Dasatinib, nilotinib and standard-dose imatinib for the first line treatment of chronic myeloid leukaemia: Systematic reviews and economic analyses

- Background Nilotinib and dasatinib are now being considered as alternative treatments to imatinib as a first-line treatment of chronic myeloid leukaemia (CML). - Objective This technology assessment reviews the available evidence for the clinical effectiveness and cost-effectiveness of dasatinib, nilotinib and standard-dose imatinib for the first-line treatment of Philadelphia chromosome-positive CML. - Data sources Databases [including MEDLINE (Ovid), EMBASE, Current Controlled Trials, ClinicalTrials.gov, the US Food and Drug Administration website and the European Medicines Agency website] were searched from search end date of the last technology appraisal report on this topic in October 2002 to September 2011. - Review methods A systematic review of clinical effectiveness and cost-effectiveness studies; a review of surrogate relationships with survival; a review and critique of manufacturer submissions; and a model-based economic analysis. - Results Two clinical trials (dasatinib vs imatinib and nilotinib vs imatinib) were included in the effectiveness review. Survival was not significantly different for dasatinib or nilotinib compared with imatinib with the 24-month follow-up data available. The rates of complete cytogenetic response (CCyR) and major molecular response (MMR) were higher for patients receiving dasatinib than for those with imatinib for 12 months' follow-up (CCyR 83% vs 72%, p < 0.001; MMR 46% vs 28%, p < 0.0001). The rates of CCyR and MMR were higher for patients receiving nilotinib than for those receiving imatinib for 12 months' follow-up (CCyR 80% vs 65%, p < 0.001; MMR 44% vs 22%, p < 0.0001). An indirect comparison analysis showed no difference between dasatinib and nilotinib for CCyR or MMR rates for 12 months' follow-up (CCyR, odds ratio 1.09, 95% CI 0.61 to 1.92; MMR, odds ratio 1.28, 95% CI 0.77 to 2.16). There is observational association evidence from imatinib studies supporting the use of CCyR and MMR at 12 months as surrogates for overall all-cause survival and progression-free survival in patients with CML in chronic phase. In the cost-effectiveness modelling scenario, analyses were provided to reflect the extensive structural uncertainty and different approaches to estimating OS. First-line dasatinib is predicted to provide very poor value for money compared with first-line imatinib, with deterministic incremental cost-effectiveness ratios (ICERs) of between £256,000 and £450,000 per quality-adjusted life-year (QALY). Conversely, first-line nilotinib provided favourable ICERs at the willingness-to-pay threshold of £20,000-30,000 per QALY. - Limitations Immaturity of empirical trial data relative to life expectancy, forcing either reliance on surrogate relationships or cumulative survival/treatment duration assumptions. - Conclusions From the two trials available, dasatinib and nilotinib have a statistically significant advantage compared with imatinib as measured by MMR or CCyR. Taking into account the treatment pathways for patients with CML, i.e. assuming the use of second-line nilotinib, first-line nilotinib appears to be more cost-effective than first-line imatinib. Dasatinib was not cost-effective if decision thresholds of £20,000 per QALY or £30,000 per QALY were used, compared with imatinib and nilotinib. Uncertainty in the cost-effectiveness analysis would be substantially reduced with better and more UK-specific data on the incidence and cost of stem cell transplantation in patients with chronic CML. - Funding The Health Technology Assessment Programme of the National Institute for Health Research.

