Showing papers by "John F. Forbes published in 2004"
TL;DR: The data did not support the widespread use of thrombolytic therapy outside the terms of the current restricted license in routine clinical practice in the NHS and the estimates of effectiveness and cost-effectiveness were imprecise.
Abstract: Background and Purpose— Thrombolytic therapy is licensed for use in highly selected patients with acute ischemic stroke. We aimed to model the health economic impact of limited use of thrombolytic therapy and to assess whether it was likely to be cost-effective when used more widely in the UK National Health Service (NHS). Methods— The authors formed a discussion panel to develop the decision-analysis model of acute stroke care. It consisted of Markov state-transition processes, with probabilities of different health states determined by certain key variables. The range of estimates of efficacy of recombinant tissue plasminogen activator (rt-PA) was taken from an update to a Cochrane systematic review of randomized trials of thrombolysis. Data on outcome after stroke were taken from our hospital-based stroke register, supplemented by data derived from relevant literature sources. Results— The model suggested that compared with standard care, if eligible patients were treated with rt-PA up to 6 hours, ther...
120 citations
TL;DR: Results show that the MBSs required for trafficking are the same as those previously found essential for the copper transport function, suggesting similar mechanisms for trafficking between copper-transporting CPx-type ATPases.
Abstract: The Wilson protein (ATP7B) is a copper-transporting CPx-type ATPase defective in the copper toxicity disorder Wilson disease In hepatocytes, ATP7B delivers copper to apo-ceruloplasmin and mediates the excretion of excess copper into bile These distinct functions require the protein to localize at two different subcellular compartments At the trans-Golgi network, ATP7B transports copper for incorporation into apo-ceruloplasmin When intracellular copper levels are increased, ATP7B traffics to post-Golgi vesicles in close proximity to the canalicular membrane to facilitate biliary copper excretion In the present study, we investigated the role of the six N-terminal MBSs (metal-binding sites) in the trafficking process Using site-directed mutagenesis, we mutated or deleted various combinations of the MBSs and assessed the effect of these changes on the localization and trafficking of ATP7B Results show that the MBSs required for trafficking are the same as those previously found essential for the copper transport function Either MBS 5 or MBS 6 alone was sufficient to support the redistribution of ATP7B to vesicular compartments The first three N-terminal motifs were not required for copper-dependent intracellular trafficking and could not functionally replace sites 4-6 when placed in the same sequence position Furthermore, the N-terminal region encompassing MBSs 1-5 (amino acids 64-540) was not essential for trafficking, with only one MBS close to the membrane channel, necessary and sufficient to support trafficking Our findings were similar to those obtained for the closely related ATP7A protein, suggesting similar mechanisms for trafficking between copper-transporting CPx-type ATPases
113 citations
TL;DR: In this article, an approximate control law is developed to shape the probability density function (PDF) of a first-order stochastic process, by developing relationships between the moments of the PDF and the coefficients in a control law parameterization.
90 citations
Harvard University1, Cancer Council Australia2, University of Sydney3, University of Cape Town4, Mater Misericordiae Hospital5, University of Lausanne6, Royal Melbourne Hospital7, St. Vincent's Health System8, University of Gothenburg9, Kantonsspital St. Gallen10, University of Bern11, European Institute of Oncology12
TL;DR: Benefits evaluated by Q-TWiST favoured the additional chemotherapy, and analysis based on patient ratings is feasible in large-scale cross-cultural clinical trials.
Abstract: We evaluated quality of life (QL) and quality-adjusted survival in International Breast Cancer Study Group Trial IX, a randomised trial including 1669 eligible patients receiving tamoxifen for 5 years or three prior cycles of cyclophosphamide, methotrexate and 5-fluorouracil (CMF) followed by 57 months tamoxifen. During the time with CMF toxicity (Tox), without symptoms and toxicity (TWiST), and following relapse (Rel), patients scored their QL indicators and a utility indicator for subjective health estimation between 'perfect' and 'worst' health. Scores were averaged within Tox, TWiST and Rel and transformed to utilities. Mean durations for the three transition times were weighted with utilities to obtain mean quality-adjusted TWiST (Q-TWiST). Patients receiving CMF reported significantly worse scores for most QL domains at month 3, but less hot flushes. After completing chemotherapy, there were no differences by treatment groups. Benefits evaluated by Q-TWiST favoured the additional chemotherapy. CMF provided 3 more months of Q-TWiST for patients with ER-negative tumours, but CMF provided no benefit in Q-TWiST for patients with ER-positive tumours. Q-TWiST analysis based on patient ratings is feasible in large-scale cross-cultural clinical trials.
