Projecting prevalence by stage of care for prostate cancer and estimating future health service needs: protocol for a modelling study

Introduction Current strategies for the management of prostate cancer are inadequate in Australia. We will, in this study, estimate current service needs and project the future needs for prostate cancer patients in Australia. Methods and analysis First, we will project the future prevalence of prostate cancer for 2010-2018 using data for 1972-2008 from the New South Wales (NSW) Central Cancer Registry. These projections, based on modelled incidence and survival estimates, will be estimated using PIAMOD (Prevalence, Incidence, Analysis MODel) software. Then the total prevalence will be decomposed into five stages of care: initial care, continued monitoring, recurrence, last year of life and long-term survivor. Finally, data from the NSW Prostate Cancer Care and Outcomes Study, including data on patterns of treatment and associated quality of life, will be used to estimate the type and amount of services that will be needed by prostate cancer patients in each stage of care. In addition, Central Cancer Registry episode data will be used to estimate transition rates from localised or locally advanced prostate cancer to metastatic disease. Medicare and Pharmaceutical Benefits data, linked with Prostate Cancer Care and Outcomes Study data, will be used to complement the Cancer Registry episode data. The methods developed will be applied Australia-wide to obtain national estimates of the future prevalence of prostate cancer for different stages of clinical care. Ethics and dissemination This study was approved by the NSW Population and Health Services Research Ethics Committee. Results of the study will be disseminated widely to different interest groups and organisations through a report, conference presentations and peer-reviewed articles.This work is supported by the Prostate Cancer Foundation of Australia (grant number: PCFA – YI 0410). Both David Smith and Xue Qin Yu are supported by an Australian NHMRC Training Fellowship (Ref 1016598, 550002). Mark Clements is supported by an Australian NHMRC Career Development Award (Ref 471491)

Antitubercular specific activity of ibuprofen and the other 2-arylpropanoic acids using the HT-SPOTi whole-cell phenotypic assay

Objectives: Lead antituberculosis (anti-TB) molecules with novel mechanisms of action are urgently required to fuel the anti-TB drug discovery pipeline. The aim of this study was to validate the use of the high-throughput spot culture growth inhibition (HT-SPOTi) assay for screening libraries of compounds against Mycobacterium tuberculosis and to study the inhibitory effect of ibuprofen (IBP) and the other 2-arylpropanoic acids on the growth inhibition of M tuberculosis and other mycobacterial species. Methods: The HT-SPOTi method was validated not only with known drugs but also with a library of 47 confirmed anti-TB active compounds published in the ChEMBL database. Three over-the-counter non-steroidal anti-inflammatory drugs were also included in the screening. The 2-arylpropanoic acids, including IBP, were comprehensively evaluated against phenotypically and physiologically different strains of mycobacteria, and their cytotoxicity was determined against murine RAW264.7 macrophages. Furthermore, a comparative bioinformatic analysis was employed to propose a potential mycobacterial target. Results: IBP showed antitubercular properties while carprofen was the most potent among the 2-arylpropanoic class. A 3,5-dinitro-IBP derivative was found to be more potent than IBP but equally selective. Other synthetic derivatives of IBP were less active, and the free carboxylic acid of IBP seems to be essential for its anti-TB activity. IBP, carprofen and the 3,5-dinitro-IBP derivative exhibited activity against multidrug-resistant isolates and stationary phase bacilli. On the basis of the human targets of the 2-arylpropanoic analgesics, the protein initiation factor infB (Rv2839c) of M tuberculosis was proposed as a potential molecular target. Conclusions: The HT-SPOTi method can be employed reliably and reproducibly to screen the antimicrobial potency of different compounds. IBP demonstrated specific antitubercular activity, while carprofen was the most selective agent among the 2-arylpropanoic class. Activity against stationary phase bacilli and multidrug-resistant isolates permits us to speculate a novel mechanism of antimycobacterial action. Further medicinal chemistry and target elucidation studies could potentially lead to new therapies against TB

Thin film dielectric microstrip kinetic inductance detectors

Microwave Kinetic Inductance Detectors, or MKIDs, are a type of low temperature detector that exhibit intrinsic frequency domain multiplexing at microwave frequencies. We present the first theory and measurements on a MKID based on a microstrip transmission line resonator. A complete characterization of the dielectric loss and noise properties of these resonators is performed, and agrees well with the derived theory. A competitive noise equivalent power of 5$\times10^{-17}$ W Hz$^{-1/2}$ at 1 Hz has been demonstrated. The resonators exhibit the highest quality factors known in a microstrip resonator with a deposited thin film dielectric.Comment: 10 pages, 4 figures, APL accepte