Debunking Weak Sustainable Consumption : Towards Strong Sustainable Consumption Governance

Achieving sustainable consumption patterns is a crucial step on the way towards sustainability. The scientific knowledge used to decide which priorities to set and how to enforce them has to converge with societal, political, and economic initiatives on various levels: from individual household decision-making to agreements and commitments in global policy processes. The aim of this thesis is to draw a comprehensive and systematic picture of sustainable consumption and to do this it develops the concept of Strong Sustainable Consumption Governance. In this concept, consumption is understood as resource consumption. This includes consumption by industries, public consumption, and household consumption. Next to the availability of resources (including the available sink capacity of the ecosystem) and their use and distribution among the Earth’s population, the thesis also considers their contribution to human well-being. This implies giving specific attention to the levels and patterns of consumption. Methods: The thesis introduces the terminology and various concepts of Sustainable Consumption and of Governance. It briefly elaborates on the methodology of Critical Realism and its potential for analysing Sustainable Consumption. It describes the various methods on which the research is based and sets out the political implications a governance approach towards Strong Sustainable Consumption may have. Two models are developed: one for the assessment of the environmental relevance of consumption activities, another to identify the influences of globalisation on the determinants of consumption opportunities. Results: One of the major challenges for Strong Sustainable Consumption is that it is not in line with the current political mainstream: that is, the belief that economic growth can cure all our problems. So, the proponents have to battle against a strong headwind. Their motivation however is the conviction that there is no alternative. Efforts have to be taken on multiple levels by multiple actors. And all of them are needed as they constitute the individual strings that together make up the rope. However, everyone must ensure that they are pulling in the same direction. It might be useful to apply a carrot and stick strategy to stimulate public debate. The stick in this case is to create a sense of urgency. The carrot would be to articulate better the message to the public that a shrinking of the economy is not as much of a disaster as mainstream economics tends to suggest. In parallel to this it is necessary to demand that governments take responsibility for governance. The dominant strategy is still information provision. But there is ample evidence that hard policies like regulatory instruments and economic instruments are most effective. As for Civil Society Organizations it is recommended that they overcome the habit of promoting Sustainable (in fact green) Consumption by using marketing strategies and instead foster public debate in values and well-being. This includes appreciating the potential of social innovation. A countless number of such initiatives are on the way but their potential is still insufficiently explored. Beyond the question of how to multiply such approaches, it is also necessary to establish political macro structures to foster them.

Complete cytogenetic response and major molecular response as surrogate outcomes for overall survival in first-line treatment of chronic myelogenous leukemia: A case study for technology appraisal on the basis of surrogate outcomes evidence

Objectives In 2012, the National Institute for Health and Care Excellence assessed dasatinib, nilotinib, and standard-dose imatinib as first-line treatment of chronic phase chronic myelogenous leukemia (CML). Licensing of these alternative treatments was based on randomized controlled trials assessing complete cytogenetic response (CCyR) and major molecular response (MMR) at 12 months as primary end points. We use this case study to illustrate the validation of CCyR and MMR as surrogate outcomes for overall survival in CML and how this evidence was used to inform National Institute for Health and Care Excellence’s recommendation on the public funding of these first-line treatments for CML. Methods We undertook a systematic review and meta-analysis to quantify the association between CCyR and MMR at 12 months and overall survival in patients with chronic phase CML. We estimated life expectancy by extrapolating long-term survival from the weighted overall survival stratified according to the achievement of CCyR and MMR. Results Five studies provided data on the observational association between CCyR or MMR and overall survival. Based on the pooled association between CCyR and MMR and overall survival, our modeling showed comparable predicted mean duration of survival (21–23 years) following first-line treatment with imatinib, dasatinib, or nilotinib. Conclusions This case study illustrates the consideration of surrogate outcome evidence in health technology assessment. Although it is often recommended that the acceptance of surrogate outcomes be based on randomized controlled trial data demonstrating an association between the treatment effect on both the surrogate outcome and the final outcome, this case study shows that policymakers may be willing to accept a lower level of evidence (i.e., observational association).

