Continuous Uniform Finite Time Stabilization of Planar Controllable Systems

Continuous homogeneous controllers are utilized in a full state feedback setting for the uniform finite time stabilization of a perturbed double integrator in the presence of uniformly decaying piecewise continuous disturbances. Semiglobal strong $\mathcal{C}^1$ Lyapunov functions are identified to establish uniform asymptotic stability of the closed-loop planar system. Uniform finite time stability is then proved by extending the homogeneity principle of discontinuous systems to the continuous case with uniformly decaying piecewise continuous nonhomogeneous disturbances. A finite upper bound on the settling time is also computed. The results extend the existing literature on homogeneity and finite time stability by both presenting uniform finite time stabilization and dealing with a broader class of nonhomogeneous disturbances for planar controllable systems while also proposing a new class of homogeneous continuous controllers

On the Absorption of X-rays in the Interstellar Medium

We present an improved model for the absorption of X-rays in the ISM intended for use with data from future X-ray missions with larger effective areas and increased energy resolution such as Chandra and XMM, in the energy range above 100eV. Compared to previous work, our formalism includes recent updates to the photoionization cross section and revised abundances of the interstellar medium, as well as a treatment of interstellar grains and the H2molecule. We review the theoretical and observational motivations behind these updates and provide a subroutine for the X-ray spectral analysis program XSPEC that incorporates our model.Comment: ApJ, in press, for associated software see http://astro.uni-tuebingen.de/nh

Evaluation of Chitosans as Coagulants—Flocculants to Improve Sand Filtration for Drinking Water Treatment

The World Health Organization (WHO) reports that two billion people worldwide lack access to safely managed water sources, including 1.2 billion who already have access to improved water sources. In many countries, household point-of-use (POU) water-treatment options are used to remove or deactivate microorganisms in water, but not all POU technologies meet WHO performance requirements to achieve safe drinking water. To improve the effectiveness of POU technologies, the use of multiple treatment barriers should be used as a way to increase overall treatment performance. The focus of this research is to evaluate multiple barrier treatment using chitosan, an organic coagulant–flocculant, to improve microbial and turbidity reductions in combination with sand filtration. Bench-scale intermittently operated sand filters with 16 cm layers of sands of two different grain sizes representing slow and rapid sand filters were dosed daily over 57 days with microbially spiked surface water volumes corresponding to household use. E. coli bacteria and MS2 coliphage virus reductions were quantified biweekly (N = 17) using culture methods. Bacteria and virus removals were significantly improved over sand filtration without chitosan pretreatment (Wilcoxon Rank-Sum, p < 0.05). When water was pretreated at an optimal chitosan dose of 10 mg/L followed by sand filtration, log10 reductions in bacteria and viruses met the two-star WHO performance level of effectiveness. Microbial and turbidity reductions generally improved over the filter operating period but showed no trends with filtration rates

Mathematical modelling of polyamine metabolism in bloodstream-form trypanosoma brucei: An application to drug target identification

© 2013 Gu et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are creditedThis article has been made available through the Brunel Open Access Publishing Fund.We present the first computational kinetic model of polyamine metabolism in bloodstream-form Trypanosoma brucei, the causative agent of human African trypanosomiasis. We systematically extracted the polyamine pathway from the complete metabolic network while still maintaining the predictive capability of the pathway. The kinetic model is constructed on the basis of information gleaned from the experimental biology literature and defined as a set of ordinary differential equations. We applied Michaelis-Menten kinetics featuring regulatory factors to describe enzymatic activities that are well defined. Uncharacterised enzyme kinetics were approximated and justified with available physiological properties of the system. Optimisation-based dynamic simulations were performed to train the model with experimental data and inconsistent predictions prompted an iterative procedure of model refinement. Good agreement between simulation results and measured data reported in various experimental conditions shows that the model has good applicability in spite of there being gaps in the required data. With this kinetic model, the relative importance of the individual pathway enzymes was assessed. We observed that, at low-to-moderate levels of inhibition, enzymes catalysing reactions of de novo AdoMet (MAT) and ornithine production (OrnPt) have more efficient inhibitory effect on total trypanothione content in comparison to other enzymes in the pathway. In our model, prozyme and TSHSyn (the production catalyst of total trypanothione) were also found to exhibit potent control on total trypanothione content but only when they were strongly inhibited. Different chemotherapeutic strategies against T. brucei were investigated using this model and interruption of polyamine synthesis via joint inhibition of MAT or OrnPt together with other polyamine enzymes was identified as an optimal therapeutic strategy.The work was carried out under a PhD programme partly funded by Prof. Ray Welland, School of Computing Science, University of Glasgo

Excess mortality among the elderly in 12 European countries, February and March 2012

