The placebo response in trials of drug treatments for cancer-related fatigue: A systematic review, meta-analysis and meta-regression

Background: Cancer-related fatigue (CRF) is one of the most distressing symptoms experienced by patients. There is no gold standard treatment, although multiple drugs have been tested with little evidence of efficacy. Randomised controlled trials (RCTs) of these drugs have commented on the existence or size of the placebo response (PR). The objective of this systematic review was to establish the magnitude of the PR in RCTs of drugs to relieve CRF and to identify contributing factors. Method: RCTs were included in which the objective was to treat CRF. A meta-analysis was conducted using the standardised mean change (SMC) between baseline and final measurement in the placebo group. To explore factors that may be associated with the PR (eg, population or drug), a meta-regression was undertaken. Risk of bias was assessed using the revised Cochrane tool. Results: From 3916 citations, 30 relevant RCTs were identified. All had limitations that increased their risk of bias. The pooled SMC in reduction in fatigue status in placebo groups was −0.23 (95% confidence intervals −0.42 to −0.04). None of the variables analysed in the meta-regression were statistically significant related to PR. Conclusion: There is some evidence, based on trials with small samples, that the PR in trials testing drugs for CRF is non-trivial in size and statistically significant. We recommend that researchers planning drug studies in CRF should consider implementing alternative trial designs to better account for PR and decrease impact on the study results

Does current UK research address priorities in palliative and end-of-life care?

The Palliative and end of life care Priority Setting Partnership uncovered 83 unanswered research questions. Florence Todd Fordham, Bridget Candy, Stevie McMillan and Sabine Best show that, as current UK research starts to address some of these questions, UK open grant data have the potential to encourage collaboratio

Molecular Evolutionary Analysis of the Thiamine-Diphosphate-Dependent Enzyme, Transketolase

Members of the transketolase group of thiamine- diphosphate-dependent enzymes from 17 different organisms including mammals, yeast, bacteria, and plants have been used for phylogenetic reconstruction. Alignment of the amino acid and DNA sequences for 21 transketolase enzymes and one putative transketolase reveals a number of highly conserved regions and invariant residues that are of predicted importance for enzyme activity, based on the crystal structure of yeast transketolase. One particular sequence of 36 residues has some similarities to the nucleotide-binding motif and we designate it as the transketolase motif. We report further evidence that the recP protein from Streptococcus pneumoniae might be a transketolase and we list a number of invariant residues which might be involved in substrate binding. Phylogenies derived from the nucleotide and the amino acid sequences by various methods show a conventional clustering for mammalian, plant, and gramnegative bacterial transketolases. The branching order of the gram-positive bacteria could not be inferred reliably. The formaldehyde transketolase (sometimes known as dihydroxyacetone synthase) of the yeast Hansenula polymorpha appears to be orthologous to the mammalian enzymes but paralogous to the other yeast transketolases. The occurrence of more than one transketolase gene in some organisms is consistent with several gene duplications. The high degree of similarity in functionally important residues and the fact that the same kinetic mechanism is applicable to all characterized transketolase enzymes is consistent with the proposition that they are all derived from one common ancestral gene. Transketolase appears to be an ancient enzyme that has evolved slowly and might serve as a model for a molecular clock, at least within the mammalian clade

Molecular Evolutionary Analysis of the Thiamine-Diphosphate-Dependent Enzyme, Transketolase