25 citations
TL;DR: In this paper, specific perturbations of the Cone of Feasible Directions are introduced as a tool to mitigate and analyze the effects of input data uncertainty on the solution of a given problem.
14 citations
TL;DR: The pronounced tumour:plasma ratio (mean 54-fold) was much higher than that from the mouse xenograft model, and gefitinib tumour concentrations will also be compared with the biomarker data as they become available.
Abstract: 581 Background: Gefitinib (‘Iressa’, ZD1839) has a high volume of distribution in animals and humans, with a volume of 1400 L in cancer patients. Consistent with these pharmacokinetic data, gefitinib is extensively distributed into the tissues of rats and mice, with tissue:blood ratios of >10 in a number of organs. Concentrations of gefitinib in mouse subcutaneous tumour xenografts (LoVo: colorectal; A549: non-small-cell lung cancer) are considerably higher (10–15-fold) than plasma. Concentrations of gefitinib have been determined in plasma and breast cancer tissue as a secondary endpoint in a study designed primarily to identify molecular alterations in human breast cancer tissue after short-term exposure of patients to gefitinib. Preliminary concentration data are reported here. Methods: BCIRG 103 is a multicentre, open-label, noncomparative, presurgical study in women with invasive adenocarcinoma of the breast. Patients receive gefitinib (250 mg) once daily for at least 14 days and up to a maximum of 4...
11 citations
02 Sep 2004
TL;DR: Feedback control laws are designed for continuous-time stochastic nonlinear processes so that the closed-loop system is indeed stationary with the PDF chosen in the control design.
Abstract: For the purposes of industrial control, it is often desirable that process variables remain near a set operating point over the long term. This type of long term process performance can be concisely summarized by the stationary probability density function (PDF). In this work, feedback control laws are designed for continuous-time stochastic nonlinear processes so that the closed-loop system is indeed stationary with the PDF chosen in the control design.
10 citations
01 Jan 2004
TL;DR: A modification of /spl mu/-interaction measure to assess the feasibility of decentralized stabilization with independent designs of loops and the results are useful for various purposes including designs of the process, control structure and optimal controller synthesis.
Abstract: This paper deals with input performance limitations of feedback control. The achievable input performance depends on the joint controllability and observability of unstable poles and is exactly quantified for single input single output (SISO) and multi input multi output (MIMO) systems with and without time delay. We also present a modification of /spl mu/-interaction measure to assess the feasibility of decentralized stabilization with independent designs of loops. The results are useful for various purposes including designs of the process, control structure and optimal controller synthesis.
7 citations
6 citations
01 Jan 2004
TL;DR: Two new local measure of nonlinearity are introduced to quantify the sensitivity of controller stability and performance for linear controllers operating on a nonlinear plant.
Abstract: Two new local measure of nonlinearity are introduced to quantify the sensitivity of controller stability and performance for linear controllers operating on a nonlinear plant. The measure quantifies the departures from optimality of locally linear quadratic regulators. In contrast to other nonlinearity measures, the measure applies generally to nonlinear systems that admit a controllable and observable linearization.
3 citations
TL;DR: Key factors affecting recruitment were infrastructure, coordination of publicity and centre performance, and Recruitment to BC prevention trials cannot rely on conventional medical sources.
Abstract: 1030 Background: IBIS 1 is a double-blind, randomised, placebo-controlled trial to evaluate tamoxifen (20 mg, o, daily, 5 years) in preventing breast cancer (BC) in healthy women aged 35–70 at increased risk of BC. Risk was based on family history (most) and high risk benign pathology. It was anticipated that recruitment needed to go beyond conventional medical sources. The trial was conducted by the ANZ BCTG in Australia and New Zealand. Methods: : A national Recruitment Coordinator developed strategies involving print and electronic media, medical sources (GP's, breast clinics, high-risk clinics and screening) and ‘word-of-mouth’ (BC patients, relatives). Monthly print media releases or Community Service Announcements (CSA's) on radio or TV were sent widely in Australia and New Zealand. A free call number was established for enquiries which were forwarded weekly to Study Coordinators (SC's) at 19 IBIS 1 centres. SC's responded to enquiries and determined eligibility. Results: Accrual targets were exceed...