Should expectations about the rate of new antiretroviral drug development impact the timing of HIV treatment initiation and expectations about treatment benefits?

Background: Many analyses of HIV treatment decisions assume a fixed formulary of HIV drugs. However, new drugs are approved nearly twice a year, and the rate of availability of new drugs may affect treatment decisions, particularly when to initiate antiretroviral therapy (ART). Objectives: To determine the impact of considering the availability of new drugs on the optimal initiation criteria for ART and outcomes in patients with HIV/AIDS. Methods: We enhanced a previously described simulation model of the optimal time to initiate ART to incorporate the rate of availability of new antiviral drugs. We assumed that the future rate of availability of new drugs would be similar to the past rate of availability of new drugs, and we estimated the past rate by fitting a statistical model to actual HIV drug approval data from 1982-2010. We then tested whether or not the future availability of new drugs affected the model-predicted optimal time to initiate ART based on clinical outcomes, considering treatment initiation thresholds of 200, 350, and 500 cells/mm 3. We also quantified the impact of the future availability of new drugs on life expectancy (LE) and quality-adjusted life expectancy (QALE). Results: In base case analysis, considering the availability of new drugs raised the optimal starting CD4 threshold for most patients to 500 cells/mm 3. The predicted gains in outcomes due to availability of pipeline drugs were generally small (less than 1%), but for young patients with a high viral load could add as much as a 4.9% (1.73 years) increase in LE and a 8% (2.43 QALY) increase in QALE, because these patients were particularly likely to exhaust currently available ART regimens before they died. In sensitivity analysis, increasing the rate of availability of new drugs did not substantially alter the results. Lowering the toxicity of future ART drugs had greater potential to increase benefit for many patient groups, increasing QALE by as much as 10%. Conclusions: The future availability of new ART drugs without lower toxicity raises optimal treatment initiation for most patients, and improves clinical outcomes, especially for younger patients with higher viral loads. Reductions in toxicity of future ART drugs could impact optimal treatment initiation and improve clinical outcomes for all HIV patients. © 2014 Khademi et al

Can Broader Diffusion of Value-Based Insurance Design Increase Benefits from US Health Care without Increasing Costs? Evidence from a Computer Simulation Model

Using a computer simulation based on US data, R. Scott Braithwaite and colleagues calculate the benefits of value-based insurance design, in which patients pay less for highly cost-effective services

Problems Associated with Making Mechanical Measurements on Water–Ice at Quasistatic and Dynamic Strain Rates

Space penetrators are a potential method of inserting instrumentation onto ice-covered bodies in the solar system. Part of a study to see whether this is feasible involves numerically simulating impact of the penetrator into ice at impact velocities of a few 100 m/s. In order to do this accurately, it is necessary to have a constitutive model for water ice that is valid at the strain rates and temperatures relevant to impact in the Outer Solar System. This paper reports certain issues and difficulties that arose during a study to obtain this data.We also thank QinetiQ plc for funding through the IRAD programme

Between-group behaviour in health care: gaps, edges, boundaries, disconnections, weak ties, spaces and holes. A systematic review

<p>Abstract</p> <p>Background</p> <p>Gaps are typically regarded as a problem to be solved. People are stimulated to close or plug them. Researchers are moved to fill deficits in the literature in order to realise a more complete knowledge base, health authorities want to bridge policy-practice disconnections, managers to secure resources to remedy shortfalls between poor and idealised care, and clinicians to provide services to patients across the divides of organisational silos.</p> <p>Despite practical and policy work in many health systems to bridge gaps, it is valuable to study research examining them for the insights provided. Structural holes, spaces between social clusters and weak or absent ties represent fissures in networks, located in less densely populated parts of otherwise closely connected social structures. Such gaps are useful as they illustrate how communication potentially breaks down or interactivity fails. This paper discusses empirical and theoretical work on this phenomenon with the aim of analysing a specific exemplar, the structures of silos within health care organisations.</p> <p>Methods</p> <p>The research literature on social spaces, holes, gaps, boundaries and edges was searched systematically, and separated into health [n = 13] and non-health [n = 55] samples. The health literature was reviewed and synthesised in order to understand the circumstances between stakeholders and stakeholder groups that both provide threats to networked interactions and opportunities to strengthen the fabric of organisational and institutional inter-relationships.</p> <p>Results</p> <p>The research examples illuminate various network structure characteristics and group interactions. They explicate a range of opportunities for improved social and professional relations that understanding structural holes, social spaces and absent ties affords. A principal finding is that these kinds of gaps illustrate the conditions under which connections are strained or have been severed, where the limits of integration between groups occurs, the circumstances in which social spaces are or need to be negotiated and the way divides are bridged. The study's limitations are that it is bounded by the focus of attention and the search terms used and there is yet to be developed a probabilistic, predictive model for gaps and how to connect them.</p> <p>Conclusions</p> <p>Gaps offer insights into social structures, and how real world behaviours of participants in workplaces, organisations and institutions are fragile. The paper highlights the circumstances in which network disjunctures and group divides manifest. Knowledge of these phenomenon provides opportunities for working out ways to improve health sector organisational communications, knowledge transmission and relationships.</p

