The Cost-Effectiveness of Monitoring Strategies for Antiretroviral Therapy of HIV Infected Patients in Resource-Limited Settings: Software Tool.

BACKGROUND The cost-effectiveness of routine viral load (VL) monitoring of HIV-infected patients on antiretroviral therapy (ART) depends on various factors that differ between settings and across time. Low-cost point-of-care (POC) tests for VL are in development and may make routine VL monitoring affordable in resource-limited settings. We developed a software tool to study the cost-effectiveness of switching to second-line ART with different monitoring strategies, and focused on POC-VL monitoring. METHODS We used a mathematical model to simulate cohorts of patients from start of ART until death. We modeled 13 strategies (no 2nd-line, clinical, CD4 (with or without targeted VL), POC-VL, and laboratory-based VL monitoring, with different frequencies). We included a scenario with identical failure rates across strategies, and one in which routine VL monitoring reduces the risk of failure. We compared lifetime costs and averted disability-adjusted life-years (DALYs). We calculated incremental cost-effectiveness ratios (ICER). We developed an Excel tool to update the results of the model for varying unit costs and cohort characteristics, and conducted several sensitivity analyses varying the input costs. RESULTS Introducing 2nd-line ART had an ICER of US$1651-1766/DALY averted. Compared with clinical monitoring, the ICER of CD4 monitoring was US$1896-US$5488/DALY averted and VL monitoring US$951-US$5813/DALY averted. We found no difference between POC- and laboratory-based VL monitoring, except for the highest measurement frequency (every 6 months), where laboratory-based testing was more effective. Targeted VL monitoring was on the cost-effectiveness frontier only if the difference between 1st- and 2nd-line costs remained large, and if we assumed that routine VL monitoring does not prevent failure. CONCLUSION Compared with the less expensive strategies, the cost-effectiveness of routine VL monitoring essentially depends on the cost of 2nd-line ART. Our Excel tool is useful for determining optimal monitoring strategies for specific settings, with specific sex-and age-distributions and unit costs.

A Flow Trace Generator using Graph-based Traffic Classification Techniques

We propose a novel methodology to generate realistic network flow traces to enable systematic evaluation of network monitoring systems in various traffic conditions. Our technique uses a graph-based approach to model the communication structure observed in real-world traces and to extract traffic templates. By combining extracted and user-defined traffic templates, realistic network flow traces that comprise normal traffic and customized conditions are generated in a scalable manner. A proof-of-concept implementation demonstrates the utility and simplicity of our method to produce a variety of evaluation scenarios. We show that the extraction of templates from real-world traffic leads to a manageable number of templates that still enable accurate re-creation of the original communication properties on the network flow level.

Holocene land-cover reconstructions for studies on land cover-climate feedbacks

The major objectives of this paper are: (1) to review the pros and cons of the scenarios of past anthropogenic land cover change (ALCC) developed during the last ten years, (2) to discuss issues related to pollen-based reconstruction of the past land-cover and introduce a new method, REVEALS (Regional Estimates of VEgetation Abundance from Large Sites), to infer long-term records of past land-cover from pollen data, (3) to present a new project (LANDCLIM: LAND cover – CLIMate interactions in NW Europe during the Holocene) currently underway, and show preliminary results of REVEALS reconstructions of the regional land-cover in the Czech Republic for five selected time windows of the Holocene, and (4) to discuss the implications and future directions in climate and vegetation/land-cover modeling, and in the assessment of the effects of human-induced changes in land-cover on the regional climate through altered feedbacks. The existing ALCC scenarios show large discrepancies between them, and few cover time periods older than AD 800. When these scenarios are used to assess the impact of human land-use on climate, contrasting results are obtained. It emphasizes the need for methods such as the REVEALS model-based land-cover reconstructions. They might help to fine-tune descriptions of past land-cover and lead to a better understanding of how long-term changes in ALCC might have influenced climate. The REVEALS model is demonstrated to provide better estimates of the regional vegetation/land-cover changes than the traditional use of pollen percentages. This will achieve a robust assessment of land cover at regional- to continental-spatial scale throughout the Holocene. We present maps of REVEALS estimates for the percentage cover of 10 plant functional types (PFTs) at 200 BP and 6000 BP, and of the two open-land PFTs "grassland" and "agricultural land" at five time-windows from 6000 BP to recent time. The LANDCLIM results are expected to provide crucial data to reassess ALCC estimates for a better understanding of the land suface-atmosphere interactions.