Determinants of farmer retirement and farm succession in Finland

In the past decade, the Finnish agricultural sector has undergone rapid structural changes. The number of farms has decreased and the average farm size has increased when the number of farms transferred to new entrants has decreased. Part of the structural change in agriculture is manifested in early retirement programmes. In studying farmers exit behaviour in different countries, institutional differences, incentive programmes and constraints are found to matter. In Finland, farmers early retirement programmes were first introduced in 1974 and, during the last ten years, they have been carried out within the European Union framework for these programmes. The early retirement benefits are farmer specific and de-pend on the level of pension insurance the farmer has paid over his active farming years. In order to predict the future development of the agricultural sector, farmers have been frequently asked about their future plans and their plans for succession. However, the plans the farmers made for succession have been found to be time inconsistent. This study estimates the value of farmers stated succession plans in predicting revealed succession decisions. A stated succession plan exists when a farmer answers in a survey questionnaire that the farm is going to be transferred to a new entrant within a five-year period. The succession is revealed when the farm is transferred to a suc-cessor. Stated and revealed behaviour was estimated as a recursive Binomial Probit Model, which accounts for the censoring of the decision variables and controls for a potential correlation between the two equations. The results suggest that the succession plans, as stated by elderly farmers in the questionnaires, do not provide information that is significant and valuable in predicting true, com-pleted successions. Therefore, farmer exit should be analysed based on observed behaviour rather than on stated plans and intentions. As farm retirement plays a crucial role in determining the characteristics of structural change in agriculture, it is important to establish the factors which determine an exit from farming among eld-erly farmers and how off-farm income and income losses affect their exit choices. In this study, the observed choice of pension scheme by elderly farmers was analysed by a bivariate probit model. Despite some variations in significance and the effects of each factor, the ages of the farmer and spouse, the age and number of potential successors, farm size, income loss when retiring and the location of the farm together with the production line were found to be the most important determi-nants of early retirement and the transfer or closure of farms. Recently, the labour status of the spouse has been found to contribute significantly to individual retirement decisions. In this study, the effect of spousal retirement and economic incentives related to the timing of a farming couple s early retirement decision were analysed with a duration model. The results suggest that an expected pension in particular advances farm transfers. It was found that on farms operated by a couple, both early retirement and farm succession took place more often than on farms operated by a single person. However, the existence of a spouse delayed the timing of early retirement. Farming couples were found to co-ordinate their early retirement decisions when they both exit through agricultural retirement programmes, but such a co-ordination did not exist when one of the spouses retired under other pension schemes. Besides changes in the agricultural structure, the share and amount of off-farm income of a farm family s total income has also increased. In the study, the effect of off-farm income on farmers retirement decisions, in addition to other financial factors, was analysed. The unknown parameters were first estimated by a switching-type multivariate probit model and then by the simulated maxi-mum likelihood (SML) method, controlling for farmer specific fixed effects and serial correlation of the errors. The results suggest that elderly farmers off-farm income is a significant determinant in a farmer s choice to exit and close down the farm. However, off-farm income only has a short term effect on structural changes in agriculture since it does not significantly contribute to the timing of farm successions.

Surviving the effects of barotrauma: assessing treatment options and a ‘natural’ remedy to enhance the release survival of line caught pink snapper (Pagrus auratus)

A new technique to ameliorate the effects of barotrauma was tested based on observations of pink snapper, Pagrus auratus (Forster), inadvertently piercing their everted stomach with their teeth and releasing trapped swim bladder gases. This technique was termed buccal venting and involved piercing the everted stomach protruding into the buccal cavity or out of the mouth with a 16-gauge hypodermic needle (a practice previously not encouraged). Short-term (~3 days) survival of buccal-vented fish was not significantly different from laterally vented fish nor untreated controls. Both buccal and lateral venting techniques were shown to cause no harm and allowed fish to return to depth. The short-term (1–3 days) post-release survival of line caught snapper was 88% with no significant difference in survival across three depth ranges tested (37–50, 51–100 and 101–180 m). Survival of sublegal pink snapper (<35 cm TL) was not significantly different (P > 0.05) from that of legal-sized fish (≥35 cm TL). Healing of the swim bladder was observed in 27% of pink snapper dissected after ≤3 days in captivity, and healing of stomachs was observed in 64% of pink snapper that had been buccal vented. Relatively high post-release survival rates of line caught pink snapper may offer some protection for snapper stocks where high fishing pressure and legal size restrictions result in the majority of the catch having to be released.