Members of the transketolase group of thiamine- diphosphate-dependent enzymes from 17 different organisms including mammals, yeast, bacteria, and plants have been used for phylogenetic reconstruction. Alignment of the amino acid and DNA sequences for 21 transketolase enzymes and one putative transketolase reveals a number of highly conserved regions and invariant residues that are of predicted importance for enzyme activity, based on the crystal structure of yeast transketolase. One particular sequence of 36 residues has some similarities to the nucleotide-binding motif and we designate it as the transketolase motif. We report further evidence that the recP protein from Streptococcus pneumoniae might be a transketolase and we list a number of invariant residues which might be involved in substrate binding. Phylogenies derived from the nucleotide and the amino acid sequences by various methods show a conventional clustering for mammalian, plant, and gramnegative bacterial transketolases. The branching order of the gram-positive bacteria could not be inferred reliably. The formaldehyde transketolase (sometimes known as dihydroxyacetone synthase) of the yeast Hansenula polymorpha appears to be orthologous to the mammalian enzymes but paralogous to the other yeast transketolases. The occurrence of more than one transketolase gene in some organisms is consistent with several gene duplications. The high degree of similarity in functionally important residues and the fact that the same kinetic mechanism is applicable to all characterized transketolase enzymes is consistent with the proposition that they are all derived from one common ancestral gene. Transketolase appears to be an ancient enzyme that has evolved slowly and might serve as a model for a molecular clock, at least within the mammalian clade

Direct multiscale coupling of a transport code to gyrokinetic turbulence codes

Direct coupling between a transport solver and local, nonlinear gyrokinetic calculations using the multiscale gyrokinetic code TRINITY [M. Barnes, Ph.D. thesis, arxiv:0901.2868] is described. The coupling of the microscopic and macroscopic physics is done within the framework of multiscale gyrokinetic theory, of which we present the assumptions and key results. An assumption of scale separation in space and time allows for the simulation of turbulence in small regions of the space-time grid, which are embedded in a coarse grid on which the transport equations are implicitly evolved. This leads to a reduction in computational expense of several orders of magnitude, making first-principles simulations of the full fusion device volume over the confinement time feasible on current computing resources. Numerical results from TRINITY simulations are presented and compared with experimental data from JET and ASDEX Upgrade plasmas.Comment: 12 pages, 13 figures, invited paper for 2009 APS-DPP meeting, submitted to Phys. Plasma

ANALISIS KEUNTUNGAN USAHA TERNAK BABI DI KECAMATAN TOMOHON BARAT KOTA TOMOHON (Studi Kasus Pada Usaha Milik Bapak Okny Mende)

PROFIT ANALYSIS OF PIG FARMING IN WEST TOMOHON DISTRICT TOMOHON CITY. (Case Study On Mr. Okny Mende's Business. The goal of this study was to investigate profit  of pig farming  in West Tomohon  District Survey method was performed on Mr Okny Mende’s farming  in Tara Tara 2 Village West Tomohon District bycase study. The pig farmers’ challenge in the production process was the high cost of production. The increase of cost  production without profit tend to be problem for farmers because input material (production costs) was very important factors in the livestock business. The Pig farming business has the potential for development in the City of Tomohon due to investment in this business does not require large costs and land, besides that the return on capital is relatively faster and although the development of pig agribusiness is limited due to socio-cultural factors, but in North Sulawesi especially Tomohon City has good prospects because of high demand of local market and the surrounding area, and there are no socio-cultural constraints. The pig farm business located in Taratara Dua Sub-District, West Tomohon District is owned by Mr. Okny Mende's family, which is a nursery business by selling weaned piglets. Results of this study  shown that the average total cost incurred per period of production  as much as IDR  38.334.531. While revenue per period of production was IDR. 68.400.000. The profit per production period was IDR. 30.065.469

Genetic and cellular studies highlight that A Disintegrin and Metalloproteinase 19 is a protective biomarker in human prostate cancer