Timing of progression from Chlamydia trachomatis infection to pelvic inflammatory disease: a mathematical modelling study

Background Pelvic inflammatory disease (PID) results from the ascending spread of microorganisms from the vagina and endocervix to the upper genital tract. PID can lead to infertility, ectopic pregnancy and chronic pelvic pain. The timing of development of PID after the sexually transmitted bacterial infection Chlamydia trachomatis (chlamydia) might affect the impact of screening interventions, but is currently unknown. This study investigates three hypothetical processes for the timing of progression: at the start, at the end, or throughout the duration of chlamydia infection. Methods We develop a compartmental model that describes the trial structure of a published randomised controlled trial (RCT) and allows each of the three processes to be examined using the same model structure. The RCT estimated the effect of a single chlamydia screening test on the cumulative incidence of PID up to one year later. The fraction of chlamydia infected women who progress to PID is obtained for each hypothetical process by the maximum likelihood method using the results of the RCT. Results The predicted cumulative incidence of PID cases from all causes after one year depends on the fraction of chlamydia infected women that progresses to PID and on the type of progression. Progression at a constant rate from a chlamydia infection to PID or at the end of the infection was compatible with the findings of the RCT. The corresponding estimated fraction of chlamydia infected women that develops PID is 10% (95% confidence interval 7-13%) in both processes. Conclusions The findings of this study suggest that clinical PID can occur throughout the course of a chlamydia infection, which will leave a window of opportunity for screening to prevent PID.

Monte Carlo simulation of a dynamic MLC: implementation and applications

PURPOSE: Study of behavior and influence of a multileaf collimator (MLC) on dose calculation, verification, and portal energy spectra in the case of intensity-modulated fields obtained with a step-and-shoot or a dynamic technique. METHODS: The 80-leaf MLC for the Varian Clinac 2300 C/D was implemented in a previously developed Monte Carlo (MC) based multiple source model (MSM) for a 6 MV photon beam. Using this model and the MC program GEANT, dose distributions, energy fluence maps and energy spectra at different portal planes were calculated for three different MLC applications. RESULTS: The comparison of MC-calculated dose distributions in the phantom and portal plane, with those measured with films showed an agreement within 3% and 1.5 mm for all cases studied. The deviations mainly occur in the extremes of the intensity modulation. The MC method allows to investigate, among other aspects, dose components, energy fluence maps, tongue-and-groove effects and energy spectra at portal planes. CONCLUSION: The MSM together with the implementation of the MLC is appropriate for a number of investigations in intensity-modulated radiation therapy (IMRT).

Ascorbic acid for amelioration of reperfusion injury in a lung autotransplantation model in sheep

BACKGROUND: Reperfusion injury is the leading cause of early graft dysfunction after lung transplantation. Activation of neutrophilic granulocytes with generation of free oxygen radicals appears to play a key role in this process. The efficacy of ascorbic acid as an antioxidant in the amelioration of reperfusion injury after lung transplantation has not been studied yet. METHODS: An in situ autotransplantation model in sheep is presented. The left lung was flushed (Euro-Collins solution) and reperfused; after 2 hours of cold storage, the right hilus was then clamped (group R [reference], n = 6). Group AA animals (n = 6) were treated with 1 g/kg ascorbic acid before reperfusion. Controls (group C, n = 6) underwent hilar preparation and instrumentation only. RESULTS: In group R, arterio-alveolar oxygen difference (AaDO2) and pulmonary vascular resistance (PVR) were significantly elevated after reperfusion. Five of 6 animals developed frank alveolar edema. All biochemical parameters showed significant PMN activation. In group AA, AaDO2, PVR, work of breathing, and the level of PMN activation were significantly lower. CONCLUSIONS: The experimental model reproduces all aspects of lung reperfusion injury reliably. Ascorbic acid was able to weaken reperfusion injury in this experimental setup.

