Downstream benefits vs upstream costs of land use change for water-yield and salt-load targets in the Macquarie Catchment, NSW

The net present value (NPV) of downstream economic benefits of changes in water-yield (W) and salt-load (S) of mean annual river flow received by a lower catchment from an upper catchment are described as a 3-dimensional (NPV,W, S) surface, where dNPV/dW > 0 and dNPV/d(S/W) < 0. Upstream changes in land use (i.e. forest clearing or forest establishment, which result in higher or lower water-yields, respectively) are driven by economic consequences for land owners. This paper defines conditions under which costs of strategic upstream land use changes could be exceeded by compensations afforded by downstream benefits from altered water-yields and/or lower salt loads. The paper presents methods, and preliminary calculations for an example river, quantifying the scope for such combinations, and raising the question of institutional designs to achieve mutually beneficial upstream and downstream outcomes. Examples refer to the Macquarie River downstream of Dubbo, NSW, and Little River, an upstream tributary.policy, markets, upstream, downstream, water, salinity, Land Economics/Use,

Analysis of Nkx3.1:Cre-driven Erk5 deletion reveals a profound spinal deformity which is linked to increased osteoclast activity

Extracellular signal-regulated protein kinase 5 (ERK5) has been implicated during development and carcinogenesis. Nkx3.1-mediated Cre expression is a useful strategy to genetically manipulate the mouse prostate. While grossly normal at birth, we observed an unexpected phenotype of spinal protrusion in Nkx3.1:Cre;Erk5fl/fl (Erk5fl/fl) mice by ~6–8 weeks of age. X-ray, histological and micro CT (µCT) analyses showed that 100% of male and female Erk5fl/fl mice had a severely deformed curved thoracic spine, with an associated loss of trabecular bone volume. Although sex-specific differences were observed, histomorphometry measurements revealed that both bone resorption and bone formation parameters were increased in male Erk5fl/fl mice compared to wild type (WT) littermates. Osteopenia occurs where the rate of bone resorption exceeds that of bone formation, so we investigated the role of the osteoclast compartment. We found that treatment of RANKL-stimulated primary bone marrow-derived macrophage (BMDM) cultures with small molecule ERK5 pathway inhibitors increased osteoclast numbers. Furthermore, osteoclast numbers and expression of osteoclast marker genes were increased in parallel with reduced Erk5 expression in cultures generated from Erk5fl/fl mice compared to WT mice. Collectively, these results reveal a novel role for Erk5 during bone maturation and homeostasis in vivo

Strategic Implementation of E-Procurement: A Case Study of an Australian Firm

The rapid development of Internet technology has made inter-organisation connectivity much easier and cheaper than ever before, hereby providing an opportunity for companies, both large and small, to realise the true value of the Internet. Despite the huge investment and complexity of implementing eprocurement, there is little empirical research to provide managerial guidelines for developing effective procurement strategies and for successfully implementing e-procurement. This paper attempts to fill this gap by reporting an Australian case study on the adoption of e-procurement. The findings offer detailed, varied and practical strategic insights into organisational redesign, critical factors, and challenges. The implications are also offered

Recommendations to facilitate the ideal fit note: are they achievable in practice?

Background: Although the UK fit note has been broadly welcomed as a tool to facilitate return to work, difficulties and uncertainties have resulted in wide variation in its use. Agreement on what constitutes the ‘ideal’ fit note from the perspective of all stakeholders is needed to inform best practice. A recent Delphi study conducted by the authors reached consensus on 67 recommendations for best practice in fit note use for employed patients. However, such recommendations are not necessarily followed in practice. The purpose of this study was therefore to investigate the perceived achievability of implementing these Delphi recommendations with a further reference panel of stakeholders. Methods: Potential participants were identified by the research team and study steering group. These included representatives of employers, government departments, trades unions, patient organisations, general and medical practitioners and occupational health organisations who were believed to have the knowledge and experience to comment on the recommendations. The consensus Delphi statements were presented to the participants on-line. Participants were invited to comment on whether the recommendations were achievable, and what might hinder or facilitate their use in practice. Free text comments were combined with comments made in the Delphi study that referred to issues of feasibility or practicality. These were synthesised and analysed thematically. Results: Twelve individuals representing a range of stakeholder groups participated. Many of the recommendations were considered achievable, such as improved format and use of the electronic fit note, completion of all fields, better application and revision of guidance and education in fit note use. However a number of obstacles to implementation were identified. These included: legislation governing the fit note and GP contracts; the costs and complexity of IT systems and software; the limitations of the GP consultation; unclear roles and responsibilities for the funding and delivery of education, guidance and training for all stakeholders, and the evaluation of practice. Conclusions: This study demonstrated that although many recommendations for the ideal fit note are considered achievable, there are considerable financial, legal, organisational and professional obstacles to be overcome in order for the recommendations to be implemented successfully

Recommendations for a large-scale European naturalistic driving observation study. PROLOGUE Deliverable D4.1.