Understanding Transdisciplinary Engineering in Public Policy: A Survey of Policy Actors' Perceptions of Engineering Expertise

The transdisciplinary engineering project aims to transform the practice of engineering for more social benefit, and be agenda driven. For this to work, a key community of non-engineering actors needs to be effectively engaged: those working in public policy. Through data gathered for a project exploring interested in a career development scheme for policy officials offered by the UK's Royal Academy of Engineering, we explore the opportunities and barriers to better engagement between engineering and this community. An explorative online survey with policy actors gathered views on the importance of (non-transdisciplinary) engineering to policy in different policy settings. While those who regard technical expertise as crucial to their policy are keen to engage with engineering, others find it more difficult to engage. We suggest this is down to three factors: narrowness in what ‘engineering' is (so a failure to understand the ability to apply engineering concepts, e.g. systems thinking, in a variety of areas); organisational arrangements that split policy practice that might more readily connect to engineering from those who do policy design; policy analysis rooted in standard microeconomic forms of analysis. We suggest ways in which these issues might be addressed through education and research to enable the effective deployment of transdisciplinary engineering practice

Stochastic Background Search Correlating ALLEGRO with LIGO Engineering Data

We describe the role of correlation measurements between the LIGO interferometer in Livingston, LA, and the ALLEGRO resonant bar detector in Baton Rouge, LA, in searches for a stochastic background of gravitational waves. Such measurements provide a valuable complement to correlations between interferometers at the two LIGO sites, since they are sensitive in a different, higher, frequency band. Additionally, the variable orientation of the ALLEGRO detector provides a means to distinguish gravitational wave correlations from correlated environmental noise. We describe the analysis underway to set a limit on the strength of a stochastic background at frequencies near 900 Hz using ALLEGRO data and data from LIGO's E7 Engineering Run.Comment: 8 pages, 2 encapsulated PostScript figures, uses IOP class files, submitted to the proceedings of the 7th Gravitational Wave Data Analysis Workshop (which will be published in Classical and Quantum Gravity

Can Weakness in End-Range Plantar Flexion After Achilles Tendon Repair Be Prevented?

Background: Disproportionate end-range plantar flexion weakness, decreased passive stiffness, and inability to perform a heel rise on a decline after Achilles tendon repair are thought to reflect increased tendon compliance or tendon lengthening. Since this was first noted, we have performed stronger repairs and avoided stretching into dorsiflexion for the first 12 weeks after surgery. Hypothesis: Using stronger repairs and avoiding stretching into dorsiflexion would eliminate end-range plantar flexion weakness and normalize passive stiffness. Study Design: Case series; Level of evidence, 4. Methods: Achilles repairs with epitendinous augmentation were performed on 18 patients. Plantar flexion torque, dorsiflexion range of motion (ROM), passive joint stiffness, and standing single-legged heel rise on a decline were assessed at 43 ± 24 months after surgery (range, 9 months to 8 years). Maximum isometric plantar flexion torque was measured at 20° and 10° of dorsiflexion, neutral position, and 10° and 20° of plantar flexion. Passive dorsiflexion ROM was measured with a goniometer. Passive joint stiffness was computed from the increase in passive torque from 10° to 20° of dorsiflexion. Tendon thickness was measured by use of digital calipers. Plantar flexion electromyographic (EMG) data were recorded during strength and functional tests. Analysis of variance and chi-square tests were used to assess weakness and function. Results: Marked weakness was evident on the involved side at 20° of plantar flexion (deficit, 26% ± 18%; Conclusion: The use of stronger repair techniques and attempts to limit tendon elongation by avoiding dorsiflexion stretching did not eliminate weakness in end-range plantar flexion. EMG data confirmed that end-range weakness was not due to neural inhibition. Physiological changes that alter the force transmission capability of the healing tendon may be responsible for this continued impairment. This weakness has implications for high-demand jumping and sprinting after Achilles tendon repair

Fluid properties at high pressures and temperatures: Experimental and modelling challenges

Thermophysical properties impact many aspects of the chemical process industries. Here three example areas, primarily in the energy sector, are highlighted to provide context for the experimental and modelling challenges associated with obtaining fluid property data at high pressures and temperatures (HPHT). These three areas include the recovery of petroleum reserves in ultra-deep reservoirs, the use of lubricants to reduce frictional losses in the automotive industries, and the use of high-pressure, common rail diesel fuel delivery to reduce soot emissions for greener environments. The accurate knowledge of thermodynamic and transport properties in these three focused areas minimizes associated operating uncertainties and accelerates safe, reliable, and robust process and product development