Individual patient data meta-analysis of diagnostic and prognostic studies in obstetrics, gynaecology and reproductive medicine

BACKGROUND: In clinical practice a diagnosis is based on a combination of clinical history, physical examination and additional diagnostic tests. At present, studies on diagnostic research often report the accuracy of tests without taking into account the information already known from history and examination. Due to this lack of information, together with variations in design and quality of studies, conventional meta-analyses based on these studies will not show the accuracy of the tests in real practice. By using individual patient data (IPD) to perform meta-analyses, the accuracy of tests can be assessed in relation to other patient characteristics and allows the development or evaluation of diagnostic algorithms for individual patients. In this study we will examine these potential benefits in four clinical diagnostic problems in the field of gynaecology, obstetrics and reproductive medicine. METHODS/DESIGN: Based on earlier systematic reviews for each of the four clinical problems, studies are considered for inclusion. The first authors of the included studies will be invited to participate and share their original data. After assessment of validity and completeness the acquired datasets are merged. Based on these data, a series of analyses will be performed, including a systematic comparison of the results of the IPD meta-analysis with those of a conventional meta-analysis, development of multivariable models for clinical history alone and for the combination of history, physical examination and relevant diagnostic tests and development of clinical prediction rules for the individual patients. These will be made accessible for clinicians. DISCUSSION: The use of IPD meta-analysis will allow evaluating accuracy of diagnostic tests in relation to other relevant information. Ultimately, this could increase the efficiency of the diagnostic work-up, e.g. by reducing the need for invasive tests and/or improving the accuracy of the diagnostic workup. This study will assess whether these benefits of IPD meta-analysis over conventional meta-analysis can be exploited and will provide a framework for future IPD meta-analyses in diagnostic and prognostic research.

Admission blood glucose is an independent predictive factor for hospital mortality in polytraumatised patients

PURPOSE: The goal of this study was to analyse a possible association of admission blood glucose with hospital mortality of polytraumatised patients and to develop an outcome prediction model for this patient group. METHODS: The outcome of adult polytraumatised patients admitted to the University Hospital of Berne, Switzerland, between 2002 and 2004 with an ISS > or = 17, and more than one severely injured organ system was retrospectively analysed. RESULTS: The inclusion criteria were met by 555 patients, of which 108 (19.5%) died. Hyperglycaemia proved to be an independent predictor for hospital mortality (P < 0.0001), following multiple regression analysis. After inclusion of admission blood glucose, the calculated mortality prediction model performed better than currently described models (P < 0.0001, AUC 0.924). CONCLUSION: In this retrospective, single-centre study in polytraumatised patients, admission blood glucose proved to be an independent predictor of hospital mortality following regression analysis controlling for age, gender, injury severity and other laboratory parameters. A reliable admission blood glucose-based mortality prediction model for polytraumatised patients could be established. This observation may be helpful in improving the precision of future outcome prediction models for polytraumatised patients. These observations warrant further prospective evaluation.

Making epothilones fluoresce: design, synthesis, and biological characterization of a fluorescent N12-aza-epothilone (azathilone)

A green fluorescent 12-aza-epothilone (azathilone) derivative has been prepared through the attachment of the 4-nitro-2,1,3-benzoxadiazole (NBD) fluorophore to the 12-nitrogen atom of the azamacrolide core structure. While less potent than natural epothilones or different N12-acylated azathilone derivatives, NBD-azathilone (3) promotes tubulin assembly, inhibits cancer cell proliferation in vitro and arrests the cell cycle at the G2/M transition. Most significantly, the binding of 3 to cellular microtubules (MTs) could be directly visualized by confocal fluorescence microscopy. Based on competition binding experiments with laulimalide-stabilized MTs in vitro, the N12-Boc substituted azathilone 1, Epo A, and NBD-azathilone (3) all interact with the same tubulin-binding site. Computational studies provided a structural model of the complexes between beta-tubulin and 1 or 3, respectively, in which the NBD moiety of 3 or the BOC moiety of 1 directly and specifically contribute to MT binding. Collectively, these data demonstrate that the cellular effects of 3 and, by inference, also of other azathilones are the result of their interactions with the cellular MT network.