AC conductivity of a quantum Hall line junction

We present a microscopic model for calculating the AC conductivity of a finite length line junction made up of two counter-or co-propagating single mode quantum Hall edges with possibly different filling fractions. The effect of density-density interactions and a local tunneling conductance (sigma) between the two edges is considered. Assuming that sigma is independent of the frequency omega, we derive expressions for the AC conductivity as a function of omega, the length of the line junction and other parameters of the system. We reproduce the results of Sen and Agarwal (2008 Phys. Rev. B 78 085430) in the DC limit (omega -> 0), and generalize those results for an interacting system. As a function of omega, the AC conductivity shows significant oscillations if sigma is small; the oscillations become less prominent as sigma increases. A renormalization group analysis shows that the system may be in a metallic or an insulating phase depending on the strength of the interactions. We discuss the experimental implications of this for the behavior of the AC conductivity at low temperatures.

Quantitative effects of in-line operations on Campylobacter and Escherichia coli through two Australian broiler processing plants

Campylobacter is an important food borne pathogen, mainly associated with poultry. A lack of through-chain quantitative Campylobacter data has been highlighted within quantitative risk assessments. The aim of this study was to quantitatively and qualitatively measure Campylobacter and Escherichia coli concentration on chicken carcasses through poultry slaughter. Chickens (n = 240) were sampled from each of four flocks along the processing chain, before scald, after scald, before chill, after chill, after packaging and from individual caeca. The overall prevalence of Campylobacter after packaging was 83% with a median concentration of 0.8 log10 CFU/mL. The processing points of scalding and chilling had significant mean reductions of both Campylobacter (1.8 and 2.9 log10 CFU/carcase) and E. coli (1.3 and 2.5 log10 CFU/carcase). The concentration of E. coli and Campylobacter was significantly correlated throughout processing indicating that E. coli may be a useful indicator organism for reductions in Campylobacter concentration. The carriage of species varied between flocks, with two flocks dominated by Campylobacter coli and two flocks dominated by Campylobacter jejuni. Current processing practices can lead to significant reductions in the concentration of Campylobacter on carcasses. Further understanding of the variable effect of processing on Campylobacter and the survival of specific genotypes may enable more targeted interventions to reduce the concentration of this poultry associated pathogen.

Natural Abundant Solid State NMR Studies in Designed Tripeptides for Differentiation of Multiple Conformers

Solid state NMR (SSNMR) experiments on heteronuclei in natural abundance are described for three synthetically designed tripeptides Piv-(L)Pro_(L)Pro-(L)Phe-OMe (1), Piv-(D)Pro_(L)Pro_(L)Phe-OMe (2), and Piv-(D)Pro_(L)Pro_(L)Phe-NHMe (3). These peptides exist in different conformation as shown by solution state NMR and single crystal X-ray analysis (Chatterjee et al., Chem Eur J 2008, 14, 6192). In this study, SSNMR has been used to probe the conformations of these peptides in their powder form. The C-13 spectrum of peptide (1) showed doubling of resonances corresponding to cis/cis form, unlike in solution where the similar doubling is attributed to cis/trans form. This has been confirmed by the chemical shift differences of C-beta and C-gamma carbon of Proline in peptide (1) both in solution and SSNMR. Peptide (2) and (3) provided single set of resonances which represented all transform across the di-Proline segment. The results are In agreement with the X-ray analysis. Solid state N-15 resonances, especially from Proline residues provided additional information, which is normally not observable in solution state NMR. H-1 chemical shifts are also obtained from a two-dimensional heteronuclear correlation experiment between H-1-C-13. The results confirm the utility of NMR as a useful tool for identifying different conformers in peptides in the solid state. (C) 2009 Wiley Periodicals, Inc. Biopolymers 91: 851-860, 2009.