Conserved active site cysteine residue of archaeal THI4 homolog is essential for thiamine biosynthesis in Haloferax volcanii

Background: Thiamine (vitamin B1) is synthesized de novo by certain yeast, fungi, plants, protozoans, bacteria and archaea. The pathway of thiamine biosynthesis by archaea is poorly understood, particularly the route of sulfur relay to form the thiazole ring. Archaea harbor structural homologs of both the bacterial (ThiS-ThiF) and eukaryotic (THI4) proteins that mobilize sulfur to thiazole ring precursors by distinct mechanisms. Results: Based on comparative genome analysis, halophilic archaea are predicted to synthesize the pyrimidine moiety of thiamine by the bacterial pathway, initially suggesting that also a bacterial ThiS-ThiF type mechanism for synthesis of the thiazole ring is used in which the sulfur carrier ThiS is first activated by ThiF-catalyzed adenylation. The only ThiF homolog of Haloferax volcanii (UbaA) was deleted but this had no effect on growth in the absence of thiamine. Usage of the eukaryotic THI4-type sulfur relay was initially considered less likely for thiamine biosynthesis in archaea, since the active-site cysteine residue of yeast THI4p that donates the sulfur to the thiazole ring by a suicide mechanism is replaced by a histidine residue in many archaeal THI4 homologs and these are described as D-ribose-1,5-bisphosphate isomerases. The THI4 homolog of the halophilic archaea, including Hfx. volcanii (HVO_0665, HvThi4) was found to differ from that of methanogens and thermococci by having a cysteine residue (Cys165) corresponding to the conserved active site cysteine of yeast THI4p (Cys205). Deletion of HVO_0665 generated a thiamine auxotroph that was trans-complemented by a wild-type copy of HVO_0665, but not the modified gene encoding an HvThi4 C165A variant. Conclusions: Based on our results, we conclude that the archaeon Hfx. volcanii uses a yeast THI4-type mechanism for sulfur relay to form the thiazole ring of thiamine. We extend this finding to a relatively large group of archaea, including haloarchaea, ammonium oxidizing archaea, and some methanogen and Pyrococcus species, by observing that these organisms code for THI4 homologs that have a conserved active site cysteine residue which is likely used in thiamine biosynthesis. Thus, archaeal members of IPR002922 THI4 family that have a conserved cysteine active site should be reexamined for a function in thiamine biosynthesis

Role of pharmacogenetics in rifampicin pharmacokinetics and the potential effect on TB–rifampicin sensitivity among Ugandan patients

BACKGROUND: Suboptimal anti-TB drugs exposure may cause multidrug-resistant TB. The role of African predominant SLCO1B1 variant alleles on rifampicin pharmacokinetics and the subsequent effect on the occurrence of Mycobacterium tuberculosis-rifampicin sensitivity needs to be defined. We describe the rifampicin population pharmacokinetics profile and investigate the relevance of SLCO1B1 genotypes to rifampicin pharmacokinetics and rifampicin-TB sensitivity status. METHODS: Fifty patients with TB (n=25 with rifampicin-resistant TB and n=25 with rifampicin-susceptible TB) were genotyped for SLOC1B1 rs4149032 (g.38664C>T), SLOC1B1*1B (c.388A>G) and SLOC1B1*5 (c.521 T>C). Steady state plasma rifampicin levels were determined among patients infected with rifampicin-sensitive TB. Data were analysed using NONMEM to estimate population rifampicin pharmacokinetics as well as the effect of SLOC1B1 genotypes on rifampicin pharmacokinetics and on rifampicin-TB sensitivity status. RESULTS: Overall allele frequencies of SLOC1B1 rs4149032, *1B and *5 were 0.66, 0.90 and 0.01, respectively. Median (IQR) Cmax and Tmax were 10.2 (8.1-12.5) mg/L and 1.7 (1.125-2.218) h, respectively. Twenty-four percent of patients exhibited Cmax below the recommended 8-24 mg/L range. SLOC1B1 genotypes, gender and age did not influence rifampicin pharmacokinetics or TB-rifampicin sensitivity. CONCLUSIONS: Although SLOC1B1 genotype, age and gender do not influence either rifampicin pharmacokinetics or rifampicin-TB sensitivity status, one in every four Ugandan TB patients achieve subtherapeutic plasma rifampicin concentrations