Quantitative model for inferring dynamic regulation of the tumour suppressor gene p53

Background: The availability of various "omics" datasets creates a prospect of performing the study of genome-wide genetic regulatory networks. However, one of the major challenges of using mathematical models to infer genetic regulation from microarray datasets is the lack of information for protein concentrations and activities. Most of the previous researches were based on an assumption that the mRNA levels of a gene are consistent with its protein activities, though it is not always the case. Therefore, a more sophisticated modelling framework together with the corresponding inference methods is needed to accurately estimate genetic regulation from "omics" datasets. Results: This work developed a novel approach, which is based on a nonlinear mathematical model, to infer genetic regulation from microarray gene expression data. By using the p53 network as a test system, we used the nonlinear model to estimate the activities of transcription factor (TF) p53 from the expression levels of its target genes, and to identify the activation/inhibition status of p53 to its target genes. The predicted top 317 putative p53 target genes were supported by DNA sequence analysis. A comparison between our prediction and the other published predictions of p53 targets suggests that most of putative p53 targets may share a common depleted or enriched sequence signal on their upstream non-coding region. Conclusions: The proposed quantitative model can not only be used to infer the regulatory relationship between TF and its down-stream genes, but also be applied to estimate the protein activities of TF from the expression levels of its target genes

Impact of generic alendronate cost on the cost-effectiveness of osteoporosis screening and treatment

Introduction: Since alendronate became available in generic form in the Unites States in 2008, its price has been decreasing. The objective of this study was to investigate the impact of alendronate cost on the cost-effectiveness of osteoporosis screening and treatment in postmenopausal women. Methods: Microsimulation cost-effectiveness model of osteoporosis screening and treatment for U.S. women age 65 and older. We assumed screening initiation at age 65 with central dual-energy x-ray absorptiometry (DXA), and alendronate treatment for individuals with osteoporosis; with a comparator of "no screening" and treatment only after fracture occurrence. We evaluated annual alendronate costs of $20 through$800; outcome measures included fractures; nursing home admission; medication adverse events; death; costs; quality-adjusted life-years (QALYs); and incremental cost-effectiveness ratios (ICERs) in 2010 U.S. dollars per QALY gained. A lifetime time horizon was used, and direct costs were included. Base-case and sensitivity analyses were performed. Results: Base-case analysis results showed that at annual alendronate costs of $200 or less, osteoporosis screening followed by treatment was cost-saving, resulting in lower total costs than no screening as well as more QALYs (10.6 additional quality-adjusted life-days). When assuming alendronate costs of$400 through $800, screening and treatment resulted in greater lifetime costs than no screening but was highly cost-effective, with ICERs ranging from$714 per QALY gained through $13,902 per QALY gained. Probabilistic sensitivity analyses revealed that the cost-effectiveness of osteoporosis screening followed by alendronate treatment was robust to joint input parameter estimate variation at a willingness-to-pay threshold of$50,000/QALY at all alendronate costs evaluated. Conclusions: Osteoporosis screening followed by alendronate treatment is effective and highly cost-effective for postmenopausal women across a range of alendronate costs, and may be cost-saving at annual alendronate costs of $200 or less. © 2012 Nayak et al