The plasticity of NBS resistance genes in sorghum is driven by multiple evolutionary processes

Background Increased disease resistance is a key target of cereal breeding programs, with disease outbreaks continuing to threaten global food production, particularly in Africa. Of the disease resistance gene families, the nucleotide-binding site plus leucine-rich repeat (NBS-LRR) family is the most prevalent and ancient and is also one of the largest gene families known in plants. The sequence diversity in NBS-encoding genes was explored in sorghum, a critical food staple in Africa, with comparisons to rice and maize and with comparisons to fungal pathogen resistance QTL. Results In sorghum, NBS-encoding genes had significantly higher diversity in comparison to non NBS-encoding genes and were significantly enriched in regions of the genome under purifying and balancing selection, both through domestication and improvement. Ancestral genes, pre-dating species divergence, were more abundant in regions with signatures of selection than in regions not under selection. Sorghum NBS-encoding genes were also significantly enriched in the regions of the genome containing fungal pathogen disease resistance QTL; with the diversity of the NBS-encoding genes influenced by the type of co-locating biotic stress resistance QTL. Conclusions NBS-encoding genes are under strong selection pressure in sorghum, through the contrasting evolutionary processes of purifying and balancing selection. Such contrasting evolutionary processes have impacted ancestral genes more than species-specific genes. Fungal disease resistance hot-spots in the genome, with resistance against multiple pathogens, provides further insight into the mechanisms that cereals use in the “arms race” with rapidly evolving pathogens in addition to providing plant breeders with selection targets for fast-tracking the development of high performing varieties with more durable pathogen resistance.

25th Anniversary of the Linked Life Insurance Commemorative Medal

Obverse: Inscription. Reverse: The life insurance emblem, a house with family inside, shekel coin on the roof of the house.

QTL analysis in multiple sorghum populations facilitates the dissection of the genetic and physiological control of tillering

Tillering in sorghum can be associated with either the carbon supply–demand (S/D) balance of the plant or an intrinsic propensity to tiller (PTT). Knowledge of the genetic control of tillering could assist breeders in selecting germplasm with tillering characteristics appropriate for their target environments. The aims of this study were to identify QTL for tillering and component traits associated with the S/D balance or PTT, to develop a framework model for the genetic control of tillering in sorghum. Four mapping populations were grown in a number of experiments in south east Queensland, Australia. The QTL analysis suggested that the contribution of traits associated with either the S/D balance or PTT to the genotypic differences in tillering differed among populations. Thirty-four tillering QTL were identified across the populations, of which 15 were novel to this study. Additionally, half of the tillering QTL co-located with QTL for component traits. A comparison of tillering QTL and candidate gene locations identified numerous coincident QTL and gene locations across populations, including the identification of common non-synonymous SNPs in the parental genotypes of two mapping populations in a sorghum homologue of MAX1, a gene involved in the control of tiller bud outgrowth through the production of strigolactones. Combined with a framework for crop physiological processes that underpin genotypic differences in tillering, the co-location of QTL for tillering and component traits and candidate genes allowed the development of a framework QTL model for the genetic control of tillering in sorghum.

Isolation of multiple novel paramyxoviruses from pteropid bat urine

Bats have been found to harbor a number of new emerging viruses with zoonotic potential and there has been a great deal of interest in identifying novel bat pathogens to determine risk to human and animal health. Many groups have identified novel viruses in bats by detection of viral nucleic acid, however virus isolation is still a challenge and there are few reports of viral isolates from bats. In recent years, our group has developed optimized procedures for virus isolation from bat urine, including the use of primary bat cells. In previous reports we have described the isolation of Hendra virus, Menangle virus and Cedar virus, in Queensland, Australia. Here, we report the isolation of four additional novel bat paramyxoviruses from urine collected from beneath pteropid bat (flying fox) colonies in Queensland and New South Wales during 2009-2011.