In February and March 2012, excess deaths among the elderly have been observed in 12 European countries that carry out weekly monitoring of all-cause mortality. These preliminary data indicate that the impact of influenza in Europe differs from the recent pandemic and post-pandemic seasons. The current excess mortality among the elderly may be related to the return of influenza A(H3N2) virus, potentially with added effects of a cold snap

Pooling European all-cause mortality: methodology and findings for the seasons 2008/2009 to 2010/2011

Several European countries have timely all-cause mortality monitoring. However, small changes in mortality may not give rise to signals at the national level. Pooling data across countries may overcome this, particularly if changes in mortality occur simultaneously. Additionally, pooling may increase the power of monitoring populations with small numbers of expected deaths, e.g. younger age groups or fertile women. Finally, pooled analyses may reveal patterns of diseases across Europe. We describe a pooled analysis of all-cause mortality across 16 European countries. Two approaches were explored. In the ‘summarized' approach, data across countries were summarized and analysed as one overall country. In the ‘stratified' approach, heterogeneities between countries were taken into account. Pooling using the ‘stratified' approach was the most appropriate as it reflects variations in mortality. Excess mortality was observed in all winter seasons albeit slightly higher in 2008/09 than 2009/10 and 2010/11. In the 2008/09 season, excess mortality was mainly in elderly adults. In 2009/10, when pandemic influenza A(H1N1) dominated, excess mortality was mainly in children. The 2010/11 season reflected a similar pattern, although increased mortality in children came later. These patterns were less clear in analyses based on data from individual countries. We have demonstrated that with stratified pooling we can combine local mortality monitoring systems and enhance monitoring of mortality across Europ

RAMPART: A model for a regulatory-ready academic-led phase III trial in the adjuvant renal cell carcinoma setting

The development of therapeutics in oncology is a highly active research area for the pharmaceutical and biotechnology industries, but also has a strong academic base. Many new agents have been developed in recent years, most with specific biological targets. This has mandated the need to look at different ways to streamline the evaluation of new agents. One solution has been the development of adaptive trial designs that allow the evaluation of multiple agents, concentrating on the most promising agents while screening out those which are unlikely to benefit patients. Another way forward has been the growth of partnerships between academia and industry with the shared goal of designing and conducting high quality clinical trials which answer important clinical questions as efficiently as possible. The RAMPART trial (NCT03288532) brings together both of these processes in an attempt to improve outcomes for patients with locally advanced renal cell carcinoma (RCC), where no globally acceptable adjuvant strategy after nephrectomy currently exist. RAMPART is led by the MRC CTU at University College London (UCL), in collaboration with other international academic groups and industry. We aim to facilitate the use of data from RAMPART, (dependent on outcomes), for a future regulatory submission that will extend the license of the agents being investigated. We share our experience in order to lay the foundations for an effective trial design and conduct framework and to guide others who may be considering similar collaborations

RAMPART: A phase III multi-arm multi-stage trial of adjuvant checkpoint inhibitors in patients with resected primary renal cell carcinoma (RCC) at high or intermediate risk of relapse

Background: 20–60% of patients with initially locally advanced Renal Cell Carcinoma (RCC) develop metastatic disease despite optimal surgical excision. Adjuvant strategies have been tested in RCC including cytokines, radiotherapy, hormones and oral tyrosine-kinase inhibitors (TKIs), with limited success. The predominant global standard-of-care after nephrectomy remains active monitoring. Immune checkpoint inhibitors (ICIs) are effective in the treatment of metastatic RCC; RAMPART will investigate these agents in the adjuvant setting. // Methods/design: RAMPART is an international, UK-led trial investigating the addition of ICIs after nephrectomy in patients with resected locally advanced RCC. RAMPART is a multi-arm multi-stage (MAMS) platform trial, upon which additional research questions may be addressed over time. The target population is patients with histologically proven resected locally advanced RCC (clear cell and non-clear cell histological subtypes), with no residual macroscopic disease, who are at high or intermediate risk of relapse (Leibovich score 3–11). Patients with fully resected synchronous ipsilateral adrenal metastases are included. Participants are randomly assigned (3,2:2) to Arm A - active monitoring (no placebo) for one year, Arm B - durvalumab (PD-L1 inhibitor) 4-weekly for one year; or Arm C - combination therapy with durvalumab 4-weekly for one year plus two doses of tremelimumab (CTLA-4 inhibitor) at day 1 of the first two 4-weekly cycles. The co-primary outcomes are disease-free-survival (DFS) and overall survival (OS). Secondary outcomes include safety, metastasis-free survival, RCC specific survival, quality of life, and patient and clinician preferences. Tumour tissue, plasma and urine are collected for molecular analysis (TransRAMPART)