Naturalistic driving observation is a relatively new research method using advanced technology for in-vehicle unobtrusive recording of driver (or rider) behaviour during ordinary driving in traffic. This method yields unprecedented knowledge primarily related to road safety, but also to environmentally friendly driving/riding and to traffic management. Distraction, inattention and sleepiness are examples of important safety-related topics where naturalistic driving is expected to provide great added value compared to traditional research methods. In order to exploit the full benefits of the naturalistic driving approach it is recommended to carry out a large-scale European naturalistic driving study. The EU project PROLOGUE has investigated the feasibility and value of carrying out such a study, and the present deliverable summarises recommendations based on the PROLOGUE project

Preventing Violence in Seven Countries: Global Convergence in Policies

Do governments take the measures that are supported by the best scientific evidence available? We present a brief review of the situation in: Australia, Canada, Germany, the Netherlands, Spain, the United Kingdom, and the United States. Our findings show surprisingly similar developments across countries. While all seven countries are moving towards evidence-based decision making regarding policies and programs to prevent violence, there remain a number of difficulties before this end can be achieved. For example, there continue to be few randomized controlled trials or rigorous quasi-experimental studies on aggression and violence. Results from experimental research are essential to both policy makers and researchers to determine the effectiveness of programs as well as increase our knowledge of the problem. Additionally, all noted that media attention for violence is high in their country, often leading to management by crisis with the result that policies are not based on evidence, but instead seek to appease public outrage. And perhaps because of attendant organizational problems (i.e., in many countries violence prevention was not under the guise of one particular agency or ministry), most have not developed a coordinated policy focusing on the prevention of violence and physical aggression. It is hypothesized that leaders in democratic countries, who must run for election every 4 to 6 years, may feel a need to focus on short-term planning rather than long-term preventive policies since the costs, but not the benefits for the latter would be incurred while they still served in office. We also noted a general absence of expertise beyond those within scientific circles. The need for these ideas to be more widely accepted will be an essential ingredient to real and sustaining change. This means that there must be better communication and increased understanding between researchers and policy makers. Toward those ends, the recent establishment of the Campbell Collaboration, formed to provide international systematic reviews of program effectiveness, will make these results more available and accessible to politicians, administrators and those charged with making key policy decision

Variability in Smoking Status for Lobectomy Among Society of Thoracic Surgeons Database Participants

BackgroundCurrent smokers undergoing lobectomy are at greater risk of complications than are former smokers. The Society of Thoracic Surgeons (STS) composite score for rating program performance for lobectomy adjusts for smoking status, a modifiable risk factor. This study examined variability in the proportion of current smokers undergoing lobectomy among STS database participants. Additionally, the study determined whether each participant's rating changed if smoking was excluded from the risk adjustment model.MethodsThis is a retrospective analysis of the STS cohort used to develop the composite score for rating program performance for lobectomy. The study summarized the variability among STS database participants for performing lobectomy on current smokers and compared star ratings developed from models with and without smoking status.ResultsThere were 24,912 patients with smoking status data: 23% current smokers, 62% former smokers, and 15% never smokers. There was significant variability among participants in the proportion of current smokers undergoing lobectomy (3% to 48.6%; P &lt; .001). Major morbidity or mortality (composite) was greater in current smokers (12.1%) than in former smokers (8.6%) and never smokers (4.2%) (P &lt; .001). Using the current risk adjustment model, participant star ratings were as follows: 1 star, n&nbsp;= 6 (3.2%); 2 stars, n&nbsp;= 170 (91.4%); and 3 stars, n&nbsp;= 10 (5.4%). When smoking status was excluded from the model, 1 participant shifted from a 2-star to a 3-star program.ConclusionsThere is substantial variability among STS database participants with regard to the proportion of current smokers undergoing lobectomy. However, exclusion of smoking status from the model did not significantly affect participant star rating

