Fundholding: learning from the past and looking to the future

The document attached has been archived with permission from the editor of the Medical Journal of Australia (26 April 2007). An external link to the publisher’s copy is included.Australian trials of healthcare initiatives that included fundholding models have not produced convincing quantitative evidence of health gains, but there is qualitative evidence of improved patient well-being and significant changes in service mix, which may produce longer-term health gains. Fundholding is most likely to improve patient outcomes when implemented within a broader healthcare initiative that has the potential to be more effective if financed outside existing funding structures. The most appropriate fundholder organisation depends on the nature of the initiative and the type of stakeholder engagement required, but technical and organisational skills will always be needed for balancing financial viability and additional patient services. Stakeholders’ willingness to engage in fundholding depends on the anticipated budget impact, how they will use the savings generated, and whether workforce needs will be fulfilled. Before including fundholding in healthcare initiatives, there must be realistic prospective analyses and community debate. Monitoring and evaluation frameworks must also be in place to provide ongoing evidence of quality of care, health and well-being outcomes and financial implications for fund contributors.Justin J Beilby and Brita Pekarsk

Indirect estimation of the comparative treatment effect in pharmacogenomic subgroups

Evidence of clinical utility is a key issue in translating pharmacogenomics into clinical practice. Appropriately designed randomized controlled trials generally provide the most robust evidence of the clinical utility, but often only data from a pharmacogenomic association study are available. This paper details a method for reframing the results of pharmacogenomic association studies in terms of the comparative treatment effect for a pharmacogenomic subgroup to provide greater insight into the likely clinical utility of a pharmacogenomic marker, its' likely cost effectiveness, and the value of undertaking the further (often expensive) research required for translation into clinical practice. The method is based on the law of total probability, which relates marginal and conditional probability. It takes as inputs: the prevalence of the pharmacogenomic marker in the patient group of interest, prognostic effect of the pharmacogenomic marker based on observational association studies, and the unstratified comparative treatment effect based on one or more conventional randomized controlled trials. The critical assumption is that of exchangeability across the included studies. The method is demonstrated using a case study of cytochrome P450 (CYP) 2C19 genotype and the anti-platelet agent clopidogrel. Indirect subgroup analysis provided insight into relationship between the clinical utility of genotyping CYP2C19 and the risk ratio of cardiovascular outcomes between CYP2C19 genotypes for individuals using clopidogrel. In this case study the indirect and direct estimates of the treatment effect for the cytochrome P450 2C19 subgroups were similar. In general, however, indirect estimates are likely to have substantially greater risk of bias than an equivalent direct estimate.Michael J. Sorich, Michael Coory, Brita A. K. Pekarsk

Caring for a marginalised community: the costs of engaging with culture and complexity

The document attached has been archived with permission from the editor of the Medical Journal of Australia. An external link to the publisher’s copy is included.The Care and Prevention Programme (CPP) began in 1998. It is based on the philosophy of primary health care, and has improved health among homosexually active men, including about a third of HIV-positive South Australians. The CPP was assessed using financial analysis and qualitative methods. Participants wanted to access care where they could feel comfortable and safe to talk about issues of sexuality and lifestyle. The CPP model is "economically" sustainable, but not "financially" sustainable within the Medicare Benefits Schedule. It is vulnerable to changes in political environment. The financing model for the CPP has been adapted by including state funding. General practitioners have adapted by lowering their personal incomes (but not quality of care). These adaptations have achieved fragile financial viability. Facilitators of sustainability for the CPP included: It is part of the community that it serves; The creation of deeply integrated networks of diversity-competent service providers; and "Virtuous non-adaptability" of service providers in refusing to compromise care standards despite financial pressure to do so. Threats to sustainability included: Difficulty maintaining a diversity-competent workforce skilled in HIV medicine; Marginal financial viability; and Political vulnerability.Gary D Rogers, Christopher A Barton, Brita A Pekarsky, Ann C Lawless, Joy M Oddy, Rebecca Hepworth and Justin J Beilb

Retinoic acid induces HL-60 cell differentiation via the upregulation of miR-663

<p>Abstract</p> <p>Background</p> <p>Differentiation of the acute myeloid leukemia (AML) cell line HL-60 can be induced by all trans-retinoic acid (ATRA); however, the mechanism regulating this process has not been fully characterized.</p> <p>Methods</p> <p>Using bioinformatics and <it>in vitro </it>experiments, we identified the microRNA gene expression profile of HL-60 cells during ATRA induced granulocytic differentiation.</p> <p>Results</p> <p>Six microRNAs were upregulated by ATRA treatment, miR-663, miR-494, miR-145, miR-22, miR-363* and miR-223; and three microRNAs were downregulated, miR-10a, miR-181 and miR-612. Additionally, miR-663 expression was regulated by ATRA. We used a lentivirus (LV) backbone incorporating the spleen focus forming virus (SFFV-F) promoter to drive miR-663 expression, as the CMV (Cytomegalovirus) promoter is ineffective in some lymphocyte cells. Transfection of LV-miR-663 induced significant HL-60 cell differentiation <it>in vitro</it>.</p> <p>Conclusions</p> <p>Our results show miR-663 may play an important role in ATRA induced HL-60 cell differentiation. Lentivirus delivery of miR-663 could potentially be used directly as an anticancer treatment in hematological malignancies</p