Reanalysis-driven climate simulation over CORDEX North America domain using the Canadian Regional Climate Model, version 5: model performance evaluation

The performance of reanalysis-driven Canadian Regional Climate Model, version 5 (CRCM5) in reproducing the present climate over the North American COordinated Regional climate Downscaling EXperiment domain for the 1989–2008 period has been assessed in comparison with several observation-based datasets. The model reproduces satisfactorily the near-surface temperature and precipitation characteristics over most part of North America. Coastal and mountainous zones remain problematic: a cold bias (2–6 °C) prevails over Rocky Mountains in summertime and all year-round over Mexico; winter precipitation in mountainous coastal regions is overestimated. The precipitation patterns related to the North American Monsoon are well reproduced, except on its northern limit. The spatial and temporal structure of the Great Plains Low-Level Jet is well reproduced by the model; however, the night-time precipitation maximum in the jet area is underestimated. The performance of CRCM5 was assessed against earlier CRCM versions and other RCMs. CRCM5 is shown to have been substantially improved compared to CRCM3 and CRCM4 in terms of seasonal mean statistics, and to be comparable to other modern RCMs.

Ankle joint pressure changes in a pes cavovarus model: supramalleolar valgus osteotomy versus lateralizing calcaneal osteotomy

BACKGROUND: A fixed cavovarus foot deformity can be associated with anteromedial ankle arthrosis due to elevated medial joint contact stresses. Supramalleolar valgus osteotomies (SMOT) and lateralizing calcaneal osteotomies (LCOT) are commonly used to treat symptoms by redistributing joint contact forces. In a cavovarus model, the effects of SMOT and LCOT on the lateralization of the center of force (COF) and reduction of the peak pressure in the ankle joint were compared. METHODS: A previously published cavovarus model with fixed hindfoot varus was simulated in 10 cadaver specimens. Closing wedge supramalleolar valgus osteotomies 3 cm above the ankle joint level (6 and 11 degrees) and lateral sliding calcaneal osteotomies (5 and 10 mm displacement) were analyzed at 300 N axial static load (half body weight). The COF migration and peak pressure decrease in the ankle were recorded using high-resolution TekScan pressure sensors. RESULTS: A significant lateral COF shift was observed for each osteotomy: 2.1 mm for the 6 degrees (P = .014) and 2.3 mm for the 11 degrees SMOT (P = .010). The 5 mm LCOT led to a lateral shift of 2.0 mm (P = .042) and the 10 mm LCOT to a shift of 3.0 mm (P = .006). Comparing the different osteotomies among themselves no significant differences were recorded. No significant anteroposterior COF shift was seen. A significant peak pressure reduction was recorded for each osteotomy: The SMOT led to a reduction of 29% (P = .033) for the 6 degrees and 47% (P = .003) for the 11 degrees osteotomy, and the LCOT to a reduction of 41% (P = .003) for the 5 mm and 49% (P = .002) for the 10 mm osteotomy. Similar to the COF lateralization no significant differences between the osteotomies were seen. CONCLUSION: LCOT and SMOT significantly reduced anteromedial ankle joint contact stresses in this cavovarus model. The unloading effects of both osteotomies were equivalent. More correction did not lead to significantly more lateralization of the COF or more reduction of peak pressure but a trend was seen. CLINICAL RELEVANCE: In patients with fixed cavovarus feet, both SMOT and LCOT provided equally good redistribution of elevated ankle joint contact forces. Increasing the amount of displacement did not seem to equally improve the joint pressures. The site of osteotomy could therefore be chosen on the basis of surgeon's preference, simplicity, or local factors in case of more complex reconstructions.