Continuation for thin film hydrodynamics and related scalar problems

This chapter illustrates how to apply continuation techniques in the analysis of a particular class of nonlinear kinetic equations that describe the time evolution through transport equations for a single scalar field like a densities or interface profiles of various types. We first systematically introduce these equations as gradient dynamics combining mass-conserving and nonmass-conserving fluxes followed by a discussion of nonvariational amendmends and a brief introduction to their analysis by numerical continuation. The approach is first applied to a number of common examples of variational equations, namely, Allen-Cahn- and Cahn-Hilliard-type equations including certain thin-film equations for partially wetting liquids on homogeneous and heterogeneous substrates as well as Swift-Hohenberg and Phase-Field-Crystal equations. Second we consider nonvariational examples as the Kuramoto-Sivashinsky equation, convective Allen-Cahn and Cahn-Hilliard equations and thin-film equations describing stationary sliding drops and a transversal front instability in a dip-coating. Through the different examples we illustrate how to employ the numerical tools provided by the packages auto07p and pde2path to determine steady, stationary and time-periodic solutions in one and two dimensions and the resulting bifurcation diagrams. The incorporation of boundary conditions and integral side conditions is also discussed as well as problem-specific implementation issues

Rucaparib maintenance treatment for recurrent ovarian carcinoma after response to platinum therapy (ARIEL3): a randomised, double-blind, placebo-controlled, phase 3 trial

Background: Rucaparib, a poly(ADP-ribose) polymerase inhibitor, has anticancer activity in recurrent ovarian carcinoma harbouring a BRCA mutation or high percentage of genome-wide loss of heterozygosity. In this trial we assessed rucaparib versus placebo after response to second-line or later platinum-based chemotherapy in patients with high-grade, recurrent, platinum-sensitive ovarian carcinoma. Methods: In this randomised, double-blind, placebo-controlled, phase 3 trial, we recruited patients from 87 hospitals and cancer centres across 11 countries. Eligible patients were aged 18 years or older, had a platinum-sensitive, high-grade serous or endometrioid ovarian, primary peritoneal, or fallopian tube carcinoma, had received at least two previous platinum-based chemotherapy regimens, had achieved complete or partial response to their last platinum-based regimen, had a cancer antigen 125 concentration of less than the upper limit of normal, had a performance status of 0–1, and had adequate organ function. Patients were ineligible if they had symptomatic or untreated central nervous system metastases, had received anticancer therapy 14 days or fewer before starting the study, or had received previous treatment with a poly(ADP-ribose) polymerase inhibitor. We randomly allocated patients 2:1 to receive oral rucaparib 600 mg twice daily or placebo in 28 day cycles using a computer-generated sequence (block size of six, stratified by homologous recombination repair gene mutation status, progression-free interval after the penultimate platinum-based regimen, and best response to the most recent platinum-based regimen). Patients, investigators, site staff, assessors, and the funder were masked to assignments. The primary outcome was investigator-assessed progression-free survival evaluated with use of an ordered step-down procedure for three nested cohorts: patients with BRCA mutations (carcinoma associated with deleterious germline or somatic BRCA mutations), patients with homologous recombination deficiencies (BRCA mutant or BRCA wild-type and high loss of heterozygosity), and the intention-to-treat population, assessed at screening and every 12 weeks thereafter. This trial is registered with ClinicalTrials.gov, number NCT01968213; enrolment is complete. Findings: Between April 7, 2014, and July 19, 2016, we randomly allocated 564 patients: 375 (66%) to rucaparib and 189 (34%) to placebo. Median progression-free survival in patients with a BRCA-mutant carcinoma was 16·6 months (95% CI 13·4–22·9; 130 [35%] patients) in the rucaparib group versus 5·4 months (3·4–6·7; 66 [35%] patients) in the placebo group (hazard ratio 0·23 [95% CI 0·16–0·34]; p&lt;0·0001). In patients with a homologous recombination deficient carcinoma (236 [63%] vs 118 [62%]), it was 13·6 months (10·9–16·2) versus 5·4 months (5·1–5·6; 0·32 [0·24–0·42]; p&lt;0·0001). In the intention-to-treat population, it was 10·8 months (8·3–11·4) versus 5·4 months (5·3–5·5; 0·36 [0·30–0·45]; p&lt;0·0001). Treatment-emergent adverse events of grade 3 or higher in the safety population (372 [99%] patients in the rucaparib group vs 189 [100%] in the placebo group) were reported in 209 (56%) patients in the rucaparib group versus 28 (15%) in the placebo group, the most common of which were anaemia or decreased haemoglobin concentration (70 [19%] vs one [1%]) and increased alanine or aspartate aminotransferase concentration (39 [10%] vs none). Interpretation: Across all primary analysis groups, rucaparib significantly improved progression-free survival in patients with platinum-sensitive ovarian cancer who had achieved a response to platinum-based chemotherapy. ARIEL3 provides further evidence that use of a poly(ADP-ribose) polymerase inhibitor in the maintenance treatment setting versus placebo could be considered a new standard of care for women with platinum-sensitive ovarian cancer following a complete or partial response to second-line or later platinum-based chemotherapy. Funding: Clovis Oncology