The expression of FHIT, PCNA and EGFR in benign and malignant breast lesions

Immunohistochemical staining for FHIT and PCNA proteins was carried out in 451 breast lesions showing nonproliferative benign breast disease (BBD) (n=263), proliferative BBD without atypia (n=128), proliferative BBD with atypia (n=11), carcinoma in situ (n=15) or invasive carcinoma (n=34) and for EGFR protein in a subset of 71 of these cases. FHIT underexpression was not detected in nonproliferative lesions, but occurred in 2% of proliferative BBD without atypia, 10% proliferative BBD with atypia, 27% of carcinoma in situ and 41% of invasive carcinoma, which suggests that it could be useful in assessing those carcinoma in situ lesions (ductal, DCIS and lobular, LCIS) that are more likely to progress to malignancy. Preliminary microarray comparisons on DCIS and invasive carcinoma samples dissected from formalin-fixed paraffin sections showed a consistent downregulation of two previously identified FHIT-related genes, caspase 1 and BRCA1 in lesions underexpressing FHIT

Sustainable Financing of Innovative Therapies: A Review of Approaches

The process of innovation is inherently complex, and it occurs within an even more complex institutional environment characterized by incomplete information, market power, and externalities. There are therefore different competing approaches to supporting and financing innovation in medical technologies, which bring their own advantages and disadvantages. This article reviews value- and cost-based pricing, as well direct government funding, and cross-cutting institutional structures. It argues that performance-based risk-sharing agreements are likely to have little effect on the sustainability of financing; that there is a role for cost-based pricing models in some situations; and that the push towards longer exclusivity periods is likely contrary to the interests of industry

The nuclear orphan receptor Nr4a2 induces Foxp3 and regulates differentiation of CD4+ T cells

Regulatory T cells (Tregs) have a central role in maintaining immune homoeostasis through various mechanisms. Although the Forkhead transcription factor Foxp3 defines the Treg cell lineage and functions, the molecular mechanisms of Foxp3 induction and maintenance remain elusive. Here we show that Foxp3 is one of the direct targets of Nr4a2. Nr4a2 binds to regulatory regions of Foxp3, where it mediates permissive histone modifications. Ectopic expression of Nr4a2 imparts Treg-like suppressive activity to naïve CD4+ T cells by inducing Foxp3 and by repressing cytokine production, including interferon-γ and interleukin-2. Deletion of Nr4a2 in T cells attenuates induction of Tregs and causes aberrant induction of Th1, leading to the exacerbation of colitis. Nr4a2-deficeint Tregs are prone to lose Foxp3 expression and have attenuated suppressive ability both in vitro and in vivo. Thus, Nr4a2 has the ability to maintain T-cell homoeostasis by regulating induction, maintenance and suppressor functions of Tregs, and by repression of aberrant Th1 induction

Accurate molecular classification of cancer using simple rules

<p>Abstract</p> <p>Background</p> <p>One intractable problem with using microarray data analysis for cancer classification is how to reduce the extremely high-dimensionality gene feature data to remove the effects of noise. Feature selection is often used to address this problem by selecting informative genes from among thousands or tens of thousands of genes. However, most of the existing methods of microarray-based cancer classification utilize too many genes to achieve accurate classification, which often hampers the interpretability of the models. For a better understanding of the classification results, it is desirable to develop simpler rule-based models with as few marker genes as possible.</p> <p>Methods</p> <p>We screened a small number of informative single genes and gene pairs on the basis of their depended degrees proposed in rough sets. Applying the decision rules induced by the selected genes or gene pairs, we constructed cancer classifiers. We tested the efficacy of the classifiers by leave-one-out cross-validation (LOOCV) of training sets and classification of independent test sets.</p> <p>Results</p> <p>We applied our methods to five cancerous gene expression datasets: leukemia (acute lymphoblastic leukemia [ALL] vs. acute myeloid leukemia [AML]), lung cancer, prostate cancer, breast cancer, and leukemia (ALL vs. mixed-lineage leukemia [MLL] vs. AML). Accurate classification outcomes were obtained by utilizing just one or two genes. Some genes that correlated closely with the pathogenesis of relevant cancers were identified. In terms of both classification performance and algorithm simplicity, our approach outperformed or at least matched existing methods.</p> <p>Conclusion</p> <p>In cancerous gene expression datasets, a small number of genes, even one or two if selected correctly, is capable of achieving an ideal cancer classification effect. This finding also means that very simple rules may perform well for cancerous class prediction.</p

MicroRNA Expression Profiling Identifies Activated B Cell Status in Chronic Lymphocytic Leukemia Cells

Chronic lymphocytic leukemia (CLL) is thought to be a disease of resting lymphocytes. However, recent data suggest that CLL cells may more closely resemble activated B cells. Using microRNA (miRNA) expression profiling of highly-enriched CLL cells from 38 patients and 9 untransformed B cells from normal donors before acute CpG activation and 5 matched B cells after acute CpG activation, we demonstrate an activated B cell status for CLL. Gene set enrichment analysis (GSEA) identified statistically-significant similarities in miRNA expression between activated B cells and CLL cells including upregulation of miR-34a, miR-155, and miR-342-3p and downregulation of miR-103, miR-181a and miR-181b. Additionally, decreased levels of two CLL signature miRNAs miR-29c and miR-223 are associated with ZAP70+ and IgVH unmutated status and with shorter time to first therapy. These data indicate an activated B cell status for CLL cells and suggest that the direction of change of individual miRNAs may predict clinical course in CLL