either ungraded or poorly graded, and were deposited by non cohesive debris flow and high density turbidity currents. The bioclastic deposit often comprises multiple sub-units that cannot be correlated between core sites; some located just 2 km apart. Multiple sub-units in the bioclastic deposit result from either flow reflection, stacking of multiple debris flow lobes, and/or multi-stage collapse of the initial landslide. This study provides unusually precise constraints on the age of this mass flow event that occurred at ca 14 ka. Few large submarine landslides have been well dated, but the slope failures that have been dated are commonly associated with periods of rapid sea-level change.

Multi-objective design optimization of morphing UAV aerofoil/wing using hybridised MOGA

The paper investigates two advanced Computational Intelligence Systems (CIS) for a morphing Unmanned Aerial Vehicle (UAV) aerofoil/wing shape design optimisation. The first CIS uses Genetic Algorithm (GA) and the second CIS uses Hybridized GA (HGA) with the concept of Nash-Equilibrium to speed up the optimisation process. During the optimisation, Nash-Game will act as a pre-conditioner. Both CISs; GA and HGA, are based on Pareto optimality and they are coupled to Euler based Computational Fluid Dynamic (CFD) analyser and one type of Computer Aided Design (CAD) system during the optimisation.

Cytokine synthesis by intestinal intraepithelial lymphocytes. Both gamma/delta T cell receptor-positive and alpha/beta T cell receptor-positive T cells in the G1 phase of cell cycle produce IFN-gamma and IL-5

Murine intestinal intraepithelial lymphocytes (IEL) have been shown to contain subsets of alpha/beta TCR+ and gamma/delta TCR+ T cells that spontaneously produce cytokines such as IFN-gamma and IL-5. We have now determined the nature and cell cycle stage of these cytokine-producing T lymphocytes in EIL by using IFN-gamma- and IL-5-specific ELISPOT assay, cytokine-specific mRNA-cDNA dot-blot hybridization and polymerase chain reaction, and flow cytometry (FACS) for DNA analysis. When CD3+ T cells from IEL of normal C3H/HeN mice were separated into low and high density fractions by discontinuous Percoll gradients, IFN-gamma and IL-5 spot-forming cells were only found in the former population. Analysis of mRNA for these cytokines by both IFN-gamma- and IL-5-specific dot-blot hybridization and polymerase chain reaction revealed that higher levels of message for IFN-gamma and IL-5 were also seen in the low density fraction. However, cell cycle analysis of these two fractions by FACS using propidium iodide showed a similar pattern of cell cycle stages in both low and high density populations (G0 + G1 approximately 96 to 98% and S/G2 + M approximately 2 to 4%). Finally, mRNA from gamma/delta TCR+ and alpha/beta TCR+ T cells in both low and high density fractions of IEL were analyzed for IFN-gamma and IL-5 message by polymerase chain reaction. After 35 cycles of amplification, both gamma/delta TCR+ and alpha/beta TCR+ T cells in the low density fraction expressed higher levels of message for these two cytokines when compared with the high density population. These results have now shown that both gamma/delta and alpha/beta TCR+ IEL can be separated into low and high density subsets and both fractions possess a similar stage of cell cycle. However, only the low density cells (in G1 phase) of both gamma/delta and alpha/beta TCR types possess increased cytokine-specific mRNA and produce the cytokines IFN-gamma and IL-5. Our results suggest that alpha/beta TCR+ and gamma/delta TCR+ IEL can produce cytokines without cell proliferation.

Time-varying bispectral analysis of visually evoked multi-channel EEG

Theoretical foundations of higher order spectral analysis are revisited to examine the use of time-varying bicoherence on non-stationary signals using a classical short-time Fourier approach. A methodology is developed to apply this to evoked EEG responses where a stimulus-locked time reference is available. Short-time windowed ensembles of the response at the same offset from the reference are considered as ergodic cyclostationary processes within a non-stationary random process. Bicoherence can be estimated reliably with known levels at which it is significantly different from zero and can be tracked as a function of offset from the stimulus. When this methodology is applied to multi-channel EEG, it is possible to obtain information about phase synchronization at different regions of the brain as the neural response develops. The methodology is applied to analyze evoked EEG response to flash visual stimulii to the left and right eye separately. The EEG electrode array is segmented based on bicoherence evolution with time using the mean absolute difference as a measure of dissimilarity. Segment maps confirm the importance of the occipital region in visual processing and demonstrate a link between the frontal and occipital regions during the response. Maps are constructed using bicoherence at bifrequencies that include the alpha band frequency of 8Hz as well as 4 and 20Hz. Differences are observed between responses from the left eye and the right eye, and also between subjects. The methodology shows potential as a neurological functional imaging technique that can be further developed for diagnosis and monitoring using scalp EEG which is less invasive and less expensive than magnetic resonance imaging.