Background: Prostate cancer is the second most frequently diagnosed cancer in men worldwide. Current treatments include surgery, androgen ablation and radiation. Introduction of more targeted therapies in prostate cancer, based on a detailed knowledge of the signalling pathways, aims to reduce side effects, leading to better clinical outcomes for the patient. ADAM19 (A Disintegrin And Metalloproteinase 19) is a transmembrane and soluble protein which can regulate cell phenotype through cell adhesion and proteolysis. ADAM19 has been positively associated with numerous diseases, but has not been shown to be a tumor suppressor in the pathogenesis of any human cancers. Our group sought to investigate the role of ADAM19 in human prostate cancer. Methods: ADAM19 mRNA and protein levels were assessed in well characterised human prostate cancer cohorts. ADAM19 expression was assessed in normal prostate epithelial cells (RWPE-1) and prostate cancer cells (LNCaP, PC3) using western blotting and immunocytochemistry. Proliferation assays were conducted in LNCaP cells in which ADAM19 was over-expressed. In vitro scratch assays were performed in PC3 cells over-expressing ADAM19. Results: Immunohistochemical studies highlighted that ADAM19 protein levels were elevated in normal prostate tissue compared to prostate cancer biopsies. Results from the clinical cohorts demonstrated that high levels of ADAM19 in microarrays are positively associated with lower stage (p = 0.02591) and reduced relapse (p = 0.00277) of human prostate cancer. In vitro, ADAM19 expression was higher in RWPE-1 cells compared to LNCaP cells. In addition, human ADAM19 over-expression reduced LNCaP cell proliferation and PC3 cell migration. Conclusions: Taken together, our immunohistochemical and microarray results and cellular studies have shown for the first time that ADAM19 is a protective factor for human prostate cancer. Further, this study suggests that upregulation of ADAM19 expression could be of therapeutic potential in human prostate cancer

Elevating zero dimensional global scaling predictions to self-consistent theory-based simulations

We have developed an innovative workflow, STEP-0D, within the OMFIT integrated modelling framework. Through systematic validation against the International Tokamak Physics Activity (ITPA) global H-mode confinement database, we demonstrated that STEP-0D, on average, predicts the energy confinement time with a mean relative error (MRE) of less than 19%. Moreover, this workflow showed promising potential in predicting plasmas for proposed fusion reactors such as ARC, EU-DEMO, and CFETR, indicating moderate H-factors between 0.9 and 1.2. STEP-0D allows theory-based prediction of tokamak scenarios, beginning with zero-dimensional (0D) quantities. The workflow initiates with the PRO-create module, generating physically consistent plasma profiles and equilibrium using the same 0D quantities as the IPB98(y,2) confinement scaling. This sets the starting point for the STEP (Stability, Transport, Equilibrium, and Pedestal) module, which further iterates between theory-based physics models of equilibrium, core transport, and pedestal to yield a self-consistent solution. Given these attributes, STEP-0D not only improves the accuracy of predicting plasma performance but also provides a path towards a novel fusion power plant (FPP) design workflow. When integrated with engineering and costing models within an optimization, this new approach could eliminate the iterative reconciliation between plasma models of varying fidelity. This potential for a more efficient design process underpins STEP-0D's significant contribution to future fusion power plant development.Comment: 12 pages, 13 figures, accepted by Physics of Plasmas 202

An Overview of the 13:8 Mean Motion Resonance between Venus and Earth

It is known since the seminal study of Laskar (1989) that the inner planetary system is chaotic with respect to its orbits and even escapes are not impossible, although in time scales of billions of years. The aim of this investigation is to locate the orbits of Venus and Earth in phase space, respectively to see how close their orbits are to chaotic motion which would lead to unstable orbits for the inner planets on much shorter time scales. Therefore we did numerical experiments in different dynamical models with different initial conditions -- on one hand the couple Venus-Earth was set close to different mean motion resonances (MMR), and on the other hand Venus' orbital eccentricity (or inclination) was set to values as large as e = 0.36 (i = 40deg). The couple Venus-Earth is almost exactly in the 13:8 mean motion resonance. The stronger acting 8:5 MMR inside, and the 5:3 MMR outside the 13:8 resonance are within a small shift in the Earth's semimajor axis (only 1.5 percent). Especially Mercury is strongly affected by relatively small changes in eccentricity and/or inclination of Venus in these resonances. Even escapes for the innermost planet are possible which may happen quite rapidly.Comment: 14 pages, 11 figures, submitted to CMD