Systematic Review of topotecan (Hycamtin) in relapsed small cell lung cancer

Background: To undertake a systematic review of the available data for oral and intravenous topotecan in adults with relapsed small cell lung cancer (SCLC) for whom re-treatment with the first line regimen is not considered appropriate. Methods: We searched six databases from 1980 up to March 2009 for relevant trials regardless of language or publication status. Relevant studies included any randomised trial of any chemotherapeutic treatment against any comparator in this licensed indication. Where possible we used apposite quantitative methods. Where meta-analysis was considered unsuitable for some or all of the data, we employed a narrative synthesis method. For indirect comparisons we used the method of Bucher et al., where available data allowed it, otherwise we used narrative descriptions. Results: Seven unique studies met the inclusion criteria, four of which could be used in our analyses. These included one study comparing oral topotecan plus best supportive care (BSC) to BSC alone, one study comparing intravenous topotecan to cyclophosphamide, adriamycin and vincristine (CAV), and two studies comparing oral topotecan with intravenous topotecan. All four studies appear to be well conducted and with low risk of bias. Oral topotecan plus BSC has advantages over BSC alone in terms of survival (hazard ratio = 0.61; 95% CI, 0.43 to 0.87) and quality of life (EQ-5 D difference: 0.15; 95% CI, 0.05 to 0.25). Intravenous topotecan was at least as effective as CAV in the treatment of patients with recurrent small-cell lung cancer and resulted in improved quality-of-life with respect to several symptoms. CAV was associated with significantly less grade 4 thrombocytopenia compared with IV topotecan (risk ratio = 5.83; 95% CI, 2.35 to 14.42). Survival (hazard ratio = 0.98; 95% CI, 0.77 to 1.25) and response (pooled risk ratio = 1.04; 95% CI, 0.58 to 1.85) data were similar for the oral and IV topotecan groups. Symptom control was also very similar between the trials and between the oral and IV groups. Toxicity data showed a significant difference in favour of oral topotecan for neutropenia (pooled risk ratio = 0.65; 95% CI, 0.47 to 0.89). Indirect evidence showed that oral topotecan was at least as good as or better than CAV on all outcomes (survival, response rates, toxicities, and symptoms) that allowed indirect comparisons, with the only exception being grade four thrombocytopenia which occurred less often on CAV treatment. Conclusions: Concerning topotecan both the oral and intravenous options have similar efficacy, and patient preference may be a decisive factor if the choice would be between the two formulations. The best trial evidence for decision making, because it was tested versus best supportive care, exists for oral topotecan. Indirectly, because we have two head-to-head comparisons of oral versus intravenous topotecan, and one comparison of intravenous topotecan versus CAV in similar patients as in the trial against best supportive care, one might infer that IV topotecan and CAV could also be superior to best supportive care, and that oral topotecan has similar effects to CAV with possibly better symptom control. From the evidence discussed above, it is evident that oral topotecan has similar efficacy to IV topotecan (direct comparison) and CAV (indirect comparison). There is no further evidence base of direct or possible indirect comparisons for other comparators than CAV of either oral or IV topotecan

Circular-SWAT for deep learning based diagnostic classification of Alzheimer\u27s disease: application to metabolome data

Background: Deep learning has shown potential in various scientific domains but faces challenges when applied to complex, high-dimensional multi-omics data. Alzheimer\u27s Disease (AD) is a neurodegenerative disorder that lacks targeted therapeutic options. This study introduces the Circular-Sliding Window Association Test (c-SWAT) to improve the classification accuracy in predicting AD using serum-based metabolomics data, specifically lipidomics. Methods: The c-SWAT methodology builds upon the existing Sliding Window Association Test (SWAT) and utilizes a three-step approach: feature correlation analysis, feature selection, and classification. Data from 997 participants from the Alzheimer\u27s Disease Neuroimaging Initiative (ADNI) served as the basis for model training and validation. Feature correlations were analyzed using Weighted Gene Co-expression Network Analysis (WGCNA), and Convolutional Neural Networks (CNN) were employed for feature selection. Random Forest was used for the final classification. Findings: The application of c-SWAT resulted in a classification accuracy of up to 80.8% and an AUC of 0.808 for distinguishing AD from cognitively normal older adults. This marks a 9.4% improvement in accuracy and a 0.169 increase in AUC compared to methods without c-SWAT. These results were statistically significant, with a p-value of 1.04 × 10ˆ-4. The approach also identified key lipids associated with AD, such as Cer(d16:1/22:0) and PI(37:6). Interpretation: Our results indicate that c-SWAT is effective in improving classification accuracy and in identifying potential lipid biomarkers for AD. These identified lipids offer new avenues for understanding AD and warrant further investigation. Funding: The specific funding of this article is provided in the acknowledgements section

Amino Acid Similarity Accounts for T Cell Cross-Reactivity and for “Holes” in the T Cell Repertoire

Background: Cytotoxic T cell (CTL) cross-reactivity is believed to play a pivotal role in generating immune responses but the extent and mechanisms of CTL cross-reactivity remain largely unknown. Several studies suggest that CTL clones can recognize highly diverse peptides, some sharing no obvious sequence identity. The emerging realization in the field is that T cell receptors (TcR) recognize multiple distinct ligands. Principal Findings: First, we analyzed peptide scans of the HIV epitope SLFNTVATL (SFL9) and found that TCR specificity is position dependent and that biochemically similar amino acid substitutions do not drastically affect recognition. Inspired by this, we developed a general model of TCR peptide recognition using amino acid similarity matrices and found that such a model was able to predict the cross-reactivity of a diverse set of CTL epitopes. With this model, we were able to demonstrate that seemingly distinct T cell epitopes, i.e., ones with low sequence identity, are in fact more biochemically similar than expected. Additionally, an analysis of HIV immunogenicity data with our model showed that CTLs have the tendency to respond mostly to peptides that do not resemble self-antigens. Conclusions: T cell cross-reactivity can thus, to an extent greater than earlier appreciated, be explained by amino acid similarity. The results presented in this paper will help resolving some of the long-lasting discussions in the field of T cel